Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies

Background: Bevacizumab is frequently combined with 5-fluorouracil-based chemotherapy for patients with metastatic colorectal cancer (mCRC). The relative benefit of bevacizumab in older patients has not been widely studied and is of interest. Patients and methods: This retrospective analysis used data from three first-line randomized controlled studies and one second-line randomized controlled study of bevacizumab plus chemotherapy in medically fit (Eastern Cooperative Oncology Group performance status 0 or 1) patients with mCRC. Overall survival (OS) and on-treatment progression-free survival (PFS) were assessed in patients aged greater than 65, greater than or equal to 65, and greater than or equal to 70 years. Results were compared using unstratified hazard ratios (HRs). Grade 3-5 adverse events were also assessed. Results: Bevacizumab statistically significantly improved PFS [HR 0.58; 95% confidence interval (CI) 0.49-0.68] and OS (HR 0.85; 95% CI 0.74-0.97) in patients aged greater than or equal to 65 years; patients aged greater than or equal to 70 years had similar improvements. Benefits were consistent across the studies, irrespective of setting, bevacizumab dose, or chemotherapy regimen. Increases in thromboembolic events were observed in patients aged greater than or equal to 65 and greater than or equal to 70 years in the bevacizumab group compared with the control group, mainly as a result of increases in arterial thromboembolic events. No other substantial age-related increases in grade 3-5 adverse events were observed. Conclusions: In medically fit older patients, bevacizumab provides similar PFS and OS benefits as in younger patients

Identification of the protein kinases Pyk3 and Phg2 as regulators of the STATc-mediated response to hyperosmolarity

Cellular adaptation to changes in environmental osmolarity is crucial for cell survival. In Dictyostelium, STATc is a key regulator of the transcriptional response to hyperosmotic stress. Its phosphorylation and consequent activation is controlled by two signaling branches, one cGMP- and the other Ca(2+)-dependent, of which many signaling components have yet to be identified. The STATc stress signalling pathway feeds back on itself by upregulating the expression of STATc and STATc-regulated genes. Based on microarray studies we chose two tyrosine-kinase like proteins, Pyk3 and Phg2, as possible modulators of STATc phosphorylation and generated single and double knock-out mutants to them. Transcriptional regulation of STATc and STATc dependent genes was disturbed in pyk3(-), phg2(-), and pyk3(-)/phg2(-) cells. The absence of Pyk3 and/or Phg2 resulted in diminished or completely abolished increased transcription of STATc dependent genes in response to sorbitol, 8-Br-cGMP and the Ca(2+) liberator BHQ. Also, phospho-STATc levels were significantly reduced in pyk3(-) and phg2(-) cells and even further decreased in pyk3(-)/phg2(-) cells. The reduced phosphorylation was mirrored by a significant delay in nuclear translocation of GFP-STATc. The protein tyrosine phosphatase 3 (PTP3), which dephosphorylates and inhibits STATc, is inhibited by stress-induced phosphorylation on S448 and S747. Use of phosphoserine specific antibodies showed that Phg2 but not Pyk3 is involved in the phosphorylation of PTP3 on S747. In pull-down assays Phg2 and PTP3 interact directly, suggesting that Phg2 phosphorylates PTP3 on S747 in vivo. Phosphorylation of S448 was unchanged in phg2(-) cells. We show that Phg2 and an, as yet unknown, S448 protein kinase are responsible for PTP3 phosphorylation and hence its inhibition, and that Pyk3 is involved in the regulation of STATc by either directly or indirectly activating it. Our results add further complexities to the regulation of STATc, which presumably ensure its optimal activation in response to different environmental cues

Expression of CXCL10 is associated with response to radiotherapy and overall survival in squamous cell carcinoma of the tongue

Five-year survival for patients with oral cancer has been disappointingly stable during the last decades, creating a demand for new biomarkers and treatment targets. Lately, much focus has been set on immunomodulation as a possible treatment or an adjuvant increasing sensitivity to conventional treatments. The objective of this study was to evaluate the prognostic importance of response to radiotherapy in tongue carcinoma patients as well as the expression of the CXC-chemokines in correlation to radiation response in the same group of tumours. Thirty-eight patients with tongue carcinoma that had received radiotherapy followed by surgery were included. The prognostic impact of pathological response to radiotherapy, N-status, T-stage, age and gender was evaluated using Cox's regression models, Kaplan-Meier survival curves and chi-square test. The expression of 23 CXC-chemokine ligands and their receptors were evaluated in all patients using microarray and qPCR and correlated with response to treatment using logistic regression. Pathological response to radiotherapy was independently associated to overall survival with a 2-year survival probability of 81 % for patients showing a complete pathological response, while patients with a non-complete response only had a probability of 42 % to survive for 2 years (p = 0.016). The expression of one CXC-chemokine, CXCL10, was significantly associated with response to radiotherapy and the group of patients with the highest CXCL10 expression responded, especially poorly (p = 0.01). CXCL10 is a potential marker for response to radiotherapy and overall survival in patients with squamous cell carcinoma of the tongue

Creatinine clearance versus serum creatinine as a risk factor in cardiac surgery

BACKGROUND: Renal impairment is one of the predictors of mortality in cardiac surgery. Usually a binarized value of serum creatinine is used to assess the renal function in risk models. Creatinine clearance can be easily estimated by the Cockcroft and Gault equation from serum creatinine, gender, age and body weight. In this work we examine whether this estimation of the glomerular filtration rate can advantageously replace the serum creatinine in the EuroSCORE preoperative risk assessment. METHODS: In a group of 8138 patients out of a total of 11878 patients, who underwent cardiac surgery in our hospital between January 1996 and July 2002, the 18 standard EuroSCORE parameters could retrospectively be determined and logistic regression analysis performed. In all patients scored, creatinine clearance was calculated according to Cockcroft and Gault. The relationship between the predicted and observed 30-days mortality was evaluated in systematically selected intervals of creatinine clearance and significance values computed by employing Monte Carlo methods. Afterwards, risk scoring was performed using a continuous or a categorical value of creatinine clearance instead of serum creatinine. The predictive ability of several risk score models and the individual contribution of their predictor variables were studied using ROC curve analysis. RESULTS: The comparison between the expected and observed 30-days mortalities, which were determined in different intervals of creatinine clearance, revealed the best threshold value of 55 ml/min. A significantly higher 30-days mortality was observed below this threshold and vice versa (both with p < 0.001). The local adaptation of the EuroSCORE is better than the standard EuroSCORE and was further improved by replacing serum creatinine (SC) by creatinine clearance (CC). Differential ROC analysis revealed that CC is superior to SC in providing predictive power within the logistic regression. Variable rank comparison identified CC as the best single variable predictor, even better than the variable age, former number 1, and SC, previously number 9 in the standard set of EuroSCORE variables. CONCLUSION: The renal function is an important determinant of mortality in heart surgery. This risk factor is not well captured in the standard EuroSCORE risk evaluation system. Our study shows that creatinine clearance, calculated according to the Cockcroft and Gault equation, should be applied to estimate the preoperative renal function instead of serum creatinine. This predictor variable replacement gains a significant improvement in the predictive accuracy of the scoring model

Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders

Personality is influenced by genetic and environmental factors1 and associated with mental health. However, the underlying genetic determinants are largely unknown. We identified six genetic loci, including five novel loci2,3, significantly associated with personality traits in a meta-analysis of genome-wide association studies (N = 123,132–260,861). Of these genomewide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N = 5,422–18,759). The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit– hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. The second genetic dimension was closely aligned with extraversion–introversion and grouped neuroticism with internalizing psychopathology (e.g., depression or anxiety)

Решение оптимизационных задач для систем массового обслуживання с отказами в условиях неопределенности

Построены математические модели расчета показателей качества функционирования вычислительных сетей, которые можно представить в виде сетей массового обслуживания с отказами. Сформулированы задачи оптимизации показателей качества функционирования таких сетей при заданных ограничениях на максимальную пропускную способность каналов связи и на выделяемые для модернизации сети ресурсы. Построены алгоритмы, которые позволяют решать поставленные оптимизационные задачи в рамках оговоренных ограничений

Improved Measurement of the Pseudoscalar Decay Constant fDsf_{D_{s}}

We present a new determination of the Ds decay constant, f_{Ds} using 5 million continuum charm events obtained with the CLEO II detector. Our value is derived from our new measured ratio of widths for Ds -> mu nu/Ds -> phi pi of 0.173+/- 0.021 +/- 0.031. Taking the branching ratio for Ds -> phi pi as (3.6 +/- 0.9)% from the PDG, we extract f_{Ds} = (280 +/- 17 +/- 25 +/- 34){MeV}. We compare this result with various model calculations.Comment: 23 page postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN

First Observation of τ→3πηντ\tau\to 3\pi\eta\nu_{\tau} and τ→f1πντ\tau\to f_{1}\pi\nu_{\tau} Decays

We have observed new channels for $\tau$ decays with an $\eta$ in the final state. We study 3-prong tau decays, using the $\eta\to\gamma\gamma$ and \eta\to 3\piz decay modes and 1-prong decays with two \piz's using the $\eta\to\gamma\gamma$ channel. The measured branching fractions are \B(\tau^{-}\to \pi^{-}\pi^{-}\pi^{+}\eta\nu_{\tau}) =(3.4^{+0.6}_{-0.5}\pm0.6)\times10^{-4} and \B(\tau^{-}\to \pi^{-}2\piz\eta\nu_{\tau} =(1.4\pm0.6\pm0.3)\times10^{-4}. We observe clear evidence for $f_1\to\eta\pi\pi$ substructure and measure \B(\tau^{-}\to f_1\pi^{-}\nu_{\tau})=(5.8^{+1.4}_{-1.3}\pm1.8)\times10^{-4}. We have also searched for $\eta'(958)$ production and obtain 90% CL upper limits \B(\tau^{-}\to \pi^{-}\eta'\nu_\tau)<7.4\times10^{-5} and \B(\tau^{-}\to \pi^{-}\piz\eta'\nu_\tau)<8.0\times10^{-5}.Comment: 11 page postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN

Search for the Decays B^0 -> D^{(*)+} D^{(*)-}

Using the CLEO-II data set we have searched for the Cabibbo-suppressed decays B^0 -> D^{(*)+} D^{(*)-}. For the decay B^0 -> D^{*+} D^{*-}, we observe one candidate signal event, with an expected background of 0.022 +/- 0.011 events. This yield corresponds to a branching fraction of Br(B^0 -> D^{*+} D^{*-}) = (5.3^{+7.1}_{-3.7}(stat) +/- 1.0(syst)) x 10^{-4} and an upper limit of Br(B^0 -> D^{*+} D^{*-}) D^{*\pm} D^\mp and B^0 -> D^+ D^-, no significant excess of signal above the expected background level is seen, and we calculate the 90% CL upper limits on the branching fractions to be Br(B^0 -> D^{*\pm} D^\mp) D^+ D^-) < 1.2 x 10^{-3}.Comment: 12 page postscript file also available through http://w4.lns.cornell.edu/public/CLNS, submitted to Physical Review Letter