tbuckley/cabot-search huggingface dataset:
Bioactivity and Prognostic Significance of Growth Differentiation Factor GDF15 Secreted by Bone Marrow Mesenchymal Stem Cells in Multiple Myeloma
Authors: Jill Corre, Elodie Labat, Nicolas Espagnolle, Benjamin Hébraud, Hervé Avet-Loiseau, Murielle Roussel, Anne Huynh, Mélanie Gadelorge, Pierre Cordelier, Bernard Klein, Philippe Moreau, Thierry Facon, Jean-Jacques Fournié, Michel Attal, Philippe Bourin
Journal: Cancer Research (2012)

Overexpression of growth differentiation factor 15 (GDF15) by bone marrow mesenchymal stem cells occurs widely in patients with multiple myeloma, but the pathophysiologic effects of GDF15 in this setting remain undefined. GDF15 has been described in numerous solid tumors but never in hematologic malignancies. In this study, we report that GDF15 significantly increases survival of stroma-dependent multiple myeloma cells including primary multiple myeloma cells. In particular, GDF15 conferred resistance to melphalan, bortezomib, and to a lesser extent, lenalidomide in both stroma-dependent and stroma-independent multiple myeloma cells. Akt-dependent signaling was critical to mediate the effects of GDF15, whereas Src and extracellular signal-regulated kinase 1/2 signaling pathways were not involved. Given these results, we tested the clinical significance of plasma concentrations of GDF15 (pGDF15) in 131 patients with multiple myeloma and found that it correlated with disease prognosis. Specifically, patients with high levels of pGDF15 had lower probabilities of event-free and overall survival 30 months after diagnosis than patients with low pGDF15 levels. Our findings suggest that tumor microenvironment-derived GDF15 is a key survival and chemoprotective factor for multiple myeloma cells, which is pathophysiologically linked to both initial parameters of the disease as well as patient survival.
Phase II Randomized Trial of Two Nonoperative Regimens of Induction Chemotherapy Followed by Chemoradiation in Patients With Localized Carcinoma of the Esophagus: RTOG 0113
Authors: Jaffer A. Ajani, Kathryn Winter, Ritsuko Komaki, David P. Kelsen, Bruce D. Minsky, Zhongxing Liao, Jeffrey Bradley, Mitchel Fromm, David Hornback, Christopher G. Willett
Journal: Journal of Clinical Oncology (2008)

Two nonoperative approaches (one without fluorouracil) using induction chemotherapy and then definitive chemoradiotherapy developed at two centers were compared in patients with localized esophageal cancer (LEC). The primary end point was to assess whether any approach would achieve a >or= 77.5% 1-year survival rate, surpassing the historical 66% rate from the Radiation Therapy Oncology Group (RTOG) protocol 9405.In a multi-institutional cooperative group setting, patients with LEC who had unresectable cancer, were unwilling to undergo surgery, or were medically unfit for surgery were randomly assigned to receive either induction with fluorouracil, cisplatin, and paclitaxel and then fluorouracil plus paclitaxel with 50.4 Gy of radiation (arm A) or induction with paclitaxel plus cisplatin and then the same chemotherapy with 50.4 Gy of radiation (arm B). Safety and survival rates were assessed.A total of 84 patients were randomly assigned (arm A, n = 41; arm B, n = 43), and 72 were assessable (arm A, n = 37; arm B, n = 35). The median survival time was 28.7 months for patients in arm A and 14.9 months for patients in arm B (18.8 months for patients in RTOG 9405). The 1-year survival rate of 75.7% in arm A was close to, but did not meet or surpass, the 77.5% goal. The 2-year survival rate was 56% for arm A and 37% for arm B. Grade 3 (arm A = 54%, arm B = 43%) and grade 4 toxicities (arm A = 27%, arm B = 40%) were frequent. Treatment-related death occurred in 3% of patients in arm A and 6% of patients in arm B.Both arms of RTOG 0113 were associated with high morbidity, and the study did not meet its 1-year survival end point.
Novel Role for Mast Cells in Omental Tissue Remodeling and Cell Recruitment in Experimental Peritoneal Dialysis
Authors: Mohammad Zareie, Paolo Fabbrini, Liesbeth H.P. Hekking, Eelco D. Keuning, Piet M. ter Wee, Robert H.J. Beelen, Jacob van den Born
Journal: Journal of the American Society of Nephrology (2006)

Because of its dynamic structure, the omentum plays a key role in the immunity of the peritoneal cavity by orchestrating peritoneal cell recruitment. Because mast cells accumulate in the omentum upon experimental peritoneal dialysis (PD) and may produce angiogenic/profibrotic factors, it was hypothesized that mast cells mediate omental tissue remodeling during PD. Daily treatment with conventional PD fluid (PDF) for 5 wk resulted in a strong omental remodeling response, characterized by an approximately 10-fold increase in mast cell density (P < 0.01), an approximately 20-fold increase in vessel density (P < 0.02), an approximately 20-fold increase in the number of milky spots (P < 0.01), and a four-fold increase in submesothelial matrix thickness (P < 0.0003) in wild-type rats. In contrast, all PDF-induced omental changes were significantly reduced in mast cell-deficient Ws/Ws rats or in wild-type rats that were treated orally with a mast cell stabilizer cromoglycate. A time-course experiment showed mast cell accumulation immediately before the formation of blood vessels and milky spots. Functionally, PDF evoked a peritoneal cell influx, which was significantly reduced in Ws/Ws rats (P < 0.04) and in wild-type rats that were treated with cromoglycate (P < 0.03). Cromoglycate treatment also completely prevented PDF-induced omental adhesions to the catheter tip (P = 0.0002). Mesothelial damage, angiogenesis, and fibrosis of mesentery and parietal peritoneum as well as glucose absorption rate and ultrafiltration capacity proved to be mast cell independent. Data strongly support the hypothesis that mast cells mediate PDF-induced omental tissue remodeling and, subsequently, peritoneal cell influx and adhesion formation, providing therapeutic possibilities of modulating omental function.
Identification of Megalin as the Sole Rat Kidney Sialoglycoprotein Containing Poly α2,8 Deaminoneuraminic Acid
Authors: MARTIN ZIAK, DONTSCHO KERJASCHKI, MARILYN G. FARQUHAR, JÜRGEN ROTH
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Recently, poly α2,8 deaminoneuraminic acid (poly α2,8 KDN) was demonstrated in various embryonic and adult mammalian tissues. This study reports the purification and characterization of the single poly α2,8 KDN-bearing glycoprotein from rat kidney. Amino acid sequences of proteolytic fragments shared homology with megalin, a member of the LDL receptor family. Immunochemical analysis supported this finding, since immunoprecipitated poly α2,8 KDN-bearing glycoprotein was immunoreactive with anti-megalin antibodies in Western blotting and conversely immunoprecipitated megalin was immunoreactive with the monoclonal anti-poly α2,8 KDN antibody. Furthermore, receptor-associated protein affinity-purified megalin reacted with the anti-poly α2,8 KDN antibody. By immunoelectron microscopy, labeling for both poly α2,8 KDN and megalin coincided in the brush border, endocytic invaginations and vesicles, and apical dense tubules of proximal convoluted tubules. Immunoreactivity for poly α2,8 KDN on purified megalin was abolished by β-elimination reaction but not by N-glycosidase F treatment. These data identified megalin as the sole glycoprotein of rat kidney, which contains poly α2,8 KDN present on O -glycosidically linked oligosaccharides. Furthermore, this study shows that megalin carries N -glycosidically linked hybrid and complex-type oligosaccharides terminating with sialic acid. Both poly α2,8 KDN and sialic acids on megalin may contribute to the binding of Ca 2+ and cationic ligands.
Investigating the relationship between quality of primary care and premature mortality in England: a spatial whole-population study
Authors: E. Kontopantelis, D. A. Springate, M. Ashworth, R. T. Webb, I. E. Buchan, T. Doran
Journal: BMJ (2015)

To quantify the relationship between a national primary care pay-for-performance programme, the UK's Quality and Outcomes Framework (QOF), and all-cause and cause-specific premature mortality linked closely with conditions included in the framework.Longitudinal spatial study, at the level of the "lower layer super output area" (LSOA).32482 LSOAs (neighbourhoods of 1500 people on average), covering the whole population of England (approximately 53.5 million), from 2007 to 2012.8647 English general practices participating in the QOF for at least one year of the study period, including over 99% of patients registered with primary care.National pay-for-performance programme incentivising performance on over 100 quality-of-care indicators.All-cause and cause-specific mortality rates for six chronic conditions: diabetes, heart failure, hypertension, ischaemic heart disease, stroke, and chronic kidney disease. We used multiple linear regressions to investigate the relationship between spatially estimated recorded quality of care and mortality.All-cause and cause-specific mortality rates declined over the study period. Higher mortality was associated with greater area deprivation, urban location, and higher proportion of a non-white population. In general, there was no significant relationship between practice performance on quality indicators included in the QOF and all-cause or cause-specific mortality rates in the practice locality.Higher reported achievement of activities incentivised under a major, nationwide pay-for-performance programme did not seem to result in reduced incidence of premature death in the population.
Control of blood pressure variability in caveolin-1-deficient mice: role of nitric oxide identified in vivo through spectral analysis
Authors: Fanny Desjardins, Irina Lobysheva, Michel Pelat, Bernard Gallez, Olivier Feron, Chantal Dessy, Jean-Luc Balligand
Journal: Cardiovascular Research (2008)

In endothelial cells, caveolin-1 (cav-1) is known to negatively modulate the activation of endothelial nitric oxide synthase, a key regulator of blood pressure (BP). However, the impact of genetic alteration of cav-1 on vascular nitric oxide (NO) production and BP homeostasis in vivo is unknown. We used spectral analysis of systolic blood pressure (SBP) variability in mice chronically equipped with telemetry implants to identify frequency ranges (0.05–0.4 Hz; very low frequency, VLF) specifically responding to NO, independently of changes in absolute BP or systemic neurohormone levels. VLF variability was inversely correlated to aortic vasodilator-stimulated Ser239 phosphoprotein (VASP) phosphorylation, reflecting NO bioactivity. We show that mice deficient in cav-1 have decreased VLF variability paralleled with enhanced systemic and vascular production of NO at unchanged mean SBP levels. Conversely, VLF variability was increased upon acute injection of mice, with a peptide containing the caveolin-scaffolding domain (CSD; residues 82–101) fused to an internalization sequence of antennapedia that decreased vascular and circulating NO in vivo. These data highlight the functional importance of cav-1 for the production of bioactive NO in conduit arteries and its control of central BP variability. Given the impact of the latter on target organ damage, this raises the interest for genetic, pharmacological, or molecular interventions that modulate cav-1 expression in diseases with NO-dependent endothelial dysfunction.
Small Intestinal Injury and Parasitic Diseases in AIDS
Authors: D P Kotler, A Francisco, F Clayton, J V Scholes, J M Orenstein
Journal: Annals of Internal Medicine (1990)

Objectives: To examine jejunal biopsies from patients with the acquired immunodeficiency syndrome (AIDS), chronic diarrhea, and weight loss, and to correlate the presence of small intestinal injury with pathogens, histopathologic changes, and absorption. Design: Prospective analysis of jejunal biopsies from 43 patients with AIDS, 10 patients with AIDS-related complex, and 6 heterosexual control volunteers. The biopsies were examined for pathogens; electron microscopy was used in 22 patients. The results of quantitative histologic measurements were correlated with histopathologic features and D-xylose absorption. Setting: A university-affiliated teaching hospital with many AIDS patients of varying demographic characteristics. Measurements and Main Results: Jejunal biopsies in 62% of the patients with AIDS had partial villus atrophy with or without crypt hyperplasia unlike those of controls, a result implying small intestinal injury. Small intestinal injury was associated with lymphoplasmacytic infiltration and cytopathic change of the villus epithelium. Light and electron microscopic examination detected cryptosporidia or microsporidia in 19 of 27 patients with small intestinal injury. The presence of these parasites was associated with significantly diminished D-xylose absorption when compared with absorption in controls or in patients with AIDS, diarrhea, weight loss, and no parasites. Conclusion: A significant proportion of patients with AIDS with severe small intestinal injury have enterocyte infections. Like cryptosporidiosis, intestinal microsporidiosis may be an important cause of enteropathy in patients with AIDS.
Short-term ventilatory effects in workers exposed to fumes containing zinc oxide: comparison of forced oscillation technique with spirometry
Authors: HG Pasker, M Peeters, P Genet, J Clement, B Nemery, KP Van de Woestijne
Journal: European Respiratory Journal (1997)

Following the occurrence of metal fume fever in some subjects after the installation of an electric furnace in a steel plant, a survey was undertaken to examine whether subjects exposed to fumes containing zinc oxide would exhibit a detectable impairment in ventilatory function, and whether a forced oscillation technique (FOT) was more suited for this detection than conventional spirometry. Pulmonary function measurements were made in 57 exposed workers (production or maintenance) and 55 nonexposed workers (maintenance or strandcasting department) at the beginning and near the end of a work shift (day or night). Maximal expiratory volumes and flows were measured by means of a pneumotachograph, and respiratory resistance (Rrs) and reactance at various frequencies by means of a FOT. These measurements were repeated 1 day later. During the day shift, there were no significant differences in pulmonary function between exposed and control workers. However, during the night shift, an influence of exposure on pulmonary function was revealed both by spirometry and by FOT: workers exposed at night showed a slight decrease in vital capacity (VC) and in forced expiratory volume in one second (FEV1), and a decline in respiratory resistance (Rrs) with oscillation frequency, that were more marked than in unexposed subjects. In contrast to the frequency dependence of Rrs, the changes of lung volumes and expiratory flows were related to differences in initial values between exposed and nonexposed workers. The decrease in FEV1 was maintained the day after exposure. The forced oscillation technique proved at least as sensitive as spirometry to detect small across-shift changes in ventilatory function. Although the effects on pulmonary function were small, it is likely that they represent a subclinical response to the inhalation of small quantities of zinc oxide.
Stat3-dependent acute Rantes production in vascular smooth muscle cells modulates inflammation following arterial injury in mice
Authors: Jason C. Kovacic, Rohit Gupta, Angela C. Lee, Mingchao Ma, Fang Fang, Claire N. Tolbert, Avram D. Walts, Leilani E. Beltran, Hong San, Guibin Chen, Cynthia St. Hilaire, Manfred Boehm
Journal: Journal of Clinical Investigation (2010)

Inflammation is a key component of arterial injury, with VSMC proliferation and neointimal formation serving as the final outcomes of this process. However, the acute events transpiring immediately after arterial injury that establish the blueprint for this inflammatory program are largely unknown. We therefore studied these events in mice and found that immediately following arterial injury, medial VSMCs upregulated Rantes in an acute manner dependent on Stat3 and NF-κB (p65 subunit). This led to early T cell and macrophage recruitment, processes also under the regulation of the cyclin-dependent kinase inhibitor p21Cip1. Unique to VSMCs, Rantes production was initiated by Tnf-α, but not by Il-6/gp130. This Rantes production was dependent on the binding of a p65/Stat3 complex to NF-κB–binding sites within the Rantes promoter, with shRNA knockdown of either Stat3 or p65 markedly attenuating Rantes production. In vivo, acute NF-κB and Stat3 activation in medial VSMCs was identified, with acute Rantes production after injury substantially reduced in Tnfa–/– mice compared with controls. Finally, we generated mice with SMC-specific conditional Stat3 deficiency and confirmed the Stat3 dependence of acute Rantes production by VSMCs. Together, these observations unify inflammatory events after vascular injury, demonstrating that VSMCs orchestrate the arterial inflammatory response program via acute Rantes production and subsequent inflammatory cell recruitment.
Rectal hyperplasia after jejunoileal bypass for morbid obesity.
Authors: G V Appleton, E E Wheeler, R Al-Mufti, D N Challacombe, R C Williamson
Journal: Gut (1988)

Jejunoileal bypass (JIB) has been widely used to treat patients with morbid obesity for the past 20 years. In rats JIB causes adaptive colonic hyperplasia and enhances colorectal neoplasia. In this study crypt cell production rate (CCPR) was measured stathmokinetically in cultured rectal biopsies from nine patients with JIB and seven controls without intestinal operations or disease. Crypt cell production rate in the group with JIB was more than double that of controls (12.80 (2.67) v 6.23 (1.49) cells/crypt/h: p less than 0.001). There were no significant differences in crypt morphometry and histological examination of rectal biopsies was normal. Patients with JIB have a marked and persistent increase in cell proliferation in the large intestine and may be at increased risk of developing colonic cancer.
Sensitive Identification of Mycobacterial Species Using PCR-RFLP on Bronchial Washings
Authors: EIKO HIDAKA, TAKAYUKI HONDA, ICHIRO UENO, YOSHITAKA YAMASAKI, KEISHI KUBO, TSUTOMU KATSUYAMA
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

In 98 patients (24 with active pulmonary tuberculosis [TB] lesions, 28 with cured TB lesions, and 46 with nontuberculous opacities [control group] in chest CT scans), we examined whether washing the bronchus after brushing the lesion, then applying polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to the bronchial washings might be useful for diagnosing TB and nontuberculous mycobacteriosis (NTMosis). After biopsy and brushing with a bronchoscope, the bronchus connecting to the lesion was washed with 20 ml saline. The saline used for washing the brushes (5 ml; brushing sample), and 3 to 10 ml saline aspirated through the forceps channel (washing sample) were examined by PCR-RFLP, which proved able to identify Mycobacterium tuberculosis and seven species of nontuberculous mycobacteria (NTM). The values obtained for the sensitivity of the PCR-RFLP with respect to the brushing sample, the washing sample, and both samples mixed together were 70, 76, and 91%, respectively, when only patients who were culture-positive or radiologically improved after antituberculous therapy were considered as showing true infection. A mixture of brushing and washing samples provides useful material for PCR and culture, and the PCR-RFLP used here is a good method for the simultaneous identification of several species of mycobacterium (including M. tuberculosis).
A study of fatty liver disease and plasma lipoproteins in a kindred with familial hypobetalipoproteinemia due to a novel truncated form of apolipoprotein B (APO B-54.5)
Authors: Patrizia Tarugi, Amedeo Lonardo, Giorgia Ballarini, Laura Erspamer, Emilio Tondelli, Stefano Bertolini, Sebastiano Calandra
Journal: Journal of Hepatology (2000)
Consensus Development Conference on the Use of Nonsteroidal Anti-Inflammatory Agents, Including Cyclooxygenase-2 Enzyme Inhibitors and Aspirin
Authors: C. Mel Wilcox, Jeroan Allison, Keith Benzuly, Marie Borum, Byron Cryer, Tilo Grosser, Richard Hunt, Uri Ladabaum, Angel Lanas, Harold Paulus
Journal: Clinical Gastroenterology and Hepatology (2006)
Drug company denies allegations of bribery in Finnish justice ministry investigation
Authors: A. O'Dowd
Journal: BMJ (2010)

Finland’s chancellor of justice is investigating claims that a government institute accepted research money from a drug company and then approved the purchase of large amounts of one of its vaccines for use in the recent swine flu pandemic.

The allegations have, however, been denied by the drug company, GlaxoSmithKline, and the Finnish National Institute for Health and Welfare.

Last week the institute recommended that vaccination with the drug in question, Pandemrix, should be halted until an explanation is found for an observed rise in cases of narcolepsy among children and adolescents in Finland who had been given it.

The chancellor of justice, whose remit includes ruling on allegations of wrongdoing by state officials, has received complaints about the decision making process for use of …
Production of Leukotrienes in Human Skin and Conjunctival Mucosa after Specific Allergen Challenge
Authors: H. Bisgaard, A. W. Ford‐Hutchinson, S. Charleson, E. Taudorf
Journal: Allergy (1985)

The production of leukotrienes has been monitored in tear fluids from subjects following a conjunctival provocation test, and skin blister fluids following initiation of a Prausnitz‐Kustner reaction. In tear fluids elevated levels of leukotriene C 4 (LTC 4 )‐immunoreactive material were measured following allergen challenge as compared to control tear fluid obtained by mechanical or reflex stimulation. Analysis by high performance liquid chromatography indicated the presence of LTC 4 , LTD 4 and LTE 4 . In the skin, significantly elevated levels of LTC 4 ‐immunoreactive material were measured following allergen challenge in the Prausnitz‐Kustner reaction. HPLC analysis indicated the presence of both LTC 4 and LTD 4 . LTB 4 immunoreactive material was detected both in the tear fluid and the skin tissue fluid. However, no significant increase occurred in either tissue after the allergic reactions. These results indicate that the SRS‐A leukotrienes are released in vivo in man following allergen challenge, and indicate these mediators may be important in human allergic diseases.
Phase I study of pazopanib and vorinostat: a therapeutic approach for inhibiting mutant p53-mediated angiogenesis and facilitating mutant p53 degradation
Authors: S. Fu, M.M. Hou, A. Naing, F. Janku, K. Hess, R. Zinner, V. Subbiah, D. Hong, J. Wheler, S. Piha-Paul, A. Tsimberidou, D. Karp, D. Araujo, B. Kee, P. Hwu, R. Wolff, R. Kurzrock, F. Meric-Bernstam
Journal: Annals of Oncology (2015)