tbuckley/cabot-search huggingface dataset:
Biomarkers predictive of venous thromboembolism in patients with newly diagnosed high-grade gliomas
Authors: J. Thaler, C. Ay, A. Kaider, E.-M. Reitter, J. Haselbock, C. Mannhalter, C. Zielinski, C. Marosi, I. Pabinger
Journal: Neuro-Oncology (2014)

High-grade gliomas (HGGs) are among the most prothrombotic of malignancies. We performed a prospective study to investigate 11 potential biomarkers for prediction of venous thromboembolism (VTE) in newly diagnosed HGG patients who had undergone a neurosurgical intervention. In addition, we tested 2 VTE risk assessment models (RAMs). The strongest predictors of VTE, which were identified by statistical forward selection, were used for the first RAM. The parameters used for the second RAM were both predictive of VTE and available in routine clinical practice. One hundred forty-one HGG patients were included in this study, and 24 (17%) of them developed VTE during follow-up. An association with the risk of future VTE was found for the following parameters: leukocyte count, platelet count, sP-selectin, prothrombin-fragment 1 + 2, FVIII activity, and D-dimer. The first RAM included low platelet count (<25th percentile of the study population) and elevated sP-selectin (≥75th percentile). The cumulative VTE probability after 12 months was 9.7% for score 0 (n = 76), 18.9% for score 1 (n = 59), and 83.3% for score 2 (n = 6). The second RAM included low platelet count (<25th percentile), elevated leukocyte count, and elevated D-dimer (≥75th percentile). The probability of VTE was 3.3% for score 0 (n = 63), 23.0% for score 1 (n = 53), and 37.7% for score 2 (n = 22) or score 3 (n = 3). We identified biomarkers suitable for assessing the VTE risk in newly diagnosed HGG patients. The application of 2 RAMs allowed identification of patients at high risk of developing VTE. We could also define patients at low risk of VTE, who would most probably not benefit from extended primary thromboprophylaxis.
Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy
Authors: Michael Gnant, Brigitte Mlineritsch, Gero Luschin-Ebengreuth, Franz Kainberger, Helmut Kässmann, Jutta Claudia Piswanger-Sölkner, Michael Seifert, Ferdinand Ploner, Christian Menzel, Peter Dubsky, Florian Fitzal, Vesna Bjelic-Radisic, Günther Steger, Richard Greil, Christian Marth, Ernst Kubista, Hellmut Samonigg, Peter Wohlmuth, Martina Mittlböck, Raimund Jakesz
Journal: The Lancet Oncology (2008)
The clinical significance ofp53 gene mutation in hepatocellular carcinomas from japan
Authors: Hiroshi Hayashi, Kenji Sugio, Takashi Matsumata, Eisuke Adachi, Kenji Takenaka, Keizo Sugimachi
Journal: Hepatology (1995)

To clarify the clinical significance of the mutation of p53 gene in hepatocellular carcinoma (HCC), 90 resected specimens from Japanese patients were assayed using a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. p53 mutations were detected in 25 cases (27.8%) at exons 4, 5, 6, 7, and 8, and the most frequent region of the mutation was at exons 5 and 7. No statistically significant correlation was observed between the p53 mutations and the clinical features except for the preoperative alpha-fetoprotein (AFP) level (P < .05). According to the pathological features, prognostic factors, such as size of the tumor, vascular invasion, fibrous capsule infiltration, and intrahepatic metastasis, showed no relationship to the existence of the mutation. However, p53 mutations were significantly associated with the degree of differentiation of HCC; that is, the mutation was found in 19 cases of 53 poorly differentiated HCCs (35.9%) and 2 of 3 cases of anaplastic HCCs (66.7%). The presence of p53 mutations was associated with a shortened cancer-free survival (P < .001, by log rank test) and a shortened survival (P < .05). A multivariate analysis by the Cox regression analysis showed that the p53 mutations were an unfavorable prognostic factor related to recurrence (P < .005), which is especially significant within the first postoperative year. These results suggest that the mutations of p53 gene of HCC might be an independent prognostic predictor to help in the selection of candidates who should undergo more intensive postoperative treatment. (Hepatology 1995; 22:1702-1707).
Ribonucleotide Reductase Small Subunit M2B Prognoses Better Survival in Colorectal Cancer
Authors: Xiyong Liu, Lily Lai, Xiaochen Wang, Lijun Xue, Sofia Leora, Jun Wu, Shuya Hu, Keqiang Zhang, Mei-Ling Kuo, Lun Zhou, Hang Zhang, Yafan Wang, Yan Wang, Bingsen Zhou, Rebecca A. Nelson, Shu Zheng, Suzhan Zhang, Peiguo Chu, Yun Yen
Journal: Cancer Research (2011)

Ribonucleotide reductase subunit RRM2B (p53R2) has been reported to suppress invasion and metastasis in colorectal cancer (CRC). Here, we report that high levels of RRM2B expression are correlated with markedly better survival in CRC patients. In a fluorescence-labeled orthotopic mouse xenograft model, we confirmed that overexpression of RRM2B in nonmetastatic CRC cells prevented lung and/or liver metastasis, relative to control cells that did metastasize. Clinical outcome studies were conducted on a training set with 103 CRCs and a validation set with 220 CRCs. All participants underwent surgery with periodic follow-up to determine survivability. A newly developed specific RRM2B antibody was employed to carry out immunohistochemistry for determining RRM2B expression levels on tissue arrays. In the training set, the Kaplan-Meier and multivariate Cox analysis revealed that RRM2B is associated with better survival of CRCs, especially in stage IV patients (HR = 0.40; 95% CI = 0.18-0.86, P = 0.016). In the validation set, RRM2B was negatively related to tumor invasion (OR = 0.45, 95% CI = 0.19-0.99, P = 0.040) and lymph node involvement (OR = 0.48, 95% CI = 0.25-0.92, P = 0.026). Furthermore, elevated expression of RRM2B was associated with better prognosis in this set as determined by multivariate analyses (HR = 0.48, 95% CI = 0.26-0.91, P = 0.030). Further investigations revealed that RRM2B was correlated with better survival of CRCs with advanced stage III and IV tumors rather than earlier stage I and II tumors. Taken together, our findings establish that RRM2B suppresses invasiveness of cancer cells and that its expression is associated with a better survival prognosis for CRC patients.
An Antibody That Locks HER3 in the Inactive Conformation Inhibits Tumor Growth Driven by HER2 or Neuregulin
Authors: Andrew P. Garner, Carl U. Bialucha, Elizabeth R. Sprague, Joan T. Garrett, Qing Sheng, Sharon Li, Olga Sineshchekova, Parmita Saxena, Cammie R. Sutton, Dongshu Chen, Yan Chen, Huiqin Wang, Jinsheng Liang, Rita Das, Rebecca Mosher, Jian Gu, Alan Huang, Nicole Haubst, Carolin Zehetmeier, Manuela Haberl, Winfried Elis, Christian Kunz, Analeah B. Heidt, Kara Herlihy, Joshua Murtie, Alwin Schuller, Carlos L. Arteaga, William R. Sellers, Seth A. Ettenberg
Journal: Cancer Research (2013)

HER2/HER3 dimerization resulting from overexpression of HER2 or neuregulin (NRG1) in cancer leads to HER3-mediated oncogenic activation of phosphoinositide 3-kinase (PI3K) signaling. Although ligand-blocking HER3 antibodies inhibit NRG1-driven tumor growth, they are ineffective against HER2-driven tumor growth because HER2 activates HER3 in a ligand-independent manner. In this study, we describe a novel HER3 monoclonal antibody (LJM716) that can neutralize multiple modes of HER3 activation, making it a superior candidate for clinical translation as a therapeutic candidate. LJM716 was a potent inhibitor of HER3/AKT phosphorylation and proliferation in HER2-amplified and NRG1-expressing cancer cells, and it displayed single-agent efficacy in tumor xenograft models. Combining LJM716 with agents that target HER2 or EGFR produced synergistic antitumor activity in vitro and in vivo. In particular, combining LJM716 with trastuzumab produced a more potent inhibition of signaling and cell proliferation than trastuzumab/pertuzumab combinations with similar activity in vivo. To elucidate its mechanism of action, we solved the structure of LJM716 bound to HER3, finding that LJM716 bound to an epitope, within domains 2 and 4, that traps HER3 in an inactive conformation. Taken together, our findings establish that LJM716 possesses a novel mechanism of action that, in combination with HER2- or EGFR-targeted agents, may leverage their clinical efficacy in ErbB-driven cancers.
Naturally acquired simian retrovirus infections in central African hunters
Authors: Nathan D Wolfe, William M Switzer, Jean K Carr, Vinod B Bhullar, Vedapuri Shanmugam, Ubald Tamoufe, A Tassy Prosser, Judith N Torimiro, Anthony Wright, Eitel Mpoudi-Ngole, Francine E McCutchan, Deborah L Birx, Thomas M Folks, Donald S Burke, Walid Heneine
Journal: The Lancet (2004)
NOD2 signalling in Crohn's disease
Authors: P. Allan, O. Brain, J. Baker, P. Simpson, T. Pichulik, E. Khatamzas, C. Reenares, A. Leslie, B. Kessler, A. Simmons
Journal: Gut (2011)

<h3>Introduction</h3> NOD2 is an intracellular pattern recognition receptor that induces autophagy in human dendritic cells (DCs) in a manner important for bacterial handling and antigen presentation. Variants of NOD2 associated with terminal ileal Crohn9s disease (CD) fail to induce autophagy normally on Nod2 stimulation and in turn display delayed bacterial handling and defective antigen presentation. We have used phosphoproteomics to map the Nod2 signalling cascade in human monocyte-derived DCs in order to identify proteins involved in Nod2 mediated autophagy and inflammatory pathway induction in these cells. The aim of this study is to determine the molecular basis of Nod2 signalling and its effect on autophagy induction and DC maturation. <h3>Methods</h3> Primary human monocytes expressing wild type (WT) NOD2 were used to generate monocyte derived DCs and the effect of stimulation of Nod2 with its ligand muramyl dipeptide (MDP) assessed using phosphoproteomics. Here phosphorylated proteins were extracted from cell lysates pre and post MDP triggering, off-gel fractionated and subject to mass spectrometry analysis by LC-MS/MS and Q-TOF. The function of differentially phosphorylated proteins on DC maturation, autophagy induction and bacterial handling was then investigated following knockdown with siRNAs. <h3>Results</h3> The Nod2 signalling cascade is diverse. One protein identified, SHP-1, is a phosphatase known to control activation thresholds in immune cells. Another is HMGB1, an alarmin that can interact with beclin to facilitate autophagy. Nod2 also differentially phosphorylates L-plastin which is known to be involved in bacterial trafficking and engulfment. <h3>Conclusion</h3> Phosphoproteomics casts light on how Nod2 signals, how this PRR might control DC maturation and inflammatory cytokine production, interact with the autophagy pathway and handle bacteria in DCs.
What does the patient want?
Authors: L. Farrell
Journal: BMJ (2003)

<h3>Abstract</h3> Many proteins contain intrinsically disordered regions (IDRs) which carry out important functions without relying on a single well-defined conformation. IDRs are increasingly recognized as critical elements of regulatory networks and have been also associated with cancer. However, it is unknown whether mutations targeting IDRs represent a distinct class of driver events associated with specific molecular and system-level properties, cancer types and treatment options. Here, we used an integrative computational approach to explore the direct role of intrinsically disordered proteins/protein regions (IDPs/IDRs) driving cancer. We showed that around 20% of cancer drivers are primarily targeted through a disordered region. The detailed analysis of these IDRs revealed that they can function in multiple ways that are distinct from the functional mechanisms of ordered drivers. Disordered drivers play a central role in context-dependent interaction networks and are enriched in specific biological processes such as transcription, gene expression regulation and protein degradation. Furthermore, their modulation represents an alternative mechanism for the emergence of all known cancer hallmarks independently of the modulation of globular proteins. Disordered drivers are also highly relevant at the sample level, and their mutations can represent the key driving event in certain individual cancer patients. However, treatment options for such patients are currently severely limited. The presented study highlights a largely overlooked class of cancer drivers associated with specific cancer types that need novel therapeutic options.
Blood Pressure: The Lower, the Better
Authors: Ehud Grossman
Journal: Diabetes Care (2011)

Hypertension is one of the major modifiable risk factors for cardiovascular (CV) morbidity and mortality. It was recently shown that 7.6 million early deaths and 92 million disabled years are attributed to hypertension (1). Lowering blood pressure (BP) reduces CV morbidity and mortality. The benefit achieved in most hypertension outcomes studies was attributed to BP reduction, and the more aggressive the BP reduction, the greater the benefit (2,3). However, it is unclear what the target BP levels should be. Lewington et al. (4) showed in a large collaborative meta-analysis that included 1 million adults with no previous vascular disease that usual BP is strongly and directly related to vascular (and overall) mortality, without any evidence of a threshold down to at least 115/75 mmHg. This observation led clinicians to believe that BP should be lowered to the lowest tolerable levels. Some of the guidelines even adopted this approach and recommended lowering BP to <140/90 mmHg in all hypertensive patients, including the elderly, and to <130/80 mmHg in diabetic and high-risk patients (5,6). The present review will analyze the available data showing that the notion “the lower, the better” is not evidence based and that there is evidence that lowering BP too aggressively may even be harmful.

One of the largest trials that addressed the question of what should be the optimal BP was the Hypertension Optimal Treatment (HOT) trial (7). This prospective study enrolled 18,790 patients who were randomly assigned to one of three diastolic BP target groups: ≤90, ≤85, or ≤80 mmHg. Mortality and CV morbidity were not different in the three different target groups, suggesting no benefit of lowering diastolic BP to <90 mmHg. However, instead of accepting the findings of the randomized trial as designed and drawing the right conclusion, the authors did …
Proteomic alteration in gastic adenocarcinomas from Japanese patients
Authors: Takahiro Yoshihara, Yoshito Kadota, Yoshiyuki Yoshimura, Yutaka Tatano, Naohiro Takeuchi, Hiroshi Okitsu, Atsushi Umemoto, Takashi Yamauchi, Kohji Itoh
Journal: Molecular Cancer (2006)

Gastric adenocarcinomas comprise one of the common types of cancers in Asian countries including Japan. Comprehensive protein profiling of paired surgical specimens of primary gastric adenocarcinomas and nontumor mucosae derived from Japanese patients was carried out by means of two-dimensional gel electrophoresis (2D-EP) and liquid chromatography-electrospray ionic tandem mass spectrometry (LC-ESI-MS) to establish gastric cancer-specific proteins as putative clinical biomarkers and molecular targets for chemotherapy.Relatively common alterations in protein expression were revealed in the tumor tissues. Increases in manganese dismutase and nonhistone chromosomal protein HMG-1 (HMG-1) were observed, while decreases in carbonic anhydrases I and II, glutatione-S-transferase and foveolin precursor (gastrokine-1) (FOV), an 18-kDa stomach-specific protein with putative tumor suppressor activity, were detected. RT-PCR analysis also revealed significant down-regulation of FOV mRNA expression in tumor tissues.A possible pathological role for down-regulation of FOV in gastric carcinogenesis was demonstrated. Evaluation of the specific decreases in gene and protein expression of FOV in patients may be utilized as clinical biomarkers for effective diagnosis and assessment of gastric cancer.
Activation of the p38 Mitogen-Activated Protein Kinase Pathway Arrests Cell Cycle Progression and Differentiation of Immature Thymocytes in Vivo
Authors: Nicole L. Diehl, Hervé Enslen, Karen A. Fortner, Chris Merritt, Nate Stetson, Colette Charland, Richard A. Flavell, Roger J. Davis, Mercedes Rincón
Journal: The Journal of Experimental Medicine (2000)

The development of T cells in the thymus is coordinated by cell-specific gene expression programs that involve multiple transcription factors and signaling pathways. Here, we show that the p38 mitogen-activated protein (MAP) kinase signaling pathway is strictly regulated during the differentiation of CD4−CD8− thymocytes. Persistent activation of p38 MAP kinase blocks fetal thymocyte development at the CD25+CD44− stage in vivo, and results in the lack of T cells in the peripheral immune system of adult mice. Inactivation of p38 MAP kinase is required for further differentiation of these cells into CD4+CD8+ thymocytes. The arrest of cell cycle in mitosis is partially responsible for the blockade of differentiation. Therefore, the p38 MAP kinase pathway is a critical regulatory element of differentiation and proliferation during the early stages of in vivo thymocyte development.
The cardiovascular risk factor, soluble CD40 ligand (CD154), but not soluble CD40 is lowered by ultra-endurance exercise in athletes
Authors: Liesel Geertsema, Samuel J E Lucas, James D Cotter, Barry Hock, Judy McKenzie, Liam J Fernyhough
Journal: British Journal of Sports Medicine (2008)

Background Soluble CD40 ligand (sCD40L) is a powerful marker of cardiovascular risk. Exercise is known to decrease cardiovascular risk, but the impact of ultra-endurance exercise on sCD40L responses is unknown. Objective To examine the relationship between ultra-endurance exercise in trained athletes and levels of sCD40L and its natural ligand sCD40. Design Control-trial, crossover design, exercise intervention study of sCD40L and sCD40 levels. Setting Outdoor exercise and laboratory testing, single centre study, School of Physical Education, University of Otago, New Zealand. Participants Nine trained ultra-endurance athletes. Interventions Athletes exercised (cycled and jogged) for 17 of 24 h. Venous blood was sampled at baseline and serially throughout exercise and 24 and 48 h after exercise. The athletes completed a 24 h control trial on a separate occasion, in randomised order. Main outcome measurements Mean levels of sCD40L and sCD40 during exercise and rest with 95% CIs. Results sCD40L levels dropped steadily from baseline (median 4128 pg/ml) to a measured nadir at 24 h following exercise (median 1409 pg/ml) (p=0.01). The levels had started to rise again by 48 h after exercise. When measured as a group, sCD40L levels remained constant during a control rest period. sCD40 levels remained constant on both exercise and control days. Conclusion Ultra-endurance exercise lowers the levels of the cardiovascular risk marker sCD40L in athletes. These results raise the possibility that exercise-induced changes in sCD40L may provide one of the mechanisms by which exercise lowers cardiovascular risk.
Differential Expression of Proteins in Radioresistant and Squamous Carcinoma Cells
Authors: P. Ramsamooj, U. Kasid, A. Dritschilo
Journal: JNCI Journal of the National Cancer Institute (1992)

Background: Previous studies support a genetic basis for cellular radioresistance. The associated biochemical and molecular events, however, are not fully understood. Purpose: We investigated the differential protein pattern as a molecular determinant of resistance or sensitivity of head and neck squamous carcinoma cells to ionizing radiation. Methods: Using two-dimensional polyacrylamide gel electro-phoresis followed by computer-assisted quantitative analysis, we compared the protein profiles of three relatively radioresistant and three relatively radiosensitive head and neck squamous carcinoma cell lines (previously characterized by in vitro and clinicale paraments as radioresistant or radiosensitive) to determine which proteins were consistently expressed or enhanced in the radioresistant compared with the radiosensitive phenotype. Results: Our analysis indicated that 14 proteins were preferentially expressed in the radioresistant cell lines SQ-20B, JSQ-3, andSCC-35 with one protein (molecular mass of 92 kd and pI of 5.5) distinctly expressed in the radioresistant cell lines. Four proteins were enhanced by greater than 10-fold, three were enhanced fivefold to 10-fold, and six were enhanced twofold to fivefold in the radioresistant cell lines. In addition, we observed a second set of 15 proteins preferentially expressed in the radiosensitive cell lines SQ-9G, SQ-38, and SCC-9. A 40-kd protein (pI 7.1) was distinctly expressed in the radiosensitive cell lines. The remaining radiosensitive cell-specific proteins were enhanced by greater than 10-fold (two proteins), fivefold to 10-fold (two proteins), or twofold to fivefold (10 proteins) compared with their counterparts in the radioresistant cell lysates. Conclusion : These results provide evidence for differential protein expression associated with phenotypic express of cellular radioresistance or radiosensitivity. Implications : This study will facilitate the characterization of these proteins correlated with the radiation response-specific phenotype. [J Natl Cancer Inst 84: 622–628, 1992]
Doctors' use of electronic medical records systems in hospitals: cross sectional survey
Authors: H. Larum, G. Ellingsen, A. Faxvaag
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objectives:</b> To compare the use of three electronic medical records systems by doctors in Norwegian hospitals for general clinical tasks. <b>Design:</b> Cross sectional questionnaire survey. Semistructured telephone interviews with key staff in information technology in each hospital for details of local implementation of the systems. <b>Setting:</b> 32 hospital units in 19 Norwegian hospitals with electronic medical records systems. <b>Participants:</b> 227 (72%) of 314 hospital doctors responded, equally distributed between the three electronic medical records systems. <b>Main outcome measures:</b> Proportion of respondents who used the electronic system, calculated for each of 23 tasks; difference in proportions of users of different systems when functionality of systems was similar. <b>Results:</b> Most tasks listed in the questionnaire (15/23) were generally covered with implemented functions in the electronic medical records systems. However, the systems were used for only 2–7 of the tasks, mainly associated with reading patient data. Respondents showed significant differences in frequency of use of the different systems for four tasks for which the systems offered equivalent functionality. The respondents scored highly in computer literacy (72.2/100), and computer use showed no correlation with respondents9 age, sex, or work position. User satisfaction scores were generally positive (67.2/100), with some difference between the systems. <b>Conclusions:</b> Doctors used electronic medical records systems for far fewer tasks than the systems supported. <h3>What is already known on this topic</h3> Electronic information systems in health care have not undergone systematic evaluation, and few comparisons between electronic medical records systems have been made Given the information intensive nature of clinical work, electronic medical records systems should be of help to doctors for most clinical tasks <h3>What this study adds</h3> Doctors in Norwegian hospitals reported a low level of use of all electronic medical records systems The systems were mainly used for reading patient data, and doctors used the systems for less than half of the tasks for which the systems were functional Analyses of actual use of electronic medical records provide more information than user satisfaction or functionality of such records systems