tbuckley/cabot-search huggingface dataset:
The Value of Histological Analysis of Occluded Biliary Endoprostheses
Authors: P. Pescatore, C. Heubner, M. Heine, B. C. Manegold
Journal: Endoscopy (1995)

Histological diagnosis of biliary strictures remains unsatisfactory, despite the availability of various endoscopic sampling procedures. The aim of our study was to assess the potential diagnostic yield of histological processing of occluded biliary endoprostheses inserted for palliation of malignant biliary stenoses.Over a period of one year, we prospectively collected biliary endoprostheses at the time of stent removal due to stent obstruction. Thirty-nine stents, inserted a mean of 94 days earlier for presumed malignant biliary strictures, were recovered. Their contents were examined histologically by two independent pathologists.Malignancy was found in 14 of 36 patients (39%). The sensitivity was highest in gallbladder carcinoma (66%), followed by choledochal and ampullary carcinoma (50%), metastatic carcinoma (33%), and pancreatic carcinoma (25%). The specificity of the method was 100%.We advocate systematic histological or cytological examination, or both, of occluded biliary endoprostheses, since the technique is of low invasiveness, has low costs, and is easy to perform, especially if other methods of tissue diagnosis have failed.
Abstract P3-04-03: Combined Epigenetic Targeting Reverses Epithelial-Mesencymal Transition (EMT) and Reduces Invasiveness of Human Breast Cancer Cells
Authors: AD Joshi, R Rao, W Fiskus, KM Buckley, S Nalluri, R Balusu, P Atadja, KN. Bhalla
Journal: Cancer Research (2010)

Abstract Background: Epithelial-Mesenchymal-transition (EMT) is a highly conserved biologic process that is involved in organ development, tissue regeneration, tumor invasion and metastasis. EMT is phenotypically associated with the loss E-cadherin and a gain of mesenchymal markers (e.g., vimentin). Both promoter methylation by DNMT1 and histone H3- K27 trimethylation by the histone methyl transferase EZH2 have been shown to cause E-cadherin expression. Several transcription factors, including ZEB1, Snail, Slug and Twist, directly bind to E-cadherin promoter, recruit histone deacetylase (HDAC) activity and repress E-cadherin. We have previously shown that the pan-HDAC inhibitor panobinostat (PS, Novartis Pharmaceuticals) depletes EZH2 and DNMT1 levels, and co-treatment with PS and DNMT1 inhibitor decitabine (DAC) synergistically depletes EZH2 and DNMT1. Methods: Here, we determined the effects of PS (20 to 100 nM) and/or DAC (0.5 to 5.0 uM) on E-cadherin levels and other EMT-associated markers, as well as on invasiveness of human breast cancer MB-231 and SUM159PT cells, which have undetectable levels of E-cadherin. Results: Treatment with PS dose dependently inhibited the migration and invasion of the breast cancer cells (by Boyden chamber assay). This was associated with induction of mRNA and protein levels of E-cadherin and decline in vimentin levels. PS treatment inhibited HDAC activity and reduced DNMT1 and EZH2 levels. Additionally PS repressed ZEB1 mRNA and protein levels. Co-treatment with bortezomib partially restored ZEB1 levels, indicating that PS treatment promotes proteasomal degradation of ZEB1. Chromatin immunoprecipitation (ChIP) analyses demonstrated that PS treatment inhibited H3K27 chromatin repressive and increased H3K4 chromatin permissive mark associated with the E-cadherin promoter. PS treatment also diminished ZEB1 occupancy on the E-cadherin promoter. Pre-treatment of MB-231 and SUM 159PT cells with DAC or 5-azacytidine (AC, also a DNMT1 inhibitor) (0.5 to 5.0 uM) further enhanced PS-mediated induction of E-cadherin, which was associated with further decline in ZEB1 levels. Additionally, co-treatment with PS and DAC caused greater inhibition of in vitro invasion by the breast cancer cells. Discussion: Collectively, these findings indicate that combined epigenetic targeting with PS and DAC depletes ZEB1, induces E-cadherin and reverses EMT, thereby, attenuating invasiveness of human breast cancer cells. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-04-03.
Statement by Nathan Pritikin
Authors: Nathan Pritikin
Journal: JAMA (1980)

To the Editor.—  On Jan 4, 1980, there appeared in the QUESTION AND ANSWER column (243:67, 1980) an inquiry from a physician asking of the merits of the program described in the book entitled The Pritikin Program for Diet and Exercise .  Therese Mondeika, RD, answered the questions by not discussing the merits of the program since she is not familiar with the program and has never inquired into the effects of the program on over 4,000 patients at the Longevity Center. Instead, she argued over quality of proteins and detailed food arguments not related to the merits of the program in restoring health. She has never requested our scientific data that documented patients who no longer require medication for angina, diabetes, and hypertension, and have returned to normal function. One study that will shortly be submitted to medical journals discusses all of the patients scheduled or recommended for coronary bypass surgery
Suppression of p53 activity and p21WAF1/CIP1 expression by vascular cell integrin alphaVbeta3 during angiogenesis.
Authors: S Strömblad, J C Becker, M Yebra, P C Brooks, D A Cheresh
Journal: Journal of Clinical Investigation (1996)

Induction of p53 activity in cells undergoing DNA synthesis represents a molecular conflict that can lead to apoptosis. During angiogenesis, proliferative endothelial cells become apoptotic in response to antagonists of integrin alphavbeta3 and this leads to the regression of angiogenic blood vessels, thereby blocking the growth of various human tumors. Evidence is presented that administration of alphavbeta3 antagonists during angiogenesis in vivo selectively caused activation of endothelial cell p53 and increased expression of the p53-inducible cell cycle inhibitor p21WAF1/CIP1. In vitro studies revealed that the ligation state of human endothelial cell alphavbeta3 directly influenced p53 activity and the bax cell death pathway. Specifically, agonists of endothelial cell alphavbeta3, but not other integrins, suppressed p53 activity, blocked p21WAF1/CIP1 expression, and increased the bcl-2/bax ratio, thereby promoting cell survival. Thus, ligation of vascular cell integrin alphavbeta3 promotes a critical and specific adhesion-dependent cell survival signal during angiogenesis leading to inhibition of p53 activity, decreased expression of p21WAF1/CIP1, and suppression of the bax cell death pathway.
Prognostic Value of Exercise Echocardiography in Patients With Left Bundle Branch Block
Authors: Alberto Bouzas-Mosquera, Jesús Peteiro, Nemesio Álvarez-García, Francisco J. Broullón, Lourdes García-Bueno, Luis Ferro, Ruth Pérez, Beatriz Bouzas, Ramón Fábregas, Alfonso Castro-Beiras
Journal: JACC. Cardiovascular imaging (2009)
Asialoagalacto-human chorionic gonadotropin, a carbohydrate-modified variant of human chorionic gonadotropin, antagonizes the stimulatory actions of bovine thyroid-stimulating hormone on thyroid function and HLA-DR expression in human thyroid in vitro and in vivo.
Authors: R Hoermann, P M Schumm-Draeger, K Rehbach, K Mann
Journal: Journal of Clinical Investigation (1991)

The concept of using thyroid-stimulating hormone (TSH) receptor antagonists in the management of Graves' disease is intriguing. Therefore, we investigated a TSH receptor antagonist derived from human chorionic gonadotropin (hCG) with respect to TSH receptor binding, adenylate cyclase activity, thyroid hormone release, and HLA class II antigen expression in vitro and in an in vivo model. A variant of hCG, asialoagalacto-hCG, like asialo-hCG and unlike hCG itself, inhibited both 125I-bTSH binding and cAMP response to bTSH in human thyroid membranes. However, like intact or deglycosylated hCG and unlike asialo-hCG, asialoagalacto-hCG displayed a limited affinity for hepatic asialoglycoprotein receptors, a likely marker for its in vivo turnover rate. It proved capable of inhibiting bTSH-stimulated thyroid hormone release in human thyroid slices as well as in the nude mouse bearing human thyroid transplants. It also prevented bTSH induced hypertrophy of transplanted thyrocytes. Further, HLA-DR expression induced by bTSH in the presence of gamma-interferon on human thyrocytes was inhibited. In conclusion, we present evidence that asialogalacto-hCG antagonizes bTSH actions on thyroid function and HLA-DR expression in human thyroid in vitro and, more importantly, in an in vivo model. Hence, the hCG variant described here or similar agents should warrant further exploration in the study and treatment of Graves' disease.
Practical Grading System for Evaluating Cisplatin Ototoxicity in Children
Authors: Kay W. Chang, Nina Chinosornvatana
Journal: Journal of Clinical Oncology (2010)

Purpose We present a new ototoxicity grading system that has clearly defined and frequency-specific audiometric criteria. The purpose of this study was to validate this grading system by assessing its correspondence to audiology treatment recommendations and comparing it with the currently utilized Common Terminology Criteria for Adverse Events (CTCAE). Patients and Methods A retrospective chart review was conducted using audiologic, demographic, and clinical data from 134 children receiving 149 courses of chemotherapy consisting of cisplatin and/or carboplatin. Pure-tone audiograms were evaluated using both our proposed grading criteria and the CTCAE criteria. The resulting grades were then compared with charted audiologic interventions and a number of clinical parameters to assess the clinical validity of the grading scale. Results Chang grade 2a or higher predicted audiologic intervention. Although both the Chang and CTCAE ototoxicity grades were significantly related to audiologist recommendations for assistive devices such as hearing aids and/or frequency modulated systems (P &lt; .0001), the Chang scale was more specific, with the CTCAE scale diverging from clinical recommendation at higher grades. As expected, patients receiving cisplatin had more severe hearing loss with concurrent carboplatin administration, radiation therapy exposure, younger age, smaller body-surface area, longer treatment exposure, and more severe disease. Conclusion This grading system provides robust and clinically useful criteria to represent clinical hearing loss induced by ototoxicity with regard to the impact on speech and language and the need for assistive hearing devices. It is both more specific and more sensitive than the traditional CTCAE criteria for identifying clinically significant ototoxicity.
PHOTOSENSITIVITY: FAMILIAL INCIDENCE, CLINICAL FEATUEES AND INCIDENCE OF EEYTHROPOIETIC PEOTOPORPHYEIA
Authors: R. T. W. PRENTICE, A. GOLDBERG, G. THOMPSON
Journal: British Journal of Dermatology (1969)

SUMMARY. Of 54 patients who had presented with skin sensitivity to sunlight, only 1 was found to have erythropoietic protoporphyria. In the remainder no cause could be found. About half of the patients with non-porphyric photo-sensitivity complained of burning, swelling and itching of the skin and about half were not protected from, sunlight by window glass. All of these clinical features are characteristic of erythropoietic protoporphyria and this underlines the fact that a definite diagnosis of erythropoietic protoporphyria depends primarily on the measurement of porphyrins in the blood. Among the 54 patients were 47 who had at least 3 episodes of photosensitivity. These 47 patients could be subdivided into 2 groups (A) in which the onset was late (mean age 45 years) and the duration of photosensitivity was less than 35% of the lifespan, and (B) in which the onset was early (mean age 12 years) and in which the duration of symptoms was greater than 35% of the lifespan. Only 3 of the 30 patients in Group (A) had a definite family history of photosensitivity, while 8 of the 17 patients in Group (B) had such a family history (P >0·05). This suggests the existence of at least 2 distinct populations within non-porphyric photosensitive patients, namely those of early onset with a genetic aetiology like erythropoietic protoporphyria, and those in whom the disease was acquired in late adult life.
Validation of the Oxford classification of IgA nephropathy
Authors: Andrew M. Herzenberg, Agnes B. Fogo, Heather N. Reich, Stéphan Troyanov, Nuket Bavbek, Alfonso E. Massat, Tracy E. Hunley, Michelle A. Hladunewich, Bruce A. Julian, Fernando C. Fervenza, Daniel C. Cattran
Journal: Kidney International (2011)
Niacin and biosynthesis of PGD2 by platelet COX-1 in mice and humans
Authors: Wen-Liang Song, Jane Stubbe, Emanuela Ricciotti, Naji Alamuddin, Salam Ibrahim, Irene Crichton, Maxwell Prempeh, John A. Lawson, Robert L. Wilensky, Lars Melholt Rasmussen, Ellen Puré, Garret A. FitzGerald
Journal: Journal of Clinical Investigation (2012)

The clinical use of niacin to treat dyslipidemic conditions is limited by noxious side effects, most commonly facial flushing. In mice, niacin-induced flushing results from COX-1–dependent formation of PGD2 and PGE2 followed by COX-2–dependent production of PGE2. Consistent with this, niacin-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD2 receptor DP1. NSAID-mediated suppression of COX-2–derived PGI2 has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD2. Here, we show that PGD2 biosynthesis is augmented during platelet activation in humans and, although vascular expression of DP1 is conserved between humans and mice, platelet DP1 is not present in mice. Despite this, DP1 deletion in mice augmented aneurysm formation and the hypertensive response to Ang II and accelerated atherogenesis and thrombogenesis. Furthermore, COX inhibitors in humans, as well as platelet depletion, COX-1 knockdown, and COX-2 deletion in mice, revealed that niacin evoked platelet COX-1–derived PGD2 biosynthesis. Finally, ADP-induced spreading on fibrinogen was augmented by niacin in washed human platelets, coincident with increased thromboxane (Tx) formation. However, in platelet-rich plasma, where formation of both Tx and PGD2 was increased, spreading was not as pronounced and was inhibited by DP1 activation. Thus, PGD2, like PGI2, may function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during niacin therapy.
Activation of the hepatocarcinogen aflatoxin B1 by forms of human hepatic cytochromes P-450: Some do and some don't Aoyama T, Yamano S, Guzelian PS, Gelboin HV, Gonzalez FJ. Five of 12 forms of vaccinia virus-expressed human hepatic cytochrome P-450 metabolically activate aflatoxin B1. Proc Natl Acad Sci USA 1990;87:4790–4793
Authors: H Bonkovsky
Journal: Hepatology (1991)
Acute viral hepatitis increases liver stiffness values measured by transient elastography
Authors: Ze‐Zhou Song
Journal: Hepatology (2008)

I read with great interest the study by Arena et al.,1 which concluded that the extent of necroinflammatory activity needs to be carefully considered in future studies aimed at further validating transient elastography, particularly in patients with absent or low-stage liver fibrosis. The study also concluded that liver stiffness measurement does not represent a reliable instrument to detect the presence of advanced fibrosis and cirrhosis in patients presenting with a clinical picture of acute hepatitis. The methods and interpretation of the results, however, raise several concerns. It is well known that transient elastography has been proposed as a rapid and noninvasive technique for the evaluation of disease progression in chronic liver diseases. That is to say, transient elastography should be performed to evaluate disease progression in chronic liver diseases by liver stiffness measurement, even if liver stiffness measurement does not represent a reliable instrument to detect the presence of advanced fibrosis and cirrhosis in patients presenting with a clinical picture of acute hepatitis. Then, it is important that transient elastography should be performed after the resolution of acute hepatitis to evaluate disease progression in chronic liver diseases. In other words, it is important that the liver stiffness values as measured by transient elastography should correspond well to the histological degree of fibrosis as confirmed by a liver biopsy after resolution of the acute liver damage. In the study by Arena et al.1, however, a liver biopsy was not taken. Therefore, the aforementioned question needs to be further addressed. The authors stated that among the 18 enrolled patients, the cause of acute viral hepatitis was hepatitis A virus in seven, hepatitis B virus in eight, and hepatitis C virus in three and that no significant difference was observed in the relationship between aminotransferase levels and liver stiffness measurement values in the different etiological groups of viral hepatitis.1 It is well known that liver stiffness values in the general population are influenced independently by gender, body mass index, and metabolic syndrome.2 In the study by Arena et al.,1 however, the difference of the aforementioned baseline parameters in the different etiological groups of viral hepatitis were not well described. Also, is there any relation between the difference of the above-mentioned baseline parameters in the different etiological groups of viral hepatitis to the relationship between aminotransferase levels and liver stiffness measurement values? In other words, were the influences of acute liver damage in liver stiffness measurement different in the different etiological groups of viral hepatitis? Ze-Zhou Song M.S.*, * Department of Ultrasound, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Consent and Confidentiality in the Health Care of Children and Adolescents: A Legal Guide
Authors: Ruth P. Zager
Journal: JAMA (1987)

The authors of this book are two practicing lawyers with a long involvement in health law and rights of minors and a pediatrician who has specialized in adolescent medicine. They present "a legal guide" for health care professionals, mainly physicians, and address the complex interface of health care and the various areas of the law pertaining to it in the United States. However, their primary aim is not necessarily to help physicians protect themselves; rather, they want to explicate how the legal system may be utilized to benefit patients and their treatment needs. The book analyzes the question of consent: Who can give consent? Under what circumstances? Who must protect the privacy of whom and to what lengths? When do public and patient interests coincide and conflict? When can a physician treat a minor, withhold information from the parents, and still expect payment for services rendered? The authors succeed well
Abstract 908: Differential role of JAK1/2-STAT3 pathway in drug response and survival of oncogenic Kras colorectal cancer
Authors: Murugan Kalimutho, Wendy Allen, Philip Dunne, Daniel Longley, Patrick Johnston, Sandra Van Schaeybroeck
Journal: Cancer Research (2012)

Abstract Mutations in the Kras proto-oncogene are found in 40%-45% of colorectal cancer (CRC) patients and confer resistance to EGFR monoclonal antibody (mAb) therapies. The identification of druggable targets uniquely required by KrasMT CRC tumours has the potential to fill a gap in the therapeutic armamentarium of advanced CRC. We carried out microarray profiling of isogenic Kras wild type (WT) and mutant (MT) in vivo CRC models, KrasMT/WT primary colon tumours, pre-treatment metastatic CRC liver biopsies and drug resistant and sensitive CRC cell lines. We have used systems biology approach incorporating pathway analyses of the microarray data followed by siRNA screening to identify novel targets/pathways which are critical for the survival of KrasMT tumours, both basally and following chemotherapy treatment. We found that JAK1/2-STAT3 signaling was essential for the survival of KrasMT CRC cells. Moreover, suppression of JAK1/2-STAT3 activity using RNAi or small molecule inhibitors resulted in more potent increase in apoptosis in KrasMT CRC cells. In addition, treatment with chemotherapy and MEK1/2 inhibition resulted in significant increases in JAK2 and STAT3 activity and this was associated with strong increase in apoptosis when JAK1/2-STAT3 RNAi or small molecule inhibitors were combined with chemotherapy and MEK1/2 inhibition, especially in KrasMT cells. Moreover, we found that these effects were not drug- or cell line-specific. Collectively, using a systems biology approach, we have identified an essential role of JAK1/2-STAT3 signalling in survival of KrasMT CRC models. These findings support the further clinical investigation of JAK/STAT3 inhibitors in conjunction with chemotherapy or MEK inhibition in KrasMT CRC tumours. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 908. doi:1538-7445.AM2012-908
Abstract 911: Vemurafenib FDG-PET preclinical imaging outcomes across BRAF V600E mutant and resistant tumors
Authors: Andreas R. Baudy, Taner Dogan, Judith E. Flores, Klaus P. Hoeflich, Fei Su, Nicholas van Bruggen, Simon P. Williams
Journal: Cancer Research (2012)

Abstract The BRAF inhibitor vemurafenib (marketed as zelboraf) has recently been FDA approved for the treatment of metastatic melanoma in patients harboring BRAF V600 mutations. PET imaging will be essential for guiding therapy in terms of gauging initial drug response, monitoring for disease relapse, and evaluating combination treatments in clinical trials. Herein, we assess 18F-FDG uptake across V600E mutant and vemurafenib resistant cells. We find that vemurafenib is equally effective at reducing FDG uptake in cell lines harboring either heterozygous or homozygous V600E BRAF but is ineffective in cells with acquired resistance or BRAF WT cells. Combination treatment with MEK inhibitor GDC-0973 results in a highly significant enhancement of efficacy across all twenty lines tested. We show that FDG uptake is driven by Glut-1, and that the membrane localization of the transporter paralleled with drug efficacy. Interestingly, we find that vemurafenib induced increased FDG uptake in cells harboring RAS mutations, as well as in tumors that have acquired vemurafenib drug resistance. Hexokinase II, CRAF, KSR and p-MEK protein levels in sensitive and drug resistant tumors were all associated with decreased measurements of FDG uptake in vivo. Overall, we have demonstrated that FDG PET imaging should be effective at monitoring the efficacy of vemurafenib in V600E melanoma mutants and that any detected increases in tumor uptake will likely be an indication of drug resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 911. doi:1538-7445.AM2012-911
Guidelines, enthusiasms, uncertainty, and the limits to purchasing
Authors: M. McKee, A. Clarke
Journal: BMJ (1995)

Recently government ministers have set out their vision of the future of purchasing.Ineffective treat- ments will be discarded and purchasing will be based on guidelines or protocols rather than activity.But have the advocates of this approach considered all the issues?This paper examines the challenges of balancing the desire for protocol based uniformity with the needs of individual patients, explores the extent to which existing purchasing structures can support this process, and questions whether such moves will actually lead to reduced costs.In each case it is concluded that oversimplistic analyses are likely to be misleading and that much of the current debate fails to recognise the complexity of health care.