Intratumoral Injection of Anlotinib Hydrogel Combined With Radiotherapy Reduces Hypoxia in Lewis Lung Carcinoma Xenografts: Assessment by Micro Fluorine-18-fluoromisonidazole Positron Emission Tomography/Computed Tomography Hypoxia Imaging.

Hypoxia is a common feature of solid tumors that increases tumor invasiveness and resistance to radiotherapy (RT) and chemotherapy. Local application of anlotinib (AL) might increase the regulation of new blood vessel growth and improve tumor hypoxia in RT. Therefore, it is essential to fully understand the drug delivery system of AL. Herein, we applied hypoxia imaging using micro fluorine-18-fluoromisonidazole positron emission tomography/computed tomography (micro 18F-FMISO PET/CT) to assess responses to intratumoral injections of an AL hydrogel (AL-HA-Tyr) combined with RT in mice bearing Lewis lung carcinoma (LLC). We formed AL-HA-Tyr by encapsulating AL with hyaluronic acid-tyramine (HA-Tyr) conjugates via the oxidative coupling of tyramine moieties catalyzed by H2O2 and horseradish peroxidase. AL-HA-Tyr restrained the proliferation of human umbilical endothelial cells (HUVECs) in colony formation assays in vitro (p < 0.001). We established a subcutaneous LLC xenograft model using C57BL/6J mice that were randomly assigned to six groups that were treated with AL, HA-Tyr, AL-HA-Tyr, RT, and RT+AL-HA-Tyr, or untreated (controls). Tumor volume and weight were dynamically measured. Post treatment changes in hypoxia were assessed in some mice using micro 18F-FMISO PET/CT, and survival was assessed in others. We histopathologically examined toxicity in visceral tissues and Ki-67, VEGF-A, γ-H2AX, and HIF-1α expression using immunohistochemistry. Direct intratumoral injections of AL-HA-Tyr exerted anti-tumor effects and improved hypoxia like orally administered AL (p > 0.05), but reduced visceral toxicity and prolonged survival. The uptake of 18F-FMISO did not significantly differ among the AL, AL-HA-Tyr, and RT+AL-HA-Tyr treated groups. Compared with the other agents, RT+AL-HA-Tyr decreased HIF-1α, Ki67, and VEGF-A expression, and increased γ-H2AX levels in tumor cells. Overall, compared with AL and AL-HA-Tyr, RT+AL-HA-Tyr improved tumor hypoxia, enhanced anti-tumor effects, and prolonged the survival of mice bearing LLC.

Boost carbon availability and value in algal cell for economic deployment of biomass.

This study elucidated storage carbon metabolism in a dynamic manner through kinetic model, metabolomics and stable metabolic flux analysis. Results revealed nutrient uptake rate, carbon availability and synthetic path rate accounted for the integration of process-compatible products. The uptake rate could be enhanced by promoting carbohydrate accumulation, inducing high performance of tricarboxylic acid cycle and anaplerotic routes. Values of specific rate for lipid from kinetic model and synthetic path rate from metabolic flux analysis revealed that conversion of carbon sinks occupied a key position in increasing productivities of lipid and astaxanthin to 302.34 and 1.83 mg g-1 d-1, respectively. Additionally, economic estimation was applied to link cultivation factors with market scenario and demonstrated that regulating such carbon metabolism raised 30% increase of biomass value. This study therefore provided a new orientation to boost carbon efficiency that helped to engineer carbon flux from carbon source to targeted products precisely and rapidly.

[The application of subjective visual gravity in assessment of vestibular compensation: a pilot study].

OBJECTIVE: To discuss the characteristics of subjective visual gravity (subjective visual vertical/horizontal, SVV/SVH) and assess its clinical application for peripheral unilateral vestibular compensation. METHODS: 69 cases of acute peripheral unilateral vestibular dysfunction patients (case group) accepted SVV/SVH, spontaneous nystagmus (SN), caloric test (CT) and other vestibular function tests. 49 healthy people (control group) accepted SVV/SVH only. SVV/SVH, SN and unilateral weakness (UW) were selected as for the observation indicators. The correlations between SVV/SVH, SN, UW and courses were investigated respectively, as well as the characteristic of SVV/SVH, SN in period of vestibular compensation. RESULTS: Among case group SVV, SVH positive in 42 patients(60.9%) and 44 patients(63.8%), the absolute values of the skew angle were in the range between 2.1°-20.0°, 2.1°-22.2°. Skew angles of SVV/SVH in control were in the range between -1.5°-2.0° and -2.0°-1.6°, and had no statistical significance with case group(t=5.336 and 5.864, P<0.05). SN-positive 28 cases (40.6%), the range of intensities at 2.4°-17.1°; UW-positive 50 cases (72.5%). In case group, positive correlation between SVV and SVH(r=0.948, P=0.00), negatively correlated between SVV/SVH and SN respectively(r values were -0.720, -0.733, P values were 0.00), no correlation between the skew angle of SVV/SVH, strength of SN and UW value(r values were 0.191, 0.189, and 0.179, P>0.05), there was no correlation between the absolute value of SVV, SVH, SN, UW with the duration (rs values were -0.075, -0.065, -0.212, and 0.126, P>0.05). CONCLUSION: Subjective visual gravity can be used not only to assess the range of unilateral peripheral vestibular dysfunction, but also help assess the static compensatory of otolithic, guidance and assessment of vestibular rehabilitation.

alpha-Lipoic acid increases energy expenditure by enhancing adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor-gamma coactivator-1alpha signaling in the skeletal muscle of aged mice.

Skeletal muscle mitochondrial dysfunction is associated with aging and diabetes, which decreases respiratory capacity and increases reactive oxygen species. Lipoic acid (LA) possesses antioxidative and antidiabetic properties. Metabolic action of LA is mediated by activation of adenosine monophosphate-activated protein kinase (AMPK), a cellular energy sensor that can regulate peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), a master regulator of mitochondrial biogenesis. We hypothesized that LA improves energy metabolism and mitochondrial biogenesis by enhancing AMPK-PGC-1alpha signaling in the skeletal muscle of aged mice. C57BL/6 mice (24 months old, male) were supplemented with or without alpha-LA (0.75% in drinking water) for 1 month. In addition, metabolic action and cellular signaling of LA were studied in cultured mouse myoblastoma C2C12 cells. Lipoic acid supplementation improved body composition, glucose tolerance, and energy expenditure in the aged mice. Lipoic acid increased skeletal muscle mitochondrial biogenesis with increased phosphorylation of AMPK and messenger RNA expression of PGC-1alpha and glucose transporter-4. Besides body fat mass, LA decreased lean mass and attenuated phosphorylation of mammalian target of rapamycin (mTOR) signaling in the skeletal muscle. In cultured C2C12 cells, LA increased glucose uptake and palmitate beta-oxidation, but decreased protein synthesis, which was associated with increased phosphorylation of AMPK and expression of PGC-1alpha and glucose transporter-4, and attenuated phosphorylation of mTOR and p70S6 kinase. We conclude that LA improves skeletal muscle energy metabolism in the aged mouse possibly through enhancing AMPK-PGC-1alpha-mediated mitochondrial biogenesis and function. Moreover, LA increases lean mass loss possibly by suppressing protein synthesis in the skeletal muscle by down-regulating the mTOR signaling pathway. Thus, LA may be a promising supplement for treatment of obesity and/or insulin resistance in older patients.

Temporal and spatial dynamics of human immunodeficiency virus type 1 circulating recombinant forms 08_BC and 07_BC in Asia.

Human immunodeficiency virus type 1 (HIV-1) CRF08_BC and CRF07_BC are two major recombinants descended from subtypes B' and C. Despite their massive epidemic impact in China, their migration patterns and divergence times remain unknown. Phylogenetic and population genetic analyses were performed on 228 HIV-1 sequences representing CRF08_BC, CRF07_BC, and subtype C strains from different locations across China, India, and Myanmar. Genome-specific rates of evolution and divergence times were estimated using a Bayesian Markov chain Monte Carlo framework under various evolutionary models. CRF08_BC originated in 1990.3 (95% credible region [CR], 1988.6 to 1991.9) in Yunnan province before spreading to Guangxi (south) and Liaoning (northeast) around 1995. Inside Guangxi region, the eastward expansion of CRF08_BC continued from Baise city (west) to Binyang (central) between 1997 and 1998 and later spread into Pingxiang around 1999 in the south, mainly through injecting drug users. Additionally, CRF07_BC diverged from its common ancestor in 1993.3 (95% CR, 1991.2 to 1995.2) before crossing the border into southern Taiwan in late 1990s. Phylogenetic analysis indicates that both CRF08_BC and CRF07_BC can trace their origins to Yunnan. The parental Indian subtype C lineage likely entered China around 1981.2 (95% CR, 1976.7 to 1985.9). Using a multiple unlinked locus model, we also showed that the dates of divergence calculated in this study may not be significantly affected by intrasubtype recombination among different lineages. This is the first phylodynamic study depicting the spatiotemporal dynamics of HIV/AIDS in East Asia.