Reevaluating Anti-Inflammatory Therapy: Targeting Senescence to Balance Anti-Cancer Efficacy and Vascular Disease.

Modulating immune function is a critical strategy in cancer and atherosclerosis treatments. For cancer, boosting or maintaining the immune system is crucial to prevent tumor growth. However, in vascular disease, mitigating immune responses can decrease inflammation and slow atherosclerosis progression.

Rational selection of TbpB variants yields a bivalent vaccine with broad coverage against Neisseria gonorrhoeae.

Neisseria gonorrhoeae is an on-going public health problem due in part to the lack of success with efforts to develop an efficacious vaccine to prevent this sexually transmitted infection. The gonococcal transferrin binding protein B (TbpB) is an attractive candidate vaccine antigen. However, it exhibits high levels of antigenic variability, posing a significant obstacle in evoking a broadly protective immune response.

The impact of highly effective modulator therapy on sinusitis and dysosmia in young children with cystic fibrosis: a prospective study protocol.

Background: Chronic rhinosinusitis (CRS) and olfactory dysfunction (OD) are prevalent disease complications in people with cystic fibrosis. These understudied comorbidities significantly impact quality of life. The impact of highly effective modulator therapy (HEMT) in young children with cystic fibrosis (YCwCF) on these disease complications is unknown.

Buparlisib and Paclitaxel in Patients with Head and Neck Squamous Cell Carcinoma: Immunogenomic Biomarkers of Efficacy from the BERIL-1 Study.

Background: BERIL-1 was a randomized phase 2 study that studied paclitaxel with either buparlisib, a pan-class I PIK3 inhibitor, or placebo in patients with recurrent or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Considering the therapeutic paradigm shift with immune checkpoint inhibitors (ICIs) now approved in the first-line setting, we present an updated immunogenomic analysis of patients enrolled in BERIL-1, including patients with immune-infiltrated tumors.

Objective: The objective of this study was to identify biomarkers predictive of treatment efficacy in the context of the post-ICI therapeutic landscape.

Defining proteoform-specific interactions for drug targeting in a native cell signalling environment.

Understanding the dynamics of membrane protein-ligand interactions within a native lipid bilayer is a major goal for drug discovery. Typically, cell-based assays are used, however, they are often blind to the effects of protein modifications. In this study, using the archetypal G protein-coupled receptor rhodopsin, we found that the receptor and its effectors can be released directly from retina rod disc membranes using infrared irradiation in a mass spectrometer.

Ultrasensitive ctDNA detection for preoperative disease stratification in early-stage lung adenocarcinoma.

Circulating tumor DNA (ctDNA) detection can predict clinical risk in early-stage tumors. However, clinical applications are constrained by the sensitivity of clinically validated ctDNA detection approaches. NeXT Personal is a whole-genome-based, tumor-informed platform that has been analytically validated for ultrasensitive ctDNA detection at 1-3 ppm of ctDNA with 99.

ADAMTS4-Specific MR Peptide Probe for the Assessment of Atherosclerotic Plaque Burden in a Mouse Model.

Introduction: Atherosclerosis is the underlying cause of multiple cardiovascular pathologies. The present-day clinical imaging modalities do not offer sufficient information on plaque composition or rupture risk. A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) is a strongly upregulated proteoglycan-cleaving enzyme that is specific to cardiovascular diseases, inter alia, atherosclerosis.

Multimodality Imaging Evaluation of Diseases of the Pulmonic Valve and Right Ventricular Outflow Tract for the Adult Cardiologist.

Disorders of the pulmonic valve (PV) receive considerably less attention than other forms of valvular heart disease. Due to the dramatically improved survival of children with congenital heart disease over the last 5 decades, there has been a steady increase in the prevalence of adults with congenital heart disease, which necessitates that clinicians become familiar with the anatomy and the evaluation of right ventricular outflow tract and PV anomalies. A multimodality imaging approach using echocardiography, cardiac computed tomography, and magnetic resonance imaging is essential for a comprehensive evaluation of the anatomy and function of the right ventricular outflow tract, PV, and supravalvular region.

Repurposing Licensed Drugs with Activity Against Epstein-Barr Virus for Treatment of Multiple Sclerosis: A Systematic Approach.

Background: Epstein-Barr virus (EBV) is implicated as a necessary factor in the development of multiple sclerosis (MS) and may also be a driver of disease activity. Although it is not clear whether ongoing viral replication is the driver for MS pathology, MS researchers have considered the prospect of using drugs with potential efficacy against EBV in the treatment of MS. We have undertaken scientific and lived experience expert panel reviews to shortlist existing licensed therapies that could be used in later-stage clinical trials in MS.

Differences in association between hypoalbuminaemia and mortality among younger versus older patients on haemodialysis.

Background: Ageing often affects biomarker production. Yet, clinical/optimal thresholds to guide clinical decisions do not consider this. Serum albumin decreases with age, but hypoalbuminaemia is defined as serum albumin <4.

Predicting RNA-seq coverage from DNA sequence as a unifying model of gene regulation.

Sequence-based machine-learning models trained on genomics data improve genetic variant interpretation by providing functional predictions describing their impact on the cis-regulatory code. However, current tools do not predict RNA-seq expression profiles because of modeling challenges. Here, we introduce Borzoi, a model that learns to predict cell-type-specific and tissue-specific RNA-seq coverage from DNA sequence.

Complex rearrangements fuel ER and HER2 breast tumours.

Breast cancer is a highly heterogeneous disease whose prognosis and treatment as defined by the expression of three receptors-oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2; encoded by ERBB2)-is insufficient to capture the full spectrum of clinical outcomes and therapeutic vulnerabilities. Previously, we demonstrated that transcriptional and genomic profiles define eleven integrative subtypes with distinct clinical outcomes, including four ER subtypes with increased risk of relapse decades after diagnosis. Here, to determine whether these subtypes reflect distinct evolutionary histories, interactions with the immune system and pathway dependencies, we established a meta-cohort of 1,828 breast tumours spanning pre-invasive, primary invasive and metastatic disease with whole-genome and transcriptome sequencing.

Molecular and cellular dynamics of the developing human neocortex.

The development of the human neocortex is highly dynamic, involving complex cellular trajectories controlled by gene regulation. Here we collected paired single-nucleus chromatin accessibility and transcriptome data from 38 human neocortical samples encompassing both the prefrontal cortex and the primary visual cortex. These samples span five main developmental stages, ranging from the first trimester to adolescence.

Safety and immunogenicity of an optimized self-replicating RNA platform for low dose or single dose vaccine applications: a randomized, open label Phase I study in healthy volunteers.

Self-replicating RNA (srRNA) technology, in comparison to mRNA vaccines, has shown dose-sparing by approximately 10-fold and more durable immune responses. However, no improvements are observed in the adverse events profile. Here, we develop an srRNA vaccine platform with optimized non-coding regions and demonstrate immunogenicity and safety in preclinical and clinical development.

DNA targeting by compact Cas9d and its resurrected ancestor.

Type II CRISPR endonucleases are widely used programmable genome editing tools. Recently, CRISPR-Cas systems with highly compact nucleases have been discovered, including Cas9d (a type II-D nuclease). Here, we report the cryo-EM structures of a Cas9d nuclease (747 amino acids in length) in multiple functional states, revealing a stepwise process of DNA targeting involving a conformational switch in a REC2 domain insertion.

Engaging dystonia networks with subthalamic stimulation.

Deep brain stimulation is an efficacious treatment for dystonia. While the internal pallidum serves as the primary target, recently, stimulation of the subthalamic nucleus (STN) has been investigated. However, optimal targeting within this structure and its surroundings have not been studied in depth.

A Global Collaborative Comparison of SARS-CoV-2 Antigenicity Across 15 Laboratories.

Setting up a global SARS-CoV-2 surveillance system requires an understanding of how virus isolation and propagation practices, use of animal or human sera, and different neutralisation assay platforms influence assessment of SARS-CoV-2 antigenicity. In this study, with the contribution of 15 independent laboratories across all WHO regions, we carried out a controlled analysis of neutralisation assay platforms using the first WHO International Standard for antibodies to SARS-CoV-2 variants of concern (source: NIBSC). Live virus isolates (source: WHO BioHub or individual labs) or spike plasmids (individual labs) for pseudovirus production were used to perform neutralisation assays using the same serum panels.

Utilization, Satisfaction, and Clinical Outcomes of People of Color and White Adults Using an Employer-Sponsored Digital Mental Health Platform.

Evaluating digital mental health services across racial and ethnic identities is crucial to ensuring health equity. We examined how People of Color (POC) and White adults were using and benefiting from an employer-sponsored digital mental health platform. A sample of 947 adults (42% POC) consented to an observational study and completed surveys on their identities and mental health outcomes at baseline and three-month follow-up.

Autogene cevumeran with or without atezolizumab in advanced solid tumors: a phase 1 trial.

Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy (n = 30) and in combination with atezolizumab (n = 183) in pretreated patients with advanced solid tumors.

Deficiency of Endothelial Impairs Pulmonary Vascular Angiogenesis and Predisposes Pulmonary Hypertension.

Background: Mechanosensitive Piezo1 channel plays a key role in pulmonary hypertension (PH). However, the role of Piezo2 in PH remains unclear.

Methods: Endothelial cell (EC)-specific knockout (, Tek-Cre; ) rats and primarily cultured pulmonary microvascular ECs were used to determine the role of Piezo2 in PH.

Real-world evaluation of an evidence-based telemental health program for PTSD symptoms.

Blended care therapy (BCT), which augments live, video-based psychotherapy sessions with asynchronous digital tools, has the potential to increase access to evidence-based treatments for posttraumatic stress disorder (PTSD). However, its effectiveness in diverse, real-world settings is not well-understood. This evaluation aimed to assess clinical outcomes of a BCT program for PTSD symptoms.

Classification of non-TCGA cancer samples to TCGA molecular subtypes using compact feature sets.

Molecular subtypes, such as defined by The Cancer Genome Atlas (TCGA), delineate a cancer's underlying biology, bringing hope to inform a patient's prognosis and treatment plan. However, most approaches used in the discovery of subtypes are not suitable for assigning subtype labels to new cancer specimens from other studies or clinical trials. Here, we address this barrier by applying five different machine learning approaches to multi-omic data from 8,791 TCGA tumor samples comprising 106 subtypes from 26 different cancer cohorts to build models based upon small numbers of features that can classify new samples into previously defined TCGA molecular subtypes-a step toward molecular subtype application in the clinic.

National Institute of Neurological Disorders and Stroke Clinical Trials Methodology Course: Summary and Accomplishments 2014-2023.

The Clinical Trials Methodology Course (CTMC), given from 2014 to 2023, was conducted to educate early-career clinical investigators from various backgrounds in neurosciences in the design of clinical trials and to provide mentorship to enhance academic careers and retention plus improve research productivity and the likelihood of successful grant applications. This summary describes the rationale, history, structure, and trainee outcomes of the CTMC. The course used small groups, consisting of 1-2 clinical faculty advisor(s), 1 faculty biostatistician, and 2-4 trainees who met remotely approximately weekly over 12 weeks.

Multi-omic profiling a defined bacterial consortium for treatment of recurrent Clostridioides difficile infection.

Donor-derived fecal microbiota treatments are efficacious in preventing recurrent Clostridioides difficile infection (rCDI), but they have inherently variable quality attributes, are difficult to scale and harbor the risk of pathogen transfer. In contrast, VE303 is a defined consortium of eight purified, clonal bacterial strains developed for prevention of rCDI. In the phase 2 CONSORTIUM study, high-dose VE303 was well tolerated and reduced the odds of rCDI by more than 80% compared to placebo.