tbuckley/cabot-search huggingface dataset:
Membrane transporters and protein traffic networks differentially affecting metal tolerance: a genomic phenotyping study in yeast
Authors: Roberta Ruotolo, Gessica Marchini, Simone Ottonello
Journal: Genome biology (2008)

Abstract Background The cellular mechanisms that underlie metal toxicity and detoxification are rather variegated and incompletely understood. Genomic phenotyping was used to assess the roles played by all nonessential Saccharomyces cerevisiae proteins in modulating cell viability after exposure to cadmium, nickel, and other metals. Results A number of novel genes and pathways that affect multimetal as well as metal-specific tolerance were discovered. Although the vacuole emerged as a major hot spot for metal detoxification, we also identified a number of pathways that play a more general, less direct role in promoting cell survival under stress conditions (for example, mRNA decay, nucleocytoplasmic transport, and iron acquisition) as well as proteins that are more proximally related to metal damage prevention or repair. Most prominent among the latter are various nutrient transporters previously not associated with metal toxicity. A strikingly differential effect was observed for a large set of deletions, the majority of which centered on the ESCRT (endosomal sorting complexes required for transport) and retromer complexes, which - by affecting transporter downregulation and intracellular protein traffic - cause cadmium sensitivity but nickel resistance. Conclusion The data show that a previously underestimated variety of pathways are involved in cadmium and nickel tolerance in eukaryotic cells. As revealed by comparison with five additional metals, there is a good correlation between the chemical properties and the cellular toxicity signatures of various metals. However, many conserved pathways centered on membrane transporters and protein traffic affect cell viability with a surprisingly high degree of metal specificity.
Routine Early Angioplasty after Fibrinolysis for Acute Myocardial Infarction
Authors: Warren J. Cantor, David Fitchett, Bjug Borgundvaag, John Ducas, Michael Heffernan, Eric A. Cohen, Laurie J. Morrison, Anatoly Langer, Vladimir Dzavik, Shamir R. Mehta, Charles Lazzam, Brian Schwartz, Amparo Casanova, Shaun G. Goodman
Journal: New England Journal of Medicine (2009)

Patients with a myocardial infarction with ST-segment elevation who present to hospitals that do not have the capability of performing percutaneous coronary intervention (PCI) often cannot undergo timely primary PCI and therefore receive fibrinolysis. The role and optimal timing of routine PCI after fibrinolysis have not been established.We randomly assigned 1059 high-risk patients who had a myocardial infarction with ST-segment elevation and who were receiving fibrinolytic therapy at centers that did not have the capability of performing PCI to either standard treatment (including rescue PCI, if required, or delayed angiography) or a strategy of immediate transfer to another hospital and PCI within 6 hours after fibrinolysis. All patients received aspirin, tenecteplase, and heparin or enoxaparin; concomitant clopidogrel was recommended. The primary end point was the composite of death, reinfarction, recurrent ischemia, new or worsening congestive heart failure, or cardiogenic shock within 30 days.Cardiac catheterization was performed in 88.7% of the patients assigned to standard treatment a median of 32.5 hours after randomization and in 98.5% of the patients assigned to routine early PCI a median of 2.8 hours after randomization. At 30 days, the primary end point occurred in 11.0% of the patients who were assigned to routine early PCI and in 17.2% of the patients assigned to standard treatment (relative risk with early PCI, 0.64; 95% confidence interval, 0.47 to 0.87; P=0.004). There were no significant differences between the groups in the incidence of major bleeding.Among high-risk patients who had a myocardial infarction with ST-segment elevation and who were treated with fibrinolysis, transfer for PCI within 6 hours after fibrinolysis was associated with significantly fewer ischemic complications than was standard treatment. (ClinicalTrials.gov number, NCT00164190.)
Sex differences in baseline neuropsychological function and concussion symptoms of collegiate athletes
Authors: T Covassin, C B Swanik, M Sachs, Z Kendrick, P Schatz, E Zillmer, C Kaminaris
Journal: British Journal of Sports Medicine (2006)

To investigate sex differences in baseline neuropsychological function and concussion symptoms between male and female collegiate athletes.A post-test only design was used to examine baseline neuropsychological test scores and concussion symptoms. A total of 1209 NCAA Division I collegiate athletes from five northeastern universities in the USA completed a baseline ImPACT test. ImPACT, a computerised neuropsychological test battery, was administered during an athlete's pre-season.Female athletes performed significantly better than male athletes on baseline verbal memory scores (p = 0.001), while male athletes performed significantly better than female athletes on baseline visual memory scores (p = 0.001). Female athletes endorsed a significant number of mild baseline symptoms as compared to male athletes.Male and female athletes exhibit differences on baseline neuropsychological test performance and concussion symptoms.
Combined MEK and VEGFR Inhibition in Orthotopic Human Lung Cancer Models Results in Enhanced Inhibition of Tumor Angiogenesis, Growth, and Metastasis
Authors: Osamu Takahashi, Ritsuko Komaki, Paul D. Smith, Juliane M. Jürgensmeier, Anderson Ryan, B. Nebiyou Bekele, Ignacio I. Wistuba, Jörg J. Jacoby, Maria V. Korshunova, Anna Biernacka, Baruch Erez, Keiko Hosho, Roy S. Herbst, Michael S. O'Reilly
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Ras/Raf/mitogen-activated protein–extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling is critical for tumor cell proliferation and survival. Selumetinib is a potent, selective, and orally available MEK1/2 inhibitor. In this study, we evaluated the therapeutic efficacy of selumetinib alone or with cediranib, an orally available potent inhibitor of all three VEGF receptor (VEGFR) tyrosine kinases, in murine orthotopic non–small cell lung carcinoma (NSCLC) models. Experimental Design: NCI-H441 or NCI-H460 KRAS-mutant human NSCLC cells were injected into the lungs of mice. Mice were randomly assigned to treatment with selumetinib, cediranib, paclitaxel, selumetinib plus cediranib, or control. When controls became moribund, all animals were sacrificed and assessed for lung tumor burden and locoregional metastasis. Lung tumors and adjacent normal tissues were subjected to immunohistochemical analyses. Results: Selumetinib inhibited lung tumor growth and, particularly at higher dose, reduced locoregional metastasis, as did cediranib. Combining selumetinib and cediranib markedly enhanced their antitumor effects, with near complete suppression of metastasis. Immunohistochemistry of tumor tissues revealed that selumetinib alone or with cediranib reduced ERK phosphorylation, angiogenesis, and tumor cell proliferation and increased apoptosis. The antiangiogenic and apoptotic effects were substantially enhanced when the agents were combined. Selumetinib also inhibited lung tumor VEGF production and VEGFR signaling. Conclusions: In this study, we evaluated therapy directed against MEK combined with antiangiogenic therapy in distinct orthotopic NSCLC models. MEK inhibition resulted in potent antiangiogenic effects with decreased VEGF expression and signaling. Combining selumetinib with cediranib enhanced their antitumor and antiangiogenic effects. We conclude that combining selumetinib and cediranib represents a promising strategy for the treatment of NSCLC. Clin Cancer Res; 18(6); 1641–54. ©2012 AACR.
Fluvoxamine in the Treatment of Binge-Eating Disorder: A Multicenter Placebo-Controlled, Double-Blind Trial
Authors: J I Hudson, S L McElroy, N C Raymond, S Crow, P E Keck, W P Carter, J E Mitchell, S M Strakowski, H G Pope, B S Coleman, J M Jonas
Journal: American Journal of Psychiatry (1998)

The purpose of this study was to assess the efficacy of fluvoxamine in the treatment of binge-eating disorder. Binge-eating disorder is a newly described eating disorder characterized by recurrent episodes of binge eating but without purging behaviors. Uncontrolled reports have suggested that serotonin selective reuptake inhibitors (SSRIs) may be effective in treating this disorder.Eighty-five outpatients with a DSM-IV diagnosis of binge-eating disorder were randomly assigned to receive either fluvoxamine (N=42) or placebo (N=43) in a 9-week, parallel-group, double-blind, flexible dose (50-300 mg) study at three centers. The primary outcome measures were frequency of binge eating, expressed as log ([binges/week]+1), and Clinical Global Impression (CGI) scale ratings. Secondary measures included the level of response (based on the percentage change in frequency of binges), body mass index, and Hamilton Rating Scale for Depression score. Except for the level of response, the outcome measures were analyzed by random regression methods; the treatment-by-time interaction was the measure of treatment effect.Compared with placebo, fluvoxamine was associated with a significantly greater rate of reduction in the frequency of binges, rate of reduction in CGI severity scores, rate of increase in CGI improvement scores, level of response for patients who completed the 9-week study, and rate of reduction in body mass index. There was no significant difference between placebo and fluvoxamine groups in the rate of decrease in Hamilton depression scale scores. A significantly greater proportion of patients receiving fluvoxamine than those receiving placebo discontinued treatment because of an adverse medical event.In this placebo-controlled trial, fluvoxamine was found to be effective according to most outcome measures in the acute treatment of binge-eating disorder.
PARAMOUNT Trial: Reopening a Window to Maintenance Therapy
Authors: Sandro Barni, Fausto Petrelli
Journal: Journal of Clinical Oncology (2014)

TO THEEDITOR:Paz-Aresetal 1 reportedintheAugust10issueof Journal of Clinical Oncology the updated survival analysis for the PARAMOUNT trial, which explored continuous maintenance treatment with pemetrexed compared with placebo after platinum-based chemotherapy. The results presented are impressive, with a median overall survival of 16 months and a 3-month significant increase in survival compared with the control. This overall survival result is 4 monthsgreaterthaninthestudybyScagliottietal, 2 atrialthatusedthe same cisplatin/pemetrexed doublet (up to six cycles) in patients with advancedNSCLCandaperformancestatusof0to1,whichisasimilar population to that in the PARAMOUNT trial. In particular, the benefit of pemetrexed maintenance was obtained with only a slight increase in overall toxicity and with no worsening of quality of life. Approximately 70% of randomly assigned patients received secondline therapies after progression of the disease. How should the results of the PARAMOUNT trial be interpreted? Are the results because of pemetrexed or because of a strategy effect? These results were obtained in a setting in which other agents failed to show a survival benefit when used for continuous maintenance therapy (gemcitabine, for example 3,4 ). Subsequently, a metaanalysis of maintenance trials confirmed only a progression-free but not an overall survival advantage with a continuous maintenance strategy. 5 Is it possible that pemetrexed, but not other drugs, could replicate this outcome in any future prospective randomized trial? Another consideration concerns the selection of the enrolled patients.Amongthe939initiallytreatedpatients,68%hadcompleted fourcyclesofinductionchemotherapyandwerenotprogressing;they were therefore randomly assigned to the maintenance phase. In total, 539 patients were effectively randomly assigned to pemetrexed or observation (58% of the total initial population). It is possible that a highly select group of patients with an excellent performance status could lead to this very good outcome. Only 38.3% of the initial population received any salvage therapy after progression (67% of the randomly assigned patients). Is this a natural and favorable selection process that permits some lucky patients to derive the greatest benefit from any form of treatment, including continuous maintenance? Third, in this trial, the authors observed a postprogression survival (calculated from the date of progression until death) of approximately10months.Theoverallsurvivalofpatientswithaperformance
Zoledronic Acid Markedly Improves Bone Mineral Density for Patients with Monoclonal Gammopathy of Undetermined Significance and Bone Loss
Authors: James R. Berenson, Ori Yellin, Ralph V. Boccia, Marshall Flam, Siu-Fun Wong, Olcay Batuman, Mehdi M. Moezi, Donald Woytowitz, Herbert Duvivier, Youram Nassir, Regina A. Swift
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Patients with monoclonal gammopathy of undetermined significance (MGUS) have increased rates of bone resorption, osteopenia, osteoporosis, and risk of fractures. This study was undertaken to determine the efficacy and safety of zoledronic acid for patients with MGUS and enhanced bone loss. Experimental Design: In this phase II open-label study, 54 patients with MGUS and osteopenia or osteoporosis were administered zoledronic acid 4 mg i.v. at 0, 6, and 12 months. The primary efficacy end point was bone mineral density, assessed using a dual-energy X-ray absorptiometry scan in the lumbar (L)-spine done at screening and at 13 months (1 month after the final zoledronic acid infusion). Results: At study end for all patients (N = 54), L-spine T-scores improved by a median of +0.27 (range, −0.38 to +3.91), corresponding to a median increase in bone mineral density of +15.0% (range, −18.0% to +1,140.0%; P &amp;lt; 0.0001). Hip T-scores improved by a median of +0.10 (range, −2.40 to +2.03), corresponding to a median increase of +6.0% (range, −350.0% to +165.0%). During the study, no new fractures, osteonecrosis of the jaw, or significant renal adverse events were reported. Conclusions: Zoledronic acid administered i.v. at a dosage of 4 mg every 6 months for three doses total was well-tolerated and substantially improved bone mineral density for patients with MGUS and bone loss. Zoledronic acid may be effective for the prevention of new fractures in this high-risk population.
Transcriptional Control of Cardiac Allograft Vasculopathy by Early Growth Response Gene-1 (Egr-1)
Authors: Morihito Okada, Catherine Y. Wang, Daniel W. Hwang, Taichi Sakaguchi, Kim E. Olson, Yasushi Yoshikawa, Kanji Minamoto, Sean P. Mazer, Shi-Fang Yan, David J. Pinsky
Journal: Circulation Research (2002)

Expression of the zinc finger transcription factor early growth response gene-1 (Egr-1) is triggered rapidly after mechanical vascular injury or after a precipitous drop in ambient oxygen, whereupon it induces the expression of diverse gene families to elicit a pathological response. Initially characterized as an early response transcriptional activator, the role of Egr-1 in more chronic forms of vascular injury remains to be defined. Studies were designed to examine whether Egr-1 induction may serve as a causal link between early preservation injury and delayed vascular consequences, such as coronary allograft vasculopathy (CAV). The preservation and transplantation of heterotopic murine cardiac allografts strongly induce Egr-1 expression, leading to increased expression of its downstream target genes, such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and platelet-derived growth factor A chain. Expression of these Egr-1–inducible gene targets is virtually obliterated in homozygous Egr-1–null donor allografts, which also exhibit attenuated parenchymal rejection and reduced CAV as long as 60 days. Congruous data are observed by treating donor hearts with a phosphorothioate antisense oligodeoxyribonucleotide directed against Egr-1 before organ harvest, which blocks subsequent expression of Egr-1 mRNA and protein and suppresses the late development of CAV. These data indicate that Egr-1 induction represents a central effector mechanism in the development of chronic rejection characterized by CAV. Blocking the expression of this proximal transcription factor solely at the time of organ harvest elicits beneficial delayed consequences for the cardiac allograft.
Inhibition of Elevated Ca <sup>2+</sup> /Calmodulin-Dependent Protein Kinase II Improves Contractility in Human Failing Myocardium
Authors: Samuel Sossalla, Nina Fluschnik, Hanna Schotola, Katharina R. Ort, Stefan Neef, Timo Schulte, Katrin Wittköpper, André Renner, Jan D. Schmitto, Jan Gummert, Ali El-Armouche, Gerd Hasenfuss, Lars S. Maier
Journal: Circulation Research (2010)

Rationale: Heart failure (HF) is known to be associated with increased Ca 2+ /calmodulin-dependent protein kinase (CaMK)II expression and activity. There is still controversial discussion about the functional role of CaMKII in HF. Moreover, CaMKII inhibition has never been investigated in human myocardium. Objective: We sought to investigate detailed CaMKIIδ expression in end-stage failing human hearts (dilated and ischemic cardiomyopathy) and the functional effects of CaMKII inhibition on contractility. Methods and Results: Expression analysis revealed that CaMKIIδ, both cytosolic δ C and nuclear δ B splice variants, were significantly increased in both right and left ventricles from patients with dilated or ischemic cardiomyopathy versus nonfailing. Experiments with isometrically twitching trabeculae revealed significantly improved force frequency relationships in the presence of CaMKII inhibitors (KN-93 and AIP). Increased postrest twitches after CaMKII inhibition indicated an improved sarcoplasmic reticulum (SR) Ca 2+ loading. This was confirmed in isolated myocytes by a reduced SR Ca 2+ spark frequency and hence SR Ca 2+ leak, resulting in increased SR Ca 2+ load when inhibiting CaMKII. Ryanodine receptor type 2 phosphorylation at Ser2815, which is known to be phosphorylated by CaMKII thereby contributing to SR Ca 2+ leak, was found to be markedly reduced in KN-93–treated trabeculae. Interestingly, CaMKII inhibition did not influence contractility in nonfailing sheep trabeculae. Conclusions: The present study shows for the first time that CaMKII inhibition acutely improves contractility in human HF where CaMKIIδ expression is increased. The mechanism proposed consists of a reduced SR Ca 2+ leak and consequently increased SR Ca 2+ load. Thus, CaMKII inhibition appears to be a possible therapeutic option for patients with HF and merits further investigation.
Some health and wellbeing boards are too "pink and fluffy" and lack spine, expert warns
Authors: A. O'Dowd
Journal: BMJ (2013)

Some of the new bodies that bring together the NHS, public health, and local authorities to coordinate health services in England lack the “stiffness of spine” to make actual improvements in healthcare, MPs have been told.

The local health and wellbeing boards, one of the less controversial aspects of the coalition government’s changes to the NHS, were discussed during an evidence session of the parliamentary communities and local government committee on 7 January.

MPs on the committee, as part of their inquiry into the role of local authorities in health issues, asked about the …
Platelet and fibrin modification by radiographic contrast media.
Authors: D A Gabriel, M R Jones, N S Reece, E Boothroyd, T Bashore
Journal: Circulation Research (1991)

The effect of the radiographic contrast agents, iopamidol and diatrizoate, on fibrin assembly and structure as well as platelet surface charge was studied. Increasing the iopamidol concentration from 0 to 4.5 mM prolongs the fibrin gelation time from 20 to 105 seconds (an anticoagulant effect) and reduces the fibrin fiber mass/length ratio from 3.2 x 10(12) to 0.5 x 10(12) Da/cm (i.e., produces very thin fibrin fibers). Ultraviolet difference spectroscopy of fibrinogen showed both a 15-nm shift in the ultraviolet difference maximum for iopamidol (suggesting binding) and a perturbation of the aromatic amino acid side chain region for fibrinogen (suggesting a conformational change in fibrinogen) as the concentration of iopamidol was increased from 0 to 9 mg/ml. Binding of iopamidol to fibrinogen was also shown by affinity chromatography using a Sepharose-fibrinogen column. Electrophoretic quasi elastic light scattering was used to show platelet interaction with iopamidol as reflected in a reduction in the platelet electrophoretic mobility from 2.0 to 0.5 (microns-cm)/(V-sec) as the concentration of iopamidol was increased from 0 to 4.5 mM. In addition, the ionic radiopaque contrast agent, Renografin, was also studied and found to inhibit fibrin monomer assembly. Although iopamidol is not shown to be thrombogenic, iopamidol does appear to reduce platelet surface charge, bind fibrinogen, and modify fibrin clot structure.
Phase 3 (P04832) Trial Results for Rolapitant, a Novel Nk-1 Receptor Antagonist, in the Prevention of Chemotherapy-Induced Nausea and Vomiting (Cinv) in Patients Receiving Cisplatin-Based Chemotherapy
Authors: M.R. Chasen, A. Poma, M.L. Hedley, R. Martell, C. Gridelli
Journal: Annals of Oncology (2014)
Doctors and managers – the Wayne Rooney syndrome?
Authors: John Main
Journal: Journal of the Royal Society of Medicine (2010)

It's obvious why doctors and managers often don't get on – the latter are an unpleasant reminder that healthcare is complex and expensive, that someone has to organize it, and someone has to pay.

Unfortunately, from the moment they thought of going to medical school, doctors have been largely insulated from these harsh realities. A medical degree is generally seen as being far more worthy than shorter, non-vocational degrees, especially those devoted to useless mumbo-jumbo like social sciences and humanities. And, of course, learning to heal the sick is the epitome of righteousness in stark contrast to grubby and morally dubious activities like business studies or accounting.

So doctors start out suffused with a great sense of their own worth and that of their virtually holy profession. The problem is compounded by the NHS being free at the point of care. This is a wonderful thing but unfortunately free at the point of care is all too often confused with free. And this culture is so deep-rooted that virtually every senior medical role model will be frequently heard blaming management for, well, everything really. And, of course, the media fuel the same delusions. In tabloid land, it is always a disgrace when expensive and near-useless treatments are denied, and in the medical press and blogland, the myth that the NHS was fine when doctors used to run it is spouted daily and never questioned. (Note to younger readers – the NHS, in England at least, was rubbish in the 70s and 80s, when we had hardly any managers.)

Doctors are the Wayne Rooneys of the NHS, undoubtedly talented but so protected from reality for so long that we have come to believe in our own myth. When it comes to us, we are the superstars, the team is built around us, and what we do is more important than anything else. We move on a more elevated plane than the rest of the world, and please don't suggest that something as trivial and tarnished as money should limit our ambitions. A manager's job is to point out these harsh realities, which of course inevitably leads to superstar sulks and the rest.

So, no solutions, but you can't start treatment without a diagnosis.