Mammalian Comparative Sequence Analysis of the Agrp Locus

Agouti-related protein encodes a neuropeptide that stimulates food intake. Agrp expression in the brain is restricted to neurons in the arcuate nucleus of the hypothalamus and is elevated by states of negative energy balance. The molecular mechanisms underlying Agrp regulation, however, remain poorly defined. Using a combination of transgenic and comparative sequence analysis, we have previously identified a 760 bp conserved region upstream of Agrp which contains STAT binding elements that participate in Agrp transcriptional regulation. In this study, we attempt to improve the specificity for detecting conserved elements in this region by comparing genomic sequences from 10 mammalian species. Our analysis reveals a symmetrical organization of conserved sequences upstream of Agrp, which cluster into two inverted repeat elements. Conserved sequences within these elements suggest a role for homeodomain proteins in the regulation of Agrp and provide additional targets for functional evaluation

Molecular prognostic factors in locally irresectable rectal cancer treated preoperatively by chemo-radiotherapy

PURPOSE: The aim of this study was to determine the relationship between survival and value of molecular markers in the primary tumour in a group of patients with irresectable rectal cancer, treated with preoperative chemo-radiotherapy. MATERIALS AND METHODS: Immunohistochemistry for p53, p21, bcl-2 and Ki-67 was performed on pre-treatment biopsy specimens of 34 patients with irresectable rectal cancer. Preoperative treatment consisted of pelvic irradiation of 45-56 Gy, combined with 5FU and leucovorin (350/20 mg/m2 x 5 d; in weeks 1 and 5 during radiotherapy). The median follow-up was 38 months. Endpoints were pathological T-stage and survival after surgery. RESULTS: Expression of p21 correlated significantly with survival (p=0.005). Survival and p21 expression also correlated significantly, when adjusted for tumour response (p=0.005, RR=4.8 (1.6-14.7)). CONCLUSION: Expression of p21 predicts a worse survival in irresectable rectal cancer treated with preoperative chemo-radiotherapy. No relationship was found between tumour response in chemo-radiotherapy and p53, bcl-2 or Ki-67

Meta-Analysis of Bilateral Versus Single Internal Thoracic Artery Grafting in Patients ≥70 Years of Age

The optimal choice of graft material in patients ≥70 years of age undergoing coronary artery bypass grafting remains unknown. A systematic review of literature was conducted by searching PubMed, Embase, Web of Science, and Cochrane Library databases for original publications that compared bilateral internal thoracic artery (BITA) grafting with single internal thoracic artery grafting in patients ≥70 years of age. Data were extracted by 2 independent investigators and meta-analyzed with the use of random effects. A total of 10 studies, including 11,185 patients, met the inclusion criteria. No differences in early mortality and morbidity, with the exemption of sternal wound complications which were more frequently observed in the BITA group (odds ratio 1.72, 95% 1.00 to 2.96 confidence interval [CI], p = 0.05; propensity score-matched population odds ratio 1.58, 95% CI 1.09 to 2.29, p = 0.02), were observed. Overall survival was superior in the overall patient population (hazard ratio [HR] 0.76, 95% CI 0.66 to 0.86, p <0.001), after applying a blanking period of 3 months to the overall patient population (HR 0.77, 95% CI 0.64 to 0.92, p = 0.005) as well as in the matched population (HR 0.72, 95% CI 0.58 to 0.89, p = 0.002); in all cases, a benefit was readily seen within a few years after surgery. The difference in freedom from major adverse cardiac and cerebrovascular events failed to reach statistical significance (overall patient population HR 0.55, 95% CI 0.27 to 1.13, p = 0.10; matched population HR 0.52, 95% CI 0.23 to 1.16, p = 0.11). In conclusion, BITA grafting can be safely performed in patients ≥70 years of age as late clinical benefits are expected to manifest themselves readily within a few years after surgery

MRI and contrast-enhanced ultrasound imaging for evaluation of focal irreversible electroporation treatment:results from a phase I-II study in patients undergoing IRE followed by radical prostatectomy

\u3cp\u3eOBJECTIVES: Irreversible electroporation (IRE) is an ablative therapy with a low side-effect profile in prostate cancer. The objective was: 1) To compare the volumetric IRE ablation zone on grey-scale transrectal ultrasound (TRUS), contrast-enhanced ultrasound (CEUS) and multiparametric MRI (mpMRI) with histopathology findings; 2) To determine a reliable imaging modality to visualize the IRE ablation effects accurately.\u3c/p\u3e\u3cp\u3eMETHODS: A prospective phase I-II study was performed in 16 patients scheduled for radical prostatectomy (RP). IRE of the prostate was performed 4 weeks before RP. Prior to, and 4 weeks after the IRE treatment, imaging was performed by TRUS, CEUS, and mpMRI. 3D-analysis of the ablation volumes on imaging and on H&amp;E-stained whole-mount sections was performed. The volumes were compared and the correlation was calculated.\u3c/p\u3e\u3cp\u3eRESULTS: Evaluation of the imaging demonstrated that with T2-weighted MRI, dynamic contrast enhanced (DCE) MRI, and CEUS, effects of IRE are visible. T2MRI and CEUS closely match the volumes on histopathology (Pearson correlation r = 0.88 resp. 0.80). However, IRE is not visible with TRUS.\u3c/p\u3e\u3cp\u3eCONCLUSIONS: mpMRI and CEUS are appropriate for assessing IRE effects and are the most feasible imaging modalities to visualize IRE ablation zone. The imaging is concordant with results of histopathological examination.\u3c/p\u3e\u3cp\u3eKEY POINTS: • mpMRI and contrast-enhanced ultrasound are appropriate imaging modalities for assessing IRE effects • mpMRI and CEUS are the most feasible imaging modalities to visualize IRE ablation zone • The imaging is concordant with results of histopathological examination after IRE • Grey-scale US is insufficient for assessing IRE ablations.\u3c/p\u3

Physiological and neurophysiological determinants of postcancer fatigue: design of a randomized controlled trial.

Contains fulltext : 109062.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Postcancer fatigue is a frequently occurring, severe, and invalidating problem, impairing quality of life. Although it is possible to effectively treat postcancer fatigue with cognitive behaviour therapy, the nature of the underlying (neuro)physiology of postcancer fatigue remains unclear. Physiological aspects of fatigue include peripheral fatigue, originating in muscle or the neuromuscular junction; central fatigue, originating in nerves, spinal cord, and brain; and physical deconditioning, resulting from a decreased cardiopulmonary function. Studies on physiological aspects of postcancer fatigue mainly concentrate on deconditioning. Peripheral and central fatigue and brain morphology and function have been studied for patients with fatigue in the context of chronic fatigue syndrome and neuromuscular diseases and show several characteristic differences with healthy controls. METHODS/DESIGN: Fifty seven severely fatigued and 21 non-fatigued cancer survivors will be recruited from the Radboud University Nijmegen Medical Centre. Participants should have completed treatment of a malignant, solid tumour minimal one year earlier and should have no evidence of disease recurrence. Severely fatigued patients are randomly assigned to either the intervention condition (cognitive behaviour therapy) or the waiting list condition (start cognitive behaviour therapy after 6 months). All participants are assessed at baseline and the severely fatigued patients also after 6 months follow-up (at the end of cognitive behaviour therapy or waiting list). Primary outcome measures are fatigue severity, central and peripheral fatigue, brain morphology and function, and physical condition and activity. DISCUSSION: This study will be the first randomized controlled trial that characterizes (neuro)physiological factors of fatigue in disease-free cancer survivors and evaluates to which extent these factors can be influenced by cognitive behaviour therapy. The results of this study are not only essential for a theoretical understanding of this invalidating condition, but also for providing an objective biological marker for fatigue that could support the diagnosis and follow-up of treatment. TRIAL REGISTRATION: The study is registered at http://ClinicalTrials.gov (NCT01096641)