Experimental Study of a Parallel Iterative Solver for Markov Chain Modeling

This paper presents the results of a preliminary experimental investigation of the performance of a stationary iterative method based on a block staircase splitting for solving singular systems of linear equations arising in Markov chain modelling. From the experiments presented, we can deduce that the method is well suited for solving block banded or more generally localized systems in a parallel computing environment. The parallel implementation has been benchmarked using several Markovian models

News on immune checkpoint inhibitors as immunotherapy strategies in adult and pediatric solid tumors

Immune checkpoint inhibitors (ICIs) have shown unprecedented benefits in various adult cancers, and this success has prompted the exploration of ICI therapy even in childhood malignances. Although the use of ICIs as individual agents has achieved disappointing response rates, combinational therapies are likely to promise better results. However, only a subset of patients experienced prolonged clinical effects, thus suggesting the need to identify robust bio-markers that predict individual clinical response or resistance to ICI therapy as the main challenge. In this review, we focus on how the use of ICIs in adult cancers can be translated into pediatric malignances. We discuss the physiological mechanism of action of each IC, including PD-1, PD-L1 and CTLA-4 and the new emerging ones, LAG-3, TIM-3, TIGIT, B7-H3, BTLA and IDO-1, and evaluate their prognostic value in both adult and childhood tumors. Furthermore, we offer an overview of preclinical models and clinical trials currently under investigation to improve the effectiveness of cancer immunotherapies in these patients. Finally, we outline the main predictive factors that influence the efficacy of ICIs, in order to lay the basis for the development of a pan-cancer immunogenomic model, able to direct young patients towards more specific immunotherapy

Poor sleep quality may independently predict suicidal risk in COVID-19 survivors: a 2-year longitudinal study

Objective: Multiple symptoms of psychiatric, neurological, and physical illnesses may be part of Post-COVID conditions and may pose COVID-19 survivors a high suicidal risk. Accordingly, we aimed to study factors contributing to suicidal risk in Post COVID-19 patients. Method: Consecutive patients with post COVID-19 conditions were followed for 2 years at the University Hospital of Ferrara at baseline (T0), 6 (T1), 12 (T2), and 24 (T3) months. Demographics, and clinical data for all patients included: disease severity, hospital length of stay, comorbidity, clinical complications, sleep quality, cognitive complaints, anxiety and stress-related symptoms, depressive symptoms, and suicidal ideation. Results: The final sample included 81 patients with post COVID survivors. The mean age was 64 + 10,6 years, 35,8% were females, 65,4% had medical comorbidities, and 69,1% had WHO severe form of COVID forms. At T0 more than 90% of patients showed poor sleep quality, 59.3% reported moderate/severe depressive symptoms, and 51.% experienced anxiety, 25.9% experienced post-traumatic stress symptoms. At T0 suicidal ideation, interested 6.1% and at T3 it increased to 7.4%. In the regression analysis, suicidal ideation at baseline was best predicted by poor sleep quality (O.R. 1.71, p=0.044) and, after 2 years, suicidal ideation was best predicted by poor sleep quality experienced at baseline (OR 67.3, p=0.001). Conclusions: Poor sleep quality may play as an independent predictor of suicidal risk in post-COVID survivors. Evaluating and targeting sleep disturbances in COVID survivors is important to prevent the consequences of disrupted sleep in mental health

Determining the effectiveness of High Resolution Melting analysis for SNP genotyping and mutation scanning at the TP53 locus

<p>Abstract</p> <p>Background</p> <p>Together single nucleotide substitutions and small insertion/deletion variants are the most common form of sequence variation in the human gene pool.</p> <p>High-resolution SNP profile and/or haplotype analyses enable the identification of modest-risk susceptibility genes to common diseases, genes that may modulate responses to pharmaceutical agents, and SNPs that can affect either their expression or function. In addition, sensitive techniques for germline or somatic mutation detection are important tools for characterizing sequence variations in genes responsible for tumor predisposition. Cost-effective methods are highly desirable. Many of the recently developed high-throughput technologies are geared toward industrial scale genetic studies and arguably do not provide useful solutions for small laboratory investigator-initiated projects. Recently, the use of new fluorescent dyes allowed the high-resolution analysis of DNA melting curves (HRM).</p> <p>Results</p> <p>Here, we compared the capacity of HRM, applicable to both genotyping and mutation scanning, to detect genetic variations in the tumor suppressor gene <it>TP53 </it>with that of mutation screening by full resequencing. We also assessed the performance of a variety of available HRM-based genotyping assays by genotyping 30 <it>TP53 </it>SNPs. We describe a series of solutions to handle the difficulties that may arise in large-scale application of HRM to mutation screening and genotyping at the <it>TP53 </it>locus. In particular, we developed specific HRM assays that render possible genotyping of 2 or more, sometimes closely spaced, polymorphisms within the same amplicon. We also show that simultaneous genotyping of 2 SNPs from 2 different amplicons using a multiplex PCR reaction is feasible; the data can be analyzed in a single HRM run, potentially improving the efficiency of HRM genotyping workflows.</p> <p>Conclusion</p> <p>The HRM technique showed high sensitivity and specificity (1.0, and 0.8, respectively, for amplicons of <400 bp) for mutation screening and provided useful genotyping assays as assessed by comparing the results with those obtained with Sanger sequencing. Thus, HRM is particularly suitable for either performing mutation scanning of a large number of samples, even in the situation where the amplicon(s) of interest harbor a common variant that may disturb the analysis, or in a context where gathering common SNP genotypes is of interest.</p

Association between polymorphisms of TAS2R16 and susceptibility to colorectal cancer

Background: Genetics plays an important role in the susceptibility to sporadic colorectal cancer (CRC). In the last 10 years genome-wide association studies (GWAS) have identified over 40 independent low penetrance polymorphic variants. However, these loci only explain around 1‑4% of CRC heritability, highlighting the dire need of identifying novel risk loci. In this study, we focused our attention on the genetic variability of the TAS2R16 gene, encoding for one of the bitter taste receptors that selectively binds to salicin, a natural antipyretic that resembles aspirin. Given the importance of inflammation in CRC, we tested whether polymorphic variants in this gene could affect the risk of developing this neoplasia hypothesizing a role of TAS2R16 in modulating chronic inflammation within the gut. Methods: We performed an association study using 6 tagging SNPs, (rs860170, rs978739, rs1357949, rs1525489, rs6466849, rs10268496) that cover all TAS2R16 genetic variability. The study was carried out on 1902 CRC cases and 1532 control individuals from four European countries. Results: We did not find any statistically significant association between risk of developing CRC and selected SNPs. However, after stratification by histology (colon vs. rectum) we found that rs1525489 was associated with increased risk of rectal cancer with a (Ptrend of = 0.0071). Conclusions: Our data suggest that polymorphisms within TAS2R16 gene do not have a strong influence on colon cancer susceptibility, but a possible role in rectal cancer should be further evaluated in larger cohorts

Variation rs2235503 C > A Within the Promoter of MSLN Affects Transcriptional Rate of Mesothelin and Plasmatic Levels of the Soluble Mesothelin-Related Peptide

Soluble mesothelin-related peptide (SMRP) is a promising biomarker for malignant pleural mesothelioma (MPM), but several confounding factors can reduce SMRP-based test’s accuracy. The identification of these confounders could improve the diagnostic performance of SMRP. In this study, we evaluated the sequence of 1,000 base pairs encompassing the minimal promoter region of the MSLN gene to identify expression quantitative trait loci (eQTL) that can affect SMRP. We assessed the association between four MSLN promoter variants and SMRP levels in a cohort of 72 MPM and 677 non-MPM subjects, and we carried out in vitro assays to investigate their functional role. Our results show that rs2235503 is an eQTL for MSLN associated with increased levels of SMRP in non-MPM subjects. Furthermore, we show that this polymorphic site affects the accuracy of SMRP, highlighting the importance of evaluating the individual’s genetic background and giving novel insights to refine SMRP specificity as a diagnostic biomarker

Arterial pressure changes monitoring with a new precordial noninvasive sensor

<p>Abstract</p> <p>Background</p> <p>Recently, a cutaneous force-frequency relation recording system based on first heart sound amplitude vibrations has been validated. A further application is the assessment of Second Heart Sound (S2) amplitude variations at increasing heart rates. The aim of this study was to assess the relationship between second heart sound amplitude variations at increasing heart rates and hemodynamic changes.</p> <p>Methods</p> <p>The transcutaneous force sensor was positioned in the precordial region in 146 consecutive patients referred for exercise (n = 99), dipyridamole (n = 41), or pacing stress (n = 6). The curve of S2 peak amplitude variation as a function of heart rate was computed as the increment with respect to the resting value.</p> <p>Results</p> <p>A consistent S2 signal was obtained in all patients. Baseline S2 was 7.2 ± 3.3 m<it>g</it>, increasing to 12.7 ± 7.7 m<it>g </it>at peak stress. S2 percentage increase was + 133 ± 104% in the 99 exercise, + 2 ± 22% in the 41 dipyridamole, and + 31 ± 27% in the 6 pacing patients (p < 0.05). Significant determinants of S2 amplitude were blood pressure, heart rate, and cardiac index with best correlation (R = .57) for mean pressure.</p> <p>Conclusion</p> <p>S2 recording quantitatively documents systemic pressure changes.</p