Genesys (United States)

INTRODUCTION: As estrogen levels decrease with menopause, the vaginal epithelium thins and becomes more predominantly parabasal, resulting in more dry and calloused tissue changes (13). This in turn leads to vaginal dryness, dyspareunia, burning, and vaginal spotting as well as urinary symptoms such as frequency, urgency, nocturia, dysuria, and recurrent urinary tract infections (UTIs) (2b). It is hypothesized that laser therapy induces controlled injury to the epidermis of the vaginal mucosa, stimulating tissue repair and remodeling (1). This works independently of estrogen, which could be of great importance in patients with decreased estrogen responsiveness or who are not candidates for estrogen therapy. OBJECTIVE: The aim of this study is to assess the efficacy of the diVa vaginal laser therapy for treating vaginal atrophy, urinary urge, urinary frequency, and stress urinary incontinence and for the prevention of urinary tract infections. METHODS: This is a retrospective survey of patients who underwent the diVa vaginal laser therapy at a tertiary care center between January 2018 and September 2020. Participation was voluntary, and patients were asked to complete a survey with questions regarding genitourinary complaints following their treatment as well as a patient satisfaction improvement inventory. In addition, physical exam findings and the occurrence of urinary tract infections, documented in the electronic medical record as part of standard clinical care, will be collected. Descriptive statistics will be used to characterize participants’ demographic, medical history, and treatment characteristics. The primary study outcome is a change in the clinical survey measures from baseline to follow-up. Each patient’s change from baseline will be calculated, and the Wilcoxon rank-sum test will be used to test whether the change is significantly different from zero. Secondary outcomes will be patients’ self-reported satisfaction and changes in physical exam findings and documented urinary tract infections present in the electronic medical record. RESULTS: 26 patients completed the post-treatment survey and had chart data available. Findings showed that 57.7% of participants felt improvement from baseline in their symptoms, and only 1 person reported their symptoms worsened somewhat. They also showed that 71.4% had improvement in vaginal atrophy on follow-up exam and 57% of patients reported that they were somewhat or very satisfied with their treatment. CONCLUSIONS: This study shows increasing support that vaginal laser therapy may have potential use in the treatment of vaginal atrophy. Future studies should also further assess the potential role of vaginal laser therapy for incontinence and recurrent urinary tract infections.Table 1Table 2

Prognostic models in oncology have a profound impact on personalized cancer care and patient profiling, but tend to be heterogeneously developed and implemented in narrow patient cohorts. Here, we develop and benchmark multiple machine learning models to predict survival in pan-cancer and 16 single-cancer settings using a de-identified clinico-genomic database of 28,079 US patients with cancer. We identify key predictors of cancer prognosis, including 15 shared across seven or more cancer types, revealing strong consistency in cancer prognostic factors. We demonstrate that pan-cancer models generally outperform or match single-cancer models in predicting survival and risk stratifying patients, especially in smaller cancer cohorts, suggesting a unique transfer learning advantage of pan-cancer models. This work demonstrates the potential of pan-cancer approaches in enhancing the accuracy and applicability of prognostic models in oncology, paving the way for more personalized and effective cancer care strategies.

Background/Objectives: Nature has evolved millions of venom-derived peptides with diverse biological functions, a substantial fraction of which target complex membrane proteins such as G-protein-coupled receptors and ion channels. Many of these peptides are stabilized by multiple disulfide bonds, endowing them with exceptional structural stability and favorable pharmacological properties. Methods: Leveraging this natural diversity, we developed a robust venom peptide therapeutics discovery system built on phage display technology and constructed a library using approximately 482 venom-derived scaffolds. The library design was guided by a machine learning (ML) model capable of predicting mutation-tolerant residues that preserve peptide foldability, maximizing structural integrity and sequence diversity. Results: The resulting VCX library was evaluated through screening against four diverse targets (CD47, DLL3, IL33, and P2X7R), yielding strong binders for all four, a success rate of 100%. Furthermore, by integrating high-throughput recombinant expression of thioredoxin-venom fusion proteins along with ML-assisted affinity maturation, we rapidly identified potential leads for DLL3 binders. Conclusions: This venom-based discovery platform offers significant advantages in both functionality and developability compared with conventional peptide discovery approaches. By combining natural structural diversity, ML-guided design, and recombinant expression, it enables efficient identification of "antibody-like" binders with molecular weights much smaller than those of antibodies. Consequently, it provides a powerful strategy for developing next-generation peptide therapeutics targeting challenging protein-protein interactions and complex membrane proteins.

Abstract Background Advanced therapies for ulcerative colitis (UC) continue to emerge, creating a complex and growing landscape of treatment options. Afimkibart, a TL1Abinding antibody, demonstrated promising efficacy in TUSCANY-2, a phase 2b trial1. We utilize indirect comparison methods to compare the efficacy of afimkibart versus adalimumab, an anti-TNF therapy, as firstline therapeutics. Methods We performed a post hoc analysis using propensity score (PS) matching across the active arms of TUSCANY2 (NCT04090411) and HIBISCUS I/II (NCT02163759/NCT02171429), two phase 3 trials1,2, to compare the efficacy of afimkibart versus adalimumab among patients who did not previously receive any biologic therapy. Outcomes included clinical remission (defined as stool frequency subscore = 0 or 1; rectal bleeding subscore = 0; and endoscopic subscore = 0 or 1), clinical response, endoscopic improvement, and endoscopic remission after an induction period of 10 or 14 weeks, respectively. PS matching (1:1) adjusted for baseline modified Mayo score, disease duration, baseline corticosteroid use, age, sex, disease extent, and region. Results Patients who met the inclusion criteria for both studies were included in this analysis. In HIBISCUS I/II, 273 patients received adalimumab and 139 received placebo; in TUSCANY2, 101 received afimkibart and 24 received placebo. Before matching, clinical remission rates were 26.0% for adalimumab vs 10.8% for placebo in HIBISCUS I/II, and 41.6% for afimkibart vs 16.7% for placebo in TUSCANY-2. After PS matching, 152 biologicnaïve patients were included in the efficacy comparison. Afimkibart demonstrated significantly greater improvement versus adalimumab (clinical remission risk difference (RD)=19.7% [95% CI 4.9-34.6], endoscopic improvement RD = 26.3% [95% CI 11.2-41.5]) in this population. Findings were directionally consistent across clinical response and endoscopic remission. Results did not change substantively with different covariate sets and model specifications. Conclusion This is the first analysis to use clinical trial data and PS methods to compare the efficacy of afimkibart with other biologics in UC. In the absence of head-to-head trials, we leveraged PS adjustment methods to generate robust comparisons of therapeutic effects, accounting for differences in baseline covariates between trials. It is worth noting that histological and lab data were not included in the PS modeling due to limited availability, and residual confounding by them and other unmeasured factors cannot be entirely ruled out. Overall, afimkibart showed greater improvement across clinical and endoscopic endpoints compared to adalimumab in biologic-naïve patients.

Introduction : La paralysie obstétricale du plexus brachial (POPB) est une lésion nerveuse périphérique fréquente chez le nouveau-né, résultant généralement d'un accouchement difficile. Elle entraîne une atteinte des racines nerveuses C5 à T1, avec des conséquences fonctionnelles variables. L’objectif de cette étude était de décrire les aspects électrophysiologiques des POPB dans notre contexte. Méthodologie : Une étude rétrospective descriptive a été menée dans un cabinet d’électrophysiologique à Abidjan de Janvier à Juin 2024. Tous les patients ayant consulté pour un électroneuromyogramme (ENMG) avec indication de POPB ont été inclus. Les données sociodémographiques et électrophysiologiques ont été recueillies. Résultats : Parmi 223 patients venus pour un ENMG, 40 (17,94%) avaient comme indication une POPB. L’âge moyen était de 26,94 mois (écart-type ± 15,2), avec une prédominance féminine (sexe-ratio 0,90). Le bras droit était atteint dans 69% des cas. L’ENMG a retrouvé une atteinte neurogène périphérique chez 80% des patients et était normal chez 20%. La plexopathie était partielle dans 62,5% des cas, avec atteinte des territoires supérieur C5-C6 dans 37,5%, inférieur C8-T1 dans 15,6%, et association C5-C6 et C7 dans 9,4% des cas ; Aucune atteinte isolée de C7 n’a été observée. La plexopathie était totale dans 37,5% des cas. Les stades de lésion étaient : neurapraxie 48,5%, axonotmésis 9,1%, neurotmésis 3%, et séquelles 30,3%. Conclusion : L’ENMG constitue un outil clé pour caractériser les lésions du plexus brachial obstétrical et orienter la prise en charge selon le type et la gravité de l’atteinte. Mots-clés : Paralysie obstétricale du plexus brachial, électroneuromyogramme.

The endoplasmic-reticulum (ER) transmembrane protein IRE1 mitigates ER stress through kinase-endoribonuclease and scaffolding activities. Cancer cells often co-opt IRE1 to facilitate growth. An IRE1-RNase inhibitor has entered clinical trials; however, recent work uncovered a significant nonenzymatic IRE1 dependency in cancer. To fully disrupt IRE1, we describe a proteolysis-targeting chimera (G6374) that couples an IRE1-kinase ligand to a compound that binds the ubiquitin Cullin-RING Ligase (CRL) substrate receptor, VHL. G6374 induces a stable, cooperative interaction between IRE1 and VHL, driving K48-linked ubiquitination on two principal lysine residues in the IRE1-kinase domain and inducing proteasomal IRE1 degradation. Cryogenic electron microscopy and mutagenesis studies reveal a 2:2 IRE1:VHL ternary-complex topology and critical interactional features, informing future designs. G6374 blocks growth of IRE1-dependent cancer cells irrespective of their dependency mode, while sparing IRE1-independent cells. We provide a proof-of-concept for VHL-based degradation of an ER-transmembrane protein, advancing strategies to fully disrupt IRE1.