5-alpha-reductase: 2013

2013年6月28日星期五

Comparison of abluminal biodegradable polymer biolimus-eluting stents and durable polymer everolimus-eluting stents in the treatment of coronary bifurcations.

Comparison of abluminal biodegradable polymer biolimus-eluting stents and durable polymer everolimus-eluting stents in the treatment of coronary bifurcations.

Catheter Cardiovasc Interv. 2013 Jun 27;

Authors: Costopoulos C, Latib A, Naganuma T, Sticchi A, Ferrarello S, Regazzoli D, Chieffo A, Figini F, Carlino M, Montorfano M, Naim C, Kawaguchi M, Gerasimou A, Giannini F, Godino C, Colombo A

Abstract
OBJECTIVES: To compare biodegradable polymer biolimus-eluting (BES) with abluminal drug elution and durable polymer everolimus-eluting (EES) stents in the treatment of bifurcation lesions.
BACKGROUND: The persistence of a polymer in drug-eluting stents (DES) following drug elution has been viewed as a possible culprit for restenosis. DES with biodegradable polymer may thus be associated with improved clinical outcomes, especially in high-risk lesions such as those at bifurcation sites.
METHODS: We performed a retrospective study of consecutive de novo bifurcation lesions treated with EES between October 2006-October 2011 and BES between February 2008-March 2012. Study endpoints included major adverse cardiac events (MACE) defined as all cause-death, myocardial infarction (MI), including peri-procedural MI, and target vessel revascularization (TVR) as well as target lesion revascularization separately (TLR).
RESULTS: We analyzed 236 bifurcation lesions treated with either BES (79 lesions in 69 patients) or EES (157 lesions in 154 patients). Patient and procedural characteristics were broadly similar between the two groups. Estimated MACE and TVR rates at 2-year follow-up were similar between the BES and EES groups (MACE=13.6 � 4.6% vs. 14.6 � 3.2% (p=0.871); TVR=6.9 � 3.5% vs. 8.0 � 2.7% (p=0.889). No significant differences were noted between the two groups following propensity-score matched analysis. There was no probable or definite stent thrombosis.
CONCLUSION: BES use in the treatment of bifurcation lesions appears to be associated with good clinical outcomes, comparable to those seen with EES, at long-term follow-up. These results are hypothesis-generating and need to be validated with larger studies. � 2013 Wiley Periodicals, Inc.

PMID: 23804318 [PubMed - as supplied by publisher]

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Preserving Flow in Liver Transplant Recipients: mTOR Inhibitors Everolimus and Sirolimus Are Not Peas From a Pod.

Preserving Flow in Liver Transplant Recipients: mTOR Inhibitors Everolimus and Sirolimus Are Not Peas From a Pod.

Am J Transplant. 2013 Jul;13(7):1633-1635

Authors: Bhat M, Charlton M

PMID: 23802724 [PubMed - as supplied by publisher]

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Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer.

Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer.

Lung Cancer. 2013 Jan;79(1):33-9

Authors: Yang JJ, Chen HJ, Yan HH, Zhang XC, Zhou Q, Su J, Wang Z, Xu CR, Huang YS, Wang BC, Yang XN, Zhong WZ, Nie Q, Liao RQ, Jiang BY, Dong S, Wu YL

Abstract
BACKGROUND: There is no published overview of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) failure modes in advanced non-small-cell lung cancer (NSCLC). This study aimed to classify the diversity of EGFR-TKI failure, and to investigate the usefulness of clinical modes in subsequent management and prognosis.
METHODS: One-hundred and twenty consecutive clinical trial patients with EGFR-TKI failure were enrolled as the training set to establish a clinical model based on clinical factors. Another 107 routine patients were enrolled as the validating set according to a Bayes discriminant analysis. EGFR mutations and c-MET amplification were analyzed. Kaplan-Meier survival analysis was used to test the differences among three clinical modes and subsequent management.
RESULTS: The duration of disease control, evolution of tumor burden, and clinical symptom were verified as feasible grouping variables. A correct grouping rate achieved 87.9%. The cohort was classified into three groups, as follows: 130 patients with dramatic progression, 42 with gradual progression, and 55 with local progression. Progression-free survivals (PFSs) for the dramatic progression, gradual progression, and local progression groups were 9.3, 12.9, and 9.2 months, respectively (P = 0.007). Overall survivals for the groups (OSs) were 17.1, 39.4, and 23.1 months, respectively (P < 0.001). TKI continuation was superior to switching chemotherapy in a subsequent setting for gradual progression (39.4 months vs. 17.8 months; P = 0.02). The difference of EGFR or c-MET among the three groups was not significant.
CONCLUSIONS: Clinical modes of EGFR-TKI failure could favor strategies for subsequent treatment and predicting a survival benefit in advanced NSCLC.

PMID: 23079155 [PubMed - indexed for MEDLINE]

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Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer.

Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer.

Lung Cancer. 2013 Jan;79(1):33-9

Authors: Yang JJ, Chen HJ, Yan HH, Zhang XC, Zhou Q, Su J, Wang Z, Xu CR, Huang YS, Wang BC, Yang XN, Zhong WZ, Nie Q, Liao RQ, Jiang BY, Dong S, Wu YL

PMID: 23079155 [PubMed - indexed for MEDLINE]

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2013年6月27日星期四

Aspirin antagonizes the cytotoxic effect of methotrexate in lung cancer cells.

Aspirin antagonizes the cytotoxic effect of methotrexate in lung cancer cells.

Oncol Rep. 2013 Jun 21;

Authors: Yan KH, Lee LM, Hsieh MC, Yan MD, Yao CJ, Chang PY, Chen TL, Chang HY, Cheng AL, Lai GM, Chuang SE

Abstract
Methotrexate (MTX) has been widely used for the treatment of cancer and rheumatoid arthritis (RA). Aspirin (ASA) is a non-selective cyclooxygenase (COX) inhibitor that contributes to the treatment of inflammatory conditions such as RA. It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression, induction of apoptosis and inhibition of angiogenesis. In the present study, we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by SRB and colony formation assays. ASA alleviated the MTX-mediated S�phase accumulation and recovered the G1�phase. MTX-mediated accumulation of the S�phase marker cyclin�A was also alleviated by ASA. Notably, FAS protein levels were upregulated by MTX in A549 cells. The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase-3, Bcl-2 and FAS but not dihydrofolate reductase (DHFR). This suggests that the alteration of caspase-3, Bcl-2 and FAS was involved in the antagonism between ASA and MTX. Exogenously added folic acid reversed the MTX-mediated DHFR inhibition following either MTX or MTX�+�ASA treatments. Most importantly, we demonstrated for the first time that the commonly used non-steroidal anti-inflammatory drug for headache ASA and possibly other COX-1/2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX. The clinical implication of our finding is obvious, i.e., the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should be avoided.

PMID: 23799623 [PubMed - as supplied by publisher]

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Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Gynecol Endocrinol. 2013 Jun 14;

Authors: Gadducci A, Sergiampietri C, Guiggi I

Abstract
Abstract The limited efficacy of endocrine therapy and chemotherapy has stimulated several researches aimed to detect novel molecularly target therapies for advanced, persistent or recurrent endometrial cancer. Prior attempts to block vascular endothelial growth factor (VEGF) with sunitinib, sorafenib and thalidomide have obtained disappointing results. Bevacizumab has shown a promising activity in a phase II study. The percentages of patients with progression-free survival ?6 months were similar for endometrioid (35%) and serous carcinoma (36%), but the number of cases was too small to assess the relevance of histological type for response to bevacizumab. In a phase II study, aflibercept was administered every 2 weeks to women with recurrent or persistent disease after chemotherapy. Forty-one percent of the patients were progression-free at 6 months, but 32% of the women had been removed from study because of toxicity. The detection of activating mutations of Fibroblast Growth Factor Receptor (FGFR)-2 in primary endometrial carcinoma has generated a new avenue for the development of molecularly target agents. Dovitinib, a tyrosine kinase inhibitor targeting both VEGF receptor (VEGFR) and FGFRs, is under clinical investigation in different malignancies including endometrial cancer.

PMID: 23767831 [PubMed - as supplied by publisher]

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Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Gynecol Endocrinol. 2013 Jun 14;

Authors: Gadducci A, Sergiampietri C, Guiggi I

PMID: 23767831 [PubMed - as supplied by publisher]

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Conserved microRNAs miR-8-5p and miR-2a-3p modulate chitin biosynthesis in response to 20-hydroxyecdysone signaling in the brown planthopper, Nilaparvata lugens.

Conserved microRNAs miR-8-5p and miR-2a-3p modulate chitin biosynthesis in response to 20-hydroxyecdysone signaling in the brown planthopper, Nilaparvata lugens.

Insect Biochem Mol Biol. 2013 Jun 21;

Authors: Chen J, Liang Z, Liang Y, Pang R, Zhang W

Abstract
Molting is an important developmental process in insects, usually along with synthesis and degradation of chitin. 20-hydroxyecdysone (20E), an insect hormone, has been reported to contribute to many processes including molting. However, little is known about the link between the chitin biosynthesis pathway and 20E signaling. Here, we report that conserved miR-8-5p (miR-8-5p) and miR-2a-3p and their new target genes are critical for ecdysone-induced chitin biosynthesis in a hemipteran insect Nilaparvata lugens. We found that membrane-bound trehalase (Tre-2) and phosphoacetylglucosamine mutase (PAGM) in the chitin biosynthesis pathway were targets of miR-8-5p and miR-2a-3p, respectively, through bioinformatic analysis and experimental verification. The levels of miR-8-5p and miR-2a-3p were reduced, whereas the levels of Tre-2 and PAGM were up-regulated in response to 20E. In addition, miR-8-5p and miR-2a-3p were transcriptionally repressed by an early-response gene, the Broad-Complex (BR-C), in the 20E signaling pathway. Moreover, the overexpression of miR-8-5p and miR-2a-3p led to a significant reduction in the survival rate along with a molting obstacles defect phenotype caused by miR-2a-3p mimics feeding, and the chitin content of N. lugens was simultaneously reduced. Thus, miR-8-5p and miR-2a-3p act as molecular link that tune the chitin biosynthesis pathway in response to 20E signaling.

PMID: 23796434 [PubMed - as supplied by publisher]

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Rechallenge with mTOR Inhibitors in Metastatic Renal Cell Carcinoma Patients Who Progressed on Previous mTOR Inhibitor Therapy.

Rechallenge with mTOR Inhibitors in Metastatic Renal Cell Carcinoma Patients Who Progressed on Previous mTOR Inhibitor Therapy.

Oncology. 2013 Jun 21;85(1):8-13

Authors: Maj-Hes A, Medioni J, Scotte F, Schmidinger M, Kramer G, Combe P, Gornadha Y, Elaidi R, Oudard S

Abstract
Objective: To determine if mammalian target of rapamycin (mTOR) inhibitor (everolimus or temsirolimus) rechallenge in the third- or fourth-line setting after sequential use of a vascular endothelial growth factor receptor (VEGF)-targeted agent and an mTOR inhibitor is a feasible and effective treatment strategy in patients with metastatic renal cell carcinoma (mRCC). Methods: Patients who received a VEGF-targeted agent, an mTOR inhibitor and rechallenge with a second mTOR inhibitor at 2 institutions (H�pital Europ�en Georges-Pompidou and Vienna Medical School) between 30 March 2001 and 15 September 2011 were included. Analyses of radiographic images were performed according to the Response Evaluation Criteria in Solid Tumors, version 1.0, to determine the objective response rate and treatment duration (TD). Results: Twelve patients met the inclusion criteria. Following 1 or 2 VEGF receptor-tyrosine kinase inhibitors, 7 patients firstly received everolimus and 5 patients received temsirolimus. Irrespective of treatment sequence, 6 of 12 patients (50%) responded to everolimus and 4 of 12 patients (33%) responded to temsirolimus; 3 patients (25%) did not respond to either. Median TDs (95% confidence interval) for everolimus ? temsirolimus and temsirolimus ? everolimus sequences were 10.3 months (8.8-19.2 months) and 5.8 months (2.9-19.3 months), respectively. Conclusions: Despite the limited number of patients, this highlights the feasibility of utilizing mTOR rechallenge as an integral part of sequential treatment strategies in mRCC.

PMID: 23797151 [PubMed - as supplied by publisher]

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2013年6月26日星期三

Effect of cardiovascular drug classes on all-cause mortality among atrial fibrillation patients treated in primary care in Sweden: a cohort study.

Effect of cardiovascular drug classes on all-cause mortality among atrial fibrillation patients treated in primary care in Sweden: a cohort study.

Eur J Clin Pharmacol. 2013 Feb;69(2):279-87

Authors: W�ndell P, Carlsson AC, Sundquist K, Johansson SE, Sundquist J

Abstract
BACKGROUND: Risk factors for stroke are well known in atrial fibrillation (AF) patients, while less is known on the effect of these factors on total mortality.
OBJECTIVE: Our aim was to study the impact of cardiovascular drug classes on mortality in AF patients treated in primary care.
METHODS: The study population was chosen based on patient data from 75 primary care centres in Sweden compiled in a database. Individuals diagnosed with AF who were older than 45 years were enrolled (n?=?12,302, of whom 6,660 were men). Cox regression analysis with mortality (years to death) as outcome was conducted in the men and women separately, as well in the age categories <80 and ? 80 years, with cardiovascular drugs as independent factors, and age, cardiovascular diagnoses and educational level as covariates.
RESULTS: Lower mortality was shown for anticoagulant treatment among men, both younger (<80 years) [adjusted hazard ratio (HR) 0.43, 95 % confidence interval (CI) 0.31-0.61] and older (? 80 years) (adjusted HR 0.47, 95 % CI 0.32-0.69), and among younger women (adjusted HR 0.46, 95 % CI 0.29-0.74), and for antiplatelet treatment in older men (adjusted HR 0.51, 95 % CI 0.35-0.74). Treatment with thiazides was associated with lower mortality among younger men (adjusted HR 0.68, 95 % CI 0.48-0.96), older men (adjusted HR 0.67, 95 % CI 0.46-0.98) and older women (adjusted HR 0.70, 95 % CI 0.52-0.94). Statins were associated with lower mortality among younger patients, in both men (adjusted HR 0.47, 95 % CI 0.32-0.68) and women (adjusted HR 0.54, 95 % CI 0.35-0.82).
CONCLUSIONS: The differences in age and gender patterns need further exploration.

PMID: 22990327 [PubMed - indexed for MEDLINE]

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[Pharmacodynamic and pharmacokinetic evaluation of respiratory fluoroquinolones. Guideline to selection of the most appropriate fluoroquinolone].

[Pharmacodynamic and pharmacokinetic evaluation of respiratory fluoroquinolones. Guideline to selection of the most appropriate fluoroquinolone].

Rev Esp Quimioter. 2012 Dec;25(4):245-51

Authors: Parra-Ruiz J, Hern�ndez-Quero J

Abstract
Since its approval, fluoroquinolones have become one of the most prescribed antibacterial agents. Because of its widespread use, serious concerns about the emergence of resistance in Streptococcus pneumoniae, Pseudomonas spp, and entrobacteriaceae, has arisen, especially because of cross-resistance between fluoroquinolones. Huge efforts has been done to identify pharmacokinetic (PK) parameters like maximum serum concentration (Cmax), area under the curve of serum concentrations (AUC) and pharmacodynamic (PD) parameters like the minimum inhibitory concentration (MIC) or the mutant prevention concentration (MPC), to optimize the use of the new fluoroquinolones, especially against these difficult to treat microorganisms. The new fluoroquinolones commercially available in Spain, levofloxacin and moxifloxacin, have significant differences in their PK (Cmax, half-life, volume of distribution, etc), PD (MIC, MPC,) and in their PK/PD parameters (AUC/MIC; AUC/MPC) that allow clinicians to establish clear preference for the utilization of one of them. Proper use of these new fluoroquinolones according to these PK/PD parameters will result in better management of respiratory infections with a reduction in the emergence of resistance. Based on data reviewed in this paper moxifloxacin use, with best PK/PD characteristics, should be preferred over levofloxacin. Should levofloxacin be used, alternative dosing strategies would be recommended to avoid selection of resistant variants.

PMID: 23303254 [PubMed - indexed for MEDLINE]

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Conserved microRNAs miR-8-5p and miR-2a-3p modulate chitin biosynthesis in response to 20-hydroxyecdysone signaling in the brown planthopper, Nilaparvata lugens.

Conserved microRNAs miR-8-5p and miR-2a-3p modulate chitin biosynthesis in response to 20-hydroxyecdysone signaling in the brown planthopper, Nilaparvata lugens.

Insect Biochem Mol Biol. 2013 Jun 21;

Authors: Chen J, Liang Z, Liang Y, Pang R, Zhang W

PMID: 23796434 [PubMed - as supplied by publisher]

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Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

J Transl Med. 2012;10:245

Authors: Chen ZY, Shi M, Peng LX, Wei W, Li XJ, Guo ZX, Li SH, Zhong C, Qian CN, Guo RP

Abstract
BACKGROUND: Dovitinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptor ?. Dovitinib is currently in clinical trials for the treatment of hepatocellular carcinoma (HCC).
METHOD: In this study, we used five HCC cell lines and five endothelial cell lines to validate molecular and cellular targets of dovitinib.
RESULTS: Tumor growth and pulmonary metastasis were significantly suppressed in an orthotopic HCC model. Immunoblotting revealed that among known dovitinib targets, only PDGFR-? was expressed in two HCC cell lines, while four of five endothelial lines expressed PDGFR-?, FGFR-1, and VEGFR-2. Dovitinib inhibited endothelial cell proliferation and motility at 0.04 ?mol/L, a pharmacologically relevant concentration; it was unable to inhibit the proliferation or motility of HCC cells at the same concentration. Immunohistochemical analyses showed that dovitinib significantly decreased the microvessel density of xenograft tumors, inhibiting proliferation and inducing apoptosis in HCC cells.
CONCLUSION: Our findings indicate that dovitinib inhibits HCC growth and metastasis preferentially through an antiangiogenic mechanism, not through direct targeting of HCC cells.

PMID: 23228017 [PubMed - indexed for MEDLINE]

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Celecoxib enhances the efficacy of 15-hydroxyprostaglandin dehydrogenase gene therapy in treating murine breast cancer.

Celecoxib enhances the efficacy of 15-hydroxyprostaglandin dehydrogenase gene therapy in treating murine breast cancer.

J Cancer Res Clin Oncol. 2013 May;139(5):797-807

Authors: Zhang B, Ma X, Li Z, Gao X, Wang F, Liu L, Shen G, Sang Y, Li M, Li Y, Zhao J, Wei Y

Abstract
PURPOSE: The overexpression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has been proved to inhibit tumor growth and metastasis through degradation of prostaglandin E2 (PGE2), which is often overexpressed in various cancers and accelerates tumor progression. Cyclooxygenase-2 (COX-2), a synthase of PGE2, actively produces much PGE2 to counteract the 15-PGDH-induced antitumor efficacy. Here, we investigated the combinational effect by using pcDNA3.1(+) encoding mouse 15-PGDH gene therapy and celecoxib, a COX-2 inhibitor, in mouse breast cancers.
METHODS: Mice bearing 4T1 were treated with short-term administration of the COX-2 inhibitor celecoxib (40 mg/kg/day) plus liposome-encapsulated mouse 15-PGDH in order to determine their synergistic antitumor activity in vivo. And the possible mechanisms were investigated.
RESULTS: We observed that the combination treatment of 15-PGDH and celecoxib significantly inhibited tumor growth and lung metastases than monotherapy or controls. Moreover, the effect of combination treatment was associated with significant reduction of PGE2 in serum, which resulted from increased 15-PDGH and decreased COX-2 in tumor tissues. The tumor tissues in combination treatment presented more apoptotic cells and less microvessel density. Notably, the number of myeloid-derived suppressor cells in the spleen was also significantly decreased in the combination treatment than others.
CONCLUSIONS: Our findings suggested that celecoxib increased the antitumor activity of 15-PGDH by synergistically blocking PGE2 pathway, which might be a new feasible way for cancer therapy.

PMID: 23385883 [PubMed - indexed for MEDLINE]

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2013年6月25日星期二

Cancer cell resistance to aurora kinase inhibitors: identification of novel targets for cancer therapy.

Cancer cell resistance to aurora kinase inhibitors: identification of novel targets for cancer therapy.

J Proteome Res. 2013 Jan 4;12(1):455-69

Authors: Hrabakova R, Kollareddy M, Tyleckova J, Halada P, Hajduch M, Gadher SJ, Kovarova H

Abstract
Drug resistance is the major obstacle to successful cancer therapy. Our study focuses on resistance to Aurora kinase inhibitors tested as anti-cancer drugs in clinical trials. We have used 2D electrophoresis in the pH ranges of 4-7 and 6-11 followed by protein identification using MALDI-TOF/TOF to compare the protein composition of HCT116 colon cancer cells either sensitive to CYC116 and ZM447439 inhibitors or resistant toward these drugs. The analysis also included p53(+/+) and p53(-/-) phenotypes of HCT116 cells. Our findings demonstrate that platelet-activating factor acetylhydrolase and GTP-binding nuclear protein Ran contribute to the development of resistance to ZM447439 only where resistance is related to p53. On the other hand, serine hydroxymethyltransferase was found to promote the tumor growth in cells resistant to CYC116 without the influence of p53. Computer modeling of interaction networks highlighted a direct link of the p53-independent mechanism of resistance to CYC116 with autophagy. Importantly, serine hydroxymethyltransferase, serpin B5, and calretinin represent the target proteins that may help overcome resistance in combination therapies. In addition, serpin B5 and calretinin appear to be candidate biomarkers that may be accessible in patients for monitoring of cancer therapy with ease.

PMID: 23151231 [PubMed - indexed for MEDLINE]

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The role of Ile3434Thr XRCC7 gene polymorphism in differentiated thyroid cancer risk in an Iranian population.

The role of Ile3434Thr XRCC7 gene polymorphism in differentiated thyroid cancer risk in an Iranian population.

Iran Biomed J. 2012;16(4):218-22

Authors: Rahimi M, Fayaz S, Fard-Esfahani A, Modarressi MH, Akrami SM, Fard-Esfahani P

Abstract
BACKGROUND: The aim of this study was to understand any association between differentiated thyroid carcinoma (DTC) and Ile3434Thr XRCC7 gene polymorphism (GenBank accession number: rs7830743). DTC is the most prevalent thyroid neoplasm, which includes papillary and follicular cell carcinoma. XRCC7 gene encodes a protein that functions in non-homologous end joining DNA repair pathway. Non-synonymous polymorphisms in this gene may alter DNA repair capacity of the cell and change the risk of developing cancers.
METHODS: DTC patients (n = 173) and cancer free individuals (n = 204) were enrolled in a case-control study. The Ile3434Thr polymorphic alleles were discriminated by using amplification refractory mutation system-PCR method. The frequencies of this single nucleotide polymorphism in case and control groups were compared. Also, risk ratio for developing DTC in dichotomized genotypes was estimated by multivariate logistic regression analysis.
RESULTS: Dichotomized genotypes into those with and without the 3434Thr allele showed that this allele was associated with DTC (OR [odd ratio]: 1.89, 95% confidence interval (CI) = 1.29-2.79, P<0.001). Also, TC genotype was significantly associated with increased risk of DTC (OR: 2.42, 95% CI = 1.55-3.81, P = 0.0001) in individuals carrying this genotype.
CONCLUSION: Allele 3434Thr in XRCC7 gene might be associated with differentiated thyroid cancer risk. Further studies with larger samples are needed to verify these initial findings.

PMID: 23183621 [PubMed - indexed for MEDLINE]

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Cancer cell resistance to aurora kinase inhibitors: identification of novel targets for cancer therapy.

Cancer cell resistance to aurora kinase inhibitors: identification of novel targets for cancer therapy.

J Proteome Res. 2013 Jan 4;12(1):455-69

Authors: Hrabakova R, Kollareddy M, Tyleckova J, Halada P, Hajduch M, Gadher SJ, Kovarova H

PMID: 23151231 [PubMed - indexed for MEDLINE]

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Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist.

Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist.

Ann Oncol. 2013 Jan;24(1):14-20

Authors: Fasolo A, Sessa C, Gianni L, Broggini M

Abstract
MET is a tyrosine kinase receptor for hepatocyte growth factor (HGF), primarily expressed on epithelial cells; the activation of MET induces several biological responses relevant for the development and growth of many human cancers. Several human malignancies present altered expression of MET and this is usually associated with poor prognosis and aggressive phenotype. The majority of MET inhibitors in clinical development target directly the receptor through the use of monoclonal antibodies (MAbs) or through small molecule inhibitors of MET kinase activity; small molecule inhibitors are very potent but less specific than MAbs. MET inhibitors are of great clinical interest because of the extensive crosstalk of the HGF/MET axis with many other signaling pathways, including growth factor-dependent pathways (like PI3K/AKT/mTOR,RAS/RAF/ERK) and vascular endothelial growth factor (VEGF) axis. In preclinical studies, the treatment with MET inhibitors could prevent or reverse resistance to inhibitors of growth factor-dependent signaling; this hypothesis is currently tested in phase III trials with anti-epidermal growth factor receptor (EGFR) inhibitors in non-small-cell lung cancer (NSCLC). Based on preclinical and preliminary clinical results, a rational strategy for the clinical development of MET antagonists should include a selection of the tumors with MET overexpression, the identification of prognostic/predictive biomarkers, the evaluation of combinations with anti-VEGF compounds.

PMID: 23110808 [PubMed - indexed for MEDLINE]

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2013年6月24日星期一

Image-based high-throughput screening for inhibitors of angiogenesis.

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

Abstract
Automated multicolor fluorescence microscopy facilitates high-throughput quantitation of cellular parameters of complex, organotypic systems. In vitro co-cultured vascular cells form capillary-like networks that model facets of angiogenesis, making it an attractive alternative for anti-angiogenic drug discovery. We have adapted this angiogenesis assay system to a high-throughput format to enable automated image-based high-throughput screening of live primary human vascular cell co-cultures with chemical libraries for anti-angiogenic drug discovery. Protocols are described for setup of a fluorescence-based co-culture assay, live cell image acquisition, image analysis of morphological parameters, and screening data handling.

PMID: 23027002 [PubMed - indexed for MEDLINE]

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Cancer cell resistance to aurora kinase inhibitors: identification of novel targets for cancer therapy.

Cancer cell resistance to aurora kinase inhibitors: identification of novel targets for cancer therapy.

J Proteome Res. 2013 Jan 4;12(1):455-69

Authors: Hrabakova R, Kollareddy M, Tyleckova J, Halada P, Hajduch M, Gadher SJ, Kovarova H

PMID: 23151231 [PubMed - indexed for MEDLINE]

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Image-based high-throughput screening for inhibitors of angiogenesis.

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

PMID: 23027002 [PubMed - indexed for MEDLINE]

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G-Quadruplex DNA as a Molecular Target for Induced Synthetic Lethality in Cancer Cells.

G-Quadruplex DNA as a Molecular Target for Induced Synthetic Lethality in Cancer Cells.

J Am Chem Soc. 2013 Jun 19;

Authors: McLuckie KI, Di Antonio M, Zecchini H, Xian J, Caldas C, Krippendorff BF, Tannahill D, Lowe C, Balasubramanian S

Abstract
Synthetic lethality is a genetic concept in which cell death is induced by the combination of mutations in two sensitive genes, while mutation of either gene alone is not sufficient to affect cell survival. Synthetic lethality can be also achieved "chemically" by combination of drug-like molecules targeting distinct but cooperative pathways. Previously, we reported that the small molecule pyridostatin (PDS) stabilizes G-quadruplexes in cells and elicits a DNA damage response (DDR) by causing the formation of DNA double strand breaks (DSB). We hypothesize that cell death mediated by ligand-induced G-quadruplex stabilization could be potentiated in cells deficient in DNA damage repair genes. Here, we demonstrated that PDS acts synergistically both with NU7441, an inhibitor of the DNA-PK kinase crucial for non-homologous end joining (NHEJ) repair of DNA DSBs, and BRCA2-deficient cells that are genetically impaired in homologous recombination-mediated DSB repair (HR). G-quadruplex targeting ligands have potential as cancer therapeutic agents, acting synergistically with inhibition or mutation of the DNA damage repair machinery.

PMID: 23782415 [PubMed - as supplied by publisher]

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Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny.

Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny.

Cancer Metastasis Rev. 2012 Dec;31(3-4):807-14

Authors: Suda K, Mizuuchi H, Maehara Y, Mitsudomi T

Abstract
Lung cancers that harbor somatic activating mutations in the gene for the epidermal growth factor receptor (EGFR) depend on mutant EGFR for their proliferation and survival; therefore, lung cancer patients with EGFR mutations often dramatically respond to orally available EGFR tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is virtually inevitable, thus limiting improvement in patient outcomes. To elucidate and overcome this acquired resistance, multidisciplinary basic and clinical investigational approaches have been applied, using in vitro cell line models or samples obtained from lung cancer patients treated with EGFR-TKIs. These efforts have revealed several acquired resistance mechanisms and candidates, including EGFR secondary mutations (T790M and other rare mutations), MET amplification, PTEN downregulation, CRKL amplification, high-level HGF expression, FAS-NF?B pathway activation, epithelial-mesenchymal transition, and conversion to small cell lung cancer. Interestingly, cancer cells harbor potential destiny and ductility together in acquiring resistance to EGFR-TKIs, as shown in in vitro acquired resistance models. Molecular mechanisms of "reversible EGFR-TKI tolerance" that occur in early phase EGFR-TKI exposure have been identified in cell line models. Furthermore, others have reported molecular markers that can predict response to EGFR-TKIs in clinical settings. Deeper understanding of acquired resistance mechanisms to EGFR-TKIs, followed by the development of molecular target drugs that can overcome the resistance, might turn this fatal disease into a chronic disorder.

PMID: 22736441 [PubMed - indexed for MEDLINE]

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2013年6月23日星期日

Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Gynecol Endocrinol. 2013 Jun 14;

Authors: Gadducci A, Sergiampietri C, Guiggi I

PMID: 23767831 [PubMed - as supplied by publisher]

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Incidence and Risk of Treatment-Related Mortality with mTOR Inhibitors Everolimus and Temsirolimus in Cancer Patients: A Meta-Analysis.

Incidence and Risk of Treatment-Related Mortality with mTOR Inhibitors Everolimus and Temsirolimus in Cancer Patients: A Meta-Analysis.

PLoS One. 2013;8(6):e65166

Authors: Qi WX, Huang YJ, Yao Y, Shen Z, Min DL

Abstract
BACKGROUND: Two novel mammalian targets of rapamycin (mTOR) inhibitors everolimus and temsirolimus are now approved by regulatory agencies and have been widely investigated among various types of solid tumors, but the risk of fatal adverse events (FAEs) with these drugs is not well defined.
METHODS: We searched PubMed, EMBASE, and Cochrane library databases for relevant trials. Eligible studies included prospective phase II and III trials evaluating everolimus and temsirolimus in patients with all malignancies and data on FAEs were available. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies.
RESULTS: A total of 3322 patients with various advanced solid tumors from 12 trials were included. The overall incidence of mTOR inhibitors associated FAEs was 1.8% (95%CI: 1.3-2.5%), and the incidences of everolimus related FAEs were comparable to that of temsirolimus (1.7% versus 1.8%). Compared with the controls, the use of mTOR inhibitors was associated with an increased risk of FAEs, with a RR of 3.24 (95%CI: 1.21-8.67, p?=?0.019). On subgroup analysis, a non-statistically significant increase in the risk of FAEs was found according to different mTOR inhibitors, tumor types or controlled therapy. No evidence of publication bias was observed.
CONCLUSION: With the present evidence, the use of mTOR inhibitors seems to increase the risk of FAEs in patients with advanced solid tumors. More high quality trials are still needed to investigate this association.

PMID: 23785409 [PubMed - in process]

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Incidence and Risk of Treatment-Related Mortality with mTOR Inhibitors Everolimus and Temsirolimus in Cancer Patients: A Meta-Analysis.

Incidence and Risk of Treatment-Related Mortality with mTOR Inhibitors Everolimus and Temsirolimus in Cancer Patients: A Meta-Analysis.

PLoS One. 2013;8(6):e65166

Authors: Qi WX, Huang YJ, Yao Y, Shen Z, Min DL

PMID: 23785409 [PubMed - in process]

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Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Gynecol Endocrinol. 2013 Jun 14;

Authors: Gadducci A, Sergiampietri C, Guiggi I

PMID: 23767831 [PubMed - as supplied by publisher]

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Image-based high-throughput screening for inhibitors of angiogenesis.

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

PMID: 23027002 [PubMed - indexed for MEDLINE]

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2013年6月22日星期六

Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Gynecol Endocrinol. 2013 Jun 14;

Authors: Gadducci A, Sergiampietri C, Guiggi I

PMID: 23767831 [PubMed - as supplied by publisher]

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Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Gynecol Endocrinol. 2013 Jun 14;

Authors: Gadducci A, Sergiampietri C, Guiggi I

PMID: 23767831 [PubMed - as supplied by publisher]

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Antiretroviral activity of protease inhibitors against Toxoplasma gondii.

Antiretroviral activity of protease inhibitors against Toxoplasma gondii.

Rev Inst Med Trop Sao Paulo. 2013 Jan-Feb;55(1):65-7

Authors: Monzote L, Rodr�guez M, Alfonso Y, Cox R

Abstract
The introduction of highly active antiretroviral therapy (HAART) has caused a marked reduction in the occurrence and severity of parasitic infections, including the toxoplasmic encephalitis (TE). These changes have been attributed to the restoration of cell-mediated immunity. This study was developed to examine the activity of six antiretroviral protease inhibitors (API) on Toxoplasma gondii tachyzoites. The six API showed anti-Toxoplasma activity, with IC50 value between 1.4 and 6.6 �g/mL. Further studies at the molecular level should be performed to clarify if the use of API could be beneficial or not for AIDS patients with TE.

PMID: 23328729 [PubMed - indexed for MEDLINE]

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Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.

Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.

Circulation. 2013 Feb 5;127(5):634-40

Authors: Dans AL, Connolly SJ, Wallentin L, Yang S, Nakamya J, Brueckmann M, Ezekowitz M, Oldgren J, Eikelboom JW, Reilly PA, Yusuf S

Abstract
BACKGROUND: The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial showed that dabigatran etexilate 150 mg BID was superior and dabigatran etexilate 110 mg BID was noninferior to warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation. In this subgroup analysis, we assess the efficacy and safety of dabigatran in patients who did and did not receive concomitant antiplatelets.
METHODS AND RESULTS: All comparisons used a Cox proportional hazards model with adjustments made for risk factors for bleeding. A time-dependent analysis was performed when comparing patients with concomitant antiplatelets with those without. Of 18 113 patients, 6952 (38.4%) received concomitant aspirin or clopidogrel at some time during the study. Dabigatran etexilate 110 mg BID was noninferior to warfarin in reducing stroke and systemic embolism, whether patients received antiplatelets (hazard ratio [HR], 0.93; 95% confidence interval [95% CI], 0.70-1.25) or not (HR, 0.87; 95% CI, 0.66-1.15; interaction P=0.738). There were fewer major bleeds than warfarin in both subgroups (HR, 0.82; 95% CI, 0.67-1.00 for patients who used antiplatelets; HR, 0.79; 95% CI, 0.64-0.96 for patients who did not; interaction P=0.794). Dabigatran etexilate 150 mg BID reduced the primary outcome of stroke and systemic embolism in comparison with warfarin. This effect seemed attenuated among patients who used antiplatelets (HR, 0.80; 95% CI, 0.59-1.08) in comparison with those who did not (HR, 0.52; 95% CI, 0.38-0.72; P for interaction=0.058). Major bleeding was similar to warfarin regardless of antiplatelet use (HR, 0.93; 95% CI, 0.76-1.12 for patients who used antiplatelets; HR, 0.94; 95% CI, 0.78-1.15 for patients who did not; P for interaction=0.875). In the time-dependent analysis, concomitant use of a single antiplatelet seemed to increase the risk of major bleeding (HR, 1.60; 95% CI, 1.42-1.82). Dual antiplatelet seemed to increased this even more (HR, 2.31; 95% CI, 1.79-2.98). The absolute risks were lowest on dabigatran etexilate 110 mg BID in comparison with dabigatran etexilate 150 mg BID or warfarin.
CONCLUSIONS: Concomitant antiplatelet drugs appeared to increase the risk for major bleeding in RE-LY without affecting the advantages of dabigatran over warfarin. Choosing between dabigatran etexilate 110 mg BID and dabigatran etexilate 150 mg BID requires a careful assessment of characteristics that influence the balance between benefit and harm.
CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00262600.

PMID: 23271794 [PubMed - indexed for MEDLINE]

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2013年6月21日星期五

Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection.

Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection.

J Clin Oncol. 2013 Apr 20;31(12):1514-21

Authors: Tsan YT, Lee CH, Ho WC, Lin MH, Wang JD, Chen PC

Abstract
PURPOSE: Statins may have protective effects against cancer, but no studies have focused on their effects in patients with chronic hepatitis C virus (HCV) infection. The purpose of this study was to investigate the association between use of statins and risk of hepatocellular carcinoma (HCC) in HCV-infected patients.
PATIENTS AND METHODS: Ours was a population-based cohort study of 260,864 HCV-infected patients enrolled in the Taiwan National Health Insurance Research Database since January 1, 1999, and observed through December 31, 2010. Cox proportional hazards regression with time-dependent covariates for drug exposures was employed to evaluate the association between statin use and HCC risk.
RESULTS: There were 27,883 cases of HCC in the HCV cohort during a follow-up period of 2,792,016.6 person-years. Among the 35,023 patients using statins (defined as ? 28 cumulative defined daily doses [cDDDs]), 1,378 had HCC. Among the 225,841 patients not using statins (< 28 cDDDs), 26,505 were diagnosed with HCC. A dose-response relationship between statin use and HCC risk was observed. The adjusted hazard ratios were 0.66 (95% CI, 0.59 to 0.74), 0.47 (95% CI, 0.40 to 0.56), and 0.33 (95% CI, 0.25 to 0.42) for patients with 28 to 89, 90 to 180, and > 180 cDDDs per year, respectively, relative to nonusers. The reduction in risk also demonstrated a progressive duration-response relationship in patients with ? 28 cDDDs per year when compared with nonusers.
CONCLUSION: Among patients with HCV infection, statin use was associated with reduced risk of HCC. Further research is needed to elucidate the mechanism responsible for this effect.

PMID: 23509319 [PubMed - indexed for MEDLINE]

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Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist.

Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist.

Ann Oncol. 2013 Jan;24(1):14-20

Authors: Fasolo A, Sessa C, Gianni L, Broggini M

PMID: 23110808 [PubMed - indexed for MEDLINE]

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Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist.

Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist.

Ann Oncol. 2013 Jan;24(1):14-20

Authors: Fasolo A, Sessa C, Gianni L, Broggini M

PMID: 23110808 [PubMed - indexed for MEDLINE]

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Cancer cell resistance to aurora kinase inhibitors: identification of novel targets for cancer therapy.

Cancer cell resistance to aurora kinase inhibitors: identification of novel targets for cancer therapy.

J Proteome Res. 2013 Jan 4;12(1):455-69

Authors: Hrabakova R, Kollareddy M, Tyleckova J, Halada P, Hajduch M, Gadher SJ, Kovarova H

PMID: 23151231 [PubMed - indexed for MEDLINE]

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Porcine hemagglutinating encephalomyelitis virus induces apoptosis in a porcine kidney cell line via caspase-dependent pathways.

Porcine hemagglutinating encephalomyelitis virus induces apoptosis in a porcine kidney cell line via caspase-dependent pathways.

Virus Res. 2013 Jun 12;

Authors: Lan Y, Zhao K, Wang G, Dong B, Zhao J, Tang B, Lu H, Gao W, Chang L, Jin Z, Gao F, He W

Abstract
Porcine hemagglutinating encephalomyelitis is an acute, highly contagious disease in piglets that is caused by the porcine hemagglutinating encephalomyelitis virus (PHEV). However, the pathogenesis of PHEV and the relationship between PHEV and the host cells are not fully understood. In this study, we investigated whether the PHEV-induced cytopathic effect (CPE) was caused by apoptosis. Replication of PHEV in a porcine kidney-derived cell line (PK-15 cells) caused an extensive CPE, leading to the destruction of the entire monolayer and the death of the infected cells. Staining with Hoechst 33342 revealed morphological changes in the nuclei and chromatin fragmentation. In addition, PHEV caused DNA fragmentation detectable by agarose gel electrophoresis 48h post-infection, increasing with the incubation time. The percentage of apoptotic cells increased with the incubation time and reached a maximum at 96h post-infection, as determined using flow cytometry and fluorescence microscopy of cells that were stained with annexin V-FITC and propidium iodide (PI). Moreover, as is commonly observed for coronavirus infections of other animals, the activities of the effecter caspase, caspase-3, and the initiator caspases, caspase-8 and caspase-9, which are representative factors in the death receptor-mediated apoptotic pathway and the mitochondrial apoptotic pathway, respectively, were increased in PHEV-infected PK-15 cells. Moreover, the tripeptide pan-ICE (caspase) inhibitor Z-VAD-FMK blocked PHEV-induced apoptosis but did not have an effect on virus production by 96h post-infection. These results suggested that PHEV induces apoptosis in PK-15 cells via a caspase-dependent pathway. Apoptotic death of infected cells is detrimental to animals because it causes cell and tissue destruction. Although the pathological characteristics of PHEV are largely unknown, apoptosis may be the pathological basis of the lesions resulting from PHEV infection.

PMID: 23770152 [PubMed - as supplied by publisher]

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2013年6月20日星期四

Death receptor 5 agonistic antibody PRO95780: preclinical pharmacokinetics and concentration-effect relationship support clinical dose and regimen selection.

Death receptor 5 agonistic antibody PRO95780: preclinical pharmacokinetics and concentration-effect relationship support clinical dose and regimen selection.

Cancer Chemother Pharmacol. 2013 Jun 16;

Authors: Xiang H, Reyes AE, Eppler S, Kelley S, Damico-Beyer LA

Abstract
PURPOSE: PRO95780, a human monoclonal antibody (mAb) against death receptor 5 (DR5/TRAIL-R2/TNFRSF10B), was developed for the treatment for cancer. Our objective was to characterize pharmacokinetics (PK) in mice, rats, and cynomolgus monkeys and concentration-effect relationships of PRO95780 in xenograft mouse models of human cancers; this would guide the selection of dose and regimen for clinical trials. METHODS: The PK profiles were determined in mice, rats, and cynomolgus monkeys. Three xenograft models with a wide range of in vitro sensitivities to PRO95780 were selected for efficacy studies. Tumoristatic serum concentrations (TSCs) were determined using PK/pharmacodynamic (PD) modeling with tumor growth as a PD endpoint. A species-invariant time PK scaling method was employed to estimate disposition in humans using PK data in cynomolgus monkeys. Furthermore, the predicted human PK parameters were used to estimate dose and regimen to achieve TSC observed in mice at the steady-state trough concentrations (C trough ss) in the clinic. RESULTS: Linear PK was observed across species. A serum concentration of 22�?g/mL was identified to be the target TSC in mice. A dose of 10�mg/kg administered once every 2�weeks (Q2W) was predicted to achieve a TSC at C trough ss in 95�% of patients. CONCLUSIONS: PRO95780 has linear PK in mice, rats, and monkeys. Estimated TSCs varied among different xenograft models. A projected target dose in humans is achievable for Q2W administration within the dose range used for other commercial mAbs.

PMID: 23771513 [PubMed - as supplied by publisher]

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Biphasic Modulation of NOS Expression, Protein and Nitrite Products by Hydroxocobalamin Underlies Its Protective Effect in Endotoxemic Shock: Downstream Regulation of COX-2, IL-1?, TNF-?, IL-6, and HMGB1 Expression.

Biphasic Modulation of NOS Expression, Protein and Nitrite Products by Hydroxocobalamin Underlies Its Protective Effect in Endotoxemic Shock: Downstream Regulation of COX-2, IL-1?, TNF-?, IL-6, and HMGB1 Expression.

Mediators Inflamm. 2013;2013:741804

Authors: Sampaio AL, Dalli J, Brancaleone V, D'Acquisto F, Perretti M, Wheatley C

Abstract
Background. NOS/(?)NO inhibitors are potential therapeutics for sepsis, yet they increase clinical mortality. However, there has been no in vivo investigation of the (in vitro) (?)NO scavenger, cobalamin's (Cbl) endogenous effects on NOS/(?)NO/inflammatory mediators during the immune response to sepsis. Methods. We used quantitative polymerase chain reaction (qPCR), ELISA, Western blot, and NOS Griess assays, in a C57BL/6 mouse, acute endotoxaemia model. Results. During the immune response, pro-inflammatory phase, parenteral hydroxocobalamin (HOCbl) treatment partially inhibits hepatic, but not lung, iNOS mRNA and promotes lung eNOS mRNA, but attenuates the LPS hepatic rise in eNOS mRNA, whilst paradoxically promoting high iNOS/eNOS protein translation, but relatively moderate (?)NO production. HOCbl/NOS/(?)NO regulation is reciprocally associated with lower 4?h expression of TNF-?, IL-1 ? , COX-2, and lower circulating TNF-?, but not IL-6. In resolution, 24?h after LPS, HOCbl completely abrogates a major late mediator of sepsis mortality, high mobility group box 1 (HMGB1) mRNA, inhibits iNOS mRNA, and attenuates LPS-induced hepatic inhibition of eNOS mRNA, whilst showing increased, but still moderate, NOS activity, relative to LPS only. experiments (LPS+D-Galactosamine) HOCbl afforded significant, dose-dependent protection in mice Conclusions. HOCbl produces a complex, time- and organ-dependent, selective regulation of NOS/(?)NO during endotoxaemia, corollary regulation of downstream inflammatory mediators, and increased survival. This merits clinical evaluation.

PMID: 23781123 [PubMed - in process]

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DNA damage-induced inhibition of rRNA synthesis by DNA-PK and PARP-1.

DNA damage-induced inhibition of rRNA synthesis by DNA-PK and PARP-1.

Nucleic Acids Res. 2013 Jun 17;

Authors: Calkins AS, Iglehart JD, Lazaro JB

Abstract
RNA synthesis and DNA replication cease after DNA damage. We studied RNA synthesis using an in situ run-on assay and found ribosomal RNA (rRNA) synthesis was inhibited 24 h after UV light, gamma radiation or DNA cross-linking by cisplatin in human cells. Cisplatin led to accumulation of cells in S phase. Inhibition of the DNA repair proteins DNA-dependent protein kinase (DNA-PK) or poly(ADP-ribose) polymerase 1 (PARP-1) prevented the DNA damage-induced block of rRNA synthesis. However, DNA-PK and PARP-1 inhibition did not prevent the cisplatin-induced arrest of cell cycle in S phase, nor did it induce de novo BrdU incorporation. Loss of DNA-PK function prevented activation of PARP-1 and its recruitment to chromatin in damaged cells, suggesting regulation of PARP-1 by DNA-PK within a pathway of DNA repair. From these results, we propose a sequential activation of DNA-PK and PARP-1 in cells arrested in S phase by DNA damage causes the interruption of rRNA synthesis after DNA damage.

PMID: 23775790 [PubMed - as supplied by publisher]

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DNA damage-induced inhibition of rRNA synthesis by DNA-PK and PARP-1.

DNA damage-induced inhibition of rRNA synthesis by DNA-PK and PARP-1.

Nucleic Acids Res. 2013 Jun 17;

Authors: Calkins AS, Iglehart JD, Lazaro JB

PMID: 23775790 [PubMed - as supplied by publisher]

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2013年6月19日星期三

Local requirement of the Drosophila insulin binding protein Imp-L2 in coordinating developmental progression with nutritional conditions.

Local requirement of the Drosophila insulin binding protein Imp-L2 in coordinating developmental progression with nutritional conditions.

Dev Biol. 2013 Jun 14;

Authors: Sarraf-Zadeh L, Christen S, Sauer U, Cognigni P, Miguel-Aliaga I, Stocker H, K�hler K, Hafen E

Abstract
In Drosophila, growth takes place during the larval stages until the formation of the pupa. Starvation delays pupariation to allow prolonged feeding, ensuring that the animal reaches an appropriate size to form a fertile adult. Pupariation is induced by a peak of the steroid hormone ecdysone produced by the prothoracic gland (PG) after larvae have reached a certain body mass. Local downregulation of the insulin/insulin-like growth factor signaling (IIS) activity in the PG interferes with ecdysone production, indicating that IIS activity in the PG couples the nutritional state to development. However, the underlying mechanism is not well understood. In this study we show that the secreted Imaginal morphogenesis protein-Late 2 (Imp-L2), a growth inhibitor in Drosophila, is involved in this process. Imp-L2 inhibits the activity of the Drosophila insulin-like peptides by direct binding and is expressed by specific cells in the brain, the ring gland, the gut and the fat body. We demonstrate that Imp-L2 is required to regulate and adapt developmental timing to nutritional conditions by regulating IIS activity in the PG. Increasing Imp-L2 expression at its endogenous sites using an Imp-L2-Gal4 driver delays pupariation, while Imp-L2 mutants exhibit a slight acceleration of development. These effects are strongly enhanced by starvation and are accompanied by massive alterations of ecdysone production resulting most likely from increased Imp-L2 production by neurons directly contacting the PG and not from elevated Imp-L2 levels in the hemolymph. Taken together our results suggest that Imp-L2-expressing neurons sense the nutritional state of Drosophila larvae and coordinate dietary information and ecdysone production to adjust developmental timing under starvation conditions.

PMID: 23773803 [PubMed - as supplied by publisher]

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