Abstract Objectives Circulating chronic lymphocytic leukemia (CLL) cells appear not to be overly utilizing aerobic glycolysis. However, recurrent contact with CLL cells in a stromal microenvironment ...leads to increased aerobic glycolysis and the cells’ overall glycolytic capacity, which promotes cell survival and proliferation. TP53-induced glycolysis and apoptosis regulator(TIGAR) has been directly implicated in cellular metabolism in the control of glycolysis. TIGAR inhibits glycolysis and protects cells from intracellular reactive oxygen species (ROS)-associated apoptosis. Methods TIGAR mRNA expression was investigated by quantitative PCR in 102 newly diagnosed CLL patients. Furthermore, the relationship between the expression of TIGAR and its clinical characteristics and prognosis were investigated. Moreover, we also investigated the correlation between TIGAR expression and apoptosis in primary CLL cells. Results Our data revealed that TIGAR overexpression was correlated with the protection from spontaneous apoptosis in CLL cells, and is strongly associated with advanced Binet stage, unmutated immunoglobulin heavy-chain variable region ( IGHV ) status, CD38 positivity, β2-microglobulin and p53 aberrations. Higher expression of TIGAR was associated with shorter treatment-free survival (median: three months vs . 51 months, P = 0.0108), worse overall survival (median: 74 months vs . not reached, P = 0.0242), and the diverse responses to fludarabine-based chemotherapy. TIGAR expression in patients resistant to chemotherapy was significantly higher than in patients sensitive to chemotherapy (mean: 0.3859 ± 0.1710 vs. 0.0974 ± 0.0291, P = 0.0290). Conclusion Taken together, our findings revealed that high TIGAR expression is closely correlated with worse clinical outcome in CLL patients, and depicted how bioenergetic characteristics could be therapeutically exploited in CLL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
DNA screening for LDL receptor mutations was performed in 170 unrelated hyperlipidemic Chinese patients and two clinically diagnosed familial hypercholesterolemia patients. Two deletions (Del e3-5 ...and Del e6-8), eight point mutations (W-18X, D69N, R94H, E207K, C308Y, I402T, A410T, and A696G), and two polymorphisms (A370T and I602V) were identified. Of these mutations, C308Y and Del e6-8 were found in homozygosity, and D69N and C308Y were seen in unrelated patients. The effects of mutations on LDL receptor function were characterized in COS-7 cells. The LDL receptor level and activity were close to those of wild type in A696G transfected cells. A novel intermediate protein and reduction of LDL receptor activity were seen in D69N transfected cells. For R94H, E207K, C308Y, I402T, and A410T mutations, only approximately 20-64% of normal receptor activities were seen. Conversely, Del e3-5 and Del e6-8 lead to defective proteins with approximately 0-13% activity. Most of the mutant receptors were localized intracellularly, with a staining pattern resembling that of the endoplasmic reticulum and Golgi apparatus (D69N, R94H, E207K, C308Y, and I402T) or endosome/lysosome (A410T and Del e6-8). Molecular analysis of the LDL receptor gene will clearly identify the cause of the patient's hyperlipidemia and allow appropriate early treatment as well as antenatal and family studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The purpose of this study was to compare the safety and efficacy of cetirizine plus pseudoephedrine (C+P) with loratadine plus pseudoephedrine (L+P) in the treatment of perennial allergic rhinitis. ...This was a double blind, randomized, parallel trial with an active control. Subjects aged 12 to 70 years with perennial allergic rhinitis for at least 2 years were enrolled and randomized to receive either of the active study medications plus a placebo resembling the other, twice daily for 4 weeks. Nasal total symptom scale (NTSS) including sneezing, rhinorrhea, nasal itching and nasal stuffiness is evaluated by subjects daily and at baseline, 2 weeks, and 4 weeks by the investigator as efficacy measurement. A total of 51 eligible patients were enrolled and 45 patients completed the treatment course. Both groups had significant reductions in NTSS after 4 weeks of treatment as assessed by the subjects, but there was no significant difference between the two groups (mean +/- SD) reduction of 4.25 +/- 2.45 with C+P vs. 3.52 +/- 2.41 with L+P, p = 0.215. As assessed by the investigator, sneezing was significantly better at 2 weeks (-1.13 vs. -0.52, p = 0.028) and nasal congestion at 4 weeks (-1.71 vs. -1.19, p = 0.031) in subjects treated with C+P compared to those treated with L+P. There were 37 treatment-related adverse events (5 in 4 subjects in the C+P group and 32 in 16 subjects in the L+P group). It was concluded that both cetirizine plus pseudoephedrine and loratadine plus pseudoephedrine are efficacious for perennial allergic rhinitis in Taiwanese subjects. Relief of sneezing and nasal congestion may be marginally better with the cetirizine preparation, which also seemed to be slightly better tolerated, although the incidence of side effects did not differ significantly.
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FFLJ, NUK, ODKLJ, UL, UM, UPUK
We summarize and combine direct measurements of the mass of the \(W\) boson in \(\sqrt{s} = 1.96 \text{TeV}\) proton-antiproton collision data collected by CDF and D0 experiments at the Fermilab ...Tevatron Collider. Earlier measurements from CDF and D0 are combined with the two latest, more precise measurements: a CDF measurement in the electron and muon channels using data corresponding to \(2.2 \mathrm{fb}^{-1}\) of integrated luminosity, and a D0 measurement in the electron channel using data corresponding to \(4.3 \mathrm{fb}^{-1}\) of integrated luminosity. The resulting Tevatron average for the mass of the \(W\) boson is \(\MW = 80\,387 \pm 16 \text{MeV}\). Including measurements obtained in electron-positron collisions at LEP yields the most precise value of \(\MW = 80\,385 \pm 15 \text{MeV}\).
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