tbuckley/cabot-search huggingface dataset:
Cost-Effectiveness of the Implantable Cardioverter-Defibrillator Versus Antiarrhythmic Drugs in Survivors of Serious Ventricular Tachyarrhythmias
Authors: Greg Larsen, Alfred Hallstrom, John McAnulty, Sergio Pinski, Anna Olarte, Sean Sullivan, Michael Brodsky, Judy Powell, Christy Marchant, Cheryl Jennings, Toshio Akiyama
Journal: Circulation (2002)

The implantable cardioverter-defibrillator (ICD) is an effective but expensive device. We used prospectively collected data from a large randomized clinical trial of secondary prevention of life-threatening ventricular arrhythmias to determine the cost-effectiveness of the ICD compared with antiarrhythmic drug (AAD) therapy, largely with amiodarone.Charges for initial and repeat hospitalizations, emergency room, and day surgery stays and the costs of antiarrhythmic drugs were collected on 1008 patients. Detailed records of all other medical encounters and expenses were collected on a subgroup of 237 patients. Regression models were then created to attribute these expenses to the rest of the patients. Charges were converted to 1997 costs using standard methods. Costs and life years were discounted at 3% per year. Three-year survival data from the Antiarrhythmics Versus Implantable Defibrillators trail were used to calculate the base-case cost-effectiveness (C/E) ratio. Six-year, twenty-year, and lifetime C/E ratios were also estimated. At 3 years, total costs were $71 421 for a patient taking AADs and $85 522 for a patient using an ICD, and the ICD provided a 0.21-year survival benefit over AAD treatment. The base-case C/E ratio was thus $66 677 per year of life saved by the ICD compared with AAD therapy (95% CI, $30 761 to $154 768). Six- and 20-year C/E ratios remained stable between $68 000 and $80 000 per year of life saved.The ICD is moderately cost-effective for secondary prevention of life-threatening ventricular arrhythmias, as judged from prospectively collected data in a randomized clinical trial.
Kidney Is the Only Source of Human Plasma Renin in 45-kb Human Renin Transgenic Mice
Authors: Yan Yan, Rong Chen, Tina Pitarresi, Curt D. Sigmund, Kenneth W. Gross, Jean E. Sealey, John H. Laragh, Daniel F. Catanzaro
Journal: Circulation Research (1998)

Abstract —Prorenin is expressed in certain extrarenal tissues, but normally only the kidneys process prorenin to renin and secrete renin into the circulation. Although transgenic animal lines containing the human renin (hREN) structural gene with either 0.9-kb or 3-kb 5′-flanking DNA express the transgene appropriately in renal juxtaglomerular cells and secrete hREN into the circulation, the source of the circulating renin is not known. In the present study, we observed that 13-kb hREN transgenic mice that contain the structural gene and 0.9-kb 5′-flanking DNA express hREN mRNA in many unusual tissues. We also observed that circulating hREN levels in 13-kb hREN mice increased after bilateral nephrectomy. These results suggested that the hREN gene is expressed at inappropriate locations where prorenin might be processed to renin. To determine if more distal sequences flanking the hREN gene might contribute to cell and tissue specificity, we used a 45-kb hREN genomic fragment that contained the structural gene and about 25-kb 5′- and 8-kb 3′-flanking DNA sequences to generate 3 separate transgenic lines that contained the intact transgene sequences. Ribonuclease protection assays revealed a much narrower tissue distribution of hREN expression than in the 13-kb hREN transgenic mice. In each 45-kb hREN line, hREN mRNA was present only in the kidney, adrenal, lung, eye, ovary, and brain. Moreover, 24 hours after nephrectomy, human plasma renin fell to very low levels, indistinguishable from those of nontransgenic littermates, indicating that their circulating hREN is of renal origin. These studies suggest that sequences flanking the structural gene, missing from previous hREN transgenic lines, suppress renin gene expression at inappropriate extrarenal sites where cellular proteases, to which prorenin is not normally exposed, could convert prorenin to renin, resulting in abnormal secretion of renin into the plasma.
Pharmacokinetics of O6-benzylguanine in Pediatric Patients with Central Nervous System Tumors
Authors: Kathleen Neville, Susan Blaney, Mark Bernstein, Patrick Thompson, Denise Adams, Alexander Aleksic, Stacey Berg
Journal: Clinical Cancer Research (2004)

To report the results of the first pharmacokinetic study in pediatric patients of O(6)-benzylguanine (O(6)BG), which irreversibly inactivates the DNA repair protein alkylguanine-alkyltransferase, thus enhancing the cytotoxicity of nitrosoureas.As part of a Pediatric Oncology Group Phase I study, 120 mg/m(2) of O(6)BG was administered i.v. over 1 h, before 1,3-bis(2-chloroethyl)-1-nitrosourea administration in children with recurrent or refractory brain tumors. Serial blood samples for plasma pharmacokinetic studies were obtained. Concentrations of O(6)BG and its active metabolite O(6)-benzyl-8-oxoguanine (8-oxo-O(6)BG) were measured by high-performance liquid chromatography. A pharmacokinetic model and additional first-order elimination rate constants for each compound were developed.O(6)BG concentration versus time data were evaluated for 25 patients. The peak concentration of O(6)BG (mean +/- SD) was 11 +/- 4 microm, and the peak concentration of its active metabolite, 8-oxo-O(6)BG, was 35 +/- 10 microm. O(6)BG was rapidly eliminated with a half-life of 85 +/- 140 min, area under the curve of 795 +/- 320 microm. min and clearance of 760 +/- 400 ml/min/m(2). The area under the curve of 8-oxo-O(6)BG when extrapolated to infinity was 22,700 +/- 11,800 microm. min. The clearance and terminal half-life of 8-oxo-O(6)BG were 30 +/- 15 ml/min/m(2) and 360 +/- 220 min, respectively.There is rapid elimination of O(6)BG after i.v. administration over 1 h. In contrast, the terminal half-life for the active metabolite, 8-oxo-O(6)BG, is 4-fold longer. The pharmacokinetic parameters for O(6)BG and 8-oxo-O(6)BG are similar to those reported previously in adults.
Desmond Lorne Marcus McNeill
Authors: S. H. G. Robb
Journal: BMJ (2014)

Born in Ootacamund, India, Desmond developed diabetes at the age of 5 in 1926, while on a family skiing holiday in Switzerland, and was first treated there with insulin. It was difficult finding a school in those days that was able to cope with a diabetic child. Under the care of R D Lawrence at Kings, he met Banting and Best. Initially he went up to Oxford to read biochemistry but changed …
Antisense gapmers selectively suppress individual oncogenic p73 splice isoforms and inhibit tumor growth in vivo
Authors: Stephan Emmrich, Weiwei Wang, Katja John, Wenzhong Li, Brigitte M Pützer
Journal: Molecular Cancer (2009)

Abstract Background Differential mRNA splicing and alternative promoter usage of the TP73 gene results in the expression of multiple NH2-truncated isoforms that act as oncogenes. Abundant levels of these p73 variants in a variety of human cancers correlated with adverse clinical prognosis and response failure to conventional therapies, underscoring their relevance as marker for disease severity and target for cancer intervention. With respect to an equally important role for amino-truncated p73 splice forms (ΔTAp73) and ΔNp73 (summarized as DNp73) in the tumorigenic process, we designed locked nucleic acid (LNA) antisense oligonucleotide (ASO) gapmers against individual species that were complementary to ΔEx2 and ΔEx2/3 splice junctions and a region in exon 3B unique for ΔN' and ΔN. Results Treatment of cancer cells with these ASOs resulted in a strong and specific reduction of tumorigenic p73 transcripts and proteins, importantly, without abolishing the wild-type p73 tumor suppressor form as observed with p73-shRNA. The specific antisense oligonucleotides rescued cells from apoptosis inhibition due to overexpression of their corresponding amino-truncated p73 isoform and decreased tumor cell proliferation. Furthermore, ASO-116 against ΔEx2/3 coupled to magnetic nanobead polyethyleneimine (MNB/PEI) carriers significantly inhibited malignant melanoma growth, which correlated with a shift in the balance between endogenous TAp73 and ΔEx2/3 towards apoptotic full-length p73. Conclusion Our study demonstrates the successful development of LNA-ASOs that selectively differentiate between the closely related p73 oncoproteins, and provide new tools to further delineate their biological properties in different human malignancies and for therapeutic cancer targeting.
Regional Differences in Known Risk Factors and the Higher Incidence of Breast Cancer in San Francisco
Authors: A. S. Robbins, J. L. Kelsey, S. Brescianini
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: The age-adjusted incidence of breast cancer in the San Francisco Bay Area has consistently been higher than that in other regions of the United States. The distribution of established risk factors for breast cancer (i.e., parity, age at first full-term pregnancy, breast-feeding, age at menarche, and age at menopause) and probable risk factors (e.g., alcohol consumption) also differs across geographic regions. Purpose: A study was planned to explore the extent to which differences in the regional distribution of established and probable risk factors could explain the increased incidence of breast cancer in the San Francisco Bay Area. Methods: Age-adjusted breast cancer incidence rates for January 1978 through December 1982 were obtained for the San Francisco Bay Area and other regions from the Surveillance, Epidemiology, and End Results (SEER) Program. Risk factor data from January 1980 through December 1982 were computed from the Cancer and Steroid Hormone Study, a population-based, case-control study of women 22-55 years of age who resided in eight SEER regions. Two different statistical methods were used to compute the relative risk (RR) of breast cancer associated with residence in the San Francisco Bay Area versus other regions, after adjusting for regional differences in known risk factors. Results: Substantial differences in the distribution of breast cancer risk factors were found between the San Francisco Bay Area and other regions. Nearly all of these differences would be expected to lead to an elevated incidence of breast cancer in the San Francisco Bay Area. With the use of incidence rates adjusted only for age, the RR for San Francisco Bay Area residence from January 1978 through December 1982 compared with residence in seven other SEER areas was 1.14 for white women and 1.10 for black women. Depending on the statistical method used, the RR was reduced to approximately 0.96-0.99 for white women and 0.75-0.83 for black women, after further adjusting for established and probable risk factors (parity, age at first full-term pregnancy, breastfeeding, age at menarche, age at menopause, and alcohol consumption). Without adjustment for alcohol consumption, the corresponding results were 0.97-1.02 for white women and 0.77-0.88 for black women. Conclusions: Among both white women and black women, the elevated breast cancer incidence rate in the San Francisco Bay Area can be completely accounted for by regional differences in known risk factors.
Stimulation of insulin secretion by infusion of free fatty acids
Authors: Stephen R. Crespin, William B. Greenough, Daniel Steinberg
Journal: Journal of Clinical Investigation (1969)

The acute elevation of plasma free fatty acid (FFA) levels by direct infusion of sodium oleate into the plasma of conscious dogs was accompanied by the rapid onset of a 2- to 12-fold increase in plasma immunoreactive insulin, and, subsequently, a marked fall in plasma glucose, even in dogs receiving intravenous glucose throughout the infusion. The magnitude of both the insulin and glucose responses correlated with the mean FFA level during infusion. A large increase in plasma insulin and fall in glucose also occurred when glycerol was infused with oleate in order to simulate endogenous lipolysis more closely. Insulin levels in pancreaticoduodenal vein blood rose markedly during oleate infusion, while plasma ketone levels rose only slightly. In contrast to the effects of oleate infusion, elevation of plasma FFA to correspondingly high levels by triolein ingestion and intravenous heparin produced only small increases in plasma insulin, which did not correlate well with the FFA level reached, and small increases in plasma glucose.The results indicate that under certain conditions elevated FFA levels may be a potent stimulus of insulin secretion. This response is modified under other conditions such as during chylomicron removal under the influence of heparin. This effect may play a role in the regulation of lipolysis and ketone formation, but determination of the exact mechanism of FFA stimulation of the pancreas and its physiological significance will require further investigation.
Establishment of Stable Reporter Expression for In Vivo Imaging of Nuclear Factor-κB Activation in Mouse Liver
Authors: Shaoduo Yan, Qiuxia Fu, Yong Zhou, Ning Zhang, Qianqian Zhou, Xiaoying Wang, Zhennan Yuan, Xiaohui Wang, Juan Du, Jingang Zhang, Linsheng Zhan
Journal: Theranostics (2013)

The nuclear factor-κB (NF-κB) signaling pathway plays a critical role in a multitude of cellular processes.Activation of the NF-κB transcription factor family is essential for the initiation of inflammation, immunity, cell proliferation and apoptosis through a list of responsive genes.In hepatic tissue, activation of the NF-κB pathway has been implicated in a number of pathological conditions.Here we described a mouse model for noninvasive quantification of NF-κB activation in the hepatic tissues.Mice were subjected to hydrodynamic delivery with a mixture of pattB-NF-κB-Fluc reporter and φC31o integrase vector.Hepatic expression of φC31o integrase mediated chromosomal integration of the pattB-NF-κB-Fluc reporter, resulting in stable luciferase expression at 300 days post transfection.We applied noninvasive imaging and were able to detect NF-κB activation under acute liver injury and hepatitis conditions.During hepatectomy-induced liver regeneration, NF-κB activation was detected locally in the tissues at the surgery site.Treatment with Sorafenib suppressed NF-κB activation, accompanied with perturbation of liver regeneration.In conclusion, we established a method for stable transfection of the hepatic tissues and applied the transfected mice to longitudinal monitoring of NF-κB activity under pathological conditions.Further exploration of this methodology for establishment of other disease models and for evaluation of novel pharmaceuticals is likely to be fruitful.
Periodontal Disease and Mortality in Type 2 Diabetes
Authors: Aramesh Saremi, Robert G. Nelson, Marshall Tulloch-Reid, Robert L. Hanson, Maurice L. Sievers, George W. Taylor, Marc Shlossman, Peter H. Bennett, Robert Genco, William C. Knowler
Journal: Diabetes Care (2005)

OBJECTIVE—Periodontal disease may contribute to the increased mortality associated with diabetes. RESEARCH DESIGN AND METHODS—In a prospective longitudinal study of 628 subjects aged ≥35 years, we examined the effect of periodontal disease on overall and cardiovascular disease mortality in Pima Indians with type 2 diabetes. Periodontal abnormality was classified as no or mild, moderate, and severe, based on panoramic radiographs and clinical dental examinations. RESULTS—During a median follow-up of 11 years (range 0.3–16), 204 subjects died. The age- and sex-adjusted death rates for all natural causes expressed as the number of deaths per 1,000 person-years of follow-up were 3.7 (95% CI 0.7–6.6) for no or mild periodontal disease, 19.6 (10.7–28.5) for moderate periodontal disease, and 28.4 (22.3–34.6) for severe periodontal disease. Periodontal disease predicted deaths from ischemic heart disease (IHD) (P trend = 0.04) and diabetic nephropathy (P trend &amp;lt; 0.01). Death rates from other causes were not associated with periodontal disease. After adjustment for age, sex, duration of diabetes, HbA1c, macroalbuminuria, BMI, serum cholesterol concentration, hypertension, electrocardiographic abnormalities, and current smoking in a proportional hazards model, subjects with severe periodontal disease had 3.2 times the risk (95% CI 1.1–9.3) of cardiorenal mortality (IHD and diabetic nephropathy combined) compared with the reference group (no or mild periodontal disease and moderate periodontal disease combined). CONCLUSIONS— Periodontal disease is a strong predictor of mortality from IHD and diabetic nephropathy in Pima Indians with type 2 diabetes. The effect of periodontal disease is in addition to the effects of traditional risk factors for these diseases.
Putative Tumor-Suppressive Function of Krüppel-Like Factor 4 in Primary Lung Carcinoma
Authors: Wenxian Hu, Wayne L. Hofstetter, Hong Li, Yanbin Zhou, Yong He, Abujiang Pataer, Li Wang, Keping Xie, Stephen G. Swisher, Bingliang Fang
Journal: Clinical Cancer Research (2009)

Krüppel-like factor 4 (KLF4) is a zinc-finger protein that plays important roles in stem cells and the development of gastric cancers. However, the role of KLF4 in primary lung cancer is unknown. The purpose of this study is to determine possible roles of KLF4 in lung cancer.The KLF4 expression in primary lung cancer tissues and case-matched normal lung tissues were determined by protein and mRNA analyses. The effects of KLF4 on cell proliferation, clonogenic formation, and cell cycle progression were determined in cultured lung cancer cells or bronchial epithelial cells after enforced KLF4 overexpression or small interfering RNA knockdown. The in vivo antitumor activity of KLF4 was evaluated by using stably transfected lung cancer cells and by adenovector-mediated gene delivery. The effect of KLF4 in regulating p21 and cyclin D1 was also evaluated.KLF4 protein and mRNA levels were dramatically decreased in most primary lung tumors compared with in case-matched normal lung tissues. Enforced expression of KLF4 resulted in marked inhibition of cell growth and clonogenic formation. The tumor-suppressive effect of KLF4 was associated with its role in up-regulating p21 and down-regulating cyclin D1, leading to cell cycle arrest at the G(1)-S checkpoint. Knockdown of KLF4 promoted cell growth in immortalized human bronchial epithelial cells. The enforced expression of KLF4 gene to lung cancer cells by ex vivo transfection or adenovector-mediated gene transfer suppressed tumor growth in vivo.Our results suggest that KLF4 plays an important role in suppressing the growth of lung carcinoma.
Back to basics: Staging and prognosis in HCC for medical oncologist
Authors: Markus Peck-Radosavljevic
Journal: Journal of Hepatology (2011)

Several different prognostic systems are currently in use worldwide to predict the outcome of patients with hepatocellular carcinoma. Some of them have been widely publicized [1,2] while others have not been acknowledged by a wider audience so far [3]. All of the systems currently in use, except for the TNM-system, have taken care of the fact that prognosis in patients with HCC is decided not only by the tumor burden but, to a very significant part, also by the degree of the underlying liver cirrhosis. The oldest of the prognostic systems still in use today, the Okuda system, has simply taken three parameters of the Child-Pugh Score and supplemented it with a very crude estimation of the tumor size on imaging, thereby deriving a very simple but also for many patients today inaccurate three-stage prognostic system [4]. In particular, Okuda staging is mostly helpful for estimating the prognosis of the early as well as the most advanced stages of disease, while leaving the majority of patients in the intermediate Okuda stage II with a very rough estimate of the survival, which made it a system of very low practical value for the management of patients with HCC. In their recently published manuscript, Huitzil-Melendez and colleagues retrospectively compare the predictive power of seven different prognostic systems with regards to the outcome of patients with advanced stage HCC, destined to undergo medical therapy for their disease [5]. Their conclusion after evaluating TNM sixth edition, Okuda, BCLC, CLIP, CUPI, JIS, and GETCH in 187 eligible patients is that CLIP, CUPI, and GETCH were the most informative systems, while BCLC and TNM lacked discriminatory power in their patients. Looking at individual parameters, the addition of performance status, AST, abdominal pain, and esophageal varices to CLIP would be able to improve its prognostic accuracy even further. The general idea of the authors was to find
Target Sequence Accessibility Limits Activation-Induced Cytidine Deaminase Activity in Primary Mediastinal B-Cell Lymphoma
Authors: Sergey W. Popov, Gerhard Moldenhauer, Beate Wotschke, Silke Brüderlein, Thomas F. Barth, Karola Dorsch, Olga Ritz, Peter Möller, Frank Leithäuser
Journal: Cancer Research (2007)

Abstract Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) in activated B lymphocytes and is potentially implicated in genomic instability of B-cell malignancies. For unknown reasons, B-cell neoplasms often lack SHM and CSR in spite of high AID expression. Here, we show that primary mediastinal B-cell lymphoma (PMBL), an immunoglobulin (Ig)–negative lymphoma that possesses hypermutated, class-switched Ig genes, expresses high levels of AID with an intact primary structure but does not do CSR in 14 of 16 cases analyzed. Absence of CSR coincided with low Ig germ-line transcription, whereas high level germ-line transcription was observed only in those two cases with active CSR. Interleukin-4/CD40L costimulation induced CSR and a marked up-regulation of germ-line transcription in the PMBL-derived cell line MedB-1. In the PMBL cell line Karpas 1106P, CSR was not inducible and germ-line transcription remained low on stimulation. However, Karpas 1106P, but not MedB-1, had ongoing SHM of the Ig gene and BCL6. These genes were transcribed in Karpas 1106P, whereas transcription was undetectable or low in MedB-1 cells. Thus, accessibility of the target sequences seems to be a major limiting factor for AID-dependent somatic gene diversification in PMBL. [Cancer Res 2007;67(14):6555–64]
Domiciliary diurnal variation of exhaled nitric oxide fraction for asthma control
Authors: Junpei Saito, David Gibeon, Patricia Macedo, Andrew Menzies-Gow, Pankaj K. Bhavsar, Kian Fan Chung
Journal: European Respiratory Journal (2013)

A major goal of asthma management is maintaining optimal control. Current assessment is based on symptoms and lung function. We evaluated whether domiciliary daily home exhaled nitric oxide fraction ( F eNO ) monitoring could be useful as an index of asthma control. 50 asthmatic subjects and 15 healthy volunteers with a range of asthma severity underwent asthma control questionnaire (ACQ), spirometry before and after salbutamol and sputum induction. F eNO and peak expiratory flow (PEF) were measured twice daily for 2 weeks. A record of exacerbations was obtained 3 months later. Diurnal F eNO variation in uncontrolled asthmatics was significantly greater than in controlled asthmatics (p&lt;0.01). PEF variation was not different. The daily variation of F eNO levels was also greater in uncontrolled asthmatics compared with controlled asthmatic and healthy subjects (p&lt;0.01). 80% of uncontrolled asthmatics experienced at least one or more exacerbations over the 3 months after the enrolment. The combination of diurnal F eNO variation ≥16.6% and ACQ scores ≥1.8 was best at predicting uncontrolled asthma (area under curve 0.91, 95% CI 0.86–0.97; p&lt;0.001). Diurnal variation in F eNO can be used as a biomarker of asthma control and as a predictor of the risk of future exacerbation. Prospective studies are warranted.