tbuckley/cabot-search huggingface dataset:
Cancer-Associated Venous Thromboembolic Disease, Version 1.2015
Authors: Michael B. Streiff, Bjorn Holmstrom, Aneel Ashrani, Paula L. Bockenstedt, Carolyn Chesney, Charles Eby, John Fanikos, Randolph B. Fenninger, Annemarie E. Fogerty, Shuwei Gao, Samuel Z. Goldhaber, Paul Hendrie, Nicole Kuderer, Alfred Lee, Jason T. Lee, Mirjana Lovrincevic, Michael M. Millenson, Anne T. Neff, Thomas L. Ortel, Rita Paschal, Sanford Shattil, Tanya Siddiqi, Kristi J. Smock, Gerald Soff, Tzu-Fei Wang, Gary C. Yee, Anaadriana Zakarija, Nicole McMillian, Anita M. Engh
Journal: Journal of the National Comprehensive Cancer Network (2015)

The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of venous thromboembolism (VTE) in adult patients with a diagnosis of cancer or for whom cancer is clinically suspected. VTE is a common complication in patients with cancer, which places them at greater risk for morbidity and mortality. Therefore, risk-appropriate prophylaxis is an essential component for the optimal care of inpatients and outpatients with cancer. Critical to meeting this goal is ensuring that patients get the most effective medication in the correct dose. Body weight has a significant impact on blood volume and drug clearance. Because obesity is a common health problem in industrialized societies, cancer care providers are increasingly likely to treat obese patients in their practice. Obesity is a risk factor common to VTE and many cancers, and may also impact the anticoagulant dose needed for safe and effective prophylaxis. These NCCN Guidelines Insights summarize the data supporting new dosing recommendations for VTE prophylaxis in obese patients with cancer.
Abstract 11255: PON1 Q192R (rs662) Genetic Variant and Response to Clopidogrel and Prasugrel
Authors: Jessica L Mega, Sandra L Close, Stephen D Wiviott, Michael Man, Suman Duvvuru, Joseph Walker, Scott S Sundseth, William L Macias, Elliott M Antman, Eugene Braunwald, Marc S Sabatine
Journal: Circulation (2011)

Background: Clopidogrel and prasugrel are pro-drugs requiring biotransformation into active metabolites. Multiple studies have validated the relationship between loss-of-function alleles in the CYP...
Targeting CD137 to enhance the antitumor efficacy of cetuximab by stimulation of innate and adaptive immunity.
Authors: Holbrook Edwin Kohrt, Roch Houot, Kipp Weiskopf, Matthew Goldstein, Peder Lund, Ruth R Lira, Emily Troutner, Lori Richards, Amanda Rajapaksa, Anton Ostashko, Wen-Kai Weng, Lieping Chen, Debra Czerwinski, A. Dimitrios Colevas, John Sunwoo, Ronald Levy
Journal: Journal of Clinical Oncology (2013)

3015 Background: Cetuximab therapy results in beneficial, yet limited, clinical improvement for patients with KRAS wildtype (WT) colorectal (CRC) and head and neck (HN) cancer. The efficacy of cetuximab, an IgG1 monoclonal antibody against EGFR, is due in part to antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells. CD137 is a costimulatory molecule expressed following activation on NK and memory, antigen-specific, CD8 T cells. Methods: We investigated the hypothesis that the combination of cetuximab with anti-CD137 mAb will enhance innate and adaptive immunity, thereby improving cetuximab’s anti-tumor efficacy in preclinical models and a prospective trial, NCT01114256. Results: NK cells increased their expression of CD137 by a factor of 30-40 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. An agonistic anti-CD137 mAb enhanced NK cell degranulation and cytotoxicity 2-fold (~45 to 90% tumor lysis assayed by chromium release). The combination of cetuximab and anti-CD137 mAbs was synergistic in a syngeneic, human-EGFR-transfected murine tumor leading to complete tumor resolution and prolonged survival. NK cell depletion, significantly, and CD8 T cell depletion, partly, abrogated the anti-tumor efficacy of this combination. A series of HN and both KRAS WT and mutant CRC xenotransplant models demonstrated synergy with cetuximab and anti-CD137 mAbs. In our clinical trial, 54 patients with HN cancer receiving cetuximab therapy, circulating and intratumoral NK cells upregulated CD137 with amplitude influenced by duration post-cetuximab and host FcyRIIIa polymorphism. Interestingly, in 10 HLA-A2 + patients, following cetuximab, an increase in EGFR-specific, CD137-expressing, CD8 T cells directly correlated with the percent increase in CD137-expressing NK cells. Conclusions: Our results demonstrate the synergy of combining an agonistic mAb, anti-CD137, augmenting ADCC and T cell memory following a tumor-targeting mAb, cetuximab, in HN and KRAS mutant and WT CRC cancer. These results support a novel, sequential antibody approach by targeting first the tumor and then the host innate and adaptive immune system. Clinical trial information: NCT01114256.
Measles outbreak in Switzerland - an update relevant for the European football championship (EURO 2008)
Authors: J L Richard, V Masserey-Spicher, S Santibanez, A Mankertz
Journal: Eurosurveillance (2008)

Since November 2006, Switzerland has been experiencing the largest measles outbreak registered in the country since the introduction of mandatory notification for this disease in 1999. The first eight months of this outbreak have already been described in this journal [1]. From November 2006 to 13 February 2008, 1,405 measles cases were reported by physicians or laboratories in Switzerland (1,106 of them in 2007). Of these, 976 cases (69%) occurred in the cantons of Lucerne (29% of the total), Basel-Land (16%), Zurich (11%) Bern (7%), and Aargau (7%). The incidence for the whole country and all ages, calculated for this 15-month period, was 19 cases per 100,000 inhabitants (15 cases per 100,000 for the year 2007). For children under the age of 16 years living in the canton of Lucerne, it was 500 per 100,000.
Juvenile arthritis disease activity score is a better reflector of active disease than the disease activity score 28 in adults with polyarticular juvenile idiopathic arthritis
Authors: Qiong Wu, Hema Chaplin, Nicola Ambrose, Debajit Sen, Maria J Leandro, Charlotte Wing, Nicola Daly, Kate Webb, Corinne Fisher, Linda Suffield, Francesca Josephs, Clarissa Pilkington, Despina Eleftheriou, Muthana Al-Obaidi, Sandrine Compeyrot-Lacassagne, Lucy R Wedderburn, Yiannis Ioannou
Journal: Annals of the Rheumatic Diseases (2015)

Juvenile arthritis disease activity score is a better reflector of active disease than the disease activity score 28 in adults with polyarticular juvenile idiopathic arthritis A considerable proportion of children with polyarticular juven-ile idiopathic arthritis (polyJIA) experience active disease into adulthood. 1However, there is no validated disease activity measure for adults with polyJIA, and they are often assessed using the disease activity score 28 (DAS28).DAS28 is validated in adults with rheumatoid arthritis (RA), and determines qualification for biological drugs in the UK and other countries. 23 In contrast to the juvenile arthritis disease activity score ( JADAS), 4 DAS28 does not fully evaluate the pattern of joint involvement often observed in polyJIA.In this study, we compared DAS28 with JADAS-10 in adolescents and adults with polyJIA.Tender and swollen joint counts out of 28, active joint count of all joints up to a maximum of 10, patient/parent and physician global assessment visual analogue scales were collected from clinics in patients aged ≥10 years with polyJIA (International League of Associations for Rheumatology classification criteria for rheumatoid factor-negative (RhF-ve) or rheumatoid factorpositive (RhF+ve) polyJIA).Erythrocyte sedimentation rate (ESR) values were taken within 30 days before or after assessment.When unavailable, values were taken within 3 months before or after, provided the patient remained stable between the ESR test and assessment.When unavailable within these time periods, patients were excluded from analysis.DAS28 and JADAS-10 were calcu-lated and compared using Spearman's rank correlation coefficient.DAS28>5.1 constitutes high-disease activity in adults with RA, ≤3.2 suggests low-disease activity or remission. 23 In children with polyJIA, JADAS-10>10.5 is considered to reflect high-disease activity, 5 ≤3.8 reflects low or inactive disease. 67 Forty-nine patients (36 polyJIA-RhF-ve, 10 polyJIA-RhF+ve, 3 unknown RhF) were analysed (range=10-27 years, median=15 years, M:F ratio 1:3.5).Good correlation was seen between the disease activity scores (Spearman's r=0.69, p<0.0001).However, when looking at values above cut-offs defined for active disease, considerable underestimation of disease activity by DAS28 was observed with 13 patients having JADAS-10>10.5 but only 1 of these patients having DAS28>5.1 (figure 1).There was no considerable difference in correlation between disease activity scores between adolescents (range=10-15 years, median=13 years, n=25, Spearman's r=0.83, p<0.0001) and adults (range=16-27 years, median=17 years, n=24, Spearman's r=0.73, p<0.
Copper nanoparticles generate reactive oxygen species (ROS) after air delivery to alveolar type-II cells in vitro
Authors: Peter S. Thorne, Jong Sung Kim, Andrea Adamcakova-Dodd
Journal: European Respiratory Journal (2011)

Rapid screening methods for NP are needed that replicate in vivo toxicity. We assessed cytotoxicity and ROS generation from Cu NP using an in vitro dynamic exposure model (IVDEM) that overcomes limitations of submerged-cell methods and mimics in vivo exposure conditions by generating and depositing airborne NP directly onto cells grown at an air-liquid interface (ALI).

A549 cells were exposed to particle-free air or Cu NP aerosols (12±1 μm) for 4 h at 0.4 μg/cm2 after which cells were incubated 4, 8, 12, or 24 h. Cytotoxicity was assessed by Alamar Blue assay of mitochondrial function and ROS using carboxy-H2DCF-DA as an indicator of steady-state levels of pro-oxidants.

Aerosolized Cu NPs were 30 nm (σg=1.9) indicating that the system produced a nanoscaled distribution of NP. Direct exposure of cells at the ALI minimized agglomeration and retained inherent particle characteristics. Viability for cells exposed to particle-free air or Cu NPs for 4 h were no different than cells maintained in the incubator (controls) indicating no trauma associated with exposure in the IVDEM. The production of intracellular ROS in particle-free, air-exposed cells was the same as controls. However, intracellular pro-oxidant levels after Cu NP exposure were increased at 4 and 8 h post-incubation (130% and 170% of control). ROS levels resolved to baseline at 24 h postexposure indicating that Cu NP-induced oxidative stress did not exceed the cells' ability to neutralize ROS.

Cu NPs generate significant intracellular ROS after air-delivery to human alveolar cells in this IVDEM. This in vitro test system using lung epithelial cells with an ALI has potential utility for NP toxicity assessment.
Diethylstilbestrol and docetaxel: A phase II study in patients with metastatic, androgen independent prostate cancer
Authors: B. Montgomery, D. Lin, C. Ryan, M. Garzotto, T. M. Beer
Journal: Journal of Clinical Oncology (2006)

4627 Background: The combination of diethylstilbestrol (DES) and docetaxel has additive to synergistic activity against prostate cancer in preclinical models and DES inhibits expression of taxane resistant tubulin isoforms. The objective of this study is to determine the effects of the combination of DES and docetaxel on PSA, overall response, and toxicity. Methods: Twenty nine patients with metastatic androgen independent prostate cancer progressing by rising PSA or scan were treated with DES 5 mg daily the day prior to docetaxel and 1 mg daily continuously in combination with Docetaxel 36mg/m 2 IV weekly for 3 weeks of a 4 week cycle. Prophylactic anticoagulation was used in all patients. All patients were assessed by PSA monthly and CT or bone scans every 3 cycles. Dose modifications for hematologic, hepatic and renal toxicity were made. The RECIST criteria and PSA decline by &gt;50% which was maintained for 4 weeks were used. Results: The median age is 69 years (56–84), SWOG PS 0 (0–1), alkaline phosphatase 120 U/L (45–523), Hgb 12.6 g/dL (9.2–16.3), PSA 67 ng/dL (6–1962). The median number of cycles is 5. The median follow up after completion of therapy is 6 mos (1–18). Soft tissue metastases were present in 46% of patients and bone metastases in 96%. Twenty four patients are evaluable for response and toxicity. Of these, 18 patients (75%) had PSA responses and the PSA declined by &gt;90% in 9 patients (38%). The overall response for was 75%. 11 patients suffered grade 3/4 toxicity. Two patients died of causes unrelated to therapy and another died from a steroid induced ulcer. The median number of cycles for responding patients is 9. Two patients developed thrombosis and were positive for Factor V mutations. Conclusions: The combination of DES and docetaxel is well tolerated and toxicity is indistinguishable from docetaxel alone. The overall response rate was 75%, with approximately half of responding patients achieving a PSA &lt; 4.0, suggesting that DES improves the therapeutic index of docetaxel substantially and is an effective regimen using easily administered drugs. (Supported by Sanofi Aventis). [Table: see text]
Complete Versus Lesion-Only Primary PCI
Authors: Gerry P. McCann, Jamal N. Khan, John P. Greenwood, Sheraz Nazir, Miles Dalby, Nick Curzen, Simon Hetherington, Damian J. Kelly, Daniel J. Blackman, Arne Ring, Charles Peebles, Joyce Wong, Thiagarajah Sasikaran, Marcus Flather, Howard Swanton, Anthony H. Gershlick
Journal: Journal of the American College of Cardiology (2015)

Complete revascularization may improve outcomes compared with an infarct-related artery (IRA)-only strategy in patients being treated with primary percutaneous coronary intervention (PPCI) who have multivessel disease presenting with ST-segment elevation myocardial infarction (STEMI). However, there is concern that non-IRA PCI may cause additional non-IRA myocardial infarction (MI). This study sought to determine whether in-hospital complete revascularization was associated with increased total infarct size compared with an IRA-only strategy. This multicenter prospective, randomized, open-label, blinded endpoint clinical trial evaluated STEMI patients with multivessel disease having PPCI within 12 h of symptom onset. Patients were randomized to either IRA-only PCI or complete in-hospital revascularization. Contrast-enhanced cardiovascular magnetic resonance (CMR) was performed following PPCI (median day 3) and stress CMR at 9 months. The pre-specified primary endpoint was infarct size on pre-discharge CMR. The study had 80% power to detect a 4% difference in infarct size with 100 patients per group. Of the 296 patients in the main trial, 205 participated in the CMR substudy, and 203 patients (98 complete revascularization and 105 IRA-only) completed the pre-discharge CMR. The groups were well-matched. Total infarct size (median, interquartile range) was similar to IRA-only revascularization: 13.5% (6.2% to 21.9%) versus complete revascularization, 12.6% (7.2% to 22.6%) of left ventricular mass, p = 0.57 (95% confidence interval for difference in geometric means 0.82 to 1.41). The complete revascularization group had an increase in non-IRA MI on the pre-discharge CMR (22 of 98 vs. 11 of 105, p = 0.02). There was no difference in total infarct size or ischemic burden between treatment groups at follow-up CMR. Multivessel PCI in the setting of STEMI leads to a small increase in CMR-detected non-IRA MI, but total infarct size was not significantly different from an IRA-only revascularization strategy. (Complete Versus Lesion-Only Primary PCI Pilot Study [CvLPRIT]; ISRCTN70913605)
Analysis of Cases in Which a Biopsy Specimen Is Positive and an Excised Lesion Is Negative for Nonmelanoma Skin Cancer
Authors: Jane Han, Naveed N. Nosrati, Tahereh Soleimani, Imtiaz A. Munshi, Roberto L. Flores, Sunil S. Tholpady
Journal: JAMA Surgery (2015)

This retrospective database study aims to determine the lesion and patient characteristics that would most strongly predict a histologically negative result for an excised lesion after a biopsy specimen had positive margins.
Allogeneic Hematopoietic Cell Transplantation Using Fludarabine, Melphalan and Bortezomib (Flu/Mel/Vel) Conditioning For Consolidation Of VGPR Or CR In Myeloma
Authors: Taiga Nishihori, Jose L. Ochoa-Bayona, Kenneth H. Shain, Daniel Sullivan, Rachid Baz, Ryan Hillgruber, Claudio Anasetti, Melissa Alsina
Journal: Blood (2013)
Burden of community diarrhoea in developing countries
Authors: Tess Baker
Journal: The Lancet Global Health (2015)

The Article by James Platts-Mills and colleagues (September, 2015),1Platts-Mills JA Babji S Bodhidatta L et al.Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED).Lancet Glob Health. 2015; 3: e564-e575Summary Full Text Full Text PDF Scopus (564) Google Scholar highlights the burden of diarrhoeal disease in young children in developing countries and also demonstrates the effect that seasonal variations have on multiple causative pathogens. Infectious gastroenteritis contributes significantly to the 1 billion episodes of diarrhoea and 3 million deaths in children under 5 years, and is the fifth leading cause of death worldwide.2Onozuka D Effect of non-stationary climate on infectious gastroenteritis transmission in Japan.Sci Rep. 2014; 4: 5157Crossref PubMed Scopus (16) Google Scholar Pathogens causing diarrhoea frequently show seasonality, suggesting that climate and enteric disease are inextricably linked. This link has important implications if we accept the very real threat of climate change on human health. WHO quantified the impact of global warming on diarrhoea, reporting that warming by 1°C was associated with a 5% increase in diarrhoea.3WHOClimate change and human health: risks and responses. World Health Organization, Geneva2004: 333Google Scholar Increased rainfall has been associated with higher incidence of norovirus4Bruggink LD Marshall JA The incidence of norovirus-associated gastroenteritis outbreaks in Victoria, Australia (2002–2007) and their relationship with rainfall.Int J Environ Res Public Health. 2010; 7: 2822-2827Crossref PubMed Scopus (20) Google Scholar whereas rotavirus often peaks in colder months. As such, extreme weather events associated with climate change are likely to alter patterns of gastroenteritis. The increased replication rate of some bacterial and viral pathogens in warm conditions,5Kolstad EW Johansson KA Uncertainties associated with quantifying climate change impacts on human health: a case study for diarrhea.Environ Health Perspect. 2011; 119: 299-305Crossref PubMed Scopus (98) Google Scholar combined with poor water and sanitation infrastructure, means that people in developing nations are particularly vulnerable. Predicting the potential effects of climate change on the incidence and distribution of infectious gastroenteritis can assist public health providers to control and prevent severe outbreaks in the future. Implementation of programmes for rotavirus vaccination clearly shows benefit and should be an adaptation strategy to help cope with climate change. More importantly, however, Platts-Mills and colleagues1Platts-Mills JA Babji S Bodhidatta L et al.Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED).Lancet Glob Health. 2015; 3: e564-e575Summary Full Text Full Text PDF Scopus (564) Google Scholar identified multiple pathogens contributing to diarrhoeal disease, highlighting the necessity for a broader mitigation plan. I declare no competing interests.
Abstract 17443: Inhibition of the Calcineurin Interaction Site on TRPV1 Reduces Myocardial Infarct Size in Rats
Authors: Eric R Gross, Nir Qvit, Garrett J Gross, Daria Mochly-Rosen
Journal: Circulation (2014)

Introduction: With recent public concerns of opioid overuse, misuse and addiction along with the heightened FDA restrictions on opioid prescribing, non-opioid cardiac-safe pain therapeutics for those with cardiovascular disease is needed. The transient receptor potential vanilloid 1 (TRPV1), a mediator of heat, pain and noxious stimuli, mediates nociception. While blocking TRPV1 reduces pain, the finding preconditioning-induced cardioprotection is lost in TRPV1 knockout mice or by TRPV1 inhibition indicates a dual role for TRPV1 both in protection from cardiac injury and in pain signaling. Hypothesis: We tested whether a peptide corresponding to a calcineurin interaction site on TRPV1 could separate the functions of TRPV1 by reducing myocardial injury while providing pain control. Methods: The peptide was synthesized using a Liberty peptide synthesizer and conjugated to TAT for intracellular entry. Male Sprague-Dawley rats 8 weeks of age were used for both isolated heart and in vivo studies consisting of 30 minutes of ischemia followed by reperfusion. Infarct size was assessed by triphenyltetrazolium staining. Results: Testing the peptide using a calcineurin activity assay kit in vitro showed the peptide inhibited calcineurin activity vs. TAT control (0.46±0.03* vs. 0.77±0.02, nmol phosphate, n=3/group, *P&lt;0.05). Further, peptide treatment of isolated hearts (1μM, infused over 10 minutes prior to ischemia) reduced infarct size and creatine phosphokinase (CPK) release when compared to TAT-treated hearts (Infarct size: 19±3%* vs. 53±4%, %infarct/left ventricle; CPK: 69±22* vs. 459±132, n=6/group, *P&lt;0.01). In an in vivo myocardial ischemia-reperfusion model, the peptide (1mg/kg), given subcutaneously to the abdominal skin prior to ischemia, reduced infarct size compared to control (50±2*% vs. 66±1%, *P&lt;0.001). Initial evidence also suggests that the peptide provides analgesia in pain models. Conclusions: Our results suggest a peptide blocking the calcineurin interaction site of TRPV1 reduces myocardial infarct size. Therefore, disrupting specific protein-protein interactions between calcineurin and TRPV1 may provide a novel strategy to design non-opioid therapeutics for cardioprotection, while also providing pain relief.