The effect of severe renal impairment on the pharmacokinetics, safety and tolerability of balcinrenone.

Aims: The aim of this phase 1 trial was to assess the pharmacokinetics, safety and tolerability of balcinrenone (previously AZD9977) in participants with severe renal impairment vs. those with normal renal function.

Methods: Participants with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.

In Vitro and In Vivo Drug-Response Profiling Using Patient-Derived High-Grade Glioma.

Background: Genomic profiling cannot solely predict the complexity of how tumor cells behave in their in vivo microenvironment and their susceptibility to therapies. The aim of the study was to establish a functional drug prediction model utilizing patient-derived GBM tumor samples for in vitro testing of drug efficacy followed by in vivo validation to overcome the disadvantages of a strict pharmacogenomics approach.

Methods: High-throughput in vitro pharmacologic testing of patient-derived GBM tumors cultured as 3D organoids offered a cost-effective, clinically and phenotypically relevant model, inclusive of tumor plasticity and stroma.

Real-World Studies Link Nonsteroidal Anti-inflammatory Drug Use to Improved Overall Lung Cancer Survival.

Inflammation is a cancer hallmark. Nonsteroidal anti-inflammatory drugs (NSAIDs) improve overall survival (OS) in certain cancers. Real-world studies explored here if NSAIDs improve non-small cell lung cancer (NSCLC) OS.

An Open-Publishing Response to the COVID-19 Infodemic.

The COVID-19 pandemic catalyzed the rapid dissemination of papers and preprints investigating the disease and its associated virus, SARS-CoV-2. The multifaceted nature of COVID-19 demands a multidisciplinary approach, but the urgency of the crisis combined with the need for social distancing measures present unique challenges to collaborative science. We applied a massive online open publishing approach to this problem using Manubot.

Understanding bias when estimating life expectancy from age at death: a simulation approach applied to Morquio syndrome A.

Objective: Life expectancy can be estimated accurately from a cohort of individuals born in the same year and followed from birth to death. However, due to the resource-consuming nature of following a cohort prospectively, life expectancy is often assessed based upon retrospective death record reviews. This conventional approach may lead to potentially biased estimates, in particular when estimating life expectancy of rare diseases such as Morquio syndrome A.

Identification and Development of Therapeutics for COVID-19.

After emerging in China in late 2019, the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread worldwide, and as of mid-2021, it remains a significant threat globally. Only a few coronaviruses are known to infect humans, and only two cause infections similar in severity to SARS-CoV-2: , a species closely related to SARS-CoV-2 that emerged in 2002, and , which emerged in 2012. Unlike the current pandemic, previous epidemics were controlled rapidly through public health measures, but the body of research investigating severe acute respiratory syndrome and Middle East respiratory syndrome has proven valuable for identifying approaches to treating and preventing novel coronavirus disease 2019 (COVID-19).

Pathogenesis, Symptomatology, and Transmission of SARS-CoV-2 through Analysis of Viral Genomics and Structure.

The novel coronavirus SARS-CoV-2, which emerged in late 2019, has since spread around the world and infected hundreds of millions of people with coronavirus disease 2019 (COVID-19). While this viral species was unknown prior to January 2020, its similarity to other coronaviruses that infect humans has allowed for rapid insight into the mechanisms that it uses to infect human hosts, as well as the ways in which the human immune system can respond. Here, we contextualize SARS-CoV-2 among other coronaviruses and identify what is known and what can be inferred about its behavior once inside a human host.

An Open-Publishing Response to the COVID-19 Infodemic.

The COVID-19 pandemic catalyzed the rapid dissemination of papers and preprints investigating the disease and its associated virus, SARS-CoV-2. The multifaceted nature of COVID-19 demands a multidisciplinary approach, but the urgency of the crisis combined with the need for social distancing measures present unique challenges to collaborative science. We applied a massive online open publishing approach to this problem using Manubot.

Dissociable Roles of Pallidal Neuron Subtypes in Regulating Motor Patterns.

We have previously established that PV neurons and Npas1 neurons are distinct neuron classes in the external globus pallidus (GPe): they have different topographical, electrophysiological, circuit, and functional properties. Aside from Foxp2 neurons, which are a unique subclass within the Npas1 class, we lack driver lines that effectively capture other GPe neuron subclasses. In this study, we examined the utility of Kcng4-Cre, Npr3-Cre, and Npy2r-Cre mouse lines (both males and females) for the delineation of GPe neuron subtypes.

Identification and Development of Therapeutics for COVID-19.

After emerging in China in late 2019, the novel coronavirus SARS-CoV-2 spread worldwide and as of mid-2021 remains a significant threat globally. Only a few coronaviruses are known to infect humans, and only two cause infections similar in severity to SARS-CoV-2: , a closely related species of SARS-CoV-2 that emerged in 2002, and , which emerged in 2012. Unlike the current pandemic, previous epidemics were controlled rapidly through public health measures, but the body of research investigating severe acute respiratory syndrome and Middle East respiratory syndrome has proven valuable for identifying approaches to treating and preventing novel coronavirus disease 2019 (COVID-19).

Pathogenesis, Symptomatology, and Transmission of SARS-CoV-2 through Analysis of Viral Genomics and Structure.

The novel coronavirus SARS-CoV-2, which emerged in late 2019, has since spread around the world and infected hundreds of millions of people with coronavirus disease 2019 (COVID-19). While this viral species was unknown prior to January 2020, its similarity to other coronaviruses that infect humans has allowed for rapid insight into the mechanisms that it uses to infect human hosts, as well as the ways in which the human immune system can respond. Here, we contextualize SARS-CoV-2 among other coronaviruses and identify what is known and what can be inferred about its behavior once inside a human host.

Proteogenomic and metabolomic characterization of human glioblastoma.

Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology.

On the heterozygosity of an admixed population.

In this study, we consider admixed populations through their expected heterozygosity, a measure of genetic diversity. A population is termed admixed if its members possess recent ancestry from two or more separate sources. As a result of the fusion of source populations with different genetic variants, admixed populations can exhibit high levels of genetic diversity, reflecting contributions of their multiple ancestral groups.

Parvalbumin and Npas1 Pallidal Neurons Have Distinct Circuit Topology and Function.

The external globus pallidus (GPe) is a critical node within the basal ganglia circuit. Phasic changes in the activity of GPe neurons during movement and their alterations in Parkinson's disease (PD) argue that the GPe is important in motor control. Parvalbumin-positive (PV) neurons and Npas1 neurons are the two principal neuron classes in the GPe.

Group testing in mediation analysis.

We consider the scenario where there is an exposure, multiple biologically defined sets of biomarkers, and an outcome. We propose a new two-step procedure that tests if any of the sets of biomarkers mediate the exposure/outcome relationship, while maintaining a prespecified familywise error rate. The first step of the proposed procedure is a screening step that removes all groups that are unlikely to be strongly associated with both the exposure and the outcome.

A virtual molecular tumor board to improve efficiency and scalability of delivering precision oncology to physicians and their patients.

Objectives: Scalable informatics solutions that provide molecularly tailored treatment recommendations to clinicians are needed to streamline precision oncology in care settings.

Materials And Methods: We developed a cloud-based virtual molecular tumor board (VMTB) platform that included a knowledgebase, scoring model, rules engine, an asynchronous virtual chat room and a reporting tool that generated a treatment plan for each of the 1725 patients based on their molecular profile, previous treatment history, structured trial eligibility criteria, clinically relevant cancer gene-variant assertions, biomarker-treatment associations, and current treatment guidelines. The VMTB systematically allows clinician users to combine expert-curated data and structured data from clinical charts along with molecular testing data to develop consensus on treatments, especially those that require off-label and clinical trial considerations.

Evidence-Based Network Approach to Recommending Targeted Cancer Therapies.

Purpose: In this work, we introduce CDGnet (Cancer-Drug-Gene Network), an evidence-based network approach for recommending targeted cancer therapies. CDGnet represents a user-friendly informatics tool that expands the range of targeted therapy options for patients with cancer who undergo molecular profiling by including the biologic context via pathway information.

Methods: CDGnet considers biologic pathway information specifically by looking at targets or biomarkers downstream of oncogenes and is personalized for individual patients via user-inputted molecular alterations and cancer type.

Npas1-Nkx2.1 Neurons Are an Integral Part of the Cortico-pallido-cortical Loop.

Within the basal ganglia circuit, the external globus pallidus (GPe) is critically involved in motor control. Aside from Foxp2 neurons and ChAT neurons that have been established as unique neuron types, there is little consensus on the classification of GPe neurons. Properties of the remaining neuron types are poorly defined.

Integrated copy number and miRNA expression analysis in triple negative breast cancer of Latin American patients.

Triple negative breast cancer (TNBC), a clinically aggressive breast cancer subtype, affects 15-35% of women from Latin America. Using an approach of direct integration of copy number and global miRNA profiling data, performed simultaneously in the same tumor specimens, we identified a panel of 17 miRNAs specifically associated with TNBC of ancestrally characterized patients from Latin America, Brazil. This panel was differentially expressed between the TNBC and non-TNBC subtypes studied ( ≤ 0.

Discovery of potential urine-accessible metabolite biomarkers associated with muscle disease and corticosteroid response in the mdx mouse model for Duchenne.

Urine is increasingly being considered as a source of biomarker development in Duchenne Muscular Dystrophy (DMD), a severe, life-limiting disorder that affects approximately 1 in 4500 boys. In this study, we considered the mdx mice-a murine model of DMD-to discover biomarkers of disease, as well as pharmacodynamic biomarkers responsive to prednisolone, a corticosteroid commonly used to treat DMD. Longitudinal urine samples were analyzed from male age-matched mdx and wild-type mice randomized to prednisolone or vehicle control via liquid chromatography tandem mass spectrometry.

The Relationship Between Haplotype-Based and Haplotype Length.

The population-genetic statistic [Formula: see text] is used widely to describe allele frequency distributions in subdivided populations. The increasing availability of DNA sequence data has recently enabled computations of [Formula: see text] from sequence-based "haplotype loci." At the same time, theoretical work has revealed that [Formula: see text] has a strong dependence on the underlying genetic diversity of a locus from which it is computed, with high diversity constraining values of [Formula: see text] to be low.

Endogenous Gastrin Collaborates With Mutant KRAS in Pancreatic Carcinogenesis.

Objective: The KRAS gene is the most frequently mutated gene in pancreatic cancer, and no successful anti-Ras therapy has been developed. Gastrin has been shown to stimulate pancreatic cancer in an autocrine fashion. We hypothesized that reactivation of the peptide gastrin collaborates with KRAS during pancreatic carcinogenesis.