tbuckley/cabot-search huggingface dataset:
Dual role of WNT10A in promoting the malignancy of glioblastoma and remodeling the tumor microenvironment
Authors: Zhiwei Xue, Xuehai Zhang, Bo Mao, Guangjing Mu, Yan Zhang, Junzhi Liu, Jiangli Zhao, Xuchen Liu, Yanfei Sun, Guo Xiang, Hongwei Wang, Wenzhe Xu, Zheng Jiang, Shuai Wang, Rolf Bjerkvig, Jian Wang, Donghai Wang, Xingang Li, Bin Huang, Mingzhi Han
Journal: Neuro-Oncology (2025)

Abstract Background Glioblastoma (GBM) represents a complex ecosystem characterized by numerous interactions between tumor cells and the surrounding tumor microenvironment (TME). Here, we show that WNT10A, a member of the WNT family, plays an important role in GBM growth where its influence is mediated via both autocrine and paracrine pathways thereby stimulating not only the tumor cells but also normal cell types within the tumor microenvironment (TME). Methods In silico analysis was performed to identify high-expressing WNT family members in GBM. Knockdown and overexpression methods were used to examine the function of WNT10A in GBM cells and in orthotopic GBM xenografts in vivo. Co-immunoprecipitation (Co-IP) was used to confirm receptor binding and chromatin immunoprecipitation (ChIP) was performed to analyze transcriptional activation of downstream genes. Results WNT10A was found to be highly expressed in GBMs and its knockdown significantly suppressed GBM malignant behavior in vitro and in vivo. Co-IP assays confirmed an interaction between WNT10A and FZD1, which activated the JNK/c-Jun/FOSB signaling pathway and enhanced the transcription of FOSB. Importantly, GBM cells secreted WNT10A into the tumor microenvironment, leading to an activation of the PI3K-AKT pathway in tumor-associated macrophages (TAMs) and the JNK pathway in tumor-associated astrocytes. The latter caused a secretion of tumor-promoting cytokines IL-6, MCP-1, and angiogenin. LGK974, a PORCN inhibitor, inhibited the secretion of WNT10A to suppress the malignant GBM phenotype. Conclusion Our findings revealed that WNT10A is a critical factor promoting GBM progression through both autocrine and paracrine mechanisms. Thus, our findings provide the foundation for WNT-targeted clinical GBM treatment.
Systemic Therapies for Psoriatic Disease and Serious Infections in Older Adults
Authors: Aaron M. Drucker, Rinku Sutradhar, Vicki Ling, Jodi M. Gatley, Lihi Eder, Christine Fahim, Michael Fralick, Tara Gomes, Ping Li, Sue MacDougall, Morris Manolson, Paula A. Rochon, Mina Tadrous
Journal: JAMA Dermatology (2025)

Importance Systemic treatments for psoriatic disease affect the immune system and may increase infection risk. Older adults are at high risk for infection, and the relative safety of systemic treatments for them is unknown. Objective To evaluate the association of systemic treatments for psoriatic disease with rates of serious infection among older adults. Design, Setting, and Participants This cohort study used linked population-based health administrative data from 2002 to 2021 in Ontario, Canada. Participants included Ontario residents 66 years and older with psoriatic disease who were dispensed their first systemic medication between April 1, 2002, and December 31, 2020. Data were analyzed between November 2021 and August 2024. Exposure Time-varying use of systemic medications categorized as (1) methotrexate; (2) other older systemic medications; (3) anti–tumor necrosis factor (anti-TNF) biologics; (4) other biologics (targeting interleukin [IL]-12, IL-23, and IL-17); and (5) tofacitinib. Main Outcomes and Measures The main outcome was time to serious infection, defined as hospitalization for any infectious cause occurring up to March 2021. Multivariable Andersen-Gill recurrent event regression was used to estimate the association between each medication category and serious infection rates. The relative rates (RRs) of serious infection with 95% CIs for time actively using each medication category vs time not using that medication category were calculated. Results Of 11 641 new users of systemic therapy, 6114 (53%) were female, and the median (IQR) age was 71 (68-76) years. There were 1967 serious infections during a median (IQR) of 4.8 (2.3-8.4) years of follow-up. There were 2.7 serious infections per 100 person-years using methotrexate, 2.5 per 100 person-years using other older systemic drugs, 2.2 per 100 person-years using anti-TNF biologics, 1.4 per 100 person-years using other biologics, and 8.9 per 100 person-years using tofacitinib. In the multivariable-adjusted model, methotrexate (RR, 0.95 [95% CI, 0.85-1.07]), other older systemic medications (RR, 0.92 [95% CI, 0.79-1.07]), and anti-TNF biologics (RR, 0.87 [95% CI, 0.69-1.10]) were not associated with serious infection compared to person-time not using those respective medications. Other biologics (RR, 0.65 [95% CI, 0.48-0.88]) were associated with lower rates of serious infection, whereas tofacitinib (RR, 2.89 [95% CI, 1.14-7.34]) was associated with higher rates of serious infection. Conclusions and Relevance In this cohort study, biologics targeting IL-12, IL-23, or IL-17 were associated with a lower rate of serious infection among older adults with psoriatic disease. These biologics may have important safety benefits for older adults with higher infection risk.
Molecular Testing and Targeted Therapies in Hepatobiliary Cancers
Authors: Diamantis I. Tsilimigras, Razelle Kurzrock, Timothy M. Pawlik
Journal: JAMA Surgery (2025)

Importance Hepatobiliary cancers are heterogeneous and molecularly complex. Recent advances in next-generation sequencing (NGS) have enhanced the understanding of their molecular landscape and enabled deployment of biomarker-based gene- and immune-targeted therapies. This review examines the role of molecular testing and targeted therapies in these malignant neoplasms. Observations Patients with hepatobiliary cancers have poor outcomes. Precision oncology studies have shown that while many common molecular alterations are not currently targetable in hepatocellular carcinoma (HCC), a large number of actionable alterations characterize biliary tract cancers (BTCs), with several therapies now approved by the US Food and Drug Administration. Immunotherapy is increasingly adopted in clinical practice, either as monotherapy or combined with cytotoxic chemotherapy, for both HCC and BTCs. Moreover, multiple solid cancer tumor-agnostic therapies are approved (larotrectinib, entrectinib, and repotrectinib for NTRK fusions; selpercatinib for RET fusions; dabrafenib and trametinib combination for BRAF V600E mutations; dostarlimab or pembrolizumab for tumors with high microsatellite instability and pembrolizumab for tumor mutation burden ≥10 mutations/megabase), highlighting the need for NGS as well as ERBB2 (formerly HER2) immunohistochemistry (IHC) (with the recent approval of solid tissue–agnostic deruxtecan trastuzumab for ERBB2-positive [IHC 3+] cancer) across cancers. N-of-1 clinical trials using customized drug combinations matched to the tumor’s molecular profile have yielded encouraging results and provide a promising framework for future clinical trial design. Conclusions and Relevance Molecular testing and gene- and immune-targeted therapies are transforming hepatobiliary cancer treatment. Tumor-agnostic and N-of-1 clinical trials have challenged traditional clinical trial paradigms and provide the foundation for truly personalized oncology for patients with these aggressive cancers. Further work is needed to determine how to leverage these novel approaches into the management of operable disease.
Single-cell eQTL mapping reveals cell-type-specific genes associated with the risk of gastric cancer
Authors: Lijun Bian, Beiping Hu, Fengyuan Li, Yuanliang Gu, Caihong Hu, Yuheng Chen, Bin Deng, Haisheng Fang, Xia Zhu, Yan Chen, Xiangjin Fu, Tianpei Wang, Qiang She, Meng Zhu, Yue Jiang, Juncheng Dai, Hao Xu, Hongxia Ma, Zekuan Xu, Zhibin Hu, Hongbing Shen, Yanbing Ding, Caiwang Yan, Guangfu Jin
Journal: Cell Genomics (2025)

Most expression quantitative trait locus (eQTL) analyses have been conducted in heterogeneous gastric tissues, limiting understanding of cell-type-specific regulatory mechanisms. Here, we employed a pooled multiplexing strategy to profile 399,683 gastric cells from 203 Chinese individuals using single-cell RNA sequencing (scRNA-seq). We identified 19 distinct gastric cell types and performed eQTL analyses, uncovering 8,498 independent eQTLs, with a considerable fraction (81%, 6,909/8,498) exhibiting cell-type-specific effects. Integration of these eQTLs with genome-wide association studies for gastric cancer (GC) revealed four co-localization signals in specific cell types. Genetically predicted cell-type-specific gene expression identified 15 genes associated with GC risk, including the upregulation of MUC1 exclusively in parietal cells, linked to decreased GC risk. Our findings highlight substantial heterogeneity in the genetic regulation of gene expression across gastric cell types and provide critical cell-type-specific annotations of genetic variants associated with GC risk, offering new molecular insights underlying GC.
Neoadjuvant Chemoradiotherapy vs Chemoimmunotherapy for Esophageal Squamous Cell Carcinoma
Authors: Xufeng Guo, Chunji Chen, Jinbo Zhao, Changchun Wang, Xinyu Mei, Jianfei Shen, Huilai Lv, Yongtao Han, Qifeng Wang, Jiahua Lv, Hainan Chen, Xiaolong Yan, Zhichao Liu, Zhengyang Zhang, Qihong Zhong, Youhua Jiang, Liwei Xu, Xiaoyang Li, Dong Qian, Dehua Ma, Minhua Ye, Chunguo Wang, Zimin Wang, Jiangbo Lin, Ziqiang Tian, Xuefeng Leng, Zhigang Li
Journal: JAMA Surgery (2025)

Importance The association of neoadjuvant chemoimmunotherapy (NCIT) vs chemoradiotherapy (NCRT) with tumor downstaging and survival in locally advanced esophageal squamous cell carcinoma (ESCC) remains unclear because of limited evidence. Objective To compare the associations of NCIT and NCRT with tumor regression and long-term survival in patients with locally advanced ESCC. Design, Setting, and Participants In this comparative effectiveness research study, from January 2016 to March 2023, patients with locally advanced ESCC who underwent esophagectomy following NCRT or NCIT were identified from a prospective database of 8 high-volume esophageal surgery centers in China. Follow-up began on the date of surgery and continued until the last recorded contact or March 2024, whichever occurred first. Data were analyzed between April and September 2024. Main Outcomes and Measures The primary end points were 2-year overall survival (OS) and disease-free survival (DFS). Secondary end points included major pathologic response (MPR) and pathologic complete response (pCR). Cox proportional hazard regression analysis was used to investigate the risk factors for OS and DFS. Results The study included 1428 patients (median [IQR] age, 63 [57-68] years; 1184 men [82.9%]), with 704 patients in the NCRT group and 724 patients in the NCIT group. After propensity score matching, there were 532 patients in each group. The 2-year OS (81.3% vs 71.3%; hazard ratio, 1.57; 95% CI, 1.26-1.96; P &amp;amp;lt; .001) and DFS (73.9% vs 63.4%; hazard ratio, 1.37; 95% CI, 1.11-1.69; P &amp;amp;lt; .001) rates were significantly higher in NCIT group than in the NCRT group. The NCRT group had a higher MPR rate than that of the NCIT group (71.8% vs 61.5%), whereas the pCR rates were similar (25.9% vs 22.9%). Multivariable Cox analysis demonstrated that NCIT and MPR were independently associated with both OS and DFS. The NCIT group exhibited a lower overall recurrence rate (126 patients [23.7%] vs 190 patients [35.7%]) and distant metastasis rate (72 patients [13.5%] vs 133 patients [25.0%]), although locoregional metastasis rates were similar (98 patients [18.4%] vs 111 patients [20.9%]). Better OS and DFS were obtained for the NCIT group than for the NCRT group, regardless of whether adjuvant immunotherapy was given. Conclusions and Relevance Compared with NCRT, patients with locally advanced ESCC receiving NCIT had better 2-year OS and DFS. The decrease in distant metastasis may be the main reason, but further prospective randomized clinical trials are needed to verify this finding.
Safety and Efficacy of Repeated Low-Dose LSD for ADHD Treatment in Adults
Authors: Lorenz Mueller, Joyce Santos de Jesus, Yasmin Schmid, Felix Müller, Anna Becker, Aaron Klaiber, Isabelle Straumann, Dino Luethi, Eline C. H. M. Haijen, Petra P. M. Hurks, Kim P. C. Kuypers, Matthias E. Liechti
Journal: JAMA Psychiatry (2025)

Importance Microdosing psychedelics, including lysergic acid diethylamide (LSD), has gained attention for its potential benefits in several psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). However, LSD’s efficacy in reducing ADHD symptoms remains unknown. Objective To determine the safety and efficacy of repeated low doses of LSD in reducing ADHD symptoms compared with placebo. Design, Setting, and Participants This was a 6-week, multicenter, double-blind, placebo-controlled, parallel-group phase 2A randomized clinical trial conducted between December 17, 2021, and December 4, 2023. Data were analyzed from March 22, 2024, to August 19, 2024. Outpatient treatment was provided at 2 centers: University Hospital in Basel, Switzerland, and Maastricht University in the Netherlands. Adults aged 18 to 65 years with a prior ADHD diagnosis who presented with moderate to severe symptoms (Adult Investigator Symptom Rating Scale [AISRS] score ≥26 and Clinical Global Impression Severity score ≥4) were eligible for inclusion. Key exclusion criteria included selected current major psychiatric or somatic disorders and the use of potentially interacting medications. Intervention Participants received either LSD (20 μg) or placebo twice weekly for 6 weeks (total of 12 doses). Main Outcome and Measures The primary outcome was the change in ADHD symptoms from baseline to week 6, assessed by the AISRS and analyzed with a mixed-effects model for repeated measures. Results A total of 53 participants were randomized to LSD (n = 27) or placebo (n = 26). Mean (SD) participant age was 37 (12) years, and 22 participants (42%) were female. The LSD group presented a mean AISRS improvement of −7.1 points (95% CI, −10.1 to −4.0). The placebo group presented a mean AISRS improvement of −8.9 points (95% CI, −12.0 to −5.8), with no difference between groups. LSD was physically safe and psychologically well tolerated overall. Conclusions and Relevance In this randomized clinical trial, repeated low-dose LSD administration was safe in an outpatient setting, but it was not more efficacious than placebo in reducing ADHD symptoms. Trial Registration ClinicalTrials.gov Identifier: NCT05200936
Concomitant Mechanical Aspiration and Appendage Closure for Recalcitrant Left Atrial Appendage Thrombi
Authors: Maryam Saleem, Abhishek Maan, Daniel R. Musikantow, Chi Zhang, Yury Malyshev, Marc A. Miller, Srinivas R. Dukkipati, Parasuram M. Krishnamoorthy, Martin Goldman, Prakash Krishnan, Vivek Y. Reddy
Journal: JAMA Cardiology (2025)

Importance It is well appreciated that a small yet high-risk subset of patients with atrial fibrillation (AF) develops persistent left atrial appendage (LAA) thrombus despite optimal oral anticoagulation (OAC). In patients with either a heightened risk of bleeding precluding enhanced doses of OAC to dissolve the thrombus, or thromboembolism despite optimal OAC, there are limited nonsurgical options. Objectives To introduce a novel management strategy for resistant LAA thrombus: percutaneous mechanical thrombus aspiration with cerebral protection, followed by LAA closure (LAAC). Design, Setting, and Participants This descriptive, prospective case series of 9 consecutive patients with persistent LAA thrombus was conducted between August 2023 and July 2024 at Mount Sinai Hospital. After placing a cerebral protection device (CPD) when anatomically feasible, balloon atrial septostomy was performed as needed to enhance transeptal access. A 20F mechanical aspiration device with a 15-mm funneled ostium was advanced to the LAA ostium, and manual vacuum aspiration of thrombus was performed. After ultrasonic confirmation of thrombectomy, an LAAC device was implanted. Main Outcomes and Measures Patient demographic, clinical, and intervention data were collected. Results Nine patients (mean [SD] age, 74.7 [13.6] years; median [IQR] CHA 2 DS 2 -VASc [congestive heart failure, hypertension, age 75 years or older, diabetes, stroke, vascular disease, age 65-74 years, and female sex] score, 5 [2-8] points) presented with LAA thrombus in the context of contraindications to OAC. CPD was placed in 8 patients; one had prohibitive aortic arch anatomy. Given the patient’s high thrombotic burden and limited alternatives, the decision was to proceed without CPD, based on a risk-benefit assessment. Balloon atrial septostomy was performed in 8 patients. In 8 patients, complete thrombus removal was achieved, followed by successful LAAC device placement. One patient had a small residual distal thrombus, presumably organized, which was strongly adherent to the LAA myocardium; this was compressed against the wall with the LAAC device. One patient had a small thrombus fragment recovered from the CPD postprocedure. During both the index procedure and during follow-up (range, 4-15 months), there were no complications. Conclusions and Relevance This cases series found that temporary cerebral protection, percutaneous mechanical vacuum thrombectomy, and mechanical LAA closure was feasible in patients with persistent LAA thrombus despite optimal OAC. Larger studies will be needed to fully assess the efficacy and safety of this approach.
Joint Associations of <i>APOC3</i> and LDL-C–Lowering Variants With the Risk of Coronary Heart Disease
Authors: Wenxiu Wang, Rui Li, Zimin Song, Ninghao Huang, Tao Huang, Xinwei Hua, Yi-Da Tang
Journal: JAMA Cardiology (2025)

Importance Despite substantial progress in low-density lipoprotein cholesterol (LDL-C)–lowering strategies, residual cardiovascular risk remains. Apolipoprotein C3 (APOC3) has emerged as a novel target for lowering triglycerides. Multiple clinical trials of small-interfering RNA therapeutics targeting APOC3 are currently underway. Objective To investigate whether genetically predicted lower APOC3 is associated with a reduction in cardiovascular risk and if the combined exposure to APOC3 and LDL-C–lowering variants is associated with a reduction in the risk of coronary heart disease (CHD). Design, Setting, and Participants This was a population-based genetic association study with 2 × 2 factorial mendelian randomization. Included were participants of European ancestry in the UK Biobank. Data were analyzed from November 2023 to July 2024. Exposures Genetic scores were constructed to mimic the effects of APOC3, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors. Main Outcomes and Measures Plasma lipid and lipoprotein levels, CHD, and type 2 diabetes (T2D). Results This study included 401 548 UK Biobank participants (mean [SD] age, 56.9 [8.0] years; 216 901 female [54.0%]). Genetically predicted lower APOC3 was associated with a lower risk of CHD (odds ratio [OR], 0.96; 95% CI, 0.93-0.98) and T2D (0.97; 95% CI, 0.95-0.99). Genetically lower APOC3 and PCSK9 were associated with a similar magnitude of risk reduction in CHD per 10-mg/dL decrease in apolipoprotein B (ApoB) level (APOC3: 0.70; 95% CI, 0.59-0.83; PCSK9: 0.71; 95% CI, 0.65-0.77). Combined exposure to genetically lower APOC3 and PCSK9 was associated with an additive lower risk of CHD (APOC3: 0.96; 95% CI, 0.92-0.99; PCSK9: 0.93; 95% CI, 0.90-0.97; combined: 0.90; 95% CI, 0.86-0.93). Genetically lower HMGCR was also associated with a lower risk of CHD, and the risk was further reduced when combined with APOC3 (0.93; 95% CI, 0.90-0.97). Conclusions and Relevance Genetically predicted lower APOC3 was associated with a reduced risk of CHD that is comparable with that associated with lower PCSK9 per unit decrease in ApoB. Combined exposure to APOC3 and LDL-C–lowering variants was associated with an additive reduction in CHD risk. Future studies are warranted to investigate the therapeutic potential of these combined therapies, particularly among high-risk patients who cannot achieve therapeutic targets with existing lipid-lowering therapies.
Fertility of Adults Born Very Preterm or With Very Low Birth Weight
Authors: Miranda Kit-Yi Wong, Nicole Tsalacopoulos, Peter Bartmann, Dieter Wolke
Journal: JAMA Network Open (2025)

Contradictory differences regarding fertility among adults born very preterm (VP; <32 weeks' gestation) or with very low birth weight (VLBW; <1500 g) have been reported at different ages. Longitudinal investigations of fertility beyond ages 20 to 29 years are lacking. To assess whether VP and VLBW are associated with lower fertility up to age 35 years. This prospective population-based cohort study was conducted in Bavaria, Germany, with participants born between January 1985 and March 1986 who required admission to a children's hospital within the first 10 days after birth. Healthy infants born at term (ie, at least 37 weeks' gestation) in the same hospital and children alive at 6 years were selected as controls. Follow-up occurred repeatedly up to 34 to 35 years. Data were analyzed from July to December 2024. Gestational age and birth weight. Cumulative incidence of having the first alive child (ie, fertility) was calculated using Kaplan-Meier estimation and the difference between participants born VP or with VLBW and term-born participants was compared with log-rank tests. Univariable and hierarchical multivariable Cox proportional hazards regressions were performed to estimate hazard ratios (HRs) for fertility associated with VP and VLBW adjusting for individual factors. Estimations were compared between early (<30 years) and late (≥30 years) reproductive windows. A total of 414 participants (212 born VP or with VLBW and 202 term-born) were included (mean [SD] age, 34.67 [0.53] years; 216 [52.2%] female). Cumulative incidence of having the first alive child was lower in participants born VP or with VLBW throughout the follow-up. The association of VP and VLBW with lower fertility was significant during the late (HR, 0.46; 95% CI, 0.31-0.68) but not early (HR, 0.73; 95% CI, 0.47-1.14) reproductive window; this association attenuated after adjusting for neonatal factors (sex and family socioeconomic status) and childhood neurosensory impairment at step 2 (HR, 0.59; 95% CI 0.40-0.88), childhood family factors (eg, parenting) at step 3 (HR, 0.61; 95% CI, 0.40-0.92), and there was no longer an association after adjusting for sociodemographic factors (eg, partnering) at step 4 (HR, 0.78; 95% CI, 0.50-1.20). Partnering (ie, being married or cohabitating with a partner) had the largest magnitude association with fertility across both the early (HR, 7.87; 95% CI, 3.44-18.00) and late (HR, 3.95; 95% CI, 2.47-6.31) reproductive windows. In this cohort study of participants born VP or with VLBW and term-born adults, VP and VLBW were associated with overall lower fertility. A major reason was an association of less partnering with lower fertility, suggesting that partnering is key to reproductive success.