tbuckley/cabot-search huggingface dataset:
Making Sense of MEK1 Mutations in Intrinsic and Acquired BRAF Inhibitor Resistance
Authors: Kim H. T. Paraiso, Keiran S. M. Smalley
Journal: Cancer Discovery (2012)

Abstract In this issue of Cancer Discovery, Shi and colleagues add further insight into the role of exon 3 MEK1 mutations in BRAF inhibitor resistance by demonstrating the presence of P124SMEK1 and I111SMEK1 mutations concurrently with V600E/KBRAF mutations at baseline in 16% of melanoma specimens. Although the presence of P124SMEK1 or I111SMEK1 mutations did not predict for resistance, and these alleles were not selected for upon BRAF inhibition, other exon 3 MEK1 mutations, such as C121S, did convey resistance, suggesting a role for defined exon 3 MEK1 mutations in acquired BRAF inhibitor resistance. Cancer Discov; 2(5); 390–2. ©2012 AACR. Commentary on Shi et al., p. 414.
High prevalence of IgG and IgA antibodies to 19‐kDa <i>Helicobacter pylori</i>‐associated lipoprotein in chronic urticaria
Authors: N. Bakos, B. Fekete, Z. Prohászka, G. Füst, L. Kalabay
Journal: Allergy (2003)

Background: Chronic urticaria has been described in patients with Helicobacter pylori infection. We studied the titer of IgG and IgA type antibodies against H. pylori in patients with and without urticaria of unknown etiology. We also investigated the prevalence of antibodies against H. pylori ‐associated lipoprotein 20 (lpp20) in patients with and without chronic urticaria. Methods: The concentration of anti‐ H. pylori antibodies (IgG and IgA) was determined by the RIDA test. The level of anti‐lpp20 antibodies was determined by Western blot using various H. pylori antigens (from 19 to 120 kDa). Results: Patients with chronic urticaria and H. pylori infection (subgroup 1, n = 33) had high IgG and IgA titers whereas all patients with chronic urticaria and without H. pylori infection (subgroup 2, n = 23) were seronegative ( P = 0.0128 for IgG and P = 0.003 for IgA). Titers in subgroup 1 did not differ significantly from a control group ( n = 33) with severe H. pylori ‐associated gastritis without urticaria. The prevalence of the anti‐lpp20 antibodies was significantly higher in subgroup 1 compared to the control group (93.9 vs 21.2%, P &lt; 0.0001 for IgG, and 46.1 vs 6.3%, P &lt; 0.0029 for IgA). Conclusions: We suggest that IgG and IgA antibodies to H. pylori ‐associated lpp20 may play role in the pathogenesis of chronic urticaria.
A hydrostatic weighing method using total lung capacity and a small tank.
Authors: J G Warner, R Yeater, L Sherwood, K Weber
Journal: British Journal of Sports Medicine (1986)

The purpose of this study was to establish the validity and reliability of a hydrostatic weighing method using total lung capacity (measuring vital capacity with a respirometer at the time of weighing) the prone position, and a small oblong tank. The validity of the method was established by comparing the TLC prone (tank) method against three hydrostatic weighing methods administered in a pool. The three methods included residual volume seated, TLC seated and TLC prone. Eighty male and female subjects were underwater weighed using each of the four methods. Validity coefficients for per cent body fat between the TLC prone (tank) method and the RV seated (pool), TLC seated (pool) and TLC prone (pool) methods were .98, .99 and .99, respectively. A randomised complete block ANOVA found significant differences between the RV seated (pool) method and each of the three TLC methods with respect to both body density and per cent body fat. The differences were negligible with respect to HW error. Reliability of the TLC prone (tank) method was established by weighing twenty subjects three different times with ten-minute time intervals between testing. Multiple correlations yielded reliability coefficients for body density and per cent body fat values of .99 and .99, respectively. It was concluded that the TLC prone (tank) method is valid, reliable and a favourable method of hydrostatic weighing.
A randomised placebo controlled study with ondansetron in patients undergoing fractionated radiotherapy
Authors: L. Franzén, J. Nyman, H. Hagberg, M. Jakobsson, B. Sorbe, A.L. Nyth, H. Lomberg, R. Henriksson
Journal: Annals of Oncology (1996)

There are few randomised studies comparing anti-emetic drugs for the prevention of nausea and vomiting in patients treated with fractionated radiotherapy. The aim of the study was to compare the anti-emetic efficacy of 8 mg dose ondansetron twice a day with placebo.One hundred eleven patients who were to commence a course of 10 or more daily fractionated radiotherapy including the abdomen were included in the study. The patients recorded daily emesis, nausea and bowel habit and graded weekly symptoms of nausea, vomiting, diarrhoea and lack of appetite. The EORTC C30 questionnaire was completed.67% of patients given ondansetron had complete control of emesis compared with 45% of patients with placebo (P < 0.05). The number of emetic episodes recorded on the worst day was 1.4 for the ondansetron group and 3.1 for the placebo group (P < 0.01). Patients given ondansetron had fewer days with emesis and nausea compared with placebo (P < 0.05). The mean sum score of patients weekly grading of symptoms showed that the ondansetron group had less inconvenience than the placebo group (P < 0.05). This difference persisted during the first three weeks, but not thereafter. Similarly, some quality of life measures showed significant differences in favour of the ondansetron group. More patients (n = 13) withdrew due to lack of efficacy in the placebo group compared with patients (n = 8) in the ondansetron group.The present study illustrates that prophylactic anti-emetic administration of ondansetron is effective in preventing nausea and vomiting in patients undergoing fractionated radiotherapy of the abdomen.
A Novel Oncolytic Herpes Simplex Virus that Synergizes with Phosphoinositide 3-kinase/Akt Pathway Inhibitors to Target Glioblastoma Stem Cells
Authors: Ryuichi Kanai, Hiroaki Wakimoto, Robert L. Martuza, Samuel D. Rabkin
Journal: Clinical Cancer Research (2011)

Abstract Purpose: To develop a new oncolytic herpes simplex virus (oHSV) for glioblastoma (GBM) therapy that will be effective in glioblastoma stem cells (GSC), an important and untargeted component of GBM. One approach to enhance oHSV efficacy is by combination with other therapeutic modalities. Experimental Design: MG18L, containing a US3 deletion and an inactivating LacZ insertion in UL39, was constructed for the treatment of brain tumors. Safety was evaluated after intracerebral injection in HSV-susceptible mice. The efficacy of MG18L in human GSCs and glioma cell lines in vitro was compared with other oHSVs, alone or in combination with phosphoinositide-3-kinase (PI3K)/Akt inhibitors (LY294002, triciribine, GDC-0941, and BEZ235). Cytotoxic interactions between MG18L and PI3K/Akt inhibitors were determined using Chou–Talalay analysis. In vivo efficacy studies were conducted using a clinically relevant mouse model of GSC-derived GBM. Results: MG18L was severely neuroattenuated in mice, replicated well in GSCs, and had anti-GBM activity in vivo. PI3K/Akt inhibitors displayed significant but variable antiproliferative activities in GSCs, whereas their combination with MG18L synergized in killing GSCs and glioma cell lines, but not human astrocytes, through enhanced induction of apoptosis. Importantly, synergy was independent of inhibitor sensitivity. In vivo, the combination of MG18L and LY294002 significantly prolonged survival of mice, as compared with either agent alone, achieving 50% long-term survival in GBM-bearing mice. Conclusions: This study establishes a novel therapeutic strategy: oHSV manipulation of critical oncogenic pathways to sensitize cancer cells to molecularly targeted drugs. MG18L is a promising agent for the treatment of GBM, being especially effective when combined with PI3K/Akt pathway–targeted agents. Clin Cancer Res; 17(11); 3686–96. ©2011 AACR.
Communicating With Patients About Chemotherapy Costs
Authors: Mário L. de Lemos
Journal: Journal of Clinical Oncology (2007)

Chemotherapy Costs TO THE EDITOR: Schrage and Hanger provided a very helpful gleam on how medical oncologists viewed their responsibilities in communicating with patients about chemotherapy costs. There are two key issues that can be further elaborated. First, although many may think that they do not usually take cost into account when recommending a treatment, the truth is that we all do, if only subconsciously. Recommendation of a treatment, even when cost is not explicitly discussed, is based on the assumption that there are resources (somehow) to support the delivery of the treatment. To take an extreme theoretical example, would one recommend a treatment that can only be administered in zero gravity, or that would cost $1 billion per treatment course? Probably not, and the patient likely would concur that this is not a realistic option. The second consideration is that a treatment is not usually categorized as simply “works” or “doesn’t work.” More commonly, it works “a little” or “quite well.” Clinical trial design, and regulatory approval, is usually based on proof of the minimal level of clinical improvement. However, this may not be enough when balanced against other factors like treatment costs, burden of disease, toxicity profiles, and so on. Funding agencies, such as the Centers for Medicare & Medicaid Services, define different levels of clinical improvement in global terms, such as “more effective” (improves by a significant, albeit small, margin as compared with established services or medical items) and “as effective but with advantages” (same effect as established services or medical items, but some advantages that some patients will prefer). However, this provides no indication of the true magnitude of benefit relative to the baseline prognosis of the patients. For example, 9 months may mean something different for patients with advanced small-cell lung cancer to those with, say, prostate cancer. Sunstrum et al showed that improvement in survival, tumor response, quality of life, and toxicity would classify a drug as being of “substantial improvement” for the purpose of setting a price by the Canadian Patented Medicine Prices Review Board. What is needed now is to relate the size of improvement in these end points to the baseline prognosis of the patients. Only then can we truly discuss how to communicate chemotherapy costs with the patients—and to the society at large.
The postdialytic plasma cyclic guanosine 3'
Authors: F Lauster, H J Fülle, R Gerzer, H Schiffl
Journal: Journal of the American Society of Nephrology (1992)

The postdialytic plasma level of cGMP, a marker for the release of atrial natriuretic peptide (ANP) in humans, is closely related to hypervolemia in chronic hemodialysis patients. In order to test the practicability of routine postdialysis cGMP determination for the detection of fluid overload, ANP and cGMP levels in the total hemodialysis population of 81 patients were measured with blood samples drawn immediately after hemodialysis. Twenty-three patients had a cGMP level of more than 20 pmol/mL. In 13 of these, pulmonary congestion was present on the chest roentgenogram. Two of these patients refused a gradual reduction of their dry body weight. In the remaining 21 patients, the weight reduction was associated with a decrease in cGMP levels in all cases and with a decrease in ANP levels in all but two cases. Fourteen of the 21 patients reached a cGMP level below 20 pmol/mL after weight reduction, and at that time, none of these showed signs of pulmonary congestion on chest x-ray. All seven patients, whose cGMP levels remained above 20 pmol/mL despite the reduction, had documented heart disease with impairment of left ventricular function. These results suggest that the plasma cGMP level after hemodialysis is more apt for the determination of dry body weight than is ANP or a chest roentgenogram.
Long-Term Effects of a Diabetes and Pregnancy Program
Authors: Denice S. Feig, Barbara Cleave, George Tomlinson
Journal: Diabetes Care (2006)

OBJECTIVE—To determine whether women with pregestational diabetes obtained long-term benefits from an intensive diabetes management program during pregnancy. RESEARCH DESIGN AND METHODS—Women with pregestational diabetes who had attended an intensive diabetes management program in pregnancy between 1991 and 1999 were interviewed regarding diabetes self-management behaviors and current glycemic control. A retrospective chart review was done to obtain information on self-management behaviors at entry to the program and at delivery and compared with the present. RESULTS—Comparing entry to the program to delivery, all diabetes self-management behaviors improved significantly, including frequency of self-monitoring of blood glucose, frequency of insulin injections, and frequency and complexity of insulin dose adjustment (IDA). HbA1c (A1C) also improved significantly from entry to delivery (mean 0.073–0.060) (P &amp;lt; 0.0001). Comparing entry to the present, frequency of insulin injections improved significantly (P = 0.0004), frequency of IDA improved significantly (P = 0.004), and complexity of IDA improved significantly (P = 0.0032). However, there was no significant change in frequency of self-monitoring of blood glucose (P = 0.766) from before pregnancy to the present, and A1C significantly worsened by 0.015 (P &amp;lt; 0.0001, 95% CI 0.009–0.021) from entry to the program to the present. CONCLUSIONS—Women participating in an intensive diabetes management program during pregnancy improve significantly from entry to delivery in diabetes self-management behaviors and glycemic control and, in the long term, retain some of these behaviors and knowledge. However, this is not reflected in an improved A1C level. This may be explained by the loss of contact with the diabetes care team and/or the discontinuation of frequent self-monitoring of blood glucose—a critical behavior necessary for achieving optimal glycemic control.
DNA Repair Capacity in Peripheral Lymphocytes Predicts Survival of Patients With Non–Small-Cell Lung Cancer Treated With First-Line Platinum-Based Chemotherapy
Authors: Li-E Wang, Ming Yin, Qiong Dong, David J. Stewart, Kelly W. Merriman, Christopher I. Amos, Margaret R. Spitz, Qingyi Wei
Journal: Journal of Clinical Oncology (2011)

Purpose Platinum-based regimens are the standard chemotherapy for patients with advanced non–small-cell lung cancer (NSCLC). DNA repair capacity (DRC) in tumor cells plays an important role in resistance to platinum-based drugs. We have previously reported that efficient DRC, as assessed by an in vitro lymphocyte-based assay, was a determinant of poor survival in patients with NSCLC in a relatively small data set. In this larger independent study of 591 patients with NSCLC, we further evaluated whether DRC in peripheral lymphocytes predicts survival of patients with NSCLC who receive platinum-based chemotherapy. Patients and Methods All patients were recruited at The University of Texas MD Anderson Cancer Center and donated blood samples before the start of any chemotherapy. We measured DRC in cultured T lymphocytes by using the host-cell reactivation assay, and we assessed associations between DRC in peripheral lymphocytes and survival of patients with NSCLC who were treated with first-line platinum-based chemotherapy. Results We found an inverse association between DRC in peripheral lymphocytes and patient survival. Compared with patients in the low tertile of DRC, patients with NSCLC in the high tertile of DRC had significantly worse overall and 3-year survival (adjusted hazard ratio [HR], 1.33; 95% CI, 1.04 to 1.71; P = .023; and HR, 1.35; 95% CI, 1.04 to 1.76; P = .025, respectively). This trend was more pronounced in patients with early-stage tumors, adenocarcinoma, or squamous cell carcinoma. Conclusion We confirmed that DRC in peripheral lymphocytes is an independent predictor of survival for patients with NSCLC treated with platinum-based chemotherapy.
British Digestive Foundation
Authors: M. J G Farthing
Journal: Gut (1990)

cence of 5-aminosalicylate decreased, suggesting a chemical reaction between 5-aminosalicylate and hypochlorite.Activated neutrophils also produced a peroxidasegenerated oxygen metabolite which reacted with 5-aminosalicylate to produce a non- fluorescent product.6We therefore propose that 5-aminosalicylate acts as a hypochlorite scavenger and also as a hypochlorite indicator.Identification and detection of neutrophil derived metabolites of 5-aminosalicylate in the faecal stream of patients receiving 5-aminosalicylate would thus provide evidence for the production of hypochlorite in the inflamed bowel and may also be useful for monitoring the progress of the disease.
Prognostic value of N-terminal pro-brain natriuretic peptide in elderly people with acute myocardial infarction: prospective observational study
Authors: L Lorgis, M Zeller, G Dentan, P Sicard, P Buffet, I L'Huillier, J C Beer, M Vincent-Martin, H Makki, P Gambert, Y Cottin
Journal: BMJ (2009)

<b>Objective</b> To examine the influence of age on the predictive value of N-terminal pro-brain natriuretic (NT-proBNP) peptide assay in acute myocardial infarction. <b>Design</b> Prospective observational study. <b>Setting</b> All intensive care units in one French region. <b>Participants</b> 3291 consecutive patients admitted for an acute myocardial infarction, from the RICO survey (a French regional survey for acute myocardial infarction). <b>Main outcome measure</b> Cardiovascular death at 1 year. <b>Results</b> Among the 3291 participants, mean age was 68 (SD 14) years and 2356 (72%) were men. In the study population, the median NT-proBNP concentration was 1053 (interquartile range 300-3472) pg/ml. Median values for age quarters 1 to 4 were 367 (119-1050), 696 (201-1950), 1536 (534-4146), and 3774 (1168-9724) pg/ml (P&lt;0.001). A multiple linear regression analysis was done to determine the factors associated with the pro-peptide concentrations in the overall population. NT-proBNP was mainly associated with age, left ventricular ejection fraction, creatinine clearance, female sex, hypertension, diabetes, and anterior wall infarction. At one year's follow-up, 384 (12%) patients had died from all causes and 372 (11%) from cardiovascular causes. In multivariate analysis, NT-proBNP remained strongly associated with the outcome, beyond traditional risk factors including creatinine clearance and left ventricular ejection fraction, in each age group except in the youngest one (&lt;54 years) (P=0.29). The addition of NT-proBNP significantly improved the performance of the statistical model in the overall study population (−2log likelihood 3179.58 <i>v</i> 3099.74, P&lt;0.001) and in each age quarter including the upper one (1523.52 <i>v</i> 1495.01, P&lt;0.001).The independent discriminative value of NT-proBNP compared with the GRACE score was tested by a diagonal stratification using the median value of the GRACE score and NT-proBNP in older patients (upper quarter). Such stratification strikingly identified a high risk group—patients from the higher NT-proBNP group and with a high risk score—characterised by a risk of death of almost 50% at one year. <b>Conclusions</b> In this large contemporary non-selected cohort of patients with myocardial infarction, NT-proBNP concentration had incremental prognostic value even in the oldest patients, above and beyond the GRACE risk score and traditional biomarkers after acute myocardial infarction. These data further support the potential interest of clinical trials specifically assessing NT-proBNP measurement as a guide to current treatment strategies, as well as novel strategies, in older patients with acute myocardial infarction.
Intravenous administration of the natriuretic peptide urodilatin at low doses during coronary reperfusion limits infarct size in anesthetized pigs
Authors: F Padilla
Journal: Cardiovascular Research (2001)

Objective: It has been shown that cGMP content is reduced in post-ischemic myocardium, and that stimulation of cGMP synthesis prevents cardiomyocyte hypercontracture and cell death in vitro. This study was aimed at determining whether administration of the natriuretic peptide urodilatin (URO) at the time of reperfusion could limit myocardial cell death secondary to transient coronary occlusion. Methods: The relation between cGMP content in reperfused myocardium and the extent of cell death was investigated in isolated rat hearts (n=62) receiving different URO concentrations during initial reperfusion. The dose of intravenous URO necessary to obtain the targeted increase in cGMP in reperfused myocardium was investigated in ten pigs submitted to transient coronary occlusion (CO), and the effect of two selected doses of URO on infarct size was investigated in 22 pigs. Results: cGMP was severely reduced in post-ischemic rat hearts. Addition of 0.01 μM URO during the first 15 min of reperfusion had no effect on myocardial cGMP content, functional recovery or LDH release in hearts submitted to 40 or 60 min of ischemia. At 0.05 μM, URO increased myocardial cGMP to 111% of values in normoxic hearts, improved functional recovery (P=0.01) and reduced peak LDH released by 40% (P=0.02). The beneficial effect of urodilatin was abolished by ANP receptor inhibition. At 1 μM, URO increased cGMP in reperfused myocardium to 363% of normoxic controls and had no beneficial effect. In pigs allocated to 47 min of CO and 5 min of reperfusion, cGMP was markedly reduced in reperfused myocardium. Intravenous URO at 10 ng/kg per min during the first 25 min of reperfusion normalized myocardial cGMP after 5 min of reflow (95% of control myocardium), and reduced infarct size by 40% (P=0.04). At 50 ng/kg per min, urodilatin increased myocardial cGMP in reperfused myocardium to 335% of control myocardium and failed to significantly reduce infarct size (46 vs. 66%, P=0.125). None of these doses had detectable hemodynamic effects. Conclusions: Intravenous low-dose URO at the time of reperfusion normalizes myocardial cGMP and limits necrosis. Large doses of URO increasing myocardial cGMP well over normal values may lack this beneficial effect.
Cytomegalovirus Esophagitis in Patients with AIDS
Authors: C. Mel Wilcox
Journal: Annals of Internal Medicine (1990)

To examine the clinical presentation, endoscopic features, laboratory diagnosis, and outcome of cytomegalovirus esophagitis in patients with the acquired immunodeficiency syndrome (AIDS).Retrospective review of endoscopy records and esophageal biopsy material from patients with AIDS during the 24-month period from 1986 to 1988.Urban medical center, central receiving county hospital.Sixteen inpatients or outpatients seen by gastroenterology consultants at a single hospital.Endoscopy with multiple mucosal biopsies and viral culture of all esophageal mucosal lesions. Proven or suspected cyclomegalovirus disease was verified in patients using immunohistochemical antibody staining of mucosal biopsy specimens.Odynophagia was the most prominent esophageal symptom, seen in 14 of 16 patients with cytomegalovirus esophagitis confirmed by immunohistochemical staining. Ulcerations of the esophagus were identified in all but 1 patient and typically appeared as large, solitary, shallow lesions. Routine hematoxylin and eosin staining of esophageal mucosal and submucosal specimens showed intranuclear inclusions in all patients, whereas cytomegalovirus culture was positive in only 8 of 14 patients. Cytomegalovirus esophagitis was associated with a poor long-term prognosis.Cytomegalovirus esophagitis in patients with AIDS is a well-defined entity with characteristic clinical symptoms and endoscopic findings, as well as histopathologic abnormalities.