Glecirasib in KRAS-mutated nonsmall-cell lung cancer: a phase 2b trial.

Glecirasib (JAB-21822) is a new covalent oral KRAS-G12C inhibitor. This multicenter, single-arm phase 2b study assessed the efficacy and safety of glecirasib administered orally at 800 mg daily in patients with locally advanced or metastatic KRAS-mutated nonsmall-cell lung cancer. The primary endpoint was the objective response rate (ORR) assessed by an independent review committee (IRC).

Rational engineering of minimally immunogenic nucleases for gene therapy.

Genome editing using CRISPR-Cas systems is a promising avenue for the treatment of genetic diseases. However, cellular and humoral immunogenicity of genome editing tools, which originate from bacteria, complicates their clinical use. Here we report reduced immunogenicity (Red)(i)-variants of two clinically relevant nucleases, SaCas9 and AsCas12a.

Evaluation of a Quadrivalent Serotype 2a, 3a, 6, and O-Specific Polysaccharide and IpaB MAPS Vaccine.

Background: Shigellosis is the leading cause of diarrheal deaths worldwide and is particularly dangerous in children under 5 years of age in low- and middle-income countries. Additionally, the rise in antibiotic resistance has highlighted the need for an effective vaccine. Previously, we have used the Multiple Antigen-Presenting System (MAPS) technology to generate monovalent and quadrivalent MAPS vaccines that induce functional antibodies against components.

ADEVO: Proof-of-concept of adenovirus-directed EVOlution by random peptide display on the fiber knob.

Directed evolution of viral vectors involves the generation of randomized libraries followed by artificial selection of improved variants. Directed evolution only yielded limited results in adenovirus (AdV) engineering until now, mainly due to insufficient complexities of randomized libraries. Meanwhile, clinical applications of AdVs as gene therapy or oncolytic vectors are still hampered by the predetermined tropism of natural types.

Preventing Site-Specific Calpain Proteolysis of Junctophilin-2 Protects Against Stress-Induced Excitation-Contraction Uncoupling and Heart Failure Development.

Background: Excitation-contraction (E-C) coupling processes become disrupted in heart failure (HF), resulting in abnormal Ca homeostasis, maladaptive structural and transcriptional remodeling, and cardiac dysfunction. Junctophilin-2 (JP2) is an essential component of the E-C coupling apparatus but becomes site-specifically cleaved by calpain, leading to disruption of E-C coupling, plasmalemmal transverse tubule degeneration, abnormal Ca homeostasis, and HF. However, it is not clear whether preventing site-specific calpain cleavage of JP2 is sufficient to protect the heart against stress-induced pathological cardiac remodeling in vivo.

Predicting soil ecological criteria of 17 metal(loid)s in China based on quantitative ion character-activity relationship - Species sensitivity distribution (QICAR-SSD) coupled model.

Soil pollution caused by metal(loid)s is increasingly serious and poses unexpected risks to terrestrial organisms. Establishing soil quality standards is essential for assessing ecological risks of metal(loid)s and protecting soil ecosystems. However, the limited availability of metal(loid) ecotoxicological data has hampered the development of soil quality standards due to financial and practical constraints on toxicity testing.

Stereodivergent access to non-natural α-amino acids via enantio- and /-selective catalysis.

The precise control of and configurations of the carbon-carbon double bond in alkene synthesis has long been a fundamental challenge in synthetic chemistry, even more pronounced when simultaneously striving to achieve enantioselectivity [(,), (,), (,), (,)]. Moreover, enantiopure non-natural α-amino acids are highly sought after in organic and medicinal chemistry. In this study, we report a ligand-controlled stereodivergent synthesis of non-natural α-quaternary amino acids bearing trisubstituted alkene moieties in high yields with excellent enantioselectivity and / selectivities.

HER2-CD3-Fc Bispecific Antibody-Encoding mRNA Delivered by Lipid Nanoparticles Suppresses HER2-Positive Tumor Growth.

The human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor and tumor-associated antigen abnormally expressed in various types of cancer, including breast, ovarian, and gastric cancer. HER2 overexpression is highly correlated with increased tumor aggressiveness, poorer prognosis, and shorter overall survival. Consequently, multiple HER2-targeted therapies have been developed and approved; however, only a subset of patients benefit from these treatments, and relapses are common.

Rutin, a natural flavonoid glycoside, ameliorates zearalenone induced liver inflammation via inhibiting lipopolysaccharide gut leakage and NF-κB signaling pathway in mice.

Zearalenone (ZEN) poses a potential threat on human and animal health partly through the nuclear factor (NF)-κB signaling pathway. In silico study suggested that rutin effective against TLR4 and NF-κB. A wetting test was designed to evaluate the effect and underlying mechanism of rutin in alleviating ZEN-induced inflammation in animals.

Search for Narrow Trijet Resonances in Proton-Proton Collisions at sqrt[s]=13 TeV.

The first search for singly produced narrow resonances decaying to three well-separated hadronic jets is presented. The search uses proton-proton collision data corresponding to an integrated luminosity of 138  fb^{-1} at sqrt[s]=13  TeV, collected at the CERN LHC. No significant deviations from the background predictions are observed between 1.

The Toxoplasma Effector GRA4 Hijacks Host TBK1 to Oppositely Regulate Anti-T. Gondii Immunity and Tumor Immunotherapy.

Toxoplasma gondii (T. gondii)-associated polymorphic effector proteins are crucial in parasite development and regulating host anti-T. gondii immune responses.

Care interruptions and mortality among adults in Europe and North America.

Objective: Interruptions in care of people with HIV (PWH) on antiretroviral therapy (ART) are associated with adverse outcomes, but most studies have relied on composite outcomes. We investigated whether mortality risk following care interruptions differed from mortality risk after first starting ART.

Design: Collaboration of 18 European and North American HIV observational cohort studies of adults with HIV starting ART between 2004 and 2019.

Improved Adenoma Detection Rate Using a Novel Colonoscopic Distal Attachment: A Multicenter Randomized Controlled Trial.

Introduction: To evaluate the effect of Embrella, a novel-designed colonoscopic distal attachment, on adenoma detection rate (ADR) and adenoma per colonoscopy (APC), compared with standard colonoscopy in routine practice.

Methods: All consecutive participants who underwent routine colonoscopic examinations at 3 endoscopy centers in China were enrolled. Participants were randomly assigned in a 1:1 ratio to the Embrella-assisted colonoscopy (EAC) or standard colonoscopy (SC) groups.

Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL.

Overexpression of BCL-xL and BCL-2 play key roles in tumorigenesis and cancer drug resistance. Advances in PROTAC technology facilitated recent development of the first BCL-xL/BCL-2 dual degrader, 753b, a VHL-based degrader with improved potency and reduced toxicity compared to previous small molecule inhibitors. Here, we determine crystal structures of VHL/753b/BCL-xL and VHL/753b/BCL-2 ternary complexes.

Rapid development of double-hit mRNA antibody cocktail against orthopoxviruses.

The Orthopoxvirus genus, especially variola virus (VARV), monkeypox virus (MPXV), remains a significant public health threat worldwide. The development of therapeutic antibodies against orthopoxviruses is largely hampered by the high cost of antibody engineering and manufacturing processes. mRNA-encoded antibodies have emerged as a powerful and universal platform for rapid antibody production.

Preparing for the bedside-optimizing a postpartum depression risk prediction model for clinical implementation in a health system.

Objective: We developed and externally validated a machine-learning model to predict postpartum depression (PPD) using data from electronic health records (EHRs). Effort is under way to implement the PPD prediction model within the EHR system for clinical decision support. We describe the pre-implementation evaluation process that considered model performance, fairness, and clinical appropriateness.

Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems.

RBM20 (RNA-binding motif protein 20) is a vertebrate- and muscle-specific RNA-binding protein that belongs to the serine-arginine-rich family of splicing factors. The gene was first identified as a dilated cardiomyopathy-linked gene over a decade ago. Early studies in knockout rodents implicated disrupted splicing of RBM20 target genes as a causative mechanism.

MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis.

Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS-STING-mediated signalling and tumour suppression. However, the precise mechanism of cGAS activation by endogenous DNA damage remains enigmatic, particularly given that high-affinity histone acidic patch (AP) binding constitutively inhibits cGAS by sterically hindering its activation by double-stranded DNA (dsDNA). Here we report that the DNA double-strand break sensor MRE11 suppresses mammary tumorigenesis through a pivotal role in regulating cGAS activation.

INO80-Dependent Remodeling of Transcriptional Regulatory Network Underlies the Progression of Heart Failure.

Background: Progressive remodeling of cardiac gene expression underlies decline in cardiac function, eventually leading to heart failure. However, the major determinants of transcriptional network switching from normal to failed hearts remain to be determined.

Methods: In this study, we integrated human samples, genetic mouse models, and genomic approaches, including bulk RNA sequencing, single-cell RNA sequencing, chromatin immunoprecipitation followed by high-throughput sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing, to identify the role of chromatin remodeling complex INO80 in heart homeostasis and dysfunction.

Induction of Broad Immunity against Invasive Salmonella Disease by a Quadrivalent Combination Salmonella MAPS Vaccine Targeting Salmonella Enterica Serovars Typhimurium, Enteritidis, Typhi, and Paratyphi A.

Bloodstream infections in low- and middle-income countries (LMICs) are most frequently attributed to invasive Salmonella disease caused by four primary serovars of enterica: Typhi, Paratyphi A, Typhimurium, and Enteritidis. We showed previously that a bivalent vaccine targeting . Typhi and .

The Molecular, Immunologic, and Clinicodemographic Landscape of MYC-Amplified Advanced Prostate Cancer.

Background: MYC is a commonly amplified, potentially targetable gene in prostate cancer (PCa). We sought to define the molecular, immunologic, and clinicodemographic landscape of MYC amplification (MYC) in advanced PCa to establish a rationale for personalized treatment combinations.

Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on PCa tumor samples.

Topologically crafted spatiotemporal vortices in acoustics.

Vortices in fluids and gases have piqued the human interest for centuries. Development of classical-wave physics and quantum mechanics highlighted wave vortices characterized by phase singularities and topological charges. In particular, vortex beams have found numerous applications in modern optics and other areas.