tbuckley/cabot-search huggingface dataset:
LIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models
Authors: Alice E. Shin, Kensuke Sugiura, Secunda W. Kariuki, David A. Cohen, Samuel P. Flashner, Andres J. Klein-Szanto, Noriyuki Nishiwaki, Dechokyab De, Neil Vasan, Joel T. Gabre, Christopher J. Lengner, Peter A. Sims, Anil K. Rustgi
Journal: Journal of Clinical Investigation (2025)

Colorectal cancer (CRC) remains a leading cause of cancer death due to metastatic spread. LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, resulting in enhanced PI3K/AKT pathway activation and liver metastasis in mice. We developed genetically modified mouse models with constitutively active Pik3ca that form intestinal tumors progressing to liver metastases with an intact immune system, addressing the limitations of previous Pik3ca-mutant models, including long tumor latency, mixed histology, and lack of distant metastases. The PI3Kα-specific inhibitor alpelisib reduced migration and invasion in vitro and metastasis in vivo. We present the first comprehensive analysis of vertical inhibition of the PI3K/AKT pathway in CRC using FDA-approved drugs alpelisib and capivasertib (an AKT inhibitor) in combination with LY2584702 (an S6K inhibitor) in CRC cell lines and mouse- and patient-derived organoids (PDOs). Tissue microarrays from CRC patients confirmed that LIN28B and PI3K/AKT pathway activation correlate with CRC progression. These findings highlight the critical role of the LIN28B-mediated PI3K/AKT pathway in CRC metastasis, the therapeutic potential of targeted inhibition, and the promise of PDOs in precision medicine in metastatic CRC.
Sequential intranasal booster triggers class switching from intramuscularly primed IgG to mucosal IgA against SARS-CoV-2
Authors: Yifan Lin, Xuejiao Liao, Xuezhi Cao, Zhaoyong Zhang, Xiuye Wang, Xiaomeng He, Huiping Liao, Bin Ju, Furong Qi, Hairong Xu, Zhenhua Ren, Yanqun Wang, Zhenxiang Hu, Jiaming Yang, Yang-Xin Fu, Jincun Zhao, Zheng Zhang, Hua Peng
Journal: Journal of Clinical Investigation (2025)

The persistent emergence of COVID-19 variants and recurrent waves of infection worldwide underscores the urgent need for vaccines that effectively reduce viral transmission and prevent infections. Current intramuscular (IM) COVID-19 vaccines inadequately protect the upper respiratory mucosa. In response, we have developed a nonadjuvanted, interferon-armed SARS-CoV-2 fusion protein vaccine with IM priming and intranasal (IN) boost sequential immunization. Our study showed that this sequential vaccination strategy of the IM+IN significantly enhances both upper respiratory and systemic antiviral immunity in a mouse model, characterized by the rapid increase in systemic and mucosal T and B cell responses, particularly the mucosal IgA antibody response. The IN boost triggered a swift secondary immune response, rapidly inducing antigen-specific IgA+ B cells. Further BCR-seq analysis indicated that these IgA+ B cells primarily arise through direct class switching from pre-existing IgG+ B cells in draining lymph nodes. Notably, our clinical studies reveal that the IN boost after IM vaccination elicited a robust systemic IgA antibody response in humans, as measured in serum. Thus, our cytokine-armed protein vaccine presents a promising strategy for inducing rapid and potent mucosal protection against respiratory viral infections.
TRAIL agonists rescue mice from radiation-induced lung, skin or esophageal injury
Authors: Jillian Strandberg, Anna Louie, Seulki Lee, Marina Hahn, Praveen Srinivasan, Andrew George, Arielle De La Cruz, Leiqing Zhang, Liz Hernandez Borrero, Kelsey E. Huntington, Payton De La Cruz, Attila A. Seyhan, Paul P. Koffer, David E. Wazer, Thomas A. DiPetrillo, Stephanie L. Graff, Christopher G. Azzoli, Sharon I. Rounds, Andres J. Klein-Szanto, Fabio Tavora, Evgeny Yakirevich, Abbas E. Abbas, Lanlan Zhou, Wafik S. El-Deiry
Journal: Journal of Clinical Investigation (2025)

Radiotherapy can be limited by pneumonitis which is impacted by innate immunity, including pathways regulated by TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound (TIC10/ONC201) could reduce pneumonitis, alveolar-wall thickness, and oxygen desaturation. Lung protection extended to late effects of radiation including less fibrosis at 22-weeks in TLY012-rescued survivors versus un-rescued surviving irradiated-mice. Wild-type orthotopic breast tumor-bearing mice receiving 20-Gy thoracic radiation were protected from pneumonitis with disappearance of tumors. At the molecular level, radioprotection appeared due to inhibition of CCL22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. Treatment with anti-CCL22 reduced lung injury in vivo but less so than TLY012. Pneumonitis severity was worse in female versus male mice, and this was associated with increased expression of X-linked TLR7. Irradiated mice had reduced esophagitis characterized by reduced epithelial disruption and muscularis externa thickness following treatment with ONC201 analogue ONC212. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from pneumonitis, dermatitis and esophagitis following high doses of thoracic radiation exposure has important translational implications.
Impaired hydrogen sulfide biosynthesis underlies eccentric contraction-induced force loss in dystrophin-deficient skeletal muscle
Authors: W. Michael Southern, Erynn E. Johnson, Elizabeth K. Fasbender, Katherine S. Fallon, Courtney L. Cavazos, Dawn A. Lowe, George G. Rodney, James M. Ervasti
Journal: Journal of Clinical Investigation (2025)

Eccentric contraction- (ECC) induced force loss is a hallmark of murine dystrophin-deficient (mdx) skeletal muscle that is used to assess efficacy of potential therapies for Duchenne muscular dystrophy. While virtually all key proteins involved in muscle contraction have been implicated in ECC force loss, a unifying mechanism that orchestrates force loss across such diverse molecular targets has not been identified. We showed that correcting defective hydrogen sulfide (H2S) signaling in mdx muscle prevented ECC force loss. We also showed that the cysteine proteome of skeletal muscle functioned as a redox buffer in WT and mdx muscle during ECCs, but that buffer capacity in mdx muscle was significantly compromised by elevated basal protein oxidation. Finally, chemo-proteomic data suggested that H2S protected several proteins central to muscle contraction against irreversible oxidation through persulfidation-based priming. Our results support a unifying, redox-based mechanism of ECC force loss in mdx muscle.
An Activin Receptor-Like Kinase 1-governed monocytic lineage shapes an immunosuppressive landscape in breast cancer metastases
Authors: Mehrnaz Safaee Talkhoncheh, Jonas Sjölund, Paulina Bolivar, Ewa Kurzejamska, Eugenia Cordero, Teia Vallès Pagès, Sara Larsson, Sophie Lehn, Gustav Frimannsson, Viktor Ingesson, Sebastian Braun, Jessica Pantaleo, Clara Oudenaarden, Martin Lauss, R Scott Pearsall, Göran B Jönsson, Charlotte Rolny, Matteo Bocci, Kristian Pietras
Journal: Journal of Clinical Investigation (2025)

The biology centered around the TGF-beta type I receptor Activin Receptor-Like Kinase (ALK)1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipated Acvrl1 expression, are effector targets for adjuvant anti-angiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the release of CD14+ monocytes into circulation, and their eventual extravasation. Notably, ACVRL1+ TAMs coincided with an immunosuppressive phenotype, and were over-represented in human cancers progressing on therapy. Accordingly, breast cancer patients with a prominent ACVRL1hi TAM signature exhibited a significantly shorter survival. In conclusion, we shed light on an unexpected multimodal regulation of tumorigenic phenotypes by ALK1 and demonstrate its utility as a target for anti-angiogenic immunotherapy.
PDGFRα inhibition reduces myofibroblast expansion in the fibrotic rim and enhances recovery after ischemic stroke
Authors: Jil Protzmann, Manuel Zeitelhofer, Christina Stefanitsch, Daniel Torrente, Milena Z. Adzemovic, Kirils Matjunins, Stella J.I. Randel, Sebastian A. Lewandowski, Lars Muhl, Ulf Eriksson, Ingrid Nilsson, Enming J. Su, Daniel A. Lawrence, Linda Fredriksson
Journal: Journal of Clinical Investigation (2025)

Ischemic stroke is a major cause of adult disability. Early treatment with thrombolytics and/or thrombectomy can significantly improve outcomes; however, following these acute interventions, treatment is limited to rehabilitation therapies. Thus, the identification of therapeutic strategies that can help restore brain function in the post-acute phase remains a major challenge. Here we report that genetic or pharmacologic inhibition of the PDGF-CC/PDGFRα pathway, which has previously been implicated in stroke pathology, significantly reduced myofibroblast expansion in the border of the fibrotic scar and improved outcome in a sensory-motor integration test after experimental ischemic stroke. This was supported by gene expression analyses of cerebrovascular fragments, showing upregulation of pro-fibrotic/pro-inflammatory genes, including genes of the TGFβ pathway, after ischemic stroke or intracerebroventricular injection of active PDGF-CC. Further, longitudinal intravital two-photon imaging revealed that inhibition of PDGFRα dampened the bi-phasic pattern of stroke-induced vascular leakage and enhanced vascular perfusion in the ischemic lesion. Importantly, we found efficacy of PDGFRα inhibition on functional recovery when initiated 24 hours after ischemic stroke. Our data implicate the PDGF-CC/PDGFRα pathway as a crucial mediator modulating post-stroke pathology and suggest a post-acute treatment opportunity for ischemic stroke patients targeting myofibroblast expansion to foster long-term CNS repair.
Accelerating the Future of Oncology Drug Development: The Role of Consortia in the Delivery of Precision Oncology Early Phase Clinical Trials
Authors: Jia Liu, Max Farrow, Lesley Seymour, Jayesh Desai, Herbert H. Loong, Percy Ivy, Takafumi Koyoma, Natalie Cook, Sarah Blagden, Elena Garralda, Christophe Massard, Anthony W. Tolcher, Jacob J. Adashek, Li Zhang, Shen Zhao, Lin Shen, Razelle Kurzrock, Wafik S. El-Deiry, Vivek Subbiah, Anthony M. Joshua
Journal: Journal of Clinical Oncology (2025)

Over the past 15 years, the landscape of early phase clinical trials (EPCTs) has undergone a remarkable expansion in both quantity and intricacy. The proliferation of sites, trials, sponsors, and contract research organizations has surged exponentially, marking a significant shift in research conduct. However, EPCT operations suffer from numerous inefficiencies, such as cumbersome start-up processes, which are particularly critical when drug safety and the recommended phase II dose need to be established in a timely manner. Networks and consortia may overcome some of these challenges of enrolling suitable patients and streamlining start-up, particularly when distance and disease trajectory come into play. In this article, we provide an overview of EPCT consortia in adult oncology across different continents assembled through systematic review of the literature and snowball sampling methodology. We illustrate their scope, structure, funding, and achievements. Fifteen EPCT consortia were identified including two in the United States, three in Europe, five in Asia-Pacific, two intercontinental consortia, and three within private oncology networks. These consortia vary in their scope, funding, and structure from government-funded models such as the National Cancer Institute Experimental Therapeutics Clinical Trials Networks through charitably funded and private research organizations. EPCT consortia play a role in collaborative research, molecular tumor boards to provide patient-centric biomarker-matched treatments, and streamlining trial conduct to improve timelines and cost efficiency. The growth in EPCT activity and complexity has resulted in expansion in the number of EPCT consortia globally. By actively engaging with regulatory bodies and pharmaceutical and contract research organization industries, consortia have an opportunity to address the evolving challenges faced in this field and to accelerate the translation of scientific discoveries into clinical practice.
Multiple synergistic anti-aging effects of vascular cell adhesion molecule 1 functionalized nanoplatform to improve age-related neurodegenerative diseases
Authors: Siqing Zhu, Yu Zhang, Chang Li, Zhiqing Deng, Ying Yin, Zhufeng Dong, Lei Kuang, Chuanming Li, Xiaoye Hu, Tieying Yin, Yazhou Wang
Journal: Journal of Controlled Release (2025)
Outcomes after medical treatment for primary aldosteronism: an international consensus and analysis of treatment response in an international cohort
Authors: Jun Yang, Jacopo Burrello, Jessica Goi, Martin Reincke, Christian Adolf, Evelyn Asbach, Denise Brűdgam, Qifu Li, Yi Song, Jinbo Hu, Shumin Yang, Fumitoshi Satoh, Yoshikiyo Ono, Renata Libianto, Michael Stowasser, Nanfang Li, Qing Zhu, Namki Hong, Drishya Nayak, Troy H Puar, Vin-Cent Wu, Anand Vaidya, Marta Araujo-Castro, Tomaz Kocjan, Samuel Matthew O'Toole, Gregory L Hundemer, Oskar Ragnarsson, André Lacroix, Stephanie Larose, Kazuki Nakai, Tetsuo Nishikawa, Daria Ladygina, Adina F Turcu, Julieta Sholinyan, Carlos E Fardella, Thomas Uslar, Marcus Quinkler, Paolo Mulatero, Giovanni Pintus, Gian Paolo Rossi, Stefanie Hahner, Laurence Amar, William M Drake, Chetna Varsani, Morris J Brown, Xilin Wu, Jaap Deinum, E Marie Freel, Gregory Kline, Mitsuhide Naruse, Aleksander Prejbisz, William F Young, Tracy Ann Williams, Peter J Fuller
Journal: The Lancet Diabetes & Endocrinology (2025)
Successful endoscopic closure of delayed perforation using hemoclips after colorectal endoscopic submucosal dissection
Authors: Nao Takeuchi, Ken Ohata, Yuki Kano, Kohei Ono, Ryoju Negishi, Yohei Minato, Hideyuki Chiba
Journal: Endoscopy (2025)

Delayed perforation following colorectal endoscopic submucosal dissection (ESD) occurs in approximately 0.4% of cases [1] [2]. Although it is rare, emergency surgery is required in nearly half of these cases [3]. Endoscopic closure for such perforations is rarely performed. No cases of successful closure of delayed perforation using hemoclips after colorectal ESD have yet been reported. Here, we present a case of delayed perforation following colon ESD that was successfully closed with hemoclips and managed conservatively.
Detection of small intestine duplication in a 16-year-old girl using small bowel enteroscopy without balloon assistance
Authors: Yanqin Long, Haojie Du, Jun Li, Xiaosun Liu, Lihua Chen
Journal: Endoscopy (2025)

A 16-year-old girl, a high school student, presented with a 2-year history of intermittent pain in the left upper abdomen. Routine laboratory tests performed at the time of admission were normal. Contrast-enhanced abdominal computed tomography revealed an intussusception-like appearance at the duodenojejunal junction ([Fig. 1]).
Ligation-assisted endoscopic full-thickness resection combined with presuture for resection of a colonic gastrointestinal stromal tumor
Authors: Zhaohui Liu, Hualin Li, Yue Chao, Dayong Sun, Ruinuan Wu
Journal: Endoscopy (2025)

Ligation-assisted endoscopic full-thickness resection (L-EFTR) is commonly used to remove tumors of the gastric muscularis propria [1] [2] but rarely to remove tumors of the colonic muscularis propria because of the limited visual field after colon perforation and the high incidence of peritonitis. Here, we report a novel method, named "ligation-assisted endoscopic full-thickness resection combined with presuture" (L-EFTR-P) ([Video 1]), for the endoscopic full-thickness resection of a gastrointestinal stromal tumor (GIST) in the transverse colon. With the use of L-EFTR-P, closure of the colonic perforation was quick and easy.
Enhanced biliary cannulation and sphincterotomy using a novel rotatable sphincterotome for surgically altered anatomy
Authors: Yasuhiro Kuraishi, Yuki Shimizu, Akira Nakamura, Takeji Umemura
Journal: Endoscopy (2025)

Balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (BE-ERCP) is effective in patients with surgically altered anatomy. However, challenges remain when performing BE-ERCP owing to limited scope and device maneuverability [1] [2]; the scope often aligns tangentially to the papilla, complicating selective biliary cannulation. Meanwhile, conventional sphincterotomes are unsuitable for performing sphincterotomy as their blades misalign with bile duct direction. A newly developed sphincterotome (Engetsu; Kaneka Medix, Osaka, Japan) features 360-degree rotational capability and adjustable blade mobility for extension and shortening ([Fig. 1]). We herein describe a successful case using this rotatable sphincterotome for biliary canulation and sphincterotomy in BE-ERCP.
Combination of the saline-immersion technique and a new thin therapeutic endoscope for endoscopic submucosal dissection of a duodenal subepithelial tumor
Authors: Kosei Hashimoto, Hisashi Fukuda, Toshihiro Fujinuma, Yoshie Nomoto, Edward J. Despott, Hironori Yamamoto
Journal: Endoscopy (2025)

Few cases of endoscopic submucosal dissection (ESD) for duodenal subepithelial tumors (SELs) have been reported, particularly in the challenging area of the duodenal bulb just behind the pyloric ring. This region presents a narrow working space, and the thin submucosal layer complicates dissection between the SEL and the muscular layer. The recent introduction of a new thin therapeutic endoscope (EG-840TP; Fujifilm, Tokyo, Japan) holds promise for ESD in such confined spaces [1] [2] [3] [4]. Despite its small diameter of 7.9 mm, this endoscope is equipped with a 3.2-mm accessory channel, a waterjet function, and an extended down angle of up to 160° ([Fig. 1], [Fig. 2]), making it well suited for therapeutic procedures [1].
Estimating the epidemiological and economic impact of providing nutritional care for tuberculosis-affected households across India: a modelling study
Authors: Christopher Finn McQuaid, Rebecca A Clark, Richard G White, Roel Bakker, Peter Alexander, Roslyn Henry, Banurekha Velayutham, Malaisamy Muniyandi, Pranay Sinha, Madhavi Bhargava, Anurag Bhargava, Rein M G J Houben
Journal: The Lancet Global Health (2025)

Approximately 20% of global tuberculosis incidence is attributable to undernutrition, increasing to more than a third in India. Targeting nutritional interventions to tuberculosis-affected households is a policy priority, but understanding of epidemiological and economic impacts is limited. We aimed to estimate the population-level epidemiological and economic effect of such an intervention. We used a previously published, age-stratified, compartmental transmission model of tuberculosis in India, and incorporated explicit BMI strata linked to disease progression and treatment outcomes. We used results from a recent trial of an intervention in which nutritional support in the form of food baskets was provided to people initiating tuberculosis treatment and to their household contacts (1200 kcal for patients and 750 kcal for contacts) to inform estimates of the impact and costs of nutritional support. We estimated the numbers of cases of tuberculosis disease and deaths due to tuberculosis disease that could be averted from 2023 to 2035 under the intervention scenario. Compared with a baseline with no nutritional intervention, at 50% coverage of adults on tuberculosis treatment and their households (around 23% of households affected by incident tuberculosis in India), providing the nutritional support intervention could prevent 361 200 (95% uncertainty interval 318 000-437 700) tuberculosis deaths and 880 700 (802 700-974 900) disease episodes from 2023 to 2035. This would be equivalent to averting approximately 4·6% (4·2-5·5) tuberculosis deaths and 2·2% (2·1-2·4) tuberculosis episodes. The additional health system cost would be US$1349 million (1221-1492), with an incremental cost-effectiveness ratio of $167 (147-187) per disability-adjusted life-year averted. The median number of households needed to treat to prevent one tuberculosis death was 24·4 and to prevent one tuberculosis case was 10·0. A nutritional intervention for tuberculosis-affected households could avert a substantial amount of tuberculosis disease and death in India, and would be highly likely to be cost-effective on the basis of the tuberculosis-specific benefits alone. None. For the Bangla and Hindi translations of the abstract see Supplementary Materials section.
A novel approach to managing biliary anastomotic stricture following orthotopic liver transplantation after failure of endoscopic retrograde cholangiopancreatography technique
Authors: Baifeng Qian, Junlong Lin, Jianpeng Cai, Yunpeng Hua
Journal: Endoscopy (2025)

Biliary stricture is the most common complication after liver transplantation, accounting for ~40% of all biliary complications [1] [2]. These complications remain a major cause of morbidity and, in severe cases, mortality. Endoscopic treatment is the first-line treatment for benign biliary stricture [3]. The success rate of endoscopic treatment of anastomotic stricture is 58%–76% in patients with living-donor liver transplantation [4] [5]. Here, we show a novel approach to managing biliary anastomotic stricture following orthotopic liver transplantation after failure of the endoscopic retrograde cholangiopancreatography (ERCP) technique, even with direct cholangioscopy.
Endoscopic papillary large balloon dilation with a novel non-slip balloon in a patient with surgically altered anatomy
Authors: Haruo Miwa, Yuichi Suzuki, Kazuki Endo, Ritsuko Oishi, Hiromi Tsuchiya, Kazushi Numata, Shin Maeda
Journal: Endoscopy (2025)

Endoscopic papillary large balloon dilation (EPLBD) in balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (BE-ERCP) is an effective procedure for stone removal [1] [2]. However, balloon slipping often occurs when an enteroscope is unstable. A novel balloon catheter (RIGEL Balloon Dilation Catheter; Japan Lifeline Co., Ltd., Tokyo, Japan) forms a waist because of the central band, which can prevent slipping during dilation ([Fig. 1]) [3] [4]. Herein, we report a case of a patient with surgically altered anatomy who underwent EPLBD with a 12-mm RIGEL balloon ([Video 1]).