Browse Articles
Discover research articles across all indexed journals
Comparison of compressed sensing and conventional 4D flow MRI for turbulent kinetic energy assessment in healthy participants and patients with aortic stenosis
Efficacy and safety of fruquintinib combined with chemotherapy versus bevacizumab combined with chemotherapy as second-line treatment for metastatic colorectal cancer: A prospective, multicenter, randomized controlled trial.
LBA3563 Background: The optimal second-line treatment for metastatic colorectal cancer (mCRC) after failure of oxaliplatin-based chemotherapy therapy remains an area of active research, while bevacizumab combined with chemotherapy is a standard option. Fruquintinib (Fru) is a highly selective and potent oral tyrosine kinase inhibitor of VEGFR 1, 2, and 3. This study aimed to compare the efficacy and safety of fruquintinib combined with chemotherapy versus bevacizumab combined with chemotherapy as second-line treatment for mCRC. Methods: This was a non-inferiority trial conducted across 12 hospitals and cancer centers in China. Patients with mCRC who had progressed on fluoropyrimidine and oxaliplatin-based first-line chemotherapy therapy were randomly assigned (1:1) to receive either Fru (4 mg orally, once daily for 3 weeks on/1 week off) plus FOLFIRI, or bevacizumab (Bev) (5 mg/kg intravenous, every 2 weeks) plus FOLFIRI. Randomization was stratified by primary tumor location and RAS/BRAF status. During combination therapy, pts who achieve disease control after 4-6 months of treatment proceeded to maintenance therapy, receiving either fruquintinib combined with capecitabine or bevacizumab combined with capecitabine. The primary endpoint was progression-free survival (PFS). Final analysis occurred after either 97 PFS events or after the last patient had completed 12 months of follow-up, whichever occurred first. The non-inferiority upper margin of HR was 1.33. Results: Between Jul 13, 2023, and Mar 4, 2025, 122 pts were enrolled and randomly assigned to the Fru group (n=60) or the Bev group (n=62). The median age was 59.0 (IQR 54-69) and 60.0 (IQR 51-70) years, 45 (75%) and 48 (77%) had left-sided tumors, 36 (60%) and 36 (58%) were RAS/BRAF mutant, respectively. At data cut-off (Feb 28, 2026), the median PFS of the Fru group was non-inferior to the Bev group, whether in the Intention to Treat Population (ITT) (9.40 vs 7.39 months, hazard ratio [HR]=0.806 [95% CI 0.522–1.244, 80% CI 0.607-1.07]; p=0.33) or the per-protocol set (PPS) (9.49 vs 7.85 months, HR=0.848 [95% CI 0.542–1.326, 80% CI 0.633-1.136]; p=0.469). In the subgroup analysis , the Fru group showed longer PFS in prior never used VEGF inhibitor pts (10.6 vs 8.5 months, HR=0.94, 95% CI 0.54-1.62), and pts without liver metastasis (14.5 vs 9.9 months, HR=0.97, 95% CI 0.43-2.22) compared to the Bev group. The objective response rate was 35.0% with Fru vs 22.6% with Bev group. Any-grade treatment-emergent adverse events (TEAEs) occurred in 100.0% (Grade ≥3, 28.1%) of the Fru group and 93.2% (Grade ≥3, 28.8%) of the Bev group. Conclusions: Fruquintinib combined with FOLFIRI demonstrated non-inferiority in PFS compared with bevacizumab combined with FOLFIRI as a second-line treatment for mCRC, with a manageable safety profile. Clinical trial information: NCT05555901 .
Active inference as a model of collision avoidance behavior in human drivers
A Self-Assembled Cage Binds Xenon via Xe–F Dispersion Interactions
Friction and wear behavior of TiN/Ti6Al4V composite material synthesized in-situ using laser directed energy deposition
ADAM trial: A multicenter, randomized, double-blinded, placebo-controlled, phase 3 trial of adjuvant avelumab (anti-PD-L1 antibody) in patients with Merkel cell carcinoma and lymph node metastases.
LBA9504 Background: Merkel cell carcinoma (MCC) with lymph node (LN) metastases (mets) is historically associated with high risk of relapse and mortality despite surgery and/or radiation therapy (RT). Previously reported adjuvant trials (ADMEC-O and STAMP) have not shown a clear benefit with adjuvant PD-(L)1 blockade. Methods: ADAM trial (NCT03271372) is an investigator-initiated, phase III, multi-center, double-blinded, placebo-controlled study. We enrolled 100 patients (pts) with MCC and LN mets (stage III) treated definitively with surgery and/or RT, and without radiologic evidence of residual MCC. Pts were randomized (1:1), stratified by primary tumor/LN status and RT status, to receive IV avelumab (A; 800 mg/dose) or placebo (P), for up to 2 years (yrs) on a de-escalating schedule. The primary endpoint was relapse-free survival (RFS). 100 patients provide 86% power to observe a statistically significant (2-sided 5%) difference in RFS assuming true hazard ratio (HR) for RFS failure of 0.4. Secondary endpoints included distant metastasis-free survival (DMFS), disease-specific survival (DSS), overall survival (OS), and safety. Point estimates were obtained using Kaplan-Meier or cumulative-incidence methods, and Cox regression (stratified, with pre-specified adjustment of confounding variables as needed) was used to estimate HRs of failure. Results: 100 eligible pts (pathologic stage IIIB - 52; IIIA - 48) were randomized to A (N=48) vs P (N=52) between 12/2017 and 01/2024. At the data cutoff date (01/15/2026), median follow-up among relapse-free survivors was 4.2 yrs [range 1.9-7.1]. Median age was 70 yrs overall (A-72 [50-86], P- 67 [35-83]) and 93% of pts had received adjuvant RT. The HRs for RFS, relapse, DMFS, DSS and OS are listed in the Table below. The point estimates for MCC relapse for A vs P arms, respectively, were 12.8% vs 40.4% at 1 year, 21.3% vs 42.3% at 2 years and 28.3% vs 44.5% at 3-, 4- and 5-year timepoints. Grade 3/4 treatment-related adverse events (TRAE) rate was 15% (n=7) in A and 0% in P arms; no grade 5 TRAEs occurred. Conclusion: In this study, adjuvant avelumab was associated with reduced risk of MCC relapse in pts with LN mets. High MCC-specific survival in both arms points to effectiveness of PD-(L)1 blockade in adjuvant and metastatic settings. These data will inform future discussions regarding adjuvant therapy in clinical practice. Clinical trial information: NCT03271372 . Efficacy endpoints. Endpoint HR for Failure, Avelumab vs Placebo (95% CI, p-value)Stratified /Adjusted stratified Number of eventsAvelumab/Placebo RFS 0.61 (0.32-1.16, p=0.132) /0.54 (0.28-1.05, p=0.069) 16/24 Relapse* 0.51 (0.26-1.00) /0.47 (0.23-0.94) 13/23 DMFS 0.93 (0.44-1.97) /0.89 (0.41-1.94) 13/15 DSS 1.81 (0.43-7.55) /** 5/3 OS 2.37 (0.73-7.73) /** 9/5 *Not a pre-specified analysis; **Not enough events to accommodate adjustment.
A mitochondria-driven quality control mechanism for peroxisomal membrane proteins
Abstract Peroxisomes are essential organelles involved in lipid and reactive oxygen species metabolism, and their function requires proper targeting of peroxisomal membrane proteins (PMPs). When peroxisome biogenesis fails, as occurs in peroxisome biogenesis disorders, PMP levels decrease markedly, yet the underlying mechanisms remain unclear. Here, using quantitative proteomics and transcriptomics in peroxisome-deficient cells, we observe widespread post-transcriptional downregulation of PMPs driven by increased protein turnover via ubiquitination and proteasomal degradation. An unbiased CRISPR screen uncovers a mitochondrial quality control axis. PMPs that fail to reach their native peroxisomal destination are rerouted to mitochondria, where the mitochondrial outer membrane E3 ligases MUL1 and MARCH5 act redundantly to promote their degradation. Importantly, the transmembrane domain of PMPs is sufficient to drive their mitochondrial turnover. Functionally, simultaneous loss of peroxisomes and mitochondrial E3 ligases severely impairs cell proliferation, underscoring the essential role of this pathway. Together, these findings provide insight into the pathology of organelle dysfunction and reveal an inter-organelle quality control axis in which mitochondria act as a surveillance hub to clear PMPs and maintain cellular proteostasis when peroxisomes are absent.
Anisotropic Amorphization of Black Titania
An IBGWO optimized feature selection framework for sentiment analysis-based fraudulent website detection using MLRNN
First-in-Human, Phase I Study of Sigvotatug Vedotin, an Integrin Beta-6–Directed Antibody-Drug Conjugate: Results From Dose Expansion in Advanced Non–Small Cell Lung Cancer
PURPOSE Integrin beta-6 (IB6) is highly expressed in non–small cell lung cancer (NSCLC) and other solid tumors and potentially associated with poor outcomes. Sigvotatug vedotin (SV), a novel IB6-directed antibody-drug conjugate, demonstrated acceptable safety and encouraging antitumor activity in dose escalation. We report updated results for dose-expansion regimens in advanced NSCLC (aNSCLC). METHODS SGNB6A-001 is an open-label, multicenter, dose-escalation/dose-expansion phase I study evaluating safety, tolerability, pharmacokinetics (PK), and antitumor activity of SV in patients with select advanced solid tumors. After dose escalation, dose expansion further explored three regimens: 1.25 mg/kg total body weight (TBW) on Days 1 and 8 of a 21-day cycle, 1.5 mg/kg TBW on Days 1 and 15 of a 28-day cycle (once every 2 weeks), and 1.8 mg/kg adjusted ideal body weight (AiBW) once every 2 weeks. Eligible patients had prior chemotherapy and immunotherapy or targeted therapy if indicated. Primary end points were safety and determination of an optimal dosing schedule. Secondary end points were antitumor activity, PK, and immunogenicity. RESULTS As of November 26, 2024, 117 patients with aNSCLC were treated in the above cohorts. Any-grade and grade ≥3 treatment-emergent adverse events occurred in 98% and 48% of all patients, respectively, and in 94% and 35% of patients receiving SV 1.8 mg/kg AiBW once every 2 weeks. Modeling revealed that the AiBW regimen resulted in lower PK variability than TBW regimens. The objective response rate and median duration of response were 19% and 11.3 months in the overall population, respectively, and 29% and 12.8 months in patients with nonsquamous, taxane-naïve NSCLC. CONCLUSION SV demonstrated a manageable safety profile and promising antitumor activity with durable responses in aNSCLC. PK and clinical data support further investigation with the recommended 1.8-mg/kg AiBW once every 2 weeks dosing regimen.
Mechanically adaptive crack-resistant hydrogels based on strain-induced macroscopic phase separation and hierarchical energy dissipation
Deprotonative Single-Electron Oxidation as a General and Controllably Selective Platform for Benzylic C–H Functionalization
Quantitative evaluation of microbiome sequencing resolution under varying experimental conditions using defined mock communities
Room 402
A poignant reflection on loss and growth, this piece traces how a medical student transforms the grief of losing her aunt in Room 402 into a compassionate and humanistic approach to caring for patients facing the end of life.
FERONIA defines intact tissue boundaries through cuticle development
A Mild and Site-Selective Nucleophilic C–H Functionalization of Pyridines via Its Stable <i>N</i> -Alkylated Salts
Intestinal colonization of weaner pigs by extended-spectrum-β-lactamase-encoding Escherichia coli classified for differential host-association using a phylogenetics-based approach
Abstract Intestinal bacteria in healthy humans and animals are important reservoirs of antimicrobial resistance (AMR) genes. Certain Escherichia coli lineages dominate the global spread of AMR, but the extent of their host specificity and its impact on transmission remains unclear. Here, 1,198 E. coli isolates from cattle, chickens, humans, and pigs across Germany, the UK, Spain, and Vietnam were classified for host-association using a phylogeny-based bioinformatic approach, with non-host-associated isolates defined as ‘generalists’. To validate this classification, 17 extended-spectrum beta-lactamase (ESBL)-producing isolates representing host-associated or generalist clusters were administered as a cocktail to three groups of weaner pigs, either untreated or treated with amoxicillin or ceftiofur. Bacterial shedding was monitored via culture and isolate-specific PCR up to 56 days post-inoculation. Colonization occurred within 24 h, with shedding peaking early and declining over time. Only 12 of 17 isolates were recovered post-inoculation; four were persistently detected, including one pig-associated, one bovine, one chicken, and one generalist isolate. These findings suggest limitations in the classification approach, possible low host selectivity in pigs, and/or incomplete knowledge of colonization mechanisms. Nonetheless, the model successfully identified isolates capable of stable colonization, supporting its utility for studying AMR E. coli host adaptation.
Molecular-Based Ecosystem to Improve Personalized Medicine in Chronic Myelomonocytic Leukemia
PURPOSE Chronic myelomonocytic leukemia (CMML) is a rare myeloid neoplasm characterized by clinical heterogeneity and is associated with poor outcomes. To date, limited molecular information has been incorporated into disease classification and risk stratification. We aimed to integrate genomic features into the clinical decision-making process for CMML. PATIENTS AND METHODS We analyzed a retrospective cohort of 3013 patients with CMML (training set) and a prospective population of 516 patients (validation set). Using an innovative framework for multimodal data analysis, we developed molecular-based disease taxonomy and prognostication. RESULTS Unsupervised clustering identified nine entities with distinct genomic features and outcomes ( P < .001), including splicing machinery, transcription factors, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures. Notably, 15% of patients showed molecular/clinical overlap with other myeloid neoplasms. We integrated molecular and clinical information to build the international CMML Prognostic Scoring System (iCPSS), incorporating mutations in nine genes together with hematologic parameters and cytogenetic abnormalities. The iCPSS identified five groups with distinct probability of overall and leukemia-free survival in both training and validation cohorts ( P < .001), outperforming existing prognostic models. Importantly, 55% of patients were reassigned to higher or lower risk groups by the iCPSS. Decision analysis demonstrated that iCPSS could refine the optimal timing of allogeneic transplantation at the individual level; compared with conventional prognostic tools, iCPSS-based decision modeling changed transplantation strategy in 31% of cases, resulting in a significant gain-in-life expectancy for eligible patient population ( P < .001). A federated learning platform was implemented to enable continuous, privacy-preserving model update across multiple centers. CONCLUSION Molecular information improves CMML classification and prognostication, supports more effective clinical decision making, and potentially refines the design of clinical trials.