tbuckley/cabot-search huggingface dataset:
Primary cilia formation requires the Leigh syndrome–associated mitochondrial protein NDUFAF2
Authors: Chien-Hui Lo, Zhiquan Liu, Siyu Chen, Frank Lin, Andrew R. Berneshawi, Charles Q. Yu, Euna B. Koo, Tia J. Kowal, Ke Ning, Yang Hu, Won-Jing Wang, Y. Joyce Liao, Yang Sun
Journal: Journal of Clinical Investigation (2024)

Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.
Cystic fibrosis–related metabolic defects: crosstalk between ion channels and organs
Authors: Sunder Sims-Lucas, Eric S. Goetzman, Thomas R. Kleyman
Journal: Journal of Clinical Investigation (2024)

Cystic fibrosis is a debilitating disease characterized by a poor medical prognosis due to devastating lung injury. Recent medical advances targeting the major genetic mutation ΔF508 of the cystic fibrosis transmembrane conductance regulator (CFTR) protein have dramatically increased the lifespan of patients with this mutation. This development has led to major changes in the field and has pushed research beyond the ion transport nature of cystic fibrosis and toward multiorgan physiological reprogramming. In this issue of the JCI, Bae, Kim, and colleagues utilized a large animal pig model prior to the onset of disease. They revealed metabolic reprogramming and organ crosstalk that occurred prior to disease progression. These findings provide paradigm-shifting insight into this complex disease.
Epigenetic developmental mechanisms underlying sex differences in cancer
Authors: Joshua B. Rubin, Tamara Abou-Antoun, Joseph E. Ippolito, Lorida Llaci, Camryn T. Marquez, Jason P. Wong, Lihua Yang
Journal: Journal of Clinical Investigation (2024)

Cancer risk is modulated by hereditary and somatic mutations, exposures, age, sex, and gender. The mechanisms by which sex and gender work alone and in combination with other cancer risk factors remain underexplored. In general, cancers that occur in both the male and female sexes occur more commonly in XY compared with XX individuals, regardless of genetic ancestry, geographic location, and age. Moreover, XY individuals are less frequently cured of their cancers, highlighting the need for a greater understanding of sex and gender effects in oncology. This will be necessary for optimal laboratory and clinical cancer investigations. To that end, we review the epigenetics of sexual differentiation and its effect on cancer hallmark pathways throughout life. Specifically, we will touch on how sex differences in metabolism, immunity, pluripotency, and tumor suppressor functions are patterned through the epigenetic effects of imprinting, sex chromosome complement, X inactivation, genes escaping X inactivation, sex hormones, and life history.
Keeping it fresh: ribosomal protein SA sustains sarcomeric function via localized translation
Authors: Abigail Nagle, Michael Regnier, Jennifer Davis
Journal: Journal of Clinical Investigation (2024)

Mechanical stress from cardiomyocyte contraction causes misfolded sarcomeric protein replacement. Sarcomeric maintenance utilizes localized pools of mRNAs and translation machinery, yet the importance of localized translation remains unclear. In this issue of the JCI, Haddad et al. identify the Z-line as a critical site for localized translation of sarcomeric proteins, mediated by ribosomal protein SA (RPSA). RPSA localized ribosomes at Z-lines and was trafficked via microtubules. Cardiomyocyte-specific loss of RPSA in mice resulted in mislocalized protein translation and caused structural dilation from myocyte atrophy. These findings demonstrate the necessity of RPSA-dependent spatially localized translation for sarcomere maintenance and cardiac structure and function.
UBE2C-induced crosstalk between mono- and polyubiquitination of SNAT2 promotes lymphatic metastasis in bladder cancer
Authors: Wenjie Li, Changhao Chen, Hanhao Zheng, Yan Lin, Mingjie An, Daiyin Liu, Yonghai Zhang, Mingchao Gao, Tianhang Lan, Wang He
Journal: Journal of Clinical Investigation (2024)

Ubiquitination plays an essential role in protein stability, subcellular localization, and interactions. Crosstalk between different types of ubiquitination results in distinct biological outcomes for proteins. However, the role of ubiquitination-related crosstalk in lymph node (LN) metastasis and the key regulatory factors controlling this process have not been determined. Using high-throughput sequencing, we found that ubiquitin-conjugating enzyme E2 C (UBE2C) was overexpressed in bladder cancer (BCa) and was strongly associated with an unfavorable prognosis. Overexpression of UBE2C increased BCa lymphangiogenesis and promoted LN metastasis both in vitro and in vivo. Mechanistically, UBE2C mediated sodium-coupled neutral amino acid transporter 2 (SNAT2) monoubiquitination at lysine 59 to inhibit K63-linked polyubiquitination at lysine 33 of SNAT2. Crosstalk between monoubiquitination and K63-linked polyubiquitination increased SNAT2 membrane protein levels by suppressing epsin 1-mediated (EPN1-mediated) endocytosis. SNAT2 facilitated glutamine uptake and metabolism to promote VEGFC secretion, ultimately leading to lymphangiogenesis and LN metastasis in patients with BCa. Importantly, inhibition of UBE2C significantly attenuated BCa lymphangiogenesis in a patient-derived xenograft model. Our results reveal the mechanism by which UBE2C mediates crosstalk between the monoubiquitination and K63-linked polyubiquitination of SNAT2 to promote BCa metastasis and identify UBE2C as a promising target for treating LN-metastatic BCa.
Distinct host preconditioning regimens differentially impact the antitumor potency of adoptively transferred Th17 cells
Authors: Megen C Wittling, Hannah M Knochelmann, Megan M Wyatt, Guillermo O Rangel Rivera, Anna C Cole, Gregory B Lesinski, Chrystal M Paulos
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown. Methods CD4 + T cells with a transgenic T-cell receptor that recognize tyrosinase-related peptide (TRP)-1 melanoma antigen were polarized to the T helper 17 (Th17) phenotype and then transferred into melanoma-bearing mice preconditioned with either total body irradiation or chemotherapy. Results We found that preconditioning mice with a non-myeloablative dose of total body irradiation (TBI of 5 Gy) was more effective than using an equivalently dosed non-myeloablative chemotherapy (cyclophosphamide (CTX) of 200 mg/kg) at augmenting therapeutic activity of antitumor TRP-1 Th17 cells. Antitumor Th17 cells engrafted better following preconditioning with TBI and regressed large established melanoma in all animals. Conversely, only half of mice survived long-term when preconditioned with CTX and infused with anti-melanoma Th17 cells. Interleukin (IL)-17 and interferon-γ, produced by the infused Th17 cells, were detected in animals given either TBI or CTX preconditioning. Interestingly, inflammatory cytokines (granulocyte colony stimulating factor, IL-6, monocyte chemoattractant protein-1, IL-5, and keratinocyte chemoattractant) were significantly elevated in the serum of mice preconditioned with TBI versus CTX after Th17 therapy. The addition of fludarabine (FLU, 200 mg/kg) to CTX (200 mg/kg) improved the antitumor response to the same degree mediated by TBI, whereas FLU alone with Th17 therapy was ineffective. Conclusions Our results indicate, for the first time, that the antitumor response, persistence, and cytokine profiles resulting from Th17 therapy are impacted by the specific regimen of host preconditioning. This work is important for understanding mechanisms that promote long-lived responses by adoptive cellular therapy, particularly as CD4 + based T-cell therapies are now emerging in the clinic.
Autoantibody-positivity before and seroconversion during treatment with anti-PD-1 is associated with immune-related adverse events in patients with melanoma
Authors: Jessica S W Borgers, Tineke J van Wesemael, Kyra A Gelderman, Theo Rispens, Els M E Verdegaal, Dirk J A R Moes, Catharina M Korse, Ellen Kapiteijn, Marij J P Welters, Sjoerd H van der Burg, Winan J van Houdt, Johannes V van Thienen, John B A G Haanen, Diane van der Woude
Journal: Journal for ImmunoTherapy of Cancer (2024)

Introduction Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases, autoantibodies might play a role and could potentially be used to identify patients at risk. Therefore, we investigated the association between autoantibody-positivity and toxicity as well as clinical response in patients with melanoma treated with anti-PD-1. Materials and methods This two-center, retrospective study included 143 patients with melanoma treated with anti-PD-1. Toxicities grade ≥2 and recurrences/responses were captured until 6 months after treatment initiation. Autoantibody measurements were performed at baseline and 3 months after treatment initiation, including IgM-rheumatoid factor (RF), antinuclear antibodies (ANA), extractable nuclear antigen, anti-cyclic citrullinated peptide antibodies (anti-CCP2) and anti-thyroid antibodies. Results 169 irAEs were experienced by 86/143 patients (137 grades 1–2, 32 grades 3–4), the most common being thyroiditis (n=25), dermatitis (n=24), and sicca problems (n=19). Patients with autoantibodies at baseline experienced more irAEs (p=0.001), predominantly associated with anti-thyroid antibodies and thyroid dysfunction. No association was observed between any irAE and anti-CCP2, RF or ANA. In women, baseline and on-treatment anti-thyroid antibody-positivity as well as seroconversion during treatment was associated with thyroid dysfunction. In men, this association was only observed on-treatment. The presence of autoantibodies was not associated with melanoma recurrence (p=0.776) or response (p=0.597). Conclusion The presence of autoantibodies prior to anti-PD-1 therapy is associated with irAEs in patients with melanoma. Both baseline positivity and seroconversion of anti-thyroid antibodies were strongly associated with thyroid dysfunction. This association was stronger in women, with all women who were baseline positive developing thyroid dysfunction.
True or false? Alzheimer’s disease is type 3 diabetes: Evidences from bench to bedside
Authors: Yong Peng, Shun-yu Yao, Quan Chen, Hong Jin, Miao-qiao Du, Ya-hui Xue, Shu Liu
Journal: Ageing Research Reviews (2024)

Globally, Alzheimer's disease (AD) is the most widespread chronic neurodegenerative disorder, leading to cognitive impairment, such as aphasia and agnosia, as well as mental symptoms, like behavioral abnormalities, that place a heavy psychological and financial burden on the families of the afflicted. Unfortunately, no particular medications exist to treat AD, as the current treatments only impede its progression.The link between AD and type 2 diabetes (T2D) has been increasingly revealed by research; the danger of developing both AD and T2D rises exponentially with age, with T2D being especially prone to AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. A critical review of the relationship between insulin resistance, Aβ, oxidative stress, mitochondrial hypothesis, abnormal phosphorylation of Tau protein, inflammatory response, high blood glucose levels, neurotransmitters and signaling pathways, vascular issues in AD and diabetes, and the similarities between the two diseases, is presented in this review. Grasping the essential mechanisms behind this detrimental interaction may offer chances to devise successful therapeutic strategies.
Membranous nephropathy: pathogenesis and treatments
Authors: Mengqiong Wang, Jingjuan Yang, Xin Fang, Weiqiang Lin, Yi Yang
Journal: MedComm (2024)

Abstract Membranous nephropathy (MN), an autoimmune disease, can manifest at any age and is among the most common causes of nephrotic syndrome in adults. In 80% of cases, the specific etiology of MN remains unknown, while the remaining cases are linked to drug use or underlying conditions like systemic lupus erythematosus, hepatitis B virus, or malignancy. Although about one‐third of patients may achieve spontaneous complete or partial remission with conservative management, another third face an elevated risk of disease progression, potentially leading to end‐stage renal disease within 10 years. The identification of phospholipase A2 receptor as the primary target antigen in MN has brought about a significant shift in disease management and monitoring. This review explores recent advancements in the pathophysiology of MN, encompassing pathogenesis, clinical presentations, diagnostic criteria, treatment options, and prognosis, with a focus on emerging developments in pathogenesis and therapeutic strategies aimed at halting disease progression. By synthesizing the latest research findings and clinical insights, this review seeks to contribute to the ongoing efforts to enhance our understanding and management of this challenging autoimmune disorder.
Organoids in gastrointestinal diseases: from bench to clinic
Authors: Qinying Wang, Fanying Guo, Qinyuan Zhang, TingTing Hu, YuTao Jin, Yongzhi Yang, Yanlei Ma
Journal: MedComm (2024)

Abstract The etiology of gastrointestinal (GI) diseases is intricate and multifactorial, encompassing complex interactions between genetic predisposition and gut microbiota. The cell fate change, immune function regulation, and microenvironment composition in diseased tissues are governed by microorganisms and mutated genes either independently or through synergistic interactions. A comprehensive understanding of GI disease etiology is imperative for developing precise prevention and treatment strategies. However, the existing models used for studying the microenvironment in GI diseases—whether cancer cell lines or mouse models—exhibit significant limitations, which leads to the prosperity of organoids models. This review first describes the development history of organoids models, followed by a detailed demonstration of organoids application from bench to clinic. As for bench utilization, we present a layer‐by‐layer elucidation of organoid simulation on host–microbial interactions, as well as the application in molecular mechanism analysis. As for clinical adhibition, we provide a generalized interpretation of organoid application in GI disease simulation from inflammatory disorders to malignancy diseases, as well as in GI disease treatment including drug screening, immunotherapy, and microbial‐targeting and screening treatment. This review draws a comprehensive and systematical depiction of organoids models, providing a novel insight into the utilization of organoids models from bench to clinic.
Pancreatic duct occlusion after endoscopic ultrasound-guided transmural pancreatic duct drainage: a pitfall and its rescue technique
Authors: Anthony Rivera Gerodias, Akihisa Ohno, Yasuhiro Komori, Yosuke Minoda, Keijiro Ueda, Tomohiko Moriyama, Nao Fujimori
Journal: Endoscopy (2024)

Endoscopic ultrasound-guided pancreatic duct drainage (EUS-PDD) is a procedure to access the pancreatic duct in cases of failed endoscopic retrograde cholangiopancreatography (ERCP) [1] [2]. In patients with surgically altered anatomy, transmural drainage is the preferred technique [3]. A single-pigtail plastic stent designed for EUS-PDD has been developed with favorable outcomes [4] ([Fig. 1]).
Safety, tolerability, and immunogenicity of an adult pneumococcal conjugate vaccine, V116 (STRIDE-3): a randomised, double-blind, active comparator controlled, international phase 3 trial
Authors: Heather L Platt, Christopher Bruno, Erik Buntinx, Enrique Pelayo, Diego Garcia-Huidobro, Elizabeth A Barranco-Santana, Folke Sjoberg, Joon Young Song, Carlos G Grijalva, Walter A Orenstein, Leslie Morgan, Doreen Fernsler, Weifeng Xu, Muhammad Waleed, Jianing Li, Ulrike K Buchwald, Michael Abdel-Malek, Jeffrey Adelglass, Sady Armad Alpizar, Duane Anderson, Charles P. Andrews, Helena Hervius Askling, Jeffrey B. Baker, Mira Baron, Elizabeth A. Barranco-Santana, John Beckes, James H. Bergthold, Peter Bosson, Erik Buntinx, Larry Marc Bush, David J. Butuk, Edgardo F. Cartagena Ayala, Hee Jung Choi, Jung Hyun Choi, Won Suk Choi, Young Hwa Choi, James R. Clark, Oliver A. Cornely, Steve E. Cox, Nizar Daboul, Luis Ignacio De La Cruz, Pamela De Silva, Olaf Degen, Valentine Ebuh, Stanton R. Elzi, Thomas Fiel, William Patrick Fitzgibbons, Neil J. Fraser, George Hartley Freeman, Christopher Galloway, Diego Garcia-Huidobro, Juan Carlos Garza, Anil George, Carl Patrick Griffin, Sridhar Guduri, Hatice Rahmet Guner, Elizabeth Gunner, Enrique Hanabergh, Charles Harold Harper, Kathleen Harris, John Matthew Hemmersmeier, John M. Hill, Ching-Tai Huang, Kuo-Chin Huang, Chad Roger Huberty, Bejamin James Image, Margret Jandl, William Henry, Jr. Johnston, Jackie Marie Kamerbeek, Oguz Karabay, Jae-Hoon Ko, Iftihar Koksal, Ki Tae Kwon, Amber Leah, Dong-Gun Lee, Jacob Lee, Thomas C. Lenzmeier, Denissa Loh, Rafael Lupercio, Andes Erik Luts, Thomas Lutz, Jose Martinez, Renae Mayer, Vicki Miller, Javier O. Morales-Ramirez, Manuel Munoz, Jesus Ovidio Navarro, Larry Lee Odekirk, Patrick Odia, Alberto J. Odio, Matthew O'Sullivan, Minesh Arun Patel, Enrique Pelayo, Carlos Perez Cortes, Syed Pervaiz, Jared Probst, Dean Richard Quinn, Kathryn R. Rigonan, Nicolas Rosario-Matos, Jeffrey Bruce Rosen, Andrej Sannesten, Axel Schaefer, Sven Schellberg, Manjoo Sharma, Lawrence D. Sher, Hyejin Shi, Gerald R. Shockey, Raj Singh, Folke Sjoberg, Brian Smith, Christohper A. Smith, Deon Smith, Susan Elizabeth Smith, Joon Young Song, Jonathan Staben, Kenneth Steil, Chien-Tien Su, Serhat Ünal, Seong-Heong Wie, Priyantha Wijewardane, Michael John Williams, Thomas A. Wolf, Yi-Ching Yang, Joon Sup Yeom
Journal: The Lancet Infectious Diseases (2024)
Once-weekly semaglutide in people with HIV-associated lipohypertrophy: a randomised, double-blind, placebo-controlled phase 2b single-centre clinical trial
Authors: Allison Ross Eckard, Qian Wu, Abdus Sattar, Kianoush Ansari-Gilani, Danielle Labbato, Theresa Foster, Aaron A Fletcher, Ruth O Adekunle, Grace A McComsey
Journal: The Lancet Diabetes & Endocrinology (2024)
Lassa fever research priorities: towards effective medical countermeasures by the end of the decade
Authors: Kristine A Moore, Julia T Ostrowsky, Angela J Mehr, Rebecca A Johnson, Angela K Ulrich, Nicolina M Moua, Petra C Fay, Peter J Hart, Josephine P Golding, Virginia Benassi, Marie-Pierre Preziosi, Ifedayo M Adetifa, George O Akpede, William K Ampofo, Danny A Asogun, Alan D T Barrett, Daniel G Bausch, Ilse de Coster, Devy M Emperador, Heinz Feldmann, Elisabeth Fichet-Calvet, Pierre B H Formenty, Robert F Garry, Donald S Grant, Stephan Günther, Swati B Gupta, Marie Jaspard, Laura T Mazzola, Sylvanus A Okogbenin, Cathy Roth, Connie S Schmaljohn, Michael T Osterholm
Journal: The Lancet Infectious Diseases (2024)
Premature mortality trends in 183 countries by cancer type, sex, WHO region, and World Bank income level in 2000–19: a retrospective, cross-sectional, population-based study
Authors: Shilpa S Murthy, Dario Trapani, Bochen Cao, Freddie Bray, Shashanka Murthy, Thomas Peter Kingham, Chandrakanth Are, André M Ilbawi
Journal: The Lancet Oncology (2024)

Cancer is a leading cause of mortality worldwide. By 2040, over 30 million new cancers are predicted, with the greatest cancer burden in low-income countries. In 2015, the UN passed the Sustainable Development Goal 3.4 (SDG 3.4) to tackle the rising burden of non-communicable diseases, which calls for a reduction by a third in premature mortality from non-communicable diseases, including cancer, by 2030. However, there is a paucity of data on premature mortality rates by cancer type. In this study, we examine annual rates of change for cancer-specific premature mortality and classify whether countries are on track to reach SDG 3.4 targets.
Measures to prevent and treat Nipah virus disease: research priorities for 2024–29
Authors: Kristine A Moore, Angela J Mehr, Julia T Ostrowsky, Angela K Ulrich, Nicolina M Moua, Petra C Fay, Peter J Hart, Josephine P Golding, Virginia Benassi, Marie-Pierre Preziosi, Christopher C Broder, Emmie de Wit, Pierre B H Formenty, Alexander N Freiberg, Emily S Gurley, Kim Halpin, Stephen P Luby, Laura T Mazzola, Joel M Montgomery, Christina F Spiropoulou, Devendra T Mourya, Shahana Parveen, Mahmudur Rahman, Cathy Roth, Lin-Fa Wang, Michael T Osterholm
Journal: The Lancet Infectious Diseases (2024)
Implications of subclinical tuberculosis for vaccine trial design and global effect
Authors: Gavin J Churchyard, Rein M G J Houben, Katherine Fielding, Andrew L Fiore-Gartland, Hanif Esmail, Alison D Grant, Molebogeng X Rangaka, Marcel Behr, Alberto L Garcia-Basteiro, Emily B Wong, Mark Hatherill, Vidya Mave, Alemnew F Dagnew, Alexander C Schmidt, Willem A Hanekom, Frank Cobelens, Richard G White
Journal: The Lancet Microbe (2024)

Tuberculosis is a leading cause of death from an infectious agent globally. Infectious subclinical tuberculosis accounts for almost half of all tuberculosis cases in national tuberculosis prevalence surveys, and possibly contributes to transmission and might be associated with morbidity. Modelling studies suggest that new tuberculosis vaccines could have substantial health and economic effects, partly based on the assumptions made regarding subclinical tuberculosis. Evaluating the efficacy of prevention of disease tuberculosis vaccines intended for preventing both clinical and subclinical tuberculosis is a priority. Incorporation of subclinical tuberculosis as a composite endpoint in tuberculosis vaccine trials can help to reduce the sample size and duration of follow-up and to evaluate the efficacy of tuberculosis vaccines in preventing clinical and subclinical tuberculosis. Several design options with various benefits, limitations, and ethical considerations are possible in this regard, which would allow for the generation of the evidence needed to estimate the positive global effects of tuberculosis vaccine trials, in addition to informing policy and vaccination strategies.
Author Correction: Prediction of recurrence risk in endometrial cancer with multimodal deep learning
Authors: Sarah Volinsky-Fremond, Nanda Horeweg, Sonali Andani, Jurriaan Barkey Wolf, Maxime W. Lafarge, Cor D. de Kroon, Gitte Ørtoft, Estrid Høgdall, Jouke Dijkstra, Jan J. Jobsen, Ludy C. H. W. Lutgens, Melanie E. Powell, Linda R. Mileshkin, Helen Mackay, Alexandra Leary, Dionyssios Katsaros, Hans W. Nijman, Stephanie M. de Boer, Remi A. Nout, Marco de Bruyn, David Church, Vincent T. H. B. M. Smit, Carien L. Creutzberg, Viktor H. Koelzer, Tjalling Bosse
Journal: Nature Medicine (2024)