tbuckley/cabot-search huggingface dataset:
TAMI-09. INTRAOPERATIVE MICRODIALYSIS AS A FEASIBLE PLATFORM FOR METABOLIC AND PHARMACODYNAMIC BIOMARKER DISCOVERY
Authors: Terence Burns, Cecile Riviere-cazaux, Alireza (Ali) Shoushtarizadeh, Karishma Rajani, Masum Rahman, Olson Ian, Lucas Carlstrom
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Progress for gliomas is slowed in part by the paucity of mechanistic feedback during treatment with experimental therapies. Access to extracellular tumor pharmacodynamic biomarkers could provide an avenue to accelerate progress. We have initiated a program of intra-operative microdialysis to accelerate biomarker discovery and to identify candidate outcome measures for translational therapies. METHODS Intraoperative microdialysis was performed with M-dialysis 100kDA catheters and 107 variable rate pumps under an IDE. Four IDH-mutant and two IDH-WT lesions were studied intraoperatively with 3 divergently placed catheters. Microperfusate (artifical CSF+ 3% dextran) was perfused at 2uL/min and collected in 20 min increments. Paired CSF was also obtained when accessible. A parallel cohort of nude mice bearing human IDH-mutant, IDH-WT, or sham intracranial xenografts (n=6-12) underwent intratumoral microdialysis. A pilot murine study of intracranial drug delivery was performed via concurrent microdialysis during convection-enhanced delivery (CED) of saline or the IDH-inhibitor AG120. RESULTS Microdialysate from IDH-mutant intracranial xenografts revealed &amp;gt;100 differentially abundant metabolites compared to sham or IDH-WT tumors, including D2-HG (21x) and MTA(18x), p&amp;lt; 10^-5. The most significantly abundant metabolite was DMA (4x, p&amp;lt; 10^-10). 15-1000uM D2HG was recovered from intra-operative human IDH-mutant tumors and 1-2uM from normal brain adjacent to IDH-WT gliomas and &amp;lt; 1uM in all IDH-WT samples. Forty metabolites differentiated enhancing tumor from adjacent brain in 3/3 paired human samples including upregulated Aminoacyl-tRNA biosynthesis and downregulated purine metabolism. Serial aliquots of microdialysate during saline CED yielded steady D2-HG levels whereas CED with AG120 yielded undetectable D2-HG within 6 hours. CONCLUSION The extracellular metabolic landscape of glioma is diverse, dynamic and reflects tumor biology and response to therapy. Collectively, these studies suggest that intra-tumoral drug testing should be feasible with realistic expectation of gaining metabolic feedback within a short timeframe. Leveraging this paradigm can provide opportunities to accelerate therapeutic translation for gliomas.
Abstract 12956: Racial and Ethnic Disparities in Post-Arrest Care
Authors: Ryan Huebinger, Summer Chavez, Benjamin Abella, Rabab Al-Araji, Jeffrey L Jarvis, Richard Witkov, John Waller-Delarosa, Normandy W Villa, Arjun Aggarwal, Micah Panczyk, Bentley Bobrow
Journal: Circulation (2021)

Introduction: Post-arrest care is essential to the chain of survival after out-of-hospital cardiac arrest (OHCA). While racial/ethnic disparities in prehospital care are well studied, there is sparse literature evaluating these disparities in post-arrest care. We sought to measure post-arrest care disparities in a statewide OHCA registry. Methods: We evaluated 2014-2020 data in Texas from the Cardiac Arrest Registry to Enhance Survival (CARES) and included all adult OHCAs surviving to hospital admission. We stratified subjects by race and ethnicity. We defined outcomes as targeted temperature management (TTM), percutaneous intervention (PCI), and early prognostication (made DNR and died &lt;72 hours of arrest), survival to discharge, and survival with CPC of 1-2 (good CPC). We used a mixed effects model logistic regression to evaluate the association between strata and outcomes, modeling receiving hospital as the random intercept. We adjusted for age, household income, sex, witnessed arrest, bystander CPR (B-CPR), and initial shockable rhythm. For early prognostication, we performed a multivariable logistic regression adjusted for bystander witnessed arrest and B-CPR. Results: Of 37,055 adult OHCAs, 9,346 (25.2%) survived to admission; median age was 62, 60.7% were male, 3,036 (32.5%) received TTM, 533 (5.7%) received PCI, 93 (1.0%) had early prognostication, 34.9% survived to discharge, and 22.0% survived with good CPC. Blacks were less likely than whites to receive PCI (2.7% v 7.9%, aOR 0.6, 95% CI 0.4-0.8), less likely to receive early prognostication (0.3% v 1.0%, aOR 0.3, 95% CI 0.1-0.6), and less likely to have good CPC (17.3% v 26.0%, aOR 0.8, 0.7-0.9). Despite a lower percentage receiving TTM, blacks had a higher odds of TTM (30.7% v 34.5%, aOR 1.2, 95% CI 1.03-1.4). Blacks had a similar survival (1.0, 95% CI 0.9-1.2). Compared to whites, Latinos had higher early prognostication (1.7%, aOR 1.7, 95% CI 1.1-2.7), worse survival (30.3%, v 37.1%, aOR 0.9, 95% CI 0.8-0.99), lower good CPC (17.8%, aOR 0.8, 95% CI 0.7-0.96). Latinos had a similar rate of TTM (aOR 1.0, 95%CI 0.8-1.2) and PCI (aOR 1.0, 95% CI 0.8-1.4). Conclusions: Black and Latino OHCA victims experienced disparities in post arrest care and outcomes, even when adjusted for receiving hospital.
Additively manufactured metallic biomaterials
Authors: Elham Davoodi, Hossein Montazerian, Anooshe Sadat Mirhakimi, Masoud Zhianmanesh, Osezua Ibhadode, Shahriar Imani Shahabad, Reza Esmaeilizadeh, Einollah Sarikhani, Sahar Toorandaz, Shima A. Sarabi, Rohollah Nasiri, Yangzhi Zhu, Javad Kadkhodapour, Bingbing Li, Ali Khademhosseini, Ehsan Toyserkani
Journal: Bioactive Materials (2021)

Metal additive manufacturing (AM) has led to an evolution in the design and fabrication of hard tissue substitutes, enabling personalized implants to address each patient's specific needs. In addition, internal pore architectures integrated within additively manufactured scaffolds, have provided an opportunity to further develop and engineer functional implants for better tissue integration, and long-term durability. In this review, the latest advances in different aspects of the design and manufacturing of additively manufactured metallic biomaterials are highlighted. After introducing metal AM processes, biocompatible metals adapted for integration with AM machines are presented. Then, we elaborate on the tools and approaches undertaken for the design of porous scaffold with engineered internal architecture including, topology optimization techniques, as well as unit cell patterns based on lattice networks, and triply periodic minimal surface. Here, the new possibilities brought by the functionally gradient porous structures to meet the conflicting scaffold design requirements are thoroughly discussed. Subsequently, the design constraints and physical characteristics of the additively manufactured constructs are reviewed in terms of input parameters such as design features and AM processing parameters. We assess the proposed applications of additively manufactured implants for regeneration of different tissue types and the efforts made towards their clinical translation. Finally, we conclude the review with the emerging directions and perspectives for further development of AM in the medical industry.
Single-cell characterization of monolayer cultured human dental pulp stem cells with enhanced differentiation capacity
Authors: Yu Cui, Wei Ji, Yongyan Gao, Yao Xiao, Huan Liu, Zhi Chen
Journal: International Journal of Oral Science (2021)

Abstract Human dental pulp stem cells (hDPSCs) are easily obtained multipotent cells, however, their potential value in regenerative medicine is hindered by the phenotypic and functional changes after conventional monolayer expansion. Here, we employed single-cell RNA sequencing (scRNA-seq) to comprehensively study the transcriptional difference between the freshly isolated and monolayer cultured DPSCs. The cell cluster analysis based on our scRNA-seq data showed that monolayer culture resulted in a significant cellular composition switch compared to the freshly isolated DPSCs. However, one subpopulation, characterized as MCAM(+)JAG(+)PDGFRA(−), maintained the most transcriptional characteristics compared to their freshly isolated counterparts. Notably, immunofluorescent staining revealed that the MCAM(+)JAG(+)PDGFRA(−) hDPSCs uniquely located in the perivascular region of human dental pulp tissue. Flow-cytometry analysis confirmed that their proportion remained relatively stable (~2%) regardless of physiological senescence or dental caries. Consistent with the annotation of scRNA-seq data, MCAM(+)JAG(+)PDGFRA(−) hDPSCs showed higher proliferation capacity and enhanced in vitro multilineage differentiation potentials (osteogenic, chondrogenic and adipogenic) compared with their counterparts PDGFRA(+) subpopulation. Furthermore, the MCAM(+)JAG(+)PDGFRA(−) hDPSCs showed enhanced bone tissue formation and adipose tissue formation after 4-week subcutaneous implantation in nude mice. Taken together, our study for the first time revealed the cellular composition switch of monolayer cultured hDPSCs compared to the freshly isolated hDPSCs. After in vitro expansion, the MCAM(+)JAG(+)PDGFRA(−) subpopulation resembled the most transcriptional characteristics of fresh hDPSCs which may be beneficial for further tissue regeneration applications.
Hydrogel Microparticle‐Templated Anti‐Solvent Crystallization of Small‐Molecule Drugs
Authors: Meghali Bora, Myat Noe Hsu, Saif A Khan, Patrick S Doyle
Journal: Advanced Healthcare Materials (2021)

Conventional formulation strategies for hydrophobic small-molecule drug products frequently include mechanical milling to decrease active pharmaceutical ingredient (API) crystal size and subsequent granulation processes to produce an easily handled powder. A hydrogel-templated anti-solvent crystallization method is presented for the facile fabrication of microparticles containing dispersed nanocrystals of poorly soluble API. Direct crystallization within a porous hydrogel particle template yields core-shell structures in which the hydrogel core containing API nanocrystals is encased by a crystalline API shell. The process of controllable loading (up to 64% w/w) is demonstrated, and tailored dissolution profiles are achieved by simply altering the template particle size. API release is well described by a shrinking core model. Overall, the approach is a simple, scalable and potentially generalizable method that enables novel means of independently controlling both API crystallization and excipient characteristics, offering a "designer" drug particle system.
In non–critically ill patients with COVID-19, therapeutic anticoagulation improved survival to discharge without organ support
Authors: Anthony A. Donato
Journal: Annals of Internal Medicine (2021)

ACP Journal ClubDecember 2021In non–critically ill patients with COVID-19, therapeutic anticoagulation improved survival to discharge without organ supportAnthony A. Donato, MD, MHPEAnthony A. Donato, MD, MHPETower Health/Reading Hospital, Reading, Pennsylvania, USA (A.A.D.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ202112210-134 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationLawler PR, Goligher EC, Berger JS, et al. Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N Engl J Med. 2021;385:790-802. https://pubmed.ncbi.nlm.nih.gov/34351721Clinical Impact RatingsEmergency Med: Hospitalists: Infectious Disease: Critical Care: References1. Kollias A, Kyriakoulis KG, Lagou S, et al. Venous thromboembolism in COVID-19: a systematic review and meta-analysis. Vasc Med. 2021;26:415-25. [PMID: 33818197] Google Scholar2. Hippensteel JA, LaRiviere WB, Colbert JF, et al. Heparin as a therapy for COVID-19: current evidence and future possibilities. Am J Physiol Lung Cell Mol Physiol. 2020;319:L211-7. [PMID: 32519894] Google Scholar3. COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health. Accessed at https://files.covid19treatmentguidelines.nih.gov/guidelines/covid19treatmentguidelines.pdf on 13 Sep 2021. Google Scholar4. Contou D, Fraissé M, Pajot O, et al. Comparison between first and second wave among critically ill COVID-19 patients admitted to a French ICU: no prognostic improvement during the second wave? Crit Care. 2021;25:3. [PMID: 33397421] Google Scholar5. Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: May 2021 update on the use of intermediate intensity anticoagulation in critically ill patients. Blood Adv. 2021;5:3951-9. [PMID: 34474482] Google Scholar Author, Article, and Disclosure InformationAffiliations: Tower Health/Reading Hospital, Reading, Pennsylvania, USA (A.A.D.)Disclosures: The commentator has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-7323.This article was published at Annals.org on 7 December 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoIn critically ill patients with COVID-19, therapeutic anticoagulation did not increase organ support–free days Anthony A. Donato Metrics December 2021Volume 174, Issue 12Page: JC134 ePublished: 7 December 2021 Issue Published: December 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Hereditary Transthyretin Amyloid Cardiomyopathy
Authors: Quentin R. Youmans, Sanjiv J. Shah, Sadiya S. Khan
Journal: JAMA Cardiology (2021)

Vibhu Parcha, MD; Gargya Malla, MD, MPH, PhD; Marguerite R. Irvin, PhD; Nicole D. Armstrong, PhD; Suzanne E. Judd, PhD; Leslie A. Lange, PhD; Mathew S. Maurer, MD; Emily B. Levitan, ScD; Parag Goyal, MD, MSc; Garima Arora, MD; Pankaj Arora, MD
Comparison with Private and Public Clonotypes Reveals That, While CLL Type Stereotyped BCR Are Produced in 90% of Healthy Subjects from 18 to 78 Years, They Are Not Accumulated and Are Mostly Found in Immature and Naïve B-Cells
Authors: Marine Dupont, Paco Derouault, Virginie Pascal, Charlotte Rivière, Benjamin Ganne, Mélanie Boulin, Sophie Perron, Jasmine Chauzeix, Nathalie Gachard, Jean Feuillard, David Rizzo
Journal: Blood (2021)
Proresolving receptor tames inflammation in atherosclerosis
Authors: Hebe Agustina Mena, Matthew Spite
Journal: Journal of Clinical Investigation (2021)

Nonresolving inflammation contributes to the progression of atherosclerosis, a chronic disease characterized by the accumulation of lipid-rich arterial plaques infiltrated with immune cells. In this issue of the JCI, Arnardottir and Thul et al. report that GPR32, a receptor for proresolving lipid mediators including resolvin D1, was decreased in human atherosclerotic lesions and that overexpression of this human receptor in mice reduced lesion area and necrosis of atherosclerotic plaques. Mechanistically, GPR32 signaling blunted the production of proinflammatory cytokines, enhanced macrophage phagocytosis, and reduced leukocyte accumulation. These results suggest that therapeutic targeting of GPR32 could be an approach to resolving chronic inflammation in atherosclerosis.
Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease
Authors: Jiansong Fang, Pengyue Zhang, Yadi Zhou, Chien-Wei Chiang, Juan Tan, Yuan Hou, Shaun Stauffer, Lang Li, Andrew A. Pieper, Jeffrey Cummings, Feixiong Cheng
Journal: Nature Aging (2021)
Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis
Authors: Amanda Fitzpatrick, Marjan Iravani, Adam Mills, Lucy Childs, Thanussuyah Alaguthurai, Angela Clifford, Isaac Garcia-Murillas, Steven Van Laere, Luc Dirix, Mark Harries, Alicia Okines, Nicholas C. Turner, Syed Haider, Andrew N.J. Tutt, Clare M. Isacke
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Cerebrospinal fluid (CSF) cytology is the gold standard diagnostic test for breast cancer leptomeningeal metastasis (BCLM), but has impaired sensitivity, often necessitating repeated lumbar puncture to confirm or refute diagnosis. Further, there is no quantitative response tool to assess response or progression during BCLM treatment. Experimental Design: Facing the challenge of working with small-volume samples and the lack of common recurrent mutations in breast cancers, cell-free DNA was extracted from the CSF and plasma of patients undergoing investigation for BCLM (n = 30). ctDNA fraction was assessed by ultra-low-pass whole genome sequencing (ulpWGS), which does not require prior tumor sequencing. Results: In this proof-of-concept study, ctDNA was detected (fraction ≥0.10) in the CSF of all 24 patients with BCLM+ (median ctDNA fraction, 0.57), regardless of negative cytology or borderline MRI imaging, whereas CSF ctDNA was not detected in the six patients with BCLM− (median ctDNA fraction 0.03, P &amp;lt; 0.0001). Plasma ctDNA was only detected in patients with extracranial disease progression or who had previously received whole brain radiotherapy. ctDNA fraction was highly concordant with mutant allele fraction measured by tumor mutation-specific ddPCR assays (r = 0.852; P &amp;lt; 0.0001). During intrathecal treatment, serial monitoring (n = 12 patients) showed that suppression of CSF ctDNA fraction was associated with longer BCLM survival (P = 0.034), and rising ctDNA fraction was detectable up to 12 weeks before clinical progression. Conclusions: Measuring ctDNA fraction by ulpWGS is a quantitative marker demonstrating potential for timely and accurate BCLM diagnosis and therapy response monitoring, with the ultimate aim to improve management of this poor-prognosis patient group.
Identification of anthelmintic parbendazole as a therapeutic molecule for HNSCC through connectivity map-based drug repositioning
Authors: Dong Liang, Chen Yu, Zhao Ma, Xingye Yang, Zhenzhen Li, Xuhui Dong, Xiaojun Qin, Lupei Du, Minyong Li
Journal: Acta Pharmaceutica Sinica B (2021)

Head and neck squamous cell carcinoma (HNSCC) is one of the most common human cancers; however, its outcome of pharmacotherapy is always very limited. Herein, we performed a batch query in the connectivity map (cMap) based on bioinformatics, queried out 35 compounds with therapeutic potential, and screened out parbendazole as a most promising compound, which had an excellent inhibitory effect on the proliferation of HNSCC cell lines. In addition, tubulin was identified as a primary target of parbendazole, and the direct binding between them was further verified. Parbendazole was further proved as an effective tubulin polymerization inhibitor, which can block the cell cycle, cause apoptosis and prevent cell migration, and it exhibited reasonable therapeutic effect and low toxicity in the in vivo and in vitro anti-tumor evaluation. Our study repositioned an anthelmintic parbendazole to treat HNSCC, which revealed a therapeutic utility and provided a new treatment option for human cancers.
Automated Segmentation of Kidney Cortex and Medulla in CT Images: A Multisite Evaluation Study
Authors: Panagiotis Korfiatis, Aleksandar Denic, Marie E. Edwards, Adriana V. Gregory, Darryl E. Wright, Aidan Mullan, Joshua Augustine, Andrew D. Rule, Timothy L. Kline
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement Volumetric measurements are needed to characterize kidney structural findings on CT images to evaluate and test their potential utility in clinical decision making. Deep learning can enable this task in a scalable and reliable manner. Although automated kidney segmentation has been previously explored, methods for distinguishing cortex from medulla have never been done before. In addition, automated methods are typically evaluated at a single institution, without testing generalizability and robustness across different institutions. The tool developed in this study performs at the level of human readers and could enable large diverse population studies to evaluate how kidney, cortex, and medulla volumes can be used in various clinical settings, and establish normative values at large scale. Background In kidney transplantation, a contrast CT scan is obtained in the donor candidate to detect subclinical pathology in the kidney. Recent work from the Aging Kidney Anatomy study has characterized kidney, cortex, and medulla volumes using a manual image-processing tool. However, this technique is time consuming and impractical for clinical care, and thus, these measurements are not obtained during donor evaluations. This study proposes a fully automated segmentation approach for measuring kidney, cortex, and medulla volumes. Methods A total of 1930 contrast-enhanced CT exams with reference standard manual segmentations from one institution were used to develop the algorithm. A convolutional neural network model was trained ( n =1238) and validated ( n =306), and then evaluated in a hold-out test set of reference standard segmentations ( n =386). After the initial evaluation, the algorithm was further tested on datasets originating from two external sites ( n =1226). Results The automated model was found to perform on par with manual segmentation, with errors similar to interobserver variability with manual segmentation. Compared with the reference standard, the automated approach achieved a Dice similarity metric of 0.94 (right cortex), 0.90 (right medulla), 0.94 (left cortex), and 0.90 (left medulla) in the test set. Similar performance was observed when the algorithm was applied on the two external datasets. Conclusions A fully automated approach for measuring cortex and medullary volumes in CT images of the kidneys has been established. This method may prove useful for a wide range of clinical applications.
Role of Income-Lifting Social Programs in Reducing Years of Life Lost to Myocardial Infarction and Sudden Death
Authors: Elizabeth Senter, Hannah Vrooman, Kaitlin Shartle
Journal: JAMA Cardiology (2021)

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Incidence and Estimated Vaccine Effectiveness Against Symptomatic SARS-CoV-2 Infection Among Persons Tested in US Retail Locations, May 1 to August 7, 2021
Authors: Ying P. Tabak, Xiaowu Sun, Troyen A. Brennan, Sreekanth K. Chaguturu
Journal: JAMA Network Open (2021)