tbuckley/cabot-search huggingface dataset:
Experimental West Nile virus infection provides lessons for recovery from enteric neuropathies
Authors: Joel C. Bornstein
Journal: Journal of Clinical Investigation (2024)

Loss of enteric neurons leading to long-term gastrointestinal dysfunction is common to many diseases, and the path to functional recovery is unclear. In this issue of the JCI, Janova et al. report that West Nile virus killed enteric neurons and glia via CD4+ and CD8+ T cells acting through the perforin and Fas ligand pathways. Enteric glial cells contributed to neurogenesis and at least partial replacement of affected neurons. While neurogenesis is important for recovery, dysmotility and disruptions to the network structure persisted. Following enteric injury, the contribution of neurogenesis and the conditions that support restoration of enteric neural circuits for functional recovery remain for further investigation.
More T cell receptors to the RAScue in cancer?
Authors: Eric Tran
Journal: Journal of Clinical Investigation (2024)

Treatment with T cells genetically engineered to express tumor-reactive T cell receptors (TCRs), known as TCR-gene therapy (TCR-T), is a promising immunotherapeutic approach for patients with cancer. The identification of optimal TCRs to use and tumor antigens to target are key considerations for TCR-T. In this issue of the JCI, Bear and colleagues report on their use of in vitro assays to characterize four HLA-A*03:01- or HLA-A*11:01-restricted TCRs targeting the oncogenic KRAS G12V mutation. The TCRs were derived from healthy donors or patients with pancreatic cancer who had received a vaccine against mutant KRAS. The most promising TCRs warrant testing in patients with KRAS G12V-positive cancers.
Activation of STAT3-mediated ciliated cell survival protects against severe infection by respiratory syncytial virus
Authors: Caiqi Zhao, Yan Bai, Wei Wang, Gaurang M Amonkar, Hongmei Mou, Judith Olejnik, Adam J Hume, Elke Mühlberger, Nicholas W Lukacs, Rachel Fearns, Paul H Lerou, Xingbin Ai
Journal: Journal of Clinical Investigation (2024)

Respiratory syncytial virus (RSV) selectively targets ciliated cells in human bronchial epithelium and can cause bronchiolitis and pneumonia, mostly in infants. To identify molecular targets of intervention during RSV infection in infants, we investigated how age regulates RSV interaction with the bronchial epithelium barrier. Employing precision-cut lung slices and air-liquid interface cultures generated from infant and adult human donors, we found robust RSV virus spread and extensive apoptotic cell death only in infant bronchial epithelium. In contrast, adult bronchial epithelium showed no barrier damage and limited RSV infection. Single nuclear RNA-Seq revealed age-related insufficiency of an antiapoptotic STAT3 activation response to RSV infection in infant ciliated cells, which was exploited to facilitate virus spread via the extruded apoptotic ciliated cells carrying RSV. Activation of STAT3 and blockade of apoptosis rendered protection against severe RSV infection in infant bronchial epithelium. Lastly, apoptotic inhibitor treatment of a neonatal mouse model of RSV infection mitigated infection and inflammation in the lung. Taken together, our findings identify a STAT3-mediated antiapoptosis pathway as a target to battle severe RSV disease in infants.
Enhanced susceptibility of pediatric airway epithelium to respiratory syncytial virus infection
Authors: Raymond J Pickles, Gang Chen, Scott H Randell
Journal: Journal of Clinical Investigation (2024)

Immature innate and adaptive immunity and vulnerability of narrower airways to obstruction increase the susceptibility of infants to severe respiratory syncytial virus (RSV) disease. In this issue of the JCI, Zhao et al. illustrated greater intrinsic susceptibility of pediatric versus adult airway epithelial cells to RSV-induced cytopathology. Using precision cut lung slices (PCLS) and air-liquid interface (ALI) airway epithelial cell cultures, the authors showed that impaired STAT3 activation in RSV-infected pediatric multiciliated cells increased cell apoptosis and viral shedding, which enhanced the spread of infection. Bolstering STAT3 activation and treatment of neonatal mice with apoptosis inhibitors suppressed virus spread, suggesting that enhancing STAT3 activation may provide therapeutic benefit.
Targeting TET3 in macrophages provides a concept strategy for the treatment of endometriosis
Authors: Hossein Hosseinirad, Md Saidur Rahman, Jae-Wook Jeong
Journal: Journal of Clinical Investigation (2024)

Endometriosis, characterized by the presence of endometrial-like tissue outside the uterus, is a condition associated with pain and infertility. In this issue of the JCI, Lv et al. illuminate the critical pathophysiological role of the ten-eleven translocation 3 (TET3) in endometriosis. TET3 expression levels were higher in macrophages of endometriotic lesions compared with control endometrial tissue, implicating TET3 as a contributing factor in the chronic inflammation that occurs in endometriosis. TGF-β1 and MCP1 are present in the peritoneal cavity of women with endometriosis, and macrophage exposure to these factors resulted in upregulation of TET3, thereby promoting their survival. Notably, Bobcat339, a selective TET inhibitor, induced apoptosis in these macrophages. Further, myeloid-specific TET3 loss reduced endometriosis in mice. RNA-Seq analysis following TET3 knockdown revealed alterations in cytokine signaling and cell-death pathways, underscoring the therapeutic potential of targeting TET3 in macrophages as a strategy for managing endometriosis.
Author correction to ‘The novel ER stress inducer Sec C triggers apoptosis by sulfating ER cysteine residues and degrading YAP via ER stress in pancreatic cancer cells’ [Acta Pharmaceutica Sinica B 12 (2022) 210-227]
Authors: Junxia Wang, Minghua Chen, Mengyan Wang, Wenxia Zhao, Conghui Zhang, Xiujun Liu, Meilian Cai, Yuhan Qiu, Tianshu Zhang, Huimin Zhou, Wuli Zhao, Shuyi Si, Rongguang Shao
Journal: Acta Pharmaceutica Sinica B (2024)

[This corrects the article DOI: 10.1016/j.apsb.2021.07.004.].
Anti-seizure effects of norepinephrine-induced free fatty acid release
Authors: Baoman Li, Qian Sun, Fengfei Ding, Qiwu Xu, Ning Kang, Yang Xue, Antonio Ladron-de-Guevara, Hajime Hirase, Pia Weikop, Sheng Gong, Nathan Smith, Maiken Nedergaard
Journal: Cell Metabolism (2024)
Inhibition of RNA splicing triggers CHMP7 nuclear entry, impacting TDP-43 function and leading to the onset of ALS cellular phenotypes
Authors: Norah Al-Azzam, Jenny H To, Vaishali Gautam, Lena A Street, Chloe B Nguyen, Jack T Naritomi, Dylan C Lam, Assael A Madrigal, Benjamin Lee, Wenhao Jin, Anthony Avina, Orel Mizrahi, Jasmine R Mueller, Willard Ford, Cara R Schiavon, Elena Rebollo, Anthony Q Vu, Steven M Blue, Yashwin L Madakamutil, Uri Manor, Jeffrey D Rothstein, Alyssa N Coyne, Marko Jovanovic, Gene W Yeo
Journal: Neuron (2024)

Amyotrophic lateral sclerosis (ALS) is linked to the reduction of certain nucleoporins in neurons. Increased nuclear localization of charged multivesicular body protein 7 (CHMP7), a protein involved in nuclear pore surveillance, has been identified as a key factor damaging nuclear pores and disrupting transport. Using CRISPR-based microRaft, followed by gRNA identification (CRaft-ID), we discovered 55 RNA-binding proteins (RBPs) that influence CHMP7 localization, including SmD1, a survival of motor neuron (SMN) complex component. Immunoprecipitation-mass spectrometry (IP-MS) and enhanced crosslinking and immunoprecipitation (CLIP) analyses revealed CHMP7's interactions with SmD1, small nuclear RNAs, and splicing factor mRNAs in motor neurons (MNs). ALS induced pluripotent stem cell (iPSC)-MNs show reduced SmD1 expression, and inhibiting SmD1/SMN complex increased CHMP7 nuclear localization. Crucially, overexpressing SmD1 in ALS iPSC-MNs restored CHMP7's cytoplasmic localization and corrected STMN2 splicing. Our findings suggest that early ALS pathogenesis is driven by SMN complex dysregulation.
Advances in triterpene drug discovery
Authors: Zoë R Goddard, Mark Searcey, Anne Osbourn
Journal: Trends in Pharmacological Sciences (2024)

Triterpenes are structurally complex natural products with promising therapeutic properties. Recalcitrance to chemical synthesis has hindered their use in drug development. Recent advances now make it possible to access and harness triterpene structural diversity using engineering biology approaches, enabling the discovery and optimisation of a new generation of drug leads.
ALCOHOL-ASSOCIATED LIVER DISEASE: NATURAL HISTORY, MANAGEMENT AND NOVEL TARGETED THERAPIES
Authors: Edilmar Alvarado-Tapias, Elisa Pose, Jordi Gratacós, Ana Clemente-Sánchez, Hugo Hugo López-Pelayo, Ramón Bataller
Journal: Clinical and Molecular Hepatology (2024)

Alcohol consumption is a leading cause of preventable morbidity and mortality worldwide and the primary cause of advanced liver disease. Alcohol use disorder (AUD) is a chronic, frequently relapsing condition characterized by persistent alcohol consumption despite its negative consequences. Alcohol-associated liver disease (ALD) encompasses a series of stages, from fatty liver (steatosis) to inflammation (steatohepatitis), fibrosis, and, ultimately, liver cirrhosis and its complications. The development of ALD is complex, involving both genetic and environmental factors, yet the exact mechanisms at play remain unclear. Alcohol-associated hepatitis (AH), a severe form of ALD, presents with sudden jaundice and liver failure. Currently, there are no approved targeted therapies able to interfere in the pathogenesis of ALD to stop the progression of the disease, making alcohol abstinence the most effective way to improve prognosis across all stages of ALD. For patients with advanced ALD who do not respond to medical therapy, liver transplantation is the only option that can improve prognosis. Recently, AH has become an early indication for liver transplantation in non-responders to medical treatment, showing promising results in carefully selected patients. This review provides an update on the epidemiology, natural history, pathogenesis, and current treatments for ALD. A deeper insight into novel targeted therapies investigated for AH focusing on new pathophysiologically-based agents is also discussed, including anti-inflammatory and antioxidative stress drugs, gut-liver axis modulators, and hepatocyte regenerative molecules.
Cutaneous fungal infections in the United States: A cross-sectional analysis of the National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS), 2005–2016
Authors: Sarah L Spaulding, A Mitchel Wride, Martin D Slade, William Damsky, Jeffrey M Cohen
Journal: Journal of the American Academy of Dermatology (2024)
Dual inheritance patterns: a spectrum of non-syndromic inherited retinal disease phenotypes with varying molecular mechanisms
Authors: Lara K Holtes, Suzanne E de Bruijn, Frans P M Cremers, Susanne Roosing
Journal: Progress in Retinal and Eye Research (2024)

Inherited retinal diseases (IRDs) encompass a variety of disease phenotypes and are known to display both clinical and genetic heterogeneity. A further complexity is that for several IRD-associated genes, pathogenic variants have been reported to cause either autosomal dominant (AD) or autosomal recessive (AR) diseases. The possibility of dual inheritance can create a challenge for variant interpretation as well as the genetic counselling of patients. This review aims to determine whether the molecular mechanisms behind the dual inheritance of each IRD-associated gene is well established, not yet properly understood, or if the association is questionable. Each gene is discussed individually in detail due to different protein structures and functions, but there are overlapping characteristics. For example, eight genes only have a limited number of reported pathogenic variants or a hotspot region implicated in the second inheritance pattern. Whereas CRX and RP1 display distinct spatial patterns for AR and AD pathogenic variants based on the variant type and/or location. The genes with a questionable dual inheritance, namely AIPL1, CRB1, and RCBTB1 highlight the importance of carefully considering allele frequency data. Finally, the crucial role relevant functional studies in animal and cell models play in validating a variant's biochemical or molecular effect is emphasised.
Hydrogel-based soft bioelectronics for personalized healthcare
Authors: Chuan Wei Zhang, Chi Chen, Sidi Duan, Yichen Yan, Ping He, Ximin He
Journal: Med-X (2024)

Abstract Soft bioelectronics have emerged as a promising platform for personalized healthcare, offering improved compatibility with biological tissues. Among various soft materials, hydrogels stand out due to their unique tissue-like properties and multifunctionality. However, the development of hydrogel-based bioelectronics faces three major challenges: (1) achieving a wide range of mechanical properties, from kilopascals to gigapascals, to match diverse tissues from soft brain to stiff tendon; (2) balancing and decoupling various material properties, particularly mechanical and electrical characteristics, and (3) achieving effective implantation and integration with target organs. This review provides a comprehensive overview of recent advancements in hydrogel-based bioelectronics, focusing on strategies to address these challenges. We first explore approaches to tune the mechanical properties of hydrogels, matching them with a wide range of tissues from soft brain tissue to stiff tendons. We then discuss innovative methods to incorporate conductivity into hydrogels while maintaining their mechanical integrity, highlighting recent developments in conductive polymers that show potential in decoupling electrical and mechanical properties. To address the challenge of implantation, we examine emerging concepts in stimuli-responsive hydrogels capable of programmable deformation, enabling targeted attachment and conformability to specific organs. We also categorize and analyze applications of hydrogel-based systems in both wearable and implantable devices, compiling the latest progress in hydrogel bioelectronics at the application level. While significant advancements have been made, integrating multiple functionalities within a single hydrogel-based device remains a considerable challenge. Further research is necessary to develop truly multimodal bioelectronic systems that can seamlessly interface with the human body, ultimately translating these promising technologies into clinical practice. Graphical Abstract
Organoids in the oral and maxillofacial region: present and future
Authors: Yufei Wu, Xiang Li, Hanzhe Liu, Xiao Yang, Rui Li, Hui Zhao, Zhengjun Shang
Journal: International Journal of Oral Science (2024)

The oral and maxillofacial region comprises a variety of organs made up of multiple soft and hard tissue, which are anatomically vulnerable to the pathogenic factors of trauma, inflammation, and cancer. The studies of this intricate entity have been long-termly challenged by a lack of versatile preclinical models. Recently, the advancements in the organoid industry have provided novel strategies to break through this dilemma. Here, we summarize the existing biological and engineering approaches that were employed to generate oral and maxillofacial organoids. Then, we detail the use of modified co-culture methods, such as cell cluster co-inoculation and air-liquid interface culture technology to reconstitute the vascular network and immune microenvironment in assembled organoids. We further retrospect the existing oral and maxillofacial assembled organoids and their potential to recapitulate the homeostasis in parental tissues such as tooth, salivary gland, and mucosa. Finally, we discuss how the next-generation organoids may benefit to regenerative and precision medicine for treatment of oral-maxillofacial illness.
Real-world effectiveness of dupilumab in a European cohort of CRSwNP (CHRINOSOR)
Authors: Sven F Seys, Sven Schneider, Joost de Kinderen, Sietze Reitsma, Carlo Cavaliere, Peter-Valentin Tomazic, Christina Morgenstern, Geoffrey Mortuaire, Martin Wagenmann, Giulia Bettio, Andrea Ciofalo, Zuzana Diamant, Julia Eckl-Dorna, Wytske J Fokkens, Clemens Holzmeister, Gert Mariën, Simonetta Masieri, Josje Otten, Kathrin Scheckenbach, Aldine Tu, Claus Bachert
Journal: Journal of Allergy and Clinical Immunology (2024)
Early geriatric assessment and management in older patients with Clostridioides difficile infection in Denmark (CLODIfrail): a randomised trial
Authors: Tone Rubak, Simon Mark Dahl Baunwall, Merete Gregersen, Sara Ellegaard Paaske, Malene Asferg, Ishay Barat, Joanna Secher-Johnsen, Mikael Groth Riis, Jeppe Bakkestrøm Rosenbæk, Troels Kjærskov Hansen, Marianne Ørum, Claire J Steves, Hanne Veilbæk, Christian Lodberg Hvas, Else Marie Skjøde Damsgaard
Journal: The Lancet Healthy Longevity (2024)
Cost-Effectiveness of Total Neoadjuvant Therapy With Selective Nonoperative Management for Locally Advanced Rectal Cancer: Analysis of Data From the Organ Preservation for Rectal Adenocarcinoma Trial
Authors: Maria Widmar, Mason McCain, Akriti Mishra Meza, Charles Ternent, Andrew Briggs, Julio Garcia-Aguilar
Journal: Journal of Clinical Oncology (2024)

PURPOSE The clinical efficacy of total neoadjuvant therapy (TNT) followed by selective nonoperative management (NOM) for locally advanced rectal cancer (LARC) was examined in the Organ Preservation for Rectal Adenocarcinoma (OPRA) trial. We investigated the cost and quality-of-life implications of adopting this treatment approach. METHODS We analyzed clinical, cost, and quality-of-life outcomes for TNT with selective NOM in comparison with chemoradiotherapy (CRT)-surgery-adjuvant chemotherapy (standard of care [SOC]) using data from OPRA, prospective cohorts, and published studies. Cost-effectiveness was evaluated over varying willingness-to-pay thresholds, and sensitivity analyses evaluated cost-effectiveness for different surgical contexts and SOC variants as well as a 10-year time horizon. RESULTS SOC was dominated by TNT with selective NOM in the base case analysis. TNT in which CRT was followed by consolidation chemotherapy (CNCT) was the least costly at $89,712 in Medicare proportionate US dollars (MP$), followed by TNT in which induction chemotherapy was followed by CRT (INCT) at MP$90,259 and SOC at MP$98,755. INCT was the preferred strategy, with 4.56 quality-adjusted life years, followed by CNCT at 4.42 and SOC at 4.29. TNT with selective NOM dominated SOC in all sensitivity analyses except when SOC omitted adjuvant chemotherapy without an impact on disease-free survival. CNCT was more cost effective than SOC when the proportion of patients entering NOM after TNT was ≥22% or ≥43%, for SOC with and without adjuvant therapy, both well below the rates seen in OPRA. CONCLUSION TNT with selective NOM is cost effective. The cost-effectiveness of CNCT with NOM relative to SOC is dependent on CNCT being made available to a sufficiently large proportion of patients with LARC. Additional analyses are needed to validate these findings from a societal perspective and in the context of other emerging treatment paradigms for LARC.
Large-Scale Pharmacogenomics Analysis of Patients With Cancer Within the 100,000 Genomes Project Combining Whole-Genome Sequencing and Medical Records to Inform Clinical Practice
Authors: Ivone U.S. Leong, Claudia P. Cabrera, Valentina Cipriani, Paul J. Ross, Richard M. Turner, Alex Stuckey, Sonali Sanghvi, Dorota Pasko, Loukas Moutsianas, Christopher A. Odhams, Greg S. Elgar, Georgia Chan, Adam Giess, Susan Walker, Rebecca E. Foulger, Eleanor M. Williams, Louise C. Daugherty, Antonio Rueda-Martin, Daniel J. Rhodes, Olivia Niblock, Alexandra Pickard, Lauren Marks, Sarah E.A. Leigh, Matthew J. Welland, Marta Bleda, Catherine Snow, Zandra Deans, Nirupa Murugaesu, Richard H. Scott, Michael R. Barnes, Matthew A. Brown, Augusto Rendon, Sue Hill, Alona Sosinsky, Mark J. Caulfield, Ellen M. McDonagh
Journal: Journal of Clinical Oncology (2024)

As part of the 100,000 Genomes Project, we set out to assess the potential viability and clinical impact of reporting genetic variants associated with drug-induced toxicity for patients with cancer recruited for whole-genome sequencing (WGS) as part of a genomic medicine service. Germline WGS from 76,805 participants was analyzed for pharmacogenetic (PGx) variants in four genes (DPYD, NUDT15, TPMT, UGT1A1) associated with toxicity induced by five drugs used in cancer treatment (capecitabine, fluorouracil, mercaptopurine, thioguanine, irinotecan). Linking genomic data with prescribing and hospital incidence records, a phenome-wide association study (PheWAS) was performed to identify whether phenotypes indicative of adverse drug reactions (ADRs) were enriched in drug-exposed individuals with the relevant PGx variants. In a subset of 7,081 patients with cancer, DPYD variants were reported back to clinicians and outcomes were collected. We identified clinically relevant PGx variants across the four genes in 62.7% of participants in our cohort. Extending this to annual prescription numbers in England for the drugs affected by these PGx variants, approximately 14,540 patients per year could potentially benefit from a reduced dose or alternative drug to reduce the risk of ADRs. Validating PGx associations in a real-world data set, we found a significant association between PGx variants in DPYD and toxicity-related phenotypes in patients treated with capecitabine or fluorouracil. Reported DPYD variants were deemed informative for clinical decision making in a majority of cases. Reporting PGx variants from germline WGS relevant to patients with cancer alongside primary findings related to their cancer can be clinically informative, informing prescribing to reduce the risk of ADRs. Extending the range of actionable variants to those found in patients of non-European ancestry is important and will extend the potential clinical impact.
Advances in Vulvar Cancer Biology and Management
Authors: Rania Chehade, Katarzyna J. Jerzak, Farideh Tavanger, Anna Plotkin, Lilian T. Gien, Eric Leung, Helen Mackay
Journal: Journal of Clinical Oncology (2024)

PURPOSE Vulvar squamous cell carcinoma (VSCC), a rare gynecologic malignancy, has been rising in incidence. Molecular classification on the basis of human papilloma virus (HPV) and tumor protein 53 (p53) status has identified three clinically distinct subtypes, but we still treat all VSCCs the same. Here, we review molecular classification of VSCC, outline treatment landscape, and highlight potential for targeted therapies in advanced VSCC. DESIGN We conducted a comprehensive review of the literature on treatment of advanced VSCC with particular focus on the implications of molecular stratification on the basis of HPV and p53 status on the treatment landscape of advanced VSCC. RESULTS Incorporation of HPV and p53 status in locoregional treatment decision making has the potential to advise (de)escalation strategies. The role of immunotherapy, alone and in combination, requires further exploration particularly earlier in the course of the disease. In advanced stages, potential for targeted therapies in VSCCs include inhibitors of vascular endothelial growth factor, endothelial growth factor receptor, cell cycle, and DNA damage response, particularly in HPV-negative (HPV–) VSCCs. Targeting the phosphoinositide 3 kinase/mammalian target of rapamycin pathway is attractive in HPV-positive and HPV–/p53 wildtype VSCCs. Trials incorporating antibody-drug conjugates (eg, trophoblast cell-surface antigen 2, human epidermal growth factor receptor 2) should be considered, and basket trials in perineal squamous cell cancers are warranted. Preclinical models are limited and should be expanded to inform trial design. CONCLUSION Like other rare cancers, vulvar cancer lags behind in the identification and optimization of precision medicine strategies. Molecular-based preclinical models and rationally designed clinical trials, incorporating high-quality translational studies, are urgently required. These trials will require international collaboration to ensure feasibility and improvement of outcomes for women diagnosed with this disease.