tbuckley/cabot-search huggingface dataset:
Active Notch1 Confers a Transformed Phenotype to Primary Human Melanocytes
Authors: Chelsea C. Pinnix, John T. Lee, Zhao-Jun Liu, Ronan McDaid, Klara Balint, Levi J. Beverly, Patricia A. Brafford, Min Xiao, Benjamin Himes, Susan E. Zabierowski, Yumi Yashiro-Ohtani, Katherine L. Nathanson, Ana Bengston, Pamela M. Pollock, Ashani T. Weeraratna, Brian J. Nickoloff, Warren S. Pear, Anthony J. Capobianco, Meenhard Herlyn
Journal: Cancer Research (2009)

The importance of mitogen-activated protein kinase signaling in melanoma is underscored by the prevalence of activating mutations in N-Ras and B-Raf, yet clinical development of inhibitors of this pathway has been largely ineffective, suggesting that alternative oncogenes may also promote melanoma. Notch is an interesting candidate that has only been correlated with melanoma development and progression; a thorough assessment of tumor-initiating effects of activated Notch on human melanocytes would clarify the mounting correlative evidence and perhaps identify a novel target for an otherwise untreatable disease. Analysis of a substantial panel of cell lines and patient lesions showed that Notch activity is significantly higher in melanomas than their nontransformed counterparts. The use of a constitutively active, truncated Notch transgene construct (N(IC)) was exploited to determine if Notch activation is a "driving" event in melanocytic transformation or instead a "passenger" event associated with melanoma progression. N(IC)-infected melanocytes displayed increased proliferative capacity and biological features more reminiscent of melanoma, such as dysregulated cell adhesion and migration. Gene expression analyses supported these observations and aided in the identification of MCAM, an adhesion molecule associated with acquisition of the malignant phenotype, as a direct target of Notch transactivation. N(IC)-positive melanocytes grew at clonal density, proliferated in limiting media conditions, and also exhibited anchorage-independent growth, suggesting that Notch alone is a transforming oncogene in human melanocytes, a phenomenon not previously described for any melanoma oncogene. This new information yields valuable insight into the basic epidemiology of melanoma and launches a realm of possibilities for drug intervention in this deadly disease.
Cardiac Arrest during Long-Distance Running Races
Authors: Jonathan H. Kim, Rajeev Malhotra, George Chiampas, Pierre d'Hemecourt, Chris Troyanos, John Cianca, Rex N. Smith, Thomas J. Wang, William O. Roberts, Paul D. Thompson, Aaron L. Baggish
Journal: New England Journal of Medicine (2012)

Approximately 2 million people participate in long-distance running races in the United States annually. Reports of race-related cardiac arrests have generated concern about the safety of this activity.We assessed the incidence and outcomes of cardiac arrest associated with marathon and half-marathon races in the United States from January 1, 2000, to May 31, 2010. We determined the clinical characteristics of the arrests by interviewing survivors and the next of kin of nonsurvivors, reviewing medical records, and analyzing postmortem data.Of 10.9 million runners, 59 (mean [±SD] age, 42-13 years; 51 men) had cardiac arrest (incidence rate, 0.54 per 100,000 participants; 95% confidence interval [CI], 0.41 to 0.70). Cardiovascular disease accounted for the majority of cardiac arrests. The incidence rate was significantly higher during marathons (1.01 per 100,000; 95% CI, 0.72 to 1.38) than during half-marathons (0.27; 95% CI, 0.17 to 0.43) and among men (0.90 per 100,000; 95% CI, 0.67 to 1.18) than among women (0.16; 95% CI, 0.07 to 0.31). Male marathon runners, the highest-risk group, had an increased incidence of cardiac arrest during the latter half of the study decade (2000-2004, 0.71 per 100,000 [95% CI, 0.31 to 1.40]; 2005-2010, 2.03 per 100,000 [95% CI, 1.33 to 2.98]; P=0.01). Of the 59 cases of cardiac arrest, 42 (71%) were fatal (incidence, 0.39 per 100,000; 95% CI, 0.28 to 0.52). Among the 31 cases with complete clinical data, initiation of bystander-administered cardiopulmonary resuscitation and an underlying diagnosis other than hypertrophic cardiomyopathy were the strongest predictors of survival.Marathons and half-marathons are associated with a low overall risk of cardiac arrest and sudden death. Cardiac arrest, most commonly attributable to hypertrophic cardiomyopathy or atherosclerotic coronary disease, occurs primarily among male marathon participants; the incidence rate in this group increased during the past decade.
Contemporary Profile of Acute Heart Failure in Southern Nigeria
Authors: Okechukwu S. Ogah, Simon Stewart, Ayodele O. Falase, Joshua O. Akinyemi, Gail D. Adegbite, Albert A. Alabi, Akinlolu A. Ajani, Julius O. Adesina, Amina Durodola, Karen Sliwa
Journal: JACC Heart Failure (2014)
Cooperative Cytotoxicity of Proteasome Inhibitors and Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand in Chemoresistant Bcl-2-Overexpressing Cells
Authors: Alessio Nencioni, Lucia Wille, Giovanna Dal Bello, Davide Boy, Gabriella Cirmena, Sebastian Wesselborg, Claus Belka, Peter Brossart, Franco Patrone, Alberto Ballestrero
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Bcl-2 overexpression is frequently detected in lymphoid malignancies, being associated with poor prognosis and reduced response to therapy. Here, we evaluated whether Bcl-2 overexpression affects the cytotoxic activity of proteasome inhibitors taken alone or in association with conventional anticancer drugs or tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Experimental Design: Jurkat cells engineered to overexpress Bcl-2 were treated with proteasome inhibitors (MG132, epoxomicin, and bortezomib), anticancer drugs (etoposide and doxorubicin), TRAIL, or combinations of these compounds. Cell death and loss of mitochondrial transmembrane potential were detected by flow cytometry. Cytosolic relocalization of cytochrome c and SMAC/Diablo, caspase cleavage, and Bcl-2 and Mcl-1 levels were determined by immunoblotting. Nuclear factor-κB inhibition was done by retroviral transduction with a dominant-negative mutant of IκBα. Results: Bcl-2 overexpression results in significant inhibition of apoptosis in response to proteasome inhibitors, antiblastics, and TRAIL. Addition of TRAIL to proteasome inhibitors results in a synergistic cytotoxic effect in Bcl-2-overexpressing cells, whereas this result is not reproduced by the combination of proteasome inhibitors with antiblastic drugs. Importantly, proteasome inhibitors plus TRAIL induce mitochondrial dysfunction irrespective of up-regulated Bcl-2. Bcl-2 cleavage to a fragment with putative proapoptotic activity and elimination of antiapoptotic Mcl-1 may both play a role in proteasome inhibitors-TRAIL cooperation. Conversely, nuclear factor-κB inhibition by proteasome inhibitors is per se insufficient to explain the observed synergy. Conclusions: Combined proteasome inhibitors and TRAIL overcome the apoptotic threshold raised by Bcl-2 and may prove useful in the treatment of chemoresistant malignancies with up-regulated Bcl-2.
Meniscal tears, repairs and replacement: their relevance to osteoarthritis of the knee
Authors: Ian McDermott
Journal: British Journal of Sports Medicine (2011)

The menisci of the knee are important load sharers and shock absorbers in the joint. Meniscal tears are common, and whenever possible meniscal tears should be surgically repaired. Meniscectomy leads to a significant increased risk of osteoarthritis, and various options now exist for replacing missing menisci, including the use of meniscal scaffolds or the replacement of the entire meniscus by meniscal allograft transplantation. The field of meniscal surgery continues to develop apace, and the future may lie in growing new menisci by tissue engineering techniques.
Trastuzumab emtansine and stereotactic radiosurgery: an unexpected increase in clinically significant brain edema
Authors: J. A. Carlson, Z. Nooruddin, C. Rusthoven, A. Elias, V. F. Borges, J. R. Diamond, B. Kavanagh, P. Kabos
Journal: Neuro-Oncology (2014)

In the last 10 years, multiple new targeted agents have been developed for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. Up to 55% of patients with HER2+ breast cancer will develop brain metastases requiring some form of radiation therapy. The interaction between radiation and these targeted agents is unknown and previously unreported.In this series, we describe 4 patients who developed clinically significant brain edema at sites of treated brain metastases. These patients were treated with stereotactic radiosurgery and trastuzumab emtansine, the newest FDA-approved agent for metastatic HER2+ breast cancer. Additionally, we present rates of clinically significant radiation necrosis among all breast cancer patients treated during this same time period.Using previously published clinical and preclinical data, we then hypothesize possible mechanisms for this striking interaction.Increased awareness of potential interactions between targeted agents and radiation to the brain is crucial.
Increased 12-Month Prevalence Rates of Mental Disorders in Patients with Chronic Somatic Diseases
Authors: Martin Härter, Harald Baumeister, Katrin Reuter, Frank Jacobi, Michael Höfler, Jürgen Bengel, Hans-Ulrich Wittchen
Journal: Psychotherapy and Psychosomatics (2007)

&lt;i&gt;Background:&lt;/i&gt; Although it is well established that chronic somatic diseases are significantly associated with a wide range of psychopathology, it remains unclear to what extent subjects with chronic somatic diseases are at increased risk of experiencing mental disorders. The present epidemiological study investigates age- and sex-adjusted 12-month prevalence rates of mental disorders in patients with cancer, and musculoskeletal, cardiovascular and respiratory tract diseases, based on comprehensive physicians’ diagnoses and compared with physically healthy probands. &lt;i&gt;Methods:&lt;/i&gt; Prevalence rates were calculated from two large epidemiological surveys. These studies investigated inpatients and patients from the general population with cancer (n = 174) and musculoskeletal (n = 1,416), cardiovascular (n = 915) and respiratory tract diseases (n = 453) as well as healthy controls (n = 1,083). The prevalence rates were based on the Munich Composite International Diagnostic Interview, a standardized interview for the assessment of mental disorders. &lt;i&gt;Results:&lt;/i&gt; Prevalence rates were very similar for inpatients (43.7%) and patients from the general population (42.2%). The adjusted odds ratios (OR) of patients with chronic somatic diseases were significantly elevated for mental disorders in comparison with healthy probands (OR: 2.2). Mood, anxiety and somatoform disorders were most frequent. The prevalence rates did not differ significantly between the somatic index diseases. The number of somatic diseases per patient had a higher association with mental disorders. &lt;i&gt;Conclusions:&lt;/i&gt; There is a strong relationship between chronic somatic diseases and mental disorders. A future task is to improve the care of mental disorders in patients with chronic physical illness, specifically with multimorbid conditions.
Serum apoptotic caspase activity as a marker of severity in HBeAg-negative chronic hepatitis B virus infection
Authors: G V Papatheodoridis, E Hadziyannis, E Tsochatzis, N Chrysanthos, A Georgiou, G Kafiri, S Manolakopoulos, D G Tiniakos, I Giannousis, E K Manesis, A J Archimandritis
Journal: Gut (2007)

In chronic hepatitis C and non-alcoholic fatty liver disease, apoptotic caspases are activated in liver, and serum caspase activity has been suggested as a sensitive marker of early liver injury. An investigation was carried out into whether the serum levels of caspase-generated fragments of cytokeratin-18 (CK-18) are associated with the severity of liver lesions in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection. Patients/CK-18 fragment serum levels were determined in 115 treatment-naive, consecutive HBV patients and 30 healthy controls. Hepatic-expression of CK-18 fragments was evaluated by immunocytochemistry in chronic hepatitis B patients.CK-18 fragment levels (U/l) were significantly lower in healthy controls (mean (SD), 154 (31)) than in 53 inactive carriers (172 (24), p = 0.003) and in 62 chronic hepatitis B patients (474 (488), p<0.001). The receiver operating characteristic curve showed excellent diagnostic accuracy (c-statistic: 0.87) for differentiating inactive carriers from chronic hepatitis B patients. A CK-18 fragment cut-off level of 240 U/l gave a sensitivity of 60%, and a specificity and positive predictive value of 100% for chronic hepatitis B diagnosis. CK-18 fragment levels were also lower in inactive carriers than in 16 chronic hepatitis B patients with transiently normal alanine aminotransferase (ALT; 327 (256), p = 0.001), offering good accuracy for such a differentiation (c-statistic: 0.78). In chronic hepatitis B patients, serum CK-18 fragments correlated positively with ALT/aspartate aminotransferase (AST), viraemia, grading score and their immunohistochemical hepatic expression, and negatively with platelet counts, but not with fibrosis or steatosis severity.Serum apoptotic caspase activity is strongly associated with the presence of liver injury in patients with HBeAg-negative chronic HBV infection. CK-18 fragment levels seem to be a very useful marker for differentiation between the inactive HBV carrier state and HBeAg-negative chronic hepatitis B, but not for estimation of the severity of liver histological lesions among HBeAg-negative chronic hepatitis B patients.
Posttraumatic Stress Disorder and Depression in Battle-Injured Soldiers
Authors: Thomas A. Grieger, Stephen J. Cozza, Robert J. Ursano, Charles Hoge, Patricia E. Martinez, Charles C. Engel, Harold J. Wain
Journal: American Journal of Psychiatry (2006)

Objective: This study examined rates, predictors, and course of probable posttraumatic stress disorder (PTSD) and depression among seriously injured soldiers during and following hospitalization. Method: The patients were 613 U.S. soldiers hospitalized following serious combat injury. Standardized screening instruments were administered 1, 4, and 7 months following injury; 243 soldiers completed all three assessments. Cross-sectional and longitudinal analyses of risk factors were performed. PTSD was assessed with the PTSD Checklist; depression was assessed with the Patient Health Questionnaire. Combat exposure, deployment length, and severity of physical problems were also assessed. Results: At 1 month, 4.2% of the soldiers had probable PTSD and 4.4% had depression; at 4 months, 12.2% had PTSD and 8.9% had depression; at 7 months, 12.0% had PTSD and 9.3% had depression. In the longitudinal cohort, 78.8% of those positive for PTSD or depression at 7 months screened negative for both conditions at 1 month. High levels of physical problems at 1 month were significantly predictive of PTSD (odds ratio=9.1) and depression at 7 months (odds ratio=5.7) when the analysis controlled for demographic variables, combat exposure, and duration of deployment. Physical problem severity at 1 month was also associated with PTSD and depression severity at 7 months after control for 1-month PTSD and depression severity, demographic variables, combat exposure, and deployment length. Conclusions: Early severity of physical problems was strongly associated with later PTSD or depression. The majority of soldiers with PTSD or depression at 7 months did not meet criteria for either condition at 1 month.
The Neutrophil-Activating Protein (Hp-Nap) of<i>Helicobacter pylori</i>Is a Protective Antigen and a Major Virulence Factor
Authors: Barbara Satin, Giuseppe Del Giudice, Vittorina Della Bianca, Stefano Dusi, Carlo Laudanna, Fiorella Tonello, Dermot Kelleher, Rino Rappuoli, Cesare Montecucco, Filippo Rossi
Journal: The Journal of Experimental Medicine (2000)

Helicobacter pylori infection induces the appearance of inflammatory infiltrates, consisting mainly of neutrophils and monocytes, in the human gastric mucosa. A bacterial protein with neutrophil activating activity (HP-NAP) has been previously identified, but its role in infection and immune response is still largely unknown. Here, we show that vaccination of mice with HP-NAP induces protection against H. pylori challenge, and that the majority of infected patients produce antibodies specific for HP-NAP, suggesting an important role of this factor in immunity. We also show that HP-NAP is chemotactic for human leukocytes and that it activates their NADPH oxidase to produce reactive oxygen intermediates, as demonstrated by the translocation of its cytosolic subunits to the plasma membrane, and by the lack of activity on chronic granulomatous disease leukocytes. This stimulating effect is strongly potentiated by tumor necrosis factor α and interferon γ and is mediated by a rapid increase of the cytosolic calcium concentration. The activation of leukocytes induced by HP-NAP is completely inhibited by pertussis toxin, wortmannin, and PP1. On the basis of these results, we conclude that HP-NAP is a virulence factor important for the H. pylori pathogenic effects at the site of infection and a candidate antigen for vaccine development.
Interferon alfa-2a in Japanese encephalitis: a randomised double-blind placebo-controlled trial
Authors: Tom Solomon, Nguyen Minh Dung, Bridget Wills, Rachel Kneen, Mary Gainsborough, Tran Vinh Diet, Tran Thi Nhu Thuy, Ha Thi Loan, Vo Cong Khanh, David W Vaughn, Nicholas J White, Jeremy J Farrar
Journal: The Lancet (2003)
Does long-distance air travel associated with the Sevens World Series increase players’ risk of injury?
Authors: Colin W Fuller, Aileen E Taylor, Martin Raftery
Journal: British Journal of Sports Medicine (2015)

Objective To assess whether players who cross ≥6 time zones and/or undertake ≥10 h air travel prior to competition experience a higher risk of injury during the Sevens World Series than players not required to undertake this level of travel. Design Five-year, prospective, cohort study. Participants All players from nine core teams competing in the Sevens World Series from 2008/2009 to 2013/2014. Results A total of 436 match injuries and 3363 player-match-hours of exposure were recorded in the study, which corresponds to an overall incidence of 129.6 injuries/1000 player-match-hours, irrespective of the nature of pretournament travel. The incidence of injury for those players crossing ≥6 time zones and undertaking ≥10 h air travel prior to competition (99.3 injuries/1000 player-match-hours) was significantly lower than that of players undertaking ≥10 h air travel but crossing ≤2 time zones prior to competition (148.8 injuries/1000 player-match-hours; p=0.003) and of those undertaking ≤3 h air travel and crossing ≤2 time zones prior to competition (146.4 injuries/1000 player-match-hours; p=0.004). There was no significant difference in the incidence of injury for players crossing ≤2 time zones in the week prior to competition, irrespective of whether the length of air travel was ≤3 h or ≥10 h (p=0.904). Precompetition air travel had no significant effect (p=0.879) on the performance of teams in terms of their final Tournament ranking positions. Conclusions There was no evidence to suggest that players were exposed to a greater risk of injury following extensive air travel and crossing multiple time zones prior to Tournaments in the Sevens World Series.
Economic Evaluation Alongside a Clinical Trial of Psycho-Educational Interventions to Improve Adjustment to Survivorship Among Patients With Breast Cancer
Authors: Jeanne S. Mandelblatt, Jennifer Cullen, William F. Lawrence, Annette L. Stanton, Bin Yi, Lorna Kwan, Patricia A. Ganz
Journal: Journal of Clinical Oncology (2008)

Purpose There is little economic research on psychosocial interventions. We aimed to collect data alongside a randomized trial to compare the costs and benefits of three psycho-educational strategies to improve transition to cancer survivorship. Methods We evaluated the incremental delivery costs per unit increase in energy (using the Medical Outcomes Study vitality scale) or decrease in distress (from the Revised Impact of Events Scale) in the 6 months postintervention. We also evaluated 1-year post-treatment health care costs. Results The costs of the control, video, and video plus counseling arms were $11.30, $25.85, and $134.47 per person, respectively. The video costs were $2.22 per unit increase in energy compared with control; among women who were the least prepared for transition, the video was more effective, resulting in even lower costs. The video cost $7,275 per unit change in distress versus control, but costs were lower in the subgroup least prepared for transition ($355). The counseling arm was more expensive and less effective than the video for virtually all end points. However, in one group, women more prepared for transition, counseling cost $1,066 per unit decrease in distress compared with the video. Health care costs tended to increase as intervention intensity increased. Conclusion There are no standards for evaluating cost-effectiveness of trials with psychosocial end points. In this trial, the educational video was the most cost-effective way to improve transition to survivorship. It will be important to confirm whether there is an increased use of services after such interventions and if this represents appropriate use of rehabilitative and supportive care or over-use.
265 DEVELOPMENT OF CIRRHOSIS IS ASSOCIATED WITH INCREASED LEVELS OF PLACENTAL GROWTH FACTOR: A DESCRIPTIVE STUDY
Authors: C. Van Steenkiste, B. Schroyen, A.M. Geerts, E. Vanheule, H. Van Vlierberghe, D. Laukens, K. Olievier, H. Reynaert, A. Geerts, P. Carmeliet, M. De Vos, I. Colle
Journal: Journal of Hepatology (2008)
A rare penetrant mutation in CFH confers high risk of age-related macular degeneration
Authors: Soumya Raychaudhuri, Oleg Iartchouk, Kimberly Chin, Perciliz L Tan, Albert K Tai, Stephan Ripke, Sivakumar Gowrisankar, Soumya Vemuri, Kate Montgomery, Yi Yu, Robyn Reynolds, Donald J Zack, Betsy Campochiaro, Peter Campochiaro, Nicholas Katsanis, Mark J Daly, Johanna M Seddon
Journal: Nature Genetics (2011)
The association between periodontal disease and joint destruction in rheumatoid arthritis extends the link between the HLA-DR shared epitope and severity of bone destruction
Authors: H Marotte
Journal: Annals of the Rheumatic Diseases (2005)

To evaluate a possible association between wrist and periodontal destruction in rheumatoid arthritis, and between periodontal destruction, dry mouth, and labial salivary gland biopsy and the contribution of genetic factors (the shared epitope (SE) and IL1B (+3954) or TNFA (-238 or -308) gene polymorphisms).147 patients with rheumatoid arthritis were enrolled. Periodontal damage was defined according to the Hugoson and Jordan criteria on panoramic dental x rays. Typing for the SE and cytokine polymorphisms was undertaken by enzyme linked oligosorbent assay. Odds ratios (OR), relative risk (RR), and chi2 values were calculated to quantify associations.An association was observed between wrist and periodontal bone destruction (chi2=11.82; p<0.001): 63 patients had both wrist and periodontal destruction, 31 had wrist destruction alone, 20 had periodontal destruction alone, and 33 had no destruction at either site. An association was seen between a positive labial salivary gland biopsy and periodontal bone destruction (RR=2.73 (95% CI, 1.35 to 5.51), p<0.01, n=41) or wrist bone destruction (RR=4.52 (1.96 to 10.45), p<0.001, n=41). The SE was associated with wrist bone destruction (OR=2.5 (1.16 to 5.42), p<0.05) and periodontal bone destruction (OR=2.2 (1.04 to 4.84), p<0.05). No association was found between the selected cytokine polymorphisms and bone destruction.A strong association was found between wrist and periodontal bone destruction. The destruction risk was further increased in patients with sicca syndrome. The SE appears to be a severity genetic marker for both wrist and periodontal bone destruction.