Citations

Abstract Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part of the CLPTM1L signal marked by rs465498) with CRISPRi revealed opposing effects on TERT expression in pancreatic versus lung cancer cells, consistent with the antagonistic pleiotropy observed for this signal. Furthermore, CRISPRi nominated an intronic CLPTM1L variable number tandem repeat (VNTR) as a potent enhancer. Long-read sequencing established VNTR polymorphisms as potential causal variants for the rs465498 signal. We showed that Hippo-pathway transcription factors mediate VNTR enhancer activity in lung and pancreatic cancer cells. Together, these findings indicate that cancer susceptibility at 5p15.33 may be mediated by both SNPs and VNTRs and provide an integrated framework for resolving complex pleiotropic loci.

Abstract Background Ceftriaxone-resistant Escherichia coli infections are increasingly common, partially because of the emergence of E. coli sequence type 131 (ST131), including its subclade C2/H30Rx, which produce extended-spectrum β-lactamases. Methods A prospective cohort including 14 US sites, which enrolled monomicrobial ceftriaxone-resistant and susceptible E. coli bloodstream infection (BSI) cases in a 1:1 ratio, was used to compare ST131 versus non-ST131 E. coli BSI, with specific attention to E. coli ST131 C2/H30Rx. Desirability of outcome ranking was determined at 30 days after infection onset. Results This analysis included 282 patients with E. coli BSI; 43% (121/282) were E. coli ST131 and 23% (66/282) belonged to the C2/H30Rx subclade. Resistance to ceftriaxone was present in 79% (96/121) ST131, 86% (57/66) E. coli ST131 C2/H30Rx, and 27% (43/161) E. coli non-ST131. Compared to patients with non-ST131 E. coli BSI, patients with ST131 BSI were older (median 70 years, [Q1 62, Q3 76] years vs 65 years, [51, 74]; P = .005) and more often admitted from long-term care facilities (21/121 [17%] vs 7/161 [4%], P < .001). Overall and empiric carbapenem use was more frequent in the treatment of patients with ST131 BSI compared with non-ST131 BSI (overall 89/121 [74%] vs 50/161 [31%]; empiric: 58/121 [48%] vs 31/161 [19%], P < .001). Desirability of outcome ranking outcomes were similar between groups. Conclusions Most ceftriaxone-resistant E. coli from US patients with E. coli BSI belong to ST131, particularly E. coli ST131 C2/H30Rx, serving as an important driver of carbapenem use.

Background Breast cancer-related lymphedema (BCRL) is a common and life-long adverse event affecting ~20% of breast cancer survivors. As existing non-pharmacologic management is burdensome, expensive, and variably effective, this systematic scoping review aims to identify pharmacologic and herbal agents for prevention and treatment for BCRL. Methods PubMED, Embase, Web of Science Core collection, and the Cumulative Index to Nursing and Allied Health Literature were searched for studies published in English between 1993 and 2025 that investigated the preventative or therapeutic effect of pharmacologic or herbal agents on BCRL among adult stage I-III breast cancer patients. Studies describing interventions with systemically absorbed anti-inflammatories, anti-thrombotics, anti-coagulants, and blood product components were included. Systematic reviews, protocols for ongoing clinical trials, preclinical and non-human studies, editorials, and studies not exclusive to BCRL were excluded. Three reviewers screened and extracted data between June and August 2025. The primary outcomes of interest were reduction in BCRL incidence or severity. Results Of the 217 articles screened, 37 were included in the final review. After full text review, 13 were excluded for repetitive data, non-English language, or irrelevant outcomes. The 24 studies included in the analysis investigated anti-diabetic, herbal, anti-inflammatory, anti-hypertensive, immunomodulatory, and microbiome modifying agents, and venoactive flavinoid derivates. Three studies explored the role of pharmacologic/herbal agents in BCRL prevention. While thiazolidinediones, anti-hypertensives, and non-steroidal anti-inflammatory drugs (NSAIDs) had no effect on BCRL incidence, glucagon-like peptide-1 receptor agonists (GLP-1 RA) were associated with BCRL prevention. In the 21 studies that assessed the effect of pharmacologic/herbal agents in BCRL treatment, NSAIDs/steroids, anti-hypertensives, microbiome/synbiotic supplements, and doxycycline showed no benefit and data for flavonoid-derived venoactive agents and herbal products were inconsistent. Immune-modulating therapies were associated with improved BCRL signs/symptoms in three studies. Conclusion This systematic scoping review found limited evidence suggesting that GLP-1 RAs may reduce the risk of BCRL and that immunomodulatory agents may improve signs/symptoms of BCRL. Rigorous prospective trials using standardized limb volume/edema, quality-of-life (QoL), and symptom measures and longer follow-up are needed to inform clinical practice aimed at preventing and treating BCRL. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD420251055134.

Evidence-Based Practice (EBP) has increased the availability of psychological treatments, yet many people do not benefit from therapy, some report deteriorations in symptoms, and dropout rates remain high. Precision Mental Health (PMH) is proposed as an extension of EBP by combining systematic measurement with predictive analytics to support the right intervention, at the right time, for the right person. Recent advances in Artificial Intelligence (AI) make PMH increasingly feasible in routine psychotherapy; however, the implementation of these approaches in routine care is still incipient. In this context, the present article has two main aims. First, we summarize key advances in PMH, particularly measurement-based care and data-informed decision making. Second, we introduce the NOVA project (Navigating Outcomes via Analytics), a multi-phase translational program designed to implement PMH in real-world psychological services. Guided by the Implementing Precision Methods framework, NOVA integrates (i) stakeholder-informed work on clinician acceptability and intention to use, (ii) pragmatic evaluation of decision support tools in routine care, (iii) development of robust and interpretable predictive models, and (iv) training and dissemination activities aligned with responsible innovation and professional competencies for AI-supported precision care. By detailing NOVA’s implementation pathway, we aim to provide a concrete roadmap for bridging AI innovation and psychological practice, accelerating the sustainable adoption of PMH in real-world settings.