tbuckley/cabot-search huggingface dataset:
Knockout Tumor Microenvironment HO-1 Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Acute Myeloid Leukemia
Authors: Zhen Zhou, Qin Fang, Dan Ma, Danna Wei, Xiuying Hu, Yudan Liao, Jishi Wang
Journal: Blood (2018)
Abstract 18088: Myocardial Delivery of Lipidoid Nanoparticle mRNA Designed for Tailored Expression of Cardiogenic Factors
Authors: Irene C Turnbull, Ahmed A Eltoukhy, Kenneth M Fish, Roger J Hajjar, Daniel G Anderson, Kevin D Costa
Journal: Circulation (2013)

Introduction: Nanoparticle-based delivery of mRNA offers a potential alternative to viral vectors for gene therapy, but efficacy has not been demonstrated in the heart. As a proof of concept, we report the first successful lipidoid nanoparticle (LNP) mediated delivery of mRNA to rat myocardium as a novel approach for controlling the timing and distribution of expression of therapeutic factors for cardiac repair. Methods and Results: Custom lipidoid formulation yielded functionally stable LNPs containing modified eGFP mRNA. LNP solution (600 uL) was delivered by injection at 8 to 10 sites into adult rat myocardium, followed by recovery. At time of sacrifice, the heart was cut in two: 1) mRNA level was quantified by real time-PCR, and 2) eGFP protein was detected by immunofluorescence of cryosections. To test the dose response (Fig. A), rats received 1, 5 or 10 ug eGFP mRNA (n = 3 per group) and were sacrificed 20 h after injection; compared to saline control, the fold increase in eGFP mRNA in the heart was 142 ± 116, 5628 ± 1292 and 5470 ± 3103 fold, respectively, with higher dosages showing a significant effect (p &lt; 0.05). Fluorescence microscopy confirmed GFP-positive cells in the subepicardium of all treated hearts. Expression kinetics at different time points after injection of 5 ug of eGFP mRNA showed that expression at 6 h (18,380 ± 5457 fold) was significantly higher than at 20 h (p &lt; 0.05), with expression still detectable at 48 h. Biodistribution of eGFP mRNA in harvested lung, liver, spleen, kidney, skeletal muscle, and brain (Fig. B) showed the delivery was cardiac specific, with off-target expression levels less than 1% of that in the heart. Conclusion: Adult rat myocardium was successfully transduced, supporting our hypothesis that lipidoid nanoparticles carrying mRNA allow effective message delivery to cardiac cells in vivo, with potential to optimize gene therapy for enhanced cardiac function and regeneration.
Aromatic solvents: the not so sweet side
Authors: Johanna Feary
Journal: Thorax (2019)

In their published article, Alif et al report the findings from a carefully conducted longitudinal study showing the effects of occupational exposures on lung function decline between the ages of 45 and 50 years.1 Data from 767 participants in the Tasmanian Longitudinal Health Study (TLHS) were examined: ‘ever’ exposure to aromatic solvents was associated with an excess decline in FEV1 over that expected by ageing (15.5 mL/year (95% CI −24.8 to 6.3)) and in FVC (14.1 mL/year (95% CI −28.8 t0 –0.7)); as was ‘ever’ exposure to metals (FEV1 (11.3 mL/year (95% CI −21.9 to –0.7)) and FVC (17.5 mL/year (95% CI −34.3 to –0.8))). This accelerated decline was also apparent for cumulative exposure to aromatic solvents, and interestingly, despite having lower overall exposures, the decline was greater in women than in men. The authors also found an excess decline in FEV1 in those with ever exposure to gases and fumes and to chlorinated solvents and in FVC in those exposed to ‘other’ solvents.

Accelerated decline in spirometric measures is important. It may, of course, herald future development of respiratory disease but has been shown to be a predictor of all-cause mortality, independent of smoking.2 As respiratory clinicians, we are often drawn towards trends in FEV1, but there is also evidence suggesting the importance of FVC as an overall marker of lung health.3 The TLHS cohort was recruited at the age of 7 years, and therefore, importantly (and unusually), the authors were able to adjust for childhood socioeconomic status, a potentially important predictor of lung function decline.

While associations between occupational exposures and lower lung function have been observed in a number of cross-sectional studies, there are only a limited number of published longitudinal studies which can provide stronger evidence to support a causal relationship.

Alif et …
A live-attenuated RhCMV/SIV vaccine shows long-term efficacy against heterologous SIV challenge
Authors: Scott G. Hansen, Emily E. Marshall, Daniel Malouli, Abigail B. Ventura, Colette M. Hughes, Emily Ainslie, Julia C. Ford, David Morrow, Roxanne M. Gilbride, Jin Y. Bae, Alfred W. Legasse, Kelli Oswald, Rebecca Shoemaker, Brian Berkemeier, William J. Bosche, Michael Hull, Jennie Womack, Jason Shao, Paul T. Edlefsen, Jason S. Reed, Ben J. Burwitz, Jonah B. Sacha, Michael K. Axthelm, Klaus Früh, Jeffrey D. Lifson, Louis J. Picker
Journal: Science Translational Medicine (2019)

Highly attenuated pp71-deleted RhCMV/SIV vectors elicit immune responses that stringently protect 59% of vaccinated monkeys from SIV challenge.
MALAT1 rs664589 Polymorphism Inhibits Binding to miR-194-5p, Contributing to Colorectal Cancer Risk, Growth, and Metastasis
Authors: Shenshen Wu, Hao Sun, Yajie Wang, Xi Yang, Qingtao Meng, Hongbao Yang, Haitao Zhu, Weiyan Tang, Xiaobo Li, Michael Aschner, Rui Chen
Journal: Cancer Research (2019)

Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) is an evolutionarily highly conserved lncRNA that contributes to colorectal cancer development. However, the exact molecular mechanisms connecting MALAT1 to colorectal cancer have not been fully elucidated. Here, we performed a case-control study in 1,078 patients with colorectal cancer and 1,175 healthy controls to evaluate the association between potentially functional genetic variants of MALAT1 and survival outcomes in patients with colorectal cancer. MALAT1 rs664589 CG/GG genotypes significantly increased the associated risk and decreased overall survival of patients with colorectal cancer compared with the CC genotype. In vitro and in vivo experiments showed that the rs664589 C to G mutation facilitated carcinogenesis and metastasis of colorectal cancer. Mechanistically, the miRNA miR-194-5p targeted MALAT1 for degradation in the nucleus in an Ago2-dependent manner; the rs664589 G allele altered the binding of MALAT1 to miR-194-5p, resulting in increased expression of MALAT1. Colorectal cancer cells and human tissues with the rs664589 CG/GG genotype expressed significantly higher MALAT1 than those with the rs664589 CC genotype. Multivariate Cox regression analysis showed that MALAT1 was a poor prognostic factor of colorectal cancer. In summary, MALAT1 with the rs664589 G allele demonstrates altered binding to miR-194-5p in the nucleus, leading to increased MALAT1 expression and enhanced colorectal cancer development. SIGNIFICANCE: These findings highlight the functional role of MALAT1 polymorphism in colorectal cancer metastasis and survival as well as the underlying mechanism.
Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance
Authors: Serena Spudich, Kevin R. Robertson, Ronald J. Bosch, Rajesh T. Gandhi, Joshua C. Cyktor, Hanna Mar, Bernard J. Macatangay, Christina M. Lalama, Charles Rinaldo, Ann C. Collier, Catherine Godfrey, Joseph J. Eron, Deborah McMahon, Jana L. Jacobs, Dianna Koontz, Evelyn Hogg, Alyssa Vecchio, John W. Mellors
Journal: Journal of Clinical Investigation (2019)

BACKGROUND. Persistence of HIV in sanctuary sites despite antiretroviral therapy (ART) presents a barrier to HIV remission and may affect neurocognitive function. We assessed HIV persistence in cerebrospinal fluid (CSF) and associations with inflammation and neurocognitive performance during long-term ART.
FDG PET/CT of Mediastinal Epithelioid Hemangioendothelioma
Authors: Nir Hod, Reut Anconina, Daniel Levin, Bertha Delgado, Julia Dudnik, Sophie Lantsberg
Journal: Clinical Nuclear Medicine (2019)

Epithelioid hemangioendothelioma is a rare low- to intermediate-grade malignant vascular neoplasm with a variable clinical course and currently no standardized treatment. We present a case of a 65-year-old woman diagnosed as having mediastinal epithelioid hemangioendothelioma, a location which is very exceptional. FDG PET/CT was more sensitive than CT for staging, revealing intense FDG uptake in the primary tumor and in the metastatic disease. Despite high FDG uptake, the disease was stable with no further specific treatment. Only few reports utilizing FDG PET/CT are available; review of the literature on this subject is included.
Expandable human cardiovascular progenitors from stem cells for regenerating mouse heart after myocardial infarction
Authors: Verena Schwach, Maria Gomes Fernandes, Saskia Maas, Sophie Gerhardt, Roula Tsonaka, Louise van der Weerd, Robert Passier, Christine L Mummery, Matthew J Birket, Daniela C F Salvatori
Journal: Cardiovascular Research (2019)

Cardiovascular diseases caused by loss of functional cardiomyocytes (CMs) are a major cause of mortality and morbidity worldwide due in part to the low regenerative capacity of the adult human heart. Human pluripotent stem cell (hPSC)-derived cardiovascular progenitor cells (CPCs) are a potential cell source for cardiac repair. The aim of this study was to examine the impact of extensive remuscularization and coincident revascularization on cardiac remodelling and function in a mouse model of myocardial infarction (MI) by transplanting doxycycline (DOX)-inducible (Tet-On-MYC) hPSC-derived CPCs in vivo and inducing proliferation and cardiovascular differentiation in a drug-regulated manner.CPCs were injected firstly at a non-cardiac site in Matrigel suspension under the skin of immunocompromised mice to assess their commitment to the cardiovascular lineage and ability to self-renew or differentiate in vivo when instructed by systemically delivered factors including DOX and basic fibroblast growth factor (bFGF). CPCs in Matrigel were then injected intra-myocardially in mice subjected to MI to assess whether expandable CPCs could mediate cardiac repair. Transplanted CPCs expanded robustly both subcutis and in the myocardium using the same DOX/growth factor inducing regime. Upon withdrawal of these cell-renewal factors, CPCs differentiated with high efficiency at both sites into the major cardiac lineages including CMs, endothelial cells, and smooth muscle cells. After MI, engraftment of CPCs in the heart significantly reduced fibrosis in the infarcted area and prevented left ventricular remodelling, although cardiac function determined by magnetic resonance imaging was unaltered.Replacement of large areas of muscle may be required to regenerate the heart of patients following MI. Our human/mouse model demonstrated that proliferating hPSC-CPCs could reduce infarct size and fibrosis resulting in formation of large grafts. Importantly, the results suggested that expanding transplanted cells in situ at the progenitor stage maybe be an effective alternative causing less tissue damage than injection of very large numbers of CMs.
Prevalence and Incidence of Anxiety and Depression Among Children, Adolescents, and Young Adults With Life-Limiting Conditions
Authors: Mary M. Barker, Bryony Beresford, Martin Bland, Lorna K. Fraser
Journal: JAMA Pediatrics (2019)

Children, adolescents, and young adults with life-limiting conditions experience various challenges that may make them more vulnerable to mental health problems, such as anxiety and depression. However, the prevalence and incidence of anxiety and depression among this population appears to be unknown.To conduct a systematic review and meta-analysis to estimate the prevalence and/or incidence of anxiety and depression in children, adolescents, and young adults with life-limiting conditions.Searches of MEDLINE (PubMed), PsycInfo, and Embase were conducted to identify studies published between January 2000 and January 2018.Studies were eligible for this review if they provided primary data of anxiety or depression prevalence and/or incidence, included participants aged 5 to 25 years with a life-limiting condition, were conducted in an Organisation for Economic Co-operation and Development country, and were available in English.Random-effects meta-analyses were generated to provide anxiety and depression prevalence estimates. Meta-regression was conducted to analyze associations between study characteristics and each prevalence estimate.Prevalence of anxiety and depression.A total of 14 866 nonduplicate articles were screened, of which 37 were included in the review. Of these, 19 studies reported anxiety prevalence, and 36 studies reported depression prevalence. The mean (range) age of participants was 15.4 (6-25) years. The meta-analysis of anxiety prevalence (n = 4547 participants) generated a pooled prevalence estimate of 19.1% (95% CI, 14.1%-24.6%). Meta-regression analysis found statistically significant differences in anxiety prevalence by assessment tool; diagnostic interviews were associated with higher anxiety prevalence (28.5% [95% CI, 13.2%-46.8%]) than self-reported or parent-reported measures (14.9% [95% CI, 10.9%-19.4%]). The depression meta-analysis (n = 5934 participants) found a pooled prevalence estimate of 14.3% (95% CI, 10.5%-18.6%). Meta-regression analysis revealed statistically significant differences in depression prevalence by the mean age of the sample (β = 0.02 [95% CI, 0.01-0.03]; P = .001).In this systematic review and meta-analysis, the prevalence of anxiety and depression among children, adolescents, and young adults with life-limiting conditions was high, highlighting the need for increased psychological assessment and monitoring. Further research is required to determine the prevalence and incidence of anxiety and depression in a larger sample of children, adolescents, and young adults with a broader range of life-limiting conditions.
A Pilot Experience of Endoscopic Submucosal Dissection of Barrett’s Dysplasia Despite Esophageal Varices and Decompensated Cirrhosis
Authors: Andrew Y. Wang, Elliot Z. Smith, Bryan G. Sauer, Zachary H. Henry, Neeral L. Shah, Stephen H. Caldwell
Journal: Hepatology (2019)

Wang, Andrew Y.; Smith, Elliot Z.; Sauer, Bryan G.; Henry, Zachary H.; Shah, Neeral L.; Caldwell, Stephen H. Author Information
Case 21-2019: A 31-Year-Old Woman with Vision Loss
Authors: Marcelo Matiello, Amy F. Juliano, Michael Bowley, Amel Karaa
Journal: New England Journal of Medicine (2019)

A 31-year-old woman was evaluated because of vision loss, which had developed in the left eye 3 weeks before presentation. Despite the administration of glucocorticoid therapy, vision loss eventually occurred in the right eye. A diagnostic test was performed.
Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial
Authors: Saad Zafar Usmani, Fredrik Schjesvold, Albert Oriol, Lionel Karlin, Michele Cavo, Robert M Rifkin, Habte Aragaw Yimer, Richard LeBlanc, Naoki Takezako, Robert Donald McCroskey, Andrew Boon Ming Lim, Kenshi Suzuki, Hiroshi Kosugi, George Grigoriadis, Irit Avivi, Thierry Facon, Sundar Jagannath, Sagar Lonial, Razi Uddin Ghori, Mohammed Z H Farooqui, Patricia Marinello, Jesus San-Miguel, Andrew Lim, George Grigoriadis, Trish Walker, Andrew Nicol, Richard LeBlanc, Donna Reece, Mohamed Elemary, Jean Samuel Boudreault Pedneault, Lionel Karlin, Thierry Facon, Michel Attal, Katja Weisel, Monika Engelhardt, Andreas Mackensen, John Quinn, Irit Avivi, Amos Cohen, Hila Magen-Nativ, Noam Benyamini, Michele Cavo, Alessandra Larocca, Naoki Takezako, Kenshi Suzuki, Hiroshi Kosugi, Morio Matsumoto, Shinsuke Iida, Takayuki Ishikawa, Yukio Kondo, Kazutaka Sunami, Kiyoshi Ando, Takanori Teshima, Takaaki Chou, Hiromi Iwasaki, Hirokazu Miki, Itaru Matsumura, Yasushi Onishi, Koji Izutsu, Masahiro Kizaki, Anupkumar George, Hillary Blacklock, David Simpson, Fredrik Schjesvold, Anders Waage, Olga Samoilova, Evgeniy Nikitin, Tatiana Chagorova, Andrew McDonald, Moosa Patel, Albert Oriol Rocafiguera, Jesus San Miguel Izquierdo, Maria Mateos, Matthew Streetly, Peter Forsyth, Graham Jackson, Stephen Jenkins, Robert Rifkin, Habte Yimer, Robert McCroskey, Danko Martincic, Stefano Tarantolo, Sarah Larson, Yacoub Faroun, Jennifer Vaughn, Rachid Baz, Gene Saylors, Amarendra Neppalli, Anastasios Raptis, Henry Fung, Maxwell Janosky, Don Stevens, Morton Coleman, Dennis Costa, Scott Cross, Suzanne Fanning, Daniel Farray Berges, Thomas Harris, Ira Zackon, Djordje Atanackovic, Kelvin Lee, Ira Oliff, Wes Lee, William Bensinger, Jose Lutzky, Ari Baron, Fadi Hayek, Eli Kirschner, Neeraj Bharany, Lindsay Overton, Siva Mannem, Allyson Harroff, Sharad Jain, Tammy Roque, Kristi McIntyre, Christopher K Yasencha, William Houck
Journal: The Lancet Haematology (2019)
Mitochondria Permeability Transition versus Necroptosis in Oxalate-Induced AKI
Authors: Shrikant Ramesh Mulay, Mohsen M. Honarpisheh, Orestes Foresto-Neto, Chongxu Shi, Jyaysi Desai, Zhi Bo Zhao, Julian A. Marschner, Bastian Popper, Ewa Miriam Buhl, Peter Boor, Andreas Linkermann, Helen Liapis, Rostyslav Bilyy, Martin Herrmann, Paola Romagnani, Ilya Belevich, Eija Jokitalo, Jan U. Becker, Hans-Joachim Anders
Journal: Journal of the American Society of Nephrology (2019)

Serum oxalate levels suddenly increase with certain dietary exposures or ethylene glycol poisoning and are a well known cause of AKI. Established contributors to oxalate crystal-induced renal necroinflammation include the NACHT, LRR and PYD domains-containing protein-3 (NLRP3) inflammasome and mixed lineage kinase domain-like (MLKL) protein-dependent tubule necroptosis. These studies examined the role of a novel form of necrosis triggered by altered mitochondrial function.To better understand the molecular pathophysiology of oxalate-induced AIK, we conducted in vitro studies in mouse and human kidney cells and in vivo studies in mice, including wild-type mice and knockout mice deficient in peptidylprolyl isomerase F (Ppif) or deficient in both Ppif and Mlkl.Crystals of calcium oxalate, monosodium urate, or calcium pyrophosphate dihydrate, as well as silica microparticles, triggered cell necrosis involving PPIF-dependent mitochondrial permeability transition. This process involves crystal phagocytosis, lysosomal cathepsin leakage, and increased release of reactive oxygen species. Mice with acute oxalosis displayed calcium oxalate crystals inside distal tubular epithelial cells associated with mitochondrial changes characteristic of mitochondrial permeability transition. Mice lacking Ppif or Mlkl or given an inhibitor of mitochondrial permeability transition displayed attenuated oxalate-induced AKI. Dual genetic deletion of Ppif and Mlkl or pharmaceutical inhibition of necroptosis was partially redundant, implying interlinked roles of these two pathways of regulated necrosis in acute oxalosis. Similarly, inhibition of mitochondrial permeability transition suppressed crystal-induced cell death in primary human tubular epithelial cells. PPIF and phosphorylated MLKL localized to injured tubules in diagnostic human kidney biopsies of oxalosis-related AKI.Mitochondrial permeability transition-related regulated necrosis and necroptosis both contribute to oxalate-induced AKI, identifying PPIF as a potential molecular target for renoprotective intervention.
Decentralized care with generic direct-acting antivirals in the management of chronic hepatitis C in a public health care setting
Authors: Radha K. Dhiman, Gagandeep S. Grover, Madhumita Premkumar, Sunil Taneja, Ajay Duseja, Sanjeev Arora, Sahaj Rathi, Sandeep Satsangi, Akash Roy
Journal: Journal of Hepatology (2019)
Genome‐wide association studies and polygenic risk scores for skin cancer: clinically useful yet?
Authors: M.R. Roberts, M.M. Asgari, A.E. Toland
Journal: British Journal of Dermatology (2019)

BackgroundGenome‐wide association studies (GWAS) have identified thousands of susceptibility variants, although most have been associated with small individual risk estimates that offer little predictive value. However, combining multiple variants into polygenic risk scores (PRS) may be more informative. Multiple studies have developed PRS composed of GWAS‐identified variants for cutaneous cancers. This review highlights data from these studies.
Effect of early detection of recurrent disease by FDG PET/CT on management of patients with squamous cell cancer of the head and neck (HNSCC).
Authors: Lale Kostakoglu, Reza Fardanesh, Eric Genden, Srikar Rao, John Doucette, Peter M. Som, Vishal Gupta, Krzysztof Misiukiewicz, Marshall R. Posner
Journal: Journal of Clinical Oncology (2013)

6062 Background: Despite the increasing cure rates a substantial fraction of HNSCC patients (pts) will present with locoregional and/or distant relapse within 3 years of definitive therapy. The prognosis of HNSCC pts after failure of first-line therapy has been poor but recent changes in the biology of HNSCC, advances in surgical techniques and radiotherapy; and new drugs may lead to improved salvage therapy. Notably, the success of these developments are implicitly dependent on early diagnosis disease. Our objective was to compare the efficacy of surveillance FDG-PET/CT to that of high resolution CT (HRCT) and physical exam (PE/E) for detection of early relapse in HNSCC after completion of primary treatment. Methods: A retrospective analysis of FDG-PET/CT, neck HRCT and PE/E was performed in 99 curatively treated HNSCC pts during post-therapy surveillance (PTS) to compare the performance characteristics of the tests in the detection of early recurrence or metachronous cancer. Results: A total of 19/99 (20%) pts had recurrence during a median follow-up of 21mo (range:9-52). Median time to first PET/CT was 3.5mo. The median time to radiological recurrence was 6 mo (range:2.3-32). PET/CT detected more disease recurrences or second primaries and did so earlier than HRCT and PE/E. Sensitivity, specificity, PPVand NPV for detecting locoregional and distant recurrence or metachronous cancer : 100%, 87.3%, 56.5% and 100% for PET/CT vs. 61.5%, 94.9%, 66.7% and 93.8% for HRCT vs. 23.1%, 98.7%, 75% and 88.6% for PE/E. In all 19 pts with a true positive PET/CT there was a significant management change prompting either salvage or definitive surgery or initiation of systemic therapy. Of the 14 recurrent pts treated with curative intent, 11 were alive with no evidence of disease at a median follow up of 31.5 mo. Conclusions: FDG-PET/CT has a high sensitivity in the early detection of relapse or second primary cancer in HNSCC, associated with significant management implications. Given improvements in therapy and changes in HNSSC biology, appropriate modifications in the current recommended algorithms of the NCCN for PTS may be required to engage effective salvage or definitive therapies.