tbuckley/cabot-search huggingface dataset:
The Coagulation and Immune Systems Are Directly Linked through the Activation of Interleukin-1α by Thrombin
Authors: Laura C. Burzynski, Melanie Humphry, Katerina Pyrillou, Kimberley A. Wiggins, Julie N.E. Chan, Nichola Figg, Lauren L. Kitt, Charlotte Summers, Kate C. Tatham, Paul B. Martin, Martin R. Bennett, Murray C.H. Clarke
Journal: Immunity (2019)

Ancient organisms have a combined coagulation and immune system, and although links between inflammation and hemostasis exist in mammals, they are indirect and slower to act. Here we investigated direct links between mammalian immune and coagulation systems by examining cytokine proproteins for potential thrombin protease consensus sites. We found that interleukin (IL)-1α is directly activated by thrombin. Thrombin cleaved pro-IL-1α at a site perfectly conserved across disparate species, indicating functional importance. Surface pro-IL-1α on macrophages and activated platelets was cleaved and activated by thrombin, while tissue factor, a potent thrombin activator, colocalized with pro-IL-1α in the epidermis. Mice bearing a mutation in the IL-1α thrombin cleavage site (R114Q) exhibited defects in efficient wound healing and rapid thrombopoiesis after acute platelet loss. Thrombin-cleaved IL-1α was detected in humans during sepsis, pointing to the relevance of this pathway for normal physiology and the pathogenesis of inflammatory and thrombotic diseases.
Driver Mutations in Normal Airway Epithelium Elucidate Spatiotemporal Resolution of Lung Cancer
Authors: Humam Kadara, Smruthy Sivakumar, Yasminka Jakubek, F. Anthony San Lucas, Wenhua Lang, Tina McDowell, Zachary Weber, Carmen Behrens, Gareth E. Davies, Neda Kalhor, Cesar Moran, Randa El-Zein, Reza Mehran, Stephen G. Swisher, Jing Wang, Jianjun Zhang, Junya Fujimoto, Jerry Fowler, John V. Heymach, Steven Dubinett, Avrum E. Spira, Erik A. Ehli, Ignacio I. Wistuba, Paul Scheet
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Uninvolved normal-appearing airway epithelium has been shown to exhibit specific mutations characteristic of nearby non-small cell lung cancers (NSCLCs). Yet, its somatic mutational landscape in patients with early-stage NSCLC is unknown.
Types of second primary cancers influence survival in chronic lymphocytic and hairy cell leukemia patients
Authors: Guoqiao Zheng, Subhayan Chattopadhyay, Amit Sud, Kristina Sundquist, Jan Sundquist, Asta Försti, Richard S. Houlston, Akseli Hemminki, Kari Hemminki
Journal: Blood Cancer Journal (2019)
Harms and benefits of opioids for management of non-surgical acute and chronic low back pain: a systematic review
Authors: Hannah-Rose Tucker, Katie Scaff, Tess McCloud, Kimberly Carlomagno, Kathleen Daly, Alessandra Garcia, Chad E Cook
Journal: British Journal of Sports Medicine (2019)

Background Consequences of prescription opioid use involve harms, addiction, tolerance and death. Despite routine prescription, opioids are not recommended for initial intervention by any major multidisciplinary low back pain (LBP) guideline. Objective Our primary purpose was to improve overall understanding of the harms and benefits associated with oral opioid interventions prescribed for treatment of acute or chronic back pain. Our second goal was to evaluate pain intensity and to compare and contrast these data with the harms. Our last objective was to evaluate conflicts of interest among the study authors and the findings. Design/data/eligibility criteria Studies incorporating oral prescription opioid management of non-surgical LBP were evaluated. After systematic assessment, no studies that met inclusion included participants with specifically acute LBP. Therefore, extracted data reflects only populations with subacute and chronic LBP. Data on reported harms, severe harms, pain outcomes and withdrawal rates were extracted and meta-analyses were completed for opioid versus placebo trials and opioids versus non-opioid trials. Results Fourteen studies met inclusion/exclusion requirements. All trials involved short-term management with limited follow-up. A high percentage of harms were identified across most studies. Opioids were not shown to be superior to other medications, and only showed superiority to placebo comparators (at cost of additional harms). Conclusion This review identified trends of higher harms rates and higher percentages of severe harms in opioid arms for the management of subacute and chronic LBP. The majority of trials that demonstrated benefits with opioids also had potential conflicts of interest. Lastly, non-opioid medications demonstrated statistically significant pain improvement compared with opioids. We feel that the results of the trial are supportive of current LBP guidelines and do not condone the initial use of opioids in management of subacute or chronic LBP. Trial registration number CRD42017070914
My patient wants to record our appointment, what should I do?
Authors: Abi Rimmer
Journal: BMJ (2019)

My patient wants to record our appointment, what should I do?A patient's request to record a consultation might leave you feeling uneasy but a recording can be a useful tool to empower patients, Abi Rimmer finds Abi RimmerThe BMJ Recordings can aid understandingKiersty Griffiths, standards policy manager for the General Medical Council, says, "The idea may be daunting at first but recordings can be a great tool for doctors and patients looking to overcome barriers to communication and understanding."For instance, a patient's concentration may be hampered by unspoken anxieties or pain, making it difficult to recall detail.Some patients need extra support because of unfamiliarity with the language or concepts discussed."Recordings give patients more time to process the sometimes complex information provided during consultations.They can also help patients to involve their family or carers in decisions about their treatment."The information in the consultation is the patient's and-providing no other patient is involved-it's perfectly legal for them to record it for their own use.
SUMO-specific protease 2 mediates leptin-induced fatty acid oxidation in skeletal muscle
Authors: Young Do Koo, Ji Seon Lee, Seung-Ah Lee, Paula G.F. Quaresma, Ratan Bhat, William G. Haynes, Young Joo Park, Young-Bum Kim, Sung Soo Chung, Kyong Soo Park
Journal: Metabolism (2019)
Efficacy of Dasatinib to Treat Molecular Relapse in an Adolescent with Philadelphia-Positive Acute Lymphoblastic Leukemia
Authors: Fara Petruzziello, Giovanna Giagnuolo, Giuseppe Menna, Giovanni Cazzaniga, Giada Muccioli Casadei, Salvatore Buffardi, Giovanna Maisto, Rosanna Parasole
Journal: Blood (2017)
ERR1- and PGC1α-associated mitochondrial alterations correlate with pan-cancer disparity in African Americans
Authors: Danthasinghe Waduge Badrajee Piyarathna, Akhila Balasubramanian, James M. Arnold, Stacy M. Lloyd, Balasubramanyam Karanam, Patricia Castro, Michael M. Ittmann, Nagireddy Putluri, Nora Navone, Jeffrey A. Jones, Wendong Yu, Vlad C. Sandulache, Andrew G. Sikora, George Michailidis, Arun Sreekumar
Journal: Journal of Clinical Investigation (2019)

BACKGROUND. African American patients have higher cancer mortality rates and shorter survival times compared with European American patients. Despite a significant focus on socioeconomic factors, recent findings strongly argue the existence of biological factors driving this disparity. Most of these factors have been described in a cancer-type specific context rather than a pan-cancer setting.
Nonmelanoma Skin Cancer in Childhood and Young Adult Cancer Survivors Previously Treated With Radiotherapy
Authors: Stefanie L. Thorsness, Azael Freites-Martinez, Michael A. Marchetti, Cristian Navarrete-Dechent, Mario E. Lacouture, Emily S. Tonorezos
Journal: Journal of the National Comprehensive Cancer Network (2019)

Radiotherapy (RT) is a risk factor for nonmelanoma skin cancer (NMSC), specifically basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), but whether features, histology, or recurrence of NMSC after RT resemble those observed in the general population is unknown.A retrospective review (1994-2017) was performed within the Adult Long-Term Follow-Up Program and Dermatology Service at Memorial Sloan Kettering Cancer Center. Demographics, clinical features, histology, treatment, and recurrence were collected for this patient cohort that was under close medical surveillance. Pathology images were reviewed when available.A total of 946 survivors (mean age, 40 years [SD, 13]) were assessed for NMSC. The mean age at first cancer diagnosis was 16 years (range, 0-40 years [11]), and the most common diagnosis was Hodgkin lymphoma (34%; n=318). In 63 survivors, 281 primary in-field lesions occurred, of which 273 (97%) were BCC and 8 (3%) were SCC. Mean intervals from time of RT to BCC and SCC diagnosis were 24 years (range, 2-44 years) and 32 years (range, 14-46 years), respectively. The most common clinical presentation of BCC was macule (47%; n=67), and the most common histologic subtypes were superficial for BCC (48%; n=131) and in situ for SCC (55%; n=5). Mohs surgery predominated therapeutically (42%; n=117), the mean duration of follow-up after treatment was 6 years (range, 12 days-23 years), and the 5-year recurrence rate was 1% (n=1).Most NMSCs arising in sites of prior RT were of low-risk subtypes. Recurrence was similar to that observed in the general population. Current guidelines recommend surgical intervention for tumors arising in sites of prior RT because they are considered to be at high risk for recurrence. These findings suggest that an expanded role for less aggressive therapy may be appropriate, but further research is needed.
Abstract 20315: Sexual Dimorphism in a Marfan Syndrome Mouse Model
Authors: Zheying Chen, Debra Rateri, Mary Sheppard, Alan Daugherty
Journal: Circulation (2017)

Objective: The effect of sexual dimorphism on aortic pathology in mouse models of Marfan Syndrome has not been defined. Therefore, we determined differences in aortic diameter expansion between sexes in fibrillin-1 hypomorphic (FBN1mgR/mgR) mice. Methods and Results: Ascending aortic diameters from male and female FBN1mgR/mgR mice and their wild type littermates were assessed every 4 weeks from 6 to 18 weeks of age by ultrasound. Measurements were taken luminal edge to luminal edge in diastole. Differences in aortic diameters between male and female FBN1mgR/mgR mice were detected as early as 6 weeks of age (1.79 ± 0.11 vs 1.40 ± 0.12 mm; p = 0.025) while there was no significant diameter differences between sexes of wild type littermates (1.11 ± 0.12 vs 1.10 ± 0.12 mm; p = 0.94). At 18 weeks of age, differences of aortic diameters between male and female FBN1mgR/mgR mice increased further (2.61 ± 0.21 vs 1.74 ± 0.17 mm; p = 0.006), while there were no significant differences between sexes of wild type lit...
Molecular endpoints for establishing target engagement by novel idiopathic pulmonary fibrosis therapies
Authors: Paul J. Wolters, Vincent Cottin
Journal: European Respiratory Journal (2019)

Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung remodelling characterised by metaplastic epithelial cells, re-epithelialised air spaces (microscopic honeycombing), lymphoid aggregates, leukocyte accumulation (including macrophages, dendritic cells and mast cells), angiogenesis, lymphangiogenesis, fibroblast foci and excess matrix deposition [1, 2]. On average, untreated patients diagnosed with IPF succumb to the disease within 3 years of diagnosis [2]. This dismal prognosis has improved following approval of pirfenidone and nintedanib for disease management [3, 4]. These drugs cut disease progression in half, and likely improve survival. By showing that IPF is a treatable condition, approval of pirfenidone and nintedanib has accelerated interest in developing other medications that effectively treat IPF, with several nearing phase 3 of development [5]. Measuring molecular endpoints in phase 2 clinical trials of IPF may be useful for designing subsequent phase 3 clinical trials <http://ow.ly/li8J30nQUJx>
Diagnostic Accuracy and Interobserver Agreement for the Vesical Imaging-Reporting and Data System for Muscle-invasive Bladder Cancer: A Multireader Validation Study
Authors: Yoshiko Ueno, Mitsuru Takeuchi, Tsutomu Tamada, Keitaro Sofue, Satoru Takahashi, Yuki Kamishima, Nobuyuki Hinata, Kenichi Harada, Masato Fujisawa, Takamichi Murakami
Journal: European Urology (2019)
Co-delivery of antigen and dual agonists by programmed mannose-targeted cationic lipid-hybrid polymersomes for enhanced vaccination
Authors: Dunwan Zhu, Chunyan Hu, Fan Fan, Yu Qin, Chenlu Huang, Zhiming Zhang, Lu Lu, Hai Wang, Hongfan Sun, Xigang Leng, Chun Wang, Deling Kong, Linhua Zhang
Journal: Biomaterials (2019)
Image Gallery: Metachronic occurrence of primary cutaneous marginal zone B-cell lymphoma and primary cutaneous Rosai-Dorfman disease in the same patient
Authors: A. González-Quesada, J. Bastida, J.C. Rivero-Vera, M.A. Piris-Pinilla, M.A. Limeres-González
Journal: British Journal of Dermatology (2017)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, A 47‐year‐old woman was diagnosed with primary cutaneous Rosai–Dorfman disease (a). The biopsy showed proliferation of histiocytoid cells with emperipolesis surrounded by polyclonal lymphocytes (b). S100 and other immunohistochemical studies confirmed the diagnosis (c). Surgical removal and methotrexate led to remission lasting 44 months. Twelve years earlier the woman had a primary cutaneous marginal zone B‐cell lymphoma in the same cheek (d). Treatment with chemotherapy and local radiotherapy led to complete remission. A single case of the synchronic appearance of both diseases in the same patient has been reported to date.1 They may be different phenotypical expressions of the same process.2 We thank Gema Godoy‐Quesada for his kind review of the English translation of our manuscript.
HSR19-097: Understanding U.S. Mutational Testing Patterns and Treatment Implications in Gastrointestinal Stromal Tumors (GIST) Patients
Authors: Khalid Mamlouk, Zach Crouch, Philina Lee, Clive Mendonca, Maria Gumina, Brian Rubin
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: In the United States, 3,000–4,000 cases of GIST occur each year. Approximately 80% of newly diagnosed GIST harbor mutations in KIT and up to 10% harbor mutations in PDGFRA, including an activation loop mutation at amino acid 842 that is associated with treatment resistance. Most patients (pts) with metastatic GIST (mGIST) respond initially to imatinib but progress and require alternative lines of therapy. However, pts with a PDGFRα D842V mutation have absolute resistance to imatinib and little to no benefit from other therapies. NCCN and ESMO GIST guidelines recommend routine mutational testing in all pts initiating therapy, though recent publications report low testing rates in this setting. This retrospective chart audit of GIST treaters further examines mutational testing and treatment decisions to better understand current practices and educational needs. Methods: Hematologist/oncologists who practiced in academic or community settings were eligible if they treated ≥5 pts with mGIST in the past 12 months. Respondents were asked to retrieve the last 4 charts of pts with metastatic/unresectable GIST of which ≥1 received ≥3 lines of therapy and answer questions geared toward assessing patient journey from diagnosis and mutation testing through treatment choices and outcomes. Results: 105 U.S. physicians (academic: 32; community: 73) reviewed and answered questions based on 403 patient charts. Overall KIT/PDGFRA mutation testing rates prior to initiating therapy was 59%, with lower rates in community settings. Further, only 34% of surveyed community physicians indicated they always perform mutational testing before initiating therapy despite it being strongly recommended in NCCN Guidelines. Top reasons cited for not performing mutation testing included questionable therapeutic impact, not part of practice’s standard protocol, cost, and lack of tissue. In our data set, 15 pts with a PDGFRα D842V mutation were identified, 12 of whom received imatinib despite known inactivity in this population. In the overall population, pts were primarily sequenced through imatinib, sunitinib, and regorafenib, with community clinicians being less likely to use regorafenib in the third-line setting. Conclusion: Continued education is needed about the role of mutational testing in GIST to ensure optimal treatment, especially among U.S. community oncology practitioners. The data also highlight the need for novel therapies that are effective in PDGFRα D842V-driven GIST.
Hope, exploration, and equilibrated action schemes
Authors: Davood G. Gozli, Ci Jun Gao
Journal: Behavioral and Brain Sciences (2019)

Abstract The concepts want, hope , and exploration cannot be organized in relation to a single type of motive (e.g., motive for food). They require, in addition, the motive for acquiring and maintaining a stable scheme that enables reward-directed activity. Facing unpredictability, the animal has to seek not only reward, but also a new equilibrated state within which reward seeking is possible.
STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death
Authors: Jianjun Wu, Yu-Ju Chen, Nicole Dobbs, Tomomi Sakai, Jen Liou, Jonathan J. Miner, Nan Yan
Journal: The Journal of Experimental Medicine (2019)

STING gain-of-function mutations cause lung disease and T cell cytopenia through unknown mechanisms. Here, we found that these mutants induce chronic activation of ER stress and unfolded protein response (UPR), leading to T cell death by apoptosis in the StingN153S/+ mouse and in human T cells. Mechanistically, STING-N154S disrupts calcium homeostasis in T cells, thus intrinsically primes T cells to become hyperresponsive to T cell receptor signaling–induced ER stress and the UPR, leading to cell death. This intrinsic priming effect is mediated through a novel region of STING that we name “the UPR motif,” which is distinct from known domains required for type I IFN signaling. Pharmacological inhibition of ER stress prevented StingN153S/+ T cell death in vivo. By crossing StingN153S/+ to the OT-1 mouse, we fully restored CD8+ T cells and drastically ameliorated STING-associated lung disease. Together, our data uncover a critical IFN-independent function of STING that regulates calcium homeostasis, ER stress, and T cell survival.
Cyclin E mRNA: Assessing Cyclin-Dependent Kinase (CDK) Activation State to Elucidate Breast Cancer Resistance to CDK4/6 Inhibitors
Authors: Sarat Chandarlapaty, Pedram Razavi
Journal: Journal of Clinical Oncology (2019)

The treatment of estrogen receptor (ER)-positive metastatic breast cancer has been dramatically transformed through the introduction of ATPcompetitive inhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6i) in combination with antiestrogen therapies.Seven phase III studies demonstrated clear improvements in progression-free survival through the addition of these agents in either the firstor later-line setting, with new studies underway to evaluate the benefit of these agents as adjuvant therapy. 1-7A core scientific premise backing these agents is that in a large subset of tumors, ER inhibition is only partially effective at blocking the G1 checkpoint kinases CDK4/ 6, either because of ineffective ER inhibition (eg, ESR1 mutations) 8-10 or hormone-independent inputs into CDK4/6 activation (eg, NF1 loss). 11The addition of highly selective CDK4/6 kinase inhibitors enables more potent and durable blockade of the cell cycle, which may accrue additional benefits such as inducing tumor cell senescence or augmenting antitumor immunity.2][3][4][5][6][7] Even with such great clinical heterogeneity, there remain virtually no biomarkers to separate these subgroups of patients.This is particularly poignant given the potential efficacy of alternative forms of therapy in ER-positive metastatic breast cancer, including mammalian target of rapamycin inhibition (everolimus) 12 as well as chemotherapy.In the companion article, Turner et al 13 use pretreatment tumor samples from the PALOMA-3 (Palbociclib [PD-0332991] Combined With Fulvestrant In Hormone Receptor1 HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial of fulvestrant versus fulvestrant plus palbociclib to investigate biomarkers that may identify tumors that are de novo resistant to the fulvestrant plus palbociclib combination and, specifically, find high levels of cyclin E1 (CCNE1) associated with an attenuated benefit.
Author Correction: Osteogenesis depends on commissioning of a network of stem cell transcription factors that act as repressors of adipogenesis
Authors: Alexander Rauch, Anders K. Haakonsson, Jesper G. S. Madsen, Mette Larsen, Isabel Forss, Martin R. Madsen, Elvira L. Van Hauwaert, Christian Wiwie, Naja Z. Jespersen, Michaela Tencerova, Ronni Nielsen, Bjørk D. Larsen, Richard Röttger, Jan Baumbach, Camilla Scheele, Moustapha Kassem, Susanne Mandrup
Journal: Nature Genetics (2019)
Low levels of urinary epidermal growth factor predict chronic kidney disease progression in children
Authors: Karolis Azukaitis, Wenjun Ju, Marietta Kirchner, Viji Nair, Michelle Smith, Zhiyin Fang, Daniela Thurn-Valsassina, Aysun Bayazit, Anna Niemirska, Nur Canpolat, Ipek Kaplan Bulut, Fatos Yalcinkaya, Dusan Paripovic, Jerome Harambat, Nilgun Cakar, Harika Alpay, Francesca Lugani, Francesca Mencarelli, Mahmut Civilibal, Hakan Erdogan, Jutta Gellermann, Enrico Vidal, Yilmaz Tabel, Charlotte Gimpel, Pelin Ertan, Onder Yavascan, Anette Melk, Uwe Querfeld, Elke Wühl, Matthias Kretzler, Franz Schaefer, Klaus Arbeiter, Alejandra Rosales, Jiri Dusek, Ariane Zaloszyc, Uwe Querfeld, Jutta Gellermann, Max Liebau, Lutz Weber, Evelin Muschiol, Rainer Büscher, Jun Oh, Anette Melk, Daniela Thurn-Valassina, Dieter Haffner, Franz Schaefer, Charlotte Gimpel, Ulrike John, Simone Wygoda, Nikola Jeck, Marianne Wigger, Sara Testa, Luisa Murer, Chiara Matteucci, Augustina Jankauskiene, Karolis Azukaitis, Dorota Drozdz, Francesca Lugani, Aleksandra Zurowska, Marcin Zaniew, Mieczyslaw Litwin, Anna Nimierska, Ana Teixeira, Amira Peco-Antic, Dusan Paripovic, Guido Laube, Ali Anarat, Aysun Bayazit, Ali Duzova, Yelda Bilginer, Salim Caliskan, Nur Canpolat, Mahmut Civilibal, Sevgi Mir, Betül Sözeri, Brigitta Kranz, Francesca Mencarelli, Brigitte Dorn, Fatos Yalcinkaya, Esra Baskin, Nilgun Cakar, Oguz Soylemezoglu, Sevinc Emre, Cengiz Candan, Aysel Kiyak, Gul Ozcelik, Harika Alpay, Rukshana Shroff, Bruno Rachin, Jerome Harambat, Maria Szczepanska, Hakan Erdogan, Osman Donmez, Ayse Balat, Nejat Aksu, Yilmaz Tabel, Pelin Ertan, Ebru Yilmaz, Ali Anarat, Aysin Bakkaloglu, Fatih Ozaltin, Amira Peco-Antic, Uwe Querfeld, Jutta Gellermann, Peter Sallay, Dorota Drożdż, Klaus-Eugen Bonzel, Anna-Margrete Wingen, Aleksandra Żurowska, Irena Balasz, Antonella Trivelli, Francesco Perfumo, Dirk-Erhard Müller-Wiefel, Kerstin Möller, Gisela Offner, Barbara Enke, Elke Wühl, Charlotte Hadtstein, Otto Mehls, Franz Schaefer, Sevinc Emre, Salim Caliskan, Sevgi Mir, Simone Wygoda, Katharina Hohbach-Hohenfellner, Nickola Jeck, Günter Klaus, Gianluigi Ardissino, Sara Testa, Giovanni Montini, Marina Charbit, Patrick Niaudet, Alberto Caldas Afonso, Ana Fernandes-Teixeira, Jiri Dušek, Chiara Matteucci, Stefano Picca, Marianne Wigger, Ulla B. Berg, Giovanni Celsi, Michel Fischbach, Joelle Terzic, Janusz Fydryk, Tomasz Urasinski, Rosanna Coppo, Licia Peruzzi, Klaus Arbeiter, Augustina Jankauskiene, Ryszard Grenda, Mieczyslaw Litwin, Thomas J. Neuhaus
Journal: Kidney International (2019)