tbuckley/cabot-search huggingface dataset:
ARRY-334543, A potent, orally active small molecule inhibitor of EGFR and ErbB-2
Authors: Greg Miknis, Eli Wallace, Joe Lyssikatos, Patrice Lee, Qian Zhao, Jeremy Hans, George Topalov, Alex Buckmelter, Gene Tarlton, Li Ren, Josh Tullis, Bryan Bernat, Lisa Pieti Opie, Ira Von Carlowitz, Janet Parry, Tony Morales, Michelle Perrier, Rich Woessner, Tracy Pheneger, Keith Hoffman, Jim Winkler, Kevin Koch
Journal: Cancer Research (2005)

3399  The growth factor receptor tyrosine kinases EGFR (ErbB-1) and ErbB-2 (HER-2/neu) play a major role in controlling cell growth, differentiation and survival. These two receptor tyrosine kinases are often over-expressed and/or abnormally active in a wide variety of tumor types. Currently several drugs have been developed that selectively inhibit either EGFR or ErbB-2. Despite some clinical success with the selective agents, data suggest concomitant inhibition of both kinases maybe a more efficacious approach for the treatment of tumors. At the present time, there are no approved therapeutic agents that target both EGFR and ErbB-2, although several compounds are currently under investigation. In a series of experiments we demonstrate that ARRY-334543 is a novel, potent, orally active dual inhibitor of EGFR and ErbB-2. The compound is a reversible ATP-competitive inhibitor with nanomolar potency against both kinases in vitro. In cell-based assays using tumor cells that over-express EGFR (A431) or ErbB-2 (BT474), ARRY-334543 potently inhibited substrate phosphorylation. ARRY-334543 was shown to be highly selective for EGFR/ErbB-2, and did not show any significant activity when screened against a panel of 104 kinases. In murine xenograft models ARRY-334543 demonstrated significant dose-related (25, 50, 100 mg/kg) tumor growth inhibition in A431-derived tumors when administered orally, BID, for 21 days. Based on potency, selectivity and efficacy data, the compound is currently in development as an anti-cancer agent.
Abstract 18193: Transcatheter Aortic Valve Replacement versus Surgical Aortic Valve Replacement in Patients With Cirrhosis: A Propensity Score Matched Analysis
Authors: Badal Thakkar, Aashay Patel, Ronak Bhimani, Nileshkumar J Patel, Parth Bhatt, Chirag Savani, Achint Patel, Samir Patel, Rajesh Sonani, Shantanu Solanki, Shilpkumar Arora, Nilay Patel, Sopan Lahewala, Abhishek Dave, Ankit Chothani, Sidakpal S Panaich, Vikas Singh, Abhishek Deshmukh, Apurva O Badheka
Journal: Circulation (2015)

Introduction: Over the past decade, Transcatheter Aortic Valve Replacement (TAVR) has emerged as a therapeutic option for treating severe aortic stenosis in high-risk patients. Patients with liver cirrhosis are at high risk for operative morbidity and mortality when they undergo cardiac surgery. In the present study, in-hospital outcomes are compared in cirrhotic patients undergoing TAVR vs. Surgical Aortic Valve Replacement (SAVR). Methods: The study population was derived from the National Inpatient Sample (NIS) for the years 2011 and 2012 using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) procedure codes 35.21 and 35.22 for SAVR, and 35.05 and 35.06 for TAVR. Patients&lt;50 years of age and those with concomitantly other valvular procedures were excluded. ICD-9-CM diagnosis codes were used to identify patients with liver cirrhosis including those with other manifestations of cirrhosis such as portal hypertension and esophageal varices. Using propensity score matching, two matched cohorts were derived in which the outcomes were compared using chi-square test, fisher’s exact test, and student’s t-test. Results: There were 30 cirrhotic patients in the SAVR and TAVR group each after propensity score matching. Compared to the TAVR group, the patients in the SAVR group had higher mean cost of hospitalization ($79,263 vs. $63,913, p=0.12), mean post-procedural length of stay (14.3 days vs. 6.2 days, p&lt;0.01), any complications rate (80.0% vs. 60.0%, p=0.09), rate of transfusion of blood or blood products (56.7% vs. 30.0%, p=0.037) and liver complications rate (20.0% vs. 10.0%, p=0.4). The in-hospital mortality rate was same in both the groups (6.7%). Conclusions: In high-risk cirrhotic patients, TAVR is a viable option for aortic valve replacement compared to SAVR.
Clonal selection drives protective memory B cell responses in controlled human malaria infection
Authors: Rajagopal Murugan, Lisa Buchauer, Gianna Triller, Cornelia Kreschel, Giulia Costa, Gemma Pidelaserra Martí, Katharina Imkeller, Christian E. Busse, Sumana Chakravarty, B. Kim Lee Sim, Stephen L. Hoffman, Elena A. Levashina, Peter G. Kremsner, Benjamin Mordmüller, Thomas Höfer, Hedda Wardemann
Journal: Science Immunology (2018)

The clonal selection of potent germline antibodies outpaces affinity maturation in human anti-PfCSP memory B cell responses.
Evaluating the cost-effectiveness of current FDA-approved PARP inhibitors for the treatment of recurrent ovarian cancer.
Authors: Juliet Elizabeth Wolford, Jiaru Bai, Ramez Hassef Eskander, Robin Keller, Lindsey E Minion, John K. Chan, Bradley J. Monk, Krishnansu Sujata Tewari
Journal: Journal of Clinical Oncology (2017)

5516 Background: Unlike approved IV administered therapies, Medicare is under no obligation to cover prescription medicines. We sought to evaluate the cost-effectiveness of the two FDA-approved orally administered PARP inhibitors (PARPi), olaparib and rucaparib. Methods: A Markov model was created in TreeAge Pro 2015 with nodes in the chain allowing patients to transition through response, hematological complications, non-hematological complications, progression, and death. Separately, the PARP inhibitors were compared with IV administered drugs approved for recurrent ovarian cancers including platinum-based, non-platinum, and bevacizumab-based regimens. Toxicity and mean PFS rates for the different agents were obtained from registration trial data. Costs of IV chemotherapy, managing toxicities, infusions, and supportive care were estimated using 2015 Medicare data. Incremental cost-effectiveness ratios (ICER) were calculated and survival was reported in quality adjusted life months. Results: Platinum-based combinations were the most cost-effective at $1,672/PFS mo as compared to non-platinum agents ($6,688/mo), bevacizumab-containing regimens ($12,482/mo), olaparib ($13,3731/mo), and rucaparib ($14,034/mo). Considering a cost of $114,478 for olaparib and $137,068 for rucaparib prior to progression, costs associated with PARPi were 7.1 to 8.3X more than platinum combinations. To better compare the registration trial data to PARPi data, probability was adjusted to 2 nd line for rucaparib, revealing it’s ICERs’ of per month of life added to be $26,997 for bevacizumab, $17,757 for non-platinum, and $79,585 for platinums. Using the adjusted-to-2 nd -line probabilities for olaparib, exhibited ICERs were $16,549 for bevacizumab, $25,637 for non-platinums and $72,083 for platinums. Conclusions: The high costs of PARPi were not balanced by costs of infusion and managing toxicities of IV drugs typically associated with lower response rates and shorter PFS in the recurrent space. Balancing incremental clinical benefit with novel therapies remains problematic and could widen disparities among those with limited access to care.
Abstract 18401: Echocardiographic Prediction of Outcomes in Fetal Pulmonary Atresia With Intact Ventricular Septum
Authors: Claudia Renaud, Bridget Zoeller, Stephanie Levasseur, Tiscar Cavalle, Marie-Josée Raboisson, Lisa Hornberger, Edgar Jaeggi
Journal: Circulation (2016)

Background: Critical pulmonary stenosis (CPS) and pulmonary atresia with an intact ventricular septum (PA-IVS) represent a spectrum of pathology that ranges from good-sized to severely hypoplastic ...
Prognosis of small tumors according to KI67 and IHC subtypes.
Authors: Antonella Ferro, Claudio Eccher, Renza Triolo, Alessia Caldara, Mattia Barbareschi, Mariachiara Dipasquale, Enzo Galligioni
Journal: Journal of Clinical Oncology (2014)

574 Background: The incidence of small ( ≤1 cm) node-negative breast cancers (BC) is increasing in mammography-screened populations. These tumors generally have good prognosis with low risk of distant and local recurrence. Methods: A retrospective review of 665 patients classified as having ≤1 cmN0 BC treated in our Institution from 1995 to 2008 was done. Clinical-pathological features and long term outcomes (EFS and OS) were analyzed according to KI67 LI, HER2 status, PR expression and intrinsic sybtypes (luminal A, B, HER2 luminal, HER2, Triple negative-TN). Results: Median age at diagnosis was 60 years (range: 23 to 86 ys).There were 30 T1mic (4.5%), 122 T1a (18.4%) and 513 T1b (77.1%) cancers. A higher proportion of pT1mic+T1a presented poor grading (G3) and had the HER2 and TN subtypes compared with pT1b BC. HER2 was over-expressed or amplificated in 89 (13.4%) of all cases. Chemotherapy with or without hormonal therapy was administered to 18 T1a (12%) and to 82 T1b (16%); hormonal therapy alone in 46 T1a (30%) and 252 T1b (49%). No one received adjuvant trastuzumab. At a 6,5 ys median follow up there were 29 (4.4%) loco-regional (LRR) or distant relapses (DR), 26 (3.9%) controlateral and 21 (31%) other tumors.Similar incidence of LRR, DR and BC related deaths between T1a and T1b was reported. High ki67 (defined as median value = 15%) confirmed its prognostic significance in term of OS, in particular T1b cases (p=0.015), but not in EFS.No difference was found between Luminal B and Luminal A subtypes for any of the outcomes analysed. TN and HER2 subtypes, but not HER2 luminals were correlated with a significantly increased BC related events if compared with the Luminal A subtype (TN 85.7%, HER2 79.4%, Her2 luminal 90.7%, Luminal A 93.7%, Luminal B 89.1%). Conclusions: Our experience confirms good prognosis of ≤ 1 cm N0 BC. However, tumors with more aggressive biological features (high Ki67, HER2 or TN subtypes) had higher incidence of relapses. In this
Mutational analysis of the CDAN1 gene in familial and sporadic congenital dyserythropoietic anaemia type 1
Authors: M R Ahmed, A Sternberg, L Zahed, A Taher, J Haidar, A Shamseddine, A M O'hea, N Bienz, O Dgany, N Avidan, J S Beckmann, H Tamary, W Wood, P Vyas, S Wickramasinghe
Journal: Blood (2003)
Abstract 18152: Gradual Decline in The Age Adjusted In-hospital Mortality Rate from STEMI Related Cardiogenic Shock Irrespective of Cause, Race or Gender with Persistent Higher Mortality Rates in Women Despite Multivariate Adjustment
Authors: Mohammad Reza Movahed, Muhhamad F Khan, Mehrnoosh Hashemzadeh, Mehrtash Hashemzadeh
Journal: Circulation (2012)

Background:  Recently we presented reduction in the age adjusted mortality rate in patient with STEMI and all Cause related mortality with persistently higher mortality in women and African American race. The goal of this study was perform multivariate analysis The goal of this study was to evaluate race and gender association after adjusting for co-morbid conditions in multivariate analysis   Method:  The Nationwide Inpatient Sample (NIS) database was utilized to calculate the age-adjusted mortality rate of cardiogenic shock from 1996 to 2006 based on ICD-9 coding in the setting of STEMI and cardiogenic shock. We used multivariate analysis adjusting for type 2 diabetes, hyperlipidemia, chronic renal failure, history of CAD, smoking, heart failure, valvular abnormalities and pulmonary hypertension.   Results:  We found gradual decrees in mortality over the last 10 years in patients suffering from all cause or STEMI related cardiogenic shock irrespective of gender or race with persistent higher mortality rate for women and African Americans but this association remained significant only for women after multivariate adjustment. .(female gender OR 1.4, CI: 1.2-1.6 , P   Conclusion:  Age adjusted in-hospital mortality has been gradually declining in patients presenting with all cause or STEMI related cardiogenic shock over the last 10 years irrespective of gender or race. However, women have persistently higher mortality despite multivariate adjustment warranting further investigation.
Abstract 14068: Effect of Tricuspid Regurgitation on Thermodilution Cardiac Output Assessment
Authors: Benjamin Koo, Dan Wang, Cesar Guerrero Miranda, Abdissa Negassa, James Tauras
Journal: Circulation (2016)

Background: It is generally accepted that tricuspid regurgitation (TR) affects the reliability of the thermodilution (TD) cardiac output technique in patients with pulmonary artery catheters. Previ...
Geospatial inequalities and determinants of nutritional status among women and children in Afghanistan: an observational study
Authors: Nadia Akseer, Zaid Bhatti, Taufiq Mashal, Sajid Soofi, Rahim Moineddin, Robert E Black, Zulfiqar A Bhutta
Journal: The Lancet Global Health (2018)

BackgroundUndernutrition is a pervasive condition in Afghanistan, and prevalence is among the highest in the world. We aimed to comprehensively assess district-level geographical disparities and determinants of nutritional status (stunting, wasting, or underweight) among women and children in Afghanistan.MethodsThe study used individualised data from the recent Afghanistan National Nutrition Survey 2013. Outcome variables were based on growth and weight anthropometry data, which we analysed linearly as Z scores and as dichotomous categories. We analysed data from a total of almost 14 000 index mother–child pairs using Bayesian spatial and generalised least squares regression models accounting for the complex survey design.FindingsWe noted that childhood stunting, underweight, and combined stunting and wasting were consistently highest in districts in Farah, Nangarhar, Nuristan, Kunar, Paktia, and Badakhshan provinces. District prevalence ranged from 4% to 84% for childhood stunting and 5% to 66% for underweight. Child wasting exceeded 20% in central and high-conflict regions that bordered Pakistan including east, southeast, and south. Among mothers, dual burden of underweight and overweight or obesity existed in districts of north, northeast, central, and central highlands (prevalence of 15–20%). Linear growth and weight of children were independently associated with household wealth, maternal literacy, maternal anthropometry, child age, food security, geography, and improved hygiene and sanitation conditions. The mother's body-mass index was determined by many of the same factors, in addition to ethnolinguistic status and parity. Younger mothers (<20 years old) were more underweight and shorter than older mothers (aged 20–49 years).InterpretationAfghanistan's rapidly changing political, socioeconomic, and insecurity landscape has both direct and indirect implications on population nutrition. Novel evidence from our study can be used to understand these multifactorial determinants and to identify granular disparities for local level tracking, planning, and implementation of nutritional interventions.FundingNone.
Abstract 17049: Dual-specificity Phosphatase-4 (DUSP4) Over-expression Prevents H/R-induced Apoptosis via the Up-regulation of eNOS
Authors: Chun-An Chen, Joanna Kilbane Myers, Mahmood Khan, Mark Angelos
Journal: Circulation (2016)

MAPK signaling cascades regulate several cellular functions, including differentiation, proliferation, and apoptosis. The duration and extent of phosphorylation of these MAPKs are critical determin...
Magnetic resonance imaging assessments of patients with RA and their association with clinical and radiographic outcomes
Authors: P. Emery, D. van der Heijde, Mikkel Østergaard, P. Conaghan, M. Genovese, E.C. Keystone, R. Fleischmann, W. Xu, S. Xu, E. Hsia, M.U. Rahman
Journal: Annals of the Rheumatic Diseases (2011)
Balloon-assisted endoscopy facilitates endoscopic submucosal dissection of difficult superficial proximal colon tumors
Authors: Takeshi Yamashina, Yoshikazu Hayashi, Hirotsugu Sakamoto, Tomonori Yano, Yoshimasa Miura, Satoshi Shinozaki, Keijiro Sunada, Alan Kawarai Lefor, Hironori Yamamoto
Journal: Endoscopy (2018)

Colorectal endoscopic submucosal dissection (ESD) can be technically difficult in some situations, such as paradoxical movement of the proximal colon. The double-balloon endoscope provides stable endoscopic maneuvering, even in the small intestine. The aim of this study was to assess the outcomes of balloon-assisted endoscopic submucosal dissection (BAESD) of colonoscopically difficult superficial proximal colon tumors.We retrospectively reviewed the records of patients who underwent BAESD of superficial proximal colon tumors where colonoscopic difficulties were encountered, from January 2011 to September 2016. Difficulties were defined as a previous incomplete colonoscopy using a conventional colonoscope or unstable endoscopic maneuverability around the tumor with a conventional colonoscope. A propensity score model was used as a secondary analysis to compare outcomes of the BAESD group with those of a non-BAESD group. RESULTS: BAESD was performed on 63 tumors in 63 patients. En bloc resection was achieved for 62 tumors (98 %) and an R0 resection was achieved for 55 tumors (87 %). Propensity score matching analysis created 59 matched pairs from the BAESD and non-BAESD groups. There were no statistically significant differences between the two groups in en bloc resection (100 % vs. 100 %; P > 0.99), R0 resection (90 % vs. 93 %; P = 0.74), perforation (0 % vs. 2 %; P > 0.99) or postoperative bleeding (3 % vs. 0 %; P = 0.50).Balloon-assisted endoscopy achieved safe and reliable ESD of colonoscopically difficult superficial proximal colon tumors.
Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome
Authors: Joseph Polex-Wolf, Brian Y.H. Lam, Rachel Larder, John Tadross, Debra Rimmington, Fàtima Bosch, Verónica Jiménez Cenzano, Eduard Ayuso, Marcella K.L. Ma, Kara Rainbow, Anthony P. Coll, Stephen O’Rahilly, Giles S.H. Yeo
Journal: Journal of Clinical Investigation (2018)

Profound hyperphagia is a major disabling feature of Prader-Willi syndrome (PWS). Characterization of the mechanisms that underlie PWS-associated hyperphagia has been slowed by the paucity of animal models with increased food intake or obesity. Mice with a microdeletion encompassing the Snord116 cluster of noncoding RNAs encoded within the Prader-Willi minimal deletion critical region have previously been reported to show growth retardation and hyperphagia. Here, consistent with previous reports, we observed growth retardation in Snord116+/–P mice with a congenital paternal Snord116 deletion. However, these mice neither displayed increased food intake nor had reduced hypothalamic expression of the proprotein convertase 1 gene PCSK1 or its upstream regulator NHLH2, which have recently been suggested to be key mediators of PWS pathogenesis. Specifically, we disrupted Snord116 expression in the mediobasal hypothalamus in Snord116fl mice via bilateral stereotaxic injections of a Cre-expressing adeno-associated virus (AAV). While the Cre-injected mice had no change in measured energy expenditure, they became hyperphagic between 9 and 10 weeks after injection, with a subset of animals developing marked obesity. In conclusion, we show that selective disruption of Snord116 expression in the mediobasal hypothalamus models the hyperphagia of PWS.
Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome
Authors: Jessica Heremans, Josselyn E. Garcia-Perez, Ernest Turro, Susan M. Schlenner, Ingele Casteels, Roxanne Collin, Francis de Zegher, Daniel Greene, Stephanie Humblet-Baron, Sylvie Lesage, Patrick Matthys, Christopher J. Penkett, Karen Put, Kathleen Stirrups, Chantal Thys, Chris Van Geet, Erika Van Nieuwenhove, Carine Wouters, Isabelle Meyts, Kathleen Freson, Adrian Liston
Journal: Journal of Allergy and Clinical Immunology (2018)
Should action take priority over further research on public health?
Authors: Simon Capewell, Paul Cairney, Aileen Clarke
Journal: BMJ (2018)

We have evidence on which to act, and inaction costs lives, argue <b>Simon Capewell</b> and <b>Paul Cairney</b>. But <b>Aileen Clarke</b> says our understanding of the human behaviour that leads to unhealthy choices is still lacking
A Window Into the Evolution of Trauma-Focused Psychotherapies for Posttraumatic Stress Disorder
Authors: Charles W. Hoge, Kathleen M. Chard
Journal: JAMA (2018)

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Risk factors, diagnosis and non-surgical treatment for meniscal tears: evidence and recommendations: a statement paper commissioned by the Danish Society of Sports Physical Therapy (DSSF)
Authors: Jonas Bloch Thorlund, Carsten Bogh Juhl, Lina Holm Ingelsrud, Søren Thorgaard Skou
Journal: British Journal of Sports Medicine (2018)

This statement aimed at summarising and appraising the available evidence for risk factors, diagnostic tools and non-surgical treatments for patients with meniscal tears. We systematically searched electronic databases using a pragmatic search strategy approach. Included studies were synthesised quantitatively or qualitatively, as appropriate. Strength of evidence was determined according to the Grading of Recommendations Assessment Development and Evaluation framework. Low-quality evidence suggested that overweight (degenerative tears, k=3), male sex (k=4), contact and pivoting sports (k=2), and frequent occupational kneeling/squatting (k=3) were risk factors for meniscal tears. There was low to moderate quality evidence for low to high positive and negative predictive values, depending on the underlying prevalence of meniscal tears for four common diagnostic tests (k=15, n=2474). Seven trials investigated exercise versus surgery (k=2) or the effect of surgery in addition to exercise (k=5) for degenerative meniscal tears. There was moderate level of evidence for exercise improving self-reported pain (Effect Size (ES)-0.51, 95% CI -1.16 to 0.13) and function (ES -0.06, 95% CI -0.23 to 0.11) to the same extent as surgery, and improving muscle strength to a greater extent than surgery (ES -0.45, 95% CI -0.62 to -0.29). High-quality evidence showed no clinically relevant effect of surgery in addition to exercise on pain (ES 0.18, 95% 0.05 to 0.32) and function (ES, 0.13 95% CI -0.03 to 0.28) for patients with degenerative meniscal tears. No randomised trials comparing non-surgical treatments with surgery in patients younger than 40 years of age or patients with traumatic meniscal tears were identified. Diagnosis of meniscal tears is challenging as all clinical diagnostic tests have high risk of misclassification. Exercise therapy should be recommended as the treatment of choice for middle-aged and older patients with degenerative meniscal lesions. Evidence on the best treatment for young patients and patients with traumatic meniscal tears is lacking.