29 research outputs found

    Uncertainty Analysis of Regional Rainfall Frequency Estimates in Northeast India

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    Estimation of rainfall quantile is an important step in regional frequency analysis for planning and design of any water resources project. Related evaluations of accuracy and uncertainty help to further assist in enhancing the reliability of design estimates. In this study, therefore, we investigate the accuracy and uncertainty of regional frequency analysis of extreme rainfall computed from genetic algorithm-based clustering. Uncertainty assessment is explored with prediction of quantiles with a new spatial Information Transfer Index (ITI) and Monte Carlo simulation framework. And, accuracy assessment is done with the comparison of regional growth curves to at-site analysis for each homogenous region. Further, uncertainty assessment with the ITI method is compared with Maximum Likelihood estimation (MLE) optimized by a genetic algorithm (GA) to check the suitability of the method. Results obtained suggest the ITI-based uncertainty assessment for regional estimates outperformed those of at-site estimates. The MLE-GA method based on at-site estimates was found to be better than at-site estimates based on L-moments, suggesting the former as a better alternative to compare with regional frequency estimates. Moreover, minimal bias and least deviation of the regional growth curve were obtained in the rainfall regions. The confidence intervals of regional estimates were seen to be well within the bounds of normality assumptions. Doi: 10.28991/cej-2021-03091762 Full Text: PD

    Replication confers β cell immaturity.

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    Pancreatic β cells are highly specialized to regulate systemic glucose levels by secreting insulin. In adults, increase in β-cell mass is limited due to brakes on cell replication. In contrast, proliferation is robust in neonatal β cells that are functionally immature as defined by a lower set point for glucose-stimulated insulin secretion. Here we show that β-cell proliferation and immaturity are linked by tuning expression of physiologically relevant, non-oncogenic levels of c-Myc. Adult β cells induced to replicate adopt gene expression and metabolic profiles resembling those of immature neonatal β that proliferate readily. We directly demonstrate that priming insulin-producing cells to enter the cell cycle promotes a functionally immature phenotype. We suggest that there exists a balance between mature functionality and the ability to expand, as the phenotypic state of the β cell reverts to a less functional one in response to proliferative cues

    Global protease activity profiling provides differential diagnosis of pancreatic cysts

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    Purpose: Pancreatic cysts are estimated to be present in 2%-3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Misregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts.Experimental Design: We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 μL of cyst fluid.Results: We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. IHC analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity.Conclusions: Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions. Clin Cancer Res; 23(16); 4865-74. ©2017 AACR

    PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance

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    Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression

    Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression

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    Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality yet anti-stromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor β (TGF-β) signaling have elevated epithelial Stat3 activity and develop a stiffer, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several Kras-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby Stat3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial Stat3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated Stat3 associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors, and highlight Stat3 and mechanics as key drivers of this phenotype

    Regulation of Cellular Identity in Cancer

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    Role of DDB2 in Senescence and EMT

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    DDB2 (Damaged DNA Binding Protein 2) is a DNA repair protein initially identified as a key player in nucleotide excision repair. Several recent studies indicated potential tumor suppressor functions of DDB2. Towards that, I identified two new tumor suppressor functions of DDB2: inhibition of epithelial to mesenchymal transition (EMT) and induction of senescence. My studies revealed that DDB2 deficient cells do not undergo premature senescence after culture shock, exogenous oxidative stress, oncogenic stress or DNA damage. The deficiency in senescence was resulted from lack of ROS accumulation. Further investigation revealed that DDB2 causes ROS accumulation by epigenetically inhibiting expression of two important anti-oxidant genes, MnSOD and Catalase. These findings were further substantiated in mice by using chemical carcinogen induced liver fibrosis model and UV induced skin carcinogenesis model. As an extension of my work on delineating tumor suppressive role of DDB2, I investigated the role of DDB2 in colon cancer because reduced DDB2 expression is correlated with aggressive progression of colon cancer. Moreover, loss of DDB2 increases tumorigenecity of colon cancer cells in vitro and in vivo. A closer analyses attributed this increased tumorigenecity phenotype to a regulation of EMT and resistance to anoikis. Further findings indicated that the EMT regulation by DDB2 is related to transcriptional repression of VEGF, Snail1 and Zeb1. Concordantly, DDB2 deficient colon carcinoma cells are more metastatic in nature. Thus, loss of DDB2 expression results in a deficiency in senescence and increased EMT leading to an aggressive cancer progression. Hence, targeting DDB2 expression would be beneficial from therapeutic perspective. Towards that, I have used a naturally occurring compound Phenethyl Isothiocyanate (PEITC), currently in clinical trial, to elevate expression of DDB2 and inhibit tumorigenesis in mice. Together, my observation provides new insights on the role of DDB2 as a tumor suppressor through its regulation of senescence and metastasis related to EMT. These functions of DDB2 involve its role in transcription repression. Also, my work shows how DDB2 can be therapeutically targeted for the treatment of colon cancer

    Regulation of Cellular Identity in Cancer

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    Neoplastic transformation requires changes in cellular identity. Emerging evidence increasingly points to cellular reprogramming, a process during which fully differentiated and functional cells lose aspects of their identity while gaining progenitor characteristics, as a critical early step during cancer initiation. This cell identity crisis persists even at the malignant stage in certain cancers, suggesting that reactivation of progenitor functions supports tumorigenicity. Here, we review recent findings that establish the essential role of cellular reprogramming during neoplastic transformation and the major players involved in it with a special emphasis on pancreatic cancer
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