tbuckley/cabot-search huggingface dataset:
Annexin A2 supports pulmonary microvascular integrity by linking vascular endothelial cadherin and protein tyrosine phosphatases
Authors: Min Luo, Elle C. Flood, Dena Almeida, LunBiao Yan, David A. Berlin, Paul M. Heerdt, Katherine A. Hajjar
Journal: The Journal of Experimental Medicine (2017)

Relative or absolute hypoxia activates signaling pathways that alter gene expression and stabilize the pulmonary microvasculature. Alveolar hypoxia occurs in disorders ranging from altitude sickness to airway obstruction, apnea, and atelectasis. Here, we report that the phospholipid-binding protein, annexin A2 (ANXA2) functions to maintain vascular integrity in the face of alveolar hypoxia. We demonstrate that microvascular endothelial cells (ECs) from Anxa2-/- mice display reduced barrier function and excessive Src-related tyrosine phosphorylation of the adherens junction protein vascular endothelial cadherin (VEC). Moreover, unlike Anxa2+/+ controls, Anxa2-/- mice develop pulmonary edema and neutrophil infiltration in the lung parenchyma in response to subacute alveolar hypoxia. Mice deficient in the ANXA2-binding partner, S100A10, failed to demonstrate hypoxia-induced pulmonary edema under the same conditions. Further analyses reveal that ANXA2 forms a complex with VEC and its phosphatases, EC-specific protein tyrosine phosphatase (VE-PTP) and Src homology phosphatase 2 (SHP2), both of which are implicated in vascular integrity. In the absence of ANXA2, VEC is hyperphosphorylated at tyrosine 731 in response to vascular endothelial growth factor, which likely contributes to hypoxia-induced extravasation of fluid and leukocytes. We conclude that ANXA2 contributes to pulmonary microvascular integrity by enabling VEC-related phosphatase activity, thereby preventing vascular leak during alveolar hypoxia.
Overall survival (OS) of men and women with breast cancer according to tumor subtype: A population-based study.
Authors: Julieta Leone, Ariel Osvaldo Zwenger, Bernardo Amadeo Leone, Carlos Teodoro Vallejo, Jose Pablo Leone
Journal: Journal of Clinical Oncology (2017)

1069 Background: The outcomes of male breast cancer (MBC) and female breast cancer (FBC) according to tumor subtype are poorly known. Our group previously reported the prognostic significance of tumor subtypes in MBC. The aim of this study was to analyze differences in OS between MBC and FBC according to tumor subtype compared with other factors. Methods: We evaluated men and women with microscopically confirmed invasive breast cancer between 2010 and 2013 with known estrogen receptor (ER) and progesterone receptor (PR) (together hormone receptor [HR]) status and human epidermal growth factor receptor 2 (HER2) status reported to the SEER program. Patients (pts) with other primary either before or after breast cancer were excluded. Pt characteristics were compared between MBC and FBC. Univariate and multivariate analyses were performed to determine the effect of each variable on OS. Results: We included 1,187 MBC and 166,054 FBC pts. Median age for MBC was 65 years (range 26-97) and for FBC was 60 years (range 18-108). Median follow-up was 21 months (range 1-48) for both groups. OS at 3 years for MBC and FBC was 85.6% and 90.4%, respectively (p = 0.0002). MBC pts were more frequently ductal, had higher grade, presented with more advanced stage and were more often HR+/HER2- (all p &lt; 0.0001). MBC had worse OS than FBC in HR+/HER2- (Hazard ratio [HaR] 1.5; p = 0.0005), HR+/HER2+ (HaR 2.8; p &lt; 0.0001) and triple negative (TN) (HaR 4.3; p &lt; 0.0001) (p for interaction &lt; 0.02). MBC had significantly worse OS than FBC in stage I and II, but similar OS in stage III and IV (p for interaction &lt; 0.01). In multivariate analysis adjusted for age, race, grade, stage, surgery, radiation and marital status; HR+/HER2+ was the only subtype with significant differences in OS between MBC and FBC (HaR 2.0; p = 0.002). Conclusions: In this cohort, we observed significant differences in the distribution of tumor subtypes between MBC and FBC. OS was significantly different in both groups. Men had worse OS in stage I and II while similar OS in stage III and IV. There were significant differences in OS according to tumor subtype; compared with women, men with HR+/HER2+ tumors had twice the risk of death.
Do patients with low-risk (T1-2 [&lt;3 cm] N0, HR+) breast cancer and anti-hormone treatment need adjuvant radiation therapy? A meta-analysis of randomized trials.
Authors: Christiane Matuschek, Edwin Boelke, Kai Kammers, Wilfried Budach
Journal: Journal of Clinical Oncology (2016)

e12075 Background: The question if older patients with low risk breast cancer (T1-2 [ < 3 cm] N0, HR+) and anti-hormone treatment require adjuvant radiotherapy after breast conserving surgery is still under debate. The results of 5 randomized trials answering this question are now available. Methods: 3766 older patients with low risk breast cancer (T1-2 [< 3 cm] N0, HR+) and anti-hormone treatment were investigated if they needed radiation therapy and were included in randomized trials. Published hazard ratios and hazard ratios extracted from available survival curves for local relapse were basis of our meta-analysis. Meta-analysis of the effect sizes on local relapse was performed using a random effects model based on parameter estimates of log hazard ratios in Cox models and their standard errors. Furthermore overall survival was examined. Results: Additional radiation therapy with tamoxifen did result in a significant improvement of local relapse (Hazard Ratio: 6.8, 95% confidence limits 4.23-10.93, p = 2.4E-15).There was no significant difference for overall survival. Conclusions: Additional radiation therapy with tamoxifen does improve local relapse in breast cancer patients but not for overall survival.
Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury
Authors: Enmanuel J. Perez, Stephen A. Tapanes, Zachary B. Loris, Darrick T. Balu, Thomas J. Sick, Joseph T. Coyle, Daniel J. Liebl
Journal: Journal of Clinical Investigation (2017)

After traumatic brain injury (TBI), glial cells have both beneficial and deleterious roles in injury progression and recovery. However, few studies have examined the influence of reactive astrocytes in the tripartite synapse following TBI. Here, we have demonstrated that hippocampal synaptic damage caused by controlled cortical impact (CCI) injury in mice results in a switch from neuronal to astrocytic d-serine release. Under nonpathological conditions, d-serine functions as a neurotransmitter and coagonist for NMDA receptors and is involved in mediating synaptic plasticity. The phasic release of neuronal d-serine is important in maintaining synaptic function, and deficiencies lead to reductions in synaptic function and plasticity. Following CCI injury, hippocampal neurons downregulated d-serine levels, while astrocytes enhanced production and release of d-serine. We further determined that this switch in the cellular source of d-serine, together with the release of basal levels of glutamate, contributes to synaptic damage and dysfunction. Astrocyte-specific elimination of the astrocytic d-serine-synthesizing enzyme serine racemase after CCI injury improved synaptic plasticity, brain oscillations, and learning behavior. We conclude that the enhanced tonic release of d-serine from astrocytes after TBI underlies much of the synaptic damage associated with brain injury.
R-CHOP VERSUS R-FC FOLLOWED BY MAINTENANCE WITH RITUXIMAB OR IFN: FIRST RESULTS OF A RANDOMIZED TRIAL FOR ELDERLY PATIENTS WITH MANTLE CELL LYMPHOMA
Authors: J. C. Kluin-Nelemans, E. Hoster, O. Hermine, J. Walewski, M. Trneny, C. H. Geisler, W. Klapper, U. Vehling-Kaiser, M. Szymczyk, C. Gisselbrecht, S. Stilgenbauer, B. Coiffier, L. Kanz, J. K. Doorduijn, M. Untherhalt, M. Dreyling
Journal: Annals of Oncology (2011)
KRAS mutation profile in colorectal cancer patients in Brazil: A cohort of 989 individuals
Authors: M. G. Zalis, F. M. Vieira, I. Zalcberg-Renault, M. H. Bonamino, C. G. Ferreira, S. Oliveira
Journal: Journal of Clinical Oncology (2009)

e15017 Background: KRAS mutation is common event in colorectal cancer occurring in around 40% of the patients. It is well- known that patients harboring the KRAS mutation do not derive benefit from cetuximab. However data available KRAS mutation profile is limited to Caucasian and Asian individuals and there is a lack of data in the population from Latin America. Brazilian population has a heterogeneous genetic background and this may have pharmacogenetic implications (Suarez-Kurtz, 2006). Methods: Between July and November 2008, we analyzed 989 consecutive patient samples sent to our laboratory for KRAS genotyping as a screening for cetuximab use. DNA was extracted from paraffin-embedded tissue, exons 1 were amplified by PCR and submitted to automatic sequencing. Codons 12 and 13 were analyzed. Results: The median age was 59 years and 53% of the patients were male and 47% female. The percentage of wild-type and mutated KRAS was 62 and 38%, respectively. Among the 375 mutated cases, 87% were in codon 12 versus 13% in codon 13. Mutation Gly12Asp was the most common being detected in 39% of the mutated cases. Due to the sample size a comparison among patients from different regions of Brazil was possible. However, no significant difference was observed in relation to the type or percentage of patients harboring the KRAS mutation. Interestingly, a significant difference in the percentage of mutated KRAS patients was observed between male and female (41 versus 35%, p= 0.05). Conclusions: The profile of KRAS mutation in the Brazilian population is similar to that reported for Caucasian and Asian populations. This is one of the largest cohorts of KRAS genotyping in colorectal cancer patients ever reported. To the best of our knowledge our data is the first to put forward the issue of a potential difference in the mutation rate according to gender. The observed higher incidence of KRAS-mutation in male than female deserves further investigation. No significant financial relationships to disclose.
Gut microbiota is critical for the induction of chemotherapy-induced pain
Authors: Shiqian Shen, Grewo Lim, Zerong You, Weihua Ding, Peigen Huang, Chongzhao Ran, Jason Doheny, Peter Caravan, Samuel Tate, Kun Hu, Hyangin Kim, Michael McCabe, Bo Huang, Zhongcong Xie, Douglas Kwon, Lucy Chen, Jianren Mao
Journal: Nature Neuroscience (2017)
Induction of INKIT by Viral Infection Negatively Regulates Antiviral Responses through Inhibiting Phosphorylation of p65 and IRF3
Authors: Bin Lu, Yujie Ren, Xueqin Sun, Cuijuan Han, Hongyan Wang, Yuxuan Chen, Qianqian Peng, Yongbo Cheng, Xiaoliang Cheng, Qiyun Zhu, Wenxin Li, Hong-Liang Li, Hai-Ning Du, Bo Zhong, Zan Huang
Journal: Cell Host & Microbe (2017)
Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjögren’s syndrome
Authors: Fan Xiao, Xiang Lin, Jie Tian, Xiaohui Wang, Qian Chen, Ke Rui, Jie Ma, Shengjun Wang, Qingwen Wang, Xiaoqi Wang, Dongzhou Liu, Lingyun Sun, Liwei Lu
Journal: Cellular and Molecular Immunology (2017)
Crimean–Congo Hemorrhagic Fever in Spain — New Arrival or Silent Resident?
Authors: Jessica R. Spengler, Dennis A. Bente
Journal: New England Journal of Medicine (2017)

Why has CCHFV hit Spain now? It has probably been there for a while, supported by sufficient populations of two competent tick vectors that don't generally coexist, but the specific ecologic contributors to the recent cases remain unclear.
Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges
Authors: Mark D. Berry, Raul R. Gainetdinov, Marius C. Hoener, Mohammed Shahid
Journal: Pharmacology & Therapeutics (2017)

The discovery in 2001 of a G protein-coupled receptor family, subsequently termed trace amine-associated receptors (TAAR), triggered a resurgence of interest in so-called trace amines. Initial optimism quickly faded, however, as the TAAR family presented a series of challenges preventing the use of standard medicinal chemistry and pharmacology technologies. Consequently the development of basic tools for probing TAAR and translating findings from model systems to humans has been problematic. Despite these challenges the last 5 years have seen considerable advances, in particular with respect to TAAR1, which appears to function as an endogenous rheostat, maintaining central neurotransmission within defined physiological limits, in part through receptor heterodimerization yielding biased signaling outputs. Regulation of the dopaminergic system is particularly well understood and clinical testing of TAAR1 directed ligands for schizophrenia and psychiatric disorders have begun. In addition, pre-clinical animal models have identified TAAR1 as a novel target for drug addiction and metabolic disorders. Growing evidence also suggests a role for TAARs in regulating immune function. This review critically discusses the current state of TAAR research, highlighting recent developments and focussing on human TAARs, their functions, and clinical implications. Current gaps in knowledge are identified, along with the research reagents and translational tools still required for continued advancement of the field. Through this, a picture emerges of an exciting field on the cusp of significant developments, with the potential to identify new therapeutic leads for some of the major unmet medical needs in the areas of neuropsychiatry and metabolic disorders.
Diabetes Enhances IL-17 Expression and Alters the Oral Microbiome to Increase Its Pathogenicity
Authors: E Xiao, Marcelo Mattos, Gustavo Henrique Apolinário Vieira, Shanshan Chen, Jôice Dias Corrêa, Yingying Wu, Mayra Laino Albiero, Kyle Bittinger, Dana T. Graves
Journal: Cell Host & Microbe (2017)
Targeting Complete Response with Upfront Bortezomib Followed By Autologous Transplantation and Consolidation Therapy for Untreated Multiple Myeloma (TUBA study)
Authors: Hideki Nakasone, Kiriko Terasako-Saito, Teiichi Hirano, Atsushi Wake, Seiichi Shimizu, Etsuko Yamazaki, Kouhei Akazawa, Kensuke Usuki, Shigeru Chiba, Koichiro Minauchi, Etsuo Miyaoka, Shuichi Ota, Shuichi Taniguchi, Yoshinobu Kanda
Journal: Blood (2016)
Identification of multiple informative genomic mutations by deep sequencing of circulating cell-free tumor DNA in plasma of metastatic melanoma patients.
Authors: Dave S. B. Hoon, Sharon Huang, Dragan Sebisanovic, LaiMun Siew, Aubrey Zapanta, Stefanie Mortimer, AmirAli Talasaz
Journal: Journal of Clinical Oncology (2014)

9018 Background: We have been assesseing the prognostic utility of genomic changes in circulating cell-free DNA(cfDNA) in melanoma patients. The limitation has been assessing a few selected genomic targets and sensitivity. The approach of cfDNA analysis in melanoma patients offers detection of potential targeted tumor-related genes mutation(mt) without tumor biopsy. Methods: AJCC stage IV melanoma patients (n=18; different metastasis sites) plasma and paired metastatic tumor tissues resected after blood draw were assessed. The assay was performed on 2 ml filtered plasma. We employed Guardant360, a single-molecule digital sequencing assay that enables detection of rare genomic abnormalities with ultra high-specificity and sensitivity. Using bioinformatics and single molecule sensitivity, rare variants could be detected in cfDNA. Results: In an initial 8 patients, BRAF and TP53 in tumor genomic DNA were sequenced. We found ctDNA with somatic mt in 6/8 matched tumor and plasma specimens(mt allele frequency of 0.2-23.1%) with an overall concordance of 86% for the status of BRAF and TP53 mt in a single bleed. To note known BRAFmt at multiple exons were detectable. Subsequently, matched tumor and plasma from 10 patients were analyzed. We found ctDNA mt in 8/10 cases (mt allele frequency of 0.1-19.1%). Well known frequent melanoma-related mt were detected in patients cfDNA(BRAF, TP53). Other known tumor mt were also detected(CDKN2A, NRAS, PTEN, NOTCH1, EGFR, JAK2) that have not been reported. We established the overall concordance of cfDNA mt with metastatic melanomas across all 54 genes and 80kbps to be 49% whereby, individual single gene concordance were significantly much higher. Conclusions: This ongoing study demonstrates that using Guardant360, cfDNA mt can be detected that match with paired melanomas. The approach offers a more comprehensive approach of monitoring metastatic melanoma patients’ blood for multiple mt during tumor progression. This unique approach will allow for much more comprehensive blood tumor genetic profiling to provide better treatment decision and monitoring for multiple drugable targeted genes without tissue biopsies.
Treatment limitations in the era of ECMO
Authors: Daniel Brodie, J Randall Curtis, Jean-Louis Vincent, Jan Bakker, Crystal E Brown, Jacques Creteur, Laurent Papazian, Robert N Sladen, V Marco Ranieri, Laurent Brochard, Michael Broome, Alain Combes, Daniel De Backer, Niall Ferguson, Luciano Gattinoi, John Laffey, Roberto Lorusso, Alain Mercat, Stefano Nava, Antonio Pesenti, Michael Quintel, Peter Rimensberger, Claudio Ronco, Arthur Slutsky, Thomas Staudinger, Fabio Taccone
Journal: The Lancet Respiratory Medicine (2017)
Primary central nervous system lymphoma: The Cleveland Clinic experience.
Authors: Manmeet Singh Ahluwalia, Hao Xie, Mital Patel, Samuel T. Chao, John H. Suh, David M. Peereboom
Journal: Journal of Clinical Oncology (2012)

2092 Background: Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extranodal non-Hodgkin lymphoma that involves the brain, leptomeninges, eyes, or spinal cord without evidence of systemic disease. Untreated PCNSL has a rapidly fatal course, with survival of approximately 1.5 months from the time of diagnosis. In this study, we sought to describe the demographics, diagnoses, management, and outcomes of patients with PCNSL at a single institution. Methods: After obtaining IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify patients with histologically proven PCNSL at the Cleveland Clinic between 1986 and 2010. Data were subjected univariate and multivariate analysis followed by recursive partitioning analysis in order to generate a prognostic model. Results: 153 patients were diagnosed with PCNSL with a median age of 61 and Karnofsky performance status (KPS) of 70. The progression-free survival (PFS) was 9.3 months; the overall survival (OS) was 27 months. The treatment regimen included methotrexate-based chemotherapy (MTX) or a combination of methotrexate-based chemotherapy and whole brain radiation therapy (WBRT). Patients treated with the MTX regimen had an OS of 65 months; those treated with the MTX + WBRT regimen had an OS of 74 months. The Cox proportional hazards regression identified age and KPS as the only prognostic indicators to OS and PFS. Recursive partitioning analysis categorized the patients into three groups according to these prognostic factors. Patients with KPS ≥ 70 had a favorable outcome compared to patients with KPS &lt; 70. This held true especially for patients age 60 and younger, whose median OS was 100 months. Conclusions: The survival and prognostic indicators approximate those reported previously and provide independent validation for a simple yet powerful prognostic model that uses age and KPS to predict survival. [Table: see text]
Encouraging long‐term outcomes reported in patients with stage I non‐small cell lung cancer treated with stereotactic ablative radiotherapy
Authors: Mary Kay Barton
Journal: CA A Cancer Journal for Clinicians (2017)

Key Points At a median of 7.2 years of follow‐up, patients with stage I NSCLC who were treated with SABR had outcomes comparable to those noted among patients with stage I disease who were treated with surgery. Research is needed to define whether SABR can be applied to a wider population of patients with NSCLC and how to optimally combine it with systemic therapy.
The effects of age and learning disabilities in the king-devick test in adolescent ice-hockey players
Authors: Laura Hokkanen, Kati Peltonen, Matti Vartiainen, Tiina Laitala-Leinonen
Journal: British Journal of Sports Medicine (2017)

Objective King-Devick (K-D) is becoming a popular screening test for sport concussion. Rapid number naming may be impaired in developmental dyslexia and other learning disabilities (LD). The aim was to study the interaction of age and LD in K-D in adolescence. The hypothesis was that those with LD perform more poorly on the test regardless of age. Design A case-control, cross-sectional nation-wide study. Setting Pre-season 2015–16 baseline tests in all junior teams in the Finnish ice hockey League. Participants A total of 805 male adolescents aged 12–21 (divided in 7 age groups), 75 of them reported LD. Outcome measures The K-D performance was measured twice. Time in the three subtests was combined to produce a sum score. Sum scores, and their difference, were used as outcome measures. Main Results In the youngest age group the mean of the K-D second trial was 49.7 (48.3–51.0, 95% confidence intervals) and in the oldest age group 44.7 (42.9–46.5). In a two-way ANOVA those with LD performed poorer (p=0.014, ηp²=0.008) but there was no interaction between age and LD. Similarly, a repeated analysis of covariance yielded a significant main effect for the trial (p&lt;0.001, ηp²=0.042) and for LD (p&lt;0.001, ηp²=0.026) but not for their interaction when the effect of age was controlled. Conclusions Adolescent players improve their performance in K-D with age, but those with learning disabilities remain slower despite maturation. If K-D is used as a single test for screening, and no baseline data is available, this needs to be recognised. Competing interests None.
Cancer trials in sub-Saharan Africa: Aligning research and care
Authors: Satish Gopal
Journal: PLoS Medicine (2017)

There is an extreme scarcity of evidence to guide cancer treatment in sub-Saharan Africa (SSA), as well as major differences between SSA and resource-rich settings regarding cancer treatment infrastructure.• A possible framework for conceptualizing cancer clinical trials in SSA is proposed, and key issues related to equipoise, innovation, and efficiency are addressed within the SSA context.• Strongly aligned cancer care and research agendas can generate forward progress for cancer treatment in the region and globally impactful clinical science that can change treatment paradigms even in resource-rich settings.