tbuckley/cabot-search huggingface dataset:
912. Strategies Using Retroviral Coexpression of Indoleamine 2,3 Dioxygenase and Fas Ligand for Allogeneic Bone Marrow Transplantation
Authors: Bagirath Gangadharan, Lucienne Ide, David Holtzclaw, David Archer, H. Trent Spencer
Journal: Molecular Therapy (2004)

Regulation of allogenic immune response could play a very significant role in establishing stable mixed chimerism for the treatment of several hematological diseases. Indoleamine 2, 3 dioxygenase (IDO) is a rate-limiting enzyme in tryptophan degradation along the kynurenine catabolic pathway and has been shown to regulate allogenic immune responses across the placental barrier. Also, engagement of CTLA4 with CD80/86 on antigen presenting cells has been shown to up-regulate IDO expression and play a significant role in immune regulation. Further, IDO responsive T-cells have been shown to be more susceptible to Fas (CD95) induced apoptosis. Fas ligand (FasL) is another protein that plays an important role in immune homeostasis, inducing apoptosis through interaction with its receptor, Fas. In this context, we generated a novel chimeric protein linking the carboxy terminus of IDO to the N-terminus of FasL with a (Gly) 4 (Ser) 3 repeat linker sequence using standard PCR cloning techniques. The cDNA encoding the chimeric protein was cloned into an MSCV retroviral vector co-expressing either eGFP or N-acetyl transferase for selection with puromycin. Control vectors encoding only IDO or FasL were also generated. The retroviral constructs were confirmed by sequencing of the entire transgene and by in vitro analysis of transfected NIH3T3 cells. Recombinant MSCV retrovirus pseudotyped with an ecotropic envelope was generated by transient transfection of GP2-293T producer cells. NIH3T3 cells were transduced with concentrated virus at an MOI of 1, and harvested after 48 hours for FasL and IDO expression. FasL and IDO-FasL modified fibroblasts showed a comparable marked reduction in their growth rate compared to IDO transduced or unmodified NIH 3T3 cells. Flow cytometric analysis of cells modified with IDO-FasL/GFP showed that all GFP expressing NIH3T3 cells were FasL positive. The slower growth rate of the fibroblasts was shown to be the result of Fas expression on NIH3T3 cells. Using the IDO-FasL/puro construct, murine bone marrow cells were transduced and plated in methylcellulose. Colony counts of the IDO-FasL gene modified cells were comparable with that of nontransduced or IDO only transduced cells, indicating expression of the chimeric protein does not change the normal growth of hematopoietic progenitor cells. IDO activity assays, determined spectrophotometrically for kynurenine production, showed similar activities between cells transduced with the IDO-FasL construct and IDO only construct, further indicating the chimeric protein is functional. To study the application of these constructs in an allotransplant setting, non-lethally irradiated mice have been transplanted with bone marrow cells transduced to express IDO, FasL, or the chimeric protein and are being followed for alloengraftment.
Tories spell out plans for NHS
Authors: Zosia Kmietowicz
Journal: BMJ (2000)

The Tories have pledged to match Labour's spending on the NHS and to expand private provision of health services under the next Conservative government.

Shadow Health Minister Dr Liam Fox told the NHS Confederation in Glasgow last week that while the NHS would continue to provide a comprehensive service, funded from central taxation, increased liaison with the private sector would enable people in Britain to “enjoy the sort of public-private partnership that is taken for granted in so many other countries.”

He also promised that Conservative health …
Quantitative 18FDG PET-CT for the assessment of pulmonary neutrophilic inflammation in COPD
Authors: David G. Parr
Journal: European Respiratory Journal (2012)

Introduction: Neutrophilic inflammation is of pathogenetic importance in COPD but non-invasive clinical assessment is problematic. We assessed the utility of 18FDG PET-CT as a spatially-informative surrogate measure of pulmonary neutrophilic inflammation in COPD.

Methods: 18FDG PET-CT imaging, CT densitometry, clinical and physiological assessment were performed in 10 patients with usual COPD. Regional pulmonary 18FDG uptake was estimated by 3-D Patlak graphical analysis as an indicator of pulmonary neutrophilic glycolytic activity and related to lung physiology and lung density.

Results: 18FDG uptake in the upper lung was greater than in the middle and lower lung regions and correlated with physiological and CT densitometric measures of disease severity (FEV1% predicted, r = -0.848, p = 0.001,; FEV1/FVC, r = -0.918, p < 0.001; Kco% predicted, r = -0.624, p = 0.027; 15th percentile point, r = -0.709, p = 0.011).

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Conclusions: The 18FDG signal seen in patients with COPD likely relates to the presence of centrilobular emphysema. The method has a potential role as an imaging biomarker in mechanistic and interventional studies in patients with usual COPD.

 [1]: pending:yes
Abstract 15509: Granulocyte Macrophage Colony-Stimulating Factor from the Kidneys is Essential for the Development of Heart Failure Through the Heart-Brain-Kidney Interaction
Authors: Katsuhito Fujiu, Ichiro Manabe, Munehiko Shibata, Ryozo Nagai
Journal: Circulation (2012)

The molecular mechanisms underlying the cardiorenal interaction are poorly understood. We previously showed that a transcription factor, KLF5, present in renal collecting duct epithelial cell contr...
Original article: Infections presenting for clinical care in early life and later risk of hay fever in two UK birth cohorts
Authors: S. A. Bremner, I. M. Carey, S. DeWilde, N. Richards, W. C. Maier, S. R. Hilton, D. P. Strachan, D. G. Cook
Journal: Allergy (2008)

Background: The ‘hygiene hypothesis’ proposes that infections in infancy protect against hay fever (HF). We investigated infections during infancy in relation to HF, including rarer ones not previously researched in this context, while examining the role of potential confounding variables. Methods: From birth cohorts derived within the General Practice Research Database (GPRD) and Doctors Independent Network (DIN) database of computerized patient records from UK general practice, we selected 3549 case–control pairs, matched for practice, age, sex and control follow‐up to case diagnosis. Conditional logistic regressions were fitted for each of 30 infections; behavioural problems (BP) acted as a control condition unrelated to HF. Odds ratios (OR), adjusted for consultation frequency were pooled across the databases using fixed effect models. We also adjusted for sibship size in GPRD and a socioeconomic marker in DIN. Results: Upper respiratory tract infections, diarrhoea and vomiting and acute otitis media in infancy were each related with a moderately increased risk of HF in both databases, as were BP. These associations were lost on adjustment for consultation frequency. Only bronchiolitis was significantly associated with a reduced pooled risk of HF after adjustment for consultations (OR = 0.8). Adjustment for sibship size in GPRD and a socioeconomic marker in DIN had little impact on the OR. Conclusions: Of 30 infectious illnesses investigated, none had strong or consistent associations with HF after adjustment for consultation frequency. Except for bronchiolitis, possibly a chance finding, none of the clinically apparent infections considered appear to have an important role in allergy prevention.
Second primary melanomas treated with BRAF blockers: study by reflectance confocal microscopy
Authors: S. Debarbieux, S. Dalle, L. Depaepe, N. Poulalhon, B. Balme, L. Thomas
Journal: British Journal of Dermatology (2013)

New primary melanomas arising in patients with stage IV melanoma and receiving BRAF inhibitors have recently been reported. This raises the question of the nature of the earliest cellular events identifiable within pre-existing moles.To use reflectance confocal microscopy (RCM) to investigate changing moles in patients using vemurafenib.In the first part of the study 23 lesions were examined by RCM before excision (performed because of digital dermoscopy changes) and histopathological examination. In the second part, 10 randomly chosen lesions in two patients were examined before and after 3 months of vemurafenib treatment.The first step permitted the highlighting of an unusual RCM pattern identified in five lesions characterized by areas of marked atypia in otherwise nondysplastic lesions. In the second step, four initially nondysplastic lesions developed focal or multifocal areas of marked atypia under treatment, which were not always correlated with digital dermoscopy changes, but did correlate with histopathology. All four lesions were finally diagnosed as melanomas.Although the clinical relevance of such findings remains questionable, RCM allowed us to observe, at the cellular level, the earliest events occurring within vemurafenib-induced changing moles. Moreover, repeated RCM examinations permitted to confirm that microscopic marked atypia that led to the histopathological diagnosis of melanoma appeared under treatment and were not pre-existing.
Abstract 15843: Do all Patients with Diabetes Mellitus Have the Same Outcome Post Percutaneous Coronary Intervention: The Impact of Lesion Complexity
Authors: Kohei Wakabayashi, Manuel A Gonzalez, Michael Mahmoudi, Gabriel Maluenda, Itsik Ben-Dor, Loic Belle, Michael A Gaglia, Cedric Delhaye, Rebecca Torguson, Zhenyi Xue, William O. Suddath, Lowell F. Satler, Kenneth M. Kent, Joseph Lindsay, Augusto D. Pichard, Ron Waksman
Journal: Circulation (2010)

Background: Patients with diabetes mellitus (DM) have usually worse outcomes post-percutaneous coronary intervention (PCI) when compared with non diabetics. This study aimed to determine the impact...
Abstract 1190: The Complement Component C5a is Present in Human Unstable Coronary Lesions in Vivo and Induces the Expression of MMP-9 in Human Macrophages via Nf-kappaB Activation In Vitro
Authors: Walter S Speidl, Stefan P Kastl, Randolp Hutter, Christoph Kaun, Gerhard Bauriedel, Valentin Fuster, Gerald Maurer, Juan J Badimon, Johann Wojta
Journal: Circulation (2007)

Background. The complement component C5a formed during activation of the complement cascade exerts chemotactic and proinflammatory effects. We have recently shown that serum levels of C5a predict cardiovascular risk in patients with advanced atherosclerosis. However, it is not known whether C5a may play an active role in the onset of acute coronary events. Methods and Results. Immunohistochemical analysis of human coronary plaques obtained by atherectomy demonstrated the presence of C5a in macrophage rich areas and the necrotic core. Unstable plaques (n=9) showed significantly higher staining for C5a than stable coronary lesions (n=10; p&lt;0.05). Double-labeling studies demonstrated colocalization of C5a and MMP-9. When human monocyte derived macrophages were stimulated in vitro with rhC5a, MMP-9 mRNA levels were increase 6-fold. In addition, MMP-9 antigen as detected by ELISA and MMP-9 activity as detected by a specific activity assay significantly increased after stimulation with rhC5a. Nuclear shift assay revealed that rhC5a stimulated NF-κB DNA binding and the NF-κB inhibitor 6-amino-4-phenoxyphenethylaminoquinazoline blocked the up-regulation of MMP-9 by rhC5a. Conclusion. C5a is increased in unstable coronary plaques, colocalizes with MMP-9 and induces the expression of MMP-9 in human macrophages via NF-κB activation. Taken this observations together, activation of the complement cascade and formation of C5a may be involved in the onset of acute coronary events.
BRUCELLA ANTIBODIES FOLLOWING CHOLERA VACCINATION
Authors: C W EISELE, N B McCULLOUGH, G A BEAL
Journal: Annals of Internal Medicine (1948)

Article1 April 1948BRUCELLA ANTIBODIES FOLLOWING CHOLERA VACCINATIONC. WESLEY EISELE, M.D., F.A.C.P., NORMAN B. MCCULLOUGH, Ph.D., M.D., GRACE A. BEALC. WESLEY EISELE, M.D., F.A.C.P., NORMAN B. MCCULLOUGH, Ph.D., M.D., GRACE A. BEALAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-28-4-833 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptBrucella agglutinins appearing after vaccination against cholera have been reported to occur in six of seven individuals.1We have suggested that this phenomenon may be a source of confusion in the diagnosis of brucellosis inasmuch as the agglutination test is widely used for this purpose and several million veterans received cholera vaccine during their military service. The present studies were undertaken to determine further the effects of cholera vaccination on brucella agglutinin production and to observe the effects on the opsonocytophagic test and on the brucellergen skin test.METHODS AND MATERIALTwenty volunteers were selected who with one exception had...Bibliography1. EISELEMCCULLOUGHBEALBURROWS CWNBGAW: Development of brucella agglutinins in humans following vaccination for cholera, Proc. Soc. Exper. Biol. and Med., 1946, lxi, 89. CrossrefGoogle Scholar2. HUDDLESON IF: Brucellosis in man and animals, 1943, The Commonwealth Fund, New York. Google Scholar3. EISELEMCCULLOUGHBEALROTTSCHAEFER CWNBGAW: Brucella agglutination tests and vaccination against cholera, Jr. Am. Med. Assoc., 1947, cxxxv, 983. CrossrefGoogle Scholar4. EISELE CW: Some problems in the diagnosis of chronic brucellosis, Med. Clin. North Am., 1947, xxxi, 182. CrossrefGoogle Scholar5. EISELEMCCULLOUGHBEAL CWNBGA: Discrepancies in the agglutination test for brucellosis as performed with various antigens and as reported from different laboratories, Jr. Lab. and Clin. Med., 1947, xxxii, 847. Google Scholar6. Iowa occupational disease statute. Workmen's Compensation Law Reports, CCH, May 6, 1947. Google Scholar7. MCGINTYGAMBRELL APWE: Chronic brucellosis, New Internat. Clin., 1939, i, 1. Google Scholar8. MCCULLOUGHEISELEBEAL NBCWGA: Antigenic relationships of brucella and Vibrio comma , Jr. Infect. Dis. In press. Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Chicago, Illinois*Received for publication June 11, 1947.From the Department of Medicine, School of Medicine, University of Chicago. Aided in part by a grant from Swift and Company. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 April 1948Volume 28, Issue 4Page: 833-837KeywordsAntigensBrucellaVibrio cholerae ePublished: 14 March 2020 Issue Published: 1 April 1948 PDF downloadLoading ...
Abstract P427: Physical Activity and Incidence of Atrial Fibrillation: the Health Professionals Follow-up Study
Authors: Anahita Ghorbani, Walter C. Willett, Dariush Mozaffarian
Journal: Circulation (2014)

Introduction: Whereas physical activity (PA) reduces IHD and stroke, effects on atrial fibrillation (AF) are controversial, with concern that vigorous PA (VPA) or even moderate PA (MPA) could increase AF. In addition, little is known about the association between sedentary activity (SA) and AF. Methods: We prospectively investigated habitual PA and new-onset AF in 28,169 US men age 68±9 years and free of AF in 2002. PA was assessed biennially via validated questionnaires including 11 recreational PAs and 6 SAs. MET-hours/week of MPA (MET&lt;=6), VPA (MET&gt;6), TPA (total PA), and hours/week of SA were quantified every 4 years from 1986 to 2010, and cumulatively averaged to assess long-term effects. Incident AF was evaluated from 2002 (first year of assessment) to 2010, based on self-reported physician diagnosis that was further confirmed by a supplementary questionnaire (positive predictive value 95% vs. medical records). We separately evaluated symptomatic vs. asymptomatic AF, based on prior evidence for ascertainment bias of the latter in this cohort (healthier people being more likely to be seen and diagnosed by their physician). Cox models estimated risk across quintiles of MPA, VPA, TPA, and SA. Results: During 231,108 person years of follow-up, 782 incident AF cases were confirmed (493 symptomatic, 283 asymptomatic, 6 symptoms unknown). In multivariable analyses, there was no significant association between MET-hours/week of MPA, VPA, or TPA and risk of symptomatic AF (p-value &lt; 0.05) (Table). Also, hours/week of SA and TV watching were not associated with AF risk. These results remained the same after mutual adjusting for other activities, after further adjusting for potential confounders or mediators, or after excluding baseline CVD. Similar results were seen for asymptomatic and total AF. Conclusion: In this cohort of middle-aged men, neither PA nor SA was significantly associated with risk of AF.
Abstract P350: Association of Plasma Levels of Soluble Receptor for Advanced Glycation End Products and Risk of Kidney Disease is Explained by Baseline Kidney Function
Authors: Casey M Rebholz, Brad C Astor, Morgan E Grams, Marc K Halushka, Mariana Lazo, Ron C Hoogeveen, Christie M Ballantyne, Josef Coresh, Elizabeth Selvin
Journal: Circulation (2014)

Introduction: Advanced glycation end products and their cell-bound receptors (RAGE) are thought to mediate the adverse effects of dysglycemia and vascular disease through oxidative stress, inflammation, and endothelial dysfunction. The soluble form of RAGE (sRAGE) is a 48-kDa, positively-charged cleavage product of RAGE. There is limited evidence on the role of sRAGE in the pathogenesis of kidney disease. Methods: We conducted cross-sectional and prospective analyses of a case-cohort study nested within the ARIC Study. Plasma sRAGE was measured at baseline (1990-92) in a cohort random sample (n=1,218) and three case groups of participants with incident chronic kidney disease [estimated glomerular filtration rate (eGFR) &lt;60 mL/min/1.73 m 2 and ≥25% eGFR decline; n=151], incident end-stage renal disease [U.S. Renal Data System registry; n=152], and incident kidney failure (eGFR &lt;15 mL/min/1.73 m 2 , U.S. Renal Data System registry, or kidney failure-related hospitalization or death; n=266). Results: Baseline sRAGE levels were inversely related to baseline eGFR (r = -0.13). After adjusting for age, sex, and race, one interquartile range increase in log 10 -transformed sRAGE was associated with development of end-stage renal disease [hazard ratio: 1.97; 95% confidence interval (CI): 1.47, 2.64; p&lt;0.001], kidney failure (hazard ratio: 1.59; 95% CI: 1.27, 2.00; p&lt;0.001), and chronic kidney disease (odds ratio: 1.39; 95% CI: 1.06, 1.83; p=0.02). However, none of these associations were significant after additional adjustment for eGFR (all p&gt;0.10; Figure). Conclusions: High sRAGE levels are associated with decreased kidney function. The association of sRAGE with kidney disease risk may be explained by its partial clearance by the kidney.
CYR61: A new measure of lung cancer outcome
Authors: Akio Mori, Julian C. Desmond, Naoki Komatsu, James O’kelly, Carl W. Miller, Ronald Legaspi, Alberto M. Marchevsky, Robert J. McKenna, Masahiro Asaka, Masahiro Imamura, Phillip Koeffler
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4545 

Cysteine-rich protein 61 (Cyr61) is a member of a family of growth factor-inducible, immediate-early genes. In this report, we measured the expression of Cyr61 mRNA in 94 human lung tumors and their normal matched lung samples. The Cyr61 mRNA levels were quantified by real time reverse transcription-polymerase chain reaction and calculated as a tumor / normal Cyr61 mRNA ratio in each case. Compared with normal matched lung tissues, expression of Cyr61 was decreased in seventy-four of ninety-four lung tumors (79%). Differences in distribution of patient characteristics, such as gender, age, tumor size, and pathological diagnosis, between high or low Cyr61 expressing groups were not statistically significant. However, differences in distribution of clinical stage between high or low Cyr61 expressing groups was statistically significant; that is, the Cyr61 low expressor group was clinically more advanced than the Cyr61 high expressor group (P=0.046). Further, Cyr61 levels of the patients with N0 and N1 disease were significantly higher than the expression in the N2 patients (P=0.047). The 3-year survival between the Cyr61 very low tumor expressor group compared to matched normal lung (39 patients) and the higher Cyr61 expressor group (52 patients) was statistically significant (59% v/s 91%; P=0.05). Taken together, Cyr61 appears to guard against metastatic disease because low expression is associated with more advanced disease; and therefore, expression levels of Cyr61 correlate with the prognosis of lung cancer.
Apoptosis induction in relation to intracellular levels of anthracyclines in leukemic cells.
Authors: Alex Bogason, Michèle Masquelier, Sigurd Vitols
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

5544 

Introduction: All standard induction treatments for acute myeloid leukaemia (AML) include daunorubicin (DNR) or idarubicin (IDA) in combination with cytarabine. IDA is more potent than DNR but the therapeutic superiority of IDA has not been established. In a previous study we showed that the cytotoxicity of DNR was reduced with increasing cell density in vitro. Aims: Our aims with this study was i) to determine whether cell density has an impact on anthracycline cytotoxicity, ii) to investigate the relationship between the intracellular concentrations of IDA/DNR and apoptosis induction in mononuclear cells isolated from patients with AML and iii) investigate the importance of drug metabolism in leukemic cells.. Methods: Intracellular concentration of anthracycline was determined by HPLC, apoptosis induction by DNA staining with propidium iodide and flow cytometry analysis while cytotoxicity was determined using MTT. Results: We observed that in vitro the cytotoxicity of IDA and DNR is greatly reduced with increasing cell density. We also showed that there is a relationship between apoptosis induction and intracellular anthracycline levels in vitro as cells with a higher anthracycline uptake undergo apoptosis faster. Cells isolated from different patients differed in their ability to take up, retain and metabolize IDA and DNR as well as in undergoing apoptosis. Interestingly we observed that IDA and DNR are equitoxic at the same intracellular concentrations. Finally we showed that in vitro cells metabolize IDA/DNR avidly into idarubicinol (IDAol) and daunorubicinol (DNRol) and that there is a metabolic variation between patients. Conclusions: We conclude that the cellular anthracycline uptake is important for cytotoxicity as cells with a higher uptake of IDA/DNR undergo apoptosis faster. Moreover the pharmacokinetic differences observed in vitro between cells from AML patients are hardly surprising but are not taken into account during treatment. Indeed AML patients receive the same body-related dose of anthracycline regardless of tumor burden and pharmacokinetic and/or metabolic differences. Further in vivo studies are needed to understand better the relation between anthracycline metabolism and pharmacokinetics to clinical effect.