Pooled safety analysis and management of sotorasib-related adverse events in KRAS G12C-mutated advanced non-small cell lung cancer.

Introduction: We describe the safety of sotorasib monotherapy in patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) and discuss practical recommendations for managing key risks.

Methods: Incidence rates of treatment-related adverse events (TRAEs) were pooled from 4 clinical trials: CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883), CodeBreaK 105 (NCT04380753), and CodeBreaK 200 (NCT04303780) and graded according to CTCAE v5.0.

The impact of mutations on the clinical outcome and immune response following immunotherapy for pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer-related death by 2030. This is driven by a high case-fatality rate with most patients even with radiologically localized PDAC at diagnosis ultimately relapsing with metastatic disease. mutations present in 90% to 95% of PDAC drive these poor statistics through its role in driving cellular growth, inhibition of apoptosis, and immunosuppression.

Multiplexed inhibition of immunosuppressive genes with Cas13d for combinatorial cancer immunotherapy.

The complex nature of the immunosuppressive tumor microenvironment (TME) requires multi-agent combinations for optimal immunotherapy. Here we describe multiplex universal combinatorial immunotherapy via gene silencing (MUCIG), which uses CRISPR-Cas13d to silence multiple endogenous immunosuppressive genes in the TME, promoting TME remodeling and enhancing antitumor immunity. MUCIG vectors targeting four genes delivered by adeno-associated virus (AAV) (Cd274/Pdl1, Lgals9/Galectin9, Lgals3/Galectin3 and Cd47; AAV-Cas13d-PGGC) demonstrate significant antitumor efficacy across multiple syngeneic tumor models, remodeling the TME by increasing CD8 T-cell infiltration while reducing neutrophils.

Deep Learning Radiomics Nomogram Based on MRI for Differentiating between Borderline Ovarian Tumors and Stage I Ovarian Cancer: A Multicenter Study.

Rationale And Objectives: To develop and validate a deep learning radiomics nomogram (DLRN) based on T2-weighted MRI to distinguish between borderline ovarian tumors (BOTs) and stage I epithelial ovarian cancer (EOC) preoperatively.

Materials And Methods: This retrospective multicenter study enrolled 279 patients from three centers, divided into a training set (n = 207) and an external test set (n = 72). The intra- and peritumoral radiomics analysis was employed to develop a combined radiomics model.

Bond strength to eroded dentin as per chlorhexidine use for controlling erosive wear or interface aging: an 18-month assay.

The aim of this study was to assess the effect of a chlorhexidine digluconate solution (CHX) applied as an antiproteolytic agent for controlling erosive tooth wear or as part of the adhesive treatment on long-term bond strength to eroded dentin. Dentin specimens were abraded with a 600-grit silicon carbide (SiC) paper for 1 min (sound dentin - S), subsequently treated with 2% CHX for 1 min (with excess removed, followed by a 6-hour rest), and eroded by exposure to Coca-Cola for 5 min, three times a day, for 5 days (CHX-treated and eroded dentin - CHXE), or only eroded (eroded dentin - E). The specimens were acid-etched (15 s), rinsed (30 s), dried (15 s), and rehydrated with 1.

CD137 agonism enhances anti-PD1 induced activation of expanded CD8 T cell clones in a neoadjuvant pancreatic cancer clinical trial.

Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy requires therapeutic combinations that induce quality T cells. Tumor microenvironment (TME) analysis following therapeutic interventions can identify response mechanisms, informing design of effective combinations. We provide a reference single-cell dataset from tumor-infiltrating leukocytes (TILs) from a human neoadjuvant clinical trial comparing the granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting allogeneic PDAC vaccine GVAX alone, in combination with anti-PD1 or with both anti-PD1 and CD137 agonist.

Effect of fezolinetant on patient-reported quality-of-life outcomes: Data from a phase 3b study (DAYLIGHT) of the treatment of moderate to severe vasomotor symptoms associated with menopause in women considered unsuitable for hormone therapy.

Objective: To report patient-reported quality-of-life (QOL) outcomes in the DAYLIGHT study.

Study Design: DAYLIGHT was a phase 3b, randomized, double-blind, 24-week, placebo-controlled study. Participants were women aged ≥40 to ≤65 years with moderate to severe vasomotor symptoms (VMS) considered unsuitable for hormone therapy (HT) (contraindications, caution, stoppers, or averse) randomized 1:1 to placebo or fezolinetant 45 mg once daily.

Early Versus Delayed Antihypertensive Treatment After Acute Ischemic Stroke by Hypertension History.

Background: We performed a prespecified subgroup analysis of the CATIS-2 trial (China Antihypertensive Trial in Acute Ischemic Stroke II) to compare the effect of early versus delayed antihypertensive treatment on death and disability in patients with and without medical history of hypertension.

Methods: CATIS-2 is a multicenter randomized clinical trial conducted in 106 hospitals in China. The trial randomized 4810 patients with acute ischemic stroke within 24 to 48 hours of symptom onset and elevated systolic blood pressure between 140 and <220 mm Hg to receive antihypertensive treatment immediately after randomization or to discontinue antihypertensive medications for 7 days and then receive treatment on day 8.

Association between triglyceride-glucose (TyG) related indices and cardiovascular diseases and mortality among individuals with metabolic dysfunction-associated steatotic liver disease: a cohort study of UK Biobank.

Background: Triglyceride-glucose (TyG) related indices, which serve as simple markers for insulin resistance, have been closely linked to metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular disease (CVD), and mortality. However, the prognostic utility of TyG-related indices in predicting the risk of CVD and mortality among patients with MASLD remains unclear.

Methods: Data of 97,331 MASLD patients, with a median age of 58.

Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A-menin to bivalent promoters.

Members of the KMT2C/D-KDM6A complex are recurrently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using genetically engineered mouse models, we demonstrate that Kmt2c/d knockout in the urothelium led to impaired differentiation, augmented responses to growth and inflammatory stimuli and sensitization to oncogenic transformation by carcinogen and oncogenes. Mechanistically, KMT2D localized to active enhancers and CpG-poor promoters that preferentially regulate the urothelial lineage program and Kmt2c/d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which leads to impaired differentiation.

Prognostic Significance of Computed Tomography-Derived Fractional Flow Reserve for Long-Term Outcomes in Individuals With Coronary Artery Disease.

Background: Data on the predictive value of coronary computed tomography angiography-derived fractional flow reserve (CT-FFR) for long-term outcomes are limited.

Methods And Results: A retrospective pooled analysis of individual patient data was performed. Deep-learning-based CT-FFR was calculated.

Network-Based Methods for Deciphering the Oxidizability of Complex Leachate DOM with OH/O via Molecular Signatures.

In landfill leachates containing complex dissolved organic matter (DOM), the link between individual DOM constituents and their inherent oxidizability is unclear. Here, we resolved the molecular signatures of DOM oxidized by OH/O using FT-ICR MS, thereby elucidating their oxidizability and resistance in concentrated leachates. The comprehensive gradual fragmentation of complex leachate DOM was then revealed through a modified machine-learning framework based on 43 key pathways during ozonation.

Toward expert-level medical question answering with large language models.

Large language models (LLMs) have shown promise in medical question answering, with Med-PaLM being the first to exceed a 'passing' score in United States Medical Licensing Examination style questions. However, challenges remain in long-form medical question answering and handling real-world workflows. Here, we present Med-PaLM 2, which bridges these gaps with a combination of base LLM improvements, medical domain fine-tuning and new strategies for improving reasoning and grounding through ensemble refinement and chain of retrieval.

High-efficiency base editing in the retina in primates and human tissues.

Stargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in the ABCA4 gene. We have designed a dual adeno-associated viral vector encoding a split-intein adenine base editor to correct the most common mutation in ABCA4 (c.5882G>A, p.

Safety and Efficacy of Remote Ischemic Conditioning in Patients With Intravenous Thrombolysis: The SERIC-IVT Trial.

Background: Approximately half of the patients with acute ischemic stroke who receive intravenous thrombolysis (IVT) do not achieve an excellent outcome. Remote ischemic conditioning (RIC) as a promising neuroprotective treatment may improve clinical outcomes in this population. This study aimed to assess the efficacy and safety of RIC in patients with IVT.

Value of Abbreviated Magnetic Resonance Sequence in Hepatocellular Carcinoma Screening: A Systematic Review and Meta-analysis.

Rationale And Objectives: To systematically review the diagnostic efficacy of abbreviated magnetic resonance imaging sequence (AMRI) screening for hepatocellular carcinoma (HCC).

Materials And Methods: Medline (via PubMed), EMbase, The Cochrane Library, Web of Science, CNKI, WanFang Data, and VIP databases were electronically searched to collect studies on the diagnostic efficacy of AMRI screening for HCC from inception to August 10th, 2024. Two reviewers independently screened literature, extracted data, and assessed the risk of bias of included studies using the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2), then, the meta-analysis with a bivariate mixed-effects regression model was performed by using Stata 14.

An mpox quadrivalent mRNA vaccine elicits sustained and protective immunity in mice against lethal vaccinia virus challenge.

Assessing the long-term efficacy of MPXV vaccine candidates is crucial for the global response to the ongoing mpox epidemic. Built upon our previous study of the mpox quadrivalent mRNA vaccine, herein we reported that MPXV-1103 could elicit sustained humoral and cellular immunity in mice, including the induction of MPXV A35/B6/A29/M1-specific IgG antibodies, VACV neutralizing antibodies and activated cytotoxic CD8T cells, which provides 100% protection against lethal VACV challenge even at 280 days after the first vaccination. Our results provide critical insights for orthopoxvirus vaccine development.

Fundus Curvature as a Clinical Marker for Posterior Staphyloma Based on Widefield Optical Coherence Tomography.

Purpose: To investigate the ability to quantify fundus curvature and detect posterior staphyloma using widefield optical coherence tomography (OCT).

Design: Cross-sectional diagnostic evaluation.

Methods: This study reviewed 205 highly myopic eyes of 205 participants.

Optimizing encephalomyocarditis virus VP1 protein assembly on pseudorabies virus envelope via US9 protein anchoring.

Live herpesvirus-vectored vaccines are critical in veterinary medicine, but they can sometimes offer insufficient protection due to suboptimal antigen expression or localization. Encephalomyocarditis virus (EMCV) is a significant zoonotic threat, with VP1 protein as a key immunogen on its capsid. To enhance immunogenicity, we explored the use of recombinant pseudorabies virus (rPRV) as a vaccine vector against EMCV.

Employing splice-switching oligonucleotides and AAVrh74.U7 snRNA to target insulin receptor splicing and cancer hallmarks in osteosarcoma.

Patients with osteosarcoma (OS), a debilitating pediatric bone malignancy, have limited treatment options to combat aggressive disease. OS thrives on insulin growth factor (IGF)-mediated signaling that can facilitate cell proliferation. Previous efforts to target IGF-1R signaling were mostly unsuccessful, likely due to compensatory signaling through alternative splicing of the insulin receptor () to the proliferative isoform.

Validation of novel grading schemes and refinement of the Leibovich risk groups for chromophobe renal cell carcinoma.

Background: Traditional grading systems have proven inadequate in stratifying chRCC patients based on recurrence risk. Recently, several novel grading schemes, including three-tiered, two-tiered, and four-tiered systems, have been proposed, but their prognostic value remains controversial and lacks external validation.

Materials And Methods: We included 528 patients with pathologically proven chRCC (chromophobe renal cell carcinoma) from multiple medical institutions and the Cancer Genome Atlas-Kidney Chromophobe cohort.

Single-Bundle Posterior Cruciate Ligament Reconstruction With Suture Tape Augmentation and Transtibial Tubercle Fixation.

The posterior cruciate ligament (PCL) is the strongest ligament of the knee and plays an important role in stabilizing the knee joint posteriorly. PCL tears are common injuries in sports injuries and traffic accidents; however, clinical outcomes after PCL reconstruction have not yet met clinicians' expectations, with a high postsurgery failure rate reported. Suture tape augmentation and supplementary fixation have shown ideal biomechanical properties in early studies.

Dual Antiplatelet Treatment up to 72 Hours After Ischemic Stroke Stratified by Risk Profile: A Post Hoc Analysis.

Background: Risk profile of recurrence may influence the effect of antiplatelet therapy. This study aimed to evaluate the efficacy and safety of clopidogrel-aspirin initiated within 72 hours after symptom onset for acute mild stroke or high-risk transient ischemic attack stratified by risk profile.

Methods: This is a secondary post hoc analysis of the INSPIRES (Intensive Statin and Antiplatelet Therapy for Acute High-risk Intracranial or Extracranial Atherosclerosis) randomized clinical trial that enrolled patients 35 to 80 years old with acute mild ischemic stroke or high-risk transient ischemic attack between 2018 and 2022.

A Comparative Theoretical Study of the Atmospheric Chemistry of Dimethyl and Bis(trifluoromethyl) Sulfides.

Dimethyl sulfide (CHSCH) is the largest natural source of atmospheric sulfur. Bis(trifluoromethyl) sulfides (CFSCF) are one of the perfluorinated thioethers with great interest as the new refrigerant fluid and dielectric replacement gas for the sake of environmental concern. In order to clarify the effect of fluorine substitution, degradation mechanisms and kinetics for the reactions of CHSCH and CFSCF with OH radicals in the atmosphere have been calculated comprehensively in a comparative manner using various high-level methods.

Association between high-density lipoprotein cholesterol and risk of abdominal aortic aneurysm among males and females aged 60 years and over.

Objective: Whether high-density lipoprotein cholesterol (HDL-C) has a protective role against abdominal aortic aneurysm (AAA) development in both older males and females remains uncertain. This study aims to assess the sex-specific association between HDL-C and incident AAA in older adults from the UK Biobank.

Methods: This cohort study included 86,184 males and 95,682 females aged ≥60 years from the UK biobank.