tbuckley/cabot-search huggingface dataset:
Enhanced lipid biosynthesis in human tumor-induced macrophages contributes to their protumoral characteristics
Authors: Katrin Rabold, Anna Aschenbrenner, Christoph Thiele, Collins K Boahen, Alexander Schiltmans, Johannes W A Smit, Joachim L Schultze, Mihai G Netea, Gosse J Adema, Romana T Netea-Maier
Journal: Journal for ImmunoTherapy of Cancer (2020)

Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME) in non-medullary thyroid carcinoma (TC) and neuroblastoma (NB), being associated with a poor prognosis for patients. However, little is known about how tumors steer the specific metabolic phenotype and function of TAMs.In a human coculture model, transcriptome, metabolome and lipidome analysis were performed on TC-induced and NB-induced macrophages. The metabolic shift was correlated to functional readouts, such as cytokine production and reactive oxygen species (ROS) production, including pharmacological inhibition of metabolic pathways.Based on transcriptome and metabolome analysis, we observed a strong upregulation of lipid biosynthesis pathways in TAMs. Subsequently, lipidome analysis revealed that tumor-induced macrophages have an increased total lipid content and enriched levels of intracellular lipids, especially phosphoglycerides and sphingomyelins. Strikingly, this metabolic shift in lipid synthesis contributes to their protumoral functional characteristics: blocking key enzymes of lipid biosynthesis in the tumor-induced macrophages reversed the increased inflammatory cytokines and the capacity to produce ROS, two well-known protumoral factors in the TME.Taken together, our data show that tumor cells can stimulate lipid biosynthesis in macrophages to induce protumoral cytokine and ROS responses and advocate lipid biosynthesis as a potential therapeutic target to reprogram the TME.
Programmable Delivery of Synergistic Cancer Drug Combinations Using Bicompartmental Nanoparticles
Authors: Jason V. Gregory, Douglas R. Vogus, Alexandra Barajas, Melissa A. Cadena, Samir Mitragotri, Joerg Lahann
Journal: Advanced Healthcare Materials (2020)

Abstract Delivery of multiple therapeutics has become a preferred method of treating cancer, albeit differences in the biodistribution and pharmacokinetic profiles of individual drugs pose challenges in effectively delivering synergistic drug combinations to and at the tumor site. Here, bicompartmental Janus nanoparticles comprised of domains are reported with distinct bulk properties that allow for independent drug loading and release. Programmable drug release can be triggered by a change in the pH value and depends upon the bulk properties of the polymers used in the respective compartments, rather than the molecular structures of the active agents. Bicompartmental nanoparticles delivering a synergistic combination of lapatinib and paclitaxel result in increased activity against HER2+ breast cancer cells. Surprisingly, the dual drug loaded particles also show significant efficacy toward triple negative breast cancer, even though this cancer model is unresponsive to lapatinib alone. The broad versatility of the nanoparticle platform allows for rapid exploration of a wide range of drug combinations where both their relative drug ratios and temporal release profiles can be optimized.
PET Reporter Gene Imaging and Ganciclovir-Mediated Ablation of Chimeric Antigen Receptor T Cells in Solid Tumors
Authors: Surya Murty, Louai Labanieh, Tara Murty, Gayatri Gowrishankar, Tom Haywood, Israt S. Alam, Corinne Beinat, Elise Robinson, Amin Aalipour, Dorota D. Klysz, Jennifer R. Cochran, Robbie G. Majzner, Crystal L. Mackall, Sanjiv S. Gambhir
Journal: Cancer Research (2020)

Imaging strategies to monitor chimeric antigen receptor (CAR) T-cell biodistribution and proliferation harbor the potential to facilitate clinical translation for the treatment of both liquid and solid tumors. In addition, the potential adverse effects of CAR T cells highlight the need for mechanisms to modulate CAR T-cell activity. The herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene has previously been translated as a PET reporter gene for imaging of T-cell trafficking in patients with brain tumor. The HSV1-TK enzyme can act as a suicide gene of transduced cells through treatment with the prodrug ganciclovir. Here we report the molecular engineering, imaging, and ganciclovir-mediated destruction of B7H3 CAR T cells incorporating a mutated version of the HSV1-tk gene (sr39tk) with improved enzymatic activity for ganciclovir. The sr39tk gene did not affect B7H3 CAR T-cell functionality and in vitro and in vivo studies in osteosarcoma models showed no significant effect on B7H3 CAR T-cell antitumor activity. PET/CT imaging with 9-(4-[18F]-fluoro-3-[hydroxymethyl]butyl)guanine ([18F]FHBG) of B7H3-sr39tk CAR T cells in an orthotopic model of osteosarcoma revealed tumor homing and systemic immune expansion. Bioluminescence and PET imaging of B7H3-sr39tk CAR T cells confirmed complete tumor ablation with intraperitoneal ganciclovir administration. This imaging and suicide ablation system can provide insight into CAR T-cell migration and proliferation during clinical trials while serving as a suicide switch to limit potential toxicities. SIGNIFICANCE: This study showcases the only genetically engineered system capable of serving the dual role both as an effective PET imaging reporter and as a suicide switch for CAR T cells.
The impact of cytogenetic risk on the outcomes of allogeneic hematopoietic cell transplantation in patients with relapsed/refractory acute myeloid leukemia: On behalf of the acute leukemia working party (<scp>ALWP</scp>) of the <scp>European group for blood and marrow transplantation (EBMT)</scp>
Authors: Monica Poiani, Myriam Labopin, Giorgia Battipaglia, Dietrich W. Beelen, Johanna Tischer, Jürgen Finke, Arne Brecht, Edouard Forcade, Arnold Ganser, Jakob R. Passweg, Helene Labussiere‐Wallet, Ibrahim Yakoub‐Agha, Kerstin Schäfer‐Eckart, Nicolaus Kroeger, Blandine Guffroy, Annalisa Ruggeri, Jordi Esteve, Arnon Nagler, Mohamad Mohty
Journal: American Journal of Hematology (2020)

Abstract Karyotypic analysis at time of diagnosis has an important value in determining initial response to treatment, remission duration and overall survival (OS) in acute myeloid leukemia (AML). Less is known about its value before allogeneic hematopoietic cell transplantation (allo‐HCT) in patients transplanted with active disease, either relapsed or primary refractory (Rel‐Ref) AML. We explored the impact of cytogenetic risk (stratification according to MRC‐UK) in 2089 patients with either Ref (n = 972) or Rel AML (n = 1117) transplanted during the period 2000‐2017. Overall, 154 patients had a favorable risk, 1283 had an intermediate risk and 652 had an adverse cytogenetic risk. Median follow‐up was 49 months. Compared to the favorable risk group, intermediate and adverse risk patients were associated with worse leukemia‐free survival and OS and also with a higher incidence of relapse. In a subgroup analysis of patients in the intermediate risk group harboring Fms‐like tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD), this remained an important prognostic factor, being associated with worse outcomes. When analyzing patients according to the intensity of the conditioning regimen, no differences were observed for the main transplant outcomes. In conclusion, in patients diagnosed with AML and transplanted with active disease, karyotype remains an important prognostic factor, allowing splitting patients into different risk groups according to their cytogenetics. Similarly, FLT3‐ITD mutation also remains a negative prognostic factor in this population.
High-Flow Nasal Cannula as Rescue Therapy in Bronchiolitis
Authors: Sharon O’Brien, Franz E. Babl, Stuart R. Dalziel
Journal: JAMA Pediatrics (2020)

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 Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications 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) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 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 Pediatrics journal
Pediatric PK/PD Phase I Trial of Pexidartinib in Relapsed and Refractory Leukemias and Solid Tumors Including Neurofibromatosis Type I–Related Plexiform Neurofibromas
Authors: Lauren H. Boal, John Glod, Melissa Spencer, Miki Kasai, Joanne Derdak, Eva Dombi, Mark Ahlman, Daniel W. Beury, Melinda S. Merchant, Christianne Persenaire, David J. Liewehr, Seth M. Steinberg, Brigitte C. Widemann, Rosandra N. Kaplan
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Simultaneously targeting the tumor and tumor microenvironment may hold promise in treating children with refractory solid tumors. Pexidartinib, an oral inhibitor of tyrosine kinases including colony stimulating factor 1 receptor (CSF-1R), KIT, and FLT3, is FDA approved in adults with tenosynovial giant cell tumor. A phase I trial was conducted in pediatric and young adult patients with refractory leukemias or solid tumors including neurofibromatosis type 1–related plexiform neurofibromas. Patients and Methods: A rolling six design with dose levels (DL) of 400 mg/m2, 600 mg/m2, and 800 mg/m2 once daily for 28-day cycles (C) was used. Response was assessed at regular intervals. Pharmacokinetics and population pharmacokinetics were analyzed during C1. Results: Twelve patients (4 per DL, 9 evaluable) enrolled on the dose-escalation phase and 4 patients enrolled in the expansion cohort: median (lower, upper quartile) age 16 (14, 16.5) years. No dose-limiting toxicities were observed. Pharmacokinetics appeared linear over three DLs. Pharmacokinetic modeling and simulation determined a weight-based recommended phase II dose (RP2D). Two patients had stable disease and 1 patient with peritoneal mesothelioma (C49+) had a sustained partial response (67% RECIST reduction). Pharmacodynamic markers included a rise in plasma macrophage CSF (MCSF) levels and a decrease in absolute monocyte count. Conclusions: Pexidartinib in pediatric patients was well tolerated at all DL tested, achieved target inhibition, and resulted in a weight-based RPD2 dose.
Why we heal: The evolution of psychological healing and implications for global mental health
Authors: Brandon A. Kohrt, Katherine Ottman, Catherine Panter-Brick, Melvin Konner, Vikram Patel
Journal: Clinical Psychology Review (2020)

Why do humans heal one another? Evolutionary psychology has advanced our understanding of why humans suffer psychological distress and mental illness. However, to date, the evolutionary origins of what drives humans to alleviate the suffering of others has received limited attention. Therefore, we draw upon evolutionary theory to assess why humans psychologically support one another, focusing on the interpersonal regulation of emotions that shapes how humans heal and console one another when in psychosocial distress. To understand why we engage in psychological healing, we review the evolution of cooperation among social species and the roles of emotional contagion, empathy, and self-regulation. We discuss key aspects of human biocultural evolution that have contributed to healing behaviors: symbolic logic including language, complex social networks, and the long period of childhood that necessitates identifying and responding to others in distress. However, both biological and cultural evolution also have led to social context when empathy and consoling are impeded. Ultimately, by understanding the evolutionary processes shaping why humans psychologically do or do not heal one another, we can improve our current approaches in global mental health and uncover new opportunities to improve the treatment of mental illness across cultures and context around the world.
Amazon fires coincide with increased respiratory illnesses in indigenous populations
Authors: Lise Alves
Journal: The Lancet Respiratory Medicine (2020)

Smoke from fires set in the Amazon region is one of the key causes of respiratory hospitalisations of indigenous people, states a recent study conducted by Brazil's Instituto Socioambiental (ISA). This year, the fires, along with the spread of COVID-19, might mean further distress to the indigenous population who live in the region.
Long-term hydroxychloroquine use in patients with rheumatic conditions and development of SARS-CoV-2 infection: a retrospective cohort study
Authors: Chris A Gentry, Mary Beth Humphrey, Sharanjeet K Thind, Sage C Hendrickson, George Kurdgelashvili, Riley J Williams
Journal: The Lancet Rheumatology (2020)

Hydroxychloroquine is one of several agents being evaluated in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We aimed to examine whether patients with rheumatological conditions receiving chronic hydroxychloroquine therapy are at less risk of developing SARS-CoV-2 infection than those not receiving hydroxychloroquine.This retrospective cohort study included de-identified information of all veterans in the US Veterans Health Administration clinical administrative database aged 18 years or older with rheumatoid arthritis, systemic lupus erythematosus, or associated rheumatological conditions (based on International Classification of Diseases, 10th edition, diagnostic codes) who were alive on March 1, 2020. A propensity score was calculated for each patient, and each patient who was receiving hydroxychloroquine was matched to two patients who were not receiving hydroxychloroquine (controls). The primary endpoint was the proportion of patients with PCR-confirmed SARS-CoV-2 infection among those receiving chronic hydroxychloroquine versus the propensity-matched patients not receiving chronic hydroxychloroquine between March 1 and June 30, 2020. Secondary outcomes were hospital admission associated with SARS-CoV-2 infection; intensive care requirement associated with SARS-CoV-2 infection; mortality associated with SARS-CoV-2 infection; and overall rates of any hospital admission and mortality (ie, all cause). Multivariate logistic regression analysis was done to determine independent variables for the development of active SARS-CoV-2 infection.Between March 1 and June 30, 2020, 10 703 patients receiving hydroxychloroquine and 21 406 patients not receiving hydroxychloroquine were included in the primary analysis. The incidence of active SARS-CoV-2 infections during the study period did not differ between patients receiving hydroxychloroquine and patients not receiving hydroxychloroquine (31 [0·3%] of 10 703 vs 78 [0·4%] of 21 406; odds ratio 0·79, 95% CI 0·52-1·20, p=0·27). There were no significant differences in secondary outcomes between the two groups in patients who developed active SARS-CoV-2 infection. For all patients in the study, overall mortality was lower in the hydroxychloroquine group than in the group of patients who did not receive hydroxychloroquine (odds ratio 0·70, 95% CI 0·55-0·89, p=0·0031). In multivariate logistic regression analysis, receipt of hydroxychloroquine was not associated with the development of active SARS-CoV-2 infection (odds ratio 0·79, 95% CI 0·51-1·42).Hydroxychloroquine was not associated with a preventive effect against SARS-CoV-2 infection in a large group of patients with rheumatological conditions.None.
Polymers for Melt Electrowriting
Authors: Juliane C. Kade, Paul D. Dalton
Journal: Advanced Healthcare Materials (2020)

Abstract Melt electrowriting (MEW) is an emerging high‐resolution additive manufacturing technique based on the electrohydrodynamic processing of polymers. MEW is predominantly used to fabricate scaffolds for biomedical applications, where the microscale fiber positioning has substantial implications in its macroscopic mechanical properties. This review gives an update on the increasing number of polymers processed via MEW and different commercial sources of the gold standard poly( ε ‐caprolactone) (PCL). A description of MEW‐processed polymers beyond PCL is introduced, including blends and coated fibers to provide specific advantages in biomedical applications. Furthermore, a perspective on printer designs and developments is highlighted, to keep expanding the variety of processable polymers for MEW.
Silk‐Based Biomaterials for Cardiac Tissue Engineering
Authors: Yu Song, Huifang Wang, Feifei Yue, Qiying Lv, Bo Cai, Nianguo Dong, Zheng Wang, Lin Wang
Journal: Advanced Healthcare Materials (2020)

Abstract Cardiovascular diseases are one of the leading causes of death globally. Among various cardiovascular diseases, myocardial infarction is an important one. Compared with conventional treatments, cardiac tissue engineering provides an alternative to repair and regenerate the injured tissue. Among various types of materials used for tissue engineering applications, silk biomaterials have been increasingly utilized due to their biocompatibility, biological functions, and many favorable physical/chemical properties. Silk biomaterials are often used alone or in combination with other materials in the forms of patches or hydrogels, and serve as promising delivery systems for bioactive compounds in tissue engineering repair scenarios. This review focuses primarily on the promising characteristics of silk biomaterials and their recent advances in cardiac tissue engineering.
The ABO histo-blood group, endothelial activation, and acute respiratory distress syndrome risk in critical illness
Authors: John P. Reilly, Nuala J. Meyer, Michael G.S. Shashaty, Brian J. Anderson, Caroline Ittner, Thomas G. Dunn, Brian Lim, Caitlin Forker, Michael P. Bonk, Ethan Kotloff, Rui Feng, Edward Cantu, Nilam S. Mangalmurti, Carolyn S. Calfee, Michael A. Matthay, Carmen Mikacenic, Keith R. Walley, James Russell, David C. Christiani, Mark M. Wurfel, Paul N. Lanken, Muredach P. Reilly, Jason D. Christie
Journal: Journal of Clinical Investigation (2020)

BACKGROUND. The ABO histo-blood group is defined by carbohydrate modifications and is associated with risk for multiple diseases, including acute respiratory distress syndrome (ARDS). We hypothesized that genetically determined blood subtype A1 is associated with increased risk of ARDS and markers of microvascular dysfunction and coagulation.
Phagosome-regulated mTOR signalling during sarcoidosis granuloma biogenesis
Authors: Elliott D. Crouser, Landon W. Locke, Mark W. Julian, Sabahattin Bicer, Wolfgang Sadee, Peter White, Larry S. Schlesinger
Journal: European Respiratory Journal (2020)

Introduction Sarcoidosis and tuberculosis are granulomatous pulmonary diseases characterised by heightened immune reactivity to Mycobacterium tuberculosis antigens. We hypothesised that an unsupervised analysis comparing the molecular characteristics of granulomas formed in response to M. tuberculosis antigens in patients with sarcoidosis or latent tuberculosis infection (LTBI) would provide novel insights into the pathogenesis of sarcoidosis. Methods A genomic analysis identified differentially expressed genes in granuloma-like cell aggregates formed by sarcoidosis (n=12) or LTBI patients (n=5) in an established in vitro human granuloma model wherein peripheral blood mononuclear cells were exposed to M. tuberculosis antigens (beads coated with purified protein derivative) and cultured for 7 days. Pathway analysis of differentially expressed genes identified canonical pathways, most notably antigen processing and presentation via phagolysosomes, as a prominent pathway in sarcoidosis granuloma formation. The phagolysosomal pathway promoted mechanistic target of rapamycin complex 1 (mTORc1)/STAT3 signal transduction. Thus, granuloma formation and related immune mediators were evaluated in the absence or presence of various pre-treatments known to prevent phagolysosome formation (chloroquine) or phagosome acidification (bafilomycin A1) or directly inhibit mTORc1 activation (rapamycin). Results In keeping with genomic analyses indicating enhanced phagolysosomal activation and predicted mTORc1 signalling, it was determined that sarcoidosis granuloma formation and related inflammatory mediator release was dependent upon phagolysosome assembly and acidification and mTORc1/S6/STAT3 signal transduction. Conclusions Sarcoidosis granulomas exhibit enhanced and sustained intracellular antigen processing and presentation capacities, and related phagolysosome assembly and acidification are required to support mTORc1 signalling to promote sarcoidosis granuloma formation.
Progression-free survival at 24 months and subsequent survival of patients with extranodal NK/T-cell lymphoma: a China Lymphoma Collaborative Group (CLCG) study
Authors: Yong Yang, Ying Wang, Xin Liu, Xia He, Li-Ling Zhang, Gang Wu, Bao-Lin Qu, Li-Ting Qian, Xiao-Rong Hou, Fu-Quan Zhang, Xue-Ying Qiao, Hua Wang, Gao-Feng Li, Yuan Zhu, Jian-Zhong Cao, Jun-Xin Wu, Tao Wu, Su-Yu Zhu, Mei Shi, Li-Ming Xu, Hang Su, Yu-Qin Song, Jun Zhu, Yu-Jing Zhang, Hui-Qiang Huang, Chen Hu, Shu-Nan Qi, Ye-Xiong Li
Journal: Leukemia (2020)

Limited evidence supports the use of early endpoints to evaluate the success of initial treatment of extranodal NK/T-cell lymphoma (ENKTCL) in the modern era. We aim to analyze progression-free survival at 24 months (PFS24) and subsequent overall survival (OS) in a large-scale multicenter cohort of patients. 1790 patients were included from the China Lymphoma Collaborative Group (CLCG) database. Subsequent OS was defined from the time of PFS24 or progression within 24 months to death. OS was compared with age- and sex-matched general Chinese population using expected survival and standardized mortality ratio (SMR). Patients who did not achieve PFS24 had a median OS of 5.3 months after progression, with 5-year OS rate of 19.2% and the SMR of 71.4 (95% CI, 62.9-81.1). In contrast, 74% patients achieved PFS24, and the SMR after achieving PFS24 was 1.77 (95% CI, 1.34-2.34). The observed OS rate after PFS24 versus expected OS rate at 5 years was 92.2% versus 94.3%. Similarly, superior outcomes following PFS24 were observed in early-stage patients (5-year OS rate, 92.9%). Patients achieving PFS24 had excellent outcome, whereas patients exhibiting earlier progression had a poor survival. These marked differences suggest that PFS24 may be used for study design and risk stratification in ENKTCL.
Publisher Correction: Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity
Authors: Shinya Tanaka, Wataru Ise, Takeshi Inoue, Ayako Ito, Chisato Ono, Yoshihito Shima, Shuhei Sakakibara, Manabu Nakayama, Kentaro Fujii, Ikuo Miura, Jafar Sharif, Haruhiko Koseki, Pandelakis A. Koni, Indu Raman, Quan-Zhen Li, Masato Kubo, Katsunori Fujiki, Ryuichiro Nakato, Katsuhiko Shirahige, Hiromitsu Araki, Fumihito Miura, Takashi Ito, Eiryo Kawakami, Yoshihiro Baba, Tomohiro Kurosaki
Journal: Nature Immunology (2020)