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Efficacy of Endoscopic Full Thickness Resection Using the Full-Thickness Resection Device for Submucosal Invasive Colorectal Cancer: The First United States Multicenter Experience.
No full textPURPOSE: Endoscopic full-thickness resection (EFTR) using full thickness resection device is used for removal of non-lifting or previously manipulated polyps. There is limited data regarding its efficacy for removal of colorectal submucosal invasive cancer (SMIC).
METHODS: We conducted retrospective multicenter study on patients who underwent EFTR using full thickness resection device for suspected or biopsy proven colorectal cancer (CRC).
RESULTS: Technical success was 100% and R0 resection rate was 85%. Overall, 6/20 were referred for surgery due to high risk features. Curative resection rate was 46.7% (7/15) in T1 CRC. Adverse events included 1 bleeding and 1 perforation, managed endoscopically and 1 bleeding and 2 post-polypectomy syndromes managed conservatively.
CONCLUSIONS: Our series provides the first multicenter experience on EFTR for resection of colorectal SMIC from the United States. Longitudinal data from large scale studies are required to validate our initial experience of EFTR for SMIC
Sensitized mast cells for targeted drug delivery and augmented cancer immunotherapy.
No full textCell-mediated drug-delivery systems have garnered significant attention for their potential to boost therapeutic efficacy in cancer treatment. Here, we engineered immunoglobulin E (IgE)-sensitized mast cells (IgE-MCs) to achieve antigen-guided delivery of oncolytic adenoviruses (OVs) and local immune activation. By harnessing tumor-specific antigens as allergens, IgE-MCs accumulated at antigen-positive tumors, enabling targeted OV delivery and releasing chemokines and inflammatory mediators that remodeled the tumor microenvironment. IgE-MCs encapsulating OVs induced robust anticancer immune responses and inhibited tumor growth in several murine models. Of note, in a humanized human epidermal growth factor receptor-2 (HER2)-positive patient-derived xenograft model, human MCs armed with anti-HER2 IgE and loaded with OVs increased intratumoral T cell responses and reduced tumor growth, demonstrating feasibility in a clinically relevant setting and supporting patient-specific IgE selection. Together, our study highlights the translational promise of IgE-MCs as an antigen-specific delivery platform for cancer immunotherapy
Ubiquitin E3 ligase KPC1 governs mesenchymal metastatic melanoma reprogramming via proteasomal degradation of ZEB1.
No full textMetastatic melanoma (MM) displays remarkable phenotypic plasticity, allowing tumor cells to transition reversibly between proliferative and mesenchymal (MES)-like states. This dynamic switching is strongly associated with therapeutic resistance and poor prognosis. Although transcriptional and epigenetic mechanisms driving these transitions have been extensively studied, the role of post-translational regulation, particularly the ubiquitin-proteasome system, remains poorly understood. Here, we identify the ubiquitin E3 ligase RNF 123 (KPC1) as a key post-translational suppressor of MES reprogramming in MM. Integrative analyses of bulk and single-cell transcriptomic datasets revealed that KPC1 expression is inversely correlated with the expression of core mesenchymal markers such as ZEB1, CDH2, and AXL, and positively associated with epithelial and melanocytic lineage genes, including CDH1 and MITF. Deconvolution of TCGA-SKCM RNA-seq data confirmed that this inverse correlation is specific to malignant melanoma cells and strongest in tumors enriched for mesenchymal gene signatures. Single-cell trajectory and enrichment analyses further demonstrated that decreasing KPC1 expression accompanies MES-like switch. Mechanistically, KPC1 binds and promotes the ubiquitination and proteasomal-mediated degradation of ZEB1, thereby suppressing cadherin switching and cell motility. Loss of KPC1 in melanoma cells prevented ZEB1 proteasomal-mediated degradation, increased expression of mesenchymal markers, and enhanced MM cells migration. Clinically, low KPC1 protein levels were associated with increased expression of ZEB1 and CDH2 and poorer overall survival. Furthermore, combined assessment of KPC1, ZEB1, and CDH2 expression improved patient stratification, suggesting the potential utility of multi-marker signatures for prognostic modeling. These findings establish KPC1 as a central post-translational regulator of melanoma cell state plasticity through targeted degradation of ZEB1. This study highlights a novel mechanism regulating MES-like transition and highlights KPC1 as a potential theragnostic target in MM
Midterm outcomes of laser in-situ fenestrated repair (LIFE) for complex thoracoabdominal and pararenal aortic pathologies: Results from the multicenter LIFE registry
No full textCommunication with patients using asynchronous telehealth medication abortion services.
No full textOBJECTIVES: Understanding patient communication with clinic providers or staff in telemedicine abortion can inform appropriate staffing.
METHODOLOGY: We describe patient-service communication when using asynchronous telemedicine abortion services from April to November 2020 (n = 504) and compare patient demographics with number of messages using Kruskal-Wallis rank sum test.
RESULTS: About half of patients communicated with staff (56%, n = 287), median of six messages per patient (interquartile range: 3-10 messages). Primary topics included (1) eligibility, (2) payment, (3) medication delivery, and (4) physical process. Message volume did not differ by patient demographics.
CONCLUSIONS: Our findings inform communication and staffing quantity and quality in telemedicine abortion provision.
IMPLICATIONS: Asynchronous telehealth abortion patients require minimal communication, and most inquiries can be addressed by nonclinical staff. These insights can inform resource allocation and staffing decisions in telehealth abortion services, improving efficiency while maintaining patient satisfaction
LM-Merger: a workflow for merging logical models with an application to gene regulatory network models.
No full textBACKGROUND: Gene regulatory network (GRN) models provide mechanistic understanding of genetic interactions that regulate gene expression and, consequently, influence cellular behavior. Dysregulated gene expression plays a critical role in disease progression and treatment response, making GRN models a promising tool for precision medicine. While researchers have built many models to describe specific subsets of gene interactions, more comprehensive models that cover a broader range of genes are challenging to build. This necessitates the development of approaches for improving the models through model merging.
RESULTS: We present LM-Merger, a workflow for semi-automatically merging logical GRN models. The workflow consists of five main steps: (a) model identification, (b) model standardization and annotation, (c) model verification, (d) model merging, and (e) model evaluation. We demonstrate the feasibility and benefit of this workflow with two pairs of published models pertaining to acute myeloid leukemia (AML). The integrated models were able to retain the predictive accuracy of the original models, while expanding coverage of the biological system. Notably, when applied to a new dataset, the integrated models outperformed the individual models in predicting patient response.
CONCLUSIONS: This study highlights the potential of logical model merging to advance systems biology research and our understanding of complex diseases. By enabling the construction of more comprehensive models, LM-Merger facilitates deeper insights into disease mechanisms and enhances predictive modeling for precision medicine applications.
CLINICAL TRIAL NUMBER: Not applicable
Efficacy and Safety of Deucravacitinib, a Selective, Allosteric TYK2 Inhibitor, by Baseline DMARD Use in a Phase 2 Psoriatic Arthritis Study: A Post Hoc Analysis.
No full textINTRODUCTION: This study aimed to evaluate the influence of background conventional synthetic disease-modifying antirheumatic drug (csDMARD) use on efficacy and safety of deucravacitinib, a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, in patients with psoriatic arthritis (PsA).
METHODS: This phase 2, double-blind trial randomized 203 patients with active PsA 1:1:1 to oral placebo, deucravacitinib 6 mg, or deucravacitinib 12 mg once daily for 16 weeks. Patients had failed or were intolerant to ≥ 1 non-steroidal anti-inflammatory drug (NSAID), glucocorticoid, csDMARD and/or one tumour necrosis factor inhibitor. Patients were not stratified by csDMARD use and were allowed one background csDMARD if used for ≥ 3 months with stable dose for \u3e 28 days prior to day 1; patients could not initiate new csDMARD treatment. This post hoc analysis evaluated the influence of background csDMARD use on efficacy outcomes, which included American College of Rheumatology (ACR) 20 responses and ACR scoring components; Psoriasis Area and Severity Index (PASI) scores; Psoriatic Arthritis Disease Activity Scores (PASDAS); and on safety measures.
RESULTS: Baseline clinical characteristics and disease activity were generally similar among subgroups regardless of csDMARD use. At baseline, 65.0% of patients were taking background csDMARDs and among these 84.1% were taking methotrexate; percentages of methotrexate use were similar across groups. Similar ACR 20 response rates at week 16 were observed with deucravacitinib treatment in patients with vs without baseline csDMARD use compared with placebo (deucravacitinib 6 mg: 57.8% vs 44.0%; deucravacitinib 12 mg: 62.8% vs 62.5%; and placebo: 31.8% vs 31.8%, respectively). Similar responses with deucravacitinib compared with placebo, regardless of background csDMARD use, were observed in individual ACR components, PASI score, and PASDAS. The safety profile of deucravacitinib treatment was similar in patients with and without csDMARD use.
CONCLUSION: Background csDMARD use did not affect the efficacy or safety of deucravacitinib in this phase 2 PsA study. Graphical Abstract available for this article.
TRIAL REGISTRATION: ClinicalTrials.gov ( https://clinicaltrials.gov ): NCT03881059
External evaluation of a commercial artificial intelligence-augmented digital auscultation platform in valvular heart disease detection using echocardiography as reference standard.
No full textOBJECTIVE: There are few studies evaluating the accuracy of commercially available AI-powered digital auscultation platforms in detecting valvular heart disease (VHD). Therefore, the utility of these systems for diagnosing clinically significant VHD remains unclear. We conducted a comprehensive external evaluation of the Eko murmur analysis software (EMAS) and report its accuracy in detecting murmurs associated with VHD using echocardiography (ECHO) as the reference standard.
METHODS: We analyzed phonocardiogram (PCG) and ECHO data from 1,029 individuals (461 females, mean (SD) age: 61 (29) years, BMI: 29 (9)) at a single academic medical center. PCGs were recorded using the EkoDUO and EkoCORE stethoscopes from the four standard auscultation positions immediately before transthoracic ECHO (TTE) testing. TTE diagnostics were used as reference to calculate the EMAS sensitivity and specificity in detecting murmurs associated with VHD. The 95% confidence intervals are reported.
RESULTS: Of the 4,081 PCGs, 79% were of sufficient quality for murmur analysis. The sensitivity and specificity of the EMAS in detecting VHD were 39.3% (95% CI: 37.2-41.3) and 82.3% (95% CI: 80.0-84.5), respectively. EMAS sensitivity in detecting murmurs associated with common VHD types was 62.5%, 75.0%, 88.9%, and 63.3% for moderate-severe and severe cases of mitral stenosis, aortic regurgitation, aortic stenosis, and mitral regurgitation, respectively.
CONCLUSION: The EMAS algorithm exhibits limited overall sensitivity in detecting VHD. The sensitivity of the algorithm varies across VHD types. These findings suggest that EMAS can be used for diagnosis of specific lesions, but not all VHD types, which limits its clinical applicability as a screening tool
A 40-week phase 2B randomized, multicenter, double-blind, placebo-controlled study evaluating the safety and efficacy of memantine in amyotrophic lateral sclerosis.
No full textINTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with no known cure, limited treatment options with minimal benefits, and significant unmet need for disease modifying therapies.
AIMS: This study investigated memantine\u27s impact on ALS progression, with an additional focus on the effects of memantine on cognitive and behavioral changes associated with the disease.
METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted from December 2018 to September 2020. ALS patients were enrolled in-person and remotely across 13 sites in the United States. Participants were randomized to memantine (20 mg twice daily) or placebo in a 2:1 ratio and completed 36 weeks of treatment. The primary outcome of disease progression was assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and blood was collected for biomarker analysis.
RESULTS: Of the 99 participants enrolled in the study, 89 were randomized to memantine or placebo (ages 24-83 years, male-to-female ratio ~3:2). Fifty-two participants completed the study treatment with no significant differences in disease progression, biomarker changes (including neurofilament light chain [NfL]), or neuropsychiatric testing noted between the groups. Initial NfL values correlated with the rate of ALSFRS-R decline.
DISCUSSION: In this study, memantine did not impact ALS disease progression or neuropsychiatric symptoms. Trials with remote enrollment may help trial participation and success
Glycemic Management and Individualized Diabetes Care in Dialysis-Dependent Kidney Failure.
No full textOf the nearly 600,000 people in the U.S. who receive dialysis for chronic kidney failure, \u3e60% have diabetes. People receiving dialysis who have diabetes have worse overall and cardiovascular survival rates than those without diabetes. Diabetes care in the dialysis setting is complicated by kidney failure-related factors that render extrapolation of glycated hemoglobin (HbA1c) targets to the dialysis population unreliable and may change the risk-benefit profiles of glucose-lowering and disease-modifying therapies. No prospective studies have established the optimal glycemic targets in the dialysis population, and few randomized clinical trials of glucose-lowering medications included individuals receiving dialysis. Observational data suggest that both lower and higher HbA1c are associated with mortality in the dialysis population. Existing data suggest the potential for safety and effectiveness of some glucose-lowering medications in the dialysis population, but firm conclusions are hindered by limitations in study design and sample size. While population-specific knowledge gaps about optimal glycemic targets and diabetes medication safety and effectiveness preclude the extension of all general population diabetes guidelines to the dialysis-dependent diabetes population, these uncertainties should not detract from the importance of providing person-centered diabetes care to people receiving dialysis. Diabetes care for individuals with and without dialysis-dependent kidney failure should be holistic, based on individual preferences and prognoses, and tailored to integrate established treatment approaches with proven benefits for glycemic control and cardiovascular risk reduction. Additional research is needed to inform how recent pharmacologic and technological advances can be applied to support such individualized care for people receiving maintenance dialysis