tbuckley/cabot-search huggingface dataset:
Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn’s Disease
Authors: Thomas W Dennison, Rachel D Edgar, Felicity Payne, Komal M Nayak, Alexander D. B. Ross, Aurelie Cenier, Claire Glemas, Federica Giachero, April R Foster, Rebecca Harris, Judith Kraiczy, Camilla Salvestrini, Georgia Stavrou, Franco Torrente, Kimberley Brook, Claire Trayers, Rasa Elmentaite, Gehad Youssef, Bálint Tél, Douglas James Winton, Nefeli Skoufou-Papoutsaki, Sam Adler, Philip Bufler, Aline Azabdaftari, Andreas Jenke, Natasha G, Natasha Thomas, Erasmo Miele, Abdulrahman Al-Mohammad, Greta Guarda, Subra Kugathasan, Suresh Venkateswaran, Menna R Clatworthy, Tomas Castro-Dopico, Ondrej Suchanek, Caterina Strisciuglio, Marco Gasparetto, Seokjun Lee, Xingze Xu, Erica Bello, Namshik Han, Daniel R. Zerbino, Sarah A Teichmann, Josquin Nys, Robert Heuschkel, Francesca Perrone, Matthias Zilbauer
Journal: Gut (2024)

Objective Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn’s disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as their potential impact on disease phenotype and outcome remain unknown. We set out to investigate the role of intestinal epithelial DNAm in CD pathogenesis. Design We generated 312 intestinal epithelial organoids (IEOs) from mucosal biopsies of 168 patients with CD (n=72), UC (n=23) and healthy controls (n=73). We performed genome-wide molecular profiling including DNAm, bulk as well as single-cell RNA sequencing. Organoids were subjected to gene editing and the functional consequences of DNAm changes evaluated using an organoid-lymphocyte coculture and a nucleotide-binding oligomerisation domain, leucine-rich repeat and CARD domain containing 5 (NLRC5) dextran sulphate sodium (DSS) colitis knock-out mouse model. Results We identified highly stable, CD-associated loss of DNAm at major histocompatibility complex (MHC) class 1 loci including NLRC5 and cognate gene upregulation. Single-cell RNA sequencing of primary mucosal tissue and IEOs confirmed the role of NLRC5 as transcriptional transactivator in the intestinal epithelium. Increased mucosal MHC-I and NLRC5 expression in adult and paediatric patients with CD was validated in additional cohorts and the functional role of MHC-I highlighted by demonstrating a relative protection from DSS-mediated mucosal inflammation in NLRC5-deficient mice. MHC-I DNAm in IEOs showed a significant correlation with CD disease phenotype and outcomes. Application of machine learning approaches enabled the development of a disease prognostic epigenetic molecular signature. Conclusions Our study has identified epigenetically regulated intestinal epithelial MHC-I as a novel mechanism in CD pathogenesis.
No Time for Cancel Culture
Authors: Michael Mengel, Roslyn B. Mannon
Journal: Journal of the American Society of Nephrology (2024)

1Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada 2Division of Nephrology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 3Medical Service, Nebraska Western Iowa VA Healthcare System, Omaha, Nebraska Correspondence: Dr. Roslyn B. Mannon, email: [email protected] See related article, "The Clinical Relevance of the Infiltrating Immune Cell Composition in Kidney Transplant Rejection," on pages 886–890.
Variability in Approach to Exercise Stress Echocardiography for Diagnosis of Heart Failure with Preserved Ejection Fraction -An International Survey on Real-World Practice
Authors: Yuta Tani, Yogesh N V Reddy, Frederik H Verbrugge, Jeong Hoon Yang, Kazuaki Negishi, Tomonari Harada, Kazuki Kagami, Yuki Saito, Naoki Yuasa, Hidemi Sorimachi, Fumitaka Murakami, Toshimitsu Kato, Naoki Wada, Hideki Ishii, Masaru Obokata
Journal:  (2024)

The diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging based on resting assessments. Exercise echocardiography is often used to unmask abnormalities that develop during exercise, but the diagnostic criteria have not been standardized. This study aimed to elucidate how cardiologists utilize exercise echocardiography to diagnose HFpEF in real-world practice.
Confetti Cure: Reversing the Genetic Kaleidoscope of Ichthyosis
Authors: Judith Fischer
Journal: British Journal of Dermatology (2024)

Journal Article Accepted manuscript Confetti Cure: Reversing the Genetic Kaleidoscope of Ichthyosis Get access Judith Fischer Judith Fischer Institute of Human Genetics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany Email:judith.fischer@uniklinik-freiburg.de https://orcid.org/0000-0002-8580-8118 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljae248, https://doi.org/10.1093/bjd/ljae248 Published: 11 June 2024 Article history Received: 03 June 2024 Accepted: 08 June 2024 Published: 11 June 2024
Nanoassemblies designed for efficient nuclear targeting
Authors: Michal Skowicki, Shabnam Tarvirdipour, Manuel Kraus, Cora-Ann Schoenenberger, Cornelia G Palivan
Journal: Advanced Drug Delivery Reviews (2024)

One of the key aspects of coping efficiently with complex pathological conditions is delivering the desired therapeutic compounds with precision in both space and time. Therefore, the focus on nuclear-targeted delivery systems has emerged as a promising strategy with high potential, particularly in gene therapy and cancer treatment. Here, we explore the design of supramolecular nanoassemblies as vehicles to deliver specific compounds to the nucleus, with the special focus on polymer and peptide-based carriers that expose nuclear localization signals. Such nanoassemblies aim at maximizing the concentration of genetic and therapeutic agents within the nucleus, thereby optimizing treatment outcomes while minimizing off-target effects. A complex scenario of conditions, including cellular uptake, endosomal escape, and nuclear translocation, requires fine tuning of the nanocarriers' properties. First, we introduce the principles of nuclear import and the role of nuclear pore complexes that reveal strategies for targeting nanosystems to the nucleus. Then, we provide an overview of cargoes that rely on nuclear localization for optimal activity as their integrity and accumulation are crucial parameters to consider when designing a suitable delivery system. Considering that they are in their early stages of research, we present various cargo-loaded peptide- and polymer nanoassemblies that promote nuclear targeting, emphasizing their potential to enhance therapeutic response. Finally, we briefly discuss further advancements for more precise and effective nuclear delivery.
Psoriatic Arthritis: A comprehensive review for the dermatologist Part I: Epidemiology, Comorbidities, Pathogenesis, and Diagnosis
Authors: Lourdes M. Perez-Chada, Scott Elman, Camila Villa-Ruiz, April W. Armstrong, Alice B. Gottlieb, Joseph F. Merola
Journal: Journal of the American Academy of Dermatology (2024)
Applying a Novel Optical Technique for Residual Cancer Detection with Accuracy Evaluation: A Cornerstone for Field Implementation
Authors: Byung Ho Oh, Ki Hean Kim
Journal: British Journal of Dermatology (2024)

Journal Article Accepted manuscript Applying a Novel Optical Technique for Residual Cancer Detection with Accuracy Evaluation: A Cornerstone for Field Implementation Get access Byung Ho Oh, Byung Ho Oh Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea Corresponding author: Byung Ho Oh, MD, PhD, Email:obh505@yuhs.ac https://orcid.org/0000-0001-9575-5665 Search for other works by this author on: Oxford Academic Google Scholar Ki Hean Kim Ki Hean Kim Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang-si, South Korea https://orcid.org/0000-0003-3410-7706 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljae246, https://doi.org/10.1093/bjd/ljae246 Published: 11 June 2024 Article history Received: 03 June 2024 Accepted: 08 June 2024 Published: 11 June 2024
Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671)
Authors: C. Proto, M. Ganzinelli, S. Manglaviti, M. Imbimbo, G. Galli, M. Marabese, F. Zollo, M.F. Alvisi, M. Perrino, N. Cordua, F. Borea, F. de Vincenzo, A. Chella, S. Cappelli, E. Pardini, Z. Ballatore, A. Lucarelli, E. Ambrosini, M. Giuliano, E. Pietroluongo, C. Mulargiu, A. Fabbri, A. Prelaj, M. Occhipinti, M. Brambilla, L. Mazzeo, T. Beninato, R. Vigorito, M. Ruggirello, F.G. Greco, G. Calareso, D. Miliziano, E. Rulli, I. De Simone, V. Torri, F.G.M. de Braud, G. Pasello, P. De Placido, R. Berardi, I. Petrini, P. Zucali, M.C. Garassino, G. Lo Russo
Journal: Annals of Oncology (2024)

Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. The RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC.
Mechanistic insights into medulloblastoma relapse
Authors: Kendell Peterson, Maria Turos-Cabal, April D. Salvador, Isabel Palomo-Caturla, Ashley J. Howell, Megan E. Vieira, Sean M. Greiner, Thibaut Barnoud, Jezabel Rodriguez-Blanco
Journal: Pharmacology & Therapeutics (2024)

Pediatric brain tumors are the leading cause of cancer-related deaths in children, with medulloblastoma (MB) being the most common type. A better understanding of these malignancies has led to their classification into four major molecular subgroups. This classification not only facilitates the stratification of clinical trials, but also the development of more effective therapies. Despite recent progress, approximately 30% of children diagnosed with MB experience tumor relapse. Recurrent disease in MB is often metastatic and responds poorly to current therapies. As a result, only a small subset of patients with recurrent MB survive beyond one year. Due to its dismal prognosis, novel therapeutic strategies aimed at preventing or managing recurrent disease are urgently needed. In this review, we summarize recent advances in our understanding of the molecular mechanisms behind treatment failure in MB, as well as those characterizing recurrent cases. We also propose avenues for how these findings can be used to better inform personalized medicine approaches for the treatment of newly diagnosed and recurrent MB. Lastly, we discuss the treatments currently being evaluated for MB patients, with special emphasis on those targeting MB by subgroup at diagnosis and relapse.
Epidemiology of Epidermolysis Bullosa in Chile
Authors: Francis Palisson, María Joao Yubero, Cristóbal Lecaros, Susanne Krämer, Constanza Fuentes, Pilar Morandé, Belkis Noya, Glenda Cofré, Jimena Castillo, Francisco Acevedo, Natalia Burattini, Antonella Muñoz, Alfred Klausseger, Ignacia Fuentes
Journal: British Journal of Dermatology (2024)

In this manuscript we are presenting the first National Epidermolysis Bullosa Epidemiology study done in South America. Our manuscript describes not only population-level estimates, such as incidence, prevalence and mortality of EB, but also genetic data that are unique to this underrepresented population. We report new data about this rare disease showing comparable life expectancy to wealthier nations, demonstrating the value of specialized EB care centres.
Retraction Notice to: The Pseudogene DUXAP8 Promotes Non-small-cell Lung Cancer Cell Proliferation and Invasion by Epigenetically Silencing EGR1 and RHOB
Authors: Ming Sun, Feng-qi Nie, Chongshuang Zang, Yunfei Wang, Jiakai Hou, Chenchen Wei, Wei Li, Xiang He, Kai-hua Lu
Journal: Molecular Therapy (2024)
Circadian clock gene polymorphisms implicated in human pathologies
Authors: Jesse R. Janoski, Ignacio Aiello, Clayton W. Lundberg, Carla V. Finkielstein
Journal: Trends in Genetics (2024)

Circadian rhythms, ~24 h cycles of physiological and behavioral processes, can be synchronized by external signals (e.g., light) and persist even in their absence. Consequently, dysregulation of circadian rhythms adversely affects the well-being of the organism. This timekeeping system is generated and sustained by a genetically encoded endogenous mechanism composed of interlocking transcriptional/translational feedback loops that generate rhythmic expression of core clock genes. Genome-wide association studies (GWAS) and forward genetic studies show that SNPs in clock genes influence gene regulation and correlate with the risk of developing various conditions. We discuss genetic variations in core clock genes that are associated with various phenotypes, their implications for human health, and stress the need for thorough studies in this domain of circadian regulation.
Where Are We With Treatment and Prevention of Heart Failure in Patients Post–Myocardial Infarction?
Authors: Jaclyn Carberry, Guillaume Marquis-Gravel, Eileen O’Meara, Kieran F. Docherty
Journal: JACC Heart Failure (2024)

As a result of the widespread use of reperfusion therapies and secondary prevention over the last 30 years, there has been a dramatic reduction in the risk of mortality and development of heart failure (HF) following acute myocardial infarction (MI). Despite this, the development of chronic HF remains a common occurrence in the days, months, and years following MI. Neurohormonal inhibition remains the mainstay of pharmacologic prevention of HF following MI, with recent trials showing an additive benefit of a neprilysin inhibitor or a sodium glucose co-transporter 2 inhibitor in reducing the risk of development of HF but no significant effect on mortality. Novel imaging tools may help refine risk stratification in high-risk patients and allow greater targeting of preventative therapies in patients most likely to benefit. Research is ongoing into novel therapies aiming to minimize the degree of myocardial damage and prevention of progressive adverse remodeling following MI.
Hypothermia for expanded criteria organ donors in kidney transplantation in France (HYPOREME): a multicentre, randomised controlled trial
Authors: Emmanuel Canet, Noëlle Brule, Morgane Pere, Fanny Feuillet, Gilles Blancho, Laurent Martin-Lefevre, Claire Garandeau, Karim Asehnoune, Bertrand Rozec, Agnès Duveau, Laurent Dube, Marc Pierrot, Stanislas Humbert, Patrice Tirot, Jean-Marc Boyer, François Labadie, René Robert, Thierry Benard, Thomas Kerforne, Antoine Thierry, Olivier Lesieur, Jean-François Vincent, Mathieu Lesouhaitier, Raphaëlle Larmet, Cécile Vigneau, Angélique Goepp, Pierre Bouju, Charlotte Quentin, Pierre-Yves Egreteau, Olivier Huet, Anne Renault, Yannick Le Meur, Jean-Christophe Venhard, Matthias Buchler, Marie-Hélène Voellmy, Fabien Herve, David Schnell, Anne Courte, Denis Glotz, Lucile Amrouche, Marc Hazzan, Nassim Kamar, Valérie Moal, Jérémy Bourenne, Moglie Le Quintrec, Emmanuel Morelon, Toufik Kamel, Philippe Grimbert, Anne-Elisabeth Heng, Pierre Merville, Aude Garin, Christian Hiesse, Brice Fermier, Christiane Mousson, Charlotte Guyot-Colosio, Nicolas Bouvier, Jean-Philippe Rerolle, Antoine Durrbach, Sarah Drouin, Sophie Caillard, Luc Frimat, Sophie Girerd, Laetitia Albano, Lionel Rostaing, Dominique Bertrand, Alexandre Hertig, Pierre-François Westeel, Florent Montini, Eric Delpierre, Didier Dorez, Eric Alamartine, Carole Ouisse, Véronique Sébille, Jean Reignier
Journal: The Lancet Respiratory Medicine (2024)
In situ tumor vaccine with optimized nanoadjuvants and lymph node targeting capacity to treat ovarian cancer and metastases
Authors: Yuan Li, Fan Tong, Yufan Wang, Jing Wang, Manqi Wu, Hanmei Li, Hongyan Guo, Huile Gao
Journal: Acta Pharmaceutica Sinica B (2024)

Tumor vaccine, a promising modality of tumor immunotherapy, needs to go through the process of tumor antigen generation and loading, antigen drainage to lymph nodes (LNs), antigen internalization by dendritic cells (DCs), DC maturation, and antigen cross-presentation to activate T-cells. However, tumor vaccines are often unable to satisfy all the steps, leading to the limitation of their application and efficacy. Herein, based on a smart nanogel system, an
Intravenous delivery of STING agonists using acid-sensitive polycationic polymer-modified lipid nanoparticles for enhanced tumor immunotherapy
Authors: Ying He, Ke Zheng, Xifeng Qin, Siyu Wang, Xuejing Li, Huiwen Liu, Mingyang Liu, Ruizhe Xu, Shaojun Peng, Zhiqing Pang
Journal: Acta Pharmaceutica Sinica B (2024)

Although cancer immunotherapy has made great strides in the clinic, it is still hindered by the tumor immunosuppressive microenvironment (TIME). The stimulator of interferon genes (STING) pathway which can modulate TIME effectively has emerged as a promising therapeutic recently. However, the delivery of most STING agonists, specifically cyclic dinucleotides (CDNs), is performed intratumorally due to their insufficient pharmacological properties, such as weak permeability across cell membranes and vulnerability to nuclease degradation. To expand the clinical applicability of CDNs, a novel pH-sensitive polycationic polymer-modified lipid nanoparticle (LNP-B) system was developed for intravenous delivery of CDNs. LNP-B significantly extended the circulation of CDNs and enhanced the accumulation of CDNs within the tumor, spleen, and tumor-draining lymph nodes compared with free CDNs thereby triggering the STING pathway of dendritic cells and repolarizing pro-tumor macrophages. These events subsequently gave rise to potent anti-tumor immune reactions and substantial inhibition of tumors in CT26 colon cancer-bearing mouse models. In addition, due to the acid-sensitive property of the polycationic polymer, the delivery system of LNP-B was more biocompatible and safer compared with lipid nanoparticles formulated with an indissociable cationic DOTAP (LNP-D). These findings suggest that LNP-B has great potential in the intravenous delivery of CDNs for tumor immunotherapy.
Novel Irritable Bowel Syndrome Subgroups are Reproducible in the Global Adult Population.
Authors: Christopher J Black, Lesley A Houghton, Robert M West, Shrikant I Bangdiwala, Olafur S Palsson, Ami D Sperber, Alexander C Ford
Journal: Clinical Gastroenterology and Hepatology (2024)

Current classification systems for irritable bowel syndrome (IBS) based on bowel habit do not consider psychological impact. We validated a classification model in a UK population with confirmed IBS, using latent class analysis, incorporating psychological factors. We applied this model in the Rome Foundation Global Epidemiological Survey (RFGES), assessing impact of IBS on the individual and the health care system, and examining reproducibility.
Interruption of the intratumor CD8+ T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy
Authors: Shannon N. Geels, Alexander Moshensky, Rachel S. Sousa, Claire Murat, Matias A. Bustos, Benjamin L. Walker, Rima Singh, Stacey N. Harbour, Giselle Gutierrez, Michael Hwang, Thorsten R. Mempel, Casey T. Weaver, Qing Nie, Dave S.B. Hoon, Anand K. Ganesan, Shivashankar Othy, Francesco Marangoni
Journal: Cancer Cell (2024)
Endoscopic ultrasound-guided cyanoacrylate injection into the perforating vein for high-risk gastric varices
Authors: Ahmed Youssef Altonbary, Fady Sabry, Hazem Hakim, Seham Seif
Journal: Endoscopy (2024)

Direct endoscopic injection of gastric varices using cyanoacrylate (CYA) is associated with significant adverse events such as bleeding from the post-injection ulcer, needle sticking in the varix, adherence of the glue to the endoscope, and embolization into pulmonary or systemic vessels [1]. Targeting the perforating vessel by endoscopic ultrasound (EUS) rather than the varix lumen may theoretically minimize the amount of CYA and thereby reduce complications [2]. A randomized controlled trial performed by our group concluded that EUS-guided CYA injection into the perforating veins achieved excellent technical success with a lesser amount of CYA, fewer number of sessions to obliteration, and fewer complications compared to direct endoscopic injection [3].
Thymidylate synthase disruption to limit cell proliferation in cell therapies
Authors: Rocio Sartori-Maldonado, Hossam Montaser, Inkeri Soppa, Solja Eurola, Juhana Juutila, Melanie Balaz, Henri Puttonen, Timo Otonkoski, Jonna Saarimäki-Vire, Kirmo Wartiovaara
Journal: Molecular Therapy (2024)

Stem and progenitor cells hold great promise for regenerative medicine and gene therapy approaches. However, transplantations of living cells entail a fundamental risk of unwanted growth, potentially exacerbated by CRISPR-Cas9 or other genetic manipulations. Here, we describe a safety system to control cell proliferation while allowing robust and efficient cell manufacture, without any added genetic elements. Inactivating TYMS, a key nucleotide metabolism enzyme, in several cell lines resulted in cells that proliferate only when supplemented with exogenous thymidine. Under supplementation, TYMS-/--pluripotent stem cells proliferate, produce teratomas and successfully differentiate into potentially therapeutic cell types such as pancreatic beta-cells. Our results suggest that supplementation with exogenous thymidine affects stem cell proliferation, but not the function of stem cell-derived cells. After differentiation, postmitotic cells do not require thymidine in vitro or in vivo, as shown by the production of functional human insulin in mice up to 5 months after implantation of stem-cell derived pancreatic tissue.
Endoscopic papillectomy of a rare isolated ampullary hamartoma
Authors: Ahmed Altonbary, Fady Sabry, Hazem Hakim, Amr Elrabat, Wagdi Elkashef
Journal: Endoscopy (2024)

An isolated hamartoma in the ampulla of Vater is very rare, with only seven cases reported in the literature in patients without either Peutz–Jeghers or Cowdens syndrome as an underlying disease [1]. Herein, we report a rare case of isolated ampullary hamartoma diagnosed by endoscopic papillectomy.
The Role of Pancreatitis Risk Genes in Endocrine Insufficiency Development After Acute Pancreatitis in Children
Authors: Maisam Abu-El-Haija, Wenying Zhang, Rebekah Karns, Gila Ginzburg, David S. Vitale, Peter Farrell, Alexander Nasr, Sherif Ibrahim, Melena D. Bellin, Tyler Thompson, Vineet Garlapally, Jessica G. Woo, Sohail Z. Husain, Lee A. Denson
Journal: Clinical Gastroenterology and Hepatology (2024)
The TRIM28/miR133a/CD47 axis acts as a potential therapeutic target in pancreatic necrosis by impairing efferocytosis
Authors: Qingtian Zhu, Chenchen Yuan, Dan Wang, Bo Tu, Weiwei Chen, Xiaowu Dong, Keyan Wu, Lide Tao, Yanbing Ding, Weiming Xiao, Lianghao Hu, Weijuan Gong, Zhaoshen Li, Guotao Lu
Journal: Molecular Therapy (2024)
Stopping Nucleos(t)ide Analogues in Chronic Hepatitis B Using HBsAg Thresholds: A Meta-Analysis and Meta-Regression
Authors: Seng Gee Lim, Ada Ee Der Teo, Edwin Shih-Yen Chan, Wah Wah Phyo, David Hsing Yu Chen, Carol Anne Hargreaves
Journal: Clinical Gastroenterology and Hepatology (2024)
Comprehensive endoscopic management of recurrent esophageal wall abscess revealing concomitant eosinophilic esophagitis
Authors: Philippe Onana Ndong, Thierry Piche, Geoffroy Vanbiervliet
Journal: Endoscopy (2024)

Esophageal wall abscesses (EWAs) are rare lesions often linked to post-traumatic or inflammatory causes. To date, no authors have described their association with a diagnosis of eosinophilic esophagitis (EoE). While typically managed surgically owing to expertise constraints, this approach carries invasive risks, including mediastinitis. Interventional endoscopy offers a less invasive alternative, aiding both comprehensive treatment and etiologic diagnostic evaluation. Here, we report a case of recurrent EWA post-surgical debridement, treated endoscopically via wall incision, purulent content aspiration, and complete abscess fenestration into the esophageal cavity. Surprisingly, endoscopy revealed concomitant EoE.