tbuckley/cabot-search huggingface dataset:
Diabetes Mellitus Enhances Vascular Matrix Metalloproteinase Activity
Authors: Shiro Uemura, Hidetsugu Matsushita, Wei Li, Alexander J. Glassford, Tomoko Asagami, Keun-Ho Lee, David G. Harrison, Philip S. Tsao
Journal: Circulation Research (2001)

Abstract —Diabetes mellitus (DM) is a primary risk factor for cardiovascular disease. Although recent studies have demonstrated an important role for extracellular matrix metalloproteinases (MMPs) in atherosclerosis, little is known about the effects of hyperglycemia on MMP regulation in vascular cells. Gelatin zymography and Western blot analysis revealed that the activity and expression of 92-kDa (MMP-9) gelatinase, but not of 72 kDa (MMP-2) gelatinase, were significantly increased in vascular tissue and plasma of two distinct rodent models of DM. Bovine aortic endothelial cells (BAECs) grown in culture did not express MMP-9 constitutively; however, chronic (2-week) incubation with high glucose medium induced MMP-9 promoter activity, mRNA and protein expression, and gelatinase activity in BAECs. On the other hand, high glucose culture did not change MMP-9 activity from vascular smooth muscle cells or macrophages. Electron paramagnetic resonance studies indicate that BAECs chronically grown in high glucose conditions produce 70% more ROS than do control cells. Enhanced MMP-9 activity was significantly reduced by treatment with the antioxidants polyethylene glycol–superoxide dismutase and N -acetyl- l -cysteine but not by inhibitors of protein kinase C. In conclusion, vascular MMP-9 activity is increased in DM, in part because of enhanced elaboration from vascular endothelial cells, and oxidative stress plays an important role. This novel mechanism of redox-sensitive MMP-9 expression by hyperglycemia may provide a rationale for antioxidant therapy to modulate diabetic vascular complications.
What tumors need
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

The field of angiogenesis began in the early 1970s when Judah Folkman proposed that tumor growth would be halted if the tumor were deprived of a blood supply. Thirty years later, Folkman's controversial idea is now widely accepted and angiogenesis inhibitors hold great promise for the treatment of cancer.
Early Mortality After Aortic Valve Replacement With Mechanical Prosthetic vs Bioprosthetic Valves Among Medicare Beneficiaries
Authors: Dongyi (Tony) Du, Stephen McKean, Jeffrey A. Kelman, John Laschinger, Chris Johnson, Rob Warnock, Chris M. Worrall, Art Sedrakyan, William Encinosa, Thomas E. MaCurdy, Hector S. Izurieta
Journal: JAMA Internal Medicine (2014)

Early mortality for patients who undergo aortic valve replacement (AVR) may differ between mechanical and biological prosthetic (hereinafter referred to as bioprosthetic) valves. Clinical trials may have difficulty addressing this issue owing to limited sample sizes and low mortality rates.To compare early mortality after AVR between the recipients of mechanical and bioprosthetic aortic valves.A retrospective analysis of patients 65 years or older in the Medicare databases who underwent AVR from July 1, 2006, through December 31, 2011. In the mixed-effects models adjusting for physician and hospital random effects, we estimated odds ratios (OR) of early mortality to compare mechanical vs bioprosthetic valves.Mechanical or bioprostheticaortic valve replacement.Early mortality was measured as death on the date of surgery, death within 1 to 30 or 31 to 365 days after the date of surgery, death within 30 days after the date of hospital discharge, and operative mortality (death within 30 days after surgery or at discharge, whichever is longer).Of the 66 453 Medicare beneficiaries who met inclusion criteria, 19 190 (28.88%) received a mechanical valve and 47 263 (71.12%) received a bioprosthetic valve. The risk for death on the date of surgery was 60% higher for recipients of mechanical valves than recipients of bioprosthetic valves (OR, 1.61 [95% CI, 1.27-2.04; P < .001]; risk ratio [RR], 1.60). The risk difference decreased to 16% during the 30 days after the date of surgery (OR, 1.18 [95% CI, 1.09-1.28; P < .001]; RR, 1.16). We found no differences within 31 to 365 days after the date of surgery and within the 30 days after discharge. The risk for operative mortality was 19% higher for recipients of mechanical compared with bioprosthetic valves (OR, 1.21 [95% CI, 1.13-1.30; P < .001]; RR, 1.19). The number needed to treat with mechanical valves to observe 1 additional death on the surgery date was 290; to observe 1 additional death within 30 days of surgery, 121. Consistent findings were observed in subgroup analyses of patients who underwent concurrent AVR and coronary artery bypass graft, but not in the subgroup undergoing isolated AVR.In this cohort analysis of Medicare beneficiaries, use of mechanical aortic valves was associated with a higher risk for death on the date of surgery and within the 30 days after surgery compared with bioprosthetic aortic valves among patients who underwent concurrent AVR and coronary artery bypass graft but not isolated AVR.
Infection with Listeria monocytogenes impairs sialic acid addition to host cell glycoproteins.
Authors: M S Villanueva, C J Beckers, E G Pamer
Journal: The Journal of Experimental Medicine (1994)

Listeria monocytogenes is a facultative intracellular bacterium that causes severe disease in neonates and immunocompromised adults. Although entry, multiplication, and locomotion of Listeria in the cytosol of infected cells are well described, the impact of such infection on the host cell is unknown. In this report, we investigate the effect of L. monocytogenes infection on MHC class I synthesis, processing, and intracellular trafficking. We show that L. monocytogenes infection interferes with normal processing of N-linked oligosaccharides on the major histocompatibility complex (MHC) class I heavy chain molecule, H-2Kd, resulting in a reduced sialic acid content. The glycosylation defect is more pronounced as the infection progresses and results from interference with the addition of sialic acid rather than its removal by a neuraminidase. The effect is found in two different cell lines and is not limited to MHC class I molecules since CD45, a surface glycoprotein, and LGP120, a lysosomal glycoprotein, are similarly affected by L. monocytogenes infection. The glycosylation defect is specific for infection by L. monocytogenes since neither Trypanosoma cruzi nor Yersinia enterocolitica, two other intracellular pathogens, reproduces the effect. The resultant hyposialylation of H-2Kd does not impair its surface expression in infected cells. Diminished sialic acid content of surface glycoproteins may enhance host-defense by increasing susceptibility to lysis and promoting clearance of Listeria-infected cells.
Views of Potential Subjects Toward Proposed Regulations for Clinical Research With Adults Unable to Consent
Authors: Dave Wendler, Rick A. Martinez, Diane Fairclough, Trey Sunderland, Ezekiel Emanuel
Journal: American Journal of Psychiatry (2002)

The authors' goal was to assess healthy individuals' attitudes toward five of the most prominent proposed safeguards regarding the consent process for research with adults unable to consent.Telephone interviews were conducted with 246 individuals with a family history of Alzheimer's disease who had participated in clinical research.The majority of respondents said that they were willing to participate in research if they lost the ability to consent. Few completed a research advance directive. Many had discussed their preferences with their families, and the majority would allow their families to make research decisions for them.Enrolling individuals who are unable to consent in research that offers no potential for medical benefit is consistent with the preferences of at least some individuals. This suggests that such research should not be prohibited, provided there is sufficient evidence that it is consistent with the preferences of individual subjects. Requiring that such evidence be provided in a formal research advance directive may be unnecessarily restrictive. More research is needed to assess whether the findings in this group of subjects generalize to other groups.
Relationship of Treatment-Related Cytopenias and Response to Lenalidomide in Patients With Lower-Risk Myelodysplastic Syndromes
Authors: Mikkael A. Sekeres, Jaroslaw P. Maciejewski, Aristotle A.N. Giagounidis, Kenton Wride, Robert Knight, Azra Raza, Alan F. List
Journal: Journal of Clinical Oncology (2008)

Patients with myelodysplastic syndromes (MDS) often require treatment with growth factors (GFs) or non-GF therapies. One non-GF drug, lenalidomide, is particularly effective at achieving transfusion independence (TI) in patients with lower-risk MDS with the del(5q) cytogenetic abnormality. However, approximately half of del(5q) patients and one quarter of non-del(5q) patients treated with lenalidomide experience significant cytopenias. Lenalidomide-induced cytopenias occurring early in treatment may serve as a surrogate marker of clonal suppression and, therefore, may be predictive of a TI response.We analyzed 362 low-risk, transfusion-dependent patients with MDS, with or without the del(5q) abnormality, enrolled in two phase II studies (MDS-003 and MDS-002) to determine whether treatment-related cytopenias are correlated with lenalidomide response. Cytopenias were assessed during the first 8 weeks of therapy, and response was defined as TI; response predictors were explored in univariate and multivariate analyses.Among patients with del(5q), 70% of those whose platelet count decreased by > or = 50% achieved TI, as compared with 42% of those whose platelet count remained stable or declined by less than 50% (P = .01). Among patients without baseline neutropenia, 82% of those whose absolute neutrophil count (ANC) decreased by > or = 75% achieved TI, as compared with 51% whose ANC remained stable or decreased by less than 75% (P = .02). These relationships were consistent in multivariate analyses. No relationship between the development of cytopenias and response could be established for lower-risk patients with MDS without del(5q).These findings support the hypothesis that a direct cytotoxic effect of lenalidomide specific to the del(5q) clone may be indicative of a TI response.
P827 INSULIN SECRETORY FUNCTION AND HBa1c ARE RELATED TO LIVER FIBROSIS IN NONALCOHOLIC FATTY LIVER DISEASE
Authors: Y. Eguchi, Y. Kitajima, H. Takahashi, M. Ono, M. Okada, H. Hyogo, Y. Sumida, N. Araki, N. Ono, T. Eguchi, R. Iwakiri, K. Anzai
Journal: Journal of Hepatology (2014)
Insulin potentiates TRPC3-mediated cation currents in normal but not in insulin-resistant mouse cardiomyocytes
Authors: J FAUCONNIER, J LANNER, A SULTAN, S ZHANG, A KATZ, J BRUTON, H WESTERBLAD
Journal: Cardiovascular Research (2006)

Recent studies show that bioactive lipids alter intracellular Ca(2+) handling of cardiac cells differently in normal and insulin-resistant cardiomyocytes. In the present study we measured non-selective cation currents (NSCC) focusing on the interaction between insulin, the bioactive lipid diacylglycerol (DAG) and canonical transient receptor potential 3 (TRPC3) channels.Whole cell patch-clamp was used to measure NSCC in ventricular cardiomyocytes isolated from adult wild-type (WT) and insulin resistant, obese ob/ob mice. Western blot, immunoprecipitation and immunofluorescence staining were used to study the concentration and cellular distribution of TRPC3 channels.Application of the membrane permeable DAG analogue (OAG, 30 microM) induced an NSCC, which was approximately 40% smaller in ob/ob than in WT cardiomyocytes. Insulin induced a small NSCC with similar amplitude in ob/ob and WT cells. Pretreatment with insulin (60 nM) increased the OAG-induced NSCC in WT (by approximately 50%) but not in ob/ob cells. OAG-induced currents were inhibited by adding anti-TRPC3 antibodies to the patch pipette solution. The expression of TRPC3 was lower in ob/ob than in WT cardiomyocytes. TRPC3 was detected in glucose transporter 4 (GLUT4) immunoprecipitates. Insulin exposure resulted in a translocation of TRPC3 to the plasma membrane in WT but not in ob/ob cardiomyocytes.Insulin-resistant ob/ob cardiomyocytes showed decreases in DAG-mediated NSCC, which were accompanied by decreased TRPC3 expression and defective insulin-mediated trafficking of this protein.
Increased serum cartilage oligomeric matrix protein levels and decreased patellar bone mineral density in patients with chondromalacia patellae
Authors: E Murphy
Journal: Annals of the Rheumatic Diseases (2002)

Chondromalacia patellae is a potentially disabling disorder characterised by features of patellar cartilage degradation.To evaluate markers of cartilage and bone turnover in patients with chondromalacia patellae.18 patients with chondromalacia patellae were studied. Serum cartilage oligomeric matrix protein (s-COMP) and bone sialoprotein (s-BSP) levels were measured by enzyme linked immunosorbent assay (ELISA) and compared with those of age and sex matched healthy control subjects. Periarticular bone mineral density (BMD) of both knee joints was assessed by dual energy x ray absorptiometry (DXA).s-COMP levels were significantly raised in all patients with chondromalacia patellae compared with healthy control subjects (p=0.0001). s-BSP levels did not differ significantly between the groups (p=0.41). BMD of the patella was significantly reduced in patients with chondromalacia patellae compared with the control subjects (p=0.016). In patients with bilateral chondromalacia patellae, BMD of the patella was lower in the more symptomatic knee joint (p=0.005). Changes in periarticular BMD were localised to the patella and were not present in femoral regions. Neither s-COMP (p=0.18) nor s-BSP (p=0.40) levels correlated with patellar BMD.Increased s-COMP levels, reflecting cartilage degradation, and reduced BMD localised to the patella may represent clinically useful markers in the diagnosis and monitoring of patients with chondromalacia patellae. Measures of cartilage degradation did not correlate with loss of patellar bone density, suggesting dissociated pathophysiological mechanisms.
Induction of Thyroid Tumors in (C57BL/6N × C3H/N)F<sub>1</sub> Mice by Oral Administration of 9-3′,4′,5′,6′-Tetrachloro-<italic>o</italic>-carboxy Phenyl-6-hydroxy-2,4,5,7-tetraiodo-3-isoxanthone Sodium (Food Red 105, Rose Bengal B)<xref ref-type="fn" rid="FN1">2</xref><xref ref-type="fn" rid="FN2">3</xref>
Authors: A Ito, H Watanabe, M Naito, H Aoyama, Y Nakagawa, N Fujimoto
Journal: JNCI Journal of the National Cancer Institute (1986)

The tumorigenicity of 9-3',4',5',6'-tetrachloro-o-carboxy phenyl-6-hydroxy-2,4,5,7-tetraiodo-3-isoxanthone sodium (CAS: 632-68-8) [also called Food Red 105 (FR 105) or Rose Bengal B], which is widely used for food or cosmetic coloring in Japan, was examined in (C57BL/6N X C3H/N)F1 mice. Animals were divided into 6 groups with 50 mice in each group, and they were given solutions of 0, 0.125, and 0.5% FR 105 in the drinking water starting at 6 weeks of age and ending at 101 weeks. The mean relative thyroid weights in both sexes of mice given 0.125 and 0.5% FR 105 were significantly increased compared to those of controls. Enlarged thyroid glands were composed exclusively of colloid goiters characterized by distended follicles lined with flattened follicular cells. The male mice given 0.5% FR 105 had follicular adenomas in the thyroid gland at an incidence of 22.9%, which was significantly higher than the incidence in controls (P less than .005). Radioactive 131I uptake in colloid goiters was markedly decreased compared to that in intact thyroid glands. The results indicate that FR 105 can induce colloid goiters and thyroid adenomas in a dose-dependent manner.
Abstract 802: The inactivation of PP2A caused by the replacement of its regulatory subunit plays a crucial role in the hemangiomagenesis
Authors: Qin Xu, Furong Xie
Journal: Cancer Research (2015)

Abstract Hemangioma is the most frequent vascular tumor of early childhood. However, the mechanism leading to their development, progression and maintenance has remained unclear. In this study, we generated an endothelial-specific PyMT-expressing transgenic (Tg) mouse (Tie2-PyMT) that spontaneously develop hemangioma. Using Tie2-PyMT transgenic mice and bEnd.3 cells, an PyMT induced mouse brain endothelial cell line idicates that the direct expression of PyMT gene in vascular endothelial cells leads to rapid cell proliferation and hemangioma development. An interaction between the core AC dimer of protein phosphatase 2A (PP2A) and PyMT, but not B regulatory subunit was verified both in hemangioma endothelial cells of Tie2-PyMT Tg mice and bEnd.3 cells by immunoprecipitation. Whereas in endothelial cells of Tg negative mice and PyMT silenced bEnd.3 cells, the B regulatory subunit binds to the core AC dimer of PP2A. PyMT binding to PP2A led to the inactivation of PP2A phosphatases and subsequently activates its downstream ERK1/2 and AKT pathway, which may be responsible for the proliferative effect of PyMT on vascular endothelial cells. Moreover, the effect of PyMT on PP2A phosphatases activity could be rescued by Okadaic acid (OA), a specific inhibitor of PP2A. Treamtment of Tie2-PyMT transgenic mice with the PP2A activator, FTY720, significantly delayed hemangiomagenesis in this model. Furthermore, PP2A complex composition and its phosphatases activity were also examined in patient hemangioma specimens. Consisten with the animal model, a decreased PP2A phosphatases activity and the dissociation of B subunit from the PP2A core dimer were observed. These findings suggest that the inactivation of PP2A caused by the replacement of its regulatory subunit plays a crucial role in the hemangiomagenesis. Citation Format: Qin Xu, Furong Xie. The inactivation of PP2A caused by the replacement of its regulatory subunit plays a crucial role in the hemangiomagenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 802. doi:10.1158/1538-7445.AM2015-802
Nitric Oxide Is a Factor in the Stabilization of Hypoxia-Inducible Factor-1α in Cancer: Role of Free Radical Formation
Authors: Marisol Quintero, Peter A. Brennan, Gareth J. Thomas, Salvador Moncada
Journal: Cancer Research (2006)

Abstract Widespread expression of the α-subunit of hypoxia-inducible factor (HIF-1α) was observed in samples of human oral squamous cell carcinoma. In all the cases, this was accompanied by a widespread distribution of nitric oxide (NO) synthases (NOS). Furthermore, in three human cell lines derived from human oral squamous cell carcinoma, the accumulation of HIF-1α was prevented either by inhibition of NOS activity with the nonspecific NOS inhibitor NG-monomethyl-l-arginine or by the antioxidants N-acetyl-l-cysteine and ascorbic acid. We suggest that, in certain forms of cancer, NO might be responsible for the accumulation of HIF-1α by a mechanism dependent on free radicals. (Cancer Res 2006; 66(2): 770-4)
Mental and Behavioral Disturbances in Dementia: Findings From the Cache County Study on Memory in Aging
Authors: Constantine G. Lyketsos, Martin Steinberg, JoAnn T. Tschanz, Maria C. Norton, David C. Steffens, John C.S. Breitner
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: The authors report findings from a study of 5,092 community residents who constituted 90% of the elderly resident population of Cache County, Utah. METHOD: The 5,092 participants, who were 65 years old or older, were screened for dementia. Based on the results of this screen, 1,002 participants (329 with dementia and 673 without dementia) underwent comprehensive neuropsychiatric examinations and were rated on the Neuropsychiatric Inventory, a widely used method for ascertainment and classification of dementia-associated mental and behavioral disturbances. RESULTS: Of the 329 participants with dementia, 214 (65%) had Alzheimer's disease, 62 (19%) had vascular dementia, and 53 (16%) had another DSM-IV dementia diagnosis; 201 (61%) had exhibited one or more mental or behavioral disturbances in the past month. Apathy (27%), depression (24%), and agitation/aggression (24%) were the most common in participants with dementia. These disturbances were almost four times more common in participants with dementia than in those without. Only modest differences were observed in the prevalence of mental or behavioral disturbances in different types of dementia or at different stages of illness: participants with Alzheimer's disease were more likely to have delusions and less likely to have depression. Agitation/aggression and aberrant motor behavior were more common in participants with advanced dementia. CONCLUSIONS: On the basis of their findings in this large community population of elderly people, the authors conclude that a wide range of dementia-associated mental and behavioral disturbances afflict the majority of individuals with dementia. Because of their frequency and their adverse effects on patients and their caregivers, these disturbances should be ascertained and treated in all cases of dementia.
Phase II Stopping Rules That Employ Response Rates and Early Progression
Authors: John R. Goffin, Dongsheng Tu
Journal: Journal of Clinical Oncology (2008)

Phase II oncology trials traditionally have used response rate (RR) as the primary end point, but newer targeted agents require the consideration of alternative end points. High rates of early progressive disease (EPD) suggest inadequate drug activity and may be useful in the early stopping of trials. This study used a simulation to define a set of rules to assess a combined end point of RR and EPD.The simulation assumed a two-stage trial with a specified alpha error and power. It randomly generated the true response rate, r, of the agent under study and its true rate of early progressive disease, epd, for each run of the simulation. Two pairs of parameters were specified: (r(nul), epd(nul)) and (r(alt), epd(alt)). A drug was considered uninteresting for further development if r was less than or equal to r(nul) and epd was greater than or equal to epd(nul) (ie, the null hypothesis) and interesting for further development if r was greater than or equal to r(alt) or epd was less than or equal to epd(alt) (ie, the alternate hypotheses). Thresholds for the required number of patients with responses, n(r) and EPD, n(p), were generated for each set of parameters.Thresholds for n(r) and n(p) that satisfied the specified error rates were generated. There was at least an 89% likelihood that a study would be stopped at the first stage of accrual if r and epd were uninteresting.The simulation was able to establish stopping rules by combining the RR and the EPD that achieved the desired error rates. High rates of early stopping suggest that this design could shorten phase II trials of inactive agents.
Identification of the second major allergen of Japanese cedar pollen
Authors: M. Sakaguch, S. Inouye, M. Taniai, S. Ando, M. Usui, T. Matuhasi
Journal: Allergy (1990)

We isolated and characterized the second major allergen (Cry j II) from Japanese cedar pollen. We found that most patients with this pollinosis had IgE antibody to this protein in addition to IgE antibody to Cry j I; however, some sera reacted only with Cry j I or Cry j II. IgE-ELISA inhibition studies revealed that Cry j I and Cry j II had no cross-allergenicity. Cry j II did not react with anti-Cry j I monoclonal antibodies. In SDS-PAGE under a non-reducing condition, Cry j II showed a band at the 37 kDa position, compared with the 45-50 kDa bands of Cry j I. N-terminal amino acid sequence of Cry j II was completely different from that of Cry j I.