Multimodal learning for mapping genotype-phenotype dynamics.

How complex phenotypes emerge from intricate gene expression patterns is a fundamental question in biology. Integrating high-content genotyping approaches such as single-cell RNA sequencing and advanced learning methods such as language models offers an opportunity for dissecting this complex relationship. Here we present a computational integrated genetics framework designed to analyze and interpret the high-dimensional landscape of genotypes and their associated phenotypes simultaneously.

Very Early Health Technology Assessment for Potential Predictive Biomarkers in the Treatment of Advanced Non-Small Cell Lung Cancer.

Objectives: Immune checkpoint inhibitor (ICI)-containing treatment is currently prescribed as first-line treatment for all patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. However, only 30-45% of patients show no progression within 12 months after treatment start. Various biomarkers are being studied to save costly and potentially harmful treatment in non-responders.

A human metabolic map of pharmacological perturbations reveals drug modes of action.

Understanding a small molecule's mode of action (MoA) is essential to guide the selection, optimization and clinical development of lead compounds. In this study, we used high-throughput non-targeted metabolomics to profile changes in 2,269 putative metabolites induced by 1,520 drugs in A549 lung cancer cells. Although only 26% of the drugs inhibited cell growth, 86% caused intracellular metabolic changes, which were largely conserved in two additional cancer cell lines.

Diagnostic utility of chest wall vessel involvement sign on ultra-high-resolution CT for primary lung cancer infiltrating the chest wall.

Objectives: Chest wall infiltration in primary lung cancer affects the surgical and therapeutic strategies. This study evaluates the efficacy of the chest wall vessel involvement in subpleural lung cancer (CWVI)　on ultra-high-resolution CT (UHR-CT) for detecting chest wall invasion.

Materials And Methods: A retrospective analysis of lung cancer cases with confirmed pleural and chest wall invasion was conducted from November 2019 to April 2022.

Cognitive reserve is associated with education, social determinants, and cognitive outcomes among older American Indians in the Strong Heart Study.

Cognitive reserve, a component of resilience, may be conceptualized as the ability to overcome accumulating neuropathology and maintain healthy aging and function. However, research measuring and evaluating it in American Indians is needed. We recruited American Indians from 3 regional centers for longitudinal examinations (2010-13, n = 818; 2017-19, n = 403) including MRI, cognitive, clinical, and questionnaire data.

The degree of cross-linking of polyacrylic acid affects the fibrogenicity in rat lungs.

Polyacrylic acid (PAA) with different concentrations of cross-linker was instilled into the trachea of rats to examine the effect of PAA crosslink density on lung disorders. Methods: F344 rats were intratracheally exposed to low and high doses of PAA with cross-linker concentrations of 0.1, 1.

Drug-induced differential culturability in diverse strains of Mycobacterium tuberculosis.

Under stress, bacteria display selective growth propensities on solid and liquid media. For Mycobacterium tuberculosis (Mtb), differentially culturable bacteria have been found in tuberculosis (TB) patient sputa. We hypothesized that antibiotic treatment can induce selective culturability in Mtb.

Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancer.

Hyperactive c-Met signaling pathway caused by altered MET is a common mechanism underlying gastric cancer and represents an attractive target for the treatment of gastric cancer with MET alterations. However, no c-Met kinase inhibitors are currently approved specifically for the treatment of c-Met-amplified gastric cancer. Recently, bozitinib, a highly selective c-Met kinase inhibitor, has shown remarkable potency in selectively inhibiting MET-altered non-small cell lung cancer and secondary glioblastoma.

Risk of second primary malignancies among survivors of cutaneous melanoma: A nationwide population-based study in the Republic of Korea.

There is limited data on the risk of second primary malignancies (SPMs) in Asian melanoma survivors. This study aimed to identify the risk of SPMs in Asian melanoma survivors. Standardized incidence ratios (SIRs) were calculated for overall and specific SPMs.

Evaluation of the genotoxic and transformation potential induced by asbestos compared to cleavage fragments.

The World Health Organization has confirmed that asbestos fibres are carcinogenic, claiming that asbestos-related diseases should be eradicated worldwide. Actinolite, amosite, anthophyllite, chrysotile, crocidolite, and tremolite are regulated asbestiform mineral phases. However, in nature, asbestos minerals occur either in a fibrous and asbestiform (original morphology characterized by high length-to-width ratio and provided of high tensile strength and flexibility) or fibrous but not asbestiform appearance.

Association between airway microbiota and systemic inflammation markers in non-small cell lung cancer patients.

Growing evidences have suggested the airway microbiota may participate in lung cancer progression. However, little was known about the relationship between airway microbiota and lung cancer associated systemic inflammation. Here we aimed to explore the association between sputum microbiota and systemic inflammation in lung cancer.

PARP inhibition-associated heterochromatin confers increased DNA replication stress and vulnerability to ATR inhibition in SMARCA4-deficient cells.

DNA replication stress (RS), a prevalent feature of various malignancies, arises from both genetic mutations and genotoxic exposure. Elevated RS levels increase the vulnerability of cancer cells to ataxia telangiectasia and Rad3-related kinase inhibitors (ATRis). Here, we screened for DNA damage response inhibitors that enhance ATRi-induced cytotoxicity using SWI/SNF complex-deficient cells and identified a potent synergy between ATRi and poly(ADP-ribose) polymerase inhibitor (PARPi), particularly in SMARCA4-deficient cells.

Single-cell transcriptomics of bronchoalveolar lavage during PRRSV infection with different virulence.

Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses in the global swine industry due to its high genetic diversity and different virulence levels, which complicate disease management and vaccine development. This study evaluated longitudinal changes in the immune cell composition of bronchoalveolar lavage fluid and the clinical outcomes across PRRSV strains with varying virulence, using techniques including single-cell transcriptomics. In highly virulent infection, faster viral replication results in an earlier peak lung-damage time point, marked by significant interstitial pneumonia, a significant decrease in macrophages, and an influx of lymphocytes.

Targeting ferroptosis: a promising approach for treating lung carcinoma.

Lung carcinoma incidence and fatality rates remain among the highest on a global scale. The efficacy of targeted therapies and immunotherapies is commonly compromised by the emergence of drug resistance and other factors, resulting in a lack of durable therapeutic benefits. Ferroptosis, a distinct pattern of cell death marked by the buildup of iron-dependent lipid peroxides, has been shown to be a novel and potentially more effective treatment for lung carcinoma.

Design, Structure Optimization, and Preclinical Characterization of JAB-21822, a Covalent Inhibitor of KRAS.

KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutation is commonly found in non-small-cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). Inhibitors that covalently modify the mutated codon 12 cysteine have completed proof-of-concept studies in the clinic. Here, we describe structure-based design and cocrystal-aided drug optimization of a series of compounds with the 1,8-naphthyridine-3-carbonitrile scaffold.

Potential risk of heavy metals release in sediments and soils of the Yellow River Basin (Henan section): A perspective on bioavailability and bioaccessibility.

The ecology of watersheds plays an important role in regulating regional climate and human activities. The sediment-soil system in the middle and lower reaches of the Yellow River Basin (Henan section) was explored. The spatial distribution characteristics of heavy metals (HMs) showed that tributaries, which are affected by anthropogenic activities, contain higher concentrations of HMs than the main channel.

Impact of variations in airborne microbiota on pneumonia infection: An exploratory study.

Background: Previous studies showed airborne bacteria affect pneumonia incidence, but specific impacts of bacterial communities on Klebsiella pneumoniae infection were unknown.

Methods: Five different ratios of bacterial community structures were randomly generated. Mice were divided into control, artificial bacterial community exposure, and corresponding Klebsiella pneumoniae challenge groups.

Budget impact of low-dose computed tomography screening for lung cancer in Argentina.

Background: Lung cancer (LC) is a leading cause of cancer mortality in Argentina. Low-dose computed tomography (LDCT) had demonstrated higher efficacy than chest radiography as a screening method for early detection and reducing LC mortality. This study estimates the Budget Impact of implementing annual LDCT screening for individuals aged 55-74 with at least 30 pack-years of smoking in Argentina.

Indoxyl sulfate (IS) mediates pro-inflammatory responses in severe pneumonia in patients with rheumatoid arthritis associated interstitial lung disease.

Object: Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) have a high risk of serious infection, in particular severe pneumonia. This study aimed to investigate the transcriptional landscape, lower respiratory tract (LRT) microbiome and metabolomic profiles in the lung of RA-ILD patients with pneumonia.

Method: A total of 10 RA-ILD with pneumonia were enrolled in this study.

Inequity of access to contrast-enhanced cardiovascular magnetic resonance in patients with chronic kidney disease: A survey from the British Society of Cardiovascular Magnetic Resonance.

Objectives: To examine the provision of cardiovascular magnetic resonance (CMR) using gadolinium-based contrast agents (GBCA) in patients with chronic kidney disease (CKD).

Methods: An electronic survey was sent to the service leads of all CMR units in the UK in October 2022 requesting information on current departmental protocols and practice.

Results: A response rate of 55% was achieved from the 82 UK CMR units surveyed.

Lung-targeted delivery of PTEN mRNA combined with anti-PD-1-mediated immunotherapy for In Situ lung cancer treatment.

mRNA-based protein replacement therapy has become one of the most widely applied forms of mRNA therapy, with lipid nanoparticles (LNPs) being extensively studied as efficient delivery platforms for mRNA. However, existing LNPs tend to accumulate in the liver or kidneys after intravenous injection, highlighting the need to develop vectors capable of targeting specific organs. In this study, we synthesized a small library of ionizable lipids and identified PPz-2R as a promising candidate, exhibiting lung-targeting capabilities, high mRNA transfection efficiency, and good stability through structure-activity relationship studies.

The potential of lazertinib and amivantamab combination therapy as a treatment strategy for uncommon EGFR-mutated NSCLC.

Uncommon epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) pose therapeutic challenge due to limited response to EGFR tyrosine kinase inhibitors (TKIs). This study presents preclinical evidence and mechanistic insights into the combination of lazertinib, a third-generation EGFR-TKI; and amivantamab, an EGFR-MET bispecific antibody, for treating NSCLC with uncommon EGFR mutations. The lazertinib-amivantamab combination demonstrates significant antitumor activity in patient-derived models with uncommon EGFR mutations either before treatment or after progressing on EGFR-TKIs.

Development and validation of a county deprivation index for assessing socio-economic disparities in the United States: Implications for public health outcomes and mitigation strategies.

Objective: To develop and validate a county deprivation index (CDI) that assesses socio-economic disparities and their impact on health outcomes at the county level.

Study Design: A retrospective, cross-sectional study using publicly available county-level data.

Methods: Hierarchical cluster analysis was used to group 18 county-level socio-economic indicators into three clusters: economic well-being and technical connectivity, socio-economic disadvantage and vulnerability, and housing affordability and quality of life.

Is pathological response an adequate surrogate marker for survival in neoadjuvant therapy with immune checkpoint inhibitors?

Pathological response (PR) is an oncological outcome measure that indicates the therapeutic response to neoadjuvant therapy. In clinical trials involving neoadjuvant or perioperative interventions, overall survival and disease/event-free survival are typically the primary outcome measures. Although some evidence suggests that pathological complete response (pCR) can serve as a surrogate marker for the primary endpoint in prospective trials, it remains uncertain whether pCR is a true surrogate marker for patients with cancer undergoing curative resection across all solid tumours.