tbuckley/cabot-search huggingface dataset:
Monoamine Transporters: From Genes to Behavior
Authors: Raul R. Gainetdinov, Marc G. Caron
Journal: The Annual Review of Pharmacology and Toxicology (2003)

Modulation of fast neurotransmission by monoamines is critically involved in numerous physiological functions and pathological conditions. Plasma membrane monoamine transporters provide one of the most efficient mechanisms controlling functional extracellular monoamine concentrations. These transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET), which are expressed selectively on the corresponding neurons, are established targets of many psychostimulants, antidepressants, and neurotoxins. Recently, genetic animal models with targeted disruption of these transporters have become available. These mice have provided opportunities to investigate the functional importance of transporters in homeostatic control of monoaminergic transmission and to evaluate, in an in vivo model system, their roles in physiology and pathology. The use of these mice as test subjects has been helpful in resolving several important issues on specificity and mechanisms of action of certain pharmacological agents. In the present review, we summarize recent advances in understanding the physiology and pharmacology of monoamine transporters gained in mice with targeted genetic deletion of DAT, SERT, and NET.
Phenotype and Functional Characterization of Long-term gp100-Specific Memory CD8+ T Cells in Disease-Free Melanoma Patients Before and After Boosting Immunization
Authors: Edwin B. Walker, Daniel Haley, Ulf Petrausch, Kevin Floyd, William Miller, Nelson Sanjuan, Greg Alvord, Bernard A. Fox, Walter J. Urba
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Effective cancer vaccines must both drive a strong CTL response and sustain long-term memory T cells capable of rapid recall responses to tumor antigens. We sought to characterize the phenotype and function of gp100 peptide-specific memory CD8+ T cells in melanoma patients after primary gp100209-2M immunization and assess the anamnestic response to boosting immunization. Experimental Design: Eight-color flow cytometry analysis of gp100-specific CD8+ T cells was done on peripheral blood mononuclear cells collected shortly after the primary vaccine regimen, 12 to 24 months after primary vaccination, and after boosting immunization. The anamnestic response was assessed by comparing the frequency of circulating gp100-specific T cells before and after boosting. Gp100 peptide-induced in vitro functional avidity and proliferation responses and melanoma-stimulated T-cell CD107 mobilization were compared for cells from all three time points for multiple patients. Results: The frequency of circulating gp100-specific memory CD8+ T cells was comparable with cytomegalovirus-specific and FLU-specific T cells in the same patients, and the cells exhibited anamnestic proliferation after boosting. Their phenotypes were not unique, and individual patients exhibited one of two distinct phenotype signatures that were homologous to either cytomegalovirus-specific or FLU-specific memory T cells. Gp100-specific memory T cells showed some properties of competent memory T cells, such as heightened in vitro peptide-stimulated proliferation and increase in central memory (TCM) differentiation when compared with T-cell responses measured after the primary vaccine regimen. However, they did not acquire enhanced functional avidity usually associated with competent memory T-cell maturation. Conclusions: Although vaccination with class I–restricted melanoma peptides alone can break tolerance to self-tumor antigens, it did not induce fully competent memory CD8+ T cells—even in disease-free patients. Data presented suggest other vaccine strategies will be required to induce functionally robust long-term memory T cells.
The Role of S100A6 in Pancreatic Cancer Development and Its Clinical Implication as a Diagnostic Marker and Therapeutic Target
Authors: Kenoki Ohuchida, Kazuhiro Mizumoto, Nami Ishikawa, Kei Fujii, Hiroyuki Konomi, Eishi Nagai, Koji Yamaguchi, Masazumi Tsuneyoshi, Masao Tanaka
Journal: Clinical Cancer Research (2005)

Abstract Recent microarray analyses showed that the S100 family contains members that are candidate diagnostic markers or therapeutic targets. In the present study, to evaluate the involvement of S100A6 in pancreatic cancer and its clinical usefulness for diagnosis, we examined S100A6 mRNA expression in pancreatic tissues and pancreatic juice from patients with different pancreatic diseases. To investigate the role of S100A6 in carcinogenesis of pancreatic cancer and the potential of S100A6 as a diagnostic marker for early detection of pancreatic cancer, we did immunohistochemistry and microdissection-based mRNA analysis of pancreatic normal ducts, pancreatic intraepithelial neoplasias, and invasive ductal carcinomas. We also used in vitro experiments and microarray analysis with RNA interference to evaluate the functional role of S100A6 and its potential as a therapeutic target for pancreatic cancer. S100A6 mRNA levels were significantly higher in carcinoma specimens than in nonneoplastic tissues. In pancreatic juice, there was a significant difference in S100A6 expression between patients with carcinoma and those with nonneoplastic disease. Receiver operating characteristic curves revealed that S100A6 might be a useful marker for diagnosis of pancreatic cancer. Immunohistochemistry and microdissection-based analysis showed differential expression of S100A6 among normal ducts, pancreatic intraepithelial neoplasias, and invasive ductal carcinomas. In vitro data showed that inhibition of S100A6 decreased proliferation and invasiveness of cancer cells, and these findings were supported by microarray data. Our present results suggest that quantitation of S100A6 mRNA is a promising tool for diagnosis of pancreatic cancer, and that S100A6 may be a promising therapeutic target for pancreatic cancer.
A Summer Plague: Polio and its Survivors
Authors: B. Inman
Journal: BMJ (1995)

Tony Gould Yale University Press, pounds sterling19.95, pp 384 ISBN 0 300 06292 3

Tony Gould and I started our adult lives with quite a lot in common. He is nine years younger but we both caught polio at the age of about 20. We both experienced breathing problems and a spell in a respirator; he can walk, where I failed. We adapted well to our problems and were successful in our chosen careers; we both married and raised families. Gould chose the life of scholarship while I chose to train as a doctor.

A Summer Plague …
Smoking interacts with genetic risk factors in the development of rheumatoid arthritis among older Caucasian women
Authors: L A Criswell, K G Saag, T R Mikuls, J R Cerhan, L A Merlino, R F Lum, K A Pfeiffer, B Woehl, M F Seldin
Journal: Annals of the Rheumatic Diseases (2006)

To determine whether the impact of tobacco exposure on rheumatoid arthritis (RA) risk is influenced by polymorphisms at the HLA-DRB1 and glutathione S-transferase M1 (GSTM1) loci.Subjects were participants from a case-control study nested within the Iowa Women's Health Study, a population based, prospective cohort study of postmenopausal women. Incident RA cases (n = 115) were identified and medical records reviewed to confirm RA diagnosis. Controls without RA (n = 466) were matched with RA cases by age and ethnic background. HLA-DRB1 typing classified subjects according to the presence of alleles encoding the RA "shared epitope" (SE) sequence. GSTM1 was genotyped using a multiplex polymerase chain reaction assay. Conditional logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals.Strong positive associations of smoking (OR = 6.0, p = 0.004), SE positivity (OR = 4.6, p = 0.0006), and GSTM1 null genotype (OR = 3.4, p = 0.007) with risk of RA, and significant gene-environment interactions (smoking by SE interaction p = 0.034; smoking by GSTM1 interaction p = 0.047) were observed. Stratified analyses indicated that exposure to tobacco smoke primarily increased the risk of RA among subjects who lacked genetic risk factors for the disease (that is, SE negative or GSTM1 present).Although these findings require confirmation in other groups, the results support the importance of considering both genetic and environmental factors, and also their interaction, in studies of complex diseases like RA.
Higher Intensity of Purifying Selection on &gt;90% of the Human Genes Revealed by the Intrinsic Replacement Mutation Rates
Authors: S. Subramanian, S. Kumar
Journal: Molecular Biology and Evolution (2006)

For over 3 decades, the rate of replacement mutations has been assumed to be equal to, and estimated from, the rate of "strictly" neutral sequence divergence in noncoding regions and in silent-codon positions where mutations do not alter the amino acid encoded. This assumption is fundamental to estimating the fraction of harmful protein mutations and to identifying adaptive evolution at individual codons and proteins. We show that the assumption is not justifiable because a much larger fraction of codon positions is involved in hypermutable CpG dinucleotides as compared with the introns, leading to a higher expected replacement mutation rate per site in a vast majority of the genes. Consideration of this difference reveals a higher intensity of purifying natural selection than previously inferred in human genes. We also show that a much smaller number of genes are expected to be evolving with positive selection than that predicted using sequence divergence at intron and silent positions in the human genome. These patterns indicate the need for using new approaches for estimating rates of amino acid-altering mutations in order to find positively selected genes and codons in genomes that contain hypermutable CpG's.
Proteomic Analysis of Early Left Ventricular Hypertrophy Secondary to Hypertension
Authors: Julio Gallego-Delgado, Alberto Lazaro, Julio I. Osende, Vanesa Esteban, Maria G. Barderas, Carmen Gomez-Guerrero, Ricardo Vega, Fernando Vivanco, Jesus Egido
Journal: Journal of the American Society of Nephrology (2006)

Untreated or poorly controlled arterial hypertension induced development of pathologic left ventricular hypertrophy (LVH), a common finding in hypertensive patients and a strong predictor of cardiovascular morbidity and mortality. The proteomic approach is a powerful technique to analyze a complex mixture of proteins in various settings. An experimental model of hypertension-induced early LVH was performed in spontaneously hypertensive rats, and the cardiac protein pattern compared with the normotensive Wistar Kyoto counterpart was analyzed. Fifteen altered protein spots were shown in the early stage of LVH. Compared with a previous animal model of established and regressed LVH, three protein spots were common in both models. These three altered protein spots corresponded to two unique proteins that were identified as Calsarcin-1 (CS-1) and ubiquinone biosynthesis protein COQ7 homolog. CS-1 is a negative regulator of the calcineurin/NF-AT pathway. Because upregulation in the expression levels of this protein was observed, the activation level of NF-kappaB by oxidative stress as an alternative pathway was investigated. It was found that antihypertensive therapies partially decreased oxidative stress and normalized the activation of NF-kappaB in the kidneys and aorta NF-kappaB activation but just moderately in the heart. This could be due to the interaction of any specific cardiac protein with any component of the NF-kappaB pathway. In this sense, CS-1 could be a good candidate because it is expressed preferentially in heart, to a lesser extent in smooth muscle cells, but not in kidney. Further investigations are necessary to elucidate the exact role of CS-1 and ubiquinone biosynthesis protein COQ7 in the setting of hypertension-induced LVH.
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Authors: Pamela J Trotter
Journal: Annual Review of Nutrition (2001)

▪ Abstract Long-chain fatty acids are a vital metabolic energy source and are building blocks of membrane lipids. The yeast Saccharomyces cerevisiae is a valuable model system for elucidation of gene-function relationships in such eukaryotic processes as fatty acid metabolism. Yeast degrades fatty acids only in the peroxisome, and recently, genes encoding core and auxiliary enzymes of peroxisomal β-oxidation have been identified. Mechanisms involved in fatty acid induction of gene expression have been described, and novel fatty acid–responsive genes have been discovered via yeast genome analysis. In addition, a number of genes essential for synthesis of the variety of fatty acids in yeast have been cloned. Advances in understanding such processes in S. cerevisiae will provide helpful insights to functional genomics approaches in more complex organisms.
Pregnancy induces numerical and functional changes of CD4+CD25high regulatory T cells in patients with rheumatoid arthritis
Authors: F Forger, N Marcoli, S Gadola, B Moller, P M Villiger, M Ostensen
Journal: Annals of the Rheumatic Diseases (2007)

In a prospective study we investigated whether numerical and functional changes of CD4+CD25(high) regulatory T cells (Treg) were associated with changes of disease activity observed during pregnancy and post partum in patients with rheumatoid arthritis (RA).The frequency of CD4+CD25(high) T cells was determined by flow cytometry in 12 patients with RA and 14 healthy women during and after pregnancy. Fluorescence-activated cell sorting (FACS) was used to sort CD4+CD25(high) T cells and CD4+CD25- T cells were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies alone or in co-culture to investigate proliferation and cytokine secretion.Frequencies of CD4+CD25(high) Treg were significantly higher in the third trimester compared to 8 weeks post partum in patients and controls. Numbers of CD4+CD25(high) Treg inversely correlated with disease activity in the third trimester and post partum. In co-culture experiments significantly higher amounts of IL10 and lowered levels of tumour necrosis factor (TNF)alpha and interferon (IFN)gamma were found in supernatants of the third trimester compared to postpartum samples. These findings were independent from health or disease in pregnancy, however postpartum TNFalpha and IFN gamma levels were higher in patients with disease flares.The amelioration of disease activity in the third trimester corresponded to the increased number of Treg that induced a pronounced anti-inflammatory cytokine milieu. The pregnancy related quantitative and qualitative changes of Treg suggest a beneficial effect of Treg on disease activity.
ERBB1 and ERBB2 Have Distinct Functions in Tumor Cell Invasion and Intravasation
Authors: Dmitriy Kedrin, Jeffrey Wyckoff, Pamela J. Boimel, Salvatore J. Coniglio, Nancy E. Hynes, Carlos L. Arteaga, Jeffrey E. Segall
Journal: Clinical Cancer Research (2009)

The epidermal growth factor receptor (ERBB1) and related family member HER-2/neu (ERBB2) are often overexpressed in aggressive breast cancers and their overexpression is correlated with poor prognosis. Clinical studies using ERBB inhibitors have focused on tumor growth effects, but ERBBs can contribute to malignancy independent of their effects on tumor growth. Our studies were designed to evaluate the effect of ERBB inhibition on tumor cell motility and intravasation in vivo using clinically relevant small-molecule inhibitors.Using in vivo mouse models of breast cancer, we test the effects of ERBB1 and ERBB2 inhibitors AC480 and lapatinib, ERBB1 inhibitor gefitinib, and ERBB2 inhibitor AG825 on in vivo tumor cell invasive properties in mammary fat pad tumors.ERBB1 and ERBB2 inhibition rapidly (within 3 h) inhibits both tumor cell motility and intravasation. Using gefitinib, ERBB1 inhibition rapidly inhibits tumor cell motility and invasion but not intravasation, whereas ERBB2 inhibition by AG825 rapidly blocks intravasation.ERBB1 and ERBB2 inhibition can rapidly block tumor cell invasive properties. In addition, we differentiate for the first time the contributions of ERBB1 and ERBB2 to the key metastatic properties of in vivo tumor cell invasion and intravasation. These experiments temporally and molecularly separate two key stages in tumor cell entry into blood vessels: invasion and intravasation. These results indicate that ERBB inhibition should be considered for blocking other tumor cell malignant properties besides growth.
Non-Hodgkin’s lymphoma in very elderly patients over 80 years. A descriptive analysis of clinical presentation and outcome
Authors: C. Thieblemont, A. Grossoeuvre, R. Houot, F. Broussais-Guillaumont, G. Salles, C. Traullé, D. Espinouse, B. Coiffier
Journal: Annals of Oncology (2007)
Developmental Changes in the Delayed Rectifier K <sup>+</sup> Channels in Mouse Heart
Authors: Li Wang, Zhong-Ping Feng, Colleen S. Kondo, Robert S. Sheldon, Henry J. Duff
Journal: Circulation Research (1996)

Expression of cardiac transient outward current and inwardly rectifying K + current is age dependent. However, little is known about age-related changes in cardiac delayed rectifier K + current (I K , with rapidly and slowly activating components, I Kr and I Ks , respectively). Accordingly, the purpose of the present study was to assess developmental changes in I K channels in fetal, neonatal, and adult mouse ventricles. Three techniques were used: conventional microelectrode to measure the action potential, voltage clamp to record macroscopic currents of I K , and radioligand assay to examine [ 3 H]dofetilide binding sites. The extent of prolongation of action potential duration at 95% repolarization (APD 95 ) by a selective I Kr blocker, dofetilide (1 μmol/L), dramatically decreased from fetal (137%±18%) to day-1 (75%±29%) and day-3 (20%±15%) neonatal mouse ventricular tissues ( P &lt;.01). Dofetilide did not prolong APD 95 in adult myocardium. I Kr is the sole component of I K in day-18 fetal mouse ventricular myocytes. However, both I Kr and I Ks were observed in day-1 neonatal ventricular myocytes. With further development, I Ks became the dominant component of I K in day-3 neonates. In adult mouse ventricular myocytes, neither I Kr nor I Ks was observed. Correspondingly, a high-affinity binding site for [ 3 H]dofetilide was present in fetal mouse ventricles but was absent in adult ventricles. The complementary data from microelectrode, voltage-clamp, and [ 3 H]dofetilide binding studies demonstrate that expression of the I K channel is developmentally regulated in the mouse heart.
Lymphomatoid papulosis in a patient with atopic eczema on long-term ciclosporin therapy
Authors: S. Laube, M. Stephens, A.G. Smith, S.J. Whittaker, B.B. Tan
Journal: British Journal of Dermatology (2005)

We report a 36-year-old man with atopic eczema who developed lymphomatoid papulosis while taking ciclosporin. Latent membrane protein 1 and in situ hybridization for Epstein-Barr virus were negative. There are only two reports in the literature of patients taking ciclosporin to control atopic eczema who developed primary cutaneous CD30+ T-cell lymphoproliferative disorders. The development of T-cell lymphoproliferative disorders including lymphomas is well described in patients with solid organ transplants who are taking ciclosporin. Also, it has been noted in patients taking ciclosporin for rheumatological conditions or psoriasis.
The Case for Using Albuminuria in Staging Chronic Kidney Disease
Authors: Ron T. Gansevoort, Paul E. de Jong
Journal: Journal of the American Society of Nephrology (2009)

The publication of the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines for the evaluation, classification, and stratification of chronic kidney disease (CKD) in 20021 has greatly raised awareness of CKD and stimulated epidemiologic research investigating the consequences of CKD. Its publication and distribution were also followed by critical commentaries. The authors of these commentaries questioned whether it is correct to claim someone has chronic disease without having firm evidence that that chronic disease will lead to a worse prognosis.2,3 They suggested that the CKD staging system be changed—one change among others—by not paying attention to stages 1 and 2 CKD, which are characterized by early signs of renal damage (albuminuria, erythrocyturia, or abnormalities on ultrasonography) and normal or near-normal estimated GFR (eGFR). Critical authors argued that this modification would make the staging system more simple and useful.2,3 In this commentary, we suggest that the discounting of stages 1 and 2 CKD is not justified on the basis of recent evidence from various epidemiologic studies and indicate further that there is need to examine more carefully the clinical prognosis of individuals with stage 3 CKD.

The main value of a CKD classification system is in providing insight regarding risk for developing ESRD. That renal function often declines gradually makes it more likely that a patient who ends with ESRD will have previously gone through the five levels of severity of CKD; that is, from a normal GFR of >90 ml/min down to a GFR of <15 ml/min. It is unreasonable to assume, however, that all patients with the earlier stages of CKD will likely progress to ESRD. Stages 1 through 3 CKD are present in ≥10% of the population,4–6 whereas each year going forward fewer than one of the 1000 of …
Increased Collagen Deposition and Diastolic Dysfunction but Preserved Myocardial Hypertrophy After Pressure Overload in Mice Lacking PKCε
Authors: Gunnar Klein, Arnd Schaefer, Denise Hilfiker-Kleiner, Dagmar Oppermann, Praphulla Shukla, Anja Quint, Eva Podewski, Andres Hilfiker, Frank Schröder, Michael Leitges, Helmut Drexler
Journal: Circulation Research (2005)

Overexpression and activation of protein kinase C-epsilon (PKCepsilon) results in myocardial hypertrophy. However, these observations do not establish that PKCepsilon is required for the development of myocardial hypertrophy. Thus, we subjected PKCepsilon-knockout (KO) mice to a hypertrophic stimulus by transverse aortic constriction (TAC). KO mice show normal cardiac morphology and function. TAC caused similar cardiac hypertrophy in KO and wild-type (WT) mice. However, KO mice developed more interstitial fibrosis and showed enhanced expression of collagen Ialpha1 and collagen III after TAC associated with diastolic dysfunction, as assessed by tissue Doppler echocardiography (Ea/Aa after TAC: WT 2.1+/-0.3 versus KO 1.0+/-0.2; P<0.05). To explore underlying mechanisms, we analyzed the left ventricular (LV) expression pattern of additional PKC isoforms (ie, PKCalpha, PKCbeta, and PKCdelta). After TAC, expression and activation of PKCdelta protein was increased in KO LVs. Moreover, KO LVs displayed enhanced activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), whereas p42/p44-MAPK activation was attenuated. Under stretch, cultured KO fibroblasts showed a 2-fold increased collagen Ialpha1 (col Ialpha1) expression, which was prevented by PKCdelta inhibitor rottlerin or by p38 MAPK inhibitor SB 203580. In conclusion, PKCepsilon is not required for the development of a pressure overload-induced myocardial hypertrophy. Lack of PKCepsilon results in upregulation of PKCdelta and promotes activation of p38 MAPK and JNK, which appears to compensate for cardiac hypertrophy, but in turn, is associated with increased collagen deposition and impaired diastolic function.