Book Reviews

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Effects of Administered Cardioprotective Drugs on Treatment Response of Breast Cancer Cells

Background: Anticancer drug treatment, particularly with anthracyclines, is frequently associated with cardiotoxicity, an effect exacerbated by trastuzumab. Several compounds are in use clinically to attenuate the cardiac-damaging effects of chemotherapy drugs, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, the anti-diabetic drug metformin, and dexrazoxane. However, there is concern that the cardiac-preserving mechanisms of these drugs may also limit the anticancer efficacy of the chemotherapeutic agents. Materials and Methods: Herein two breast cancer cell lines, SKBr3 and BT474, overexpressing human epithelial receptor 2 (HER2), the target of the humanised antibody trastuzumab, were treated with a range of concentrations (20-2000 nM) of doxorubicin with and without trastuzumab in the presence of clinically relevant doses of the ACE inhibitor enalapril, the beta-blocker carvedilol, metformin or dexrazoxane, and cell survival determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: None of the drugs reduced the anticancer effect of doxorubicin or trastuzumab (nor of the two drugs combined). Using Chou and Talalay's combination index, dexrazoxane and doxorubicin were found to act synergistically on the SKBr3 cells. ¹⁸F-Fluoro-2-deoxy-D-glucose (¹⁸F-FDG) incorporation was reduced by treatment of SKBr3 cells with doxorubicin and this was shown to be due to reduced phosphorylation of ¹⁸F-FDG in doxorubicin-treated cells. Treatment of SKBr3 cells with doxorubicin and dexrazoxane further reduced ¹⁸F-FDG incorporation, indicating that the synergy in the cytotoxicity of these two drugs was reflected in their combined effect on ¹⁸F-FDG incorporation. Conclusion: Commonly administered cardioprotective drugs do not interfere with anticancer activity of doxorubicin or tratsuzumab. Further studies to establish the effect of cardioprotective drugs on anticancer drug efficacy would be beneficial.

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CRCT1 regulated by microRNA-520 g inhibits proliferation and induces apoptosis in esophageal squamous cell cancer

Abstract

Cysteine-rich C-terminal 1 (CRCT1) is encoded by the epidermal differentiation complex (EDC), a gene cluster that was recently linked to esophageal cancer. However, the role of CRCT1 in esophageal squamous cell cancer (ESCC) and the underlying mechanism remain unclear. In the present study, we show that CRCT1 is downregulated in ESCC in association with TNM stage and lymph node metastasis. Restoring CRCT1 in ESCC cells by lentivirus-mediated gene transfer inhibited cell proliferation and xenograft tumor formation. CRCT1 overexpression promoted ESCC cell apoptosis and upregulated the expression of apoptosis-related proteins. CRCT1 expression was inversely correlated with the levels of microRNA-520 g (miR-520 g) in ESCC tissues, and CRCT1 was identified as a direct target gene of miR-520 g in ESCC cells. Consistent with the effects of CRCT1 overexpression, knockdown of miR-520 g inhibited growth and induced apoptosis in ESCC cells. Our results suggest that CRCT1 functions as a tumor suppressor gene in ESCC and is regulated by miR-520 g, providing potential therapeutic targets for the treatment of ESCC.

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LKB1/AMPK inhibits TGF-β1 production and the TGF-β signaling pathway in breast cancer cells

Abstract

Adenosine monophosphate-activated protein kinase (AMPK) acts as a fuel gauge that maintains energy homeostasis in both normal and cancerous cells, and has emerged as a tumor suppressor. The present study aims to delineate the functional relationship between AMPK and transforming growth factor beta (TGF-β). Our results showed that expression of liver kinase B1 (LKB1), an upstream kinase of AMPK, impeded TGF-β-induced Smad phosphorylation and their transcriptional activity in breast cancer cells, whereas knockdown of LKB1 or AMPKα1 subunit by short hairpin RNA (shRNA) enhanced the effect of TGF-β. Furthermore, AMPK activation reduced the promoter activity of TGF-β1. In accordance, type 2 diabetic patients taking metformin displayed a trend of reduction of serum TGF-β1, as compared with those without metformin. A significant reduction of serum TGF-β1 was found in mice after treatment with metformin. These results suggest that AMPK inhibits the transcription of TGF-β1, leading to reduction of its concentration in serum. Finally, metformin suppressed epithelial-to-mesenchymal transition of mammary epithelial cells. Taken together, our study demonstrates that AMPK exerts multiple actions on TGF-β signaling and supports that AMPK can serve as a therapeutic drug target for breast cancer.

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Place du curage ganglionnaire avant radiothérapie exclusive dans la prise en charge des carcinomes épidermoïdes localement évolués des voies aérodigestives supérieures

Publication date: Available online 31 December 2015
Source:Cancer/Radiothérapie
Author(s): A. Modesto, J. Sarini, A. Benlyazid, M. Ouali, A. Laprie, P. Graff, S. Vergez, E. Uro-Coste, I. Fauquet, J.-P. Delord, M. Rives
IntroductionLa place du curage cervical dans la prise en charge conservatrice des carcinomes épidermoïdes localement évolués des voies aérodigestives supérieures demeure largement débattue. L'objectif de cette étude était d'analyser les caractéristiques, les facteurs pronostiques et le suivi des patients qui ont bénéficié d'un curage cervical avant une irradiation exclusive (traitement dissocié).Patients et méthodesSoixante-trois patients chez qui une atteinte ganglionnaire volumineuse (de 3cm ou plus) ou nécrotique a été mise en évidence lors de la scanographie initiale ont fait l'objet d'un traitement dissocié entre 2000 et 2012 à l'institut Claudius-Regaud (Toulouse, France). La lésion primitive était oropharyngée, hypopharyngée ou laryngée dans respectivement 63, 21 et 13 % des cas.RésultatsLes taux de contrôle locorégional et de survie globale à 3ans étaient de 88 % et 68 % avec un suivi médian de 4ans. Un seul patient a été atteint d'une récidive ganglionnaire isolée. En analyse unifactorielle, les variables significativement associées à un allongement de la survie sans maladie étaient : la réalisation d'un curage fonctionnel par opposition à non conservateur, (hazard ratio [HR] : 0,39 ; intervalle de confiance à 95 % [IC 95 %] : 0,16–0,94 ; p=0,03) et l'indice de performance de l'OMS (1–2 contre 0 ; HR=6,27 ; IC 95 %=2,73–14,39 ; p<0,0001). En analyse multifactorielle, seul l'indice de performance de l'OMS reste significatif.ConclusionLa réalisation d'un curage cervical avant la réalisation d'une (chimio)radiothérapie exclusive permet un bon taux de contrôle locorégional malgré une atteinte ganglionnaire initiale importante et permet de s'affranchir de la complexité d'une chirurgie cervicale de rattrapage en territoire irradié tout en gardant l'avantage d'une approche conservatrice sur la lésion primitive.PurposeOptimal timing of neck dissection remains debated in the conservative management of patients with locoregionally advanced squamous cell carcinoma of the head and neck.Patients and methodsThe files of 63 patients with radiographic evidence of bulky or necrotic nodal metastases treated by up-front neck dissection and definitive radiotherapy between 2000 and 2012 at two institutions were retrospectively reviewed.ResultsThe primary site was oropharyngeal, hypopharyngeal or laryngeal in 63%, 21% and 13% cases, respectively. Overall, 83% of the tumours were staged pN2b or more. Extracapsular spread was found in 48 cases (77%). After a 48-month median follow-up, the 3-year locoregional control and overall survival were 88% and 68%, respectively. Only one isolated failure occurred in the dissected neck.ConclusionThis combination therapy provides a good locoregional tumour control. It should be considered as an option in laryngeal, hypopharyngeal or oropharyngeal squamous cell carcinomas with bulky or necrotic nodal metastases at presentation.



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Virtual colonoscopy an alternative to fecal occult blood test and colonoscopy for colorectal cancer screening?

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Reduced and Full-Preparation CT Colonography, Fecal Immunochemical Test, and Colonoscopy for Population Screening of Colorectal Cancer: A Randomized Trial

Background:

Population screening for colorectal cancer (CRC) is widely adopted, but the preferred strategy is still under debate. We aimed to compare reduced (r-CTC) and full cathartic preparation CT colonography (f-CTC), fecal immunochemical test (FIT), and optical colonoscopy (OC) as primary screening tests for CRC.

Methods:

Citizens of a district of Florence, Italy, age 54 to 65 years, were allocated (8:2.5:2.5:1) with simple randomization to be invited by mail to one of four screening interventions: 1) biennial FIT for three rounds, 2) r-CTC, 3) f-CTC, 4) OC. Patients tested positive to FIT or CTC (at least one polyp ≥6mm) were referred to OC work-up. The primary outcomes were participation rate and detection rate (DR) for cancer or advanced adenoma (advanced neoplasia). All statistical tests were two-sided.

Results:

Sixteen thousand eighty-seven randomly assigned subjects were invited to the assigned screening test. Participation rates were 50.4% (4677/9288) for first-round FIT, 28.1% (674/2395) for r-CTC, 25.2% (612/2430) for f-CTC, and 14.8% (153/1036) for OC. All differences between groups were statistically significant (P = .047 for r-CTC vs f-CTC; P < .001 for all others). DRs for advanced neoplasia were 1.7% (79/4677) for first-round FIT, 5.5% (37/674) for r-CTC, 4.9% (30/612) for f-CTC, and 7.2% (11/153) for OC. Differences in DR between CTC groups and FIT were statistically significant (P < .001), but not between r-CTC and f-CTC (P = .65).

Conclusions:

Reduced preparation increases participation in CTC. Lower attendance and higher DR of CTC as compared with FIT are key factors for the optimization of its role in population screening of CRC.

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