👤 Sudarshan Rajagopal

The association of germline pathogenic and likely pathogenic variants (GPVs) in hereditary breast cancer genes with underlying tumor biology and clinical outcomes remain incompletely understood. This study characterized differences in somatic alterations and intrinsic subtypes between sporadic and hereditary breast cancers associated with GPVs in ATM, BRCA1, BRCA2, CHEK2, or PALB2. This retrospective cohort study included women with breast cancer and an ATM, BRCA1, BRCA2, CHEK2, or PALB2 GPV who underwent tumor sequencing and whole transcriptome RNA expression analysis. Clinicopathologic features, intrinsic subtypes, somatic alterations, and survival were compared by GPV status and immunohistochemistry-defined subtype, and to sporadic cases. All significance tests were 2-sided. 4,988 women with breast cancer included 98 BRCA1, 126 BRCA2, 74 PALB2, 54 ATM, and 83 CHEK2 GPVs. Compared to sporadic cases, HR+/HER2- tumors in BRCA1 GPVs were significantly enriched for basal subtype (45.5% vs 11.4%, p < 0.001), while CHEK2 carriers had a higher prevalence of luminal A subtype (80.4% vs 60.3%, p = 0.006). In HR+/HER2- breast cancers, BRCA1 GPVs were enriched for TP53 alterations (84.6% vs 29.8%, q < 0.001), ATM GPVs with FGFR1 alterations (35.4% vs 12.7%, q = 0.04), and BRCA2 GPVs with APC alterations (10.1% vs 1.5%, q = 0.004). Conversely, BRCA2 GPVs were inversely associated with PIK3CA alterations (13.0% vs 34.1%, q = 0.005), and CHEK2 GPVs with TP53 alterations (8.0% vs 29.8%, q = 0.02). GPVs in BRCA1, BRCA2, ATM, CHEK2, and PALB2 are associated with distinct intrinsic breast cancer subtypes and somatic genomic alterations. These findings may enhance precision in risk stratification and guide personalized treatment strategies. Show less

Familial hypercholesterolemia (FH) is a frequently underdiagnosed genetic disorder characterized by elevated low-density lipoprotein (LDL) levels. Genetic testing of LDLR, APOB, and PCSK9 genes can identify variants in up to 80% of clinically diagnosed patients. However, limitations in time, scalability, and cost have hindered effective next-generation sequencing of these genes. Additionally, pharmacogenomic variants are associated with statin-induced adverse effects in FH patients. To address these challenges, we developed a multiplex primer-based amplicon sequencing approach for FH genetic testing. Multiplex primers were designed for the exons of the LDLR, APOB, and PCSK9 genes, as well as for pharmacogenomic variants rs4149056 (SLCO1B1:c.521T > A), rs2306283 (SLCO1B1:c.388A > G), and rs2231142 (ABCG2:c.421C > A). Analytical validation using samples with known pathogenic variants and clinical validation with 12 FH-suspected probands were conducted. Library preparation was based on a bead-based tagmentation method, and sequencing was conducted on the NovaSeq 6000 platform. Our approach ensured no amplicon dropouts, with over 100× coverage on each amplicon. Known variants in 2 samples were successfully detected. Further, we identified one heterozygous LDLR (p.Glu228Ter) variant and 2 homozygous cases of LDLR (p.Lys294Ter) and LDLR (p.Ser177Leu) variants in patients. Pharmacogenomic analysis revealed that overall 3 patients may require reduced statin doses. Our approach offered reduced library preparation time (approximately 3 h), greater scalability, and lower costs (under $50) for FH genetic testing. Our method effectively sequences LDLR, APOB, and PCSK9 genes including pharmacogenomic variants that will guide appropriate screening and statin dosing, thus increasing both efficiency and affordability. Show less

In conventional, the biologically treated tannery wastewaters are rich in dissolved organics and the application of reverse osmosis (RO) to biologically treated tannery wastewater was challenged with fouling and failure of RO membrane due to existence of lingering dissolved organic compounds. In present investigation the bacterial cell immobilized packed bed reactor (CIPBR) was operated to remove the dissolved organic compounds in biologically treated post-tanning wastewater to avoid membrane fouling in RO. The efficient microbial syndicate to eliminate dissolved organics in post-tanning wastewater was isolated and immobilized on to the carbon silica matrix (CSM) in the range of 2.98 ± 0.2 × 10 Show less

Researchers have long investigated a hypothesized interaction between genetic risk and stressful life events in the etiology of depression, but studies on the topic have yielded inconsistent results. We conducted a genome-wide by environment interaction study (GWEIS) in 18,532 patients with depression from hospital-based settings and 20,184 population controls. All individuals were drawn from the iPSYCH2012 case-cohort study, a nationally representative sample identified from Danish national registers. Information on stressful life events including family disruption, serious medical illness, death of a first-degree relative, parental disability, and child maltreatment was identified from the registers and operationalized as a time-varying count variable. Hazard ratios for main and interaction effects were estimated using Cox regressions weighted to accommodate the case-cohort design. Our replication sample included 22,880 depression cases and 50,378 controls from the UK Biobank. The GWEIS in the iPSYCH2012 sample yielded three novel, genome-wide-significant ( In this large, population-based GWEIS, we did not find any replicable hits for interaction. Future gene-by-stress research in depression should focus on establishing even larger collaborative GWEISs to attain sufficient power. Show less

Crosstalk between T cells, dendritic cells, and macrophages in temporal leukocyte clusters within barrier tissues provides a new concept for T cell activation in the skin. Activated T cells from these leukocyte clusters play critical roles in the efferent phase of allergic contact hypersensitivity (CHS). However, the cytokines driving maintenance and survival of pathogenic T cells during and following CHS remain mostly unknown. Upon epicutaneous allergen challenge, we here report that macrophages produce IL-27 which then induces IL-15 production from epidermal keratinocytes and dermal myeloid cells within leukocyte clusters. In agreement with the known role of IL-15 as a T cell survival factor and growth cytokine, this signaling axis enhances BCL2 and survival of skin T cells. Genetic depletion or pharmacological blockade of IL-27 in CHS mice leads to abrogated epidermal IL-15 production resulting in a decrease in BCL2 expression in T cells and a decline in dermal CD8 Show less