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Juan-Min Zha,1,* Mei Zhang,1,* Tao Wang,2,* Hua-Shan Li,1,2,* Quan-Yao Ban,1,* Mei Liu,1 Xue-Xue Jiang,1 Shi-Ying Guo,2 Jing Wang,2 Ya-Ru Zhou,2 Yu-Hong Liu,2 Wei-Qi He,1,2 Hong Xu1 1Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, People’s Republic of China; 2Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Suda (CAM-SU) Genomic Resource Center, Medical College of Soochow University, Suzhou, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei-Qi He; Hong Xu, Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, People’s Republic of China, Tel +86-512-6588-3545, Email whe@suda.edu.cn; hongxusuda@outlook.comObjective: This cross-sectional study aimed to explore the association of overweight and inflammatory indicators with breast cancer risk in Chinese patients.Methods: Weight, height, and peripheral blood inflammatory indicators, including white blood cell count (WBC), neutrophil count (NE), lymphocyte count (LY), platelet count (PLT) and the concentration of hypersensitivity C-reactive protein (hsCRP), were collected in 383 patients with benign breast lumps (non-cancer) and 358 patients with malignant breast tumors (cancer) at the First Affiliated Hospital of Soochow University, China, from March 2018 to July 2020. Body mass index (BMI), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) were determined according to the ratio equation. The correlations among overweight, inflammatory indicators, and the proportion of non-cancer or cancer cases were analyzed.Results: BMI is associated with an increased breast cancer risk. Compared with non-cancer patients, the average WBC count, NE count, NLR, and level of hsCRP were significantly higher in cancer patients. The level of hsCRP was closely associated with the size of malignant breast tumors.Conclusion: We conclude that overweight and high levels of hsCRP may serve as putative risk factors for malignant breast tumors in Chinese women.Keywords: breast cancer, body mass index, overweight, chronic inflammation, inflammatory indicator

Li-Zhi Chen,1,2,&ast; Han-Shu Li,1,2,&ast; Gao-Wei Han,1,2,&ast; Yong Su,1,3 Tian-Zhu Lu,1– 3 Hong-Hui Xie,1,3 Xiao-Chang Gong,1,3 Jin-Gao Li,1,3 Yun Xiao1,3 1NHC Key Laboratory of Personalized Diagnosis and Treatment of Nasopharyngeal Carcinoma, Jiangxi Clinical Research Center for Cancer, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330029, People’s Republic of China, Nanchang, Jiangxi, 330029, People’s Republic of China; 2Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330029, People’s Republic of China; 3Department of Radiation Oncology, Jiangxi Clinical Research Center for Cancer, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330029, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jin-Gao Li; Yun Xiao, Department of Radiation Oncology, Jiangxi Clinical Research Center for Cancer, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, 519 East Beijing Road, Nanchang, Jiangxi, 330029, People’s Republic of China, Tel +86-791-88313632, Fax +86-791-8321742, Email lijingao@hotmail.com; 813898920@qq.comPurpose: This study aimed to assess the prognostic and predictive value of a circulating hematological signature (CHS) and to develop a CHS-based nomogram for predicting prognosis and guiding individualized chemotherapy in non-metastatic nasopharyngeal carcinoma (NPC) patients.Patients and Methods: NPC patients were recruited between January 2014 and December 2017 at the Jiangxi Cancer Hospital. The CHS was constructed based on a series of hematological indicators. The nomogram was developed by CHS and clinical factors.Results: A total of 779 patients were included. Three biomarkers were selected by least absolute shrinkage and selection operator regression, including prognostic nutritional index, albumin-to-fibrinogen ratio, and prealbumin-to-fibrinogen ratio, were used to construct the CHS. The patients in the low-CHS group had better 5-year DMFS and OS than those in the high-CHS group in the training (DMFS: 85.0% vs 56.6%, p< 0.001; OS: 90.3% vs 65.4%, p< 0.001) and validation cohorts (DMFS: 92.3% vs 43.6%, p< 0.001; OS: 92.1% vs 65.5%, p< 0.001). The nomogram_CHS showed better performance than clinical stage in predicting distant metastasis (concordance index: 0.728 vs 0.646). In the low-TRS (total risk scores) group, the patients received RT alone, CCRT and IC plus CCRT had similar 5-year DMFS and OS (p> 0.05). In the middle-TRS group, the patients received RT alone had worse 5-year DMFS (58.7% vs 80.8% vs 90.8%, p=0.002) and OS (75.0% vs 94.1% vs 95.0%, p=0.001) than those received CCRT or IC plus CCRT. In the high-TRS group, the patients received RT alone and CCRT had worse 5-year DMFS (18.6% vs 31.3% vs 81.5%, p< 0.001) and OS (26.9% vs 53.2% vs 88.8%, p< 0.001) than those received IC plus CCRT.Conclusion: The developed nomogram_CHS had satisfactory prognostic accuracy in NPC patients and may individualize risk estimation to facilitate the identification of suitable IC candidates.Keywords: nasopharyngeal carcinoma, circulating hematological signature, induction chemotherapy, distant metastasis-free survival, overall survival

Ji-sheng Wang,1,2,* Xue-feng Gong,3,4,* Jun-long Feng,1,2,* Hai-song Li,2 Xiao Li,5 Sheng Deng,1,2 Pei-zhong Ren,3,4 Jia-mei Wang,3,4 Ming-sheng Lv,3,4 Rui-feng Jin,3,4 Qiu-yi Chen,3,4 Bin Wang,2 Hong-sheng Cui4 1First Clinical Medical College, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2Andrology Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, People’s Republic of China; 3The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 4Pneumology Department, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 5Department of Andrology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450046, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bin WangAndrology Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, People’s Republic of ChinaEmail dayiwangbln@sina.comHong-sheng CuiPneumology Department, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of ChinaEmail Hshcui@sina.comBackground: Jiawei Shengjiang Powder (JWSJP) is a classical Chinese medicinal formula, which has been widely applied in the treatment of asthma and complications for many years due to its curative effect.Aim: To verify the effect of JWSJP in improving abnormal sperm motility caused by asthma and to explore its potential mechanism.Materials and Methods: The active compounds of JWSJP were obtained from high performance liquid chromatography tandem mass spectrometry and the Traditional Chinese Medicine System Pharmacology. The key active components and targets of JWSJP were predicted based on network pharmacological analysis and bioinformatics research. Rats were randomly divided into normal, model and treatment groups. The rat model of allergic asthma was induced by intraperitoneal injection of ovalbumin solution. The experiment judged improvement of semen quality by evaluating sperm motility, and detected the expression of related proteins in testicular tissue of Sprague-Dawley rats by RT-qPCR and Western blot methods. Hematoxylin and eosin (HE) staining was used to observe the changes in testicular tissue structure in rats.Results: Through the analysis of network pharmacology and bioinformatics, it was found that beta-sitosterol, quercetin, gallic acid, pelargonidin and kaempferol were the key active components of Jiawei Shengjiang Powder. Tumor necrosis factor (TNF), interleukin-6 (IL-6) and insulin (INS) genes are crucial targets of JWSJP in the treatment of spermatogenic dysfunction caused by acute asthma. After 8 weeks of intervention, compared with the model group, the treatment group had significantly improved sperm motility (P < 0.05). There were significant differences in TNF, IL6, and INS proteins in the treatment group, and the HE staining of testicular tissue structure in the treatment group was significantly improved.Conclusion: JWSJP can improve the abnormal sperm motility induced by asthma, and its mechanism may be related to the expression of related proteins and mRNA of TNF, IL6, and INS.Keywords: Jiawei Shengjiang Powder, asthmatic attack, asthenospermia, network pharmacology

Pui Yu Yeung,1 LL Louise Wong,2 Chun Chung Chan,2 Cho Yiu Yung,3 LM Jess Leung,2 Yuen Yee Tam,3 Lap Nin Tang,3 Hiu Sze Li,3 Mei Ling Lau3 1Department of Medicine, Tung Wah Eastern Hospital, Causeway Bay, Hong Kong Special Administrative Region, People’s Republic of China; 2Private Practice, Tsim Sha Tsui and Central, Hong Kong Special Administrative Region, People’s Republic of China; 3Department of Medicine and Geriatrics, United Christian Hospital, Kwun Tong, Hong Kong Special Administrative Region, People’s Republic of ChinaCorrespondence: Pui Yu YeungDepartment of Medicine, Tung Wah Eastern Hospital, 19 Eastern Hospital Road, Causeway Bay, Hong Kong Special Administrative Region, People’s Republic of ChinaTel +852- 2162 6888Email yeunpy3@ha.org.hkBackground and Purpose: The study evaluated the performance between norm-derived age and education adjusted vs single cutoff scores of the Montreal Cognitive Assessment, Hong Kong version (HK-MoCA) in classifying cognitive impairment in Chinese older adults.Methods: Total scores of HK-MoCA were collected from 315 subjects (128 with dementia, 122 with mild cognitive impairment (MCI) and 65 normal) attending a public district hospital-based cognition clinic from 2012 to 2017. The HK-MoCA total scores were evaluated using different cutoffs. Norm-derived age and education adjusted cutoff scores were at 16th, 7th, and 2nd percentiles. Comparison was made with the single cutoff scores validated in a local study with 21/22 for MCI and 18/19 for dementia.Results: Single cutoff score of HK-MoCA differentiated MCI from normal with sensitivity of 0.861 and specificity of 0.723. To detect dementia, its sensitivity was 0.922, and specificity was 0.923. In identifying cognitive impairment, the sensitivity and specificity were 0.932 and 0.723, respectively. However, age and education adjusted cutoff scores achieved high specificities at all levels of cognitive impairment with trade-off of sensitivities. The accuracy of correctly classifying tested subjects into appropriate groups was 85.3% if single cutoff was used though the consistency between norm-derived cutoffs and expert diagnoses were only 59.0%, 54.2%, and 53.9% at 16th, 7th, and 2nd percentiles, respectively. The consistency decreased with older age and lower education level, and majority of misclassifications were false negatives.Conclusion: HK-MoCA is a convenient screening tool to detect cognitive impairment. Administration time is relatively short, and it has incorporated essential cognitive domains. Single cutoff scores with inherent simple education adjustment achieved screening purpose of mild cognitive impairment and dementia in Chinese older adults.Keywords: dementia, Hong Kong, mild cognitive impairment, Montreal Cognitive Assessment, MoCA, screening

This study aims to analyze the impact of Consumer Cultural Identity on the fashion preferences and buying patterns of hijab wearers. A mixed-method approach to gather data on the fashion consumption habits of young citizen women who wear hijabs. The study revealed that religious beliefs significantly influence the fashion choices and purchasing behavior of Muslim young citizens women. Consumer Cultural Identity plays a crucial role in shaping fashion consciousness, with implications for marketing strategies and product development in the hijab fashion industry. The findings highlight the importance of considering religious devotion and cultural influences. Marketers and designers can leverage these insights to create more tailored and culturally sensitive products and campaigns. This research provides valuable insights for businesses looking to engage with the hijab fashion market, emphasizing the need to align products and marketing strategies with the religious and cultural values of the target consumers.

Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Summary: Background: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. Methods: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. Findings: The 3-DF joint test revealed two significant loci with p-value

T-cell receptor (TCR) plays critical roles in recognizing antigen peptides and mediating adaptive immune response against disease. High-throughput technologies have enabled the sequencing of TCR repertoire at the single nucleotide level, allowing researchers to characterize TCR sequences with high resolutions. The TCR sequences provide important information about patients’ adaptive immune system, and have the potential to improve clinical outcome prediction. However, it is challenging to incorporate the TCR repertoire data for prediction, because the data is unstructured, highly complex, and TCR sequences vary widely in their compositions and abundances across different individuals. We introduce TCRpred, an analytic tool for incorporating TCR repertoire for clinical outcome prediction. The TCRpred is able to utilize features that can be extracted from the TCR amino acid sequences, as well as features that are hidden in the TCR amino acid sequences and are hard to extract. Simulation studies show that the proposed approach has a good performance in predicting clinical outcome and tends to be more powerful than potential alternative approaches. We apply the TCRpred to real cancer datasets and demonstrate its practical utility in clinical outcome prediction.

Summary: Background: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. Methods: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). Findings: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10−5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10−5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). Interpretation: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion’s Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.

Purpose – The purpose of this study was to examine the challenges experienced by in-service English as a Second Language (ESL) teachers in an open distance learning (ODL) institution of higher learning in Malaysia. Many in-service ESL teachers who do not have the necessary teaching qualifications are seeking to obtain their teaching qualifications via the ODL mode of studies as it allows them to work as teachers while obtaining their teaching qualifications at the same time. They face multiple challenges which lead to high attrition rates, a concern for ODL institutions of higher learning worldwide. Design/methodology/approach – A qualitative research design using a case study approach was used in this study where in-depth interviews were conducted with four in-service ESL teachers who are currently enrolled in an undergraduate Teaching English as a Second Language (TESL) programme conducted via ODL. Findings – The research is exploratory in nature. Findings highlighted four major challenges by these in-service ESL teachers: (1) financial difficulties, (2) work commitments, (3) family sacrifices and (4) emotional stress. However, technological use was not considered a challenge as mentioned by literature. Practical implications – Findings from the study may be useful to ODL institutions to provide relevant support to ODL students to improve student retention rates in ODL institutions. Originality/value – This study may be considered as a baseline analysis on the challenges experienced by in-service ESL teachers in ODL institution of higher learning in Malaysia. Further in-depth studies are needed to understand how ODL institutions can better support their education programme students to complete their teacher education programmes.

Abstract Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values

Abstract Background Genetic testing can identify cancer risk early, enabling prevention and early detection. We describe use of risk management interventions following genetic testing in the Cancer Health Assessment Reaching Many (CHARM) study. CHARM assessed risk and provided genetic testing to low income, low literacy, and other underserved populations that historically face barriers to accessing cancer genetic services. Methods CHARM was implemented in Kaiser Permanente Northwest (KPNW) and Denver Health (DH) between 2018 and 2020. We identified post‐testing screening (mammography, breast MRI, colonoscopy) and surgical (mastectomy, oophorectomy) procedures using electronic health records. We examined utilization in participants who did and did not receive actionable risk management recommendations from study genetic counselors following national guidelines. Results CHARM participants were followed for an average of 15.4 months (range: 0.4–27.8 months) after results disclosure. Less than 2% (11/680) received actionable risk management recommendations (i.e., could be completed in the initial years following testing) based on their test result. Among those who received actionable recommendations, risk management utilization was moderate (54.5%, 6/11 completed any procedure) and varied by procedure (mammogram: 0/3; MRI: 2/4; colonoscopy: 4/5; mastectomy: 1/5; oophorectomy: 0/3). Cancer screening and surgery procedures were rare in participants without actionable recommendations. Conclusion Though the number of participants who received actionable risk management recommendations was small, our results suggest that implementing CHARM's risk assessment and testing model increased access to evidence‐based genetic services and provided opportunities for patients to engage in recommended preventive care, without encouraging risk management overuse.

Abstract Background The anti‐tumor immune response plays a key role in colorectal cancer (CRC) progression and survival. The T cell‐inflamed gene expression profile (GEP) is a biomarker predicting response to checkpoint inhibitor immunotherapy across immunogenic cancer types, but the prognostic value in CRC is unknown. We evaluated associations with disease‐specific survival, somatic mutations, and examined its differentially expressed genes and pathways among 84 sporadic CRC patients from the Seattle Colon Cancer Family Registry. Methods Gene expression profiling was performed using Nanostring's nCounter PanCancer IO 360 panel. Somatic mutations were identified by a targeted DNA sequencing panel. Results The T cell‐inflamed GEP was positively associated with tumor mutation burden and microsatellite instability high (MSI‐H). Higher T cell‐inflamed GEP had favorable CRC‐specific survival (hazard ratio [HR] per standard deviation unit = 0.50, p = 0.004) regardless of hypermutation or MSI status. Analysis of recurrently mutated genes having at least 10 mutation carriers, suggested that the T cell‐inflamed GEP is positively associated with RYR1, and negatively associated with APC. However, these associations were attenuated after adjusting for hypermutation or MSI status. We also found that expression of genes RPL23, EPCAM, AREG and ITGA6, and the Wnt signaling pathway was negatively associated with the T cell‐inflamed GEP, which might indicate immune‐inhibitory mechanisms. Conclusions Our results show that the T cell‐inflamed GEP is a prognostic biomarker in non‐hypermutated microsatellite‐stable CRC. This also suggests that patient stratification for immunotherapy within this CRC subgroup should be explored further. Moreover, reported immune‐inhibitory gene expression signals may suggest targets for therapeutic combination with immunotherapy.

Abstract Future exploration efforts of the Moon, Mars, and other bodies are poised to focus heavily on persistent and sustainable survey and research efforts, especially given the recent interest in a long‐term sustainable human presence at the Moon. Key to these efforts understands a number of important processes on the lunar surface for both scientific and operational purposes. We discuss the potential value of in situ artificial substrate witness plates, powerful tools that can supplement familiar remote sensing and sample acquisition techniques and provide a sustainable way of monitoring processes in key locations on planetary surfaces while maintaining a low environmental footprint. These tools, which we call Biscuits, can use customized materials as wide ranging as zircon‐based spray coatings to metals potentially useable for surface structures, to target specific processes/questions as part of a small, passive witness plate that can be flexibly placed with respect to location and total time duration. We examine and discuss unique case studies to show how processes such as water presence/transport, presence and contamination of biologically relevant molecules, solar activity related effects, and other processes can be measured using Biscuits. Biscuits can yield key location sensitive, time integrated measurements on these processes to inform scientific understanding of the Moon and enable operational goals in lunar exploration. While we specifically demonstrate this on a simulated traverse and for selected examples, we stress all groups interested in planetary surfaces should consider these adaptable, low footprint, and highly informative tools for future exploration.

Abstract Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene–environment (G × E) interactions and may provide information on the underlying biological pathway. We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based G × E approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case–control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4839 genes with available genetically predicted expression. We pooled results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. We used a false discovery rate of 0.2 to identify genes with suggestive evidence of an interaction. We found suggestive evidence of interaction with folate intake on CRC risk for genes including glutathione S-Transferase Alpha 1 (GSTA1; p = 4.3E−4), Tonsuko Like, DNA Repair Protein (TONSL; p = 4.3E−4), and Aspartylglucosaminidase (AGA: p = 4.5E−4). We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk. Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein.

Abstract Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC.

Germline biallelic pathogenic MUTYH variants predispose patients to colorectal cancer (CRC); however, approaches to identify MUTYH variant carriers are lacking. Here, the authors evaluated mutational signatures that could distinguish MUTYH carriers in large CRC cohorts, and found MUTYH-associated somatic mutations.

Abstract Background T cell receptors (TCRs) play critical roles in adaptive immune responses, and recent advances in genome technology have made it possible to examine the T cell receptor (TCR) repertoire at the individual sequence level. The analysis of the TCR repertoire with respect to clinical phenotypes can yield novel insights into the etiology and progression of immune-mediated diseases. However, methods for association analysis of the TCR repertoire have not been well developed. Methods We introduce an analysis tool, TCR-L, for evaluating the association between the TCR repertoire and disease outcomes. Our approach is developed under a mixed effect modeling, where the fixed effect represents features that can be explicitly extracted from TCR sequences while the random effect represents features that are hidden in TCR sequences and are difficult to be extracted. Statistical tests are developed to examine the two types of effects independently, and then the p values are combined. Results Simulation studies demonstrate that (1) the proposed approach can control the type I error well; and (2) the power of the proposed approach is greater than approaches that consider fixed effect only or random effect only. The analysis of real data from a skin cutaneous melanoma study identifies an association between the TCR repertoire and the short/long-term survival of patients. Conclusion The TCR-L can accommodate features that can be extracted as well as features that are hidden in TCR sequences. TCR-L provides a powerful approach for identifying association between TCR repertoire and disease outcomes.

Abstract Identification of new genetic markers may improve the prediction of colorectal cancer prognosis. Our objective was to examine genome-wide associations of germline genetic variants with disease-specific survival in an analysis of 16,964 cases of colorectal cancer. We analyzed genotype and colorectal cancer-specific survival data from a consortium of 15 studies. Approximately 7.5 million SNPs were examined under the log-additive model using Cox proportional hazards models, adjusting for clinical factors and principal components. Additionally, we ran secondary analyses stratifying by tumor site and disease stage. We used a genome-wide p-value threshold of 5 × 10–8 to assess statistical significance. No variants were statistically significantly associated with disease-specific survival in the full case analysis or in the stage-stratified analyses. Three SNPs were statistically significantly associated with disease-specific survival for cases with tumors located in the distal colon (rs698022, HR = 1.48, CI 1.30–1.69, p = 8.47 × 10–9) and the proximal colon (rs189655236, HR = 2.14, 95% CI 1.65–2.77, p = 9.19 × 10–9 and rs144717887, HR = 2.01, 95% CI 1.57–2.58, p = 3.14 × 10–8), whereas no associations were detected for rectal tumors. Findings from this large genome-wide association study highlight the potential for anatomical-site-stratified genome-wide studies to identify germline genetic risk variants associated with colorectal cancer-specific survival. Larger sample sizes and further replication efforts are needed to more fully interpret these findings.

Purpose – The purpose of this study aims to compare the academic performance and types of learning strategies used by APEL and regular entry undergraduates. It also explored the relationship between the academic performance and the types of learning strategies utilised by these two groups of undergraduate. Design/methodology/approach – This quantitative study involved 400 undergraduates from an open distance learning (ODL) institution. A correlational research design was used in this study. Data were collected through archival data and questionnaire. Independent t-test and Pearson’s correlation analyses were performed using SPSS. Findings – Regular entrants were found to perform slightly better than APEL entrants. There is no significant difference between the types of learning strategies used by APEL and regular entrants. For both groups, the higher performers adopted time and study environment management as well as effort regulation strategies. Besides this, there was no correlation between cognitive skills and peer learning with their academic performance. Meta-cognitive self-regulation and help-seeking which were found to affect the regular entrants’ academic performance did not correlate with those of APEL entrants. Research limitations/implications – This study was conducted within only one institution. The generalisation of findings may therefore be limited. Future studies could be conducted to include students from several institutions. Practical implications – Time management training could be provided to students. Additional support, like foundation courses and supplementary readings, could be provided to APEL entrants to support their learning. Originality/value – The findings would be beneficial to ODL institutions who offer APEL entry to understand the academic performance and learning strategies used by APEL entrants relative to regular entrants.

Background: In recent decades, the prevalence of food allergy (FA) in children has increased in Western countries; however, there have been only limited studies on FA, especially among young children, in Asian countries, including Taiwan. In this study, we identified prenatal and perinatal risk factors associated with FA in young children in Taiwan. Methods: For this prospective birth cohort study, we adopted the Southern Taiwan Allergy Research Alliance (STARA)-FA questionnaire to collect data related to prenatal and perinatal risk factors and self-reported allergic symptoms in children aged 1–3 years in the well-baby clinics of 4 medical centers located in 3 cities, Chia-Yi, Tainan, and Kaohsiung, Taiwan. The STARA-FA questionnaire consisted of 99 questions to investigate the association of prenatal and perinatal risk factors with FA. Results: We recruited 903 young children aged 1–3 years in Taiwan. Among those, 95 (14.7%) children had allergic reactions to foods. The most common food allergens were eggs (26/95, 27.3%), milk (22/95, 23.2%), fruits (13/95, 13.7%), and seafood (12/95, 12.6%). We also found that there were 134 (14.8%) children with eczema, 86 (9.5%) with wheezing, and 240 (26.6%) with rhinitis. Children with a personal history of eczema (adjusted odds ratio [AOR], 2.48; 95% confidence interval [CI], 1.38–4.45) and a family allergy history (AOR, 2.06; 95% CI, 1.18–3.57) had a significantly increased risk of FA. Maternal peanut consumption during pregnancy was associated with a decreased risk of FA in children (AOR, 0.57; 95% CI, 0.33–0.98). Conclusions: In this study, the prevalence of FA in a cohort of Taiwanese young children was 14.7%. Risk factors associated with FA were a personal eczema history and a family allergy history, which might serve as predictive or prevention factors for the development of FA in young children in Taiwan.

Abstract Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

Abstract Background Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. Methods In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P

Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds.

In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.

Abstract Background Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. Methods To improve statistical power and interpretation for gene‐environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype‐Tissue Expression Project for all genes with heritability ≥1%. We used a mixed‐effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI‐CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR

Physical activity has been linked to lower risks of colorectal and breast cancer. Here, the authors present a Mendelian randomisation analysis supporting a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer.

Gene expression data have been used to infer gene-gene networks (GGN) where an edge between two genes implies the conditional dependence of these two genes given all the other genes. Such gene-gene networks are of-ten referred to as gene regulatory networks since it may reveal expression regulation. Most of existing methods for identifying GGN employ penalized regression with L1 (lasso), L2 (ridge), or elastic net penalty, which spans the range of L1 to L2 penalty. However, for high dimensional gene expression data, a penalty that spans the range of L0 and L1 penalty, such as the log penalty, is often needed for variable selection consistency. Thus, we develop a novel method that em-ploys log penalty within the framework of an earlier network identification method space (Sparse PArtial Correlation Estimation), and implement it into a R package space-log. We show that the space-log is computationally efficient (source code implemented in C), and has good performance comparing with other methods, particularly for networks with hubs.Space-log is open source and available at GitHub, https://github.com/wuqian77/SpaceLog

The spectrophotometric properties of two study areas in the Ingenii swirl region show that the combined effects of multiple processes are required to explain the regolith’s mineralogical and physical properties. Production of the swirl regions requires mobilization of the regolith in addition to preferential radiation shielding of subareas. The discovery of topographic correlations between on- and off-swirl (dark lanes) clearly shows that the on-swirl regions are statistically lower than the off-swirl dark lanes by 2–3 m. Photometric analyses show no microscale roughness differences between on- and off-swirl, suggesting no differences in the regolith’s fairy-castle structure between the two swirl regions. The photometric properties of one of the study areas suggest that off-swirl dark lanes may have a more complicated grain structure than on-swirl areas. Enhanced abundances of plagioclase are observed on-swirl in both study areas. Enhanced abundances of FeO and orthopyroxene are observed off-swirl in both areas. No variations in olivine or clinopyroxene abundance were observed for either study area. The discovery of topographic correlations coupled with the similarities in structural properties provides new constraints on the types of processes acting on lunar swirl surfaces.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Purpose - The purpose of this paper is to highlight how accreditation of prior experiential learning (APEL) is implemented, the challenges faced by the APEL assessors while assessing candidates as well as to suggest recommendations for improving the APEL process. Design/methodology/approach - This paper is written based on the critical reflection of two accreditation of prior experiential learning: admissions (APEL-A) assessors appointed from a Malaysian Qualifications Agency approved assessment centre. This process would add depth and breadth to the study based on the assessor’s experience. Findings - The study identified five challenges in the implementation of APEL-A. They are limited literature and records of the existing practices, conceptualisation of the APEL process, complicated and time-consuming APEL process, standard of acceptance vary according to discipline and lack of continuous training for APEL assessors. The four recommendations for improvements are as follows: the need for transparent and clear guidelines, ensuring consistency in practices and fairness to those from conventional learning, integrating APEL as part of the institution’s academic policy and providing continuous training for all APEL assessors. Originality/value - Until now, not much research has been done regarding its implementation in Malaysia. The number of learners enrolled through this form of assessment may be low but growing. The feedback on the implementation of the APEL-A assessment process would be greatly beneficial to the stakeholders involved in improving its implementation process. The highlighted challenges faced as well as the recommendations put forth may also be useful for the continuous improvement of the APEL-A assessment process. Relevant stakeholders would benefit from this study.

Building upon prior research on intergenerational income mobility, we assess class effects versus racial effects on the probability of becoming a poor adult, broken down by gender. We define the class effect (for each race-and-gender group) as the difference between the probability that a person who was born into the lowest income quintile becomes poor and the probability that a person who was born into the highest income quintile becomes poor. For each minority-by-gender group, using Whites as the baseline, the racial effect is defined as the average racial differential in the probability of becoming a poor adult, irrespective of class origins. The results indicate that, for all minority-by-gender groups, the class effect is larger than the racial effect. Our findings underscore the continuing significance of the comparatively large effects of class origins, which have not been adequately acknowledged in recent research.

Genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants associated with various phenotypes, but together they explain only a fraction of heritability, suggesting many variants have yet to be discovered. Recently it has been recognized that incorporating functional information of genetic variants can improve power for identifying novel loci. For example, S-PrediXcan and TWAS tested the association of predicted gene expression with phenotypes based on GWAS summary statistics by leveraging the information on genetic regulation of gene expression and found many novel loci. However, as genetic variants may have effects on more than one gene and through different mechanisms, these methods likely only capture part of the total effects of these variants. In this paper, we propose a summary statistics-based mixed effects score test (sMiST) that tests for the total effect of both the effect of the mediator by imputing genetically predicted gene expression, like S-PrediXcan and TWAS, and the direct effects of individual variants. It allows for multiple functional annotations and multiple genetically predicted mediators. It can also perform conditional association analysis while adjusting for other genetic variants (e.g., known loci for the phenotype). Extensive simulation and real data analyses demonstrate that sMiST yields p-values that agree well with those obtained from individual level data but with substantively improved computational speed. Importantly, a broad application of sMiST to GWAS is possible, as only summary statistics of genetic variant associations are required. We apply sMiST to a large-scale GWAS of colorectal cancer using summary statistics from ∼120, 000 study participants and gene expression data from the Genotype-Tissue Expression (GTEx) project. We identify several novel and secondary independent genetic loci.

The R package frailtySurv for simulating and fitting semi-parametric shared frailty models is introduced. Package frailtySurv implements semi-parametric consistent estimators for a variety of frailty distributions, including gamma, log-normal, inverse Gaussian and power variance function, and provides consistent estimators of the standard errors of the parameters' estimators. The parameters' estimators are asymptotically normally distributed, and therefore statistical inference based on the results of this package, such as hypothesis testing and confidence intervals, can be performed using the normal distribution. Extensive simulations demonstrate the flexibility and correct implementation of the estimator. Two case studies performed with publicly available datasets demonstrate applicability of the package. In the Diabetic Retinopathy Study, the onset of blindness is clustered by patient, and in a large hard drive failure dataset, failure times are thought to be clustered by the hard drive manufacturer and model.

The objective of this study was to propose a standardised methodology for assessing the accuracy of three-dimensional printed (3DP) full-arch dental models and the impact of storage using two printing technologies. A reference model (RM) comprising seven spheres was 3D-printed using digital light processing (MAX UV, MAX) and stereolithography (Form 2, F2) five times per printer. The diameter of the spheres (n = 35) represented the dimensional trueness (DT), while twenty-one vectors (n = 105) extending between the sphere centres represented the full-arch trueness (FT). Samples were measured at two (T1) and six (T2) weeks using a commercial profilometer to assess their dimensional stability. Significant (p < 0.05) contraction in DT occurred at T1 and T2 with a medium deviation of 108 µm and 99 µm for MAX, and 117 µm and 118 µm for F2, respectively. No significant (p > 0.05) deviations were detected for FT. The detected median deviations were evenly distributed across the arch for MAX at p < 0.05). The proposed methodology was able to assess the accuracy of 3DP. Storage significantly impacted the full-arch accuracy of the models up to 6 weeks post-printing.

Abstract Background Previous population-based studies have described first primary breast cancer tumor characteristics and their association with contralateral breast cancer (CBC) risk. However, information on influential covariates such as treatment, family history of breast cancer, and BRCA1/2 mutation carrier status was not available. In a large, population-based, case-control study, we evaluated whether tumor characteristics of the first primary breast cancer are associated with risk of developing second primary asynchronous CBC, overall and in subgroups of interest, including among BRCA1/2 mutation non-carriers, women who are not treated with tamoxifen, and women without a breast cancer family history. Methods The Women’s Environmental Cancer and Radiation Epidemiology Study is a population-based case-control study of 1521 CBC cases and 2212 individually-matched controls with unilateral breast cancer. Detailed information about breast cancer risk factors, treatment for and characteristics of first tumors, including estrogen receptor (ER) and progesterone receptor (PR) status, was obtained by telephone interview and medical record abstraction. Multivariable risk ratios (RRs) and 95% confidence intervals (CIs) were estimated in conditional logistic regression models, adjusting for demographics, treatment, and personal medical and family history. A subset of women was screened for BRCA1/2 mutations. Results Lobular histology of the first tumor was associated with a 30% increase in CBC risk (95% CI 1.0–1.6). Compared to women with ER+/PR+ first tumors, those with ER-/PR- tumors had increased risk of CBC (RR = 1.4, 95% CI 1.1–1.7). Notably, women with ER-/PR- first tumors were more likely to develop CBC with the ER-/PR- phenotype (RR = 5.4, 95% CI 3.0–9.5), and risk remained elevated in multiple subgroups: BRCA1/2 mutation non-carriers, women younger than 45 years of age, women without a breast cancer family history, and women who were not treated with tamoxifen. Conclusions Having a hormone receptor negative first primary breast cancer is associated with increased risk of CBC. Women with ER-/PR- primary tumors were more likely to develop ER-/PR- CBC, even after excluding BRCA1/2 mutation carriers. Hormone receptor status, which is routinely evaluated in breast tumors, may be used clinically to determine treatment protocols and identify patients who may benefit from increased surveillance for CBC.