Author: "Ern Yu Tan" - Searchworks@Jio Institute Digital Library Search Results

142 results on '"Ern Yu Tan"'

1. Alterations to DNA methylation patterns induced by chemotherapy treatment are associated with negative impacts on the olfactory pathway

Author: Peh Joo Ho, Alexis Jiaying Khng, Benita Kiat-Tee Tan, Geok Hoon Lim, Su-Ming Tan, Veronique Kiak Mien Tan, Ryan Shea Ying Cong Tan, Elaine Hsuen Lim, Philip Tsau-Choong Iau, Ying Jia Chew, Yi Ying Lim, Mikael Hartman, Ern Yu Tan, and Jingmei Li
Subjects: Epigenetic modification, Breast cancer, Treatment response, DNA methylation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Exposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in breast cancer patients. Methods We performed DNAm analysis in 125 breast cancer patients with blood drawn before and after chemotherapy, using the Illumina MethylationEPIC array. DNAm changes of 588,798 individual CpGs (including 41,207 promoter regions) were evaluated using linear regression models adjusted for monocyte proportion. Gene set enrichment analyses (GSEA) were conducted to identify key Gene Ontology (GO) biological processes or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with chemotherapy. Results were validated in a separate cohort of breast cancer patients who were treated (n = 1273) and not treated (n = 872) by chemotherapy (1808 blood, 337 saliva). Results A total of 141 differentially methylated CpGs and 11 promoters were significantly associated with chemotherapy after multiple testing corrections in both the paired sample and single time point analyses. GSEA of promoter regions (pre-ranked by test statistics) identified six suppressed biological processes (p
Published: 2023
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2. Post-Operative Radiation in Early Breast Cancer with N1 Disease: 10-Year Follow-Up

Author: Ee Ling Serene Tang, E-Jan Sim, Wei-Wen Ang, Jun Su, Juliana Jia Chuan Chen, Mun Yew Patrick Chan, Bok Ai Choo, and Ern Yu Tan
Subjects: nodal radiation, recurrence, survival, Medicine
Abstract: Post-operative radiotherapy for post-menopausal women with early breast cancer and N1 disease is controversial. Although locoregional control is improved, overall survival (OS) benefit is unclear. The clinical benefit of post-operative irradiation in this group of patients over 10 years was reviewed. We aimed to evaluate the OS, disease-free survival (DFS), and factors affecting OS and DFS. A retrospective review of 191 post-menopausal women with early breast cancer and N1 disease from 2004 to 2011 was performed. Demographics, post-operative histology, adjuvant treatment, OS, and DFS were evaluated. Post-operative radiation was given to 95 of 191 women (49.7%). Younger age at diagnosis (p < 0.001), a greater number of involved nodes (p = 0.004), lymphovascular invasion (LVI), and a higher tumor grade (p = 0.001) were more likely in women who received post-operative radiation. Nodal radiation did not improve 10-year DFS (p = 0.084) or OS (p = 0.203). Post-operative nodal radiation was associated with significant improvement in 10-year OS in women who received only hormonal therapy (p = 0.047) and no other systemic therapy. Women with unfavorable risk factors were more likely to receive post-operative radiation, likely due to a perceived higher risk of recurrence. Nodal radiation did not significantly improve 10-year DFS or OS in early breast cancer patients with N1 disease, and the benefit was not clearly demonstrated. However, in those who were on hormonal therapy, radiotherapy was beneficial in improving overall survival.
Published: 2024
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3. Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis

Author: Jieqiong Zhang, Zhenhua Hu, Hwa Hwa Chung, Yun Tian, Kah Weng Lau, Zheng Ser, Yan Ting Lim, Radoslaw M. Sobota, Hwei Fen Leong, Benjamin Jieming Chen, Clarisse Jingyi Yeo, Shawn Ying Xuan Tan, Jian Kang, Dennis Eng Kiat Tan, Ieng Fong Sou, Urszula Lucja McClurg, Manikandan Lakshmanan, Thamil Selvan Vaiyapuri, Anandhkumar Raju, Esther Sook Miin Wong, Vinay Tergaonkar, Ravisankar Rajarethinam, Elina Pathak, Wai Leong Tam, Ern Yu Tan, and Wee-Wei Tee
Subjects: Science
Abstract: Abstract Cancer cells undergo transcriptional reprogramming to drive tumor progression and metastasis. Using cancer cell lines and patient-derived tumor organoids, we demonstrate that loss of the negative elongation factor (NELF) complex inhibits breast cancer development through downregulating epithelial-mesenchymal transition (EMT) and stemness-associated genes. Quantitative multiplexed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (qPLEX-RIME) further reveals a significant rewiring of NELF-E-associated chromatin partners as a function of EMT and a co-option of NELF-E with the key EMT transcription factor SLUG. Accordingly, loss of NELF-E leads to impaired SLUG binding on chromatin. Through integrative transcriptomic and genomic analyses, we identify the histone acetyltransferase, KAT2B, as a key functional target of NELF-E-SLUG. Genetic and pharmacological inactivation of KAT2B ameliorate the expression of EMT markers, phenocopying NELF ablation. Elevated expression of NELF-E and KAT2B is associated with poorer prognosis in breast cancer patients, highlighting the clinical relevance of our findings. Taken together, we uncover a crucial role of the NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis.
Published: 2023
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4. Mammography screening is associated with more favourable breast cancer tumour characteristics and better overall survival: case-only analysis of 3739 Asian breast cancer patients

Author: Zi Lin Lim, Peh Joo Ho, Alexis Jiaying Khng, Yen Shing Yeoh, Amanda Tse Woon Ong, Benita Kiat Tee Tan, Ern Yu Tan, Su-Ming Tan, Geok Hoon Lim, Jung Ah Lee, Veronique Kiak-Mien Tan, Jesse Hu, Jingmei Li, and Mikael Hartman
Subjects: Breast cancer, Mammography screening, Cancer survival, Sociodemographics and health outcomes, Medicine
Abstract: Abstract Background Early detection of breast cancer (BC) through mammography screening (MAM) is known to reduce mortality. We examined the differential effect that mammography has on BC characteristics and overall survival and the sociodemographic determinants of MAM utilization in a multi-ethnic Asian population. Methods This study included 3739 BC patients from the Singapore Breast Cancer Cohort (2010–2018). Self-reported sociodemographic characteristics were collected using a structured questionnaire. Clinical data were obtained through medical records. Patients were classified as screeners (last screening mammogram ≤ 2 years before diagnosis), non-screeners (aware but did not attend or last screen > 2years), and those unaware of MAM. Associations between MAM behaviour (MB) and sociodemographic factors and MB and tumour characteristics were examined using multinomial regression. Ten-year overall survival was modelled using Cox regression. Results Patients unaware of screening were more likely diagnosed with late stage (ORstage III vs stage I (Ref) [95% CI]: 4.94 [3.45–7.07], p < 0.001), high grade (ORpoorly vs well-differentiated (reference): 1.53 [1.06–2.20], p = 0.022), nodal-positive, large size (OR>5cm vs ≤2cm (reference): 5.06 [3.10–8.25], p < 0.001), and HER2-positive tumours (ORHER2-negative vs HER2-positive (reference): 0.72 [0.53–0.97], p = 0.028). Similar trends were observed between screeners and non-screeners with smaller effect sizes. Overall survival was significantly shorter than screeners in the both groups (HRnon-screeners: 1.89 [1.22–2.94], p = 0.005; HRunaware: 2.90 [1.69–4.98], p < 0.001). Non-screeners and those unaware were less health conscious, older, of Malay ethnicity, less highly educated, of lower socioeconomic status, more frequently ever smokers, and less physically active. Among screeners, there were more reported personal histories of benign breast surgeries or gynaecological conditions and positive family history of breast cancer. Conclusions Mammography attendance is associated with more favourable BC characteristics and overall survival. Disparities in the utility of MAM services suggest that different strategies may be needed to improve MAM uptake.
Published: 2022
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5. Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy

Author: Shijun Ma, Yue Zhao, Wee Chyan Lee, Li-Teng Ong, Puay Leng Lee, Zemin Jiang, Gokce Oguz, Zhitong Niu, Min Liu, Jian Yuan Goh, Wenyu Wang, Matias A. Bustos, Sidse Ehmsen, Adaikalavan Ramasamy, Dave S. B. Hoon, Henrik J. Ditzel, Ern Yu Tan, Qingfeng Chen, and Qiang Yu
Subjects: Science
Abstract: Hypoxia can promote tumor escape from immune surveillance and immunotherapy. Here, the authors show that hypoxia induces T and NK cell dysfunction through HIF1α-mediated epigenetic suppression of effector gene expression, conferring resistance to anti-PD1 blockade in triple negative breast cancer models.
Published: 2022
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6. Overlap of high-risk individuals predicted by family history, and genetic and non-genetic breast cancer risk prediction models: implications for risk stratification

Author: Peh Joo Ho, Weang Kee Ho, Alexis J. Khng, Yen Shing Yeoh, Benita Kiat-Tee Tan, Ern Yu Tan, Geok Hoon Lim, Su-Ming Tan, Veronique Kiak Mien Tan, Cheng-Har Yip, Nur-Aishah Mohd-Taib, Fuh Yong Wong, Elaine Hsuen Lim, Joanne Ngeow, Wen Yee Chay, Lester Chee Hao Leong, Wei Sean Yong, Chin Mui Seah, Siau Wei Tang, Celene Wei Qi Ng, Zhiyan Yan, Jung Ah Lee, Kartini Rahmat, Tania Islam, Tiara Hassan, Mei-Chee Tai, Chiea Chuen Khor, Jian-Min Yuan, Woon-Puay Koh, Xueling Sim, Alison M. Dunning, Manjeet K. Bolla, Antonis C. Antoniou, Soo-Hwang Teo, Jingmei Li, and Mikael Hartman
Subjects: Breast cancer, Polygenic risk score, Gail model, Protein-truncating variants, Risk-based screening, Medicine
Abstract: Abstract Background Family history, and genetic and non-genetic risk factors can stratify women according to their individual risk of developing breast cancer. The extent of overlap between these risk predictors is not clear. Methods In this case-only analysis involving 7600 Asian breast cancer patients diagnosed between age 30 and 75 years, we examined identification of high-risk patients based on positive family history, the Gail model 5-year absolute risk [5yAR] above 1.3%, breast cancer predisposition genes (protein-truncating variants [PTV] in ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, or TP53), and polygenic risk score (PRS) 5yAR above 1.3%. Results Correlation between 5yAR (at age of diagnosis) predicted by PRS and the Gail model was low (r=0.27). Fifty-three percent of breast cancer patients (n=4041) were considered high risk by one or more classification criteria. Positive family history, PTV carriership, PRS, or the Gail model identified 1247 (16%), 385 (5%), 2774 (36%), and 1592 (21%) patients who were considered at high risk, respectively. In a subset of 3227 women aged below 50 years, the four models studied identified 470 (15%), 213 (7%), 769 (24%), and 325 (10%) unique patients who were considered at high risk, respectively. For younger women, PRS and PTVs together identified 745 (59% of 1276) high-risk individuals who were not identified by the Gail model or family history. Conclusions Family history and genetic and non-genetic risk stratification tools have the potential to complement one another to identify women at high risk.
Published: 2022
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7. Germline breast cancer susceptibility genes, tumor characteristics, and survival

Author: Peh Joo Ho, Alexis J. Khng, Hui Wen Loh, Weang-Kee Ho, Cheng Har Yip, Nur Aishah Mohd-Taib, Veronique Kiak Mien Tan, Benita Kiat-Tee Tan, Su-Ming Tan, Ern Yu Tan, Swee Ho Lim, Suniza Jamaris, Yirong Sim, Fuh Yong Wong, Joanne Ngeow, Elaine Hsuen Lim, Mei Chee Tai, Eldarina Azfar Wijaya, Soo Chin Lee, Ching Wan Chan, Shaik Ahmad Buhari, Patrick M. Y. Chan, Juliana J. C. Chen, Jaime Chin Mui Seah, Wai Peng Lee, Chi Wei Mok, Geok Hoon Lim, Evan Woo, Sung-Won Kim, Jong Won Lee, Min Hyuk Lee, Sue K. Park, Alison M. Dunning, Douglas F. Easton, Marjanka K. Schmidt, Soo-Hwang Teo, Jingmei Li, and Mikael Hartman
Subjects: Breast cancer, Protein-truncating variants, Overall survival, Medicine, Genetics, QH426-470
Abstract: Abstract Background Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent. Methods Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease. Results PTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35–5.17], moderately vs well-differentiated 2.33 [1.56–3.49]), as well as luminal B [HER−] and triple-negative subtypes (vs luminal A 2.15 [1.58–2.92] and 2.85 [2.17–3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2−] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16–2.28]). Conclusions PTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.
Published: 2021
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8. EZH2-mediated PP2A inactivation confers resistance to HER2-targeted breast cancer therapy

Author: Yi Bao, Gokce Oguz, Wee Chyan Lee, Puay Leng Lee, Kakaly Ghosh, Jiayao Li, Panpan Wang, Peter E. Lobie, Sidse Ehmsen, Henrik J. Ditzel, Andrea Wong, Ern Yu Tan, Soo Chin Lee, and Qiang Yu
Subjects: Science
Abstract: Resistance to anti-HER2 therapies in breast cancer remains a significant clinical challenge. Here, the authors demonstrate that EZH2 regulates response to HER2-targeting therapies in breast cancer, in part, by modulating the expression of PPP2R2B.
Published: 2020
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9. European polygenic risk score for prediction of breast cancer shows similar performance in Asian women

Author: Weang-Kee Ho, Min-Min Tan, Nasim Mavaddat, Mei-Chee Tai, Shivaani Mariapun, Jingmei Li, Peh-Joo Ho, Joe Dennis, Jonathan P. Tyrer, Manjeet K. Bolla, Kyriaki Michailidou, Qin Wang, Daehee Kang, Ji-Yeob Choi, Suniza Jamaris, Xiao-Ou Shu, Sook-Yee Yoon, Sue K. Park, Sung-Won Kim, Chen-Yang Shen, Jyh-Cherng Yu, Ern Yu Tan, Patrick Mun Yew Chan, Kenneth Muir, Artitaya Lophatananon, Anna H. Wu, Daniel O. Stram, Keitaro Matsuo, Hidemi Ito, Ching Wan Chan, Joanne Ngeow, Wei Sean Yong, Swee Ho Lim, Geok Hoon Lim, Ava Kwong, Tsun L. Chan, Su Ming Tan, Jaime Seah, Esther M. John, Allison W. Kurian, Woon-Puay Koh, Chiea Chuen Khor, Motoki Iwasaki, Taiki Yamaji, Kiak Mien Veronique Tan, Kiat Tee Benita Tan, John J. Spinelli, Kristan J. Aronson, Siti Norhidayu Hasan, Kartini Rahmat, Anushya Vijayananthan, Xueling Sim, Paul D. P. Pharoah, Wei Zheng, Alison M. Dunning, Jacques Simard, Rob Martinus van Dam, Cheng-Har Yip, Nur Aishah Mohd Taib, Mikael Hartman, Douglas F. Easton, Soo-Hwang Teo, and Antonis C. Antoniou
Subjects: Science
Abstract: Polygenic risk scores predict the likelihood that an individual will develop a certain cancer, however these are often specific for a given population. Here, the authors show that a risk score developed to assess the risk of breast cancer in European women can also predict risk in Asian populations.
Published: 2020
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10. Cohort profile: The Singapore Breast Cancer Cohort (SGBCC), a multi-center breast cancer cohort for evaluation of phenotypic risk factors and genetic markers.

Author: Peh Joo Ho, Yen Shing Yeoh, Hui Miao, Swee Ho Lim, Ern Yu Tan, Benita Kiat Tee Tan, Veronique Kiak Mien Tan, Su Ming Tan, Wei Sean Yong, Fuh Yong Wong, Preetha Madhukumar, Ching Wan Chan, Philip Tsau Choong Iau, Soo Chin Lee, Thomas Putti, Shaik Ahmad Buhari, Jin Yee Lee, Geok Hoon Lim, Evan Woo, Zhiyan Yan, Patrick Mun Yew Chan, Juliana Jia Chuan Chen, Sarah Qinghui Lu, Rebecca Dent, Wai Peng Lee, Chi Wei Mok, Jaime Chin Mui Seah, Xueling Sim, Rob Martinus van Dam, Kee Seng Chia, Jingmei Li, and Mikael Hartman
Subjects: Medicine, Science
Abstract: This article aims to provide a detailed description of the Singapore Breast Cancer Cohort (SGBCC), an ongoing multi-ethnic cohort established with the overarching goal to identify genetic markers for breast cancer risk, prognosis and treatment response, as well as to understand the ethnic differences in disease risk and outcome in an Asian setting. The cohort comprises of breast cancer patients aged 21 years and above from six public hospitals which diagnose and treat nearly 76% breast cancer cases in Singapore. Self-reported data on sociodemographic and lifestyle, reproductive risk factors, medical history and family history of breast or ovarian cancer is collected using a structured questionnaire. Clinical data on tumour characteristics, and treatment modalities are obtained through medical record. Bio-specimens (blood or saliva) is collected at recruitment. Follow-up on survival information is done through routine linkage with the Registry of Births and Deaths. As of 31 December 2016, 7,768 subjects have been recruited to the study with 76% subjects contributed bio-specimens. The SGBCC provides a valuable platform which offers a unique, large and rich resource for new research ideas on breast cancer related phenotypic risk factors and genetic markers.
Published: 2021
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11. A potent neutralizing antibody with therapeutic potential against all four serotypes of dengue virus

Author: Meihui Xu, Roland Zuest, Sumathy Velumani, Farhana Tukijan, Ying Xiu Toh, Ramapraba Appanna, Ern Yu Tan, Daniela Cerny, Paul MacAry, Cheng-I Wang, and Katja Fink
Subjects: Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Dengue: A single vaccine candidate for all strains An antibody-vaccine candidate has been discovered that neutralizes and confers protection against all four strains of dengue virus. Katja Fink, of the Singapore Immunology Network and Nanyang Technological University, Singapore, describes this as the first time a highly neutralizing antibody has shown efficacy against all four strains. Fink’s team, consisting of scientists from institutions across the country, tested the candidate (SIgN-3C-LALA) in both pre-exposure and post-exposure mouse models. The findings showed it reduced blood-virus levels, protected from lethal infection, and also offered improved safety—without compromising efficacy—the latter by way of intentional mutations to the antibody’s structure. As the global cost of dengue treatment is as high as 9 billion US$ per year, further study is needed to evaluate the suitability of the antibody candidate for the treatment of dengue in humans.
Published: 2017
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12. Selective susceptibility of human skin antigen presenting cells to productive dengue virus infection.

Author: Daniela Cerny, Muzlifah Haniffa, Amanda Shin, Paul Bigliardi, Bien Keem Tan, Bernett Lee, Michael Poidinger, Ern Yu Tan, Florent Ginhoux, and Katja Fink
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: Dengue is a growing global concern with 390 million people infected each year. Dengue virus (DENV) is transmitted by mosquitoes, thus host cells in the skin are the first point of contact with the virus. Human skin contains several populations of antigen-presenting cells which could drive the immune response to DENV in vivo: epidermal Langerhans cells (LCs), three populations of dermal dendritic cells (DCs), and macrophages. Using samples of normal human skin we detected productive infection of CD14(+) and CD1c(+) DCs, LCs and dermal macrophages, which was independent of DC-SIGN expression. LCs produced the highest viral titers and were less sensitive to IFN-β. Nanostring gene expression data showed significant up-regulation of IFN-β, STAT-1 and CCL5 upon viral exposure in susceptible DC populations. In mice infected intra-dermally with DENV we detected parallel populations of infected DCs originating from the dermis and migrating to the skin-draining lymph nodes. Therefore dermal DCs may simultaneously facilitate systemic spread of DENV and initiate the adaptive anti-viral immune response.
Published: 2014
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13. Adopting Ambulatory Breast Cancer Surgery as the Standard of Care in an Asian Population

Author: Yvonne Ying Ru Ng, Patrick Mun Yew Chan, Juliana Jia Chuan Chen, Melanie Dee Wern Seah, Christine Teo, and Ern Yu Tan
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Introduction. Ambulatory surgery is not commonly practiced in Asia. A 23-hour ambulatory (AS23) service was implemented at our institute in March 2004 to allow more surgeries to be performed as ambulatory procedures. In this study, we reviewed the impact of the AS23 service on breast cancer surgeries and reviewed surgical outcomes, including postoperative complications, length of stay, and 30-day readmission. Methods. Retrospective review was performed of 1742 patients who underwent definitive breast cancer surgery from 1 March 2004 to 31 December 2010. Results. By 2010, more than 70% of surgeries were being performed as ambulatory procedures. Younger women (P
Published: 2014
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14. Impact of cytochrome P450 2D6 polymorphisms on decision-making and clinical outcomes in adjuvant hormonal therapy for breast cancer

Author: Ern-Yu, Tan, Lavina, Bharwani, Yee-Hong, Chia, Richie C T, Soong, Sherylyn S Y, Lee, Juliana J C, Chen, and Patrick M Y, Chan
Subjects: Oncology
Abstract: There are concerns that tamoxifen is less effective in Asian women because of the high prevalence of impaired function cytochrome P450 2D6 (To evaluate how knowledge ofEighty-two women were recruited. Seventy-eight completedMore than 70% of the women had an IM phenotype, 32% an extensive or ultra metabolizer phenotype, and 0% had a poor metabolizer phenotype. Regardless of genotype, more women opted for aromatase inhibitors. Overall, 80% of women completed 5 years of hormonal therapy. Five women developed recurrence, 3 contralateral breast cancer, 5 died, and 1 was diagnosed with a second primary cancer. Five-year recurrence-free and overall survival were slightly better in women with the extensive or ultra metabolizer phenotype compared to those with the IM phenotype, though not statistically significant [The IM phenotype was highly prevalent but was not associated with clinical outcome.
Published: 2022

15. Supplementary Figures from Significant Effect of Polymorphisms in CYP2D6 on Response to Tamoxifen Therapy for Breast Cancer: A Prospective Multicenter Study

Author: Yusuke Nakamura, Soo Chin Lee, Ching-Wan Chan, Mikael Hartman, Ern Yu Tan, Arata Shimo, Koichiro Tsugawa, Daisuke Shimizu, Kazuhiro Shimada, Akimitsu Yamada, Shinichi Baba, Yasuaki Sagara, Ayami Matsukata, Mai Onomura, Hisamitsu Zaha, Minoru Okazaki, Fukino Satomi, Hiroaki Shima, Goro Kutomi, Yoshie Hasegawa, Hiroshi Matsumoto, Kana Miyahara, Takashi Ishikawa, Hiroyuki Takei, Tomoko Takamaru, Chie Watanabe, Takashi Kuwayama, Sadako Akashi-Tanaka, Seigo Nakamura, and Hitoshi Zembutsu
Abstract: Supplementary Figure S1. ã€€ER status in breast cancer tissues was associated with Ki-67 response after tamoxifen therapy. (A) Ki-67 response was lower in the tissues in which the proportion of ER-positive cells was less than 2/3 than in the tissues in which the proportion of ER-positive cells was 2/3 or more. (B) In Allred score, a semi quantitative system, that takes into consideration the proportion of positive cells (scored on a scale of 0-5) and staining intensity (scored on a scale of 0-3), tissues with score of 7 or less showed lower Ki-67 response than those with score of 8. Supplementary Figure S2. Correlation between Ki-67 response and tumor response after tamoxifen therapy. No significant tumor response was observed by short-term pre-operative tamoxifen therapy. No correlation was also observed between the tumor response and Ki-67 response (Pearson correlation coefficient; R = -0.12). Tumor response was measured in bi-directional maximum dimension using ultrasound. Supplementary Figure S3. Relationship between Ki-67 response and pathological response after tamoxifen therapy. The breast cancer tissues with no pathological response (Grade 0) showed significantly lower Ki-67 response than those with Grade 1a or more pathological response. Supplementary Figure S4. Association between CYP2D6 genotypes and Ki-67 labeling index in pre-treatment tissue. CYP2D6 genotype was not associated with Ki-67 labeling index in pre-treatment tissue.
Published: 2023

16. Supplementary Table from Significant Effect of Polymorphisms in CYP2D6 on Response to Tamoxifen Therapy for Breast Cancer: A Prospective Multicenter Study

Author: Yusuke Nakamura, Soo Chin Lee, Ching-Wan Chan, Mikael Hartman, Ern Yu Tan, Arata Shimo, Koichiro Tsugawa, Daisuke Shimizu, Kazuhiro Shimada, Akimitsu Yamada, Shinichi Baba, Yasuaki Sagara, Ayami Matsukata, Mai Onomura, Hisamitsu Zaha, Minoru Okazaki, Fukino Satomi, Hiroaki Shima, Goro Kutomi, Yoshie Hasegawa, Hiroshi Matsumoto, Kana Miyahara, Takashi Ishikawa, Hiroyuki Takei, Tomoko Takamaru, Chie Watanabe, Takashi Kuwayama, Sadako Akashi-Tanaka, Seigo Nakamura, and Hitoshi Zembutsu
Abstract: Supplementary Table S1 Association between all CYP2D6 genotype and ER status in pre-treatment tissue.
Published: 2023

17. Data from Significant Effect of Polymorphisms in CYP2D6 on Response to Tamoxifen Therapy for Breast Cancer: A Prospective Multicenter Study

Author: Yusuke Nakamura, Soo Chin Lee, Ching-Wan Chan, Mikael Hartman, Ern Yu Tan, Arata Shimo, Koichiro Tsugawa, Daisuke Shimizu, Kazuhiro Shimada, Akimitsu Yamada, Shinichi Baba, Yasuaki Sagara, Ayami Matsukata, Mai Onomura, Hisamitsu Zaha, Minoru Okazaki, Fukino Satomi, Hiroaki Shima, Goro Kutomi, Yoshie Hasegawa, Hiroshi Matsumoto, Kana Miyahara, Takashi Ishikawa, Hiroyuki Takei, Tomoko Takamaru, Chie Watanabe, Takashi Kuwayama, Sadako Akashi-Tanaka, Seigo Nakamura, and Hitoshi Zembutsu
Abstract: Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, “endoxifen.” There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy.Experimental Design: We enrolled 279 patients with hormone receptor–positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes.Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor–positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele).Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019–26. ©2016 AACR.
Published: 2023

18. Ethnic disparity in chemotherapy–induced febrile neutropenia incidence in Asian breast cancer patients: A retrospective cohort study

Author: Zi Lin Lim, Peh Joo Ho, Mikael Hartman, Ern Yu Tan, Nur Khaliesah Binte Mohamed Riza, Elaine Hsuen Lim, Phyu Nitar, Fuh Yong Wong, and Jingmei Li
Abstract: Background Majority of published findings on chemotherapy–induced febrile neutropenia (FN) are restricted to three ethnic groups: Asians, Caucasians, and African Americans. In this two–part study, we examined FN incidence and risk factors in Chinese, Malay and Indian chemotherapy–treated breast cancer (BC) patients in Southeast Asia. Methods Hospital records or ICD codes (fever:ICD9/10:2880/D70 and neutropenia:ICD9/10:7806/R509) were used to identify patients with FN, during or within 30 days from the last chemotherapy session. In both Singapore Breast Cancer Cohort (SGBCC) and Joint Breast Cancer Registry (JBCR), time to first FN from start of chemotherapy was estimated using Cox regression. Multinomial regression was used to evaluate differences in patient, tumour, and treatment characteristics across ethnicities. Results FN was observed in 170 of 1,014 patients (16.7%) in SGBCC. Cox model showed that non–Chinese were at higher risk of developing FN (HRMalay[95% CI]:2.04[1.44–2.88], p Indian:1.88[1.11–3.18], p = 0.018). In JBCR, FN was observed in 965 of 7449 patients (13.0%). Indian patients, lower baseline absolute neutrophil count, non– luminal A proxy subtypes, and anthracycline–containing regimens were identified as risk factors for FN in the univariable Cox models. Disparities across ethnicities risk (HRMalay: 1.29 [1.07–1.54], p = 0.006; HRIndian: 1.50 [1.19–1.88], p Malay vs Chinese(ref):3.65[1.45–9.16],p = 0.006;ORIndian vs Chinese(ref):4.43[1.45–13.60],p = 0.009) were significantly more likely to develop multiple episodes of FN during treatment. Conclusion Ethnic differences in chemotherapy–induced FN among BC patients exist. Further studies can focus on investigating pharmacogenetic differences across ethnicities.
Published: 2023

19. Predicting the Likelihood of Carrying a BRCA1 or BRCA2 Mutation in Asian Patients With Breast Cancer

Author: Boon Hong Ang, Weang Kee Ho, Eldarina Wijaya, Pui Yoke Kwan, Pei Sze Ng, Sook Yee Yoon, Siti Norhidayu Hasan, Joanna M.C. Lim, Tiara Hassan, Mei-Chee Tai, Jamie Allen, Andrew Lee, Nur Aishah Mohd Taib, Cheng Har Yip, Mikael Hartman, Swee Ho Lim, Ern Yu Tan, Benita K.T. Tan, Su-Ming Tan, Veronique K.M. Tan, Peh Joo Ho, Alexis J. Khng, Alison M. Dunning, Jingmei Li, Douglas F. Easton, Antonis C. Antoniou, and Soo Hwang Teo
Subjects: Cancer Research, Oncology
Abstract: PURPOSE With the development of poly (ADP-ribose) polymerase inhibitors for treatment of patients with cancer with an altered BRCA1 or BRCA2 gene, there is an urgent need to ensure that there are appropriate strategies for identifying mutation carriers while balancing the increased demand for and cost of cancer genetics services. To date, the majority of mutation prediction tools have been developed in women of European descent where the age and cancer-subtype distributions are different from that in Asian women. METHODS In this study, we built a new model (Asian Risk Calculator) for estimating the likelihood of carrying a pathogenic variant in BRCA1 or BRCA2 gene, using germline BRCA genetic testing results in a cross-sectional population-based study of 8,162 Asian patients with breast cancer. We compared the model performance to existing mutation prediction models. The models were evaluated for discrimination and calibration. RESULTS Asian Risk Calculator included age of diagnosis, ethnicity, bilateral breast cancer, tumor biomarkers, and family history of breast cancer or ovarian cancer as predictors. The inclusion of tumor grade improved significantly the model performance. The full model was calibrated (Hosmer-Lemeshow P value = .614) and discriminated well between BRCA and non- BRCA pathogenic variant carriers (area under receiver operating curve, 0.80; 95% CI, 0.75 to 0.84). Addition of grade to the existing clinical genetic testing criteria targeting patients with breast cancer age younger than 45 years reduced the proportion of patients referred for genetic counseling and testing from 37% to 33% ( P value = .003), thereby improving the overall efficacy. CONCLUSION Population-specific customization of mutation prediction models and clinical genetic testing criteria improved the accuracy of BRCA mutation prediction in Asian patients.
Published: 2022

20. Can Contrast-Enhanced Spectral Mammography (CESM) Reduce Benign Breast Biopsy?

Author: Amanda Ling Fung Liew, Hollie Mei Yeen Lim, Elizabeth Chun Mei Fok, Siu Cheng Loke, Ern Yu Tan, Bee Kiang Chong, Yeong Shyan Lee, Patrick Mun Yew Chan, and Niketa Chotai
Subjects: Adult, Article Subject, Oncology, Biopsy, Internal Medicine, Contrast Media, Humans, Breast Neoplasms, Female, Surgery, Prospective Studies, Middle Aged, Mammography
Abstract: Objectives. To evaluate the potential of contrast-enhanced spectral mammography (CESM) in reducing benign breast biopsy rate, thereby improving resource utilization. To explore its potential as a value-adding modality in the management of BI-RADS 4/5 lesions. Materials and Methods. This was a prospective study conducted between July 2016 and September 2018. Patients with BI-RADS 4/5 lesions detected on conventional imaging (mammogram, digital breast tomosynthesis, and ultrasound) were enrolled for adjunct CESM. Histopathologic correlation was done for all lesions. Additional suspicious lesions detected on CESM were all identified on second-look ultrasound and subsequently biopsied. Images were evaluated independently by two radiologists trained in breast imaging using BI-RADS classification. Presence of enhancement on CESM, BI-RADS score, and histopathology of each lesion were analyzed and tested with the chi-square/fisher-exact test for statistical significance. Results. The study included 105 lesions in 63 participants—1 man and 62 women, an average age of 53.7 ± 10.8 years. On CESM, 22 (20.9%) of the lesions did not show enhancement. All 22 lesions had been classified as BI-RADS 4A and were subsequently proven to be benign. Of the remaining 83 enhancing lesions, 54 (65.1%) were malignant and 29 (34.9%) were benign ( p < 0.05 ). CESM detected 6 additional lesions which were not identified on initial conventional imaging. Four of these were proven malignant and were in a different quadrant than the primary lesion investigated. Conclusion. There is evidence that the absence of enhancement in CESM strongly favors benignity. It may provide the reporting radiologist with greater confidence in imaging assessment, especially in BI-RADS 4A cases, where a proportion of them are in actuality BI-RADS 3. Greater accuracy of BI-RADS grading can reduce nearly half of benign biopsies and allow better resource allocation. CESM also increases the detection rate of potentially malignant lesions, thereby changing the treatment strategies.
Published: 2022

21. Polygenic risk scores for prediction of breast cancer risk in Asian populations

Author: Weang-Kee Ho, Mei-Chee Tai, Joe Dennis, Xiang Shu, Jingmei Li, Peh Joo Ho, Iona Y. Millwood, Kuang Lin, Yon-Ho Jee, Su-Hyun Lee, Nasim Mavaddat, Manjeet K. Bolla, Qin Wang, Kyriaki Michailidou, Jirong Long, Eldarina Azfar Wijaya, Tiara Hassan, Kartini Rahmat, Veronique Kiak Mien Tan, Benita Kiat Tee Tan, Su Ming Tan, Ern Yu Tan, Swee Ho Lim, Yu-Tang Gao, Ying Zheng, Daehee Kang, Ji-Yeob Choi, Wonshik Han, Han-Byoel Lee, Michiki Kubo, Yukinori Okada, Shinichi Namba, Sue K. Park, Sung-Won Kim, Chen-Yang Shen, Pei-Ei Wu, Boyoung Park, Kenneth R. Muir, Artitaya Lophatananon, Anna H. Wu, Chiu-Chen Tseng, Keitaro Matsuo, Hidemi Ito, Ava Kwong, Tsun L. Chan, Esther M. John, Allison W. Kurian, Motoki Iwasaki, Taiki Yamaji, Sun-Seog Kweon, Kristan J. Aronson, Rachel A. Murphy, Woon-Puay Koh, Chiea-Chuen Khor, Jian-Min Yuan, Rajkumar Dorajoo, Robin G. Walters, Zhengming Chen, Liming Li, Jun Lv, Keum-Ji Jung, Peter Kraft, Paul D.B. Pharoah, Alison M. Dunning, Jacques Simard, Xiao-Ou Shu, Cheng-Har Yip, Nur Aishah Mohd Taib, Antonis C. Antoniou, Wei Zheng, Mikael Hartman, Douglas F. Easton, Soo-Hwang Teo, and Project, BioBank Japan
Subjects: Multifactorial Inheritance, Risk Factors, Humans, Bayes Theorem, Breast Neoplasms, Female, Genetic Predisposition to Disease, Prospective Studies, Polymorphism, Single Nucleotide, Genetics (clinical), Genome-Wide Association Study
Abstract: Purpose Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. Methods The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). Results The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. Conclusion PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.
Published: 2022

22. Deep learning applied to breast imaging classification and segmentation with human expert intervention

Author: Rory Wilding, Vivek M. Sheraton, Lysabella Soto, Niketa Chotai, and Ern Yu Tan
Subjects: Machine Learning, Deep Learning, Internal Medicine, Humans, Breast Neoplasms, Female, Radiology, Nuclear Medicine and imaging, Ultrasonography, Mammary, General Medicine, Algorithms
Abstract: Automatic classification and segmentation of tumors in breast ultrasound images enables better diagnosis and planning treatment strategies for breast cancer patients.We collected 953 breast ultrasound images from two open-source datasets and classified them with help of an expert radiologist according to BI-RADS criteria. The data was split into normal, benign and malignant classes. We then used machine learning to develop classification and segmentation algorithms.We found 3.92% of the images across the open-source datasets had erroneous classifications. Post-radiologist intervention, three algorithms were developed based on the classification categories. Classification algorithms distinguished images with healthy breast tissue from those with abnormal tissue with 96% accuracy, and distinguished benign from malignant images with 85% accuracy. Both algorithms generated robust F1 and AUROC metrics. Finally, the masses within images were segmented with an 80.31% DICE score.Our work illustrates the potential of deep learning algorithms to improve the accuracy of breast ultrasound assessments and to facilitate automated assessments.
Published: 2022

23. A novel survival prediction signature outperforms PAM50 and artificial intelligence-based feature-selection methods

Author: Reuben Jyong Kiat Foo, Siqi Tian, Ern Yu Tan, Wilson Wen Bin Goh, School of Chemical and Biomedical Engineering, Lee Kong Chian School of Medicine (LKCMedicine), School of Biological Sciences, Tan Tock Seng Hospital, and Centre for Biomedical Informatics
Subjects: Computational Mathematics, Structural Biology, Organic Chemistry, Breast Cancer, Data Science, Biological sciences [Science], Medicine [Science], Biochemistry
Abstract: The robustness of a breast cancer gene signature, the super-proliferation set (SPS), is initially tested and investigated on breast cancer cell lines from the Cancer Cell Line Encyclopaedia (CCLE). Previously, SPS was derived via a meta-analysis of 47 independent breast cancer gene signatures, benchmarked on survival information from clinical data in the NKI dataset. Here, relying on the stability of cell line data and associative prior knowledge, we first demonstrate through Principal Component Analysis (PCA) that SPS prioritizes survival information over secondary subtype information, surpassing both PAM50 and Boruta, an artificial intelligence-based feature-selection algorithm, in this regard. We can also extract higher resolution 'progression' information using SPS, dividing survival outcomes into several clinically relevant stages ('good', 'intermediate', and 'bad) based on different quadrants of the PCA scatterplot. Furthermore, by transferring these 'progression' annotations onto independent clinical datasets, we demonstrate the generalisability of our method on actual patient data. Finally, via the characteristic genetic profiles of each quadrant/stage, we identified efficacious drugs using their gene reversal scores that can shift signatures across quadrants/stages, in a process known as gene signature reversal. This confirms the power of meta-analytical approaches for gene signature inference in breast cancer, as well as the clinical benefit in translating these inferences onto real-world patient data for more targeted therapies. Ministry of Education (MOE) National Research Foundation (NRF) Submitted/Accepted version This research/project is supported by the National Research Foundation, Singapore under its Industry Alignment Fund – Pre-positioning (IAF-PP) Funding Initiative. Any opinions, findings and conclusions or recommendations expressed in this material are those of the author(s) and do not reflect the views of National Research Foundation, Singapore. WWBG also acknowledges support from a Ministry of Education (MOE), Singapore Tier 1 grant (Grant No. RS08/21).
Published: 2023

24. Label-Free Detection of MiRNA Biomarkers Using Broadband Multi-Resonant Infrared Metasurfaces for Early Breast Cancer Diagnosis

Author: Shuyan Zhang, Qing Yang Steve Wu, Yi Fan Chen, Melissa Hum, Chi Lok Wong, Ern Yu Tan, Ann Siew Gek Lee, Jinghua Teng, Dinish U.S, and Malini Olivo
Subjects: General Materials Science
Abstract: Breast cancer is the most prevalent cancer globally. Early detection is crucial and can be achieved by detecting cancer biomarkers in blood, such as circulating miRNAs (microRNAs). In this study,...
Published: 2023

25. 16S rRNA sequencing for profiling microbial communities in idiopathic granulomatous mastitis

Author: Seeu Si Ong, Jia Xu, Choon Kiat Sim, Alexis Jiaying Khng, Peh Joo Ho, Philip Kam Weng Kwan, Aarthi Ravikrishnan, Kiat-Tee Benita Tan, Qing Ting Tan, Ern Yu Tan, Su-Ming Tan, Thomas Choudary Putti, Swee Ho Lim, Ee Ling Serene Tang, Niranjan Nagarajan, Neerja Karnani, Jingmei Li, and Mikael Hartman
Abstract: BackgroundIdiopathic granulomatous mastitis (IGM) is a rare, chronic, and benign inflammatory breast disease with ambiguous aetiology. Contrastingly, lactational mastitis (LM) is commonly diagnosed in breastfeeding women. To investigate IGM aetiology, we profiled the microbial flora of pus and skin in IGM and LM patients.MethodsIGM patients were recruited from 2018 to 2020; LM patients were recruited as controls. 16S rRNA sequencing libraries were constructed from 16S rRNA gene amplified from total DNA extracted from pus and skin swabs. Metagenomic analysis was conducted using modified microbiome abundance analysis-suite customised R-resource for paired pus and skin samples. Microbiome multivariable association analyses were performed using linear models.Results21 IGM and 3 LM paired pus and skin samples underwent metagenomic analysis. Bray-Curtis ecological dissimilarity distance showed dissimilarity across four sample types (IGM-pus, IGM-skin, LM-pus, LM-skin; PERMANOVA, pCorynebacterium kroppenstedtii, reportedly associated with IGM in literature, was higher in IGM pus samples than paired skin sample (Wilcoxon, p=0.022). Three other species and nineteen genera were statistically significant in paired IGM pus-skin comparison after antibiotic treatment adjustment, and multiple comparisons correction.ConclusionsMicrobial profiles are unique between IGM and LM patients. Inter-patient variability and polymicrobial IGM pus samples cannot implicate specific genus or species as an infectious cause for IGM.
Published: 2022

26. Replication Study for the Association of Five SNPs Identified by GWAS and Trastuzumab-Induced Cardiotoxicity in Japanese and Singaporean Cohorts

Author: Chihiro Udagawa, Sherwin Kuah, Tatsunori Shimoi, Ken Kato, Teruhiko Yoshida, Mari Hara Nakano, Arata Shimo, Yasuyuki Kojima, Reiko Yoshie, Koichiro Tsugawa, Taisei Mushiroda, Ern Yu Tan, and Hitoshi Zembutsu
Subjects: Pharmacology, Singapore, Japan, Receptor, ErbB-2, Neoplasms, Pharmaceutical Science, Humans, General Medicine, Trastuzumab, Polymorphism, Single Nucleotide, Cardiotoxicity, Genome-Wide Association Study
Abstract: Trastuzumab (herceptin) is an effective drug for human epidermal growth factor receptor type 2 (HER2)-positive cancer. However, cardiotoxicity remains a serious complication. In our previous genome-wide association study (GWAS), we identified potential associations for five single nucleotide polymorphisms (SNPs) with trastuzumab-induced cardiotoxicity in a Japanese population. To validate this association, here we performed replication studies using Japanese and Singaporean case-control cohorts (Japan: 6 cases and 206 controls; Singapore: 22 cases and 178 controls). Although none of the SNPs showed a statistically significant association with trastuzumab-induced cardiotoxicity, we show that three (rs8032978, rs7406710 and rs9316695) and four (rs8032978, rs7406710, rs28415722 and rs11932853) SNPs had an effect in the same direction in the Japanese and the Singaporean cohort, respectively, as that in our previous study. Combining the previous study with the current replication studies, we find a strong association for two SNPs, rs8032978 and rs7406710, with trastuzumab-induced cardiotoxicity (P
Published: 2022

27. IFI16-dependent STING signaling is a crucial regulator of anti-HER2 immune response in HER2+ breast cancer

Author: Li-Teng Ong, Wee Chyan Lee, Shijun Ma, Gokce Oguz, Zhitong Niu, Yi Bao, Mubaraka Yusuf, Puay Leng Lee, Jian Yuan Goh, Panpan Wang, Kylie Su Mei Yong, Qingfeng Chen, Wenyu Wang, Adaikalavan Ramasamy, Dave S. B. Hoon, Henrik J. Ditzel, Ern Yu Tan, Soo Chin Lee, and Qiang Yu
Subjects: Multidisciplinary, Receptor, ErbB-2, Immunity, Membrane Proteins, Nuclear Proteins, Breast Neoplasms, Trastuzumab, Phosphoproteins, Chemokine CXCL11, Chemokine CXCL10, Gene Expression Regulation, Neoplastic, Mice, Antineoplastic Agents, Immunological, Drug Resistance, Neoplasm, Cell Line, Tumor, Animals, Humans, Neoplasm Recurrence, Local, Signal Transduction
Abstract: Relapse to anti-HER2 monoclonal antibody (mAb) therapies, such as trastuzumab in HER2 + breast cancer (BC), is associated with residual disease progression due to resistance to therapy. Here, we identify interferon-γ inducible protein 16 (IFI16)-dependent STING signaling as a significant determinant of trastuzumab responses in HER2 + BC. We show that down-regulation of immune-regulated genes (IRG) is specifically associated with poor survival of HER2 + , but not other BC subtypes. Among IRG, IFI16 is identified as a direct target of EZH2, the underexpression of which leads to deficient STING activation and downstream CXCL10/11 expression in response to trastuzumab treatment. Dual inhibition of EZH2 and histone deacetylase (HDAC) significantly activates IFI16-dependent immune responses to trastuzumab. Notably, a combination of a novel histone methylation inhibitor with an HDAC inhibitor induces complete tumor eradication and long-term T cell memory in a HER2 + BC mouse model. Our findings demonstrate an epigenetic regulatory mechanism suppressing the expression of the IFI16-CXCL10/11 signaling pathway that provides a survival advantage to HER2 + BC to confer resistance to trastuzumab treatment.
Published: 2022

28. DNA methylation and breast cancer-associated variants

Author: Swee Ho Lim, Patrick M. Y. Chan, Siau Wei Tang, Yirong Sim, Qing Ting Tan, Mikael Hartman, Benita Kiat Tee Tan, Zhiyan Yan, Joanne Ngeow, Ern Yu Tan, Seeu Si Ong, Su-Ming Tan, Juliana Chen Jia Chuan, Rajkumar Dorajoo, Alexis Jiaying Khng, Veronique Kiak Mien Tan, Peh Joo Ho, Ivna Ivanković, Jingmei Li, and Ching Wan Chan
Subjects: 0301 basic medicine, Genetics, Cancer Research, Candidate gene, dNaM, Genome-wide association study, Biology, Quantitative trait locus, medicine.disease, Minor allele frequency, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Breast cancer, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Expression quantitative trait loci, medicine
Abstract: A breast cancer polygenic risk score (PRS) comprising 313 common variants reliably predicts disease risk. We examined possible relationships between genetic variation, regulation, and expression to clarify the molecular alterations associated with these variants. Genome-wide methylomic variation was quantified (MethylationEPIC) in Asian breast cancer patients (1152 buffy coats from peripheral whole blood). DNA methylation (DNAm) quantitative trait loci (mQTL) mapping was performed for 235 of the 313 variants with minor allele frequencies > 5%. Stability of identified mQTLs (p
Published: 2021

29. Abstract P6-01-44: Alteration of DNA methylation landscape in breast patients treated with adjuvant chemotherapy

Author: Peh Joo Ho, Alexis Jiaying Khng, Benita Kiat Tee Tan, Ern Yu Tan, Geok hoon Lim, Su-Ming Tan, Veronique Kiak Mien Tan, Elaine Hsuen Lim, Mikael Hartman, and Jingmei Li
Subjects: Cancer Research, Oncology
Abstract: Background Exposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in treated patients. Methods We performed DNAm analysis in 1,244 and 897 breast cancer patients treated and not treated by adjuvant chemotherapy using the Illumina MethylationEPIC array (1,804 blood, 337 saliva). DNAm changes of 620,095 individual CpGs and 41,581 promoters were evaluated using linear regression models, adjusting for age at diagnosis, ethnicity, years between sample collection and diagnosis and cell-type heterogeneity. Results from datasets normalized separately were combined by meta-analysis (random effects model). Gene set enrichment analyses were conducted to identify key processes or pathways associated with chemotherapy treatment. Results A total of 425 differentially methylated CpGs and 20 promoters were significantly associated with chemotherapy treatment (p< 5e-8). Enriched gene sets among 3,495 chemotherapy-associated promoters (unadjusted p< 0.05, preranked by Z scores) included three suppressed Gene Ontology (GO) terms that survived Bonferroni correction (GO:0002376, immune system process; GO:0009605, response to external stimulus; and GO:1903034: regulation of response to wounding). Using meta-analysis regression coefficients for all promoters as a ranking metric, olfactory transduction (KEGG, hsa04740) was found to be significantly suppressed (unadjusted p=6.38e-06, adjusted p=0.002). Taste transduction (hsa04742, unadjusted p=1.73e-03, adjusted p=0.565) was the next most significantly suppressed pathway. Conclusion The enrichment of imprinted genes within biological processes and pathways suggests a biological mechanism by which chemotherapy treatment could affect immune response, wound healing and changes in the perceptions of smell and taste. Citation Format: Peh Joo Ho, Alexis Jiaying Khng, Benita Kiat Tee Tan, Ern Yu Tan, Geok hoon Lim, Su-Ming Tan, Veronique Kiak Mien Tan, Elaine Hsuen Lim, Mikael Hartman, Jingmei Li. Alteration of DNA methylation landscape in breast patients treated with adjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-44.
Published: 2023

30. Temporal release of a three-component protein subunit vaccine from polymer multilayers

Author: Jianzhu Chen, Julien Lescar, Victor Ho, Divakara S. S. M. Uppu, Paula T. Hammond, Yanpu He, Michelle E. Turvey, Ern Yu Tan, Katell Bidet, Anagha D. Tambe, Abdul Rahim Mohammed Sharif, and Katja Fink
Subjects: Polymers, medicine.medical_treatment, Protein subunit, Pharmaceutical Science, 02 engineering and technology, Mice, 03 medical and health sciences, Immune system, Adjuvants, Immunologic, Antigen, In vivo, medicine, Animals, 030304 developmental biology, 0303 health sciences, Chemistry, Immunogenicity, Vaccination, 021001 nanoscience & nanotechnology, Cell biology, Protein Subunits, Vaccines, Subunit, 0210 nano-technology, Adjuvant, Ex vivo
Abstract: Sustained antigen and adjuvant availability have been shown to improve antiviral immune responses following vaccination. Transcutaneous delivery of vaccines using microneedles has also shown promise and may be particularly relevant for mosquito-borne viruses. We aim to combine these traits to create a three-component Protein Subunit vaccine on Microneedle Arrays (PSMNs) for transcutaneous delivery using layer-by-layer (LbL) assembly. Polymer multilayer thin films were generated to co-deliver a model combination of three chemically distinct vaccine components, a dengue virus Envelope protein Domain III (EDIII) subunit antigen and two adjuvants, a double-stranded RNA (Poly (inosinic:cytidylic acid) (PolyI:C)) and an amphiphilic hexapeptide, Pam3CSK4. Following application of PSMNs to the skin, implanted thin films facilitated sustained and temporal release of individual vaccine components from polymer multilayers. By modulating LbL composition and architecture, component release profiles in the skin could be independently tuned to allow release of adjuvants and antigen from days up to two weeks. Uptake of antigen and adjuvant from implanted vaccine films by antigen-presenting cells was demonstrated using in vivo mouse and ex vivo human skin models. Overall, we believe that such modular vaccine strategies offer design principles for enhancing the immunogenicity of protein subunit vaccines.
Published: 2020

31. Relevance of the MHC region for breast cancer susceptibility in Asians

Author: Peh Joo Ho, Alexis Jiaying Khng, Benita Kiat-Tee Tan, Ern Yu Tan, Su-Ming Tan, Veronique Kiak Mien Tan, Geok Hoon Lim, Kristan J. Aronson, Tsun L. Chan, Ji-Yeob Choi, Joe Dennis, Weang-Kee Ho, Ming-Feng Hou, Hidemi Ito, Motoki Iwasaki, Esther M. John, Daehee Kang, Sung-Won Kim, Allison W. Kurian, Ava Kwong, Artitaya Lophatananon, Keitaro Matsuo, Nur Aishah Mohd-Taib, Kenneth Muir, Rachel A. Murphy, Sue K. Park, Chen-Yang Shen, Xiao-Ou Shu, Soo Hwang Teo, Qin Wang, Taiki Yamaji, Wei Zheng, Manjeet K. Bolla, Alison M. Dunning, Douglas F. Easton, Paul D. P. Pharoah, Mikael Hartman, Jingmei Li, Li, Jingmei [0000-0001-8587-7511], Apollo - University of Cambridge Repository, Dennis, Joe [0000-0003-4591-1214], Easton, Douglas [0000-0003-2444-3247], and Pharoah, Paul [0000-0001-8494-732X]
Subjects: Genotype, Breast cancer subtypes, Breast Neoplasms, General Medicine, Polymorphism, Single Nucleotide, HLA, Oncology, Asian People, HLA Antigens, Humans, Pharmacology (medical), Radiology, Nuclear Medicine and imaging, Female, Genetic Predisposition to Disease, Breast cancer risk, Alleles
Abstract: Background Human leukocyte antigen (HLA) genes play critical roles in immune surveillance, an important defence against tumors. Imputing HLA genotypes from existing single-nucleotide polymorphism datasets is low-cost and efficient. We investigate the relevance of the major histocompatibility complex region in breast cancer susceptibility, using imputed class I and II HLA alleles, in 25,484 women of Asian ancestry. Methods A total of 12,901 breast cancer cases and 12,583 controls from 12 case–control studies were included in our pooled analysis. HLA imputation was performed using SNP2HLA on 10,886 quality-controlled variants within the 15–55 Mb region on chromosome 6. HLA alleles (n = 175) with info scores greater than 0.8 and frequencies greater than 0.01 were included (resolution at two-digit level: 71; four-digit level: 104). We studied the associations between HLA alleles and breast cancer risk using logistic regression, adjusting for population structure and age. Associations between HLA alleles and the risk of subtypes of breast cancer (ER-positive, ER-negative, HER2-positive, HER2-negative, early-stage, and late-stage) were examined. Results We did not observe associations between any HLA allele and breast cancer risk at P P = 1.08e−3). Ninety-five percent of the effect sizes (OR) observed were between 0.90 and 1.23. Similar results were observed when different subtypes of breast cancer were studied (95% of ORs were between 0.85 and 1.18). Conclusions No imputed HLA allele was associated with breast cancer risk in our large Asian study. Direct measurement of HLA gene expressions may be required to further explore the associations between HLA genes and breast cancer risk.
Published: 2022

32. Profiling Microbial Communities in Idiopathic Granulomatous Mastitis

Author: Seeu Si Ong, Jia Xu, Choon Kiat Sim, Alexis Jiaying Khng, Peh Joo Ho, Philip Kam Weng Kwan, Aarthi Ravikrishnan, Kiat-Tee Benita Tan, Qing Ting Tan, Ern Yu Tan, Su-Ming Tan, Thomas Choudary Putti, Swee Ho Lim, Ee Ling Serene Tang, Niranjan Nagarajan, Neerja Karnani, Jingmei Li, and Mikael Hartman
Subjects: Inorganic Chemistry, Organic Chemistry, General Medicine, idiopathic granulomatous mastitis, metagenomic sequencing, microbiota, 16S rRNA, Corynebacterium, MaAsLin 2, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Catalysis, Computer Science Applications
Abstract: Idiopathic granulomatous mastitis (IGM) is a rare and benign inflammatory breast disease with ambiguous aetiology. Contrastingly, lactational mastitis (LM) is commonly diagnosed in breastfeeding women. To investigate IGM aetiology, we profiled the microbial flora of pus and skin in patients with IGM and LM. A total of 26 patients with IGM and 6 patients with LM were included in the study. The 16S rRNA sequencing libraries were constructed from 16S rRNA gene amplified from total DNA extracted from pus and skin swabs in patients with IGM and LM controls. Constructed libraries were multiplexed and paired-end sequenced on HiSeq4000. Metagenomic analysis was conducted using modified microbiome abundance analysis suite customised R-resource for paired pus and skin samples. Microbiome multivariable association analyses were performed using linear models. A total of 21 IGM and 3 LM paired pus and skin samples underwent metagenomic analysis. Bray−Curtis ecological dissimilarity distance showed dissimilarity across four sample types (IGM pus, IGM skin, LM pus, and LM skin; PERMANOVA, p < 0.001). No characteristic dominant genus was observed across the IGM samples. The IGM pus samples were more diverse than corresponding IGM skin samples (Shannon and Simpson index; Wilcoxon paired signed-rank tests, p = 0.022 and p = 0.07). Corynebacterium kroppenstedtii, reportedly associated with IGM in the literature, was higher in IGM pus samples than paired skin samples (Wilcoxon, p = 0.022). Three other species and nineteen genera were statistically significant in paired IGM pus–skin comparison after antibiotic treatment adjustment and multiple comparisons correction. Microbial profiles are unique between patients with IGM and LM. Inter-patient variability and polymicrobial IGM pus samples cannot implicate specific genus or species as an infectious cause for IGM.
Published: 2023

33. Overlap of high-risk individuals predicted by family history, and genetic and non-genetic breast cancer risk prediction models: implications for risk stratification

Author: Peh Joo Ho, Weang Kee Ho, Alexis J. Khng, Yen Shing Yeoh, Benita Kiat-Tee Tan, Ern Yu Tan, Geok Hoon Lim, Su-Ming Tan, Veronique Kiak Mien Tan, Cheng-Har Yip, Nur-Aishah Mohd-Taib, Fuh Yong Wong, Elaine Hsuen Lim, Joanne Ngeow, Wen Yee Chay, Lester Chee Hao Leong, Wei Sean Yong, Chin Mui Seah, Siau Wei Tang, Celene Wei Qi Ng, Zhiyan Yan, Jung Ah Lee, Kartini Rahmat, Tania Islam, Tiara Hassan, Mei-Chee Tai, Chiea Chuen Khor, Jian-Min Yuan, Woon-Puay Koh, Xueling Sim, Alison M. Dunning, Manjeet K. Bolla, Antonis C. Antoniou, Soo-Hwang Teo, Jingmei Li, Mikael Hartman, Antoniou, Antonis [0000-0001-9223-3116], Li, Jingmei [0000-0001-8587-7511], and Apollo - University of Cambridge Repository
Subjects: Protein-truncating variants, Risk-based screening, Male, Breast Neoplasms, General Medicine, Risk Assessment, Breast cancer, Polygenic risk score, Asian People, Humans, Female, Genetic Predisposition to Disease, Gail model, Research Article
Abstract: Background Family history, and genetic and non-genetic risk factors can stratify women according to their individual risk of developing breast cancer. The extent of overlap between these risk predictors is not clear. Methods In this case-only analysis involving 7600 Asian breast cancer patients diagnosed between age 30 and 75 years, we examined identification of high-risk patients based on positive family history, the Gail model 5-year absolute risk [5yAR] above 1.3%, breast cancer predisposition genes (protein-truncating variants [PTV] in ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, or TP53), and polygenic risk score (PRS) 5yAR above 1.3%. Results Correlation between 5yAR (at age of diagnosis) predicted by PRS and the Gail model was low (r=0.27). Fifty-three percent of breast cancer patients (n=4041) were considered high risk by one or more classification criteria. Positive family history, PTV carriership, PRS, or the Gail model identified 1247 (16%), 385 (5%), 2774 (36%), and 1592 (21%) patients who were considered at high risk, respectively. In a subset of 3227 women aged below 50 years, the four models studied identified 470 (15%), 213 (7%), 769 (24%), and 325 (10%) unique patients who were considered at high risk, respectively. For younger women, PRS and PTVs together identified 745 (59% of 1276) high-risk individuals who were not identified by the Gail model or family history. Conclusions Family history and genetic and non-genetic risk stratification tools have the potential to complement one another to identify women at high risk.
Published: 2021

34. IMPACT OF SUBSIDY ON THE USE OF PERSONALIZED MEDICINE IN BREAST CANCER

Author: Cynthia Chen, Jue Tao Lim, Swee Ho Lim, Ern Yu Tan, Veronique Kiak Mien Tan, Su Ming Tan, Tira Tan, and Mikael Hartman
Subjects: Health (social science), Life-span and Life-course Studies, Health Professions (miscellaneous)
Abstract: Advances in adjuvant therapy have led to increased survival rates after cancer prognosis. Herceptin, a targeted therapy, had first been introduced to Singapore in 2006. We aimed to assess whether subsidies for Herceptin from 2012 will lead to changes in uptake among Human Epidermal Growth Factor Receptor 2 (HER2) positive patients by socio-economic groups. Two-level random-intercept logistic regression was used to model diagnostic test and Herceptin uptake using the Singapore Breast Cancer Cohort from 2006 to 2018, adjusting for covariates such as education, housing type and marital status before and after subsidies. Interrupted time series (ITS) analysis was used to evaluate the impact of Herceptin subsidy on treatment uptake. The concentration index was also computed to measure inequality in uptake by ethnicity and education. We found that the odds of diagnostic testing were not associated with socioeconomic factors. However, before subsidies, the highest education attained (OR = 4.57, 95% CI= (1.90, 11.02), P< 0.01) significantly increased the odds of Herceptin uptake. These odds were levelled after the introduction of subsidies to Herceptin treatment in 2012. After subsidy, we also found that Herceptin uptake increased significantly by 11.4% (95% CI= (3.47%, 19.4%), P=0.016). Also, inequality of Herceptin use decreased especially amongst the Indians, where at least 40% were used in the higher educated group prior to the subsidy. Subsidies have lowered the barriers to Herceptin uptake for marginalized individuals. Having targeted subsidies for socio-economically disadvantaged groups may work more efficiently in providing ease of access than a blanket subsidy in Herceptin.
Published: 2022

35. Circulating <scp>microRNA</scp> breast cancer biomarker detection in patient sera with surface plasmon resonance imaging biosensor

Author: Patrick M. Y. Chan, Ann Siew Gek Lee, Ern Yu Tan, Malini Olivo, Hann Qian Lim, Ghayathri Balasundaram, Sau Yeen Loke, Bee Kiang Chong, Chi Lok Wong, Lee Kong Chian School of Medicine (LKCMedicine), Institute of Molecular and Cell Biology, A*STAR, and Tan Tock Seng Hospital
Subjects: Breast Cancer Biomarker, General Physics and Astronomy, Breast Neoplasms, Biosensing Techniques, General Biochemistry, Genetics and Molecular Biology, Nuclear magnetic resonance, Breast cancer, Surface plasmon resonance imaging, Circulating miRNA, Biomarkers, Tumor, medicine, Humans, Medicine [Science], General Materials Science, In patient, Circulating MicroRNA, Plasmon, Chemistry, General Engineering, Resonance, General Chemistry, Surface Plasmon Resonance, medicine.disease, Biomarker (cell), Female, Gold, Biosensor
Abstract: In this article, we report for the first time, the detection of circulating miRNA as a breast cancer biomarker in patient sera using surface plasmon resonance imaging biosensor. The advantage of this approach lies in the rapid, label-free and sensitive detection. The sensor excites plasmonic resonance on the gold sensor surface and specific DNA-miRNA molecular bindings elucidate responses in the plasmonic resonance image. Experiments of detecting synthetic miRNA molecules (miR-1249) were performed and the sensor resolution was found to be 63.5 nM. The sensor was further applied to screen 17 patient serum samples from National Cancer Centre Singapore and Tan Tock Seng Hospital. Sensor intensity response was found to differ by 20% between malignant and benign cases and thus forms, a potential and an important metric in distinguishing benignity and malignancy. Agency for Science, Technology and Research (A*STAR) This work was supported by Agency of Science, Technology and Research (A*STAR), under its Industry alignment fund prepositioning programme, Award H19H6a0025 , Agency for Science, Technology and Research’s (A*STAR) BMRC Central Research Fund (CRF, UIBR) Award and A*ccelerate under GAP funding (ETPL/14-R15GAP-0027). This project was partially funded by the NCC Research Fund.
Published: 2021

36. Recurrence of breast cancer after regional or general anaesthesia: a randomised controlled trial

Author: Daniel I Sessler, Lijian Pei, Yuguang Huang, Edith Fleischmann, Peter Marhofer, Andrea Kurz, Douglas B Mayers, Tanja A Meyer-Treschan, Martin Grady, Ern Yu Tan, Sabry Ayad, Edward J Mascha, Donal J Buggy, Gang Tan, Zhiyong Zhang, Helen Keane, Maurice Stokes, Oliver Zotti, Michael Gnant, Silvia Perez-Protto, Jiang Wu, Ivan Parra-Sanchez, Dongsheng Yang, Manal Hassan, and John BL Tey
Subjects: Adult, Surgical stress, Breast pain, Breast Neoplasms, Kaplan-Meier Estimate, Anesthesia, General, 030204 cardiovascular system & hematology, law.invention, Sevoflurane, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Randomized controlled trial, Anesthesia, Conduction, law, Humans, Medicine, General anaesthesia, 030212 general & internal medicine, Mastectomy, Aged, Neoplasm Staging, Aged, 80 and over, Pain, Postoperative, business.industry, Hazard ratio, Nerve Block, General Medicine, Perioperative, Odds ratio, Middle Aged, medicine.disease, Analgesics, Opioid, Lymphatic Metastasis, Anesthesia, Anesthetics, Inhalation, Female, Neoplasm Grading, Neoplasm Recurrence, Local, medicine.symptom, business, Follow-Up Studies
Abstract: Three perioperative factors impair host defence against recurrence during cancer surgery: the surgical stress response, use of volatile anaesthetic, and opioids for analgesia. All factors are ameliorated by regional anaesthesia-analgesia. We tested the primary hypothesis that breast cancer recurrence after potentially curative surgery is lower with regional anaesthesia-analgesia using paravertebral blocks and the anaesthetic propofol than with general anaesthesia with the volatile anaesthetic sevoflurane and opioid analgesia. A second hypothesis was that regional anaesthesia-analgesia reduces persistent incisional pain.We did a randomised controlled trial at 13 hospitals in Argentina, Austria, China, Germany, Ireland, New Zealand, Singapore, and the USA. Women (age85 years) having potentially curative primary breast cancer resections were randomised by computer to either regional anaesthesia-analgesia (paravertebral blocks and propofol) or general anaesthesia (sevoflurane) and opioid analgesia. The primary outcome was local or metastatic breast cancer recurrence. The secondary outcome was incisional pain at 6 months and 12 months. Primary analyses were done under intention-to-treat principles. This trial is registered with ClinicalTrials.gov, NCT00418457. The study was stopped after a preplanned futility boundary was crossed.Between Jan 30, 2007, and Jan 18, 2018, 2132 women were enrolled to the study, of whom 24 were excluded before surgery. 1043 were assigned to regional anaesthesia-analgesia and 1065 were allocated to general anaesthesia. Baseline characteristics were well balanced between study groups. Median follow-up was 36 (IQR 24-49) months. Among women assigned regional anaesthesia-analgesia, 102 (10%) recurrences were reported, compared with 111 (10%) recurrences among those allocated general anaesthesia (hazard ratio 0·97, 95% CI 0·74-1·28; p=0·84). Incisional pain was reported by 442 (52%) of 856 patients assigned to regional anaesthesia-analgesia and 456 (52%) of 872 patients allocated to general anaesthesia at 6 months, and by 239 (28%) of 854 patients and 232 (27%) of 852 patients, respectively, at 12 months (overall interim-adjusted odds ratio 1·00, 95% CI 0·85-1·17; p=0·99). Neuropathic breast pain did not differ by anaesthetic technique and was reported by 87 (10%) of 859 patients assigned to regional anaesthesia-analgesia and 89 (10%) of 870 patients allocated to general anaesthesia at 6 months, and by 57 (7%) of 857 patients and 57 (7%) of 854 patients, respectively, at 12 months.In our study population, regional anaesthesia-analgesia (paravertebral block and propofol) did not reduce breast cancer recurrence after potentially curative surgery compared with volatile anaesthesia (sevoflurane) and opioids. The frequency and severity of persistent incisional breast pain was unaffected by anaesthetic technique. Clinicians can use regional or general anaesthesia with respect to breast cancer recurrence and persistent incisional pain.Sisk Healthcare Foundation (Ireland), Eccles Breast Cancer Research Fund, British Journal of Anaesthesia International, College of Anaesthetists of Ireland, Peking Union Medical College Hospital, Science Fund for Junior Faculty 2016, Central Bank of Austria, and National Healthcare Group.
Published: 2019

37. Mammography screening is associated with more favorable breast cancer tumor characteristics and better overall survival: Case-only analysis of 3,739 Asian breast cancer patients

Author: Mikael Hartman, Zi Lin Lim, Peh Joo Ho, Alexis Jiaying Khng, Yen Shing Yeoh, Amanda Tse Woon Ong, Benita Kiat Tee Tan, Ern Yu Tan, Su-Ming Tan, Geok Hoon Lim, Kiak Mien Veronique Tan, and Jingmei Li
Subjects: Cancer Research, Oncology
Abstract: e22500 Background: Early detection of breast cancer (BC) through mammography screening (MAM) is known to reduce mortality. We examined the differential effect that mammography has on BC characteristics and overall survival and the sociodemographic determinants of MAM utilisation in a multi-ethnic Asian population. Methods: This study included 3,739 BC patients from the Singapore Breast Cancer Cohort (2010–2018). Self-reported socio-demographic characteristics were collected using a structured questionnaire. Clinical data were obtained through medical records. Patients were classified as screeners (last screening mammogram ≤two years before diagnosis), non-screeners (aware but did not attend or last screen > 2years) and those unaware of MAM. Associations between MAM behaviour (MB) and sociodemographic factors and MB and tumour characteristics were examined using multinomial regression. Ten-year overall survival was modelled using Cox regression. Results: Patients unaware of screening were more likely diagnosed with late stage (ORstage III vs stage I(Ref) [95%CI]:4.94[3.45-7.07], p < 0.001), high grade (ORpoorly- vs well-differentiated(reference): 1.53 [1.06-2.20], p = 0.022), nodal-positive, large size (OR> 5cm vs ≤2cm(reference): 5.06 [3.10-8.25], p < 0.001), and HER2-positive tumors (ORHER2-negative VS -positive(reference): 0.72[0.53-0.97], p = 0.028). Similar trends were observed between screeners and non-screeners with smaller effect sizes. Overall survival was significantly shorter than screeners in the both groups(non-screeners HR: 1.89 [1.22-2.94], p = 0.005; unaware HR: 2.90[1.69-4.98], p < 0.001). Non-screeners and those unaware were less health-conscious, older, of Malay ethnicity, less highly educated, of lower socioeconomic status, more frequently ever smokers and less physically active. Among screeners, there were more reported personal histories of benign breast surgeries or gynaecological conditions and positive family history of breast cancer. Conclusions: Mammography attendance is associated with more favourable BC characteristics and overall survival. Disparities in the utility of MAM services suggest that different strategies may be needed to improve MAM uptake.
Published: 2022

38. Impact of Subsidy on the Use of Personalized Medicine in Breast Cancer

Author: Jue Tao Lim, Jemima Jia En Koh, Peh Joo Ho, Jenny Liu, Swee Ho Lim, Ern Yu Tan, Benita Kiat Tee Tan, Veronique Kiak Mien Tan, Su Ming Tan, Wei Sean Yong, Mikael Hartman, and Cynthia Chen
Subjects: Cohort Studies, Singapore, Health Policy, Economics, Econometrics and Finance (miscellaneous), Humans, Breast Neoplasms, Female, Precision Medicine, Trastuzumab, Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
Abstract: Advances in adjuvant therapy have led to increased survival rates after cancer prognosis. Herceptin, a targeted therapy, had first been introduced to Singapore in 2006. We aimed to assess whether subsidies for Herceptin from 2012 will lead to changes in uptake among HER2-positive patients by socioeconomic groups.Random-intercept logistic regression was used to model diagnostic test and Herceptin uptake using the Singapore Breast Cancer Cohort from 2006 to 2018, adjusting for covariates such as education, housing type, and marital status before and after subsidies. Interrupted time series analysis was used to evaluate the impact of Herceptin subsidy on treatment uptake. Concentration index was also computed by ethnicity and education to measure inequality in uptake.We found that the odds of diagnostic testing were not associated with socioeconomic factors. Nevertheless, before subsidies, highest education attained (odds ratio 4.57; 95% confidence interval 1.90-11.02; P.01) significantly increased the odds of Herceptin uptake. These odds were leveled after the introduction of subsidies to Herceptin treatment from 2012. After subsidy, we also found that Herceptin uptake increased significantly by 11.4% (95% confidence interval 3.47-19.4; P=.016). In addition, inequality of Herceptin use decreased especially among the Indians, where at least 40% were used in the higher educated group before subsidy.Subsidies have lowered the barriers to Herceptin uptake for marginalized individuals. Having targeted subsidies for socioeconomically disadvantaged groups may work more efficiently in providing ease of access than a blanket subsidy in Herceptin.
Published: 2021

39. Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore

Author: Joanna Lim, Rick A. C. M. Boonen, Milan Sharma, Ern Yu Tan, Craig Luccarini, Su-Ming Tan, Jingmei Li, Douglas F. Easton, Sabine Knaup, Benita Kiat Tee Tan, Soo Hwang Teo, Weang Kee Ho, Alison M. Dunning, Chan Eng Chong, Shivaani Mariapun, Kartini Rahmat, Sara Carvalho, Rob M. van Dam, Mee Hoong See, Eldarina Wijaya, Pei Sze Ng, Caroline Baynes, Swee Ho Lim, Antonis C. Antoniou, Sook-Yee Yoon, Haico van Attikum, Mikael Hartman, Cheng Har Yip, Nur Aishah Taib, Veronique Kiat-Mien Tan, Ng, Pei Sze [0000-0001-5403-2065], Yoon, Sook-Yee [0000-0002-9992-0901], Teo, Soo Hwang [0000-0002-0444-590X], and Apollo - University of Cambridge Repository
Subjects: Male, 0301 basic medicine, PALB2, Population, Breast Neoplasms, Biology, Germline, Mice, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Germline mutation, Genetics, medicine, Animals, Humans, Missense mutation, education, Cancer genetics, Genetics (clinical), genetic predisposition to disease, Singapore, education.field_of_study, Malaysia, medicine.disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Relative risk, Mutation testing, Female, Fanconi Anemia Complementation Group N Protein, germ-line mutation
Abstract: BackgroundRare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (PALB2) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in PALB2 in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population.MethodsMutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays.ResultsPTVs in PALB2 were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, pPALB2 were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in PALB2. However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks.ConclusionDespite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.
Published: 2021

40. Development of a microRNA Panel for Classification of Abnormal Mammograms for Breast Cancer

Author: Mikael Hartman, Su Lin Jill Wong, Shu Yun Sherylyn Lee, Choon Hua Thng, Sue Zann Lim, Ruiyang Zou, Yew Chung Tang, Ann Siew Gek Lee, Swee Tian Quek, Wei Sean Yong, Soo-Chin Lee, Lihan Zhou, Preetha Madhukumar, Yik Ying Teo, Mun Yew Patrick Chan, Heng-Phon Too, Pooja Jagmohan, Ern Yu Tan, Sau Yeen Loke, Bee Kiang Chong, Teng Swan Juliana Ho, Eunice Png, Veronique Kiak Mien Tan, Ngiap Chuan Tan, Boon Kheng James Khoo, Benita Kiat Tee Tan, and Yirong Sim
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Article, 03 medical and health sciences, Breast cancer screening, 0302 clinical medicine, Breast cancer, breast cancer, Internal medicine, medicine, Mammography, Stage (cooking), RC254-282, medicine.diagnostic_test, business.industry, Cancer, biomarkers, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, qRT-PCR, abnormal mammograms, medicine.disease, Circulating MicroRNA, 030104 developmental biology, 030220 oncology & carcinogenesis, Cohort, circulating microRNAs, Biomarker (medicine), business
Abstract: Simple Summary Breast cancer screening by mammography suffers from high rates of false positivity, resulting in unnecessary investigative imaging and biopsies. There is an unmet need for biomarkers that can distinguish between malignant and benign breast lesions. We performed miRNA profiling on 638 patients with abnormal mammograms and 100 healthy controls. A six-miRNA panel was identified and validated in an independent cohort that had an AUC of 0.881 when differentiating between cases versus those with benign lesions or healthy individuals with normal mammograms. In addition, biomarker panel scores increased with tumor size, stage and number of lymph nodes involved. This study demonstrates that circulating miRNAs can potentially be used in conjunction with mammography to differentiate between patients with malignant and benign breast lesions. Abstract Mammography is extensively used for breast cancer screening but has high false-positive rates. Here, prospectively collected blood samples were used to identify circulating microRNA (miRNA) biomarkers to discriminate between malignant and benign breast lesions among women with abnormal mammograms. The Discovery cohort comprised 72 patients with breast cancer and 197 patients with benign breast lesions, while the Validation cohort had 73 and 196 cancer and benign cases, respectively. Absolute expression levels of 324 miRNAs were determined using RT-qPCR. miRNA biomarker panels were identified by: (1) determining differential expression between malignant and benign breast lesions, (2) focusing on top differentially expressed miRNAs, and (3) building panels from an unbiased search among all expressed miRNAs. Two-fold cross-validation incorporating a feature selection algorithm and logistic regression was performed. A six-miRNA biomarker panel identified by the third strategy, had an area under the curve (AUC) of 0.785 and 0.774 in the Discovery and Validation cohorts, respectively, and an AUC of 0.881 when differentiating between cases versus those with benign lesions or healthy individuals with normal mammograms. Biomarker panel scores increased with tumor size, stage and number of lymph nodes involved. Our work demonstrates that circulating miRNA signatures can potentially be used with mammography to differentiate between patients with malignant and benign breast lesions.
Published: 2021

41. Germline breast cancer susceptibility genes, tumor characteristics, and survival

Author: Douglas F. Easton, Jingmei Li, Eldarina Wijaya, Ching Wan Chan, Alison M. Dunning, Min Hyuk Lee, Veronique Kiak Mien Tan, Shaik Ahmad Buhari, Ern Yu Tan, Soo-Chin Lee, Sue K. Park, Yirong Sim, Jong Won Lee, Mikael Hartman, Jaime Chin Mui Seah, Swee Ho Lim, Peh Joo Ho, Su-Ming Tan, Chi Wei Mok, Suniza Jamaris, Cheng Har Yip, Benita Kiat Tee Tan, Weang Kee Ho, Alexis Jiaying Khng, Nur Aishah Mohd-Taib, Wai Peng Lee, Elaine Hsuen Lim, Evan Woo, Geok Hoon Lim, Juliana J. C. Chen, Marjanka K. Schmidt, Soo Hwang Teo, Patrick M. Y. Chan, Hui Wen Loh, Joanne Ngeow, Fuh Yong Wong, Mei Chee Tai, Sung-Won Kim, Li, Jingmei [0000-0001-8587-7511], Apollo - University of Cambridge Repository, Easton, Douglas [0000-0003-2444-3247], Lee Kong Chian School of Medicine (LKCMedicine), Tan Tock Seng Hospital, Institute of Molecular and Cell Biology, A*STAR, National Cancer Centre Singapore, and Duke-NUS Medical School
Subjects: Oncology, medicine.medical_specialty, PALB2, Breast Neoplasms, Disease, QH426-470, Breast cancer, Internal medicine, Breast Cancer, Genetics, medicine, Odds Ratio, Humans, Medicine [Science], Genetic Predisposition to Disease, Overall survival, Genetic Testing, skin and connective tissue diseases, Molecular Biology, CHEK2, Protein-Truncating Variants, Genetics (clinical), Germ-Line Mutation, Genetic testing, Protein-truncating variants, medicine.diagnostic_test, business.industry, Proportional hazards model, BRCA1 Protein, Research, Hazard ratio, Odds ratio, medicine.disease, Germ Cells, Medicine, Molecular Medicine, Female, business
Abstract: Background Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent. Methods Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease. Results PTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35–5.17], moderately vs well-differentiated 2.33 [1.56–3.49]), as well as luminal B [HER−] and triple-negative subtypes (vs luminal A 2.15 [1.58–2.92] and 2.85 [2.17–3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2−] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16–2.28]). Conclusions PTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.
Published: 2021

42. Role of mammogram and ultrasound imaging in predicting breast cancer subtypes in screening and symptomatic patients

Author: Niketa Chotai, Ern Yu Tan, and Tay Wei Ming Ian
Subjects: medicine.medical_specialty, Triple-negative cancer, medicine.diagnostic_test, business.industry, Radiogenomics, Cancer, Odds ratio, Ductal carcinoma, medicine.disease, Hormone receptor, Molecular subtype, Breast cancer screening, Breast cancer, Oncology, Retrospective Study, medicine, Mammography, Radiology, Stage (cooking), business, Ultrasonography
Abstract: BACKGROUND Breast cancer (BC) radiogenomics, or correlation analysis of imaging features and BC molecular subtypes, can complement genetic analysis with less resource-intensive diagnostic methods to provide an early and accurate triage of BC. This is pertinent because BC is the most prevalent cancer amongst adult women, resulting in rising demands on public health resources. AIM To find combinations of mammogram and ultrasound imaging features that predict BC molecular subtypes in a sample of screening and symptomatic patients. METHODS This retrospective study evaluated 328 consecutive patients in 2017-2018 with histologically confirmed BC, of which 237 (72%) presented with symptoms and 91 (28%) were detected via a screening program. All the patients underwent mammography and ultrasound imaging prior to biopsy. The images were retrospectively read by two breast-imaging radiologists with 5-10 years of experience with no knowledge of the histology results to ensure statistical independence. To test the hypothesis that imaging features are correlated with tumor subtypes, univariate binomial and multinomial logistic regression models were performed. Our study also used the multivariate logistic regression (with and without interaction terms) to identify combinations of mammogram and ultrasound (US) imaging characteristics predictive of molecular subtypes. RESULTS The presence of circumscribed margins, posterior enhancement, and large size is correlated with triple-negative BC (TNBC), while high-risk microcalcifications and microlobulated margins is predictive of HER2-enriched cancers. Ductal carcinoma in situ is characterized by small size on ultrasound, absence of posterior acoustic features, and architectural distortion on mammogram, while luminal subtypes tend to be small, with spiculated margins and posterior acoustic shadowing (Luminal A type). These results are broadly consistent with findings from prior studies. In addition, we also find that US size signals a higher odds ratio for TNBC if presented during screening. As TNBC tends to display sonographic features such as circumscribed margins and posterior enhancement, resulting in visual similarity with benign common lesions, at the screening stage, size may be a useful factor in deciding whether to recommend a biopsy. CONCLUSION Several imaging features were shown to be independent variables predicting molecular subtypes of BC. Knowledge of such correlations could help clinicians stratify BC patients, possibly enabling earlier treatment or aiding in therapeutic decisions in countries where receptor testing is not readily available.
Published: 2021

43. The therapeutic dilemma of idiopathic granulomatous mastitis

Author: Ern Yu Tan, Ee Ling Serene Tang, Patrick M. Y. Chan, Juliana Jia Chuan Chen, Chi Shern Bernard Ho, Mui Heng Goh, and Lee Kong Chian School of Medicine (LKCMedicine)
Subjects: Adult, medicine.medical_specialty, medicine.drug_class, Antibiotics, Granulomatous mastitis, Quality of life, Chronic Mastitis, Internal medicine, medicine, Humans, Medicine [Science], Granulomatous Mastitis, Retrospective Studies, business.industry, Significant difference, Retrospective cohort study, General Medicine, Odds ratio, medicine.disease, Confidence interval, Anti-Bacterial Agents, Treatment Outcome, Clinical diagnosis, Quality of Life, Female, Breast Inflammation, business
Abstract: Introduction: Idiopathic granulomatous mastitis (IGM) is a rare, benign, chronic breast condition that can cause repeated abscesses or mass formation in bilateral breasts. The condition can severely impact the quality of life of affected women. This study aims to evaluate effective treatment modalities, as well as understand the demographics and clinical presentation of patients with IGM. Methods: An 11-year retrospective review was performed of patients diagnosed with IGM from 1 January 2008 to 31 December 2018 at a tertiary breast unit. Results: A total of 77 patients were included in the study. The median age at presentation was 36 years old. IGM presented most commonly as a breast lump (98.1%). The median number of flares was 2 (1–12). Of the 77 patients, 68.8% (53) were treated with antibiotics, 50.6% (39) with steroids, and 44.2% (34) underwent surgery, in the course of their IGM treatment. Forty-five (59.2%) of the 76 patients with IGM required a multimodal treatment approach to achieve remission. There was no significant difference in the number of flares no matter the initial treatment (P=0.411), or subsequent treatment modality (P=0.343). Smokers had 10 times greater odds of having a “high flare” of IGM compared to those who did not smoke (P=0.031, odds ratio 10.444, 95% confidence interval 1.092–99.859). Conclusion: IGM is a clinical diagnosis. It is a rare, relapsing breast inflammatory condition that affects young females with no superior treatment modality. Smoking is associated with higher number of flares of IGM and should be discouraged in IGM patients Keywords: Breast inflammation, chronic mastitis, idiopathic granulomatous mastitis, recurrent breast abscess
Published: 2021

44. Timing of surgery following SARS-CoV-2 infection: an international prospective cohort study

Author: Dmitri, Nepogodiev, Joana Ff Simoes, Elizabeth, Li, Maria, Picciochi, James, C Glasbey, Glauco, Baiocchi, Ruth, Blanco-Colino, Daoud, Chaudhry, Ehab, Alameer, Kariem, El-Boghdadly, Funmilola, Wuraola, Dhruva, Ghosh, Rohan, R Gujjuri, Ewen, M Harrison, Herman, Lule, Haytham, Kaafarani, Mohammad, Khosravi, Irmgard, Kronberger, Sezai, Leventoğlu, Harvinder, Mann, Kenneth, A Mclean, Mengistu Gebreyohanes Mengesha, Maria Marta Modolo, Faustin, Ntirenganya, Lisa, Norman, Oumaima, Outani, Riinu, Pius, Peter, Pockney, Ahmad Uzair Qureshi, April Camilla Roslani, Sohei, Satoi, Catherine, Shaw, Aneel, Bhangu, Omar, M Omar, Waheed-Ul-Rahman, Ahmed, Leah, Argus, Alasdair, Ball, Edward, P Bywater, Amanpreet, Brar, Brett, E Dawson, Irani, Duran, Muhammed, Elhadi, Conor, S Jones, Sivesh, K Kamarajah, James, M Keatley, Samuel, Lawday, Ella, J Marson, Riinu, Ots, Irène, Santos, Elliott, H Taylor, Isobel, M Trout, Chris, Varghese, Mary, L Venn, William, Xu, Irida, Dajti, Arben, Gjata, Salah Eddine Oussama Kacimi, Luis, Boccalatte, Daniel, Cox, Philip, Townend, Felix, Aigner, Irmgard Elisabeth Kronberger, Elgun, Samadov, Amer, Alderazi, Kamral, Hossain, Greg, Padmore, Gabrielle van Ramshorst, Ismaïl, Lawani, Anis, Cerovac, Samir, Delibegovic, Gustavo Mendonça Ataíde Gomes, Igor Lima Buarque, Muhammad, Gohar, Mihail, Slavchev, Chukwuemeka, Nwegbu, Arnav, Agarwal, Janet, Martin, Joshua, Ng-Kamstra, Maricarmen, Olivos, Wenhui, Lou, Dong-Lin, Ren, Jose Andres Calvache, Carlos, J Perez Rivera, Ana Danic Hadzibegovic, Tomislav, Kopjar, Jakov, Mihanovic, Pablo Mijahil Avilés Jiménez, Nikolaos, Gouvas, Jaroslav, Klat, René, Novysedlák, Nicolas, Amisi, Peter, Christensen, Alaa, El-Hussuna, Sylvia, Batista, Eddy, Lincango-Naranjo, Sameh, Emile, Danilo Alfonso Arévalo Sandoval, Hailu, Dhufera, Samuel, Hailu, Mengistu, G Mengesha, Joonas, H Kauppila, Alexis, P Arnaud, Zaza, Demetrashvili, Markus, Albertsmeier, Hans, Lederhuber, Markus, W Löffler, Daniel Kwesi Acquah, Bernard, Ofori, Stephen, Tabiri, Symeon, Metallidis, Georgios, Tsoulfas, Maria-Lorena, Aguilera-Arevalo, Gustavo, Recinos, Tamás, Mersich, Dániel, Wettstein, Gabriele, Kembuan, Peiman Brouki Milan, Mohammad Hossein Khosravi, Masoud, Mozafari, Ahmed, Hilmi, Helen, Mohan, Oded, Zmora, Gaetano, Gallo, Francesco, Pata, Gianluca, Pellino, Yuki, Fujimoto, Naoto, Kuroda, Mohamad, K Abou Chaar, Faris, Ayasra, Ildar, Fakhradiyev, Intisar Hisham Said Hamdun, Jang, Jin-Young, Mohammad, Jamal, Lina, Karout, Aiste, Gulla, Fanjandrainy, Rasoaherinomenjanahary, Luc Hervé Samison, Iran Irani Durán Sánchez, Diana Samantha Gonzalez, Laura, Martinez, María José Martínez, Alejandra, Nayen, Antonio Ramos-De la Medina, Jade, Nunez, Pueya Rashid Nashidengo, Rakesh, Shah, Ashish Lal Shrestha, Pascal, Jonker, Schelto, Kruijff, Milou, Noltes, Pieter, Steinkamp, Deborah, Wright, Lukman, Abdur-Rahman, Adesoji, Ademuyiwa, Adewale, Adisa, Babatunde, Osinaike, Justina, Seyi-Olajide, Omolara, Williams, Emmanuel, Williams, Sofija, 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Volpe, Arthur, Gatti, Caroline, Nardi, Ramon, Oliva, Layze Braz de Oliveira, Herica Emilia Félix de Carvalho, Ivonizete Pires Ribeiro, Gabriel Renan Soares Rodrigues, Álvaro Francisco Lopes de Sousa, Michel, Chebel, Paulo Henrique de Sousa Fernandes, Marcelo Augusto Faria Freitas, Juliano Rodrigues da Cunha, Zeenia, Ather, Dobromir, Dimitrov, Emil, Filipov, Elitsa, Gyokova, Ivelina, Ilieva, Tsvetomir, Ivanov, Martin, Karamanliev, Vasil, Neykov, Boyko, Atanasov, Nikolay, Belev, Paolina, Kamenova, Kaloyan, Tonev, Tsanko, Yotsov, Evguenia, Hristova, Kolyo, Spassov, Tsanko, Tsankov, Dragomir, Dardanov, Petar, Gribnev, Manol, Sokolov, James, Brown, John, Tanyi, Heather, Hurdle, Anthony, Maclean, Michael, Sander, Salim Al Riyami, Krittika, Bali, David, Bigam, Khaled, Dajani, Mehran, Anvari, Rafik, Bolis, David, Choi, Susan, Ellis, Michael, Gupta, Wael, Hanna, Dennis, Hong, Cynthia, Horner, Lea, Luketic, Peter, Moisiuk, Yaron, Shargall, Hilda, Alfaro, Nawar, Alkhamesi, Laura, Allen, Muriel, Brackstone, Eunice, Chan, Davy, Cheng, Jason, Chui, Nelson, Gonzalez, Brent, Lanting, S Danielle MacNeil, Robert, Mayer, Jacob, Mcgee, Mahesh, Nagappa, Nicholas, Power, Agya, Prempeh, Mehdi, Qiabi, Hassan, Razvi, Emil, Schemitsch, Herman, Sehmbi, Ushma, Shah, Yamini, Subramani, Edward, Vasarhelyi, Kelly, Vogt, Homer, Yang, Ali Ghorbani Abdehgah, Saba, Balvardi, Liane, Feldman, Julio Flavio Fiore Jr, Melissa, Hanson, Brent, Hopkins, Pepa, Kaneva, Lawrence, Lee, Julia, Leonard, Jad, Abou-Khalil, Andre, Martel, James, Stevenson, Susan, Lee, Richard, Merchant, Samuel, Avoine, Laurence, Belanger, Mathieu, Belanger, Etienne, Belzile, Anne-Sophie, Blais, Sofia, Boucher-Kovalik, Cindy, Boulanger-Gobeil, Etienne, Cardinal, Pierre-Olivier, Champagne, Jonathan, Cloutier, Simon, Corriveau-Durand, Mathieu, Cote, Maxime, Cote, Mathilde, Côté, Valérie, Courval, Suzanne, Demers, Christine, Desbiens, Mehdi El Ouazzani, Karine, Girard, Ève-Marie, Girard, Karo, Gosselin, Helene, Khuong, Nathalie, 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Pu, Hanlin, Yin, Camilo, Caicedo, Diego Felipe Tellez Beltran, Alejandro, Escobar, Carolina Perez Granados, Lisbeth Alexandra Urueña Pinzon, Carlos, Bonilla, Diana, Santana, Oscar, Serrano, Andrea, Garcia, Fernando Giron Luque, Nasly, G Patino-Jaramillo, Laura Giselle Contreras Baquero, Nestor Augusto Muñoz Botero, Jhoana Andrea Murillo Castellanos, Andrea Juliana Vega Calvera, Lina, M Acosta Buitrago, Maria Paz Bohórquez-Tarazona, Paulo Andrés Cabrera Rivera, J Felipe Casas, Valeria Cormane Alfaro, Julian, Corso, Bayron, Guerra, Albert Franz Guerrero-Becerra, Akram Kadamani Abiyomaa, Felix Ramon Montes, Manuel Santiago Mosquera Paz, Camilo Andrés Polanía Sandoval, Natalia, Quintana, Carlos Fernando Roman Ortega, Carlos, Santacruz, Manuela, Téllez, Camilo Alejandro Velandia Sánchez, Fernando, Arias-Amézquita, Luis Felipe Cabrera Vargas, Natalia Cortes Murgueitio, Elkin, Escorcia, Kemel Ahmed Ghotme Ghotme, Jorge Luis Gomez-Mayorga, Alvaro Felipe Guerrero Vergel, Gabriel, Herrera-Almario, Eduardo, Londono-Schimmer, Juan, A Mejia, Guillermo, Monsalve, Camilo, Rodriguez, Juan Nicolas Rodriguez Niño, Luis Martín Rodríguez Ortegón, Daniel, Sanabria, Andres, Alvarez, Arnulfo, Andrade, Javier, Ardila-Montealegre, David, Baquero, Edgar Mauricio Barrios Vidales, María Alejandra Caicedo Giraldo, María Camila Carvajal, Maria, Castillo, Maria Carolina Castillo Florez, María Angelica Cendales, Danny Conde Monroy, Henry, Cortes, Mario, Daniel, Jairo De la Peña, Elena Leonor Delgado-Nieto, Hernando, Espitia, Carlos Figueroa Avendaño, Edgar Oswaldo Hernandez Burgos, Andres, Isaza-Restrepo, German, Londono, Margarita Maria Maldonado, Andrea, Montenegro, Juan Carlos Navarro, Jorge, Navarro-Alean, Katherine Parra Abaunza, Eliana, Pulido, Erika, M Ramírez Amaya, Carlos Eduardo Rey Chaves, Natalia Andrea Rivera Rincón, William Mauricio Riveros Castillo, Lizeth Rodriguez Sanchez, Wilson, Rubiano, Maria, Russi, Juan Carlos Sabogal Olarte, Javier Mauricio Salgado Tovar, Maria Juliana Sanchez, David Mauricio Solano Varela, Paula Torres Gomez, Marcial, Trillos, Ana María Vargas Patiño, Felipe, Vargas-Barato, Juan Pablo Villate Leon, María Alejandra Wagner Useche, Jesus, Acosta, Adriana, Almeciga, Luis Becerra Mendez, Rafael Jose Beltran, Ana, Bonilla, Miguel, Buitrago, Marino, Cabrera, Pedro Hernando Calderon Quiroz, Diego, Camacho-Nieto, Carlos Andrés Carvajal Fierro, Sergio Cervera Bonilla, Sandra, Diaz, Helena, Facundo, Jorge, Forero, Mauricio Garcia Mora, Karena Victoria Garcia Tirado, German Fabian Godoy Perez, Felipe, Gonzalez, Oscar, Guevara, Jairo Alonso Hernandez, David Ricardo Herrera Mora, Juan David Lalinde, Carlos, Lehmann, Eduardo Leon Llanos, Byron Eduardo Lopez De Mesa Lopez, Ivan, Mariño, Monica, Medina, Raúl Eduardo Pinilla Morales, Angela, Puerto, Andrea, Quintero-Ortíz, Juliana Rendón Hernández, Elio Fabio Sánchez Cortés, Alvaro Eduardo Sánchez Hernández, Raul, Suarez, Oscar, Suescun, Marco, Vanegas, Rodolfo, Varela, Jorge Luis Velez 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Alvarez, Cesar David Galindo Regino, Angela Maria Giraldo Velasquez, Carlos Enrique Melo Moreno, Jorman, H Tejada, Jesus Hernan Tovar, German Alirio Tovar, Edison Alexander Benavides Hernández, Claudia Milena Orozco-Chamorro, Gustavo Adolfo Angel, Christian Ali Buesaquillo, Victor David Olave Montaño, Andrés, Sánchez-Gómez, Daniela Patricia Escalante Ureche, Jairo Martinez Garrido, Eben-Ezer, Genda, Fabrice, Eboma, Kristina, Bitunjac, Karlo, Grulović, Marijana, Vučković, Goran, Šantak, Emanuel, Borovic, Ana Bosak Versic, Damir, Hasandić, Natasa Poldan Grabar, Suzana Srsen Medancic, Lucija, Brkic, Sara, Cokarić, Petra Pavic Palac, Zeljka, Samac, Josipa, Tomić, Marija, Vrdoljak, Ivan, Bacic, Bernarda, Bakmaz, Nikolina Bratošević Vučičić, Domagoj, Brzic, Samir, Canovic, Emilio, Dijan, Maja Grgec Dragicevic, Robert, Karlo, Suzana, Konjevoda, Petra, Kovačević, Ivan, Kovačić, Frane, Markulić, Luka, Matak, Domagoj, Morović, Gordan, Perišić, Andrea, Simic, Neven, Skitarelić, Matea, Veršić, 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Ioanna, Pozotou, Olga, Stavrinidou, Anneza, Yiallourou, Lukáš, Burda, Michal, Dosoudil, Lubomir, Martinek, Wladyslaw, B Gawel, Milan, Lerch, Matúš, Peteja, Jan, Žatecký, Toman, Daniel, Martin, Formánek, Veronika, Javurkova, Markéta, Kepičová, Nicole, Macečková, Petr, Matousek, Ondrej, Simetka, Petr, Vavra, Karol, Zelenik, Jan, Černý, Sami, Khan, Robert, Lischke, Martin, Přibyl, Temoore, Younus, Yenuksha, Amarasena, Karel, Klíma, Setareh, Pirmorad, Zuzana, Hotová, Aleš, Mladěnka, Nulvin, Bozo, Julie Lykke Harbjerg, Louise, Hviid, Helle, Ø Kristensen, Mira, Mekhael, Mette Fugleberg Nielsen, Laerke, Paulsen, Saija, Sinimäki, Louise Zinck Mogensen, Peter, Bonde, Anders Lyng Ebbehøj, Anne-Sophie, Fenger, Aleksander Fjeld Haugstvedt, Christine Hangaard Hansen, Maria Lovisa Jönsson, Lars, N Jorgensen, Peter-Martin, Krarup, Anne-Louise, Lihn, Christian, Meyhoff, Helena, Otte, Anas Ould Si Amar, Henrik, Palm, Nis, Schlesinger, Henry, Smith, Ida, Tryggedsson, Anne Reiss Axelsen, Jens Kristian Baelum, Mark Bremholm Ellebaek, Signe Bremholm Ellebaek, Anders, Hogh, Maria, Acosta, Yancy, Acosta, Pedro, Baez, Luis Alfredo Betances, Luis Rodolfo Bonilla, Daniel, Cabreja, Wilton Cabrera Cruz, María Mabel Collado Expósito, Aldo, Crespo, Octavio, Cruz-Pineda, Claudio Samuel D'óleo García, Pedro, Díaz, Remberto, Escoto, Jatnna, Figueroa, Luis, Garcia, U Garcia-Dubus Rodriguez, Humberto, Gomez, Adrian, Grullon, Fatherin, Guerrero, Lillian, Guzman, Thelma Rocío Jiménez Mosquea, Engels, Lazala, Ariela, Lopez, Leeany Maletta Francisco, Jhomayri, Mercado, Herisardy, Munoz, Jeffrey, Paulino, Maricely Ambar Perez Fernandez, Rudeily, Reyes, Lilia Rosa Reyes Guilamo, Ruben, Rivas, Claudia Alejandra Rivas Torres, Ada, Rodríguez, Madelin Tamar Rosario Villa, Eleazar, Santana, Joel, Soto, Nassin, Tactuk, Cristina Kristel Tonos Sardiñas, Raul, Ubinas, Jose, Victoria, Aaron, Villegas, Ricardo, Acra-Tolari, Larissa, Beltran, Luis Fernand Betances, Alejandro, Blaubach, Denisse Idalia Campos Mejía, Nathalia, Capellan, María Fernanda Cedeño Bruzual, Saray Cordero Spencer, Gabriella Cuevas Lantigua, Luis De Jesus, Gabriela, Díaz, Pedro Pablo Díaz Vásquez, Karla, Disla, Jesús Antonio Echavarría Uceta, Paola Irina Eusebio Jimenez, Damaris, Fernandez, Marlin Fernandez Camilo, Jiomar Manuel Figueroa Germosen, Maruel, Fortunato, Leyla Gabriel Fernández, Alicia German Dihmes, Héctor, Herrera, Elizabeth Leon Cuevas, Jose Alejandro Mata, Mirian Mateo De La Cruz, Dolores Mejia De la Cruz, Marcos, Mirambeaux, Fabio Ortiz De La Cruz, Henry, Paulino, Gabriela, Pelletier, Merycarla, Pichardo, Rodriguez Pumarol Próspero Enrique, Julio, Rivas, Ann Stephany Sanchez Marmolejos, Roman Santana Santana, Irina Suero Almanzar, María Magdalena Vásquez Sánchez, Nicolás, Campuzano, José Ricardo Negrete Ocampo, Maria, Armas, Alvaro Santiago LeMarie Guerra, Gustavo León Vizcaya, Omar Ahmed Abdelwahab, Ahmed, O Elmehrath, Mohammed Ezzat Mostafa, Gamal, Amira, Ibrahim, Sallam, Mohamed, Sherief, Ahmed, Abdelmajeed, Mostafa, Abdou, Ahmed Abo Shanab, Aya, Abodeeb, Roger, Aboelkhel, Nour Eldin Abosamak, Amna Abou Bakr, Samar, Aboubakr, Yossof, Abouelnagah, Omar, Aboumadawy, Dina, Adel, Nermeen, Afifi, Sara, Ahmed, Abedelrahman, Ahmed, Mohamed Al Sayed, Abdelrahman, Alberkamy, Mohamed, Aldahma, Ahmed, Ali, Mostafa, Ali, Mohamed Amin Bakr, Alaa, Anter, Doaa, Asal, Fouad, Ashoush, Olfat, Ashraf, Abdel Rahman Ashraf, Rewan, Atta, Salma, Badr, Mohamed, Bahaaeldin, Mostafa, Bastawesy, Sara, Darwish, Rasha El Kharashy, Ziad, Elassar, Seifeldin, Elbadawy, Dina, Elkhity, Alromisaa, Elsaka, Manal, Elsayed, Mostafa Elsayed Elsayed Hewalla, Mohamed, Elshafey, Youssof, Eshac, Fares, Eshac, Amr, Essameldin, Moataz, Ewedah, Yara, Ezz, Mohamed, Farag, Inas, Gadelkarim, Ziyad, Gadelrab, Dina, Gamal, Mira, Ghaly, Nathalie, Girgis, Omar, Gouda, Nancy, H El Goweini, Nour, Hafez, Youssef, Hafez, Abdelkader Hamed Abdin, Rodina, Hanno, Aliaa, Hassanin, Mohamed, Hassanin, Hanan, M Hemead, Abdelrahman, Hemida, Maher, Hosain, Ahmed, Hossam, Hamza Hussein Aly Salama Aly, Mohamed, Ibrahim, Abdelrahman, Ibrahim, Nourhan, Ibrahim, Noha Mohamed Salah Ibrahim Moussa Hamouda, Monica, Iskander, Islam, Khalifa, Mostafa, Kotb, Nada, Mahmoud, Alaa Mahmoud Abo Shabana, Nora, Mamdouh, Maram, Metwalli, Khaled, Metwally, Mahmoud, Moghazy, Moustafa, Mohamed, Mohamed, Mourad, Esraa, Moustafa, Kamilia, Mubarek, Nour Eldin Nader, Ahmed, Nasser, Samaa, Omar, Mostafa Shehata Qatora, Mohamed, Ragab, Marawan, Ragal, Dina, Ramadan, Rana, Ramadan, Sara, Ramadan, John, Romany, Ahmed, Sabry, Yasmeen, Said, Sara, Salamah, Ahmed Mostafa Saleh, Mona Saleh Mesbah Mohamed Elkaffas, Alaa, Salem, Hashem, Salim, Ahmed, Samih, Ahmed Samir Abdelaal, Ahmed, Shaheen, Yassmeen Sharafeldin Mohammed, Abdelrahman, Shehata, Mohamed, Shemeis, Karim, Shenit, Mennatallah, Sheta, Asmaa, Soffar, Yousef, Tanas, Ahmed, Tarek, Nermin, Yehia, Omar Khaled Mohamed Eid, Ammar Yasser Abdulfattah, Ahmed, Elsaghir, Mohamed Fouad Elganainy, Omar Ibrahim Elsayed, Omar, Elmandouh, Omar, Hamam, Mostafa Ahmed Shehata, Areej, A Abdelaziz, Ahmed, M Abbas, Wael Abd El-Ghani, Hossam Aldein, S Abd Elazeem, Mustafa Abd Elsayed, Ahmed Yassien Abd-Elkariem, Shimaa, Abdalla, Mahmoud, Abdel-Aleem, Khaled, Abdelazeem, Mahmoud, Abdelfattah, Mohammed, Abdelhafez, Mohamed, M Abdelkarem, Ali, Abdelraouf, Lamess, Abdullaha, Hossam, Abubeih, Moaiad Eldin Ahmed, Nagm Eldin Abu Elnga Ahmed, Ahmed, Ahmed, Sarah Ahmed Saad, Sherif, Alaa, Ali, Alhussaini, Abdelrahman Ahmed Abdelrahman Ali, Ibrahim, Ali, Wagdi, Ali, Mohamed Ali Mohamed, Mohamed, Ashraf, Muhammad, Bassiouni, Mohamed, G El-Adawy, Mohammad, El-Sharkawi, Hussein, Elkhayat, Khaled, Elmaghraby, Shady, Elsdfy, Mohamed, Elsharkawy, Almoutaz, Eltayeb, Mohamed Esmat Mohamed, Esraa, Essam, Mahmoud, Fahd, Osama, Farouk, Rabea, Gadelkareem, Ahmed, Ghoneim, Mohammed Hamada Takrouney, Ahmed, Hamdan, Abd El-Rahman Hamed, Ahmad, Hasan, Mohamed Abdelghafor Hassanin, Islam, Hawal, Kerollos, Henes, Mohamed Omar Herdan, Helal, F Hetta, Omar, Ibrahem, Mostafa, Ibrahim, Islam, H Ibrahim, Mahmoud, Kamel, Mohamed, Khallaf, Shrouk, M Elghazaly, Abobakr, Mahfouz, Osman, Mahmoud, Wesam, Mahran, Doha, Mahrous, Abadeer, Marsis, Ayman, Mohamed, Aliae Mohamed Hussein, Amr Mohamed Sayed, Mahmoud, M Mohammed, Ahmed, Mokhtar, Fatma, A Monib, Ahmed, Nageeb, Mariam Albatoul Nageh, Mohammed, Nageh, Nehal Gamal Omar, Abdelrahman, Ragab, Abdelrahman, Ramadan, Abdallah Rashad Temerik, Aya, Sabry, Hadeer, Safwat, Omar, Salah, Ahmed Elhussiny Salah Mahmoud, Ahmed, Saleh, Mahmoud, Sallam, Ahmed, Samir, Reem, Sayad, Esraa, Sayed, Ahmed, S Sedik, Mohammed, Shahine, Antonios, Soliman, Wael, Soliman, Mohamed Gamal Taher, Randa, Wanees, Ebrahim Ahmed Yousof, Ahmed, Youssef, Omar Zein Elabedeen, Ahmed Emad Sayed Hassan, Shrouk Abdel Fattah, Ahmed, Abostate, Samar, Ali, Saad Ali Saad Salama, Mohamed, Allam, Ahmed, Alsadek, Ebrahim, Arafa, Ahmed, Barakat, Mohammed El Sherpiny, Gehad, Elbehairy, Mahmoud, Eleisawy, 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Venkateshwaran, Narasiman, Meer, Chisthi, Gejoe, George, Harihara, Jothi, Dilber, Pareed, Godwin David, C Mathew, Livingston, Abel, Mansi, Agrawal, Rabindranath, B, Manish, Baldia, Ravi Kishore Barla, Manisha, Beck, Santosh, Benjamin, Jeremy, Bliss, Lisa, Cherian, Sreekar, Devarakonda, Geley, Ete, Arun Jacob Philip George, Amish, Gohil, Deeptiman, James, Mark Ranjan Jesudason, Lallu, Joseph, Treasa, Joseph, Kathir, Joyson, Gomathi, Karnan, Albert, Kota, Pushplata, Kumari, Anitha, Loganathan, Vasanth Mark Samuel, John, Mathew, Senthil, K Nathan, Joby Elizabeth Ninan, Ajay, Philip, R Priyadarshini Priyadarshini, Suganya, S, Habie, Samuel, Gilbert, Samuel, Daniel, Selvaraj, Srujan, Sharma, Suraj, Surendran, D Hariharan, T, Santhosh Kumar Thangaraj, Vinotha, Thomas, Varghese, Thomas, John, K Thomas, S Harish, Y, Manobhiram, Boggavarapu, Murali Krishna Voonna, Marilaeta Cindryani Lolobali, Christopher, Ryalino, Tjokorda Gde Agung Senapathi, Mahadewa, Tjokorda, I Made Gede Widnyana, Dita, Aditianingsih, Aino, Auerkari, Susilo, Chandra, Fachreza Aryo Damara, Mohammad Adya Firmansha Dilmy, Achmad Kemal Harzif, Sidharta Kusuma Manggala, Dedy, Pratama, Affan, Priyambodo, Andi Ade Ramlan, Ratna Farida Soenarto, Adhrie, Sugiarto, Ilham Utama Surya, Tamara, Tango, Aida Rosita Tantri, Raihanita, Zahra, Dedy, Fachrian, Andi, Hasyim, Ade, Susanti, Teddy, Saputra, Erwin, Syarifuddin, Andi Asadul Islam, Hendra, Pajan, Ahmad Hannan Amrullah, Khoirul, Anam, Thirza, Hadipranata, Julius Albert Sugianto, Aidyl, Fitrisyah, Mayang Indah Lestari, Nur Rachmat Lubis, Rizal, Zainal, Zulkifli, Zulkifli, Erick Gamaliel Amba, Warren, Lie, Andika Adiputra Thehumury, Tedy, Apriawan, Yunus Kuntawi Aji, Roidah Taqiyya Zahra Wathoni, Sumadi Lukman Anwar, Teguh, Aryandono, Wirsma Arif Harahap, Juni, Kurniawaty, Djayanti, Sari, Artanto, Wahyono, Yunita, Widyastuti, Akhmad Yun Jufan, Parisa, Arjmand, Mohammad, Etezadpour, Babak, Ganjeifar, Masoumeh, Hosseinpoor, Hassan, Mehrad-Majd, Mohsen, Rajati, 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Orlaith, Kelly, Rory, Kennelly, Aoife, Kiernan, Sean, T Martin, Nawar, Masarani, Damian, Mccartan, Enda, W McDermott, Ben, Murphy, Kin Cheung Ng, Nwabundo, Njeze, Aine, O'Neill, Ruth, S Prichard, Ned, Quirke, Ian Sean Reynolds, Des, Winter, Rowan, Casey, Mutaz, Elamin, Amy, Gillis, Dara, Kavanagh, Michael, Kelly, Áine, Mcnamee, Paul, Neary, Patrick, Owens, Akshaya, Ravi, Paul, Ridgway, Paul, Carroll, Chris, Collins, Amenah, Dhannoon, Amy, Fowler, Aisling, Hogan, Aoife, Lowery, Peter, Mcanena, Charlie, Timon, Stewart, Walsh, Wisam, Al-Ramli, Imran, Azeem, Muhammad Usaama Bahadoor, Zsolt, Bodnar, Hassan, Elmusharaf, Faisal Saeed Hassan, Adam, Hingum, Huilun, Huan, Seamus, Jennings, Mohamed Hamed Khalid, Mariya, Kuteva, Syed Nadeem Mujtaba, Shanell, Peeriyah, Hina, Rehman, Muhammad Assam Sarwar, Tony, Shaju, Ian, Stephens, Michael, Sugrue, Joseph, Thomas, Manvydas, Varzgalis, Saqib, Zeeshan, Alisha, Jaffer, Larne, Jones-Whiting, Colin, Peirce, Sean, Johnston, Seantee, Lim, Alwaleed, 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Baccellieri, Luca, Bertoglio, Giulia, Bonavina, Massimo, Candiani, Giorgio, Candotti, Arianna, Casiraghi, Laura Mariangela Castellano, Paolo Ivo Cavoretto, Roberto, Chiesa, Federica, Cipriani, Paola De Nardi, Guido, Fiorentini, Filippo, Gagliardi, Alessandro, Galdini, Alessandro, Grandi, Elena, Marotta, Simonetta, Massaron, Andrea, Melloni, Pietro, Mortini, Gianluca, Nocera, Martina, Piloni, Mirko, Pozzoni, Francesca, Ratti, Riccardo, Rosati, Alessandro Ferdinando Ruffolo, Pierpaolo, Sileri, Alfio, Spina, Andrea, Vignali, Cristina, Barberio, Luigi, Beretta, Francesca, Cavenago, Nora Di Tomasso, Stefano, Fresilli, Giovanni, Landoni, Stefano, Lazzari, Gaetano, Lombardi, Marilena, Marmiere, Fabrizio, Monaco, Gabriele, Todaro, Stefano, Turi, Alberto, Zangrillo, Francesca, Bertolina, Giorgio, Bogani, Stefano, Bonomi, Pierfrancesco, Cadenelli, Valentina, Chiappa, Stefano Piero Bernardo Cioffi, Davide, Citterio, Lara Valentina Comini, Umberto, Cortinovis, Maurizio, Cosimelli, Antonino, Ditto, Massimiliano, Gennaro, Lorenzo, Giannini, Marcello, Guaglio, Marco, Guzzo, Andrea, Leva, Alberto, Macchi, Elena, Manzo, Fabio, Martinelli, Ilaria, Mattavelli, Vincenzo Maria Mazzaferro, Francesco, Raspagliesi, Luigi, Rolli, Laura, Sala, Roberto, Salvioni, Mario, Santinami, Silvia, Segattini, Luca, Sorrentino, Carlotta, Zaborra, Alexandre, Anesi, Gianmaria Casoni Pattacini, Mattia Di Bartolomeo, Francesca, Pecchini, Arrigo, Pellacani, Micaela, Piccoli, Federico, Fusini, Andrea, Gattolin, Marco, Migliore, Roberto, Rimonda, Diego, Sasia, Elisabetta, Travaglio, Federica, Brunetti, Marco, Cereda, Marco, Ceresoli, Luca, Cigagna, Cristina, Dell'Oro, Alessandro, Fogliati, Robert, Fruscio, Tommaso, Grassi, Maini Marzia Isabella, Luca Carlo Nespoli, Massimo, Oldani, Sara, Ornaghi, Nicolò, Tamini, Carmine, Antropoli, Antonio, Castaldi, Alessio, Palumbo, Gaia, Altieri, Umberto, Bracale, Francesco, Corcione, Marcello De Luca, Giovanni Domenico De Palma, Maria Michela Di Nuzzo, Ruggero, Lionetti, 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Matteo, Filardo, Marika Sharmayne Milani, Franco, Ragni, Andrea de Manzoni Garberini, Edoardo, Baldini, Diana, Carpaneto, Michele, Cauteruccio, Corrado, Ciatti, Luigi, Conti, Serena, Gattoni, Pietro, Maniscalco, Gerardo, Palmieri, Calogero Puma Pagliarello, Giuseppe, Caristo, Raffaele, Galleano, Michele, Malerba, Marcello, Calabrò, Francesca, Farnesi, Elia Giuseppe Lunghi, Andrea, Muratore, Nicoletta Sveva Pipitone Federico, Joel Reuben Abel, Lorenzo, Andreani, Darienzo, Antonio, Vittorio, Aprile, Riccardo, Balestri, Giacomo, Benettini, Stefano, Berrettini, Luca, Bruschini, Massimo, Chiarugi, Federico, Coccolini, Simone, Colangeli, Camilla, Cremonini, Lodovica Cristofani Mencacci, Iacopo, Dallan, Silvia De Santi, Gregorio Di Franco, Lorena Di Girolami, Giacomo, Fiacchini, Niccolò, Furbetta, Stylianos, Korasidis, Marco, Lucchi, Andrea, Morandi, Luca, Morelli, Serena, Musetti, Carlo Maria Neri, Matteo, Palmeri, Miriana, Picariello, Francesco, Porcelli, Marco, Puccini, Nicolo, Roffi, Erica, Statuti, Dario, Tartaglia, Alberto, Tonelli, Matteo, Vianini, Gianluca, Baronio, Mauro, Montuori, Enrico, Pinotti, Stefano Maria Massimiliano Basso, Federica, Maffeis, Paolo, Ubiali, Lorenzo, Aguzzoli, Saverio, Coiro, Giuseppe, Falco, Vincenzo Dario Mandato, Valentina, Mastrofilippo, Simone, Mele, Caterina, Baldi, Carlo, Corbellini, Gianluca Matteo Sampietro, Massimo, Dugo, Mauro, Garino, Chiara, Marafante, Antonio, Masciandaro, Elisabetta, Moggia, Alessandra, Murgese, Felice Eugenio Agro, Gabriella Teresa Capolupo, Filippo, Carannante, Marco, Caricato, Vincenzo, Denaro, Erica, Mazzotta, Rocco, Papalia, Giuseppe, Pascarella, Alessandro, Strumia, Biagio, Zampogna, Matteo, Cinquepalmi, Marco, Colasanti, Celeste Del Basso, Federica, Falaschi, Nicola, Guglielmo, Roberto Luca Meniconi, Alessandra, Pecoraro, Sofia, Usai, Giacomo, Crescentini, Antonella, Larcinese, Emanuele, Picone, Giovanni, Sinibaldi, Annamaria, Agnes, Salvatore, Agnes, Sergio, Alfieri, Francesco, Belia, Valentina, Bianchi, Giuseppe, Bianco, Alberto, Biondi, Paola, Campennì, Valerio, Cozza, Sabatino, D'Archi, Domenico, D'Ugo, Veronica De Simone, Marta Di Grezia, Sofia Di Lorenzo, Federica, Ferracci, Valeria, Fico, Gianluca, Franceschini, Pietro, Fransvea, Giulio, Gasparini, Luca, Gordini, Antonio La Greca, Francesco, Litta, Celestino Pio Lombardi, Angelo Alessandro Marra, Angelo, Parello, Marco Maria Pascale, Romeo, Patini, Gilda, Pepe, Roberto, Persiani, Caterina, Puccioni, Carlo, Ratto, Fausto, Rosa, Gianmarco, Saponaro, Lorenzo, Scardina, Tedesco, Silvia, Giuseppe, Tropeano, Maria, Benevolo, Daniele, Bugada, Flaminia, Campo, Maria Gabriella Dona, Valentina, Manciocco, Paolo, Marchesi, Riccardo, Mastroianni, Francesco, Mazzola, Silvia, Moretto, Raul, Pellini, Gerardo, Petruzzi, Barbara, Pichi, Giuseppe, Simone, Gabriele, Tuderti, Jacopo, Zocchi, Luigi Marino Cosentino, Andrea, Sagnotta, Roberta, Angelico, Vittoria, Bellato, Michela, Campanelli, Marzia, Franceschilli, Michele, Grande, Giorgio, Lisi, Tommaso Maria Manzia, Lorenzo, Petagna, Bruno, Sensi, Giuseppe, Sica, Leandro, Siragusa, Giuseppe, Tisone, Marco, Assenza, Barbara, Binda, Massimo, Biondi, Gioia, Brachini, Placido, Bruzzaniti, Mauro, Casagrande, Flavia, Ciccarone, Pierfranco Maria Cicerchia, Bruno, Cirillo, Daniele, Crocetti, Giancarlo, D'Ambrosio, Vito, D'Andrea, Francesca De Felice, Giorgio De Toma, Carlo Della Rocca, Giulia, Duranti, Pietro, Familiari, Enrico, Fiori, Giovanni Battista Fonsi, Alessandro, Frati, Stefania La Rocca, Filippo La Torre, Pierfrancesco, Lapolla, Giovanni, Marruzzo, Simona, Meneghini, Andrea, Mingoli, Andrea, Picchetto, Antonella, Polimeni, Diego, Ribuffo, Maurizio, Salvati, Antonio, Santoro, Paolo, Sapienza, Luigi, Simonelli, Valentino, Valentini, Martina, Zambon, Giuseppa, Zancana, Emma, Zuppi, Simone, D'Annunzio, Cosimo De Nunzio, Silvia, Fiorelli, Mohsen, Ibrahim, Chiara, Loffredo, Domenico, Massullo, Cecilia, Menna, Rocco, Monica, Massimiliano, Pelli, Erino Angelo Rendina, Leonardo, Teodonio, Andrea, Tubaro, Giulio, Argenio, Giulio, Accarino, Accarino, Giancarlo, Antonio Nicola Giordano, Luca, Cardinali, Elisa, Sebastiani, Grazia, Travaglini, Erika, Andreatta, Emanuele Luigi Giuseppe Asti, Daniele, Bernardi, Luigi, Bonavina, Caterina, Froiio, Andrea, Lovece, Chiara, Copelli, Alfonso, Manfuso, Pasquale Di Maio, Marco, Giudice, Oreste, Iocca, Rosario, Cennamo, Tommaso, Cornali, Francesco Di Marzo, Cristian, Altana, Francesco, Bussu, Giampiero, Capobianco, Anna Giacomina Carta, Sandro, Ciccarello, Maria Laura Cossu, Pietrina, Cottu, Giacomo De Riu, Salvatore, Dessole, Francesco, Dessole, Salvatora, Dettori, Carlo, Doria, Alessandro, Fancellu, Claudio, F Feo, Giorgio Carlo Ginesu, Giuliana, Giuliani, Marco Giuseppe Iannuccelli, Massimo, Madonia, Roberto, Mancino, Olindo, Massarelli, Gianfranco, Meloni, Fabio, Milia, Andrea, Mulliri, Teresa, Perra, Marco, Petrillo, Antonio, Piras, Franco, Piredda, Francesco, Pisanu, Alberto, Porcu, Davide, Rizzo, Angelino, Sanna, Antonio Mario Scanu, Fabrizio, Scognamillo, Damiano, Soma, Anna Rita Tanca, Alessandro, Tedde, Matteo, Tedde, Luigi Angelo Vaira, Andrea Bartalini Cinughi de Pazzi, Osvaldo Carpineto Samorani, Daniele, Fusario, Luigi, Marano, Gaia, Oldrà, Anna Lisa Pesce, Stefania Angela Piccioni, Luca, Resca, Vincenzo, Ricchiuti, Franco, Roviello, Vinno, Savelli, Alberto, Abrate, Pierpaolo, Bordoni, Lorenzo, Bosio, Guglielmo, Clarizia, Francesco, Fleres, Marco, Franzini, Antonio, Fratto, Pierluigi, Giumelli, Alessandro, Grechi, Alessandro, Longhini, Fabrizio, Lorusso, Elisa, Scarnecchia, Federica, Scolari, Alessandro, Spolini, Vincenzo, Maiuri, Matteo, Papandrea, Arturo, Roncone, Lorenzo, Conti, Andrea, Rizzi, Marco, Rovagnati, Alberto, Brolese, Tommaso, Cai, Francesco Antonio Ciarleglio, Francesca, Dalprà, Gianni, Malossini, Liliana, Mereu, Irene, Tamanini, Saverio, Tateo, Giovanni, Viel, Enrico, Battistella, Paolo Boscolo Rizzo, Cristoforo, Fabbris, Marco, Massani, Giacomo, Spinato, Roberta, Tutino, Ugo, Grossi, Alessandro, Iacomino, Simone, Novello, Maurizio, Romano, Serena, Rossi, Giulio, Santoro, Giacomo, Zanus, Sokol, Trungu, Giada, Aizza, Gabriele, Bellio, Selene, Bogoni, Marina, Bortul, Biagio, Casagranda, Sara, Cortinovis, Nicolò de Manzini, Davide, Drigo, Paola, Germani, Manuela, Mastronardi, Lucia, Paiano, Silvia, Palmisano, Pier Luigi Filosso, Francesco, Guerrera, Matteo, Marro, Mauro, Rinaldi, Enrico, Ruffini, Stefano, Salizzoni, Laura, Bardelli, Mattia, Berselli, Giacomo, Borroni, Eugenio, Cocozza, Matteo, Desio, Bottazzoli, Elisa, Giuseppe, Ietto, Valentina, Iori, Domenico, Iovino, Lorenzo, Livraghi, Valentina, Marchionini, Stefano, Megna, Emma Amal Nahal, Mara, Palumbo, Valeria, Quintodei, Alessandra, Zullo, Lucrezia, D'Alimonte, Giovanni, Pirozzolo, Chiara, Vignotto, Tommaso, Campagnaro, Andrea, Caravati, Simone, Conci, Carlotta De Cristofaro, Gabriele, Gecchele, Tommaso, Giuliani, Jacopo, Graziosi, Alfredo, Guglielmi, Salvatore, Paiella, Corrado, 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Rakotoarisoa, Maharo, Ramifehiarivo, Solonirina Harinarindra Ranaivoson, Hajamihamina Marina Parfaite Randriantsoa, Narindra Njarasoa Mihaja Razafimanjato, Jeannie Ba Razafindrahita, Solofoarimanana, Solofoarimanana, Guillaume Odilon Tsiambanizafy, Rakotonaivo Mamisoa Judicaël, Corinne Eulalie Solo, Tojomamy Herinjaka Ralaizafindraibe, Fanonjomahasoa Safiry Andofenohasina, Hanta, Rasataharifetra, Vanona Barijaona Razafindraibe, Angelin Sablon Herinirina, Andre, Das, Thanga, Ganapathy, Yohesuwary, Gunarasa, Kalyani, Mariapan, Maathichsudhaar, Muniandy, Mohd Firdauss Osman, Mohd Azem Fathi Mohammad Azmi, Jien Yen Soh, Wan Zainira Wan Zain, Andee Dzulkarnaen Zakaria, Zaidi, Zakaria, Kheng Hooi Chan, Firdaus, Hayati, Syamim, Johan, Jin Jiun Mah, Ratha Krishnan Sriram, Sentilnathan, Subramaniam, Nur Shahirah Binti Muhammad Shahimi, Khairul Hazim Hamdan, Mohd Razali Ibrahim, Guhan, Muthkumaran, Ju Ann Tan, Mohana Raj Thanapal, Dayang Anita Abdul Aziz, Mae-Lynn, Bastion, Mohd Hairul Nizam Harun, Farrah-Hani, Imran, Norshamsiah Md Din, Ayesha Mohd Zain, Mushawiahti, Mustapha, Syed, Nabil, Ainal Adlin Naffi, Abd Jabar Nazimi, Roszalina, Ramli, Bee Hong Soon, Pavin, Bal, Joo Qing Cheng, Mohd Rusdi Draman, Ahmad Nazran Fadzli, Sakina, Ghauth, Weipin, Hung, Suniza, Jamaris, Peng Soon Koh, Sivakumar, Krishnasamy, Yeong Sing Lee, Yew Toong Liew, Jeffery Zk Lim, Raymond Chung Siang Lim, Hiong Chin Lim, Siti Farhan Moh Pauzi, Shireen Anne Nah, Ashvin Krishna Nair, Doris Sin Wen Ng, Yuki Julius Ng We Yong, Kamarajan, Ramayah, Rahmah, Saaid, Anand, Sanmugam, Mee Hoong See, Kanesh Kumaran Seevalingam, Neha, Sethi, Srihari, Singaravel, Syeda Nureena Syed Jafer Hussain Zaidi, Chu Yik Tang, Li Ying Teoh, Kian Boon Wong, Ruben, Xavier, Ahmad Shuib Yahaya, Norhafiza, Ab, Rahman, Islah Munjih Ab, Rashid, Mohd Fahmi Abd Aziz, Mohd Norhisham Azmi Abdul Rahman, Nasser Muhammad Amjad, Shahidah Che Alhadi, Faisal, Elagili, Mohd Nazli Kamarulzaman, Azmi Md Nor, Ahmad Faidzal Othman, Mohd Yusof Sainal, Mat Salleh Sarif, Richelle, Chua, Aini Fahriza Ibrahim, Abdul Rauf Bin Ahmad, Yii Ling Lau, Ka Yee Liew, Kandasami, Palayan, Hui Yu Wong, Jasiah, Zakaria, Nor Azimah Abd Aziz, Norazila Abdul Rahim, Noorneza Abdul Rahman, Bahiyah, Abdullah, Mohamed Faizal Bin Sikkandar, Fatin, Firman, Nik Mohd Hazleigh, Intan Kartika Kamarudin, Shahril, Khalid, Mohd Fairudz Mohd Miswan, Akmal Zulayla Mohd Zahid, Norasyikin, Mustafa, Kadhim, Obaid, Mohd Yusoff Bin Yahaya Yahaya, Ahmad Ramzi Yusoff, Predrag, Andrejevic, Jeremy Borg Myatt, Svetlana, Brincat, Clifford, Caruana, Kurt Lee Chircop, Francesca, Chircop, Daniel Mario Chircop, Charles, Cini, Viktoria, Czok, Melanie, Farrugia, Gabriella, Grima, Fatimah Mj Hassan Almukhariq, Esther, Muscat, Darryl, Pisani, Mohsin Hassan Khan Roshan, Nicholas, Schembri, Mohamed, Shoukry, Neville, Spiteri, Gilbert, Tanti, Ziad Aboharp Hasan, Alberto Bazan Soto, Cedillo Rodrìguez Jonathan Rubén, Gustavo Esteban Lugo Zamudio, David Gerardo Miranda Gómez, José Alfredo Pérez Meave, Victor Pinto Angulo, Antonio Rojas Aguilar, Erik Efrain Sosa Duran, Alejandro Vàzquez Perez, Diego, Arroyo, Jose, Corona-Cruz, Hector, Martinez-Said, Heriberto, Medina-Franco, Manuel, Mendez, Teresa Moreno, Y Suárez Ma, Dolores Orta Díaz, Martha Patricia Pérez de León Vázquez, Angélica Azucena Soto Carvajal, Fidel Soto Hernández, Juan Ignacio Stenner, Adriana Valenzuela López, Mauricio Rene Hernandez, Rey Jesus Romero, Aldo Bernal Hernandez, Ana Olivia Cortes-Flores, Carlos Jose Zuloaga Fernandez Del Valle, Carlos Andres Colunga Tinajero, Jaime, Orozco-Perez, Laura Gabriela Peña Balboa, Guillermo, Yanowsky-Reyes, Víctor Hugo Alcalá Torres, Francisco José Barbosa Camacho, Irma Valeria Brancaccio Perez, Miguel Angel Calderon-Llamas, Aldo Camacho Gomez, Edgar-Joaquin, Cortes-Torres, Esteban, Cueva-Martinez, Oscar Durán Anguiano, Isaac Esparza Estrada, Roberto, Fierro-Rizo, Paola Flores Becerril, Clotilde Fuentes Orozco, Miguel García Castillo, Alejandro Gonzalez Ojeda, Ana Sofia Gonzalez Rubio, Erick Alonso González-García de Rojas, Luis Humberto Govea-Camacho, Jose Aldo Guzman Barba, Juan Carlos Ibarrola Peña, César Íñiguez Martínez, Francisco Javier Llamas-Macias, Ruben Eduardo Morán Galaviz, Cesar, Nuño-Escobar, Oscar-Everardo, Olvera-Flores, Jaqueline, Osuna-Rubio, Jose Victor Pérez-Navarro, Rodrigo, Prieto-Aldape, Luis Ricardo Ramirez Gonzalez, Marco Vinicio Ramírez Sánchez, Emilio, Reyes, Olaya Moramay Romero-Limón, Carlos Beas Ruiz-Velasco, José Antonio Sánchez Martínez, Guillermo, Sanchez-Villaseñor, Ismael, Sedano-Portillo, Gabriela Ambriz Gonzalez, Pedro Berrones Moreno Berrones Moreno, Ana Beatriz Calderon Alvarado, José de Jesús Cárdenas Barón, Araceli, Hernández, Francisco Javier León Frutos, Edgard Efren Lozada Hernandez, Eduardo Morales Valencia, Karla Daniela Pérez, Francina, Bolanos-Morales, Julio, Herrera-Zamora, Patricio, Santillan-Doherty, David Omar Arriaga Zavala, Salvador Francisco Campos Campos, Lizette, Carmona, Antonio Galindo Nava, Blanca, Santos, Juan Roberto Torres Cisneros, Katya, Bozada-Gutiérrez, Jose Jesus Herrera, Mucio Moreno Portillo, Francisco Pérez López, Mario, Trejo-Avila, Carlos Valenzuela Salazar, Maria Regina Alvarez, Fernando, Cordera, Marco Antonio de la Rosa Abaroa, Antonio, Gómez-Pedraza, Roberto, Hernandez, Antonio, Maffuz-Aziz, José Antonio Posada, Carlos Robles Vidal, Jose-Luis, Beristain-Hernandez, Blas Eduardo Quintero Sada, Nicolás Uxmal Soruco Heredia, Ernesto, Anaya, Ricardo, Arceo-Olaiz, Bernardo Gutiérrez Sougarret, Sonia Lopez Flores, Francisco, J Ochoa Carrillo, Raymundo Alfredo Pérez Uribe, Ludwigvan Adriano Bustamante Silva, Arianne, I Lupián-Angulo, Christian Enrique Soulé Martínez, Francisco César Becerra García, Ernesto Javier Guerrero Casillas, Edgar, Uribe, Nereida Esparza Arias, J Mindy Hernández-Nava, David, Isla-Ortiz, Javier, Melchor-Ruan, Esmeralda Romero Bañuelos, Rosa, Salcedo-Hernández, Diana, Vilar-Compte, Paola Zinser Peniche, Jorge, L Aguilar Frasco, Alejandro, Alfaro-Goldaracena, Gabriela Alejandra Buerba, Emma, Castro, Carlos, Chan, Ruben, Cortes, Ismael, Dominguez-Rosado, Daniel Garay Lechuga, Miguel, Herrera, Carlos, Hinojosa, Gabriel, Lopez-Pena, Edgar, Martos, Miguel Ángel Mercado, Paulina Moctezuma Velázquez, Roberto, Moguel, Mariano, Oropeza, Emmanuel Peña Gómez Portugal, Oscar Emmanuel Posadas-Trujillo, Noel, Salgado-Nesme, Oscar Santes Jasso, Catherine, Sarre, Karla Yareli Hernandez Skewes, Cristian, Jimenez, Roque Delfino Licona-Meníndez, Guillermo, Montiel, Alberto, Navarrete-Peón, Shannat, Ortega, Fernanda Romero Lechuga, Oscar, Roque, Fernando, Sevilla, Rogelio, González-López, Roberto Ángel Núñez-González, José Antonio Ortega-Jiménez, Antonio, Alvarado, Alfonso Alvarez Manilla Orendain, José Alberto Atristain Pesquera, Diego, Frutos, Felipe, Garcia, Juan Antonio González León, Marlin, Guzman, Dorihela, Herappe, Jesús Giovanni Inzunza Miranda, Miguel Angel Jimenez Botello, Ricardo, Lerma, Fabián Hilario Mendoza Pedraza, Monica Noguez Castillo, Jose Anatolio Resendiz, Oscar Alejandro Sánchez García, Laura Elena Fernandez Rios, Pamela, Frigerio, Iset, Garcia, Gloria Isela Mendoza Frías, Emmanuel, Moreno, Raquel, Quiroga, Alejandra Anzures Mendoza, Arantza Govela Hinojosa, Aldo, Izaguirre, Luis Hdez Miguelena, Jose Manuel Luna Vazquez, Indalecio Barcelata Rodriguez, Raul Ramos Mange, Carlos Reyes Utrera, David Zarate Saenz, Miguel Angel Zavala Gonzalez, Francisco Andrade González, Ludivina, Cortes, David, Roman, Aaron, Sanchez, Radu, Gurghiș, Gheorghe, Rojnoveanu, Marin, Vozian, Petru, Caraja, Gheorghe, Croitor, Roman, Mosneaga, Sarnai, Erdene, Lundeg, Ganbold, Sergelen, Orgoi, Soyombo, Orsoo, Altanchimeg, Sainbayar, Erdene, Sandag, Burmaa, Sanjaa, Rita Ait Benhamou, Abdessamad El Azhari, Bennis, Ghita, Sara, Lhassani, Sidi Mamoun Louraoui, Mounir, Rghioui, Sarra, Saaf, Taha, Gadouali, Iltimass, Gouazar, Moniba, Korch, Ahmed, Letrache, Amina, Louari, Anas, Zamame, Samia, Ousouss, Meryem, 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Alexander, Borgstein, Suzanne, Gisbertz, Sarah, Mikdad, Mark van Berge Henegouwen, Roel, Bakx, Marc, Besselink, Daniel Hl Lemmers, Anne-Jasmin, Roelofs, Paul van Amstel, Claire van Helsdingen, Ludi, Smeele, Niels, Harlaar, Frederik, Jonker, Sjirk van der Burg, Justin, Y van Oostendorp, Saranda, Ombashi, Tim van der Voort, Martijn van Geldorp, Lisanne, Posma-Bouman, Hans Donald de Boer, Annette, Olieman, Henriette, Smid-Nanninga, Jean-Paul P, M De Vries, Rianne, Hogenbirk, Tyche, Derksen, Josephine, Franken, Steven, Oosterling, Peter, Nolte, Jelle van der List, Ian, Alwayn, Okker, Bijlstra, Andries, Braat, Ruth, Bulder, Michèle de Kok, Robin, Faber, Ben, Goudsmit, Jaap, Hamming, Sven, Mieog, Alexander, Vahrmeijer, Fenna E, M van de Leemkolk, Joost van der Vorst, Jan van Schaik, Merel, Verhagen, Kim, Albers, Larsa, Gawria, Harry Van Goor, Michiel, Warle, Tessa, M van Ginhoven, Charlotte, Viëtor, Evert-Jan, Boerma, Lara, Lallitsch, Donald, Schweitzer, Wouter, Leclercq, Julie, Sijmons, 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Mohammad, Altuwaijri, Muath, Alwabel, Mohamed, Aly, Mosa, Alzahrani, Adel, Assiri, Ahmed, Bakhsh, Mohammed, Sbaih, Jubran Al Faifi, Shehanah Al Omair, Saad, Alobaysi, Khalid, Beidas, Nawaf, Modahi, Norah, Musallam, Khaled El Gazzar, Khaled, Ghabban, Ahmed, Abdulmohsen, Hussam, Adi, Amgad, Afifi, Khaled Ai Nwijy, Turki Ai Zahrani, Jehad, Akiely, Abdulaziz Al Harthi, Attiya Al Zahrani, Feras, Alahmad, Ahmad, Alayed, Abdallah, Alghazo, Nawaf, Alharthi, Sultan, Alharthi, Mohammad, Alnoaiji, Bandar, Alqahtani, Abdulellah, Alqarni, Noorsabah, Alrubays, Mohammed, Alshehri, Abdulmajeed, Alshehri, Mamdouh, Alzaibak, Majed Attoun Attoun, Ahmed, Awaji, Yaquob, Daghriri, Reda, Daoud, Aymad, Eltawab, Sherif, Emara, Ayman, Farouk, Anas, Fatani, Mojahid, Ghazi, Talal, Khewater, Elsayed, Monier, Nizar, Musawa, Magdy, S El-Bahnasawy, Mahmoud, Zakaria, Saleh, Alghamdi, Waleed, Althobaiti, Ivan, Paunovic, Nikola, Slijepcevic, Nouf, Alajaji, Lidija, Aleksić, Goran, Barisic, Aleksandar, Bogdanovic, Miljan, Ceranic, Ivan, Dimitrijevic, Keramatollah, Ebrahimi, Daniel, Galun, Željko, Grubač, Nikola, Grubor, Nenad, Ivanović, Jelenko, Jelenkovic, Stefan, Kmezić, Djordje, Knezevic, Zoran, Krivokapic, Stojan, Latinčić, Velimir, Markovic, Slavko, Matić, Marko, Miladinov, Aleksandar, Ninic, Maja, Pavlov, Ivana, Pavlovic, Ilija, Pejovic, Zeljko, Radojkovic, Slobodan, Rašić, Milorad, Reljic, Predrag, Sabljak, Aleksandar, Sekulić, Vladimir, Šljukić, Boris, Tadic, Jovica, Vasljević, Dejan, Veličković, Marko, Zivanovic, Pavle, Gregoric, Zlatibor, Loncar, Dusan, Micic, Drago, Jelovac, Srbislav, Pajić, Milan, Petrovic, Sanela, Sumrak, Vladimir, Bascarevic, Ivan, Bogdanovic, Danica, Grujičić, Rosanda, Ilic, Miloš, Joković, Mihailo, Milićević, Filip, Milisavljević, Aleksandar, Miljković, Aleksandra, Paunovic, Vuk, Šćepanović, Aleksandar, Stanimirovic, Marko, Todorovic, Miljan, Folic, Ana, Jotic, Sanja Krejovic Trivic, Jovica, Milovanovic, Aleksandar, Trivic, Lazar, Davidovic, Stefan, Ducic, Igor, Koncar, 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Sanja, Zahorjanski, Adrian, Chiow, Jun Xian Hing, Lip Seng Lee, Sey Kiat Terence Lim, Chi Wei Mok, Su-Ming, Tan, Hiang Jin Tan, Hana, Arbab, Candy, Choo, Doris Mae Dimatatac, Yee, Low, Hui Wen Chua, Tousif, Kabir, Sabrina, Ngaserin, Lester, Ong, Kiat Tee Benita Tan, Alvin, Tan, Wei-Wen, Ang, Yew-Lam, Chong, Jeffrey, J Leow, Biquan, Liu, Ming Ngan Aloysius Tan, Ern Yu Tan, Kar Yong Wong, Sharon, Yeo, Ladislav, Czako, Branislav, Gális, Kristián, Šimko, Radoslav, Morochovič, Martin, Paulo, Marián, Sedlák, Jan, Grosek, Ales, Tomazic, Leyla Al Mahdawi, Nuhi, Arslani, Andrej, Avsenak, Andrej, Bergauer, Krešimir, Blažević, Dejan, Bratus, Dalibor, Cankoski, Andrej, Cokan, Bojana, Crnobrnja, Andraz, Dovnik, Vojko, Flis, Samo, Fokter, Urska, Gajsek, Minja, Gregorič, Marko, Hazabent, Tomaz, Jagric, Niko, Kavčič, Jure, Knez, Nina, Kobilica, Rok, Kovačič, Lara, Lukman, Urska, Marolt, Jan, Mlakar, Tamara, Mohorko, Andrej, Moličnik, Ivan, Perić, Stojan, Potrč, Milena Senica Verbic, Mateja, Sirše, 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Raquel Angulo Artal, Luis, Barbier, Guillermo, García-Operé, Marta, Jiménez-Jiménez, Héctor, Marín, Mikel, Oñate, Luis Antonio Pascua-Gómez, María Alexandra Pesántez Peralta, Ibabe Villalabeitia Ateca, Ladislao Cayetano Paniagua, Joan, Camí, Pablo, Collera, Martínez, David, Carlos Javier Gómez Díaz, Jordi Querolt Coll, M Dolors Rosines Cubells, Cristina Soto Montesinos, Guillermo, Triana, Marina, Xicola, Alfonso, Alias, Albert, Baduell, Mariano, Balaguer-Castro, María Pilar Camacho Carrasco, Marina Cámara Vallejo, Borja Campuzano Bitterling, Guillem, Claret, Francisco, J Cuesta-González, Alberto Di Somma, Joaquim Enseñat Nora, Neus, Fabregas, Ada Ferrer Fuertes, Abel, Ferrés, Cesar, Ginesta, Jose Juan Gonzalez Sanchez, Isabel, Gracia, Jhon Alexander Hoyos Castro, Montsant, Jornet-Gibert, Xavier, Morales, Alejandra, Mosteiro-Cadaval, Leire, Pedrosa, José Poblete Carrizo, Marina, Renau-Cerrillo, Luis Alberto Reyes Figueroa, Pedro Roldan Ramos, Jordi Rumià Arboix, Marta, Sabater-Martos, 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Barbara, Algar-Yañez, Gutiérrez, Bérénice, Olga De La Varga-Martínez, Paula, Fernandez-Valdes-Bango, Sandra Maria Gadin-Lopez, José María Martínez-Gómiz, Elena, Nieto-Moreno, Ana, Nieto-Moreno, Montserrat Ocampos Hernandez, Maria Laura Pelegrina-Lopez, Alicia Ruiz Escobar, Elena, Sáez-Ruiz, Beatriz, Vazquez-Rivero, Antonio, Lara, Belén Vielva Del Campo, Fernando Alcaide Matas, Simbad, Costas-Ochoa, José María García Pérez, Elizabeth, Marmol, Paula Troncoso Pereira, Maria Del Pilar Concejo Cutoli, Juan Ramón Gómez López, Juan Carlos Martín Del Olmo, Paloma Guillamot Ruano, Javier Páramo Zunzunegui, Antonio Albarracín Marín Blázquez, Alfonso, Aliaga-Sanchez, Marta María Arroyo Domingo, Miriam Artés Artés, Ana Isabel Avellaneda Camarena, Aida, Blaya, Emny Rochell Bobadilla Romero, Pedro Vicente Fernández-Fernández, Lorena Galindo Iñiguez, Víctor Javier García Porcel, Clara Giménez Francés, Antonio Javier Gomez Poveda, Rebeca Gonzalez Celdran, Francisco Miguel González Valverde, Laura Guillamon Vivancos, Elena, Gurrea-Almela, Alejandra Jara Maquilón, Jose David Jimenez Parra, Abd Al Aziz Lanagrán Torres, Raquel Lax Perez, Carmen Maria Lopez Lopez, Francisco, Machado, Alfonso Marco Garrido, Florencio Manuel Marin Martinez, Victoria Martínez Muñoz, Esther, Medina, Olimpia, Molina, José Manuel Muñoz Camarena, Julian, Onate, Pedro Antonio Parra Baños, Emilio Peña Ros, Enrique, Rubio, Marina Sánchez Robles, Carlos Sanchez Rodriguez, María Valero Soriano, María Teresa Yepes García, Felipe, Alconchel, Andrés Balaguer Román, Valentín, Cayuela, Ana, Conesa, Ana Delegido García, Pedro José Gil Vázquez, Paula Gómez Valles, Francisco, Gómez-Bosch, Vicente, J León-Muñoz, Francisco, Martínez, Alvaro, Navarro-Barrios, Tatiana, Nicolás-López, Pablo Ramirez Romero, Emiliano, Cano-Trigueros, María Concepcion Alonso González, Leticia Gómez Viana, Ana Pastor Zapata, Elisa Contreras Saiz, Tamara Díaz Vico, Maria, Fernandez-Hevia, Luis Joaquín García Flórez, Raquel, Rodríguez-Uria, Sandra, Sanz, Lorena, Solar-Garcia, Aida Suárez Sánchez, Jaume, Gelonch, Dietmar, Reinaldo, Miriam Abdulkarim Polo, Asier, Aguirre, Marta Alomar Bofill, Santiago, Baena, Ashish, Bartakke, Carmen Cabeza Oliver, Marta Castro Suárez, José Andrés Cifuentes Rodenas, Olga Claramonte Bellmunt, Ant Onia Crespí Mir, Anabel De La Llave Serralvo, Mar, Escales, Isabel Rosa Fernández Burgos, Pablo Gandia Gonzalez, Juan Lliteras Jorge, María Cristina Martínez Canto, Javier, Mata, Andreu, Morell, Naila, Pagès, Sara Pérez Palao, Cristian Plaza Valiente, Catalina Ramon Barcelo, Carmen Reyero Fernández, Albert Reyes Claret, Leticia Rodriguez Vaquero, Maialen Saez de Vicuña Salinas, Pilar Santos Cidon, Concepcion, Segura, Aina, Serra, Maria Serra Guivernau, Maria Soler Pedrola, Marta, Tasende, Marta Torrent Lluch, María Inmaculada Valldeperas Hernández, Rosa-Maria, Yañez-Lpez, Andrea, Craus-Miguel, Laura Fernández Vega, Natalia Pujol Cano, Juan José Segura-Sampedro, Laura Colet Oliver, Ivan Dot Pascuet, Mireia, Duart, Isabel Tello Galindo, Eduardo Arrea Salto, Jaume Cámara Cabrera, Marta Camats Terré, Juan Gabriel Castro Ríos, Marta de la Rosa-Estadella, Anna, Fernandez-Colorado, Anna, Gasulla-Rodriguez, Antonio, Gimenez-Gaibar, Elena, Gonzalez, Yeray Maldonado Sotoca, Matilde, Molina-Corbacho, Montserrat Monfort Mira, Josep, Rodoreda, Marta Santos Espí, Arnau Verdaguer Figuerola, Elisa Angela Diego-Alonso, Jaime, López-Sánchez, Luis, Muñoz-Bellvis, Jacobo, Trebol, Borja, Aguinagalde, Cristina Gabriela Alzate Arsuaga, Ainhoa Andres Imaz, Iñigo, Arana, Coro Aranzabal Urrutia, Mikel, Armendariz, Lorena, Arrabal, Iñigo, Augusto, Adolfo, Beguiristain, Laura, Busto, Ainhoa, Cuevas, Itziar De Ariño, Alejandro, Elúa, Leticia, Fernandez, Arantza, Fernandez-Monge, Lander, Gallego, Alba, Garcia, Amaia Garcia Dominguez, Gregorio, Garmendia, Carmen, Grañén, Pelayo Hevia Rodríguez, Maria, Iraola, José Miguel Izquierdo, Aintzane, Lizarazu, Jon Ander Lizarbe, Claudia Cristina Lopes Moreira, Iker, López, Ruth Marquina González, Tania, Pastor, Adrián Recio Ayesa, Ana Paula Riverola Aso, Carballo, Rodríguez, Araceli, Rodrìguez, Maria Inmaculada Ruiz Montesinos, Patricia, Torres, Jose, Undabeitia, Ainara, Villafruela, Maria Barrionuevo Ramos, David, Blanco, Marta, Calderón, Eva Corral Rubio, Angel, Cuadrado-García, Daniela, Cubek, Ignacio, Fariña, Maria Fernandez LLorente, Natalia Flores Amador, Mariana García Virosta, Luis Garcia-Sancho Tellez, Adelina Gonzalez Martinez, María, Hernandez, Rubén Herreros Ruiz-Valdepeñas, Carmen Jimenez Sanchez, Eduardo Llamazares Cobo, María, López, Javier, López-Martin, Teresa Martínez Marivela, Luis Miguel Martinez Parra, Paloma Maté Mate, Paloma, Medrano, Manuel Moriche Carretero, Sara Núñez O'Sullivan, Manuel Ortega Oria de Rueda, María Begoña Pastor Nieto, Clara, Pérez, Antonio, L Picardo, Remedios Revilla Amores, Carmen Rodríguez Haro, Jose Alberto Rojo López, Fatima Sanchez Cabezudo Noguera, Cristina, Sanz, Daniel Serralta de Colsa, Cristina Valor Garcia, Marta Velasco Martinez, Iván Andújar Lara, Aranzazu, Calero-Lillo, Enrique, López-Ruiz, Alberto Díaz García, Alejandro Menéndez Moreno, Luis Eduardo Pérez-Sánchez, Ángela, Pascual, Miguel Adeba García, Marta Alonso Fernández, Javier Alvarez Gama, Roberto, Ballestero, Loreto Berjon De La Vega, Paola Calleja Hermosa, Mariana, Carrillo-Rivas, Alfonso, Casado, Andrea, Cerveró, Bonifacio Cimadevilla Calvo, Patricia Corriols Noval, Paloma de la Dehesa Cueto-Felgueroso, Miren Jasone Diez Zapirain, José Estevez Tesouro, José Antonio Fernández-Dívar Sánchez, Lucia Garcia Alcalde, Juan García Cardo, Tito García Moreno, Daniel, García-López, Belen Garcia-Montesinos Perea, Miren Gonzalez Benito, Rocio, Gonzalez-Aguado, Miguel Ángel Gordo Vega Gordo-Vega, Jose, Gutierrez-Banos, Jaime Jimeno Fraile, Yolanda Jubete Castañeda, Patricia Lopez Gomez, Antonia Jesús López López, David Mato Mañas, Carmelo, Morales-Angulo, Dieter, Morales-Garcia, Sara, Naranjo, Jose Luis Rabago, Jose Manuel Rabanal, Rocio Revuelta Zorrilla, Adriana Reyes Echeverría, Juan Carlos Rodríguez-Sanjuán, Juan Ramón Sanz, Isabel Simal Badiola, Guillermo, Tejón, Enrique Toledo Martínez, Raquel Varea Malo, Begoña, Fadrique, Tania, Funes, Elena González Revilla, Isaias, Alarcón, Daniel Aparicio Sánchez, Pablo Beltran Miranda, Carmen, Cepeda-Franco, María Josefa Cuevas López, Sandra, Dios-Barbeito, Virginia María Durán Muñoz-Cruzado, Carlos Gonzalez De Pedro, Rosa, M Jimenez-Rodriguez, Francisco, Manresa-Manresa, Gabriel, Marin, Cristobalina, Martin-Garcia, Sara, Martínez-Núñez, Juan Manuel Martos Martinez, Lucas, Mengíbar, Felipe Pareja Ciuro, Eduardo Perea Del Pozo, Veronica Pino Diaz, José, Pintor-Tortolero, Claudia, Quintero-Pérez, Maria Luisa Reyes Diaz, Mercedes Rubio Manzanares Dorado, Alejandro Sanchez Arteaga, Ana, Senent-Boza, Luis, Tallon-Aguilar, Jose, Tinoco-Gonzalez, Luis-Cristobal, Capitan-Morales, Juan Cintas Catena, Javier, Valdes-Hernandez, María Del Campo Lavilla, Alina López De Fernández, Miriam Abellan Lucas, Alba Diaz Padillo, Maria Gómez Romero, Linda Grace Puerto Tamayo, El Mostafa El Yaqine Er Raoudi, Melody García Domínguez, María Ángeles Gascón Domínguez, Marta González Pérez, Alba Hernáez Arzoz, Joana San Anton, Cristian, Ruminot, Hander Guillermo Acosta Diaz, Daniella, Laguado, Kristina, Aghababyan, Alba, Jr, Enrique, Artigues, Rocío, Belda, Miguel, Beltran, Jose Ignacio Blanes, Elena Campos Carot, Miriam, Cantos, Laura, Costa, Carolina Ferrer Gomez, José María Gallego Sánchez, Oscar, Gil-Albarova, Juan, Gilabert-Estellés, Emilio Lopez Alcina, Isabel López Sánchez, Severiano Marin Bertolin, Carolina, Martinez-Perez, Antonio Melero Abellán, Claudia Mulas Fernández, Beatriz, Novoa, Ruth, Nuñez, Pablo Renovell Ferrer, Guijarro-Jorge, Ricardo, Carolina Soledad Romero Garcia, Miguel Sanfeliu Giner, Silvia, M West, Enrique, Zapater, Ignacio, Miranda, Ana, Monís, Alejandro Roselló Añón, María José Sangüesa, Jorge Sanz Romera, Marcos, Adrianzén, Maria Barrios Carvajal, Mireia, Bauzá, Ana Benítez Riesco, Jose Antonio Carbonell Lopez, María-Carmen, Fernández-Moreno, Ricardo Gadea Mateo, Francisco, Garcia, Maris Luisa García-Pérez, Luisa Paola Garzon, Ana, Izquierdo, Maria Lapeña Rodríguez, Carlos, León-Espinoza, Fernando, Lopez, Rosa Martí Fernández, Sara Martínez Castro, Berta Monleón López, Isabel Mora Oliver, David, Moro-Valdezate, Ernesto Muñoz Sornosa, Sara Palomares Casasús, Leticia Pérez Santiago, Mara Albert Fort, Reyes, Balanzá, Lorena Bermell Marco, Carla Carratalá Pérez, Claudia Pilar Clemente Tomas, Marta, Córcoles, Jose Ángel Diez Ares, Carlos Domingo Del Pozo, Nuria Estellés Vidagany, Gonzalo, Garrigos, Mar Gimeno Gimeno Vicente, Blanca Alastrue Giner, Segundo, Gomez-Abril, Paloma, Gonzalez, Paula Gonzálvez Guardiola, Guillermo Sebastian Martínez Fernández, Charo Martínez García, Lucía, Martínez-Costa, Luz María Moratalla Charcos, Sergio Navarro Martínez, Carmen, Payá-Llorente, Álvaro Pérez Rubio, Nuria, Peris, Eduardo Picazo Pineda, Jordi Planelles Gómez, Francisco Ripoll Vidal, Andrea, Roca, Enrique, Salmerón-González, Raquel Segura Roselló, Ramon Trullenque Juan, Cristina Verdejo Gimeno, Jose Miguel Zaragozá García, Gema Zomeño Bravo, Marcos Bruna Esteban, Hanna, Cholewa, Milton de Jesus, Matteo, Frasson, Luis Oliver García, Héctor, J Aguado, Antonio Jose Alonso Villalba, Francisco, Ardura, Carmen Elena Badillo Bercebal, María Bedate Núnez, Alvarez-Ramos Begoña Aranzazu, Juan Beltrán de Heredia, Hugo, Bermejo, Juan Berrocal Cuadrado, Maria Bragado González, Juan, Bustamante-Munguira, Raul Calvo Gonzalez, Yolanda, Carrascal, Ana Belén Casas Marcos, María Carmen Cervera, Sergio Chávez Valladares, Ángel Cilleruelo Ramos, Susana, Cortes, Jesús, Crespo-Sanjuán, María, Cuaresma, Luis Antonio Cuellar Martin, Carlos Ferreras García, Alvaro, Fuentes-Martín, Abel, Ganso, Elena García García, Luis, Garcia-Florez, Virginia, Garcia-Virto, Juan, Gatón, Julio Alberto Gobernado Tejedor, Tania Gómez Sanz, Jose Ignacio González Martín, María Begoña Gregorio Crespo, Ana Herranz Arriero, Jose, Herreros, Marta Ibáñez Nieto, César, Infante, Carlos, Jezieniecki, Moises, Juarez, Gregorio de Jesus Labrador Hernandez, Ana Patricia Legido Morán, Ricardo León Fernández, Alejandro, Leon-Andrino, Almudena, Llorente, Maria Lopez Pais, Mauricio Loucel Bellino, Sergio, Martin, Miguel Angel Martin-Ferrero, Gonzalo Martinez Municio, Elvira Mateos Alvarez, José María Matilla, Luis María Merino Peñacoba, Mario, Montes-Manrique, Fernando Natal Álvarez, David, C Noriega, Henar Nuñez Del Barrio, Francisco Javier Ortiz de Solórzano Aurusa, Lucía, Pañeda, Victoria Pascual Escudero, Miguel Pascual Samaniego, Adela, Pereda, Marta Pérez Febles, Laura, Pesquera, Maria, Plata, Emma Puertas Ruiz, Mario, Rodriguez-Lopez, Alejandro Romero de Diego, Ana, Ruano, María Ruiz Soriano, Cristina Sánchez Torralvo, Silvia Santiago Maniega, Bárbara, Segura-Méndez, Clarisa Simon Perez, José, Soro-García, Paula Suárez Mansilla Suárez-Mansilla, Jeancarlos Trujillo Díaz, Mª Esther Valsero Herguedas, Andrea Vazquez Fernandez, Eduardo Velasco García, Ana, Zabalza, Álvaro Zamora Horcajada, Fernando Acebes García, Enrique Asensio Díaz, Martín, Bailón, Alejandro David Bueno Cañones, Alvaro Centeno Velasco, Ekta Choolani Bhojwani, Fernando Labarga Rodríguez, Sara, Mambrilla, Pablo, Marcos-Santos, Toledano, Miguel, David Pacheco Sánchez, Baltasar, Pérez-Saborido, Pilar, Pinto, Katherine, Plua, Javier Sanchez Gonzalez, Vicente, Simo, Rosalía Velasco López, Sandra Veleda Belanche, Fabiola Eugenia Michel Campos, Iciar Muñoz Lindez, Maria, Balluerca, Maite, Camuera, Pablo, Helguera, Imanol, Herrero, Patricia Paunero Vazquez, María, Sánchez-Rubio, Isami, Soeda, María Dolores Arribas Del Amo, Vicente Manuel Borrego Estella, Estefania, Casas, Néstor Castán Villanueva, Daniel Delfau Lafuente, Elena Delgado Blanco, María, Domingo, Ismael Gil Romea, Azucena, Gonzalo, Emilio Lagunas Lostao, Noelia Lete Aguirre, Yaiza Martinez Lahoz, Jesús Víctor Pérez-Tierra Ruiz, Maria Del Mar Soriano, Isabel Valero Lázaro, Esmeralda Carnicer Escusol, Guillermo Pola Bandres, Juan Luis Blas Laina, Beatriz, Cros, Patricio Andrés Freile Pazmiño, David, Garcia-Aguilera, Ana Mejía Casado, Ana, Nogués, Issa Talal El-Abur, Carlos, Yánez, Isabel Gascon Ferrer, Carlos, Gracia-Roche, Ursula María Jariod Ferrer, María Victoria Simón Sanz, Tomas, Uson, Waseem, Ahamed, Sumudu, Jayasinghe, Eranda, Karunadasa, Prathibha, Nelihela, Sujeewa Priyantha Bandara Thalgaspitiya, Dickson, Wickramarathna, Nagenthiram, Harivallavan, Pirashanthan, Nagarasa, Eranga, Perera, Kanapathipillai, Piratheep, Vithranage Srimantha Dewsiri Rodrigo, Meera, Thayalan, Rajendram, Thayaparren, Arulprashanth, Arulanantham, Kanishka De Silva, Gagana, Ganga, Anuja Nadeeshan Kumarasinghe, Mahanada, Udukala, Koculen, Vimaleswaran, Prashanthan, Yogarajah, Ravindri, Jayasinghe, Probhodana, Ranaweera, Mohamed, Rishard, Dharmabandhu, N Samarasekera, Sanjeewa, Seneviratne, Sivasuriya, Sivaganesh, Chamal, Fernando, Nishantha, Mendis, Balasingam, Balagobi, Balasupramaniam, Sathesan, Lanka, Dasanayake, Malitha, Patabendige, Wickramasooriya, Dj, Kugarajh, Ganeshapillai, Sathyamoorthy, Prasanna, Dileepa, Ediriweera, Sumudu, Kumarage, Asanka, Jayawardane, Athula, Kaluarachchi, Pituwala Liyanage Adithya Sirisena, Abubakr, Abubakr, Hozifa, Mohamed, Ismail, Mustafa, Mogahid, Sharfeldein, Samir, Ismail, Reem, Musa, Monira, Sarih, Mussab, Abaker, Eman Adam Abdalla, Mohamad, Abdelbagi, Alsafe, Adlan, Ahmed, Alnaeem, Safa, Atyah, Yasir, Awad, Rsheeda, Dawelbait, Mohamed El Hag, Ibrahim, Elbashir, Sami, Eldirdiri, Samwal, Eldirdiri, Mohammed Eltahier Abdalla Omer, Lana Abdalgadir Ahmed Mohamed, Hiba Hassan Rehmtallah Ahmed, Mohammed Balla Yousif Balla, Abdulmoiz, Aljafari, Abdulmalek, Aljafari, Elsagad, Mohamed, Abdulkader, Mohammad, Abdulkader, Shaar, Mohamed Nafea Shaar, Maab Hussein Yousif Elhafiz, Mohammed Husien Yosif Elhafiz, Abubakr Ali Mohammed Alhassan Humidan, Almigdad, Ali, Hisham, Eljack, Mohamedyasin, Elrashid, Manhal, Ahmed, Albrra, Alhag, Douaa, Ali, Mohammed Ahmed Babikir, Imad, Bakheit, Hytham K, S Hamid, Sami, Mohamed, Walid, Shaban, Nidhal, Siddig, Mohamed, Suliman, Rihab Yasir Abdelmagid, Abubaker, Yassin, Omer, Abbas, Eltahir, Abdelrahim, Muhammed, Ahmed, Mohamed, Elobaid, Adil, Hashim, Ali, Mohamed, Omer, Mohamed, Khalid, Osman, Abdallah, Yousif, Safaa, Abdulaal, Marwa, Elsadig, Mohammed, Hussain, Malaz Amir Ataalmanan, Doha Amir AtaAlmanan, Tebyan Amir AtaAlmanan, Alaa, Elgaili, Maria, Mohamed, Usra, Omara, Alkhansa, Osman, Amna, Osman, Safaa, Saad, Abdelkareem, Ahmed, Ali Adil Ali Karar, Aya, Alhassan, Mohanad, Alsidig, Mohamed, Eljack, Mohammed Ibrahim Mohammed Ali, Awad Kamal Awad Osman, Liena, Mohamed, Samah Ibrahim Omer Mohamed Osman Mohamed Osman, Altayeb, Mohammed, Ayman, Mohammed, Khadija, Muhmmed, Eltahir, Musa, Egbal Sahal Abdelmajed, Khalid Z M, Y Hamid, Omnia M, M Yousif, Mahmoud, Saleh, Osman, Bashir, Yassein, Elhussein, Omar, Madani, Eva, Angenete, Jennifer, Park, Lars, Gillberg, Monir, Jawad, Linas, Pieteris, Yousif, Saeed, Sergej, Safonov, Martin, Spångfors, Henrik, Andersson, Hans, Bahlmann, Karin Björnström Karlsson, Michelle, Chew, Lara, Daham, Lina De Geer, Helen, Didriksson, Gunilla, Gagnö, Carina, Jonsson, Anna, Oscarsson, Pamela, Buchwald, Mathilde, Delorme, Marie-Louise, Lydrup, Shahin, Mohseni, Arvid, Pourlotfi, Souheil, Reda, Kajsa, Anderin, Nina, Blomme, Josefin, Segelman, Malin, Simlund, Anders, Thorell, Fredrik, Wogensen, Daniel, Danielsson, Peter, Elbe, Rebecka, Hultgren, Boel, Hynning, Fredrik, Klevebro, Karin, Lind, Ebba, K Lindqvist, Carl, Montan, Ernesto, Sparrelid, Clara Svenberg Lind, Jeremy, Wales, Andreas, Älgå, Martin, Nordberg, Emil, Pieniowski, Ioannis, Gkekas, Niklas, Löfgren, Karolina, Niska, Robert, Zürner, Silvio, Däster, Otto, Kollmar, Savas, Soysal, Stephanie, Taha-Mehlitz, Athanasios, Tampakis, Dominik Valentin Flury, Marie, Heyne-Pietschmann, Gregor Jan Kocher, Ana, M Calinescu, Barbara, Wildhaber, Markus, Gass, Jürg, Metzger, Andreas, Scheiwiller, Lukas, Briner, Oliver, Dwidar, Steven, Grandjean, Pietro, Ricciardi, Alexandra, Calmels, Christodoulou, Michel, Morena, Antonilli, Dimitrios, Christoforidis, Alessandra, Cristaudi, Jacopo, Galafassi, Maria Luisa Gasparri, Francesco, Mongelli, Martino, Munini, Andrea, Papadia, Sotirios Georgios Popeskou, Alex, Alfieri, Thomas, Bächler, Matteo, Giardini, Christian, Gingert, Laura, Guglielmetti, Inna, Meyer, Tobias, Müller, Daniel, Schöni, Folco, Solimene, Frank, Weidner, Marco, Bueter, Daniel, Gero, Amelie, Müller, Carmen, Portenkirchner, Andreas, Thalheimer, Jeannette, Widmer, Ahmad, Hmaideh, Alaa, Kour, Saleem, Swaes, Omar, Alannaz, Ramez, Aljasem, Ezeddin, Dabbagh, M Wafa Hamoud Alhussein, Amr, Hamza, Mazen, Mohammad, Abd El-Fattah Mouhandes, Mohamad, Shareeda, Mohammad Nour Shashaa, Mousa, Sifat, Sheraa, Tahhan, Rahaf, Toutounji, Mohamed, Abdulrahman, Albaraa, Abdulsalam, Ziad Al Jarad, Hala, Alayyoubi, Dina, Alfarra, Ahmad, Alhamid, Mahmoud, Alnasser, Mulham, Gharib, Ruwaid, Gharib, Obaida, Kabel, Osama, Kherallah, Abdulqader, Klaho, Mohamed Shukri Najjar, Ahmad, Razouk, Joud, Shiekhoni, Wael, Alkhaleel, Amira, Almosa, Mohammad, Aloulou, Maen, Alzaeem, Khaled, Arnaout, Muhamad Zakaria Brimo Alsaman, Mohamad, Estanbouli, Hanadi, Hawa, Ahmad Nbrass Kabawi, Ghina, Maarawi, Yehia, Mashhadany, Sana Shaikh Torab, Waleed, Abd, Tayma Abd Alghafour, Hani, Abdalnour, Nazeeh Al Aktaa, Marwan Al Aliwy, M Maher Al Arje, Tasneem Al Najjar, Ahmad, Al-Mouakeh, Ahmad, Aldakhil, Aos, Alhamid, Hasan, Alhasan, Mohamad Shadi Alkarrash, Jumaa, Alkhamis, Sara, Alshekh, Ahmad Yamen Arnaout, Oula, Azizeh, Mohammed, Dalaleh, Aghyad, Danial, Zain, Douba, Raghad, Ghadri, Mohammad Maen Ghannam, Anas, Ghawi, Luma Haj Kassem, M Yasser Halwani, Shahed, Hamadieh, Mohammad, Hanino, Ala Aldeen Hasan, Haya, Jawish, Nasr Ullah Kabbani, Saadullah, Kabbany, Mohamad, Kadi, Lama, Kadoura, Ahmad Amir Kayali, Ammar, Kayyali, Aya, Kelzia, Amana, Kezze, Abdullah, Khalaf, Maymona, Khayata, Mohammad Nour Kitaz, Mohammad, Kour, Raghad, Makki, Ruqaya, Masri, Joseph, Masri, Noor, Masri, Muhammad, Mazketly, Shiar, Mustafa, Ezzeldin, Nashed, Yaman Qoudra Danial, Hasan, Raslan, Rima, Salem, Mohammed Asaad Salem, Thabet Sayed Bakir, Manaf, Sharabaji, Majd Sheikh Alganameh, Duaa Sheikh Kadro, Joudy, Shurbatji, Mohammad Noor Sultan, Dana, Sultan, Hala, Swied, Bakri Tarras Jarkas, Tayf, Toutounji, Fadi, Ward, Rama, Zazo, Aya, Zazo, Zainab, Zeino, Mohamed, Alaktaa, Wael, Alsado, Hala, Fares, Nouran, Hawa, Hamza, Ibrahim, Abdulmonem, Kawas, Mourad, Niazi, Bayan, Toutounji, Mohammad, Abdow, Mohamad, Ahmad, Tareq, Ahmad, Rawan Al Azhar, Hiba Al Hage Diab, Rahaf Al Mulke, Mohammad, Al-Jadaan, Ahmad, Alhussein, Zahra, Alnajem, Omar, Alneser, Bayan, Alsaid, Elias, Azar, Lubna, Bakr, Ammar, Hamza, Yara, Houdifa, Sami, Jomaa, Samer, Kefo, Hiba, Mardini, Alaa, Mohammad, Fadi, Rayya, Fatima, Razzouk, Mohannad, Saleh, Anwar, Shamandi, Ammar Youzkatli Alkhatib, Omar Abdul Salam, Dany, Ajami, Mohammad, Alhamid, Ahmad, Alkhaledi, Danny, Hadidi, Massa, Jabra, Mamdouh, Kallas, Antoine, Laktine, Joelle, Naem, Naya, Naoum, Ghena Mohammed Fawaz Ashour, Ahmad, Alhouri, Deema, Fallouh, Ahmad, N Mohammad, Ahmad, Rmman, Ali, Slitin, Christine, Tanos, Ibrahim, Wakim, Hanaa, Zahrawi, Majd, Abouassi, Layth, Abouassi, Ayham, Aboutrab, Basel, Ahmad, Ahmad Mustafa Ahmad, Aya, Ahmad, Afaf, Ahmad, Mohamad, Alabras, Mohammad, Albasheer, Ola, Alkasser, Mhd Khaled Alkasser, Ali, Alkhdor, Marah, Azkoul, Mohammad Karam Chaaban, Haya, Deeb, Basel, Jazieh, Basel, Kouz, Youssef, Kozah, Raied, Mohamad, Ammar, Mohammad, Mhd Zied Nasri, Mohammed Mouaz Shebani, Mohammed, Shwin, Alaa, Sommaq, Amal, Youssef, Tala Al Asadi, Suhad, Alkhateb, Rasha Khalil Alsayyad, Roula, Altom, Mhd Amin Alzabibi, Batoul, Bakkar, Hlma, Ismail, Salma Khadem Alsrouji, Sara, Melhem, Mohamad, Sankari, Mosa, Shibani, Noura, Shujaa, Ibrahim, Adham, Salma, Al-Houssami, Maram, Balouli, Yazan, Rahmeh, Simon, Yanni, Sally, Yousef, Aline, Ahmad, Marah, Ali, Abdulrahman, Almjersah, Aya, Almoustafa, Hiba, Dahhan, Bashar Haj Hassan, Alaa, Hamdan, Salah, Hammed, Rawan, Harfoush, Rama, Hasan, Natalie, Jarkas, Moufid, Mahfoud, Ahmed, Moussa, Alaa, Sulaiman, Siba, Suliman, Yu-Ning, Hu, Jun-Neng, Roan, Meng-Ta, Tsai, Yi-Chen, Wang, Thammawat, Parakonthun, Nicha, Srisuworanan, Voraboot, Taweerutchana, Somcharoen, Saeteng, Sophon, Siwachat, Apichat, Tantraworasin, Danielle, Dimsoy, Shane, Khan, Akash, Ramsaroop, Shivanand, Ramsubhagh, Karim, Ayed, Oussama, Baraket, Mohamed Hedi Ghalloussi, Abbassi, Imed, Nahla, Kechiche, Waad, Farhat, Ammar, Houssem, Erdal Birol Bostanci, Volkan, Oter, Erol, Pişkin, Cihangir, Akyol, Sibel, Demirel, Mehmet Ali Koç, Can, Konca, Özge, Yanık, Basak, Bolukbasi, Huseyin, Gobut, Emre, Gülçek, Kerim, Karabulut, Ramazan, Kozan, Farshad, Noori, Elif, Özeller, Can, Şahin, Ali, Yalcinkaya, Mesut, Yavaş, Aydın, 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Giorgini, Carlo Ingaldi, Elio Jovine, Kenji Kawamukai, Antonio Lanci Lanci, Raffaele Lombardi, Maria Elisa Lozano Miralles, Claudio Marchetti, Michele Masetti, Francesco Minni, Daniele Morezzi, Daniele Parlanti, Alice Pellegrini, Anna Myriam Perrone, Anna paola Pezzuto, Marco Pignatti, Gianluigi Pilu, Valentina Pinto, Gilberto Poggioli, Silvana Bernadetta Puglisi, Diego Raimondo, Matteo Ravaioli, Claudio Ricci, Sara Ricciardi, Francesco Ricotta, Roberta Rizzo, Angela Romano, Matteo Rottoli, Riccardo Schiavina, Renato Seracchioli, Matteo Serenari, Margherita Serra, Piergiorgio Solli, Gioia Sorbi, Mario Taffurelli, Marta Tanzanu, Achille Tarsitano, Marco Tesei, Gabriele Vago, Tommaso Violante, Simone Zanotti, Tommaso Frisoni, leonardo solaini, giorgio ercolani, Fruscio, R, Ornaghi, S, Collaborative, Covidsurg, Collaborative, Globalsurg, Palmisano, Silvia, de Manzini, Nicolo', Žundienė, Laura, Dulskas, Audrius, Kuliavas, Justas, Čekauskas, Albertas, Kielaitė-Gulla, Aistė, Poškus, Tomas, Strupas, Kęstutis, Želvys, Arūnas, COVIDSurg Collaborative, GlobalSurg Collaborative, Department of Surgery, HUS Abdominal Center, Simoes, Jff, Li, E, Picciochi, M, Glasbey, Jc, Baiocchi, G, Blanco-Colino, R, Chaudhry, D, Alameer, E, El-Boghdadly, K, Wuraola, F, Ghosh, D, Gujjuri, Rr, Harrison, Em, Lule, H, Kaafarani, H, Khosravi, M, Kronberger, I, Leventoglu, S, Mann, H, Mclean, Ka, Mengistu, Gm, Modolo, Mm, Ntirenganya, F, Norman, L, Outani, O, Pius, R, Pockney, P, Qureshi, Au, Roslani, Ac, Satoi, S, Shaw, C, Bhangu, A, Omar, Om, Ahmed, Wur, Argus, L, Ball, A, Bywater, Ep, Brar, A, Dawson, Be, Duran, I, Elhadi, M, Jones, C, Kamarajah, Sk, Keatley, Jm, Lawday, S, Marson, Ej, Ots, R, Santos, I, Taylor, Eh, Trout, Im, Varghese, C, Venn, Ml, Xu, W, Dajti, I, Gjata, A, Kacimi, Seo, Boccalatte, L, Cox, D, Townend, P, Aigner, F, Kronberger, Ie, Samadov, E, Alderazi, A, Hossain, K, Padmore, G, van Ramshorst, G, Lawani, I, Cerovac, A, Delibegovic, S, Gomes, Gma, Buarque, Il, Gohar, M, Slavchev, M, Nwegbu, C, Agarwal, A, Martin, J, Ng-Kamstra, J, Olivos, M, Lou, Wh, Ren, Dl, Calvache, Ja, Rivera, Cjp, Hadzibegovic, Ad, Kopjar, T, Mihanovic, J, Jimenez, Pma, Gouvas, N, Klat, J, Novysedlak, R, Amisi, N, Christensen, P, El-Hussuna, A, Batista, S, Lincango-Naranjo, E, Emile, S, Sandoval, Daa, Dhufera, H, Hailu, S, Mengesha, Mg, Kauppila, Jh, Arnaud, Ap, Demetrashvili, Z, Albertsmeier, M, Lederhuber, H, Loffler, Mw, Acquah, Dk, Ofori, B, Tabiri, S, Metallidis, S, Tsoulfas, G, Aguilera-Arevalo, Ml, Recinos, G, Mersich, T, Wettstein, D, Kembuan, G, Milan, Pb, Khosravi, Mh, Mozafari, M, Hilmi, A, Mohan, H, Zmora, O, Gallo, G, Pata, F, Pellino, G, Fujimoto, Y, Kuroda, N, Abou Chaar, Mk, Ayasra, F, Fakhradiyev, I, Hamdun, Ih, Jin-Young, J, Jamal, M, Karout, L, Gulla, A, Rasoaherinomenjanahary, F, Samison, Lh, Sanchez, Iid, Gonzalez, D, Martinez, L, Martinez, Mj, Nayen, A, and Ramos-De la Medina, A
Subjects: Male, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], MULTICENTER, infectious diseases, 0302 clinical medicine, 030202 anesthesiology, Anesthesiology, Cirugía, 80 and over, Prospective Studies, Young adult, Child, Lung, Aged, 80 and over, COVID-19, delay, SARS-CoV-2, surgery, timing, SARS‐CoV‐2 infection, Operative, Child, Preschool, Pneumonia & Influenza, Infection, Cohort study, Human, medicine.medical_specialty, Clinical Sciences, Sars-cov-2, GlobalSurg Collaborative, Settore MED/28 - MALATTIE ODONTOSTOMATOLOGICHE, 03 medical and health sciences, Clinical Research, Biodefense, Correspondence, Humans, PULMONARY COMPLICATIONS, CRIANÇAS EM IDADE PRÉ-ESCOLAR, Aged, Science & Technology, Cirurgia, Prevention, Infant, Odds ratio, Pneumonia, Prospective Studie, Clinical research, Surgery, Human medicine, 610 Medizin und Gesundheit, 1109 Neurosciences, Internationality, Settore MED/29 - CHIRURGIA MAXILLOFACCIALE, Settore MED/18 - CHIRURGIA GENERALE, Adolescent, Adult, Cohort Studies, Female, Middle Aged, Surgical Procedures, Operative, Time, Young Adult, Practice Guidelines as Topic, gastroenterology, Medicine and Health Sciences, 030212 general & internal medicine, Prospective cohort study, Mortality rate, Covid19, Infectious Diseases, Patient Safety, medicine.symptom, 6.4 Surgery, Life Sciences & Biomedicine, 610 Medicine & health, COVID-19, SARS-CoV-2, delay, surgery, timing, Asymptomatic, NO, COVIDSurg Collaborative, Vaccine Related, All institutes and research themes of the Radboud University Medical Center, medicine, Mortalitat, ddc:610, Mortality, Preschool, LS7_4, Surgical Procedures, business.industry, Neurosciences, Evaluation of treatments and therapeutic interventions, 1103 Clinical Sciences, 3126 Surgery, anesthesiology, intensive care, radiology, Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10], Anesthesiology and Pain Medicine, Emerging Infectious Diseases, Good Health and Well Being, Mortalidad, Cohort Studie, business
Abstract: Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4-1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0-2 weeks, 3-4 weeks and 5-6 weeks of the diagnosis (odds ratio (95%CI) 4.1 (3.3-4.8), 3.9 (2.6-5.1) and 3.6 (2.0-5.2), respectively). Surgery performed ≥ 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5 (0.9-2.1)). After a ≥ 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2-8.7) vs. 2.4% (95%CI 1.4-3.4) vs. 1.3% (95%CI 0.6-2.0), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms ≥ 7 weeks from diagnosis may benefit from further delay. ispartof: ANAESTHESIA vol:76 issue:6 pages:748-758 ispartof: location:England status: published
Published: 2021

45. Emergence of spatio-temporal variations in chemotherapeutic drug efficacy: in-vitro and in-Silico 3D tumour spheroid studies

Author: Peter M. A. Sloot, Ern Yu Tan, Muniraj Vivek Sheraton, Geraldine Giap Ying Chiew, Valentin Melnikov, Nishith Verma, Kathy Qian Luo, Computational Science Lab (IVI, FNWI), Interdisciplinary Graduate School (IGS), School of Chemical and Biomedical Engineering, and Complexity Institute
Subjects: 0301 basic medicine, Drug, Cancer Research, Cytotoxicity, media_common.quotation_subject, Cell, Population, Antineoplastic Agents, Apoptosis, Transfection, Reaction-diffusion model, lcsh:RC254-282, 03 medical and health sciences, chemistry.chemical_compound, Imaging, Three-Dimensional, 0302 clinical medicine, Neoplasms, Spheroids, Cellular, Genetics, medicine, Humans, Medicine [Science], Pharmacokinetics, education, Mitosis, Cell Proliferation, media_common, Cisplatin, Mitotic spindle stabilization, education.field_of_study, Spheroid, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Reaction-diffusion Model, 030104 developmental biology, medicine.anatomical_structure, Pharmacodynamics, Oncology, Paclitaxel, chemistry, 030220 oncology & carcinogenesis, embryonic structures, Cancer research, Female, Intracellular, Research Article, HeLa Cells, medicine.drug
Abstract: BackgroundThe mechanisms of action and efficacy of cisplatin and paclitaxel at cell population level are well studied and documented, however the localized spatio-temporal effects of the drugs are less well understood. We explore the emergence of spatially preferential drug efficacy resulting from variations in mechanisms of cell-drug interactions.Methods3D spheroids of HeLa-C3 cells were treated with drugs, cisplatin and paclitaxel. This was followed by sectioning and staining of the spheroids to track the spatio-temporal apoptotic effects of the drugs. A mechanistic drug-cell interaction model was developed and simulated to analyse the localized efficacy of these drugs.ResultsThe outcomes of drug actions on a local cell population was dependant on the interactions between cell repair probability, intracellular drug concentration and cell’s mitosis phase. In spheroids treated with cisplatin, drug induced apoptosis is found to be scattered throughout the volume of the spheroids. In contrast, effect of paclitaxel is found to be preferentially localized along the periphery of the spheroids. Combinatorial treatments of cisplatin and paclitaxel result in varying levels of cell apoptosis based on the scheduling strategy.ConclusionsThe preferential action of paclitaxel can be attributed to the cell characteristics of the peripheral population. The model simulations and experimental data show that treatments initiated with paclitaxel are more efficacious due to the cascading of spatial effects of the drugs.
Published: 2020

46. Association between Breast Cancer Polygenic Risk Score and Chemotherapy-Induced Febrile Neutropenia: Null Results

Author: Seeu Si Ong, Peh Joo Ho, Alexis Jiaying Khng, Elaine Hsuen Lim, Fuh Yong Wong, Benita Kiat-Tee Tan, Swee Ho Lim, Ern Yu Tan, Su-Ming Tan, Veronique Kiak Mien Tan, Rebecca Dent, Tira Jing Ying Tan, Joanne Ngeow, Preetha Madhukumar, Julie Liana Bte Hamzah, Yirong Sim, Geok Hoon Lim, Jinnie Siyan Pang, Veronica Siton Alcantara, Patrick Mun Yew Chan, Juliana Jia Chuan Chen, Sherwin Kuah, Jaime Chin Mui Seah, Shaik Ahmad Buhari, Siau Wei Tang, Celene Wei Qi Ng, Jingmei Li, and Mikael Hartman
Subjects: Cancer Research, Oncology, febrile neutropenia, neutropenic fever, breast cancer, polygenic risk score, PRS
Abstract: Background: The hypothesis that breast cancer (BC) susceptibility variants are linked to chemotherapy-induced toxicity has been previously explored. Here, we investigated the association between a validated 313-marker-based BC polygenic risk score (PRS) and chemotherapy-induced neutropenia without fever and febrile neutropenia (FNc) in Asian BC patients. Methods: This observational case-control study of Asian BC patients treated with chemotherapy included 161 FNc patients, 219 neutropenia patients, and 936 patients who did not develop neutropenia. A continuous PRS was calculated by summing weighted risk alleles associated with overall, estrogen receptor- (ER-) positive, and ER-negative BC risk. PRS distributions neutropenia or FNc cases were compared to controls who did not develop neutropenia using two-sample t-tests. Odds ratios (OR) and corresponding 95% confidence intervals were estimated for the associations between PRS (quartiles and per standard deviation (SD) increase) and neutropenia-related outcomes compared to controls. Results: PRS distributions were not significantly different in any of the comparisons. Higher PRSoverall quartiles were negatively correlated with neutropenia or FNc. However, the associations were not statistically significant (PRS per SD increase OR neutropenia: 0.91 [0.79–1.06]; FNc: 0.87 [0.73–1.03]). No dose-dependent trend was observed for the ER-positive weighted PRS (PRSER-pos) and ER-negative weighted PRS (PRSER-neg). Conclusion: BC PRS was not strongly associated with chemotherapy-induced neutropenia or FNc.
Published: 2022

47. Associations between Pre-Diagnostic Physical Activity with Breast Cancer Characteristics and Survival

Author: Zi Lin Lim, Geok Hoon Lim, Peh Joo Ho, Alexis Jiaying Khng, Yen Shing Yeoh, Amanda Tse Woon Ong, Benita Kiat Tee Tan, Ern Yu Tan, Su-Ming Tan, Veronique Kiak-Mien Tan, Jingmei Li, and Mikael Hartman
Subjects: Cancer Research, Oncology, breast cancer, physical activity, retrospective cohort study, cancer survival
Abstract: Physical activity (PA) is known to reduce breast cancer (BC) risk and improve patient prognosis. However, the association between pre-diagnostic PA and the aggressiveness of BC is unclear. We investigated the associations between PA, BC tumour characteristics, and survival. This retrospective observational study included 7688 BC patients from the Singapore Breast Cancer Cohort (2010–2016). PA information from the questionnaire included intensity (light/moderate/vigorous) and duration (2 h per week). A PA score (1–5) incorporating intensity and duration was calculated. Associations between PA score and tumour characteristics such as stage, histological grade, nodal and hormone receptor status were examined using multinomial regression. Moreover, 10-year overall survival was estimated using Cox regression analysis in 6572 patients after excluding patients with invalid survival data and stage IV disease. Breast tumours associated with higher PA score were more likely to be non-invasive (ORinvasivevs.non-invasive(reference) [95% CI]: 0.71 [0.58–0.87], p-trend = 0.001), of lower grade (ORpoorlyvs.well differentiated(reference): 0.69 [0.52–0.93], p = 0.014), ER-positive (ORER-negativevs.ER-positive(reference): 0.94 [0.89–1.00], p-trend = 0.049), PR-positive (ORPR-negativevs.PR-positive(reference): 0.82 [0.67–0.99], p = 0.041), HER2-negative (ORHER2-negativevs.HER2-positive(reference): 1.29 [1.02–1.62], p-trend = 0.002), and less likely to be of HER2-overexpressed subtype (ORHER2-overexpressedvs.Luminal A(reference): 0.89 [0.81–0.98], p-trend = 0.018). These associations (odds ratios) were more pronounced among post-menopausal patients. A higher PA score did not improve survival. Higher levels of pre-diagnostic PA were associated with less aggressive tumours in BC patients. This illustrated another benefit of PA in addition to its known role in BC risk reduction.
Published: 2022

48. DNA methylation and breast cancer-associated variants

Author: Peh Joo, Ho, Rajkumar, Dorajoo, Ivna, Ivanković, Seeu Si, Ong, Alexis Jiaying, Khng, Benita Kiat-Tee, Tan, Veronique Kiak Mien, Tan, Swee Ho, Lim, Ern Yu, Tan, Su-Ming, Tan, Qing Ting, Tan, Zhiyan, Yan, Joanne, Ngeow, Yirong, Sim, Patrick, Chan, Juliana Chen Jia, Chuan, Ching Wan, Chan, Siau Wei, Tang, Mikael, Hartman, and Jingmei, Li
Subjects: Multifactorial Inheritance, Adolescent, Quantitative Trait Loci, Humans, Breast Neoplasms, Female, DNA Methylation, Middle Aged, Child, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract: A breast cancer polygenic risk score (PRS) comprising 313 common variants reliably predicts disease risk. We examined possible relationships between genetic variation, regulation, and expression to clarify the molecular alterations associated with these variants.Genome-wide methylomic variation was quantified (MethylationEPIC) in Asian breast cancer patients (1152 buffy coats from peripheral whole blood). DNA methylation (DNAm) quantitative trait loci (mQTL) mapping was performed for 235 of the 313 variants with minor allele frequencies 5%. Stability of identified mQTLs (p 5e-8) across lifetime was examined using a public mQTL database. Identified mQTLs were also mapped to expression quantitative trait loci (eQTLs) in the Genotype-Tissue Expression Project and the eQTLGen Consortium.Breast cancer PRS was not associated with DNAm. A higher proportion of significant cis-mQTLs were observed. Of 822 significant cis-mQTLs (179 unique variants) identified in our dataset, 141 (59 unique variants) were significant (p 5e-8) in a public mQTL database. Eighty-six percent (121/141) of the matched mQTLs were consistent at multiple time points (birth, childhood, adolescence, pregnancy, middle age, post-diagnosis, or treatment). Ninety-three variants associated with DNAm were also cis-eQTLs (35 variants not genome-wide significant). Multiple loci in the breast cancer PRS are associated with DNAm, contributing to the polygenic nature of the disease. These mQTLs are mostly stable over time.Consistent results from DNAm and expression data may reveal new candidate genes not previously associated with breast cancer.
Published: 2020

49. Cohort profile: The Singapore Breast Cancer Cohort (SGBCC), a multi-center breast cancer cohort for evaluation of phenotypic risk factors and genetic markers

Author: Shaik Ahmad Buhari, Kee Seng Chia, Mikael Hartman, Wei Sean Yong, Jingmei Li, Ching Wan Chan, Xueling Sim, Soo Chin Lee, Juliana Jia Chuan Chen, Philip Iau, Veronique Kiak Mien Tan, Jin Yee Lee, Geok Hoon Lim, Evan Woo, Chi Wei Mok, Patrick M. Y. Chan, Zhiyan Yan, Sarah Qinghui Lu, Peh Joo Ho, Wai Peng Lee, Preetha Madhukumar, Yen Shing Yeoh, Rebecca Dent, Jaime Chin Mui Seah, Ern Yu Tan, Rob M. van Dam, Su Ming Tan, Benita Kiat Tee Tan, Hui Miao, Swee Ho Lim, Fuh Yong Wong, and Thomas Choudary Putti
Subjects: Skin Neoplasms, Epidemiology, Cancer Treatment, Cohort Studies, Geographical Locations, Risk Factors, Surveys and Questionnaires, Breast Tumors, Medicine and Health Sciences, Breast, Longitudinal Studies, Family history, Skin Tumors, Aged, 80 and over, Ovarian Neoplasms, Singapore, Multidisciplinary, Medical record, Cancer Risk Factors, Middle Aged, Prognosis, Oncology, Cohort, Medicine, Female, Cohort study, Research Article, Adult, Genetic Markers, medicine.medical_specialty, Asia, Science, MEDLINE, Breast Neoplasms, Dermatology, Ethnic Epidemiology, Breast cancer, Diagnostic Medicine, Internal medicine, Breast Cancer, medicine, Cancer Detection and Diagnosis, Humans, Medical history, Genetic Predisposition to Disease, Aged, business.industry, Cancers and Neoplasms, medicine.disease, Medical Risk Factors, People and Places, Ovarian cancer, business
Abstract: This article aims to provide a detailed description of the Singapore Breast Cancer Cohort (SGBCC), an ongoing multi-ethnic cohort established with the overarching goal to identify genetic markers for breast cancer risk, prognosis and treatment response, as well as to understand the ethnic differences in disease risk and outcome in an Asian setting. The cohort comprises of breast cancer patients aged 21 years and above from six public hospitals which diagnose and treat nearly 76% breast cancer cases in Singapore. Self-reported data on sociodemographic and lifestyle, reproductive risk factors, medical history and family history of breast or ovarian cancer is collected using a structured questionnaire. Clinical data on tumour characteristics, and treatment modalities are obtained through medical record. Bio-specimens (blood or saliva) is collected at recruitment. Follow-up on survival information is done through routine linkage with the Registry of Births and Deaths. As of 31 December 2016, 7,768 subjects have been recruited to the study with 76% subjects contributed bio-specimens. The SGBCC provides a valuable platform which offers a unique, large and rich resource for new research ideas on breast cancer related phenotypic risk factors and genetic markers.
Published: 2020

50. Characterisation of protein-truncating and missense variants in

Author: Pei Sze, Ng, Rick Acm, Boonen, Eldarina, Wijaya, Chan Eng, Chong, Milan, Sharma, Sabine, Knaup, Shivaani, Mariapun, Weang Kee, Ho, Joanna, Lim, Sook-Yee, Yoon, Nur Aishah, Mohd Taib, Mee Hoong, See, Jingmei, Li, Swee Ho, Lim, Ern Yu, Tan, Benita Kiat-Tee, Tan, Su-Ming, Tan, Veronique Kiat-Mien, Tan, Rob Martinus, van Dam, Kartini, Rahmat, Cheng Har, Yip, Sara, Carvalho, Craig, Luccarini, Caroline, Baynes, Alison M, Dunning, Antonis, Antoniou, Haico, van Attikum, Douglas F, Easton, Mikael, Hartman, and Soo Hwang, Teo
Subjects: Male, Mice, Singapore, Malaysia, Animals, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Fanconi Anemia Complementation Group N Protein, Germ-Line Mutation
Abstract: Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays.PTVs inDespite genetic and lifestyle differences between Asian and other populations, the population prevalence of
Published: 2020

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