Identifying the impact of structurally and functionally high-risk nonsynonymous SNPs on human patched protein using In-Silico approach

Gene Reports ◽  
2021 ◽  
pp. 101097
Author(s):  
Jigna S. Joshi ◽  
Nutan V. Badgujar ◽  
Hitarth V. Patel ◽  
Apexa P. Raval ◽  
Bhoomi V. Tarapara ◽  
...  
Keyword(s):  
High Risk ◽  
In Silico ◽  
Nonsynonymous Snps ◽  
The Impact

scholarly journals Identification of High risk nsSNPs in Human TP53 Gene Associated with Li–Fraumeni Syndrome: An In Silico Analysis Approach

2020 ◽  
Author(s):  
Mujahed I. Mustafa ◽  
Naseem S. Murshed ◽  
Mazen A. Elbasher ◽  
Abdelrafie M. Makhawi
Keyword(s):  
High Risk ◽  
In Silico ◽  
3D Structure ◽  
In Silico Analysis ◽  
Tp53 Gene ◽  
Li Fraumeni Syndrome ◽  
Functional Inference ◽  
Li Fraumeni ◽  
The Impact ◽  
Silico Analysis

AbstractBackgroundLi–Fraumeni syndrome (LFS) is a cancer–prone conditions caused by a germline mutation of the TP53 gene on chromosome 17p13.1. It has an autosomal dominant pattern of inheritance with high penetrance.PurposeThe aim of this study is to identify the high-risk pathogenic nsSNPs in PT53 gene that could be involved in the pathogenesis of Li–Fraumeni syndrome.MethodsThe nsSNPs in the human PT53 gene retrieved from NCBI, were analyzed for their functional and structural consequences using various in silico tools to predict the pathogenicity of each SNP. SIFT, Polyphen, PROVEAN, SNAP2, SNPs&Go, PHD-SNP, and P-Mut were chosen to study the functional inference while I-Mutant 3.0, and MUPro tools were used to test the impact of amino acid substitutions on protein stability by calculating ΔΔG value. The effects of the mutations on 3D structure of the PT53 protein were predicted using RaptorX and visualized by UCSF Chimera.ResultsA total of 845 PT53 nsSNPs were analyzed. Out of 7 nsSNPs of PT53 three of them (T118L, C242S, and I251N) were found high-risk pathogenic.ConclusionIn this study, out of 7 predicted high-risk pathogenic nsSNPs, three high-risk pathogenic nsSNPs of PT53 gene were identified, which could be used as diagnostic marker for this gene. The combination of sequence-based and structure-based approaches is highly effective for pointing pathogenic regions.

Welfare Reform and the Delivery of Welfare-to-Work Programs to AAPIs: What Works?

2007 ◽  
Vol 5 (2) ◽  
pp. 77-97 ◽  
Author(s):  
Julian Chow ◽  
Grace Yoo ◽  
Catherine Vu
Keyword(s):  
High Risk ◽  
Welfare Reform ◽  
Asian American ◽  
Low Income ◽  
Personal Responsibility ◽  
Welfare To Work ◽  
Work Program ◽  
What Works ◽  
One Stop ◽  
The Impact

The passage of the Personal Responsibility and Work Opportunity Act (PRWORA) of 1996 has major implications for low-income Asian American and Pacific Islander (AAPI) populations. The purpose of this paper is to provide an overview of the research currently examining the impact of welfare reform on AAPI recipients and the welfare-to-work services available to this population. This article highlights AAPI participation and their timing-out rates in California’s CalWORKs program and their barriers to transitioning to work. Four welfare-to-work program models and recommendations are presented to illustrate strategies that can be used to address the unique needs of AAPI in order to alleviate their high risk for timing-out: one-stop-shops, transitional jobs programs, providing comprehensive and family focused services, and additional research and evaluation of programs specific to assisting the AAPI population on CalWORKs.

Decision Aids for Generating Analytical Review Alternatives: The Impact of Goal Framing and Audit-Risk Level

2002 ◽  
Vol 14 (1) ◽  
pp. 157-177 ◽  
Author(s):  
Jennifer M. Mueller ◽  
John C. Anderson
Keyword(s):  
High Risk ◽  
Cognitive Load ◽  
Information Search ◽  
Decision Aid ◽  
Decision Aids ◽  
Risk Level ◽  
Audit Risk ◽  
Goal Framing ◽  
Analytical Review ◽  
The Impact

An auditor generating potential explanations for an unusual variance in analytical review may utilize a decision aid, which provides many explanations. However, circumstances of budgetary constraints and limited cognitive load deter an auditor from using a lengthy list of explanations in an information search. A two-way between-subjects design was created to investigate the effects of two complementary approaches to trimming down the lengthy list on the number of remaining explanations carried forward into an information search. These two approaches, which represent the same goal (reducing the list) but framed differently, are found to result in a significantly different number of remaining explanations, in both low- and high-risk audit environments. The results of the study suggest that the extent to which an auditor narrows the lengthy list of explanations is important to the implementation of decision aids in analytical review.

scholarly journals Cisplatin +/− rucaparib after preoperative chemotherapy in patients with triple-negative or BRCA mutated breast cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Maitri Kalra ◽  
Yan Tong ◽  
David R. Jones ◽  
Tom Walsh ◽  
Michael A. Danso ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Neoadjuvant Therapy ◽  
Triple Negative ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Parp Inhibition ◽  
High Risk Population ◽  
Risk Population ◽  
The Impact

AbstractPatients with triple-negative breast cancer (TNBC) who have residual disease after neoadjuvant therapy have a high risk of recurrence. We tested the impact of DNA-damaging chemotherapy alone or with PARP inhibition in this high-risk population. Patients with TNBC or deleterious BRCA mutation (TNBC/BRCAmut) who had >2 cm of invasive disease in the breast or persistent lymph node (LN) involvement after neoadjuvant therapy were assigned 1:1 to cisplatin alone or with rucaparib. Germline mutations were identified with BROCA analysis. The primary endpoint was 2-year disease-free survival (DFS) with 80% power to detect an HR 0.5. From Feb 2010 to May 2013, 128 patients were enrolled. Median tumor size at surgery was 1.9 cm (0–11.5 cm) with 1 (0–38) involved LN; median Residual Cancer Burden (RCB) score was 2.6. Six patients had known deleterious BRCA1 or BRCA2 mutations at study entry, but BROCA identified deleterious mutations in 22% of patients with available samples. Toxicity was similar in both arms. Despite frequent dose reductions (21% of patients) and delays (43.8% of patients), 73% of patients completed planned cisplatin. Rucaparib exposure was limited with median concentration 275 (82–4694) ng/mL post-infusion on day 3. The addition of rucaparib to cisplatin did not increase 2-year DFS (54.2% cisplatin vs. 64.1% cisplatin + rucaparib; P = 0.29). In the high-risk post preoperative TNBC/BRCAmut setting, the addition of low-dose rucaparib did not improve 2-year DFS or increase the toxicity of cisplatin. Genetic testing was underutilized in this high-risk population.

scholarly journals Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants

2021 ◽  
Author(s):  
Elmo Christian Saarentaus ◽  
Aki Samuli Havulinna ◽  
Nina Mars ◽  
Ari Ahola-Olli ◽  
Tuomo Tapio Johannes Kiiskinen ◽  
...  
Keyword(s):  
High Risk ◽  
Educational Attainment ◽  
Household Income ◽  
Copy Number ◽  
Copy Number Variants ◽  
Well Being ◽  
Subjective Health ◽  
Polygenic Risk Score ◽  
The Impact ◽  
Health Cognition

AbstractCopy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66–0.89]) and lower household income (OR = 0.77 [0.66–0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38–0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32–0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26–0.37]), lower-income (OR = 0.66 [0.57–0.77]), lower subjective health (OR = 0.72 [0.61–0.83]), and increased mortality (Cox’s HR = 1.55 [1.21–1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of traditional high-risk variants such as CNVs should be analyzed in a broader genetic context, rather than evaluated in isolation.

scholarly journals Effectiveness of Yoga Lifestyle on Lipid Metabolism in a Vulnerable Population—A Community Based Multicenter Randomized Controlled Trial

Medicines ◽  
2021 ◽  
Vol 8 (7) ◽  
pp. 37
Author(s):  
Raghuram Nagarathna ◽  
Saurabh Kumar ◽  
Akshay Anand ◽  
Ishwara N. Acharya ◽  
Amit Kumar Singh ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
High Risk ◽  
Controlled Trial ◽  
Density Lipoprotein ◽  
Lipid Profiles ◽  
Community Based ◽  
Randomized Controlled ◽  
Rural And Urban ◽  
Yoga Group ◽  
The Impact

Background: Dyslipidemia poses a high risk for cardiovascular disease and stroke in Type 2 diabetes (T2DM). There are no studies on the impact of a validated integrated yoga lifestyle protocol on lipid profiles in a high-risk diabetes population. Methods: Here, we report the results of lipid profile values of 11,254 (yoga 5932 and control 5322) adults (20–70 years) of both genders with high risk (≥60 on Indian diabetes risk score) for diabetes from a nationwide rural and urban community-based two group (yoga and conventional management) cluster randomized controlled trial. The yoga group practiced a validated integrated yoga lifestyle protocol (DYP) in nine day camps followed by daily one-hour practice. Biochemical profiling included glycated hemoglobin and lipid profiles before and after three months. Results: There was a significant difference between groups (p < 0.001 ANCOVA) with improved serum total cholesterol, triglycerides, low-density lipoprotein, and high-density lipoprotein in the yoga group compared to the control group. Further, the regulatory effect of yoga was noted with a significant decrease or increase in those with high or low values of lipids, respectively, with marginal or no change in those within the normal range. Conclusion: Yoga lifestyle improves and regulates (lowered if high, increased if low) the blood lipid levels in both genders of prediabetic and diabetic individuals in both rural and urban Indian communities.

scholarly journals TissueCypher Barrett’s esophagus assay impacts clinical decisions in the management of patients with Barrett’s esophagus

2021 ◽  
Vol 09 (03) ◽  
pp. E348-E355
Author(s):  
David L. Diehl ◽  
Harshit S. Khara ◽  
Nasir Akhtar ◽  
Rebecca J. Critchley-Thorne
Keyword(s):  
High Risk ◽  
Barrett’S Esophagus ◽  
Barrett's Esophagus ◽  
Clinical Decision Making ◽  
Eradication Therapy ◽  
Low Risk ◽  
Management Approach ◽  
Low Grade ◽  
Management Decisions ◽  
The Impact

Abstract Background and study aims The TissueCypher Barrett’s Esophagus Assay is a novel tissue biomarker test, and has been validated to predict progression to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) in patients with Barrett’s esophagus (BE). The aim of this study was to evaluate the impact of TissueCypher on clinical decision-making in the management of BE. Patients and methods TissueCypher was ordered for 60 patients with non-dysplastic (ND, n = 18) BE, indefinite for dysplasia (IND, n = 25), and low-grade dysplasia (LGD, n = 17). TissueCypher reports a risk class (low, intermediate or high) for progression to HGD or EAC within 5 years. The impact of the test results on BE management decisions was assessed. Results Fifty-two of 60 patients were male, mean age 65.2 ± 11.8, and 43 of 60 had long segment BE. TissueCypher results impacted 55.0 % of management decisions. In 21.7 % of patients, the test upstaged the management approach, resulting in endoscopic eradication therapy (EET) or shorter surveillance interval. The test downstaged the management approach in 33.4 % of patients, leading to surveillance rather than EET. In the subset of patients whose management plan was changed, upstaging was associated with a high-risk TissueCypher result, and downstaging was associated with a low-risk result (P < 0.0001). Conclusions TissueCypher was used as an adjunct to support a surveillance-only approach in 33.4 % of patients. Upstaging occurred in 21.7 % of patients, leading to therapeutic intervention or increased surveillance. These results indicate that the TissueCypher test may enable physicians to target EET for TissueCypher high-risk BE patients, while reducing unnecessary procedures in TissueCypher low-risk patients.

scholarly journals Impact of Carbohydrate Counting Error on Glycemic Control in Open-Loop Management of Type 1 Diabetes: Quantitative Assessment Through an in silico Trial

2021 ◽  
pp. 193229682110123
Author(s):  
Chiara Roversi ◽  
Martina Vettoretti ◽  
Simone Del Favero ◽  
Andrea Facchinetti ◽  
Pratik Choudhary ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glycemic Control ◽  
In Silico ◽  
Open Loop ◽  
Random Errors ◽  
Linear Regression Models ◽  
Reference Case ◽  
Counting Error ◽  
The Impact

Background: In the management of type 1 diabetes (T1D), systematic and random errors in carb-counting can have an adverse effect on glycemic control. In this study, we performed an in silico trial aiming at quantifying the impact of different levels of carb-counting error on glycemic control. Methods: The T1D patient decision simulator was used to simulate 7-day glycemic profiles of 100 adults using open-loop therapy. The simulation was repeated for different values of systematic and random carb-counting errors, generated with Gaussian distribution varying the error mean from -10% to +10% and standard deviation (SD) from 0% to 50%. The effect of the error was evaluated by computing the difference of time inside (∆TIR), above (∆TAR) and below (∆TBR) the target glycemic range (70-180mg/dl) compared to the reference case, that is, absence of error. Finally, 3 linear regression models were developed to mathematically describe how error mean and SD variations result in ∆TIR, ∆TAR, and ∆TBR changes. Results: Random errors globally deteriorate the glycemic control; systematic underestimations lead to, on average, up to 5.2% more TAR than the reference case, while systematic overestimation results in up to 0.8% more TBR. The different time in range metrics were linearly related with error mean and SD ( R2>0.95), with slopes of [Formula: see text], [Formula: see text] for ∆TIR, [Formula: see text], [Formula: see text] for ∆TAR, and [Formula: see text], [Formula: see text] for ∆TBR. Conclusions: The quantification of carb-counting error impact performed in this work may be useful understanding causes of glycemic variability and the impact of possible therapy adjustments or behavior changes in different glucose metrics.

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