Combined RNAi-Mediated Suppression of Rictor and EGFR Resulted in Complete Tumor Regression in an Orthotopic Glioblastoma Tumor Model

The PI3K/AKT/mTOR pathway is commonly over activated in glioblastoma (GBM), and Rictor was shown to be an important regulator downstream of this pathway. EGFR overexpression is also frequently found in GBM tumors, and both EGFR and Rictor are associated with increased proliferation, invasion, metastasis and poor prognosis. This research evaluated in vitro and in vivo whether the combined silencing of EGFR and Rictor would result in therapeutic benefits. The therapeutic potential of targeting these proteins in combination with conventional agents with proven activity in GBM patients was also assessed. In vitro validation studies were carried out using siRNA-based gene silencing methods in a panel of three commercially available human GBM cell lines, including two PTEN mutant lines (U251MG and U118MG) and one PTEN-wild type line (LN229). The impact of EGFR and/or Rictor silencing on cell migration and sensitivity to chemotherapeutic drugs in vitro was determined. In vivo validation of these studies was focused on EGFR and/or Rictor silencing achieved using doxycycline-inducible shRNA-expressing U251MG cells implanted orthotopically in Rag2M mice brains. Target silencing, tumor size and tumor cell proliferation were assessed by quantification of immunohistofluorescence-stained markers. siRNA-mediated silencing of EGFR and Rictor reduced U251MG cell migration and increased sensitivity of the cells to irinotecan, temozolomide and vincristine. In LN229, co-silencing of EGFR and Rictor resulted in reduced cell migration, and increased sensitivity to vincristine and temozolomide. In U118MG, silencing of Rictor alone was sufficient to increase this line’s sensitivity to vincristine and temozolomide. In vivo, while the silencing of EGFR or Rictor alone had no significant effect on U251MG tumor growth, silencing of EGFR and Rictor together resulted in a complete eradication of tumors. These data suggest that the combined silencing of EGFR and Rictor should be an effective means of treating GBM.     

A Minimal Intervention to Promote Smoke-Free Homes among 2-1-1 Callers: North Carolina Randomized Effectiveness Trial

This study examined the extent to which delivery of the minimal Smoke-Free Homes intervention by trained 2-1-1 information and referral specialists had an effect on the adoption of home smoking bans in low-income households. A randomized controlled trial was conducted among 2-1-1 callers (n = 500) assigned to control or intervention conditions. 2-1-1 information and referral specialists collected baseline data and delivered the intervention consisting of 3 mailings and 1 coaching call; university-based data collectors conducted follow-up interviews at 3 and 6 months post-baseline. Data were collected from June 2013 through July 2014. Participants were mostly female (87.2%), African American (61.4%), and smokers (76.6%). Participants assigned to the intervention condition were more likely than controls to report a full ban on smoking in the home at both 3- (38.1% vs 19.3%, p = < .001) and 6-month follow-up (43.2% vs 33.2%, p = .02). The longitudinal intent-to-treat analysis showed a significant intervention effect over time (OR = 1.31, p = .001), i.e. OR = 1.72 at 6 months. This study replicates prior findings showing the effectiveness of the minimal intervention to promote smoke-free homes in low-income households, and extends those findings by demonstrating they can be achieved when 2-1-1 information and referral specialists deliver the intervention. Findings offer support for this intervention as a generalizable and scalable model for reducing secondhand smoke exposure in homes.     

The Incidence Patterns Model to Estimate the Distribution of New HIV Infections in Sub-Saharan Africa: Development and Validation of a Mathematical Model

BackgroundProgrammatic planning in HIV requires estimates of the distribution of new HIV infections according to identifiable characteristics of individuals. In sub-Saharan Africa, robust routine data sources and historical epidemiological observations are available to inform and validate such estimates.ConclusionsIt is possible to reliably predict the distribution of new HIV infections acquired using data routinely available in many countries in the sub-Saharan African region with a single relatively simple mathematical model. This tool would complement more specific analyses to guide resource allocation, data collection, and programme planning.     

Impact of New Diagnostic Approaches for Invasive Candidiasis on Antifungal Stewardship

Background

Invasive candidiasis (IC) including candidemia and deep-seated candidiasis is associated with up to 50 % overall mortality and up to $80,000 in attributable cost (2015 US$). Rapid diagnostic tests (RDTs) for Candida have been developed. However, whether RDTs along with real-time decision support translate to better attainment of stewardship goals—improve clinical outcomes, minimize unintended consequences of antifungal use, and reduce healthcare costs—is unknown. The purpose of this systematic review was to provide an up-to-date review of recently published studies that have assessed how RDTs for IC impact attainment of these goals.

Methods

Three electronic bibliographic databases were searched using a pre-defined search strategy evaluating the impact of RDTs for IC on attainment of antifungal stewardship goals. Quality assessments were performed by two reviewers using established study methodology metrics.

Results and Conclusions

Eight studies were identified of which five had sufficient information to be included in the review. Despite the limitations of the various studies and the different methodologies employed, the studies all produced similar conclusions. Compared to conventional methods and baseline stewardship activities, the integration of RDTs for IC and real-time decision support, mainly through antifungal stewardship, was associated with decreased mortality, more optimal use of antifungals, and reduced healthcare costs. However, larger clinical studies are needed to confirm these trends.

     

Metastatic Tissue Proteomic Profiling Predicts 5-Year Outcomes in Patients with Colorectal Liver Metastases

Colorectal cancer (CRC) is one of the most common cancers in the developed countries, and nearly 70% of patients with CRC develop colorectal liver metastases (CRLMs). During the last decades, several scores have been proposed to predict recurrence after CRLM resection. However, these risk scoring systems do not accurately reflect the prognosis of these patients. Therefore, this investigation was designed to identify a proteomic profile in human hepatic tumor samples to classify patients with CRLM as “mild” or “severe” based on the 5-year survival. The study was performed on 85 CRLM tumor samples. Firstly, to evaluate any distinct tumor proteomic signatures between mild and severe CRLM patients, a training group of 57 CRLM tumor samples was characterized by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, and a classification and regression tree (CART) analysis was subsequently performed. Finally, 28 CRLM tumor samples were used to confirm and validate the results obtained. Based on all the protein peaks detected in the training group, the CART analysis was generated, and four peaks were considered to be the most relevant to construct a diagnostic algorithm. Indeed, the multivariate model yielded a sensitivity of 85.7% and a specificity of 86.1%, respectively. In addition, the receiver operating characteristic (ROC) curve showed an excellent diagnostic accuracy to discriminate mild from severe CRLM patients (area under the ROC: 0.903). Finally, the validation process yielded a sensitivity and specificity of 68.8% and 83.3%, respectively. We identified a proteomic profile potentially useful to determine the prognosis of CRLM patients based on the 5-year survival.     

Serotypes and Clonal Diversity of Streptococcus pneumoniae Causing Invasive Disease in the Era of PCV13 in Catalonia,Spain

The aim of this study was to study the serotypes and clonal diversity of pneumococci causing invasive pneumococcal disease in Catalonia, Spain, in the era of 13-valent pneumococcal conjugate vaccine (PCV13). In our region, this vaccine is only available in the private market and it is estimated a PCV13 vaccine coverage around 55% in children. A total of 1551 pneumococcal invasive isolates received between 2010 and 2013 in the Molecular Microbiology Department at Hospital Sant Joan de Déu, Barcelona, were included. Fifty-two serotypes and 249 clonal types—defined by MLST—were identified. The most common serotypes were serotype 1 (n = 182; 11.7%), 3 (n = 145; 9.3%), 19A (n = 137; 8.8%) and 7F (n = 122; 7.9%). Serotype 14 was the third most frequent serotype in children < 2 years (15 of 159 isolates). PCV7 serotypes maintained their proportion along the period of study, 16.6% in 2010 to 13.4% in 2013, whereas there was a significant proportional decrease in PCV13 serotypes, 65.3% in 2010 to 48.9% in 2013 (p<0.01). This decrease was mainly attributable to serotypes 19A and 7F. Serotype 12F achieved the third position in 2013 (n = 22, 6.4%). The most frequent clonal types found were ST306 (n = 154, 9.9%), ST191 (n = 111, 7.2%), ST989 (n = 85, 5.5%) and ST180 (n = 80, 5.2%). Despite their decrease, PCV13 serotypes continue to be a major cause of disease in Spain. These results emphasize the need for complete PCV13 vaccination.     

The contribution of <Emphasis Type="Italic">Potamogeton crispus</Emphasis> to the phosphorus budget of an urban shallow lake: Lake Monger,Western Australia

Lake Monger (Perth, Western Australia) is a highly eutrophic lake, characterised by very low species richness of macrophytes with the dominance of Potamogeton crispus. Mesocosm experiments were performed using water and plants collected from the lake to determine the effects of vegetation decay on the phosphorus (P) concentrations in the overlying waters. After 2 weeks of experimental incubation of mesocosms with and without re-oxygenation, P concentrations in the water column were significantly higher, showing a quite similar effect of P. crispus on the phosphorus release in different mesocosms. The results of our study provide clear evidence that the P concentrations in overlying waters mainly depend upon the plant P content and developmental stage. Although many sources contribute to the nutrient load of Lake Monger, macrophyte harvesting, prior to its senescence, might constitute a significant in-lake measure for reducing the internal P load.     

Diversity and trophic structure of insects associated with grains of three maize landraces in San Agustín Loxicha,Oaxaca, Mexico

Diversity and trophic structure of grain insect communities were examined in Olotillo, Nal‐Tel and Comiteco maize landraces cultivated within a milpa agroecosystem by Zapotec ethnic groups in Mexico. Higher insect diversity was expected in Olotillo, whose cultivation comprises a wide variety of agroecosystems, and low insect abundance in Nal‐Tel with small grains and thick testa. Forty Olotillo cobs were collected at low, medium and high elevations, and 40 each of Nal‐Tel at low elevation and Comiteco at high elevation. Cobs were monitored for 30 days under controlled laboratory conditions until all insects emerged. Thickness of testa of 400 grains from each landrace was measured. Community composition and trophic structure were described and standard diversity indices were estimated. A total of 9,708 insects, corresponding to five orders, 24 families and 36 species, were recorded, with six species not previously reported in this region. Insect guilds were composed of 70% phytophages, 22% parasitoids and 8% predators. Species richness was S = 27, 16 and 8 in Olotillo, Comiteco and Nal‐Tel, respectively. Nal‐Tel and Olotillo had the highest diversity index values (H′ = 1.32 and 1.2, respectively) and no significant differences; Comiteco had the lowest value (H′ = 0.65) and differed significantly from the other landraces. Comiteco and Olotillo, which have large grains and thin testa, showed higher insect abundance than Nal‐Tel, which has small grains and thick testa and showed lower abundance. Results support our hypotheses and highlight the role of traditional crop management in insect agrobiodiversity maintenance and conservation.     

Origin of a Core Bacterial Gene via Co-option and Detoxification of a Phage Lysin

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