tbuckley/cabot-search huggingface dataset:
Functional evidence that in the cardiovascular system AT angiotensin II receptors are AT prejunctionally and AT postjunctionally
Authors: Serafim Guimarães, Helder Pinheiro
Journal: Cardiovascular Research (2005)

Numerous studies have shown that angiotensin II causes vasoconstriction both by a direct action on smooth muscle cells (postjunctional effect) and indirectly through the facilitation of noradrenaline release from postganglionic sympathetic neurons (prejunctional effect). The receptors through which angiotensin II exerts its actions were first divided into AT1 and AT2 subtypes. A further subdivision of AT1 receptors into AT1A and AT1B subtypes was based on cloning and receptor binding studies: AT1A showed a high affinity for losartan, but low affinity for PD123319, while AT1B receptors showed nearly 100-fold lower affinity for losartan and 10,000-fold higher affinity for PD123319 relative to AT1 sites. The present review deals with functional evidence supporting the existence of AT1A and AT1B subtypes in the cardiovascular system. Taken together, all the functional results obtained in vivo and in vitro–in a wide variety of vascular tissues from different species–allow one to conclude that angiotensin II AT1 receptors are different pre- and postjunctionally and also that prejunctional and postjunctional angiotensin II receptors most probably belong to AT1B and AT1A subtypes, respectively.
Risk factors for early onset neonatal group B streptococcal sepsis: case-control study
Authors: S. Oddie
Journal: BMJ (2002)

<h3>abstract</h3> <b>Objectives:</b> To quantify risk factors for and the prevalence of early onset group B streptococcal sepsis in neonates in a geographically defined population. <b>Design</b>: Cases were collected prospectively for two years from April 1998 and compared with four controls each, matched for time and place of delivery. <b>Setting</b>: The former Northern health region of the United Kingdom. <b>Participants</b>: Infants infected with group B streptococcus in the first week of life. <b>Results</b>: The prevalence of early onset group B streptococcal sepsis was 0.57 per 1000 live births. Premature infants comprised 38% of all cases and 83% of the deaths. Prematurity (odds ratio 10.4, 95% confidence interval 3.9 to 27.6), rupture of the membranes more than 18 hours before delivery (25.8, 10.2 to 64.8), rupture of the membranes before the onset of labour (11.1, 4.8 to 25.9), and intrapartum fever (10.0, 2.4 to 40.8) were significant risk factors for infection. Had the interim recommendations on best practice issued by the Group B Streptococcus Working Group of the Public Health Laboratory Service been uniformly applied to the fetuses alive at the onset of labour, 29 of 37 (78%) might have been given antibiotic prophylaxis during labour. At least 23 of these 29 (79%) could have had antibiotics for four hours or more before delivery. To achieve this, 16% of all women would have been given antibiotics during labour. <b>Conclusions:</b> Early onset group B streptococcal sepsis remains an important problem in the United Kingdom. Prevention based on risk factors might reduce the prevalence at the cost of treating many women with risk factors. Using rupture of the membranes before the onset of labour as a risk factor might be expected to improve the success of guidelines for prophylaxis.
Additive Beneficial Effects of Fenofibrate Combined With Candesartan in the Treatment of Hypertriglyceridemic Hypertensive Patients
Authors: Kwang Kon Koh, Michael J. Quon, Seung Hwan Han, Wook-Jin Chung, Jeong Yeal Ahn, Jeong-a Kim, Yonghee Lee, Eak Kyun Shin
Journal: Diabetes Care (2006)

OBJECTIVE—Mechanisms underlying fibric acid and angiotensin II type 1 receptor blocker therapies differ. Signaling from peroxisome proliferator-activated receptor α may cross-talk with the angiotensin II system. We investigated vascular and metabolic responses to these therapies either alone or in combination in hypertriglyceridemic hypertensive patients. RESEARCH DESIGN AND METHODS—This was a randomized, double-blind, placebo-controlled, cross-over trial with three treatment arms (each 2 months) and two washout periods (each 2 months). Forty-four patients were given 200 mg fenofibrate and placebo, 200 mg fenofibrate and 16 mg candesartan, or 16 mg candesartan and placebo daily during each treatment period. RESULTS—Fenofibrate, combined therapy, or candesartan therapy significantly reduced blood pressure. However, combined therapy significantly reduced blood pressure more than fenofibrate or candesartan alone (P &amp;lt; 0.001 by ANOVA). When compared with candesartan, fenofibrate or combined therapy significantly improved the lipoprotein profile. All three treatment arms significantly improved flow-mediated dilator response to hyperemia. Combined therapy significantly decreased plasma malondialdehyde, high-sensitivity C-reactive protein, and soluble CD40L levels relative to baseline measurements. Importantly, these parameters were changed to a greater extent with combined therapy when compared with monotherapy (P &amp;lt; 0.001, P = 0.002, P = 0.050, and P = 0.032 by ANOVA, respectively). Fenofibrate, combined therapy, and candesartan significantly increased plasma adiponectin levels and insulin sensitivity relative to baseline measurements. However, the magnitude of these increases were not significantly different among the three therapies (P = 0.246 and P = 0.153 by ANOVA, respectively). CONCLUSIONS—Fenofibrate combined with candesartan improves endothelial function and reduces inflammatory markers to a greater extent than monotherapy in hypertriglyceridemic hypertensive patients.
Induction of complete tumor necrosis may reduce intrahepatic metastasis and prolong survival in patients with hepatocellular carcinoma undergoing locoregional therapy: a prospective study
Authors: T.-I. Huo, Y.-H. Huang, J.-C. Wu, P.-C. Lee, F.-Y. Chang, S.-D. Lee
Journal: Annals of Oncology (2004)

Transarterial chemoembolization (TACE) and percutaneous acetic acid injection (PAI) are effective locoregional therapies for hepatocellular carcinoma (HCC). This study aimed to investigate whether HCC patients who had initial complete response to these treatments had a subsequent lower risk of intrahepatic metastasis.A total of 152 patients who underwent locoregional therapy (94 received PAI and 58 received both TACE and PAI) for HCC (tumor size < or =5 cm) were prospectively evaluated.In all, 60 (39%) patients had a complete tumor necrosis after treatment. The cumulative incidence of the development of intrahepatic metastasis was lower for patients with complete remission (P = 0.005) and for patients with smaller (< or =3 cm) tumor size (P = 0.083). Cox multivariate survival analysis showed that absence of complete remission [relative risk (RR) 2.7; 95% confidence interval (CI) 1.4-5.3; P = 0.003] was the only independent factor that predicted the occurrence of intrahepatic metastasis. Patients with complete remission had a significantly better long-term survival than those without (P = 0.002), and the occurrence of intrahepatic metastasis over time independently predicted a decreased survival (RR 3.2; 95% CI 2.0-6.1; P = 0.019).Induction of complete tumor necrosis in HCC patients undergoing locoregional therapy may decrease the risk of intrahepatic metastasis and improve survival.
Outcomes Research in Oncology: History, Conceptual Framework, and Trends in the Literature
Authors: Stephanie J. Lee, Craig C. Earle, Jane C. Weeks
Journal: JNCI Journal of the National Cancer Institute (2000)

"Outcomes research" is a commonly used term, but what does it really mean? In this review article, we 1) briefly review the historic background of outcomes research, paying particular attention to the social and political movements that helped shape the field; 2) present a conceptual framework to help classify the major areas of research and provide a working definition of outcomes research; and 3) review the oncology literature in the English language from 1966 through 1998 to examine temporal trends and characterize the body of work being presented to the practicing oncology community. We conclude that outcomes research is a broad concept, which, in its current usage, describes an array of distinct types of research. However, common themes are apparent when outcomes research is viewed in the context of its historic origins and is contrasted with other established disciplines, especially clinical trials. Our literature review shows that outcomes studies are increasing in absolute numbers, in relative proportion of the oncology literature, and in quality. We suggest that as different branches of investigation develop their own literature and methodology-in effect, outgrowing the generic label of outcomes research-they become identified by separate, more precise terms.
Increased Prevalence of Significant Coronary Artery Calcification in Patients With Diabetes
Authors: Sunita Schurgin, Stuart Rich, Theodore Mazzone
Journal: Diabetes Care (2001)

Evidence of Macrovascular Complications Elevated plasma total homocysteine (tHcy) levels are a powerful risk factor for atherosclerotic vascular disease (1), but it is still unclear by which pathophysiological mechanisms tHcy may promote atherothrombosis.In both experimental animal and cell culture studies (2,3), acute hyperhomocysteinemia induces endothelial dysfunction, leading to a low-grade inflammatory state that results in increased leukocyte adher-
Quantitative Lung Colony Assay for Tumor Immunity in Mice2
Authors: Charles W. Boone, Eric Lundberg, Thomas Orme, Ronald Gillette
Journal: JNCI Journal of the National Cancer Institute (1973)

We describe a lung colony assay for measuring tumor immunity in mice. This assay is a useful alternative to the conventional method of counting the number of tumor “takes” after subcutaneous challenge with graded doses of tumor cells. Mice to be tested were challenged with tumor cells intravenously. Two weeks later the lungs were removed, and each lobe was separately fixed and embedded in flattened form (<1 mm thick). Sections were made at one~third and two-thirds the distance through the flattened lobes and stained with hematoxylin and eosin. The tumor cell colonies could then be easily seen and counted microscopically. Cells from a transplantable squamous cell carcinoma, a breast adenocarcinoma, and a fibrosarcoma were tested. The mean coefficient of variation of the colony count in the 2 sections through the flattened lobes was 12.8%. The lung-colonizing efficiency of the 3 tumor lines was 167–208 colonies/106 cells injected. The use of lung colony counts to assay tumor immunity was demonstrated with a transplantable simian virus 40-transformed fibrosarcoma and a tissue culture-transformed BALB/3T3 fibrosarcoma.
What happened to caring?
Authors: Des Spence
Journal: BMJ (2012)

I stubbed out my cigarette and fell into sleep, and into my recurring dream of drowning. Sweating, I jerked awake, my pager bleeping, its wicked green numbers flashing the number of the ward I had just left. I bleeped.⇑

The unspoken intention of residency was to systematically break you—a compassionless humiliation to eradicate any foolish arrogance of youth, to ingrain emotional detachment, to aspire for nothing more than just to sink or swim. It was hard to “care” in this professional darkness. I clung to caring; lived by the junior …
Deficient biosynthesis of N-acetylglucosaminyl-phosphatidylinositol, the first intermediate of glycosyl phosphatidylinositol anchor biosynthesis, in cell lines established from patients with paroxysmal nocturnal hemoglobinuria.
Authors: M Takahashi, J Takeda, S Hirose, R Hyman, N Inoue, T Miyata, E Ueda, T Kitani, M E Medof, T Kinoshita
Journal: The Journal of Experimental Medicine (1993)

Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic disorder caused by a deficiency of biosynthesis of the glycosyl phosphatidylinositol (GPI) anchor, but the biochemical defect is not completely understood. In the present study, we have analyzed affected cell lines established recently from two Japanese patients with PNH. Two lines of evidence indicate that these cells do not synthesize N-acetylglucosaminyl-phosphatidylinositol, the first intermediate in the GPI anchor biosynthesis. First, somatic cell hybridization analysis using Thy-1-deficient murine thymoma cell lines with known biochemical defects as fusion partners showed that the PNH cell lines belong to complementation class A, which is known not to synthesize N-acetylglucosaminyl-phosphatidylinositol. Second, analysis of in vitro glycolipid biosynthesis demonstrated that cell lysates of these PNH cell lines in fact did not support biosynthesis of N-acetylglucosaminyl-phosphatidylinositol. Thus, we have characterized for the first time the exact biochemical defect leading to PNH.
The Novel Chemical Entity YTR107 Inhibits Recruitment of Nucleophosmin to Sites of DNA Damage, Suppressing Repair of DNA Double-Strand Breaks and Enhancing Radiosensitization
Authors: Konjeti R. Sekhar, Yerramreddy Thirupathi Reddy, Penthala Narsimha Reddy, Peter A. Crooks, Amudhan Venkateswaran, William Hayes McDonald, Ling Geng, Soumya Sasi, Robert P. Van Der Waal, Joseph L. Roti Roti, Kenneth J. Salleng, Girish Rachakonda, Michael L. Freeman
Journal: Clinical Cancer Research (2011)

Radiation therapy continues to be an important therapeutic strategy for providing definitive local/regional control of human cancer. However, oncogenes that harbor driver mutations and/or amplifications can compromise therapeutic efficacy. Thus, there is a need for novel approaches that enhance the DNA damage produced by ionizing radiation.A forward chemical genetic approach coupled with cell-based phenotypic screening of several tumor cell lines was used to identify a novel chemical entity (NCE) that functioned as a radiation sensitizer. Proteomics, comet assays, confocal microscopy, and immunoblotting were used to identify the biological target.The screening process identified a 5-((N-benzyl-1H-indol-3-yl)-methylene)pyrimidine-2,4,6(1H,3H,5H)trione as an NCE that radiosensitized cancer cells expressing amplified and/or mutated RAS, ErbB, PIK3CA, and/or BRAF oncogenes. Affinity-based solid-phase resin capture followed by liquid chromatography/tandem mass spectrometry identified the chaperone nucleophosmin (NPM) as the NCE target. SiRNA suppression of NPM abrogated radiosensitization by the NCE. Confocal microscopy showed that the NCE inhibited NPM shuttling to radiation-induced DNA damage repair foci, and the analysis of comet assays indicated a diminished rate of DNA double-strand break repair.These data support the hypothesis that inhibition of DNA repair due to inhibition of NPM shuttling increases the efficacy of DNA-damaging therapeutic strategies.
Trends in the Cost and Use of Targeted Cancer Therapies for the Privately Insured Nonelderly: 2001 to 2011
Authors: Ya-Chen Tina Shih, Fabrice Smieliauskas, Daniel M. Geynisman, Ronan J. Kelly, Thomas J. Smith
Journal: Journal of Clinical Oncology (2015)

Purpose This study sought to define and identify drivers of trends in cost and use of targeted therapeutics among privately insured nonelderly patients with cancer receiving chemotherapy between 2001 and 2011. Methods We classified oncology drugs as targeted oral anticancer medications, targeted intravenous anticancer medications, and all others. Using the LifeLink Health Plan Claims Database, we studied and disaggregated trends in use and in insurance and out-of-pocket payments per patient per month and during the first year of chemotherapy. Results We found a large increase in the use of targeted intravenous anticancer medications and a gradual increase in targeted oral anticancer medications; targeted therapies accounted for 63% of all chemotherapy expenditures in 2011. Insurance payments per patient per month and in the first year of chemotherapy for targeted oral anticancer medications more than doubled in 10 years, surpassing payments for targeted intravenous anticancer medications, which remained fairly constant throughout. Substitution toward targeted therapies and growth in drug prices both at launch and postlaunch contributed to payer spending growth. Out-of-pocket spending for targeted oral anticancer medications was ≤ half of the amount for targeted intravenous anticancer medications. Conclusion Targeted therapies now dominate anticancer drug spending. More aggressive management of pharmacy benefits for targeted oral anticancer medications and payment reform for injectable drugs hold promise. Restraining the rapid rise in spending will require more than current oral drug parity laws, such as value-based insurance that makes the benefits and costs transparent and involves the patient directly in the choice of treatment.
Making Sense of the Latest Advice on Vitamin D Therapy
Authors: Rebeca D. Monk, David A. Bushinsky
Journal: Journal of the American Society of Nephrology (2011)

The Institute of Medicine recently published recommendations for the daily intake and optimal serum levels of vitamin D based on an extensive review of the existing literature. Here we examine the issue and put levels of vitamin D in context for the general population and in patients with chronic kidney disease. Large randomized controlled trials are necessary to ensure that current recommendations are appropriate.
An Address ON THE ACTIVITY OF THE CELLS AND FLUIDS OF THE BODY IN THE PREVENTION AND CURE OF DISEASE: A PLEA FOR MORE THOROUGH PATHOLOGICAL INVESTIGATION
Authors: J. M. Beattie
Journal: BMJ (1910)

THE advances which have taken place in pathological science within recent years have been so great that specialization in certain directions has been forced upon the workers on the subject.Such specialization, like specialization in any other direction, has led observers to magnify one -aspect in the problem of disease and to minimize another, which may, after all, be the more important.In fact, I do not think it is too much to say * Delivered before a combined.meeting of the Nottingham Medico-
Intergrin α<sub>9</sub>β<sub>1</sub>potentially plays a role in reducing airway smooth muscle contraction
Authors: Mark Spears
Journal: Thorax (2012)

Intergrin α 9 β 1 potentially plays a role in reducing airway smooth muscle contraction Contraction of airway smooth muscle in response to innocuous stimuli is pathognomonic of asthma.However the mechanisms responsible for the loss of normal control are only partially understood.Therefore the authors sought to explore the modulatory role of integrin α 9 β 1 on airway smooth muscle contraction given previous results demonstrating high expression levels in mouse airway smooth muscle and the respiratory phenotype of α 9 knockout (KO) mice.Through a number of elegant experiments the protective effect of intergrin α 9 β 1 was found to be related to control of calcium release from the sarcoplasmic reticulum following G protein coupled receptor ligation.The authors established that ligation of α 9 β 1 reduces local levels of phosphatidylinositol 4,5-bisphosphate (PIP2) through co-localisation of the enzymes phosphatidylinositol-4-phosphate 5-kinase 1α (PIP5K1γ (responsible for production of PIP2)) and spermidine/spermine N 1 -acetyltransferase (SSAT).As PIP5K1γ activity requires the presence of higher order polyamines for full function the co-localisation with SSAT and hence its activity resulted in a localised reduction of higher order polyamines leading to reduced PIP2 and hence Inositol trisphosphate (IP 3 ).The reduction in IP 3 resulted in a reduction in intracellular calcium oscillations from the sacroplasmic reticulum and hence airway smooth muscle contraction.The authors also confirmed some of their findings in ex vivo human airways.Further exploration and confirmation of the role for intergrin α 9 β 1 in the airway hyperresponsiveness characteristic of human asthma should be considered.Pharmacological manipulation of either PIP5K1γ or SSATor promotion of their co-localisation may be of clinical relevance.
Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Authors: M. Ducreux, A. Sa. Cuhna, C. Caramella, A. Hollebecque, P. Burtin, D. Goéré, T. Seufferlein, K. Haustermans, J.L. Van Laethem, T. Conroy, D. Arnold
Journal: Annals of Oncology (2015)
Assessment of Thyrotropin-Releasing Hormone and Thyrotropin Reserve in Man
Authors: Peter A. Singer, John T. Nicoloff
Journal: Journal of Clinical Investigation (1973)

Endogenous thyrotropin-releasing hormone (TRH) reserve and pituitary thyrotropin (TSH) reserve were assessed in four normal subjects, three patients post-cryohypophysectomy, one patient with a hypothalamic lesion secondary to trauma, and four patients with Sheehan's syndrome. TSH reserve was determined by the immunoassayable TSH response to 500 mug TRH given i.v. (TRH stimulation test). TRH reserve was assessed by the rebound response in thyroidal iodine release (TIR) following withdrawal of pharmacologic doses of prednisolone (glucocorticoid withdrawal test). When compared with normals, the post-cryohypophysectomy patients demonstrated parallel impairment of TRH stimulation and glucocorticoid withdrawal testing. The patient with the hypothalamic lesion and the four patients with Sheehan's syndrome all had normal TRH stimulation tests, indicating adequate TSH reserve capacity, yet had abnormal glucocorticoid withdrawal tests, indicative of impairment in endogenous TRH reserve or neurohumoral transport. Three of the patients (hypothalamic injury and two Sheehan's) with impaired TRH reserve were euthyroid. THE FOLLOWING CONCLUSIONS WERE REACHED: (a) A combination of the TRH stimulation test and glucocorticoid withdrawal test may allow for differentiation between pituitary and suprahypophyseal disorders. (b) Certain cases of Sheehan's syndrome appear to have impaired endogenous TRH reserve or transport. (c) Euthyroidism can be maintained in spite of diminished TRH reserve.
Variation in Bleomycin Hydrolase Gene Is Associated With Reduced Survival After Chemotherapy for Testicular Germ Cell Cancer
Authors: Esther C. de Haas, Nynke Zwart, Coby Meijer, Janine Nuver, H. Marike Boezen, Albert J.H. Suurmeijer, Harald J. Hoekstra, Gerrit van der Steege, Dirk Th. Sleijfer, Jourik A. Gietema
Journal: Journal of Clinical Oncology (2008)

Response to chemotherapy may be determined by gene polymorphisms involved in metabolism of cytotoxic drugs. A plausible candidate is the gene for bleomycin hydrolase (BLMH), an enzyme that inactivates bleomycin, an essential component of chemotherapy regimens for disseminated testicular germ-cell cancer (TC). We investigated whether the single nucleotide polymorphism (SNP) A1450G of the BLMH gene (rs1050565) is associated with survival.Data were collected on survival and BLMH genotype of 304 patients with TC treated with bleomycin-containing chemotherapy at the University Medical Center Groningen, the Netherlands, between 1977 and 2003. Survival according to genotype was analyzed using Kaplan-Meier curves with log-rank testing and Cox regression analysis with adjustment for confounders.BLMH gene SNP A1450G has a significant effect on TC-related survival (log-rank P = .001). The homozygous variant (G/G) genotype (n = 31) is associated with decreased TC related survival compared with the heterozygous variant (A/G; n = 133) and the wild-type (A/A; n = 140). With Cox regression the G/G genotype proves to be an unfavorable prognostic factor, in addition to the commonly used International Germ Cell Consensus Classification prognosis group, with a hazard ratio of 4.97 (95% CI, 2.17 to 11.39) for TC-related death. Furthermore, the G/G genotype shows a higher prevalence of early relapses.The homozygous variant G/G of BLMH gene SNP A1450G is associated with reduced survival and higher prevalence of early relapses in TC patients treated with bleomycin-containing chemotherapy. This association is hypothesis generating and may eventually be of value for risk classification and selection for alternative treatment strategies in patients with disseminated TC.