tbuckley/cabot-search huggingface dataset:
Carvedilol?A new nonselective beta blocker
Authors: Ewan Forrest, Adrian Stanley, Peter Hayes
Journal: Hepatology (2000)

patients with PTLD in both studies is small (6 in the study of Hezode et al. and 13 in our study) increasing the probability of type 2 statistical error.The distribution of underlying liver diseases before transplantation is different between the two studies with a larger percent of patients transplanted for HCV-related cirrhosis in the study by Hezode et al. compared with a larger percent of patients transplanted for cholestatic liver diseases in our study.Viral factors including the HCV genotype and HCV RNA titers may also play a role and may have been different between the two populations.Finally, host-related factors such as genetic predisposition may potentially be important for the development of PTLD in the setting of HCV infection.Host predisposition may also explain discrepancies found in the literature related to HCV infection and B-cell non-Hodgkin' s lymphoma in immunocompetent patients with chronic HCV.Although studies from Italy 2,3 and the United States 4 (Hispanic population) suggested a link between HCV and B-cell lymphomas, two reports from the United Kingdom 5,6 failed to demonstrate it.In conclusion, we propose that more studies are needed before PTLD can be listed as one of the extrahepatic manifestations of HCV infection in liver transplant recipients.
Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atheroscierosis in the Atherosclerosis Risk in Communities (ARIC) Study: a case-cohort study
Authors: Veikko Salomaa, Carmen Matei, Nena Aleksic, Leticia Sansores-Garcia, Aaron R Folsom, Harinder Juneja, Lloyd E Chambless, Kenneth K Wu
Journal: The Lancet (1999)
Strategies for expanding colorectal cancer screening at community health centers
Authors: Mona Sarfaty, Mary Doroshenk, James Hotz, Durado Brooks, Seiji Hayashi, Terry C. Davis, Djenaba Joseph, David Stevens, Donald L. Weaver, Michael B. Potter, Richard Wender
Journal: CA A Cancer Journal for Clinicians (2013)

Community health centers are uniquely positioned to address disparities in colorectal cancer (CRC) screening as they have addressed other disparities. In 2012, the federal Health Resources and Services Administration, which is the funding agency for the health center program, added a requirement that health centers report CRC screening rates as a standard performance measure. These annually reported, publically available data are a major strategic opportunity to improve screening rates for CRC. The Patient Protection and Affordable Care Act enacted provisions to expand the capacity of the federal health center program. The recent report of the Institute of Medicine on integrating public health and primary care included an entire section devoted to CRC screening as a target for joint work. These developments make this the ideal time to integrate lifesaving CRC screening into the preventive care already offered by health centers. This article offers 5 strategies that address the challenges health centers face in increasing CRC screening rates. The first 2 strategies focus on improving the processes of primary care. The third emphasizes working productively with other medical providers and institutions. The fourth strategy is about aligning leadership. The final strategy is focused on using tools that have been derived from models that work. CA Cancer J Clin 2013;63:221–231 . © 2013 American Cancer Society, Inc .
Feminizing chicks: a model for avian sex determination based on titration of Hint enzyme activity and the predicted structure of an Asw-Hint heterodimer
Authors: Helen C Pace, Charles Brenner
Journal: Genome biology (2003)

In birds and some lizards, females are heterogametic with a ZW karyotype, while males are ZZ homogametes. The molecular basis for sexual differentiation in birds is unknown: arguments exist for doses of Z masculinizing chicks and for W information feminizing. ASW was identified as a tandemly repeated gene conserved on avian W chromosomes that is expressed in early female development and appears to be an inactive form of avian Z-encoded HINT. Hint is a dimeric enzyme that hydrolyzes AMP linked to lysine, whose enzyme activity is required for regulation of the Cdk7 homologous Kin28 kinase in yeast. Of 16 residues most conserved across all life forms for AMP interactions, 15 are sexually dimorphic in birds, that is, altered in the female-specific Asw protein. Genomic and expression data suggest that Asw may feminize chicks, dominantly interfering with Hint function by heterodimerization.We consider whether positive cooperativity could explain how Hint heterodimerization with an inert enzyme might reduce specific activity by more than 50% and provide data sufficient to reject this model. Instead, we hypothesize that Asw carries a signal for mislocalization and/or proteolysis, and/or dominantly suppresses the remaining Hint active site to function as a dominant negative.Molecular modeling suggests that Asw and Hint can heterodimerize and that Gln 127, an Asw-specific alteration for Trp123, dominantly interferes with the Hint active site. An extra dose of HINT in ZZW chicks, and thus more Hint homodimer, may partially overcome the feminizing influence of ASW and lead to the observed intersexual characteristics of ZZW triploids.
Acute Myeloid Leukemia and Myelodysplastic Syndromes in Older Patients
Authors: Elihu Estey
Journal: Journal of Clinical Oncology (2007)

The median age of patients with acute myeloid leukemia (AML) is 65 to 70 years. The majority of older patients with AML probably do not receive specific treatment, and those who receive standard regimens have a median survival time of less than 1 year. This suggests that, in general, older patients should receive investigational therapy; however, factors other than age influence survival after administration of standard treatment and need to be accounted for when making treatment recommendations. In some cases where investigational therapy is unavailable, palliative care may be the best option. Like AML, myelodysplastic syndrome (MDS) is a disease of the elderly. It is divided into higher and lower risk groups. The natural history of high-risk MDS (eg, &gt; 10% marrow blasts) bears more resemblance to that of AML than to that of an indolent disorder; accordingly, similar therapeutic considerations apply. The more benign natural history of lower risk MDS leads to consideration of reduction in transfusion needs and improvement in quality of life as primary goals of therapy. Lenalidomide, azacitidine, and decitabine, each recently approved by the US Food and Drug Administration, are useful in achieving these objectives.
Researchers find no clear link between air pollution and heart attack or strokes
Authors: J. Wise
Journal: BMJ (2014)

A new analysis has found no clear evidence that short term increases in air pollution are linked to a rise in heart attacks or strokes.1 However, the research indicates levels of particulate matter are linked to an increased risk of arrhythmia, atrial fibrillation, and pulmonary embolism.

The study, published in the journal Heart , used the Myocardial Ischaemia National Audit Project (MINAP) database to identify all acute admissions for myocardial infarction and stroke in England and Wales together with hospital episode statistics on emergency …
Multiple Distinct Sets of Stereotyped Antigen Receptors Indicate a Role for Antigen in Promoting Chronic Lymphocytic Leukemia
Authors: Bradley T. Messmer, Emilia Albesiano, Dimitar G. Efremov, Fabio Ghiotto, Steven L. Allen, Jonathan Kolitz, Robin Foa, Rajendra N. Damle, Franco Fais, Davorka Messmer, Kanti R. Rai, Manlio Ferrarini, Nicholas Chiorazzi
Journal: The Journal of Experimental Medicine (2004)

Previous studies suggest that the diversity of the expressed variable (V) region repertoire of the immunoglobulin (Ig)H chain of B-CLL cells is restricted. Although limited examples of marked constraint in the primary structure of the H and L chain V regions exist, the possibility that this level of restriction is a general principle in this disease has not been accepted. This report describes five sets of patients, mostly with unmutated or minimally mutated IgV genes, with strikingly similar B cell antigen receptors (BCRs) arising from the use of common H and L chain V region gene segments that share CDR3 structural features such as length, amino acid composition, and unique amino acid residues at recombination junctions. Thus, a much more striking degree of structural restriction of the entire BCR and a much higher frequency of receptor sharing exists among patients than appreciated previously. The data imply that either a significant fraction of B-CLL cells was selected by a limited set of antigenic epitopes at some point in their development and/or that they derive from a distinct B cell subpopulation with limited Ig V region diversity. These shared, stereotyped Ig molecules may be valuable probes for antigen identification and important targets for cross-reactive idiotypic therapy.
Weekly low-dose docetaxel in the treatment of lung metastases from angiosarcoma of the head
Authors: M. Yamada, N. Hatta, M. Mizuno, N. Oishi, K. Takehara
Journal: British Journal of Dermatology (2005)

Journal Article Weekly low‐dose docetaxel in the treatment of lung metastases from angiosarcoma of the head Get access M. Yamada, M. Yamada Department of Dermatology, Kanazawa University School of Medicine, 13‐1 Takara‐machi, Kanazawa‐shi, Ishikawa 920‐8641, Japan E‐mail: mizuki@derma.m.kanazawa‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar N. Hatta, N. Hatta Department of Dermatology, Kanazawa University School of Medicine, 13‐1 Takara‐machi, Kanazawa‐shi, Ishikawa 920‐8641, Japan E‐mail: mizuki@derma.m.kanazawa‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar M. Mizuno, M. Mizuno Department of Dermatology, Kanazawa University School of Medicine, 13‐1 Takara‐machi, Kanazawa‐shi, Ishikawa 920‐8641, Japan E‐mail: mizuki@derma.m.kanazawa‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar N. Oishi, N. Oishi Department of Dermatology, Kanazawa University School of Medicine, 13‐1 Takara‐machi, Kanazawa‐shi, Ishikawa 920‐8641, Japan E‐mail: mizuki@derma.m.kanazawa‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar K. Takehara K. Takehara Department of Dermatology, Kanazawa University School of Medicine, 13‐1 Takara‐machi, Kanazawa‐shi, Ishikawa 920‐8641, Japan E‐mail: mizuki@derma.m.kanazawa‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 152, Issue 4, 1 April 2005, Pages 811–812, https://doi.org/10.1111/j.1365-2133.2005.06503.x Published: 01 April 2005
A Phase I and Pharmacologic Trial of Two Schedules of the Proteasome Inhibitor, PS-341 (Bortezomib, Velcade), in Patients with Advanced Cancer
Authors: Grace K. Dy, James P. Thomas, George Wilding, Laura Bruzek, Sumithra Mandrekar, Charles Erlichman, Dona Alberti, Kim Binger, Henry C. Pitot, Steven R. Alberts, Lorelei J. Hanson, Rebecca Marnocha, Kendra Tutsch, Scott H. Kaufmann, Alex A. Adjei
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies. Patients and Methods: Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and 4 female) received PS-341 twice weekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity. Results: The most common toxicity was thrombocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule I. Grade ≥3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade ≥3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2, and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response. Conclusion: PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.
Perception-consciousness and action-consciousness?
Authors: D. M. Armstrong
Journal: Behavioral and Brain Sciences (1995)

Abstract Block's distinction between phenomenal and access consciousness is accepted, and it is agreed that one may be found without the other, but his account of the distinction is challenged. Phenomenal consciousness is perceptual consciousness, and it is a matter of gaining information of a detailed, nonverbal sort about the subject's body and environment. Access consciousness is good, old-fashioned introspection.
Implications of Familial Colorectal Cancer Risk Profiles and Microsatellite Instability Status
Authors: Steven J. Lubbe, Emily L. Webb, Ian P. Chandler, Richard S. Houlston
Journal: Journal of Clinical Oncology (2009)

Estimating familial colorectal cancer (CRC) risk is clinically important in being able to discriminate between high- and low-risk groups. To quantify familial CRC risks associated with mismatch repair (MMR) deficient and microsatellite stable (MSS) tumors, we analyzed 2,941 population-based cases of CRC.MMR status in CRCs was established by testing for microsatellite instability (MSI). MUTYH status was assigned by screening for Y165C and G382D variants. Age-specific relative and absolute CRC risks in first-degree relatives (FDRs) were calculated, and the most likely genetic models of familial aggregation were derived.CRC risks in FDRs were strongly associated with MSI status (MSI, standardized incidence ratio [SIR] = 4.28, 95% CI, 3.51 to 5.17; MSS, SIR = 1.91, 95% CI, 1.73 to 2.11), early-onset disease (MSI patient age < 55 years, SIR = 10.96, 95% CI, 8.32 to 14.17; MSS patient age < 55 years, SIR = 2.3, 95% CI, 1.88 to 2.85), and having more than one affected FDR (MSI, SIR = 10.00, 95% CI, 7.74 to 12.72; MSS, SIR = 2.78, 95% CI, 2.18 to 3.48). The familial aggregation of CRC associated with MSI cancer was parsimonious with dominant model conferring a high CRC risk at early ages. Approximately 69% of the excess familial risk in FDRs can be ascribed to MSS CRC, and although the pattern of familial risk supports recessive susceptibility in addition to MUTYH, the absolute risk of CRC is at best modest.The results from this analysis should enable an individual's risk of CRC to be more accurately estimated, thus maximizing the value of screening programs. Results also have utility in the design of genetic analyses to identify novel disease alleles.
Prevention of Cytomegalovirus Infection–enhanced Experimental Obliterative Bronchiolitis by Antiviral Prophylaxis or Immunosuppression in Rat Tracheal Allografts
Authors: JUSSI M. TIKKANEN, ERKKI A. KALLIO, CATHRIEN A. BRUGGEMAN, PETRI K. KOSKINEN, KARL B. LEMSTRÖM
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

In this study, the prevention of rat cytomegalovirus (RCMV) infection-enhanced experimental obliterative bronchiolitis in rat tracheal allografts was investigated. RCMV infection markedly enhanced cell proliferation and histological changes of obliterative bronchiolitis, a form of chronic rejection after lung transplantation. These alterations were linked to increased interleukin (IL)-2 and tumor necrosis factor-alpha (TNF-alpha) immunoreactivity, and reduction of IL-10 expression. In recipient rats with acute RCMV infection, prophylaxis with either ganciclovir (DHPG) or hyperimmune serum (HIS) totally prevented RCMV infection-enhanced tracheal occlusion. DHPG treatment initiated during acute RCMV infection also reduced lesion development but markedly less than DHPG prophylaxis. Treatment of acute RCMV infection with HIS alone or in combination with DHPG had no significant effect on tracheal occlusion. Inhibition of the transcription of cytokines by high doses of cyclosporine A significantly reduced RCMV infection-enhanced tracheal obliteration. In rats with chronic RCMV infection, obliterative alterations were prevented by DHPG prophylaxis initiated at the time of transplantation. Prophylaxis either with DHPG or HIS did not affect the amount of infectious RCMV recovered from host salivary glands, nor were there differences seen in RCMV major immediate early DNA expression in tracheal allografts between different antiviral drug regimens. Immunohistochemical analysis of allografts revealed that inhibition of tracheal occlusion by antiviral prophylaxis was associated with a reduction in the number of ED1(+) macrophages and cells staining for Th1 cytokines and TNF-alpha, while immune modulation by cyclosporine A up-regulated IL-10 production. In conclusion, the results of the present study suggest that the CMV infection-enhanced chronic rejection develops independently of viral load but requires both immune activation and simultaneous CMV gene expression beyond immediate early genes.
Stimulation of the Stress-Activated Mitogen-Activated Protein Kinase Subfamilies in Perfused Heart
Authors: Marie A. Bogoyevitch, Judith Gillespie-Brown, Albert J. Ketterman, Stephen J. Fuller, Rachel Ben-Levy, Alan Ashworth, Christopher J. Marshall, Peter H. Sugden
Journal: Circulation Research (1996)

It has recently been recognized that cellular stresses activate certain members of the mitogen-activated protein kinase (MAPK) superfamily. One role of these "stress-activated" MAPKs is to increase the transactivating activity of the transcription factors c-Jun, Elk1, and ATF2. These findings may be particularly relevant to hearts that have been exposed to pathological stresses. Using the isolated perfused rat heart, we show that global ischemia does not activate the 42- and 44-kD extracellular signal-regulated (protein) kinase (ERK) subfamily of MAPKs but rather stimulates a 38-kD activator of MAPK-activated protein kinase-2 (MAPKAPK2). This activation is maintained during reperfusion. The molecular characteristics of this protein kinase suggest that it is a member of the p38/reactivating kinase (RK) group of stress-activated MAPKs. In contrast, stress-activated MAPKs of the c-Jun N-terminal kinase (JNK/SAPKs) subfamily are not activated by ischemia alone but are activated by reperfusion following ischemia. Furthermore, transfection of ventricular myocytes with activated protein kinases (MEKK1 and SEK1) that may be involved in the upstream activation of JNK/ SAPKs induces increases in myocyte size and transcriptional changes typical of the hypertrophic response. We speculate that activation of multiple parallel MAPK pathways may be important in the responses of hearts to cellular stresses.
Molecular Pathogenesis of Necrotizing Fasciitis
Authors: Randall J. Olsen, James M. Musser
Journal: Annual Review of Pathology Mechanisms of Disease (2009)

Necrotizing fasciitis, also known as the flesh-eating disease, is a severe invasive infection associated with very high rates of human morbidity and mortality. It is most commonly caused by group A Streptococcus(GAS), a versatile human pathogen that causes diseases ranging in severity from uncomplicated pharyngitis (or strep throat) to life-threatening infections such as necrotizing fasciitis. Herein, we review recent discoveries bearing on the molecular pathogenesis of GAS necrotizing fasciitis. Importantly, the integration of new technologies and the development of human-relevant animal models have markedly expanded our understanding of the key pathogen-host interactions underlying GAS necrotizing fasciitis. For example, we now know that GAS organisms secrete a variety of proteases that disrupt host tissue and that these proteolytic enzymes are regulated by multiple transcriptional and posttranslational processes. This pathogenesis knowledge will be crucial to supporting downstream efforts that seek to develop novel vaccines and therapeutic agents for this serious human infection.
Christiaan Neethling Barnard Abdulla Mohamed Bugaighis John Calam Terence Mark Hardiker Ian Martin Jackson William Gwyn Lewis Olivia (Libby) Potterton Anthony Robinson Alan Mark Vincent
Authors: T. Treasure, A. Bugaighis, I. Calder, H. Hodgson, I W Manson, M. Baum, S. Lewis, A Shetty, A-M O'Neill, G. Hambleton, D. Darby
Journal: BMJ (2001)
744 IN VIVO AND IN VITRO RESISTANCE TO SILIBININ, A COMPONENT OF SILYMARIN AND POTENT INHIBITOR OF HCV REPLICATION
Authors: S. Chevaliez, A. Ahmed-Belkacem, A. Soulier, K. Zinober, T.-M. Scherzer, R. Brillet, P. Ferenci, J.-M. Pawlotsky
Journal: Journal of Hepatology (2010)
Characterization of a Novel PKA Phosphorylation Site, Serine-2030, Reveals No PKA Hyperphosphorylation of the Cardiac Ryanodine Receptor in Canine Heart Failure
Authors: Bailong Xiao, Ming Tao Jiang, Mingcai Zhao, Dongmei Yang, Cindy Sutherland, F. Anthony Lai, Michael P. Walsh, David C. Warltier, Heping Cheng, S. R. Wayne Chen
Journal: Circulation Research (2005)

Hyperphosphorylation of the cardiac Ca2+ release channel (ryanodine receptor, RyR2) by protein kinase A (PKA) at serine-2808 has been proposed to be a key mechanism responsible for cardiac dysfunction in heart failure (HF). However, the sites of PKA phosphorylation in RyR2 and their phosphorylation status in HF are not well defined. Here we used various approaches to investigate the phosphorylation of RyR2 by PKA. Mutating serine-2808, which was thought to be the only PKA phosphorylation site in RyR2, did not abolish the phosphorylation of RyR2 by PKA. Two-dimensional phosphopeptide mapping revealed two major PKA phosphopeptides, one of which corresponded to the known serine-2808 site. Another, novel, PKA phosphorylation site, serine 2030, was identified by Edman sequencing. Using phospho-specific antibodies, we showed that the novel serine-2030 site was phosphorylated in rat cardiac myocytes stimulated with isoproterenol, but not in unstimulated cells, whereas serine-2808 was considerably phosphorylated before and after isoproterenol treatment. We further showed that serine-2030 was stoichiometrically phosphorylated by PKA, but not by CaMKII, and that mutations of serine-2030 altered neither the FKBP12.6-RyR2 interaction nor the Ca2+ dependence of [3H]ryanodine binding. Moreover, the levels of phosphorylation of RyR2 at serine-2030 and serine-2808 in both failing and non-failing canine hearts were similar. Together, our data indicate that serine-2030 is a major PKA phosphorylation site in RyR2 responding to acute beta-adrenergic stimulation, and that RyR2 is not hyperphosphorylated by PKA in canine HF.