tbuckley/cabot-search huggingface dataset:
The role of prostaglandin E2 receptors in the pathogenesis of rheumatoid arthritis
Authors: Jennifer M. McCoy, Joan R. Wicks, Laurent P. Audoly
Journal: Journal of Clinical Investigation (2002)

Rheumatoid arthritis (RA) is a chronic inflammatory disorder leading to bone and cartilage destruction. A substantial body of evidence suggests that prostaglandin E2 (PGE2) contributes to the pathogenesis of RA, and nonsteroidal anti-inflammatory drugs, inhibitors of the synthesis of PGE2 and other prostanoids, continue to be used in the treatment of this disease. To begin to understand the mechanism by which prostaglandins modulate the pathophysiology of this disease, we examined mice lacking each of the four known PGE2 (EP) receptors after generation of collagen antibody-induced arthritis, an animal model of RA. Homozygous deletion of the EP1, EP2, or EP3 receptors did not affect the development of arthritis, whereas EP4 receptor-deficient mice showed decreased incidence and severity of disease. These animals also showed reduced inflammation as assessed by circulating IL-6 and serum amyloid A levels. Joint histopathology of EP4(-/-) animals revealed reduced bone destruction, proteoglycan loss, and type II collagen breakdown in cartilage compared with EP4(+/+) mice. Furthermore, liver and macrophages isolated from EP4(-/-) animals produced significantly less IL-1 beta and IL-6 than control samples. Thus, PGE2 contributes to disease progression at least in part by binding to the EP4 receptor. Antagonists of this receptor might therefore provide novel agents for the treatment of RA.
c-Myb–Dependent Cell Cycle Progression and Ca <sup>2+</sup> Storage in Cultured Vascular Smooth Muscle Cells
Authors: Mansoor Husain, Kiflai Bein, Lianwei Jiang, Seth L. Alper, Michael Simons, Robert D. Rosenberg
Journal: Circulation Research (1997)

Considerable controversy surrounds the role of the c-myb proto-oncogene in vascular smooth muscle cells (VSMCs). Previous investigations using antisense approaches have suggested a relationship between c-myb expression, cell cycle progression, and cytoplasmic Ca2+ concentration ([Ca2+]cyt). However, the ability of certain antisense oligonucleotides to bind and inactivate growth factors allows alternative explanations. To define more specifically the role of c-Myb in cultured VSMCs (SVE and A10 cell lines), we have generated stable cell clones expressing a dominant-negative c-Myb lacking critical elements of the DNA binding domain (delta5-SVE) and transiently transfected cell populations (GRE-MEn-SVE and GRE-MEn-A10) expressing a glucocorticoid-inducible chimeric protein that targets the Drosophila Engrailed repressor domain to c-Myb-responsive promoters. The delta5-SVE clones and GRE-MEn cell populations exhibit a 60% reduction in mean intracellular c-Myb activity, as measured by cotransfection assays with a c-Myb-responsive reporter, a 42% decrease in the mean S phase entry of growth-arrested (G[0]) cells after serum stimulation, and a 36% inhibition of mean cell proliferation over 4 days. These cells also display 28% (34-nmol/L) and 30% (42-nmol/L) reductions in mean [Ca2+]cyt at G(0) and at the G1/S interface, respectively, as well as significant reductions in the peak [Ca2+]cyt responses to thapsigargin (5 micromol/L) and caffeine (10 mmol/L). These latter reductions in operationally defined Ca2+ pools were observed both at different stages of the cell cycle and after transient induction of the dominant-interfering construct, suggesting that c-Myb regulates these releasable Ca2+ stores independent of its effects on cell cycle progression.
ATP and purinergic receptor–dependent membrane traffic in bladder umbrella cells
Authors: Edward C.Y. Wang, Jey-Myung Lee, Wily G. Ruiz, Elena M. Balestreire, Maximilian von Bodungen, Stacey Barrick, Debra A. Cockayne, Lori A. Birder, Gerard Apodaca
Journal: Journal of Clinical Investigation (2005)

The umbrella cells that line the bladder are mechanosensitive, and bladder filling increases the apical surface area of these cells; however, the upstream signals that regulate this process are unknown. Increased pressure stimulated ATP release from the isolated uroepithelium of rabbit bladders, which was blocked by inhibitors of vesicular transport, connexin hemichannels, ABC protein family members, and nucleoside transporters. Pressure-induced increases in membrane capacitance (a measure of apical plasma membrane surface area where 1 μF ≈ 1 cm2) were inhibited by the serosal, but not mucosal, addition of apyrase or the purinergic receptor antagonist PPADS. Upon addition of purinergic receptor agonists, increased capacitance was observed even in the absence of pressure. Moreover, knockout mice lacking expression of P2X2 and/or P2X3 receptors failed to show increases in apical surface area when exposed to hydrostatic pressure. Treatments that prevented release of Ca2+ from intracellular stores or activation of PKA blocked ATPγS-stimulated changes in capacitance. These results indicate that increased hydrostatic pressure stimulates release of ATP from the uroepithelium and that upon binding to P2X and possibly P2Y receptors on the umbrella cell, downstream Ca2+ and PKA second messenger cascades may act to stimulate membrane insertion at the apical pole of these cells.
Proof-of-principle rapid noninvasive prenatal diagnosis of autosomal recessive founder mutations
Authors: David A. Zeevi, Gheona Altarescu, Ariella Weinberg-Shukron, Fouad Zahdeh, Tama Dinur, Gaya Chicco, Yair Herskovitz, Paul Renbaum, Deborah Elstein, Ephrat Levy-Lahad, Arndt Rolfs, Ari Zimran
Journal: Journal of Clinical Investigation (2015)

BACKGROUND. Noninvasive prenatal testing can be used to accurately detect chromosomal aneuploidies in circulating fetal DNA; however, the necessity of parental haplotype construction is a primary drawback to noninvasive prenatal diagnosis (NIPD) of monogenic disease. Family-specific haplotype assembly is essential for accurate diagnosis of minuscule amounts of circulating cell-free fetal DNA; however, current haplotyping techniques are too time-consuming and laborious to be carried out within the limited time constraints of prenatal testing, hampering practical application of NIPD in the clinic. Here, we have addressed this pitfall and devised a universal strategy for rapid NIPD of a prevalent mutation in the Ashkenazi Jewish (AJ) population.
Identification of fusion genes in breast cancer by paired-end RNA-sequencing
Authors: Henrik Edgren, Astrid Murumagi, Sara Kangaspeska, Daniel Nicorici, Vesa Hongisto, Kristine Kleivi, Inga H. Rye, Sandra Nyberg, Maija Wolf, Anne Lise Borresen-Dale, Olli Kallioniemi
Journal: Genome biology (2011)

Abstract Background Until recently, chromosomal translocations and fusion genes have been an underappreciated class of mutations in solid tumors. Next-generation sequencing technologies provide an opportunity for systematic characterization of cancer cell transcriptomes, including the discovery of expressed fusion genes resulting from underlying genomic rearrangements. Results We applied paired-end RNA-seq to identify 24 novel and 3 previously known fusion genes in breast cancer cells. Supported by an improved bioinformatic approach, we had a 95% success rate of validating gene fusions initially detected by RNA-seq. Fusion partner genes were found to contribute promoters (5' UTR), coding sequences and 3' UTRs. Most fusion genes were associated with copy number transitions and were particularly common in high-level DNA amplifications. This suggests that fusion events may contribute to the selective advantage provided by DNA amplifications and deletions. Some of the fusion partner genes, such as GSDMB in the TATDN1-GSDMB fusion and IKZF3 in the VAPB-IKZF3 fusion, were only detected as a fusion transcript, indicating activation of a dormant gene by the fusion event. A number of fusion gene partners have either been previously observed in oncogenic gene fusions, mostly in leukemias, or otherwise reported to be oncogenic. RNA interference-mediated knock-down of the VAPB-IKZF3 fusion gene indicated that it may be necessary for cancer cell growth and survival. Conclusions In summary, using RNA-sequencing and improved bioinformatic stratification, we have discovered a number of novel fusion genes in breast cancer, and identified VAPB-IKZF3 as a potential fusion gene with importance for the growth and survival of breast cancer cells.
Abdominal Hysterctomy with Treatment of the Pedicle by the Intraperitoneal Method
Authors: A. W. M. Robson
Journal: BMJ (1894)

~'-'~~Q~E MEDICL JOURNARecently, for severe pain in the renal region, I cut down and found no stone, but the patient has been well ever since, and this has been frequently noted by others.OVARIOTo3MY TWICE PERFORMED ON TIIE SAME PATIENT.In 1882, M. G., aged 43, was sent to me by Dr. Allan, suffering.from an abdominal tumour, whichl we diagnosed as ovarian.The patient was put under chloroform, aiid, assisted by Drs.Allan and $eatson, I reiiioved the cyst of the riglit ovary, which was multilocular;tlhe pedicle was tied.The other ovary appeared to be healthy.The case did well, and she went lhome in three weeks.In Februiary, 1892, Dr.Allan wrote me that our old patient was agaiin suffering from an ovarian tumour.Slhe was admitted to the Blytllswood Home, and on February 2cth ether was administered by Dr. Garnet Wilson, and, assisted by Dr.4llan, Dr. Dudgeon, of Pekin, and Dr. Bryce, I removed the tumour, which-was multilocular, adherent, and more difficult to deal with tllani the first.The pedicle was tied; the abdominal inicision was made a little to one side of the former one, and it was interesting to note the firm line of union in the first.The patient did well, and went home in a imionth.
Adjuvant treatment for elderly patients with stage III colon cancer in the southern Netherlands is affected by socioeconomic status, gender, and comorbidity
Authors: V.E.P.P. Lemmens, A.H. van Halteren, M.L.G. Janssen-Heijnen, G. Vreugdenhil, O.J. Repelaer van Driel, J.W.W. Coebergh
Journal: Annals of Oncology (2005)
Chronic obstructive pulmonary disease * 12: New treatments for COPD
Authors: P J Barnes
Journal: Thorax (2003)

Drugs currently available or under development for the treatment of chronic obstructive pulmonary disease (COPD) are reviewed. More research on the basic cellular and molecular mechanisms of COPD and emphysema is urgently needed to aid the logical development of new treatments for this common and important disease for which no effective preventative treatments currently exist.

There is a major need to develop new treatments for chronic obstructive pulmonary disease (COPD), as no currently available drug therapy reduces the relentless progression of the disease. In particular, there is a need to develop drugs that control the underlying inflammatory and destructive processes. There have been few therapeutic advances in the drug treatment of COPD, in contrast to the enormous advances made in asthma management which reflect a much better understanding of the underlying disease.1–3 Although COPD is commonly treated with drugs developed for asthma, this is often inappropriate as the inflammatory processes in the two conditions differ markedly.4,5 Recognition of the global importance and rising prevalence of COPD and the absence of effective treatments has now led to a concerted effort to develop new drugs for this disease.6,7

Rational treatment depends on understanding the underlying disease process and there have been recent advances in understanding the cellular and molecular mechanisms that may be involved. COPD involves a chronic inflammation in the small airways and lung parenchyma with the involvement of neutrophils, macrophages, and cytotoxic (CD8+) T lymphocytes. This inflammation results in fibrosis with narrowing of the small airways (chronic obstructive bronchitis) and lung parenchymal destruction due to the action of various proteases such as neutrophil elastase and matrix metalloproteinases (emphysema). This inflammation is quite different from that seen in asthma, indicating that different treatments are likely to be needed.4

There are several reasons why drug …
Interaction of T-cell and antigen presenting cell co-stimulatory genes in childhood IgE
Authors: R. W. B. Bottema, D. S. Postma, N. E. Reijmerink, C. Thijs, F. F. Stelma, H. A. Smit, C. P. van Schayck, B. Brunekreef, G. H. Koppelman, M. Kerkhof
Journal: European Respiratory Journal (2009)

It is likely that multiple genes contribute to immunoglobulin (Ig)E production. Co-stimulatory molecules are crucial for the cross-talk between antigen presenting cells and T-lymphocytes which drives the IgE response. We evaluated gene-gene interactions of haplotype tagging polymorphisms in a pathway of 24 co-stimulatory genes in relation to serum IgE levels. We assessed this at ages 1-2 yrs and 6-8 yrs in 3,062 Dutch children from a pooled data set of three birth cohorts: PIAMA (Prevention and Incidence Asthma and Mite Allergy), PREVASC (Prevention of Asthma in Children) and KOALA (Child, parents and health: lifestyle and genetic constitution). Single- and multi-locus associations with serum IgE levels (3rd versus 1st tertile) were evaluated by Chi-squared tests and the multifactor dimensionality reduction (MDR) method in the following co-stimulatory genes: VTCN1, TNFRSF4, TNFRSF18, TNFRSF14, TNFSF18, TNFSF4, CD28, CTLA4, ICOS, PDCD1, BTLA, CD80, CD86, HLA-G, CD274, PDCD1LG2, CD276, LILRA4, LILRB1, LILRB2, LILRB4, CD40, ICOSLG, and CD40LG. We found multiple statistically significant single-locus ((S)) and multi-locus ((M)) associations for the genes VTCN1(SM), TNFSF18(SM), TNFSF4(S), CD28(S), CTLA4(M), ICOS(S), BTLA(M), CD80(M), CD86(SM), CD274(SM), PDCD1LG2(M), LILRA4(SM), LILRB4(M), and CD40(SM) with serum IgE. Two-locus interactions of CD86 with VTCN1 and CD274 with LILRA4 were confirmed by logistic regression. In conclusion, serum IgE levels are regulated by multiple gene-gene interaction effects in the co-stimulatory pathway. We suggest using research strategies that model multiple gene-gene interactions in genetic studies.
Mechanisms of action of therapeutic amyloidogenic hexapeptides in amelioration of inflammatory brain disease
Authors: Michael P. Kurnellas, Jill M. Schartner, C. Garrison Fathman, Ann Jagger, Lawrence Steinman, Jonathan B. Rothbard
Journal: The Journal of Experimental Medicine (2014)

Amyloid fibrils composed of peptides as short as six amino acids are effective therapeutics for experimental autoimmune encephalomyelitis (EAE). Immunosuppression arises from at least two pathways: (1) expression of type 1 IFN by pDCs, which were induced by neutrophil extracellular traps arising from the endocytosis of the fibrils; and (2) the reduced expression of IFN-γ, TNF, and IL-6. The two independent pathways stimulated by the fibrils can act in concert to be immunosuppressive in Th1 indications, or in opposition, resulting in inflammation when Th17 T lymphocytes are predominant. The generation of type 1 IFN can be minimized by using polar, nonionizable, amyloidogenic peptides, which are effective in both Th1 and Th17 polarized EAE.
Adjuvant interferon alfa treatment for patients with malignant melanoma stimulates transporter proteins associated with antigen processing and proteasome activator 28
Authors: Faris Abuzahra, Ruth Heise, Sylvia Joussen, Alexandra Dreuw, Hans Merk, Gabriele Zwadlo-Klarwasser, Jens M Baron
Journal: The Lancet Oncology (2004)
Novel genetic marker for dilated end stage oesophagus and oesophageal adenocarcinoma risk?
Authors: Johannes Lenglinger, Martin Riegler
Journal: Gut (2010)

With interest we read the article by Asling et al ,1 entitled “Collagen type III (COL3A1) is a gastro-oesophageal reflux disease (GORD) susceptibility gene and a male risk factor for hiatus hernia”, which has been published in a recent issue of Gut . The major findings of the study were that a single nucleotide polymorphism within the gene encoding for collagen type III (COL3A1) was associated with GORD in both sexes and …
Quantitative antibody responses to structural (core) and nonstructural (NS3, NS4, and NS5) hepatitis C virus proteins among seroconverting injecting drug users: Impact of epitope variation and relationship to detection of HCV RNA in blood
Authors: Marcel Beld, Maarten Penning, Marieke van Putten, Vladimir Lukashov, Anneke van den Hoek, Martin McMorrow, Jaap Goudsmit
Journal: Hepatology (1999)

To gain insight into the natural history of hepatitis C virus (HCV), 13 human immunodeficiency virus (HIV)–seronegative injecting drug users were studied who seroconverted for HCV as determined by third–generation enzyme–linked immunosorbent assay, showed an ensuing antibody response to HCV, and were not treated with any antiviral drugs during follow–up. Subjects included 13 untreated HIV–negative individuals, of whom 5 (38.5%) apparently cleared HCV and were polymerase chain reaction (PCR)–negative in at least 3 consecutive samples, 3 (23.1%) showed transient viremia and were PCR–negative in 1 sample during the study period, and the other 5 (38.5%) showed persistent viremia. Viremia was determined longitudinally by reverse–transcription PCR (RT–PCR) and quantified by branched DNA (bDNA). HCV genotypes were determined on serial samples during follow–up. Quantitative antibody levels to core, NS3, NS4, and NS5 were determined using the Chiron RIBA HCV–titering Strip Immunoblot Assay, which is based on HCV genotype 1. The antibody responses to core, NS3, NS4, and NS5 were erratic. In individuals infected with HCV genotype 1, significantly higher median antibody responses to core ( P = .02) and to NS4 ( P = .04) were found as compared with those infected with other genotypes, showing a significant impact of HCV genotype specificity of the assay. In groups infected with HCV genotype 1, significantly higher median NS3 antibody titers (2.61 relative intensity [RI] vs. 0.38 RI; P = .003) were found in the individuals with persistent viremia than in those with apparent resolution of HCV RNA in blood. In groups infected with genotypes other than genotype 1, significantly higher median NS3 antibody titers (0.89 RI vs. 0.03 RI; P = .0004) and NS5 antibody titers (1.86 RI vs. 0.01 RI; P = .006) were found in the individuals with persistent viremia than in those with apparent resolution of HCV RNA in blood. Individuals with viral persistence had higher HCV–RNA loads with higher antibody responses as compared with individuals with apparent viral clearance from blood. Apparent viral clearance from blood was observed in an unexpectedly high percentage (38.5%), associated with a significant decrease of antibodies to NS3, independent of HCV genotype, as compared with individuals with persistent viremia ( P &lt; .005). Apparent viral clearance from blood with gradual loss of antibodies to various HCV proteins, independent of HCV genotype, was observed in 4 of the 5 individuals within approximately 1 year after HCV seroconversion, whereas 1 of these individuals apparently cleared the virus from blood, with complete seroreversion.
Chronic atrial fibrillation up-regulates β1-Adrenoceptors affecting repolarizing currents and action potential duration
Authors: Marta González de la Fuente, Adriana Barana, Ricardo Gómez, Irene Amorós, Pablo Dolz-Gaitón, Sandra Sacristán, Felipe Atienza, Ana Pita, Ángel Pinto, Francisco Fernández-Avilés, Ricardo Caballero, Juan Tamargo, Eva Delpón
Journal: Cardiovascular Research (2012)

β-adrenergic stimulation has profound influence in the genesis and maintenance of atrial fibrillation (AF). However, the effects of β-Adrenoceptor stimulation on repolarizing currents and action potential (AP) characteristics in human atrial myocytes from left (LAA) and right atrial appendages (RAA) obtained from sinus rhythm (SR) and chronic atrial fibrillation (CAF) patients have not been compared yet. Currents and APs were recorded using whole-cell patch-clamp in RAA and LAA myocytes from SR and CAF patients. Isoproterenol concentration-dependently decreased the Ca2+-independent 4-aminopyridine-sensitive component of the transient outward current (Ito1) and the inward rectifying current (IK1). CAF significantly enhanced this inhibition, this effect being more marked in the left than in the right atria. CAF dramatically enhanced β-Adrenoceptor-mediated increase in the slow component of the delayed rectifier current (IKs), whose density was already markedly increased by CAF. Conversely, the ultrarapid component of the delayed rectifier current (IKur) of both SR and CAF myocytes was insensitive to low isoproterenol concentrations. As a consequence, stimulation of β1-Adrenoceptors in SR myocytes lengthened, whereas in CAF myocytes shortened, the AP duration. Quantitative PCR revealed that CAF up-regulated β1-Adrenoceptor expression, preferentially in the left atria. The present results demonstrate that CAF increases the effects of β1-Adrenoceptor stimulation on repolarizing currents by means of a chamber-specific up-regulation of the receptors. This, together with the ion channel derangements produced by CAF, could contribute to the long-term stabilization of the arrhythmia by shortening the AP duration.
The<b><i>Ews/Fli-1</i></b>Fusion Gene Switches the Differentiation Program of Neuroblastomas to Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumors
Authors: Checo J. Rorie, Venetia D. Thomas, Pengchin Chen, Heather Hanson Pierce, John P. O’Bryan, Bernard E. Weissman
Journal: Cancer Research (2004)

Abstract Neuroblastoma (NB) and the Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumor (PNET) family are pediatric cancers derived from neural crest cells. Although NBs display features of the sympathetic nervous system, ES/PNETs express markers consistent with parasympathetic differentiation. To examine the control of these differentiation markers, we generated NB × ES/PNET somatic cell hybrids. NB-specific markers were suppressed in the hybrids, whereas ES/PNET-specific markers were unaffected. These results suggested that the Ews/Fli-1 fusion gene, resulting from a translocation unique to ES/PNETs, might account for the loss of NB-specific markers. To test this hypothesis, we generated two different NB cell lines that stably expressed the Ews/Fli-1 gene. We observed that heterologous expression of the Ews/Fli-1 protein led to the suppression of NB-specific markers and de novo expression of ES/PNET markers. To determine the extent of changes in differentiation, we used the Affymetrix GeneChip Array system to observe global transcriptional changes of genes. This analysis revealed that the gene expression pattern of the Ews/Fli-1-expressing NB cells resembled that observed in pooled ES/PNET cell lines and differed significantly from the NB parental cells. Therefore, we propose that Ews/Fli-1 contributes to the etiology of ES/PNET by subverting the differentiation program of its neural crest precursor cell to a less differentiated and more proliferative state.