tbuckley/cabot-search huggingface dataset:
P276-00, a cyclin-dependent kinase inhibitor, modulates cell cycle and induces apoptosis in vitro and in vivo in mantle cell lymphoma cell lines
Authors: Nitesh P Shirsath, Sonal M Manohar, Kalpana S Joshi
Journal: Molecular Cancer (2012)

Abstract Background Mantle cell lymphoma (MCL) is a well-defined aggressive lymphoid neoplasm characterized by proliferation of mature B-lymphocytes that have a remarkable tendency to disseminate. This tumor is considered as one of the most aggressive lymphoid neoplasms with poor responses to conventional chemotherapy and relatively short survival. Since cyclin D1 and cell cycle control appears as a natural target, small-molecule inhibitors of cyclin-dependent kinases (Cdks) and cyclins may play important role in the therapy of this disorder. We explored P276-00, a novel selective potent Cdk4-D1, Cdk1-B and Cdk9-T1 inhibitor discovered by us against MCL and elucidated its potential mechanism of action. Methods The cytotoxic effect of P276-00 in three human MCL cell lines was evaluated in vitro . The effect of P276-00 on the regulation of cell cycle, apoptosis and transcription was assessed, which are implied in the pathogenesis of MCL. Flow cytometry, western blot, immunoflourescence and siRNA studies were performed. The in vivo efficacy and effect on survival of P276-00 was evaluated in a Jeko-1 xenograft model developed in SCID mice. PK/PD analysis of tumors were performed using LC-MS and western blot analysis. Results P276-00 showed a potent cytotoxic effect against MCL cell lines. Mechanistic studies confirmed down regulation of cell cycle regulatory proteins with apoptosis. P276-00 causes time and dose dependent increase in the sub G1 population as early as from 24 h. Reverse transcription PCR studies provide evidence that P276-00 treatment down regulated transcription of antiapoptotic protein Mcl-1 which is a potential pathogenic protein for MCL. Most importantly, in vivo studies have revealed significant efficacy as a single agent with increased survival period compared to vehicle treated. Further, preliminary combination studies of P276-00 with doxorubicin and bortezomib showed in vitro synergism. Conclusion Our studies thus provide evidence and rational that P276-00 alone or in combination is a potential therapeutic molecule to improve patients’ outcome in mantle cell lymphoma.
Multicenter Phase II Trial of Temozolomide in Mycosis Fungoides/Sézary Syndrome: Correlation with <i>O</i>6-Methylguanine-DNA Methyltransferase and Mismatch Repair Proteins
Authors: Christiane Querfeld, Steven T. Rosen, Joan Guitart, Alfred Rademaker, David S. Pezen, M. Eileen Dolan, Joseph Baron, Daniel B. Yarosh, Francine Foss, Timothy M. Kuzel
Journal: Clinical Cancer Research (2011)

Temozolomide (TMZ) is an oral derivative of dacarbazine that induces DNA damage by methylating nucleotide bases. Resistance has been associated with high levels of O⁶-methylguanine-DNA methyltransferase (MGMT). Malignant CD4(+) T cells of patients with mycosis fungoides/Sézary syndrome (MF/SS) have been shown to have low levels of MGMT and may be particularly sensitive to this methylator.The efficacy of TMZ was evaluated in a multicenter phase II trial of patients with advanced stages of MF/SS. TMZ was given orally at daily doses of 200 mg/m² for 5 days every 28 days. MGMT and mismatch repair protein expression was assessed by quantitative immunofluorescence and immunohistochemistry in skin and blood samples.Twenty-six patients (stages IB-IVB) were evaluable for response. Patients had a median of four prior treatments. Median follow-up time was 19 months (range, 1-95). The overall response was 27% with two complete remissions (8%) and five partial remissions (19%). Median disease-free survival was 4 months. The median overall survival was 24 months. The most frequent toxicities included constitutional symptoms, gastrointestinal symptoms, and hematologic toxicities. Treatment was discontinued in three patients following grade 3 thrombocytopenia, lymphopenia, and skin reaction. The relationship between pretreatment MGMT and mutL homolog 1 (MLH1)/mutS homolog 2 (MSH2) mismatch repair protein expression levels in skin biopsies of cutaneous lesions and clinical response to TMZ were evaluated.Pretreatment levels of MGMT and MLH1/MSH2 protein levels are not predictive of response to TMZ in MF/SS, suggesting that other resistance mechanisms are important.
Points: ABC of poisoning: salicylates
Authors: T R O Beringer, H Taggart
Journal: BMJ (1984)

<h3>Introduction</h3> Pneumococcal conjugate vaccines (PCVs) prevent disease through both direct protection of vaccinated individuals and indirect protection of unvaccinated individuals by reducing nasopharyngeal (NP) carriage and transmission of vaccine-type (VT) pneumococci. While the indirect effects of PCV vaccination are well described, the PCV coverage required to achieve the indirect effects is unknown. We will investigate the relationship between PCV coverage and VT carriage among undervaccinated children using hospital-based NP pneumococcal carriage surveillance at three sites in Asia and the Pacific. <h3>Methods and analysis</h3> We are recruiting cases, defined as children aged 2–59 months admitted to participating hospitals with acute respiratory infection in Lao People’s Democratic Republic, Mongolia and Papua New Guinea. Thirteen-valent PCV status is obtained from written records. NP swabs are collected according to standard methods, screened using <i>lytA</i> qPCR and serotyped by microarray. Village-level vaccination coverage, for the resident communities of the recruited cases, is determined using administrative data or community survey. Our analysis will investigate the relationship between VT carriage among undervaccinated cases (indirect effects) and vaccine coverage using generalised estimating equations. <h3>Ethics and dissemination</h3> Ethical approval has been obtained from the relevant ethics committees at participating sites. The results are intended for publication in open-access peer-reviewed journals and will demonstrate methods suitable for low- and middle-income countries to monitor vaccine impact and inform vaccine policy makers about the PCV coverage required to achieve indirect protection.
Risk of Cardiovascular and All-Cause Mortality in Individuals With Diabetes Mellitus, Impaired Fasting Glucose, and Impaired Glucose Tolerance
Authors: Elizabeth L.M. Barr, Paul Z. Zimmet, Timothy A. Welborn, Damien Jolley, Dianna J. Magliano, David W. Dunstan, Adrian J. Cameron, Terry Dwyer, Hugh R. Taylor, Andrew M. Tonkin, Tien Y. Wong, John McNeil, Jonathan E. Shaw
Journal: Circulation (2007)

Background— Diabetes mellitus increases the risk of cardiovascular disease (CVD) and all-cause mortality. The relationship between milder elevations of blood glucose and mortality is less clear. This study investigated whether impaired fasting glucose and impaired glucose tolerance, as well as diabetes mellitus, increase the risk of all-cause and CVD mortality. Methods and Results— In 1999 to 2000, glucose tolerance status was determined in 10 428 participants of the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). After a median follow-up of 5.2 years, 298 deaths occurred (88 CVD deaths). Compared with those with normal glucose tolerance, the adjusted all-cause mortality hazard ratios (HRs) and 95% confidence intervals (CIs) for known diabetes mellitus and newly diagnosed diabetes mellitus were 2.3 (1.6 to 3.2) and 1.3 (0.9 to 2.0), respectively. The risk of death was also increased in those with impaired fasting glucose (HR 1.6, 95% CI 1.0 to 2.4) and impaired glucose tolerance (HR 1.5, 95% CI 1.1 to 2.0). Sixty-five percent of all those who died of CVD had known diabetes mellitus, newly diagnosed diabetes mellitus, impaired fasting glucose, or impaired glucose tolerance at baseline. Known diabetes mellitus (HR 2.6, 95% CI 1.4 to 4.7) and impaired fasting glucose (HR 2.5, 95% CI 1.2 to 5.1) were independent predictors for CVD mortality after adjustment for age, sex, and other traditional CVD risk factors, but impaired glucose tolerance was not (HR 1.2, 95% CI 0.7 to 2.2). Conclusions— This study emphasizes the strong association between abnormal glucose metabolism and mortality, and it suggests that this condition contributes to a large number of CVD deaths in the general population. CVD prevention may be warranted in people with all categories of abnormal glucose metabolism.
Identification of CDK2 substrates in human cell lysates
Authors: Yong Chi, Markus Welcker, Asli A Hizli, Jeffrey J Posakony, Ruedi Aebersold, Bruce E Clurman
Journal: Genome biology (2008)

Abstract Background Protein phosphorylation regulates a multitude of biological processes. However, the large number of protein kinases and their substrates generates an enormously complex phosphoproteome. The cyclin-dependent kinases - the CDKs - comprise a class of enzymes that regulate cell cycle progression and play important roles in tumorigenesis. However, despite intense study, only a limited number of mammalian CDK substrates are known. A comprehensive understanding of CDK function requires the identification of their substrate network. Results We describe a simple and efficient approach to identify potential cyclin A-CDK2 targets in complex cell lysates. Using a kinase engineering strategy combined with chemical enrichment and mass spectrometry, we identified 180 potential cyclin A-CDK2 substrates and more than 200 phosphorylation sites. About 10% of these candidates function within pathways related to cell division, and the vast majority are involved in other fundamental cellular processes. We have validated several candidates as direct cyclin A-CDK2 substrates that are phosphorylated on the same sites that we identified by mass spectrometry, and we also found that one novel substrate, the ribosomal protein RL12, exhibits site-specific CDK2-dependent phosphorylation in vivo . Conclusions We used methods entailing engineered kinases and thiophosphate enrichment to identify a large number of candidate CDK2 substrates in cell lysates. These results are consistent with other recent proteomic studies, and suggest that CDKs regulate cell division via large networks of cellular substrates. These methods are general and can be easily adapted to identify direct substrates of many other protein kinases.
The Netherlands: regulated competition behind the dykes?
Authors: G. P Westert, J. S Burgers, H. Verkleij
Journal: BMJ (2009)

<h3>BACKGROUND:</h3> A low serum vitamin D level may represent a marker of other perplexing factors that may lead to increased asthma prevalence and severity. Our aim was to assess the correlation between vitamin D levels and asthma and allergy markers in a subgroup of children with fewer confounding factors. <h3>METHODS:</h3> Non-obese children (6–18 y old) with asthma who were not receiving anti-inflammatory treatment were recruited. Subjects underwent spirometry with a methacholine challenge test, and fractional exhaled nitric oxide (F<sub>ENO</sub>), serum vitamin D levels, total immunoglobulin E (IgE) levels, blood eosinophil counts, and high-sensitivity C-reactive protein levels were determined. The primary end point was the correlation between vitamin D level and airway hyper-responsiveness as assessed by a methacholine challenge test. The secondary end point was the correlation between vitamin D level and F<sub>ENO</sub>, systemic inflammatory markers, and allergy. <h3>RESULTS:</h3> Seventy-one children with asthma (25 females, 35%; 12.5 ± 3.6 y of age) were included. The median vitamin D level was 23 ng/mL (range of 6 – 48.5, mean of 23.02 ± 7.74), the median IgE level was 305 IU/mL (range of 4.3–4,240), the median provocational concentration of methacholine that produced a 20% decrease in FEV<sub>1</sub> was 1.1 mg/mL (range of 0–13.9), and the median F<sub>ENO</sub> was 26.5 ppb (range of 3.6–285). No correlation was found between vitamin D level and response to the methacholine challenge test, F<sub>ENO</sub>, high-sensitivity C-reactive protein levels, IgE levels, eosinophil counts, and frequency of allergic rhinitis or atopic dermatitis. <h3>CONCLUSIONS:</h3> In our group of children with asthma, no correlation was found between the level of vitamin D and the degree of airway reactivity, airway inflammation, and allergy. The cause-and-effect relationship between vitamin D, asthma, and allergy should be further clarified.
RGS17, an Overexpressed Gene in Human Lung and Prostate Cancer, Induces Tumor Cell Proliferation Through the Cyclic AMP-PKA-CREB Pathway
Authors: Michael A. James, Yan Lu, Yan Liu, Haris G. Vikis, Ming You
Journal: Cancer Research (2009)

We have identified RGS17 as a commonly induced gene in lung and prostate tumors. Through microarray and gene expression analysis, we show that expression of RGS17 is up-regulated in 80% of lung tumors, and also up-regulated in prostate tumors. Through knockdown and overexpression of RGS17 in tumor cells, we show that RGS17 confers a proliferative phenotype and is required for the maintenance of the proliferative potential of tumor cells. We show through exon microarray, transcript analysis, and functional assays that RGS17 promotes cyclic AMP (cAMP)-responsive element binding protein (CREB)-responsive gene expression, increases cAMP levels, and enhances forskolin-mediated cAMP production. Furthermore, inhibition of cAMP-dependent kinase prevents tumor cell proliferation, and proliferation is partially rescued by RGS17 overexpression. In the present study, we show a role for RGS17 in the maintenance of tumor cell proliferation through induction of cAMP signaling and CREB phosphorylation. The prevalence of the induction of RGS17 in tumor tissues of various types further implicates its importance in the maintenance of tumor growth.
ACTION OF X-RAYS ON MAMMALIAN CELLS
Authors: Theodore T. Puck, Philip I. Marcus
Journal: The Journal of Experimental Medicine (1956)

The effects of x-irradiation have been quantitatively studied on single cells of a human cervical carcinoma (HeLa) under conditions such that 100 per cent of the unirradiated cells reproduce in isolation to form macroscopic colonies. This technique eliminates complexities due to interactions of members of large cell populations. Survival of single cells (defined as the ability to form a macroscopic colony within 15 days) yields a typical 2 hit curve when plotted against x-ray dose. The initial shoulder extends to about 75 r, after which a linear logarithmic survival rate is obtained, in which the dose needed to reduce survivors to 37 per cent is 96 r. This radiation sensitivity is tens to hundreds of times greater than that of any microorganism for which the equivalent function bas been studied. Evidence, though not proof, is presented that the lethal effect is due to a radiation-induced genetic defect which, however, cannot be a simple single gene inactivation. The locus of the action could be chromosomal. Beginning at doses of 100 r, or possibly earlier, growth-delaying effects of radiation are visible. Cells in which the ability to reproduce has been destroyed by doses below 800 r, can still multiply several times. At higher doses even a single cell division is precluded. A large proportion of the cells killed by radiation at any dose gives rise to one or more giant cells. These metabolize actively, grow to huge proportions but never reproduce under the experimental conditions employed. Methods of preparing large populations of giant cells are described. These giants are particularly susceptible to virus action. Some of the irradiated cells disappear from the plate, presumably by disintegration. This action of radiation is by far the least efficient, since even after 10,000 r, 5 to 10 per cent of the original cell inoculum is recoverable as giants.
Effect of Intra-arterial Insulin on Tissue Cholesterol and Fatty Acids in Alloxan-Diabetic Dogs
Authors: ANATOLIO B. CRUZ, DONALD S. AMATUZIO, FRANCISCO GRANDE, LYLE J. HAY
Journal: Circulation Research (1961)

Insulin and saline were injected into the right and left femoral arteries respectively of 19 alloxan-diabetes-mellitus dogs for 1 to 28 weeks. A significant increase of artery tissue cholesterol and total fatty acids was found on comparing the insulin-administered right leg with the saline-administered left leg. Similarly, a significant increase of total fatty acids in muscle was found on comparing the right with the left leg of the alloxan-diabetes mellitus dogs. No significant differences were observed in the normal animals when the insulin-injected side was compared with the noninjected.
Associations of diabetes mellitus with site-specific cancer mortality in the Asia-Pacific region
Authors: E.K.K. Lam, G.D. Batty, R.R. Huxley, A.L.C. Martiniuk, F. Barzi, T.H. Lam, C.M.M. Lawes, G.G. Giles, T. Welborn, H. Ueshima, A. Tamakoshi, J. Woo, H.C. Kim, X. Fang, S. Czernichow, M. Woodward
Journal: Annals of Oncology (2010)
Disuniting Uniformity: A Pied Cladistic Canvas of mtDNA Haplogroup H in Eurasia
Authors: Eva-Liis Loogväli, Urmas Roostalu, Boris A. Malyarchuk, Miroslava V. Derenko, Toomas Kivisild, Ene Metspalu, Kristiina Tambets, Maere Reidla, Helle-Viivi Tolk, Jüri Parik, Erwan Pennarun, Sirle Laos, Arina Lunkina, Maria Golubenko, Lovorka Barać, Marijana Peričić, Oleg P. Balanovsky, Vladislava Gusar, Elsa K. Khusnutdinova, Vadim Stepanov, Valery Puzyrev, Pavao Rudan, Elena V. Balanovska, Elena Grechanina, Christelle Richard, Jean-Paul Moisan, André Chaventré, Nicholas P. Anagnou, Kalliopi I. Pappa, Emmanuel N. Michalodimitrakis, Mireille Claustres, Mukaddes Gölge, Ilia Mikerezi, Esien Usanga, Richard Villems
Journal: Molecular Biology and Evolution (2004)

It has been often stated that the overall pattern of human maternal lineages in Europe is largely uniform. Yet this uniformity may also result from an insufficient depth and width of the phylogenetic analysis, in particular of the predominant western Eurasian haplogroup (Hg) H that comprises nearly a half of the European mitochondrial DNA (mtDNA) pool. Making use of the coding sequence information from 267 mtDNA Hg H sequences, we have analyzed 830 mtDNA genomes, from 11 European, Near and Middle Eastern, Central Asian, and Altaian populations. In addition to the seven previously specified subhaplogroups, we define fifteen novel subclades of Hg H present in the extant human populations of western Eurasia. The refinement of the phylogenetic resolution has allowed us to resolve a large number of homoplasies in phylogenetic trees of Hg H based on the first hypervariable segment (HVS-I) of mtDNA. As many as 50 out of 125 polymorphic positions in HVS-I were found to be mutated in more than one subcluster of Hg H. The phylogeographic analysis revealed that sub-Hgs H1*, H1b, H1f, H2a, H3, H6a, H6b, and H8 demonstrate distinct phylogeographic patterns. The monophyletic subhaplogroups of Hg H provide means for further progress in the understanding of the (pre)historic movements of women in Eurasia and for the understanding of the present-day genetic diversity of western Eurasians in general.
Toll-like Receptor Polymorphisms in Infants With Likely Milk/Egg Allergy: Consortium for Food Allergy Research (CoFAR)
Authors: A.H. Liu, S.H. Sicherer, A.M. Schiltz, A. Henning, D. Stablein, R.A. Wood, A.W. Burks, S.M. Jones, D.M. Fleischer, D.Y.M. Leung, W.G. Shreffler, R. Lindblad, L. Mayer, H.A. Sampson
Journal: Journal of Allergy and Clinical Immunology (2010)
G protein-coupled receptor kinase 6 controls chronicity and severity of dextran sodium sulphate-induced colitis in mice
Authors: N. Eijkelkamp, C. J Heijnen, A. Lucas, R. T Premont, S. Elsenbruch, M. Schedlowski, A. Kavelaars
Journal: Gut (2007)

Infiltration of inflammatory cells into the colon plays an important role in the onset and course of inflammatory bowel disease. G-protein-coupled receptor kinase 6 (GRK6) is an intracellular kinase that regulates the sensitivity of certain G-protein-coupled receptors, including those involved in the migration of inflammatory cells. Therefore, it is hypothesised that GRK6 plays a role in determining the course of inflammation.To analyse the role of GRK6 in the course of dextran sodium sulphate (DSS)-induced colitis.Colitis was induced by administering 1% DSS in drinking water to GRK6(-/-), GRK6(+/-) and wild-type (WT) mice for 6 days. The severity of colitis was assessed on the basis of clinical signs, colon length and histology. Moreover, keratinocyte-derived chemokine (KC) levels, granulocyte infiltration, interleukin 1beta (IL1beta), CD4, CD8 and forkhead box protein P3 (FoxP3) expression in the colon were determined. In addition, regulatory T cell function in WT and GRK6(-/-) mice was analysed. The chemotactic response of granulocytes to colon culture supernatants was assessed using a transendothelial migration assay.The severity of colitis was increased in GRK6(-/-) and GRK6(+/-) mice and was accompanied by increased KC levels and increased granulocyte infiltration. Moreover, the chemotactic response of GRK6(-/-) granulocytes to supernatants of colon cultures was enhanced. Interestingly, the WT mice completely recovered from colitis, whereas the GRK6(-/-) and GRK6(+/-) mice developed chronic colitis, which was accompanied by increased IL1beta and CD4 expression and decreased FoxP3 expression. Moreover, regulatory T cell function was impaired in the GRK6(-/-) mice.The intracellular level of GRK6 is an important factor in determining the onset, severity and chronicity of DSS-induced colitis.
HLA-DR antigens and HLA-DQ beta chain polymorphism in susceptibility to rheumatoid arthritis.
Authors: J Ilonen, H Reijonen, H Arvilommi, I Jokinen, T Mottonen, P Hannonen
Journal: Annals of the Rheumatic Diseases (1990)

Forty four patients with rheumatoid arthritis (RA) were studied for HLA-DR antigens and for HLA-DQ beta chain gene restriction fragment length polymorphism using DNA hybridisation. A significant increase in the prevalence of the DR4 antigen and a tendency towards an increase of DR1 was found in patients with RA. No allelic form of HLA-DQ restriction fragment length polymorphism patterns was increased, but the prevalence of an allele characterised by a combination of 7.5 and 3 kb fragments was decreased among patients with RA. The DQw8 subtype represented by a 12 kb fragment was the most common DR4 associated allele, and a 3.7 kb fragment related to DQw7 was found in only 5/25 (20%) DR4 positive patients and 2/12 (17%) controls. The results support the hypothesis that RA susceptibility factors are primarily located within HLA-DR genes but HLA-DQ genes may have a role in protection from the disease.
CD4+ T-cell clones specific for wild-type factor VIII: a molecular mechanism responsible for a higher incidence of inhibitor formation in mild/moderate hemophilia A
Authors: Marc Jacquemin, Valérie Vantomme, Cécile Buhot, Renaud Lavend'homme, Wivine Burny, Nathalie Demotte, Pascal Chaux, Kathelijne Peerlinck, Jos Vermylen, Bernard Maillere, Pierre van der Bruggen, Jean-Marie Saint-Remy
Journal: Blood (2003)