tbuckley/cabot-search huggingface dataset:
CD39 Produced from Human GMSCs Regulates the Balance of Osteoclasts and Osteoblasts through the Wnt/β-Catenin Pathway in Osteoporosis
Authors: Wenbin Wu, Zexiu Xiao, Ye Chen, Yanan Deng, Donglan Zeng, Yan Liu, Feng Huang, Julie Wang, Yanying Liu, Joseph A. Bellanti, Limin Rong, Song Guo Zheng
Journal: Molecular Therapy (2020)

Osteoporosis is a disease in which the density and quality of bone are reduced, causing bones to become weak and so brittle that a fall or even mild stresses can cause a fracture. Current drug treatment consists mainly of antiresorptive agents that are unable to stimulate new bone formation. Our recent studies have defined a critical role of gingiva-derived mesenchymal stem cells (GMSCs) in attenuating autoimmune arthritis through inhibition of osteoclast formation and activities, but it remains to be ruled out whether the administration of GMSCs to patients with osteoporosis could also regulate osteoblasts and eventually affect bone formation and protection. With the use of an ovariectomized mouse model, we here demonstrated that adoptive transfer of GMSCs regulated the balance of osteoclasts and osteoblasts, eventually contributing to dynamic bone formation. Validation by RNA sequencing (RNA-seq), single-cell sequencing, revealed a unique population of CD39+ GMSC that plays an important role in promoting bone formation. We further demonstrated that CD39 produced from GMSC exerted its osteogenic capacity through the Wnt/β-catenin pathway. Our results not only establish a previously unidentified role and mechanism of GMSC for bone promotion but also a potential therapeutic target for management of patients with osteoporosis and other bone loss conditions. Osteoporosis is a disease in which the density and quality of bone are reduced, causing bones to become weak and so brittle that a fall or even mild stresses can cause a fracture. Current drug treatment consists mainly of antiresorptive agents that are unable to stimulate new bone formation. Our recent studies have defined a critical role of gingiva-derived mesenchymal stem cells (GMSCs) in attenuating autoimmune arthritis through inhibition of osteoclast formation and activities, but it remains to be ruled out whether the administration of GMSCs to patients with osteoporosis could also regulate osteoblasts and eventually affect bone formation and protection. With the use of an ovariectomized mouse model, we here demonstrated that adoptive transfer of GMSCs regulated the balance of osteoclasts and osteoblasts, eventually contributing to dynamic bone formation. Validation by RNA sequencing (RNA-seq), single-cell sequencing, revealed a unique population of CD39+ GMSC that plays an important role in promoting bone formation. We further demonstrated that CD39 produced from GMSC exerted its osteogenic capacity through the Wnt/β-catenin pathway. Our results not only establish a previously unidentified role and mechanism of GMSC for bone promotion but also a potential therapeutic target for management of patients with osteoporosis and other bone loss conditions.
Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome
Authors: Nicholas S. Hendren, Mark H. Drazner, Biykem Bozkurt, Leslie T. Cooper
Journal: Circulation (2020)

Coronavirus disease 2019 (COVID-19) is a rapidly expanding global pandemic caused by severe acute respiratory syndrome coronavirus 2, resulting in significant morbidity and mortality. A substantial minority of patients hospitalized develop an acute COVID-19 cardiovascular syndrome, which can manifest with a variety of clinical presentations but often presents as an acute cardiac injury with cardiomyopathy, ventricular arrhythmias, and hemodynamic instability in the absence of obstructive coronary artery disease. The cause of this injury is uncertain but is suspected to be related to myocarditis, microvascular injury, systemic cytokine-mediated injury, or stress-related cardiomyopathy. Although histologically unproven, severe acute respiratory syndrome coronavirus 2 has the potential to directly replicate within cardiomyocytes and pericytes, leading to viral myocarditis. Systemically elevated cytokines are also known to be cardiotoxic and have the potential to result in profound myocardial injury. Prior experience with severe acute respiratory syndrome coronavirus 1 has helped expedite the evaluation of several promising therapies, including antiviral agents, interleukin-6 inhibitors, and convalescent serum. Management of acute COVID-19 cardiovascular syndrome should involve a multidisciplinary team including intensive care specialists, infectious disease specialists, and cardiologists. Priorities for managing acute COVID-19 cardiovascular syndrome include balancing the goals of minimizing healthcare staff exposure for testing that will not change clinical management with early recognition of the syndrome at a time point at which intervention may be most effective. This article aims to review the best available data on acute COVID-19 cardiovascular syndrome epidemiology, pathogenesis, diagnosis, and treatment. From these data, we propose a surveillance, diagnostic, and management strategy that balances potential patient risks and healthcare staff exposure with improvement in meaningful clinical outcomes.
AAV-CRISPR Gene Editing Is Negated by Pre-existing Immunity to Cas9
Authors: Ang Li, Mark R. Tanner, Ciaran M. Lee, Ayrea E. Hurley, Marco De Giorgi, Kelsey E. Jarrett, Timothy H. Davis, Alexandria M. Doerfler, Gang Bao, Christine Beeton, William R. Lagor
Journal: Molecular Therapy (2020)

Adeno-associated viral (AAV) vectors are a leading candidate for the delivery of CRISPR-Cas9 for therapeutic genome editing in vivo. However, AAV-based delivery involves persistent expression of the Cas9 nuclease, a bacterial protein. Recent studies indicate a high prevalence of neutralizing antibodies and T cells specific to the commonly used Cas9 orthologs from Streptococcus pyogenes (SpCas9) and Staphylococcus aureus (SaCas9) in humans. We tested in a mouse model whether pre-existing immunity to SaCas9 would pose a barrier to liver genome editing with AAV packaging CRISPR-Cas9. Although efficient genome editing occurred in mouse liver with pre-existing SaCas9 immunity, this was accompanied by an increased proportion of CD8
Complement C5 Protein as a Marker of Subclinical Atherosclerosis
Authors: Diego Martínez-López, Raquel Roldan-Montero, Fernando García-Marqués, Estefania Nuñez, Inmaculada Jorge, Emilio Camafeita, Pablo Minguez, Santiago Rodriguez de Cordoba, Beatriz López-Melgar, Enrique Lara-Pezzi, Antonio Fernández-Ortiz, Borja Ibáñez, Jose Manuel Valdivielso, Valentín Fuster, Jean-Baptiste Michel, Luis Miguel Blanco-Colio, Jesús Vázquez, Jose Luis Martin-Ventura
Journal: Journal of the American College of Cardiology (2020)

The mechanisms underlying early atherosclerotic plaque formation are not completely understood. Moreover, plasma biomarkers of subclinical atherosclerosis are lacking. The purpose of this study was to analyze the temporal and topologically resolved protein changes taking place in human aortas with early atherosclerosis to find new potential diagnostic and/or therapeutic targets. The protein composition of healthy aortas (media layer) or with early atheroma (fatty streak and fibrolipidic, media and intima layers) was analyzed by deep quantitative multiplexed proteomics. Further analysis was performed by Western blot, immunohistochemistry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. Plasma levels of complement C5 were analyzed in relation to the presence of generalized (>2 plaques) or incipient (0 to 2 plaques) subclinical atherosclerosis in 2 independent clinical cohorts (PESA [Progression of Early Subclinical Atherosclerosis] [n = 360] and NEFRONA [National Observatory of Atherosclerosis in Nephrology] [n = 394]). Proteins involved in lipid transport, complement system, immunoglobulin superfamily, and hemostasis are increased in early plaques. Components from the complement activation pathway were predominantly increased in the intima of fibrolipidic plaques. Among them, increased C5 protein levels were further confirmed by Western blot, enzyme-linked immunosorbent assay and immunohistochemistry, and associated with in situ complement activation. Plasma C5 was significantly increased in individuals with generalized subclinical atherosclerosis in both PESA and NEFRONA cohorts, independently of risk factors. Moreover, in the PESA study, C5 plasma levels positively correlated with global plaque volume and coronary calcification. Activation of the complement system is a major alteration in early atherosclerotic plaques and is reflected by increased C5 plasma levels, which have promising value as a novel circulating biomarker of subclinical atherosclerosis.
Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19
Authors: Xiaoyan Liu, Zhe Li, Shuai Liu, Jing Sun, Zhanghua Chen, Min Jiang, Qingling Zhang, Yinghua Wei, Xin Wang, Yi-You Huang, Yinyi Shi, Yanhui Xu, Huifang Xian, Fan Bai, Changxing Ou, Bei Xiong, Andrew M. Lew, Jun Cui, Rongli Fang, Hui Huang, Jincun Zhao, Xuechuan Hong, Yuxia Zhang, Fuling Zhou, Hai-Bin Luo
Journal: Acta Pharmaceutica Sinica B (2020)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with COVID-19, we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. FDA approved drug library, we identified an anticoagulation agent dipyridamole (DIP) in silico, which suppressed SARS-CoV-2 replication in vitro. In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers (P < 0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.
Long-term disease-free survival (LTDFS) after biochemotherapy (BioCT) for stage IV melanoma: The experience of the Hospital Sírio-Libanês, Brazil
Authors: W. N. William, R. A. Schmerling, F. A. Belfort, H. E. Fonseca, A. C. Buzaid
Journal: Journal of Clinical Oncology (2006)

18013 Background: A small subset of patients with metastatic melanoma treated with BioCT may experience LTDFS. Methods: We retrospectively reviewed all patients with stage IV melanoma and a follow-up of at least 12 months (mo) who received BioCT between 1/1998 -1/2005 under the supervision of one of the co-authors (ACB). Treatment consisted of two 3-week-cycles of cisplatin 25 mg/m 2 IV D1–3, vinblastine 2 mg/m 2 IV D1–3, dacarbazine 800 mg/m 2 IV D1, IL-2 9 MIU/m 2 IVCI D1–4, and interferon alpha-2b (IFN) 5 MIU SC D1–5. Responding patients received up to 4 additional cycles, depending on tolerance. Metastasectomy was performed for residual disease at the discretion of the attending physician. Results: A total of 57 pts (36 men, median age 45 years, median follow-up 50 months) received 190 cycles of BioCT (median 3 cycles/pt). No deaths occurred during treatment. To date, 48 pts (84%) have recurred and 41 pts (72%) have died. Median time to progression and overall survival were 8 and 17 mo, respectively. Response rates using RECIST: CR 19%, PR 32%, for an overall response rate of 51%. LTDFS, defined as pts alive and recurrence-free at 24+ mo after BioCT, was observed in 8 of the 57 pts treated (29+, 30+, 51+, 58+, 69+, 71+, 80+, and 97+ mo). 4 of the 8 pts were rendered disease-free by surgery following BioCT (2 CR, 1 PR and 1 SD; 3 with viable melanoma at pathology and 1 with pathologic CR). The remaining 4 pts achieved CR and LTDFS with BioCT alone (see Table for clinical characteristics). Conclusions: LTDFS can be achieved in approximately 7% of pts with stage IV melanoma treated with BioCT alone. Although small, this subset of pts justifies the use of BioCT for young and highly selected pts. Further studies such as gene profiling designed to better identify individuals who could potentially benefit most from BioCT are clearly warranted. [Table: see text] No significant financial relationships to disclose.
Altered gut microbial profile is associated with abnormal metabolism activity of Autism Spectrum Disorder
Authors: Zhou Dan, Xuhua Mao, Qisha Liu, Mengchen Guo, Yaoyao Zhuang, Zhi Liu, Kun Chen, Junyu Chen, Rui Xu, Junming Tang, Lianhong Qin, Bing Gu, Kangjian Liu, Chuan Su, Faming Zhang, Yankai Xia, Zhibin Hu, Xingyin Liu
Journal: Gut Microbes (2020)

Autism Spectrum Disorder (ASD) is a severe neurodevelopmental disorder. To enhance the understanding of the gut microbiota structure in ASD children at different ages as well as the relationship between gut microbiota and fecal metabolites, we first used the 16S rRNA sequencing to evaluate the gut microbial population in a cohort of 143 children aged 2–13 years old. We found that the α-diversity of ASD group showed no significant change with age, while the TD group showed increased α-diversity with age, which indicates that the compositional development of the gut microbiota in ASD varies at different ages in ways that are not consistent with TD group. Recent studies have shown that chronic constipation is one of the most commonly obvious gastrointestinal (GI) symptoms along with ASD core symptoms. To further investigate the potential interaction effects between ASD and GI symptoms, the 30 C-ASD and their aged-matched TD were picked out to perform metagenomics analysis. We observed that C-ASD group displayed decreased diversity, depletion of species of Sutterella, Prevotella, and Bacteroides as well as dysregulation of associated metabolism activities, which may involve in the pathogenesis of C-ASD. Consistent with metagenomic analysis, liquid chromatography-mass spectrometry (LC/MS) revealed some of the differential metabolites between C-ASD and TD group were involved in the metabolic network of neurotransmitters including serotonin, dopamine, histidine, and GABA. Furthermore, we found these differences in metabolites were associated with altered abundance of specific bacteria. The study suggested possible future modalities for ASD intervention through targeting the specific bacteria associated with neurotransmitter metabolism.
Abstract B26: Comparative analysis of breast tumor microbiome in Black non-Hispanic (BNH) and White non-Hispanic (WNH) women
Authors: Srikantha Thyagarajan, Yan Zhang, Santosh Thapa, Michael S. Allen, Nicole Phillips, Jamboor K. Vishwanatha
Journal: Cancer Research (2020)

Abstract African American women are approximately twice as likely to be diagnosed with highly aggressive estrogen receptor-negative (ER-) and TNBC subtypes of breast cancer than Caucasian women. Among biologic factors, microbiota has been implicated in the etiology of several kinds of cancer including breast cancer. Few recent studies have shown that the breast niche-specific microbiota may have a major influence on breast tumorigenesis as shown by a decreased abundance of bacterial species with known immunomodulatory and probiotic effect in paired tumor tissue as compared to normal tissue derived from healthy patients, including different microbiota profiles in different subtypes of breast cancer. To understand whether the breast tissue harbors microbiota profiles that are uniquely race-specific we have analyzed tumor and matched normal and tumor tissue using 16S rRNA targeted sequencing strategy. Two distinct breast tumor types derived from women were included in this study: triple-negative breast cancer (TNBC) and triple-positive breast cancer (TPBC) derived from BNH and WNH women. The data were analyzed for microbiota composition, abundance, and diversity parameters, alpha diversity and beta diversity. The preliminary microbiome analysis revealed specific differences in abundance both at the phylum and genus levels between WNH and BNH women breast tissues; the alpha diversity matric, Shannon index measuring both richness and evenness of microbiota diversity showed differences in microbial diversity between normal breast tumor tissue and the matched normal adjacent to tumor tissue. The microbiota richness was relatively lower in BNH TNBC tumor tissue as compared to its matched normal adjacent to tumor zone as defined by pathologic analysis. In contrast, the microbiota richness was higher in WNH TNBC tumor tissue as compared to its matched normal breast tissue. The multivariate analysis of beta diversity revealed a distinct clustering in BNH and WNH TNBC microbiota between both tumors as compared to normal tissue and BNH as compared to WNH racial groups. Research reported in this publication was supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under Award Numbers S21MD012472 and U54MD006882. Note: This abstract was not presented at the conference. Citation Format: Srikantha Thyagarajan, Yan Zhang, Santosh Thapa, Michael S. Allen, Nicole Phillips, Jamboor K. Vishwanatha. Comparative analysis of breast tumor microbiome in Black non-Hispanic (BNH) and White non-Hispanic (WNH) women [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B26.
<sup>89</sup>Zr-PET imaging of DNA double-strand breaks for the early monitoring of response following α- and β-particle radioimmunotherapy in a mouse model of pancreatic ductal adenocarcinoma
Authors: Sophie Poty, Komal Mandleywala, Edward O'Neill, James C. Knight, Bart Cornelissen, Jason S. Lewis
Journal: Theranostics (2020)

Rationale:The evaluation of early treatment response is critical for patient prognosis and treatment planning.When the current methods rely on invasive protocols that evaluate the expression of DNA damage markers on patient biopsy samples, we aim to evaluate a non-invasive PET imaging approach to monitor the early expression of the phosphorylated histone γH2AX in the context of pancreatic cancer targeted radionuclide therapy.Pancreatic ductal adenocarcinoma has a poor patient prognosis due to the absence of curative treatment for patients with advanced disease.There is therefore a critical need for the fast clinical translation of new therapeutic options.In line with these observations, our group has been focusing on the development of radiotheranostic agents based on a fully human monoclonal antibody (5B1) with exceptional affinity for CA19.9, an antigen overexpressed in PDAC.Two on-going clinical trials resulted from these efforts, one with 89 Zr (diagnosis) and one with 177 Lu (β-particle therapy).More recently, we successfully developed and evaluated in PDAC mouse models a targeted α-therapy strategy with high clinical translation potential.We aim to expedite the clinical translation of the developed radioimmunotherapy approaches by investigating the early therapeutic response and effect of radiation therapy in a PDAC mouse model via PET imaging.Methods: Mice bearing BxPC3 tumor xenografts were treated with αand β-particle pretargeted radioimmunotherapy (PRIT), external beam radiotherapy (EBRT), or sham-treated (vehicle).The phosphorylated histone γH2AX produced as a response to DNA double strand breaks was quantified with the PET radiotracer, [ 89 Zr]Zr-DFO-anti-γH2AX-TAT.Results: PET imaging studies in BxPC3 PDAC mouse models demonstrated increased uptake of [ 89 Zr]Zr-DFO-anti-γH2AX-TAT (6.29 ± 0.15 %IA/g) following β-PRIT in BxPC3 PDAC xenografts as compared to the saline control group (4.58 ± 0.76 %IA/g) and EBRT control group (5.93 ± 0.76 %IA/g).Similarly, significantly higher uptake of [ 89 Zr]Zr-DFO-anti-γH2AX-TAT was observed in tumors of the 225 Ac-PRIT and EBRT (10 Gy) cohorts (7.37 ± 1.23 and 6.80 ± 1.24 %IA/g, respectively) compared to the negative control cohort (5.08 ± 0.95 %IA/g).Ex vivo γH2AX immunohistochemistry and immunofluorescence analysis correlated with in vivo 89 Zr-anti-γH2AX PET/CT imaging with increased γH2AX positive cell and γH2AX foci per cell in the treated cohorts.When α-PRIT resulted in prolonged overall survival of treated animals (107.5 days) as compared to β-PRIT (73.0 days), no evidence of difference in [ 89 Zr]Zr-DFO-anti-γH2AX-TAT uptake at the tumor site was observed, highlighting that DNA damage is not the sole radiobiology paradigm and that off-targeted (bystander) effects should be considered. Ivyspring
Systemic Immunomodulatory Treatments for Patients With Atopic Dermatitis
Authors: Aaron M. Drucker, Alexandra G. Ellis, Michal Bohdanowicz, Soudeh Mashayekhi, Zenas Z. N. Yiu, Bram Rochwerg, Sonya Di Giorgio, Bernd W. M. Arents, Tim Burton, Phyllis I. Spuls, Denise Küster, Doreen Siegels, Jochen Schmitt, Carsten Flohr
Journal: JAMA Dermatology (2020)

Most clinical trials assessing systemic immunomodulatory treatments for patients with atopic dermatitis are placebo-controlled. To compare the effectiveness and safety of systemic immunomodulatory treatments for patients with atopic dermatitis in a systematic review and network meta-analysis. The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of Eczema Trials database, and clinical trial registries were searched from inception to October 28, 2019. English-language randomized clinical trials of 8 weeks or more of treatment with systemic immunomodulatory medications for moderate to severe atopic dermatitis were included. Titles, abstracts, and articles were screened in duplicate. Of 10 324 citations, 39 trials were included. Data were extracted in duplicate, and the review adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-Analyses guidelines. Random-effects bayesian network meta-analyses were performed and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. Prespecified outcomes were change in signs of disease, symptoms, quality of life, itch, withdrawals, and serious adverse events. A total of 39 trials with 6360 patients examining 20 medications and placebo were included. Most trials were conducted for adults receiving up to 16 weeks of therapy. Dupilumab, 300 mg every 2 weeks, was associated with improvement in the Eczema Area and Severity Index score vs placebo (mean difference, 11.3-point reduction; 95% credible interval [CrI], 9.7-13.1 [high certainty]). Cyclosporine (standardized mean difference, -1.1; 95% CrI, -1.7 to -0.5 [low certainty]) and dupilumab (standardized mean difference, -0.9; 95% CrI, -1.0 to -0.8 [high certainty]) were similarly effective vs placebo in clearing clinical signs of atopic dermatitis and may be superior to methotrexate (standardized mean difference, -0.6; 95% CrI, -1.1 to 0.0 [low certainty]) and azathioprine (standardized mean difference, -0.4; 95% CrI, -0.8 to -0.1 [low certainty]). Several investigational medications for atopic dermatitis are promising, but data to date are limited to small early-phase trials. Safety analyses were limited by low event rates. Dupilumab and cyclosporine may be more effective for up to 16 weeks of treatment than methotrexate and azathioprine for treating adult patients with atopic dermatitis. More studies directly comparing established and novel treatments beyond 16 weeks are needed and will be incorporated into future updates of this review.