Geographic Coincidence of Increased Malaria Transmission Hazard and Vulnerability Occurring at the Periphery of two Tanzanian Villages.

The goal of malaria elimination necessitates an improved understanding of any fine-scale geographic variations in transmission risk so that complementary vector control tools can be integrated into current vector control programmes as supplementary measures that are spatially targeted to maximize impact upon residual transmission. This study examines the distribution of host-seeking malaria vectors at households within two villages in rural Tanzania. Host-seeking mosquitoes were sampled from 72 randomly selected households in two villages on a monthly basis throughout 2008 using CDC light-traps placed beside occupied nets. Spatial autocorrelation in the dataset was examined using the Moran's I statistic and the location of any clusters was identified using the Getis-Ord Gi* statistic. Statistical associations between the household characteristics and clusters of mosquitoes were assessed using a generalized linear model for each species. For both Anopheles gambiae sensu lato and Anopheles funestus, the density of host-seeking females was spatially autocorrelated, or clustered. For both species, houses with low densities were clustered in the semi-urban village centre while houses with high densities were clustered in the periphery of the villages. Clusters of houses with low or high densities of An. gambiae s.l. were influenced by the number of residents in nearby houses. The occurrence of high-density clusters of An. gambiae s.l. was associated with lower elevations while An. funestus was also associated with higher elevations. Distance from the village centre was also positively correlated with the number of household occupants and having houses constructed with open eaves. The results of the current study highlight that complementary vector control tools could be most effectively targeted to the periphery of villages where the households potentially have a higher hazard (mosquito densities) and vulnerability (open eaves and larger households) to malaria infection

Mesenchymal cell survival in airway and interstitial pulmonary fibrosis

Fibrotic reactions in the airways of the lung or the pulmonary interstitium are a common pathologic outcome after exposure to a wide variety of toxic agents, including metals, particles or fibers. The survival of mesenchymal cells (fibroblasts and myofibroblasts) is a key factor in determining whether a fibroproliferative response that occurs after toxic injury to the lung will ultimately resolve or progress to a pathologic state. Several polypeptide growth factors, including members of the platelet-derived growth factor (PDGF) family and the epidermal growth factor (EGF) family, are prosurvival factors that stimulate a replicative and migratory mesenchymal cell phenotype during the early stages of lung fibrogenesis. This replicative phenotype can progress to a matrix synthetic phenotype in the presence of transforming growth factor-β1 (TGF-β1). The resolution of a fibrotic response requires growth arrest and apoptosis of mesenchymal cells, whereas progressive chronic fibrosis has been associated with mesenchymal cell resistance to apoptosis. Mesenchymal cell survival or apoptosis is further influenced by cytokines secreted during Th1 inflammation (e.g., IFN-γ) or Th2 inflammation (e.g., IL-13) that modulate the expression of growth factor activity through the STAT family of transcription factors. Understanding the mechanisms that regulate the survival or death of mesenchymal cells is central to ultimately developing therapeutic strategies for lung fibrosis

Dicer Is Required for Maintaining Adult Pancreas

Dicer1, an essential component of RNA interference and the microRNA pathway, has many important roles in the morphogenesis of developing tissues. Dicer1 null mice have been reported to die at E7.5; therefore it is impossible to study its function in adult tissues. We previously reported that Dicer1-hypomorphic mice, whose Dicer1 expression was reduced to 20% in all tissues, were unexpectedly viable. Here we analyzed these mice to ascertain whether the down-regulation of Dicer1 expression has any influence on adult tissues. Interestingly, all tissues of adult (8–10 week old) Dicer1-hypomorphic mice were histologically normal except for the pancreas, whose development was normal at the fetal and neonatal stages; however, morphologic abnormalities in Dicer1-hypomorphic mice were detected after 4 weeks of age. This suggested that Dicer1 is important for maintaining the adult pancreas

Dicer Is Required for Maintaining Adult Pancreas

Dicer1, an essential component of RNA interference and the microRNA pathway, has many important roles in the morphogenesis of developing tissues. Dicer1 null mice have been reported to die at E7.5; therefore it is impossible to study its function in adult tissues. We previously reported that Dicer1-hypomorphic mice, whose Dicer1 expression was reduced to 20% in all tissues, were unexpectedly viable. Here we analyzed these mice to ascertain whether the down-regulation of Dicer1 expression has any influence on adult tissues. Interestingly, all tissues of adult (8–10 week old) Dicer1-hypomorphic mice were histologically normal except for the pancreas, whose development was normal at the fetal and neonatal stages; however, morphologic abnormalities in Dicer1-hypomorphic mice were detected after 4 weeks of age. This suggested that Dicer1 is important for maintaining the adult pancreas

Genome-wide examination of the transcriptional response to ecdysteroids 20-hydroxyecdysone and ponasterone A in Drosophila melanogaster

<p>Abstract</p> <p>Background</p> <p>The 20-hydroxyecdysone (20E) hierarchy of gene activation serves as an attractive model system for studying the mode of steroid hormone regulated gene expression and development. Many structural analogs of 20E exist in nature and among them the plant-derived ponasterone A (PoA) is the most potent. PoA has a higher affinity for the 20E nuclear receptor, composed of the ecysone receptor (EcR) and Ultraspiracle proteins, than 20E and a comparison of the genes regulated by these hormones has not been performed. Furthermore, in <it>Drosophila </it>different cell types elicit different morphological responses to 20E yet the cell type specificity of the 20E transcriptional response has not been examined on a genome-wide scale. We aim to characterize the transcriptional response to 20E and PoA in <it>Drosophila </it>Kc cells and to 20E in salivary glands and provide a robust comparison of genes involved in each response.</p> <p>Results</p> <p>Our genome-wide microarray analysis of Kc167 cells treated with 20E or PoA revealed that far more genes are regulated by PoA than by 20E (256 vs 148 respectively) and that there is very little overlap between the transcriptional responses to each hormone. Interestingly, genes induced by 20E relative to PoA are enriched in functions related to development. We also find that many genes regulated by 20E in Kc167 cells are not regulated by 20E in salivary glands of wandering 3^rdinstar larvae and we show that 20E-induced levels of <it>EcR </it>isoforms <it>EcR-RA, ER-RC</it>, and <it>EcR-RD/E </it>differ between Kc cells and salivary glands suggesting a possible cause for the observed differences in 20E-regulated gene transcription between the two cell types.</p> <p>Conclusions</p> <p>We report significant differences in the transcriptional responses of 20E and PoA, two steroid hormones that differ by only a single hydroxyl group. We also provide evidence that suggests that PoA induced death of non-adapted insects may be related to PoA regulating different set of genes when compared to 20E. In addition, we reveal large differences between Kc cells and salivary glands with regard to their genome-wide transcriptional response to 20E and show that the level of induction of certain EcR isoforms differ between Kc cells and salivary glands. We hypothesize that the differences in the transcriptional response may in part be due to differences in the EcR isoforms present in different cell types.</p

The Feasibility of performing resistance exercise with acutely ill hospitalized older adults

BACKGROUND: For older adults, hospitalization frequently results in deterioration of mobility and function. Nevertheless, there are little data about how older adults exercise in the hospital and definitive studies are not yet available to determine what type of physical activity will prevent hospital related decline. Strengthening exercise may prevent deconditioning and Pilates exercise, which focuses on proper body mechanics and posture, may promote safety. METHODS: A hospital-based resistance exercise program, which incorporates principles of resistance training and Pilates exercise, was developed and administered to intervention subjects to determine whether acutely-ill older patients can perform resistance exercise while in the hospital. Exercises were designed to be reproducible and easily performed in bed. The primary outcome measures were adherence and participation. RESULTS: Thirty-nine ill patients, recently admitted to an acute care hospital, who were over age 70 [mean age of 82.0 (SD= 7.3)] and ambulatory prior to admission, were randomized to the resistance exercise group (19) or passive range of motion (ROM) group (20). For the resistance exercise group, participation was 71% (p = 0.004) and adherence was 63% (p = 0.020). Participation and adherence for ROM exercises was 96% and 95%, respectively. CONCLUSION: Using a standardized and simple exercise regimen, selected, ill, older adults in the hospital are able to comply with resistance exercise. Further studies are needed to determine if resistance exercise can prevent or treat hospital-related deterioration in mobility and function

Nanotechnology in Head and Neck Cancer: The Race Is On

Rapid advances in the ability to produce nanoparticles of uniform size, shape, and composition have started a revolution in the sciences. Nano-sized structures herald innovative technology with a wide range of potential therapeutic and diagnostic applications. More than 1000 nanostructures have been reported, many with potential medical applications, such as metallic-, dielectric-, magnetic-, liposomal-, and carbon-based structures. Of these, noble metallic nanoparticles are generating significant interest because of their multifunctional capacity for novel methods of laboratory-based diagnostics, in vivo clinical diagnostic imaging, and therapeutic treatments. This review focuses on recent advances in the applications of nanotechnology in head and neck cancer, with special emphasis on the particularly promising plasmonic gold nanotechnology

Dual EGFR and mTOR targeting in squamous cell carcinoma models, and development of early markers of efficacy

The epidermal growth factor receptor (EGFR) is a validated target in squamous cell carcinoma (SCC) of the head and neck. Most patients, however, do not respond or develop resistance to this agent. Mammalian target of rapamycin (mTOR) is involved in the pathogenesis of SCC of the head and neck (SCCHN). This study aimed to determine if targeting mTOR in combination with EGFR is effective in SCC, and to develop early pharmacodynamic markers of efficacy. Two SCC cell lines, one resistant (HEP2) and one of intermediate susceptibility (Detroit 562) to EGFR inhibitors, were xenografted in vivo and treated with an mTOR inhibitor (temsirolimus), an EGFR inhibitor (erlotinib) or a combination of both. Temsirolimus exerted superior growth arrest in both cell lines than erlotinib. The combined treatment resulted in synergistic antitumor effects in the Detroit 562 cell line. Immunohistochemical assessment of pharmacodynamic effects in fine-needle aspiration (FNA) biopsies early after treatment using phospho MAPK, Phospho-P70 and Ki67 as end points demonstrated pathway abrogation in the Detroit 562 tumours treated with the combination, the only group where regressions were seen. In conclusion, an mTOR inhibitor showed antitumor activity in EGFR-resistant SCC cell lines. Marked antitumor effects were associated with dual pathway inhibition, which were detected by early FNA biopsies

A multicenter phase II study of induction chemotherapy with FOLFOX-4 and cetuximab followed by radiation and cetuximab in locally advanced oesophageal cancer

"Background: Preoperative chemoradiotherapy (CRT) improves the survival of patients with oesophageal cancer when compared with surgery alone.. . Methods: We conducted a phase II, multicenter trial of FOLFOX-4 and cetuximab in patients with locally advanced oesophageal cancer (LAEC) followed by daily radiotherapy (180 cGy fractions to 5040 cGy) with concurrent weekly cetuximab. Cytokines levels potentially related to cetuximab efficacy were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, at week 8 and at week 17. Primary end point was complete pathological response rate (pCR).. . Results: In all, 41 patients were enroled. Among 30 patients who underwent surgery, a pCR was observed in 8 patients corresponding to a rate of 27%. The most frequent grade 3\/4 toxicity was skin (30%) and neutropenia (30%). The 36-month survival rates were 85 and 52% in patients with pathological CR or PR vs 38 and 33% in patients with SD or PD.. . Conclusions: Incorporating cetuximab into a preoperative regimen for LAEC is feasible; no correlation between cytokines changes and patient outcome was observed. Positron emission tomography\/computed tomography study even if influenced by the small number of patients appears to be able to predict patients outcome both as early and late metabolic response.. . "Background: Preoperative chemoradiotherapy (CRT) improves the survival of patients with oesophageal cancer when compared with surgery alone. Methods: We conducted a phase II, multicenter trial of FOLFOX-4 and cetuximab in patients with locally advanced oesophageal cancer (LAEC) followed by daily radiotherapy (180 cGy fractions to 5040 cGy) with concurrent weekly cetuximab. Cytokines levels potentially related to cetuximab efficacy were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, at week 8 and at week 17. Primary end point was complete pathological response rate (pCR). Results: In all, 41 patients were enroled. Among 30 patients who underwent surgery, a pCR was observed in 8 patients corresponding to a rate of 27%. The most frequent grade 3/4 toxicity was skin (30%) and neutropenia (30%). The 36-month survival rates were 85 and 52% in patients with pathological CR or PR vs 38 and 33% in patients with SD or PD. Conclusions: Incorporating cetuximab into a preoperative regimen for LAEC is feasible; no correlation between cytokines changes and patient outcome was observed. Positron emission tomography/computed tomography study even if influenced by the small number of patients appears to be able to predict patients outcome both as early and late metabolic response. © 2011 Cancer Research UK All rights reserved