tbuckley/cabot-search huggingface dataset:
Open label evaluation of ECG in patients with chronic lymphocytic leukemia (CLL) receiving ibrutinib monotherapy.
Authors: David Loury, Juthamas Sukbuntherng, Fong Clow, Danelle Frances James, Lori A. Kunkel
Journal: Journal of Clinical Oncology (2013)

7057 Background: Ibrutinib is a first-in-class selective small molecule inhibitor of Bruton’s tyrosine kinase (BTK) under development for the treatment of B-cell malignancies. The aim of this study was to characterize the possible effect of ibrutinib on ECG intervals in patients with CLL. Methods: A Phase Ib/II study (PCYC-1102-CA) of oral dosing of ibrutinib was conducted in patients with treatment-naïve (TN) or relapsed/refractory (R/R) CLL. Patients were enrolled into 6 groups treated with ibrutinib at 420 mg/day or 840 mg/day (n=132). One cycle was 28 days. ECG data were obtained along with the blood samples during Cycle 1. Additional ECG measurement was performed on Day 28 of Cycles 3, 6, 12, 18, and 24 and at the end of study. An interim ECG analysis was performed using the data from R/R patients at 420 mg/day (n=18), TN patients at 420 mg/day (n=20), and R/R patients at 840 mg/day (n=29). For ECG analysis, the pre-dose values on Cycle 1 Day 1 were used as the baseline for each post-dose time-point for all ECG parameters. The QT and RR values for each beat were used for both Fridericia's correction (QTcF) and Bazett's correction (QTcB). The relationship between plasma concentrations of ibrutinib and ΔQTcF (change-from-baseline QTcF) was investigated by a linear mixed-effects modeling approach. Results: Median ages for R/R 420 mg, TN 420 mg, and R/R 840 mg dose groups were 59, 71, and 62 years, respectively. There was no clinically significant change in heart rate (HR) relative to baseline observed in either dose groups or between R/R and TN populations. There was no evidence of PR interval prolongation above 240 msec. There were no treatment-related effects on QRS duration in any of the Treatment Groups. A total of 467 ΔQTcF measurements were included in the analysis. The population mean of baseline QTcF values was 402.0 msec with a SD of 15.2 msec. A concentration-dependent effect of ibrutinib on QTcF was not identified. Conclusions: Interim analyses of the data indicated that there was no evidence of clinically significant ECG findings or QTc prolongation with continuous daily dosing of ibrutinib at either the 420 mg or 840 mg dose in patients with TN or R/R CLL. Clinical trial information: NCT01105247.
Abstract 15888: N-3 Polyunsaturated Fatty Acids in Erythrocyte Membranes and Risk of Sudden Cardiac Death in Primary and Secondary Prevention
Authors: Stephanie E Chiuve, Nancy R Cook, Martin J Vandenburgh, Eric B Rimm, JoAnn E Manson, Christine M Albert
Journal: Circulation (2015)

Introduction: Long-chain n-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-arrhythmic effects in experimental studies and blood levels of EPA + DHA, an objective marker of intake, have been associated with lower risk of sudden cardiac death (SCD) in healthy populations. However, data from observational studies and clinical trials of n-3 PUFAs in secondary prevention have been mixed. Methods: We conducted a nested, case-control study among individuals from 6 prospective cohort studies. RBC levels of α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), and DHA were measured in 442 cases of SCD and 852 controls matched on age, sex, race, smoking status, fasting status and prevalent and incident CVD using risk-set sampling. The Omega-3 Index was estimated as EPA + DHA. Multivariable conditional logistic regression was used to estimate the relative risk (RR) separately in each cohort. The RRs were combined using random effect meta-analyses and stratified by presence of absence of known CVD prior to SCD. Results: In this population, the mean age was 64 years, 51% were women and 41% had prior CVD. Higher EPA and DHA levels, as summarized by the Omega-3 Index, were associated with lower risk of SCD in the entire population (Table). Compared to the lowest quintile, the RR in the highest quintile of the Omega-3 Index was 0.40 (95%CI, 0.21-0.77; P, trend= 0.04). When stratified by history of prior CVD, this association was restricted to individuals without prior CVD (Table, P, trend = 0.03). Neither DPA nor ALA was associated with risk of SCD in those with or without CVD. Conclusions: In this prospective nested, case-control study, the inverse association between long-chain n-3 PUFAs and SCD was limited to individuals without prior CVD. These data suggest that the utility of n-3 PUFAs as markers of SCD and/or as preventative dietary supplements may be greater in a primary prevention population.
The Natural Course of Unruptured Cerebral Aneurysms in a Japanese Cohort
Journal: New England Journal of Medicine (2012)

From January 2001 through April 2004, we enrolled patients with newly identified, unruptured cerebral aneurysms in Japan. Information on the rupture of aneurysms, deaths, and the results of periodic follow-up examinations were recorded. We included 5720 patients 20 years of age or older (mean age, 62.5 years; 68% women) who had saccular aneurysms that were 3 mm or more in the largest dimension and who initially presented with no more than a slight disability.
The first 48 hours of investigation and intervention of an outbreak of legionellosis in the Netherlands
Authors: J. E. van Steenbergen, F. A.N. Slijkerman, P Speelman
Journal: Eurosurveillance (1999)

The Westfriese Flora is a one week flower show held every year in Bovenkarspel, in the north west of the Netherlands, with agricultural and consumer demonstrations on the same grounds. This year’s show, held from 19 to 28 February, attracted 80 000 visito
Molecular profiling of uveal melanoma patients.
Authors: Zoran Gatalica, Kathleen D Danenberg, Matthew Jerome McGinniss, Anatole Ghazalpour, Ryan P Bender, Raheela Ashfaq, David Arguello, Brian Wright, Nicole Griffin, Gargi D. Basu
Journal: Journal of Clinical Oncology (2012)

10630 Background: Although uveal melanoma represents only 5% of all melanomas, it is the most common primary intraocular malignancy of the adult eye. Approximately 50% of patients will develop metastases which are resistant to medical interventions. There is a great need for improved therapy as the prognosis is poor for advanced stages. Our study was undertaken to investigate the presence of novel therapeutic targets. Methods: We analyzed 49 uveal melanoma patients with immunohistochemistry for 16 markers including cKIT, PDGFR, cMET, PTEN and IGF1R. Further, microarray analysis was performed on 29 samples using the Illumina platform. We also investigated amplification of EGFR and mutational analysis of cKIT, BRAF, KRAS and NRAS on a smaller patient subset. Results: Overexpression of KIT at the protein and RNA level was 74% (28 out of 38) and 45% (13 out of 29), respectively. Expression of cKIT did not correlate with gain-of-function cKIT mutations in any of the 34 samples tested. In our study, MET was overexpressed in 15 out of 17 cases at the RNA level and IGF1R was high in 4 out of 6 patients indicating poor prognosis. PTEN expression by IHC was present in 90% (36 out of 40) patients indicating the PI3K pathway is not activated in the majority of uveal melanoma patients. BRAF was wildtype in all 42 patients tested. Similarly, no KRAS or NRAS mutations were detected. Protein and RNA expression of PDGFR were low in our patients. MGMT was lost in 16 out of 40 patients at the protein level and 10 out of 29 patients at the RNA level. EGFR expression, copy number and protein levels were low in the patients tested. Conclusions: Our data on cKIT suggests that it is a promising target in uveal melanoma. Low expression of MGMT in about a third of our patients may indicate the likelihood of favorable response to dacarbazine and temozolomide. There are currently several clinical trials investigating various cKIT inhibitors, as well as temozolomide in advanced uveal melanoma patients. Our findings highlight the importance of molecular profiling uveal melanoma patients.
Selective Toxicity of Investigational Ixazomib for Human Leukemia Cells Expressing Mutant Cytoplasmic NPM1: Role of Reactive Oxygen Species
Authors: Jacqueline S. Garcia, Min Huang, Bruno C. Medeiros, Beverly S. Mitchell
Journal: Clinical Cancer Research (2015)

Abstract Purpose: This study was performed to determine whether the investigational proteasome inhibitor ixazomib demonstrated selective antineoplastic activity against acute myelogenous leukemia cells expressing a mutated nucleophosmin-1 gene and to gain a better understanding of its mechanisms of action. Experimental Design: The cytotoxic effects of ixazomib treatment were analyzed in human acute myelogenous leukemia (AML) cell lines and primary AML samples expressing wild-type or mutated NPM1 (NPMc+). The potential roles of oxidative stress in mediating cytotoxic activity were determined using flow cytometry, enzyme-based assays, and Western blots. Results: Apoptosis induced by ixazomib was abrogated by knockdown of NPM1/NPMc+ expression using an inducible shRNA construct and enhanced by NPMc+ overexpression. Cytotoxicity was associated with superoxide generation and was reduced by the addition of the antioxidant N-acetylcysteine. AML cells expressing NPMc+ had significantly reduced levels of intracellular glutathione and NADPH associated with reduced antioxidant responses to drug treatment. Treatment of 3 patients with relapsed NPMc+ AML resulted in an antileukemic effect in 1 patient as demonstrated by a marked reduction of leukemic blasts in the peripheral blood. Efficacy was associated with superoxide generation, reduced glutathione levels, and reduced mRNA and protein expression of antioxidant effectors in responding cells. Conclusions: In this study, a direct association was observed between NPMc+ expression in AML, reduced antioxidant responses, and enhanced sensitivity to an oral proteasome inhibitor that induces oxidative stress. These data suggest that intracellular determinants of antioxidant responses may be good predictors of therapeutic response to ixazomib. Clin Cancer Res; 22(8); 1978–88. ©2015 AACR.
Targeted plasma proteome profiling for early prediction of chemotherapy response and toxicity in colorectal cancer (CRC)
Authors: W. Chua, S. Randall, M. J. McKay, L. Horvath, S. J. Clarke, M. P. Molloy
Journal: Journal of Clinical Oncology (2009)

e15063 Background: Accurate predictors of chemotherapy response and toxicity in CRC are required to improve the safety, efficacy and costs of treatment. Plasma proteomic profiling using multiple reaction monitoring mass spectrometry (MRM-MS) couples assay multiplexing with high specificity to determine levels of pre-selected biomarker proteins. Our aims were to investigate the utility of plasma proteomic profiling using MRM-MS for predicting: (1) early haematological toxicity, (2) response and (3) survival for patients receiving chemotherapy for CRC. Methods: Patients with locally advanced and metastatic CRC receiving chemotherapy were enrolled. Plasma collection was performed pre-chemotherapy, at day 3 and day 15 of treatment. Toxicity assessments (NCI Criteria v3.0) were prospectively collected for all patients and treatment response (RECIST) assessed for patients with metastatic disease. MRM-MS assays were designed for 39 peptides representing 31 liver derived plasma proteins with reported roles in inflammation and/or cancer. Statistical analysis was performed using the 2-sample t-test to assess statistically significant fold change differences (p&lt;0.05) between sample days for: (1) patients with absence or presence of ≥ Grade 2 neutropenia after two cycles and (2) responders (CR and PR) versus non-responders (SD or PD). Results: Plasma proteomic profiling for 39 peptides was performed for 17 patients. The greatest change in protein levels was observed between Day 3 and 15 with 9% of proteins showing a 1.5 fold or greater change with some proteins showing a ≥ 200-fold change in level. Three proteins (clusterin, paraoxanse and apolipoprotein A1) were significantly different in the group analysed for neutropenia and four proteins (kininogen I, serum paraoxonase/ arylestease 1, apolipoprotein A-1 and complement C4a) were significantly different in the group analysed according to response. Survival analysis was not performed due to the short follow up. Discussion: Our results are encouraging for the use of a robust mass spectrometry technique for early prediction of neutropenia and chemotherapeutic response in CRC. No significant financial relationships to disclose.
Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies
Authors: Geoffrey M. Matthews, Parinaz Mehdipour, Leonie A. Cluse, Katrina J. Falkenberg, Eric Wang, Mareike Roth, Fabio Santoro, Eva Vidacs, Kym Stanley, Colin M. House, James R. Rusche, Christopher R. Vakoc, Johannes Zuber, Saverio Minucci, Ricky W. Johnstone
Journal: Blood (2015)
Autologous peripheral blood progenitor cell transplantation mobilized with high-dose cytarabine in acute myeloid leukemia in first complete remission
Authors: S. Pavlovsky, I. Fernández, G. Milone, J. Martinez Rolón, C. Corrado, P. Desmery, C. Dignani, M. Michelet, M. Juni
Journal: Annals of Oncology (1998)
Nucleotide sequence comparison of the rp49 gene region between Drosophila subobscura and D. melanogaster.
Authors: M Aguadé
Journal: Molecular Biology and Evolution (1988)

A 1.6-kb fragment encompassing the rp49 gene, which codes for a ribosomal protein, has been cloned and sequenced in Drosophila subobscura. The rp49 coding region has accumulated 46 nucleotide differences out of 402 bp since D. subobscura diverged from D. melanogaster. Forty-three percent of the effectively silent sites have changed since both species diverged. Both silent and replacement differences are distributed at random between the two exons of the gene. The frequency of silent differences in exons does not differ from that observed in the 5' leader sequence and in the intron. The frequency of silent differences in exon and intron sites is much greater than the number of amino acid replacement differences. This observation indicates strong purifying selection against amino acid replacements.
Combined Angiotensin Receptor Modulation in the Management of Cardio-Metabolic Disorders
Authors: Ludovit Paulis, Sébastien Foulquier, Pawel Namsolleck, Chiara Recarti, Ulrike Muscha Steckelings, Thomas Unger
Journal: Drugs (2015)

Cardiovascular and metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or obesity are linked with chronic low-grade inflammation and dysregulation of the renin–angiotensin system (RAS). Consequently, RAS inhibition by ACE inhibitors or angiotensin AT1 receptor (AT1R) blockers is the evidence-based standard for cardiovascular risk reduction in high-risk patients, including diabetics with albuminuria. In addition, RAS inhibition reduces the new onset of diabetes mellitus. Yet, the high and increasing prevalence of metabolic disorders, and the high residual risk even in properly treated patients, calls for additional means of pharmacological intervention. In the past decade, the stimulation of the angiotensin AT2 receptor (AT2R) has been shown to reduce inflammation, improve cardiac and vascular remodeling, enhance insulin sensitivity and increase adiponectin production. Therefore, a concept of dual AT1R/AT2R modulation emerges as a putative means for risk reduction in cardio-metabolic diseases. The approach employing simultaneous RAS blockade (AT1R) and RAS stimulation (AT2R) is distinct from previous attempts of double intervention in the RAS by dual blockade. Dual blockade abolishes the AT1R-linked RAS almost completely with subsequent risk of hypotension and hypotension-related events, i.e. syncope or renal dysfunction. Such complications might be especially prominent in patients with renal impairment or patients with isolated systolic hypertension and normal-to-low diastolic blood pressure values. In contrast to dual RAS blockade, the add-on of AT2R stimulation does not exert significant blood pressure effects, but it may complement and enhance the anti-inflammatory and antifibrotic/de-stiffening effects of the AT1R blockade and improve the metabolic profile. Further studies will have to investigate these putative effects in particular for settings in which blood pressure reduction is not primarily desired.
Initial Surgery and Survival in Stage IV Breast Cancer in the United States, 1988-2011
Authors: Alexandra Thomas, Seema A. Khan, Elizabeth A. Chrischilles, Mary C. Schroeder
Journal: JAMA Surgery (2015)

<h3>Importance</h3> Management of the primary tumor site in patients with metastatic breast cancer remains controversial. <h3>Objective</h3> To evaluate the patterns of receipt of initial breast surgery for female patients with stage IV breast cancer in the United States, with particular attention to women who survived at least 10 years. <h3>Design, Setting, and Participants</h3> A retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) program. Female patients diagnosed as having stage IV breast cancer between 1988 and 2011 and who did not receive radiation therapy as part of the first course of treatment were included (N = 21 372). Kaplan-Meier estimates of median survival and descriptive statistics were used to compare patient and tumor characteristics by receipt of breast surgery at diagnosis. A Royston-Parmar survival model and logistic regression analysis assessed demographic and clinical factors associated with survival and prolonged survival (of at least 10 years). <h3>Main Outcomes and Measures</h3> Differences in survival, particularly survival of at least 10 years, by receipt of initial surgery to the primary tumor. <h3>Results</h3> Among the 21 372 patients, the median survival increased from 20 months (1988-1991) to 26 months (2007-2011). During this time, the rate of surgery declined (odds ratio [OR], 0.16; 95% CI, 0.12-0.21). Even so, receipt of surgery was associated with improved survival in multivariate analysis, which controlled for patient and clinical characteristics, along with time period (hazard ratio, 0.60; 95% CI, 0.57-0.63). For women diagnosed as having cancer before 2002 (n = 7504), survival of at least 10 years was seen in 9.6% (n = 353) and 2.9% (n = 107) of those who did and did not receive surgery, respectively (OR, 3.61; 95% CI, 2.89-4.50). In multivariate analysis, survival of at least 10 years was associated with receipt of surgery (odds ratio, 2.80; 95% CI, 2.08-3.77), hormone receptor–positive disease (OR, 1.76; 95% CI, 1.25-2.48), older age (OR, 0.41; 95% CI, 0.32-0.54), larger tumor size (OR, 0.37; 95% CI, 0.27-0.51), marital status of being separated at the time of diagnosis (OR, 0.67; 95% CI, 0.51-0.88), and more recent year of diagnosis (OR, 1.43; 95% CI, 1.02-1.99). <h3>Conclusions and Relevance</h3> Survival in stage IV breast cancer has improved and is increasingly of prolonged duration, particularly for some women undergoing initial breast surgery. As systemic therapy advances provide better control of distant disease in stage IV breast cancer, and as women present with lower distant disease burdens, these findings on initial surgery to the primary tumor may be of importance.
WITHDRAWN: Neuroprotective action of Gmelina arborea (bark) and Punica granatum (peel) extracts
Authors: Pai Vasudev, C.S. Shreedhara, K.S. Chandrashekar, D. Yamini
Journal: Asian Journal of Pharmaceutical Sciences (2015)

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
Homocysteine Lowering and Cognitive Performance
Authors: Michael Dettling, Carolin Opgen-Rhein, Ion-George Anghelescu
Journal: New England Journal of Medicine (2006)

To the Editor: McMahon et al. (June 29 issue)1 report that lowering plasma homocysteine concentrations by means of treatment with B vitamins did not improve the cognitive performance of healthy elderly volunteers with elevated homocysteine concentrations. Yet in the study population, there was little need to decrease homocysteine concentrations, no cognitive impairment to improve, and no association between elevated homocysteine concentrations and cognitive impairment to dissolve. What does it mean to improve an already quite normal cognitive performance and a mean score on the Mini–Mental State Examination of 29.2, given a possible score of 30? How can one define a clinically meaningful difference between two groups of healthy elderly volunteers? Whereas the usual definition of the upper limit of the normal range is 15 μmol per liter,2-4 McMahon et al. defined as “elevated” homocysteine concentrations as low as 13 μmol per liter. Thus, a good 62% of their healthy volunteers had elevated homocysteine concentrations, as compared with a reported prevalence of hyperhomocysteinemia of 18% among elderly New Zealand women.5 The already small sample was thus diluted by the large presence of elderly persons who were falsely classified as having hyperhomocysteinemia. Consistently, at baseline, the mean plasma folate and vitamin B12 concentrations were already rather high. Moreover, after baseline, the mean homocysteine concentration in the placebo group was below or near the upper limit of the normal range throughout the trial. Ugo Lucca, M.Sc. Mauro Tettamanti, Ph.D.
Cantharidin Poisoning
Authors: M. A. Lecutier
Journal: BMJ (1954)

SUBACUTE NEPHRITIS MEDICAL JOURNAL1399tertian fever, and malaria parasites were found in his blood.The fever was allowed to continue for 13 days, after which mepacrine was given.During the time of his infection the oedema and albuminuria increased, the blood urea rose to 165 mg. per 100 ml., and he was very ill.Sixteen days after the fever started he had a good diuresis, and two days later the blood chemistry started to return to normal.One month after the malaria the blood cholesterol had fallen to 198 mg. per 100 ml., the serum albumin had risen to 4 g.%, and the urine was free from albumin for the first time for 11 months.Since this time the bov has been free from oedema, and his urine is comple.elynormal.When last seen in May, 1954. the plasma proteins were 6.6 g.0%, with a serum albu- min of 4.2 g.O, and the blood cholesterol was 155 mg. per 100 ml.He is now back at school and extremely well on normal diet and no special treatment.