tbuckley/cabot-search huggingface dataset:
Dual Protease Inhibitor Therapy in HIV-Infected Patients: Pharmacologic Rationale and Clinical Benefits
Authors: Charles Flexner
Journal: The Annual Review of Pharmacology and Toxicology (2000)

HIV protease inhibitors, as components of combination antiretroviral drug regimens, have substantially reduced the morbidity and mortality associated with HIV infection. They selectively block the action of the virus-encoded protease and stop the virus from replicating. In general, these drugs have poor systemic bioavailability and must be dosed with respect to meals for optimal absorption. Protease inhibitor-containing regimens require ingestion of a large number of capsules, are costly, and produce or are susceptible to metabolic drug interactions. Simultaneous administration of two protease inhibitors takes advantage of beneficial pharmacokinetic interactions and may circumvent many of the drugs' undesirable pharmacologic properties. For example, ritonavir increases saquinavir concentrations at steady state by up to 30-fold, allowing reduction of saquinavir dose and dosing frequency. Ritonavir decreases the systemic clearance of indinavir and overcomes the deleterious effect of food on indinavir bioavailability. These benefits reflect inhibition of presystemic clearance and first-pass metabolism, as well as inhibition of systemic clearance mediated by hepatic cytochrome P450 3A4. Several dual protease inhibitor combination regimens have shown great promise in clinical trials and are now recommended as components of salvage therapy for HIV-infected patients.
A phase I–II study of rituximab, ifosfamide, mitoxantrone andetoposide (R-IME) for B cell non-Hodgkin’s lymphoma prior to and after high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT)
Authors: R.M. Joyce, M. Regan, J. Ottaway, T. Umiel, J.-C. Tetreault, J. Levine, D. McDermott, D. Hurley, N. Giallombardo, T. Smith, D. Lamontagne, L. Uhl, D. Avigan
Journal: Annals of Oncology (2003)
Ability of Recombinant Factor VIIa to Generate Thrombin During Inhibition of Tissue Factor in Human Subjects
Authors: Philip W. Friederich, Marcel Levi, Kenneth A. Bauer, George P. Vlasuk, William E. Rote, Daan Breederveld, Tijmen Keller, Marco Spataro, Samad Barzegar, Harry R. Büller
Journal: Circulation (2001)

Background —In view of the central role of the tissue factor–factor VIIa pathway in the initiation of blood coagulation, novel therapeutic strategies aimed at inhibiting this catalytic complex are currently being evaluated. A limitation of this new class of anticoagulants may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs. The aim of this study was to investigate the in vivo potential of recombinant factor VIIa (rVIIa) to induce thrombin generation in healthy subjects pretreated with recombinant nematode anticoagulant protein c2, a specific inhibitor of the tissue factor–factor VIIa complex, in a double-blind randomized crossover study. Methods and Results —Administration of nematode anticoagulant protein c2 (3.5 μg/kg) caused a prolongation of the prothrombin time from 13.7±0.6 to 16.9±1.2 seconds. The subsequent injection of rVIIa (90 μg/kg) resulted in an immediate and complete correction of the prothrombin time and a marked generation of thrombin, reflected by increased levels of prothrombin activation fragment F1+2 and thrombin-antithrombin complexes from 0.75±0.64 to 3.29±6.3 nmol/L and from 2.4±0.6 to 10.7±3.9 μg/mL, respectively. Factor X and IX activation peptides showed a 3.5-fold and a 3.8-fold increase, respectively, after the administration of rVIIa in the presence of nematode anticoagulant protein c2. Conclusions —During treatment with an inhibitor of the tissue factor–factor VIIa complex, the infusion of rVIIa resulted in thrombin generation. Our results indicate that rVIIa may be a good candidate as an antidote for inhibitors of tissue factor.
Terminology and classification of muscle injuries in sport: The Munich consensus statement
Authors: Hans-Wilhelm Mueller-Wohlfahrt, Lutz Haensel, Kai Mithoefer, Jan Ekstrand, Bryan English, Steven McNally, John Orchard, C Niek van Dijk, Gino M Kerkhoffs, Patrick Schamasch, Dieter Blottner, Leif Swaerd, Edwin Goedhart, Peter Ueblacker
Journal: British Journal of Sports Medicine (2012)

Objective To provide a clear terminology and classification of muscle injuries in order to facilitate effective communication among medical practitioners and development of systematic treatment strategies. Methods Thirty native English-speaking scientists and team doctors of national and first division professional sports teams were asked to complete a questionnaire on muscle injuries to evaluate the currently used terminology of athletic muscle injury. In addition, a consensus meeting of international sports medicine experts was established to develop practical and scientific definitions of muscle injuries as well as a new and comprehensive classification system. Results The response rate of the survey was 63%. The responses confirmed the marked variability in the use of the terminology relating to muscle injury, with the most obvious inconsistencies for the term strain . In the consensus meeting, practical and systematic terms were defined and established. In addition, a new comprehensive classification system was developed, which differentiates between four types: functional muscle disorders (type 1: overexertion-related and type 2: neuromuscular muscle disorders) describing disorders without macroscopic evidence of fibre tear and structural muscle injuries (type 3: partial tears and type 4: (sub)total tears/tendinous avulsions) with macroscopic evidence of fibre tear, that is, structural damage. Subclassifications are presented for each type. Conclusions A consistent English terminology as well as a comprehensive classification system for athletic muscle injuries which is proven in the daily practice are presented. This will help to improve clarity of communication for diagnostic and therapeutic purposes and can serve as the basis for future comparative studies to address the continued lack of systematic information on muscle injuries in the literature. What are the new things Consensus definitions of the terminology which is used in the field of muscle injuries as well as a new comprehensive classification system which clearly defines types of athletic muscle injuries. Level of evidence Expert opinion, Level V.
Therapy of hepatitis C: Interferon alfa-2a trials
Authors: W M Lee
Journal: Hepatology (1997)

Interferon alfa-2a resembles other recombinant α interferons in structure and pharmacology. Studies delineating its efficacy suggest that after 6 to 12 months of therapy, sustained biochemical responses occur in 4% to 49% of patients, providing adequate doses (&gt; or = 3 million units three times weekly) are used. Overall, a dose-response curve is evident in regard to biochemical responses, decrease in histological scores for inflammation, and virological responses (percent negative serum hepatitis C virus [HCV] RNA) after treatment. Differences in response rates between studies probably reflect patient selection and particularly the percent of patients with established cirrhosis, because these patients respond less well than those with earlier histological stages of disease. A variety of regimens of interferon alfa-2a have been used, including use of higher doses, longer periods of treatment, induction using higher doses initially, and intermittent pulse therapy. Both longer periods of therapy and induction dosing show strong but not significant trends toward improvement in response rates, which reach significance when the two strategies are combined. Outcome is not significantly improved by escalating doses during therapy when inadequate responses are seen, or by pulse therapy. The side effect profile of interferon alfa-2a is similar to that of other interferons. Long-term follow-up studies have demonstrated that 90% of patients with a sustained biochemical response at 6 months after therapy maintain the response, and 95% remain negative for HCV RNA in serum. Challenges for the future include better delineation of the advantages of induction dosing, the optimal duration of therapy, and further understanding of the frequent discordance between HCV RNA data and aminotransferase levels. This latter finding suggests that use of both parameters is necessary to evaluate fully responses to therapy.
Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis
Authors: M H Schiff
Journal: Annals of the Rheumatic Diseases (2005)

To assess the safety of adalimumab in global clinical trials and postmarketing surveillance among patients with rheumatoid arthritis (RA).Safety data for adalimumab treated patients from randomised controlled trials, open label extensions, and two phase IIIb open label trials were analysed. In addition, postmarketing spontaneous reports of adverse events in the United States were collected following Food and Drug Administration approval of adalimumab on 31 December 2002.As of 15 April 2005, the RA clinical trial safety database analysed covered 10,050 patients, representing 12,506 patient-years (PYs) of adalimumab exposure. The rate of serious infections, 5.1/100 PYs, was comparable to that reported on 31 August 2002 (4.9/100 PYs), and to published reports of RA populations naive to anti-tumour necrosis factor (TNF) therapy. Following implementation of tuberculosis (TB) screening in clinical trials, the rate of TB decreased. There were 34 cases of TB as of this analysis (0.27/100 PYs). The standardised incidence ratio for lymphoma was 3.19 (95% CI 1.78 to 5.26), consistent with the observed increased incidence in the general RA population. As of 30 June 2005, there were an estimated 78 522 PYs of exposure to adalimumab in the US postmarketing period. Seventeen TB cases were spontaneously reported (0.02/100 PYs) from the US. Rates of other postmarketing events of interest, such as congestive heart failure, systemic lupus erythematosus, opportunistic infections, blood dyscrasias, lymphomas, and demyelinating disease, support observations from clinical trials.Analyses of these data demonstrate that long term adalimumab treatment is generally safe and well tolerated in patients with RA.
The origin of a Robertsonian chromosomal translocation in house mice inferred from linked microsatellite markers
Authors: C Riginos, M W Nachman
Journal: Molecular Biology and Evolution (1999)

The western European house mouse, Mus domesticus, includes many distinct Robertsonian (Rb) chromosomal races. Two competing hypotheses may explain the distribution of Rb translocations found in different populations: they may have arisen independently multiple times, or they may have arisen once and been spread through long-distance dispersal. We investigated the origin of the Rb 5.15 translocation using six microsatellite loci linked to the centromeres of chromosomes 5 and 15 in 84 individuals from three Rb populations and four neighboring standard-karyotype populations. Microsatellite variation on the 5.15 metacentric chromosomes was significantly reduced relative to the amount of variation found on acrocentric chromosomes 5 and 15, suggesting that linked microsatellite loci can track specific mutational events. Phylogenetic analyses resulted in trees which are consistent with multiple origins of the 5.15 metacentric chromosomes found in the three Rb populations. These results suggest that cytologically indistinguishable mutations have arisen independently in natural populations of house mice.
Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice
Authors: Lijian Wang, Lynne Harrington, Estela Trebicka, Hai Ning Shi, Jonathan C. Kagan, Charles C. Hong, Herbert Y. Lin, Jodie L. Babitt, Bobby J. Cherayil
Journal: Journal of Clinical Investigation (2009)

Mice deficient in the hemochromatosis gene, Hfe, have attenuated inflammatory responses to Salmonella infection associated with decreased macrophage TNF-alpha and IL-6 biosynthesis after exposure to LPS. In this study, we show that the abnormal cytokine production is related to impaired TLR4 signaling. Despite their abnormal response to LPS, Hfe KO macrophages produced amounts of TNF-alpha similar to those in WT cells after TLR2 stimulation. Consistent with this finding, LPS-induced activation of Mal/MyD88-dependent events was normal in the mutant macrophages. However, LPS-induced IFN-beta expression, a TRAM/TRIF-dependent response activated by TLR4, was reduced by Hfe deficiency. This reduction could be replicated in WT macrophages with the use of iron chelators. In contrast, TLR3-activated expression of IFN-beta, a TRIF-dependent response, was normal in Hfe KO macrophages and was unaffected by iron chelation. Our data suggest that low intracellular iron selectively impairs signaling via the TLR4/TRAM/TRIF pathway proximal to TRIF and results in reduced LPS-induced cytokine expression. Furthermore, by mimicking the altered iron metabolism associated with Hfe deficiency, we found that 3 different inhibitors of hepcidin attenuated Salmonella-induced and noninfectious enterocolitis. Thus, manipulation of iron homeostasis could represent a new therapeutic approach to controlling inflammation.
Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk
Authors: Annegret Fischer, David Ellinghaus, Marcel Nutsua, Sylvia Hofmann, Courtney G. Montgomery, Michael C. Iannuzzi, Benjamin A. Rybicki, Martin Petrek, Frantisek Mrazek, Stefan Pabst, Christian Grohé, Johan Grunewald, Marcus Ronninger, Anders Eklund, Leonid Padyukov, Violeta Mihailovic-Vucinic, Dragana Jovanovic, Martina Sterclova, Jiri Homolka, Markus M. Nöthen, Stefan Herms, Christian Gieger, Konstantin Strauch, Juliane Winkelmann, Bernhard O. Boehm, Stephan Brand, Carsten Büning, Manfred Schürmann, Eva Ellinghaus, Hansjörg Baurecht, Wolfgang Lieb, Almut Nebel, Joachim Müller-Quernheim, Andre Franke, Stefan Schreiber
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far.To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci.Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms.Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3.Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics.
Lenalidomide therapy in myelofibrosis with myeloid metaplasia
Authors: Ayalew Tefferi, Jorge Cortes, Srdan Verstovsek, Ruben A. Mesa, Deborah Thomas, Terra L. Lasho, William J. Hogan, Mark R. Litzow, Jacob B. Allred, Dan Jones, Catriona Byrne, Jerome B. Zeldis, Rhett P. Ketterling, Rebecca F. McClure, Francis Giles, Hagop M. Kantarjian
Journal: Blood (2006)
Early Initiation of Dialysis Fails to Prolong Survival in Patients with End-Stage Renal Failure
Authors: Jamie P Traynor, Keith Simpson, Colin C Geddes, Christopher J Deighan, Jonathan G Fox
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. There is a trend to start dialysis earlier in patients with chronic renal failure. Studies that suggest improved survival from earlier initiation of dialysis are flawed in that they have measured survival from start of dialysis rather than from a time point before dialysis, when patients have the same renal function. This flaw is termed lead-time bias. Using the electronic patient record at the renal unit of Glasgow Royal Infirmary, all patients were identified who had received dialysis for chronic renal failure and who had sufficient data to calculate the time point at which they reached an estimated creatinine clearance (eC<sub>Cr</sub>) of 20 ml/min (<i>n</i> = 275). This date was used to time survival. The patients were divided into early and late start groups by the median eC<sub>Cr</sub> for all patients at initiation of dialysis, which was 8.3 ml/min. There was no significant benefit in patient survival from earlier initiation of dialysis. A Cox proportional hazards model demonstrated a significant inverse relationship between eC<sub>Cr</sub> at start of dialysis and survival (hazard ratio, 1.1; <i>P</i> = 0.02), <i>i.e.</i>, patients who started dialysis with a lower eC<sub>Cr</sub> tended to survive longer. This relationship retained significance when gender, age, weight, presence of diabetes, mode of first dialysis, initial dialysis access, hemoglobin, serum albumin, blood leukocyte count, Wright/Khan index, and eC<sub>Cr</sub> at the start of dialysis were taken into account. This study fails to support a policy of earlier initiation of dialysis for patients with end-stage renal failure.
Effects of vitamin E on the endothelium: equivocal? α-tocopherol and endothelial dysfunction
Authors: F Visioli
Journal: Cardiovascular Research (2001)

oxidative stress: the formation of peroxynitrite (the 'ugly' this issue.side of nitric oxide [9]) that follows this reaction, and the subsequent reaction of peroxynitrite with carbon dioxide, to form a highly reactive nitrosoperoxocarbonate inter-
Drug helps patients with relapsed myeloma
Authors: J. Hopkins Tanne
Journal: BMJ (2003)

Bortezomib, the first of a new class of drugs called proteasome inhibitors, produced a 35% response rate in patients with relapsed, refractory multiple myeloma, an unusually high rate in these patients, for whom there is no other treatment.

A phase II study published in the New England Journal of Medicine (2003;348: 2609-17 led the US Food and Drug Administration to grant accelerated approval to Millennium Pharmaceuticals to provide the drug to patients whose disease …
Vasoconstrictor Potential of Coronary Aspirate From Patients Undergoing Stenting of Saphenous Vein Aortocoronary Bypass Grafts and Its Pharmacological Attenuation
Authors: Petra Kleinbongard, Dirk Böse, Theodor Baars, Stefan Möhlenkamp, Thomas Konorza, Sandra Schöner, Miriam Elter-Schulz, Holger Eggebrecht, Hubertus Degen, Michael Haude, Bodo Levkau, Rainer Schulz, Raimund Erbel, Gerd Heusch
Journal: Circulation Research (2010)

Rationale: Stent implantation into atherosclerotic plaques releases, apart from particulate debris, soluble substances that contribute to impaired microvascular perfusion. Objective: To quantify the release of vasoconstrictors and to determine the efficacy of coronary dilators to attenuate their action. Methods and Results: Using a distal protection/aspiration device, coronary arterial blood was retrieved before and during stenting in 22 patients with severe saphenous vein aorto-coronary bypass stenoses. The release of catecholamines, endothelin, serotonin, thromboxane B 2 , and tumor necrosis factor (TNF)α was measured. The response of rat mesenteric arteries with intact (+E) and denuded (−E) endothelium to aspirate plasma was normalized to that by KCl. Responses to selective receptor blockade, adenosine, nitroprusside, and verapamil against the aspirate-induced constriction were determined. The coronary arterial plasma withdrawn before stenting induced 21±5% and the aspirate plasma after stenting induced 95±8% of maximum KCl-induced vasoconstriction. Serotonin, thromboxane B 2 , and TNFα release into aspirate plasma increased by 1.9±0.2 μmol/L, 25.6±3.1 pg/mL, and 19.7±6.1 pg/mL, respectively, during stenting. The aspirate-induced vasoconstriction was largely antagonized by selective serotonin receptor blockade, with little further antagonism by additional thromboxane receptor blockade. TNFα did not induce constriction per se but potentiated the constriction with serotonin and the thromboxane-analog U-46619 in arteries +E. The concentrations to induce half-maximal vasodilation were comparable for nitroprusside (+E, 3.3×10 −8 ; −E, 1.9×10 −8 mol/L) and verapamil (+E, 8.3×10 −8 ; −E, 7.8×10 −8 mol/L), and the vasoconstriction was eventually eliminated. The vasodilator response to adenosine was dependent on functional endothelium and weaker. Conclusion: Serotonin is the main coronary vasoconstrictor after stenting, and thromboxane and TNFα somewhat potentiate the serotonin response. Nitroprusside and verapamil are more potent than adenosine to attenuate the aspirate plasma-induced vasoconstriction, and they are not dependent on functional endothelium.
Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries.
Authors: L F Paszat, W J Mackillop, P A Groome, C Boyd, K Schulze, E Holowaty
Journal: Journal of Clinical Oncology (1998)

To compare the risk for fatal myocardial infarction (MI) after adjuvant radiotherapy (RT) for left-sided breast cancer with the risk for MI after adjuvant RT for right-sided breast cancer.We studied women with local- and regional-stage breast cancer diagnosed from 1973 to 1992 from the Surveillance, Epidemiology, and End-Results (SEER) cancer registries. We performed life-table analysis, the log-rank test, and Cox proportional hazards regression to compare the time to fatal MI from diagnosis between left-sided and right-sided cases, censoring deaths from other causes.Among irradiated patients, the relative risk (RR) for fatal MI in women with left-sided breast cancer was 1.17 (95% confidence interval [CI], 1.01 to 1.36), controlling for age, compared with those with right-sided breast cancer. The RR for fatal MI among left-sided cases was increased for those under the age of 60 years (RR = 1.98; 95% CI, 1.31 to 2.97) compared with right-sided cases, but not at age 60 years or older. Among women with irradiated regional-stage cancer who were younger than 60 years of age, the risk was significantly increased (RR = 2.24; 95% CI, 1.38 to 3.64) for those with left-sided compared with right-sided breast cancer, but not among patients aged 60 years or older. Among irradiated local-stage cases, the risk for those with left-sided breast cancer was not significantly elevated in either age category. Analysis of 5-year conditional survival cohorts showed an increased risk for irradiated left-sided cases among women younger than 60 years of age in the 10- to 15-year conditional survival cohort (RR = 5.28; 95% CI, 1.82 to 15.3).Adjuvant RT for left-sided breast cancer diagnosed in women younger than 60 years of age is associated with a higher risk for fatal MI 10 to 15 years later compared with adjuvant RT for right-sided cases.