Xalnesiran with or without an Immunomodulator in Chronic Hepatitis B.

Background: Xalnesiran, a small interfering RNA molecule that targets a conserved region of the hepatitis B virus (HBV) genome and silences multiple HBV transcripts, may have efficacy, with or without an immunomodulator, in patients with chronic HBV infection.

Methods: We conducted a phase 2, multicenter, randomized, controlled, adaptive, open-label platform trial that included the evaluation of 48 weeks of treatment with xalnesiran at a dose of 100 mg (group 1), xalnesiran at a dose of 200 mg (group 2), xalnesiran at a dose of 200 mg plus 150 mg of ruzotolimod (group 3), xalnesiran at a dose of 200 mg plus 180 μg of pegylated interferon alfa-2a (group 4), or a nucleoside or nucleotide analogue (NA) alone (group 5) in participants with chronic HBV infection who had virologic suppression with NA therapy. The primary efficacy end point was hepatitis B surface antigen (HBsAg) loss (HBsAg level, <0.

Aficamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an inherited disease of the sarcomere resulting in excessive cardiac contractility. The first-in-class cardiac myosin inhibitor, mavacamten, improves symptoms in obstructive HCM. Here we present aficamten, a selective small-molecule inhibitor of cardiac myosin that diminishes ATPase activity by strongly slowing phosphate release, stabilizing a weak actin-binding state.

Cardiac Troponin Activator Increases Cardiac Contractility in Rats.

Novel cardiac troponin activators were identified using a high throughput cardiac myofibril ATPase assay and confirmed using a series of biochemical and biophysical assays. HTS hit increased rat cardiomyocyte fractional shortening without increasing intracellular calcium concentrations, and the biological target of and was determined to be the cardiac thin filament. Subsequent optimization to increase solubility and remove PDE-3 inhibition led to the discovery of and enabled pharmacological evaluation of cardiac troponin activation without the competing effects of PDE-3 inhibition.

Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits similar B cell expansion, neutralizing responses, and protection from Omicron.

SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-matched vaccines would enhance protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron.

A dataset of the mid-brunhes period at site MD05-2925, Solomon Sea: Surface-subsurface planktonic foraminifera stable C-O isotope and Mg/Ca ratios.

Here we present derived thermal-hydrological variations data during the Marine isotope stages (MISs) 10-12 using surface and subsurface dwelling planktonic foraminiferal geochemical proxies of a sedimentary core of MD05-2925 (9.3S, 151.5E, water depth 1661 m, core depth 1842-2430 cm), Solomon Sea.

Minicircles for a two-step blood biomarker and PET imaging early cancer detection strategy.

Early cancer detection can dramatically increase treatment options and survival rates for patients, yet detection of early-stage tumors remains difficult. Here, we demonstrate a two-step strategy to detect and locate cancerous lesions by delivering tumor-activatable minicircle (MC) plasmids encoding a combination of blood-based and imaging reporter genes to tumor cells. We genetically engineered the MCs, under the control of the pan-tumor-specific Survivin promoter, to encode: 1) Gaussia Luciferase (GLuc), a secreted biomarker that can be easily assayed in blood samples; and 2) Herpes Simplex Virus Type 1 Thymidine Kinase mutant (HSV-1 sr39TK), a PET reporter gene that can be used for highly sensitive and quantitative imaging of the tumor location.

Engineered immune cells as highly sensitive cancer diagnostics.

Endogenous biomarkers remain at the forefront of early disease detection efforts, but many lack the sensitivities and specificities necessary to influence disease management. Here, we describe a cell-based in vivo sensor for highly sensitive early cancer detection. We engineer macrophages to produce a synthetic reporter on adopting an M2 tumor-associated metabolic profile by coupling luciferase expression to activation of the arginase-1 promoter.

Molecular mechanism and therapeutic implications of selinexor (KPT-330) in liposarcoma.

Exportin-1 mediates nuclear export of multiple tumor suppressor and growth regulatory proteins. Aberrant expression of exportin-1 is noted in human malignancies, resulting in cytoplasmic mislocalization of its target proteins. We investigated the efficacy of selinexor against liposarcoma cells both in vitro and in vivo.

Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure.

Background: Although metabolic reprogramming is critical in the pathogenesis of heart failure, studies to date have focused principally on fatty acid and glucose metabolism. Contribution of amino acid metabolic regulation in the disease remains understudied.

Methods And Results: Transcriptomic and metabolomic analyses were performed in mouse failing heart induced by pressure overload.

Evaluation of Fetal First and Second Cervical Vertebrae: Normal or Abnormal?

Objectives: To use 3-dimensional sonographic volumes to evaluate the variable appearance of the normal fetal cervical spine and craniocervical junction, which if unrecognized may lead to misdiagnosis of malalignment at the first and second cervical vertebrae (C1 and C2).

Methods: Three-dimensional sonographic volumes of the fetal cervical spine were obtained from 24 fetuses at gestational ages between 12 weeks 6 days and 35 weeks 1 day. The volumes were reviewed on 4-dimensional software, and the vertebral level was determined by labeling the first rib-bearing vertebra as the first thoracic vertebra.

Bond characterization of a unique thiathiophthene derivative: combined charge density study and X-ray absorption spectroscopy.

Thiathiophthene (TTP), a planar molecule with two fused heterocyclic five-membered rings and an essentially linear S-S-S bond, is a molecule of great interest due to its unique chemical bondings. To elucidate the remarkable bonding nature, a combined experimental and theoretical study on the electron density distribution of 2,5-dimethyl-3,4-trimethylene-6a-TTP (1) is investigated based on a multipole model through high-resolution X-ray diffraction data experimentally and on the density functional calculations (DFT) theoretically. In addition, S K-edge X-ray absorption spectroscopy (XAS) is measured to verify the chemical bonding concerning the sulfur atoms.

Acid aspiration provokes the pneumonia caused by multidrug-resistant Acinetobacter baumannii in BALB/c mice.

Objective: To determine whether acid aspiration provokes the development of multidrug-resistant Acinetobacter baumannii (MDRAB) pneumonia in its host.

Methods: Groups of mice were inoculated intratracheally (IT) with 50 μl of 0.1N HCl and 1 × 10(8) colony-forming units (CFU) Ab396 (A+Ab group), or 50 μl of 0.

Gly482Ser polymorphism in the peroxisome proliferator-activated receptor gamma coactivator-1alpha gene is associated with oxidative stress and abdominal obesity.

The objective of the study was to o investigate the relationship of the Gly482Ser (G482S) polymorphism in the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PPARGC1A) gene and type 2 diabetes mellitus (T2DM), obesity, and oxidative status in Chinese adults. We enrolled 276 T2DM patients and 1049 nondiabetic subjects aged at least 35 years. The G482S variant was detected using polymerase chain reaction and restriction enzyme digestion.

Use of preoperative three-dimensional computed tomography to quantify glenoid bone loss in shoulder instability.

Purpose: The purpose of this study was to determine if three-dimensional computed tomography (3-D CT) scans of the glenoid can be used to accurately quantify, by means of a glenoid index, bone loss in patients with anterior glenohumeral instability, and to compare the results with arthroscopic measurements to determine if the 3-D CT scan can preoperatively predict which patients with anterior glenohumeral instability will benefit from a bone grafting procedure.

Methods: From 2003 to 2006, 188 patients with anterior glenohumeral instability underwent arthroscopic evaluation and treatment by the senior author (S.S.

CYP24, the enzyme that catabolizes the antiproliferative agent vitamin D, is increased in lung cancer.

1Alpha,25-dihydroxyvitamin D3 (1,25D3) displays potent antiproliferative activity in a variety of tumor model systems and is currently under investigation in clinical trials in cancer. Studies were initiated to explore its potential in nonsmall cell lung cancer (NSCLC), as effective approaches to the treatment of that disease are needed. In evaluating factors that may affect activity in NSCLC, the authors found that CYP24 (25-hydroxyvitamin D3-24-hydroxylase), the enzyme that catabolizes 1,25D3, is frequently expressed in NSCLC cell lines but not in the nontumorigenic bronchial epithelial cell line, Beas2B.

Beta cell function declines with age in glucose tolerant Caucasians.

Objective: As type 2 diabetes results from an imbalance between insulin sensitivity and beta cell function, either or both may worsen with age. However, existing data are controversial on the effect of ageing on both insulin sensitivity and beta cell function.

Subjects And Design: We enrolled 149 healthy, glucose tolerant and normotensive Caucasians (age 35 +/- 1 years, body mass index 26.

A single in vitro point mutation in the first non-translated exon silences transcription of the human apolipoprotein B gene in HepG2 cells.

Hepatic cell-specific expression of the human apolipoprotein B (apoB) gene is controlled by at least four cis-acting elements located within the -128 to +122 promoter region (S.S. Chuang, H.