tbuckley/cabot-search huggingface dataset:
RWJ-241947 (MCC-555), A Unique Peroxisome Proliferator-Activated Receptor-γ Ligand with Antitumor Activity against Human Prostate Cancer <b> <i>in Vitro</i> </b> and in Beige/Nude/ X-Linked Immunodeficient Mice and Enhancement of Apoptosis in Myeloma Cells Induced by Arsenic Trioxide
Authors: Takashi Kumagai, Takayuki Ikezoe, Dorina Gui, James O’Kelly, Xiang-Jun Tong, Fredric J. Cohen, Jonathan W. Said, H. Phillip Koeffler
Journal: Clinical Cancer Research (2004)

Abstract Purpose: RWJ-241947 (MCC-555) is a novel peroxisome proliferator-activated receptor-γ ligand of the thiazolidinedione class that was recently developed as an antidiabetic drug with unique properties. Some thiazolidinediones have anticancer activity against solid and hematological malignancies; the anticancer potency of RWJ-241947 has not been examined. We, therefore, investigated these effects in vitro and in vivo either alone or in combination with other compounds. Experimental Design: Tumor growth was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, soft agar colony assay in vitro, and xenografts in nude mice. Its effects on cell cycle, differentiation, and apoptosis were examined. Results: In vitro studies using various solid and hematological tumor cell lines showed that RWJ-241947 had antiproliferative activity against prostate cancer cells, with the strongest effect against the androgen-independent PC-3 prostate cancer cells. It increased expression of cyclin-dependent kinase inhibitor p21WAF1, deceased cyclin E, and induced apoptosis in PC-3 cells. It increased E-cadherin and lowered protein expression of prostate-specific antigen without down-regulating the androgen receptor in androgen-dependent LNCaP prostate cancer cells. Reporter gene assays showed that this peroxisome proliferator-activated receptor-γ ligand inhibited androgen activation of the androgen receptor response elements of the prostate-specific antigen gene. Remarkably, in vivo treatment of male beige/nude/X-linked immunodeficient (BNX) mice with RWJ-241947 profoundly suppressed growth of PC-3 prostate cancer xenografts with prominent apoptosis, as well as fibrosis, including inflammatory and giant cell reaction in the remaining tumor tissue. Notably, the experimented mice had a significantly decreased cholesterol. In addition, we studied the combination of arsenic trioxide (As2O3), which is used in the treatment of multiple myeloma, and RWJ-241947; these two reagents together prominently inhibited proliferation and caused apoptosis of multiple myeloma cells. Conclusions: RWJ-241947 has surprisingly potent antiproliferative effects against prostate cancer cells in vivo, and it enhances the antitumor activity of As2O3 against myeloma cells. Small, well-defined clinical studies using RWJ-241947 are in order for these cancers.
Multiple Cytokines and Acute Inflammation Raise Mouse Leptin Levels: Potential Role in Inflammatory Anorexia
Authors: Pasha Sarraf, Robert C. Frederich, Ewa M. Turner, Grace Ma, Nora T. Jaskowiak, Dennis J. Rivet, Jeffrey S. Flier, Bradford B. Lowell, Douglas L. Fraker, H. Richard Alexander
Journal: The Journal of Experimental Medicine (1997)

Several inflammatory cytokines, most notably tumor necrosis factor (TNF) and IL-1, induce anorexia and loss of lean body mass, common manifestations of acute and chronic inflammatory conditions. In C57BL/6 female mice, the administration of TNF, IL-1, and, to a lesser extent, leukemia inhibitory factor (LIF), produced a prompt and dose-dependent increase in serum leptin levels and leptin mRNA expression in fat. IL-10, IL-4, ciliary neurotrophic factor, and IL-2, cytokines not known to induce anorexia or decrease food intake, had no effect on leptin gene expression or serum leptin levels. After administration of Escherichia coli lipopolysaccharide (LPS), leptin gene expression and leptin levels were increased. These findings suggest that leptin levels may be one mechanism by which anorexia is induced during acute inflammatory conditions.
Development and Measurement of Guideline-Based Indicators for Patients With Non-Hodgkin's Lymphoma
Authors: Lianne Wennekes, Petronella B. Ottevanger, John M. Raemaekers, Harry C. Schouten, Marjorie W.E. de Kok, Cornelis J.A. Punt, Richard P. Grol, Hub C. Wollersheim, Rosella P. Hermens
Journal: Journal of Clinical Oncology (2011)

Purpose Patients with cancer are not always treated according to available guidelines. Factors such as age and comorbidities are frequently used as arguments for nonadherence. The aim of this study was to measure guideline adherence with guideline-based indicators for patients with non-Hodgkin's lymphoma (NHL) and to examine the need for improvement, considering relevant arguments. Methods A RAND-modified Delphi procedure was used to systematically develop NHL indicators. We evaluated their improvement potential (defined as &lt; 90% score) in a random sample of patients with NHL (N = 431) diagnosed in 2006-2007 in 22 hospitals in the Netherlands with data from medical records. Multilevel logistic regression analyses were used to estimate the relationship between indicator scores and factors: comorbidity index (combined with age), stage, patient's objections, and lymphoma type. Scores were adjusted for significant factors. Results Of the 20 indicators developed, 16 had improvement potential. Scores were lowest for assessment of International Prognostic Index, 21%; imaging of neck, thorax, and abdomen and bone marrow examination during the diagnostic process, 23%, and after chemotherapy, 37%; adequate pathology reporting, 11%; and multidisciplinary discussion of patients, 21%. Scores for eight indicators were better for patients with a low Charlson index, stage III or IV disease, no objections to care, and aggressive lymphoma. After adjustments, adherence to all but one indicator (administration of the combination of rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone) remained &lt; 90%. Conclusion In the Netherlands, almost all indicators for NHL needed improvement. This should be evaluated in other countries as well. International efforts should be undertaken to improve the quality of care of this often curable malignancy.
Phosphorylation of S955 at the Protein Kinase A Consensus Promotes Maturation of the α Subunit of the Colonic H+,K+-ATPase
Authors: Juan Codina, Jingfang Liu, Anthony J. Bleyer, Raymond B. Penn, Thomas D. DuBose
Journal: Journal of the American Society of Nephrology (2006)

All the α subunits of the Na<sup>+</sup>,K<sup>+</sup>-ATPases and H<sup>+</sup>,K<sup>+</sup>-ATPases have a protein kinase A (PKA) consensus sequence near or in the ninth transmembrane domain. The role of this domain in influencing α subunit synthesis/degradation, plasma membrane localization, and <sup>86</sup>Rb<sup>+</sup> uptake has not been established for the α subunit of the colonic H<sup>+</sup>,K<sup>+</sup>-ATPase. This study examined the effect of mutating S<sup>955</sup> (within the PKA consensus site of the α subunit of the colonic H<sup>+</sup>,K<sup>+</sup>-ATPase [HKα<sub>2</sub>]) to alanine (S<sup>955</sup>/A) or aspartic acid (S<sup>955</sup>/D) on α subunit expression and function. The results demonstrate that a negatively charged amino acid at position 955 of HKα<sub>2</sub> promotes higher expression levels of both whole-cell and plasma membrane–localized HKα<sub>2</sub>. Moreover, inhibition of PKA reduced expression of wild-type HKα<sub>2</sub> and associated <sup>86</sup>Rb<sup>+</sup> uptake. Last, the activity of the HKα<sub>2</sub> S<sup>955</sup>/A was rescued by treatment with 4-phenylbutyric acid, a compound that was shown previously to restore function to the cystic fibrosis transmembrane conductance regulator.
Scotland to start screening programme for diabetic retinopathy
Authors: B. Christie
Journal: BMJ (2002)

Scotland is planning to introduce what is said to be the world's first national screening programme for diabetic retinopathy, to help prevent a condition that can damage eyes and lead to blindness.

The Health Technology Board for Scotland has produced recommendations on how the programme should be organised, and an implementation group has been set up to work with Scottish health boards on its introduction. The …
Atony of Female Bladder
Authors: M. A. D. Crawford
Journal: BMJ (1959)

Loss of sensory function leads to atrophy or death within the developing CNS, yet little is known about the physiology of remaining synapses. After bilateral deafening, gramicidin-perforated-patch recordings were obtained from gerbil inferior colliculus neurons in a brain slice preparation. Afferent-evoked IPSPs had a diminished ability to block current-evoked action potentials in deafened neurons. This change could be attributed, in part, to a loss of potassium-dependent chloride transport function, with little change in K-Cl cotransporter expression. Treatments that suppressed chloride cotransport (bumetanide, cesium, and genistein) had little or no effect on neurons from deafened animals. These same treatments depolarized the <i>E</i><sub>IPSC</sub> of control neurons. Semiquantitative RT-PCR and immunohistochemical staining indicated no change in the expression of chloride cotransporter mRNA or protein after deafness. Therefore, profound hearing loss leads rapidly to the disruption of chloride homeostasis, which is likely attributable to the dysfunction of the potassium-dependent chloride cotransport mechanism, rather than a downregulation of its expression. This results in inhibitory synapses that are less able to block excitatory events.
Enhancing Efficacy of Recombinant Anticancer Vaccines With Prime/Boost Regimens That Use Two Different Vectors
Authors: K. R. Irvine, R. S. Chamberlain, E. P. Shulman, D. R. Surman, S. A. Rosenberg, N. P. Restifo
Journal: JNCI Journal of the National Cancer Institute (1997)

The identification of tumor-associated antigens and the cloning of DNA sequences encoding them have enabled the development of anticancer vaccines. Such vaccines target tumors by stimulating an immune response against the antigens. One method of vaccination involves the delivery of antigen-encoding DNA sequences, and a number of recombinant vectors have been used for this purpose. To optimize the efficacy of recombinant vaccines, we compared primary and booster treatment regimens that used a single vector (i.e., homologous boosting) with regimens that used two different vectors (i.e., heterologous boosting).Pulmonary tumors (experimental metastases) were induced in BALB/c mice inoculated with CT26.CL25 murine colon carcinoma cells, which express recombinant bacterial beta-galactosidase (the model antigen). Protocols for subsequent vaccination used three vectors that encoded beta-galactosidase--vaccinia (cowpox) virus, fowlpox virus, naked bacterial plasmid DNA. Mouse survival was evaluated in conjunction with antibody and cytotoxic T-lymphocyte responses to beta-galactosidase.Heterologous boosting resulted in significantly longer mouse survival than homologous boosting (all P<.0001, two-sided). Potent antigen-specific cytotoxic T lymphocytes were generated following heterologous boosting with poxvirus vectors. This response was not observed with any of the homologous boosting regimens. Mice primed with recombinant poxvirus vectors generated highly specific antibodies against viral proteins.The poor efficacy of homologous boosting regimens with viral vectors was probably a consequence of the induction of a strong antiviral antibody response. Heterologous boosting augmented antitumor immunity by generating a strong antigen-specific cytotoxic T-lymphocyte response. These data suggest that heterologous boosting strategies may be useful in increasing the efficacy of recombinant DNA anticancer vaccines that have now entered clinical trials.
Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial
Authors: Guglielmo Ronco, Paolo Giorgi-Rossi, Francesca Carozzi, Massimo Confortini, Paolo Dalla Palma, Annarosa Del Mistro, Bruno Ghiringhello, Salvatore Girlando, Anna Gillio-Tos, Laura De Marco, Carlo Naldoni, Paola Pierotti, Raffaella Rizzolo, Patrizia Schincaglia, Manuel Zorzi, Marco Zappa, Nereo Segnan, Jack Cuzick
Journal: The Lancet Oncology (2010)
Nurse staffing and education and hospital mortality in nine European countries: a retrospective observational study
Authors: Linda H Aiken, Douglas M Sloane, Luk Bruyneel, Koen Van den Heede, Peter Griffiths, Reinhard Busse, Marianna Diomidous, Juha Kinnunen, Maria Kózka, Emmanuel Lesaffre, Matthew D McHugh, M T Moreno-Casbas, Anne Marie Rafferty, Rene Schwendimann, P Anne Scott, Carol Tishelman, Theo van Achterberg, Walter Sermeus
Journal: The Lancet (2014)
Helicobacter pylori Seropositivity and Subsite-Specific Gastric Cancer Risks in Linxian, China
Authors: P. J. Limburg, Y.-L. Qiao, S. D. Mark, G.-Q. Wang, G. I. Perez-Perez, M. J. Blaser, Y.-P. Wu, X.-N. Zou, Z.-W. Dong, P. R. Taylor, S. M. Dawsey
Journal: JNCI Journal of the National Cancer Institute (2001)

Helicobacter pylori carriage (i.e., persistent exposure to the organism without gastric epithelial cell invasion) is an established risk factor for noncardia gastric cancer. However, its association with the risk of cancer of the gastric cardia is controversial. Consequently, we designed this prospective, nested case-control study to further explore the subsite-specific gastric cancer risks associated with H. pylori seropositivity (a surrogate marker for persistent exposure).A total of 99 patients with gastric cardia cancer, 82 patients with noncardia gastric cancer, and 192 cancer-free subjects were selected from among the participants (n = 29 584) of a nutrition intervention trial previously conducted in Linxian, China. H. pylori seropositivity was determined by assaying for the presence of H. pylori whole cell and CagA antibodies in baseline serum samples from all subjects. Seropositivity was defined as one or both serum assays being positive. Odds ratios (ORs) for subsite-specific gastric cancer were estimated by multivariate logistic regression analyses. All statistical comparisons were two-sided (alpha =.05).H. pylori seropositivity rates for subjects with gastric cardia cancer, noncardia gastric cancer, and gastric cardia and noncardia cancers combined were 70% (P =.02), 72% (P: =.01), and 71% (P =.003) compared with 56% for cancer-free control subjects. OR estimates for H. pylori seropositivity were 1.87 (95% confidence interval [CI] = 1.10 to 3.17) for gastric cardia cancer, 2.29 (95% CI = 1.26 to 4.14) for noncardia gastric cancer, and 2.04 (95% CI = 1.31 to 3.18) for gastric cardia and noncardia cancers combined.H. pylori seropositivity was associated with increased risks for both gastric cardia cancer and noncardia gastric cancer in this well-characterized cohort. Thus, H. pylori carriage may increase the risk of cancer throughout the stomach.
Long-term restoration of the human T-cell compartment after thymectomy during infancy: a role for thymic regeneration?
Authors: Rogier van Gent, Alvin W. L. Schadenberg, Sigrid A. Otto, Rutger A. J. Nievelstein, Gertjan T. Sieswerda, Felix Haas, Frank Miedema, Kiki Tesselaar, Nicolaas J. G. Jansen, José A. M. Borghans
Journal: Blood (2011)
Carbohydrate moieties of major histocompatibility complex class I alloantigens are not required for their recognition by T lymphocytes.
Authors: S A Goldstein, M F Mescher
Journal: The Journal of Experimental Medicine (1985)

The ability to generate specific cytotoxic responses using purified major histocompatibility complex (MHC) antigen in liposomes has made it possible to directly assess the importance of class I carbohydrate moieties in T cell recognition of alloantigen. Deglycosylation of affinity-purified H-2Kk to yield a single glycan-free product did not alter the specificity, the magnitude, nor the dose range of the cytotoxic T lymphocyte (CTL) response to the class I antigen. It can be concluded that carbohydrate moieties are not required to maintain the necessary conformation of the MHC protein, nor to interact with either the antigen-specific receptor or accessory proteins on precursor CTL.
Dermoscopic and histopathological findings of polymorphous vessels in amelanotic cutaneous metastasis of pigmented cutaneous melanoma
Authors: A. Minagawa, H. Koga, K. Sakaizawa, K. Sano, T. Saida
Journal: British Journal of Dermatology (2009)

Journal Article Dermoscopic and histopathological findings of polymorphous vessels in amelanotic cutaneous metastasis of pigmented cutaneous melanoma Get access A. Minagawa, A. Minagawa Department of Dermatology, Shinshu University School of Medicine, 3‐1‐1 Asahi, Matsumoto, Nagano 390‐8621, Japan *Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan E‐mail: akn@shinshu‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar H. Koga, H. Koga Department of Dermatology, Shinshu University School of Medicine, 3‐1‐1 Asahi, Matsumoto, Nagano 390‐8621, Japan *Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan E‐mail: akn@shinshu‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar K. Sakaizawa, K. Sakaizawa Department of Dermatology, Shinshu University School of Medicine, 3‐1‐1 Asahi, Matsumoto, Nagano 390‐8621, Japan *Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan E‐mail: akn@shinshu‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar K. Sano, K. Sano Department of Dermatology, Shinshu University School of Medicine, 3‐1‐1 Asahi, Matsumoto, Nagano 390‐8621, Japan *Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan E‐mail: akn@shinshu‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar T. Saida T. Saida Department of Dermatology, Shinshu University School of Medicine, 3‐1‐1 Asahi, Matsumoto, Nagano 390‐8621, Japan *Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan E‐mail: akn@shinshu‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 160, Issue 5, 1 May 2009, Pages 1134–1136, https://doi.org/10.1111/j.1365-2133.2009.09103.x Published: 01 May 2009
Axin downregulates TCF-4 transcription via β-catenin, but not p53, and inhibits the proliferation and invasion of lung cancer cells
Authors: Lian-He Yang, Hong-Tao Xu, Yang Han, Qing-Chang Li, Yang Liu, Yue Zhao, Zhi-Qiang Yang, Qian-Ze Dong, Yuan Miao, Shun-Dong Dai, En-Hua Wang
Journal: Molecular Cancer (2010)

We previously reported that overexpression of Axin downregulates T cell factor-4 (TCF-4) transcription. However, the mechanism(s) by which Axin downregulates the transcription and expression of TCF-4 is not clear. It has been reported that beta-catenin promotes and p53 inhibits TCF-4 transcription, respectively. The aim of this study was to investigate whether beta-catenin and/or p53 is required for Axin-mediated downregulation of TCF-4.Axin mutants that lack p53/HIPK2 and/or beta-catenin binding domains were expressed in lung cancer cells, BE1 (mutant p53) and A549 (wild type p53). Expression of Axin or AxinDeltap53 downregulates beta-catenin and TCF-4, and knock-down of beta-catenin upregulates TCF-4 in BE1 cells. However, expression of AxinDeltabeta-ca into BE1 cells did not downregulate TCF-4 expression. These results indicate that Axin downregulates TCF-4 transcription via beta-catenin. Although overexpression of wild-type p53 also downregulates TCF-4 in BE1 cells, cotransfection of p53 and AxinDeltabeta-ca did not downregulate TCF-4 further. These results suggest that Axin does not promote p53-mediated downregulation of TCF-4. Axin, AxinDeltap53, and AxinDeltabeta-ca all downregulated beta-catenin and TCF-4 in A549 cells. Knock-down of p53 upregulated beta-catenin and TCF-4, but cotransfection of AxinDeltabeta-ca and p53 siRNA resulted in downregulation of beta-catenin and TCF-4. These results indicate that p53 is not required for Axin-mediated downregulation of TCF-4. Knock-down or inhibition of GSK-3beta prevented Axin-mediated downregulation of TCF-4. Furthermore, expression of Axin and AxinDeltap53, prevented the proliferative and invasive ability of BE1 and A549, expression of AxinDeltabeta-ca could only prevented the proliferative and invasive ability effectively.Axin downregulates TCF-4 transcription via beta-catenin and independently of p53. Axin may also inhibits the proliferation and invasion of lung cancer cells via beta-catenin and p53.
Estimating the Rate of Adaptive Molecular Evolution in the Presence of Slightly Deleterious Mutations and Population Size Change
Authors: A. Eyre-Walker, P. D. Keightley
Journal: Molecular Biology and Evolution (2009)

The prevalence of adaptive evolution relative to genetic drift is a central problem in molecular evolution. Methods to estimate the fraction of adaptive nucleotide substitutions (α) have been developed, based on the McDonald–Kreitman test, that contrast polymorphism and divergence between selectively and neutrally evolving sites. However, these methods are expected to give downwardly biased estimates of α if there are slightly deleterious mutations, because these inflate polymorphism relative to divergence. Here, we estimate α by simultaneously estimating the distribution of fitness effects of new mutations at selected sites from the site frequency spectrum and the number of adaptive substitutions. We test the method using simulations. If data meet the assumptions of the analysis model, estimates of α show little bias, even when there is little or no recombination. However, population size differences between the divergence and polymorphism phases may cause α to be over or underestimated by a predictable factor that depends on the magnitude of the population size change and the shape of the distribution of effects of deleterious mutations. We analyze several data sets of protein-coding genes and noncoding regions from hominids and Drosophila. In Drosophila genes, we estimate that approximately 50% of amino acid substitutions and approximately 20% of substitutions in introns are adaptive. In protein-coding and noncoding data sets of humans, comparison to macaque sequences reveals little evidence for adaptive substitutions. However, the true frequency of adaptive substitutions in human-coding DNA could be as high as 40%, because estimates based on current polymorphism may be strongly downwardly biased by a decrease in the effective population size along the human lineage.