Cytotoxic CD4+ T cells in patients with B cell chronic lymphocytic leukemia kill via a perforin-mediated pathway

Background and Objectives: B-cell chronic lymphocytic leukemia (B-CLL) is a clonal expansion of CD5+B cells that accumulate due to their uncontrolled growth and resistance to apoptosis. We have previously shown that up to 50% of blood CD4+ T cells in BCLL patients have a cytotoxicity-related CD28-CD57+ phenotype and high content of both granzyme B and perforin (PF). In this study we investigate the cytotoxic potential of these cells against autologous B-CLL cells. Design and Methods: Blood CD4+ or CD8+ T cells were positively isolated from B-CLL patients and cultured under a range of conditions with autologous purified B-CLL cells and with bispecific [anti-CD3 x anti-CD19] antibodies. Apoptosis of labeled B-CLL cells was assessed using the change of mitochondrial membrane potential with the fluorescent dye DiOC6 and confirmed by annexin V binding. Results: There was time- and dose-dependent killing of B-CLL cells by both CD8+ and CD4+ T cells and this ranged from 6.6 - 68.0% for CD4+ cells and 6.4 - 57.8% for CD8+ cells. Almost complete inhibition by concanamycin A suggests that CD4+ T cells like CD8+ T cells induced apoptosis through a perforin-mediated pathway, but not via Fas/FasL (as indicated by lack of blocking with brefeldin A), tumor necrosis factor or TRAIL. Interpretation and Conclusions: This study shows that blood CD4+PF+ T cells enriched in B-CLL patients, are able to kill autologous B-CLL cells ex vivo, through bispecific antibodies via a perforin mediated mechanism

Urban–Rural Differences in Older Adult Depression: A Systematic Review and Meta-analysis of Comparative Studies

Context: Depression among older adults (aged 60 years or older) is a problem that could be exacerbated by global trends in urbanization and population aging. The study purpose was to assess whether urban, relative to rural, residence is associated with depression among older adults and whether associations differ in countries with developed versus developing economies. Evidence acquisition: In 2017, the authors identified and extracted information from comparative studies of urban–rural depression prevalence among older adults. Studies were identified in PubMed, PsychINFO, and Web of Science and limited to English language articles published after 1985. Eighteen studies met inclusion criteria. Random effects meta-analysis was conducted to produce weighted pooled ORs estimating the association between urban–rural residence and depression for all study participants (N=31,598) and sub-analyses were conducted for developed (n=12,728) and developing (n=18,870) countries. Evidence synthesis: Depression prevalence was significantly higher among urban residents in ten studies and significantly higher among rural residents in three studies (all three conducted in China). Associations between urban–rural residence and depression generally remained significant after adjusting for covariates. In developed countries, the odds of depression were significantly higher among urban than rural residents (pooled OR=1.44, 95% CI=1.10, 1.88). However, in developing countries, this association was not observed (pooled OR=0.91, 95% CI=0.46, 1.77). Conclusions: Converging trends of urbanization and population aging could increase the global burden of depression among older adults. The pathways through which urban–rural residence influences depression risk among older adults might differ by country context. Future research should focus on measuring variation in these contexts

Depression and alcohol misuse among older adults: exploring mechanisms and policy impacts using agent-based modelling

Purpose: To: (1) explore how multi-level factors impact the longitudinal prevalence of depression and alcohol misuse among urban older adults (≥ 65 years), and (2) simulate the impact of alcohol taxation policies and targeted interventions that increase social connectedness among excessive drinkers, socially isolated and depressed older adults; both alone and in combination. Methods: An agent-based model was developed to explore the temporal co-evolution of depression and alcohol misuse prevalence among older adults nested in a spatial network. The model was based on Los Angeles and calibrated longitudinally using data from the Multi-Ethnic Study of Atherosclerosis. Results: Interventions with a social component targeting depressed and socially isolated older adults appeared more effective in curbing depression prevalence than those focused on excessive drinkers. Targeting had similar impacts on alcohol misuse, though the effects were marginal compared to those on depression. Alcohol taxation alone had little impact on either depression or alcohol misuse trajectories. Conclusions: Interventions that improve social connectedness may reduce the prevalence of depression among older adults. Targeting considerations could play an important role in determining the success of such efforts

Examining the possible impact of daily transport on depression among older adults using an agent-based model

_Objectives:_ Daily transport may impact depression risk among older adults through several pathways including facilitating the ability to meet basic needs, enabling and promoting contact with other people and nature, and promoting physical activity (e.g. through active transportation such as walking or walking to public transit). Both daily transport and depression are influenced by the neighborhood environment. To provide insights into how transport interventions may affect depression in older adults, we developed a pilot agent-based model to explore the contribution of daily transport and neighborhood environment to older adults’ depression in urban areas. _Method:_ The model includes about 18,500 older adults (i.e. agents) between the ages of 65 and 85 years old, living in a hypothetical city. The city has a grid space with a number of neighborhoods and locations. Key dynamic processes in the model include aging, daily transport use and feedbacks, and the development of depression. Key parameters were derived from US data sources. The model was validated using empirical studies. _Results:_ An intervention that combines a decrease in bus fares, shorter bus waiting times, and more bus lines and stations is most effective at reducing depression. Lower income groups are likely to be more sensitive to the public transit-oriented intervention. _Conclusion:_ Preliminary results suggest that promoting public transit use may be a promising strategy to increase daily transport and decrease depression. Our results may have implications for transportation policies and interventions to prevent depression in older adults

Development of an immunochromatographic lateral flow dipstick for the detection of Mycobacterium tuberculosis 16 kDa antigen (Mtb-strip)

Mycobacterium tuberculosis (Mtb) is a pathogenic bacterium that causes tuberculosis (TB). This contagious disease remains a severe health problem in the world. The disease is transmitted via inhalation of airborne droplets carrying Mtb from TB patients. Early detection of the disease is vital to prevent transmission of the infection to people in close contact with the patients. To date, there is a need of a simple, rapid, sensitive and specific diagnostic test for TB. Previous studies showed the potential of Mtb 16 kDa antigen (Ag16) in TB diagnosis. In this study, lateral flow immunoassay, also called simple strip immunoassay or immunochromatographic test (ICT) for detection of Ag16 was developed (Mtb-strip) and assessed as a potential rapid TB diagnosis method. A monoclonal antibody against Ag16 was optimized as the capturing and detection antibody on the Mtb-strip. Parameters affecting the performance of the Mtb-strip were also optimized before a complete prototype was developed. Analytical sensitivity showed that Mtb-strip was capable to detect as low as 125 ng of purified Ag16. The analytical sensitivity of Mtb-strip suggests its potential usefulness in different clinical applications

Large-scale transcriptome-wide association study identifies new prostate cancer risk regions

Although genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here we integrate the largest PrCa GWAS (N = 142,392) with gene expression measured in 45 tissues (N = 4458), including normal and tumor prostate, to perform a multi-tissue transcriptome-wide association study (TWAS) for PrCa. We identify 217 genes at 84 independent 1 Mb regions associated with PrCa risk, 9 of which are region

An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk

It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for Cp

Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility

Several susceptibility loci for classical Hodgkin lymphoma (cHL) have been reported, however much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies (GWAS), a new GWAS, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all cHL at 6q22.33 (rs9482849, P=1.52 × 10-8) and for nodular sclerosis HL (NSHL) at 3q28 (rs4459895, P=9.43 × 10-17), 6q23.3 (rs6928977, P=4.62 × 10-55 11), 10p14 (rs3781093, P=9.49 × 10-13), 13q34 (rs112998813, P=4.58 × 10-8) and 16p13.13 (rs34972832, P=2.12 × 10-8). Additionally, independent loci within the HLA region are observed for NSHL (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity HL (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response.In the United Kingdom, Bloodwise (LLR; 10021) provided principal funding for the study. Support from Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and the Lymphoma Research Trust is also acknowledged. A.S. is supported by a clinical fellowship from Cancer Research UK. For the UK-GWAS, sample and data acquisition were supported by Breast Cancer Now, the European Union and the Lymphoma Research Trust. The UK-GWAS made use of control genotyping data generated by the WTCCC. For further information, please visit the publishr's website

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight

Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events42Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases