tbuckley/cabot-search huggingface dataset:
Mechanisms of extrahepatic vasodilation in portal hypertension
Authors: M Hennenberg, J Trebicka, T Sauerbruch, J Heller
Journal: Gut (2008)

In liver cirrhosis, abnormal persistent extrahepatic vasodilation leads to hyperdynamic circulatory dysfunction which essentially contributes to portal hypertension. Since portal hypertension is a major factor in the development of complications in cirrhosis, the mechanisms underlying this vasodilation are of paramount interest. Extensive studies performed in cirrhotic patients and animals revealed that this vasodilation is associated on the one hand with enhanced formation of vasodilators, and on the other hand with vascular hyporesponsiveness to vasoconstrictors. The latter phenomenon has been termed “vascular hypocontractility”. It is caused by a combination of different mechanisms and factors described in this review.
Effect of cervical spinal cord stimulation on regional blood flow and oxygenation in advanced head and neck tumours
Authors: B. Clavo, F. Robaina, L. Catalá, J.L. Pérez, M. Lloret, M.á. Caramés, J. Morera, L. López, G. Suárez, D. Macías, J. Rivero, M.A. Hernández
Journal: Annals of Oncology (2004)
Relationship between cigarette smoking and histological type of lung cancer in women
Authors: A. Kennedy
Journal: Thorax (1973)

In recent years there has been an increase in the incidence of lung cancer in women so much so that the rate of increase exceeds the rate of increase in men. This change in incidence has been associated with cigarette smoking and as it is considered that smoking is connected mainly with the squamous and undifferentiated forms of tumour it might be expected that a recent change in the proportions of the different histological groups would be demonstrable. All histological sections of proven cases of lung cancer in women seen between 1955 and 1971 at the Sheffield Royal Infirmary have been reviewed. A rise in the proportion of female cases attending hospital was noted but this rise has been associated with an increase in the proportion of cigarette smokers only in recent years. However, there is no good evidence of a change in the histological pattern of the disease and no statistically significant evidence of a connection between cigarette smoking and any particular cell type in the cases studied. Comparison with other studies confirms that cigarette smoking has only a small influence on the cell type of lung cancers in British women, but in American women there is a strong association between smoking and tumours of Kreyberg9s group I. This appears to be a real and unexplained difference between the behaviour of lung cancers in British and American women.
Identification of Subtypes in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Reveals a Gene Signature Prognostic of Outcome
Authors: Johan Staaf, Markus Ringnér, Johan Vallon-Christersson, Göran Jönsson, Pär-Ola Bendahl, Karolina Holm, Adalgeir Arason, Haukur Gunnarsson, Cecilia Hegardt, Bjarni A. Agnarsson, Lena Luts, Dorthe Grabau, Mårten Fernö, Per-Olof Malmström, Oskar Th. Johannsson, Niklas Loman, Rosa B. Barkardottir, Åke Borg
Journal: Journal of Clinical Oncology (2010)

PURPOSE Human epidermal growth factor receptor 2 (HER2) gene amplification or protein overexpression (HER2 positivity) defines a clinically challenging subgroup of patients with breast cancer (BC) with variable prognosis and response to therapy. We aimed to investigate the heterogeneous biologic appearance and clinical behavior of HER2-positive tumors using molecular profiling. PATIENTS AND METHODS Hierarchical clustering of gene expression data from 58 HER2-amplified tumors of various stage, histologic grade, and estrogen receptor (ER) status was used to construct a HER2-derived prognostic predictor that was further evaluated in several large independent BC data sets. RESULTS Unsupervised analysis identified three subtypes of HER2-positive tumors with mixed stage, histologic grade, and ER status. One subtype had a significantly worse clinical outcome. A prognostic predictor was created based on differentially expressed genes between the subtype with worse outcome and the other subtypes. The predictor was able to define patient groups with better and worse outcome in HER2-positive BC across multiple independent BC data sets and identify a sizable HER2-positive group with long disease-free survival and low mortality. Significant correlation to prognosis was also observed in basal-like, ER-negative, lymph node-positive, and high-grade tumors, irrespective of HER2 status. The predictor included genes associated with immune response, tumor invasion, and metastasis. CONCLUSION The HER2-derived prognostic predictor provides further insight into the heterogeneous biology of HER2-positive tumors and may become useful for improved selection of patients who need additional treatment with new drugs targeting the HER2 pathway.
Cluster Analysis and Clinical Asthma Phenotypes
Authors: Pranab Haldar, Ian D. Pavord, Dominic E. Shaw, Michael A. Berry, Michael Thomas, Christopher E. Brightling, Andrew J. Wardlaw, Ruth H. Green
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: Heterogeneity in asthma expression is multidimensional, including variability in clinical, physiologic, and pathologic parameters. Classification requires consideration of these disparate domains in a unified model.Objectives: To explore the application of a multivariate mathematical technique, k-means cluster analysis, for identifying distinct phenotypic groups.Methods: We performed k-means cluster analysis in three independent asthma populations. Clusters of a population managed in primary care (n = 184) with predominantly mild to moderate disease, were compared with a refractory asthma population managed in secondary care (n = 187). We then compared differences in asthma outcomes (exacerbation frequency and change in corticosteroid dose at 12 mo) between clusters in a third population of 68 subjects with predominantly refractory asthma, clustered at entry into a randomized trial comparing a strategy of minimizing eosinophilic inflammation (inflammation-guided strategy) with standard care.Measurements and Main Results: Two clusters (early-onset atopic and obese, noneosinophilic) were common to both asthma populations. Two clusters characterized by marked discordance between symptom expression and eosinophilic airway inflammation (early-onset symptom predominant and late-onset inflammation predominant) were specific to refractory asthma. Inflammation-guided management was superior for both discordant subgroups leading to a reduction in exacerbation frequency in the inflammation-predominant cluster (3.53 [SD, 1.18] vs. 0.38 [SD, 0.13] exacerbation/patient/yr, P = 0.002) and a dose reduction of inhaled corticosteroid in the symptom-predominant cluster (mean difference, 1,829 μg beclomethasone equivalent/d [95% confidence interval, 307–3,349 μg]; P = 0.02).Conclusions: Cluster analysis offers a novel multidimensional approach for identifying asthma phenotypes that exhibit differences in clinical response to treatment algorithms.
Abstract 4478: BAY 80-6946, a highly potent and efficacious class I PI3K inhibitor, induces complete tumor regression or tumor stasis in rat xenograft tumor models with PIK3CA mutant or PTEN deletion
Authors: Ningshu Liu, Andrea Haegebarth, Cathy Bull, Christoph Schatz, Stefan Wiehr, Peter Hauff, Bernd J. Pichler, Dominik Mumberg, Susan Jenkins, Thomas Schwarz, Karl Ziegelbauer
Journal: Cancer Research (2010)

Abstract We report on BAY 80-6946, a highly selective and potent pan class I PI3K inhibitor currently in Phase I clinical trials. The PI3K pathway is aberrantly activated in many tumors either by growth factor receptor tyrosine kinases, or by the genetic mutation and amplification of key pathway components. BAY 80-6946 was evaluated in a panel of human xenograft tumor models. This compound was administered every second (Q2D) day or once weekly using intravenous (i.v.) bolus dosing. BAY 80-6946 was well tolerated with a MTD of 10 mg/kg (Q2D) in athymic rats. In the rat KPL-4 breast tumor model (PIK3CAH1047R and HER2O/E (protein levels)), BAY 80-6946 showed robust and dose-dependent tumor growth inhibition with complete tumor regressions (10/10 CRs) observed at the 3.0 and 6.0 mg/kg doses. The animals remained tumor-free until termination of the study on day 65. BAY 80-6946 also demonstrated complete tumor stasis in the human H460 large cell lung carcinoma and HCT116 colorectal carcinoma models (bearing PIK3CA (E545K and H1047R respectively) along with mutations in KRAS), In U87MG human glioma tumor model (PTEN-deletion) dosed Q2D schedule partial regressions (PRs) were observed. The robust in vivo anti-tumor activities for this class I pan PI3K inhibitor correlated very well with the potent and sustained pharmacodynamic inhibition of p-Akt in tumors, which allowed several i.v. dosing schedules including a once weekly schedule. Thus, BAY 80-6946 given at 6mg/kg, BID once weekly demonstrated similar efficacy as given every other day (Q2D) at 6 mg/kg. Further investigation of pharmacodynamic biomakers revealed that i.v. bolus injection of BAY 80-6946 1 and 6 mg/kg produced a significant dose-dependent reduction in [18F]FDG uptake measured by decrease in SUV in rat H460 tumors supporting the clinical exploration of [18F]FDG imaging to monitor pharmacodynamic drug activity in patients. In conclusion, BAY 80-6946 is a highly efficacious and well tolerated PI3K inhibitor in preclinical rat tumor models expressing HER2, PIK3CA mutant and PTEN-deletion. BAY 80-6946 is currently in phase I clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4478.
<i>In vivo</i> Generation of Angiostatin Isoforms by Administration of a Plasminogen Activator and a Free Sulfhydryl Donor: A Phase I Study of an Angiostatic Cocktail of Tissue Plasminogen Activator and Mesna
Authors: Gerald A. Soff, Hao Wang, Deborah L. Cundiff, Keyi Jiang, Brenda Martone, Alfred W. Rademaker, Jennifer A. Doll, Timothy M. Kuzel
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Angiostatin4.5 (AS4.5), the endogenous human angiostatin, is derived from plasminogen in a two-step process. A plasminogen activator converts plasminogen to plasmin, then plasmin undergoes autoproteolysis to AS4.5. A free sulfhydryl donor can mediate plasmin autoproteolysis. To translate this process to human cancer therapy, we conducted a phase I trial of administration of a tissue plasminogen activator (tPA) with a free sulfhydryl donor (mesna). Patients and Methods: Fifteen patients with advanced solid tumors were treated. The dose of tPA was escalated (cohorts; 1, 2, 3, 5, and 7.5 mg/h for 6 hours). Mesna was administered as a 240 mg/m2 bolus followed by an infusion of 50 mg/h, concurrent with tPA. Both tPA and mesna were administered 3 consecutive days every 14 days. Results: No dose-limiting toxicity was observed. Two AS4.5 isoforms were generated, Lys-AS4.5 and Glu-AS4.5. Mean baseline Lys-AS4.5 level was 20.4 nmol/L (SE, 2.9). In the 5 mg/h tPA cohort, Lys-AS4.5 levels increased by an average of 143% or 24 nmol/L (SE, 4.9) above baseline. Glu-AS4.5 (Mr ∼ 62,000) was also generated (additional 77 amino acids at amino terminus compared with Lys-AS4.5). Glu-AS4.5 level at baseline was undetectable in four of five patients in the 5 mg/h tPA cohort, but at end of infusion, was ∼67 nmol/L (SE, 20). Two patients in the 5 mg/h tPA cohort experienced decreases in tumor markers with treatment, although no clinical objective responses were observed. Conclusion: This study shows that in vivo generation of AS4.5 is safe in humans and may provide a practical approach to achieve antiangiogenic therapy.
The value of microsatellite instability in the detection of HNPCC families and of sporadic colorectal cancers with special biological features: An investigation on a series of 100 consecutive cases
Authors: D. Furlan, M.G. Tibiletti, M. Taborelli, L. Albarello, M. Cornaggia, C. Capella
Journal: Annals of Oncology (1998)
Clearance of HBV markers and HCC risk: who is safe?
Authors: Helmut M Diepolder
Journal: Gut (2014)

Despite highly effective antiviral treatment options, chronic hepatitis B and its complications remain a medical challenge worldwide. Hepatocellular carcinoma (HCC) is still the fifth most common cause of cancer death in men and albeit surveillance programmes can principally reduce morbidity and mortality from HCC, the effect is modest and implementation of surveillance programmes is still inadequate.1 Depending on geographic region, hepatitis B is implicated as a cause of HCC in 5%–80% of patients. While antiviral therapy with interferon-α and nucleos(t)id analogues may stop disease progression in chronic hepatitis B, therapy is expensive, usually of long duration and not available in all parts of the world, particularly in many developing countries with a high prevalence of chronic hepatitis B. Moreover, depending on disease stage, a significant risk of HCC development may persist despite adequate viral suppression. Disappointingly, even in countries with high medical standards, implementation of treatment guidelines is far from complete.

Non-invasive and readily available markers for risk stratification are therefore of great importance to identify patients with the highest risk of HCC so that treatment and surveillance can be focused on those …
Levels of HdmX Expression Dictate the Sensitivity of Normal and Transformed Cells to Nutlin-3
Authors: John T. Patton, Lindsey D. Mayo, Aatur D. Singhi, Andrei V. Gudkov, George R. Stark, Mark W. Jackson
Journal: Cancer Research (2006)

Abstract Hdm2 and HdmX coordinately regulate the stability and function of p53. Each is overexpressed in subsets of many different types of malignancy, and most of these subsets maintain wild-type p53. Nutlins, newly discovered small-molecule inhibitors of the Hdm2-p53 interaction, offer a novel strategy for therapy of tumors with wild-type p53. We now show that Nutlin-3 efficiently induces apoptosis and diminishes long-term survival of human fibroblasts transformed in vitro by Hdm2 but not HdmX. The resistance of cells overexpressing HdmX to Nutlin-3 is due to its inability to disrupt the p53-HdmX interaction, resulting in continued suppression of p53 activity. Although HdmX overexpression yielded cells resistant to Nutlin-3, ablation of HdmX expression by short hairpin RNA sensitized tumor cells to Nutlin-3–mediated cell death or arrest. Furthermore, deletion of the COOH-terminal RING finger domain of HdmX completely reversed the resistance to Nutlin-3, probably reflecting the requirement of the RING finger for interaction with Hdm2. Thus, the relative abundance of Hdm2 and HdmX and the specificity of Nutlin-3 for Hdm2 influence the sensitivity of cells to p53-dependent apoptosis or arrest in response to Nutlin-3. Our findings establish Hdm2 and HdmX as independent therapeutic targets with respect to reactivating wild-type p53 as a means for cancer therapy. (Cancer Res 2006; 66(6): 3169-76)
Relationship between exhaled air temperature and exhaled nitric oxide in childhood asthma
Authors: G.L. Piacentini, A. Bodini, L. Zerman, S. Costella, L. Zanolla, D.G. Peroni, A.L. Boner
Journal: European Respiratory Journal (2002)

Airway inflammation is a characteristic of asthma. Exhaled nitric oxide (eNO) has been demonstrated to be related to actual levels of airway inflammation in asthmatic patients. The purpose of this study was to investigate whether the temperature of exhaled air is related to eNO levels. Temperature of exhaled air and eNO were measured in 52 asthmatic children with a cross-sectional design. A significant relationship was demonstrated between eNO and temperature of peak and plateau exhaled air temperature. The relationship between both the peak and the plateau values and eNO was more evident when it was corrected for environmental temperature. These results suggest a relationship between exhaled nitric oxide and the temperature of exhaled air in asthmatic patients not treated with systemic steroids.
On-Pump and Off-Pump Coronary Bypass Surgery
Authors: Bruce W. Lytle
Journal: Circulation (2007)

C oronary bypass surgery performed without the use of cardiopulmonary bypass (off-pump surgery) has been used sporadically since the beginning of the bypass surgery era in 1967, but the use of this strategy increased dramatically during the 1990s.The major reason for the increased use of off-pump surgery was the hope that this strategy would decrease perioperative morbidity and possibly mortality by eliminating cardiopulmonary bypass (on-pump surgery).The fear concerning off-pump surgery has been that the difficulty of operating with the heart beating would lead to less complete and less effective revascularization at the time of surgery and worse long-term outcomes.
A phase I and pharmacokinetic study of capecitabine in combination with epirubicin and cisplatin in patients with inoperable oesophago-gastric adenocarcinoma
Authors: T.R.J. Evans, G. Pentheroudakis, J. Paul, A. McInnes, R. Blackie, N. Raby, R. Morrison, G.M. Fullarton, M. Soukop, A.C. McDonald
Journal: Annals of Oncology (2002)
The Neural Basis of Addiction: A Pathology of Motivation and Choice
Authors: Peter W. Kalivas, Nora D. Volkow
Journal: American Journal of Psychiatry (2005)

A primary behavioral pathology in drug addiction is the overpowering motivational strength and decreased ability to control the desire to obtain drugs. In this review the authors explore how advances in neurobiology are approaching an understanding of the cellular and circuitry underpinnings of addiction, and they describe the novel pharmacotherapeutic targets emerging from this understanding.Findings from neuroimaging of addicts are integrated with cellular studies in animal models of drug seeking.While dopamine is critical for acute reward and initiation of addiction, end-stage addiction results primarily from cellular adaptations in anterior cingulate and orbitofrontal glutamatergic projections to the nucleus accumbens. Pathophysiological plasticity in excitatory transmission reduces the capacity of the prefrontal cortex to initiate behaviors in response to biological rewards and to provide executive control over drug seeking. Simultaneously, the prefrontal cortex is hyperresponsive to stimuli predicting drug availability, resulting in supraphysiological glutamatergic drive in the nucleus accumbens, where excitatory synapses have a reduced capacity to regulate neurotransmission.Cellular adaptations in prefrontal glutamatergic innervation of the accumbens promote the compulsive character of drug seeking in addicts by decreasing the value of natural rewards, diminishing cognitive control (choice), and enhancing glutamatergic drive in response to drug-associated stimuli.
Clonotypic structures involved in antigen-specific human T cell function. Relationship to the T3 molecular complex.
Authors: S C Meuer, K A Fitzgerald, R E Hussey, J C Hodgdon, S F Schlossman, E L Reinherz
Journal: The Journal of Experimental Medicine (1983)

Monoclonal antibodies were produced against a human cytotoxic T cell clone, CT8III (specificity: HLA-A3), with the view of defining clonally restricted (clonotypic) surface molecules involved in its antigen recognition function. Two individual antibodies, termed anti-Ti1A and anti-Ti1B, reacted exclusively with the CT8III clone when tested on a panel of 80 additional clones from the same donor, resting or activated T cells, B cells, macrophages, thymocytes, or other hematopoietic cells. More importantly, the two antibodies inhibited cell-mediated killing and antigen-specific proliferation of the CT8III clone but did not affect the functions of any other clone tested. This inhibition was not secondary to generalized abrogation of the CT8III clone's function, because interleukin 2 responsiveness was enhanced. To examine the relationship of the structures defined by anti-clonotypic antibodies with known T cell surface molecules, antibody-induced modulation studies and competitive binding assays were performed. The results indicated that the clonotypic structures were associated with, but distinct from, the 20,000-mol wt T3 molecule expressed on all mature T lymphocytes. Moreover, in contrast to anti-T3, anti-Ti1A and anti-Ti1B each immunoprecipitated two molecules of 49,000 and 43,000-mol wt from 131I-labeled CT8III cells under reducing conditions. The development of monoclonal antibodies to such polymorphic T cell surface structures should provide important probes to further define the surface receptor for antigen.
Influence of Glycemic Index/Load on Glycemic Response, Appetite, and Food Intake in Healthy Humans
Authors: Rita C.G. Alfenas, Richard D. Mattes
Journal: Diabetes Care (2006)

sure glycemic index; however, nonstandard methods were used (2).Discarding means with inconsistent values is questionable; bootstrap analysis of our data (2) suggests, paradoxically, that the discarded means may be more reliable estimates of the true mean than the remaining ones.Different blood sampling schedules influence the mean and variation of glycemic index values (3).Using our data (five foods tested by 47 subjects) (2), we found that the average SD of glycemic index values calculated from glucose results for the blood sampling times used by Alfenas and Mattes was 35, compared with 29 for the recommended seven blood samples.If a glucose meter is used to measure glycemic index the SD is increased by ϳ15% (4); thus, we estimate the SD of glycemic index values determined using Alfenas-Mattes methodology to be 35 ϫ 1.15 ϭ 40.With SD ϭ 40 and n ϭ 3, the 95% CI of a mean glycemic index value is Ϯ99, and the chance of obtaining a mean within Ϯ10 of the true mean is only ϳ33%.Thus, it is likely that the glycemic index category (high or low glycemic index) of many of the foods was misclassified.This is consistent with the failure to detect a difference in glucose response on day 1 of the period when subjects consumed only one food for breakfast.Also, Alfenas and Mattes compared glycemic responses elicited by low-and high-glycemic index foods in different groups of subjects.Since large betweensubject variation of glycemic responses exists, groups of normal subjects can have different means; e.g., the mean response after 50 g glucose in different groups of 10 subjects of similar ethnicity varied from 153 to 210 (2).Between-subject variation is a confounding variable the authors have not accounted for.