tbuckley/cabot-search huggingface dataset:
Combination Iron Depletion Therapy
Authors: R. Taetle, J. M. Honeysett, R. Bergeron
Journal: JNCI Journal of the National Cancer Institute (1989)

Iron (Fe) depletion with anti-transferrin (Tf) receptor monoclonal antibodies (MAbs), Fe chelators, or gallium (Ga) salts inhibits in vitro and in vivo growth of tumor cells. The present studies examined the cytotoxic effects of an IgA anti-human Tf receptor MAb, 42/6, combined with parabactin, a powerful Fe chelator, or Ga nitrate. Parabactin inhibited in vitro growth of human hematopoietic and solid tumor cells, and the rank order of their sensitivities to the Fe chelator was identical to their relative sensitivity to MAb 42/6 as demonstrated in previous studies. When the most parabactin and MAb 42/6-sensitive (HL60 leukemia) and -resistant (KB carcinoma) cells were incubated with various concentrations of parabactin, cell killing was time and dose dependent over the first 24 hours. Little additional cytotoxicity occurred, however, when cells were exposed to parabactin for 48 hours. HL60 cells were slightly more sensitive than KB cells to parabactin cytotoxicity. Addition of optimally effective concentrations of anti-Tf receptor MAb 42/6 to parabactin increased cytotoxicity to HL60 cells over a narrow parabactin dose range but had little effect on cytotoxicity to KB cells. Cell cycle analysis of cells treated with parabactin for 24 hours showed that doses causing variable cytotoxicity increased the percentage of cells in S phase, but higher parabactin concentrations consistently arrested cells in G1 phase or at the G1/S interface. MAb 42/6 also increased toxicity of parabactin to granulocyte/macrophage colony-stimulating factors and normal marrow granulocyte/macrophage progenitors. When HL60 or KB cells were treated with MAb 42/6 combined with Ga nitrate, MAb 42/6 increased cytotoxicity of Ga for HL60 cells but had little or no effect on Ga cytotoxicity to KB cells. In contrast, MAb 42/6 had minimal effects on cytotoxicity of the ribonucleotide reductase inhibitor, isoquinaldehyde thiosemicarbazone, to either HL60 or KB cells. Both hematopoietic and solid tumors were killed by Fe depletion, but the present studies suggested that hematopoietic cells are more sensitive than solid tumor cells to cytotoxic effects of Fe depletion. Combined Fe depletion therapy by the use of MAb 42/6 with an Fe chelator or Ga salt increased toxicity to MAb 42/6-sensitive cells, such as HL60, but was not more effective against MAb 42/6-resistant solid tumor cells. Combination Fe depletion therapy of hematopoietic cell tumors merits evaluation in experimental in vivo tumor systems.
Effects of Vitamin E on Cardiovascular and Microvascular Outcomes in High-Risk Patients With Diabetes
Authors: Eva Lonn, Salim Yusuf, Byrcon Hoogwerf, Janice Pogue, Qilong Yi, Bernard Zinman, Jackie Bosch, Gilles Dagenais, Johannes F.E. Mann, Hertzel C. Gerstein
Journal: Diabetes Care (2002)

OBJECTIVES—Experimental and observational studies suggest that vitamin E may reduce the risk of cardiovascular (CV) events and of microvascular complications in people with diabetes. However, data from randomized clinical trials are limited. Therefore, we evaluated the effects of vitamin E supplementation on major CV outcomes and on the development of nephropathy in people with diabetes. RESEARCH DESIGN AND METHODS—The Heart Outcomes Prevention Evaluation (HOPE) trial is a randomized clinical trial with a 2 × 2 factorial design, which evaluated the effects of vitamin E and of ramipril in patients at high risk for CV events. Patients were eligible for the study if they were 55 years or older and if they had CV disease or diabetes with at least one additional coronary risk factor. The study was designed to recruit a large number of people with diabetes, and the analyses of the effects of vitamin E in this group were preplanned. Patients were randomly allocated to daily treatment with 400 IU vitamin E and with 10 mg ramipril or their respective placebos and were followed for an average of 4.5 years. The primary study outcome was the composite of myocardial infarction, stroke, or CV death. Secondary outcomes included total mortality, hospitalizations for heart failure, hospitalizations for unstable angina, revascularizations, and overt nephropathy. RESULTS—There were 3,654 people with diabetes. Vitamin E had a neutral effect on the primary study outcome (relative risk = 1.03, 95% CI 0.88–1.21; P = 0.70), on each component of the composite primary outcome, and on all predefined secondary outcomes. CONCLUSIONS—The daily administration of 400 IU vitamin E for an average of 4.5 years to middle-aged and elderly people with diabetes and CV disease and/or additional coronary risk factor(s) has no effect on CV outcomes or nephropathy.
Effect of VIA Screening by Primary Health Workers: Randomized Controlled Study in Mumbai, India
Authors: S. S. Shastri, I. Mittra, G. A. Mishra, S. Gupta, R. Dikshit, S. Singh, R. A. Badwe
Journal: JNCI Journal of the National Cancer Institute (2014)

Cervical cancer is the leading cause of cancer mortality among women in India. Because Pap smear screening is not feasible in India, we need to develop effective alternatives.A cluster-randomized controlled study was initiated in 1998 in Mumbai, India, to investigate the efficacy of visual inspection with acetic acid (VIA) performed by primary health workers in reducing cervical cancer mortality. Four rounds of cancer education and VIA screening were conducted at 24-month intervals in the screening group, whereas cancer education was offered once at entry to the control group. The study was planned for 16 years to include four screening rounds followed by four monitoring rounds. We present results after 12 years of follow-up. Poisson regression method was used to calculate the rate ratios (RRs); two-sided χ(2) was used to calculate the probability.We recruited 75360 women from 10 clusters in the screening group and 76178 women from 10 comparable clusters in the control group. In the screening group, we achieved 89% participation for screening and 79.4% compliance for diagnosis confirmation. The incidence of invasive cervical cancer was 26.74 per 100000 (95% confidence interval [CI] = 23.41 to 30.74) in the screening group and 27.49 per 100000 (95% CI = 23.66 to 32.09) in the control group. Compliance to treatment for invasive cancer was 86.3% in the screening group and 72.3% in the control group. The screening group showed a statistically significant 31% reduction in cervical cancer mortality (RR = 0.69; 95% CI = 0.54 to 0.88; P = .003).VIA screening by primary health workers statistically significantly reduced cervical cancer mortality. Our study demonstrates the efficacy of an easily implementable strategy that could prevent 22000 cervical cancer deaths in India and 72600 deaths in resource-poor countries annually.
1122-171 Atherogenic low-density lipoprotein impairs vascular endothelial cell survival by disrupting the FGF2-PI3K-Akt autoregulatory loop
Authors: Wei Jiang, Jonathan Lu, Jun-Hai Yang, Po-Yuang Chang, Yuan-Teh Lee, Marco Marcelli, Philip D Henry, Warren S Liao, Chu-Huang Chen
Journal: Journal of the American College of Cardiology (2004)
The multiple sex chromosomes of platypus and echidna are not completely identical and several share homology with the avian Z
Authors: Willem Rens, Patricia CM O'Brien, Frank Grutzner, Oliver Clarke, Daria Graphodatskaya, Enkhjargal Tsend-Ayush, Vladimir A Trifonov, Helen Skelton, Mary C Wallis, Steve Johnston, Frederic Veyrunes, Jennifer AM Graves, Malcolm A Ferguson-Smith
Journal: Genome biology (2007)

Sex-determining systems have evolved independently in vertebrates. Placental mammals and marsupials have an XY system, birds have a ZW system. Reptiles and amphibians have different systems, including temperature-dependent sex determination, and XY and ZW systems that differ in origin from birds and placental mammals. Monotremes diverged early in mammalian evolution, just after the mammalian clade diverged from the sauropsid clade. Our previous studies showed that male platypus has five X and five Y chromosomes, no SRY, and DMRT1 on an X chromosome. In order to investigate monotreme sex chromosome evolution, we performed a comparative study of platypus and echidna by chromosome painting and comparative gene mapping. Chromosome painting reveals a meiotic chain of nine sex chromosomes in the male echidna and establishes their order in the chain. Two of those differ from those in the platypus, three of the platypus sex chromosomes differ from those of the echidna and the order of several chromosomes is rearranged. Comparative gene mapping shows that, in addition to bird autosome regions, regions of bird Z chromosomes are homologous to regions in four platypus X chromosomes, that is, X1, X2, X3, X5, and in chromosome Y1. Monotreme sex chromosomes are easiest to explain on the hypothesis that autosomes were added sequentially to the translocation chain, with the final additions after platypus and echidna divergence. Genome sequencing and contig anchoring show no homology yet between platypus and therian Xs; thus, monotremes have a unique XY sex chromosome system that shares some homology with the avian Z.
Are Subjects in Pharmacological Treatment Trials of Depression Representative of Patients in Routine Clinical Practice?
Authors: Mark Zimmerman, Jill I. Mattia, Michael A. Posternak
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: The methods used to evaluate the efficacy of antidepressants differ from treatment for depression in routine clinical practice. The rigorous inclusion/exclusion criteria used to select subjects for participation in efficacy studies potentially limit the generalizability of these trials' results. It is unknown how much impact these criteria have on the representativeness of subjects in efficacy trials. This study estimated the proportion of depressed patients treated in routine clinical practice who would meet standard inclusion/exclusion criteria for an efficacy trial. METHOD: A total of 803 individuals, aged 16–65 years, who were seen at intake at an outpatient practice underwent a thorough diagnostic evaluation, including the administration of semistructured diagnostic interviews; 346 patients had current major depression. Common inclusion/exclusion criteria used in efficacy studies of antidepressants were applied to the depressed patients to determine how many would have qualified for an efficacy trial. RESULTS: Approximately one-sixth of the 346 depressed patients would have been excluded from an efficacy trial because they had a bipolar or psychotic subtype of depression. The presence of a comorbid anxiety or substance use disorder, insufficient severity of depressive symptoms, or current suicidal ideation would have excluded 86.0% (N=252) of the remaining 293 outpatients with nonpsychotic unipolar major depressive disorder from an antidepressant efficacy trial. CONCLUSIONS: Subjects treated in antidepressant trials represent a minority of patients treated for major depression in routine clinical practice. These results show that antidepressant efficacy trials tend to evaluate a subset of depressed individuals with a specific clinical profile.
Analysis of ciliary beat pattern and beat frequency using digital high speed imaging: comparison with the photomultiplier and photodiode methods
Authors: M. A Chilvers
Journal: Thorax (2000)

<h3>BACKGROUND</h3> The aim of this study was to determine the relationship of the power and recovery stroke of respiratory cilia using digital high speed video imaging. Beat frequency measurements made using digital high speed video were also compared with those obtained using the photomultiplier and modified photodiode techniques. <h3>METHOD</h3> Ciliated epithelium was obtained by brushing the inferior nasal turbinate of 20 healthy subjects. Ciliated edges were observed by microscopy and the deviation of cilia during their recovery stroke relative to the path travelled during their power stroke was measured. Beat frequency measurements made by digital high speed video analysis were compared with those obtained using the photomultiplier and modified photodiode. <h3>RESULTS</h3> Cilia were found to beat with a forward power stroke and a backward recovery stroke within the same plane. The mean angular deviation of the cilia during the recovery stroke from the plane of the forward power stroke was only 3.6°(95% CI 3.1 to 4.1). There was a significant difference in beat frequency measurement between the digital high speed video (13.2 Hz (95% CI 11.8 to 14.6)) and both photomultiplier (12.0 Hz (95% CI 10.8 to 13.1), p = 0.01) and photodiode (11.2 Hz (95% CI 9.9 to 12.5), p&lt;0.001) techniques. The Bland-Altman limits of agreement for the digital high speed video were –2.75 to 5.15 Hz with the photomultiplier and –2.30 to 6.06 Hz with the photodiode. <h3>CONCLUSION</h3> Respiratory cilia beat forwards and backwards within the same plane without a classical sideways recovery sweep. Digital high speed video imaging allows both ciliary beat frequency and beat pattern to be evaluated.
Ischemic Nephropathy
Authors: Stephen C. Textor
Journal: Journal of the American Society of Nephrology (2004)

Identification and reversing the loss of kidney function beyond occlusive disease of the renal arteries poses a major clinical challenge. Recent studies indicate that atherosclerotic renal artery stenosis develops as a function of age and is commonly associated with other microvascular disease, including nephrosclerosis and diabetic nephropathy. The risks of renal artery stenosis are related both to declining kidney function and to accelerated cardiovascular disease, with increased morbidity and mortality. Newer drugs, including agents that block the renin-angiotensin system, have improved the level of BP control for renovascular hypertension. Progressive renovascular disease during medical therapy can produce refractory hypertension, congestive heart failure, and renal failure with tubulointerstitial fibrosis. Recent studies indicate a complex interplay of oxidative stress, endothelial dysfunction, and activation of fibrogenic cytokines as a result of experimental atherosclerosis and renal hypoperfusion. Advances in imaging and interventional devices offer major new opportunities to prevent progressive loss of kidney function. Recent series indicate that although 25 to 30% of patients with impaired renal function can recover glomerular filtration after revascularization, many have no apparent change in kidney function and 19 to 25% experience a significant loss of kidney function, in some cases as a result of atheroemboli. To select patients who are most likely to benefit from vascular intervention, clinicians should understand the pathophysiology of developing ischemic nephropathy and the potential hazards of revascularization in the setting of diffuse atherosclerotic disease. Further research should be directed toward identification of critical disease, regulation of fibrogenesis, and the interaction with other atherosclerotic processes.
Novel Injectable Bioartificial Tissue Facilitates Targeted, Less Invasive, Large-Scale Tissue Restoration on the Beating Heart After Myocardial Injury
Authors: Theo Kofidis, Darren R. Lebl, Eliana C. Martinez, Grant Hoyt, Masashi Tanaka, Robert C. Robbins
Journal: Circulation (2005)

Background— Implantation of bioartificial patches distorts myocardial geometry, and functional improvement of the recipient heart is usually attributed to reactive angiogenesis around the graft. With the liquid bioartificial tissue compound used in this study, we achieved targeted large-scale support of the infarcted left ventricular wall and improvement of heart function. Methods and Results— A liquid compound consisting of growth factor-free Matrigel and 10 6 green fluorescent protein (GFP)-positive mouse (129sv) embryonic stem cells (ESCs) was generated and injected into the area of ischemia after ligation of the left anterior descending artery in BALB/c mice (group I). Left anterior descending artery-ligated mice (group II) and mice with Matrigel (group III) or ESC treatment alone (group IV) were used as the control groups (n=5 in all groups). The hearts were harvested for histology 2 weeks later after echocardiographic assessment with a 15-MHz probe. The liquid injectable tissue solidified at body temperature and retained the geometry of the infarcted lateral wall. Immunofluorescence stains revealed voluminous GFP grafts. The quality of restoration (graft/infarct area ratio) was 45.5±10.8% in group I and 29.1±6.7% in group IV ( P =0.034). ESCs expressed connexin 43 at intercellular contact sites. The mice treated with the compound had a superior heart function compared with the controls ( P &lt;0.0001 by ANOVA/Bonferroni test; group I: 27.1±5.4, group II:11.9±2.4, group III:16.2±2.8, group IV: 19.1±2.7). Conclusions— Injectable bioartificial tissue restores the heart’s geometry and function in a targeted and nondistorting fashion. This new method paves the way for novel interventional approaches to myocardial repair, using both stem cells and matrices.
Antiarrhythmic Agents: The Modulated Receptor Mechanism of Action of Sodium and Calcium Channel-Blocking Drugs
Authors: L M Hondeghem, B G Katzung
Journal: The Annual Review of Pharmacology and Toxicology (1984)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Molecular mechanisms of McArdle's disease (muscle glycogen phosphorylase deficiency). RNA and DNA analysis.
Authors: S Gautron, D Daegelen, F Mennecier, D Dubocq, A Kahn, J C Dreyfus
Journal: Journal of Clinical Investigation (1987)

Lack of muscle glycogen phosphorylase activity leads to McArdle's disease, a rare metabolic myopathy. To investigate its molecular basis at the nucleic acid level, we isolated muscle phosphorylase cDNA clones from a human cDNA library in Escherichia coli plasmid pBR 322. Subcloning of one insertion of M13 bacteriophage permitted its definite identification by sequencing. Northern blot experiments revealed one specific messenger RNA of 3.4 kilobases found uniquely in tissues expressing muscle phosphorylase. We show that McArdle's disease exhibits a molecular heterogeneity at the messenger RNA level. In eight unrelated cases of McArdle's disease in which no inactive proteins had been detected, we assayed muscle biopsies for phosphorylase mRNA by Northern blotting. In five cases, no muscle phosphorylase mRNA could be detected, while in three other cases, normal length mRNA was present in lower amounts. Moreover, Southern blot analysis of DNA isolated from white blood cells in four McArdle patients revealed no major deletion or rearrangements of the phosphorylase gene as compared with controls.
Economic Evaluation of Angiotensin Receptor Blockers in Type 2 Diabetes, Hypertension, and Nephropathy
Authors: Maura Ravera, Michela Re, Simone Vettoretti
Journal: Journal of the American Society of Nephrology (2006)

There is a rising incidence and prevalence of ESRD as a result of diabetes, with poor outcome and growing costs. Recently, two large trials, the Irbesartan Diabetic Nephropathy Trial (IDNT) and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL), showed that angiotensin receptor blockers (ARB) are more effective than traditional antihypertensive therapies at reducing progression toward ESRD in hypertensive patients with type 2 diabetes and overt nephropathy, regardless of changes in BP. The results of these two trials were used to compare the costs of ARB with those of renal replacement therapy (dialysis and renal transplantation) in an effort to establish whether ARB are cost-saving because they delay ESRD. Two different pharmacoeconomic approaches were used. With regard to the RENAAL trial, the number of ESRD days on losartan therapy as compared with the number of ESRD days on standard antihypertensive therapy was calculated, and the difference between the two was combined with the costs of ESRD. In the IDNT trial, Markov models were applied to assess the economic impact of irbesartan and to extrapolate future clinical and cost outcomes. Several economic analyses were performed in the United States and in European countries. Applying pharmacoeconomic models showed that treatment with ARB was associated with a greater improvement in life expectancy and lower total costs compared with amlodipine and standard antihypertensive therapy. Therefore, treating patients with type 2 diabetes, nephropathy, and hypertension with ARB is life- and cost-saving compared with traditional antihypertensive therapy.
EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study
Authors: Robert Pirker, Jose R Pereira, Joachim von Pawel, Maciej Krzakowski, Rodryg Ramlau, Keunchil Park, Filippo de Marinis, Wilfried EE Eberhardt, Luis Paz-Ares, Stephan Störkel, Karl-Maria Schumacher, Anja von Heydebreck, Ilhan Celik, Kenneth J O'Byrne
Journal: The Lancet Oncology (2011)
Metabolic Syndrome, Inflammation, and Risk of Symptomatic Peripheral Artery Disease in Women
Authors: David Conen, Kathryn M. Rexrode, Mark A. Creager, Paul M Ridker, Aruna D. Pradhan
Journal: Circulation (2009)

The metabolic syndrome (MetS) is associated with incident myocardial infarction and stroke and is linked with subclinical inflammation; however, prospective data pertaining to MetS and future peripheral artery disease (PAD) are sparse, with few studies examining the role of inflammation. We therefore evaluated the relationship between MetS, inflammation, and incident PAD.We conducted a prospective cohort study among 27 111 women free of baseline cardiovascular disease who were participating in the Women's Health Study. Subjects were followed for incident symptomatic PAD (n=114; median cohort follow-up 13.3 years). We used Cox proportional hazards models to compare PAD risk among women with and without MetS. We also evaluated relationships between MetS and subclinical inflammation as measured by high-sensitivity C-reactive protein and soluble intercellular adhesion molecule-1 and adjusted for these biomarkers in multivariable models. Women with MetS had a 62% increased risk of future PAD (hazard ratio 1.62, 95% confidence interval 1.10 to 2.38). After multivariable adjustment, MetS remained significantly associated with PAD (adjusted hazard ratio 1.48, 95% confidence interval 1.01 to 2.18), with a 21% risk increase per additional MetS-defining trait (adjusted hazard ratio 1.21, 95% confidence interval 1.06 to 1.39). In women with and without MetS, respectively, median levels of high-sensitivity C-reactive protein were 4.0 versus 1.5 mg/L (P<0.0001), and median levels of soluble intercellular adhesion molecule-1 were 374 versus 333 ng/mL (P<0.0001). When high-sensitivity C-reactive protein and soluble intercellular adhesion molecule-1 were added to multivariable models, risk associated with MetS was substantially attenuated and no longer significant (hazard ratio 1.14, 95% confidence interval 0.75 to 1.73).MetS is associated with an increased risk of future symptomatic PAD in women. This risk appears to be mediated largely by the effects of inflammation and endothelial activation.