tbuckley/cabot-search huggingface dataset:
Vascular Protection of Dual Therapy (Atorvastatin-Amlodipine) in Hypertensive Patients
Authors: José Luis Martín-Ventura, José Tuñon, Mari Carmen Duran, Luis Miguel Blanco-Colio, Fernando Vivanco, Jesús Egido
Journal: Journal of the American Society of Nephrology (2006)

Hypertension frequently coexists with other cardiovascular risk factors, such as hypercholesterolemia, and their combination is associated with a greater rate of cardiovascular events. Recent clinical data support that treatment of hypertensive patients with a combination of antihypertensive and lipid-lowering therapies leads to a higher reduction in the incidence of cardiovascular events. In the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA), an optimal prevention of cardiovascular events was reached in patients who were randomly assigned to atorvastatin and the amlodipine treatment. However, the potential underlying mechanisms of these vascular protective effects are not fully elucidated. Because experimental studies have shown that statins and calcium channel blockers have antiatherosclerotic effects, the effect of atorvastatin alone or in combination with amlodipine was analyzed in the protein secretion profile of atherosclerotic plaques that were cultured ex vivo. In this respect, the addition of atorvastatin and amlodipine to atherosclerotic plaques normalized the levels of the different released proteins to that obtained from healthy arteries. This review highlights recent clinical and experimental studies that support that a combined treatment of hypertensive patients with both statins and calcium channel blockers could promote a higher reduction in their global cardiovascular risk profile and associated mortality. As an example, the application of a proteomic approach to assess the modulation by atorvastatin alone or in combination with amlodipine on the proteins that are released by atherosclerotic plaques has allowed the identification of novel therapeutic targets by which these drugs could promote their additive/synergic effects.
Allergic Conjunctivitis, Rhinitis and Asthma: One Disease?
Authors: C.A. Riedi, G.G.L.C. Westphal, N.A. Rosario, H.L.B.S. Santos, K. Takizawa, R.V.S. Souza, C.D. Aguilera
Journal: Journal of Allergy and Clinical Immunology (2009)
STAMP1 Is Both a Proliferative and an Antiapoptotic Factor in Prostate Cancer
Authors: Ling Wang, Yang Jin, Yke Jildouw Arnoldussen, Ida Jonson, Su Qu, Gunhild M. Mælandsmo, Alexandr Kristian, Bjørn Risberg, Håkon Wæhre, Håvard E. Danielsen, Fahri Saatcioglu
Journal: Cancer Research (2010)

STAMP1 is predicted to encode a six-transmembrane protein whose expression is highly prostate enriched and is deregulated in prostate cancer. However, the biological role of STAMP1 in prostate cancer cells, or its expression profile at the protein level, is unknown. Here, we find that ectopic expression of STAMP1 significantly increased proliferation of DU145 prostate cancer cells as well as COS-7 cells in vitro; conversely, small interfering RNA-mediated knockdown of STAMP1 expression in LNCaP cells inhibited cell growth and, at least partially, induced cell cycle arrest. In parallel, there were alterations in cell cycle-regulatory gene expression. Knockdown of STAMP1 expression in LNCaP cells also induced significant apoptosis under basal conditions as well as in response to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) alone, or TRAIL + AKT inhibitor LY294002, previously established apoptotic agents in LNCaP cells. Consistently, LNCaP cells with short hairpin RNA-mediated knockdown of STAMP1 were dramatically retarded in their ability to grow as xenografts in nude mice. Interestingly, activation of extracellular signal-regulated kinase, which has previously been implicated in prostate cancer progression, was significantly increased on ectopic expression of STAMP1 in DU145 cells and, conversely, was strongly downregulated on STAMP1 knockdown in LNCaP cells. In the normal prostate, STAMP1 protein is localized to the cytosol and the cell membrane of the prostate epithelial cells; furthermore, its expression is increased in prostate cancer compared with normal prostate. Taken together, these data suggest that STAMP1 is required for prostate cancer growth, which may be a useful target in prostate cancer treatment.
Interleukin-8 gene induction in the myocardium after ischemia and reperfusion in vivo.
Authors: G L Kukielka, C W Smith, G J LaRosa, A M Manning, L H Mendoza, T J Daly, B J Hughes, K A Youker, H K Hawkins, L H Michael
Journal: Journal of Clinical Investigation (1995)

Neutrophil adhesion and direct cytotoxicity for cardiac myocytes require chemotactic stimulation and are dependent upon CD18-ICAM-1 binding. To characterize the potential role of IL-8 in this interaction, canine IL-8 cDNA was cloned and the mature recombinant protein expressed in Escherichia coli BL21 cells. Recombinant canine IL-8 markedly increased adhesion of neutrophils to isolated canine cardiac myocytes. This adhesion resulted in direct cytotoxicity for cardiac myocytes. Both processes were specifically blocked by antibodies directed against CD18 and IL-8. In vivo, after 1 h of coronary occlusion, IL-8 mRNA was markedly and consistently induced in reperfused segments of myocardium. IL-8 mRNA was not induced in control (normally perfused) myocardial segments. Minimal amounts of IL-8 mRNA were detected after 3 or 4 h of ischemia without reperfusion. Highest levels of induction were evident in the most ischemic myocardial segments. IL-8 mRNA peaked in the first 3 h of reperfusion and persisted at high levels beyond 24 h. IL-8 staining was present in the inflammatory infiltrate near the border between necrotic and viable myocardium, as well as in small veins in the same area. These findings provide the first direct evidence for regulation of IL-8 in ischemic and reperfused canine myocardium and support the hypothesis that IL-8 participates in neutrophil-mediated myocardial injury.
Changes in the incidence and prevalence of rheumatoid arthritis in Kamitonda, Wakayama, Japan, 1965-1996
Authors: K. Shichikawa, K. Inoue, S. Hirota, A. Maeda, H. Ota, M. Kimura, T. Ushiyama, M. Tsujimoto
Journal: Annals of the Rheumatic Diseases (1999)

<h3>OBJECTIVE</h3> To evaluate secular trends in the incidence and prevalence of rheumatoid arthritis (RA) in Japan. <h3>METHODS</h3> The incidence and prevalence of RA were determined in a longitudinal population based study in the Kamitonda district, Wakayama, Japan, from 1965 to 1996. <h3>RESULTS</h3> In the study area consisting of about 3000 inhabitants, 16 incident cases, satisfying definite RA by the Rome criteria were detected during the study period. The age and sex adjusted incidence in both men and women combined and the age adjusted incidence in women significantly decreased (p&lt;0.025 and p&lt;0.01, respectively). The age and sex adjusted prevalence in all inhabitants tended to decrease (p&lt;0.1), and the age adjusted prevalence in women significantly declined (p&lt;0.025). In men, however, neither incidence nor prevalence showed significant change. <h3>CONCLUSIONS</h3> The decline of incidence and prevalence of female RA may be reducible to some environmental changes preferentially occurring more obviously in Japanese women than in men. Because the use of oral contraceptives has been extremely low in Japan, the decline should be explained by other factors.
Pappenheimer bodies: A brief historical review
Authors: David A. Sears, Mark M. Udden
Journal: American Journal of Hematology (2004)

Abstract Pappenheimer is credited with describing the intraerythrocytic collections of iron, or siderotic granules, as they appear on Wright‐stained blood smears of certain patients after splenectomy. The history of their description and elucidation of their origin and disposition shows the interaction of morphology with the increasing understanding of red cell physiology in the mid‐twentieth century. Am. J. Hematol. 75:249–250, 2004. © 2004 Wiley‐Liss, Inc.
Progress in Breast Cancer: Overview
Authors: Carlos L. Arteaga
Journal: Clinical Cancer Research (2013)

Abstract This edition of CCR Focus titled Research in Breast Cancer: Frontiers in Genomics, Biology, and Clinical Investigation reviews six topics that cover areas of translational research of high impact in breast cancer. These topics represent areas of breast cancer research where significant progress has occurred but also where very important challenges remain. The papers in this CCR Focus section are contributed by experts in the respective areas of investigation. Herein, key aspects of these contributions and the research directions they propose are reviewed. Clin Cancer Res; 19(23); 6353–9. ©2013 AACR.
Fixed versus flexible features in dissociable neural processing subsystems
Authors: E. Darcy Burgund, Chad J. Marsolek
Journal: Behavioral and Brain Sciences (1998)

Implementational-level evidence of dissociable neural subsystems is a critical element that is missing from the analysis in the Schyns et al. target article. The question of whether fixed or flexible features are used in visual form recognition may have different answers for different subsystems; the evidence that features typically are created during category learning may apply most directly to a specific visual form subsystem.
Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Treatment and <i>RAS</i> Mutations in Colorectal Cancer
Authors: Eric Van Cutsem, Heinz-Josef Lenz, Claus-Henning Köhne, Volker Heinemann, Sabine Tejpar, Ivan Melezínek, Frank Beier, Christopher Stroh, Philippe Rougier, J. Han van Krieken, Fortunato Ciardiello
Journal: Journal of Clinical Oncology (2015)

The phase III CRYSTAL study demonstrated that addition of cetuximab to fluorouracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival, progression-free survival, and objective response in the first-line treatment of patients with KRAS codon 12/13 (exon 2) wild-type metastatic colorectal cancer (mCRC). Outcome was reassessed in subgroups defined by extended RAS mutation testing.Existing DNA samples from KRAS exon 2 wild-type tumors from CRYSTAL study patients were reanalyzed for other RAS mutations in four additional KRAS codons (exons 3 and 4) and six NRAS codons (exons 2, 3, and 4) using beads, emulsion, amplification, and magnetics technology. No tissue microdissection was performed. A ≥ 5% mutant allele cutoff was used to call mutations.Mutation status was evaluable in 430 (64.6%) of 666 patients with KRAS exon 2 wild-type tumors. Other RAS mutations were detected in 63 (14.7%) of 430 patients. In those with RAS wild-type tumors, a significant benefit across all efficacy end points was associated with the addition of cetuximab to FOLFIRI. In patients with other RAS tumor mutations, no difference in efficacy outcomes between treatment groups was seen. The safety profile in RAS subgroups was similar and in line with expectations.In the first-line treatment of mCRC, patients with RAS wild-type tumors derived a significant benefit from the addition of cetuximab to FOLFIRI; patients with RAS tumor mutations did not. Molecular testing of tumors for all activating RAS mutations is essential before considering anti-epidermal growth factor receptor therapy, thereby allowing the further tailoring of cetuximab administration to maximize patient benefit.
Difficulty accessing data from randomised trials of drugs for heart failure: a call for action
Authors: Robert Fleetcroft, John Ford, Nicholas D Gollop, Pieter MacKeith, Kosala Perera, Ashia A Shafi, Jhenaan Sorefan, Caroline Thurlow, Rachel Wakelin, Martin R Cowie, Nicholas Steel
Journal: BMJ (2015)

When <b>Robert Fleetcroft and colleagues</b> attempted a systematic review of the treatment of heart failure, they were unable to answer their research question because of poor reporting and non-disclosure of data. And yet the necessary studies had been done. Here they discuss their experience and possible solutions
Recent advances in pathogenesis and management of hypereosinophilic syndromes
Authors: F. Roufosse, E. Cogan, M. Goldman
Journal: Allergy (2004)

Idiopathic hypereosinophilic syndrome is a largely heterogeneous disorder defined until now as persistent marked hypereosinophilia of unknown origin generally complicated by end‐organ damage. Recent studies clearly indicate that many patients fulfilling the diagnostic criteria of this syndrome can now be classified as presenting one of two major disease variants: the myeloproliferative or the lymphocytic variant. Research in cellular and molecular biology has provided firm evidence for the existence of discrete hematological disorders underlying these variants, questioning the pertinence of continued reference to ‘idiopathic’ hypereosinophilic syndrome in such patients. Furthermore, identification of these variants has a number of prognostic and therapeutic implications that must be taken into consideration for adequate management of these patients.
Frequency of UV-Inducible NRAS Mutations in Melanomas of Patients With Germline CDKN2A Mutations
Authors: M. Eskandarpour, J. Hashemi, L. Kanter, U. Ringborg, A. Platz, J. Hansson
Journal: JNCI Journal of the National Cancer Institute (2003)

Background: Germline alterations in cyclin-dependent kinase inhibitor 2A (CDKN2A) are important genetic factors in familial predisposition to melanoma. Activating mutations of the NRAS proto-oncogene are among the most common somatic genetic alterations in cutaneous malignant melanomas. We investigated the occurrence of NRAS mutations in melanomas and dysplastic nevi in individuals with germline CDKN2A mutations. Methods: Genomic DNA was extracted from 39 biopsy samples (including primary melanomas, metastatic melanomas, and dysplastic nevi) from 25 patients in six Swedish families with a hereditary predisposition to melanoma who carried germline CDKN2A mutations. DNA was also extracted from 10 biopsy samples from patients with sporadic melanomas. NRAS was analyzed using polymerase chain reaction, single-strand conformation polymorphism analysis, and nucleotide sequence analysis. Differences in NRAS mutation frequency between hereditary and sporadic melanomas were analyzed by the chi-square test. All statistical tests were two-sided. Results: Activating mutations in NRAS codon 61, all of which were either CAA(Gln)-AAA(Lys) or CAA(Gln)-CGA(Arg) mutations, were found in 95% (20/21) of primary hereditary melanomas but in only 10% (1/10) of sporadic melanomas (P<.001). Multiple activating NRAS mutations were detected in tumor cells from different regions of individual primary melanomas in nine patients. Activating mutations that were detected in the primary melanomas of these patients were also retained in their metastases. NRAS mutations at sites other than codon 61 were also present in the primary melanomas, indicating genetic instability of this locus. NRAS codon 61 mutations were also detected in dysplastic nevi and in an in situ melanoma, suggesting a role for such mutations during early melanoma development. Conclusions: The high frequency of NRAS codon 61 mutations detected in these hereditary melanomas may be the result of a hypermutability phenotype associated with a hereditary predisposition for melanoma development in patients with germline CDKN2A mutations.
Physician Workforce Projections in an Era of Health Care Reform
Authors: Darrell G. Kirch, Mackenzie K. Henderson, Michael J. Dill
Journal: Annual Review of Medicine (2011)

In 2020, the United States may face shortages of 45,400 primary care physicians and 46,100 medical specialists—a total of 91,500 too few doctors. Unfortunately, health workforce shortages like these are being advanced as cause for repealing or “defunding” the Affordable Care Act (ACA). The extension of health insurance coverage to millions of Americans is a critical first step toward a healthier America. It would be a national failure to leave millions of Americans without health insurance coverage because they will generate additional demand. Rather, the solution is to find ways to meet that demand. Workforce projections utilizing real data and carefully formulated assumptions to assess how and why supply and demand change over time can greatly assist policy makers in finding those solutions. With implementation of the ACA under way, it is time to understand what lessons such projections can teach, and to begin to heed those lessons.
Inflammatory processes: molecular mechanisms and therapeutic opportunities
Authors: Y T KONTTINEN
Journal: Annals of the Rheumatic Diseases (2001)

Inflammatory processes: molecular mechanisms and therapeutic opportunities . Eds L Gordon Letts Jr, Douglas W Morgan. (Pp160; DM198.) Basel: Birkhauser Verlag AG, 2000. ISBN 3-7643-6025-9.

Presentations and workshops held from 1 to 5 November 1998, at the 9th International Conference of the Inflammation Research Association at Hershey Lodge and the Convention Centre at Hershey, Pennsylvania, are the basis of this book. It deals particularly with molecular mechanisms of inflammation and therapeutic opportunities. It is mainly suitable for colleagues in rheumatology who are engaged in inflammation research and also for those who want to look ahead at new targets for …
Schizophrenia as a Disorder of Neurodevelopment
Authors: David A. Lewis, Pat Levitt
Journal: Annual Review of Neuroscience (2002)

▪ Abstract A combination of genetic susceptibility and environmental perturbations appear to be necessary for the expression of schizophrenia. In addition, the pathogenesis of the disease is hypothesized to be neurodevelopmental in nature based on reports of an excess of adverse events during the pre- and perinatal periods, the presence of cognitive and behavioral signs during childhood and adolescence, and the lack of evidence of a neurodegenerative process in most individuals with schizophrenia. Recent studies of neurodevelopmental mechanisms strongly suggest that no single gene or factor is responsible for driving a highly complex biological process. Together, these findings suggest that combinatorial genetic and environmental factors, which disturb a normal developmental course early in life, result in molecular and histogenic responses that cumulatively lead to different developmental trajectories and the clinical phenotype recognized as schizophrenia.
Role of Reduced β-Cell Mass Versus Impaired β-Cell Function in the Pathogenesis of Type 2 Diabetes
Authors: Juris J. Meier, Riccardo C. Bonadonna
Journal: Diabetes Care (2013)

Although it has long been assumed that insulin resistance is the leading factor in the pathogenesis of type 2 diabetes (1), evidence for the importance of the pancreatic β-cells has accumulated over the past decades. In fact, the vast majority of genes associated with type 2 diabetes have been linked to the β-cell, and impairments in β-cell mass and in insulin secretion have been reported in numerous studies in patients with type 2 diabetes. One misconception that has prevented the appreciation of the β-cell defects for a long time is the idea of a “hyperinsulinemia” in patients with type 2 diabetes. This concept has arisen from the observation that patients with type 2 diabetes often present with higher fasting insulin concentrations than nondiabetic individuals. However, if insulin concentrations are interpreted in the context of the concurrently elevated glucose levels in patients with type 2 diabetes, a relative insulin deficit rather than hyperinsulinemia becomes apparent. Furthermore, when insulin secretion is evaluated under stimulated conditions (e.g., after intravenous glucose administration), the typical defects, especially in early-phase insulin release, can be unmasked (2,3).

It has also been suggested that obesity causes type 2 diabetes through impaired insulin action. Undoubtedly, the risk of developing type 2 diabetes increases markedly with BMI. However, if obesity were really the cause of type 2 diabetes, one would expect the vast majority of obese individuals to develop hyperglycemia, whereas in reality ∼80% of obese individuals remain free of diabetes (4). These findings suggest that obesity and insulin resistance are indeed important cofactors that increase the individual risk of diabetes but that the actual cause of the disease seems to be clearly linked to the β-cells.

If one accepts this notion, the next question is whether β-cell defects are primarily functional in nature or whether a …
Intercellular adhesion molecule-1 dimerization and its consequences for adhesion mediated by lymphocyte function associated-1.
Authors: J Miller, R Knorr, M Ferrone, R Houdei, C P Carron, M L Dustin
Journal: The Journal of Experimental Medicine (1995)

Intercellular adhesion molecule-1 (ICAM-1, CD54) is a ligand for the integrins lymphocyte function associated-1 (LFA-1, CD11a/CD18) and complement receptor-3 (Mac-1, CD11b/CD18) making it an important participant in many immune and inflammatory processes. Modified recombinant soluble ICAM-1 formed dimers. This result indicated that the ectodomain of ICAM-1 contains homophilic interaction sites. Soluble ICAM-1 dimers bind to solid-phase purified LFA-1 with high avidity (dissociation constant [Kd] = 8 nM) in contrast to soluble ICAM-1 monomers whose binding was not measurable. Cell surface ICAM-1 was found to be dimeric based on two distinct criteria. First, a monoclonal antibody specific for monomeric soluble ICAM-1, CA7, binds normal ICAM-1 poorly at the cell surface; this antibody, however, binds strongly to two mutant forms of ICAM-1 when expressed at the cell surface, thus identifying elements required for dimer formation. Second, chemical cross-linking of cell surface ICAM-1 on transfected cells and tumor necrosis factor-activated endothelial cells results in conversion of a portion of ICAM-1 to a covalent dimer. Cell surface ICAM-1 dimers are more potent ligands for LFA-1-dependent adhesion than ICAM-1 monomers. While many extracellular matrix-associated ligands of integrins are multimeric, this is the first evidence of specific, functionally important homodimerization of a cell surface integrin ligand.
Recommendations for the Establishment of Primary Stroke Centers
Authors: Mark J. Alberts
Journal: JAMA (2000)

To develop recommendations for the establishment and operation of primary stroke centers as an approach to improve the medical care of patients with stroke.Members of the Brain Attack Coalition (BAC), a multidisciplinary group of representatives from major professional organizations involved with delivering stroke care. Supplemental input was obtained from other experts involved in acute stroke care.A review of literature published from 1966 to March 2000 was performed using MEDLINE. More than 600 English-language articles that had evidence from randomized clinical trials, meta-analyses, care guidelines, or other appropriate methods supporting specific care recommendations for patients with acute stroke that could be incorporated into a stroke center model were selected.Articles were reviewed initially by 1 author (M.J.A.). Members of the BAC reviewed each recommendation in the context of current practice parameters, with special attention to improving the delivery of care to patients with acute stroke, cost-effectiveness, and logistical issues related to the establishment of primary stroke centers. Consensus was reached among all BAC participants before an element was added to the list of recommendations.Randomized clinical trials and observational studies suggest that several elements of a stroke center would improve patient care and outcomes. Key elements of primary stroke centers include acute stroke teams, stroke units, written care protocols, and an integrated emergency response system. Important support services include availability and interpretation of computed tomography scans 24 hours everyday and rapid laboratory testing. Administrative support, strong leadership, and continuing education are also important elements for stroke centers. Adoption of these recommendations may increase the use of appropriate diagnostic and therapeutic modalities and reduce peristroke complications. The establishment of primary stroke centers has the potential to improve the care of patients with stroke. JAMA. 2000.