tbuckley/cabot-search huggingface dataset:
Postoperative treatment of nonmetastatic visible residual neuroblastoma: a Pediatric Oncology Group study.
Authors: R Nitschke, E I Smith, G Altshuler, D Altmiller, J Shuster, A Green, R Castleberry, F A Hayes, B Golembe, R Ducos
Journal: Journal of Clinical Oncology (1991)

The Pediatric Oncology Group (POG) evaluated in a prospective study the hypothesis that patients who had localized, visible residual neuroblastoma without regional lymph node involvement after surgery (POG stage B) have a favorable prognosis when treated with moderate intensive chemotherapy. Eligible patients were initially treated with five courses of Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co., Evansville, IN) and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) followed by surgery (CY/AD +/- surgery). Those patients not achieving a complete remission (CR) crossed over to five courses of cisplatin and teniposide (PL/VM) +/- surgery. Radiation therapy (XRT) was given to selected patients who still were not in CR after the crossover therapy. Of the 61 eligible patients, 38 (62%) patients achieved CR after CY/AD proven by clinical (31) or surgical (seven) evaluation. One (2%) patient in clinical partial remission (PR-C) entered CR without further therapy. Nineteen (31%) patients achieved CR with the following salvage therapies: surgery (five), PL/VM +/- surgery (five) followed by XRT (three) or autologous bone marrow transplant (ABMT) (one) and further courses of CY/AD +/- PL/VM instead of courses of PL/VM (five). The overall CR rate was 95% (58 of 61). Four patients had recurrence of the disease. The probability of being disease-free at 3 years after initial or salvage therapy was estimated at 84% (SE, 5%). The overall prognosis of children older than 1 year and younger than 1 year was similar (P = .26). If, however, the three remission deaths (all younger than 1 year) were censored, there was only one other failure in 32 children younger than one versus seven of 29 children older than 1 year (P = .018). These results confirm the excellent prognosis for patients with POG stage B neuroblastoma and indicate that most patients are curable with CY/AD +/- surgery, and those not achieving CR with this therapy are curable with alternate therapy.
Transient correction of the basic defect in sweat glands in an individual with cystic fibrosis carrying the complex CFTR allele F508del-R553Q
Authors: B Tummler, F Stanke, I Bronsveld, H Veeze, M Ballmann
Journal: Thorax (2009)

The molecular pathology of mutant F508del CFTR is partially corrected in vitro by the secondary amino acid substitution R553Q in the ABC signature motif. An individual with the <i>CFTR</i> genotype R553X/F508del-R553Q showed the typical symptoms and electrophysiological anomalies of cystic fibrosis in the airways and intestine. Sweat chloride concentrations were normal early in life, but were later raised into the range that is diagnostic for cystic fibrosis, suggesting that R553Q could temporarily correct the basic defect in sweat glands. R553Q caused a delay in diagnosis because of false negative sweat tests but was not a disease reverting suppressor mutation as had been inferred from cellular models.
Resveratrol Inhibits Tumor Growth of Human Neuroblastoma and Mediates Apoptosis by Directly Targeting Mitochondria
Authors: Paul R. van Ginkel, Dhruv Sareen, Lalita Subramanian, Quintisha Walker, Soesiawati R. Darjatmoko, Mary J. Lindstrom, Amol Kulkarni, Daniel M. Albert, Arthur S. Polans
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Neuroblastoma is an aggressive childhood disease of the sympathetic nervous system. Treatments are often ineffective and have serious side effects. Because resveratrol, a natural plant product, has been reported to have limited toxicity at chemotherapeutic levels, we investigated its efficacy in the treatment of neuroblastoma as well as its underlying mechanism of action. Experimental Design: Resveratrol was tested in mouse xenograft models of human neuroblastoma and in vitro using human cell lines. Results: Resveratrol inhibited the outgrowth of tumors by as much as 80%. The bioavailability of the drug in serum was in the low micromolar range (2-10 μmol/L) and no accumulation was observed in tumor tissue. When resveratrol levels were increased by peritumor injection, rapid tumor regression occurred. Resveratrol decreased tumor cell viability in vitro by 75% to 90%, resulting from an inhibition of cell proliferation and an induction of apoptosis. Loss of mitochondrial membrane potential was an early response to resveratrol. In addition, resveratrol treatment of isolated mitochondria also led to depolarization, suggesting that the drug may target mitochondria directly. Following depolarization, resveratrol caused the release of cytochrome c and Smac/Diablo from the mitochondria and subsequently the activation of caspase-9 (4- to 8-fold) and caspase-3 (4- to 6-fold). Conclusions: These studies indicate that, despite low bioavailability, resveratrol is effective at inhibiting tumor growth. Elevated levels of resveratrol enhance its antitumor potency leading to tumor regression, associated with widespread tumor cell death, the underlying mechanism of which involves the direct activation of the mitochondrial intrinsic apoptotic pathway.
Neurobiological Mechanisms of the Onset of Puberty in Primates*
Authors: Ei Terasawa, David L. Fernandez
Journal: Endocrine Reviews (2001)

Abstract An increase in pulsatile release of LHRH is essential for the onset of puberty. However, the mechanism controlling the pubertal increase in LHRH release is still unclear. In primates the LHRH neurosecretory system is already active during the neonatal period but subsequently enters a dormant state in the juvenile/prepubertal period. Neither gonadal steroid hormones nor the absence of facilitatory neuronal inputs to LHRH neurons is responsible for the low levels of LHRH release before the onset of puberty in primates. Recent studies suggest that during the prepubertal period an inhibitory neuronal system suppresses LHRH release and that during the subsequent maturation of the hypothalamus this prepubertal inhibition is removed, allowing the adult pattern of pulsatile LHRH release. In fact,γ -aminobutyric acid (GABA) appears to be an inhibitory neurotransmitter responsible for restricting LHRH release before the onset of puberty in female rhesus monkeys. In addition, it appears that the reduction in tonic GABA inhibition allows an increase in the release of glutamate as well as other neurotransmitters, which contributes to the increase in pubertal LHRH release. In this review, developmental changes in several neurotransmitter systems controlling pulsatile LHRH release are extensively reviewed.
Enrichment, solubilization, and partial characterization of digitonin-solubilized muscarinic receptors derived from canine ventricular myocardium.
Authors: A S Manalan, D K Werth, L R Jones, A M Watanabe
Journal: Circulation Research (1983)

The subcellular distribution of cardiac muscarinic receptors was defined in canine ventricular myocardium, and receptors were solubilized from subcellular fractions enriched in muscarinic receptor content. The subcellular location of muscarinic receptors in cardiac tissue was determined by measurement of the distribution of [3H](+/-)quinuclidinyl benzilate-binding activity in particulate fractions isolated from canine ventricular myocardium. Based upon excellent correlation between [3H](+/-)quinuclidinyl benzilate binding and activity of the sarcolemmal Na+,K+-ATPase throughout the subcellular fractions, muscarinic receptors appeared to be localized to sarcolemma in canine ventricular myocardium. Therefore, membrane fractions enriched in sarcolemma were used as a source of cardiac muscarinic receptors for solubilization. Treatment of membrane vesicle fractions with digitonin (0.6%) resulted in solubilization of [3H](+/-)quinuclidinyl benzilate-binding activity with an extraction yield of 25-35%. Criteria of pharmacological specificity and stereospecificity established the identity of the solubilized binding activity of muscarinic receptors. Solubilization of muscarinic receptors was documented by demonstration of hydrodynamic behavior consistent with molecularly dispersed material. Upon glycerol gradient centrifugation, digitonin-solubilized muscarinic receptors from cardiac tissue sedimented with an apparent sedimentation coefficient of 9S. Pharmacological characterization of the digitonin-solubilized receptors revealed 8- to 39-fold reductions in affinities for muscarinic antagonists compared to the affinities exhibited by receptors in the membrane-bound state. Substantially greater reductions in agonist affinities (reduction of at least 700-fold for all agonists studied) suggested selective loss of ability of the digitonin-solubilized receptors to exhibit high affinity agonist interactions. In contrast to membrane-bound receptors, digitonin-solubilized receptors also demonstrated a loss of guanine nucleotide regulation, as well as steep agonist:radioligand competition curves with slope factors of 1.0, suggesting a homogeneous population of agonist-binding sites. Interpreted within the context of a model of state interconversion for membrane-bound receptors, the results suggested that either muscarinic receptors of a single state were selectively solubilized, or that solubilization induced conversion of all receptors to a single low affinity state, possibly by removal of constituents necessary for assumption of a high affinity agonist conformation.
Identification of Local- and Habitat-Dependent Selection: Scanning Functionally Important Genes in Nine-Spined Sticklebacks (Pungitius pungitius)
Authors: T. Shikano, J. Ramadevi, J. Merila
Journal: Molecular Biology and Evolution (2010)

Understanding the selective forces promoting adaptive population divergence is a central issue in evolutionary biology. The role of environmental salinity in driving adaptation and evolution in aquatic organisms is still poorly understood. We investigated the relative impacts of habitat type (cf. saltwater vs. freshwater) and geographic area in shaping adaptive population divergence, as well as genes responsible for adaptation to different salinities in nine-spined sticklebacks (Pungitius pungitius). To this end, we employed a hitchhiking mapping approach with 111 microsatellite loci and one insertion/deletion locus including 63 loci situated within or close to genes with important physiological functions such as osmoregulation, growth, and thermal response. Using three pairs of marine and freshwater populations from different geographic areas, we identified several loci showing consistent evidence of being under directional selection in different outlier tests. Analyses of molecular variance at the loci under selection indicated that geographic area rather than habitat type has been acting as a central force in shaping adaptive population divergence. Nevertheless, both outlier tests and a spatial analysis method indicated that two loci (growth hormone receptor 2 and DEAD box polypeptide 56) are involved in adaptation to different habitats, implying that environmental salinity has been affecting them as a selective force. These loci are promising candidates for further investigations focusing on the molecular mechanisms of adaptation to marine and freshwater environments.
Initial Trophic vs Full Enteral Feeding in Patients With Acute Lung Injury: The EDEN Randomized Trial
Authors: T. W. Rice, A. P. Wheeler, B. T. Thompson, J. Steingrub, R. D. Hite, M. Moss, A. Morris, N. Dong, P. Rock
Journal: JAMA (2012)

Context-The amount of enteral nutrition patients with acute lung injury need is unknown.Objective-To determine if initial lower-volume trophic enteral feeding would increase ventilator-free days and decrease gastrointestinal intolerances compared with initial full enteral feeding. Design, Setting, and Participants-The EDEN study, a randomized, open-label, multicenter trial conducted from January 2, 2008, through April 12, 2011.Participants were 1000 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network.Interventions-Participants were randomized to receive either trophic or full enteral feeding for the first 6 days.After day 6, the care of all patients who were still receiving mechanical ventilation was managed according to the full feeding protocol.Main Outcome Measures-Ventilator-free days to study day 28.Results-Baseline characteristics were similar between the trophic-feeding (n=508) and fullfeeding (n=492) groups.The full-feeding group received more enteral calories for the first 6 days, about 1300 kcal/d compared with 400 kcal/d (P<.001).Initial trophic feeding did not increase the number of ventilator-free days (14.9 [95% CI, 13.9 to 15.8] vs 15.0 [95% CI, 14.1 to 15.9]; difference, -0.1 [95% CI, -1.4 to 1.2]; P=.89) or reduce 60-day mortality (23.2% [95% CI, 19.6% to 26.9%] vs 22.2% [95% CI, 18.5% to 25.8%]; difference, 1.0% [95% CI, -4.1% to 6.3%]; P=77) compared with full feeding.There were no differences in infectious complications between the
Loss of <i>Mdm4</i> Results in <i>p53</i> -Dependent Dilated Cardiomyopathy
Authors: Shunbin Xiong, Carolyn S. Van Pelt, Ana C. Elizondo-Fraire, Belen Fernandez-Garcia, Guillermina Lozano
Journal: Circulation (2007)

Although several loci for familial dilated cardiomyopathy (DCM) have been mapped, the origin of a large percentage of DCM remains unclear. Mdm2, a p53-negative regulator, protects cardiomyocytes from ischemic and reperfusion-induced cell death. Mdm4, a homolog of Mdm2, inhibits p53 activity in numerous cell types. It is unknown whether Mdm4 plays a role in the inhibition of p53 in fully differentiated tissues such as adult cardiomyocytes and whether this role is associated with DCM.The conditional knockout of Mdm4 in the heart by use of cardiomyocyte-specific Cre (alphaMyHC-Cre) allele does not result in any developmental defects. With time, however, mice with deletion of Mdm4 in the adult heart developed DCM and had a median survival of 234 days. More interestingly, the onset of DCM occurs significantly earlier in male mice than in female mice, which mimics human DCM disease. DCM in Mdm4 mutant mice was caused by loss of cardiomyocytes by apoptosis, and it was p53-dose dependent.Activity of p53 was inhibited by Mdm4 even in the fully differentiated cardiomyocyte. Elevated apoptosis mediated by the p53 pathway in cardiomyocytes may be a mechanism for DCM.
ABC of nutrition. Obesity: diagnosis and risks.
Authors: A S Truswell
Journal: BMJ (1985)

It is easy to diagnose moderate and gross obesity before the patient undresses.The difficulty with these patients is to organise the time and summon up the enthusiasm to embark on treatment which will be lengthy and may be unsuccessful.When our profession can transplant a human heart, manage in vitro fertilisation, and eliminate smallpox, to treat obesity is a challenge for a conscientious practitioner.A health service, like the British NHS, which provides an annual fee per patient is a suitable framework.* Weighing the patient under the same conditions on the same scale.* About /4 hour talk with the same practitioner each visit.* Opportunity to bring wife or husband.* The therapist not be obese.The first four conditions are easier for the patient in general practice.Two general practitioners' books about their work with obese patients can be recommended.
Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial
Authors: Robert J Motzer, Bernard Escudier, Piotr Tomczak, Thomas E Hutson, M Dror Michaelson, Sylvie Negrier, Stephane Oudard, Martin E Gore, Jamal Tarazi, Subramanian Hariharan, Connie Chen, Brad Rosbrook, Sinil Kim, Brian I Rini
Journal: The Lancet Oncology (2013)
Phase III Multinational, Randomized, Double-Blind, Placebo-Controlled Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Erlotinib Alone in Previously Treated Patients With Locally Advanced or Metastatic Nonsquamous Non–Small-Cell Lung Cancer
Authors: Giorgio Scagliotti, Joachim von Pawel, Silvia Novello, Rodryg Ramlau, Adolfo Favaretto, Fabrice Barlesi, Wallace Akerley, Sergey Orlov, Armando Santoro, David Spigel, Vera Hirsh, Frances A. Shepherd, Lecia V. Sequist, Alan Sandler, Jeffrey S. Ross, Qiang Wang, Reinhard von Roemeling, Dale Shuster, Brian Schwartz
Journal: Journal of Clinical Oncology (2015)

Purpose Tivantinib, a MET receptor tyrosine kinase inhibitor, demonstrated increased anticancer activity in preclinical and early clinical studies when combined with erlotinib. Our study aimed to confirm efficacy and safety of the combination in previously treated patients with non–small-cell lung cancer (NSCLC). Patients and Methods Patients with advanced nonsquamous NSCLC previously treated with one to two systemic regimens, including a platinum doublet, were randomly assigned at a 1:1 ratio to receive erlotinib 150 mg daily plus oral tivantinib 360 mg twice daily (E + T) or erlotinib plus placebo (E + P) until disease progression. Tumor specimens were evaluated for EGFR and KRAS mutations, MET expression, and MET gene amplification. The primary end point was overall survival (OS). Secondary and exploratory objectives included progression-free survival (PFS), OS in molecular subgroups, and safety. Results The study enrolled 1,048 patients and was discontinued for futility at the interim analysis. OS did not improve with E + T versus E + P (median OS, 8.5 v 7.8 months, respectively; hazard ratio [HR], 0.98; 95% CI, 0.84 to 1.15; P = .81), even though PFS increased (median PFS, 3.6 v 1.9 months; HR, 0.74; 95% CI, 0.62 to 0.89; P &lt; .001). Exploratory subgroup analyses suggested OS improvement in patients with high MET expression (HR, 0.70; 95% CI, 0.49 to 1.01). Most common adverse events occurring with E + T versus E + P were rash (33.1% v 37.3%, respectively), diarrhea (34.6% v 41.0%), asthenia or fatigue (43.5% v 38.1%), and neutropenia (grade 3 to 4; 8.5% v 0.8%). Conclusion E + T was well tolerated and increased PFS but did not improve OS in the overall nonsquamous NSCLC population.
Efficacy and Safety of Monthly versus Quarterly Ranibizumab Treatment in Neovascular Age-related Macular Degeneration: The EXCITE Study
Authors: Ursula Schmidt-Erfurth, Bora Eldem, Robyn Guymer, Jean-François Korobelnik, Reinier O. Schlingemann, Ruth Axer-Siegel, Peter Wiedemann, Christian Simader, Margarita Gekkieva, Andreas Weichselberger
Journal: Ophthalmology (2010)
A liver angioma colonized by colon cancer cells in a patient with two primitive localizations by colon adenocarcinoma: biologic, diagnostic and therapeutic implications
Authors: G. Facchini, F. Fiore, M. Caraglia, R. D'Angelo, G. Nasti, F. Caponigro, R. Formato, A. Budillon, R.V. Iaffaioli
Journal: Annals of Oncology (2005)
Acute and Chronic Effects of an Adrenergic Beta-Receptor Blocking Agent (Propranolol) in Treatment of Cardiac Arrhythmias
Authors: MYRON H. LURIA, EDWARD I. ADELSON, ALBERT J. MILLER
Journal: Circulation (1966)

The effects of intravenous and oral administration of propranolol, an adrenergic beta-receptor blocking agent, have been studied in 29 patients with various cardiac arrhythmias. The ventricular responses in chronic or paroxysmal ectopic supraventricular arrhythmias were decreased at rest or during exercise. Sinus tachycardias were regularly slowed. Two supraventricular tachycardias and one ventricular tachycardia, all consistently precipitated by exogenous stimuli, were prevented. Six instances of digitalis-induced arrhythmias were responsive to treatment. Propranolol, especially when given orally, is of definite value in selected disturbances of cardiac rhythm. Reasonable caution should be exercised, however, because of the risk of precipitation of congestive heart failure or hypotension in patients with limited cardiac reserves.
Allergy and infection: understanding their relationship
Authors: A. Custovic, C. Murray, A. Simpson
Journal: Allergy (2005)

Sensitization to indoor allergens has long been recognized as a risk factor for asthma and its associated phenotypes. Immunoglobulin E antibody quantification may be used to confirm that a particular sensitization has a role in the development of respiratory symptoms. However, in order to use quantitative information effectively, it is essential to understand the factors that contribute to the deterioration of symptoms and cause exacerbations. One such risk factor is high allergen exposure. Worsening asthma control is also associated with virus infections, in particular rhinovirus infection. Each of these factors in isolation is unlikely to have a major effect on symptoms. However, the combination of respiratory virus infection, allergen sensitization and concurrent high exposure to allergens markedly increases the risk for hospitalization. Further investigation of this synergism could help to understand the mechanisms of asthma exacerbations and lead to the development of strategies for prevention.
A quantitative ultrastructural study of microtubule content and secretory granule accumulation in parathyroid glands of phosphate- and colchicine-treated rats.
Authors: E P Reaven, G M Reaven
Journal: Journal of Clinical Investigation (1975)

Microtubule involvement in secretory events of the parathyroid gland was investigated in rats treated with colchicine and/or phosphorus, agents which have been shown to modify parathyroid secretion. Quantitative ultrastructural techniques were used in an effort to assess the cytoplasmic microtubule and secretory granule content of chief cells 3 h after treatment, when hypocalcemia was well established. After cochicine administration, the chief cells appeared to have lost all assembled microtubules and accumulated greater than normal amounts of cytoplasmic secretory granules. On the other hand, phosphorus treatment was associated with increased microtubule content although the cytoplasmic content of secretory granules remained unchanged. When colchicine and phosphorus were given concomitantly, microtubules were again absent, but the secretory granule content of the cells was markedly increased. These data provide direct evidence that colchicine disrupts assembled microtubules in chief cells of rat parathyroids; the consequence of this effect appears to be a blockage of hormone release which is reflected in the accumulation of secretory granules in the cell. The fact that microtubules also show a significant increase in content when hormone release from chief cells is presumed to increase, suggests that microtubules may participate in the physiological control of parathyroid hormone secretion.
Praecordial mapping of Q waves and RS ratio changes in acute myocardial infarction
Authors: A. P. SELWYN, J. P. SHILLINGFORD
Journal: Cardiovascular Research (1977)

The theory related to the loss of R waves and appearance of Q waves in acute myocardial infarction is discussed. A method of praecordial mapping of RS ratio changes and the appearance of Q waves that occur in acute myocardial infarction is described. The serial changes in these electrocardiographic signs in 17 patients during acute infarction are recorded. The potential value of these serial measurements in delineating the extent of myocardial injury in patients with acute infarction, and evaluating the effects of any treatment aimed at limiting infarct size is discussed.