tbuckley/cabot-search huggingface dataset:
Preclinical activity of ABT-869, a multi-targeted receptor tyrosine kinase inhibitor
Authors: Daniel H. Albert, Paul Tapang, Terrance J. Magoc, Lori J. Pease, David R. Reuter, Junling Li, Jun Guo, Nayereh S. Ghoreishi-Haack, Jason V. Brooks, Gail T. Bukofzer, Yi-Chun Wang, Jason A. Stavropoulos, Kresna Hartandi, Amanda L. Niquette, Ru-Qi Wei, J. Owen McCall, Jennifer J. Bouska, Yanping Luo, Cherrie K. Donawho, Yujia Dai, Patrick A. Marcotte, Keith B. Glaser, Michael R. Michaelides, Steven K. Davidsen
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

676 

ABT-869 is a recently identified, structurally novel, receptor tyrosine kinase inhibitor. The agent is multi-targeted in that it is a potent inhibitor of all members of the VEGF and PDGF receptor families (e.g., KDR IC50 value of 4 nM), but has much less activity (IC50 values >1 μM) against unrelated receptor tyrosine kinases, soluble tyrosine kinases or serine/threonine kinases. The kinase inhibition profile of ABT-869 is evident in cellular assays of RTK phosphorylation (IC50 values of 2, 4 and 7 nM for PDGFRβ, KDR and CSF-1R, respectively) and VEGF-stimulated proliferation (0.2 nM IC50 for human endothelial cells). ABT-869 is not a general antiproliferative agent since, in most cancer cells, >1,000-fold higher concentrations of ABT-869 are required for inhibition of proliferation. However, ABT-869 exhibits potent antiproliferative and apoptotic effects on cancer cells whose proliferation is known to be dependent on mutant, constitutively active, kinases like FLT3 and KIT. In vivo ABT-869 is effective when given orally in mechanism-based models such as VEGF-induced uterine edema (ED50: 0.5 mg/kg) and VEGF and bFGF-induced angiogenesis (>50% inhibition at 15 mg/kg in mouse cornea). In preclinical tumor growth studies, as a single agent, ABT-869 exhibits efficacy in human fibrosarcoma and human breast, colon, and small cell lung carcinoma xenograft models (ED50: 3-10 mg/kg/day). In addition ABT-869 is effective (>50% inhibition of tumor growth) in orthotopic breast, prostate and glioma models. Tumor regression was observed in epidermoid carcinoma and leukemia xenograft models. In combination studies ABT-869 produced at least additive effects when given with cytotoxic or with other experimental targeted therapies. Based on pharmacokinetic analysis from the murine tumor growth studies, efficacy correlated more strongly with time over a threshold value, such as the cellular KDR IC50 corrected for plasma protein binding (21 nM ≥ 7 hours ), than with plasma AUC or Cmax. These results provide the foundation for future assessment of ABT-869 as a therapeutic agent in the treatment of cancer.
Lithium treatment of manic episodes with psychotic features in prepubertal children
Authors: T M Varanka, R A Weller, E B Weller, M A Fristad
Journal: American Journal of Psychiatry (1988)

The authors describe the manic symptoms, family psychiatric histories, and psychotic symptoms of 10 prepubertal children 6-12 years old who had a DSM-III diagnosis of manic episode with psychotic features. All of the children improved when treated with lithium alone. Improvement in both manic and psychotic symptoms was noted an average of 11 days after lithium administration was started.
Novel combinations with a CDK inhibitor for the treatment of human mantle cell lymphoma cells
Authors: Subhra Mohapatra, Jianguo Tao, Sophie Dessureault, Said Sebti, Eduardo Sotomayor, W. Pledger
Journal: Cancer Research (2007)

3260  Mantle cell lymphoma (MCL) arises from the neoplastic transformation of naive B cells in the mantle zone of the B cell follicle. It is an aggressive and incurable B cell neoplasm. It accounts for 5% to 8% of non-Hodgkin’s lymphomas. Patients with MCL respond initially to chemotherapy but ultimately relapse. Mean survival time is only three to four years. Thus, the need for new treatments that effectively combat MCL is obvious and imperative. Defects in cell cycle regulation and apoptosis are primary events in MCL. It is characterized by the presence of a chromosomal translocation t (11:14)(q13:q32), which results in deregulated cyclin D1 expression. Cyclin D1 overexpression in MCL is thought to play a major role in lymphomagenesis, although the precise mechanisms by which tumor formation and progression occur are not fully understood. Subsets of MCLs also exhibit constitutive activity of two proteins previously implicated in tumor cell survival: the serine/threonine kinase AKT and signal transducer and activator of transcription 3 (Stat3). Toward the search for novel therapies for MCLs, we examined the potential of roscovitine (Rosc), an inhibitor of cyclin dependent kinase (CDK), as a single agent or in combination with either LY294002 (LY), a PI3K/Akt inhibitor, or cucurbitacin-I (CuI), a Jak/Stat3 inhibitor, in inducing apoptosis of various MCL lines as well as in MCL patient samples. Roscovitine or CuI modestly increased the percentage of apoptotic cells (~30%), whereas LY had no effect. However, when added in combination, Rosc/CuI or Rosc/LY induced apoptosis in more than 70% of cells. We also identified three targets of the latter combination: cyclin D1 and the anti-apoptotic proteins myeloid cell leukemia-1 (Mcl-1) and X-linked Inhibitor of Apoptosis (XIAP). Roscovitine eliminated Mcl-1 expression, slightly reduced XIAP abundance and had very little effect on abundance of cyclin D1. Conversely, LY reduced cyclin D1 expression and slightly reduced the abundance of Mcl-1 and XIAP. A larger decrease in XIAP abundance is seen in cultures treated with a combination of Rosc/LY. On the basis of these findings, we suggest that agents that target Mcl-1, XIAP and cyclin D1 will be most effective in inducing apoptosis of human MCLs.
Prognostic Value of the Physical Examination in Patients With Heart Failure and Atrial Fibrillation
Authors: Guillem Caldentey, Paul Khairy, Denis Roy, Hugues Leduc, Mario Talajic, Normand Racine, Michel White, Eileen O'Meara, Marie-Claude Guertin, Jean L Rouleau, Anique Ducharme
Journal: JACC Heart Failure (2014)

This study sought to assess the prognostic value of physical examination in a modern treated heart failure population. The physical examination is the cornerstone of the evaluation and monitoring of patients with heart failure. Yet, the prognostic value of congestive signs (i.e., peripheral edema, jugular venous distension, a third heart sound, and pulmonary rales) has not been assessed in the current era. A post-hoc analysis was conducted on all 1,376 patients, 81% male, mean age 67 ± 11 years, with symptomatic left ventricular systolic dysfunction enrolled in the AF-CHF (Atrial Fibrillation and Congestive Heart Failure) trial. The prognostic value of baseline physical examination findings was assessed in univariate and multivariate Cox regression analyses. Peripheral edema was observed in 425 (30.9%), jugular venous distension in 297 (21.6%), a third heart sound in 207 (15.0%), and pulmonary rales in 178 (12.9%) patients. Death from cardiovascular causes occurred in 357 (25.9%) patients over a mean follow-up of 37 ± 19 months. All 4 physical examination findings were associated with cardiovascular mortality in univariate analyses (all p values <0.01). In multivariate analyses, taking all 4 signs as potential covariates, only rales (hazard ratio 1.41; 95% confidence interval: 1.07 to 1.86; p = 0.013) and peripheral edema (hazard ratio: 1.25; 95% confidence interval: 1.00 to 1.57; p = 0.048) were associated with cardiovascular mortality, independent of other variables. In the modern era, congestive signs on the physical examination (i.e., peripheral edema, jugular venous distension, a third heart sound, and pulmonary rales) continue to provide important prognostic information in patients with congestive heart failure.
Abstract 2479: What is the Long-Term Outcome of Transseptal Puncture Using a 12-French Sheath?
Authors: Vivek Y Reddy
Journal: Circulation (2009)

Introduction: The transseptal puncture procedure has proven to be invaluable for a variety of interventions. Serial transesophageal echocardiography (TEE) studies after puncture with 8Fr sheaths have revealed that this residual atrial septal defect (ASD) eventually closes. However, there is no data on the integrity of the atrial septum after puncture with larger caliber sheaths - an important issue given the increasing use of large sheaths for electrophysiological and interventional procedures such AF ablation using balloon catheters, LAA occlusion and percutaneous valve procedures. To this end, this study examined atrial septal integrity after transseptal puncture using a 12-Fr sheath. Methods: The study cohort included patients enrolled in PROTECT-AF, an investigational trial of left atrial appendage occlusion (Watchman, Atritech, Inc). The procedure involves use of a transseptal sheath with a 12Fr inner and 14Fr outer diameter. Systematic evaluation of the iatrogenic ASD was possible because the protoc...
Abstract B34: Diagnostics of pancreatic duct hypertension by the serotonin-stimulated magnetic resonance cholangiopancreatography
Authors: Alexey Kashintsev, Konstantin Pavelets, Nikolai Kokhanenko, Evgeny Imyanitov
Journal: Cancer Research (2015)

Abstract Background: Serotonin is a neurotransmitter and humoral enhancer which stimulates the pancreatic secretion. Unlike secretin serotonin doesn’t change the proteinogramm of pancreatic juice1. Pancreatic and periampullary tumors can cause the dilatation of the main pancreatic duct. Its partial stenosis can remain undiagnosed on conventional MRCP. Increasing secretion of pancreatic juice after serotonin stimulation can improve the diagnosis, particularly the location and length of a lesion. Method: Eighteen patients with pancreatic cancer (n=14) and tumor of papilla Vateri (n=4) were included into the study. Median age was 64.9 years with range 45-84 years. Serotonin (0,01mg/kg) was administered perorally (n=2), intramuscularly (n=2), or intravenously with dilution (n=5) and without it (n=9). MRCP was performed before the drug application and 7 minutes after that. Results: In cases where serotonin was administered perorally, intramuscularly or intravenously with dilution we have not received any significant results (Tab. 1). The positive results were obtained in 5 (55.6%) of 9 cases when MRCP was performed 7 minutes after intravenous administration of concentrated solution. The mean increase in width of the main pancreatic duct was 1.1 mm (range 0.9-1.9 mm). Conclusion: The method of serotonin-stimulated MRCP can improve the diagnosis of pancreatic ductal hypertension. In these 5 cases the presented technique allowed us to detect the size and localization of a lesion more precisely: tumor of a papilla (n=2), cancer of a pancreatic head (n=3) including one case with involvement of the pancreatic body. In cases of primary ductal dilatation more than 5 mm (n=3) we have not received any positive results, so these patients were excluded from the study. Note: This abstract was not presented at the conference. Citation Format: Alexey Kashintsev, Konstantin Pavelets, Nikolai Kokhanenko, Evgeny Imyanitov. Diagnostics of pancreatic duct hypertension by the serotonin-stimulated magnetic resonance cholangiopancreatography. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B34.
Abstract 2250: Is Atrial Fibrillation in Hypertrophic Cardiomyopathy Due to Left Atrial Structural Remodeling as Determined by Speckle-Derived Atrial Strain Imaging?
Authors: Ying Shan, Grace Lin, Toshinori Yuasa, Fletcher A Miller, Steve R Ommen, Peter A Brady
Journal: Circulation (2008)

Background: Atrial fibrillation (AF) is common in HCM yet the mechanisms are poorly understood but are likely secondary to either the consequences of left atrial structural remodeling (LASR) or myopathy, or triggers arising from pulmonary and other thoracic veins. The presence and severity of LASR as characterized by left atrial strain (LA ϵ), and its relationship to AF in HCM, has not been determined. Therefore, we measured LA ϵ and strain rate (SR) in Pts with HCM both with (AF+) and without (AF−) prior AF and compared these measures to those in age and gender matched controls without HCM or AF. Methods: Two-dimensional speckle-derived LA longitudinal peak ϵ, SR during systole (SR S ), early (SR E ) and late diastole (SR A ) were measured at the basal and mid portions of the lateral, septal, and posterior LA walls using Vector Velocity Imaging during sinus rhythm and were averaged. Results: Mean age of Pts in each of the matched groups was 56 ± 2 years (16 males; 59%). Significant left ventricular outflow tract obstruction was present in all Pts with HCM. Diastolic dysfunction was similar in both HCM groups and worse when compared to controls. Peak LA 3 , SR S , SR E , and SR A for each group is shown (table 1 ). HCM was associated with significantly lower LA ϵ and SR compared to controls. Although LA size was increased in Pts with HCM when compared to controls there was no correlation between LA size and ϵ or SR (p&gt;0.05 for all). No differences in LA ϵ and SR were found between AF+ versus AF− Pts. Conclusion: HCM is associated with LASR as determined by decreased LA ϵ and SR. However, LA ϵ and SR were similar in AF+ versus AF− Pts suggesting that the occurrence of AF in HCM is not due to LASR alone. Table 1. Left Atrial Strain and Strain Rate in Hypertrophic Cardiomyopathy
Functional sites of neuroleptic drug action in the human brain: PET/FDG studies with and without haloperidol
Authors: H H Holcomb, N G Cascella, G K Thaker, D R Medoff, R F Dannals, C A Tamminga
Journal: American Journal of Psychiatry (1996)

The functional pathways through which antipsychotic drugs act in the brain to decrease psychosis remain unknown, despite our knowledge that their site of initial action is through blockade of dopamine D2 receptors. The authors sought to define the brain regions that are functionally altered by neuroleptic drugs.Regional cerebral glucose metabolism was studied in 12 subjects with schizophrenia while they were receiving a fixed dose of haloperidol, again 5 days after withdrawal of the drug, and a third time 30 days after withdrawal. Positron emission tomography with an [18F]fluorodeoxyglucose tracer was used in a within-subject design.The analysis demonstrated a decrease in glucose metabolism in the caudate and putamen 30 days after withdrawal, indicating that haloperidol treatment enhanced glucose utilization in these areas. The thalamus, bilaterally but only in anterior areas, showed the same response to haloperidol. Only in the frontal cortex and in the anterior cingulate had metabolism increased 30 days after withdrawal, indicating that in those two cortical areas haloperidol depressed glucose metabolism. In the 5-day drug free scans, no regions differed significantly from those in the haloperidol condition, despite numerical changes.It appears that 5 days of neuroleptic withdrawal are inadequate to escape the effects of neuroleptic drugs on regional cerebral glucose metabolism. The pattern and localization of changes in metabolic activity between the haloperidol condition and the 30-day drug-free condition suggest that haloperidol exerts its primary antidopaminergic action in the basal ganglia. It is proposed that the additional changes in the thalamus and cortex are secondary to this primary site of drug action, mediated through classically described striato-thalamo-cortical pathways.
Abstract 1666: Urinary Tract Infection in Pregnancy as a Risk Factor for Congenital Heart Defects
Authors: Mario Cleves, Sadia Malik, Shengping Yang, Tonia Carter, Charlotte A Hobbs
Journal: Circulation (2007)

OBJECTIVE: In a population-based case-control study, we investigated the association between congenital heart defects and maternal urinary tract infections. METHODS: The National Birth Defects Prev...
Abstract 9708: Strain Rate of Mitral Papillary Muscles: a New Imaging Prognostic Tool for Mitral Valve Repair
Authors: Julia Grapsa, David Dawson, Gentaj Jakaj, Prakash P Punjabi, Petros Nihoyannopoulos
Journal: Circulation (2011)

Purpose: New imaging modalities have been employed for the accurate anatomical mapping of the mitral apparatus. The aim of the study was to assess strain of mitral apparatus (papillary muscles and chordae) with a computational speckle tracking model and to associate strain with residual regurgitation post mitral valve surgical repair. Methods: 50 patients with posterior mitral leaflet prolapse underwent mitral valve repair. The left ventricular ejection fraction (LVEF), mitral regurgitant volume (Mvol), the longitudinal strain of the anterolateral papillary muscle (AL), posteromedial papillary muscle (PM) and their chordae (CAL, CPM) were calculated before and 6 months after the repair.Speckle tracking was performed with Toshiba Artida, from apical 2 chamber view and on the same timepoint of the cardiac cycle for all measurements. The groups (pre and post surgical repair) were compared and the strain on papillary muscles was associated with the recurrence of mitral regurgitation post-repair.The global strain of mitral apparatus (Σstrain ) was calculated as: Σstrain= (AL + CAL) - (PM + CPM). Results: Six patients (15%) had residual mitral regurgitation of grade II and III. LVEF before and after the operation did not differ (pre: 69 ± 5%, post: 68.2 ± 3%, p&lt;0.01). PM had significantly higher strain when compared to AL (PM pre: (-18.9) ± (-3)% compared to AL pre: (-4) ± (-1.1) %, p&lt;0.01), while post repair the strain between PM and AL was similar. Patients with residual mitral regurgitation had residual high PM longitudinal strain ((-15.3) ± (-1.4) %). Σstrain overall was significantly reduced post repair (Σstrain pre : (-19.2) ± (-3) % , Σstrain post: (-2.2) ± (-0.6) %, p&lt;0.01). Conclusions: Longitudinal strain of mitral valve apparatus by utilising speckle tracking can be a useful prognostic tool for post repair mitral regurgitation. It seems that a global strain of papillary muscles and chordate (Σstrain) almost equal to zero is associated with trivial regurgitation.
Nonspecific Ulcers of the Colon
Authors: J E Losanoff, B W Richman, J R Foerst, A D Griesemer, G M Mundis, J W Jones
Journal: Endoscopy (2003)

Nonspecific colonic ulcers (NSCUs) are rare and potentially life-threatening lesions of unknown etiology; the diagnosis is based on histologic findings showing nonspecific inflammatory changes. The condition's variable symptoms can include nonspecific abdominal discomfort, gastrointestinal bleeding, perforation, and peritonitis. Radiologic imaging can be helpful in locating the lesions, but colonoscopy facilitates early definitive diagnosis and aggressive treatment. The potential of NSCUs to recur is currently unknown, and morbidity rates remain high. Long-term colonoscopic follow-up may improve the prognosis.
Abstract 16524: A Metalloendopeptidase Nardilysin Controls Lipid and Glucose Metabolism Through the Modulation of PPAR-alpha Activity
Authors: Tatsuhiko Matsuoka, Kiyoto Nishi, Mikiko Ohno, Yoshinori Hiraoka, Toru Kita, Takeshi Kimura, Eiichiro Nishi
Journal: Circulation (2010)

Nardilysin (N-arginine dibasic convertase (NRDc)), a metalloendopeptidase of the M16 family, is a potent activator for ectodomain shedding of multiple membrane proteins. We have recently reported that NRDc regulates axonal maturation and myelination in the central and peripheral nervous system, but the role of NRDc in lipid and glucose metabolism has not been clarified. Homozygous mutant of NRDc-deficient mice (NRDc−/−) showed lean phenotype. The mass of visceral fat is much less in NRDc−/− compared with wild-type mice (NRDc+/+). While NRDc−/− displayed normal glucose tolerance, serum insulin level was much lower than that of NRDc+/+. NRDc−/− also displayed enhanced insulin sensitivity in insulin tolerance test. Measurement of plasma lipid levels showed no significant difference between NRDc+/+ and NRDc−/− in the total cholesterol content, while the triglyceride is significantly lower in NRDc−/− (57 ± 11 mg/dL) compared with NRDc+/+ (111 ± 5 mg/dL). These data strongly suggested that NRDc is an important ...
Surveillance and epidemiology of hepatitis B and C in Europe – a review
Authors: Merja Rantala, M J van de Laar
Journal: Eurosurveillance (2008)

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are frequent causes of acute and chronic hepatitis worldwide and leading causes for hepatic cirrhosis and cancer. There is a distinct geographical variation in HBV and HCV incidence and prevalence in the European Union (EU) and European Economic Area/European Free Trade Association (EEA/EFTA) member states and neighbouring countries. The HBV carrier prevalence ranges from 0.1 to 8.0% and that of HCV from 0.1 to 6.0%. Within the last few years, the HBV incidence has decreased while the HCV incidence has increased. Both diseases are concentrated in certain subpopulations, such as injecting drug users, with tens of times higher prevalence than in the general population. Most EU and EEA/EFTA countries have a surveillance system for HBV and HCV infections, but due to differences in system structures, reporting practices, data collection methods and case definitions used, the surveillance data are difficult to compare across countries. The harmonisation and strengthening of HBV and HCV surveillance at the European level is of utmost importance to obtain more robust data on these diseases.
Abstract 17295: Predictors of Adverse Events in Patients with Postpericardiotomy Syndrome Following Cardiac Surgery
Authors: M Chadi Alraies, Balaji Tamarappoo, Wael AlJaroudi, Cyrus Shabrang, Allan L Klein
Journal: Circulation (2011)

Background: Post-pericardiotomy syndrome (PPS) is relatively common and troublesome complication following cardiac surgery. Criteria for the diagnosis of PPS have been suggested in previous studies. It can occur a few days to several weeks following cardiac surgery and patients who fail medical therapy with anti-inflammatory medications are at risk for future adverse events. Hypothesis: To identify clinical risk factors that may predict which patients with PPS may have a high likelihood of experiencing adverse events which include: recurrent pericarditis, pericardial effusion, and need for pericardiocentesis, pericardial window, or pericardiectomy. Methods: We examined 239 consecutive patients who developed PPS after cardiac surgery from 2007-2010 (table). Logistic regression was used to examine univariate predictors of adverse events. Significant univariate predictors were added to the multivariable model in a step-wise fashion to identify the most significant predictors of adverse events among individuals with PPS. Results: Out of 239 patients (mean age, 58±16, 72% male) with PPS (mean time to diagnosis 27±18 days), 75 (31.1%) patients experienced significant adverse events. Younger age, pericardial effusion size, and post-operative NYHA class III-IV were significant univariate predictors (p&lt;0.05). The combined use of NSAIDs, colchicine, and corticosteroids (triple-therapy) was associated with a reduced risk of adverse events. In a multivariable model, triple-therapy was a negative predictor but younger age, effusion size, and pericardial constriction were associated with increased risk of developing adverse events (p&lt;0.05). Conclusions: This study identifies younger age, post-operative constriction, and failure to use triple-therapy as predictors of increased risk of adverse events and pericardial intervention among patients with PPS following cardiac surgery.
The abnormal eosinophils are part of the leukemic cell population in acute myelomonocytic leukemia with abnormal eosinophils (AML M4Eo) and carry the pericentric inversion 16: a combination of May-Grunwald- Giemsa staining and fluorescence in situ hybridization
Authors: T Haferlach, M Winkemann, H Loffler, R Schoch, W Gassmann, C Fonatsch, C Schoch, M Poetsch, K Weber-Matthiesen, B Schlegelberger
Journal: Blood (1996)