tbuckley/cabot-search huggingface dataset:
RET Is Constitutively Activated by Novel Tandem Mutations that Alter the Active Site Resulting in Multiple Endocrine Neoplasia Type 2B
Authors: Aaron N. Cranston, Cristiana Carniti, Kim Oakhill, Elzbieta Radzio-Andzelm, Eric A. Stone, Andrew S. McCallion, Shirley Hodgson, Sue Clarke, Piera Mondellini, Jean Leyland, Marco A. Pierotti, Joanne Whittaker, Susan S. Taylor, Italia Bongarzone, Bruce A.J. Ponder
Journal: Cancer Research (2006)

Constitutive activation of the RET receptor tyrosine kinase underlies the genesis and progression of multiple endocrine neoplasia type 2 (MEN 2), a dominantly inherited cancer predisposition. Importantly, although kinase activation represents a common theme in neoplasias, not all activating mutations are functionally equivalent. Consistent with this, we ascertained a patient with classical features of MEN 2B, but lacking either of the classical mutations in RET (M918T or A883F). Instead, the patient harbors a novel pair of germ line missense mutations in cis at codons 804 and 805. We evaluated the potential physiochemical effects of these substitutions in silico, predicting both to be moderately deleterious in isolation, but severely deleterious in combination. Consistent with this postulate, we show that the identified tandem mutations (V804M/E805K) are biologically active, transforming cells in culture and that their transforming capacity in combination is distinctly synergistic. Furthermore, the V804M/E805K tandem lesion confers resistance to the small molecule receptor tyrosine kinase inhibitor, PP1, suggesting a mode of action distinct from that known for classical MEN 2B mutations. To address this question, we used homology molecular modeling in silico to model the active site of RET. We predict that RET804 constitutes a critical gatekeeper residue that, when mutated in combination with RET805, induces a conformational change in the hinge region that locks the active site in a position permissive for ATP hydrolysis. Our findings have implications both in the clinic and in the successful development of novel kinase-targeted anticancer drugs.
Evaluation of ultra-short dialysis.
Authors: J A Trafford, P Sharpstone, R Evans, R Ireland
Journal: BMJ (1979)

A study was carried out to compare the effects of three dialysis regimens of different durations. Nineteen patients dialysed over 1975--7 for an average of only 11.2 hours per week were compared with nine dialysed for 24 hours per week (1974--6) and 10 dialysed for 27 hours (1971--3). Clinical, biochemical, and haematological results showed that the short dialysis regimen was as effective as the longer regimens, except that patients had to take a phosphate binder regularly, and that it was considerably cheaper. Short dialysis has social and economic benefits, since patients have more free time and more patients can be treated with the same number of staff and dialysis stations. As in many areas there is a shortage of places for patients needing dialysis, a short regimen is recommended.
Multiple variants in toll-like receptor 4 gene modulate risk of liver fibrosis in Caucasians with chronic hepatitis C infection
Authors: Yonghong Li, Monica Chang, Olivia Abar, Veronica Garcia, Charles Rowland, Joseph Catanese, David Ross, Samuel Broder, Mitchell Shiffman, Ramsey Cheung, Teresa Wright, Scott L. Friedman, John Sninsky
Journal: Journal of Hepatology (2009)
Factors influencing late right ventricular ejection
Authors: V. RAIZADA, D J SAHN, J W COVELL
Journal: Cardiovascular Research (1988)

Forward flow from the right ventricle into the pulmonary artery continues longer than contraction in the right ventricular free wall. The momentum of blood flow, contraction of other areas of the right ventricular free wall, and movement of the interventricular septum are possible mechanisms regulating late right ventricular ejection. In this study the changes in shortening in right ventricular free wall and in free wall to septum distance were measured using sonomicrometry. Right ventricular free wall shortening was studied in both outflow and inflow regions in hoop and apex to base axes. Pulmonary artery flow was simultaneously measured using an electromagnetic flowmeter. Right ventricular free wall in the hoop axis was motionless during late ejection. The inflow segment in the hoop axis stopped shortening before all other segments (p less than 0.01). Both outflow and inflow segments in the hoop axis lengthened after the end of shortening. Both shortening of the right ventricular free wall in the apex to base axis and decrease in free wall to septum distance were continued until the end of ejection (p less than 0.01). Compared with the right ventricular outflow segment, the inflow segment shortened for a longer duration. It is concluded that forward flow during late right ventricular ejection is associated with continued shortening of the free wall in the apex to base axis. However, the results of this study do not exclude the role of septal bulge into the right ventricle during late ejection.
Leptin Mediates Tumor–Stromal Interactions That Promote the Invasive Growth of Breast Cancer Cells
Authors: Ines Barone, Stefania Catalano, Luca Gelsomino, Stefania Marsico, Cinzia Giordano, Salvatore Panza, Daniela Bonofiglio, Gianluca Bossi, Kyle R. Covington, Suzanne A.W. Fuqua, Sebastiano Andò
Journal: Cancer Research (2012)

Abstract Obesity confers risks to cancer development and progression but the mechanisms underlying these risks remain unclear. In this study, we identify a role for the obesity cytokine leptin, which has been implicated previously in breast cancer development, as a determinant for the tumor-promoting activity of cancer-associated fibroblasts (CAF) in both wild-type (WT) and K303R mutant estrogen receptor-α (ERα)–expressing breast cancer cells. Human CAFs stimulated a greater increase in the proliferation and migration of breast cancer cells expressing the K303R-ERα hyperactive receptor than WT-ERα–expressing cells. A concomitant increase was seen in leptin receptor isoform expression and activation of the leptin signaling pathway in cells expressing K303R-ERα compared with WT-ERα, correlating with leptin effects on cell growth, motility, and invasiveness in mutant cells. Epidermal growth factor and other factors secreted by K303R-ERα cells stimulated CAF proliferation, migration, and subsequent leptin secretion. Moreover, K303R-ERα expression generated a leptin hypersensitive phenotype in vivo. Together, our results reveal a bidirectional cross-talk between breast cancer cells and “educated” CAFs that drives tumor progression via leptin signaling. In elucidating a mechanism that connects obesity and cancer, these findings reinforce the concept that blocking cancer–stromal cell communication may represent an effective strategy for targeted therapy of breast cancer. Cancer Res; 72(6); 1416–27. ©2012 AACR.
Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes
Authors: Lorenzo Cosmi, Francesco Liotta, Elena Lazzeri, Michela Francalanci, Roberta Angeli, Benedetta Mazzinghi, Veronica Santarlasci, Roberto Manetti, Vittorio Vanini, Paola Romagnani, Enrico Maggi, Sergio Romagnani, Francesco Annunziato
Journal: Blood (2003)
Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease
Authors: R Antonelli Incalzi, L Fuso, M De Rosa, F Forastiere, E Rapiti, B Nardecchia, R Pistelli
Journal: European Respiratory Journal (1997)

The aim of this study was to assess the prognostic role of co-morbidity in severe chronic obstructive pulmonary disease (COPD). A cohort of 270 COPD patients, mean (+/-SD) age 67+/-9 yrs, consecutively discharged from a University Hospital after an acute exacerbation was studied. Mean (+/-SD) forced expiratory volume in one second (FEV1) was 34+/-16% of predicted and FEV1/forced vital capacity (FVC) was 40.5+/-13.8%. The most common co-morbid diseases were: hypertension (28%), diabetes mellitus (14%), and ischaemic heart disease (10%). Clinical, electrocardiogram (ECG), and respiratory function data taken at the time of discharge were collected from the clinical records. The Charlson's index was used to quantify co-morbidity. Follow-up was conducted by means of telephone calls. Multivariate survival analysis was used to identify the independent predictors of death. The median survival of the cohort was 3.1 yrs. Death was predicted by the following variables: age (hazard rate (HR) 1.04; 95% confidence intervals (95% CI) 1.02-1.05), ECG signs of right ventricular hypertrophy (HR 1.76; 95% CI 1.30-2.38), chronic renal failure (HR 1.79; 95% CI 1.05-3.02), ECG signs of myocardial infarction or ischaemia (HR 1.42; 95% CI 1.02-1.96), FEV1 < 590 mL (HR 1.49; 95% CI 0.97-2.27). A score based upon these variables predicted mortality at 5 yrs with a sensitivity of 63% and a specificity of 77%. Selected co-morbid diseases and electrocardiogram signs of right ventricular hypertrophy play a major prognostic role in advanced chronic obstructive pulmonary disease. The clinical assessment of patients with chronic obstructive pulmonary disease should include these important and easily measurable variables.
Elevated Physiologic Tumor Pressure Promotes Proliferation and Chemosensitivity in Human Osteosarcoma
Authors: Saminathan S. Nathan, Gene R. DiResta, Jorge E. Casas-Ganem, Bang H. Hoang, Rebecca Sowers, Rui Yang, Andrew G. Huvos, Richard Gorlick, John H. Healey
Journal: Clinical Cancer Research (2005)

Abstract Purpose: This study investigates the effect of constitutively raised interstitial fluid pressure on osteosarcoma physiology and chemosensitivity. Experimental Design: We did pressure and blood flow assessments at the time of open biopsy in patients with the diagnosis of high-grade osteosarcoma and correlated this to survival and chemotherapy-associated tumor necrosis. Osteosarcoma cell lines were then evaluated for proliferative and therapeutic indices in a replicated high-pressure environment. Results: Sixteen osteosarcomas in vivo were assessed and exhibited elevated interstitial fluid pressures (mean 35.2 ± SD, 18.6 mmHg). This was not associated with significantly impeded blood flow as measured by a Doppler probe at a single site (P &amp;lt; 0.12). Nonetheless, greater chemotherapy-associated necrosis and associated longer survival were seen in tumors with higher interstitial fluid pressures (P &amp;lt; 0.05). In vitro, cells undergo significant physiologic changes under pressure. Osteosarcoma cell lines grown in a novel hydrostatically pressurized system had variable cell line–specific growth proportional to the level of pressure. They were more proliferative as indicated by cell cycle analysis with more cells in S phase after 48 hours of pressurization (P &amp;lt; 0.01). There was a significant elevation in the cell cycle–related transcription factors E2F-1 (P &amp;lt; 0.03) and E2F-4 (P &amp;lt; 0.002). These changes were associated with increased chemosensitivity. Cells tested under pressure showed an increased sensitivity to cisplatin (P &amp;lt; 0.00006) and doxorubicin (P &amp;lt; 0.03) reminiscent of the increased chemotherapy-associated necrosis seen in tumors with higher interstitial fluid pressure in the clinical study. Conclusions: The results of this study suggest that cells in the in vivo pressurized environment are at a higher state of regenerative activity than is demonstrable in conventional cell culture systems. Variations in tumor interstitial fluid pressure have the potential to alter chemotherapeutic effects.
Predictors of adherence to tuberculosis treatment in a supervised therapy programme for prisoners before and after release. Study Group of Adherence to Tuberculosis Treatment of Prisoners
Authors: A Marco, JA Cayla, M Serra, R Pedro, C Sanrama, R Guerrero, N Ribot
Journal: European Respiratory Journal (1998)

The prison population is a high-risk group for tuberculosis (TB). This investigation aimed to study predictive factors of treatment adherence among prisoners involved in a pilot programme of supervised treatment. The study included TB patients from the Men's Penitentiary Center of Barcelona (MPCB) in 1995. Directly observed therapy (DOT) was carried out in the infirmary or in a methadone programme. Released prisoners were referred to the municipal maintenance methadone programmes (MMP) and other social resources. Incentives and enablers were used to improve compliance (economic aid for nutritional and housing needs, methadone programmes and admittance to a sociosanitary centre). The outcome of the patients' adherence was classified as follows: completed, defaulted, dead or transferred out. Factors associated with adherence were investigated through logistic regression. The programme included 62 patients, 43 of whom were intravenous drug users (IVDU) and 46 were infected with the human immunodeficiency virus (HIV). Nineteen had previously had TB and 32 were released from prison during TB treatment. Overall adherence was 89%; 97% among those who completed treatment in prison, and 79% among those who completed treatment outside prison (p=0.05). Ninety-five per cent of IVDU in an MMP completed treatment. Homeless or alcoholic exprisoners completed treatment only if they were admitted to sociosanitary centres. DOT throughout treatment resulted in better adherence (odds ratio (OR)= 16.80; confidence interval (CI): 2.42-116.2)). Those who were incarcerated throughout treatment also showed better adherence (OR= 7.36; CI: 0.79-48.16). Antituberculosis treatment adherence in prisoners was high even after release with adequate co-ordination among intrapenitentiary and extrapenitentiary programmes. Maintenance methadone programmes proved very useful in intravenous drug users, as did admittance to sociosanitary centres for indigent or alcoholic exprisoners undergoing treatment.
The potential role of human endogenous retrovirus K10 in the pathogenesis of rheumatoid arthritis: a preliminary study
Authors: H D Ejtehadi
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To examine whether human endogenous retrovirus K10 is associated with autoimmune rheumatic disease. <b>Design:</b> A novel multiplex reverse transcription polymerase chain reaction (RT-PCR) system was developed to investigate HERV-K10 mRNA expression in patients with rheumatoid arthritis. <b>Methods:</b> 40 patients with rheumatoid arthritis, 17 with osteoarthritis, and 27 healthy individuals were recruited and total RNA was extracted from peripheral blood mononuclear cells (PBMCs) and analysed using multiplex RT-PCR for the level of HERV-K10 gag mRNA expression. Southern blot and DNA sequencing confirmed the authenticity of the PCR products. <b>Results:</b> Using the histidyl tRNA synthetase (HtRNAS) gene as a housekeeping gene in the optimised multiplex RT-PCR, a significantly higher level of HERV-K10 gag mRNA expression was found in rheumatoid arthritis than in osteoarthritis (p = 0.01) or in the healthy controls (p = 0.02). <b>Conclusion:</b> There is enhanced mRNA expression of the HERV-K10 gag region in rheumatoid arthritis compared with osteoarthritis or healthy controls. This could contribute to the pathogenesis of rheumatoid arthritis.
Pegylated Arginine Deiminase Treatment of Patients With Unresectable Hepatocellular Carcinoma: Results From Phase I/II Studies
Authors: Francesco Izzo, Paolo Marra, Gerardo Beneduce, Giuseppe Castello, Paolo Vallone, Vincenzo De Rosa, Franco Cremona, C. Mark Ensor, Frederick W. Holtsberg, John S. Bomalaski, Mike A. Clark, Chaan Ng, Steven A. Curley
Journal: Journal of Clinical Oncology (2004)

Purpose Recently, we reported that a large number of human hepatocellular cancer (HCC) cell lines were auxotrophic for arginine. Here we report the results obtained with the amino acid–degrading enzyme arginine deiminase (ADI) conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw) as a means of lowering plasma arginine to treat HCC. The study was a cohort dose-escalation phase I/II study. Patients and Methods Pharmacodynamic studies indicated an ADI-SS PEG 20,000 mw dose level of 160 U/m 2 was sufficient to lower plasma arginine from a resting level of approximately 130 μmol/L to below the level of detection (&lt; 2 μmol/L) for more than 7 days, a dose later defined as the optimal biologic dose. All patients were to receive three cycles at the optimum biologic dose. Results This therapy was well tolerated, even in patients who had no detectable plasma arginine for 3 continuous months of therapy. Of the 19 patients enrolled, two had a complete response, seven had a partial response, seven had stable disease, and three had progressive disease. The median survival for the 19 patients enrolled on this study was 410 days, with four patients still alive at present (&gt; 680 days). Conclusion Elimination of all detectable plasma arginine in patients with HCC was well tolerated and seemed to be effective in the treatment of some patients with HCC. Further testing of ADI-SS PEG 20,000 mw in a larger population of individuals with HCC as well as other human tumors auxotrophic for arginine is warranted.
Predictive equations for total lung capacity and residual volume calculated from radiographs in a random sample of the Michigan population.
Authors: K H Kilburn, R H Warshaw, J C Thornton, K Thornton, A Miller
Journal: Thorax (1992)

Published predicted values for total lung capacity and residual volume are often based on a small number of subjects and derive from different populations from predicted spirometric values. Equations from the only two large studies gave smaller predicted values for total lung capacity than the smaller studies. A large number of subjects have been studied from a population which has already provided predicted values for spirometry and transfer factor for carbon monoxide.Total lung capacity was measured from standard posteroanterior and lateral chest radiographs and forced vital capacity by spirometry in a population sample of 771 subjects. Prediction equations were developed for total lung capacity (TLC), residual volume (RV) and RV/TLC in two groups--normal and total. Subjects with signs or symptoms of cardiopulmonary disease were combined with the normal subjects and equations for all subjects were also modelled.Prediction equations for TLC and RV in non-smoking normal men and women were square root transformations which included height and weight but not age. They included a coefficient for duration of smoking in current smokers. The predictive equation for RV/TLC included weight, age, age and duration of smoking for current smokers and ex-smokers of both sexes. For the total population the equations took the same form but the height coefficients and constants were slightly different.These population based prediction equations for TLC, RV and RV/TLC provide reference standards in a population that has provided reference standards for spirometry and single breath transfer factor for carbon monoxide.
Internal Medicine Certification: Scores Slip; Spirochete Survives-Reply
Authors: John J. Norcini
Journal: JAMA (1990)

In Reply. —  Dr Cary makes several good points about our article and Dr Dan's editorial, but we differ with his conclusion. He is correct that the Medical College Admission Test scores and grades of medical students have not fallen. It is further true that any 2-year decrement in candidate performance is small in absolute numbers of questions, although these differences are considerable in a statistical sense (as a proportion of the SD). In any event, the decline is cumulative, and during the 6 years of the study it almost certainly reflects a decrease in the medical knowledge of the reference-group candidates.  More importantly, Dr Cary cites several areas of new medical knowledge and argues that residents must learn them at the expense of others. This argument fails to acknowledge that some informaltion becomes outdated during that same period and no longer needs to be retained (in fact should be
Oxidative Stress Regulates Left Ventricular PDE5 Expression in the Failing Heart
Authors: Zhongbing Lu, Xin Xu, Xinli Hu, Sangjin Lee, Jay H. Traverse, Guangshuo Zhu, John Fassett, Yi Tao, Ping Zhang, Cris dos Remedios, Marc Pritzker, Jennifer L. Hall, Daniel J. Garry, Yingjie Chen
Journal: Circulation (2010)

Background— Phosphodiesterase type 5 (PDE5) inhibition has been shown to exert profound beneficial effects in the failing heart, suggesting a significant role for PDE5 in the development of congestive heart failure (CHF). The purpose of this study is to test the hypothesis that oxidative stress causes increased PDE5 expression in cardiac myocytes and that increased PDE5 contributes to the development of CHF. Methods and Results— Myocardial PDE5 expression and cellular distribution were determined in left ventricular samples from patients with end-stage CHF and normal donors and from mice after transverse aortic constriction (TAC)-induced CHF. Compared with donor human hearts, myocardial PDE5 protein was increased ≈4.5-fold in CHF samples, and the increase of myocardial PDE5 expression was significantly correlated with myocardial oxidative stress markers 3′-nitrotyrosine or 4-hydroxynonenal expression ( P &lt;0.05). Histological examination demonstrated that PDE5 was mainly expressed in vascular smooth muscle in normal donor hearts, but its expression was increased in both cardiac myocytes and vascular smooth muscle of CHF hearts. Myocardial PDE5 protein content and activity also increased in mice after TAC-induced CHF ( P &lt;0.05). When the superoxide dismutase (SOD) mimetic M40401 was administered to attenuate oxidative stress, the increased PDE5 protein and activity caused by TAC was blunted, and the hearts were protected against left ventricular hypertrophy and CHF. Conversely, increased myocardial oxidative stress in superoxide dismutase 3 knockout mice caused a greater increase of PDE5 expression and CHF after TAC. In addition, administration of sildenafil to inhibit PDE5 attenuated TAC-induced myocardial oxidative stress, PDE5 expression, and CHF. Conclusions— Myocardial oxidative stress increases PDE5 expression in the failing heart. Reducing oxidative stress by treatment with M40401 attenuated cardiomyocyte PDE5 expression. This and selective inhibition of PDE5 protected the heart against pressure overload-induced left ventricular hypertrophy and CHF.
THE IMMUNOLOGICAL SPECIFICITY OF TYPE II PNEUMOCOCCUS AND ITS SEPARATION INTO PARTIAL SPECIFICITIES
Authors: Michael Heidelberger, John Adams
Journal: The Journal of Experimental Medicine (1956)

The specificity of Type II pneumococcus determined by its capsular polysaccharide (S II) may be separated into three partial specificities, each characteristic of one of the three component sugars of S II, namely, glucuronic acid, glucose, and rhamnose. By far the largest portion of antibodies in Type II antipneumococcus horse sera which cross-react with carbohydrates containing one or more of these sugars are reactive with those characterized by multiple groupings of glucuronic acid. This confirms, extends, and explains earlier observations. In confirmation of predictions based upon existing information tamarind seed polysaccharide (jellose), in which much of the glucose exists as 1,4,6-branch points, was found to react in Type II antisera. Several instances are given of cross-reactions in these antisera apparently due to the L-rhamnose component of the reacting polysaccharides. The antisera contain far more antibody capable of precipitating with substances with multiple units of glucuronic acid than with those so far tested containing multiple 1,4,6-branch points of glucose or multiple groupings of rhamnose. The long known increase of titer of gum arabic on partial hydrolysis is now fully explained and discussed, and a chemical picture is given of the change in "avidity." The sum of the partial specificities measured does not equal the whole. Quantitative data illustrating these points are given.
Concomitant ALK translocation and EGFR mutation in lung cancer: a comparison of direct sequencing and sensitive assays and the impact on responsiveness to tyrosine kinase inhibitor
Authors: J.K. Won, B. Keam, J. Koh, H.J. Cho, Y.K. Jeon, T.M. Kim, S.H. Lee, D.S. Lee, D.W. Kim, D.H. Chung
Journal: Annals of Oncology (2014)