tbuckley/cabot-search huggingface dataset:
Tissue-resident CD8 <sup>+</sup> T cells drive compartmentalized and chronic autoimmune damage against CNS neurons
Authors: David Frieser, Aurora Pignata, Leila Khajavi, Danielle Shlesinger, Carmen Gonzalez-Fierro, Xuan-Hung Nguyen, Alexander Yermanos, Doron Merkler, Romana Höftberger, Virginie Desestret, Katharina M. Mair, Jan Bauer, Frederick Masson, Roland S. Liblau
Journal: Science Translational Medicine (2022)

The mechanisms underlying the chronicity of autoimmune diseases of the central nervous system (CNS) are largely unknown. In particular, it is unclear whether tissue-resident memory T cells (T RM ) contribute to lesion pathogenesis during chronic CNS autoimmunity. Here, we observed that a high frequency of brain-infiltrating CD8 + T cells exhibit a T RM -like phenotype in human autoimmune encephalitis. Using mouse models of neuronal autoimmunity and a combination of T single-cell transcriptomics, high-dimensional flow cytometry, and histopathology, we found that pathogenic CD8 + T cells behind the blood-brain barrier adopt a characteristic T RM differentiation program, and we revealed their phenotypic and functional heterogeneity. In the diseased CNS, autoreactive tissue-resident CD8 + T cells sustained focal neuroinflammation and progressive loss of neurons, independently of recirculating CD8 + T cells. Consistently, a large fraction of autoreactive tissue-resident CD8 + T cells exhibited proliferative potential as well as proinflammatory and cytotoxic properties. Persistence of tissue-resident CD8 + T cells in the CNS and their functional output, but not their initial differentiation, were crucially dependent on CD4 + T cells. Collectively, our results point to tissue-resident CD8 + T cells as essential drivers of chronic CNS autoimmunity and suggest that therapies targeting this compartmentalized autoreactive T cell subset might be effective for treating CNS autoimmune diseases.
Editing <i>TINF2</i> as a potential therapeutic approach to restore telomere length in dyskeratosis congenita
Authors: Seunga Choo, Franziska K. Lorbeer, Samuel G. Regalado, Sarah B. Short, Shannon Wu, Gabrielle Rieser, Alison A. Bertuch, Dirk Hockemeyer
Journal: Blood (2022)

Mutations in the TINF2 gene, encoding the shelterin protein TIN2, cause telomere shortening and the inherited bone marrow (BM) failure syndrome dyskeratosis congenita (DC). A lack of suitable model systems limits the mechanistic understanding of telomere shortening in the stem cells and thus hinders the development of treatment options for BM failure. Here, we endogenously introduced TIN2-DC mutations in human embryonic stem cells (hESCs) and human hematopoietic stem and progenitor cells (HSPCs) to dissect the disease mechanism and identify a gene-editing strategy that rescued the disease phenotypes. The hESCs with the T284R disease mutation exhibited the short telomere phenotype observed in DC patients. Yet, telomeres in mutant hESCs did not trigger DNA damage responses at telomeres or show exacerbated telomere shortening when differentiated into telomerase-negative cells. Disruption of the mutant TINF2 allele by introducing a frameshift mutation in exon 2 restored telomere length in stem cells and the replicative potential of differentiated cells. Similarly, we introduced TIN2-DC disease variants in human HSPCs to assess the changes in telomere length and proliferative capacity. Lastly, we showed that editing at exon 2 of TINF2 that restored telomere length in hESCs could be generated in TINF2-DC patient HSPCs. Our study demonstrates a simple genetic intervention that rescues the TIN2-DC disease phenotype in stem cells and provides a versatile platform to assess the efficacy of potential therapeutic approaches in vivo.
Clostridioides difficile positivity rate and PCR ribotype distribution on retail potatoes in 12 European countries, January to June 2018
Authors: Valerija Tkalec, Virginie Viprey, Georgina Davis, Sandra Janezic, Béatrice Sente, Nathalie Devos, Mark Wilcox, Kerrie Davies, Maja Rupnik
Journal: Eurosurveillance (2022)

BackgroundWhile human-to-human transmission of Clostridioides difficile occurs often, other infection sources, including food, animals and environment, are under investigation.AimWe present a large study on C. difficile in a food item in Europe, encompassing 12 European countries (Austria, France, Greece, Ireland, Italy, the Netherlands, Poland, Slovakia, Spain, Sweden, Romania and the United Kingdom).MethodsPotato was selected because of availability, ease of sampling and high C. difficile positivity rates. Identical protocols for sampling and isolation were used, enabling a direct comparison of the C. difficile positivity rate.ResultsFrom C. difficile-positive potato samples (33/147; 22.4%), we obtained 504 isolates, grouped into 38 PCR ribotypes. Positivity rates per country varied (0-100%) and were at least 10% in 9/12 countries. No geographical clustering of samples with high positivity rates or in PCR ribotype distribution was observed. The most frequently detected PCR ribotypes (014/020, 078/126, 010 and 023) are also commonly reported in Europe among human clinically relevant isolates, in animal isolates and in the environment. Whole genome sequencing revealed several genetically related strain pairs (Spain/RT126, France/RT010, Austria and Sweden/RT276) and a cluster of very similar strains in RT078/126.ConclusionOur results suggest, the high potato contamination rates could have public health relevance. They indicate potatoes can serve as a vector for introducing C. difficile spores in the household environment, where the bacterium can then multiply in sensitive hosts with disrupted or unmature microbiota. Potato contamination with PCR ribotypes shared between humans, animals and soil is supportive of this view.
Genome-wide functional perturbation of human microsatellite repeats using engineered zinc finger transcription factors
Authors: Y. Esther Tak, Gaylor Boulay, Lukuo Lee, Sowmya Iyer, Nicholas T. Perry, Hayley T. Schultz, Sara P. Garcia, Liliane Broye, Joy E. Horng, Shruthi Rengarajan, Beverly Naigles, Angela Volorio, Jeffry D. Sander, Jingyi Gong, Nicolò Riggi, J. Keith Joung, Miguel N. Rivera
Journal: Cell Genomics (2022)

Repeat elements can be dysregulated at a genome-wide scale in human diseases. For example, in Ewing sarcoma, hundreds of inert GGAA repeats can be converted into active enhancers when bound by EWS-FLI1. Here we show that fusions between EWS and GGAA-repeat-targeted engineered zinc finger arrays (ZFAs) can function at least as efficiently as EWS-FLI1 for converting hundreds of GGAA repeats into active enhancers in a Ewing sarcoma precursor cell model. Furthermore, a fusion of a KRAB domain to a ZFA can silence GGAA microsatellite enhancers genome wide in Ewing sarcoma cells, thereby reducing expression of EWS-FLI1-activated genes. Remarkably, this KRAB-ZFA fusion showed selective toxicity against Ewing sarcoma cells compared with non-Ewing cancer cells, consistent with its Ewing sarcoma-specific impact on the transcriptome. These findings demonstrate the value of ZFAs for functional annotation of repeats and illustrate how aberrant microsatellite activities might be regulated for potential therapeutic applications.
Editor's Note: Fibroblast Growth Factor Receptor 2–Positive Fibroblasts Provide a Suitable Microenvironment for Tumor Development and Progression in Esophageal Carcinoma
Authors: Chunyu Zhang, Li Fu, Jianhua Fu, Liang Hu, Hong Yang, Tie-Hua Rong, Yan Li, Haibo Liu, Song-Bin Fu, Yi-Xin Zeng, Xin-Yuan Guan
Journal: Clinical Cancer Research (2022)
Metagenomic and metabolomic remodeling in nonagenarians and centenarians and its association with genetic and socioeconomic factors
Authors: Qian Xu, Chunyan Wu, Qi Zhu, Renyuan Gao, Jianquan Lu, Mireia Valles-Colomer, Jian Zhu, Fang Yin, Linsheng Huang, Lulu Ding, Xiaohui Zhang, Yonghui Zhang, Xiao Xiong, Miaomiao Bi, Xiang Chen, Yefei Zhu, Lin Liu, Yongqiang Liu, Yongshen Chen, Jian Fan, Yan Sun, Jun Wang, Zhan Cao, Chunsun Fan, S. Dusko Ehrlich, Nicola Segata, Nan Qin, Huanlong Qin
Journal: Nature Aging (2022)
The role of extracellular vesicles in the transfer of drug resistance competences to cancer cells
Authors: Cristina P.R. Xavier, Dimas Carolina Belisario, Rita Rebelo, Yehuda G. Assaraf, Elisa Giovannetti, Joanna Kopecka, M. Helena Vasconcelos
Journal: Drug Resistance Updates (2022)

Drug resistance remains a major hurdle to successful cancer treatment, being accountable for approximately 90% of cancer-related deaths. In the past years, increasing attention has been given to the role of extracellular vesicles (EVs) in the horizontal transfer of drug resistance in cancer. Indeed, many studies have described the dissemination of therapy resistance traits mediated by EVs, which may be transferred from drug resistant tumor cells to their drug sensitive counterparts. Importantly, different key players of drug resistance have been identified in the cargo of those EVs, such as drug efflux pumps, oncoproteins, antiapoptotic proteins, or microRNAs, among others. Interestingly, the EVs-mediated crosstalk between cells from the tumor microenvironment (TME) and tumor cells has emerged as another important mechanism that leads to cancer cells drug resistance. Recently, the cargo of the TME-derived EVs responsible for the transfer of drug resistance traits has also become a focus of attention. In addition, the possible mechanisms involved in drug sequestration by EVs, likely to contribute to cancer drug resistance, are also described and discussed herein. Despite the latest scientific advances in the field of EVs, this is still a challenging area of research, particularly in the clinical setting. Therefore, further investigation is needed to assess the relevance of EVs to the failure of cancer patients to drug treatment, to identify biomarkers of drug resistance in the EV's cargo, and to develop effective therapeutic strategies to surmount drug resistance. This up-to-date review summarizes relevant literature on the role of EVs in the transfer of drug resistance competences to cancer cells, and the relevance of tumor cells and of TME cells in this process. Finally, this knowledge is integrated with a discussion of possible future clinical applications of EVs as biomarkers of drug resistance.
Antiseizure Medications for Adults With Epilepsy
Authors: Andres M. Kanner, Manuel Melo Bicchi
Journal: JAMA (2022)

Epilepsy affects approximately 65 million people worldwide. Persistent seizures are associated with a 20% to 40% risk of bodily injuries (eg, fractures, burns, concussions) over 12-month follow-up. The primary goal of epilepsy treatment is to eliminate seizures while minimizing adverse effects of antiseizure drugs (ASDs).An epileptic seizure is defined as a sudden occurrence of transient signs and symptoms caused by abnormal and excessive or synchronous neuronal activity in the brain. Focal and generalized epilepsy are the 2 most frequent types of epilepsy; diagnosis is based on the type of seizures. There are 26 US Food and Drug Administration-approved medications for epilepsy, of which 24 have similar antiseizure efficacy for focal epilepsy and 9 have similar efficacy for generalized epilepsy. The decision to initiate an ASD should be individualized, but should be strongly considered after 2 unprovoked seizures or after 1 unprovoked seizure that occurred during sleep and/or in the presence of epileptiform activity on an electroencephalogram and/or in the presence of a structural lesion on the brain magnetic resonance imaging. The ASDs must be selected based on the seizure and epilepsy types, the epilepsy syndrome, and the adverse effects associated with the drug. For focal epilepsy, oxcarbazepine and lamotrigine are first-line therapy, while levetiracetam can be also considered if there is no history of psychiatric disorder. For generalized epilepsy, the selection of the ASD is based on the type of epilepsy syndrome and the patient's sex, age, and psychiatric history. Seizure freedom is achieved in approximately 60% to 70% of all patients. A total of 25% to 50% of patients also experience neurologic, psychiatric, cognitive, or medical disorders, such as mood, anxiety, and attention deficit disorders and migraines. For these patients, selecting an ASD should consider the presence of these disorders and concomitant use of medications to treat them. ASDs with cytochrome P450 enzyme-inducing properties (eg, carbamazepine, phenytoin) may worsen comorbid coronary and cerebrovascular disease by causing hyperlipidemia and accelerating the metabolism of concomitant drugs used for their treatment. They can also facilitate the development of osteopenia and osteoporosis.Epilepsy affects approximately 65 million people worldwide and is associated with increased rates of bodily injuries and mortality when not optimally treated. For focal and generalized epilepsy, selection of ASDs should consider the seizure and epilepsy types and epilepsy syndrome, as well as the patient's age and sex, comorbidities, and potential drug interactions.
Corrigendum to ‘Baveno VII – Renewing consensus in portal hypertension’ [J Hepatol (2022) 959-974]
Authors: Roberto de Franchis, Jaime Bosch, Guadalupe Garcia-Tsao, Thomas Reiberger, Cristina Ripoll, Juan G. Abraldes, Agustin Albillos, Anna Baiges, Jasmohan Bajaj, Rafael Bañares, Marta Barrufet, Lina Benajiba, Annalisa Berzigotti, Christophe Bureau, Vincenza Calvaruso, Andres Cardenas, Gennaro D’Amico, Andrea De Gottardi, Alessandra Dell’Era, Angels Escorsell, Jonathan Fallowfield, Hector Ferral, Sven Francque, Ron Gaba, Juan Carlos Garcia-Pagàn, Joan Genescà, Susana Gomes Rodrigues, Jordi Gracia-Sanscho, Guohong Han, Virginia Hernandez-Gea, Jidong Jia, Jean Jacques Kiladjian, Aleksander Krag, Wim Laleman, Vincenzo La Mura, Sabela Lens, Xuefeng Luo, Mattias Mandorfer, Sarwa Darwish Murad, Valerie Paradis, David Patch, Salvatore Piano, Massimo Pinzani, Aurelie Plessier, Massimo Primignani, Bogdan Procopet, Pierre Emmanuel Rautou, Marika Rudler, Shiv K. Sarin, Filippo Schepis, Marco Senzolo, Vijay Shah, Akash Shukla, Puneeta Tandon, Luis Tellez, Dominique Thabut, Maja Thiele, Jonel Trebicka, Dhiraj Tripathi, Emmanouil Tsochatzis, Laura Turco, Fanny Turon, Dominique Valla, Candid Villanueva, Ian Wanless, Hitoshi Yoshiji
Journal: Journal of Hepatology (2022)
Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small cell lung cancer: the phase 2 B-F1RST trial
Authors: Edward S. Kim, Vamsidhar Velcheti, Tarek Mekhail, Cindy Yun, Sarah M. Shagan, Sylvia Hu, Young Kwang Chae, Ticiana A. Leal, Jonathan E. Dowell, Michaela L. Tsai, Christopher S. R. Dakhil, Philip Stella, Yanling Jin, David S. Shames, Erica Schleifman, David A. Fabrizio, See Phan, Mark A. Socinski
Journal: Nature Medicine (2022)

Abstract Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies. Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST ( NCT02848651 ), an open-label, phase 2 trial that evaluated bTMB as a predictive biomarker for first-line atezolizumab monotherapy in locally advanced or metastatic stage IIIB–IVB non-small cell lung cancer ( n = 152). The co-primary endpoints were investigator-assessed objective response rate (ORR) per RECIST version 1.1 and investigator-assessed progression-free survival (PFS) between high and low bTMB subgroups at the pre-defined bTMB ≥ 16 (14.5 mutations per megabase) cutoff. Secondary endpoints included investigator-assessed PFS, overall survival (OS) and duration of response at various bTMB cutoffs, as well as safety. Investigator-assessed PFS in the bTMB ≥ 16 versus bTMB &lt; 16 groups was not statistically significant. However, bTMB ≥ 16 was associated with higher ORR, and ORR improved as bTMB cutoffs increased. No new safety signals were seen. In exploratory analyses, patients with maximum somatic allele frequency (MSAF) &lt; 1% had higher ORR than patients with MSAF ≥ 1%. However, further analysis showed that this effect was driven by better baseline prognostics rather than by MSAF itself. At 36.5-month follow-up, an exploratory analysis of OS found that bTMB ≥ 16 was associated with longer OS than bTMB &lt; 16. Further study and assay optimization will be required to develop bTMB as a predictive, standalone biomarker of immunotherapy or for use in conjunction with other biomarkers.
MLDRL: Multi-loss disentangled representation learning for predicting esophageal cancer response to neoadjuvant chemoradiotherapy using longitudinal CT images
Authors: Hailin Yue, Jin Liu, Junjian Li, Hulin Kuang, Jinyi Lang, Jianhong Cheng, Lin Peng, Yongtao Han, Harrison Bai, Yuping Wang, Qifeng Wang, Jianxin Wang
Journal: Medical Image Analysis (2022)
Multidimensional single-cell analysis of human peripheral blood reveals characteristic features of the immune system landscape in aging and frailty
Authors: Oscar Junhong Luo, Wen Lei, Guodong Zhu, Zhiyao Ren, Yudai Xu, Chanchan Xiao, Hongyi Zhang, Junxiang Cai, Zhiping Luo, Lijuan Gao, Jun Su, Lei Tang, Wei Guo, Huanxing Su, Zhang-Jin Zhang, Evandro Fei Fang, Yijun Ruan, Sean Xiao Leng, Zhenyu Ju, Huiling Lou, Junling Gao, Nan Peng, Jie Chen, Zhijun Bao, Feng Liu, Guobing Chen
Journal: Nature Aging (2022)
High expression level of ROR1 and ROR1-signaling associates with venetoclax resistance in chronic lymphocytic leukemia
Authors: Emanuela M. Ghia, Laura Z. Rassenti, Michael Y. Choi, Miguel Quijada-Álamo, Elvin Chu, George F. Widhopf, Thomas J. Kipps
Journal: Leukemia (2022)

Abstract Although the BH3-mimetic venetoclax is highly cytotoxic for chronic lymphocytic leukemia (CLL) cells, some patients with CLL fail to clear minimal residual disease (MRD). We examined the CLL cells of seven such patients (CLL1-7) and found each had high-level expression of ROR1. By examining the CLL cells from such patients prior to therapy at SC1 and then more than 1 year later (Sample Collection 2 (SC2)), when they had progressive increases in MRD despite continued venetoclax therapy, we found the levels of ROR1 expressed on CLL cells at SC2 were significantly higher than that on CLL cells collected at SC1. At SC2, we also observed upregulation of genes induced by Wnt5a-induced ROR1 signaling, including BCL2L1 . Transduction of the CLL-cell-line MEC1 to express ROR1 enhanced expression of target genes induced by ROR1-signaling, increased expression of BCL-XL, and enhanced resistance to venetoclax, even in MEC1 made to express mutant forms of BCL2 , which are associated with venetoclax resistance. Treatment of primary CLL cells with Wnt5a also increased their resistance to venetoclax, an effect that could be inhibited by the anti-ROR1 mAb (UC-961, zilovertamab). Collectively, these studies indicate that Wnt5a-induced ROR1-signaling can enhance resistance to venetoclax therapy.
Asthma endotypes in elite athletes: A cross‐sectional study of European athletes participating in the Olympic Games
Authors: Søren Malte Rasmussen, Erik Søren Halvard Hansen, Trine Stensrud, Katja Radon, Bernd Wolfarth, Marcin Kurowski, Jean Bousquet, Sergio Bonini, Matteo Bonini, Luis Delgado, André Moreira, Franchek Drobnic, Nikolaos G. Papadopoulos, Sofia Vakali, Christina Gratziou, Leo Pekka Malmberg, Tari Haahtela, Vibeke Backer
Journal: Allergy (2022)

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Authors: Hui Shi, Jason S. Knight, Yogendra Kanthi
Journal: Arthritis & Rheumatology (2022)

We appreciate Dr. Palmer-Toy et al's interest in our article. We agree that vWF is an important mediator of thromboinflammation. After activation of endothelial cells and platelets, vWF is released from Weibel-Palade bodies and platelet alpha granules, respectively, leading to a cascade of heterotypic cellular interactions that support a procoagulant and proinflammatory milieu (1). Correlations between increases in the circulating pool of vWF and severity of COVID-19 or death resulting from complications of COVID-19 have been reported by many investigators (2-7), including Palmer-Toy and colleagues. Because polyclonal COVID-19 antibody fractions have been shown to activate neutrophils and platelets, as well as to suppress physiologic antiviral responses, we focused on autoantibodies in our study's exploration of endothelial dysfunction in COVID-19. Of note, we reported that purified IgG fractions from patient COVID-19 serum samples, especially from patients with elevated circulating antiphospholipid antibodies, recapitulated activation of endothelial cells by intact COVID-19 serum, suggesting that the circulating antibody milieu in COVID-19 bears a foudroyant capacity to transform the endothelial surface and facilitate leukocyte adhesion. The specific targets of these antibodies and whether they ligate receptors or recognize antigens at the endothelial surface remain unknown and are worthy of investigation. Additional mechanisms of endothelial activation in COVID-19 include denudation of the protective glycocalyx, mobilization of Weibel-Palade bodies, and sex-specific steroid effects. In our opinion, defining these upstream stimuli that trigger the shift away from a quiescent state likely supersedes understanding the kinetics by which the endothelium acquires a thromboinflammatory phenotype. Although we did not examine platelet–endothelial interactions in our study, these have been described in COVID-19 and have been shown to be, at least in part, attributable to the actions of vWF (8). Polyclonal COVID-19 IgG pools enriched in antiphospholipid antibodies may facilitate platelet–endothelial interactions through vWF string formation, as previously reported in antiphospholipid syndrome (9, 10). We certainly support the intent of Palmer-Toy and colleagues to promote the exploration of endothelial and hematopoietic cell interactions in pursuit of understanding the mechanisms that differentiate normal physiologic responses from their maladaptive counterparts that result in tissue injury.
Immunoglobulin superfamily member 8 maintains myeloid leukemia stem cells through inhibition of β-catenin degradation
Authors: Koji Jimbo, Yaeko Nakajima-Takagi, Takahiro Ito, Shuhei Koide, Yasuhito Nannya, Atsushi Iwama, Arinobu Tojo, Takaaki Konuma
Journal: Leukemia (2022)
Correction: Alternative Splicing of EZH2 pre-mRNA by SF3B3 Contributes to the Tumorigenic Potential of Renal Cancer
Authors: Ke Chen, Haibing Xiao, Jin Zeng, Gan Yu, Hui Zhou, Chunhua Huang, Weimin Yao, Wei Xiao, Junhui Hu, Wei Guan, Lily Wu, Jiaoti Huang, Qihong Huang, Hua Xu, Zhangqun Ye
Journal: Clinical Cancer Research (2022)

In the original version of this article (1), errors exist in three figures and two figure legends: the legend for Fig. 2H incorrectly stated that the ACHN cells were “stably transfected” instead of “stably expressing Flag-EZH2, Flag-EZH2D14, or control vector”; Fig. 5C uses the same “merge” picture for EdU+DAPI ACHN-sh-SF3B3-1# and ACHN-sh-SF3B3-2#; Fig. 5E has incorrect “786O invasion” backup images of both the “sh-LacZ” group and the “sh-SF3B3-1#” group; the legend for Fig. 5F did not clarify that both Fig. 2H and Fig. 5F used the same controls; and Supplementary Fig. S9B has incorrect “786O migration/invasion” backup images of both the “sh-SF3B3-1#” group and the “sh-SF3B3-1# + Flag-EZH2” group. These errors have been corrected in the latest online HTML and PDF versions of the article. The authors regret these errors.