A New Model for Raf Kinase Inhibitory Protein Induced Chemotherapeutic Resistance

Therapeutic resistance remains the most challenging aspect of treating cancer. Raf kinase inhibitory protein (RKIP) emerged as a molecule capable of sensitizing cancerous cells to radio- and chemotherapy. Moreover, this small evolutionary conserved molecule, endows significant resistance to cancer therapy when its expression is reduced or lost. RKIP has been shown to inhibit the Raf-MEK-ERK, NFκB, GRK and activate the GSK3β signaling pathways. Inhibition of Raf-MEK-ERK and NFκB remains the most prominent pathways implicated in the sensitization of cells to therapeutic drugs. Our purpose was to identify a possible link between RKIP-KEAP 1-NRF2 and drug resistance. To that end, RKIP-KEAP 1 association was tested in human colorectal cancer tissues using immunohistochemistry. RKIP miRNA silencing and its inducible overexpression were employed in HEK-293 immortalized cells, HT29 and HCT116 colon cancer cell lines to further investigate our aim. We show that RKIP enhanced Kelch-like ECH-associated protein1 (KEAP 1) stability in colorectal cancer tissues and HT29 CRC cell line. RKIP silencing in immortalized HEK-293 cells (termed HEK-499) correlated significantly with KEAP 1 protein degradation and subsequent NRF2 addiction in these cells. Moreover, RKIP depletion in HEK-499, compared to control cells, bestowed resistance to supra physiological levels of H2O2 and Cisplatin possibly by upregulating NF-E2-related nuclear factor 2 (NRF2) responsive genes. Similarly, we observed a direct correlation between the extent of apoptosis, after treatment with Adriamycin, and the expression levels of RKIP/KEAP 1 in HT29 but not in HCT116 CRC cells. Our data illuminate, for the first time, the NRF2-KEAP 1 pathway as a possible target for personalized therapeutic intervention in RKIP depleted cancers

Downregulation of RKIP Is Associated with Poor Outcome and Malignant Progression in Gliomas

Malignant gliomas are highly infiltrative and invasive tumors, which precludes the few treatment options available. Therefore, there is an urgent need to elucidate the molecular mechanisms underlying gliomas aggressive phenotype and poor prognosis. The Raf Kinase Inhibitory protein (RKIP), besides regulating important intracellular signaling cascades, was described to be associated with progression, metastasis and prognosis in several human neoplasms. Its role in the prognosis and tumourigenesis of gliomas remains unclear

Comparing Fatigue when Using Large Horizontal and Vertical Multi-Touch Interaction Displays

We report on a user study that compared muscle fatigue experienced when using a large multi-touch display in horizontal and vertical configurations over a one-hour period. Muscle fatigue is recognized as the reduction in a muscle’s capacity to generate force or power output and was measured objectively and subjectively before and after a puzzle-solving task. While subjective measures showed a significant level of overall arm muscle fatigue after the task for both configurations, objective measures showed a significant level of muscle fatigue on the middle deltoids and the non-dominant extensor digitorum for the vertical configuration only. We discuss the design implications of these findings and suggest relevant future areas of investigation

Two-marker protein profile predicts poor prognosis in patients with early rectal cancer

The aim of this study was to establish an immunohistochemical protein profile to complement preoperative staging and identify rectal cancer patients at high-risk of adverse outcome. Immunohistochemistry was performed on a tissue microarray including 482 rectal cancers for APAF-1, EphB2, MST1, Ki67, p53, RHAMM, RKIP and CD8+ tumour infiltrating lymphocytes (TILs). After resampling of the data and multivariable analysis, the most reproducible markers were combined and prognosis evaluated as stratified by pT and pN status. In multivariable analysis, only positive RHAMM (P<0.001; HR=1.94 (1.44–2.61)) and loss of CD8+ TILs (P=0.006; HR=0.63 (0.45–0.88)) were independent prognostic factors. The 5-year cancer-specific survival rate for RHAMM+/TIL− patients was 30% (95% CI 21–40%) compared to 76% (95% CI: 66–84%) for RHAMM−/TIL+ patients (P<0.001). The 5-year cancer-specific survival of T1/T2/RHAMM+/TIL− patients was 48% (20–72%) and significantly worse compared to T3/T4/RHAMM−/TIL+ patients (71% 95% CI 56–82%); P=0.039). Stratifying by nodal status, only N+/RHAMM+/TIL− patients demonstrated a significantly worse prognosis than N0/RHAMM+/TIL− patients (P=0.005). Loss of CD8+ TILs was predictive of local recurrence in RHAMM+ tumours (P=0.009) only. RHAMM and CD8+ TILs may assist in identifying early stage rectal cancer patients facing a particularly poor prognosis and who may derive a benefit from preoperative therapy

Genotype-phenotype correlations among BRCA1 4153delA and 5382insC mutation carriers from Latvia

<p>Abstract</p> <p>Background</p> <p>Mutations in the high penetrance breast and ovarian cancer susceptibility gene <it>BRCA1 </it>account for a significant percentage of hereditary breast and ovarian cancer cases. Genotype-phenotype correlations of <it>BRCA1 </it>mutations located in different parts of the <it>BRCA1 </it>gene have been described previously; however, phenotypic differences of specific <it>BRCA1 </it>mutations have not yet been fully investigated. In our study, based on the analysis of a population-based series of unselected breast and ovarian cancer cases in Latvia, we show some aspects of the genotype-phenotype correlation among the <it>BRCA1 </it>c.4034delA (4153delA) and c.5266dupC (5382insC) founder mutation carriers.</p> <p>Methods</p> <p>We investigated the prevalence of the <it>BRCA1 </it>founder mutations c.4034delA and c.5266dupC in a population-based series of unselected breast (n = 2546) and ovarian (n = 795) cancer cases. Among the <it>BRCA1 </it>mutation carriers identified in this analysis we compared the overall survival, age at diagnosis and family histories of breast and ovarian cancers.</p> <p>Results</p> <p>We have found that the prevalence of breast and ovarian cancer cases (breast: ovarian cancer ratio) differs significantly among the carriers of the c.5266dupC and c.4034delA founder mutations (OR = 2.98, 95%CI = 1.58 to 5.62, P < 0.001). We have also found a difference in the prevalence of breast and ovarian cancer cases among the 1^stand 2^nddegree relatives of the c.4034delA and c.5266dupC mutation carriers. In addition, among the breast cancer cases the c.4034delA mutation has been associated with a later age of onset and worse clinical outcomes in comparison with the c.5266dupC mutation.</p> <p>Conclusions</p> <p>Our data suggest that the carriers of the c.4034delA and c.5266dupC founder mutations have different risks of breast and ovarian cancer development, different age of onset and prognosis of breast cancer.</p

Processing and characterization of high environmental efficiency composites based on PLA and hazelnut shell flour (HSF) with biobased plasticizers derived from epoxidized linseed oil (ELO)

[EN] Different amounts of epoxidized linseed oil (ELO) have been added to poly(lactic acid)-PLA composites with hazelnut shell flour (HSF) to provide a plasticizing effect and improve the low intrinsic ductile properties of PLA/HSF composites. Mechanical, thermal, thermo-mechanical and dynamic mechanical properties have been studied in terms of the weight percentage ELO. Mechanical resistant properties in both tensile and flexural tests decrease with wt.% ELO while a remarkable increase with wt.% ELO is obtained. These results reveal a clear plasticization effect of ELO but, in addition, internal structure of PLA/HSF/ELO composites shows good PLA-HSF (matrix-particle) interactions so that indicating that ELO also provides a coupling effect between PLA matrix and HSF filler. ELO addition leads to a decrease in storage modulus (G ) obtained by dynamic mechanical thermal analysis (DMTA) in torsion mode thus giving clear evidence of the plasticization effect of ELO. Overall, the use of ELO in PLA/HSF composites is an attracting way to improve the low intrinsic fragility of these green composites; furthermore, ELO provides an improvement on thermal stability and a coupling effect between the polymer matrix and the surrounding lignocellulosic filler.This research was supported by the Ministry of Economy and Competitiveness - MINECO, Grant Number: MAT2014-59242-C2-1-R. Authors also thank to "Conselleria d'Educacio, Cultura i Esport" - Generalitat Valenciana, Grant Number: GV/2014/008 for financial support.Balart Gimeno, JF.; Fombuena Borrás, V.; Fenollar Gimeno, OÁ.; Boronat Vitoria, T.; Sánchez Nacher, L. (2016). Processing and characterization of high environmental efficiency composites based on PLA and hazelnut shell flour (HSF) with biobased plasticizers derived from epoxidized linseed oil (ELO). Composites Part B: Engineering. 86:168-177. https://doi.org/10.1016/j.compositesb.2015.09.063S1681778

Continuous low- to moderate-intensity exercise training is as effective as moderate- to high-intensity exercise training at lowering blood HbA1c in obese type 2 diabetes patients

Aims/hypothesis: Exercise represents an effective interventional strategy to improve glycaemic control in type 2 diabetes patients. However, the impact of exercise intensity on the benefits of exercise training remains to be established. In the present study, we compared the clinical benefits of 6 months of continuous low- to moderate-intensity exercise training with those of continuous moderate- to high-intensity exercise training, matched for energy expenditure, in obese type 2 diabetes patients. Methods: Fifty male obese type 2 diabetes patients (age 59∈±∈8 years, BMI 32∈± ∈4 kg/m2) participated in a 6 month continuous endurance-type exercise training programme. All participants performed three supervised exercise sessions per week, either 55 min at 50% of whole body peak oxygen uptake left(VO2peak) (low to moderate intensity) or 40 min at 75% of VO2peak (moderate to high intensity). Oral glucose tolerance, blood glycated haemoglobin, lipid profile, body composition, maximal workload capacity, whole body and skeletal muscle oxidative capacity and skeletal muscle fibre type composition were assessed before and after 2 and 6 months of intervention. Results: The entire 6 month intervention programme was completed by 37 participants. Continuous endurance-type exercise training reduced blood glycated haemoglobin levels, LDL-cholesterol concentrations, body weight and leg fat mass, and increased VO2peak, lean muscle mass and skeletal muscle cytochrome c oxidase and citrate synthase activity (p∈<∈0. 05). No differences were observed between the groups training at low to moderate or moderate to high intensity. Conclusions/interpretation: When matched for energy cost, prolonged continuous low- to moderate-intensity endurance-type exercise training is equally effective as continuous moderate- to high-intensity training in lowering blood glycated haemoglobin and increasing whole body and skeletal muscle oxidative capacity in obese type 2 diabetes patients. © 2009 Springer-Verlag

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Molecular detection (k-ras) of exfoliated tumour cells in the pelvis is a prognostic factor after resection of rectal cancer?

<p>Abstract</p> <p>Background</p> <p>After total mesorectal excision (TME) for rectal cancer around 10% of patients develops local recurrences within the pelvis. One reason for recurrence might be spillage of cancer cells during surgery. This pilot study was conducted to investigate the incidence of remnant cancer cells in pelvic lavage after resection of rectal cancer. DNA from cells obtained by lavage, were analysed by denaturing capillary electrophoresis with respect to mutations in hotspots of the <it>k-ras </it>gene, which are frequently mutated in colorectal cancer.</p> <p>Results</p> <p>Of the 237 rectal cancer patients analyzed, 19 had positive lavage fluid. There was a significant survival difference (p = 0.006) between patients with <it>k-ras </it>positive and negative lavage fluid.</p> <p>Conclusion</p> <p>Patients with <it>k-ras </it>mutated cells in the lavage immediately after surgery have a reduced life expectation. Detection of exfoliated cells in the abdominal cavity may be a useful diagnostic tool to improve the staging and eventually characterize patients who may benefit from aggressive multimodal treatment of rectal cancer.</p

KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients

Contains fulltext : 96042.pdf (publisher's version ) (Open Access)BACKGROUND: KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor antibody in metastatic colorectal cancer (CRC). KRAS mutation analysis is usually performed on primary tumour tissue because metastatic tissue is often not available. However, controversial data are available on the concordance of test results between primary tumours and corresponding metastases. We assessed the concordance of KRAS mutation status in a study of 305 primary colorectal tumours and their corresponding liver metastases. METHODS: Patients with histologically confirmed CRC who underwent surgical resection of the primary tumour and biopsy or surgical resection of the corresponding liver metastasis were included. KRAS mutation analysis was performed for codons 12 and 13. RESULTS: KRAS mutation was detected in 108 out of 305 primary tumours (35.4%). In 11 cases (3.6%), we found a discordance between primary tumour and metastasis: 5 primary tumours had a KRAS mutation with a wild-type metastasis, 1 primary tumour was wild type with a KRAS mutation in the metastasis, and in 5 cases the primary tumour and the metastasis had a different KRAS mutation. CONCLUSION: We observed a high concordance of KRAS mutation status of 96.4% (95% CI 93.6-98.2%) between primary colorectal tumours and their corresponding liver metastases. In only six patients (2.0%; 95% CI 0.7-4.2%), the discordance was clinically relevant. In this largest and most homogenous study to date, we conclude that both primary tumours and liver metastases can be used for KRAS mutation analysis