tbuckley/cabot-search huggingface dataset:
Abstract A41: Somatic mutations in human cancer cell lines predict sorafenib response
Authors: Daniel R. Rhodes, Scott H. Kaufmann, Xue Wei Meng, Peter Wyngaard, Gary Daubresse, Judith S. Leopold
Journal: Clinical Cancer Research (2010)

Abstract It is now widely accepted that a spectrum of somatic alterations occur in human cancer and that particular alterations are associated with response or lack of response to anti-cancer therapies. Here, we undertook a systematic correlation analysis of somatic mutations, copy number aberrations and drug response across 300+ human cancer cell lines. We studied the RAF and VEGFR inhibitor, sorafenib, evaluating associations between sorafenib response and somatic mutations in 35 common cancer genes and high-level amplifications and homozygous deletions in more than 100 minimal common regions of gain and loss, which include many known oncogenes and tumor suppressor genes. Notably, we found that NRAS mutations, among other alterations, were significantly associated with sensitivity to sorafenib (odds ratio = 7, p-value = 0.003), whereas activating BRAF mutations were strongly associated with a lack of response (odds ratio = 4.9, p-value = 0.012). Specifically, 64% (7 of 11) of NRAS mutant cell lines were sensitive to sorafenib, while only 20% (34 of 170) of NRAS wild-type lines were sensitive. On the contrary, just 6.7% (2 of 30) of BRAF mutant lines were sensitive to sorafenib. Because NRAS mutations occur frequently in leukemia and no leukemia cell lines were included in the original analysis, we selected 5 NRAS mutant and 5 NRAS wild-type leukemia cell lines for further evaluation. Consistent with our previous observation, the four most sensitive leukemia cell lines were all NRAS mutant, each line exhibiting greater than 50% growth inhibition after 72 hours of exposure to 4μM sorafenib. These results confirm the original association and suggest that across both solid tumors and hematologic malignancies, NRAS mutations may identify a subset of cancers that are likely to respond sorafenib. In addition, this work demonstrates that systematic analysis of somatic alterations and drug response across a large collection of cancer cell lines is capable of discovering novel predictive biomarkers. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A41
Modulation of immune responses to hepatitis C virus envelope E2 protein following injection of plasmid DNA using single or combined delivery routes
Authors: Anne Fournillier, Isao Nakano, Ludmila Vitvitski, Erik Depla, Olivier Vidalin, Geert Maertens, Christian Trépo, Genevieve Inchauspé
Journal: Hepatology (1998)

Different delivery routes of plasmid DNA may result in the induction of differential humoral and cellular immunity. We have studied the influence of two main routes of plasmid injection, performed intramuscularly and intraepidermally using a gene gun, for the induction of immune responses specific to hepatitis C virus (HCV) envelope protein E2. Three plasmids expressing different immunogenic domains of E2 (amino acids [aa] 384-443, aa 504-555, and aa 384-746) were injected into BALB/c mice according to five different protocols using various combinations of intramuscular (i.m.) or intraepidermal (i.e.) primary and booster injections. Seroconversion rates, antibody titers and isotypes, epitope recognition, and T-helper (Th) release cytokine profiles were analyzed. Antibody titers and epitope recognition were linked to either or both the nature of the immunogen expressed and the delivery route chosen. In all cases, the lowest antibody titers were obtained using single i.m.-based protocols. Independently of the antibody titers generated, only some specific i.e.-combined delivery routes induced antibodies able to recognize determinants located in the N-terminal of E2 (aa 384-411 and aa 411-437) and mimicked by synthetic peptides. By contrast, the antibody isotypes and the splenic cytokine production identified were independent of the plasmids used and the delivery route implemented. All conditions resulted in Th-1 like responses suggested by the exclusive detection of IgG2a and 2b antibodies and the production of interferon gamma (INF-γ) but no interleukin-4 (IL-4). Overall, our results suggest that the combination of i.m. and i.e. delivery routes provides the most efficient way to induce a broad immune response against HCV-E2.
Long term effects of aerosolised rhDNase on pulmonary disease progression in patients with cystic fibrosis
Authors: C. E Milla
Journal: Thorax (1998)

<h3>BACKGROUND</h3> After multiple studies, including clinical trials, suggested some mild clinical benefits from the use of rhDNase by patients with cystic fibrosis, a widespread acceptance of the drug has followed. However, long term effects, specifically on lung disease progression, have not been demonstrated. Experience with the use of this drug in a single cystic fibrosis centre is presented and compared with the trends seen in the patient population of the centre before the introduction of the drug. <h3>METHODS</h3> Patients with cystic fibrosis routinely followed at the University of Minnesota Cystic Fibrosis Center and prescribed rhDNase for at least two years were included in this retrospective study. Data on spirometric parameters (FEV<sub>1</sub> and FEV<sub>1</sub>/FVC), allometric index, and admissions to hospital were retrieved from the centre’s database for the two years preceding the prescription of rhDNase and the two years that followed. Trends in pulmonary function and allometric index were analysed by mixed linear modelling, and hospital admission rates for both periods were calculated and compared. <h3>RESULTS</h3> One hundred and ninety patients met the inclusion criteria for the study. In the two years preceding the prescription of rhDNase the trends noted were those of a mild decline in FEV<sub>1</sub>, a stable FEV<sub>1</sub>/FVC, and a mild improvement in allometric index. In the two years that followed the prescription of rhDNase a mild decline in all these parameters occurred which was a significant change from the previous period (all p &lt;0.009). There was no difference between females and males in the trends experienced after the start of rhDNase. By logistic regression analysis only the presence of malnutrition at the time of prescription was associated with a positive trend after the introduction of rhDNase. No significant change in the hospital admission rates occurred, with rates of 0.52 (0.16) and 0.56 (0.21) admissions/patient/year for the periods before and after the prescription of rhDNase, respectively. <h3>CONCLUSIONS</h3> The introduction of rhDNase to the regimen of patients with cystic fibrosis cared for at this centre has not been followed by a positive trend in lung function and nutritional parameters. There are some differences between this patient population and those who participated in previous studies which may help to explain the contrasting findings of this study. However, it is also possible that factors other than mucus clearance need to be improved to achieve a favourable response in disease progression. Patients on this treatment should be followed closely and the benefit judged on an individual basis. More studies are needed to define better the specific indications and use of this form of treatment.
Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B
Authors: Man-Fung Yuen, Yasuhito Tanaka, Daniel Yee-Tak Fong, James Fung, Danny Ka-Ho Wong, John Chi-Hang Yuen, David Yiu-Kuen But, Annie On-On Chan, Benjamin Chun-Yu Wong, Masashi Mizokami, Ching-Lung Lai
Journal: Journal of Hepatology (2008)
Diabetes in Ontario
Authors: Janet E. Hux, Frank Ivis, Virginia Flintoft, Adina Bica
Journal: Diabetes Care (2002)

Accurate information about the magnitude and distribution of diabetes can inform policy and support health care evaluation. We linked physician service claims (PSCs) and hospital discharge abstracts (HDAs) to determine diabetes prevalence and incidence.A retrospective cohort was constructed using administrative data from the national HDA database, PSCs for Ontario (population 11 million), and registries carrying demographics and vital statistics. All HDAs and PSCs bearing a diagnosis of diabetes (ICD9-CM 250) were selected for 1991-1999. Two previously reported algorithms for identification of diabetes were applied as follows: "1-claim" (any HDA or PSC showing diabetes) and "2-claim" (one HDA or two PSCs within 2 years showing diabetes). Incident cases were defined as individuals who met the criteria for diabetes for the first time after at least 2 years of observation. For validation, diagnostic data abstracted from primary care charts (n=3,317) of 57 randomly selected physicians were linked to the administrative data cohort, and sensitivity and specificity were calculated.-In 1998, 696,938 individuals met the 1-claim criteria and 528,280 met the 2-claim criteria. Sensitivity for diabetes was 90 and 86%; for the 1- and 2-claim algorithms, specificity was 92 and 97%, respectively, and positive predictive values were 61 and 80%, respectively. Using the 2-claim algorithm, the all-age prevalence increased from 3.2% in 1993 to 4.5% in 1998 (6.1% in adults). Incidence remained stable.Administrative data can be used to establish population-based incidence and prevalence of diabetes. Diabetes prevalence is increasing in Ontario and is considerably higher than self-reported rates.
EFFECT OF SIZE OF RADIOLABELED ANTIBODY AND FRAGMENTS ON TUMOR UPTAKE AND DISTRIBUTION IN NEPHRECTOMIZED MICE
Authors: S. E. Halpern, F. Buchegger, M. Schreyer, J. -P. Mach. Ludwig
Journal: Clinical Nuclear Medicine (1984)

The importance of molecular size in tumor (T) uptake of intact monoclonal antibody (MAb) or MAb fragments (frag.) is difficult to assess because frag. are excreted by the kidney. To obviate this problem nephrectomized nude mice (M) bearing carcinoembryonic antigen (CEA) secreting human colon T were used in the following experiments. Following nephrectomy 3 groups of M were injected intervenously with intact In-111 anti-CEA MAb and simultaneously with I-125 intact, F(ab')2 or Fab anti-CEA-MAb. Iodination was by chloramine T and In-111 labeling by bifunctional chelation. All M were killed 8 h after injection, T and normal tissues (NT) dissected, weighed, and counted against a standard of the injectate. The distribution of intact I-125 and In-111-MAb were nearly identical allowing In-111MAb to be used for comparison with the I-125 frag. T concentration (conc.) of I-125-F(ab')2 were 25% greater and L cone. were 63% lower than for intact In-111-MAb. T cone, of I-125-Fab were 86% greater and L cone. 64% lower than for intact In-111-MAb. Large T, which produce higher serum CEA levels, increased the L cone. of intact MAb but not I-125 frag. In conclusion, when renal excretion is prevented there is (a) an inverse relationship between size of a MAb moiety and its T cone. indicating that the improved T/NT ratios observed with frag. are not due only to renal excretion, (b) the Fc portion of the MAb appears to be critical for L uptake of MAb or immune complexes.
Cutaneous Leishmaniasis Encountered in Philadelphia
Authors: George W. Hambrick
Journal: JAMA (1966)

Four cases of cutaneous leishmaniasis, one due to<i>Leishmania braziliensis</i>, acquired in Guatemala, and three due to L tropica, probably acquired in Israel. In three of the patients with oriental sore, the majority of lesions were on the legs, and one of varying size and development on the hand. All lesions resolved within one year without therapy. In the American cutaneous case the picture was that of chiclero ulcer. All four patients reacted to a common antigen prepared from L<i>tropica</i>, indicating cross reactivity. Gradual transition from an acute inflammatory process with many Leishman-Donovan organisms to a granulomatous lesion with few or no organisms occurred. Physicians should advise prophylactic use of repellents and insecticides for patients traveling to endemic areas. In all likelihood this would decrease the probability of acquiring this insect-borne disease.
Randomised controlled trial of day patient versus inpatient psychiatric treatment.
Authors: F Creed, D Black, P Anthony, M Osborn, P Thomas, B Tomenson
Journal: BMJ (1990)

OBJECTIVE--To assess the proportion of acutely ill psychiatric patients who can be treated in a day hospital and compare the outcome of day patient and inpatient treatment. DESIGN--Prospective randomised controlled trial of day patient versus inpatient treatment after exclusion of patients precluded by severity of illness or other factors from being treated as day patients. All three groups assessed at three and 12 months. SETTING--Teaching hospital serving small socially deprived inner city area. Day hospital designed to take acute admissions because of few beds. PATIENTS--175 Patients were considered, of whom 73 could not be allocated. Of the remaining 102 patients, 51 were allocated to each treatment setting but only 89 became established in treatment--namely, 41 day patients and 48 inpatients. 73 Of these 89 patients were reassessed at three months and 70 at one year. INTERVENTIONS--Standard day patient and inpatient treatment. MAIN OUTCOME MEASURES--Discharge from hospital and return to previous level of social functioning; reduction of psychiatric symptoms, abnormal behaviour, and burden on relatives. RESULTS--33 Of 48 inpatients were discharged at three months compared with 17 of 41 day patients. But at one year 9 of 48 inpatients and three of 41 day patients were in hospital. 18 Of 35 day patients and 16 of 39 inpatients were at their previous level of social functioning at one year. The only significant difference at three months was a greater improvement in social role performance in the inpatients. At one year there was no significant difference between day patients and inpatients in present state examination summary scores and social role performance, burden, or behaviour. CONCLUSIONS--Roughly 40% of all acutely ill patients presenting for admission to a psychiatric unit may be treated satisfactorily in a well staffed day hospital. The outcome of treatment is similar to that of inpatient care but might possibly reduce readmissions. The hospital costs seem to be similar but further research is required to assess the costs in terms of extra demands on relatives, general practitioners, and other community resources.
Polybrominated diphenyl ethers in maternal and fetal blood samples.
Authors: Anita Mazdai, Nathan G Dodder, Mary Pell Abernathy, Ronald A Hites, Robert M Bigsby
Journal: Environmental Health Perspectives (2003)

Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants in consumer goods, such as plastics, electronics, textiles, and construction material. PBDEs have been found in human milk, fat, and blood samples. Rodent studies indicate that PBDEs may be detrimental to neurodevelopment, possibly by lowering thyroid hormone concentrations in blood. In the present study, we determined concentrations of PBDEs and thyroid hormones in human fetal and maternal serum. Patients presenting in labor to Indiana University and Wishard Memorial County hospitals in Indianapolis, who were older than 18 years, were recruited to participate. Twelve paired samples of maternal and cord blood were obtained and analyzed using gas chromatographic mass spectrometry; thyroid hormone concentrations were determined by radioimmunoassay. Six congeners of PBDE were measured in maternal and fetal serum samples. The concentrations of total PBDEs found in maternal sera ranged from 15 to 580 ng/g lipid, and the concentrations found in fetal samples ranged from 14 to 460 ng/g lipid. Individual fetal blood concentrations did not differ from the corresponding maternal concentrations, indicating that measurement of maternal PBDE blood levels is useful in predicting fetal exposure; similarly, other reports have shown a high correlation between PBDE in mother's milk and fetal exposure. In accord with reports on other biologic samples, the tetrabrominated PBDE congener BDE-47 accounted for 53-64% of total PBDEs in the serum. The concentrations of PBDEs found in maternal and fetal serum samples were 20-106-fold higher than the levels reported previously in a similar population of Swedish mothers and infants. In this small sample, there was no apparent correlation between serum PBDEs and thyroid hormone concentrations. Our study shows that human fetuses in the United States may be exposed to relatively high levels of PBDEs. Further investigation is required to determine if these levels are specific to central Indiana and to assess the toxic potential of these exposure levels.
Smoking Drivers: Standard or Optional?-Reply
Authors: Joseph R. DiFranza
Journal: JAMA (1987)

In Reply.—  I agree with Dr West that the inclusion of cigarette lighters and ashtrays as standard equipment in vehicles is an example of the tacit approval that our society gives smoking. Whether removing them represents good preventive medicine is debatable. Smokers have 50% more traffic accidents than nonsmokers, in part because they are distracted while lighting and manipulating their cigarettes. 1 Making it more difficult to smoke while driving might result in more accidents. Similarly, eliminating ashtrays from vehicles could increase the number of fires caused by cigarettes thrown from vehicles. For these reasons, it seems that a ban on smoking while driving would have to precede the elimination of lighters and ashtrays.  Still, I share Dr West's concern that smoking has come to be accepted as normal in our society. One would not expect that a disease that causes one out of four deaths would be treated with
Complete recovery in plasma of enzymes lost from the heart after permanent coronary artery occlusion in the dog.
Authors: W T Hermens, F H van der Veen, G M Willems, M L Mullers-Boumans, A Schrijvers-van Schendel, R S Reneman
Journal: Circulation (1990)

Plasma activities of creatine kinase (CK) and alpha-hydroxybutyrate dehydrogenase (HBD) were measured after permanent coronary artery occlusion in the dog. Cumulative release of enzymes in plasma was calculated from these data by using a previously validated two-compartment model for circulating enzymes. Regional myocardial ischemia was measured by injection of radiolabeled microspheres. After 48 hours, the dogs were killed, and a detailed map of left ventricular enzyme activity was obtained from 108 tissue samples. Cumulative release into plasma of CK and HBD was 96 +/- 20% and 112 +/- 26%, respectively, of the total activities depleted from the heart (mean +/- SD, n = 11). The scatter in these values is inherent to the calculations, and it is concluded that both enzymes are recovered completely in plasma and, thus, can be used as quantitative markers of injury. Discrepancies between this result and earlier reports on the recovery of CK are only partly apparent and can be explained partly by underestimation of the elimination rate of CK from plasma, irregardless of tissue edema and incomplete extraction of enzyme activity from tissue.
Effect of regional ischemia on the left ventricular end-systolic pressure-volume relationship of isolated canine hearts.
Authors: K Sunagawa, W L Maughan, K Sagawa
Journal: Circulation Research (1983)

We studied the effects of regional ischemia on the left ventricular isovolumic end-systolic pressure-volume relationship (ESPVR) in six excised, blood-perfused canine ventricles. We created different extents of regional ischemia by ligating various branches of the coronary arteries while keeping the coronary arterial pressure constant (80 mm Hg). The extent of regional ischemia (Rm) relative to the total mass of the left ventricular myocardium was determined by regional myocardial blood flow measured by the radioactive microsphere technique. With regional ischemia, the ESPVR shifted rightward without significant change in slope in the physiologic end-systolic pressure range. In the subphysiological end-systolic pressure range, however, its slope became lower than control. In order to quantify the degree of the rightward shift, we measured the extrapolated volume axis intercept (Vo) by fitting a straight line to the ESPVR in the physiological range under control and ischemic conditions. The shift in Vo (delta Vo) associated with ischemia was linearly correlated with Rm (delta Vo = 50.7Rm-0.6, n = 28, r = 0.944, P less than 0.001). We conclude that the major effect of acute regional ischemia on the ESPVR in the physiological pressure range is a parallel rightward shift. This forms a striking contrast to the effect of global ischemia (under which only the slope is affected without a substantial change in Vo).
Is There Tension in Hypertension?
Authors: Raz Gross
Journal: JAMA (1994)

To the Editor.  —The interesting study by Dr Markovitz and colleagues 1 about psychological predictors of hypertension and the accompanying Editorial 2 shed extra light on the pathophysiological role and prognostic importance of psychological factors in organic diseases. 3,4 However, one must question the criteria for hypertension used by the authors: (1) systolic blood pressure of 160 mm Hg or higher, diastolic blood pressure of 95 mm Hg or higher, or both; and (2) the use of antihypertensive medications. 1   I get the impression that a single blood pressure measurement satisfied the investigators. The recent report of the Joint National Committee on Detection, Evaluation, and Treatment on High Blood Pressure states that hypertension should not be diagnosed on the basis of a single measurement and requires at least three elevated readings during 1 to several weeks (unless systolic blood pressure is 210 mm Hg or higher and/or diastolic blood pressure
The Use of Computed Body Tomography in Malignant Melanoma
Authors: Irene Kostrubiak, Nancy O. Whitley, Joseph Aisner, Pamela Goose, Russell R. DeLuca, Mukund S. Didolkar, E. George Elias
Journal: JAMA (1988)

MALIGNANT melanoma has no predictable clinical behavior. The Breslow depth and Clark's level of invasion are important prognostic factors, but their prognostic values are overshadowed by the presence of regional lymph node metastasis (stage III disease).<sup>1</sup>In patients with stage III disease, the number and size of lymph nodes involved are prognostic indicators. For patients at high risk of recurrence, various therapeutic trials have tested surgery and radiation therapy, surgery and regional perfusion therapy, and immunotherapy and various chemotherapeutic agents, alone and in combinations. These studies have helped to define prognostic factors, but have had little impact on disease-free or overall survival. Response rates for treatment of advanced disease have varied considerably and may be related to sites and bulk of disease. Assessment of the amount and the extent of disease is necessary for evaluation of any therapy. Computed tomography (CT) has proved accurate in evaluating adenopathy,<sup>2-4</sup>but
Aspirin Use and Cardiovascular Disease in Women
Authors: Barbara P. Yawn
Journal: JAMA (1992)

<h3>To the Editor.</h3> —Manson et al<sup>1</sup>have used their large data set on registered nurses to provide some interesting information regarding the use of aspirin and the risk of future MI. While they have accounted for confounding factors in their analysis, I believe an important one did not receive sufficient attention. Unlike randomized clinical trials, these women chose their dose of aspirin. More in-depth information on why these women chose various levels of long-term drug self-treatment may provide data on risk factors associated with MIs in women. Some of these factors may be related to the apparent lack of protection of higher doses of aspirin in preventing first MIs. While such in-depth retrospective analysis of data is not always possible, future studies may want to consider the implications of increased musculoskeletal discomfort and more severe or more frequent headaches requiring higher weekly doses of aspirin. Could these represent