tbuckley/cabot-search huggingface dataset:
Ambient Air Pollution Is Associated With Increased Risk of Hospital Cardiac Readmissions of Myocardial Infarction Survivors in Five European Cities
Authors: Stephanie von Klot, Annette Peters, Pasi Aalto, Tom Bellander, Niklas Berglind, Daniela D’Ippoliti, Roberto Elosua, Allmut Hörmann, Markku Kulmala, Timo Lanki, Hannelore Löwel, Juha Pekkanen, Sally Picciotto, Jordi Sunyer, Francesco Forastiere
Journal: Circulation (2005)

Ambient air pollution has been associated with increases in acute morbidity and mortality. The objective of this study was to evaluate the short-term effects of urban air pollution on cardiac hospital readmissions in survivors of myocardial infarction, a potentially susceptible subpopulation.In this European multicenter cohort study, 22,006 survivors of a first myocardial infarction were recruited in Augsburg, Germany; Barcelona, Spain; Helsinki, Finland; Rome, Italy; and Stockholm, Sweden, from 1992 to 2000. Hospital readmissions were recorded in 1992 to 2001. Ambient nitrogen dioxide, carbon monoxide, ozone, and mass of particles <10 microm (PM10) were measured. Particle number concentrations were estimated as a proxy for ultrafine particles. Short-term effects of air pollution on hospital readmissions for myocardial infarction, angina pectoris, and cardiac causes (myocardial infarction, angina pectoris, dysrhythmia, or heart failure) were studied in city-specific Poisson regression analyses with subsequent pooling. During follow-up, 6655 cardiac readmissions were observed. Cardiac readmissions increased in association with same-day concentrations of PM10 (rate ratio [RR] 1.021, 95% CI 1.004 to 1.039) per 10 microg/m3) and estimated particle number concentrations (RR 1.026 [95% CI 1.005 to 1.048] per 10,000 particles/cm3). Effects of similar strength were observed for carbon monoxide (RR 1.014 [95% CI 1.001 to 1.026] per 200 microg/m3 [0.172 ppm]), nitrogen dioxide (RR 1.032 [95% CI 1.013 to 1.051] per 8 microg/m3 [4.16 ppb]), and ozone (RR 1.026 [95% CI 1.001 to 1.051] per 15 microg/m3 [7.5 ppb]). Pooled effect estimates for angina pectoris and myocardial infarction readmissions were comparable.The results suggest that ambient air pollution is associated with increased risk of hospital cardiac readmissions of myocardial infarction survivors in 5 European cities.
Cardiovascular Proteomics
Authors: D. Kent Arrell, Irina Neverova, Jennifer E. Van Eyk
Journal: Circulation Research (2001)

The development of proteomics is a timely one for cardiovascular research. Analyses at the organ, subcellular, and molecular levels have revealed dynamic, complex, and subtle intracellular processes associated with heart and vascular disease. The power and flexibility of proteomic analyses, which facilitate protein separation, identification, and characterization, should hasten our understanding of these processes at the protein level. Properly applied, proteomics provides researchers with cellular protein "inventories" at specific moments in time, making it ideal for documenting protein modification due to a particular disease, condition, or treatment. This is accomplished through the establishment of species- and tissue-specific protein databases, providing a foundation for subsequent proteomic studies. Evolution of proteomic techniques has permitted more thorough investigation into molecular mechanisms underlying cardiovascular disease, facilitating identification not only of modified proteins but also of the nature of their modification. Continued development should lead to functional proteomic studies, in which identification of protein modification, in conjunction with functional data from established biochemical and physiological methods, has the ability to further our understanding of the interplay between proteome change and cardiovascular disease.
Human Epidermal Growth Factor Receptor 2 Status Modulates Subcellular Localization of and Interaction with Estrogen Receptor α in Breast Cancer Cells
Authors: Zhibo Yang, Christopher J. Barnes, Rakesh Kumar
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Approximately two-thirds of breast cancer patients respond to endocrine therapy, and this population of patients is estrogen receptor (ER) positive. However, a significant proportion of patients do not respond to hormone therapy. ER hormone responsiveness is widely believed to be influenced by enhanced cross-talk of ER with overexpressed human epidermal growth factor receptor 2 (HER2), and a subgroup of ER-positive tumors coexpress high HER2. Experimental Design: Breast cancer cells with or without HER2 overexpression were analyzed for ER status, subcellular localization, and interactions with HER2 signaling components by biochemical and immunological methods. Experiments explored the regulatory interactions between the HER2 and ER pathways and the sensitivity of breast cancer cells to tamoxifen. Results: Stable or transient or natural HER2 overexpression in ER-positive breast cancer cells promoted the nucleus-to-cytoplasm relocalization of ER, enhanced interactions of ER with HER2, inhibited ER transactivation function, and induced resistance to tamoxifen-mediated growth inhibition of breast cancer cells. In addition, HER2 up-regulation resulted in ER interaction with Sos, a component of Ras signaling, and hyperstimulation of the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2). Conversely, down-regulation of HER2 by the anti-HER2 monoclonal antibody Herceptin led to suppression of ERK1/2 stimulation, restoration of ER to the nucleus, and potentiation of the growth-inhibitory action of tamoxifen. Conclusion: The results presented here show for the first time that ER redistribution to the cytoplasm and its interaction with HER2 are important downstream effects of HER2 overexpression, that ERK1/2 is important for ER cytoplasmic localization, and that subcellular localization of ER may play a mechanistic role in determining the responsiveness of breast cancer cells to tamoxifen.
The Cell-Cycle Regulator CDK4: An Emerging Therapeutic Target in Melanoma
Authors: Karen E. Sheppard, Grant A. McArthur
Journal: Clinical Cancer Research (2013)

Abstract The recent clinical success of targeted therapies in melanoma directed at the oncogene BRAF validates the concept of targeting oncogenes. The p16-cyclin D-CDK4/6-retinoblastoma protein pathway (CDK4 pathway) is dysregulated in 90% of melanomas, and is, therefore, an obvious therapeutic target for this disease. The main outcome of CDK4 activation is the phosphorylation and, thus, inhibition of the retinoblastoma protein leading to G1–S cell-cycle transition. In addition, CDK4 directly phosphorylates other proteins that promote cell-cycle progression and inhibit both cell senescence and apoptosis. In preclinical studies, the response to CDK4 inhibition correlates with genomic changes that increase CDK4 activity, most notably where the tumor suppressor CDKN2A (p16INK4A) is deleted. A central question is whether melanomas with activating events in the CDK4 pathway have become “addicted” to this signaling pathway, in which case inhibition of CDK4 would not simply induce cell-cycle arrest but induce cell death and tumor regression. Recently, a number of selective CDK4/6 inhibitors have entered clinical trials, and these compounds are showing great promise in that they are well tolerated and show clinical benefit. This review discusses the CDK4 pathway, its dysregulation in melanoma, the consequences of CDK4 pathway inhibition, and potential novel combinational strategies for the treatment of melanoma. Clin Cancer Res; 19(19); 5320–8. ©2013 AACR.
The role of thrombophilic risk factors in the severity of pulmonary thromboembolism
Authors: I.K. Oguzulgen, N.N. Ekim, N. Akar, K. Demirel, M. Kitapci
Journal: European Respiratory Journal (2002)

High plasma factor-VIIIc concentration, presence of factor‐V 1691 G‐A (FVL) and prothrombin 20210A (PT 20210A ) mutations were shown to be significant risk factors for venous thromboembolism (VTE) and recurrent VTE. The objective of this study was to investigate the role of these thrombotic risk factors in the severity of pulmonary thromboembolism (PTE). The plasma concentrations of factor VIIIc, presence of FVL and PT 20210A mutations were studied in 32 patients with PTE. Eleven of the patients had documented recurrent VTE. Lung perfusion scans were scored according to the percentage of vascular obstruction. Patients who had a pulmonary vascular obstruction score (PVOs) &gt;50% were compared to those with PVOs&lt;50%. There was no significant difference between the patients with PVOs &gt;50% and those with PVOs &lt;50%, with regard to the presence of FVL and PT 20210A mutation. However, patients with PVOs &gt;50% had a significantly higher factor-VIIIc concentration than those with PVOs &lt;50% (factor-VIIIc levels were 253.3±29.1 International Units (IU)·dL −1 and 138.5±16.2 IU·dL −1 , respectively; p&lt;0.005). Factor-VIIIc concentrations were significantly correlated with PVOs (r=0.52, p&lt;0.005). Patients with recurrent VTE had significantly higher factor-VIIIc concentrations than those in which it occurred for the first time (factor-VIIIc concentrations were 232.6±30.9 IU·dL −1 and 158.3±20.6 IU·dL −1 , respectively; p&lt;0.05). The authors conclude that in addition to being a risk factor for venous thromboembolism, high factor-VIIIc concentration is an important factor in the severity of pulmonary thromboembolism.
PROCALCITONIN IS A MARKER OF INFECTION AFTER SURGERY FOR VALVULAR HEART DISEASE IN A PREDOMINANTLY RHEUMATIC POPULATION
Authors: Antonio C. Bacelar, Flavio Tarasoutchi, Guilherme Spina, Antonio A. Lopes, Roney Sampaio, Tarso Accorsi, Ricardo S. Casalino, Fernando V. Reiche
Journal: Journal of the American College of Cardiology (2010)
Improving immunisation coverage in rural India: clustered randomised controlled evaluation of immunisation campaigns with and without incentives
Authors: A. V. Banerjee, E. Duflo, R. Glennerster, D. Kothari
Journal: BMJ (2010)

<b>Objective</b> To assess the efficacy of modest non-financial incentives on immunisation rates in children aged 1-3 and to compare it with the effect of only improving the reliability of the supply of services. <b>Design</b> Clustered randomised controlled study. <b>Setting</b> Rural Rajasthan, India. <b>Participants</b> 1640 children aged 1-3 at end point. <b>Interventions</b> 134 villages were randomised to one of three groups: a once monthly reliable immunisation camp (intervention A; 379 children from 30 villages); a once monthly reliable immunisation camp with small incentives (raw lentils and metal plates for completed immunisation; intervention B; 382 children from 30 villages), or control (no intervention, 860 children in 74 villages). Surveys were undertaken in randomly selected households at baseline and about 18 months after the interventions started (end point). <b>Main outcome measures</b> Proportion of children aged 1-3 at the end point who were partially or fully immunised. <b>Results</b> Among children aged 1-3 in the end point survey, rates of full immunisation were 39% (148/382, 95% confidence interval 30% to 47%) for intervention B villages (reliable immunisation with incentives), 18% (68/379, 11% to 23%) for intervention A villages (reliable immunisation without incentives), and 6% (50/860, 3% to 9%) for control villages. The relative risk of complete immunisation for intervention B versus control was 6.7 (4.5 to 8.8) and for intervention B versus intervention A was 2.2 (1.5 to 2.8). Children in areas neighbouring intervention B villages were also more likely to be fully immunised than those from areas neighbouring intervention A villages (1.9, 1.1 to 2.8). The average cost per immunisation was $28 (1102 rupees, about £16 or €19) in intervention A and $56 (2202 rupees) in intervention B. <b>Conclusions</b> Improving reliability of services improves immunisation rates, but the effect remains modest. Small incentives have large positive impacts on the uptake of immunisation services in resource poor areas and are more cost effective than purely improving supply. <b>Trial registration</b> IRSCTN87759937.
Resolving the paradox of common, harmful, heritable mental disorders: Which evolutionary genetic models work best?
Authors: Matthew C. Keller, Geoffrey Miller
Journal: Behavioral and Brain Sciences (2006)

Given that natural selection is so powerful at optimizing complex adaptations, why does it seem unable to eliminate genes (susceptibility alleles) that predispose to common, harmful, heritable mental disorders, such as schizophrenia or bipolar disorder? We assess three leading explanations for this apparent paradox from evolutionary genetic theory: (1) ancestral neutrality (susceptibility alleles were not harmful among ancestors), (2) balancing selection (susceptibility alleles sometimes increased fitness), and (3) polygenic mutation-selection balance (mental disorders reflect the inevitable mutational load on the thousands of genes underlying human behavior). The first two explanations are commonly assumed in psychiatric genetics and Darwinian psychiatry, while mutation-selection has often been discounted. All three models can explain persistent genetic variance in some traits under some conditions, but the first two have serious problems in explaining human mental disorders. Ancestral neutrality fails to explain low mental disorder frequencies and requires implausibly small selection coefficients against mental disorders given the data on the reproductive costs and impairment of mental disorders. Balancing selection (including spatio-temporal variation in selection, heterozygote advantage, antagonistic pleiotropy, and frequency-dependent selection) tends to favor environmentally contingent adaptations (which would show no heritability) or high-frequency alleles (which psychiatric genetics would have already found). Only polygenic mutation-selection balance seems consistent with the data on mental disorder prevalence rates, fitness costs, the likely rarity of susceptibility alleles, and the increased risks of mental disorders with brain trauma, inbreeding, and paternal age. This evolutionary genetic framework for mental disorders has wide-ranging implications for psychology, psychiatry, behavior genetics, molecular genetics, and evolutionary approaches to studying human behavior.
Multiple-channel scaffolds to promote spinal cord axon regeneration
Authors: Michael J. Moore, Jonathan A. Friedman, Eric B. Lewellyn, Sara M. Mantila, Aaron J. Krych, Syed Ameenuddin, Andrew M. Knight, Lichun Lu, Bradford L. Currier, Robert J. Spinner, Richard W. Marsh, Anthony J. Windebank, Michael J. Yaszemski
Journal: Biomaterials (2005)
The Efficacy of IGF-I Receptor Monoclonal Antibody against Human Gastrointestinal Carcinomas is Independent of <i>k-ras</i> Mutation Status
Authors: Masanori Ii, Hua Li, Yasushi Adachi, Hiroyuki Yamamoto, Hirokazu Ohashi, Hiroaki Taniguchi, Yoshiaki Arimura, David P. Carbone, Kohzoh Imai, Yasuhisa Shinomura
Journal: Clinical Cancer Research (2011)

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal cancers. We have previously shown successful targeting therapy for colorectal, pancreatic, gastric, and esophageal carcinomas using recombinant adenoviruses expressing dominant negative IGF-IR. Mutation in k-ras is one of key factors in gastrointestinal cancers. In this study, we sought to evaluate the effect of a new monoclonal antibody for IGF-IR, figitumumab (CP-751,871), on the progression of human gastrointestinal carcinomas with/without k-ras mutation.We assessed the effect of figitumumab on signal transduction, proliferation, and survival in six gastrointestinal cancer cell lines with/without k-ras mutation, including colorectal and pancreatic adenocarcinoma, esophageal squamous cell carcinoma, and hepatoma. Combination effects of figitumumab and chemotherapy were also studied. Then figitumumab was evaluated in the treatment of xenografts in nude mice.Figitumumab blocked autophosphorylation of IGF-IR and its downstream signals. The antibody suppressed proliferation and tumorigenicity in all cell lines. Figitumumab inhibited survival by itself and up-regulated chemotherapy (5-FU and gemcitabine) induced apoptosis. Moreover, the combination of this agent and chemotherapy was effective against tumors in mice. The effect of figitumumab was not influenced by the mutation status of k-ras. Figitumumab reduced expression of IGF-IR but not insulin receptor in these xenografted tumors. The drug did not affect murine body weight or blood concentrations of glucose, insulin, IGF binding protein 3, and growth hormone.IGF-IR might be a good molecular therapeutic target and figitumumab may thus have therapeutic value in human gastrointestinal malignancies even in the presence of k-ras mutations.
Male gonadal dysfunction in patients with Hodgkin’s disease prior to treatment
Authors: U. Rueffer, K. Breuer, A. Josting, B. Lathan, M. Sieber, O. Manzke, F.-J. Grotenhermen, H. Tesch, H. Bredenfeld, P. Koch, H. Nisters-Backes, J. Wolf, A. Engert, V. Diehl
Journal: Annals of Oncology (2001)
Feasibility of radiotherapy with concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma: a prospective dose finding phase I–II study
Authors: S. Laurent, E. Monsaert, T. Boterberg, A. Demols, I. Borbath, M. Polus, A. Hendlisz, B. de Hemptinne, C. Mahin, P. Scalliet, J.-L. Van Laethem, M. Peeters
Journal: Annals of Oncology (2009)
Passive ventricular restaint
Authors: S Goldstein
Journal: Cardiovascular Research (1999)

See article by Power et al. [4] (pages 549–555) in this issue. 

The importance of ventricular remodeling as a factor in the progression of heart failure has been a recent concept supported by an abundance of animal and human research. The serial echocardiographic measurements obtained in clinical studies in heart failure provide evidence for the occurrence of progressive remodeling and its direct relationship to clinical morbidity and mortality events. The ability of angiotensin converting enzyme inhibitors to modify this progressive remodeling has been the foundation of the medical therapy for heart failure during the last decade. Attempts to decrease left ventricular size or modify the remodeling process by mechanical or surgical intervention with procedures like dynamic cardiomyoplasty and ventricular reduction surgery have been less than successful. The effect of left ventricular … 

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Alkaline phosphatase activity of glutaraldehyde-treated bovine pericardium used in bioprosthetic cardiac valves.
Authors: A R Maranto, F J Schoen
Journal: Circulation Research (1988)

Bioprosthetic valves fail frequently because of pathological mineralization, a process that begins in cell remnants of the glutaraldehyde (GLUT) fixed tissue. Other pathological cardiovascular calcification and physiological mineralization in skeletal/dental tissues are both largely initiated in cell-derived membranous structures (often called "matrix vesicles"), and the enzyme alkaline phosphatase (AP) likely has an important function in the pathogenesis of mineral nucleation. This study tested the hypothesis that AP might also be present in and contribute to calcification of bioprosthetic valves. AP activity of fresh and GLUT-treated bovine pericardium was measured by the conversion of p-nitrophenyl phosphate to p-nitrophenol. Following 24 hours in 0.6% HEPES-buffered GLUT and storage for 2 weeks in 0.2% GLUT, considerable AP hydrolytic activity remained in GLUT-treated tissue relative to that of fresh tissue (Vmax, 24 vs. 45 mumol reaction product/min/mg tissue protein, respectively), although binding was somewhat reduced (Km, 1.9 X 10(3) vs. 1.4 X 10(3) microM substrate, respectively). Enzyme reaction product was demonstrated in both fixed and fresh tissue by light microscopic histochemical studies, confirming the biochemical results. Reaction product was noted along membranes of vascular endothelial cells and interstitial fibroblasts, the sites of early calcific deposits in bioprosthetic valves, by ultrastructural examination of GLUT-treated tissue. We conclude that GLUT-treated bovine pericardium retains much of the hydrolytic activity of AP, an enzyme associated with normal skeletal and pathological cardiovascular and noncardiovascular mineralization, and suggest that further examination of the mechanistic role of this enzyme may stimulate new approaches for slowing or preventing calcification of bioprosthetic tissue.
A phase II study of topotecan plus gemcitabine in the treatment of patients with relapsed ovarian cancer after failure of first-line chemotherapy
Authors: J. Sehouli, D. Stengel, G. Oskay, O. Camara, H.-J. Hindenburg, P. Klare, J. Blohmer, G. Heinrich, D. Elling, P. Ledwon, W. Lichtenegger
Journal: Annals of Oncology (2002)
Use of statins with ciclosporin
Authors: B. Camilleri
Journal: BMJ (2008)

Sathasivam and Lecky say that lipophilic statins (simvastatin, atorvastatin, lovastatin) are more likely to produce muscular effects than are relatively hydrophilic agents (pravastatin, rosuvastatin, fluvastatin).1

However, simvastatin, atorvastatin, …
Genetics of childhood and adolescent depression: insights into etiological heterogeneity and challenges for future genomic research
Authors: Frances Rice
Journal: Genome Medicine (2010)

There is heterogeneity between depression in childhood, adolescence and adulthood in terms of the gender composition of affected cases, prevalence, rates of recurrence and risk factors. This raises complex questions for refining the phenotype for molecular genetic studies of depression and the selection of appropriate proband groups. This article aims to provide a review of issues arising from family, twin and adoption studies of relevance to molecular genetic studies, and to summarize molecular genetic findings on childhood/adolescent depression. While retrospective studies of adults suggest greater familial aggregation among those with an earlier age of onset, prospective studies do not confirm this association. In fact, taken together, evidence from family and twin studies suggests that prepubertal depression is more strongly associated with psychosocial adversity, is less heritable and shows lower levels of continuity with adult depression than either adolescent or adult depression. Adolescent depressive symptoms and disorder show similar levels of heritability to depression in adult life, although there is only one twin study of adolescent depressive disorder, and heritability estimates of depressive symptoms vary widely between studies. This variability in heritability estimates is partly attributable to age and informant effects. Adoption studies and other intergenerational transmission designs show that the transmission of depression between parents and children involves genetic and environmental processes, with converging evidence that environmental processes are most important. Molecular genetic studies of childhood/adolescent depression have to date used a candidate gene approach and focused on genes already examined in adult studies. Prospective longitudinal studies of community and high-risk samples are needed to clarify issues of etiological heterogeneity in depression, and these should in turn inform the planning of molecular genetic studies.