Dendritic Cells Release HLA-B-Associated Transcript-3 Positive Exosomes to Regulate Natural Killer Function

NKp30, a natural cytotoxicity receptor expressed on NK cells is critically involved in direct cytotoxicity against various tumor cells and directs both maturation and selective killing of dendritic cells. Recently the intracellular protein BAT3, which is involved in DNA damage induced apoptosis, was identified as a ligand for NKp30. However, the mechanisms underlying the exposure of the intracellular ligand BAT3 to surface NKp30 and its role in NK-DC cross talk remained elusive. Electron microscopy and flow cytometry demonstrate that exosomes released from 293T cells and iDCs express BAT3 on the surface and are recognized by NKp30-Ig. Overexpression and depletion of BAT3 in 293T cells directly correlates with the exosomal expression level and the activation of NK cell-mediated cytokine release. Furthermore, the NKp30-mediated NK/DC cross talk resulting either in iDC killing or maturation was BAT3-dependent. Taken together this puts forward a new model for the activation of NK cells through intracellular signals that are released via exosomes from accessory cells. The manipulation of the exosomal regulation may offer a novel strategy to induce tumor immunity or inhibit autoimmune diseases caused by NK cell-activation

Analgesic activity of Cissus quadrangularis linn with Zingiber officinale rosc in male wistar rats

Background: The global scenario, human beings are using various forms of treatment for relief of pain; among them, medicinal plant products have gained popularity because of its wide range of use and less side effects.Methods: Adult Albino rats of either sex were selected and divided into 5 groups. The Eddy’s hot plate was used and maintained temperature (55±0.5ºC), the animals were placed on the hot plate and the time taken for paw licking or jumping was recorded and considered as nociceptive response. The reaction time was observed on 0, 30, 60, and 90 minute.Results: The hot plate reaction time in sec was collected in the intervals of 0, 30, 60 and 90 minutes in all groups. Reaction times as follows: group III (Cissus quadrangularis Linn.) were 2.18±0.04, 3.13±0.05**, 5.83±0.05**, 5.39±0.04**;  Group IV (Zingiber officinale Rosc.) were 2.12±0.03, 4.13±0.04**, 7.43±0.07**, 7.16±0.06**; Group V Cissus quadrangularis Linn+ Zingiber officinale Rosc.) were 2.21±0.75, 4.67±0.98**, 8.15±0.89**, 9.02±0.75**; Group II (Dexamethasone) were 2.14±0.05, 5.53±0.05**, 8.14±0.06**, 10.08±0.10** respectively, Results are presented as mean±SEM, (n=6), *p<0.01, **p<0.05 dunnet test used as compared to control.Conclusions: Present study reveals that, the combination treatment of Zingiber officinale Rosc. + Cissus quadrangularis Linn. has been shown significant analgesic effect. High analgesic effect was observed with combination therapy; the effect was shown same as standard drug dexamethasone

Compromised BRCA1-PALB2 interaction is associated with breast cancer risk.

The major breast cancer suppressor proteins BRCA1 and BRCA2 play essential roles in homologous recombination (HR)-mediated DNA repair, which is thought to be critical for tumor suppression. The two BRCA proteins are linked by a third tumor suppressor, PALB2, in the HR pathway. While truncating mutations in these genes are generally pathogenic, interpretation of missense variants remains a challenge. To date, patient-derived missense variants that disrupt PALB2 binding have been identified in BRCA1 and BRCA2; however, there has not been sufficient evidence to prove their pathogenicity in humans, and no variants in PALB2 that disrupt either its BRCA1 or BRCA2 binding have been reported. Here we report on the identification of a novel PALB2 variant, c.104T>C (p.L35P), that segregates in a family with a strong history of breast cancer. Functional analyses showed that L35P abrogates the PALB2-BRCA1 interaction and completely disables its abilities to promote HR and confer resistance to platinum salts and PARP inhibitors. Whole-exome sequencing of a breast cancer from a c.104T>C carrier revealed a second, somatic, truncating mutation affecting PALB2, and the tumor displays hallmark genomic features of tumors with BRCA mutations and HR defects, cementing the pathogenicity of L35P. Parallel analyses of other germline variants in the PALB2 N-terminal BRCA1-binding domain identified multiple variants that affect HR function to varying degrees, suggesting their possible contribution to cancer development. Our findings establish L35P as the first pathogenic missense mutation in PALB2 and directly demonstrate the requirement of the PALB2-BRCA1 interaction for breast cancer suppression

Polycomb-mediated silencing in neuroendocrine prostate cancer

BACKGROUND: Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PCa) for which the median survival remains less than a year. Current treatments are only palliative in nature, and the lack of suitable pre-clinical models has hampered previous efforts to develop novel therapeutic strategies. Addressing this need, we have recently established the first in vivo model of complete neuroendocrine transdifferentiation using patient-derived xenografts. Few genetic differences were observed between parental PCa and relapsed NEPC, suggesting that NEPC likely results from alterations that are epigenetic in nature. Thus, we sought to identify targetable epigenetic regulators whose expression was elevated in NEPC using genome-wide profiling of patient-derived xenografts and clinical samples. RESULTS: Our data indicate that multiple members of the polycomb group (PcG) family of transcriptional repressors were selectively upregulated in NEPC. Notably, CBX2 and EZH2 were consistently the most highly overexpressed epigenetic regulators across multiple datasets from clinical and xenograft tumor tissues. Given the striking upregulation of PcG genes and other transcriptional repressors, we derived a 185-gene list termed 'neuroendocrine-associated repression signature' (NEARS) by overlapping transcripts downregulated across multiple in vivo NEPC models. In line with the striking upregulation of PcG family members, NEARS was preferentially enriched with PcG target genes, suggesting a driving role for PcG silencing in NEPC. Importantly, NEARS was significantly associated with high-grade tumors, metastatic progression, and poor outcome in multiple clinical datasets, consistent with extensive literature linking PcG genes and aggressive disease progression. CONCLUSIONS: We have explored the epigenetic landscape of NEPC and provided evidence of increased PcG-mediated silencing associated with aberrant transcriptional regulation of key differentiation genes. Our results position CBX2 and EZH2 as potential therapeutic targets in NEPC, providing opportunities to explore novel strategies aimed at reversing epigenetic alterations driving this lethal disease

Quantitative prioritization of potentially critical glacial Lakes in the Indus River basin using satellite derived parameters

Glacial Lake Outburst Floods (GLOFs) in a deglaciating environment, representing significant threat to downstream people and infrastructure, increasing the necessity of prioritization and assessment of potentially critical glacial lakes (PCGLs). In this current study, a comprehensive updated inventory of glacial lakes for the Indus River basin has been prepared, resulting in 5335 lakes (≥ 0.0025 ± 0.0006 km2), covering a total area of 173.95 ± 10.13 km2. Parameters have been derived using satellite data for two purposes, ‘preliminary screening’ and ‘quantitative assessment’. Using 4 parameters, 367 lakes were preliminary screened-in for further analysis, and 6 quantitative parameters were analysed using Equal Weights (EW) and Unequal Weights methods (UEW). These both methods were applied for two scenarios, scenario-1 which considers 73 lakes (≥ 0.1 km2), and scenario-2 which considers all 367 preliminary screened-in lakes (≥ 0.02 km2). UEW outperformed EW analysis and identified 20 and 48 high potential lakes for scenario-1 and scenario-2 respectively, where all 20 lakes of scenario-1 have been found in common with those of scenario-2, with a difference in their rank. But only 10 of them have storage volume ≥ 10 MCM and has been flagged as high-risk lakes, of which 6 are end-moraine dammed lakes and have been considered as PCGLs, due to their high bursting potential and self-destructive nature. Rest 4 high risk lakes along with remaining 38 lakes with volume < 10 MCM, are considered as critical lakes in case of dynamic mode of failure, caused due to mass movement of avalanche, landslide, heavy precipitation, etc. Highlights 152 historic GLOF events has been reported from 28 sites that occurred in Indus River basin Updated glacial lake inventory of Indus River basin using high resolution IRS satellite data Total of 5335 GL’s were mapped, and 48 of them are identified as high potential lakes UEW outperformed EW method to evaluate weighted integrated index for potentiality assessment 6 lakes are found to be as potentially critical glacial lakes (PCGLs) in the Indus River basi