tbuckley/cabot-search huggingface dataset:
Overcoming hypoxia-induced functional suppression of NK cells
Authors: Kristen Solocinski, Michelle R Padget, Kellsye P Fabian, Benjamin Wolfson, Fabiola Cecchi, Todd Hembrough, Stephen C Benz, Shahrooz Rabizadeh, Patrick Soon-Shiong, Jeffrey Schlom, James W Hodge
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Natural killer (NK) cells are immune cells capable of killing virally infected cells and tumor cells without the need for antigen stimulation. Tumors, however, can create a suppressive microenvironment that decreases NK function. A feature of many tumors is hypoxia (low oxygen perfusion), which has been previously shown to decrease NK function. A high affinity NK (haNK) cell has been engineered to express a high affinity CD16 receptor as well as internal interleukin (IL)-2 for increased antibody-dependent cellular cytotoxicity (ADCC) and activation, respectively. We sought to investigate the tolerance of NK cells versus haNK cells to hypoxia. Methods We exposed healthy donor (HD) NK and X-irradiated haNK cells to normoxia (20% oxygen) as well as hypoxia (0% oxygen) and investigated their ability to kill prostate, breast and lung tumor cell lines after 5 hours. We also used monoclonal antibodies cetuximab (anti-EGFR) or avelumab (antiprogrammed death-ligand 1) to investigate the effects of hypoxia on NK ADCC. Genomic and proteomic analyzes were done to determine the effect of hypoxia on the expression of factors important to NK cell function. Results While HD NK cell cytolytic abilities were markedly and significantly impaired under hypoxic conditions, haNK cells maintained killing capacity under hypoxic conditions. NK killing, serial killing and ADCC were maintained under hypoxia in haNK cells. IL-2 has been previously implicated in serial killing and perforin regeneration and thus the endogenous IL-2 produced by haNK cells is likely a driver of the maintained killing capacity of haNK cells under hypoxic conditions. Activation of signal transducer and activator of transcription 3 (STAT3) is not seen in haNKs under hypoxia but is significant in HD NK cells. Pharmaceutical activation of STAT3 in haNKs led to reduced killing, implicating active STAT3 in reduced NK cell function. Conclusions In contrast to HD NK cells, haNK cells are resistant to acute hypoxia. The potent cytolytic function of haNK cells was maintained in an environment comparable to what would be encountered in a tumor. The data presented here provide an additional mechanism of action for haNK cells that are currently being evaluated in clinical trials for several tumor types.
16S rRNA sequencing analysis: the devil is in the details
Authors: Amy M. Tsou, Scott W. Olesen, Eric J. Alm, Scott B. Snapper
Journal: Gut Microbes (2020)

User-friendly computational tools for 16S ribosomal RNA (rRNA) sequencing analysis enable researchers who are not bioinformaticians to analyze and interpret sequencing data from microbial communities. These tools' easy-to-use interfaces belie the sophisticated and rapidly-evolving science of their underlying algorithms. When analyzing 16S data from a simple microbiome experiment, we found that superficially unimportant decisions about the bioinformatic pipeline led to results with radically different biological interpretations. We share these results as a cautionary tale whose moral is that, in 16S analysis, the devil is in the details. Wet bench researchers should therefore strongly consider partnering with bioinformaticians or computational biologists when analyzing 16S data.
Neutrophil Extracellular Traps Participate in Cardiovascular Diseases
Authors: Yvonne Döring, Peter Libby, Oliver Soehnlein
Journal: Circulation Research (2020)

Neutrophil extracellular traps (NETs) have recently emerged as a newly recognized contributor to venous and arterial thrombosis. These strands of DNA extruded by activated or dying neutrophils, decorated with various protein mediators, become solid-state reactors that can localize at the critical interface of blood with the intimal surface of diseased arteries and propagate and amplify the regional injury. NETs thus furnish a previously unsuspected link between inflammation, innate immunity, thrombosis, oxidative stress, and cardiovascular diseases. In response to disease-relevant stimuli, neutrophils undergo a specialized series of reactions that culminate in NET formation. DNA derived from either nuclei or mitochondria can contribute to NET formation. The DNA liberated from neutrophils forms a reticular mesh that resembles morphologically a net, rendering the acronym NETs particularly appropriate. The DNA backbone of NETs not only presents intrinsic neutrophil proteins (eg, MPO [myeloperoxidase] and various proteinases) but can gather other proteins found in blood (eg, tissue factor procoagulant). This review presents current concepts of neutrophil biology, the triggers to and mechanisms of NET formation, and the contribution of NETs to atherosclerosis and to thrombosis. We consider the use of markers of NETs in clinical studies. We aim here to integrate critically the experimental literature with the growing body of clinical information regarding NETs.
Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort
Authors: Martin Mynarek, Katja von Hoff, Torsten Pietsch, Holger Ottensmeier, Monika Warmuth-Metz, Brigitte Bison, Stefan Pfister, Andrey Korshunov, Tanvi Sharma, Natalie Jaeger, Marina Ryzhova, Olga Zheludkova, Andrey Golanov, Elisabeth Jane Rushing, Martin Hasselblatt, Arend Koch, Ulrich Schüller, Andreas von Deimling, Felix Sahm, Martin Sill, Markus J. Riemenschneider, Hildegard Dohmen, Camelia Maria Monoranu, Clemens Sommer, Ori Staszewski, Christian Mawrin, Jens Schittenhelm, Wolfgang Brück, Katharina Filipski, Christian Hartmann, Matthias Meinhardt, Klaus Pietschmann, Christine Haberler, Irene Slavc, Nicolas U. Gerber, Michael Grotzer, Martin Benesch, Paul Gerhardt Schlegel, Frank Deinlein, André O. von Bueren, Carsten Friedrich, Björn-Ole Juhnke, Denise Obrecht, Gudrun Fleischhack, Robert Kwiecien, Andreas Faldum, Rolf Dieter Kortmann, Marcel Kool, Stefan Rutkowski
Journal: Journal of Clinical Oncology (2020)

The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy.From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) from the HIT group and Russia.Five years after diagnosis, patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN; n = 42) had 93% progression-free survival (5y-PFS), 100% overall survival (5y-OS), and 93% CSI-free (5y-CSI-free) survival. Patients with CMB/LCA (n = 45) had 37% 5y-PFS, 62% 5y-OS, and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in patients with CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS, 36%; n = 14) relapsed more frequently than the SHH-INF group (5y-PFS, 93%; n = 28) or group 4 patients (5y-PFS, 83%; n = 6; P < .001). SHH-INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I, 73%, v iSHH-II, 83%; P = .25; n = 99). Intelligence quotient (IQ) was significantly lower in patients after CSI (mean IQ, 90 [no radiotherapy], v 74 [CSI]; P = .012).Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in patients with non-wingless (WNT)/non-SHH disease with CMB/LCA was not improved by local radiotherapy. Patients with group 4 disease had more favorable survival rates than those with group 3 medulloblastoma.
Rib Plasmacytoma With Unusual Sunburst Periosteal Reaction
Authors: Vijay Singh, Ajay Kumar Suraj, Vineet Mishra, Manish Ora, Sanjay Gambhir
Journal: Clinical Nuclear Medicine (2020)

Abstract A 39-year-old man presented with progressive painful swelling on the left chest since 6 months. Examination revealed osseous consistency mass. CT of the thorax suggested mass arising from left fourth rib with intrathoracic and extrathoracic soft tissue components. It had extensive sunburst periosteal reaction consistent with primary malignant bone tumor. True cut biopsy revealed plasmacytoma. Routine hematological, biochemical, and bone marrow examinations were normal. Patient referred for whole-body 18 F-FDG PET/CT to look for skeletal and bone marrow lesions. It revealed intensely metabolic left fourth rib lesion with periosteal reaction and no other lesion in the rest of the body.
Current Knowledge and Research Priorities in the Digestive Manifestations of COVID-19
Authors: Olga C. Aroniadis, Christopher J. DiMaio, Rebekah E. Dixon, B. Joseph Elmunzer, Jennifer M. Kolb, Robin Mendelsohn, Collins O. Ordiah, Don C. Rockey, Amit G. Singal, Rebecca L. Spitzer, William M. Tierney, Sachin Wani, Dhiraj Yadav
Journal: Clinical Gastroenterology and Hepatology (2020)
A Commentary on the article: Visualising improved peritoneal perfusion at lower intra-abdominal pressure by fluorescent imaging during laparoscopic surgery: A randomised controlled study, Int J Surg. 2020 Mar 17. pii: S1743-9191(20)30231-4. doi: 10.1016/j.ijsu.2020.03.019
Authors: Faramarz Karimian
Journal: International Journal of Surgery (2020)
Non-apoptotic cell death induced by opening the large conductance mechanosensitive channel MscL in hepatocellular carcinoma HepG2 cells
Authors: Xiaoxu Wen, Siyang Tang, Feifan Hong, Xiaomin Wang, Sihan Chen, Lang Hong, Jia Ye, Xia Li, Shiqiang Shang, Mizu Jiang, Jianhua Mao, Qiang Shu, Yuezhou Li
Journal: Biomaterials (2020)
Cathepsin S Regulates Antigen Processing and T Cell Activity in Non-Hodgkin Lymphoma
Authors: Elie Dheilly, Elena Battistello, Natalya Katanayeva, Stephanie Sungalee, Justine Michaux, Gerben Duns, Sarah Wehrle, Jessica Sordet-Dessimoz, Marco Mina, Julien Racle, Pedro Farinha, George Coukos, David Gfeller, Anja Mottok, Robert Kridel, Bruno E. Correia, Christian Steidl, Michal Bassani-Sternberg, Giovanni Ciriello, Vincent Zoete, Elisa Oricchio
Journal: Cancer Cell (2020)
Editor's Note: Identification of Insulin-Like Growth Factor Binding Protein-3 as a Farnesyl Transferase Inhibitor SCH66336-Induced Negative Regulator of Angiogenesis in Head and Neck Squamous Cell Carcinoma
Authors: Seung-Hyun Oh, Woo-Young Kim, Jai-Hyun Kim, Maher N. Younes, Adel K. El-Naggar, Jeffrey N. Myers, Merril Kies, Pinchas Cohen, Fadlo Khuri, Waun K. Hong, Ho-Young Lee
Journal: Clinical Cancer Research (2019)
Recovery of transverse strain in high-stress tendons following exercise [Conference Abstract]
Authors: Scott Wearing, Simon Locke, Jill Cook, Craig Purdam, James Smeathers
Journal: British Journal of Sports Medicine (2013)

Background. This study evaluated the time course of recovery of transverse strain in the Achilles and patellar tendons following a bout of resistance exercise. Methods. Seventeen healthy adults underwent sonographic examination of the right patellar (n = 9) or Achilles (n = 8) tendons immediately prior to and following 90 repetitions of weight–bearing exercise. Quadriceps and gastrocnemius exercise were performed against an effective resistance of 175% and 250% body weight, respectively. Sagittal tendon thickness was determined 20 mm from the tendon enthesis and transverse strain was repeatedly monitored over a 24 hour recovery period. Results. Resistance exercise resulted in an immediate decrease in Achilles (t7 = 10.6, P<.01) and patellar (t8 = 8.9, P<.01) tendon thickness, resulting in an average transverse strain of 0.14 ± 0.04 and 0.18 ± 0.05. While the average strain was not significantly different between tendons, older age was associated with a reduced transverse strain response (r=0.63, P<.01). Recovery of transverse strain, in contrast, was prolonged compared with the duration of loading and exponential in nature. The mean primary recovery time was not significantly different between Achilles (6.5 ± 3.2 hours) and patellar (7.1 ± 3.2 hours) tendons and body weight accounted for 62% and 64% of the variation in recovery time, respectively. Discussion. Despite structural and biochemical differences between the Achilles and patellar tendons [1], the mechanisms underlying transverse creep–recovery in vivo appear similar and are highly time dependent. Primary recovery required about 7 hours in healthy tendons, with full recovery requiring up to 24 hours. These in vivo recovery times are similar to those reported for axial creep recovery of the vertebral disc in vitro [2], and may be used clinically to guide physical activity to rest ratios in healthy adults. Optimal ratios for high–stress tendons in clinical populations, however, remain unknown and require further attention in light of the knowledge gained in this study.
Postponement of Frontiers in Cardiovascular Biomedicine (FCVB) 2020 due to COVID-19: a look forward to 2021
Authors: Péter Ferdinandy, Ákos Koller, Christian Weber, Johannes Waltenberger
Journal: Cardiovascular Research (2020)

Frontiers in Cardiovascular Biomedicine (FCVB; previously called Frontiers in Cardiovascular Biology) is the main biennial congress of the Council on Basic Cardiovascular Science (CBCS) of the European Society of Cardiology (ESC).It is a widely inclusive congress in collaboration with several scientific cardiovascular sister societies.By now, FCVB meetings are considered to be one of the most relevant exchange platforms for basic and translational cardiovascular biomedicine in Europe and beyond.The change of the name of the congress from Frontiers in Cardiovascular Biology to Frontiers in Cardiovascular Biomedicine was intended to reflect and emphasize the focus of these meetings being the facilitation of laboratory findings into clinical medicine.
Covid-19: Care home deaths in England and Wales double in four weeks
Authors: Gareth Iacobucci
Journal: BMJ (2020)

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Efficacy and Safety of Generic Imatinib after Switching from Innovator Imatinib in Patients Treated for Chronic Myeloid Leukemia
Authors: Iman Aboudalle, Hagop M. Kantarjian, Jan A. Burger, Zeev Estrov, Maro Ohanian, Elias J. Jabbour, Srdan Verstovsek, Farhad Ravandi, Gautam Borthakur, Guillermo Garcia-Manero, Jorge E. Cortes
Journal: Blood (2017)
Abstract 109: Understanding Multi-allelic Heterozygous Variant Contributions to Cardiomyopathy Using iPSCs
Authors: Cassandra Happe, Kevin Tenerelli, Dekker C Deacon, Vivien Tran, Hermes Taylor-Weiner, Eric D Adler, Neil C Chi, Adam J Engler
Journal: Circulation Research (2016)

Dilated cardiomyopathy (DCM) is a multivariate disease with poorly understood mechanisms, but recently hundreds of variants in 30+ genes have been suggested to contribute to disease pathology. As evidence that two seemingly unrelated heterozygous variants could combine to induce disease, we have identified a family with multiple cases of DCM detected across four generations, where DCM cosegregates with heterozygous variants of thin filament-associated α-tropomyosin (TPM1; +/c.G97A) and intercalated disc-associated vinculin (VCL; +/c.659dupA) (Fischer Exact p-value &lt; 10 -3 ; LOD score = 3.21). To understand disease mechanism, we generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from the family cohort carrying these variants to test the hypothesis that multiple, heterozygous variants can uniquely combine to cause disease where their single heterozygous variant counterparts do not; variants were also isogenically modeled using CRISPR in human embryonic stem cell-derived CMs (hESC-CMs). Proband and affected cousin CMs had half of the protein expressed for both variants with morphological and cytoskeletal abnormalities relative to non-carriers. This resulted in reduced contractile energy, prolonged calcium transients, and more irregular timing compared to non-carrier CMs. Decreased sodium and potassium channel expression accompanied slowed action potential kinetics in affected vs. non-carrier patient-derived CMs, which together suggests that heterozygous VCL and TPM1 mutations may cause unique downstream transcriptome regulation that leads to the observed dysfunction in vitro . CRISPR edited hESC-CMs exhibited identical alterations relative to their isogenic controls along with losing gap junction protein connexin43 expression, suggesting that dysfunctional force generation and transmission combine, which would likely lead to more severe disease and DCM observed when the variants co-segregated. Given the lack of disease in single variant carriers, these data provide a unique set of analyses that result in identification of how dissimilar but co-segregating variants can result in disease.
Metagenomics reveals impact of geography and acute diarrheal disease on the Central Indian human gut microbiome
Authors: Tanya M. Monaghan, Tim J. Sloan, Stephen R. Stockdale, Adam M. Blanchard, Richard D. Emes, Mark Wilcox, Rima Biswas, Rupam Nashine, Sonali Manke, Jinal Gandhi, Pratishtha Jain, Shrejal Bhotmange, Shrikant Ambalkar, Ashish Satav, Lorraine A. Draper, Colin Hill, Rajpal Singh Kashyap
Journal: Gut Microbes (2020)

Background The Central Indian gut microbiome remains grossly understudied. Herein, we sought to investigate the burden of antimicrobial resistance and diarrheal diseases, particularly Clostridioides difficile, in rural-agricultural and urban populations in Central India, where there is widespread unregulated antibiotic use. We utilized shotgun metagenomics to comprehensively characterize the bacterial and viral fractions of the gut microbiome and their encoded functions in 105 participants.Results We observed distinct rural-urban differences in bacterial and viral populations, with geography exhibiting a greater influence than diarrheal status. Clostridioides difficile disease was more commonly observed in urban subjects, and their microbiomes were enriched in metabolic pathways relating to the metabolism of industrial compounds and genes encoding resistance to 3rd generation cephalosporins and carbapenems. By linking phages present in the microbiome to their bacterial hosts through CRISPR spacers, phage variation could be directly related to shifts in bacterial populations, with the auxiliary metabolic potential of rural-associated phages enriched for carbon and amino acid energy metabolism.Conclusions We report distinct differences in antimicrobial resistance gene profiles, enrichment of metabolic pathways and phage composition between rural and urban populations, as well as a higher burden of Clostridioides difficile disease in the urban population. Our results reveal that geography is the key driver of variation in urban and rural Indian microbiomes, with acute diarrheal disease, including C. difficile disease exerting a lesser impact. Future studies will be required to understand the potential role of dietary, cultural, and genetic factors in contributing to microbiome differences between rural and urban populations.
Thangkhali Hospital at Night II
Authors: Andrew Dimitri
Journal: JAMA (2020)

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Preclinical studies of a pan PI3K inhibitor (SF1126) in renal cell carcinoma
Authors: Qiong Peng, Pradip De, Nandini Dey, Joseph Garlich, Donald Durden
Journal: Cancer Research (2007)

2378  The phosphatidylinositol 3-kinase /PTEN/AKT pathway is an important pathway that regulates a wide spectrum of tumor-related biological processes. These processes include cell proliferation, cell migration, invasion, survival and angiogenesis. In this study, we investigated effect of a novel PI-3K inhibitor, SF1126, which is an RGD targeted, water soluble prodrug of LY294002. We sought to determine if SF1126 has antitumor and/or antiangiogenic activity in Renal Cell Carcinoma (RCC) models in vitro and in vivo. Our data demonstrate that SF1126 markedly suppresses pathways downstream of PI-3 kinase including p-AKT and p-ERK in the RCC cell line (786-0) at 5 µM and 10 µM concentration. The 786-0, RCC cell line has been reported to show high levels of hypoxia induced HIF2α expression (VHL mutated cell line). Interestingly, SF1126 treatment under hypoxic conditions abrogates the hypoxic stabilization of HIF2α in these cells. Moreover, SF1126 administrated to RCC xenografted mice at 25 mg/kg/dose administered three times per week for three weeks results in marked inhibition of tumor growth (>90% inhibition) (p
Donald Trump: a political determinant of covid-19
Authors: Gavin Yamey, Gregg Gonsalves
Journal: BMJ (2020)

the World Health Organization told all governments to get ready for the transmission of a novel coronavirus in their countries."Be prepared," it said, "for containment, including active surveillance, early detection, isolation and case management, contact tracing and prevention of onward spread." 1 Some countries listened.South Korea, for example, acted swiftly to contain its covid-19 epidemic. 2But US President Donald Trump was unmoved by WHO's warning, downplaying the threat and calling criticisms of his failure to act "a new hoax."