tbuckley/cabot-search huggingface dataset:
Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer
Authors: Mariana C. Stern, Jie Lin, Jonine D. Figueroa, Karl T. Kelsey, Anne E. Kiltie, Jian-Min Yuan, Giuseppe Matullo, Tony Fletcher, Simone Benhamou, Jack A. Taylor, Donatella Placidi, Zuo-Feng Zhang, Gunnar Steineck, Nathaniel Rothman, Manolis Kogevinas, Debra Silverman, Nuria Malats, Stephen Chanock, Xifeng Wu, Margaret R. Karagas, Angeline S. Andrew, Heather H. Nelson, D. Timothy Bishop, Sei Chung Sak, Ananya Choudhury, Jennifer H. Barrett, Faye Elliot, Román Corral, Amit D. Joshi, Manuela Gago-Dominguez, Victoria K. Cortessis, Yong-Bing Xiang, Yu-Tang Gao, Paolo Vineis, Carlotta Sacerdote, Simonetta Guarrera, Silvia Polidoro, Alessandra Allione, Eugen Gurzau, Kvetoslava Koppova, Rajiv Kumar, Peter Rudnai, Stefano Porru, Angela Carta, Marcello Campagna, Cecilia Arici, Sung Shim Lani Park, Montserrat Garcia-Closas
Journal: Cancer Research (2009)

Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01-1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01-1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% CI, 1.00-1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis.
Restricted nucleocytoplasmic relationship in activation of T and B lymphocytes.
Authors: T Watanabe, Y Eda, J Ohara
Journal: The Journal of Experimental Medicine (1982)

Nuclei of murine T lymphocytes or B lymphocytes were purified and transferred into lethally irradiated whole spleen cells or B or T lymphocytes by means of polyethyleneglycol-mediated cell fusion. Transfer of lymphocyte nuclei could save the irradiated cells from cell death, and such reconstituted cells could respond to mitogens. The present study showed that nuclei of T cells could be activated in the concanavalin A-stimulated T cell cytoplasms but not in the lipopolysaccharide-stimulated B cell cytoplasms. On the other hand, nuclei of B cells were activated in the lipopolysaccharide-stimulated B cells but not in the concanavalin A-stimulated T cell cytoplasms. These data suggested that a specific interaction between cytoplasm and nucleus might exist in the activation of nuclei of each lymphocyte subset.
ON THE MECHANISM OF SPECIFIC PRECIPITATION
Authors: William C. Boyd
Journal: The Journal of Experimental Medicine (1942)

A study of the precipitability by the appropriate antisera of 34 different haptens, containing from one to six reactive groups, leads to the conclusion that the possibility of framework ("lattice") formation is neither necessary nor sufficient for specific precipitation, but that instead precipitation depends upon the reduction, by mutual neutralization of polar groups of antibody and antigen (or hapten) and mechanical blocking off of polar groups of closely neighboring molecules of antibody, of the solubility of the complex below the point at which it can remain in solution. The decisive factors appear to be the number of polar groups of the antigen (hapten) left free, and the distance separating the different reactive groups, which determines the amount of steric hindrance exerted by one antibody molecule on another. No hypothesis is offered as to how these primary insoluble aggregates unite with each other to produce the larger aggregates which are finally observed.
Increased expression of CCL18, CCL19, and CCL17 by dendritic cells from patients with rheumatoid arthritis, and regulation by Fc gamma receptors
Authors: T R D J Radstake
Journal: Annals of the Rheumatic Diseases (2004)

Dendritic cells (DC) have a role in the regulation of immunity and tolerance, attracting inflammatory cells by the production of various chemokines (CK). Fc gamma receptors (Fc gamma R) may be involved in regulation of the DC function.To assess the expression of CK by immature (iDC) and mature DC (mDC) and its regulation by Fc gamma R in patients with RA and healthy donors (HC).Expression of CK by DC from patients with RA and from HC was determined by real time quantitative PCR and ELISA. DC were derived from monocytes following standardised protocols. To study the potential regulation by Fc gamma R, iDC were stimulated with immune complexes (IC) during lipopolysaccharide (LPS) induced maturation. The presence of CK was studied in synovial tissue from patients with RA, osteoarthritis, and healthy subjects by RT-PCR and immunohistochemistry.iDC from patients with RA had markedly increased mRNA levels of the CK CCL18 and CXCL8. Upon maturation with LPS, expression of CCL18, CCL19, CXCL8, CCL3, and CCL17 increased dramatically, reaching significantly higher levels in patients with RA. Monocytes failed to express these CK, except for CXCL8 and CCL3. IC-mediated triggering of the Fc gamma R on DC from patients with highly active RA down regulated all CK, whereas the reverse was seen when DC from patients with low disease activity and healthy donors were stimulated. CCL18 was significantly increased in RA synovial tissue.Increased CK expression by DC was found in patients with RA. This expression is partly regulated by Fc gamma R triggering and results in an inhibitory DC subtype in RA upon Fc gamma R-mediated triggering.
The JAK inhibitor CP-690,550 (tofacitinib) inhibits TNF-induced chemokine expression in fibroblast-like synoviocytes: autocrine role of type I interferon
Authors: Sanna Rosengren, Maripat Corr, Gary S Firestein, David L Boyle
Journal: Annals of the Rheumatic Diseases (2011)

Objectives The objective of this study was to investigate the effect of the novel Janus kinase inhibitor CP-690,550 in fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA). Methods RA FLSs were isolated from tissue obtained by arthroplasty, cultured and serum-starved 48 h prior to stimulation. Messenger RNA and protein levels were determined by quantitative PCR and ELISA or multiplex bead assay, respectively. Phosphorylation of STAT (signal transducers and activators of transcription) proteins was determined by western blot. Results Interleukin-6-induced phosphorylation of STAT1 and STAT3 was inhibited by CP-690,550 with IC 50 values of 23 and 77 nM, respectively. Unexpectedly, although tumour necrosis factor (TNF) did not induce immediate phosphorylation of either STAT, CP-690,550 inhibited TNF-induced expression of several chemokines (IP-10, RANTES and MCP1) at the messenger RNA and protein levels. Chemokine expression was inhibited by cycloheximide, implying a need for de novo protein synthesis, and cycloheximide abolished the effect of CP-690,550 (tofacitinib). TNF induced early interferon (IFN) β expression and STAT1 phosphorylation beginning at 3 h, which was blocked by CP-690,550. The dependence of TNF-induced chemokine expression on type I IFN was confirmed in FLSs from mice lacking type I IFN receptors (IFNARs) and in RA FLSs using an IFNAR blocking antibody. Conclusions The Janus kinase/STAT pathway in FLS is indirectly activated by TNF through autocrine expression of type I IFN, resulting in IFNAR engagement and production of T cell chemokines. These findings illuminate a novel role of CP-690,550 in the treatment of RA: the reduction of chemokine synthesis by FLS, thereby limiting recruitment of T cells and other infiltrating leucocytes.
Renin Lineage Cells Repopulate the Glomerular Mesangium after Injury
Authors: Charlotte Starke, Hannah Betz, Linda Hickmann, Peter Lachmann, Björn Neubauer, Jeffrey B Kopp, Maria Luisa S Sequeira-Lopez, R Ariel Gomez, Bernd Hohenstein, Vladimir T Todorov, Christian P M Hugo
Journal: Journal of the American Society of Nephrology (2014)

Mesangial cell injury has a major role in many CKDs. Because renin-positive precursor cells give rise to mesangial cells during nephrogenesis, this study tested the hypothesis that the same phenomenon contributes to glomerular regeneration after murine experimental mesangial injury. Mesangiolysis was induced by administration of an anti-mesangial cell serum in combination with LPS. In enhanced green fluorescent protein-reporter mice with constitutively labeled renin lineage cells, the size of the enhanced green fluorescent protein-positive area in the glomerular tufts increased after mesangial injury. Furthermore, we generated a novel Tet-on inducible triple-transgenic LacZ reporter line that allowed selective labeling of renin cells along renal afferent arterioles of adult mice. Although no intraglomerular LacZ expression was detected in healthy mice, about two-thirds of the glomerular tufts became LacZ positive during the regenerative phase after severe mesangial injury. Intraglomerular renin descendant LacZ-expressing cells colocalized with mesangial cell markers α8-integrin and PDGF receptor-β but not with endothelial, podocyte, or parietal epithelial cell markers. In contrast with LacZ-positive cells in the afferent arterioles, LacZ-positive cells in the glomerular tuft did not express renin. These data demonstrate that extraglomerular renin lineage cells represent a major source of repopulating cells for reconstitution of the intraglomerular mesangium after injury.
Intrinsic mechanisms controlling the mammalian gastro-oesophageal sphincter deprived of extrinsic nerve supply
Authors: C. V. Mann, C. F. Code, J. F. Schlegel, F. H. Ellis
Journal: Thorax (1968)

The oesophagus and gastro-oesophageal junction of 13 guinea-pigs and 14 3-week-old kittens were removed and placed in oxygenated Tyrode9s solution at 36 to 37° C. Sphincteric pressures were recorded before and after oesophageal distension. In these preparations changes in the tone of the gastro-oesophageal sphincter were observed in response to lower oesophageal distension. The sphincter of the guinea-pig responded by relaxation, whereas the sphincter of the kitten responded more often by contraction. The relaxation/contraction responses of the sphincter to oesophageal distension were independent of any extrinsic nerve supply and could be abolished by removal of a circular cuff of oesophageal muscle between the source of the stimulus and the gastro-oesophageal sphincter. The intramural mechanisms affecting gastro-oesophageal sphincteric tone probably are present in all mammals, including man.
H1N1: Can a Pandemic Cycle Be Broken?
Authors: Ethan C. Settembre, Philip R. Dormitzer, Rino Rappuoli
Journal: Science Translational Medicine (2010)

The influenza virus that caused the 2009 H1N1 swine-origin flu pandemic is antigenically similar to the one that caused the devastating 1918 pandemic. Over time, the human population became susceptible to a modified version of the 1918 pandemic H1N1 virus that had been archived in swine. Now, two papers, one in this issue of Science Translational Medicine and one in Science, shed mechanistic light on how glycosylation gave rise to seasonal human flu viruses that are immunologically distinct from their 1918 pandemic precursor and the 2009 pandemic strain. These findings suggest strategies to anticipate and prevent future pandemics.
Antibody negative coeliac disease presenting in elderly people—an easily missed diagnosis
Authors: David S Sanders, David P Hurlstone, Mark E McAlindon, Marios Hadjivassiliou, Simon S Cross, Graeme Wild, Christopher J Atkins
Journal: BMJ (2005)

Epidemiological studies screening cohorts of healthy volunteers in the United States of America, the United Kingdom, and other European countries have determined that the prevalence of adult coeliac disease in the general population is in the magnitude of 1 per 100 to 200.1–4

The diagnosing of coeliac disease is often delayed,3–7 perhaps owing to a failure to recognise the protean manifestations of this disease in both primary and secondary care.5–9 Coeliac disease used to be perceived as involving gastrointestinal symptoms suggestive of malabsorption, but this manner of presentation is now described as the classic (typical) form.4 Patients with coeliac disease may have the silent or atypical form (no gastrointestinal symptoms), and the condition may present insidiously—for example, with iron deficiency anaemia, osteoporosis, cryptogenic hypertransaminasaemia, or neurological symptoms.5–10 The increasing recognition of coeliac disease is attributed to the use of new serological assays that have a high sensitivity and specificity.4 Antibody testing, however, is not the absolute method of diagnosis. We present a case of an elderly man presenting with coeliac disease in whom the condition would not have been recognised without a second duodenal biopsy.

In May 2003 a 79 year old man with longstanding dyspepsia presented to his general practitioner with worsening indigestion, tiredness, and rapid weight loss. Blood tests arranged by the doctor showed a macrocytic anaemia with low concentrations of vitamin B-12 and folate. The patient subsequently had a …
“Right-to-Try” Legislation: Progress or Peril?
Authors: Y. Tony Yang, Brian Chen, Charles Bennett
Journal: Journal of Clinical Oncology (2015)

Since 2014, state legislators have increased their efforts to find a way for terminally ill patients to gain legal access to experimental drugs not yet approvedbytheU.S.FoodandDrugAdministration(FDA).AsofJune1, 2015,40statesandtheDistrictofColumbiahadexaminedorwillexamine this burgeoning issue with bills that have already been filed and 18 signed so-called “Right-to-Try” laws (Table 1). Patients who are terminally ill and who are facing less than 1 year of life expectancy are willing to take greater risks and endure a higher danger of potential adverse effects than other patients, including taking experimental drugs with unknown risk-benefit ratios. For patients who have exhausted existing pharmacotherapy options, there are two conventional ways to access potentially life-prolonging investigational drugs: join a clinical trial if they are well enough to meet rigorous entry criteria or apply for FDA’s “compassionate use” exception. Although the FDA accepted 5,816 of the 5,849 expanded access applications it received in the last 4 years, some argue that the FDA approval process for allowing expanded access to experimental drugs has been slow and cumbersome. Besides, many of the delays in the process occur before submission to FDA when the drug sponsor is deciding whether or not to provide the drug in question. Although the compassionate use of investigational drugs has been a contentious issue, public debate has centered on whether the gain in providing the terminally ill with a slim chance at prolonging life is worth endangering a process designed to ensure the public health and the development of safe, effective medicines.
Phase III Study of Craniospinal Radiation Therapy Followed by Adjuvant Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma
Authors: Roger J. Packer, Amar Gajjar, Gilbert Vezina, Lucy Rorke-Adams, Peter C. Burger, Patricia L. Robertson, Lisa Bayer, Deborah LaFond, Bernadine R. Donahue, MaryAnne H. Marymont, Karin Muraszko, James Langston, Richard Sposto
Journal: Journal of Clinical Oncology (2006)

To determine the event-free survival (EFS) and overall survival of children with average-risk medulloblastoma and treated with reduced-dose craniospinal radiotherapy (CSRT) and one of two postradiotherapy chemotherapies.Four hundred twenty-one patients between 3 years and 21 years of age with nondisseminated medulloblastoma (MB) were prospectively randomly assigned to treatment with 23.4 Gy of CSRT, 55.8 Gy of posterior fossa RT, plus one of two adjuvant chemotherapy regimens: lomustine (CCNU), cisplatin, and vincristine; or cyclophosphamide, cisplatin, and vincristine. Results Forty-two of 421 patients enrolled were excluded from analysis. Sixty-six of the remaining 379 patients had incompletely assessable postoperative studies. Five-year EFS and survival for the cohort of 379 patients was 81% +/- 2.1% and 86% +/- 9%, respectively (median follow-up over 5 years). EFS was unaffected by sex, race, age, treatment regimen, brainstem involvement, or excessive anaplasia. EFS was detrimentally affected by neuroradiographic unassessability. Patients with areas of frank dissemination had a 5-year EFS of 36% +/- 15%. Sixty-seven percent of progressions had some component of dissemination. There were seven second malignancies. Infections occurred more frequently on the cyclophosphamide arm and electrolyte abnormalities were more common on the CCNU regimen.This study discloses an encouraging EFS rate for children with nondisseminated MB treated with reduced-dose craniospinal radiation and chemotherapy. Additional, careful, step-wise reductions in CSRT in adequately staged patients may be possible.
Improving Implementation: Building Research Capacity in Maternal, Neonatal, and Child Health in Africa
Authors: James Whitworth, Nelson K. Sewankambo, Valerie A. Snewin
Journal: PLoS Medicine (2010)

This paper is part of a PLoS Medicine series on maternal, neonatal, and child health in Africa.This PLoS Medicine series began by outlining how much we fail mothers, newborns, and children in Africa by not implementing effectively what we know saves lives and improves health [1,2].It is clear that countries in Africa are falling behind not only on improving maternal, newborn, and child health but on the Millennium Development Goals 4, 5, and 6 more generally.Why is there such a wide gap between what we know and what we do?While technical knowledge about what could be done is available, actual implementation is neither straightforward nor easy in the often difficult circumstances on the ground.The many competing priorities-along with limited logistic capacity, a lack of political will, and inadequate infrastructure-also constrain the extent to which effective health packages are delivered to those who need them most.The Essay section contains opinion pieces on topics of broad interest to a general medical audience.
Balancing between Antitumor Efficacy and Autoimmune Pathology in T-Cell–Mediated Targeting of Carcinoembryonic Antigen
Authors: Rinke Bos, Suzanne van Duikeren, Hans Morreau, Kees Franken, Ton N.M. Schumacher, John B. Haanen, Sjoerd H. van der Burg, Cornelis J.M. Melief, Rienk Offringa
Journal: Cancer Research (2008)

Abstract Carcinoembryonic antigen (CEA) is intensively studied as a potential target for immunotherapy of colorectal cancers. Although overexpressed by tumors, CEA is also expressed in normal tissues, raising questions about the feasibility and safety of CEA-targeted immunotherapy. We investigated these issues in transgenic mice in which the expression of human CEA in normal tissues closely resembles that in man. Our data show that the T-cell response against CEA in these mice is blunted by both thymic and peripheral tolerance. Consequently, effective tumor targeting is only achieved by adoptive transfer of T cells from nontolerant donors in combination with interventions that eliminate peripheral immune regulatory mechanisms. However, such treatments can result in severe intestinal autoimmune pathology associated with weight loss and mortality. Interestingly, preconditioning of recipient mice by depletion of T-regulatory cells results in immune-mediated tumor control in the absence of toxicity. In this setting, CEA-specific T-cell responses are lower than those induced by toxic regimens and accompanied by additional T-cell responses against non-self antigen. These findings illustrate the importance of testing adoptive immunotherapies targeting self antigens such as CEA in preclinical in vivo models and show that the choice of immune intervention regimen critically determines the balance between therapeutic efficacy and toxicity. [Cancer Res 2008;68(20):8446–55]
Expression in in-vivo and in-vitro growing and maturing oocytes: focus on regulation of expression at the translational level
Authors: U Eichenlaub-Ritter, M Peschke
Journal: Human Reproduction Update (2002)

Studies of expression in in-vivo and in-vitro maturing oocytes have the potential to elucidate signalling pathways involved in the intricate crosstalk between the oocyte and its somatic compartment during differentiation and morphogenetic processes, and the origin of disturbances in oocyte maturation possibly involved in reduced fertility. This review summarizes data on expression studies with focus on regulation of expression at the translational level in the maturing oocyte. The regulation of gene expression at the translational level as analysed in in-vitro maturing oocytes is complex and highly conserved between different species. It is characterized by differential degradation, and by storage and recruitment of distinct maternal mRNAs involving conserved consensus sequences in the 5′ or 3′ untranslated regions (UTRs) of mRNAs. Proteins interacting with such sequences affect the temporal 3′ polyadenylation, and bring the 5′ and 3′ UTRs of mRNAs into close proximity for efficient initiation of translation. Post-translational modifications of mRNA-associated proteins contribute to maturation- and developmentally controlled and to cell cycle-dependent expression. New methodologies for analysis of ovary-specific gene expression and function of genes in oogenesis are also reviewed, e.g. RT–PCR, SAGE–PCR, real-time rapid cycle fluorescence monitored RT–PCR, differential display techniques, and microinjection of anti-sense RNA, double-stranded RNAs or mRNAs expressing green fluorescent protein-tagged proteins into maturing oocytes.
Exogenous administration of bone marrow-derived stem cells in experimental COPD
Authors: Borja Lobo, Raquel Puig-Pey, Elisabet Ferrer, David Domínguez-Fandos, Núria Coll, Jéssica García, Cristina Bonjoch, Joan A. Barberà, Víctor I. Peinado
Journal: European Respiratory Journal (2013)

Background   Adult bone marrow-derived stem cells (BMDSC) might be useful for treating advanced lung diseases such as COPD. Among others, potential side effects in the vascular system, may argue against the applicability of such approach. The aim of the study was to evaluate BMDSC homing into the lungs after local administration by means of two approaches in guinea pigs exposed to cigarette smoke (CS).   Methods   30 guinea pigs were exposed or sham exposed to CS for 1 month. In parallel, the adherent fraction of BMDSC from 8 naive guinea pigs was isolated and cultured in vitro. After CS exposure, animals were administered with 2.5 million BMDSC labeled with a fluorescent cell tracker; half of them via tracheal instillation (TR) and the other half via cardiac puncture (CP). 24h after cell administration, animals were sacrificed and labeled cells localized into lung structures by microscopy. Lung sections from naive animals were used as negative controls.   Results   The number of labeled BMDSC in lung tissue was significantly greater (p   Conclusions   In experimental COPD, exogenous BMDSC localize in alveolar septa regardless of the route of administration, indicating cell recruitment by injured lungs. In this model, exogenous intratracheal or intravascular BMDSC administrations does not localize in pulmonary vessels.  Supported by a grant FIS PS09-00536.