tbuckley/cabot-search huggingface dataset:
Ir-genes in H-2 regulate generation of anti-viral cytotoxic T cells. Mapping to K or D and dominance of unresponsiveness.
Authors: R M Zinkernagel, A Althage, S Cooper, G Kreeb, P A Klein, B Sefton, L Flaherty, J Stimpfling, D Shreffler, J Klein
Journal: The Journal of Experimental Medicine (1978)

H-2 dependent and virus-specific Ir genes regulate the generation of primary virus-specific K or D restricted cytotoxic T-cell responses in vivo. The following examples have been analyzed in some detail: first, Dk restricted responses to vaccinia in Sendai viruses are at least 30 times lower than the corresponding K-restricted responses irrespective of the H-2 haplotypes (k, b, d, dxs, dxq) of K and I regions; in contrast, LCMV infection generates high responses to Dk. These findings are consistent with but do not prove that this Ir gene maps to D. Second, Db restricted responses to vaccinia and Sendai viruses are high in strains possessing the Kq or KbIb, KbaIb haplotype, are very low in strains with Kk, and relatively low in mouse strains of the KdI-Ad haplotype; LCMV generates high Db restricted response in the presence of Kk. This Ir gene for the response to vaccinia and Sendai viruses maps to K since B10.BYR (KqIkdDb) is a responder and B10.A (2R) is a nonresponder (KkIkdDb). Third, virus and K or D allele specific nonresponsiveness is dominant with variable penetrance; in heterozygous mice the nonresponder Kk allele over-rides responsiveness normally found in KbDb or KqDb combinations. Fourth, when (responder X nonresponder)F1 lymphocytes are stimulated in an environment expressing vaccinia virus plus only a high responder Kb or Kq allelle and Db, response to vaccinia Db is high; in contrast when the same F1 cells are stimulated in an environment expressing the low responder allele Kk, response to vaccinia Db is low. Thus absence of Kk during immunization allows generation of high responsive Db restricted vaccinia specific cytotoxic T cells. The Dk dependent low response to vaccinia Dk can be explained by a preclusion rule or by failure of vaccinia to complex with Db; however the analysis of Kk dependent low response to vaccinia Db does not support these explanations or that self-tolerance is responsible for this Ir effect but is compatible with the interpretation that Kk vaccinia is immunodominant over Db vaccinia. These results are discussed with respect to (a) possible mechanisms of regulation by Ir genes and (b) H-2 polymorphism and HLA-disease association.
Area Specificity and Topography of Thalamocortical Projections Are Controlled by ephrin/Eph Genes
Authors: Audrey Dufour, Julie Seibt, Lara Passante, Vanessa Depaepe, Thomas Ciossek, Jonas Frisén, Klas Kullander, John G. Flanagan, Franck Polleux, Pierre Vanderhaeghen
Journal: Neuron (2003)
Quantitative Immuno-Positron Emission Tomography Imaging of HER2-Positive Tumor Xenografts with an Iodine-124 Labeled Anti-HER2 Diabody
Authors: Matthew K. Robinson, Mohan Doss, Calvin Shaller, Deepa Narayanan, James D. Marks, Lee P. Adler, Dinko E. González Trotter, Gregory P. Adams
Journal: Cancer Research (2005)

Abstract Positron emission tomography (PET) provides an effective means of both diagnosing/staging several types of cancer and evaluating efficacy of treatment. To date, the only U.S. Food and Drug Administration–approved radiotracer for oncologic PET is 18F-fluoro-deoxyglucose, which measures glucose accumulation as a surrogate for malignant activity. Engineered antibody fragments have been developed with the appropriate targeting specificity and systemic elimination properties predicted to allow for effective imaging of cancer based on expression of tumor associated antigens. We evaluated a small engineered antibody fragment specific for the HER2 receptor tyrosine kinase (C6.5 diabody) for its ability to function as a PET radiotracer when labeled with iodine-124. Our studies revealed HER2-dependent imaging of mouse tumor xenografts with a time-dependent increase in tumor-to-background signal over the course of the experiments. Radioiodination via an indirect method attenuated uptake of radioiodine in tissues that express the Na/I symporter without affecting the ability to image the tumor xenografts. In addition, we validated a method for using a clinical PET/computed tomography scanner to quantify tumor uptake in small-animal model systems; quantitation of the tumor targeting by PET correlated with traditional necropsy-based analysis at all time points analyzed. Thus, diabodies may represent an effective molecular structure for development of novel PET radiotracers.
Altered DNA Methylation Landscapes of Polycomb-Repressed Loci Are Associated with Prostate Cancer Progression and ERG Oncogene Expression in Prostate Cancer
Authors: Ken Kron, Dominique Trudel, Vaijayanti Pethe, Laurent Briollais, Neil Fleshner, Theodorus van der Kwast, Bharati Bapat
Journal: Clinical Cancer Research (2013)

To assess differentially methylated "landscapes" according to prostate cancer Gleason score (GS) and ERG oncogene expression status, and to determine the extent of polycomb group (PcG) target gene involvement, we sought to assess the genome-wide DNA methylation profile of prostate cancer according to Gleason score and ERG expression.Genomic DNA from 39 prostate cancer specimens was hybridized to CpG island microarrays through differential methylation hybridization. We compared methylation profiles between Gleason score and ERG expression status as well as Gleason score stratified by ERG expression status. In addition, we compared results from our dataset to publicly available datasets of histone modifications in benign prostate cells.We discovered hundreds of distinct differentially methylated regions (DMR) associated with increasing Gleason score and ERG. Furthermore, the number of DMRs associated with Gleason score was greatly expanded by stratifying samples into ERG-positive versus ERG-negative, with ERG-positive/GS-associated DMRs being primarily hypermethylated as opposed to hypomethylated. Finally, we found that there was a significant overlap between either Gleason score-related or ERG-hypermethylated DMRs and distinct regions in benign epithelial cells that have PcG signatures (H3K27me3, SUZ12) and lack active gene expression signatures (H3K4me3, RNA pol II).This work defines methylation landscapes of prostate cancer according to Gleason score, and suggests that initiating genetic events may influence the prostate cancer epigenome, which is further perturbed as prostate cancer progresses. Moreover, CpG islands with silent chromatin signatures in benign cells are particularly susceptible to prostate cancer-related hypermethylation.
Netrin-1 as a novel therapeutic target in cardiovascular disease: to activate or inhibit?
Authors: Kerry Layne, Albert Ferro, Gabriella Passacquale
Journal: Cardiovascular Research (2015)

Netrins are a family of laminin-like proteins, which were initially identified for their role in embryonic axonal guidance. Over recent years, it has become apparent that netrin-1 may additionally be involved in the underlying pathology of several multisystem diseases, making it an attractive potential therapeutic target. It is involved in postnatal angiogenesis, particularly in the context of an ischaemic insult, although there are conflicting reports as to whether netrin-1 acts in a pro- or anti-angiogenic capacity. In atherosclerosis, opposing effects have similarly been reported on plaque progression, due to the ability of netrin-1 to inhibit both macrophage egress from and monocyte ingress into lesions. Netrin-1 has also been shown to exert a cardioprotective action in the context of ischaemia-reperfusion injury following myocardial infarction. Moreover, urinary netrin-1 levels rise in response to acute kidney injury and at a faster rate than traditional markers of renal impairment, highlighting a potential clinical role for netrin-1 as a biomarker of renal function. The increased urinary excretion of netrin-1 during kidney disease is paralleled by a down-regulation of its plasma levels, with potential implications at a systemic level. In summary, the role of netrin-1 in cardiovascular disease is an emerging area of research requiring further in-depth study to elucidate its mechanism of action and potential as a therapeutic target, especially in view of its seemingly contradictory actions in certain physiological pathways which serve to highlight its manifold and often opposite effects in numerous physiological and pathophysiological processes.
Serum Concentrations of Polychlorinated Biphenyls in Relation to <i>in Vitro</i> Fertilization Outcomes
Authors: John D. Meeker, Arnab Maity, Stacey A. Missmer, Paige L. Williams, Shruthi Mahalingaiah, Shelley Ehrlich, Katharine F. Berry, Larisa Altshul, Melissa J. Perry, Daniel W. Cramer, Russ Hauser
Journal: Environmental Health Perspectives (2011)

Human exposure to polychlorinated biphenyls (PCBs) remains widespread. PCBs have been associated with adverse reproductive health outcomes including reduced fecundability and increased risk of pregnancy loss, although the human data remain largely inconclusive.Our goal was to explore the relationship between serum PCB concentrations and early pregnancy loss among a large cohort of women undergoing in vitro fertilization (IVF) between 1994 and 2003.Concentrations of 57 PCB congeners were measured in serum samples collected during 827 IVF/intracytoplasmic sperm injection cycles from 765 women. Joint statistical models that accommodate multiple outcomes and multiple cycles per woman were used to assess the relationship between serum PCB quartiles and implantation failure, chemical pregnancies (human chorionic gonadotropin level > 5.0 mIU/mL) that did not result in clinical pregnancy, or spontaneous abortion, while also adjusting for confounders.PCB-153 was the congener present in the highest concentration (median, 46.2 ng/g lipid). Increasing quartiles of PCB-153 and the sum of all measured PCB congeners (ΣPCBs) were associated with significantly elevated dose-dependent odds of failed implantation. Adjusted odds ratios (95% confidence interval) for highest versus lowest quartile were 2.0 (1.2-3.4) for PCB-153 and 1.7 (1.0-2.9) for ΣPCBs. There were suggestive trends for increased odds of implantation failure for PCB-118 and cytochrome P450-inducing congeners (p-values for trend = 0.06). No statistically significant associations between PCBs and chemical pregnancy or spontaneous abortion were found.Serum PCB concentrations at levels similar to the U.S. general population were associated with failed implantation among women undergoing IVF. These findings may help explain previous reports of reduced fecundability among women exposed to PCBs.
Chromosomal Rearrangements Leading to MLL Gene Fusions: Clinical and Biological Aspects
Authors: David P. Harper, Peter D. Aplan
Journal: Cancer Research (2008)

Abstract Rearrangements of the MLL gene located at 11q23 are common chromosomal abnormalities associated with acute leukemia, especially infant and therapy-related leukemias. A variety of chimeric oncoproteins resulting from these rearrangements has been described; all of these include the NH2-terminal region of MLL implicated in protein-protein interactions and transcriptional repression. Although the molecular basis for the oncogenic activity of MLL chimeric proteins is incompletely understood, it seems to be derived, at least in part, through activation of clustered homeobox (HOX) genes. Here, we survey MLL gene rearrangements that are associated with acute leukemia and discuss molecular pathways leading to these rearrangements. [Cancer Res 2008;68(24):10024–7]
In vivo gene delivery by embryonic-stem-cell–derived astrocytes for malignant gliomas
Authors: Mahmud Uzzaman, Gordon Keller, Isabelle M. Germano
Journal: Neuro-Oncology (2008)

The treatment of malignant gliomas with current therapies remains a challenge in neurooncology. Our recent work showed that embryonic stem cell (ESC)-derived astrocytes conditionally expressing genes can be used to induce apoptosis in malignant glioma cells in vitro. The tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) gene has been shown to induce apoptosis in a variety of tumor cells, including gliomas. The aim of this study was to assess the proapoptotic effects of transgenic TRAIL delivered by ESC-derived astrocytes on malignant gliomas in vivo. Malignant glioma A172 cells were used to induce heterotopic xenografts in nude mice. ESC-derived astrocytes conditionally expressing TRAIL were injected into the xenografts. TRAIL expression was documented in the malignant glioma xenografts by reverse transcription PCR and immunohistochemistry after external gene induction. A significant reduction in tumor volume occurred 48 h after a single injection (14%) and double injections (31%) in the experimental groups. Terminal dUTP nick end labeling (TUNEL) revealed abundant apoptotic tumor cells in the experimental groups. Seven days after injection, the tumor had undergone severe necrosis, with only scattered residual tumor cells at the periphery. Death receptor DR4 expression increased significantly in the experimental groups compared with controls. Our data suggest that ESC-derived astrocytes conditionally expressing TRAIL should be considered as vectors to deliver gene therapy for malignant gliomas.
Expansion and tissue infiltration of an allospecific CD4+CD25+CD45RO+IL-7Rαhigh cell population in solid organ transplant recipients
Authors: Laura Codarri, Laure Vallotton, Donatella Ciuffreda, Jean-Pierre Venetz, Miguel Garcia, Karine Hadaya, Leo Buhler, Samuel Rotman, Manuel Pascual, Giuseppe Pantaleo
Journal: The Journal of Experimental Medicine (2007)

It has been recently shown (Seddiki, N., B. Santner-Nanan, J. Martinson, J. Zaunders, S. Sasson, A. Landay, M. Solomon, W. Selby, S.I. Alexander, R. Nanan, et al. 2006. J. Exp. Med. 203:1693–1700.) that the expression of interleukin (IL) 7 receptor (R) α discriminates between two distinct CD4 T cell populations, both characterized by the expression of CD25, i.e. CD4 regulatory T (T reg) cells and activated CD4 T cells. T reg cells express low levels of IL-7Rα, whereas activated CD4 T cells are characterized by the expression of IL-7Rαhigh. We have investigated the distribution of these two CD4 T cell populations in 36 subjects after liver and kidney transplantation and in 45 healthy subjects. According to a previous study (Demirkiran, A., A. Kok, J. Kwekkeboom, H.J. Metselaar, H.W. Tilanus, and L.J. van der Laan. 2005. Transplant. Proc. 37:1194–1196.), we observed that the T reg CD25+CD45RO+IL-7Rαlow cell population was reduced in transplant recipients (P &amp;lt; 0.00001). Interestingly, the CD4+CD25+CD45RO+IL-7Rαhigh cell population was significantly increased in stable transplant recipients compared with healthy subjects (P &amp;lt; 0.00001), and the expansion of this cell population was even greater in patients with documented humoral chronic rejection compared with stable transplant recipients (P &amp;lt; 0.0001). The expanded CD4+CD25+CD45RO+IL-7Rαhigh cell population contained allospecific CD4 T cells and secreted effector cytokines such as tumor necrosis factor α and interferon γ, thus potentially contributing to the mechanisms of chronic rejection. More importantly, CD4+IL-7Rα+and CD25+IL-7Rα+ cells were part of the T cell population infiltrating the allograft of patients with a documented diagnosis of chronic humoral rejection. These results indicate that the CD4+CD25+IL-7Rα+ cell population may represent a valuable, sensitive, and specific marker to monitor allospecific CD4 T cell responses both in blood and in tissues after organ transplantation.
Cellular protein kinase C activity in asthma.
Authors: I. Vachier, P. Chanez, T. Radeau, C. Le Doucen, C. Leger, Pascale Godard
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Protein kinase C (PKC) is a primary group of enzymes mediating signal transduction for a wide variety of functions in many different cell types. Its activation has been implicated in various inflammatory diseases. In asthma, inflammatory cells, such as alveolar macrophages (AM) and polymorphonuclear neutrophils (PMN), are primed and activated compared with those obtained from control subjects. In particular, they release higher amounts of reactive oxygen species. PKC has been known to play an important role in the respiratory burst of human leukocytes. In this study, the PKC activity was measured in blood neutrophils and alveolar macrophages from control (n = 16) and asthmatic subjects (n = 28). In PMN, the total PKC activity was significantly lower in PMN from stable (182.00 +/- 27.20) and unstable (108.40 +/- 14.15) asthmatic patients, compared with control subjects (257.35 +/- 29.70 pmol/10(7) cells/min with p < 0.05 and p < 0.0005, respectively). In AM, PKC activity was 479.50 +/- 71.80 for controls and 254.00 +/- 25.90 pmol/10(7) cells/min for asthmatic patients. Moreover the percentage of membrane PKC was significantly higher in stable asthmatic patients in both cell types. After stimulation of neutrophils with PMA, a significant decrease in total PKC activity was observed in both control and asthmatic subjects. We have found an abnormal regulation of PKC activity in both blood PMNs and AM in asthmatic patients. These findings are consistent with the functional hyperreactivity of inflammatory cells observed in asthma.
Association Between Casino Opening or Expansion and Risk of Childhood Overweight and Obesity
Authors: Jessica C. Jones-Smith, William H. Dow, Kristal Chichlowska
Journal: JAMA (2014)

<h3>Importance</h3> Economic resources have been inversely associated with risk of childhood overweight/obesity. Few studies have evaluated whether this association is a direct effect of economic resources or is attributable to unmeasured confounding or reverse causation. American Indian–owned casinos have resulted in increased economic resources for some tribes and provide an opportunity to test whether these resources are associated with overweight/obesity. <h3>Objective</h3> To assess whether openings or expansions of American Indian–owned casinos were associated with childhood overweight/obesity risk. <h3>Design, Setting, and Participants</h3> We used repeated cross-sectional anthropometric measurements from fitness testing of American Indian children (aged 7-18 years) from 117 school districts that encompassed tribal lands in California between 2001 and 2012. Children in school districts encompassing American Indian tribal lands that either gained or expanded a casino were compared with children in districts with tribal lands that did not gain or expand a casino. <h3>Main Outcomes and Measures</h3> Per capita annual income, median annual household income, percentage of population in poverty, total population, child overweight/obesity (body mass index [BMI] ≥85th age- and sex-specific percentile) and BMI<i>z</i>score. <h3>Results</h3> Of the 117 school districts, 57 gained or expanded a casino, 24 had a preexisting casino but did not expand, and 36 never had a casino. The mean slots per capita was 7 (SD, 12) and the median was 3 (interquartile range [IQR], 0.3-8). Among districts where a casino opened or expanded, the mean change in slots per capita was 13 (SD, 19) and the median was 3 (IQR, 1-11). Forty-eight percent of the anthropometric measurements were classified as overweight/obese (11 048/22 863). Every casino slot machine per capita gained was associated with an increase in per capita annual income (β = $541; 95% CI, $245-$836) and a decrease in percentage in poverty (β = −0.6%; 95% CI, −1.1% to −0.20%) among American Indians living on tribal lands. Among American Indian children, every slot machine per capita gained was associated with a decreased probability of overweight/obesity by 0.19 percentage points (95% CI, −0.26 to −0.11 percentage points) and a decrease in BMI<i>z</i>score (β = −0.003; 95% CI, −0.005 to −0.0002). <h3>Conclusions and Relevance</h3> In this study, opening or expanding a casino was associated with increased economic resources and decreased risk of childhood overweight/obesity. Given the limitations of an ecological study, further research is needed to better understand the mechanisms behind this association.
Heart Disease: A Textbook of Cardiovascular Medicine.
Journal: Annals of Internal Medicine (1984)

PART I General Considerations of Cardiovascular Disease PART II Examination of the Patient PART III Normal and Abnormal Cardiac Function: Heart Failure and Arrhythmias PART IV Hypertensive and Atherosclerotic Cardiovascular Disease PART V Diseases of the Heart, Pericardium and Pulmonary Vascular Bed PART VI Molecular Biology and Genetics PART VII Cardiovascular Disease in Special Populations PART VIII Cardiovascular Disease and Disorders of other Organ Systems
The Molecular Ggenetics of the Long QT Syndrome: Genes Causing Fainting and Sudden Death
Authors: G. Michael Vincent, MD
Journal: Annual Review of Medicine (1998)

The congenital long QT syndrome is an autosomal-dominant genetic disorder of cardiac electrical repolarization. It is caused by mutations of at least six genes, of which four, all encoding for cardiac ion channels, have been identified: KVLQT1, HERG, and Min K encode for cardiac potassium ion channels, and SCN5A encodes for the cardiac sodium ion channel. In each case the altered ion channel function produces prolongation of the action potential and propensity to torsade de pointes ventricular tachycardia. A fifth gene locus is known to be on chromosome 4, but the gene has not been isolated. At least one other gene must exist, and there may be several more. Long QT syndrome is a frequent but often overlooked cause of unexpected syncope and sudden death in children and young adults. Characteristic findings are prolongation of the QT interval and T wave abnormalities on the electrocardiogram. However, the QT interval at presentation is normal about 10% of the time and just borderline prolonged another 30%, so diagnosis may be difficult. Symptoms are syncope and sudden death, typically occurring during exercise or emotional upset. The manifestations vary, depending on the genotype present. The phenotype also probably varies, depending on the specific mutation involved. Phenotypic heterogeneity is also caused by variable penetrance and expressivity.
The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors
Authors: William R Marrs, Jacqueline L Blankman, Eric A Horne, Aurore Thomazeau, Yi Hsing Lin, Jonathan Coy, Agnes L Bodor, Giulio G Muccioli, Sherry Shu-Jung Hu, Grace Woodruff, Susan Fung, Mathieu Lafourcade, Jessica P Alexander, Jonathan Z Long, Weiwei Li, Cong Xu, Thomas Möller, Ken Mackie, Olivier J Manzoni, Benjamin F Cravatt, Nephi Stella
Journal: Nature Neuroscience (2010)
Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1
Authors: Kathryn L. Lipson, Sonya G. Fonseca, Shinsuke Ishigaki, Linh X. Nguyen, Elizabeth Foss, Rita Bortell, Aldo A. Rossini, Fumihiko Urano
Journal: Cell Metabolism (2006)