tbuckley/cabot-search huggingface dataset:
Endothelial NADPH Oxidase as the Source of Oxidants in Lungs Exposed to Ischemia or High K <sup>+</sup>
Authors: Abu B. Al-Mehdi, Guochang Zhao, Chandra Dodia, Kasumi Tozawa, Karen Costa, Vladimir Muzykantov, Chris Ross, Frank Blecha, Mary Dinauer, Aron B. Fisher
Journal: Circulation Research (1998)

Abstract —We have previously demonstrated the generation of reactive oxygen species (ROS) in cultured bovine pulmonary artery endothelial cells (BPAECs) and in isolated perfused rat lungs exposed to high K + and during global lung ischemia. The present study evaluates the NADPH oxidase pathway as a source of ROS in these models. ROS production, detected by oxidation of the fluorophore, dichlorodihydrofluorescein, increased 2.5-fold in BPAECs and 6-fold in rat or mouse lungs exposed to high (24 mmol/L) K + . ROS generation was markedly inhibited by diphenyliodonium, a flavoprotein inhibitor, and by the synthetic peptide PR-39, an inhibitor of NADPH oxidase assembly, whereas allopurinol had no effect. With ischemia (1 hour), ROS generation by rat and mouse lungs increased 7-fold; PR-39 showed concentration-dependent inhibition of ROS production, with 50% inhibition at 3 μmol/L PR-39. ROS production in lungs exposed to high K + or ischemia was essentially abolished in mice with a “knockout” of gp91 phox , a membrane-localized cytochrome component of NADPH oxidase; increased ROS production by these lungs after anoxia/reoxygenation was similar to control . PR-39 also inhibited ischemia and the high K + –mediated increase in lung thiobarbituric acid reactive substance. Western blotting of BPAECs and immunocytochemistry of BPAECs and rat and mouse lungs showed the presence of p47 phox , a cytoplasmic component of NADPH oxidase and the putative target for PR-39 inhibition. In situ fluorescence imaging in the intact lung demonstrated that the increased dichlorofluorescein fluorescence in these models of ROS generation was localized primarily to the pulmonary endothelium. These studies demonstrate that ROS production in lungs exposed to ischemia or high K + results from assembly and activation of a membrane-associated NAPDH oxidase of the pulmonary endothelium.
Flt3 ligand expands CD103<sup>+</sup>dendritic cells and FoxP3<sup>+</sup>T regulatory cells, and attenuates Crohn's-like murine ileitis
Authors: Colm B Collins, Carol M Aherne, Eóin N McNamee, Matthew D P Lebsack, Holger Eltzschig, Paul Jedlicka, Jesús Rivera-Nieves
Journal: Gut (2011)

<h3>Background</h3> Imprinting an effector or regulatory phenotype on naïve T cells requires education at induction sites by dendritic cells (DC). <h3>Objectives</h3> To analyse the effect of inflammation on the frequency of mononuclear phagocytes (MP) and the effect of altering their frequency by administration of Flt3-L in chronic ileitis. <h3>Methods</h3> Using a tumour necrosis factor (TNF) driven model of ileitis (ie, TNFΔARE) that recapitulates many features of Crohn9s disease (CD), dynamic changes in the frequency and functional state of MP within the inflamed ileum were assessed by flow cytometry, immunofluorescence and real-time reverse-transcription PCR and by generating CX<sub>3</sub>CR1 GFP-reporter TNFΔARE mice. The effect of Flt3-L supplementation on the severity of ileitis, and the frequency of CD103<sup>+</sup> DC and of FoxP3<sup>+</sup> regulatory T cells was also studied in TNFΔARE mice. <h3>Results</h3> CD11c<sup>Hi</sup>/MHCII<sup>+</sup> MP accumulated in inflamed ilea, predominantly mediated by expansion of the CX<sub>3</sub>CR1<sup>+</sup> MP subpopulation. This coincided with a decreased pro-regulatory CD103<sup>+</sup> DC. The phenotype of these MP was that of activated cells, as they expressed increased CD80 and CD86 on their surface. Flt3-ligand administration resulted in a preferential expansion of CD103<sup>+</sup> DC that attenuated the severity of ileitis in 20-week-old TNFΔARE mice, mediated by increased CD4<sup>+</sup>/CD25<sup>+</sup>/FoxP3<sup>+</sup> regulatory T cells. <h3>Conclusions</h3> Results support a role for Flt3-L as a potential therapeutic agent in Crohn9s-like ileitis.
Relevance of male accessory gland infection for subsequent fertility with special focus on prostatitis
Authors: W Weidner
Journal: Human Reproduction Update (1999)

Infections of the male genitourinary tract may contribute to infertility to a various extent depending on the site of inflammation. Especially in prostatitis, the exact classification of the infection contributes to its impact on changes in the ejaculate. Similarly, in urethritis, epididymitis and orchitis, only a clear clinical diagnosis allows a rational approach to altered sperm parameters. Several inflammatory and reactive alterations of sperm quality seem to be proven; nevertheless, the impact of these findings on male fertility remains in many cases unclear. Even therapeutic trials do not provide more insights into the association of male genital infections and impaired fertility, although the efficacy of antibiotic trials seems to be proven. For the future, it may be decisive to evaluate inflammatory changes in the ejaculate not only on the basis of standard but also on functional parameters, thus providing new definitions of the interactions between male urogenital tract infection and disturbances of male fertility.
Antitumor Immunotherapeutic and Toxic Properties of an HDL-Conjugated Chimeric IL-15 Fusion Protein
Authors: Maria C. Ochoa, Jessica Fioravanti, Inmaculada Rodriguez, Sandra Hervas-Stubbs, Arantza Azpilikueta, Guillermo Mazzolini, Alfonso Gúrpide, Jesus Prieto, Julian Pardo, Pedro Berraondo, Ignacio Melero
Journal: Cancer Research (2012)

Interleukin (IL)-15 effects on CD8 T and natural killer (NK) lymphocytes hold promise to treat cancer. Fusion proteins have been engineered to provide IL-15 receptor alpha (IL-15Rα) mediated trans-presentation to lymphocytes and extend the plasma half-life of the cytokine. In this study, we report on a triple fusion protein combining apolipoprotein A-I (Apo A-I), IL-15, and IL-15Rα's sushi domain. Apo A-I conveys IL-15 to high-density lipoproteins (HDL), from which the cytokine is trans-presented by the IL-15Rα's sushi domain. Such a construction was tested by hydrodynamic gene transfer to the liver of mice. Lethal toxicity was observed upon injection of 10 μg of the expression plasmid. Mice died from an acute lymphocytic pneumonitis in which T and NK cells dominate a severe inflammatory infiltrate. Importantly, mice devoid of NK cells were not susceptible to such toxicity and mice lacking granzymes A and B also survived the otherwise lethal gene transfer. Lower plasmid doses (<2.5 μg) were tolerated and dramatically increased the numbers of NK and memory CD8 T lymphocytes in the liver, spleen, and lungs, to the point of rescuing the deficiency of such lymphocyte subsets in IL-15Rα(-/-) mice. Doses of plasmid within the therapeutic window successfully treated metastatic tumor models, including B16OVA lung metastasis of melanoma and MC38 colon cancer liver metastasis. Sushi-IL-15-Apo as a recombinant protein was also bioactive in vivo, became conjugated to HDL, and displayed immunotherapeutic effects against metastatic disease.
LKB1 Is Necessary for Akt-Mediated Phosphorylation of Proapoptotic Proteins
Authors: Diansheng Zhong, Xiuju Liu, Fadlo R. Khuri, Shi-Yong Sun, Paula M. Vertino, Wei Zhou
Journal: Cancer Research (2008)

Abstract LKB1 plays the role of tumor suppressor, opposite to Akt, by negatively regulating mammalian target of rapamycin through the activation of AMP-activated protein kinase and TSC signaling. We have discovered a novel, potentially oncogenic role for LKB1 as a supporter of Akt-mediated phosphorylation of proapoptotic proteins. We found that Akt activation led to increased phosphorylation of FoxO3a at Thr32 in LKB1 wild-type cells but not in LKB1-null cells. Depletion of LKB1 in the cells with wild-type LKB1 resulted in attenuation of that phosphorylation of FoxO3a by activated Akt, whereas the restoration of LKB1 function in LKB1-null cells reestablished Akt-mediated FoxO3a phosphorylation. On expanding our analysis to other Akt targets, using isogenic LKB1 knockdown cell line pairs and a phospho-specific antibody microarray, we observed that there was a requirement for LKB1 in the phosphorylation of other Akt downstream targets, including Ask1 (Ser83), Bad (Ser136), FoxO1 (Ser319), FoxO4 (Ser197), and glycogen synthase kinase 3β (GSK3β; Ser9). Because the phosphorylation of these sites by Akt suppresses apoptosis, the requirement of LKB1 suggests that LKB1 may have an antiapoptotic role in tumor cells with constitutively active Akt. Indeed, we found that the suppression of LKB1 expression led to apoptosis in three cell lines in which Akt is constitutively active but not in two cell lines without Akt activation. This observation may explain the lack of LKB1 somatic mutations in brain, breast, and colon cancers, where Akt is frequently activated due to mutations in phosphatidylinositol 3-kinase, PTEN, or Akt itself. [Cancer Res 2008;68(18):7270–7]
Thrombocytosis in rheumatoid arthritis.
Authors: R M Hutchinson, P Davis, M I Jayson
Journal: Annals of the Rheumatic Diseases (1976)

Of 75 patients with rheumatoid arthritis, 39 had a thrombocytosis and 36 normal platelet count. A highly significant relationship existed between the platelet count and disease severity and an inverse correlation with level of haemoglobin. An association appeared to exist between thrombocytosis and extra-articular manifestations of rheumatoid disease. By 75Selenomethionine labelling platelet and fibrinogen survival and turnover were determined. In 3 rheumatoid patients with thrombocytosis platelet survival was decreased and turnover increased. In these and a further rheumatoid patient with a normal platelet count there was reduced fibrinogen survival and increased fibrinogen turnover, and in addition excess fibrin degradation products were detected. The results suggest that thrombocytosis accompanies the more severe cases of rheumatoid disease and is due to a compensatory increase in platelet production associated with active intravascular coagulation.
Uptake of Workplace HIV Counselling and Testing: A Cluster-Randomised Trial in Zimbabwe
Authors: Elizabeth L Corbett, Ethel Dauya, Ronnie Matambo, Yin Bun Cheung, Beauty Makamure, Mary T Bassett, Steven Chandiwana, Shungu Munyati, Peter R Mason, Anthony E Butterworth, Peter Godfrey-Faussett, Richard J Hayes
Journal: PLoS Medicine (2006)

Background HIV counselling and testing is a key component of both HIV care and HIV prevention, but uptake is currently low. We investigated the impact of rapid HIV testing at the workplace on uptake of voluntary counselling and testing (VCT). Methods and Findings The study was a cluster-randomised trial of two VCT strategies, with business occupational health clinics as the unit of randomisation. VCT was directly offered to all employees, followed by 2 y of open access to VCT and basic HIV care. Businesses were randomised to either on-site rapid HIV testing at their occupational clinic (11 businesses) or to vouchers for off-site VCT at a chain of free-standing centres also using rapid tests (11 businesses). Baseline anonymised HIV serology was requested from all employees. HIV prevalence was 19.8% and 18.4%, respectively, at businesses randomised to on-site and off-site VCT. In total, 1,957 of 3,950 employees at clinics randomised to on-site testing had VCT (mean uptake by site 51.1%) compared to 586 of 3,532 employees taking vouchers at clinics randomised to off-site testing (mean uptake by site 19.2%). The risk ratio for on-site VCT compared to voucher uptake was 2.8 (95% confidence interval 1.8 to 3.8) after adjustment for potential confounders. Only 125 employees (mean uptake by site 4.3%) reported using their voucher, so that the true adjusted risk ratio for on-site compared to off-site VCT may have been as high as 12.5 (95% confidence interval 8.2 to 16.8). Conclusions High-impact VCT strategies are urgently needed to maximise HIV prevention and access to care in Africa. VCT at the workplace offers the potential for high uptake when offered on-site and linked to basic HIV care. Convenience and accessibility appear to have critical roles in the acceptability of community-based VCT.
Statistics in Medicine — Reporting of Subgroup Analyses in Clinical Trials
Authors: Rui Wang, Stephen W. Lagakos, James H. Ware, David J. Hunter, Jeffrey M. Drazen
Journal: New England Journal of Medicine (2007)

The analysis of subgroups is often used as a way to glean additional information from data sets. The strengths and weaknesses of this approach and new Journal policies concerning the reporting of subgroup analyses are discussed in this article.
Points from letters: Drought backache 1976
Authors: J M. Kennedy
Journal: BMJ (1976)

Government's spokesmen, including the Prime Minister, admit that the counter-inflation policy of 1975-6 was unjust to certain members of the community, including consultants on the incremental scale.They argue, however, that the steps were necessary in the national interest.The professions' negotiators did not 'acquiesce' in the imposition of this counterinflation policy, but vigorously opposed it- and succeeded in securing the modification for 1976-7 which has allowed the incremental scales to be reactivated.The withholding of contractual increments (and distinction awards) which has in effect meant for some consultants a 12-month wait for what they were entitled to was secured by the Remuneration, Charges, and Grants Act 1975-which rapidly went through Parliament without opposition and specifically allows employing authorities to breach contracts in this respect."-ED, BMJ. Keeping tabs on trainers
Relationship between Helicobacter pylori infection and gastric atrophy and the stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence: results from the FINBAR case-control study
Authors: L A Anderson, S J Murphy, B T Johnston, R G P Watson, H R Ferguson, K B Bamford, A Ghazy, P McCarron, J McGuigan, J V Reynolds, H Comber, L J Murray
Journal: Gut (2007)

A number of studies have shown an inverse association between infection with Helicobacter pylori and oesophageal adenocarcinoma (OAC). The mechanism of the apparent protection against OAC by H pylori infection and, in particular, the role of gastric atrophy is disputed. The relationship between all stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence and H pylori infection and gastric atrophy was explored.A case-control study involving 260 population controls, 227 OAC, 224 Barrett's oesophagus (BO) and 230 reflux oesophagitis (RO) patients recruited within Ireland was carried out. H pylori and CagA (cytotoxin-associated gene product A) infection was diagnosed serologically by western blot, and pepsinogen I and II levels were measured by enzyme immunoassay. Gastric atrophy was defined as a pepsinogen I/II ratio of <3.H pylori seropositivity was inversely associated with OAC, BO and RO; adjusted ORs (95% CIs), 0.49 (0.31 to 0.76), 0.35 (0.22 to 0.56) and 0.42 (0.27 to 0.65), respectively. Gastric atrophy was uncommon (5.3% of all subjects), but was inversely associated with non-junctional OAC, BO and RO; adjusted ORs (95% CIs), 0.34 (0.10 to 1.24), 0.23 (0.05 to 0.96) and 0.27 (0.08 to 0.88), respectively. Inverse associations between H pylori and the disease states remained in gastric atrophy-negative patients.H pylori infection and gastric atrophy are associated with a reduced risk of OAC, BO and RO. While use of the pepsinogen I/II ratio as a marker for gastric atrophy has limitations, these data suggest that although gastric atrophy is involved it may not fully explain the inverse associations observed with H pylori infection.
Intergenic Transcripts Containing a Novel Human Cytochrome P450 2C Exon 1 Spliced to Sequences from the CYP2C9 Gene
Authors: Susan C. Warner, Csaba Finta, Peter G. Zaphiropoulos
Journal: Molecular Biology and Evolution (2001)

The cytochrome P450 2C (CYP2C) gene locus was found to include a novel exon 1 sequence with high similarity to the canonical exon 1 of CYP2C18. Rapid amplification of cDNA ends (RACE) and PCR amplifications of human liver cDNA revealed the presence of several intergenic species containing the CYP2C18 exon 1–like sequence spliced to different combinations of exonic and intronic sequences from the CYP2C9 gene. One splice variant was found to have an open reading frame starting at the canonical translation initiation codon of the CYP2C18 exon 1–like sequence. Another variant consisted of the nine typical CYP2C9 exons spliced after the CYP2C18 exon 1–like sequence through a segment of CYP2C9 5′ flanking sequences. Moreover, analysis of bacterial artificial chromosome (BAC) clones revealed that the CYP2C18 exon 1–like sequence was located in the intergenic region between the CYP2C19 and CYP2C9 genes. The finding that a solitary exon is spliced with sequences from a neighboring gene may be interpreted as representing a general evolutionary mechanism aimed at using the full expression potential of a cell's genomic informational content.
HLA antigens in patients with various courses after hepatitis B virus infection
Authors: Jan Van Hattum, Geziena M. Th. Schreuder, Solko W. Schalm
Journal: Hepatology (1987)

The course after hepatitis B virus infection seems to be determined by the host's immune response, which in turn may be regulated by the major histocompatibility complex. In order to find a possible relationship between the course of disease and the phenotype frequency of HLA determinants, we studied 396 Dutch subjects of northern European local race. Six groups of individuals with various courses after hepatitis B virus infection were compared to healthy controls. The hepatitis B patients were grouped according to standard criteria: 47 had recovered from acute symptomatic hepatitis B virus infection; 60 had recovered from asymptomatic hepatitis B virus infection; 26 were asymptomatic hepatitis B surface antigen carriers; 16 had chronic persistent hepatitis B; 37 had chronic active hepatitis B, and 10 had chronic active hepatitis after elimination of hepatitis B antigens. Twenty-nine Class I and 13 Class II HLA antigens were assayed by standard microlymphocytotoxicity tests. The phenotype frequency of the Class II antigen DQw1 appeared to be significantly lower in patients with chronic active hepatitis B virus infection. Some other HLA specificities showed deviations from control values, but they were not statistically significant after correction for the number of antigens tested. In conclusion, we have found no evidence that the elimination of hepatitis B virus is related to HLA phenotype. DQw1, however, may affect the morphologic type of chronic hepatitis B infection, since its presence may protect against chronic active hepatitis.
Network analysis of skin tumor progression identifies a rewired genetic architecture affecting inflammation and tumor susceptibility
Authors: David A Quigley, Minh D To, Il Jin Kim, Kevin K Lin, Donna G Albertson, Jonas Sjolund, Jesús Pérez-Losada, Allan Balmain
Journal: Genome biology (2011)

Germline polymorphisms can influence gene expression networks in normal mammalian tissues and can affect disease susceptibility. We and others have shown that analysis of this genetic architecture can identify single genes and whole pathways that influence complex traits, including inflammation and cancer susceptibility. Whether germline variants affect gene expression in tumors that have undergone somatic alterations, and the extent to which these variants influence tumor progression, is unknown. Using an integrated linkage and genomic analysis of a mouse model of skin cancer that produces both benign tumors and malignant carcinomas, we document major changes in germline control of gene expression during skin tumor development resulting from cell selection, somatic genetic events, and changes in the tumor microenvironment. The number of significant expression quantitative trait loci (eQTL) is progressively reduced in benign and malignant skin tumors when compared to normal skin. However, novel tumor-specific eQTL are detected for several genes associated with tumor susceptibility, including IL18 (Il18), Granzyme E (Gzme), Sprouty homolog 2 (Spry2), and Mitogen-activated protein kinase kinase 4 (Map2k4). We conclude that the genetic architecture is substantially altered in tumors, and that eQTL analysis of tumors can identify host factors that influence the tumor microenvironment, mitogen-activated protein (MAP) kinase signaling, and cancer susceptibility.
What Should Be Done To Tackle Ghostwriting in the Medical Literature?
Authors: Peter C Gøtzsche, Jerome P Kassirer, Karen L Woolley, Elizabeth Wager, Adam Jacobs, Art Gertel, Cindy Hamilton
Journal: PLoS Medicine (2009)

Background to the Debate Ghostwriting occurs when someone makes substantial contributions to a manuscript without attribution or disclosure. It is considered bad publication practice in the medical sciences, and some argue it is scientific misconduct. At its extreme, medical ghostwriting involves pharmaceutical companies hiring professional writers to produce papers promoting their products but hiding those contributions and instead naming academic physicians or scientists as the authors. To improve transparency, many editors' associations and journals allow professional medical writers to contribute to the writing of papers without being listed as authors provided their role is acknowledged. This debate examines how best to tackle ghostwriting in the medical literature from the perspectives of a researcher, an editor, and the professional medical writer.
Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study
Authors: Jane S Paulsen, Jeffrey D Long, Christopher A Ross, Deborah L Harrington, Cheryl J Erwin, Janet K Williams, Holly James Westervelt, Hans J Johnson, Elizabeth H Aylward, Ying Zhang, H Jeremy Bockholt, Roger A Barker
Journal: The Lancet Neurology (2014)
Circulating Levels of the Antiangiogenic Marker Soluble FMS-Like Tyrosine Kinase 1 Are Elevated in Women With Pregestational Diabetes and Preeclampsia
Authors: Allison Cohen, Kee-Hak Lim, Young Lee, Sarosh Rana, S. Ananth Karumanchi, Florence Brown
Journal: Diabetes Care (2007)

Preeclampsia is characterized by the development of proteinuria and hypertension after 20 weeks gestation, and it is associated with maternal and fetal morbidity. Preeclampsia affects ∼5% of pregnancies, though women with preexisting diabetes are three to four times more likely to develop preeclampsia (1). Preeclampsia is associated with altered angiogenic factors, including increased levels of circulating soluble FMS-like tyrosine kinase 1 (sFlt1) and reduced levels of vascular endothelial growth factor and placental growth factor (PlGF). Hypertension and proteinuria of preeclampsia may be caused by an imbalance of these angiogenic factors (2–10). Circulating sFlt1, an antiangiogenic protein, binds to proangiogenic proteins, vascular endothelial growth factor, and PlGF, preventing their interaction with endothelial cell receptors and inducing endothelial dysfunction. Rats given sFlt1 develop proteinuria, hypertension, and glomerular endotheliosis, which are hallmarks of preeclampsia (3). Alterations in sFlt1 and PlGF are observed several weeks before symptoms (2).

It is unknown whether alterations in sFlt1 and PlGF are present in women with diabetes who then develop preeclampsia or whether a different pathway is responsible. Ultimately, it would be helpful to have a way to diagnose and predict preeclampsia in women with pregestational diabetes, as they frequently have preexisting hypertension and/or proteinuria, which make it difficult to differentiate superimposed preeclampsia.

We evaluated a small group of women with diabetes and compared levels of sFlt1 and PlGF at delivery in both those who developed preeclampsia and those …