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The facility location plays an important role in an industry's supply chain management to facilitate logistics management requirements, making the sourcing and distribution process smooth and fast. The purpose of this study is to determine the ideal place to determine the location of a garment industry. This research uses the Center of Gravity method to calculate the optimal location that will be considered. This method employs an (X-Y) coordinate system to cover the geographical map of the study areas and identifies the coordinates for the new facility's location. It endeavored to identify the optimal location for the garment industry in Bangladesh. It was pinpointed where the industry can obtain raw materials from various regions of the country and a market, labor force, and energy source. Information was gathered regarding the volume of business activity at existing facilities. From the results of this study, it was found that the selected facility's location at the coordinates (23.68497454, 90.5928119), the arable land of the village of Sreepatir Char, Sonargaon, Narayanganj, which is the centralized position according to the supplier's distance, market distance, and availability of labor. Finally, we have shown that the identified location is appropriate for the facility's placement.

Background: Mucinous carcinoma is the third most common histological subtype of breast cancer after ductal and lobular carcinomas, accounting for approximately 3% of invasive breast cancers. Although considered a favourable subtype with de-escalation of treatment recommended in the National Comprehensive Cancer Network guidelines, recurrence can occur and supporting data is limited. We thus examined prognostic factors of pure mucinous breast cancer (PMBC) in an international multicentre cohort study. Methods: Patients diagnosed between January 2000 to December 2015 with hormone receptor-positive HER2-negative stage I to III PMBC, invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) at 6 centers in Singapore, Taiwan, Korea and Japan were evaluated. Cox proportional hazards regression analyses were used to compare relapse-free survival (RFS), distant relapse-free survival (DRFS) and overall survival (OS) by histological subtypes, and to identify prognostic factors for PMBC. Results: Of 23,105 women eligible for analysis, 20,684 had IDC, 1,475 had ILC and 946 had PMBC. The median follow-up was 6.6 years; 5-year RFS, DRFS and OS for PMBC were 94.6%, 96.5% and 98.1% respectively. On multivariable cox regression analyses, PMBC demonstrated superior RFS (hazard ratio [HR] = 0.70, 95% CI: 0.56 - 0.88), DRFS (HR = 0.69, 95% CI: 0.53 - 0.89) and OS (HR = 0.70, 95% CI: 0.52 - 0.93) compared to IDC, while ILC had comparable survival outcomes as IDC. When restricted to only PMBC, significant independent prognostic factors for RFS included ethnicity (vs Chinese, “Others” [non-Chinese/Japanese/Korean, mainly Malay and Indian]: HR = 2.62, 95% CI 1.23 – 5.57), older age (vs < 40 years, >70 years: HR = 3.53, 95% CI 1.67 – 7.46), tumor size (vs T1, T3-4: HR = 2.79, 95% CI 1.45 – 5.37), positive lymph nodes (HR = 2.04, 95% CI: 1.10 – 3.77), use of radiotherapy (HR = 0.54, 95% CI 0.33 – 0.91) and endocrine therapy (HR = 0.31, 95% CI 0.12 – 0.77). On further analysis, the inferior RFS, DRFS and OS in older patients (>70 years) were driven largely by non-breast cancer deaths rather than relapses. Use of endocrine therapy was also associated with superior DRFS (HR = 0.26, 95% CI 0.09 – 0.73) but not OS. In a subgroup analysis, use of chemotherapy was associated with improved DRFS (HR = 0.25, 95% CI 0.08 – 0.82) and OS (HR = 0.07, 95% CI 0.01 – 0.37) with a trend in RFS (HR = 0.41, 95% CI 0.14 – 1.24) for lymph node-positive PMBC; no differences in outcomes were observed for the lymph node-negative subgroup. Conclusions: Larger tumor size, lymph node positivity and ethnicity were significant factors for RFS in PMBC. Use of endocrine therapy was associated with superior RFS and DRFS, while chemotherapy was associated with better DRFS and OS for lymph-node positive PMBC. Citation Format: Ryan Tan, Whee Sze Ong, Kyung-Hun Lee, Seri Park, Jabed Iqbal, Yeon Hee Park, Jeong-Eon Lee, Jong Han Yu, Ching-Hung Lin, Yen-Shen Lu, Makiko Ono, Takayuki Ueno, Yoichi Naito, Tatsuya Onishi, Geok hoon Lim, Su-Ming Tan, Han-Byoel Lee, Jiwon Koh, Han Suk Ryu, Wonshik Han, Veronique Kiak Mien Tan, Fuh-Yong Wong, Seock-Ah Im, Puay Hoon Tan, Yoon-Sim Yap. Prognostic factors in non-metastatic hormone receptor-positive HER2-negative mucinous breast cancer: an international multicentre cohort study [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 P3-05-36.

Signaling between cancer and nonmalignant (stromal) cells in the tumor microenvironment (TME) is a key to tumor progression. Here, we deconvoluted bulk tumor transcriptomes to infer cross-talk between ligands and receptors on cancer and stromal cells in the TME of 20 solid tumor types. This approach recovered known transcriptional hallmarks of cancer and stromal cells and was concordant with single-cell, in situ hybridization and IHC data. Inferred autocrine cancer cell interactions varied between tissues but often converged on Ephrin, BMP, and FGFR-signaling pathways. Analysis of immune checkpoints nominated interactions with high levels of cancer-to-immune cross-talk across distinct tumor types. Strikingly, PD-L1 was found to be highly expressed in stromal rather than cancer cells. Overall, our study presents a new resource for hypothesis generation and exploration of cross-talk in the TME.Significance:This study provides deconvoluted bulk tumor transcriptomes across multiple cancer types to infer cross-talk in the tumor microenvironment.

Supplementary results and methods

Mutations in the PI3K pathway, particularly of PIK3CA, were reported to be intimately associated with triple negative breast cancer (TNBC) progression and development of treatment resistance. We profiled PIK3CA and other genes on 166 early-stage TNBC tumors from Singapore, for comparison to publicly available TNBC cohorts. These tumors were profiled transcriptionally using a Nanostring panel of immune genes and multiplex immunohistochemistry, then manually scored for PD-L1-positivity using two clinically relevant clones, SP142 and 22C3. We discovered a higher rate of PIK3CA mutations in our TNBC cohort as compared to non-Asian cohorts, along with TP53, BRCA1, PTPN11, and MAP3K1 alterations. PIK3CA mutations did not affect overall or recurrence-free survival, and when compared to PIK3CAWT tumors, there were no differences in immune infiltration. Using two clinically approved antibodies, PIK3CAmut tumors were associated with PD-L1 negativity. Analysis of co-mutation frequencies further revealed that PIK3CA mutations tended to be accompanied by MAP kinase pathway mutation. The mechanism and impact of PIK3CA alterations on the TNBC tumor immune microenvironment and PD-L1 positivity warrant further study.

BackgroundBurnout is a serious issue plaguing the medical profession with potential negative consequences on patient care. Burnout symptoms are observed as early as medical school. Based on a Job Demands-Resources model, this study aims to assess associations between specific job resources measured at the beginning of the first year of medical school with burnout symptoms occurring later in the first year.MethodsThe specific job resources of grit, tolerance for ambiguity, social support and gender were measured in Duke-NUS Medical School students at the start of Year 1. Students were then surveyed for burnout symptoms at approximately quarterly intervals throughout the year. Using high ratings of cynicism and exhaustion as the definition of burnout, we investigated the associations of the occurrence of burnout with student job resources using multivariable logistic regression analysis.ResultsOut of 59 students, 19 (32.2%) indicated evidence of burnout at some point across the first year of medical school. Stepwise multivariable logistic regression analysis identified grit as having a significant protective effect against experiencing burnout (Odds Ratio, 0.84; 95%CI 0.74 to 0.96). Using grit as a single predictor of burnout, area under the ROC curve was 0.76 (95%CI: 0.62 to 0.89).ConclusionsGrit was identified as a protective factor against later burnout, suggesting that less gritty students are more susceptible to burnout. The results indicate that grit is a robust character trait which can prognosticate burnout in medical students. These students would potentially benefit from enhanced efforts to develop grit as a personal job resource.

BackgroundProgrammed death-ligand 1 (PD-L1) monoclonal antibody therapy has recently gained approval for treating metastatic triple-negative breast cancer (TNBC) -, in particular in the PD-L1+patient subgroup of the recent IMpassion130 trial. The SP142 PD-L1 antibody clone was used as a predictive assay in this trial, but this clone was found to be an outlier in previous harmonisation studies in lung cancer.AimsTo address the comparability of PD-L1 clones in TNBC, we evaluated the concordance between conventional immunohistochemistry (IHC) and multiplex immunohistochemistry/immunofluorescence (mIHC/IF) that allowed simultaneous quantification of three different PD-L1 antibodies (22C3, SP142 and SP263).MethodsOur cohort comprised 25 TNBC cases, 12 non-small-cell lung carcinomas and 8 other cancers. EpCAM labelling was used to distinguish tumour cells from immune cells.ResultsModerate-to-strong correlations in PD-L1 positivity were found between results obtained through mIHC/IF and IHC. Individual concordance rates in the study ranged from 67% to 100%, with Spearman’s rank correlation coefficient values up to 0.88.ConclusionsmIHC/IF represents a promising tool in the era of cancer immunotherapy, as it can simultaneously detect and quantify PD-L1 labelling with multiple antibody clones, and allow accurate evaluation of tumour and immune cells. Clinicians and pathologists require this information to predict patient response to anti-PD-1/PD-L1 therapy. The adoption of this assay may represent a significant advance in the management of therapeutically challenging cancers. Further analysis and assay harmonisation are essential for translation to a routine diagnostic setting.

Xenogeneic grafts are promising candidates for transplantation therapy due to their easily accessible sources. Nevertheless, the immune and inflammatory responses induced by xenografts need to be addressed for clinical use. A novel and facile method was introduced for the attenuation of immune and inflammatory responses by extending the immune evasion potential of albumin to the tissue engineering field and coating albumin, which could passivate biomaterial surfaces, onto xenografts. Albumin was first modified by dopamine to enhance its adhesion on graft surfaces. Porcine chondrocytes derived living hyaline cartilage graft (LhCG) and decellularized LhCG (dLhCG) were applied as xenograft models implanted in the omentum of rats. Both LhCG which contained porcine chondrocytes as well as secreted ECM and dLhCG which was mainly composed of the porcine source ECM showed alleviated immune and inflammatory responses after being coated with albumin at cell, protein and gene levels, respectively. Significantly less inflammatory cells including neutrophils, macrophages and lymphocytes were recruited according to pathological analysis and immunohistochemistry staining with lower gene expression encoding inflammation-related cytokines including MCP-1, IL-6 and IL-1β after employing LhCG and dLhCG with albumin passivation coating.

Coronavirus disease-19 (COVID-19) is caused by the newly discovered coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the lung remains the primary target site of COVID-19 injury, damage to myocardium, and other organs also contribute to the morbidity and mortality of this disease. There is also increasing demand to visualize viral components within tissue specimens. Here we discuss the cardiac autopsy findings of 12 intensive care unit (ICU) naïve and PCR-positive COVID-19 cases using a combination of histological, Immunohistochemical/immunofluorescent and molecular techniques. We performed SARS-CoV-2 qRT-PCR on fresh tissue from all cases; RNA-ISH and IHC for SARS-CoV-2 were performed on selected cases using FFPE tissue from heart. Eight of these patients also had positive post-mortem serology for SARS-CoV-2. Histopathologic changes in the coronary vessels and inflammation of the myocardium as well as in the endocardium were documented which support the reports of a cardiac component to the viral infection. As in the pulmonary reports, widespread platelet and fibrin thrombi were also identified in the cardiac tissue. In keeping with vaccine-induced activation of virus-specific CD4+ and CD8+ T cells, and release of cytokines such as interferon-gamma (IFNγ), we observed similar immune cellular distribution and cytokines in these patients. Immunohistochemical and immunofluorescent localisation for the viral Spike (S-protein) protein and the nucleocapsid protein (NP) were performed; presence of these aggregates may possibly contribute to cardiac ischemia and even remodelling.

Simple Summary Triple-negative breast cancer (TNBC) has been associated with worse prognoses due to the limited treatment options. Thus, there is a need to characterise new biomarkers or treatment targets to improve patient outcomes. Cancer testis antigens (CTAs) are a group of antigens that are preferentially expressed in tumours and exhibit strong immunogenicity, as such, CTAs hold great promise as potential treatment targets and biomarkers in cancer. Previous reports have implicated roles for CTAs in different subtypes of breast cancer, including TNBC. Multiple clinical trials are in progress investigating CTAs as treatment targets in various cancers. This review aims to discuss the roles of CTAs in TNBC and discuss the potential applications and benefits of incorporating CTAs in clinical practice. Abstract Breast cancer cells commonly express tumour-associated antigens that can induce immune responses to eradicate the tumour. Triple-negative breast cancer (TNBC) is a form of breast cancer lacking the expression of hormone receptors and cerbB2 (HER2) and tends to be more aggressive and associated with poorer prognoses due to the limited treatment options. Characterisation of biomarkers or treatment targets is thus of great significance in revealing additional therapeutic options. Cancer-testis antigens (CTAs) are tumour-associated antigens that have garnered strong attention as potential clinical biomarkers in targeted immunotherapy due to their cancer-restricted expressions and robust immunogenicity. Previous clinical studies reported that CTAs correlated with negative hormonal status, advanced tumour behaviour and a poor prognosis in a variety of cancers. Various studies also demonstrated the oncogenic potential of CTAs in cell proliferation by inhibiting cell death and inducing metastasis. Multiple clinical trials are in progress to evaluate the role of CTAs as treatment targets in various cancers. CTAs hold great promise as potential treatment targets and biomarkers in cancer, and further research could be conducted on elucidating the mechanism of actions of CTAs in breast cancer or combination therapy with other immune modulators. In the current review, we summarise the current understandings of CTAs in TNBC, addressing the role and utility of CTAs in TNBC, as well as discussing the potential applications and advantage of incorporating CTAs in clinical practise.

Aims: Radial approach is gaining the momentum as a default technique for coronary procedures. Limited trails are available for post coronary artery bypass graft (CABG) patients to compare the merits of femoral & radial access. Methods: It is a single-center study conducted in between January, 2013 to December, 2015. During this study period, post CABG patients were blindly assigned to its five high volume operators. Coronary angiography & intervention procedures were performed by left radial or femoral approach as per assigned operator's choice. Contrast volume was the primary endpoint whereas the procedure & fluoroscopy time, procedural success, access site major bleeding, pre discharge major adverse cardiac event (MACE) were the secondary endpoint both for coronary angiogram (CAG) & percutaneous coronary intervention (PCI). Results: Total 380 post CABG patients were included in this study period. Radial access (n=155) was lower than femoral access (n=225). Compared with femoral access, diagnostic CAG required relatively lower contrast volume though statistically not significant via radial access (70±34 vs. 72±40 ml, p=0.267). Procedure time (25.2±10.7 vs. 26.9±6.8 min, p=0.735), fluoroscopy time (10.7±5.5 vs. 9.5±4.7 min, p=0.424) were almost similar in both access for CAG. Other secondary clinical endpoints were similar among both groups. Interestingly, adhoc PCI was more frequent in radial group (n=54 out of 155, 34.8%) than in femoral group (n=44 out of 225, 19.6%) with p=0.01. Contrast volume in between two groups was pretty similar with p=0.226. The incidence of other secondary endpoints was also not statistically significant. Conclusion: Coronary angiography for post CABG patients through left radial approach seems to be effective, non-inferior in terms of contrast volume, procedure & fluoroscopy time & other clinical end points comparing to femoral access. Anwer Khan Modern Medical College Journal Vol. 10, No. 1: Jan 2019, P 11-16

We used multiplex immunofluorescence (mIF) to determine whether mitotic rate represents an independent prognostic marker in triple-negative breast cancer (TNBC). Secondary aims were to confirm the prognostic significance of immune cells in TNBC, and to investigate the relationship between immune cells and proliferating tumour cells. A retrospective Asian cohort of 298 patients with TNBC diagnosed from 2003 to 2015 at the Singapore General Hospital was used in the present study. Formalin-fixed, paraffin-embedded breast cancer samples were analysed on tissue microarrays using mIF, which combined phospho-histone H3 (pHH3) expression with cytokeratin (CK) and leukocyte common antigen (CD45) expression to identify tumour and immune cells, respectively. Multivariate analysis showed that a high pHH3 index was associated with significantly improved overall survival (OS; p = 0.004), but this was not significantly associated with disease-free survival (DFS; p = 0.22). Similarly, multivariate analysis also revealed that a pHH3 positive count of > 1 cell per high-power field in the malignant epithelial compartment was an independent favourable prognostic marker for OS (p = 0.033) but not for DFS (p = 0.250). Furthermore, a high CD45 index was an independent favourable prognostic marker for DFS (p = 0.018), and there was a significant positive correlation between CD45 and pHH3 index (Spearman rank correlation coefficient, 0.250; p

The proliferation marker Ki-67 is frequently used to assess aggressiveness in the pathological evaluation of cancer, but its role remains uncertain in triple-negative breast cancer (TNBC). We aimed to quantify and localize Ki-67 expression in both epithelial and immune compartments in TNBC and investigate its association with clinicopathological parameters and survival outcomes. A total of 406 TNBC cases diagnosed between 2003 and 2015 at Singapore General Hospital were recruited. Using state-of-the-art, 7-colour multiplex immunofluorescence (mIF) tissue microarrays (TMAs) were stained to assess the abundance, density and spatial distribution of Ki-67-positive tumour cells and immune cells co-decorated with cytokeratin (CK) and leukocyte common antigen (CD45) respectively. Furthermore, MKI67 mRNA profiles were analysed using NanoString technology. In multivariate analysis adjusted for tumour size, histologic grade, age at diagnosis, and lymph node stage, a high Ki-67 labelling index (LI) > 0.3% was associated with improved disease-free survival (DFS; HR = 0.727; p = 0.027). High Ki-67-positive immune cell count per TMA was a favourable prognostic marker for both DFS (HR = 0.379; p = 0.00153) and overall survival (OS; HR = 0.473; p = 0.0482). The combination of high Ki-67 LI and high MKI67 expression was associated with improved DFS (HR = 0.239; p = 0.00639) and OS (HR = 0.213; p = 0.034). This study is among the first to highlight that Ki-67 is associated with favourable prognosis in an adjuvant setting in TNBC, and the mIF-based evaluation of Ki-67 expression on both tumour and immune cells represents a novel prognostic approach.

AimPhyllodes tumours (PTs) categorised as benign, borderline and malignant, account for 1% of all breast tumours. Histological assessment does not always predict tumour behaviour, hindering determination of the clinical course and management.Epithelial–mesenchymal transition (EMT) is an important process during embryogenesis. Dysregulation of EMT causes loss of cell polarity, decreased intercellular adhesion, increased motility and invasiveness, promoting tumour progression. Similarly, cancer stem cells (CSCs) promote tumour growth, resistance and recurrence. The aim of this study is to evaluate expression of CSC markers; enhancer of zeste homolog 2 (EZH2), CD24 and CD44 and EMT associated proteins; ezrin (EZR) and high-mobility group AT-hook 2 (HMGA2) in PTs.MethodUing tissue microarray sections, immunohistochemistry was performed on 360 PTs. Epithelial and stromal expressions of EZH2, EZR, HMGA2, CD24 and CD44 were evaluated to assess their impact on disease progression and behaviour in correlation with clinicopathological parameters.ResultsStromal expression of EZH2, EZR and HMGA2 was observed in 73 (20.3%), 53 (14.7%) and 28 (7.8%) of tumours, epithelial expression in 121 (35.9%), 3 (0.8%) and 351 (97.5%) tumours, respectively. CD24 and CD44 staining was absent in both components.ConclusionExpression of biomarkers correlated significantly with aggressive tumour traits such as stromal hypercellularity, atypia, mitoses and permeative tumour borders.Stromal expression of EZH2 and EZR shortened disease-free survival and overall survival; HMGA2 expression did not alter patient survival. EZH2 and EZR may thus be useful in predicting PT behaviour.

Signaling between cancer and nonmalignant (stromal) cells in the tumor microenvironment (TME) is a key to tumor progression. Here, we deconvoluted bulk tumor transcriptomes to infer cross-talk between ligands and receptors on cancer and stromal cells in the TME of 20 solid tumor types. This approach recovered known transcriptional hallmarks of cancer and stromal cells and was concordant with single-cell, in situ hybridization and IHC data. Inferred autocrine cancer cell interactions varied between tissues but often converged on Ephrin, BMP, and FGFR-signaling pathways. Analysis of immune checkpoints nominated interactions with high levels of cancer-to-immune cross-talk across distinct tumor types. Strikingly, PD-L1 was found to be highly expressed in stromal rather than cancer cells. Overall, our study presents a new resource for hypothesis generation and exploration of cross-talk in the TME. Significance: This study provides deconvoluted bulk tumor transcriptomes across multiple cancer types to infer cross-talk in the tumor microenvironment.

Background Stromal and collagen biology has a significant impact on tumorigenesis and metastasis. Collagen is a major structural extracellular matrix component in breast cancer, but its role in cancer progression is the subject of historical debate. Collagen may represent a protective layer that prevents cancer cell migration, while increased stromal collagen has been demonstrated to facilitate breast cancer metastasis. Methods Stromal remodeling is characterized by collagen fiber restructuring and realignment in stromal and tumoral areas. The patients in our study were diagnosed with triple-negative breast cancer in Singapore General Hospital from 2003 to 2015. We designed novel image processing and quantification pipelines to profile collagen structures using numerical imaging parameters. Our solution differentiated the collagen into two distinct modes: aggregated thick collagen (ATC) and dispersed thin collagen (DTC). Results Extracted parameters were significantly associated with bigger tumor size and DCIS association. Of numerical parameters, ATC collagen fiber density (CFD) and DTC collagen fiber length (CFL) were of significant prognostic value for disease-free survival and overall survival for the TNBC patient cohort. Using these two parameters, we built a predictive model to stratify the patients into four groups. Conclusions Our study provides a novel insight for the quantitation of collagen in the tumor microenvironment and will help predict clinical outcomes for TNBC patients. The identified collagen parameters, ATC CFD and DTC CFL, represent a new direction for clinical prognosis and precision medicine. We also compared our result with benign samples and DICS samples to get novel insight about the TNBC heterogeneity. The improved understanding of collagen compartment of TNBC may provide insights into novel targets for better patient stratification and treatment.

Xenogeneic extracellular matrix (ECM) based tissue engineering graft is one of the most promising products for transplantation therapies, which could alleviate the pain of patients and reduce surgery cost. However, in order to put ECM based xenografts into clinical use, the induced inflammatory and immune responses have yet to be resolved. Cell membrane is embedded with membrane proteins for regulation of cell interactions including self-recognition and potent in reducing foreign body rejections. In this study, a novel and facile method for evasion from immune system was developed by coating autologous red blood cell membrane as a disguise on xenogeneic ECM based tissue engineering graft surface. Porcine source Living Hyaline Cartilage Graft (LhCG) and decellularized LhCG (dLhCG) established by our group for cartilage tissue engineering were chosen as model grafts. The cell membrane coating was quite stable on xenografts with no obvious decrease in amount for 4 weeks. The autologous cell membrane coated xenograft has been proved to be recognized as "self" by immune system on cell, protein and gene levels according to the 14-day lasting in vivo study on rats with less inflammatory cells infiltrated and low inflammation-related cytokines gene expression, showing alleviated acute immune and inflammatory responses.

Patients with chronic myeloid leukemia (CML) who are treated with tyrosine kinase inhibitors (TKIs) experience significant heterogeneity regarding depth and speed of responses. Factors intrinsic and extrinsic to CML cells contribute to response heterogeneity and TKI-resistance. Among extrinsic factors, cytokine-mediated TKI-resistance has been demonstrated in CML progenitors, but the underlying mechanisms remain obscure. Using RNA-sequencing, we identified differentially expressed splicing factors in primary CD34(+) chronic phase (CP) CML progenitors and controls. We found SRSF1 expression to be increased as a result of both BCR-ABL1- and cytokine-mediated signaling. SRSF1 overexpression conferred cytokine-independence to untransformed hematopoietic cells and impaired imatinib sensitivity in CML cells, while SRSF1 depletion in CD34(+) CP CML cells prevented the ability of extrinsic cytokines to decrease imatinib sensitivity. Mechanistically, PRKCH and PLCH1, were upregulated by elevated SRSF1 levels, and contributed to impaired imatinib sensitivity. Importantly, very high SRSF1 levels in the bone marrow of CML patients at presentation correlated with poorer clinical TKI responses. In summary, we find SRSF1 levels to be maintained in CD34(+) CP CML progenitors by cytokines despite effective BCR-ABL1 inhibition, and that elevated levels promote impaired imatinib responses. Together, our data supports an SRSF1/PRKCH/PLCH1 axis in contributing to cytokine-induced impaired imatinib sensitivity in CML.

Additional file 1: Supplementary Figure 1. Collagen length and density in comparison with tumour size and grades. Supplementary Figure 2. Kaplan Meier survival curves for Two individual parameters of prognostic value. Supplementary Figure 3. Kaplan Meier survival curves for tumour size and grade. Supplementary Figure 4. Some other key aspects on the collagen structural differences in the four given groups. Supplementary Figure 5. Kaplan Meier Survival curves for the Lymph node status. Supplementary Figure 6. Lymph node status(+/-) distributions in the four groups of patients. Supplementary Figure 7. Comparison of the ATC Area Ratio between the four groups of patients, Benign samples and the DCIS patient cohort. Supplementary Figure 8. Comparison of the ATC CFD between the four groups of patients, Benign samples and the DCIS patient cohort. Supplementary Figure 9. Comparison of the DTC CFL between the four groups of patients, Benign samples and the DCIS patient cohort. Supplementary Table 1. Comprehensive Parameters List measured in SHG/TPE images for TNBC patient cohort. Supplementary Table 2. Key Parameters List and their definition for TNBC patient cohort. Supplementary Table 3. Pairwise P-values for the set of features measured in 4 groups.

Aim: The new radioimmunotherapeutic regime GAP15R aims to stimulate glucocorticoid-induced TNF-related protein (G) to overcome Treg suppression; add IFN-α (A) to promote inflammatory milieu; block PD1 (P) to disinhibit T effector cytotoxicity; add IL-15 (15) to enhance danger signals & T-cell expansion; and apply radiation (R) at critical time point to sustain localized inflammation. Patients & methods/materials & methods: This was tested in a murine 4T1 metastatic breast carcinoma model given GAP15R with regular monitoring of tumor volume and complications. Results: We had demonstrated long-term complete remission up to 50% of treated mice, which is not associated with major treatment-related complication, in cases with specific tumor burden. Conclusion: GAP15R is efficacious with potential to be applicable to other tumors.

// Timothy Kwang Yong Tay 1 , Aye Aye Thike 1 , Nirmala Pathmanathan 1, 2 , Ana Richelia Jara-Lazaro 1, 3 , Jabed Iqbal 1 , Adeline Shi Hui Sng 1 , Heng Seow Ye 1 , Jeffrey Chun Tatt Lim 1 , Valerie Cui Yun Koh 1 , Jane Sie Yong Tan 1 , Joe Poh Sheng Yeong 1 , Zi Long Chow 1 , Hui Hua Li 4 , Chee Leong Cheng 1 and Puay Hoon Tan 5 1 Department of Anatomical Pathology, Singapore General Hospital, Singapore 2 Current affiliation: Westmead Breast Cancer Institute, Westmead Hospital, Westmead, NSW, Australia 3 Current affiliation: Q 2 Solutions – Central Laboratories, Singapore Science Park One, Singapore 4 Division of Medicine, Singapore General Hospital, Singapore 5 Division of Pathology, Singapore General Hospital, Singapore Correspondence to: Puay Hoon Tan, email: tan.puay.hoon@singhealth.com.sg Keywords: Ki67; breast cancer; computer assisted image analysis; prognosis Received: October 10, 2017 Accepted: January 25, 2018 Published: February 05, 2018 ABSTRACT Background: Ki67 positivity in invasive breast cancers has an inverse correlation with survival outcomes and serves as an immunohistochemical surrogate for molecular subtyping of breast cancer, particularly ER positive breast cancer. The optimal threshold of Ki67 in both settings, however, remains elusive. We use computer assisted image analysis (CAIA) to determine the optimal threshold for Ki67 in predicting survival outcomes and differentiating luminal B from luminal A breast cancers. Methods: Quantitative scoring of Ki67 on tissue microarray (TMA) sections of 440 invasive breast cancers was performed using Aperio ePathology ImmunoHistochemistry Nuclear Image Analysis algorithm, with TMA slides digitally scanned via Aperio ScanScope XT System. Results: On multivariate analysis, tumours with Ki67 ≥14% had an increased likelihood of recurrence (HR 1.941, p=0.021) and shorter overall survival (HR 2.201, p=0.016). Similar findings were observed in the subset of 343 ER positive breast cancers (HR 2.409, p=0.012 and HR 2.787, p=0.012 respectively). The value of Ki67 associated with ER+HER2-PR

BackgroundTriple-negative breast cancers (TNBCs) are defined by their lack of oestrogen receptor, progesterone receptor and epidermal growth factor receptor 2. Although heterogeneous, the majority are aggressive and treatment options are limited. Caveolin acts as tumour suppressor or promoter depending on the cancer type.AimIn this study, we aimed to determine if the expression levels of the candidate biomarker caveolin-1 on stromal or tumour cells were associated with clinicopathological parameters and disease outcomes in TNBCs from an ethnically diverse cohort of Asian women.MethodsTumour specimens from 699 women with TNBC were subjected to immunohistochemical analysis of the frequency and intensity of caveolin-1 expression in tumour and stromal cells. A subset of 141 tumour samples also underwent Nanostring measurement ofCAV1mRNA. Results were correlated with clinicopathological parameters and disease outcomes.ResultsExpression of caveolin-1 in stromal cells was observed in 14.4% of TNBC cases. TNBCs of the basal-like phenotype (85% of samples) were significantly more likely to exhibit stromal cell caveolin-1 expression (p=0.028), as were those with a trabecular growth pattern (p=0.007). Lack of stromal caveolin-1 expression in both TNBCs and those with the basal-like phenotype was significantly associated with worse overall survival (p=0.009 and p=0.026, respectively): accordingly, increasing mRNA levels ofCAV1in TNBC samples predicted better overall survival. Caveolin-1 expression on TNBC tumour cells was not associated with clinical outcome.ConclusionStromal, but not tumoural, caveolin-1 expression is significantly associated with survival in Asian women with TNBC.

Purpose The role of Forkhead Box Protein 3 (Foxp3) expressing regulatory T cells (Tregs) in breast cancer remains unclear. We examined the abundance and localisation of total T cells, B cells and Tregs within samples from triple-negative breast cancers (TNBCs) and asked whether these parameters were associated with clinicopathological features of the cancer or clinical outcomes.

Massive Pulmonary Embolism (PE) is associated with significant mortality, especially if compounded by haemodynamic instability, right ventricular dysfunction and right atrial thrombus. Thrombolysis can be lifesaving in patients with major embolism and cardiogenic shock, and accelerates the resolution of thrombus. Only three fibrinolytic agents - namely streptokinase, urokinase, and recombinant tissue plasminogen activator (Alteplase) have been approved in the treatment of PE, with studies demonstrating similar safety profiles. We report the case of a 33 year old Bangladeshi female with a history of recent ankle fracture and immobilization, who presented with massive PE, leading to cardiac arrest. Upon rapid resuscitation, urgent echocardiogram revealed right ventricular dysfunction with floating right atrial thrombus, and she was successfully treated with 1.5 million IU of Streptokinase over 2 hours as per accelerated regimen recommended by the European Society of Cardiology (ESC) guidelines, resulting in successful resolution of the right heart thrombus, and significant clinical improvement. Subsequent CT Pulmonary Angiogram confirmed the diagnosis of PE, and she was anticoagulated to a PT/INR of 2.0 to 3.0.Anwer Khan Modern Medical College Journal Vol. 7, No. 1: Jan 2016, P 60-63

Signaling between cancer and nonmalignant (stromal) cells in the tumor microenvironment (TME) is key to tumorigenesis yet challenging to decipher from tumor transcriptomes. Here, we report an unbiased, data-driven approach to deconvolute bulk tumor transcriptomes and predict crosstalk between ligands and receptors on cancer and stromal cells in the TME of 20 solid tumor types. Our approach recovers known transcriptional hallmarks of cancer and stromal cells and is concordant with single-cell and immunohistochemistry data, underlining its robustness. Pan-cancer analysis reveals previously unrecognized features of cancer-stromal crosstalk. We find that autocrine cancer cell cross-talk varied between tissues but often converged on known cancer signaling pathways. In contrast, many stromal cross-talk interactions were highly conserved across tumor types. Interestingly, the immune checkpoint ligand PD-L1 was overexpressed in stromal rather than cancer cells across all tumor types. Moreover, we predicted and experimentally validated aberrant ligand and receptor expression in cancer cells of basal and luminal breast cancer, respectively. Collectively, our findings validate a data-driven method for tumor transcriptome deconvolution and establishes a new resource for hypothesis generation and downstream functional interrogation of the TME in tumorigenesis and disease progression.

Triple-negative breast cancers (TNBC) are aggressive tumours that exhibit abundant lymphoid infiltrates which modulate tumour behaviour. Recent findings suggest that TNBC with higher densities of plasma cells are associated with a favourable prognosis, and tertiary lymphoid structures (TLS) have prognostic significance. Here, we studied the phenotype and function of plasma cells in TNBCs by assessing their association with IgG Kappa light chain expression, B cells, and TLS. A retrospective analysis of 269 TNBC cases was performed. Tumour-infiltrating CD38+ plasma cells, CD20+ B cells, and TLS were evaluated on conventional haematoxylin–eosin-stained and immunohistochemical-stained sections of TNBC. We then selected TNBC cases demonstrating the highest and lowest densities of plasma cells, and examined their association with TLS, B cells, as well as immunoglobulin expression using Opal-Vectra multiplex immunofluorescence (IF). TNBC with high density of plasma cells showed significantly higher numbers of IgG Kappa+ CD38+ cells (p = 0.0089, p

Great progress has been achieved on the study of hydrogels, which were presented for the first time in 1960 by Otto Wichterle and Drahoslav Lím. The two crucial properties of hydrogels, namely high water content and biocompatibility, have made hydrogels ideal compositions in the development of bioadhesives in recent years. Chondroitin sulfate (CS), a sulfated glycosaminoglycan (GAG), is distributed throughout animal bodies, including cartilage and the extracellular matrix (ECM), and it has been widely utilized in the dietary supplement and pharmaceutical industries. Besides, CS has been reported to have excellent pain-relief and anti-inflammation properties. Some studies have even reported CS's wound healing promoting ability. In this study, taking advantage of CS's excellent physical and chemical properties, DOPA groups were functionalized onto CS backbones. After that, the potential of the newly established CS-DOPA (CSD) hydrogel to work as a bioadhesive in multiple internal medical conditions was evaluated through in vitro and in vivo means. The outcomes of the in vivo assessments demonstrated CSD's promising potential to be further commercialized into an adhesive hydrogel product, and to be utilized in diverse clinical medications in the future. Ministry of Education (MOE) The work was financially supported by Grant AcRF Tier 2 Academic Research Fund (MOE2016-T2-1-138 (S) to Wang Dong-An), Ministry of Education (MOE), Singapore.

Table S1. Comparison of clinicopathological features of TNBC patients bearing high or low PD-L1 tumor cell expression and PD-1+ immune infiltrates. Table S2. Details of antibodies used for IHC labeling of TNBC sections. Table S3. IHC expression of immune markers in TNBCs. Table S4. Correlation between PD-L1 tumor cell expression, PD-1+ immune infiltrates and RNA expression of the relevant genes in TNBCs. Table S5. Correlation between PD-1+ immune infiltrates and the RNA expression of the relevant genes in TNBCs. Table S6. Analysis of PDCD1 and CD274 expression levels and survival outcomes in TNBC using data from the European Genome-Phenome Archive. n = 320. Table S7. Correlation between CD274, PDCD1 and HLA mRNA expression in triple negative breast cancer. Figure S1. TNBC with high PDCD1 and high CD274 expression exhibit distinct gene expression signatures. Heat map of the 77 significantly differentially-expressed genes (P

Ductal carcinoma in situ (DCIS) refers to neoplastic epithelial cells proliferating within the mammary ducts of the breast, which have not breached the basement membrane nor invaded surrounding tissues. Traditional thinking holds that DCIS represents an early step in a linear progression towards invasive ductal carcinoma (IDC). However, as only approximately half of DCIS cases progress to IDC, important questions around the key determinants of malignant progression need to be answered. Recent studies have revealed that molecular differences between DCIS and IDC cells are not found at the genomic level; instead, altered patterns of gene expression and post-translational regulation lead to distinct transcriptomic and proteomic profiles. Therefore, understanding malignant progression will require a different approach that takes into account the diverse tumour cell extrinsic factors driving changes in tumour cell gene expression necessary for the invasive phenotype. Here, we review the roles of the tumour stroma (including mesenchymal cells, immune cells and the extracellular matrix) and myoepithelial cells in malignant progression and make a case for a more integrated approach to the study and assessment of DCIS and its progression, or lack thereof, to invasive disease.

Takayasu arteritis, formerly known as “pulseless disease”, is a chronic idiopathic vasculitis which affects the large vessels in the body. First described in the 1800’s, this rare condition is more commonly found in Asian women in their 40’s. Herein, we report the case of a young woman whose exertional angina and claudication were the initial presentation of active Takayasu arteritis. The importance of modern technology of imaging such as CT, MRI and angiography, can often have paramount importance for confirming a diagnosis and the extent of the pathology. Newer modalities of investigation helps in evaluation of vascular involvement and its haemodynamic effects on cardiovascular system. Previously majority of patient had to be diagnosed clinically. Now a days by CT peripheral Angiogram this disease can be diagnosed. Invasive procedure of peripheral Angiogram is troublesome but single IV dye injection can revealed the actual scenario. So it has got important scientific value.Bangladesh Heart Journal 2015; 30(2) : 92-95