tbuckley/cabot-search huggingface dataset:
High potency STING agonists engage unique myeloid pathways to reverse pancreatic cancer immune privilege
Authors: Casey R Ager, Akash Boda, Kimal Rajapakshe, Spencer Thomas Lea, Maria Emilia Di Francesco, Priyamvada Jayaprakash, Ravaen B Slay, Brittany Morrow, Rishika Prasad, Meghan A Dean, Colm R Duffy, Cristian Coarfa, Philip Jones, Michael A Curran
Journal: Journal for ImmunoTherapy of Cancer (2021)

Intratumoral injection of cyclic dinucleotide (CDN) agonists of the stimulator of interferon genes (STING) pathway engages innate immune activation and priming of adaptive immune effectors to foster local and distal tumor clearance. Despite proven therapeutic efficacy in preclinical models, a thorough understanding of how CDNs reprogram suppressive myeloid stroma in mouse and man is lacking.Here, we perform deep transcript-level and protein-level profiling of myeloid-derived suppressor cells and M2 macrophages following stimulation with CDNs of ascending potency. Additionally, we leverage orthotopic Kras+/G12DTP53+/R172HPdx1-Cre (KPC) derived models of pancreatic adenocarcinoma (PDAC) to determine the capacity for locally administered CDNs to sensitize PDAC to immune checkpoint blockade. We use bioluminescent in vivo imaging and 30-parameter flow cytometry to profile growth kinetics and remodeling of the tumor stroma post-therapy.Highly potent synthetic STING agonists repolarize suppressive myeloid populations of human and murine origin in part through inhibition of Myc signaling, metabolic modulation, and antagonism of cell cycle. Surprisingly, high-potency synthetic agonists engage qualitatively unique pathways as compared with natural CDNs. Consistent with our mechanistic observations, we find that intratumoral injection of the highest activity STING agonist, IACS-8803, into orthotopic pancreatic adenocarcinoma lesions unmasks sensitivity to checkpoint blockade immunotherapy. Dimensionality reduction analyses of high parameter flow cytometry data reveals substantial contributions of both myeloid repolarization and T cell activation underlying the in vivo therapeutic benefit of this approach.This study defines the molecular basis of STING-mediated myeloid reprogramming, revealing previously unappreciated and qualitatively unique pathways engaged by CDNs of ascending potency during functional repolarization. Furthermore, we demonstrate the potential for high potency CDNs to overcome immunotherapy resistance in an orthotopic, multifocal model of PDAC.
Melphalan Dose in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation with Reduced-Intensity Fludarabine and Melphalan
Authors: Kaito Harada, Shinichiro Machida, Masamitsu Yanada, Heiwa Kanamori, Makoto Onizuka, Yukiyasu Ozawa, Hikaru Kobayashi, Masashi Sawa, Junya Kanda, Tatsuo Ichinohe, Yoshiko Atsuta, Shingo Yano
Journal: Blood (2017)
Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial
Authors: Hai-Qiang Mai, Qiu-Yan Chen, Dongping Chen, Chaosu Hu, Kunyu Yang, Jiyu Wen, Jingao Li, Ying-Rui Shi, Feng Jin, Ruilian Xu, Jianji Pan, Shenhong Qu, Ping Li, Chunhong Hu, Yi-Chun Liu, Yi Jiang, Xia He, Hung-Ming Wang, Wan-Teck Lim, Wangjun Liao, Xiaohui He, Xiaozhong Chen, Zhigang Liu, Xianglin Yuan, Qi Li, Xiaoyan Lin, Shanghua Jing, Yanju Chen, Yin Lu, Ching-Yun Hsieh, Muh-Hwa Yang, Chia-Jui Yen, Jens Samol, Hui Feng, Sheng Yao, Patricia Keegan, Rui-Hua Xu
Journal: Nature Medicine (2021)
Cancer cachexia.
Authors: Marcus E Martignoni, Philipp Kunze, Helmut Friess
Journal: Molecular Cancer (2003)

In recent years many efforts of researchers and clinicians were made to improve our knowledge of cachexia syndrome. Not only cancer, but also many chronic or end-stage diseases such as AIDS, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, tuberculosis and Crohn's disease are associated with cachexia, a condition of abnormally low weight, weakness, and general bodily decline which deteriorates quality of life and reduces the prognosis of the patients who suffer from it. In the present editorial we will focus cachexia related on cancer and provide some insight into this prognosis-limiting syndrome.
Clemens von Pirquet
Authors: Clemens Scheinecker, Dietrich Kraft
Journal: Annals of the Rheumatic Diseases (2021)

Clemens Peter Freiherr von Pirquet, a great physician-scientist who described serum sickness and opened the field of allergy, was born in Hirschstetten near Vienna on 12 May 1874 into a distinguished family of the old Austrian-Hungarian empire (see figure 1). His father Peter Zeno von Pirquet held important positions in the Austrian parliament. His mother belonged to an assimilated Jewish banking family. After his school years in Vienna, Clemens, started theological studies on request of his mother, first at the University of Innsbruck and later at the Philosophical Faculty at the University of Leuven in Belgium. After having finished his theological studies with a master degree, he began to study medicine in Vienna and subsequently in Konigsberg and Graz where he received his MD degree in 1900. After a military service, he started his training in paediatrics at the Charite in Berlin where he also met his future wife Maria Christina van Husen. In 1901, they returned to Vienna where he became junior doctor at the St. Anna Children’s Hospital led by Theodor Escherich (1857–1911), who discovered the Escherichia coli bacteria. At the same time he worked with Rudolf Kraus, the first scientist to demonstrate precipitation of antibody and antigen at the Institute for Serotherapy at Vienna University.



Figure 1 
Photograph of Clemens von Pirquet.



Between 1903 and 1910, Pirquet made his most important, pioneering contributions investigating host reactions to foreign substances and thereby providing much of the foundation for today’s modern immunology.

In 1905, he published the first fundamental analysis of the ‘serum sickness’.1 At that time, the established treatment of diphtheria infection was the application of an antiserum obtained from horses that had been immunised with diphtheria toxin. This therapy was protective against and was able to cure the disease but …
A Deep Eutectic Solvent‐Based Approach to Intravenous Formulation
Authors: Jayoung Kim, Yujie Shi, Christopher J. Kwon, Yongsheng Gao, Samir Mitragotri
Journal: Advanced Healthcare Materials (2021)

Abstract Clinically viable formulations of hydrophobic drugs, for example, chemotherapeutics, require strategies to promote sufficient drug solubilization. However, such strategies often involve the use of organic solvents that pose a significant risk in generating toxic, unstable products. Using verteporfin as a drug, a deep eutectic solvent (DES)‐based approach to solvate drugs in a simple one‐step process is reported. Lipoidal DES composed of choline and oleate is used to successfully solvate verteporfin, resulting in stable sub‐100 nm nanocomplexes. The nanocomplexes successfully demonstrate efficient cellular uptake as well as retention, tumor spheroid penetration, and tumor accumulation in vivo. Systemic administration of the formulation significantly inhibits the primary tumor growth and its lung metastasis in the orthotopic 4T1 murine breast tumor model. Collectively, biocompatible DES shows great potential as a novel material for intravenous formulation of chemotherapeutics.
Impairment of mitophagy and autophagy accompanies calcific aortic valve stenosis favouring cell death and the severity of disease
Authors: Giampaolo Morciano, Simone Patergnani, Gaia Pedriali, Paolo Cimaglia, Elisa Mikus, Simone Calvi, Alberto Albertini, Carlotta Giorgi, Gianluca Campo, Roberto Ferrari, Paolo Pinton
Journal: Cardiovascular Research (2021)

In the last 15 years, some observations tried to shed light on the dysregulation of the cellular self-digestion process in calcific aortic valve stenosis (CAVS), but the results obtained remain still controversial. This work is aimed to definitively establish the trend of autophagy in patients affected by CAVS, to analyse the putative involvement of other determinants, which impact on the mitochondrial quality control mechanisms and to explore possible avenues for pharmacological interventions in the treatment of CAVS.This observational study, performed exclusively in ex vivo human samples (cells and serum), by using biochemical approaches and correlations with clinical data, describes new biological features of the calcified valve in terms of mitochondrial dysfunctions. In detail, we unveiled a significant deficiency in mitochondrial respiration and in ATP production coupled to increase production of lactates. In addition, mitochondrial population in the pathologic group is aged with significant alterations in biogenesis and mitophagy pathways. We are also reporting an updated view about autophagy accompanying the calcification process and advanced stages of the disease. We provided evidence for a rapamycin-based therapeutic strategy to revert the calcified phenotype to the wild type one.Our data suggest that the CAVS phenotype is featured by defects in mitochondrial quality control mechanisms and that autophagy is not activated enough to counteract cell death and sustain cell functions. Thus, boosting autophagy and mitophagy from short- to long-term reverts quite all pathological phenotypes.
急性呼吸窮迫症候群【JST・京大機械翻訳】
Authors: A Matthay Michael, L Zemans Rachel, A Zimmerman Guy, M Arabi Yaseen, R Beitler Jeremy, Mercat Alain, Herridge Margaret, G Randolph Adrienne, S Calfee Carolyn
Journal: Nature Reviews Disease Primers (2019)
Abusive Head Trauma and Infant Crying—A Flawed Analysis—Reply
Authors: Niels Lynøe, Anders Eriksson
Journal: JAMA Pediatrics (2021)

In Reply Unfortunately, disapproval of our Viewpoint1 seems to have resulted in fatal misinterpretations and blinded the authors from our constructive suggestion for improvements in future studies. We would like to reply to each of the authors’ points accordingly.
Mycophenolate Mofetil for First-Line Treatment of Immune Thrombocytopenia
Authors: Charlotte A. Bradbury, Julie Pell, Quentin Hill, Catherine Bagot, Nichola Cooper, Jenny Ingram, Katie Breheny, Rebecca Kandiyali, Rachel Rayment, Gillian Evans, Kate Talks, Ian Thomas, Rosemary Greenwood
Journal: New England Journal of Medicine (2021)

Immune thrombocytopenia is a rare autoimmune disorder with associated bleeding risk and fatigue. Recommended first-line treatment for immune thrombocytopenia is high-dose glucocorticoids, but side effects, variable responses, and high relapse rates are serious drawbacks.In this multicenter, open-label, randomized, controlled trial conducted in the United Kingdom, we assigned adult patients with immune thrombocytopenia, in a 1:1 ratio, to first-line treatment with a glucocorticoid only (standard care) or combined glucocorticoid and mycophenolate mofetil. The primary efficacy outcome was treatment failure, defined as a platelet count of less than 30×109 per liter and initiation of a second-line treatment, assessed in a time-to-event analysis. Secondary outcomes were response rates, side effects, occurrence of bleeding, patient-reported quality-of-life measures, and serious adverse events.A total of 120 patients with immune thrombocytopenia underwent randomization (52.4% male; mean age, 54 years [range 17 to 87]; mean platelet level, 7×109 per liter) and were followed for up to 2 years after beginning trial treatment. The mycophenolate mofetil group had fewer treatment failures than the glucocorticoid-only group (22% [13 of 59 patients] vs. 44% [27 of 61 patients]; hazard ratio, 0.41; range, 0.21 to 0.80; P = 0.008) and greater response (91.5% of patients having platelet counts greater than 100×109 per liter vs. 63.9%; P<0.001). We found no evidence of a difference between the groups in the occurrence of bleeding, rescue treatments, or treatment side effects, including infection. However, patients in the mycophenolate mofetil group reported worse quality-of-life outcomes regarding physical function and fatigue than those in the glucocorticoid-only group.The addition of mycophenolate mofetil to a glucocorticoid for first-line treatment of immune thrombocytopenia resulted in greater response and a lower risk of refractory or relapsed immune thrombocytopenia, but with somewhat decreased quality of life. (Funded by the U.K. National Institute for Health Research; FLIGHT ClinicalTrials.gov number, NCT03156452; EudraCT number, 2017-001171-23.).
In–Situ‐Sprayed Dual‐Functional Immunotherapeutic Gel for Colorectal Cancer Postsurgical Treatment
Authors: Xinghui Si, Guofeng Ji, Sheng Ma, Yudi Xu, Jiayu Zhao, Yu Zhang, Zichao Huang, Zhaohui Tang, Wantong Song, Xuesi Chen
Journal: Advanced Healthcare Materials (2021)

Surgery remains the most preferred treatment options for colorectal cancer (CRC). Paradoxically, local recurrence and distant metastasis are usually accelerated postsurgery as a consequence of local and systemic immunosuppression caused by surgery. Therefore, modulating tumor postoperative immune microenvironment and activating systemic antitumor immunity are necessary supplementaries for CRC therapy. Here, an in-situ-sprayed immunotherapeutic gel loaded with anti-OX40 antibody (iSGels@aOX40) is reported for CRC postsurgical treatment. The iSGel is formed instantly after spraying with strong adhesion ability via crosslinking between tannic acid (TA) and poly(l-glutamic acid)-g-methoxy poly(ethylene glycol)/phenyl boronic acid (PLG-g-mPEG/PBA). TA not only serves as one component of the iSGel but also relieves the postsurgical immunosuppressive microenvironment by inhibiting the activity of cyclo-oxygenase-2 (COX-2). The aOX40 serves as an immune agonistic antibody and is released from the iSGel in a constant manner lasting for over 20 days. In a subcutaneous murine CRC model, the iSGels@aOX40 results in complete inhibition on tumor recurrence. In addition, the cured mice show resistance to tumor re-challenge, suggesting that immune memory effects are established after the iSGels@aOX40 treatment. In an orthotopic CRC peritoneal metastatic model, the iSGels@aOX40 also remarkably inhibits the growth of the abdominal metastatic tumors, suggesting great potential for clinical CRC therapy.
Exploring the Causes of Death Among Patients With Metastatic Prostate Cancer—A Changing Landscape
Authors: Samuel W. D. Merriel, Tanimola Martins, Sarah E. R. Bailey
Journal: JAMA Network Open (2021)

Ahmed O. Elmehrath; Ahmed M. Afifi, MBCCh; Muneer J. Al-Husseini, MBCCh; Anas M. Saad, MD; Nathaniel Wilson, MD; Kyrillus S. Shohdy, MBCCh; Patrick Pilie, MD; Mohamad Bassam Sonbol, MD; Omar Alhalabi, MD
P-79 HGCSG1901: A retrospective cohort study evaluating the safety and efficacy of S-1 and irinotecan plus bevacizumab in patients with metastatic colorectal cancer: Analysis of second-line treatment after anti-EGFR antibody
Authors: A. Yoshikawa, K. Ito, S. Yuki, Y. Kawamoto, R. Saito, T. Yamamura, M. Yagisawa, A. Ishiguro, O. Muto, K. Hatanaka, H. Okuda, A. Sato, Y. Sasaki, M. Nakamura, T. Sasaki, T. Kobayashi, M. Dazai, H. Nakatsumi, A. Ueda, Y. Sakata, Y. Komatsu
Journal: Annals of Oncology (2021)
PAX9 Determines Epigenetic State Transition and Cell Fate in Cancer
Authors: Zibo Zhao, Aileen P. Szczepanski, Natsumi Tsuboyama, Hiam Abdala-Valencia, Young Ah Goo, Benjamin D. Singer, Elizabeth T. Bartom, Feng Yue, Lu Wang
Journal: Cancer Research (2021)

Abnormalities in genetic and epigenetic modifications can lead to drastic changes in gene expression profiles that are associated with various cancer types. Small cell lung cancer (SCLC) is an aggressive and deadly form of lung cancer with limited effective therapies currently available. By utilizing a genome-wide CRISPR-Cas9 dropout screen in SCLC cells, we identified paired box protein 9 (PAX9) as an essential factor that is overexpressed in human malignant SCLC tumor samples and is transcriptionally driven by the BAP1/ASXL3/BRD4 epigenetic axis. Genome-wide studies revealed that PAX9 occupies distal enhancer elements and represses gene expression by restricting enhancer activity. In multiple SCLC cell lines, genetic depletion of PAX9 led to significant induction of a primed-active enhancer transition, resulting in increased expression of a large number of neural differentiation and tumor-suppressive genes. Mechanistically, PAX9 interacted and cofunctioned with the nucleosome remodeling and deacetylase (NuRD) complex at enhancers to repress nearby gene expression, which was reversed by pharmacologic HDAC inhibition. Overall, this study provides mechanistic insight into the oncogenic function of the PAX9/NuRD complex epigenetic axis in human SCLC and suggests that reactivation of primed enhancers may have potential therapeutic efficacy in treating SCLC expressing high levels of PAX9. SIGNIFICANCE: A genome-wide screen in small cell lung cancer reveals PAX9/NuRD-mediated epigenetic enhancer silencing and tumor progression, supporting the development of novel personalized therapeutic approaches targeting the PAX9-regulated network.
Effect of Exercise Training on Ambulatory Blood Pressure Among Patients With Resistant Hypertension
Authors: Susana Lopes, José Mesquita-Bastos, Catarina Garcia, Susana Bertoquini, Verónica Ribau, Manuel Teixeira, Ilda P. Ribeiro, Joana B. Melo, José Oliveira, Daniela Figueiredo, Guilherme V. Guimarães, Linda S. Pescatello, Jorge Polonia, Alberto J. Alves, Fernando Ribeiro
Journal: JAMA Cardiology (2021)

Limited evidence suggests exercise reduces blood pressure (BP) in individuals with resistant hypertension, a clinical population with low responsiveness to drug therapy.To determine whether an aerobic exercise training intervention reduces ambulatory BP among patients with resistant hypertension.The Exercise Training in the Treatment of Resistant Hypertension (EnRicH) trial is a prospective, 2-center, single-blinded randomized clinical trial performed at 2 hospital centers in Portugal from March 2017 to December 2019. A total of 60 patients with a diagnosis of resistant hypertension aged 40 to 75 years were prospectively enrolled and observed at the hospitals' hypertension outpatient clinic.Patients were randomly assigned in a 1:1 ratio to a 12-week moderate-intensity aerobic exercise training program (exercise group) or a usual care control group. The exercise group performed three 40-minute supervised sessions per week in addition to usual care.The powered primary efficacy measure was 24-hour ambulatory systolic BP change from baseline. Secondary outcomes included daytime and nighttime ambulatory BP, office BP, and cardiorespiratory fitness.A total of 53 patients completed the study, including 26 in the exercise group and 27 in the control group. Of these, 24 (45%) were women, and the mean (SD) age was 60.1 (8.7) years. Compared with the control group, among those in the exercise group, 24-hour ambulatory systolic BP was reduced by 7.1 mm Hg (95% CI, -12.8 to -1.4; P = .02). Additionally, 24-hour ambulatory diastolic BP (-5.1 mm Hg; 95% CI, -7.9 to -2.3; P = .001), daytime systolic BP (-8.4 mm Hg; 95% CI, -14.3 to -2.5; P = .006), and daytime diastolic BP (-5.7 mm Hg; 95% CI, -9.0 to -2.4; P = .001) were reduced in the exercise group compared with the control group. Office systolic BP (-10.0 mm Hg; 95% CI, -17.6 to -2.5; P = .01) and cardiorespiratory fitness (5.05 mL/kg per minute of oxygen consumption; 95% CI, 3.5 to 6.6; P < .001) also improved in the exercise group compared with the control group.A 12-week aerobic exercise program reduced 24-hour and daytime ambulatory BP as well as office systolic BP in patients with resistant hypertension. These findings provide clinicians with evidence to embrace moderate-intensity aerobic exercise as a standard coadjutant therapy targeting this patient population.ClinicalTrials.gov Identifier: NCT03090529.
Cause of death in patients with newly diagnosed chronic lymphocytic leukemia (CLL) stratified by the CLL-International Prognostic Index
Authors: Yucai Wang, Sara J. Achenbach, Kari G. Rabe, Tait D. Shanafelt, Timothy G. Call, Wei Ding, Saad S. Kenderian, Eli Muchtar, Jose F. Leis, Amber B. Koehler, Susan M. Schwager, James R. Cerhan, Susan L. Slager, Neil E. Kay, Sameer A. Parikh
Journal: Blood Cancer Journal (2021)
Differences Between Children and Adults With Hidradenitis Suppurativa
Authors: Katherine K. Hallock, Marylena R. Mizerak, Alison Dempsey, Steven Maczuga, Joslyn S. Kirby
Journal: JAMA Dermatology (2021)

Up to 50% of patients may have hidradenitis suppurativa (HS) onset between age 10 and 21 years. To our knowledge, little is known about how adolescents with HS utilize health care during their journey to receiving a diagnosis.To assess the clinical characteristics and health care utilization patterns of pediatric vs adult patients with HS.This retrospective cohort study included adult and pediatric patients with HS claims from the MarketScan medical claims database during the study period, January 1, 2012, to December 31, 2016. The data were analyzed between March 1 and March 31, 2021.Clinical characteristics and health care utilization patterns of pediatric vs adult patients with HS.Health care utilization patterns were examined and included concurrent diagnoses, outpatient care by discipline, and emergency/urgent care and inpatient claims.This study included 8727 members, comprising 1094 pediatric (155 male [14.2%] and 939 female patients [85.8%]; mean [SD] age, 14.3 [2.47] years) and 7633 adult patients (1748 men [22.9%] and 5885 women [77.1%]; mean [SD] age, 37.2 [12.99] years). Pediatric patients were likely to see pediatricians, dermatologists, emergency department (ED) staff, and family physicians before diagnosis and commonly received diagnoses of folliculitis and comedones. Pediatric patients with HS had high rates of comorbid skin and general medical conditions, including acne vulgaris (558 [51.0%]), acne conglobata (503 [45.9%]), obesity (369 [33.7%]), and anxiety disorders (367 [33.6%]). A higher percentage of pediatric than adult patients had HS-specific claims for services rendered by emergency and urgent care physicians (35.6% vs 28.2%; P < .001; and 18.1% vs 13.4%; P < .001; respectively). However, adult patients were more likely to have inpatient stays (2.38% vs 4.22%; P = .002). Pediatric patients had 2.24 ED claims per person, while adults had 3.5 claims per person. The mean cost per ED claim was similar between groups ($413.27 vs $682.54; P = .18). The largest component of the total 5-year disease-specific cost was the cost of inpatient visits for pediatric and adult patients with HS.This cohort study suggests that pediatric patients utilize high-cost ED care when HS can often be treated as an outpatient. These data suggest that there are opportunities to improve recognition of HS in pediatric patients by nondermatologists and dermatologists.
Abstract 14601: Rheumatoid Arthritis is the Risk of Progression on Aortic Valve Stenosis in Elderly Patients
Authors: Satoko Ojima, Takuro Kubozono, Shin Kawasoe, Hideo Ohtsubo, Masaaki Miyata, Mitsuru Ohishi
Journal: Circulation (2018)

Introduction: Rheumatoid arthritis (RA) is known as a chronic autoimmune condition resulting in systemic inflammation, which leads to various cardiovascular diseases including atherosclerosis. On t...
Computer-aided detection versus advanced imaging for detection of colorectal neoplasia: a systematic review and network meta-analysis
Authors: Marco Spadaccini, Andrea Iannone, Roberta Maselli, Matteo Badalamenti, Madhav Desai, Viveksandeep Thoguluva Chandrasekar, Harsh K Patel, Alessandro Fugazza, Gaia Pellegatta, Piera Alessia Galtieri, Gianluca Lollo, Silvia Carrara, Andrea Anderloni, Douglas K Rex, Victor Savevski, Michael B Wallace, Pradeep Bhandari, Thomas Roesch, Ian M Gralnek, Prateek Sharma, Cesare Hassan, Alessandro Repici
Journal: The Lancet. Gastroenterology & hepatology (2021)