Citations

Type 1 diabetes (T1D) is a complex autoimmune disease characterized by the destruction of insulin-producing pancreatic β cells. Both genetic susceptibility and epigenetic dysregulation contribute to T1D risk. Recent studies have reported β-cell dysfunction before disease onset, suggesting that β-cell-intrinsic mechanisms contribute to pathogenesis. However, the mechanistic link between disease-associated variants and β-cell dysfunction remains poorly understood. We hypothesized that a subset of T1D-associated variants directly influences cell type-specific candidate cis-regulatory elements (cCREs) by disrupting transcription factor (TF) binding and altering gene expression. To define cell type-specific cCREs in human islets, we integrated publicly available epigenomic datasets, including bulk histone modification profiles and single-cell multiomic data from human pancreatic islets. We combined these data with T1D genome-wide association study (GWAS) variants to identify disease-associated SNPs located within enhancer regions. Using multiomic datasets from PANC-DB, we characterized cell type-specific chromatin accessibility in nondiabetic and T1D islets and identified regulatory regions that may control gene expression in β cells and other islet cell types. We then applied ChromBPNet, a deep learning model that predicts base-pair-resolution chromatin accessibility from scATAC-seq data, to evaluate how specific variants may alter local regulatory activity. In parallel, we used TF footprinting to nominate TFs likely to bind these variant-containing regions. These analyses identified several T1D-associated SNPs predicted to alter chromatin accessibility at candidate TF binding sites, suggesting mechanisms by which noncoding variants may contribute to β-cell dysfunction and T1D susceptibility. Our findings link T1D-associated variants to cell type-specific enhancer activity and regulatory pathways and provide candidates for future mechanistic studies.

Background and Objective: This study aimed to investigate glaucoma progression following secondary intraocular lens (SIOL) implantation by surgical approach. Patients and Methods: This was a single-center retrospective study of 440 eyes that received SIOL implantation, including scleral-sutured, scleral-fixated, anterior chamber, and sulcus-fixated. Glaucoma progression was defined as new diagnosis, procedure for intraocular pressure (IOP) control, or IOP elevation ≥ 24 mmHg or ≥ 5 mmHg above baseline requiring additional medications. Risk factors were assessed using multivariable analysis. Results: Mean age at surgery was 71.3 years and 29.3% of patients had prior glaucoma. Overall, 33.2% developed glaucoma progression. Prior glaucoma (hazard ratio 2.08 [95% CI 1.47–2.94], P < .001) and cystoid macular edema (1.63 [1.06–2.52], P = .026) were associated with glaucoma progression on multivariable analysis. There was no difference in glaucoma progression between scleral-sutured, scleral-fixated, anterior chamber, or sulcus-fixated implantation techniques. Conclusion: Our results suggest that surgeons should use their preferred SIOL implantation technique but closely monitor postoperative IOP.

Abstract Background Regorafenib and anti-EGFR monoclonal antibodies are standard therapies for RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC) in the refractory setting, but the optimal sequencing remains unknown. Herein, we report results from REVERCE II, a randomized phase II trial evaluating the efficacy and safety of sequencing these therapies. Methods Patients with RAS WT mCRC previously treated with fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive (R-E) regorafenib followed by anti-EGFR therapy ± irinotecan or (E-R) anti-EGFR therapy ± irinotecan, followed by regorafenib sequentially. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) with initial (PFS1) and second treatment (PFS2), sequential treatment PFS (stPFS), objective response rate (ORR), and safety. Exploratory endpoints included serial biomarker analyses. Unfortunately, the trial was closed prematurely due to slow enrollment and lack of funding. Results Twenty-two patients were enrolled (R-E: n = 12; E-R: n = 10) with sequential treatment initiated in 33% (4/12) and 80% (8/10) of patients in R-E and E-R, respectively. Median OS for R-E and E-R was 21.9 and 13.3 months, respectively (one-sided P = .114). PFS1 was 2.5 (R-E) vs 5.6 months (E-R) (one-sided P = .998), while PFS2 was 3.7 vs 2.0 months (one-sided P = .086). stPFS was similar (9.3 vs 9.6 months; one-sided P = .358). ORR for initial treatment was 0% in R-E and 20% (2/8) in E-R. Sequential treatment ORR was 25% (n = 1/4) in R-E and 0% in E-R. No significant differences were observed adverse effects between arms. Conclusion While the study was closed prematurely prior to completion, the sequence of regorafenib before to anti-EGFR therapy suggested a possible survival benefit. Further studies may help better determine the optimal treatment sequencing strategy in refractory mCRC.

ABSTRACT Coeliac disease (CeD) and immunoglobulin A deficiency (IgAD) frequently co‐occur and share a genetic background within the HLA‐DQ2 region. Although this has been known for decades, the underlying mechanisms linking the two conditions remain unclear. We conducted a scoping review to evaluate the prevalence, clinical characteristics, diagnostic challenges and histopathological features of IgAD in patients with CeD. Thirty‐one studies published between 1985 and 2024 were included. IgAD was more prevalent among individuals with CeD, 1.4%–4.8% than in the general population, and CeD occurred in 5.9%–14.1% of patients with IgAD. Most patients presented with gastrointestinal symptoms, although selection bias was common. IgG‐based serology remains essential for diagnosis and monitoring, but its reliability during follow‐up is limited by the slow decline of antibodies. Histological findings indicate compensatory IgM and IgG responses and persistent mucosal immune activation. Improved strategies for diagnosis and long‐term monitoring of patients with both conditions are warranted.

Multiple myeloma (MM) outcomes have improved with proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies, and transplantation, yet a subset of patients with high-risk MM (HRMM) continues to relapse early and die prematurely. Immune effector therapies (IET)—B-cell maturation antigen (BCMA)- and G protein–coupled receptor class C group 5 member D (GPRC5D)-directed chimeric antigen receptor T cells (CAR-T) and bispecific antibodies—have transformed the treatment of relapsed/refractory MM. However, their benefit in HRMM remains incompletely defined. This review describes how HRMM is defined in the IET-era distinguishing baseline biological/genomic risk, clinical high-risk phenotypes, and IET-specific adverse predictors. The International Myeloma Society/International Myeloma Working Group consensus integrates adverse cytogenetics and beta-2 microglobulin, whereas functional high-risk disease, extramedullary disease (EMD), plasma cell leukemia (PCL), high tumor burden, inflammation, and prior BCMA exposure identify aggressive disease in relapsed patients. Across pivotal trials, CAR-T therapy, particularly ciltacabtagene autoleucel, and selected bispecific antibodies retain activity in high-risk cytogenetic subgroups, whereas EMD and PCL remain associated with inferior responses and short progression-free survival. Emerging dual-antigen and trispecific engagers, along with novel targets such as FcRH5 and CD70, aim to overcome antigen escape. Prospective, biology-informed studies are needed to achieve durable disease control in HRMM.