Whole Mitochondrial Genome Analysis Highlights India's Role in Pig Domestication and Maternal Lineage Diversification.
Explore the source record for details and available documents.
Domestication↗
SEARCH · Search PubMed
Results for “tumor-infiltrating T cells”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Improved quality of life and prolonged survival with add-on homeopathic treatment in patients with non-small cell lung cancer: a prospective, randomized, placebo-controlled, double-blind, three-arm, multicenter study.
BACKGROUND: Alongside conventional anticancer treatment, add-on homeopathy might help to alleviate adverse effects of conventional therapy. AIM: The aim of this study was to replicate previous studies on the effect of adjunctive homeopathy on quality of life (QoL) and survival in non-small cell lung cancer (NSCLC) patients. METHOD: In this prospective, randomized, placebo-controlled, double-blind, three-arm multicenter phase III study with quadruple-checked data analysis, we investigated the potential effects of an add-on homeopathic treatment compared to placebo in patients with stage IV NSCLC in terms of QoL. Ninety-eight received either individualized homeopathic medicinal products (HMPs; n = 51) or placebo (n = 47) in a double-blinded fashion. Fifty-two control patients without homeopathic treatment were only observed in terms of their survival rate. The ingredients of the various HMPs were mainly prepared of plant, mineral, or animal origin. The data entry and statistical analysis were subject to an exceptional quadruple-checked data analysis process. The analysis presented in this article was inspired by our earlier report of this trial published in The Oncologist in 2020, which was retracted by that journal in November 2025 after two corrections; a majority of the co-authors disagreed with this decision. The present article is based on the same trial dataset but was deliberately designed to highlight the unique research methodology: design and preparation by a lead statistician, data entry, data clearing and independent statistical evaluation were performed in four mutually independent steps, reporting follows the CONSORT statement, and the interpretation of the findings has been reframed conservatively. RESULTS: Global health status (QoL) was higher in the homeopathy group than in the placebo group after 9 weeks and after 18 weeks (p < 0.001). With the exception of cognitive functioning at 9 weeks and of pain, diarrhea and financial difficulties at 9 weeks, all functional and symptom scales of the EORTC QLQ-C30 favored the homeopathy group (p < 0.001 for the multivariate comparisons), with between-group differences exceeding the threshold of 10 points that is generally regarded as clinically meaningful. Median survival time over the 730-day observation period was 435 days in the homeopathy group, 257 days in the placebo group (p = 0.010), and 228 days in the non-randomized control group (p < 0.001); the corresponding 2-year survival rates were 45.1%, 23.4%, and 13.5% (homeopathy vs. placebo p = 0.020; homeopathy vs. control p < 0.001). The difference between the placebo group and the non-randomized control group was not statistically significant (p = 0.154). CONCLUSION: In this trial, add-on homeopathy was associated with better quality of life across most functional and symptom domains, with clinically meaningful effect sizes congruently to a previous open study. Survival time was significantly longer in the homeopathy group compared to both the placebo and control groups. Independent replication, ideally within contemporary immuno-oncological treatment regimens is required. TRIALS REGISTRATION: ClinicalTrials.gov; No.: NCT01509612; January 7, 2012.
Humans↗
Associations of red blood cell fatty acids with personality traits: 10-year follow-up in the Kibbutzim Family Study (KFS).
BACKGROUND: The ability of hostility and type-A personality to predict cardiovascular outcomes makes understanding antecedents of these personality traits an important public health objective. OBJECTIVES: This study aimed to examine whether blood-measured fatty acids (the exposure) are associated with hostility and type-A personality (the outcome), while accounting for lifestyle, sociodemographic factors, and polygenic background. METHODS: Personality traits, sociodemographic, and lifestyle data were obtained in 1992-1993 from 452 family members living in kibbutz settlements in Israel (visit 1) and remeasured 8 to 10 y later in 379 individuals (visit 2). Red blood cell (RBC) fatty acid concentrations were determined in visit 1 by gas chromatography. Longitudinal associations of visit 1 fatty acids with visit 2 personality traits were examined using linear models, before and after controlling for baseline personality scores. The contribution of environmental factors to personality scores beyond heritability was estimated by variance decomposition. RESULTS: In longitudinal analysis, 1% increase in visit 1 total n-6 (ω-6) fatty acid was associated with a 0.328-unit decrease in visit 2 type-A score [95% confidence interval (CI): -0.571, -0.085]. After adjustment for baseline personality levels, the association was slightly attenuated (β= -0.204; CI: -0.399, -0.009). One percent higher total n-6 was also associated with 1.119 units lower visit 2 hostility score (CI: -2.777, 0.038; P = 0.055). Finally, independent of the genetic contribution (32%-38% of adjusted variability in hostility and type-A personality), 1% increase in total n-3 and total n-6 was associated with 2.539 (CI: -3.907, -1.171) and 0.201 (CI: -0.365, -0.037) units lower hostility and type-A scores, respectively. CONCLUSIONS: Higher RBC total n-6 fatty acid concentrations are associated with lower type-A personality scores. After adjustment for baseline personality levels, the associations between total n-6 and hostility and between total n-3 and hostility are attenuated. These findings support further investigation of the relationship between fatty acid biology and personality traits using study designs better suited to causal inference.
Humans↗
"Everybody thinks that it won't happen to them": A mixed-methods study of HIV prevention strategies among people experiencing homelessness who use drugs.
BACKGROUND: HIV disproportionately affects people experiencing homelessness, particularly those who use drugs. Although effective prevention strategies exist, uptake remains suboptimal in high-risk populations. Limited research has examined how this population engages with HIV prevention strategies and the contextual factors shaping behaviors. METHODS: We conducted a mixed-methods study of adults (≥18 years) experiencing homelessness with recent drug use, recruited from three Boston sites (Feb 2024-Jan 2025). Participants completed a survey assessing HIV prevention strategy uptake. A subsample completed in-depth interviews on factors influencing behavior. Guided by the Theoretical Domains Framework, we coded qualitative data and identified themes to help contextualize uptake. RESULTS: Among 196 participants, mean age was 48; 61% identified as male and 44% as non-Hispanic White. Forty-two percent reported condomless sex, and among those who had ever injected drugs (n = 123), 24% reported syringe sharing in the prior three months. Only 9% reported current PrEP use, and 12% had ever used HIV self-tests. Qualitative findings highlighted perceived control as a key facilitator, while low perceived HIV risk hindered uptake across strategies. Additional barriers varied by strategy and included partner dynamics and substance use affecting condom use, structural constraints affecting syringe use, and knowledge, stigma, and cost concerns affecting PrEP and self-testing. CONCLUSION: In this cohort of people experiencing homelessness who use drugs, HIV prevention strategy uptake was suboptimal, with particularly low PrEP and HIV self-testing use. Qualitative findings suggest that interventions to promote HIV prevention strategy uptake in this population should leverage perceived control, address perceived risk, and target strategy-specific interpersonal and structural barriers.
Humans↗
Efficacy of current approaches to non-invasive diagnosis of skin cancer and the potential impact of artificial intelligence: A systematic review and meta-analysis.
BACKGROUND: Skin cancer is one of the most prevalent malignancies worldwide, particularly within Caucasian populations. This systematic review and meta-analysis aimed to quantitatively review the current literature on non-invasive diagnosis of skin cancer and evaluate the current evidence to support the use of tools in addition to, or in replacement of clinician face-to-face assessment. METHODS: A literature search was conducted for publications in PubMed, Medline and Embase databases. Articles describing accuracy, sensitivity, specificity and outcomes of their mode of assessment were included. A total of 208 articles met the inclusion criteria. RESULTS AND CONCLUSION: This systematic review and meta-analysis showed that the diagnostic performance of artificial intelligence (AI) in the interpretation of dermatoscopic images was high for melanoma diagnosis, basal cell carcinoma or malignancy, in comparison to dermatoscopic assessment alone by clinicians and experts. Although AI interpretation of images demonstrated higher sensitivity for melanoma diagnosis in comparison to clinical assessment combined with dermatoscopic assessment, it is unclear if this is also the case for basal cell carcinoma and squamous cell carcinoma diagnosis. Reflectance confocal microscopy, a non-invasive high resolution imaging technique, is known to have a high sensitivity for diagnosing cutaneous malignancy, and this may have applications within secondary care. Therefore, AI could help reduce resource burden and aid in clinical assessment, particularly within primary care settings.
Humans↗
Human iPSC-EV-loaded nanofiber stent coatings accelerate vascular repair by enhancing EGFR/HIF-1α signaling and suppressing ROCK1-mediated remodeling.
Arterial disease management is shifting from antiproliferative drug-eluting stents toward approaches that restore endothelial function and modulate smooth muscle cell (SMC) behavior. Stem cell-derived extracellular vesicles (EVs) carry miRNAs that promote endothelial proliferation and migration while restraining aberrant SMC growth and inflammation. Here, human induced pluripotent stem cell (iPSC)-derived EVs were collected by ultracentrifugation and incorporated into 50:50 poly (lactic-co-glycolic acid) (PLGA 503) core-shell nanofibrous membranes, which were fabricated as stent coatings for sustained release to overcome rapid clearance and poor tissue retention. EVs derived from three independent iPSC lines all enhanced tube formation in human umbilical vein endothelial cells (HUVECs) under hypoxic and serum-starved conditions and revealed a trend toward reduced platelet-derived growth factor-BB (PDGF-BB)-induced smooth muscle cell (SMC) migration. The fabricated core-shell nanofibers enabled sustained EV release, maintaining therapeutic efficacy for 28 days. Small RNA sequencing (NGS) analysis demonstrated that EVs from these independent iPSC lines shared miR-148a-3p and members of the miR-92 family, which collectively accounted for more than 75% of the reads within the 25 top-expressed miRNA set. In vitro, iPSC-EVs enhanced HUVEC proliferation and survival signaling by downregulating the negative regulators ERRFI1 and VHL, which are specific targets of miR-148a-3p and the miR-92 family, thereby activating the EGFR and HIF-1α axes and driving downstream ERK1/2 and VEGF expression under hypoxic and serum starvation stress conditions. Concurrently, iPSC-EVs prevented PDGF-BB-induced SMC phenotypic switching by downregulating ROCK1, a target of miR-148a-3p, thereby inhibiting downstream AKT and ERK signaling and preserving contractile markers while suppressing the synthetic phenotype. In vivo, the iPSC-EV-functionalized scaffolds significantly accelerated re-endothelialization and inhibited neointimal hyperplasia, evidenced by the upregulation of angiogenic factors (VEGF, CD31) and the concurrent suppression of pathological remodeling markers (α-SMA, MMPs) and inflammatory cytokines (IL-6, TGF-β1). Therefore, iPSC-EVs enriched with specific miRNAs and delivered via PLGA 503 core-shell nanofibers promote endothelial repair while suppressing SMC overgrowth, providing a promising strategy for vascular healing.
Core-shell nanofibers↗
Diversification of yeast proteins as an approach for the development of sustainable food systems.
Despite growing trend in sustainable protein sources, yeast proteins have mainly been explored as a source of bioactive peptides using a monospecies and general protein approach. The contribution of highly abundant protein fractions in the yeast proteome to peptide formation remains insufficiently investigated, limiting a comprehensive understanding of yeast proteins as optimized peptide sources. The current review presents a systematic analysis of yeast proteins as emerging protein sources and evaluates the suitability of high-abundance proteins as bioactive peptide precursors by in silico techniques. Moreover, brewery by-product and single-cell yeast protein approaches are compared in terms of composition and techno-functionality whereas peptide formation mechanisms (in situ and ex situ) and regulatory aspects for food applications are also addressed. Cytoplasmic metabolic proteins, particularly glycolytic enzymes (GAPDH), are identified as highly abundant fractions of the yeast proteome. Proteins associated with cell and organelle membranes also contribute substantially based on cellular localization. These findings imply that such proteins may act as key precursors of yeast-derived bioactive peptides. In silico hydrolysis with Alcalase suggests a tendency toward the generation of short-chain peptides (3-11/14 aa), which may support biological activity. Moreover, peptide profiles appear to vary across yeast species, highlighting the role of species diversity in peptide generation. While single-cell yeast protein allows more controlled production than brewery by-products, nucleic acid content in both may limit applications. Overall, yeast proteins appear to be metabolically adaptable and species-diverse sources for various biological peptides.
Saccharomyces cerevisiae↗
Nitrogen sources and concentrations shape algal odor compounds: Key drivers of β-cyclocitral and β-ionone in water bodies of the lower Yangtze River.
Taste and odor (T&O) compounds derived from cyanobacterial blooms pose escalating threats to freshwater security worldwide, yet the drivers of specific T&O metabolites remain poorly constrained. Here, we investigated the dual effects of nitrogen (N) sources and concentrations on the production of β-cyclocitral and β-ionone, two algal-derived T&O compounds, through integrated field surveys (54 sites across lakes and rivers) in the eutrophic lower Yangtze River, China, and laboratory cultivation of typical cyanobacteria (Microcystis aeruginosa and Pseudanabaena cinerea). Our field data revealed that the concentrations of β-cyclocitral and β-ionone in lakes and rivers were not significantly different, but increased with the trophic level index. Redundancy analysis and Mantel analysis showed that Microcystis and Pseudanabaena were potentially dominant contributors to β-cyclocitral and β-ionone in the water column. Structural equation modeling and variation partitioning analysis showed that enhanced nitrate (NO3--N) significantly promoted the production of these compounds. Laboratory experiments demonstrated that inorganic N (NaNO₃) maximized total T&O yields by promoting algal biomass, whereas organic N (urea and glutamic acid) elevated the T&O production per unit biomass by 1.5- to 9.5-fold. Notably, Pseudanabaena exhibited a 2.3-fold higher β-ionone yield than Microcystis, with greater sensitivity to N concentrations. Our study highlights the critical role of nitrogen pollution, both source and concentration, in the production of T&O compounds by phytoplankton and provides reference data for managing T&O issues in rivers and shallow lakes.
Norisoprenoids↗
Translational reprogramming of TGF-β signaling via TRMT61A-mediated tRNA m1A drives prostatic fibrosis and hyperplasia.
Dysregulation of the epitranscriptomic landscape is closely linked to pathological proliferation, but its specific role in benign prostatic hyperplasia (BPH) remains unclear. Here, we identify the tRNA methyltransferase TRMT61A as a critical driver of BPH progression. We found that TRMT61A and global N1-methyladenosine (m1A) levels are aberrantly upregulated in human BPH tissues. Functionally, TRMT61A knockdown potently suppresses prostate cell proliferation and reduces stromal fibrosis, inducing G1 cell cycle arrest and reversing pathological remodeling both in vitro and in vivo. By integrating ribosome profiling (Ribo-seq) and tRNA-seq, we observed that TRMT61A drives translational reprogramming. TRMT61A preserves the stability of specific tRNA isoacceptors (e.g., tRNA-Leu-CAA), which is required for the efficient decoding of mRNAs containing m1A-dependent codons. Consequently, TRMT61A selectively promotes the translational elongation of the key receptor TGFβR1. This amplifies downstream TGF-β/SMAD signaling and drives epithelial-mesenchymal transition (EMT) without affecting mRNA transcription. In summary, our study reveals how TRMT61A drives BPH progression through TGFβR1 translation, highlighting the therapeutic potential of targeting epitranscriptomic pathways to reverse prostatic hyperplasia and fibrosis.
Male↗
Optimized AAV5-RPGR ORF15 Gene Therapy Rescues Photoreceptor Structure and Function in X-Linked Retinitis Pigmentosa Mouse Model.
PURPOSE: To develop and evaluate an rAAV5-based gene therapy vector expressing an optimized human RPGR ORF15 transgene (rAAV5-RPGR) for the treatment of X-linked retinitis pigmentosa caused by RPGR mutations, addressing the challenges of cloning the unstable wild-type ORF15 sequence. DESIGN: This was a prospective experimental study. SUBJECTS: This was an animal study. METHODS: An optimized RPGR ORF15 sequence was designed to eliminate problematic secondary structures and cryptic splice sites. In vitro expression was validated in HEK 293T and photoreceptor-like 661 W cells. A complete Rpgr knockout mouse model (Rpgr-knockout [KO]) was generated and characterized phenotypically. Therapeutic efficacy was assessed in Rpgr-KO mice via subretinal injection of rAAV5-RPGR at low (1 × 10⁹ vg/eye), medium (3 × 10⁹ vg/eye), or high (1 × 10¹⁰ vg/eye) doses. Structural and functional outcomes were evaluated at 12- and 14-month postinjection. Short-term safety was assessed in rabbits 1 month after subretinal injection. MAIN OUTCOME MEASURES: Level of RPGR protein expression and Protein isoform profile (elimination of truncated isoforms), Cellular localization of transgene expression and Dose-dependence of expression, outer nuclear layer thickness, and electroretinography parameters. RESULTS: (1) The optimized vector increased RPGR protein expression 3.3-fold in vitro compared to wild-type and eliminated truncated isoforms. (2) Subretinal delivery of rAAV5-RPGR in mice demonstrated dose-dependent transgene expression localized correctly to photoreceptor inner segments. (3) In Rpgr-KO mice, high-dose treatment significantly preserved outer nuclear layer thickness at the injection site (42% greater than controls at 14 months, P < .01) and central retina (P < .05), reduced aberrant rhodopsin mislocalization (P < .01), and partially restored retinal function. ERG showed significantly improved scotopic a-wave (≥100 vs <90 µV in controls at 10 cd·s/m²) and photopic b-wave amplitudes (49-66 vs 31-46 µV at 30 cd·s/m²) in treated mice. (4) No vector-related toxicity was observed in rabbits. CONCLUSIONS: rAAV5-RPGR mediated efficiently, targeted expression of optimized RPGR-ORF15, significantly preserved photoreceptor structure and function in a severe X-linked retinitis pigmentosa mouse model, and demonstrated a favorable safety profile. This study provides preclinical proof-of-concept for RPGR-targeted gene replacement therapy.
Animals↗
Advanced/Novel Stenting for Pediatric Dynamic Airway Collapse.
Pediatric dynamic airway collapse is a complex condition that can impact all levels of the pediatric airway. These conditions can pose life threatening risk to pediatric patients and carry lasting impacts. While traditionally, tracheostomy has been used to address all levels of dynamic collapse, recent advances have allowed for more individualized, anatomy-specific stenting and splinting strategies for treatment. This article covers pathophysiology and the latest evidence on strategies to address nasopharyngeal, oropharyngeal, proximal trachea, and tracheobronchial dynamic collapse.
Humans↗
Transient acoustic stimulation induces time-dependent synaptic remodeling and enhancement of auditory nerve output after threshold recovery.
BACKGROUND: Acoustic stress can alter cochlear function even in the absence of permanent threshold elevation; however, synaptic consequences of transient acoustic stimulation remain incompletely understood. OBJECTIVE: This study aimed to investigate whether transient acoustic stimulation induces changes in the auditory nerve output and cochlear ribbon synapse morphology following hearing threshold recovery. METHODS: Young adult CBA/CaJ mice were exposed to band-limited acoustic stimulation (45-2,000 Hz, 95 dB SPL, 2 h). Auditory brainstem responses (ABRs), hair cell and spiral ganglion neuron survival, and synaptic morphology were evaluated before exposure and up to 2 weeks post-exposure. RESULTS: ABR thresholds were transiently elevated immediately after exposure but largely recovered by 1 day post-exposure. In contrast, ABR wave I amplitudes significantly increased after threshold recovery across multiple test frequencies. Ribbon-associated puncta in both inner and outer hair cell regions exhibited biphasic temporal changes, with an initial decrease immediately after exposure followed by an increase at 1 day post-exposure. The ribbon-associated punctal area also increased after exposure and remained elevated at later post-exposure time points. No significant loss of hair cells or spiral ganglion neurons was observed. Exploratory genomic analysis suggested enrichment of pathways related to metabolic defense and cellular stress responses. CONCLUSIONS: Transient acoustic stimulation induces time-dependent synaptic remodeling and enhancement of peripheral auditory nerve output without overt cellular degeneration. These findings support a model in which early cochlear responses to acoustic perturbation include adaptive synaptic plasticity and gain regulation, extending current concepts of noise-induced cochlear change beyond irreversible synaptic loss.
Animals↗
MARK1 suppresses infectious bursal disease virus replication via phosphorylating VP3.
Infectious bursal disease virus (IBDV) of the Birnaviridae family is a non-envelope, double-stranded RNA virus that encodes a VP3 protein with multiple functions, which controls viral genome replication, IFN-β production, and virus traffic in infected cells. Posttranslational modifications (PTMs), such as ubiquitination, of VP3 have been demonstrated for affecting its function and stability. To clarify the mechanism by which VP3 is regulated in IBDV infected cells, we focused on the phosphorylation of VP3. Mass spectrometry analysis identified that microtubule-affinity regulating kinases 1 (MARK1) was a kinase interacting protein of VP3. Inhibitory function of MARK1 in affecting viral replication was validated. We describe the phosphorylation event at the serine 130 (S130) and serine 163 (S163) residues of VP3 mediated by MARK1 via mass spectrometry analysis. Alanine replacement of the phosphorylation sites in VP3 significantly enhanced its RNA-binding activity. Additionally, the mutation of two serine residues led to remarkably improved in its polymerase-enhancing function. We then incorporated the two mutations to rescue recombinant IBDV. Viral growth curve analysis revealed that replication of mutant IBDV was significantly enhanced relative to wild type (WT) virus. In conclusion, we found that VP3 functions are specifically regulated by MARK1 mediated phosphorylation at S130 and S163 and that this regulation suppresses IBDV replication ultimately.
Infectious bursal disease virus↗
Integrative multi-omics reveals a fibroblast-centered, ZFHX3-prioritized regulatory framework linking sick sinus syndrome and atrial fibrillation.
OBJECTIVE: To define shared genetic and multi-scale mechanisms underlying comorbidity between sick sinus syndrome (SSS) and atrial fibrillation (AF). METHODS: We integrated genome-wide association study (GWAS) summary statistics for SSS and AF with Genotype-Tissue Expression (GTEx) expression and splicing quantitative trait loci (eQTL/sQTL), atrial single-cell and spatial transcriptomics, and epigenomics. We identified trait-relevant tissues and pathways, prioritized shared cell types, quantified genome-wide and local genetic sharing, detected joint loci by cross-trait meta-analysis, and linked loci to regulatory programs via colocalization and cell-prioritized co-expression networks. RESULTS: Both traits showed strongest enrichment in cardiac tissue, especially Heart Atrial Appendage. Fibroblasts from the left atrial appendage were consistently prioritized as the key shared cell population. SSS and AF displayed significant positive genome-wide genetic correlation, with multiple locally shared regions, including six major loci. Cross-trait meta-analysis identified eight joint-phenotype SNPs implicating four susceptibility genes. ZFHX3 was the leading tissue-cell-gene candidate, acting as a hub in fibroblast co-expression modules and colocalizing with cardiac regulatory signals. CONCLUSION: Shared liability for SSS and AF is highly tissue- and cell-specific, converging on regulatory networks in atrial appendage fibroblasts, with ZFHX3 serving as a central mechanistic and biomarker node.
Humans↗
Genome-Wide Impact of Human DBR1 Depletion on RNA Processing Networks Reveal a Connection Between Pre-mRNA Splicing, mRNA Surveillance and Stress Granule Dynamics.
The RNA lariat debranching enzyme DBR1 is essential for intron turnover and RNA metabolism, yet its broader impact on transcriptome regulation remains incompletely defined. To elucidate the consequences of DBR1 depletion, we performed transcriptome-wide RNA sequencing of DBR1-knockdown and wild-type HEK293 cells. Differential expression analysis revealed widespread perturbations in pathways linked to RNA splicing, mRNA surveillance, translational control, and stress-granule biology. Many of the most significantly altered transcripts encode splicing factors and RNA quality-control components, underscoring DBR1's influence on post-transcriptional regulation. Alternative splicing analysis showed changes across multiple event types, with exon skipping accounting for >50% of events, followed by mutually exclusive exons, alternative 5' and 3' splice sites, and retained introns, indicating that DBR1 depletion induces pervasive splicing defects. Direct spliceosome inhibition using isoginkgetin (blocks tri-snRNP recruitment) and pladienolide B (targets SF3B1) reproduced the DBR1-KD mis-splicing patterns of cell signaling genes and factors involved in RNA metabolism, supporting a functional link between DBR1 activity and alternative splicing. Notably, DBR1 knockdown revealed a subset of transcripts that are both NMD-sensitive and enriched within stress granules. Consistent with this observation, G3BP1 immunopurification and confocal microscopy further support a role for DBR1 and UPF1 in stress-granule dynamics, suggesting that these factors may participate at distinct stages to influence mRNA fate under stress conditions. Together, these findings indicate that DBR1 functions beyond lariat RNA turnover as a common regulator of RNA processing, transcriptome stability, and stress granule homeostasis, revealing intricate crosstalk between RNA splicing and RNA quality control pathways in human cells.
Humans↗
Adjuvant alectinib versus chemotherapy in resected ALK-positive non-small-cell lung cancer (ALINA): health-related quality-of-life and safety outcomes from a randomised, open-label, phase 3 trial.
BACKGROUND: For patients with resected, ALK-positive non-small-cell lung cancer (NSCLC), adjuvant alectinib significantly improved disease-free survival versus platinum-based chemotherapy in the global, phase 3, open-label, randomised ALINA trial. We report safety and health-related quality-of-life (HRQoL) outcomes from the ALINA trial. METHODS: Eligible patients aged 18 years or older with resected, ALK-positive, stage IB (≥4 cm)-IIIA NSCLC (per the American Joint Committee on Cancer and the Union for International Cancer Control Cancer Staging Manual 7th edition) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) via a block-stratified randomisation method to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy for four 3-week cycles. Randomisation was stratified according to disease stage and race. The primary endpoint, previously reported, was disease-free survival. Safety was a secondary endpoint and HRQoL was an exploratory endpoint. Safety was assessed by the investigator as per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5·0 until 28 days after the last alectinib dose or chemotherapy cycle. HRQoL was assessed via the Short-Form 36-item health survey version 2 (SF-36v2) questionnaire at baseline, every 3 weeks to week 12, then every 12 weeks until disease recurrence, consent withdrawal, death, or week 96. Norm-based scoring was applied; clinically meaningful changes were defined using the SF-36v2 manual. Safety was assessed in the safety-evaluable population and HRQoL in the intention-to-treat population. This study is registered with ClinicalTrials.gov (NCT03456076) and is ongoing. FINDINGS: Between Aug 16, 2018, and Dec 8, 2021, 257 patients were assigned to receive alectinib (n=130) or chemotherapy (n=127). 123 (48%) patients were male and 134 (52%) were female; 143 (56%) were Asian. The safety-evaluable population comprised 128 patients who received alectinib and 120 patients who received chemotherapy; median duration of safety follow-up was 24·8 months (IQR 22·0-24·9) in the alectinib group and 3·7 months (IQR 3·7-3·8) in the chemotherapy group. The safety of adjuvant alectinib was generally consistent with its known profile. The most common grade 3-4 adverse events were blood creatine phosphokinase increased (eight [6%] of 128), alanine aminotransferase increased (two [2%] of 128), and blood bilirubin increased (two [2%] of 128) in the alectinib group, and neutrophil count decreased (12 [10%] of 120), neutropenia (ten [8%] of 120), and nausea (five [4%] of 120) in the chemotherapy group. Serious treatment-related adverse events occurred in two (2%; one each with appendicitis and pneumonitis) of 128 patients in the alectinib group and eight (7%) of 120 patients in the chemotherapy group ( most common were gastrointestinal disorders in three [3%] patients). No deaths due to adverse events were reported in either group. There were fewer discontinuations due to adverse events with alectinib (seven [5%]) versus chemotherapy (15 [13%]). A clinically meaningful difference in improvement from baseline was seen at week 12 for bodily pain, role physical, mental health, social functioning, and vitality SF-36v2 domains with alectinib; improvements in physical and mental HRQoL were maintained over 2 years of active treatment (at week 96, mean Mental Component Summary score: 49·9 [SD 10·4]; mean Physical Component Summary score: 48·8 [SD 7·2]) and reached levels similar to the general population (population norm: 50). INTERPRETATION: For patients with resected ALK-positive NSCLC, adjuvant alectinib had a manageable safety profile; HRQoL improved and was maintained over 2 years of active treatment. Together with the disease-free survival benefit seen in ALINA, these data support adjuvant alectinib as an important new standard-of-care for patients with resected ALK-positive NSCLC. FUNDING: F Hoffmann-La Roche.
Adult↗
Descemet Stripping Only in Fuchs Endothelial Corneal Dystrophy: Results of a Randomized Clinical Trial of Topical Ripasudil and Directions for Future Innovation.
PURPOSE: To review history of Descemet stripping only (DSO) in Fuchs endothelial corneal dystrophy, describe the results of a clinical trial of topical ripasudil after DSO (K-321-201 study), and discuss future directions. METHODS: A 1-year, phase 2, randomized, placebo-controlled multicenter clinical trial of two doses of K-321 (ripasudil) administered for 12 weeks after DSO surgery in Fuchs endothelial corneal dystrophy was performed. The primary endpoint, central corneal endothelial cell density (ECD) at 12 weeks after surgery, was determined by an independent reading center that was masked to study group assignment. Duration of corneal edema, need for medical or surgical rescue therapy, corneal thickness, and central ECD throughout the entire study period were also examined. Adverse events and exploratory endpoints were collected. RESULTS: Sixty-five subjects were enrolled (21 in the QID group, 22 in the BID, and in the placebo group). Over 95% of subjects completed the trial. The QID group had a higher central ECD 12 weeks after DSO than the placebo group (531 ± 312 cells/mm2 vs 228 ± 298 cells/mm2, P = .0065). Corneal edema cleared in 17/21 (81.0%) of the QID group at 12 weeks, compared with 2/22 (9.1%) of the placebo group (P < .0001). Rescue was required in 2/21 (9.5%) subjects in the QID group and 6/22 (27.3%) subjects in the placebo group (P = .0092). Adverse events were mild and did not lead to discontinuation of treatment. CONCLUSIONS: Topical K-321 given QID improves DSO outcomes, as demonstrated by a higher ECD, more rapid resolution of corneal edema, and reduced failure rate. The medication was well-tolerated.
Humans↗
HRAS promotes mutant NRAS-driven transformation with codon and allele specificity.
Wild-type RAS family members determine the signaling and therapeutic response in cancers driven by mutant HRAS and KRAS because they activate alternate RAS effector pathways. Here, we found that the requirement for wild-type RAS to support mutant NRAS-driven transformation correlated with codon-specific differences in GTP hydrolysis. NRAS with mutations at either Gly12 (G12X) or Gly13 (G13X), which retained the GDP-GTP cycling function, had modest autonomous transforming potential. In contrast, NRAS with GTP-locking mutations at Gln61 (Q61X mutants) was uncoupled from receptor tyrosine kinase (RTK) input, rendering wild-type RAS an obligate partner for RTK-stimulated signaling and oncogenesis. In RASless cells expressing mutant NRAS, reintroduction of wild-type HRAS was sufficient to restore signaling and transformation. Global dependency mapping in human cancer cells revealed functional partitioning, wherein mutant NRAS promoted MAPK signaling and wild-type HRAS promoted PI3K-AKT survival signaling. Consequently, allele-specific or pan-RAS(ON) inhibitors synergized with inhibitors of proximal RTK signaling or of wild-type HRAS or KRAS to overcome this signaling plasticity. Pan-RAS(ON) and HRAS inhibition was synergistic for all NRAS mutants tested, with Q61X mutants showing greater sensitivity. These findings define the signaling partnership between mutant NRAS and wild-type HRAS as a targetable vulnerability and provide a biochemical blueprint for dual RAS inhibition in NRAS-mutated malignancies.
Humans↗