Dual EGFR inhibition in combination with anti-VEGF treatment: a phase I clinical trial in non-small cell lung cancer.

BackgroundPreclinical data indicate EGFR signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic in animal models.MethodsWe conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with non-small cell lung cancer (NSCLC) was analyzed for safety and response.ResultsThirty-four patients with NSCLC (median four prior therapies) received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (n=14, 41%), hypomagnesemia (n=9, 27%), and fatigue (n=5, 15%). Seven patients (21%) achieved stable disease (SD) ≥6 months, two achieved a partial response (PR) (6%), and two achieved an unconfirmed partial response (uPR) (6%) (total=32%). We observed SD≥6 months/PR/uPR in patients who had received prior erlotinib and/or bevacizumab, those with brain metastases, smokers, and patients treated at lower dose levels. Five of 16 patients (31%) with wild-type EGFR experienced SD≥6 months or uPR. Correlation between grade of rash and rate of SD≥6 months/PR was observed (p less than 0.01).ConclusionThe combination of erlotinib, cetuximab, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with NSCLC

The epidemiology of hospitalized influenza in children, a two year population-based study in the People's Republic of China

<p>Abstract</p> <p>Background</p> <p>The epidemiology and disease burden of annual influenza in children in mainland People's Republic of China have not been reported in detail. To understand the incidence and epidemiology of laboratory-proven influenza hospitalization in children in China, a review of available laboratory and hospital admission data was undertaken.</p> <p>Methods</p> <p>We conducted a retrospective population-based study in Suzhou and the surrounding area of Jiangsu province, China for hospitalized cases of respiratory illness at Suzhou Children's Hospital. Cases of pneumonia or respiratory illness were identified from hospital computer data bases. Routine virological testing by fluorescent monoclonal antibody assay of all hospitalized children identified influenza and other viruses. We calculated incidence rates using census population denominators.</p> <p>Results</p> <p>Of 7,789 specimens obtained during 2007 and 2008, 85 were positive for influenza A and 25 for influenza B. There were 282 specimens with parainfluenza virus and 1392 with RSV. Influenza occurred throughout the year, with peaks in the winter, and in August/September. Overall estimated annual incidence of laboratory-proven influenza hospitalization was 23-27/100,000 children 0-4 years old, and 60/100,000 in infants 0-6 months, with an average hospitalization of 9 days.</p> <p>Conclusions</p> <p>Influenza disease in young children in this part of China is a relatively common cause of hospitalization, and occurs throughout the year. The use of influenza vaccine in Chinese children has the potential to reduce the effect of influenza in the children, as well as in their communities. Studies are needed to further assess the burden of influenza, and to develop and refine effective strategies of immunization of young children in China.</p

Phase I Study of mTORC1/2 Inhibitor Sapanisertib (CB-228/TAK-228) in Combination with Metformin in Patients with mTOR/AKT/PI3K Pathway Alterations and Advanced Solid Malignancies

BACKGROUND: Sapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of 5\u27-AMP-activated protein kinase (AMPK) suggesting combination therapy may enhance antitumor activity of sapanisertib. We report preliminary safety, tolerability, and efficacy from the dose-escalation study of sapanisertib in combination with metformin in patients with advanced solid tumors. METHODS: Patients with advanced metastatic solid tumors resistant or refractory to standard treatment, with and without mTOR/AKT/PI3K pathway alterations, received sapanisertib 3 or 4 mg daily together with metformin once to three times daily (500-1,500 mg). All patients underwent 14-day titration period for metformin in cycle 1. Tumor measurements were performed following cycle 2 and subsequently every 8 weeks. RESULTS: A total of 30 patients were enrolled across four cohorts (3 mg/500 mg; 3 mg/1,000 mg, 4 mg/1,000 mg; 4 mg/1,500 mg). 19 were female (63%), median age was 57 (range: 30-77), all were Eastern Cooperative Oncology Group performance status 1. Tumor types included sarcoma (6), breast (4), ovarian (4), head and neck (3), colorectal (2), lung (2), renal cell (2), endometrial (2), gastroesophageal junction (1), prostate (1), stomach (1), urachus (1), and cervical cancer (1). Median number of prior lines of therapy was 4. Most common genomic alterations included PIK3CA (27%), PTEN (17%), AKT1/2 (10%), mTOR (10%). Of 30 patients evaluable for response, 4 patients achieved partial response (PR); 15 patients achieved stable disease (SD) as best response. Disease control rate (PR+SD) was 63%. Of the responders in PR, 3 of 4 patients had documented PTEN mutations (3/5 patients enrolled with PTEN mutations had PR); 2 of 4 of patients in PR had comutations (patient with leiomyosarcoma had both PTEN and TSC; patient with breast cancer had both PTEN and STK11); 1 of 4 patients in PR had AKT and mTOR mutation; tumor types included leiomyosarcoma (n = 2), breast (n = 1), and endometrial cancer (n = 1). Most common treatment-emergent adverse events included nausea, anorexia, diarrhea, and rash. Grade (G) 3-5 treatment-related adverse events included hyperglycemia (4/30; 13%), fatigue (2/30; 7%), hypertriglyceridemia (1/30; 3%), rash (2/20; 7%), diarrhea (2/30; 7%), creatinine increase (1/30; 3%), acidosis (1/30; 3%). No dose-limiting toxicities (DLT) were reported in the 3 mg/500 mg cohort. One of 6 patient had DLT in the 3 mg/1,000 mg cohort (G3 diarrhea) and 2 of 11 patients had DLTs in the 4 mg/1,500 mg cohort (G3 fatigue, G3 rash). 4 mg/1,000 mg was defined as the MTD. CONCLUSIONS: The safety profile of mTORC1/2 inhibitor sapanisertib in combination with metformin was generally tolerable, with antitumor activity observed in patients with advanced malignancies harboring PTEN mutations and AKT/mTOR pathway alterations. SIGNIFICANCE: Sapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, next-generation dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of AMPK suggesting combination therapy may enhance antitumor activity of sapanisertib. This dose-escalation study of sapanisertib and metformin in advanced solid tumors and mTOR/AKT/PI3K pathway alterations, demonstrates safety, tolerability, and early clinical activity in advanced malignancies harboring PTEN mutations and AKT/mTOR pathway alterations.Clinical trial information: NCT03017833

Zoning Optimization Method of a Riverfront Greenspace Service Function Oriented to the Cooling Effect: A Case Study in Shanghai

Blue-green space commonly provides multiple ecological service functions, especially thermal environment comfort for citizens. The greenspace of the riparian buffers along 22 river channels in Shanghai was selected as the study object, and remote sensing and GIS technologies were used to obtain the quantitative composition and morphological indices of riverfront greenspace and the spatial distribution data of the land surface temperature in the study area. Through BRT modelling and statistical analyses, the interactive correlations among the three aspects, namely, the spatial patterns of riverfront greenspace, their specific functional zoning, and cooling island differentiation characteristics, were explored. The results showed that different river types served for different functional zones of the city, namely, high-density built-up zoning, new urban-growth zoning in built-up areas, suburban areas, and rural areas, and had specific regular patterns of morphosis and service function of riverfront greenspace. These also led to a significant spatial differentiation pattern of cooling intensity levels, which generally appeared in the approximate circle differentiation structure of the cooling island in the city riverfront area. The study further proposed the key factors and corresponding strategies for optimizing the greenspace pattern to strengthen the cooling intensity levels of different river types. This study summarizes the landscape composition paradigm of riverfront greenspaces at the urban mesoscale and provides adaptive planning methods for better local microclimate conditions

The development of the peripheral nervous system in drosophila: molecular and genetic characterizations of a cyclin B mutant

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

Comparative Study on the Cooling Effects of Green Space Patterns in Waterfront Build-Up Blocks: An Experience from Shanghai

Different structural patterns of waterfront green space networks in built-up areas have different synergistic cooling characteristics in cities. This study&rsquo;s aim is to determine what kinds of spatial structures and morphologies of waterfront green spaces offer a good cooling effect, combined with three different typical patterns in Shanghai. A multidimensional spatial influence variable system based on the cooling effect was constructed to describe the spatial structural and morphological factors of the green space network. The ENVI-met 4.3 software, developed by Michael Bruse at Bochum, German, was used to simulate the microclimate distribution data, combined with the boosted regression tree (BRT) model and the correlation analysis method. The results showed that at the network level, the distance from the water body and the connectivity of green space had a stronger cooling correlation. The orientation of green corridors consistent with a summer monsoon had larger cooling effect ranges. In terms of spatial morphology, the vegetation sky view factor (SVF) and Vegetation Surface Albedo (VSAlbedo) had an important correlation with air temperature (T), and the green corridor with a 20&ndash;25 m width had the largest marginal effect on cooling. These results will provide useful guidance for urban climate adaptive planning and design

Impact Factors Analysis of Diesel Particulate Filter Regeneration Performance Based on Model and Test

In the application of DPFs (diesel particulate filters), temperature prediction and control technology during the regeneration phase has always been a great challenge, which directly affects the safety and performance of diesel vehicles. In this study, based on theoretical analysis and sample gas bench test results, a one-dimensional simulation model is built with GT-POWER software. The effects of soot loading quantity and oxygen concentration on regeneration temperature performance are studied. Simulation results show that, when the soot loading quantity exceeds 46 g (12.7 g/L), the maximum temperature inside DPF during the regeneration phase would be higher than 800 °C, and the risk of burning crack would be high. When the oxygen concentration in the exhaust gas is low (lower than 7%), the fuel injected into exhaust gas fails to give off enough heat, and the exhaust gas temperature fails to reach the target regeneration temperature, hydrocarbon emission could be found from the DPF outlet position; when the oxygen concentration in the exhaust gas reaches 7% or above, the DPF inlet temperature could reach the target temperature, accompanied by less hydrocarbon emission. Combined with the simulation results, engine test bench validation was carried out. The results show that the simulation results and test results agree well