tbuckley/cabot-search huggingface dataset:
Emergence of Extracellular Vesicles as “Liquid Biopsy” for Neurological Disorders: Boom or Bust
Authors: Ashish Kumar, Michael A. Nader, Gagan Deep
Journal: Pharmacological Reviews (2023)

<h3>Abstract</h3> Extracellular vesicles (EVs) have emerged as an attractive liquid biopsy approach in the diagnosis and prognosis of multiple diseases and disorders. The feasibility of enriching specific subpopulations of EVs from biofluids based on their unique surface markers has opened novel opportunities to gain molecular insight from various tissues and organs, including the brain. Over the past decade, EVs in bodily fluids have been extensively studied for biomarkers associated with various neurological disorders, such as Alzheimer9s disease, Parkinson9s disease, schizophrenia, bipolar disorder, major depressive disorders, substance use disorders, human immunodeficiency virus–associated neurocognitive disorder, and cancer/treatment-induced neurodegeneration. These studies have focused on the isolation and cargo characterization of either total EVs or brain cells, such as neuron-, astrocyte-, microglia-, oligodendrocyte-, pericyte-, and endothelial-derived EVs from biofluids to achieve early diagnosis and molecular characterization and to predict the treatment and intervention outcomes. The findings of these studies have demonstrated that EVs could serve as a repetitive and less invasive source of valuable molecular information for these neurological disorders, supplementing existing costly neuroimaging techniques and relatively invasive measures, like lumbar puncture. However, the initial excitement surrounding blood-based biomarkers for brain-related diseases has been tempered by challenges, such as lack of central nervous system specificity in EV markers, lengthy protocols, and the absence of standardized procedures for biological sample collection, EV isolation, and characterization. Nevertheless, with rapid advancements in the EV field, supported by improved isolation methods and sensitive assays for cargo characterization, brain cell–derived EVs continue to offer unparallel opportunities with significant translational implications for various neurological disorders. <h3>Significance Statement</h3> Extracellular vesicles present a less invasive liquid biopsy approach in the diagnosis and prognosis of various neurological disorders. Characterizing these vesicles in biofluids holds the potential to yield valuable molecular information, thereby significantly impacting the development of novel biomarkers for various neurological disorders. This paper has reviewed the methodology employed to isolate extracellular vesicles derived from various brain cells in biofluids, their utility in enhancing the molecular understanding of neurodegeneration, and the potential challenges in this research field.
Dysregulated germinal center reaction with expanded T follicular helper cells in autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy lymph nodes
Authors: Iivo Hetemäki, Joona Sarkkinen, Nelli Heikkilä, Karen Drechsel, Mikko I. Mäyränpää, Anniina Färkkilä, Saila Laakso, Outi Mäkitie, T. Petteri Arstila, Eliisa Kekäläinen
Journal: Journal of Allergy and Clinical Immunology (2023)

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, also called APS-1) is an inborn error of immunity with clear signs of B-cell autoimmunity such as neutralizing anti-IFN antibodies. In APECED, mutations in the AIRE gene impair thymic negative selection of T cells. The resulting T-cell alterations may then cause dysregulation of B-cell responses. However, no analysis of interactions of T and B cells in the germinal centers (GCs) in patients' secondary lymphatic tissues has been reported.
Bik promotes proteasomal degradation to control low-grade inflammation
Authors: Yohannes A. Mebratu, Jane T. Jones, Congjian Liu, Zerihun H. Negasi, Mizanur Rahman, Joselyn Rojas-Quintero, George T. O’Connor, Wei Gao, Josée Dupuis, Michael H. Cho, Augusto A. Litonjua, Scott Randell, Yohannes Tesfaigzi
Journal: Journal of Clinical Investigation (2023)

Although chronic low-grade inflammation does not cause immediate clinical symptoms, over longer term can enhance other insults or of age-dependent damage to organ systems and thereby contribute to age-related disorders, such as respiratory disorders, heart disease, metabolic disorders, autoimmunity, and cancer. However, the molecular mechanisms governing low-level inflammation are largely unknown. We discovered that Bik-deficiency causes low level inflammation even at baseline and the development of spontaneous emphysema in female but not male mice. Similarly, a single nucleotide polymorphism that reduced Bik levels was associated with increased inflammation and enhanced decline in lung function in humans. Transgenic expression of Bik in the airways of Bik-deficient mice inhibited allergen- or LPS-induced lung inflammation and reversed emphysema in female mice. Bik-deficiency increased nuclear but not cytosolic p65 levels, because Bik by modifying the BH4 domain of Bcl-2 interacted with Rpn1 and Rpn2 and enhanced proteasomal degradation of nuclear proteins. Bik-deficiency increased inflammation primarily in females because Bcl-2 and Bik levels were reduced in lung tissues and airway cells of female compared with male mice. Therefore, controlling low-grade inflammation by modifying the unappreciated role of Bik and Bcl-2 in facilitating proteasomal degradation of nuclear proteins may be crucial in treating chronic age-related diseases.
KCTD1/KCTD15 complexes control ectodermal and neural crest cell functions, and their impairment causes aplasia cutis
Authors: Jackelyn R. Raymundo, Hui Zhang, Giovanni Smaldone, Wenjuan Zhu, Kathleen E. Daly, Benjamin J. Glennon, Giovanni Pecoraro, Marco Salvatore, William A. Devine, Cecilia W. Lo, Luigi Vitagliano, Alexander G. Marneros
Journal: Journal of Clinical Investigation (2023)

Aplasia cutis congenita (ACC) is a congenital epidermal defect of the midline scalp and has been proposed to be due to a primary keratinocyte abnormality. Why it forms mainly at this anatomic site has remained a longstanding enigma. KCTD1 mutations cause ACC, ectodermal abnormalities, and kidney fibrosis, whereas KCTD15 mutations cause ACC and cardiac outflow tract abnormalities. Here, we find that KCTD1 and KCTD15 can form multimeric complexes and can compensate for each other's loss, and that disease mutations are dominant-negative, resulting in lack of KCTD1/KCTD15 function. We demonstrate that KCTD15 is critical for cardiac outflow tract development, whereas KCTD1 regulates distal nephron function. Combined inactivation of KCTD1/KCTD15 in keratinocytes results in abnormal skin appendages, but not in ACC. Instead, KCTD1/KCTD15 inactivation in neural crest cells results in ACC linked to midline skull defects, demonstrating that ACC is not caused by a primary defect in keratinocytes but is a secondary consequence of impaired cranial neural crest cells giving rise to midline cranial suture cells that express keratinocyte-promoting growth factors. Our findings explain the clinical observations in patients with KCTD1 versus KCTD15 mutations, establish KCTD1/KCTD15 as critical regulators of ectodermal and neural crest cell functions, and define ACC as a neurocristopathy.
New insights in the complex relationship between psoriasis and vitamin D…and, not to forget, obesity!
Authors: Charlotte Näslund-Koch, Lone Skov
Journal: British Journal of Dermatology (2023)

Journal Article Accepted manuscript New insights in the complex relationship between psoriasis and vitamin D – and not to forget -obesity! Get access Charlotte Näslund-Koch, Charlotte Näslund-Koch Department of Dermatology and Allergy, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, DenmarkDepartment of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Correspondence: Charlotte Näslund-Koch, Email: charlotte.sigrid.erika.naeslund.koch@regionh.dk Search for other works by this author on: Oxford Academic Google Scholar Lone Skov Lone Skov Department of Dermatology and Allergy, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, DenmarkDepartment of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark https://orcid.org/0000-0002-4784-9680 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljad506, https://doi.org/10.1093/bjd/ljad506 Published: 19 December 2023 Article history Received: 08 December 2023 Revision received: 09 December 2023 Accepted: 18 December 2023 Published: 19 December 2023
GIInger predicts homologous recombination deficiency and patient response to PARPi treatment from shallow genomic profiles
Authors: Christian Pozzorini, Gregoire Andre, Tommaso Coletta, Adrien Buisson, Jonathan Bieler, Loïc Ferrer, Rieke Kempfer, Pierre Saintigny, Alexandre Harlé, Davide Vacirca, Massimo Barberis, Pauline Gilson, Cristin Roma, Alexandra Saitta, Ewan Smith, Floriane Consales Barras, Lucia Ripol, Martin Fritzsche, Ana Claudia Marques, Amjad Alkodsi, Ray Marin, Nicola Normanno, Christoph Grimm, Leonhard Müllauer, Philipp Harter, Sandro Pignata, Antonio Gonzalez-Martin, Ursula Denison, Keiichi Fujiwara, Ignace Vergote, Nicoletta Colombo, Adrian Willig, Eric Pujade-Lauraine, Pierre-Alexandre Just, Isabelle Ray-Coquard, Zhenyu Xu
Journal: Cell Reports Medicine (2023)

Homologous recombination deficiency (HRD) is a predictive biomarker for poly(ADP-ribose) polymerase 1 inhibitor (PARPi) sensitivity. Routine HRD testing relies on identifying BRCA mutations, but additional HRD-positive patients can be identified by measuring genomic instability (GI), a consequence of HRD. However, the cost and complexity of available solutions hamper GI testing. We introduce a deep learning framework, GIInger, that identifies GI from HRD-induced scarring observed in low-pass whole-genome sequencing data. GIInger seamlessly integrates into standard BRCA testing workflows and yields reproducible results concordant with a reference method in a multisite study of 327 ovarian cancer samples. Applied to a BRCA wild-type enriched subgroup of 195 PAOLA-1 clinical trial patients, GIInger identified HRD-positive patients who experienced significantly extended progression-free survival when treated with PARPi. GIInger is, therefore, a cost-effective and easy-to-implement method for accurately stratifying patients with ovarian cancer for first-line PARPi treatment.
Fusion-negative rhabdomyosarcoma 3D organoids to predict effective drug combinations: A proof-of-concept on cell death inducers
Authors: Clara Savary, Léa Luciana, Paul Huchedé, Arthur Tourbez, Claire Coquet, Maëlle Broustal, Alejandro Lopez Gonzalez, Clémence Deligne, Thomas Diot, Olivier Naret, Mariana Costa, Nina Meynard, Virginie Barbet, Kevin Müller, Laurie Tonon, Nicolas Gadot, Cyril Degletagne, Valéry Attignon, Sophie Léon, Christophe Vanbelle, Alexandra Bomane, Isabelle Rochet, Virginie Mournetas, Luciana Oliveira, Paul Rinaudo, Christophe Bergeron, Aurélie Dutour, Martine Cordier-Bussat, Aline Roch, Nathalie Brandenberg, Sophie El Zein, Sarah Watson, Daniel Orbach, Olivier Delattre, Frédérique Dijoud, Nadège Corradini, Cécile Picard, Delphine Maucort-Boulch, Marion Le Grand, Eddy Pasquier, Jean-Yves Blay, Marie Castets, Laura Broutier
Journal: Cell Reports Medicine (2023)

Rhabdomyosarcoma (RMS) is the main form of pediatric soft-tissue sarcoma. Its cure rate has not notably improved in the last 20 years following relapse, and the lack of reliable preclinical models has hampered the design of new therapies. This is particularly true for highly heterogeneous fusion-negative RMS (FNRMS). Although methods have been proposed to establish FNRMS organoids, their efficiency remains limited to date, both in terms of derivation rate and ability to accurately mimic the original tumor. Here, we present the development of a next-generation 3D organoid model derived from relapsed adult and pediatric FNRMS. This model preserves the molecular features of the patients' tumors and is expandable for several months in 3D, reinforcing its interest to drug combination screening with longitudinal efficacy monitoring. As a proof-of-concept, we demonstrate its preclinical relevance by reevaluating the therapeutic opportunities of targeting apoptosis in FNRMS from a streamlined approach based on transcriptomic data exploitation.
Unified framework for patient-derived, tumor-organoid-based predictive testing of standard-of-care therapies in metastatic colorectal cancer
Authors: Tao Tan, Dmitri Mouradov, Margaret Lee, Grace Gard, Yumiko Hirokawa, Shan Li, Cong Lin, Fuqiang Li, Huijuan Luo, Kui Wu, Michelle Palmieri, Evelyn Leong, Jordan Clarke, Anuratha Sakthianandeswaren, Helen Brasier, Jeanne Tie, Niall C. Tebbutt, Azim Jalali, Rachel Wong, Antony W. Burgess, Peter Gibbs, Oliver M. Sieber
Journal: Cell Reports Medicine (2023)

Predictive drug testing of patient-derived tumor organoids (PDTOs) holds promise for personalizing treatment of metastatic colorectal cancer (mCRC), but prospective data are limited to chemotherapy regimens with conflicting results. We describe a unified framework for PDTO-based predictive testing across standard-of-care chemotherapy and biologic and targeted therapy options. In an Australian community cohort, PDTO predictions based on treatment-naive patients (n = 56) and response rates from first-line mCRC clinical trials achieve 83% accuracy for forecasting responses in patients receiving palliative treatments (18 patients, 29 treatments). Similar assay accuracy is achieved in a prospective study of third-line or later mCRC treatment, AGITG FORECAST-1 (n = 30 patients). "Resistant" predictions are associated with inferior progression-free survival; misclassification rates are similar by regimen. Liver metastases are the optimal site for sampling, with testing achievable within 7 weeks for 68.8% cases. Our findings indicate that PDTO drug panel testing can provide predictive information for multifarious standard-of-care therapies for mCRC.
Spatiotemporal Quantification of HER2-targeting Antibody–Drug Conjugate Bystander Activity and Enhancement of Solid Tumor Penetration
Authors: Qing Wei, Teng Yang, Jiayu Zhu, Ziwen Zhang, Le Yang, Yuchao Zhang, Can Hu, Jiahui Chen, Jinchao Wang, Xuefei Tian, Takaya Shimura, Jianmin Fang, Jieer Ying, Mengyang Fan, Peng Guo, Xiangdong Cheng
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Antibody–drug conjugate (ADC) has had a transformative effect on the treatment of many solid tumors, yet it remains unclear how ADCs exert bystander activity in the tumor microenvironment. Experimental Design: Here, we directly visualized and spatiotemporally quantified the intratumor biodistribution and pharmacokinetics of different ADC components by developing dual-labeled fluorescent probes. Results: Mechanistically, we found that tumor penetration of ADCs is distinctly affected by their ability to breach the binding site barrier (BSB) in perivascular regions of tumor vasculature, and bystander activity of ADC can only partially breach BSB. Furthermore, bystander activity of ADCs can work in synergy with coadministration of their parental antibodies, leading to fully bypassing BSBs and enhancing tumor penetration via a two-step process. Conclusions: These promising preclinical data allowed us to initiate a phase I/II clinical study of coadministration of RC48 and trastuzumab in patients with malignant stomach cancer to further evaluate this treatment strategy in humans.
Burden of noncommunicable diseases among children and adolescents aged 10–24 years in China, 1990–2019: A population-based study
Authors: Jing Zhang, Chenyan Shi, Zhen Liang, Chenye Jin, Lei Wang, Ying Zhong, Yongze Li
Journal: Cell Reports Medicine (2023)

China has hundreds of millions of children and adolescents aged 10-24 years, accounting for one-sixth of their total counterparts worldwide. We perform this study to clarify the priority of noncommunicable disease (NCD) control among youth in China via the Global Burden of Diseases Study 2019. The highest disability-adjusted life years (DALYs) from NCDs among youth in China remain in mental disorders, while the most increasing incidence is from diabetes and kidney diseases during 1990-2019. Bullying victimization and high BMI are the top risk factors for DALYs from mental disorders and diabetes mellitus, respectively. The most substantial gender differences are found for alcohol use disorders among the 20-24 age subgroup, which is also the top risk factor for neoplasm DALYs. Targeted interventions for NCDs among youth in China should focus on high body mass, alcohol usage, and bullying victimization, providing crucial information for resource-limited settings across the world.
A personalized network framework reveals predictive axis of anti-TNF response across diseases
Authors: Shiran Gerassy-Vainberg, Elina Starosvetsky, Renaud Gaujoux, Alexandra Blatt, Naama Maimon, Yuri Gorelik, Sigal Pressman, Ayelet Alpert, Haggai Bar-Yoseph, Tania Dubovik, Benny Perets, Adir Katz, Neta Milman, Meital Segev, Yehuda Chowers, Shai S. Shen-Orr
Journal: Cell Reports Medicine (2023)

Personalized treatment of complex diseases has been mostly predicated on biomarker identification of one drug-disease combination at a time. Here, we use a computational approach termed Disruption Networks to generate a data type, contextualized by cell-centered individual-level networks, that captures biology otherwise overlooked when performing standard statistics. This data type extends beyond the "feature level space", to the "relations space", by quantifying individual-level breaking or rewiring of cross-feature relations. Applying Disruption Networks to dissect high-dimensional blood data, we discover and validate that the RAC1-PAK1 axis is predictive of anti-TNF response in inflammatory bowel disease. Intermediate monocytes, which correlate with the inflammatory state, play a key role in the RAC1-PAK1 responses, supporting their modulation as a therapeutic target. This axis also predicts response in rheumatoid arthritis, validated in three public cohorts. Our findings support blood-based drug response diagnostics across immune-mediated diseases, implicating common mechanisms of non-response.
Urinary Albumin-to-Creatinine Ratio in Normal Range, Cardiovascular Health, and All-Cause Mortality
Authors: Nayili Mahemuti, Jiao Zou, Chuanlang Liu, Zhiyi Xiao, Fengchao Liang, Xueli Yang
Journal: JAMA Network Open (2023)

Importance Although cumulative evidence suggests that elevated urinary albumin-to-creatinine ratio (UACR) in the normal range (&amp;amp;lt;30 mg/g) may be associated with an increased risk of mortality, few studies have investigated whether cardiovascular health (CVH) modifies the harmful outcomes of high-normal UACR. Objective To investigate associations of traditionally normal UACR and CVH with all-cause mortality. Design, Setting, and Participants This cohort study used National Health and Nutrition Examination Survey data from 2005 through 2018 and linked mortality information until 2019. Data were analyzed from March 1 through October 31, 2023. The study included adult participants aged 20 to 79 years with a normal UACR (&amp;amp;lt;30 mg/g) based on Kidney Disease: Improving Global Outcomes criteria. Exposures The UACR was treated as a continuous variable and categorized into tertiles delineated as low (&amp;amp;lt;4.67 mg/g), medium (4.67-7.67 mg/g), and high (7.68 to &amp;amp;lt;30 mg/g). Cardiovascular health was assessed using Life’s Essential 8 scores and grouped as poor (0-49 points), moderate (50-79 points), and ideal (80-100 points). Main Outcomes and Measures Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of UACR with all-cause mortality in total participants and as stratified by CVH groups. Results The study included 23 697 participants (mean [SD] age, 45.58 [15.44] years; 11 806 women [49.7%] and 11 891 men [50.3%]). During the median 7.8 years (range, 4.5-11.1 years) of follow-up, 1403 deaths were recorded. Near-linear associations were observed for continuous UACR and CVH with all-cause mortality. Compared with the low UACR group, high UACR in the normal range showed an increased mortality risk in the moderate and poor CVH groups (CVH [50-79]: HR, 1.54 [95% CI, 1.26-1.89]; CVH [0-49]: HR, 1.56 [95% CI, 1.10-2.20]), with a significant multiplicative interaction of UACR and CVH ( P &amp;amp;lt; .001). Conclusions and Relevance The findings suggest that high UACR within the normal range is associated with a significantly increased risk of all-cause mortality, with the association more pronounced in adults with poor CVH status. These findings highlight the importance of risk management for early kidney dysfunction, particularly among individuals with poor CVH.
The anabolic response to protein ingestion during recovery from exercise has no upper limit in magnitude and duration in vivo in humans
Authors: Jorn Trommelen, Glenn A.A. van Lieshout, Jean Nyakayiru, Andrew M. Holwerda, Joey S.J. Smeets, Floris K. Hendriks, Janneau M.X. van Kranenburg, Antoine H. Zorenc, Joan M. Senden, Joy P.B. Goessens, Annemie P. Gijsen, Luc J.C. van Loon
Journal: Cell Reports Medicine (2023)
Challenges to Door-In-Door-Out Time Thresholds for Patients With Stroke—Reply
Authors: Brian Stamm, Regina Royan, Shyam Prabhakaran
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Use of Donanemab in Early Symptomatic Alzheimer Disease—Reply
Authors: Cynthia D. Evans, John R. Sims
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal