tbuckley/cabot-search huggingface dataset:
Interleukin-23 receptor expressing γδ T cells locally promote early atherosclerotic lesion formation and plaque necrosis in mice
Authors: Jesus Gil-Pulido, Núria Amézaga, Ivana Jorgacevic, Helga D Manthey, Melanie Rösch, Theresa Brand, Peter Cidlinsky, Sarah Schäfer, Andreas Beilhack, Antoine-Emmanuel Saliba, Kristina Lorenz, Louis Boon, Immo Prinz, Ari Waisman, Thomas Korn, Clément Cochain, Alma Zernecke
Journal: Cardiovascular Research (2021)

Atherosclerosis is a chronic inflammatory disease of the vessel wall controlled by local and systemic immune responses. The role of interleukin-23 receptor (IL-23R), expressed in adaptive immune cells (mainly T-helper 17 cells) and γδ T cells, in atherosclerosis is only incompletely understood. Here, we investigated the vascular cell types expressing IL-23R and addressed the function of IL-23R and γδ T cells in atherosclerosis.IL-23R+ cells were frequently found in the aortic root in contrast to the aorta in low-density lipoprotein receptor deficient IL-23R reporter mice (Ldlr-/-Il23rgfp/+), and mostly identified as γδ T cells that express IL-17 and GM-CSF. scRNA-seq confirmed γδ T cells as the main cell type expressing Il23r and Il17a in the aorta. Ldlr-/-Il23rgfp/gfp mice deficient in IL-23R showed a loss of IL-23R+ cells in the vasculature, and had reduced atherosclerotic lesion formation in the aortic root compared to Ldlr-/- controls after 6 weeks of high-fat diet feeding. In contrast, Ldlr-/-Tcrδ-/- mice lacking all γδ T cells displayed unaltered early atherosclerotic lesion formation compared to Ldlr-/- mice. In both HFD-fed Ldlr-/-Il23rgfp/gfp and Ldlr-/-Tcrδ-/- mice a reduction in the plaque necrotic core area was noted as well as an expansion of splenic regulatory T cells. In vitro, exposure of bone marrow-derived macrophages to both IL-17A and GM-CSF induced cell necrosis, and necroptotic RIP3K and MLKL expression, as well as inflammatory mediators.IL-23R+ γδ T cells are predominantly found in the aortic root rather than the aorta and promote early atherosclerotic lesion formation, plaque necrosis, and inflammation at this site. Targeting IL-23R may thus be explored as a therapeutic approach to mitigate atherosclerotic lesion development.
Autophagy promotes hepatic cystogenesis in polycystic liver disease by depletion of cholangiocyte ciliogenic proteins
Authors: Anatoliy I. Masyuk, Tatyana V. Masyuk, Christy E. Trussoni, Nicholas E. Pirius, Nicholas F. LaRusso
Journal: Hepatology (2021)

Abstract Backgrounds and Aims Polycystic liver disease (PLD) is characterized by defective cholangiocyte cilia that regulate progressive growth of hepatic cysts. Because formation of primary cilia is influenced by autophagy through degradation of proteins involved in ciliogenesis, we hypothesized that ciliary defects in PLD cholangiocytes (PLDCs) originate from autophagy‐mediated depletion of ciliogenic proteins ADP‐ribosylation factor‐like protein 3 (ARL3) and ADP‐ribosylation factor‐like protein 13B (ARL13B) and ARL‐dependent mislocation of a ciliary‐localized bile acid receptor, Takeda G‐protein‐coupled receptor 5 (TGR5), the activation of which enhances hepatic cystogenesis (HCG). The aims here were to determine whether: (1) ciliogenesis is impaired in PLDC, is associated with increased autophagy, and involves autophagy‐mediated depletion of ARL3 and ARL13B; (2) depletion of ARL3 and ARL13B in PLDC cilia impacts ciliary localization of TGR5; and (3) pharmacological inhibition of autophagy re‐establishes cholangiocyte cilia and ciliary localization of ARL3, ARL3B, and TGR5 and reduces HCG. Approach and Results By using liver tissue from healthy persons and patients with PLD, in vitro and in vivo models of PLD, and in vitro models of ciliogenesis, we demonstrated that, in PLDCs: ciliogenesis is impaired; autophagy is enhanced; ARL3 and ARL13B are ubiquitinated by HDAC6, depleted in cilia, and present in autophagosomes; depletion of ARL3 and ARL13B impacts ciliary localization of TGR5; and pharmacological inhibition of autophagy with mefloquine and verteporfin re‐establishes cholangiocyte cilia and ciliary localization of ARL3, ARL13B, and TGR5 and reduces HCG. Conclusions The intersection between autophagy, defective cholangiocyte cilia, and enhanced HCG contributes to PLD progression and can be considered a target for therapeutic interventions.
Nasally inhaled therapeutics and vaccination for COVID‐19: Developments and challenges
Authors: Jinxiang Xi, Lameng Ray Lei, William Zouzas, Xiuhua April Si
Journal: MedComm (2021)

Abstract The nose is the initial site of viral infection, replication, and transmission in the human body. Nasally inhaled vaccines may act as a promising alternative for COVID‐19 management in addition to intramuscular vaccination. In this review, the latest developments of nasal sprays either as repurposed or antiviral formulations were presented. Nasal vaccines based on traditional medicines, such as grapefruit seed extract, algae‐isolated carrageenan, and Yogurt‐fermenting Lactobacillus , are promising and under active investigations. Inherent challenges that hinder effective intranasal delivery were discussed in detail, which included nasal device issues and human nose physiological complexities. We examined factors related to nasal spray administration, including the nasal angiotensin I converting enzyme 2 (ACE2) locations as the delivery target, nasal devices, medication translocation after application, delivery methods, safety issues, and other nasal delivery options. The effects of human factors on nasal spray efficacy, such as nasal physiology, disease‐induced physiological modifications, intersubject variability, and mucociliary clearance, were also examined. Finally, the potential impact of nasal vaccines on COVID‐19 management in the developing world was discussed. It is concluded that effective delivery of nasal sprays to ACE2‐rich regions is urgently needed, especially in the context that new variants may become unresponsive to current vaccines and more refractory to existing therapies.
GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity
Authors: Sabine Heitzeneder, Kristopher R. Bosse, Zhongyu Zhu, Doncho Zhelev, Robbie G. Majzner, Molly T. Radosevich, Shaurya Dhingra, Elena Sotillo, Samantha Buongervino, Guillem Pascual-Pasto, Emily Garrigan, Peng Xu, Jing Huang, Benjamin Salzer, Alberto Delaidelli, Swetha Raman, Hong Cui, Benjamin Martinez, Scott J. Bornheimer, Bita Sahaf, Anya Alag, Irfete S. Fetahu, Martin Hasselblatt, Kevin R. Parker, Hima Anbunathan, Jennifer Hwang, Min Huang, Kathleen Sakamoto, Norman J. Lacayo, Dorota D. Klysz, Johanna Theruvath, José G. Vilches-Moure, Ansuman T. Satpathy, Howard Y. Chang, Manfred Lehner, Sabine Taschner-Mandl, Jean-Phillipe Julien, Poul H. Sorensen, Dimiter S. Dimitrov, John M. Maris, Crystal L. Mackall
Journal: Cancer Cell (2021)

Pediatric cancers often mimic fetal tissues and express proteins normally silenced postnatally that could serve as immune targets. We developed T cells expressing chimeric antigen receptors (CARs) targeting glypican-2 (GPC2), a fetal antigen expressed on neuroblastoma (NB) and several other solid tumors. CARs engineered using standard designs control NBs with transgenic GPC2 overexpression, but not those expressing clinically relevant GPC2 site density (∼5,000 molecules/cell, range 1-6 × 10
Integrated Molecular Characterization of Patient-Derived Models Reveals Therapeutic Strategies for Treating CIC-DUX4 Sarcoma
Authors: Marianna Carrabotta, Maria Antonella Laginestra, Giorgio Durante, Caterina Mancarella, Lorena Landuzzi, Alessandro Parra, Francesca Ruzzi, Lisa Toracchio, Alessandra De Feo, Veronica Giusti, Michela Pasello, Alberto Righi, Pier-Luigi Lollini, Emanuela Palmerini, Davide Maria Donati, Maria Cristina Manara, Katia Scotlandi
Journal: Cancer Research (2021)

Abstract Capicua-double homeobox 4 (CIC-DUX4)–rearranged sarcomas (CDS) are extremely rare, highly aggressive primary sarcomas that represent a major therapeutic challenge. Patients are treated according to Ewing sarcoma protocols, but CDS-specific therapies are strongly needed. In this study, RNA sequencing was performed on patient samples to identify a selective signature that differentiates CDS from Ewing sarcoma and other fusion-driven sarcomas. This signature was used to validate the representativeness of newly generated CDS experimental models—patient-derived xenografts (PDX) and PDX-derived cell lines—and to identify specific therapeutic vulnerabilities. Annotation analysis of differentially expressed genes and molecular gene validation highlighted an HMGA2/IGF2BP/IGF2/IGF1R/AKT/mTOR axis that characterizes CDS and renders the tumors particularly sensitive to combined treatments with trabectedin and PI3K/mTOR inhibitors. Trabectedin inhibited IGF2BP/IGF2/IGF1R activity, but dual inhibition of the PI3K and mTOR pathways was required to completely dampen downstream signaling mediators. Proof-of-principle efficacy for the combination of the dual AKT/mTOR inhibitor NVP-BEZ235 (dactolisib) with trabectedin was obtained in vitro and in vivo using CDS PDX-derived cell lines, demonstrating a strong inhibition of local tumor growth and multiorgan metastasis. Overall, the development of representative experimental models (PDXs and PDX-derived cell lines) has helped to identify the unique sensitivity of the CDS to AKT/mTOR inhibitors and trabectedin, revealing a mechanism-based therapeutic strategy to fight this lethal cancer. Significance: This study identifies altered HMGA2/IGF2BP/IGF2 signaling in CIC-DUX4 sarcomas and provides proof of principle for combination therapy with trabectedin and AKT/mTOR dual inhibitors to specifically combat the disease.
Surface phenotypes of naive and memory B cells in mouse and human tissues
Authors: Nadine M. Weisel, Stephen M. Joachim, Shuchi Smita, Derrick Callahan, Rebecca A. Elsner, Laura J. Conter, Maria Chikina, Donna L. Farber, Florian J. Weisel, Mark J. Shlomchik
Journal: Nature Immunology (2021)
Sincalide-Stimulated Cholescintigraphy
Authors: Anil Vasireddi, Nghi C. Nguyen
Journal: Clinical Nuclear Medicine (2021)

Current guidelines for sincalide-stimulated cholescintigraphy (SSC) call for a 60-minute sincalide infusion, and a gallbladder ejection fraction (GBEF) ≥38% is considered normal. In this retrospective study, we hypothesize that most patients reach a normal GBEF by 30 minutes.Eligible patients had undergone a 60-minute SSC from January to December 2019. The clinical SSC data were previously processed on a Xeleris workstation (GE Healthcare). In subjects with GBEF ≥38% based on standard SSC, the GBEF at 20 minutes and 30 minutes were retrospectively calculated using manual pixel height measurements. Receiving operating characteristic was analyzed to determine the best GBEF cutoff at 30 minutes.Of 302 subjects, mean age of 46 ± 17 years, 33 (10.9%) showed an abnormal GBEF <38% suggestive of functional gallbladder disorder. In the remaining 269 patients (89.1%) with a normal GBEF, 60.6% and 86.6% reached a normal GBEF at 20 minutes and 30 minutes, respectively. Moreover, a GBEF threshold >29.1% at 30 minutes was associated with a negative predictive value of 99.6%, indicating that a 60-minute SSC was not necessary. The GBEF values were not associated with sex, age, patient symptoms, or type of referral. Manually calculated GBEFs on the time-activity curve showed excellent correlation with the primary values. We propose a modified workflow that splits the 60-minute SSC into two 30-minute image sets to allow for a screening GBEF at 30 minutes. If GBEF is >29.1% at 30 minutes, the second image set may be stopped, and the examination is complete.The majority of patients (77.2%) undergoing the standard 60-minute SSC reach a normal GBEF already by 30 minutes. The proposed workflow shortens the SCC procedure by 30 minutes, while maintaining high diagnostic accuracy and contributing to improved procedure efficiency and reduced patient discomfort as well as symptoms.
Ignorance matters
Authors: Amanda Royka, Julian Jara-Ettinger
Journal: Behavioral and Brain Sciences (2021)

Abstract The ability to reason about ignorance is an important and often overlooked representational capacity. Phillips and colleagues assume that knowledge representations are inevitably accompanied by ignorance representations. We argue that this is not necessarily the case, as agents who can reason about knowledge often fail on ignorance tasks, suggesting that ignorance should be studied as a separate representational capacity.
Preparing for Omicron as a covid veteran
Authors: Eric Kutscher
Journal: BMJ (2021)

internal medicine physicianIt feels like the world is slowly closing in on me as I hear the ambulances pass my window at home.I remember the last time I felt this way-March 2020.News, social media, and texts from friends and work are all focused on the same thing: potential impending doom from covid-19.Except it's no longer the first, or second, or third wave.At this point, I've lost count.Omicron is coming, and I don't know if I'm ready.
JAMA Dermatology
Journal: JAMA Dermatology (2021)

Mission Statement JAMA Dermatology publishes information concerning the skin, its diseases, and their treatment.Its mission is to explicate the structure and function of the skin and its diseases and the art of using this information to deliver optimal medical and surgical care to the patient.We attempt to enhance the understanding of cutaneous pathophysiology and improve the clinician's ability to diagnose and treat skin disorders.This journal has a particular interest in publishing clinical and laboratory studies that reveal new information pertinent to the interests and needs of the medical dermatologist, dermatologic surgeon, and all those concerned with state-of-the-art care of cutaneous disease.We believe that knowledge derived from well-designed clinical trials and studies of cost-eff ectiveness are especially important for improving the practice of dermatology.Studies that increase the understanding of the outcome of treatment or the means by which the burden of dermatologic disease can be measured and reduced to promote the health of patients with skin disease will receive special priority.The journal regularly publishes reports on clinical investigations, editorials, and reviews.It also features reports and discussions on clinicopathologic correlations; clinical disorders of unique didactic value; pharmacologic, medical and surgical therapeutics; and ethical, moral, socioeconomic, and political issues.
Risk factors for PICU admission and death among children and young people hospitalized with COVID-19 and PIMS-TS in England during the first pandemic year
Authors: Joseph L. Ward, Rachel Harwood, Clare Smith, Simon Kenny, Matthew Clark, Peter J. Davis, Elizabeth S. Draper, Dougal Hargreaves, Shamez Ladhani, Michael Linney, Karen Luyt, Steve Turner, Elizabeth Whittaker, Lorna K. Fraser, Russell M. Viner
Journal: Nature Medicine (2021)
Hepatic fibrosis 2022: Unmet needs and a blueprint for the future
Authors: Scott L. Friedman, Massimo Pinzani
Journal: Hepatology (2021)

Abstract Steady progress over four decades toward understanding the pathogenesis and clinical consequences of hepatic fibrosis has led to the expectation of effective antifibrotic drugs, yet none has been approved. Thus, an assessment of the field is timely, to clarify priorities and accelerate progress. Here, we highlight the successes to date but, more importantly, identify gaps and unmet needs, both experimentally and clinically. These include the need to better define cell–cell interactions and etiology‐specific elements of fibrogenesis and their link to disease‐specific drivers of portal hypertension. Success in treating viral hepatitis has revealed the remarkable capacity of the liver to degrade scar in reversing fibrosis, yet we know little of the mechanisms underlying this response. Thus, there is an exigent need to clarify the cellular and molecular mechanisms of fibrosis regression in order for therapeutics to mimic the liver’s endogenous capacity. Better refined and more predictive in vitro and animal models will hasten drug development. From a clinical perspective, current diagnostics are improving but not always biologically plausible or sufficiently accurate to supplant biopsy. More urgently, digital pathology methods that leverage machine learning and artificial intelligence must be validated in order to capture more prognostic information from liver biopsies and better quantify the response to therapies. For more refined treatment of NASH, orthogonal approaches that integrate genetic, clinical, and pathological data sets may yield treatments for specific subphenotypes of the disease. Collectively, these and other advances will strengthen and streamline clinical trials and better link histologic responses to clinical outcomes.
Protein kinase N2 mediates flow-induced endothelial NOS activation and vascular tone regulation
Authors: Young-June Jin, Ramesh Chennupati, Rui Li, Guozheng Liang, ShengPeng Wang, András Iring, Johannes Graumann, Nina Wettschureck, Stefan Offermanns
Journal: Journal of Clinical Investigation (2021)

Formation of NO by endothelial NOS (eNOS) is a central process in the homeostatic regulation of vascular functions including blood pressure regulation, and fluid shear stress exerted by the flowing blood is a main stimulus of eNOS activity. Previous work has identified several mechanosensing and -transducing processes in endothelial cells, which mediate this process and induce the stimulation of eNOS activity through phosphorylation of the enzyme via various kinases including AKT. How the initial mechanosensing and signaling processes are linked to eNOS phosphorylation is unclear. In human endothelial cells, we demonstrated that protein kinase N2 (PKN2), which is activated by flow through the mechanosensitive cation channel Piezo1 and Gq/G11-mediated signaling, as well as by Ca2+ and phosphoinositide-dependent protein kinase 1 (PDK1), plays a pivotal role in this process. Active PKN2 promoted the phosphorylation of human eNOS at serine 1177 and at a newly identified site, serine 1179. These phosphorylation events additively led to increased eNOS activity. PKN2-mediated eNOS phosphorylation at serine 1177 involved the phosphorylation of AKT synergistically with mTORC2-mediated AKT phosphorylation, whereas active PKN2 directly phosphorylated human eNOS at serine 1179. Mice with induced endothelium-specific deficiency of PKN2 showed strongly reduced flow-induced vasodilation and developed arterial hypertension accompanied by reduced eNOS activation. These results uncover a central mechanism that couples upstream mechanosignaling processes in endothelial cells to the regulation of eNOS-mediated NO formation, vascular tone, and blood pressure.
A Mg2+/polydopamine composite hydrogel for the acceleration of infected wound healing
Authors: Zhaoyuan Guo, Zhuangzhuang Zhang, Nan Zhang, Wenxia Gao, Jing Li, Yuji Pu, Bin He, Jing Xie
Journal: Bioactive Materials (2021)

Bacterial infection is a vital factor to delay the wound healing process. The antibiotics abuse leads to drug resistance of some pathogenic bacteria. Non-antibiotic-dependent multifunctional biomaterials with accelerated wound healing performance are urgently desired. Herein, we reported a composite antibacterial hydrogel PDA-PAM/Mg2+ that shows excellent self-healing and tissue adhesive property, and photothermal antibacterial functions for accelerating wound healing. The gel was composed of polyacrylamide (PAM), polydopamine (PDA), and magnesium (Mg2+) and prepared via a two-step procedure: an alkali-induced dopamine pre-polymerization and followed radical polymerization process. The composite gel shows excellent tissue adhesiveness and Mg2+-synergized photothermal antibacterial activity, inducing a survival rate of 5.29% for S. aureus and 7.06% for E. coli after near infrared light irradiation. The composite hydrogel further demonstrated efficient bacteria inhibition, enhanced wound healing and collagen deposition in a full-thickness skin defect rat model. Together, the PDA-PAM/Mg2+ hydrogel presents an excellent wound dressing with excellent tissue adhesion, wound healing, and antibacterial functions.
Prospective Phase II Open-Label Randomized Controlled Trial to Compare Mandibular Preservation in Upfront Surgery With Neoadjuvant Chemotherapy Followed by Surgery in Operable Oral Cavity Cancer
Authors: Devendra Chaukar, Kumar Prabash, Pawan Rane, Vijay Maruti Patil, Shivakumar Thiagarajan, Sarbani Ghosh-Laskar, Shilpi Sharma, Prathamesh S. Pai, Pankaj Chaturvedi, Gouri Pantvaidya, Anuja Deshmukh, Deepa Nair, Sudhir Nair, Richa Vaish, Vanita Noronha, Asawari Patil, Supreeta Arya, Anil D'Cruz
Journal: Journal of Clinical Oncology (2021)

The objective of this study was to explore the potential role and safety of neoadjuvant chemotherapy (NACT) in tumor shrinkage and resultant mandibular preservation in oral cancers compared with conventional surgical treatment.This study was a single-center, randomized, phase II trial of treatment-naive histologically confirmed squamous cell carcinoma of the oral cavity with cT2-T4 and N0/N+, M0 (American Joint Committee on Cancer, seventh edition) stage, necessitating resection of the mandible for paramandibular disease in the absence of clinicoradiologic evidence of bone erosion. The patients were randomly assigned (1:1) to either upfront surgery (segmental resection) followed by adjuvant treatment (standard arm [SA]) or two cycles of NACT (docetaxel, cisplatin, and fluorouracil) at 3-week intervals (intervention arm [IA]), followed by surgery dictated by postchemotherapy disease extent. All patients in the IA received adjuvant chemoradiotherapy, and patients in the SA were treated as per final histopathology report. The primary end point was mandible preservation rate. The secondary end points were disease-free survival and treatment-related toxicity.Sixty-eight patients were enrolled over 3 years and randomly assigned to either SA (34 patients) or IA (34 patients). The median follow-up was 3.6 years (interquartile range, 0.95-7.05 years). Mandibular preservation was achieved in 16 of 34 patients (47% [95% CI, 31.49 to 63.24]) in the IA. The disease-free survival (P = .715, hazard ratio 0.911 [95% CI, 0.516 to 1.607]) and overall survival (P = .747, hazard ratio 0.899 [95% CI, 0.510 to 1.587]) were similar in both the arms. Complications were similar in both arms, but chemotherapy-induced toxicity was observed in the majority of patients (grade III: 14, 41.2%; grade IV: 11, 32.4%) in the IA.NACT plays a potential role in mandibular preservation in oral cancers with acceptable toxicities and no compromise in survival. However, this needs to be validated in a larger phase III randomized trial.