tbuckley/cabot-search huggingface dataset:
Corrigendum to “A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants.” Kidney Int. 2023;103:962–972
Authors: Georgia Malakasioti, Daniela Iancu, Anastasiia Milovanova, Alexey Tsygin, Tomoko Horinouchi, China Nagano, Kandai Nozu, Koichi Kamei, Shuichiro Fujinaga, Kazumoto Iijima, Hee Gyung Kang, Rajiv Sinha, Biswanath Basu, William Morello, Giovanni Montini, Aoife Waters, Olivia Boyer, Zeynep Yürük Yıldırım, Sibel Yel, İsmail Dursun, Hugh J. McCarthy, Marina Vivarelli, Larisa Prikhodina, Martine T.P. Besouw, Eugene Yu-hin Chan, Wenyan Huang, Markus J. Kemper, Sebastian Loos, Chanel Prestidge, William Wong, Galia Zlatanova, Rasmus Ehren, Lutz T. Weber, Hassib Chehade, Nakysa Hooman, Marcin Tkaczyk, Małgorzata Stańczyk, Michael Miligkos, Kjell Tullus, Georgia Malakasioti, Daniela Iancu, Anastasiia Milovanova, Alexey Tsygin, Kandai Nozu, Koichi Kamei, Shuichiro Fujinaga, Kazumoto Iijima, Rajiv Sinha, Biswanath Basu, William Morello, Giovanni Montini, Aoife Waters, Olivia Boyer, Zeynep Yürük Yıldırım, Sibel Yel, İsmail Dursun, Hugh J. McCarthy, Marina Vivarelli, Larisa Prikhodina, Martine T.P. Besouw, Eugene Yu-hin Chan, Wenyan Huang, Markus J. Kemper, Sebastian Loos, Chanel Prestidge, William Wong, Galia Zlatanova, Rasmus Ehren, Lutz T. Weber, Hassib Chehade, Nakysa Hooman, Marcin Tkaczyk, Małgorzata Stańczyk, Kjell Tullus, Vitor Hugo Martins, Roberta Camilla, Bruno Gianoglio, Andrew Maxted, Michel Tsimaratos, Harika Alpay, Valerie Said-Conti, Anamarija Meglič, Paula Bresso, Paula Coccia, Andromachi Mitsioni, Yok-Chin Yap
Journal: Kidney International (2024)
KDIGO 2024 Clinical Practice Guideline for the management of LUPUS NEPHRITIS
Authors: Brad H. Rovin, Isabelle M. Ayoub, Tak Mao Chan, Zhi-Hong Liu, Juan Manuel Mejía-Vilet, Jürgen Floege
Journal: Kidney International (2024)

The Kidney Disease: Improving Global Outcomes (KDIGO) 2024 Clinical Practice Guideline for the Management of Lupus Nephritis represents a focused update of the Lupus nephritis chapter from the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. The aim is to assist clinicians caring for individuals with lupus nephritis. The update takes into consideration evidence from randomized controlled trials published since February 2022. As in 2021, the chapter follows the same template, providing guidance related to diagnosis, treatment, and special situations. Based on the evidence, this update is focused on guidance related to treatment of lupus nephritis. This guideline update followed an explicit process of evidence review and appraisal. Treatment approaches and guideline recommendations are based on systematic reviews of relevant studies, and appraisal of the strength of recommendations and certainty of the evidence following the “Grading of Recommendations Assessment, Development and Evaluation” (GRADE) approach. Limitations of the evidence are discussed and areas of future research are presented.
The extracellular matrix as hallmark of cancer and metastasis: From biomechanics to therapeutic targets
Authors: Jelle J. F. Sleeboom, Gilles S. van Tienderen, Katja Schenke-Layland, Luc J. W. van der Laan, Antoine A. Khalil, Monique M. A. Verstegen
Journal: Science Translational Medicine (2024)

The extracellular matrix (ECM) is essential for cell support during homeostasis and plays a critical role in cancer. Although research often concentrates on the tumor’s cellular aspect, attention is growing for the importance of the cancer-associated ECM. Biochemical and physical ECM signals affect tumor formation, invasion, metastasis, and therapy resistance. Examining the tumor microenvironment uncovers intricate ECM dysregulation and interactions with cancer and stromal cells. Anticancer therapies targeting ECM sensors and remodelers, including integrins and matrix metalloproteinases, and ECM-remodeling cells, have seen limited success. This review explores the ECM’s role in cancer and discusses potential therapeutic strategies for cell-ECM interactions.
Incidental Bleeding Gastrointestinal Stromal Tumor Identified on 99mTc-RBC Scintigraphy
Authors: Chenxi Wu, Ekaterina Menshikova, Ila Sethi
Journal: Clinical Nuclear Medicine (2023)

Abstract Various pathologies could lead to occult gastrointestinal (GI) bleeding. Here we report the case of a 73-year-old woman who presented with hematochezia and syncope, and was found to have a large bleeding GI stromal tumor incidentally from 99m Tc-RBC scintigraphy. This study was done after negative workup with CT angiography, colonoscopy, and capsule endoscopy for the source of GI bleeding. Final pathology confirmed the mass being a low-grade GI stromal tumor after exploratory laparotomy.
Ventilator induced lung injury: a case for a larger umbrella?
Authors: Luciano Gattinoni, Francesca Collino, Luigi Camporota
Journal: Intensive Care Medicine (2024)

Mechanical ventilation and VILIVentilator-induced lung injury (VILI) is a general term indicating the structural and physiological lung alterations caused by mechanical ventilation (MV).Given that MV is only a supportive treatment, the best MV settings are those providing sufficient gas exchange without generating additional injury.Therefore, VILI detection allows to discriminate between an "innocent" and a "harmful" MV. Conceptual and mechanistic evolution of ventilator-induced lung injury BarotraumaThis was the first described injury associated with MV in acute respiratory distress syndrome (ARDS).The mechanism of these injuries was elucidated by Macklin et al. [1], who found that alveolar rupture leads to a gas escaping along the pulmonary vascular sheaths toward the mediastinum with consequent pneumomediastinum, subcutaneous emphysema, and pneumothorax.
Splicing modulators impair DNA damage response and induce killing of cohesin-mutant MDS and AML
Authors: Emily C. Wheeler, Benjamin J. E. Martin, William C. Doyle, Sofia Neaher, Caroline A. Conway, Caroline N. Pitton, Rebecca A. Gorelov, Melanie Donahue, Johann C. Jann, Omar Abdel-Wahab, Justin Taylor, Michael Seiler, Silvia Buonamici, Yana Pikman, Jacqueline S. Garcia, Roger Belizaire, Karen Adelman, Zuzana Tothova
Journal: Science Translational Medicine (2024)

Splicing modulation is a promising treatment strategy pursued to date only in splicing factor-mutant cancers; however, its therapeutic potential is poorly understood outside of this context. Like splicing factors, genes encoding components of the cohesin complex are frequently mutated in cancer, including myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (AML), where they are associated with poor outcomes. Here, we showed that cohesin mutations are biomarkers of sensitivity to drugs targeting the splicing factor 3B subunit 1 (SF3B1) H3B-8800 and E-7107. We identified drug-induced alterations in splicing, and corresponding reduced gene expression, of a number of DNA repair genes, including BRCA1 and BRCA2 , as the mechanism underlying this sensitivity in cell line models, primary patient samples and patient-derived xenograft (PDX) models of AML. We found that DNA damage repair genes are particularly sensitive to exon skipping induced by SF3B1 modulators due to their long length and large number of exons per transcript. Furthermore, we demonstrated that treatment of cohesin-mutant cells with SF3B1 modulators not only resulted in impaired DNA damage response and accumulation of DNA damage, but it sensitized cells to subsequent killing by poly(ADP-ribose) polymerase (PARP) inhibitors and chemotherapy and led to improved overall survival of PDX models of cohesin-mutant AML in vivo. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS and AML.
Preclinical characterization of macrophage-adhering gadolinium micropatches for MRI contrast after traumatic brain injury in pigs
Authors: Lily Li-Wen Wang, Yongsheng Gao, Vineeth Chandran Suja, Masen L. Boucher, Suyog Shaha, Neha Kapate, Rick Liao, Tao Sun, Ninad Kumbhojkar, Supriya Prakash, John R. Clegg, Kaitlyn Warren, Morgan Janes, Kyung Soo Park, Michael Dunne, Bolu Ilelaboye, Andrew Lu, Solomina Darko, Camilo Jaimes, Rebekah Mannix, Samir Mitragotri
Journal: Science Translational Medicine (2024)

The choroid plexus (ChP) of the brain plays a central role in orchestrating the recruitment of peripheral leukocytes into the central nervous system (CNS) through the blood-cerebrospinal fluid (BCSF) barrier in pathological conditions, thus offering a unique niche to diagnose CNS disorders. We explored whether magnetic resonance imaging of the ChP could be optimized for mild traumatic brain injury (mTBI). mTBI induces subtle, yet influential, changes in the brain and is currently severely underdiagnosed. We hypothesized that mTBI induces sufficient alterations in the ChP to cause infiltration of circulating leukocytes through the BCSF barrier and developed macrophage-adhering gadolinium [Gd(III)]-loaded anisotropic micropatches (GLAMs), specifically designed to image infiltrating immune cells. GLAMs are hydrogel-based discoidal microparticles that adhere to macrophages without phagocytosis. We present a fabrication process to prepare GLAMs at scale and demonstrate their loading with Gd(III) at high relaxivities, a key indicator of their effectiveness in enhancing image contrast and clarity in medical imaging. In vitro experiments with primary murine and porcine macrophages demonstrated that GLAMs adhere to macrophages also under shear stress and did not affect macrophage viability or functions. Studies in a porcine mTBI model confirmed that intravenously administered macrophage-adhering GLAMs provide a differential signal in the ChP and lateral ventricles at Gd(III) doses 500- to 1000-fold lower than those used in the current clinical standard Gadavist. Under the same mTBI conditions, Gadavist did not offer a differential signal at clinically used doses. Our results suggest that macrophage-adhering GLAMs could facilitate mTBI diagnosis.
The hazards of genotype imputation when mapping disease susceptibility variants
Authors: Winston Lau, Aminah Ali, Hannah Maude, Toby Andrew, Dallas M. Swallow, Nikolas Maniatis
Journal: Genome biology (2024)

Abstract Background The cost-free increase in statistical power of using imputation to infer missing genotypes is undoubtedly appealing, but is it hazard-free? This case study of three type-2 diabetes (T2D) loci demonstrates that it is not; it sheds light on why this is so and raises concerns as to the shortcomings of imputation at disease loci, where haplotypes differ between cases and reference panel. Results T2D-associated variants were previously identified using targeted sequencing. We removed these significantly associated SNPs and used neighbouring SNPs to infer them by imputation. We compared imputed with observed genotypes, examined the altered pattern of T2D-SNP association, and investigated the cause of imputation errors by studying haplotype structure. Most T2D variants were incorrectly imputed with a low density of scaffold SNPs, but the majority failed to impute even at high density, despite obtaining high certainty scores. Missing and discordant imputation errors, which were observed disproportionately for the risk alleles, produced monomorphic genotype calls or false-negative associations. We show that haplotypes carrying risk alleles are considerably more common in the T2D cases than the reference panel, for all loci. Conclusions Imputation is not a panacea for fine mapping, nor for meta-analysing multiple GWAS based on different arrays and different populations. A total of 80% of the SNPs we have tested are not included in array platforms, explaining why these and other such associated variants may previously have been missed. Regardless of the choice of software and reference haplotypes, imputation drives genotype inference towards the reference panel, introducing errors at disease loci.
NAD <sup>+</sup> precursors and bile acid sequestration treat preclinical refractory environmental enteric dysfunction
Authors: Atika Malique, Shengxiang Sun, Kanta Chandwe, Beatrice Amadi, Talin Haritunians, Umang Jain, Brian D. Muegge, Jennifer Frein, Yo Sasaki, Amanda Foster, Chad E. Storer, Emebet Mengesha, Justin Kern, Dermot P.B. McGovern, Richard D. Head, Paul Kelly, Ta-Chiang Liu
Journal: Science Translational Medicine (2024)

Environmental enteric dysfunction (EED) is a diffuse small bowel disorder associated with poor growth, inadequate responses to oral vaccines, and nutrient malabsorption in millions of children worldwide. We identify loss of the small intestinal Paneth and goblet cells that are critical for innate immunity, reduced villous height, increased bile acids, and dysregulated nicotinamide adenine dinucleotide (NAD + ) synthesis signaling as potential mechanisms underlying EED and which also correlated with diminished length-for-age z score. Isocaloric low-protein diet (LPD) consumption in mice recapitulated EED histopathology and transcriptomic changes in a microbiota-independent manner, as well as increases in serum and fecal bile acids. Children with refractory EED harbor single-nucleotide polymorphisms in key enzymes involved in NAD + synthesis. In mice, deletion of Nampt , the gene encoding the rate-limiting enzyme in the NAD + salvage pathway, from intestinal epithelium also reduced Paneth cell function, a deficiency that was further aggravated by LPD. Separate supplementation with NAD + precursors or bile acid sequestrant partially restored LPD-associated Paneth cell defects and, when combined, fully restored all histopathology defects in LPD-fed mice. Therapeutic regimens that increase protein and NAD + contents while reducing excessive bile acids may benefit children with refractory EED.
Corrigendum to “Disease-free Survival Analysis for Patients with High-risk Muscle-invasive Urothelial Carcinoma from the Randomized CheckMate 274 Trial by PD-L1 Combined Positive Score and Tumor Cell Score” [Eur. Urol. 83(5) (2024) 432–440]
Authors: Matthew D. Galsky, Dean F. Bajorin, Johannes Alfred Witjes, Jürgen E. Gschwend, Yoshihiko Tomita, Federico Nasroulah, Jun Li, Sandra Collette, Begoña P. Valderrama, Marc-Oliver Grimm, Leonard Appleman, Gwenaelle Gravis, Andrea Necchi, Dingwei Ye, Frank Stenner, Megan Wind-Rotolo, Joshua Zhang, Keziban Ünsal-Kaçmaz
Journal: European Urology (2024)
Punctate inner choroidopathy: A review of the current diagnostic and therapeutic approaches
Authors: Dimitrios Kalogeropoulos, Najiha Rahman, Farid Afshar, Nigel Hall, Andrew John Lotery
Journal: Progress in Retinal and Eye Research (2024)

Punctate inner choroidopathy (PIC) is an uncommon idiopathic inflammatory condition characterized by multifocal chorioretinopathy that primarily affects young adults, with a predilection for myopic females. Clinically, it manifests as small, yellowish-white lesions in the inner choroid and outer retina, often associated with inflammatory changes. Accurate diagnosis remains a challenge due to its resemblance to other posterior uveitic entities, necessitating an astute clinical eye and advanced imaging techniques for differentiation. Multimodal imaging plays a crucial role by offering valuable insights, as it enables the visualization of various abnormalities related to uveitis. The pathogenesis of PIC is still a subject of debate, with a complex interplay of genetic, immunological, and environmental factors proposed. Managing PIC presents multiple challenges for clinicians. Firstly, variable disease severity within and among patients requires diverse treatments, from observation to aggressive immunosuppression and/or anti-VEGF therapy. Secondly, treatment must distinguish between primary causes of vision loss. New or worsening PIC lesions suggest active inflammation, while new neovascular membranes may indicate secondary neovascular processes. Thirdly, deciding on maintenance therapy is complex, balancing PIC prognosis variability against immunosuppression risks. Some patients have long periods of inactivity and remission, while others face sudden, vision-threatening episodes during quiescent phases. Through a systematic review of the literature, this paper sheds light on the current understanding of PIC, its challenges, and the prospects for future research. By synthesizing existing knowledge, it aims to aid clinicians in accurate diagnosis and guide treatment decisions for improved visual outcomes in individuals affected by PIC.
Predictive Value of CTA-Derived Extracellular Volume for Pacemaker Implantation Post-TAVR in Low-Flow Low-Gradient Aortic Stenosis
Authors: Pankaj Malhotra, Donghee Han, Billy Chen, Robert Siegel, John Friedman, Damini Dey, Raj Makkar, Daniel S. Berman, Balaji Tamarappoo
Journal: JACC. Cardiovascular imaging (2024)
Guanosine diphosphate–mannose suppresses homologous recombination repair and potentiates antitumor immunity in triple-negative breast cancer
Authors: Jia-Han Ding, Yi Xiao, Fan Yang, Xiao-Qing Song, Ying Xu, Xiao-Hong Ding, Rui Ding, Zhi-Ming Shao, Gen-Hong Di, Yi-Zhou Jiang
Journal: Science Translational Medicine (2024)

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis. TNBCs with high homologous recombination deficiency (HRD) scores benefit from DNA-damaging agents, including platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, whereas those with low HRD scores still lack therapeutic options. Therefore, we sought to exploit metabolic alterations to induce HRD and sensitize DNA-damaging agents in TNBCs with low HRD scores. We systematically analyzed TNBC metabolomics and identified a metabolite, guanosine diphosphate (GDP)–mannose (GDP-M), that impeded homologous recombination repair (HRR). Mechanistically, the low expression of the upstream enzyme GDP-mannose-pyrophosphorylase-A (GMPPA) led to the endogenous up-regulation of GDP-M in TNBC. The accumulation of GDP-M in tumor cells further reduced the interaction between breast cancer susceptibility gene 2 (BRCA2) and ubiquitin-specific peptidase 21 (USP21), which promoted the ubiquitin-mediated degradation of BRCA2 to inhibit HRR. Therapeutically, we illustrated that the supplementation of GDP-M sensitized DNA-damaging agents to impair tumor growth in both in vitro (cancer cell line and patient-derived organoid) and in vivo (xenograft in immunodeficient mouse) models. Moreover, the combination of GDP-M with DNA-damaging agents activated STING-dependent antitumor immunity in immunocompetent syngeneic mouse models. Therefore, GDP-M supplementation combined with PARP inhibition augmented the efficacy of anti–PD-1 antibodies. Together, these findings suggest that GDP-M is a crucial HRD-related metabolite and propose a promising therapeutic strategy for TNBCs with low HRD scores using the combination of GDP-M, PARP inhibitors, and anti–PD-1 immunotherapy.
Adjuvanted SARS-CoV-2 spike protein vaccination elicits long-lived plasma cells in nonhuman primates
Authors: Madhu Prabhakaran, Flavio Matassoli, David Leggat, Abigayle Hoover, Abhinaya Srikanth, Weiwei Wu, Amy R. Henry, Jennifer Wang, Bob C. Lin, I-Ting Teng, Chaim A. Schramm, Mike Castro, Leonid Serebryannyy, Nazaire Jean-Baptiste, Christopher Moore, Suprabhath Gajjala, John-Paul M. Todd, Elizabeth McCarthy, Sandeep Narpala, Joseph Francica, VRC Production Program, Kizzmekia S. Corbett-Helaire, Daniel C. Douek, Peter D. Kwong, Robert A. Seder, Sarah F. Andrews, Adrian B. McDermott
Journal: Science Translational Medicine (2024)

Durable humoral immunity is mediated by long-lived plasma cells (LLPCs) that reside in the bone marrow. It remains unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein vaccination is able to elicit and maintain LLPCs. Here, we describe a sensitive method to identify and isolate antigen-specific LLPCs by tethering antibodies secreted by these cells onto the cell surface. Using this method, we found that two doses of adjuvanted SARS-CoV-2 spike protein vaccination are able to induce spike protein–specific LLPC reservoirs enriched for receptor binding domain specificities in the bone marrow of nonhuman primates that are detectable for several months after vaccination. Immunoglobulin gene sequencing confirmed that several of these LLPCs were clones of memory B cells elicited 2 weeks after boost that had undergone further somatic hypermutation. Many of the antibodies secreted by these LLPCs also exhibited improved neutralization and cross-reactivity compared with earlier time points. These findings establish our method as a means to sensitively and reliably detect rare antigen-specific LLPCs and demonstrate that adjuvanted SARS-CoV-2 spike protein vaccination establishes spike protein–specific LLPC reservoirs.
The influence of the gut microbiome on ovarian aging
Authors: Feiling Huang, Ying Cao, Jinghui Liang, Ruiyi Tang, Si Wu, Peng Zhang, Rong Chen
Journal: Gut Microbes (2024)

Ovarian aging occurs prior to the aging of other organ systems and acts as the pacemaker of the aging process of multiple organs. As life expectancy has increased, preventing ovarian aging has become an essential goal for promoting extended reproductive function and improving bone and genitourinary conditions related to ovarian aging in women. An improved understanding of ovarian aging may ultimately provide tools for the prediction and mitigation of this process. Recent studies have suggested a connection between ovarian aging and the gut microbiota, and alterations in the composition and functional profile of the gut microbiota have profound consequences on ovarian function. The interaction between the gut microbiota and the ovaries is bidirectional. In this review, we examine current knowledge on ovary-gut microbiota crosstalk and further discuss the potential role of gut microbiota in anti-aging interventions. Microbiota-based manipulation is an appealing approach that may offer new therapeutic strategies to delay or reverse ovarian aging.
Pasteurized <i>Akkermansia muciniphila</i> improves irritable bowel syndrome-like symptoms and related behavioral disorders in mice
Authors: Maëva Meynier, Valentine Daugey, Geoffroy Mallaret, Sandie Gervason, Mathieu Meleine, Julie Barbier, Youssef Aissouni, Stéphane Lolignier, Mathilde Bonnet, Denis Ardid, Willem M. De Vos, Matthias Van Hul, Peter Suenaert, Amandine Brochot, Patrice D. Cani, Frédéric A. Carvalho
Journal: Gut Microbes (2024)

Gut – brain communications disorders in irritable bowel syndrome (IBS) are associated with intestinal microbiota composition, increased gut permeability, and psychosocial disturbances. Symptoms of IBS are difficult to medicate, and hence much research is being made into alternative approaches. This study assesses the potential of a treatment with pasteurized Akkermansia muciniphila for alleviating IBS-like symptoms in two mouse models of IBS with different etiologies. Two clinically relevant animal models were used to mimic IBS-like symptoms in C57BL6/J mice: the neonatal maternal separation (NMS) paradigm and the Citrobacter rodentium infection model. In both models, gut permeability, colonic sensitivity, fecal microbiota composition and colonic IL-22 expression were evaluated. The cognitive performance and emotional state of the animals were also assessed by several tests in the C. rodentium infection model. The neuromodulation ability of pasteurized A. muciniphila was assessed on primary neuronal cells from mice dorsal root ganglia using a ratiometric calcium imaging approach. The administration of pasteurized A. muciniphila significantly reduced colonic hypersensitivity in both IBS mouse models, accompanied by a reinforcement of the intestinal barrier function. Beneficial effects of pasteurized A. muciniphila treatment have also been observed on anxiety-like behavior and memory defects in the C. rodentium infection model. Finally, a neuroinhibitory effect exerted by pasteurized A. muciniphila was observed on neuronal cells stimulated with two algogenic substances such as capsaicin and inflammatory soup. Our findings demonstrate novel anti-hyperalgesic and neuroinhibitory properties of pasteurized A. muciniphila, which therefore may have beneficial effects in relieving pain and anxiety in subjects with IBS.