Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths

Microarray profiling reveals the integrated stress response is activated by halofuginone in mammary epithelial cells

<p>Abstract</p> <p>Background</p> <p>The small molecule Halofuginone (HF) is a potent regulator of extracellular matrix (ECM ) gene expression and is unique in its therapeutic potential. While the basis for HF effects is unknown, inhibition of TGFβ signaling and activation of the amino acid restriction response (AAR) have been linked to HF transcriptional control of a number of ECM components and amelioration of fibrosis and alleviation of autoimmune disease by regulation of Th17 cell differentiation, respectively. The aim of this study was to generate a global expression profile of HF targets in epithelial cells to identify potential mediators of HF function in this cell type.</p> <p>Results</p> <p>We report that HF modulation of the expression of the ECM remodeling protein Mmp13 in epithelial cells is separable from previously reported effects of HF on TGFβ signal inhibition, and use microarray expression analysis to correlate this with transcriptional responses characteristic of the Integrated Stress Response (ISR).</p> <p>Conclusions</p> <p>Our findings suggest activation of the ISR may be a common mechanism underlying HF biological effects.</p

A study of lymph node ratio in stage IV colorectal cancer

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: The finding of metastasis in colorectal cancer, stage IV disease, has a major impact on prognosis and treatment strategy. Known important factors include the extent of the metastasis and the patients &apos; performance status. The lymph node factors are of known importance in earlier cancer stages but less described in metastatic disease. The aim of the study was to evaluate lymph node status and ratio as prognostic markers in stage IV colorectal cancer. Methods: The study was retrospective and assessing all patients operated, with bowel resection, for an initial stage IV colorectal cancer during 1999–2003 (n = 136). Basic demographic data as well as given treatment was assessed. The Lymph node ratio (LNR), the quota between the number of lymph node metastasis and assessed lymph nodes, was calculated. LNR groups were created by ratio thirds, 3 equally sized groups. The analysis was made by LNR group and by eligibility for chemotherapy with cancer specific survival as outcome parameter. Results: The median survival (CSS) for the entire group was 431 days with great variability. For the patients eligible for chemotherapy it ranged from 791 days in LNR-group 1 to 433 days for th

The Atacama Cosmology Telescope: Extragalactic Sources at 148 GHz in the 2008 Survey

We report on extragalactic sources detected in a 455 square-degree map of the southern sky made with data at a frequency of 148 GHz from the Atacama Cosmology Telescope 2008 observing season. We provide a catalog of 157 sources with flux densities spanning two orders of magnitude: from 15 to 1500 mJy. Comparison to other catalogs shows that 98% of the ACT detections correspond to sources detected at lower radio frequencies. Three of the sources appear to be associated with the brightest cluster galaxies of low redshift X-ray selected galaxy clusters. Estimates of the radio to mm-wave spectral indices and differential counts of the sources further bolster the hypothesis that they are nearly all radio sources, and that their emission is not dominated by re-emission from warm dust. In a bright (>50 mJy) 148 GHz-selected sample with complete cross-identifications from the Australia Telescope 20 GHz survey, we observe an average steepening of the spectra between 5, 20, and 148 GHz with median spectral indices of $\alpha_{\rm 5-20} = -0.07 \pm 0.06$, $\alpha_{\rm 20-148} = -0.39 \pm0.04$, and $\alpha_{\rm 5-148} = -0.20 \pm 0.03$. When the measured spectral indices are taken into account, the 148 GHz differential source counts are consistent with previous measurements at 30 GHz in the context of a source count model dominated by radio sources. Extrapolating with an appropriately rescaled model for the radio source counts, the Poisson contribution to the spatial power spectrum from synchrotron-dominated sources with flux density less than 20 mJy is C^{\rm Sync} = (2.8 \pm 0.3) \times 10^{-6} \micro\kelvin^2.Comment: Accepted to Ap

Comprehensive Study in the Inhibitory Effect of Berberine on Gene Transcription, Including TATA Box

Berberine (BBR) is an established natural DNA intercalator with numerous pharmacological functions. However, currently there are neither detailed reports concerning the distribution of this alkaloid in living cells nor reports concerning the relationship between BBR's association with DNA and the function of DNA. Here we report that the distribution of BBR within the nucleus can be observed 30 minutes after drug administration, and that the content of berberine in the nucleus peaks at around 4 µmol, which is twelve hours after drug administration. The spatial conformation of DNA and chromatin was altered immediately after their association with BBR. Moreover, this association can effectively suppress the transcription of DNA in living cell systems and cell-free systems. Electrophoretic mobility shift assays (EMSA) demonstrated further that BBR can inhibit the association between the TATA binding protein (TBP) and the TATA box in the promoter, and this finding was also attained in living cells by chromatin immunoprecipitation (ChIP). Based on results from this study, we hypothesize that berberine can suppress the transcription of DNA in living cell systems, especially suppressing the association between TBP and the TATA box by binding with DNA and, thus, inhibiting TATA box-dependent gene expression in a non-specific way. This novel study has significantly expanded the sphere of knowledge concerning berberine's pharmacological effects, beginning at its paramount initial interaction with the TATA box

Introgression of Chromosome 3Ns from Psathyrostachys huashanica into Wheat Specifying Resistance to Stripe Rust

Wheat stripe rust is a destructive disease in the cool and humid wheat-growing areas of the world. Finding diverse sources of stripe rust resistance is critical for increasing genetic diversity of resistance for wheat breeding programs. Stripe rust resistance was identified in the alien species Psathyrostachys huashanica, and a wheat- P. huashanica amphiploid line (PHW-SA) with stripe rust resistance was reported previously. In this study, a P. huashanica 3Ns monosomic addition line (PW11) with superior resistance to stripe rust was developed, which was derived from the cross between PHW-SA and wheat J-11. We evaluated the alien introgressions PW11-2, PW11-5 and PW11-8 which were derived from line PW11 for reaction to new Pst race CYR32, and used molecular and cytogenetic tools to characterize these lines. The introgressions were remarkably resistant to CYR32, suggesting that the resistance to stripe rust of the introgressions thus was controlled by gene(s) located on P. huashanica chromosome 3Ns. All derived lines were cytologically stable in term of meiotic chromosome behavior. Two 3Ns chromosomes of P. huashanica were detected in the disomic addition line PW11-2. Chromosomes 1B of substitution line PW11-5 had been replaced by a pair of P. huashanica 3Ns chromosomes. In PW11-8, a small terminal segment from P. huashanica chromosome arm 3NsS was translocated to the terminal region of wheat chromosomes 3BL. Thus, this translocated chromosome is designated T3BL-3NsS. These conclusions were further confirmed by SSR analyses. Two 3Ns-specific markers Xgwm181 and Xgwm161 will be useful to rapidly identify and trace the translocated fragments. These introgressions, which had significant characteristics of resistance to stripe rust, could be utilized as novel germplasms for wheat breeding

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Correlation of microarray-based breast cancer molecular subtypes and clinical outcomes: implications for treatment optimization

<p>Abstract</p> <p>Background</p> <p>Optimizing treatment through microarray-based molecular subtyping is a promising method to address the problem of heterogeneity in breast cancer; however, current application is restricted to prediction of distant recurrence risk. This study investigated whether breast cancer molecular subtyping according to its global intrinsic biology could be used for treatment customization.</p> <p>Methods</p> <p>Gene expression profiling was conducted on fresh frozen breast cancer tissue collected from 327 patients in conjunction with thoroughly documented clinical data. A method of molecular subtyping based on 783 probe-sets was established and validated. Statistical analysis was performed to correlate molecular subtypes with survival outcome and adjuvant chemotherapy regimens. Heterogeneity of molecular subtypes within groups sharing the same distant recurrence risk predicted by genes of the Oncotype and MammaPrint predictors was studied.</p> <p>Results</p> <p>We identified six molecular subtypes of breast cancer demonstrating distinctive molecular and clinical characteristics. These six subtypes showed similarities and significant differences from the Perou-Sørlie intrinsic types. Subtype I breast cancer was in concordance with chemosensitive basal-like intrinsic type. Adjuvant chemotherapy of lower intensity with CMF yielded survival outcome similar to those of CAF in this subtype. Subtype IV breast cancer was positive for ER with a full-range expression of HER2, responding poorly to CMF; however, this subtype showed excellent survival when treated with CAF. Reduced expression of a gene associated with methotrexate sensitivity in subtype IV was the likely reason for poor response to methotrexate. All subtype V breast cancer was positive for ER and had excellent long-term survival with hormonal therapy alone following surgery and/or radiation therapy. Adjuvant chemotherapy did not provide any survival benefit in early stages of subtype V patients. Subtype V was consistent with a unique subset of luminal A intrinsic type. When molecular subtypes were correlated with recurrence risk predicted by genes of Oncotype and MammaPrint predictors, a significant degree of heterogeneity within the same risk group was noted. This heterogeneity was distributed over several subtypes, suggesting that patients in the same risk groups require different treatment approaches.</p> <p>Conclusions</p> <p>Our results indicate that the molecular subtypes established in this study can be utilized for customization of breast cancer treatment.</p