Loss of PTEN Is Not Associated with Poor Survival in Newly Diagnosed Glioblastoma Patients of the Temozolomide Era

Introduction: Pre-temozolomide studies demonstrated that loss of the tumor suppressor gene PTEN held independent prognostic significance in GBM patients. We investigated whether loss of PTEN predicted shorter survival in the temozolomide era. The role of PTEN in the PI3K/Akt pathway is also reviewed. Methods: Patients with histologically proven newly diagnosed GBM were identified from a retrospective database between 2007 and 2010. Cox proportional hazards analysis was used to calculate the independent effects of PTEN expression, age

The phosphatase and tensin homologue deleted on chromosome 10 mediates radiosensitivity in head and neck cancer

BACKGROUND: For locally advanced squamous cell carcinoma of the head and neck (HNSCC), the recurrence rate after surgery and postoperative radiotherapy is between 20 and 40%, and the 5- year overall survival rate is similar to 50%. Presently, no markers exist to accurately predict treatment outcome. Expression of proteins in the human epidermal growth factor receptor (EGFR) pathway has been reported as a prognostic marker in several types of cancer. METHODS: The aim of this study was to investigate the prognostic value of proteins in the EGFR pathway in HNSCC. For this purpose, we collected surgically resected tissue of 140 locally advanced head and neck cancer patients, all treated with surgery and postoperative radiotherapy. RESULTS: In a multivariate analysis, expression of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was significantly related to worse locoregional control (LRC; HR: 2.2, 95% CI: 1.1-4.6; P = 0.03), independent of lymph node metastases (HR: 5.6, 95% CI: 1.2-27.4; P = 0.03) and extranodal spread (HR: 2.7; 95% CI: 1.2- 6.5; P = 0.02). In vitro clonogenic radiosensitivity assays confirmed that overexpression of PTEN resulted in increased radioresistance. CONCLUSION: Our study is the first report showing that expression of PTEN mediates radiosensitivity in vitro and that increased expression in advanced HNSCC predicts worse LRC. British Journal of Cancer (2010) 102, 1778-1785. doi: 10.1038/sj.bjc.6605707 www.bjcancer.com Published online 25 May 2010 (C) 2010 Cancer Research U

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer

Ovarian cancer is the most frequent cause of death from gynaecological cancer in the Western world. Current prognostic factors do not allow reliable prediction of response to chemotherapy and survival for individual ovarian cancer patients. Epidermal growth factor receptor (EGFR) and HER-2/neu are frequently expressed in ovarian cancer but their prognostic value remains unclear. In this study, we investigated the expression and prognostic value of EGFR, EGFR variant III (EGFRvIII), HER-2/neu and important downstream signalling components in a large series of epithelial ovarian cancer patients. Immunohistochemical staining of EGFR, pEGFR, EGFRvIII, Her-2/neu, PTEN (phosphatase and tensin homologue deleted on chromosome 10), total and phosphorylated AKT (pAKT) and phosphorylated ERK (pERK) was performed in 232 primary tumours using the tissue microarray platform and related to clinicopathological characteristics and survival. In addition, EGFRvIII expression was determined in 45 tumours by RT–PCR. Our results show that negative PTEN immunostaining was associated with stage I/II disease (P=0.006), non-serous tumour type (P=0.042) and in multivariate analysis with a longer progression-free survival (P=0.015). Negative PTEN staining also predicted improved progression-free survival in patients with grade III or undifferentiated serous carcinomas (P=0.011). Positive pAKT staining was associated with advanced-stage disease (P=0.006). Other proteins were expressed only at low levels, and were not associated with any clinicopathological parameter or survival. None of the tumours were positive for EGFRvIII. In conclusion, our results indicate that tumours showing negative PTEN staining could represent a subgroup of ovarian carcinomas with a relatively favourable prognosis

Evidence-based guidelines for use of probiotics in preterm neonates

<p>Abstract</p> <p>Background</p> <p>Current evidence indicates that probiotic supplementation significantly reduces all-cause mortality and definite necrotising enterocolitis without significant adverse effects in preterm neonates. As the debate about the pros and cons of routine probiotic supplementation continues, many institutions are satisfied with the current evidence and wish to use probiotics routinely. Because of the lack of detail on many practical aspects of probiotic supplementation, clinician-friendly guidelines are urgently needed to optimise use of probiotics in preterm neonates.</p> <p>Aim</p> <p>To develop evidence-based guidelines for probiotic supplementation in preterm neonates.</p> <p>Methods</p> <p>To develop core guidelines on use of probiotics, including strain selection, dose and duration of supplementation, we primarily used the data from our recent updated systematic review of randomised controlled trials. For equally important issues including strain identification, monitoring for adverse effects, product format, storage and transport, and regulatory hurdles, a comprehensive literature search, covering the period 1966-2010 without restriction on the study design, was conducted, using the databases PubMed and EMBASE, and the proceedings of scientific conferences; these data were used in our updated systematic review.</p> <p>Results</p> <p>In this review, we present guidelines, including level of evidence, for the practical aspects (for example, strain selection, dose, duration, clinical and laboratory surveillance) of probiotic supplementation, and for dealing with non-clinical but important issues (for example, regulatory requirements, product format). Evidence was inadequate in some areas, and these should be a target for further research.</p> <p>Conclusion</p> <p>We hope that these evidence-based guidelines will help to optimise the use of probiotics in preterm neonates. Continued research is essential to provide answers to the current gaps in knowledge about probiotics.</p

Thermal Transport in Micro- and Nanoscale Systems

Small-scale (micro-/nanoscale) heat transfer has broad and exciting range of applications. Heat transfer at small scale quite naturally is influenced – sometimes dramatically – with high surface area-to-volume ratios. This in effect means that heat transfer in small-scale devices and systems is influenced by surface treatment and surface morphology. Importantly, interfacial dynamic effects are at least non-negligible, and there is a strong potential to engineer the performance of such devices using the progress in micro- and nanomanufacturing technologies. With this motivation, the emphasis here is on heat conduction and convection. The chapter starts with a broad introduction to Boltzmann transport equation which captures the physics of small-scale heat transport, while also outlining the differences between small-scale transport and classical macroscale heat transport. Among applications, examples are thermoelectric and thermal interface materials where micro- and nanofabrication have led to impressive figure of merits and thermal management performance. Basic of phonon transport and its manipulation through nanostructuring materials are discussed in detail. Small-scale single-phase convection and the crucial role it has played in developing the thermal management solutions for the next generation of electronics and energy-harvesting devices are discussed as the next topic. Features of microcooling platforms and physics of optimized thermal transport using microchannel manifold heat sinks are discussed in detail along with a discussion of how such systems also facilitate use of low-grade, waste heat from data centers and photovoltaic modules. Phase change process and their control using surface micro-/nanostructure are discussed next. Among the feature considered, the first are microscale heat pipes where capillary effects play an important role. Next the role of nanostructures in controlling nucleation and mobility of the discrete phase in two-phase processes, such as boiling, condensation, and icing is explained in great detail. Special emphasis is placed on the limitations of current surface and device manufacture technologies while also outlining the potential ways to overcome them. Lastly, the chapter is concluded with a summary and perspective on future trends and, more importantly, the opportunities for new research and applications in this exciting field

Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas

Trastuzumab resistance hampers its well-known efficacy to control HER2-positive breast cancer. The involvement of PI3K/Akt pathway in this mechanism is still not definitively confirmed. We selected 155 patients treated with trastuzumab after development of metastasis or as adjuvant/neoadjuvant therapy. We performed immunohistochemistry for HER2, ER/PR, epidermal growth factor 1-receptor (EGFR), α -insulin-like growth factor 1-receptor (IGF1R), phosphatase and tensin homologue (PTEN), p110 α, pAkt, pBad, pmTOR, pMAPK, MUC1, Ki67, p53 and p27; mutational analysis of PIK3CA and PTEN, and PTEN promoter hypermethylation. We found 46% ER/PR-positive tumours, overexpression of EGFR (15%), α -IGF1R (25%), p110 α (19%), pAkt (28%), pBad (22%), pmTOR (23%), pMAPK (24%), MUC1 (80%), PTEN loss (20%), and PTEN promoter hypermethylation (20%). PIK3CA and PTEN mutations were detected in 17% and 26% tumours, respectively. Patients receiving adjuvant trastuzumab with α -IGF1R or pBad overexpressing tumours presented shorter progression-free survival (PFS) (all P ⩽0.043). Also, p110 α and mTOR overexpression, liver and brain relapses implied poor overall survival (OS) (all P ⩽0.041). In patients with metastatic disease, decreased PFS correlated with p110 α expression (P =0.024), whereas for OS were the presence of vascular invasion and EGFR expression (P ⩽0.019; Cox analysis). Our results support that trastuzumab resistance mechanisms are related with deregulation of PTEN/PI3K/Akt/mTOR pathway, and/or EGFR and IGF1R overexpression in a subset of HER2-positive breast carcinomas

Taking stock of 10 years of published research on the ASHA programme: Examining India’s national community health worker programme from a health systems perspective

Background: As India’s accredited social health activist (ASHA) community health worker (CHW) programme enters its second decade, we take stock of the research undertaken and whether it examines the health systems interfaces required to sustain the programme at scale. Methods: We systematically searched three databases for articles on ASHAs published between 2005 and 2016. Articles that met the inclusion criteria underwent analysis using an inductive CHW–health systems interface framework. Results: A total of 122 academic articles were identified (56 quantitative, 29 mixed methods, 28 qualitative, and 9 commentary or synthesis); 44 articles reported on special interventions and 78 on the routine ASHA program. Findings on special interventions were overwhelmingly positive, with few negative or mixed results. In contrast, 55% of articles on the routine ASHA programme showed mixed findings and 23% negative, with few indicating overall positive findings, reflecting broader system constraints. Over half the articles had a health system perspective, including almost all those on general ASHA work, but only a third of those with a health condition focus. The most extensively researched health systems topics were ASHA performance, training and capacity-building, with very little research done on programme financing and reporting, ASHA grievance redressal or peer communication. Research tended to be descriptive, with fewer influence, explanatory or exploratory articles, and no predictive or emancipatory studies. Indian institutions and authors led and partnered on most of the research, wrote all the critical commentaries, and published more studies with negative results. Conclusion: Published work on ASHAs highlights a range of small-scale innovations, but also showcases the challenges faced by a programme at massive scale, situated in the broader health system. As the programme continues to evolve, critical comparative research that constructively feeds back into programme reforms is needed, particularly related to governance, intersectoral linkages, ASHA solidarity, and community capacity to provide support and oversight