Differential expression of Toll-like receptor (TLR) and B cell receptor (BCR) signaling molecules in primary diffuse large B-cell lymphoma of the central nervous system.

Primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) is a distinct and aggressive lymphoma that is confined to CNS. Since, central nervous system is barrier-protected and immunologically silent; role of TLR/BCR signaling in pathogenesis and biology of CNS DLBCL is intriguing. Genomic mutations in key regulators of TLR/BCR signaling pathway (MYD88/CD79B/CARD11) have recently been reported in this disease. These observations raised possible implications in novel targeted therapies; however, expression pattern of molecules related to TLR/BCR pathways in this lymphoma remains unknown. We have analyzed the expression of 19 genes encoding TLR/BCR pathways and targets in CNS DLBCLs (n = 20) by Nanostring nCounter™ analysis and compared it with expression patterns in purified reactive B-lymphocytes and systemic diffuse large B cell lymphoma (DLBCL) (n = 20). Relative expression of TLR4, TLR5, TLR9, CD79B and BLNK was higher in CNS DLBCLs than in control B-lymphocytes; where as TLR7, MALT1, BCL10, CD79A and LYN was lower in CNS DLBCLs (P < 0.0001). When compared with systemic DLBCL samples, higher expression of TLR9, CD79B, CARD11, LYN and BLNK was noted in CNS DLBCL (>1.5 fold change; P < 0.01). The B cell receptor molecules like BLNK and CD79B were also associated with higher expression of MYD88 dependent TLRs (TLR4/5/9). In conclusion, we have shown over expression of TLR/BCR related genes or their targets, where genomic mutations have commonly been identified in CNS DLBCL. We have also demonstrated that TLR over expression closely relate with up regulation of genes associated with BCR pathway like CD79B/BLNK and CARD11, which play an important role in NF-kB pathway activation. Our results provide an important insight into the possibility of TLR and/or B-cell receptor signaling molecules as possible therapeutic targets in CNS DLBCL.

New insights into the potential of exosomal circular RNAs in mediating cancer chemotherapy resistance and their clinical applications.

Chemotherapy resistance typically leads to tumour recurrence and is a major obstacle to cancer treatment. Increasing numbers of circular RNAs (circRNAs) have been confirmed to be abnormally expressed in various tumours, where they participate in the malignant progression of tumours, and play important roles in regulating the sensitivity of tumours to chemotherapy drugs. As exosomes mediate intercellular communication, they are rich in circRNAs and exhibit a specific RNA cargo sorting mechanism. By carrying and delivering circRNAs, exosomes can promote the efflux of chemotherapeutic drugs and reduce intracellular drug concentrations in recipient cells, thus affecting the cell cycle, apoptosis, autophagy, angiogenesis, invasion and migration. The mechanisms that affect the phenotype of tumour stem cells, epithelial-mesenchymal transformation and DNA damage repair also mediate chemotherapy resistance in many tumours. Exosomal circRNAs are diagnostic biomarkers and potential therapeutic targets for reversing chemotherapy resistance in tumours. Currently, the rise of new fields, such as machine learning and artificial intelligence, and new technologies such as biosensors, multimolecular diagnostic systems and platforms based on circRNAs, as well as the application of exosome-based vaccines, has provided novel ideas for precision cancer treatment. In this review, the recent progress in understanding how exosomal circRNAs mediate tumour chemotherapy resistance is reviewed, and the potential of exosomal circRNAs in tumour diagnosis, treatment and immune regulation is discussed, providing new ideas for inhibiting tumour chemotherapy resistance.

Societal discrimination and mental health among transgender athletes: a systematic review and Meta-analysis.

BACKGROUND: Discrimination and inequality have been identified as significant problems faced by transgender individuals in sports participation. However, uncertainties remain regarding the effectiveness of interventions aimed at promoting equality. OBJECTIVES: This systematic review and meta-analysis aimed to examine the experiences of transgender athletes in sports, focusing on mental health issues and factors contributing to inequality among transgender and other sexual minorities. METHODS: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and searched 10 electronic databases, including PubMed, Google Scholar, and Web of Science, to identify eligible studies published between 2005 and 2022. The search yielded 1430 articles, of which only 12 studies met the inclusion criteria for this review. RESULTS: The meta-analysis of the 12 studies included in this review revealed that transgender athletes faced social discrimination and inequality in sports participation, resulting in mental health problems and higher rates of suicide. From a cohort of 21,565 participants in the studies, 7152 (33%) were subjected to discrimination in sports participation and healthcare, with a rate of 0.61 (95% confidence interval [CI]: 0.35, 0.81). However, transgender athletes who felt welcomed and embraced by their respective teams accounted for 0.39 (95% CI: 0.19, 0.65). These results indicated significant differences between how transgender athletes are treated in healthcare settings and when participating in sports. CONCLUSION: The study findings underscore the need for policies, cultural research, and interventions to address discrimination and inequality faced by transgender athletes in sports participation. Promoting equality and safeguarding the rights of transgender athletes can mitigate the risk of mental health problems and increase physical activity among sexual minorities.

Public acceptability of COVID-19 control measures in Singapore, Hong Kong, and Malaysia: A cross-sectional survey.

BACKGROUND: Several countries have implemented control measures to limit SARS-CoV-2 spread, including digital contact tracing, digital monitoring of quarantined individuals, and testing of travelers. These raise ethical issues around privacy, personal freedoms, and equity. However, little is known regarding public acceptability of these measures. METHODS: In December 2020, we conducted a survey among 3635 respondents in Singapore, Hong Kong, and Malaysia to understand public perceptions on the acceptability of COVID-19 control measures. FINDINGS: Hong Kong respondents were much less supportive of digital contact tracing and monitoring devices than those in Malaysia and Singapore. Around three-quarters of Hong Kong respondents perceived digital contact tracing as an unreasonable restriction of individual freedom; <20% trusted that there were adequate local provisions preventing these data being used for other purposes. This was the opposite in Singapore, where nearly 3/4 of respondents agreed that there were adequate data protection rules locally. In contrast, only a minority of Hong Kong respondents viewed mandatory testing and vaccination for travelers as unreasonable infringements of privacy or freedom. Less than 2/3 of respondents in all territories were willing to be vaccinated against COVID-19, with a quarter of respondents undecided. However, support for differential travel restrictions for vaccinated and unvaccinated individuals was high in all settings. INTERPRETATION: Our findings highlight the importance of sociopolitical context in public perception of public health measures and emphasize the need to continually monitor public attitudes toward such measures to inform implementation and communication strategies.

Comparison of protein-based cell-of-origin classification to the Lymph2Cx RNA assay in a cohort of diffuse large B-cell lymphomas in Malaysia.

AIMS: The cell of origin (COO) based molecular characterisation into germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) subtypes are central to the pathogenesis and clinical course in diffuse large B-cell lymphoma (DLBCL). Globally, clinical laboratories employ pragmatic but less than ideal immunohistochemical (IHC) assay for COO classification. Novel RNA-based platforms using routine pathology samples are emerging as new gold standard and offer unique opportunities for assay standardisation for laboratories across the world. We evaluated our IHC protocols against RNA-based technologies to determine concordance; additionally, we gauged the impact of preanalytical variation on the performance of Lymph2Cx assay. METHODS: Diagnostic biopsies (n=104) were examined for COO classification, employing automated RNA digital quantification assay (Lymph2Cx). Results were equated against IHC-based COO categorisation. Assay performance was assessed through its impact on overall survival (OS). RESULTS: 96 (92%) informative samples were labelled as GCB (38/96; 40%) and non-GCB (58/96; 60%) by IHC evaluation. Lymph2Cx catalogued 36/96 (37%) samples as GCB, 45/96 (47%) as ABC and 15/96 (16%) as unclassified. Lymph2Cx being reference, IHC protocol revealed sensitivity of 81% for ABC and 75% for GCB categorisation and positive predictive value of 81% versus 82%, respectively. Lymph2Cx-based COO classification performed superior to Hans algorithm in predicting OS (log rank test, p=0.017 vs p=0.212). CONCLUSIONS: Our report show that current IHC-based protocols for COO classification of DLBCL at UKM Malaysia are in line with previously reported results and marked variation in preanalytical factors do not critically impact Lymph2Cx assay quality.

Characterisation of immunogenotypes of diffuse large B-cell lymphoma

@#Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive type of non-Hodgkin lymphoma with variable clinical outcomes. The immunogenotypic features of this heterogeneous disease in Malaysia were not well characterized. Materials & Methods: In total 141 local series of DLBCL cases from UKM Medical Centre were retrospectively studied. Results: Of these cases, we classified our patients into two subtypes: 32.7% (37/113) GCB and non-GCB 67.3% (76/113) by Hans algorithm and the results showed strong agreement with the results by Choi algorithm (κ = 0.828, P<0.001). Survival analysis indicated significant difference in between GCB and non-GCB subtypes (P=0.01), elevated serum LDH (P=0.016), age more than 60-year-old (P=0.021) and the presence of B symptoms (P=0.04). We observed 12% DLBCL cases were CD5 positive and 81.8% of them died of the disease (P=0.076). Analysis on the dual expression of MYC/ BCL2 revealed that there is no significant difference in DE and non-DE groups (P=0.916). FISH study reported there were 9.22% (13/141) rearranged cases observed in our population at which highest frequency of BCL6 gene rearrangement (76.9%), followed by MYC (15.4%) and BCL2 (7.7%); no BCL10 and MALT-1 gene rearrangement found regardless of using TMAs or whole tissue samples. More cases of MYC protein overexpression observed compared to MYC translocation. Conclusion: Relatively lower frequency of GCB tumours and low gene rearrangement rates were observed in Malaysian population. A national study is therefore warranted to know better the immunogenotypic characteristics of DLBCL in Malaysia and their implications on the survival.