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Mountains play an outsized role in water resource availability, and the amount and timing of water they provide depend strongly on temperature. To that end, we ask the question: How well are atmospheric models capturing mountain temperatures? We synthesize results showing that high-resolution, regionally relevant climate models produce 2-m air temperature (T2m) measurements colder than what is observed (a 'cold bias'), particularly in snow-covered midlatitude mountain ranges during winter. We find common cold biases in 44 studies across global mountain ranges, including single-model and multimodel ensembles. We explore the factors driving these biases and examine the physical mechanisms, data limitations, and observational uncertainties behind T2m. Our analysis suggests that the biases are genuine and not due to observation sparsity or resolution mismatches. Cold biases occur primarily on mountain peaks and ridges, whereas valleys are often warm biased. Our literature review suggests that increasing model resolution does not clearly mitigate the bias. By analyzing data from the Surface Atmosphere Integrated Field Laboratory (SAIL) field campaign in the Colorado Rocky Mountains, we test various hypotheses related to cold biases and find that local wind circulations, longwave (LW) radiation, and surface-layer parameterizations contribute to the T2m biases in this particular location. We conclude by emphasizing the value of coordinated model evaluation and development efforts in heavily instrumented mountain locations for addressing the root cause(s) of T2m biases and improving predictive understanding of mountain climates. SIGNIFICANCE STATEMENT: Mountain climates are rapidly changing, and along with them are the temperature-sensitive components of the water budget that societies have relied on. Yet atmospheric models, from those that predict the weather to those that predict the future climate, are several degrees too cold on average in these same mountain regions. This cold bias has not been systematically identified in the published literature yet, so we discuss evidence of its pervasiveness across models, its potential causes, and pathways to eliminate it using targeted models and observations. With community support, this bias can be uprooted, thereby enabling model projections that better project the climatic and water resource changes in these vital regions. KEYWORDS: Mountain meteorology; Model evaluation/ performance; Temperature; Climate, 1. Introduction In this study, we compile evidence suggesting that many types of high-resolution atmospheric models (Gutowski et al. 2020) report cold biases in 2-m air temperature ('T2m') measurements across [...]

Human immunodeficiency virus (HIV) is a retrovirus that infects and destroys CD4 T cells. In the United States, HIV infection affects an estimated 1,189,700 individuals 13 years and older. (1) [...]

Background BRCA1 and BRCA2 (BRCA1/2) are the most frequently investigated genes among Caucasian pancreatic cancer patients, whereas limited reports are available among Asians. We aimed to investigate the prevalence of BRCA1/2 germline variants in Pakistani pancreatic cancer patients. Methods One hundred and fifty unselected and prospectively enrolled pancreatic cancer patients were comprehensively screened for BRCA1/2 germline variants using denaturing high-performance liquid chromatography and high-resolution melting analyses, followed by DNA sequencing of the variant fragments. The novel variants were analyzed for their pathogenic effect using in-silico tools. Potentially functional variants were further screened in 200 cancer-free controls. Results Protein truncating variant was detected in BRCA2 only, with a prevalence of 0.7% (1/150). A frameshift BRCA2 variant (p.Asp946Ilefs*14) was identified in a 71-year-old male patient of Pathan ethnicity, with a family history of abdominal cancer. Additionally, we found a novel variant in BRCA2 (p.Glu2650Gln), two previously reported variants in BRCA1 (p.Thr293Ser) and BRCA2 (p.Ile2296Leu) and a recurrent nonsense variant in BRCA2 (p.Lys3326Ter). These variants were classified as variants of uncertain significance (VUS). It is noteworthy that none of these VUS carriers had a family history of pancreatic or other cancers. Conclusions In this first study, BRCA1/2 pathogenic variant is identified with a low frequency in pancreatic cancer patients from Pakistan. Comprehensive multigene panel testing is recommended in the Pakistani pancreatic cancer patients to enhance genetic understanding in this population. Keywords: BRCA1, BRCA2, Germline variants, Pancreatic cancer, Pakistan, Author(s): Noor Muhammad[sup.1,2], Ayesha Azeem[sup.1], Shumaila Arif[sup.1], Humaira Naeemi[sup.1], Iqra Masood[sup.3], Usman Hassan[sup.4], Bushra Ijaz[sup.2], Faisal Hanif[sup.5,6], Aamir Ali Syed[sup.5], Muhammed Aasim Yusuf[sup.7] and Muhammad Usman Rashid[sup.1] Background Pancreatic cancer [...]

The incidence and prevalence of hypothyroidism in pregnancy have increased over the past two decades, leading to the occurrence of neuropsychiatric disorders. However, the underlying mechanisms of thyroid hormone (TH)-regulated gene expression and neuropsychiatric development during the postnatal period remain unknown. Recent achievements have shown that reelin, a large extracellular glycoprotein, plays a crucial role in neuronal migration and localization during the development of neocortex and cerebellar cortex, thereby participating in the development of neuropsychiatric diseases. Reelin- induced neuronal migration requires triiodothyronine (T3) from the deiodination of thyroxine (T4) by fetal brain deiodinases. Previous studies have reported decreased reelin levels and abnormal gene expression, which are the same as the pathological alternations in reelin-induced neuropsychiatric disorders including schizophrenia and autism. Low T3 in the fetal brain due to hypothyroxinemia during pregnancy may be detrimental to neuronal migration, leading to neuropsychiatric disorders. In this review, we focus on the reelin expression between hypothyroidism and neuropsychiatric disorders. Key words: thyroid hormones, reelin, neurological diseases, pregnancy L'incidence et la prevalence de l'hypothyroidie de grossesse ont augmente au cours des vingt dernieres annees, ce qui a mene a la survenue de troubles neuropsychiatriques. Cependant, les modes d'action sous-jacents de l'expression genique regulee par l'hormone thyroidienne (HT) et le developpement neuropsychiatrique au cours de la periode postnatale demeurent inconnus. De recents travaux ont montre que la reeline, une proteine extracellulaire de grande taille, joue un role central dans la migration et la localisation des neurones au cours du developpement du neocortex et du cortex cerebelleux, participant par le fait meme a l'apparition de maladies neuropsychiatriques. La migration neuronale engendree par la reeline exige la presence de triiodothyronine (T3) issue de la deiodination de la thyroxine (T4) par les deiodinases du cerveau foetal. Des etudes anterieures ont rapporte une diminution des taux de reeline et une expression genique anormale, qui sont les memes modifications pathologiques que dans les troubles neuropsychiatriques qu'engendre la reeline, y compris la schizophrenie et l'autisme. Un abaissement de la T3 dans le cerveau foetal an raison de l'hypothyroxinemie pendant la grossesse peut etre nefaste a la migration neuronale et mener a des troubles neuropsychiatriques. Cet article de synthese est axe sur l'expression de la reeline entre l'hypothyroidie et certains troubles neuropsychiatriques. [Traduit par la Redaction] Mots-cles : hormones thyroidiennes, reeline, maladies neurologiques, grossesse, 1. Introduction Recent studies have shown that maternal hypothyroidism is a common endocrine disease, which leads to a high risk of adverse pregnancy outcomes, including pre-eclampsia, premature delivery, postnatal asphyxia, [...]

Purpose Severe community-acquired pneumonia (CAP) requiring intensive care unit admission is associated with significant acute and long-term morbidity and mortality. We hypothesized that downregulation of systemic and pulmonary inflammation with prolonged low-dose methylprednisolone treatment would accelerate pneumonia resolution and improve clinical outcomes. Methods This double-blind, randomized, placebo-controlled clinical trial recruited adult patients within 72-96 h of hospital presentation. Patients were randomized in 1:1 ratio; an intravenous 40 mg loading bolus was followed by 40 mg/day through day 7 and progressive tapering during the 20-day treatment course. Randomization was stratified by site and need for mechanical ventilation (MV) at the time of randomization. Outcomes included a primary endpoint of 60-day all-cause mortality and secondary endpoints of morbidity and mortality up to 1 year of follow-up. Results Between January 2012 and April 2016, 586 patients from 42 Veterans Affairs Medical Centers were randomized, short of the 1420 target sample size because of low recruitment. 584 patients were included in the analysis. There was no significant difference in 60-day mortality between the methylprednisolone and placebo arms (16% vs. 18%; adjusted odds ratio 0.90, 95% CI 0.57-1.40). There were no significant differences in secondary outcomes or complications. Conclusions In patients with severe CAP, prolonged low-dose methylprednisolone treatment did not significantly reduce 60-day mortality. Treatment was not associated with increased complications., Author(s): G. Umberto Meduri [sup.1] [sup.2], Mei-Chiung Shih [sup.3] [sup.4], Lisa Bridges [sup.1] [sup.2], Thomas J. Martin [sup.5] [sup.6] [sup.7], Ali El-Solh [sup.8] [sup.9], Nitin Seam [sup.10], Anne Davis-Karim [sup.11], [...]

Hyponatremia, especially if acute and severe, can be a life-threatening condition. Several conditions can trigger hyponatremia. In this review, we will discuss two conditions that can determine euvolemic hyponatremia: the cerebral/renal salt wasting (CRSW) syndrome and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), including the two subtypes: reset osmostat (RO) and nephrogenic syndrome of inappropriate antidiuresis (NSIAD) and their differential diagnoses. Despite the passage of over 70 years since its first description, to date, the true etiopathogenesis of CRSW syndrome, a rare cause of hypovolemic/euvolemic hyponatremia, is almost unknown. SIADH, including RO and NSIAD, is sometimes difficult to differentiate from CRSW syndrome; in its differential diagnosis, the clinical approach based on the evaluation of the extracellular volume (ECV) was proven insufficient. We therefore suggest a simple diagnostic algorithm based on the assessment of the degree of hyponatremia, urinary osmolality, and the assessment of the fraction of urate excretion (FEUa) in conditions of hyponatremia and after serum sodium correction, to be applied in children over 1 year of life., Author(s): Flaminia Bardanzellu [sup.1] , Maria Antonietta Marcialis [sup.1] , Roberta Frassetto [sup.1] , Alice Melis [sup.1] , Vassilios Fanos [sup.1] Author Affiliations: (1) grid.7763.5, 0000 0004 1755 3242, Neonatal [...]

Multidrug resistance (MDR) is often a major impediment to successful chemotherapy in the treatment of cancer. A common mechanism for MDR is the overexpression of an active ATP-binding cassette (ABC) transporter protein, P-glycoprotein (P-gp/ABCBl, also known as MDR1), multidrug resistance protein 1 (MRP1/ABCC1), or breast cancer resistant protein (BCRP/ABCG2), on the plasma membrane of cancer cells. These transporters can pump many structurally diverse anticancer drugs out of the cancer cells and render these drugs ineffective at a therapeutic dosage, i.e., multidrug resistance. Coadministration of a potent ABC transporter inhibitor with an anticancer drug has been evaluated in several clinical trials to overcome MDR but has led to a disappointing outcome. By taking advantage of the pseudo-dimeric structure of ABC transporters, we demonstrated that some flavonoid dimers, using polyvalent interactions, can be potent inhibitors of ABC transporters. Selective inhibition of the three different transporters with flavonoid dimers can be achieved by placing the two flavonoid moieties at an optimal distance apart specific for each transporter. In addition to being potent and selective inhibitors of the transporters, flavonoid dimers are found to be nontoxic to normal cells at their corresponding effective concentrations. The in vivo efficacy of flavonoid dimers was demonstrated. Further investigation of these flavonoid dimers as clinical candidates to overcome MDR in cancer chemotherapy is warranted Key words: click chemistry, CuAAC reaction, multidrug resistance, P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), breast cancer resistant protein (BCRP), modulators, flavonoids. La multirésistance aux médicaments est souvent un obstacle majeur à la réussite d'une chimiothérapie dans le traitement du cancer. La multirésistance aux médicaments est souvent le résultat de la surexpression d'un transporteur actif ABC (ATP binding cassette) - soit la glycoprotéine P (P gp/ABCBl, également connue sous le nom de MDR1), la protéine de multirésistance aux médicaments 1 (MRP1/ABCC1) ou la protéine de résistance du cancer du sein (BCRP/ABCG2) - sur la membrane plasmique des cellules cancéreuses. Ces transporteurs sont capables de pomper de nombreux agents anticancéreux de structures diverses hors des cellules cancéreuses et les rendre inefficaces aux doses thérapeutiques. On parle alors de multirésistance aux médicaments. La co-administration d'un inhibiteur puissant du transporteur ABC avec un agent anticancéreux a été évaluée dans le cadre de plusieurs essais cliniques afin de contrer la multirésistance aux médicaments, mais les résultats ont été décevants. En tirant parti de la structure pseudo-dimérique des transporteurs ABC, nous avons démontré que certains dimères de flavonoïdes, par des interactions polyvalentes, peuvent agir comme de puissants inhibiteurs des transporteurs ABC. Il est possible d'obtenir une inhibition sélective des trois transporteurs différents par les dimères de flavonoïdes en positionnant les deux groupes flavonoïdes à une distance optimale propre à chacun des transporteurs. Non seulement les dimères de flavonoïdes sont des inhibiteurs puissants et sélectifs des transporteurs, mais ils sont aussi non toxiques pour les cellules normales à leurs concentrations efficaces respectives. Nous avons fait la démonstration de l'efficacité in vivo des dimères de flavonoïdes. Une étude plus approfondie de ces dimères de flavonoïdes comme candidats cliniques pour contrer la multirésistance aux médicaments s'impose dans le contexte de la chimiothérapie contre le cancer. [Traduit par la Rédaction] Mots-clés : chimie clic, réaction CuAAC, multirésistance aux médicaments, glycoprotéine P (P gp), protéine de multirésistance aux médicaments 1 (MRP1), protéine de résistance du cancer du sein (BCRP), modulateurs, flavonoids., 1. Introduction 1.1. ATP-binding cassette transporter proteins ATP-binding cassette (ABC) transporters are a superfamily of proteins in the membrane. They transport a variety of compounds through membranes against concentration gradients, [...]

There is a pervasive and comprehensive history of sexism in the pursuit of scientific truth, extending back beyond the days of 'hysteria' and continuing still. Herein, we discuss a disparity in scientific research on a disorder thought to affect less than 8% of the adult population in the USA with the number of women diagnosed with the disorder estimated to be two to three times higher than that of men. While post-traumatic stress disorder (PTSD) is more likely to be experienced by women, we find that the overwhelming majority of published scientific literature on PTSD involves male combat veterans. For example, since March 2019, according to a widely used medical research search engine, specifically the electronic database PubMed (https://www.ncbi.nlm.nih.gov/pubmed/), over 1,100 articles can be found with the keywords, 'veteran and PTSD' while using the keywords, 'sexual assault and PTSD' yields a little over 100 total articles. While not all victims of sexual assault are female and not all combat veterans are male, the majority sex in each category is such that much of the research on 'veteran' was specifically carried out with male veterans and much of the work on 'sexual abuse' was carried out exclusively with females. This creates a perception that both overinflates the incidence of PTSD experienced by male combat veterans and underemphasizes the experience of PTSD in female victims of sexual assault. Differences in symptoms of PTSD do vary by war and what little research exists on PTSD after sexual assault suggests that it is likely that symptoms as well as associated comorbidities will vary depending on the cause, type, number, and age at first trauma, among other factors. This study focuses on the specific comorbidities of pain, addiction, and immune function in those who experience PTSD following war-based or sexually-based traumas. It is our hope that in reviewing the currently available research, we spotlight the need for research focused on PTSD experienced after sexual assault. Doing so has the potential to lead to better and more tailored treatments for PTSD, thus enriching outcomes for all sufferers of PTSD. Keywords: Sex-differences, PTSD, Bias in research, Introduction Culture, politics, the legal and judicial systems as well as institutionalized 'truths' suffuse our fundamental understanding of biology in a way that usually promotes the status quo to foster [...]

The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy.sup.1,2. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations. Here we develop T cell exome TREC tool (T cell ExTRECT), a method for estimation of T cell fraction from WES samples using a signal from T cell receptor excision circle (TREC) loss during V(D)J recombination of the T cell receptor-[alpha] gene (TCRA (also known as TRA)). TCRA T cell fraction correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females than in males and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma. Using a meta-analysis of tumours treated with immunotherapy, we show that tumour TCRA T cell fraction predicts immunotherapy response, providing value beyond measuring tumour mutational burden. Applying T cell ExTRECT to a multi-sample pan-cancer cohort reveals a high diversity of the degree of immune infiltration within tumours. Subclonal loss of 12q24.31-32, encompassing SPPL3, is associated with reduced TCRA T cell fraction. T cell ExTRECT provides a cost-effective technique to characterize immune infiltrate alongside somatic changes. A robust, cost-effective technique based on whole-exome sequencing data can be used to characterize immune infiltrates, relate the extent of these infiltrates to somatic changes in tumours, and enables prediction of tumour responses to immune checkpoint inhibition therapy., Author(s): Robert Bentham [sup.1] [sup.2] , Kevin Litchfield [sup.2] [sup.3] , Thomas B. K. Watkins [sup.4] , Emilia L. Lim [sup.2] [sup.4] , Rachel Rosenthal [sup.4] , Carlos Martínez-Ruiz [sup.1] [...]

Progress in defining genomic fitness landscapes in cancer, especially those defined by copy number alterations (CNAs), has been impeded by lack of time-series single-cell sampling of polyclonal populations and temporal statistical models.sup.1-7. Here we generated 42,000 genomes from multi-year time-series single-cell whole-genome sequencing of breast epithelium and primary triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), revealing the nature of CNA-defined clonal fitness dynamics induced by TP53 mutation and cisplatin chemotherapy. Using a new Wright-Fisher population genetics model.sup.8,9 to infer clonal fitness, we found that TP53 mutation alters the fitness landscape, reproducibly distributing fitness over a larger number of clones associated with distinct CNAs. Furthermore, in TNBC PDX models with mutated TP53, inferred fitness coefficients from CNA-based genotypes accurately forecast experimentally enforced clonal competition dynamics. Drug treatment in three long-term serially passaged TNBC PDXs resulted in cisplatin-resistant clones emerging from low-fitness phylogenetic lineages in the untreated setting. Conversely, high-fitness clones from treatment-naive controls were eradicated, signalling an inversion of the fitness landscape. Finally, upon release of drug, selection pressure dynamics were reversed, indicating a fitness cost of treatment resistance. Together, our findings define clonal fitness linked to both CNA and therapeutic resistance in polyclonal tumours. Whole-genome sequencing of human cancer cells in patient-derived mouse xenograft models indicates a key role for TP53 in determining the fitness landscape of polyclonal cancer cell populations., Author(s): Sohrab Salehi [sup.1] , Farhia Kabeer [sup.1] [sup.2] , Nicholas Ceglia [sup.3] , Mirela Andronescu [sup.1] [sup.2] , Marc J. Williams [sup.3] , Kieran R. Campbell [sup.4] , Tehmina [...]

In 2017, a National Academies of Sciences, Engineering, and Medicine (NASEM) report comprehensively evaluated the body of evidence regarding cannabis health effects through the year 2016. The objectives of this study are to identify and map the most recently (2016-2019) published literature across approved conditions for medical cannabis and to evaluate the quality of identified recent systematic reviews, published following the NASEM report. Following the literature search from 5 databases and consultation with experts, 11 conditions were identified for evidence compilation and evaluation: amyotrophic lateral sclerosis, autism, cancer, chronic noncancer pain, Crohn's disease, epilepsy, glaucoma, human immunodeficiency virus/AIDS, multiple sclerosis (MS), Parkinson's disease, and posttraumatic stress disorder. A total of 198 studies were included after screening for condition-specific relevance and after imposing the following exclusion criteria: preclinical focus, non-English language, abstracts only, editorials/commentary, case studies/series, and non-U.S. study setting. Data extracted from studies included: study design type, outcome definition, intervention definition, sample size, study setting, and reported effect size. Few completed randomized controlled trials (RCTs) were identified. Studies classified as systematic reviews were graded using the Assessing the Methodological Quality of Systematic Reviews-2 tool to evaluate the quality of evidence. Few high-quality systematic reviews were available for most conditions, with the exceptions of MS (9 of 9 graded moderate/high quality; evidence for 2/9 indicating cannabis improved outcomes; evidence for 7/9 indicating cannabis inconclusive), epilepsy (3 of 4 graded moderate/high quality; 3 indicating cannabis improved outcomes; 1 indicating cannabis inconclusive), and chronic noncancer pain (12 of 13 graded moderate/high quality; evidence for 7/13 indicating cannabis improved outcomes; evidence from 6/7 indicating cannabis inconclusive). Among RCTs, we identified few studies of substantial rigor and quality to contribute to the evidence base. However, there are some conditions for which significant evidence suggests that select dosage forms and routes of administration likely have favorable risk-benefit ratios (i.e., epilepsy and chronic noncancer pain). The body of evidence for medical cannabis requires more rigorous evaluation before consideration as a treatment option for many conditions, and evidence necessary to inform policy and treatment guidelines is currently insufficient for many conditions. Keywords: Medical marijuana, Cannabis, Cannabinoids, Cannabidiol, Marijuana efficacy, Commonly recommended conditions for marijuana treatment, Marijuana clinical outcomes, Author(s): Sebastian Jugl [a,b]; Aimalohi Okpeku [a,b]; Brianna Costales [a,b]; Earl J. Morris [a,b]; Golnoosh Alipour-Haris [a,b]; Juan M. Hincapie-Castillo [a,b]; Nichole E. Stetten [c]; Ruba Sajdeya [d]; Shailina Keshwani [...]

Background Carnitine plays a key role in energy production in the myocardium and is efficiently removed by continuous kidney replacement therapy (CKRT). Effects of levocarnitine supplementation on myocardial function in children receiving CKRT have not been investigated. Methods This controlled pilot cohort study of 48 children investigated effects of levocarnitine supplementation on myocardial strain in children receiving CKRT for acute kidney injury (AKI). Children (n = 9) with AKI had total (TC) and free plasma carnitine (FC) measurements and echocardiogram for longitudinal and circumferential strain at baseline (prior to CKRT) and follow-up (on CKRT for 1 week with intravenous levocarnitine supplementation, 20 mg/kg/day). Intervention group was compared with three controls: (1) CKRT controls (n = 10) received CKRT 1 week (+AKI, no levocarnitine), (2) ICU controls (n = 9) were parenteral nutrition-dependent for 1 week (no AKI, no levocarnitine), and (3) healthy controls (n = 20). Results In the Intervention group, TC and FC increased from 36.0 and 18 [mu]mol/L to 93.5 and 74.5 [mu]mol/L after supplementation. TC and FC of unsupplemented CKRT controls declined from 27.2 and 18.6 [mu]mol/L to 12.4 and 6.6 [mu]mol/L, which was lower vs. ICU controls (TC 32.0, FC 26.0 [mu]mol/L), p < 0.05. Longitudinal and circumferential strain of the Intervention group improved from - 18.5% and - 18.3% to - 21.1% and - 27.6% after levocarnitine supplementation; strain of CKRT controls (-14.4%, -20%) remained impaired and was lower vs. Intervention and Healthy Control groups at follow-up, p < 0.05. Conclusions Levocarnitine supplementation is associated with repletion of plasma carnitine and improvement in myocardial strain and may benefit pediatric patients undergoing prolonged CKRT., Author(s): Kristen Sgambat [sup.1] , Sarah Clauss [sup.2] , Asha Moudgil [sup.1] Author Affiliations: (1) grid.239560.b, 0000 0004 0482 1586, Department of Nephrology, Children's National Hospital, , 111 Michigan Avenue [...]

Whole-genome doubling (WGD) is common in human cancers, occurring early in tumorigenesis and generating genetically unstable tetraploid cells that fuel tumour development.sup.1,2. Cells that undergo WGD (WGD.sup.+ cells) must adapt to accommodate their abnormal tetraploid state; however, the nature of these adaptations, and whether they confer vulnerabilities that can be exploited therapeutically, is unclear. Here, using sequencing data from roughly 10,000 primary human cancer samples and essentiality data from approximately 600 cancer cell lines, we show that WGD gives rise to common genetic traits that are accompanied by unique vulnerabilities. We reveal that WGD.sup.+ cells are more dependent than WGD.sup.- cells on signalling from the spindle-assembly checkpoint, DNA-replication factors and proteasome function. We also identify KIF18A, which encodes a mitotic kinesin protein, as being specifically required for the viability of WGD.sup.+ cells. Although KIF18A is largely dispensable for accurate chromosome segregation during mitosis in WGD.sup.- cells, its loss induces notable mitotic errors in WGD.sup.+ cells, ultimately impairing cell viability. Collectively, our results suggest new strategies for specifically targeting WGD.sup.+ cancer cells while sparing the normal, non-transformed WGD.sup.- cells that comprise human tissue. Cancer cells that have undergone whole-genome doubling are more reliant than their near-diploid counterparts on DNA-replication factors, the spindle-assembly checkpoint and a mitotic kinesin protein, KIF18A., Author(s): Ryan J. Quinton [sup.1] , Amanda DiDomizio [sup.1] , Marc A. Vittoria [sup.1] , Kristýna Kotýnková [sup.1] , Carlos J. Ticas [sup.1] , Sheena Patel [sup.1] , Yusuke Koga [...]

Most (if not all) tumors emerge and progress under a strong evolutionary pressure imposed by trophic, metabolic, immunological, and therapeutic factors. The relative impact of these factors on tumor evolution changes over space and time, ultimately favoring the establishment of a neoplastic microenvironment that exhibits considerable genetic, phenotypic, and behavioral heterogeneity in all its components. Here, we discuss the main sources of intratumoral heterogeneity and its impact on the natural history of the disease, including sensitivity to treatment, as we delineate potential strategies to target such a detrimental feature of aggressive malignancies. The many levels of heterogeneity within tumors dictate their response to therapy and should be considered in future therapeutic regimes., Author(s): Ilio Vitale [sup.1] [sup.2] , Efrat Shema [sup.3] , Sherene Loi [sup.4] [sup.5] , Lorenzo Galluzzi [sup.6] [sup.7] [sup.8] [sup.9] [sup.10] Author Affiliations: (1) IIGM - Italian Institute for [...]

Background Colorectal cancer (CRC) is a highly prevalent disease in developed countries. Inherited Mendelian causes account for approximately 5% of CRC cases, with Lynch syndrome and familial adenomatous polyposis being the most prevalent forms. Scientific efforts are focused on the discovery of new candidate genes associated with CRC and new associations of phenotypes with well-established cancer-related genes. BRCA1-associated ring domain (BARD1) gene deleterious germline variants are associated with a moderate increase in the relative risk of breast cancer, but their association with other neoplasms, such as CRC, remains unclear. Case presentation We present the case of a 49-year-old male diagnosed with rectal adenocarcinoma whose maternal family fulfilled Amsterdam clinical criteria for Lynch syndrome. Genetic test confirmed the presence in heterozygosis of a germline pathogenic deletion of exons 8-11 in BARD1 gene. The predictive genetic study of the family revealed the presence of this pathogenic variant in his deceased cancer affected relatives, confirming co-segregation of the deletion with the disease. Conclusions To the best of our knowledge, this is the first published work in which this BARD1 deletion is detected in a family with familial colorectal cancer type X (FCCTX) syndrome, in which the clinical criteria for Lynch syndrome without alteration of the DNA mismatch repair (MMR) system are fulfilled. Whether this incidental germline finding is the cause of familial colorectal aggregation remains to be elucidated in scientific forums. Patients should be carefully assessed in specific cancer genetic counseling units to account for hypothetical casual findings in other genes, in principle unrelated to the initial clinical suspicion, but with potential impact on their health. Keywords: Colorectal cancer, Hereditary, BARD1, Pathogenic variant, Deletion, Amsterdam clinical criteria, Familial colorectal cancer type X syndrome, Cancer genetic counseling, Author(s): Sergio Carrera[sup.1], Ana Belén Rodríguez-Martínez[sup.2], Intza Garin[sup.3], Esther Sarasola[sup.2], Cristina Martínez[sup.3], Hiart Maortua[sup.3], Almudena Callejo[sup.4], Abigail Ruiz de Lobera[sup.4], Alberto Muéoz[sup.4], Nagore Miéambres[sup.4] and Pablo Jiménez-Labaig[sup.4] Background CRC is [...]

Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis. Single-cell analysis of lung cancer progression uncovers developmental and regenerative programs co-opted by cancer cells and immune-mediated pruning during metastatic outbreak, Author(s): Ashley M. Laughney [sup.1] [sup.2] [sup.3] [sup.4] [sup.5] , Jing Hu [sup.1] , Nathaniel R. Campbell [sup.1] [sup.2] [sup.6] , Samuel F. Bakhoum [sup.7] [sup.8] , Manu Setty [sup.2] [...]

Immune checkpoint blockade (ICB) of PD-1 and CTLA-4 to treat metastatic melanoma (MM) has variable therapeutic benefit. To explore this in peripheral samples, we characterized CD8.sup.+ T cell gene expression across a cohort of patients with MM receiving anti-PD-1 alone (sICB) or in combination with anti-CTLA-4 (cICB). Whereas CD8.sup.+ transcriptional responses to sICB and cICB involve a shared gene set, the magnitude of cICB response is over fourfold greater, with preferential induction of mitosis- and interferon-related genes. Early samples from patients with durable clinical benefit demonstrated overexpression of T cell receptor-encoding genes. By mapping T cell receptor clonality, we find that responding patients have more large clones (those occupying >0.5% of repertoire) post-treatment than non-responding patients or controls, and this correlates with effector memory T cell percentage. Single-cell RNA-sequencing of eight post-treatment samples demonstrates that large clones overexpress genes implicated in cytotoxicity and characteristic of effector memory T cells, including CCL4, GNLY and NKG7. The 6-month clinical response to ICB in patients with MM is associated with the large CD8.sup.+ T cell clone count 21 d after treatment and agnostic to clonal specificity, suggesting that post-ICB peripheral CD8.sup.+ clonality can provide information regarding long-term treatment response and, potentially, facilitate treatment stratification. Transcriptomic analysis of peripheral CD8.sup.+ T cells in a cohort of patients with metastatic melanoma receiving checkpoint inhibitors shows that the number of large clones early post-treatment is strongly associated with six-month clinical outcome., Author(s): Benjamin P. Fairfax [sup.1] [sup.2] [sup.3] , Chelsea A. Taylor [sup.1] [sup.2] , Robert A. Watson [sup.1] [sup.2] , Isar Nassiri [sup.1] [sup.2] , Sara Danielli [sup.2] [sup.3] , [...]

Background Risk assessment for hereditary cancer syndromes is recommended in primary care, but family history is rarely collected in enough detail to facilitate risk assessment and referral - a roadblock that disproportionately impacts individuals with healthcare access barriers. We sought to qualitatively assess a literacy-adapted, electronic patient-facing family history tool developed for use in diverse, underserved patient populations recruited in the Cancer Health Assessments Reaching Many (CHARM) Study. Methods Interview participants were recruited from a subpopulation of CHARM participants who experienced barriers to tool use in terms of spending a longer time to complete the tool, having incomplete attempts, and/or providing inaccurate family history in comparison to a genetic counselor-collected standard. We conducted semi-structured interviews with participants about barriers and facilitators to tool use and overall tool acceptability; interviews were recorded and professionally transcribed. Transcripts were coded based on a codebook developed using inductive techniques, and coded excerpts were reviewed to identify overarching themes related to barriers and facilitators to family history self-assessment and acceptability of the study tool. Results Interviewees endorsed the tool as easy to navigate and understand. However, they described barriers related to family history information, literacy and language, and certain tool functions. Participants offered concrete, easy-to-implement solutions to each barrier. Despite experience barriers to use of the tool, most participants indicated that electronic family history self-assessment was acceptable or preferable in comparison to clinician-collected family history. Conclusions Even for participants who experienced barriers to tool use, family history self-assessment was considered an acceptable alternative to clinician-collected family history. Barriers experienced could be overcome with minor adaptations to the current family history tool. Trial registration This study is a sub-study of the Cancer Health Assessments Reaching Many (CHARM) trial, ClinicalTrials.gov, NCT03426878. Registered 8 February 2018. Keywords: Underserved, Hereditary cancer risk assessment, Digital health, Genetics, Author(s): Kathleen F. Mittendorf[sup.1], Hannah S. Lewis[sup.2], Devan M. Duenas[sup.2], Donna J. Eubanks[sup.3], Marian J. Gilmore[sup.4], Katrina A. B. Goddard[sup.5], Galen Joseph[sup.6], Tia L. Kauffman[sup.3], Stephanie A. Kraft[sup.2,7], Nangel M. [...]

Malignant mesothelioma (MM) is an aggressive cancer primarily diagnosed on the basis of histological criteria.sup.1. The 2015 World Health Organization classification subdivides mesothelioma tumors into three histological types: epithelioid, biphasic and sarcomatoid MM. MM is a highly complex and heterogeneous disease, rendering its diagnosis and histological typing difficult and leading to suboptimal patient care and decisions regarding treatment modalities.sup.2. Here we have developed a new approach--based on deep convolutional neural networks--called MesoNet to accurately predict the overall survival of mesothelioma patients from whole-slide digitized images, without any pathologist-provided locally annotated regions. We validated MesoNet on both an internal validation cohort from the French MESOBANK and an independent cohort from The Cancer Genome Atlas (TCGA). We also demonstrated that the model was more accurate in predicting patient survival than using current pathology practices. Furthermore, unlike classical black-box deep learning methods, MesoNet identified regions contributing to patient outcome prediction. Strikingly, we found that these regions are mainly located in the stroma and are histological features associated with inflammation, cellular diversity and vacuolization. These findings suggest that deep learning models can identify new features predictive of patient survival and potentially lead to new biomarker discoveries. Deep convolutional neural networks predict survival of mesothelioma patients and identify histological features associated with outcome that transcend current histological classifications., Author(s): Pierre Courtiol [sup.1] , Charles Maussion [sup.1] , Matahi Moarii [sup.1] , Elodie Pronier [sup.1] , Samuel Pilcer [sup.1] , Meriem Sefta [sup.1] , Pierre Manceron [sup.1] , Sylvain [...]

A large number of children with developmental disorders like autism spectrum disorder (ASD), learning disabilities, and attention deficit hyperactivity disorder have high anxiety. It has also been shown that the high anxiety has harmful effects on them, directly and indirectly. In this study, we conducted a survey on community samples on the level of anxiety of children with developmental disorders in Japan that had hardly been studied so far, and compared them with the anxiety in children in a general population sample in previous studies. Analysis on the 203 participants showed that children with developmental disorders have high anxiety as compared to children as in previous studies in other countries. Particularly children with ASD had a higher anxiety compared with children with developmental disorders without ASD., Author(s): Yuma Ishimoto [sup.1] , Takahiro Yamane [sup.2] , Yuki Matsumoto [sup.3] Author Affiliations: (Aff1) 0000 0001 0663 5064, grid.265107.7, Teacher Education Center, Tottori University, , 4-101 Minami, Koyama-cho, 680-8550, [...]

Myocardial infarction (MI) in mice results in cardiac rupture at 4-7 days after MI, whereas cardiac fibrosis and dysfunction occur later. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) has anti-inflammatory, anti-fibrotic, and pro-angiogenic properties. We hypothesized that Ac-SDKP reduces cardiac rupture and adverse cardiac remodeling, and improves function by promoting angiogenesis and inhibiting detrimental reactive fibrosis and inflammation after MI. C57BL/6J mice were subjected to MI and treated with Ac-SDKP (1.6 mg/kg per day) for 1 or 5 weeks. We analyzed (1) intercellular adhesion molecule-1 (ICAM-1) expression; (2) inflammatory cell infiltration and angiogenesis; (3) gelatinolytic activity; (4) incidence of cardiac rupture; (5) p53, the endoplasmic reticulum stress marker CCAAT/enhancer binding protein homology protein (CHOP), and cardiomyocyte apoptosis; (6) sarcoplasmic reticulum [Ca.sup.2+] ATPase (SERCA2) expression; (7) interstitial collagen fraction and capillary density; and (8) cardiac remodeling and function. Acutely, Ac-SDKP reduced cardiac rupture, decreased ICAM-1 expression and the number of infiltrating macrophages, decreased gelatinolytic activity, p53 expression, and myocyte apoptosis, but increased capillary density in the infarction border. Chronically, Ac-SDKP improved cardiac structures and function, reduced CHOP expression and interstitial collagen fraction, and preserved myocardium SERCA2 expression. Thus, Ac-SDKP decreased cardiac rupture, ameliorated adverse cardiac remodeling, and improved cardiac function after MI, likely through preserved SERCA2 expression and inhibition of endoplasmic reticulum stress. Key words: Ac-SDKP, mice, myocardial infarction, SERCA2, endoplasmic reticulum stress, cardiac function. L'infarctus du myocarde (IM) chez la souris entraine des ruptures cardiaques de 4 a 7 jours apres l'IM, mais la fibrose et le dysfonctionnement surviennent plus tard. La N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) dispose de proprietes antiinflammatoires, anti-fibrotiques et angiogeniques. Nous avons formule l'hypothese selon laquelle l'Ac-SDKP permet de reduire la frequence des ruptures, d'attenuer le remodelage nefaste et d'ameliorer le fonctionnement du creur en favorisant l'angiogenese et en inhibant la fibrose et l'inflammation nuisibles en reaction a l'IM. Nous avons cree un IM chez des souris C57BL/6J auxquelles nous avons ensuite administre de l'Ac-SDKP (1,6 mg/kg par jour) pendant 1 ou 5 semaines. Nous avons etudie les phenomenes suivants : (1) expression de la molecule 1 d'adherence intercellulaire (ICAM-1); (2) infiltration de cellules inflammatoires et angiogenese; (3) activite gelatinolytique; (4) frequence des ruptures cardiaques; (5) p53, proteine CHOP (pour <>) comme marqueur du stress impose au reticulum endoplasmique et apoptose des cardiomyocytes; (6) expression de la pompe [Ca.sup.2+] ATPase dans le reticulum sarcoplasmique (SERCA2); (7) fraction de collagene et densite des capillaires interstitiels; et (8) fonctionnement et remodelage du creur. A court terme, l'Ac-SDKP permettait de reduire la frequence des ruptures cardiaques, de diminuer l'expression de l'ICAM-1 et le nombre de macrophages infiltres, de diminuer l'activite gelatinolytique et l'expression de p53, ainsi que d'attenuer l'apoptose des myocytes, mais le produit permettait d'augmenter la densite des capillaires en bordure de l'infarctus. A long terme, l'Ac-SDKP permettait d'ameliorer le fonctionnement du creur et ses structures, de diminuer l'expression de la proteine CHOP et la fraction de collagene interstitiel, ainsi que de preserver l'expression de la SERCA2 dans le myocarde. Par consequent, l'Ac-SDKP permettait de reduire la frequence des ruptures cardiaques, d'attenuer le remodelage cardiaque nefaste, ainsi que d'ameliorer le fonctionnement du creur apres un IM, probablement par l'intermediaire de la preservation de l'expression de la SERCA2 et de l'inhibition du stress impose au reticulum endoplasmique. [Traduit par la Redaction] Mots-cles: Ac-SDKP, souris, infarctus du myocarde, SERCA2, stress impose au reticulum endoplasmique, fonction cardiaque., Introduction Myocardial infarction (MI) is a leading cause of human death. MI is associated with high rates of acute death caused by ventricular wall rupture, arrhythmias, or cardiogenic shock, and [...]

The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low.sup.1-5, highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation.sup.6-13. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST.sup.14) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1-PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNF-[alpha] signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types. A pick-the-winner clinical trial design in patients with metastatic triple-negative breast cancer shows that immune induction with doxorubicin or cisplatin may improve clinical responses to PD-1 blockade and induce a more favorable tumor microenvironment., Author(s): Leonie Voorwerk [sup.1] , Maarten Slagter [sup.1] [sup.2] [sup.3] , Hugo M. Horlings [sup.4] , Karolina Sikorska [sup.5] , Koen K. van de Vijver [sup.4] [sup.6] , Michiel de [...]

Background Adenine phosphoribosyltransferase (APRT) deficiency is a hereditary purine metabolism disorder that causes kidney stones and chronic kidney disease (CKD). The purpose of this study was to examine the course of APRT deficiency in patients who presented in childhood. Methods The disease course of 21 (35%) patients in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, who presented with manifestations of APRT deficiency and/or were diagnosed with the disorder before the age of 18 years, was studied. The effect of pharmacotherapy on renal manifestations and outcomes was thoroughly assessed. Results Fourteen children were placed on allopurinol, 100 (25-200) mg/day, at the age of 2.6 (0.6-16.5) years. Six of these patients had experienced kidney stone events and three had developed acute kidney injury (AKI) prior to allopurinol treatment. During 18.9 (1.7-31.5) years of pharmacotherapy, stones occurred in two patients and AKI in three. Six adult patients started allopurinol treatment, 200 (100-300) mg/day, at age 29.8 (20.5-42.4) years. Five of these patients had experienced 28 stone episodes and AKI had occurred in two. Stone recurrence occurred in four patients and AKI in two during 11.2 (4.2-19.6) years of allopurinol therapy. Lack of adherence and insufficient dosing contributed to stone recurrence and AKI during pharmacotherapy. At latest follow-up, estimated glomerular filtration rate (eGFR) was 114 (70-163) and 62 (10-103) mL/min/1.73 m.sup.2 in those who initiated treatment as children and adults, respectively. All three patients with CKD stages 3-5 at the last follow-up were adults when pharmacotherapy was initiated. Conclusion Timely diagnosis and treatment of APRT deficiency decreases renal complications and preserves kidney function., Author(s): Hrafnhildur Linnet Runolfsdottir [sup.1] [sup.2] , Runolfur Palsson [sup.1] [sup.2] , Inger MSch Agustsdottir [sup.3] , Olafur S Indridason [sup.2] , Vidar O Edvardsson [sup.1] [sup.3] Author Affiliations: (Aff1) [...]

Byline: Shivanshu. Misra, Shankar. Balasubramanian, B. Srikanth, Saravana. Kumar, S. Christinajoice, Deepa. Nandhini, P. Raj Context: The importance of upper gastrointestinal (UGI) contrast study following sleeve gastrectomy (SG) is equivocal. [...]

Background Cardiovascular disease is a leading cause of death in general population and the second leading cause of mortality and morbidity in cancer survivors after recurrent malignancy in the United States. The growing awareness of cancer therapy-related cardiac dysfunction (CTRCD) has led to an emerging field of cardio-oncology; yet, there is limited knowledge on how to predict which patients will experience adverse cardiac outcomes. We aimed to perform unbiased cardiac risk stratification for cancer patients using our large-scale, institutional electronic medical records. Methods and findings We built a large longitudinal (up to 22 years' follow-up from March 1997 to January 2019) cardio-oncology cohort having 4,632 cancer patients in Cleveland Clinic with 5 diagnosed cardiac outcomes: atrial fibrillation, coronary artery disease, heart failure, myocardial infarction, and stroke. The entire population includes 84% white Americans and 11% black Americans, and 59% females versus 41% males, with median age of 63 (interquartile range [IQR]: 54 to 71) years old. We utilized a topology-based K-means clustering approach for unbiased patient-patient network analyses of data from general demographics, echocardiogram (over 25,000), lab testing, and cardiac factors (cardiac). We performed hazard ratio (HR) and Kaplan-Meier analyses to identify clinically actionable variables. All confounding factors were adjusted by Cox regression models. We performed random-split and time-split training-test validation for our model. We identified 4 clinically relevant subgroups that are significantly correlated with incidence of cardiac outcomes and mortality. Among the 4 subgroups, subgroup I (n = 625) has the highest risk of de novo CTRCD (28%) with an HR of 3.05 (95% confidence interval (CI) 2.51 to 3.72). Patients in subgroup IV (n = 1,250) had the worst survival probability (HR 4.32, 95% CI 3.82 to 4.88). From longitudinal patient-patient network analyses, the patients in subgroup I had a higher percentage of de novo CTRCD and a worse mortality within 5 years after the initiation of cancer therapies compared to long-time exposure (6 to 20 years). Using clinical variable network analyses, we identified that serum levels of NT-proB-type Natriuretic Peptide (NT-proBNP) and Troponin T are significantly correlated with patient's mortality (NT-proBNP > 900 pg/mL versus NT-proBNP = 0 to 125 pg/mL, HR = 2.95, 95% CI 2.28 to 3.82, p 0.05 [mu]g/L versus Troponin T [less than or equal to] 0.01 [mu]g/L, HR = 2.08, 95% CI 1.83 to 2.34, p < 0.001). Study limitations include lack of independent cardio-oncology cohorts from different healthcare systems to evaluate the generalizability of the models. Meanwhile, the confounding factors, such as multiple medication usages, may influence the findings. Conclusions In this study, we demonstrated that the patient-patient network clustering methodology is clinically intuitive, and it allows more rapid identification of cancer survivors that are at greater risk of cardiac dysfunction. We believed that this study holds great promise for identifying novel cardiac risk subgroups and clinically actionable variables for the development of precision cardio-oncology., Author(s): Yuan Hou 1, Yadi Zhou 1, Muzna Hussain 2,3, G. Thomas Budd 4, Wai Hong Wilson Tang 1,2,5, James Abraham 4, Bo Xu 2, Chirag Shah 6, Rohit Moudgil [...]

Cancer treatment by immune checkpoint blockade (ICB) can bring long-lasting clinical benefits, but only a fraction of patients respond to treatment. To predict ICB response, we developed TIDE, a computational method to model two primary mechanisms of tumor immune evasion: the induction of T cell dysfunction in tumors with high infiltration of cytotoxic T lymphocytes (CTL) and the prevention of T cell infiltration in tumors with low CTL level. We identified signatures of T cell dysfunction from large tumor cohorts by testing how the expression of each gene in tumors interacts with the CTL infiltration level to influence patient survival. We also modeled factors that exclude T cell infiltration into tumors using expression signatures from immunosuppressive cells. Using this framework and pre-treatment RNA-Seq or NanoString tumor expression profiles, TIDE predicted the outcome of melanoma patients treated with first-line anti-PD1 or anti-CTLA4 more accurately than other biomarkers such as PD-L1 level and mutation load. TIDE also revealed new candidate ICB resistance regulators, such as SERPINB9, demonstrating utility for immunotherapy research. An algorithm-selected gene signature focused on tumor immune evasion and suppression predicts response to immune checkpoint blockade in melanoma, exceeding the accuracy of current clinical biomarkers., Author(s): Peng Jiang [sup.1] [sup.2] , Shengqing Gu [sup.3] , Deng Pan [sup.4] [sup.5] , Jingxin Fu [sup.6] , Avinash Sahu [sup.1] [sup.2] , Xihao Hu [sup.1] [sup.2] , Ziyi [...]

Countless times each day, the acute inflammatory response protects us from invading microbes, injuries, and insults from within, as in surgery-induced tissue injury. These challenges go unnoticed because they are self-limited and naturally resolve without progressing to chronic inflammation. Peripheral blood markers of inflammation are present in many common diseases, including inflammatory bowel disease, cardiovascular disease, neurodegenerative disease, and cancer. While acute inflammation is protective, excessive swarming of neutrophils amplifies collateral tissue damage and inflammation. Hence, understanding the mechanisms that control the resolution of acute inflammation provides insight into preventing and treating inflammatory diseases in multiple organs. This Review focuses on the resolution phase of inflammation with identification of specialized pro-resolving mediators (SPMs) that involve three separate biosynthetic and potent mediator families, which are defined using the first quantitative resolution indices to score this vital process. These are the resolvins, protectins, and maresins: bioactive metabolomes that each stimulate self-limited innate responses, enhance innate microbial killing and clearance, and are organ-protective. We briefly address biosynthesis of SPMs and their activation of endogenous resolution programs as terrain for new therapeutic approaches that are not, by definition, immunosuppressive, but rather new immunoresolvent therapies., Protection versus uncontrolled inflammation: first responders and resolution New evidence indicates that uncontrolled inflammation is a prominent component of many common diseases, including well-known inflammatory diseases such as arthritis and [...]

Insight into the cancer cell populations that are responsible for relapsed disease is needed to improve outcomes. Here we report a single-cell-based study of B cell precursor acute lymphoblastic leukemia at diagnosis that reveals hidden developmentally dependent cell signaling states that are uniquely associated with relapse. By using mass cytometry we simultaneously quantified 35 proteins involved in B cell development in 60 primary diagnostic samples. Each leukemia cell was then matched to its nearest healthy B cell population by a developmental classifier that operated at the single-cell level. Machine learning identified six features of expanded leukemic populations that were sufficient to predict patient relapse at diagnosis. These features implicated the pro-BII subpopulation of B cells with activated mTOR signaling, and the pre-BI subpopulation of B cells with activated and unresponsive pre-B cell receptor signaling, to be associated with relapse. This model, termed 'developmentally dependent predictor of relapse' (DDPR), significantly improves currently established risk stratification methods. DDPR features exist at diagnosis and persist at relapse. By leveraging a data-driven approach, we demonstrate the predictive value of single-cell 'omics' for patient stratification in a translational setting and provide a framework for its application to human cancer., Author(s): Zinaida Good [1, 2, 3, 4]; Jolanda Sarno [5, 6]; Astraea Jager [1, 2, 5]; Nikolay Samusik [1, 2]; Nima Aghaeepour [1, 2]; Erin F Simonds [1, 2]; Leah [...]

Despite the many studies that have shown minimal health risks to individuals living outside of Japan following the Fukushima Nuclear Accident, there are persisting concerns regarding the consumption of Pacific seafood that may be contaminated with radioactive species from Fukushima. To address these concerns, the activity concentrations of anthropogenic [.sup.134]Cs and [.sup.137]Cs, as well as naturally occurring [.sup.40]K, were measured in Pacific salmon collected from Kilby Provincial Park, British Columbia (BC), in 2013 and from the Quesnel River, BC, in 2014 using low-background gamma-ray spectroscopy. In addition, soil samples and a single roof-debris sample were collected and analysed to provide a record of Fukushima-derived contamination in BC. Cesium-134 was not detected in the salmon samples. Cesium-137 was not detected in any of the sockeye or chum samples, although it was detected in all of the Chinook samples. The weighted average ([+ or -]1[sigma]) [.sup.137]Cs activity concentration in the Chinook salmon collected in 2013 and 2014 was 0.23 (3) and 0.20 (3) Bq/kg fresh weight, respectively. A conservative annual dose estimate for an adult who consumes the average Canadian quantity of seafood per year, contaminated with radiocesium at the maximum concentrations measured in this campaign, was calculated to be 0.054 [micro]Sv per year. Cesium-134 was detected in all but two of the soil samples. A weak positive correlation was observed between presence of [.sup.134]Cs and of [.sup.7]Be suggesting that the [.sup.134]Cs arrived via atmospheric deposition. Cesium-137 was present in every soil sample, although the total radiocesium activity concentrations measured were significantly less than action levels set by Health Canada. Key words: Fukushima, Pacific salmon, dose estimate, low-background gamma-ray spectroscopy, soil, [.sup.134]Cs, [.sup.137]Cs, [.sup.7]Be. Malgre les nombreuses etudes qui ont demontre, a la suite de l'accident nucleaire de Fukushima, que les risques pour la sante des personnes vivant en dehors du Japon sont minimes, des preoccupations demeurent quant a la consommation de poissons et fruits de mer du Pacifique qui pourraient avoir ete contamines par des especes radioactives provenant de Fukushima. Afin de repondre a ces preoccupations, nous avons mesure les radioconcentrations de [.sup.134]Cs et de [.sup.137]Cs anthropiques ainsi que celles du [.sup.40]K naturellement present dans le saumon du Pacifique capture en 2013 dans le parc provincial Kilby, en Colombie-Britannique, et en 2014 dans la riviere Quesnel, egalement en Colombie-Britannique, a l'aide de la spectrometrie gamma a faible bruit de fond. Par ailleurs, nous avons recueilli et analyse des echantillons de sol ainsi qu'un echantillon de debris de toit afi n dresser un portrait de la contamination radioactive issue de Fukushima en Colombie-Britannique. Nous n'avons pas deteete de cesium-134 dans les echantillons de saumon. Pour ce qui est du cesium-137, nous ne l'avons detecte dans aucun echantillon de saumon sockeye ou keta, mais dans tous les echantillons de saumon quinnat. La moyenne ponderee ([+ or -]1[sigma]) de la radioconcentration du [.sup.137]Cs dans le saumon quinnat capture en 2013 et en 2014 etait de 0,23(3) et de 0,20(3) Bq/kg de saumon frais, respectivement. Selon une estimation prudente, nous avons calcule que la dose annuelle a laquelle serait expose un adulte consommant la quantite annuelle moyenne de poissons et fruits de mer au Canada, en supposant que ces derniers soient contamines par le cesium radioactif aux concentrations maximales mesurees dans la presente etude, est de 0,054 [micro]Sv par annee. Nous avons deteete du cesium-134 dans tous les echantillons de sol sauf deux d'entre eux. Nous avons observe une faible correlation positive entre la presence de [.sup.134]Cs et de [.sup.7]Be, ce qui laisse presumer que le [.sup.134]Cs est proviendrait des depots atmospheriques. Le cesium-137 etait present dans tous les echantillons de sol, bien que les radioconcentrations totales de cesium que nous avons mesurees aient ete bien en deca des limites etablies par Sante Canada. [Traduit par la Redaction] Mots-cles : Fukushima, saumon du Pacifique, estimation de la dose, spectrometrie gamma a faible bruit de fond, sols, [.sup.134]Cs, [.sup.137]Cs, [.sup.7]Be., Introduction Following the Fukushima Nuclear Accident (FNA) in 2011, large quantities of fission fragments and nuclear fuel were released into the environment from the damaged Fukushima Dai-ichi Nuclear Power Plant. [...]

The excited-state proton transfer (ESPT) dynamical behavior of aloesaponarin I (ASI) was studied using density functional theory (DFT) and time-dependent DFT (TDDFT) methods. Our calculated vertical excitation energies based on TDDFT reproduced the experimental absorption and fluorescence spectra well [Nagaoka et al. J. Phys. Chem. B, 117, 4347 (2013)]. Two intramolecular hydrogen bonds were confirmed to be strengthened in the [S.sub.1] state, which makes ESPT possible. Herein, the ESPT process is more likely to happen, along with one hydrogen bond ([O.sub.1]-[H.sub.2]***[O.sub.3]). Qualitative analyses about charge distribution further demonstrate that the ESPT process could occur because of the intramolecular charge transfer. Our constructed potential energy surfaces of both [S.sub.0] and [S.sub.1] states show that a single proton transfer reactive is more reasonable along with the intramolecular hydrogen bond ([O.sub.1]-[H.sub.2]***[O.sub.3]) rather than [O.sub.4]--[H.sub.5]***[O.sub.6] in the [S.sub.1] stated potential energy surface. Then, ASI-SPT* decays to the ground state with a 640 nm fluorescence; subsequently, the ASI-SPT form shows that reverse ground state single-proton transfer back to the ASI structure occurs. Particularly, dependent on relatively accurate potential energy barriers among these excited-state stable structures, we confirmed the excited-state single proton transfer process rather than using the controversial nodal plane model. Key words: proton transfer, intramolecular hydrogen bond, PES, frontier molecular orbital. Nous avons etudie le comportement dynamique du transfert de proton a l'etat excite (TPEE) de l'aloesaponarine I (ASI) a l'aide des methodes de la theorie de la fonctionnelle de la densite (DFT) et de la DFT dependante du temps (TDDFT). Les energies d'excitation verticales que nous avons obtenues par calculs bases sur la TDDFT concordaient bien avec les spectres d'absorption et de fluorescence experimentaux [Nagaoka et al. J. Phys. Chem. B, 117 (2013) 4347-4353]. Nous avons demontre que les deux liaisons hydrogene intramoleculaires se trouvaient renforcees dans l'etat S1, ce qui indique la possibilite qu'un TPEE reactif puisse se produire. Dans le cadre des presents travaux, nous montrons que le processus de TPEE est plus susceptible de se produire le long d'une des liaisons hydrogene ([O.sub.1]-[H.sub.2]...O3). Des analyses quantitatives de la distribution de charge permettent de demontrer de maniere plus convaincante que le TPEE pourrait se produire par transfert de charge intramoleculaire. D'apres les surfaces d'energie potentielle des etats [S.sub.0] et [S.sub.1] que nous avons elaborees, nous montrons que, sur la surface d'energie potentielle de l'etat S1, le transfert d'un proton reactif unique est plus susceptible de se produire le long de la liaison hydrogene intramoleculaire [O.sub.1]-[H.sub.2]...[O.sub.3] que le long de la liaison [O.sub.4]-[H.sub.5]...[O.sub.6]. Par la suite, la forme excitee de l'ASI* en transfert de proton unique retourne a l'etat fondamental en emettant une bande de fluorescence a 640 nm, puis subit un retrotransfert de proton unique a l'etat fondamental pour reformer la structure de l'ASI. En nous basant sur les barrieres d'energie potentielle relativement exactes entre ces structures stables a l'etat excite, nous avons demontre que le processus de transfert de proton unique a l'etat excite constituait une hypothese plus plausible que le controverse modele de plan nodal. [Traduit par la Redaction] Mots-cles: transfert de proton, liaison hydrogene intramoleculaire, SEP, orbitale moleculaire frontiere., Introduction Proton transfer, a fundamental kind of photochemical and photophysical process, is ubiquitous. (1-5) In general, in chemical and biological acid-base dynamics, proton transfer is very important, resulting from site-specific [...]

Background 16-25% of colorectal cancers (CRCs) diagnosed under age 50 are associated with hereditary cancer syndromes. Advanced adenomas are considered precursors to CRC. Although polyp removal prevents cancer, polypectomy does not change underlying genetic risk. Patients with isolated advanced polyps do not currently qualify for genetic testing unless they have a personal or family history of cancer. Aim Describe the prevalence of hereditary cancer syndromes among patients with advanced colorectal polyps. Methods We performed a single center retrospective review from 2015 to 2019 of patients who underwent germline genetic testing with indication for testing listed as colorectal polyp. We excluded patients with a personal history of CRC and those with [greater than or equai to]10 cumulative polyps. We collected patient demographics, polyp characteristics, family history data and genetic testing results from the medical record. Discrete variables were reported as frequency and percentages and continuous variables reported as mean with range. Results A total of 42 patients underwent genetic testing due to a personal history of advanced adenoma. 17% of patients met current genetic testing criteria. All patients underwent multi-gene panel testing. Two patients (4.8%) had a germline pathogenic mutation (one in MLH1 and one in CHEK2). The patient with an MLH1 mutation met current criteria for genetic testing (PREMM5 score 5.8), however the patient with the CHEK2 mutation did not. Both mutation carriers had a personal history of synchronous or metachronous advanced adenomas. 38% had a variant of uncertain significance. Conclusions 5% of patients with advanced adenomas in our retrospective series had a pathogenic germline mutation in a cancer predisposition gene. Though the patient with a pathogenic mutation in MLH1 met current clinical criteria for genetic testing, this was not recognized prior to referral; he was referred based on a personal history of advanced adenoma. Advanced polyps may be a red flag to identify patients who are at risk for hereditary cancer syndromes. Keywords: Colorectal cancer, Colorectal polyps, Adenomas, Genetic testing, Lynch syndrome, Author(s): Swati G. Patel[sup.1,2], Heather Hampel[sup.3], Derek Smith[sup.4], Dexiang Gao[sup.4], Myles Cockburn[sup.5,6] and Fay Kastrinos[sup.7] Introduction Up to 10% [1] of all colorectal cancers (CRCs) and 16% [2] of CRCs [...]

Background There are growing concerns that antenatal corticosteroid administration may harm children's neurodevelopment. We investigated the safety of antenatal corticosteroid administration practices for children's overall developmental health (skills and behaviors) at early school age. Methods and findings We linked population health and education databases from British Columbia (BC), Canada to identify a cohort of births admitted to hospital between 31 weeks, 0 days gestation (31+0 weeks), and 36+6 weeks, 2000 to 2013, with routine early school age child development testing. We used a regression discontinuity design to compare outcomes of infants admitted just before and just after the clinical threshold for corticosteroid administration of 34+0 weeks. We estimated the median difference in the overall Early Development Instrument (EDI) score and EDI subdomain scores, as well as risk differences (RDs) for special needs designation and developmental vulnerability ( Conclusions Our study did not find that that antenatal corticosteroid administration practices were associated with child development at early school age. Our findings may be useful for supporting clinical counseling about antenatal corticosteroids administration at late preterm gestation, when the balance of harms and benefits is less clear., Author(s): Jennifer A. Hutcheon 1,*, Sam Harper 2, Jessica Liauw 1, M. Amanda Skoll 1, Myriam Srour 3, Erin C. Strumpf 2,4 Introduction Clinical practice guidelines have long recommended that [...]

Background Congestion score index (CSI), a semiquantitative evaluation of congestion on chest radiography (CXR), is associated with outcome in patients with heart failure (HF). However, its diagnostic value in patients admitted for acute dyspnea has yet to be evaluated. Methods and findings The diagnostic value of CSI for acute HF (AHF; adjudicated from patients' discharge files) was studied in the Pathway of dyspneic patients in Emergency (PARADISE) cohort, including patients aged 18 years or older admitted for acute dyspnea in the emergency department (ED) of the Nancy University Hospital (France) between January 1, 2015 and December 31, 2015. CSI (ranging from 0 to 3) was evaluated using a semiquantitative method on CXR in consecutive patients admitted for acute dyspnea in the ED. Results were validated in independent cohorts (N = 224). Of 1,333 patients, mean (standard deviation [SD]) age was 72.0 (18.5) years, 686 (51.5%) were men, and mean (SD) CSI was 1.42 (0.79). Patients with higher CSI had more cardiovascular comorbidities, more severe congestion, higher b-type natriuretic peptide (BNP), poorer renal function, and more respiratory acidosis. AHF was diagnosed in 289 (21.7%) patients. CSI was significantly associated with AHF diagnosis (adjusted odds ratio [OR] for 0.1 unit CSI increase 1.19, 95% CI 1.16-1.22, p 0.80, whether alone (area under the receiver operating characteristic curve [AUROC] 0.84, 95% CI 0.82-0.86) or in addition to the clinical model (AUROC 0.87, 95% CI 0.85-0.90). CSI improved diagnostic accuracy on top of clinical variables (net reclassification improvement [NRI] = 94.9%) and clinical variables plus BNP (NRI = 55.0%). Similar diagnostic accuracy was observed in the validation cohorts (AUROC 0.75, 95% CI 0.68-0.82). The key limitation of our derivation cohort was its single-center and retrospective nature, which was counterbalanced by the validation in the independent cohorts. Conclusions In this study, we observed that a systematic semiquantified assessment of radiographic pulmonary congestion showed high diagnostic value for AHF in dyspneic patients. Better use of CXR may provide an inexpensive, widely, and readily available method for AHF triage in the ED., Author(s): Masatake Kobayashi 1, Amine Douair 2, Kevin Duarte 1, Déborah Jaeger 1,2, Gaetan Giacomin 2, Adrien Bassand 2, Victor Jeangeorges 2, Laure Abensur Vuillaume 3, Gregoire Preud'homme 1, Olivier [...]

explore les proprietes optiques, electrochimiques et chimiques de ces derives. Nous avons examine la reaction de cycloaddition moieties, are synthesized to afford polarized pentacenes. The optical, electrochemical, and chemical properties [...]

Abstract: Lactoferrin (Lf) is the major whey protein in milk, with multiple beneficial health effects including direct antimicrobial activities, anti-inflammatory effects, and iron homeostasis. Oral Lf supplementation in human preterm [...]

OBJECTIVES: To investigate patterns of survival among brain cancer patients in Canada. METHODS: Canadian Cancer Registry data were obtained for all patients with first-ever primary malignant brain tumours diagnosed between 1992 and 2008 (n = 38,095). Follow-up ended with patient death or December 31,2008, whichever occurred first. Crude Kaplan-Meier estimates were calculated at one, two and five years post-diagnosis. Cox proportional hazard models were used to obtain adjusted hazard ratios by region for major histology types. A time-specific generalized linear model was used to obtain 5-year survival estimates for specific age group, sex and region for major histology types. RESULTS: The overall five-year survival rate was 27%. No significant difference in survival rate over time is observed. The highest 5-year survival rate was 65% (95% CI: 62.5%-67.4%) for oligodendrogliomas and the lowest was 4.0% (95% CI: 3.7%-4.3%) for glioblastomas. Compared to Ontario, the adjusted 5-year glioblastoma survival estimates were lower in British Columbia, Alberta and the Prairie provinces (Manitoba and Saskatchewan), while the survival estimates were lower in all other regions for diffuse astrocytoma, and lower in Manitoba and Saskatchewan for anaplastic astrocytomas. Estimates were significantly higher for oligodendrogliomas in Alberta, and for anaplastic oligodendrogliomas in Alberta and Quebec (p < 0.05). CONCLUSION: These data are consistent with previous literature in observing higher survival rates at younger ages, in female patients and for tumours with mixed oligo components. There is a need to further explore the underlying reasons for the observed variation in survival rates by region in an effort to improve the prognosis of brain cancer in the Canadian patient population. KEY WORDS: Brain neoplasms; survival rate; Canada OBJECTIFS: Etudier les profils de survie des patients atteints d'un cancer du cerveau au Canada. METHODE: Nous avons obtenu les donnees du Registre canadien du cancer sur tous les patients atteints d'une premiere tumeur cerebrale maligne primaire diagnostiquee entre 1992 et 2008 (n = 38 095). Le suivi s'est termine au deces des patients ou au 31 decembre 2008, selon la premiere des deux eventualites. Des estimations de Kaplan-Meier brutes ont ete calculees a un, deux et cinq ans apres le diagnostic. Nous avons utilise des modeles des risques proportionnels de Cox pour obtenir des coefficients de danger ajustes par region pour les grands types histologiques, respectivement. Un modele lineaire generalise dans le temps a servi a obtenir des estimations de survie apres 5 ans par groupe d'age, par sexe et par region pour les grands types histologiques. RESULTATS: Le taux de survie global etait de 27%. On n'observe aucun ecart significatif dans le taux de survie au fil du temps. Le taux de survie le plus eleve apres 5 ans etait de 65% (IC de 95%: 62,5%-67,4%) pour les oligodendrogliomes; le plus faible etait de 4% (IC de 95%: 3,7%-4,3%) pour les glioblastomes. Comparativement a l'Ontario, les estimations ajustees de survie au glioblastome apres 5 ans etaient inferieures en Colombie-Britannique, en Alberta et dans les provinces des Prairies (Manitoba et Saskatchewan), tandis que les estimations de survie etaient inferieures dans toutes les autres regions pour les astrocytomes diffus, et inferieures au Manitoba et en Saskatchewan pour les astrocytomes anaplasiques. Les estimations etaient sensiblement plus elevees pour les oligodendrogliomes en Alberta, et pour les oligodendrogliomes anaplasiques en Alberta et au Quebec (p < 0,05). CONCLUSION: Ces donnees sont conformes a celles d'etudes anterieures ou l'on a observe des taux de survie superieurs chez les jeunes patients, chez les femmes et pour les tumeurs mixtes (oligo-astrocytomes). Il faudrait pousser la recherche sur les raisons sous-jacentes de la variation observee des taux de survie par region afin d'ameliorer le pronostic du cancer du cerveau dans la population de patients au Canada. MOTS CLES: tumeurs du cerveau; taux de survie; Canada La traduction du resume se trouve a la fin de l'article. Can J Public Health 2016;107(1):e37-e42 doi: 10.17269/CJPH.107.5209, There is little information available on brain tumour incidence and survival among the Canadian population. (1,2) Available information provides an overall estimate of brain cancer survival without an assessment of [...]