tbuckley/cabot-search huggingface dataset:
Rad GTPase Deficiency Leads to Cardiac Hypertrophy
Authors: Lin Chang, Jifeng Zhang, Yu-Hua Tseng, Chang-Qing Xie, Jacob Ilany, Jens C. Brüning, Zhongcui Sun, Xiaojun Zhu, Taixing Cui, Keith A. Youker, Qinglin Yang, Sharlene M. Day, C. Ronald Kahn, Y. Eugene Chen
Journal: Circulation (2007)

Rad (Ras associated with diabetes) GTPase is the prototypic member of a subfamily of Ras-related small G proteins. The aim of the present study was to define whether Rad plays an important role in mediating cardiac hypertrophy.We document for the first time that levels of Rad mRNA and protein were decreased significantly in human failing hearts (n=10) compared with normal hearts (n=3; P<0.01). Similarly, Rad expression was decreased significantly in cardiac hypertrophy induced by pressure overload and in cultured cardiomyocytes with hypertrophy induced by 10 micromol/L phenylephrine. Gain and loss of Rad function in cardiomyocytes significantly inhibited and increased phenylephrine-induced hypertrophy, respectively. In addition, activation of calcium-calmodulin-dependent kinase II (CaMKII), a strong inducer of cardiac hypertrophy, was significantly inhibited by Rad overexpression. Conversely, downregulation of CaMKIIdelta by RNA interference technology attenuated the phenylephrine-induced hypertrophic response in cardiomyocytes in which Rad was also knocked down. To further elucidate the potential role of Rad in vivo, we generated Rad-deficient mice and demonstrated that they were more susceptible to cardiac hypertrophy associated with increased CaMKII phosphorylation than wild-type littermate controls.The present data document for the first time that Rad is a novel mediator that inhibits cardiac hypertrophy through the CaMKII pathway. The present study will have significant implications for understanding the mechanisms of cardiac hypertrophy and setting the basis for the development of new strategies for treatment of cardiac hypertrophy.
Association Between a Polymorphism in Cannabinoid Receptor 2 and Severe Necroinflammation in Patients With Chronic Hepatitis C
Authors: Nicola Coppola, Rosa Zampino, Giulia Bellini, Margherita Macera, Aldo Marrone, Mariantonietta Pisaturo, Adriana Boemio, Bruno Nobili, Giuseppe Pasquale, Sabatino Maione, Luigi Elio Adinolfi, Laura Perrone, Evangelista Sagnelli, Emanuele Miraglia Del Giudice, Francesca Rossi
Journal: Clinical Gastroenterology and Hepatology (2013)
Non-human primate research: whither now?
Authors: EJH Moore
Journal: Journal of the Royal Society of Medicine (2008)

The recent report of a working group, chaired by Professor Sir David Weatherall, on the use of non-human primates in research1 has engendered little interest from doctors. This is regrettable because not only does the report address the scientific, moral and emotional issues, it presents views on research audit, medical ethics and public opinion, all of which are of direct concern to the profession.

The report was sponsored by the Academy of Medical Sciences, the Medical Research Council, the Royal Society and the Wellcome Trust. Its central goal was ‘to examine the scientific case for the use of non-human primates for research into the prevention or treatment of disease, or for fundamental research that has the long-term potential of achieving the same end’. The working group's deliberations were informed by evidence from 31 organizations and 64 individuals, most of whom were academic scientists, and it paid particular attention to the fields of communicable disease and neuroscience. The report's findings were targeted at ‘policy-makers in government, research funders, universities, scientific societies and relevant professional and regulatory bodies, as well as all other interested parties’. Its recommendations on sharing and publication of research findings, audit, development of alternatives and improving animal welfare will be perceived as well-founded, whereas its arguments for the scientific and moral justification of such research may be seen as contentious.
Folic acid-conjugated liposomal vincristine for multidrug resistant cancer therapy
Authors: Chenyu Wang, Linglin Feng, Xiangkun Yang, Fei Wang, Weiyue Lu
Journal: Asian Journal of Pharmaceutical Sciences (2013)

We encapsulated vincristine into folic acid-conjugated PEGylated liposomes to improve the anti-tumor efficacy on multidrug resistant cancers. It was observed that the drug delivery system we constructed exhibited maximum cytotoxicity on KBv200 cells (multidrug resistant variant) compared with any other formulations. The semi-quantitative analysis of region of interest revealed that there was a great increase in area under curve (AUC) of a near-infrared fluorescein in solid tumors due to folic acid-mediated accumulation. Folic acid-conjugated PEGylated liposomes showed a significant tumor growth inhibiting effect in vitro and in vivo. TUNEL assay revealed that folic acid-conjugated PEGylated liposomes could induce cell apoptosis much more greatly than others. This study demonstrated that it had potential application prospective for the treatment of multidrug resistant cancer.
Is Mammographic Breast Density a Breast Cancer Risk Factor in Women With <i>BRCA</i> Mutations?
Authors: Kavitha Passaperuma, Ellen Warner, Kimberley A. Hill, Anoma Gunasekara, Martin J. Yaffe
Journal: Journal of Clinical Oncology (2010)

Increased mammographic breast density is well recognized as a breast cancer risk factor in the general population. However, it is unclear whether it is a risk factor in women with BRCA mutations. We present the results of a nested case-control screening study investigating the relationship between breast density and breast cancer incidence in this population.Women ages 25 to 65 years with known BRCA mutations were enrolled onto a single-center, high-risk breast cancer screening program. Using a computer-aided technique (Cumulus), quantitative percentage density (PD) was measured for each participant on her baseline mammogram by a single, blinded observer.Between November 1997 and March 2008, 462 women (mean age, 44 years; 245 BRCA1 and 217 BRCA2) were screened and 50 breast cancers were diagnosed (38 invasive, 12 ductal carcinoma in situ [DCIS]). Density was not measured in 40 women of whom four developed cancer (three invasive, one DCIS). Mean PD (+/- standard deviation [SD]) for 376 women who did not develop breast cancer was 34% (23) compared with 31% (21) for 46 women with cancer (P = .51). Logistic regression model of breast cancer incidence and PD revealed an odds ratio of 0.99 (+/- 0.01 SD) for a one-unit increase in PD (P = .44). Results remained nonsignificant in multivariate analysis, as well as when women with pure DCIS were excluded.Increased mammographic breast density is not associated with higher breast cancer incidence in women with BRCA mutations. On the basis of these findings, density should not be considered a factor for these women in decision making regarding prophylactic surgery or chemoprevention.
Monocyte activation in patients with Wegener's granulomatosis
Authors: A. C M. Kobold, C. G M Kallenberg, J. W. C. Tervaert
Journal: Annals of the Rheumatic Diseases (1999)

Wegener's granulomatosis (WG) is an inflammatory disorder characterised by granulomatous inflammation, vasculitis, and necrotising vasculitis and is strongly associated with anti-neutrophil cytoplasmic antibodies (ANCA). Activated monocytes/macrophages are present in renal biopsy specimens and participate in granuloma formation by synthesising and secreting a variety of chemoattractants, growth factors, and cytokines. In view of these findings, in vivo monocyte activation was evaluated in patients with WG and the findings related to parameters of clinical disease activity.Monocyte activation was analysed by measuring plasma concentrations of soluble products of monocyte activation, that is neopterin and interleukin 6 (IL6), by ELISA, and by quantitating the surface expression of activation markers on circulating monocytes by flow cytometry.Twenty-four patients with active WG were included in this study. Ten of these patients were also analysed at the time of remission. Twelve patients with sepsis served as positive controls, and 10 healthy volunteers as negative controls for monocyte activation. Patients with active disease had increased monocyte activation compared with healthy controls as shown by increased concentrations of neopterin (p < 0.0001) and increased surface expression of CD11b (p < 0.05) and CD64 (p < 0.05). In those patients with increased concentrations of IL6 during active disease plasma concentrations of IL6 decreased during follow up when patients went into remission (p < 0.0001). In addition, neopterin (r = 0.37, r = 0.44), IL6 (r = 0.37, r = 0.60) and CD63 expression (r = 0.39, r = 0.45) correlated significantly with disease activity as measured by the Birmingham Vasculitis Activity Score and C reactive protein values, respectively. Compared with patients with sepsis, all markers of monocyte activation in patients with vasculitis were lower.It is concluded that disease activity in WG correlates with the extent of activation of monocytes, compatible with their role in the pathophysiology of this disease.
Ultraviolet Radiation Exposure and Risk of Malignant Lymphomas
Authors: K. E. Smedby, H. Hjalgrim, M. Melbye, A. Torrang, K. Rostgaard, L. Munksgaard, J. Adami, M. Hansen, A. Porwit-MacDonald, B. A. Jensen, G. Roos, B. B. Pedersen, C. Sundstrom, B. Glimelius, H.-O. Adami
Journal: JNCI Journal of the National Cancer Institute (2005)

Background: The incidence of malignant lymphomas has been increasing rapidly, but the causes of these malignancies remain poorly understood. One hypothesis holds that exposure to ultraviolet (UV) radiation increases lymphoma risk. We tested this hypothesis in a population-based case–control study in Denmark and Sweden. Methods: A total of 3740 patients diagnosed between October 1, 1999, and August 30, 2002, with incident malignant lymphomas, including non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Hodgkin lymphoma, and 3187 population controls provided detailed information on history of UV exposure and skin cancer and information on other possible risk factors for lymphomas. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by logistic regression. Statistical tests were two-sided. Results: Multivariable-adjusted analyses revealed consistent, statistically significant negative associations between various measures of UV light exposure and risk of non-Hodgkin lymphoma. A high frequency of sun bathing and sunburns at age 20 years and 5–10 years before the interview and sun vacations abroad were associated with 30%–40% reduced risks of non-Hodgkin lymphoma (e.g., for sunbathing four times a week or more at age 20 versus never sunbathing, OR = 0.7, 95% CI = 0.6 to 0.9; for two or more sunburns a year at age 20 versus no sunburns, OR = 0.6, 95% CI = 0.5 to 0.8). These inverse associations increased in strength with increasing levels of exposure (all Ptrend ≤.01). Similar, albeit weaker, associations were observed for Hodgkin lymphoma. There were no clear differences among non-Hodgkin lymphoma subtypes, although associations were stronger for B-cell than for T-cell lymphomas. A history of skin cancer was associated with a doubling in risks of both non-Hodgkin and Hodgkin lymphoma. Conclusions: A history of high UV exposure was associated with reduced risk of non-Hodgkin lymphoma. The positive association between skin cancer and malignant lymphomas is, therefore, unlikely to be mediated by UV exposure.
Exhaled breath condensate pH is a robust and reproducible assay of airway acidity
Authors: J. Vaughan, L. Ngamtrakulpanit, T.N. Pajewski, R. Turner, T-A. Nguyen, A. Smith, P. Urban, S. Hom, B. Gaston, J. Hunt
Journal: European Respiratory Journal (2003)

Exhaled breath condensate (EBC) pH is low in several lung diseases and it normalises with therapy. The current study examined factors relevant to EBC pH monitoring. Intraday and intraweek variability were studied in 76 subjects. The pH of EBC collected orally and from isolated lower airways was compared in an additional 32 subjects. Effects of ventilatory pattern (hyperventilation/hypoventilation), airway obstruction after methacholine, temperature (-44 to +13 degrees C) and duration of collection (2-7 min), and duration of sample storage (up to 2 yrs) were examined. All samples were collected with a disposable condensing device, and de-aerated with argon until pH measurement stabilised. Mean EBC pH (n=76 subjects, total samples=741) was 7.7+/-0.49 (mean+/-SD). Mean intraweek and intraday coefficients of variation were 4.5% and 3.5%. Control of EBC pH appears to be at the level of the lower airway. Temperature of collection, duration of collection and storage, acute airway obstruction, subject age, saliva pH, and profound hyperventilation and hypoventilation had no effect on EBC pH. The current authors conclude that in health, exhaled breath condensate pH is slightly alkaline, held in a narrow range, and is controlled by lower airway source fluid. Measurement of exhaled breath condensate pH is a simple, robust, reproducible and relevant marker of disease.
Biological Characteristics in Bladder Cancer Depend on the Type of Genetic Instability
Authors: Yoshiaki Yamamoto, Hideyasu Matsuyama, Shigeto Kawauchi, Tomoko Furuya, Xiu Ping Liu, Kenzo Ikemoto, Atsunori Oga, Katsusuke Naito, Kohsuke Sasaki
Journal: Clinical Cancer Research (2006)

Malignant tumors show an inherent genetic instability that can be classified as microsatellite instability (MSI) or chromosomal instability (CIN). To elucidate the differences in biological characteristics of bladder cancer between the two types of genetic instability, the expression of the mismatch repair (MMR) proteins, Aurora-A and p53 proteins, the number of centrosomes, numerical aberrations of chromosomes and 20q13, and DNA ploidy were examined in 100 human urothelial carcinomas of the bladder.Expressions of the MLH1, MSH2, Aurora-A, and p53 proteins and the numbers of centrosomes were immunohistochemically assessed. Numerical aberrations of chromosomes 7, 9, 17, and 20q13 spots were evaluated by fluorescence in situ hybridization, and DNA ploidy was assessed by laser scanning cytometry.The expression levels of the MMR related-proteins decreased in 9 of 100 tumors. Tumors with low MLH1 or MSH2 expression (designated as MSI cancers) were not linked with centrosome amplification, Aurora-A overexpression, increased p53 immunoreactivity, 20q13 gain, DNA aneuploidy, and disease progression. MSI cancers showed a favorable prognosis. CIN cancers (49 cases), defined as tumors with a large intercellular variation in centromere copy numbers, were associated more frequently with centrosome amplification, Aurora-A overexpression, increased p53 immunoreactivity, and 20q13 gain than the others (51 cases). Tumors with disease progression were included in the CIN cancer group.The present observations suggest that there are differences in the biological characteristics of the two types of genetic instability.
Do Radiation-Associated Soft Tissue Sarcomas Have the Same Prognosis As Sporadic Soft Tissue Sarcomas?
Authors: Rebecca A. Gladdy, Li-Xuan Qin, Nicole Moraco, Mark A. Edgar, Cristina R. Antonescu, Kaled M. Alektiar, Murray F. Brennan, Samuel Singer
Journal: Journal of Clinical Oncology (2010)

Purpose To determine the prognostic significance of histologic type in radiation-associated soft tissue sarcomas (RASs) and determine whether RASs are associated with an inferior prognosis compared with sporadic soft tissue sarcomas (STSs). Patients and Methods One hundred thirty primary RASs were identified from 7,649 STS patients from 1982 to 2007. Multivariate analysis of clinicopathologic factors for disease-specific survival (DSS) was performed for RASs, and a multivariate analysis of radiation exposure was also performed for RASs and sporadic sarcomas. A matched-cohort analysis was performed for radiation-associated and sporadic malignant fibrous histiocytoma (MFH). Results Most RASs were high grade (83%), deep (87%), and truncal (61.5%). The median interval between radiation therapy and RAS development was 10 years (range, 1.3 to 74 years), which varied significantly by histologic type (P = .003). The 5-year DSS was 58%, and independent predictors were size &gt; 5 cm, margin positivity, and histologic type. Multivariate analysis of histologic types of primary, high-grade radiation-associated and sporadic STSs showed that RAS was associated with a worse DSS (hazard ratio, 1.7; range, 1.1 to 2.4; P = .007). For pleomorphic MFH—the most common RAS type—the 5-year DSS was 44% versus 66% in a matched cohort of sporadic MFH patients (P = .07). DSS was significantly worse in primary RAS malignant peripheral nerve sheath tumors (MPNSTs) compared with unmatched sporadic MPNSTs (P = .001). Conclusion Histologic type, margin status, and tumor size are the most important independent predictors of DSS in patients with RASs. DSS in patients with primary RAS is significantly worse compared with sporadic STS independent of sarcoma histologic type.
Induction of partial chimerism in nonirradiated B-lymphocyte-deficient CBA/N mice.
Authors: D Volf, L L Sensenbrenner, S J Sharkis, G J Elfenbein, I Scher
Journal: The Journal of Experimental Medicine (1978)

Nonirradiated B-lymphocyte-deficient CBA/N mice given T6T6 chromosome-marked normal CBA/CaHN spleen cells became lymphoid chimeras exhibiting donor-type mitoses. Normal CBA/CaHN recipients did not exhibit significant numbers of donor-type mitoses. The lymphoid cell chimerism in the CBA/N host appeared in spleen, lymph nodes, and Peyer's patches, but not in marrow or thymus. Stimulation of CBA/N-recipient spleen cells in vitro suggested that the chimerism involved donor T6T6 cells which were responsive to the B-lymphocyte mitogen, lipopolysaccharide, but not to the T-lymphocyte mitogen, phytohemagglutinin. These data indicate that stable, long-term chimerism of a specific class of lymphocytes is possible in nonirradiated, B-lymphocyte-deficient CBA/N mice.
Activation of the Free Wall of the Right Ventricle Experimental Right Bundle Branch Block
Authors: LOYAL L. CONRAD, T. EDWARD CUDDY
Journal: Circulation Research (1959)

Right bundle branch block was produced in dogs, and activation of the free wall of the right ventricle was studied by means of multipolar electrodes. After block, accession spread radially at the earliest activated endocardial point and tangentially at later activated points. Direct current stimulation of selected endocardial points resulted in patterns of activation resembling those obtained after right bundle branch block in controls and after block. It is concluded that the Purkinje network does not participate in normal fashion in endocardial spread of the excitation impulse after right bundle branch block.
Gene Array and Fluorescence <i>In situ</i> Hybridization Biomarkers of Activity of Saracatinib (AZD0530), a Src Inhibitor, in a Preclinical Model of Colorectal Cancer
Authors: John J. Arcaroli, Basel M. Touban, Aik Choon Tan, Marileila Varella-Garcia, Rebecca W. Powell, S. Gail Eckhardt, Paul Elvin, Dexiang Gao, Wells A. Messersmith
Journal: Clinical Cancer Research (2010)

To evaluate the efficacy of saracatinib (AZD0530), an oral Src inhibitor, in colorectal cancer (CRC) and to identify biomarkers that predict antitumor activity.Twenty-three CRC cell lines were exposed to saracatinib, and baseline gene expression profiles of three sensitive and eight resistant cell lines in vitro and in vivo were used to predict saracatinib sensitivity in an independent group of 10 human CRC explant tumors using the gene array K-Top Scoring Pairs (K-TSP) method. In addition, fluorescence in situ hybridization (FISH) and immunoblotting determined both Src gene copy number and activation of Src, respectively.Two of 10 explant tumors were determined to be sensitive to saracatinib. The K-TSP classifier (TOX>GLIS2, TSPAN7>BCAS4, and PARD6G>NXN) achieved 70% (7 of 10) accuracy on the test set. Evaluation of Src gene copy number by FISH showed a trend toward significance (P = 0.066) with respect to an increase in Src gene copy and resistance to saracatinib. Tumors sensitive to saracatinib showed an increase in the activation of Src and FAK when compared with resistant tumors.Saracatinib significantly decreased tumor growth in a subset of CRC cell lines and explants. A K-TSP classifier (TOX>GLIS2, TSPAN7>BCAS4, and PARD6G>NXN) was predictive for sensitivity to saracatinib. In addition, increased activation of the Src pathway was associated with sensitivity to saracatinib. These results suggest that FISH, a K-TSP classifier, and activation of the Src pathway have potential in identifying CRC patients that would potentially benefit from treatment with saracatinib.
Changes in cardiac output and total peripheral resistance during development of renal hypertension in the rabbit: lack of confomity with the autoregulation theory.
Authors: P J Fletcher, P I Korner, J A Angus, J R Oliver
Journal: Circulation Research (1976)

Serial measurements of cardiac output (CO), mean arterial pressure (MAP), heart rate, and total peripheral resistance (TPR), were made on unanesthetized rabbits with previously implanted Doppler flowmeters. After 2 days of control measurements the rabbits were subjected alternatively to bilateral renal cellophane wrapping (wrap group) or to sham operation and additional measurements were made 1, 2, 4, 8, 16, 25, and 32 days after operation. During the 1st week after operation changes in CO were identical in the wrap and sham-operated groups, with an overall increase to a value of 110% of control on day 4 (P less than 0.05). Thereafter CO fell gradually, reaching 75% of control by day 32 in the wrap group, but only 95% of control in the sham-operated group. When CO was expressed per unit of body weight the latter differences were somewhat reduced, but still were significant. In wrap animals MAP and TPR rose progressively to 155% and 194% of control by day 32. In the sham-operated group the corresponding increases to 108% and 118% of control were significantly smaller. The MAP and TPR of the renal wrap rabbits exceeded the values in sham-operated rabbits, even over the 1st week after operation, by an average for MAP of 8.6 +/- 1.4% (P less than 0.001), and for TPR of 8.0 +/- 2.5% (P = 0.01). The results suggest that the changes in CO during the 1st week were a nonspecific consequence of the preceding wrap or sham operation. They bore no apparent relationship to the subsequent development of the hypertension which was "resistance-mediated" from the earliest stages. We conclude that the present findings for the rabbit differ from those reported for other species and do not conform to the changes predicted by the autoregulation theory of the pathogenesis of hypertension.