Extravascular lung water (EVLW) is a sensitive prognostic indicator of pulmonary edema. Thus, EVLW may be an advantageous method of fluid management. This study aims to evaluate the outcomes of using EVLW and pulmonary artery wedge pressure (PAWP) as strategies for fluid management in patients with acute respiratory distress syndrome (ARDS).
Twenty-nine patients were randomly divided into the EVLW and PAWP groups. The survival rate, ICU (Intensive Care Unit) length of stay, duration of mechanical ventilation, acute lung injury scores, and oxygenation index of the EVLW and PAWP groups were compared.
No significant difference in the survival rates at 28 and 60 days (d) after treatment was found between the two groups (p = 0.542). The duration of mechanical ventilation and ICU length of stay were significantly lower (p < 0.05) in the EVLW group than in the PAWP group. The 7 d cumulative fluid balance was -783 ± 391 ml in the EVLW group and -256 ± 514 ml in the PAWP group (p < 0.05). Compared with the PAWP group, the EVLW group showed improved oxygenation index (p = 0.006).
EVLW for fluid management improved clinical results in patients with ARDS better than PAWP.
Acute respiratory distress syndrome; Extravascular lung water; Fluid management; Pulmonary artery wedge pressure
Streptomyces phage φC31 integrase induces efficient site-specific recombination capable of integrating exogenous genes at pseudo attP sites in human, mouse, rat, rabbit, sheep, Drosophila, and bovine genomes. However, the φC31-mediated recombination between attB and the corresponding pseudo attP sites has not been investigated in Capra hircus. Here, we identified eight pseudo attP sites located in the intron or intergenic regions of the C. hircus genome, and demonstrated different levels of foreign gene expression after φC31 integrase-mediated integration. These pseudo attP sites share similar sequences with each other and with pseudo attP sites in other mammalian genomes, and these are associated with a neighboring consensus motif found in other genomes. The application of the φC31 integrase system in C. hircus provides a new option for genetic engineering of this economically important goat species.
Bisphosphonates have been shown to inhibit and deplete macrophages. The effects of bisphosphonates on other cell types in the tumor microenvironment have been insufficiently studied. Here, we sought to determine the effects of bisphosphonates on ovarian cancer angiogenesis and growth via their effect on the microenvironment, including macrophage, endothelial and tumor cell populations.
Using in vitro and in vivo models, we examined the effects of clodronate on angiogenesis and macrophage density, and the overall effect of clodronate on tumor size and metastasis.
Clodronate inhibited the secretion of pro-angiogenic cytokines by endothelial cells and macrophages, and decreased endothelial migration and capillary tube formation. In treated mice, clodronate significantly decreased tumor size, number of tumor nodules, number of tumor-associated macrophages and tumor capillary density.
Clodronate is a potent inhibitor of tumor angiogenesis. These results highlight clodronate as a potential therapeutic for cancer.
anti-angiogenesis; bisphosphonate; clodronate; ovarian cancer; tumor angiogenesis; tumor microenvironment; tumor-associated macrophages
We investigated the relationship between telomere length and lung cancer in a pooled analysis from three prospective cohort studies: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, conducted among men and women in the United States, and previously published data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial conducted among male smokers in Finland, and the Shanghai Women's Health Study (SWHS), which is comprised primarily of never-smokers. The pooled population included 847 cases and 847 controls matched by study, age, and sex. Leukocyte telomere length was measured by a monochrome multiplex quantitative PCR assay. We used conditional logistic regression models to calculate odds ratios (OR) and their 95% confidence intervals (CI) for the association between telomere length and lung cancer risk, adjusted for age and pack-years of smoking. Longer telomere length was associated with increased lung cancer risk in the pooled analysis (OR(95% CI) by quartile: 1.00; 1.24(0.90–1.71); 1.27(0.91–1.78); and 1.86(1.33–2.62); P-trend=0.000022). Findings were consistent across the three cohorts and strongest for subjects with very long telomere length, i.e., lung cancer risks for telomere length (OR(95% CI)) in the upper half of the fourth quartile were 2.41(1.28–4.52), 2.16(1.11–4.23) and 3.02(1.39–6.58) for the PLCO trial, the ATBC trial, and the SWHS, respectively. In addition, the association persisted among cases diagnosed more than six years after blood collection and was particularly evident for female adenocarcinoma cases. Telomere length in white blood cell DNA may be a biomarker of future increased risk of lung cancer in diverse populations.
Leukocytes; Lung cancer; Prospective; Telomeres
Subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion develops with progressive white matter and cognitive impairments, yet no effective therapy is available. We investigated the temporal effects of minocycline on an experimental SIVD exerted by right unilateral common carotid arteries occlusion (rUCCAO). Minocycline treated at the early stage (day 0–3), but not the late stage after rUCCAO (day 4–32) alleviated the white matter and cognitive impairments, and promoted remyelination. The actions of minocycline may not involve the inhibition of microglia activation, based on the effects after the application of a microglial activation inhibitor, macrophage migration inhibitory factor, and co-treatment with lipopolysaccharides. Furthermore, minocycline treatment at the early stage promoted the proliferation of oligodendrocyte progenitor cells (OPCs) in subventricular zone, increased OPC number and alleviated apoptosis of mature oligodendrocytes in white matter. In vitro, minocycline promoted OPC proliferation and increased the percentage of OPCs in S and G2/M phases. We provided direct evidence that early treatment is critical for minocycline to alleviate white matter and cognitive impairments after chronic cerebral hypoperfusion, which may be due to its robust effects on OPC proliferation and mature oligodendrocyte loss. So, early therapeutic time window may be crucial for its application in SIVD.
The combustion of
biomass and coal is the dominant source of household
air pollution (HAP) in China, and contributes significantly to the
total burden of disease in the Chinese population. To characterize
HAP exposure related to solid fuel use and ventilation patterns, an
exposure assessment study of 163 nonsmoking female heads of households
enrolled from 30 villages was conducted in Xuanwei and Fuyuan, two
neighboring rural counties with high incidence of lung cancer due
to the burning of smoky coal (a bituminous coal, which in health evaluations
is usually compared to smokeless coal—an anthracite coal available
in some parts of the area). Personal and indoor 24-h PM2.5 samples were collected over two consecutive days in each household,
with approximately one-third of measurements retaken in a second season.
The overall geometric means (GM) of personal PM2.5 concentrations
in Xuanwei and Fuyuan were 166 [Geometric Standard Deviation (GSD):2.0]
and 146 (GSD:1.9) μg/m3, respectively, which were
similar to the indoor PM2.5 air concentrations [GM(GSD):162
(2.1) and 136 (2.0) μg/m3, respectively]. Personal
PM2.5 was moderately highly correlated with indoor PM2.5 (Spearman r = 0.70, p < 0.0001). Burning wood or plant materials (tobacco stems, corncobs
etc.) resulted in the highest personal PM2.5 concentrations
(GM:289 and 225 μg/m3, respectively), followed by
smoky coal, and smokeless coal (GM:148 and 115 μg/m3, respectively). PM2.5 levels of vented stoves were 34–80%
lower than unvented stoves and firepits across fuel types. Mixed effect
models indicated that fuel type, ventilation, number of windows, season,
and burning time per stove were the main factors related to personal
PM2.5 exposure. Lower PM2.5 among vented stoves
compared with unvented stoves and firepits is of interest as it parallels
the observation of reduced risks of malignant and nonmalignant lung
diseases in the region.
Notch pathway plays an important role in the growth of high-grade serous ovarian (HGS-OvCa) and other cancers, but its clinical and biological mechanisms are not well understood. Here, we found that the Notch pathway alterations are prevalent and significantly related to poor clinical outcome in patients with ovarian cancer. Particularly, Notch3 alterations, including amplification and upregulation, were highly associated with poor patient survival. Targeting Notch3 inhibited OvCa growth and induced apoptosis. Importantly, we found that DNM-mediated endocytosis was required for selectively activating Jagged-1-mediated Notch3 signaling. Cleaved Notch3 expression was the critical determinant of response to Notch-targeted therapy. Collectively, these data identify previously unknown mechanisms underlying Notch3 signaling and identify new, biomarker-driven approaches for therapy.
Residual disease (RD) following primary cytoreduction is associated with adverse overall survival in patients with epithelial ovarian cancer. Accurate identification of patients at high risk of RD has been elusive, lacking external validity and prompting many to undergo unnecessary surgical exploration. Our goal was to identify and validate molecular markers associated with high rates of residual disease.
We interrogated two publicly available datasets from chemonaïve primary high-grade serous ovarian tumors for genes overexpressed in patients with RD and significant at a 10% false discovery rate (FDR) in both datasets. We selected genes with wide dynamic range for validation in an independent cohort using qRT-PCR to assay gene expression, followed by blinded prediction of a patient subset at high risk for RD. Predictive success was evaluated using a one-sided Fisher’s exact test.
Forty-seven probesets met the 10% FDR criterion in both datasets. These included FABP4 and ADH1B, which tracked tightly, showed dynamic ranges >16-fold, and had high expression levels associated with increased incidence of RD. In the validation cohort (n=189), FABP4 and ADH1B were again highly correlated. Using the top quartile of FABP4 PCR values as a pre-specified threshold, we found 30/35 cases of RD in the predicted high-risk group (positive predictive value 86%), and 54/104 among the remaining patients (P=0.0002; odds ratio 5.5).
High FABP4 and ADH1B expression are associated with significantly higher risk of residual disease in high-grade serous ovarian cancer. Patients with high tumoral levels of these genes may be candidates for neoadjuvant chemotherapy.
Ovarian cancer; residual disease; neoadjuvant chemotherapy; biomarker; FABP4
Group A protein phosphatases 2Cs (PP2Cs) are essential components of abscisic acid (ABA) signaling in Arabidopsis; however, the function of group F2 subfamily PP2Cs is currently less known. In this study, TaPP2C1 which belongs to group F2 was isolated and characterized from wheat. Expression of the TaPP2C1-GFP fusion protein suggested its ubiquitous localization within a cell. TaPP2C1 expression was downregulated by abscisic acid (ABA) and NaCl treatments, but upregulated by H2O2 treatment. Overexpression of TaPP2C1 in tobacco resulted in reduced ABA sensitivity and increased salt resistance of transgenic seedlings. Additionally, physiological analyses showed that improved resistance to salt stress conferred by TaPP2C1 is due to the reduced reactive oxygen species (ROS) accumulation, the improved antioxidant system, and the increased transcription of genes in the ABA-independent pathway. Finally, transgenic tobacco showed increased resistance to oxidative stress by maintaining a more effective antioxidant system. Taken together, these results demonstrated that TaPP2C1 negatively regulates ABA signaling, but positively regulates salt resistance. TaPP2C1 confers salt resistance through activating the antioxidant system and ABA-independent gene transcription process.
Vandetanib is an oral tyrosine kinase inhibitor of VEGFR-2/3, EGFR and RET, which has demonstrated clinical activity as a single agent and in combination with taxanes. We explored the efficacy, safety and toxicity of docetaxel and vandetanib in women with recurrent ovarian cancer (OC).
Women with refractory or progressive OC were randomized 1:1 to docetaxel (75 mg/m2, IV)+vandetanib (100 mg daily, PO, D+V) or docetaxel (75 mg/m2,D). Up to 3 additional cytotoxic regimens for recurrence and prior anti-angiogenic agents (as primary therapy) were allowed. The primary endpoint was progression free survival (PFS). The study had 84% power to detect a PFS hazard ratio of 0.65, using a one-sided P of 0.1. This corresponds to an increase in median PFS from 3.6 months to 5.6 months. Patients progressing on D were allowed to receive single agent vandetanib (D→V).
131 patients were enrolled; 2 were excluded. 16% had received prior anti-angiogenic therapy. The median PFS estimates were 3.0 mos (D+V) vs. 3.5 (D); HR:0.99 (80% CI:0.79-1.26). 61 patients on D+V were assessable for toxicity; 20(33%) had treatment-related Grade (G) 4 events, primarily hematologic. Similarly, 17(27%) of 64 patients receiving D had G4 events, primarily hematologic. 27 evaluable patients crossed-over to V. 1/27(4%) experienced a G4 event. G3 diarrhea was observed in 4% D→V patients. Median OS was 14 mos (D+V) vs. 18 mos(D→V); HR(OS):1.25 (80% CI:0.93-1.68). Crossover vandetanib response was 4%(1/27 evaluable patients). High plasma IL-8 levels were associated with response to D+V.
Combination docetaxel+vandetanib did not prolong PFS relative to docetaxel alone in OC patients. No unexpected safety issues were identified.
Ovarian Cancer; Primary Peritoneal Cancer; Fallopian Tube Cancer; Epithelial Cancer; Chemotherapy; Taxanes; Vandetanib; Clinical Trial; Randomized phase II
Atherosclerotic lesions are accelerated in patients with diabetes. M1 (classically activated in contrast to M2 alternatively activated) macrophages play key roles in the progression of atherosclerosis. Since advanced glycation end products (AGEs) are major pathogenic factors and active inflammation inducers in diabetes mellitus, this study assessed the effects of AGEs on macrophage polarization. The present study showed that AGEs significantly promoted macrophages to express IL-6 and TNF-α. M1 macrophage markers such as iNOS and surface markers including CD11c and CD86 were significantly upregulated while M2 macrophage markers such as Arg1 and CD206 remained unchanged after AGEs stimulation. AGEs significantly increased RAGE expression in macrophages and activated NF-κB pathway, and the aforementioned effects were partly abolished by administration of anti-RAGE antibody or NF-κB inhibitor PDTC. In conclusion, our results suggest that AGEs enhance macrophage differentiation into proinflammatory M1 phenotype at least partly via RAGE/NF-κB pathway activation.
Ubiquitin-specific protease 22 (USP22) removes ubiquitin from histones, thus regulating gene transcription. The expression frequency and expression levels of USP22 were significantly higher in hepatocellular carcinoma (HCC) than in normal liver tissues. High USP22 expression in HCC was significantly correlated with clinical stage and tumor grade. Kaplan-Meier analysis showed that elevated USP22 expression predicted poorer overall survival and recurrence-free survival. High USP22 expression was also associated with shortened survival time in patients at advanced tumor stages and with high grade HCC. Multivariate analyses revealed that USP22 expression is an independent prognostic parameter in HCC. These findings provide evidence that high USP22 expression might be important in tumor progression and serves as an independent molecular marker for poor HCC prognosis. Thus, USP22 overexpression identifies patients at high risk and represents a novel therapeutic molecular target for this tumor.
hepatocellular carcinoma; ubiquitin-specific protease 22; prognosis; cancer biomarker
Three cases of avian influenza virus H10N8 were reported in Nanchang, China, as of April 2014. To identify the knowledge, attitudes, and practices (KAP) related to H10N8 among farmers’ market workers, a cross-sectional survey was conducted in 63 farmers’ markets in Nanchang. Using the resulting data, characteristics of poultry and non-poultry workers’ knowledge, attitudes, and practice were described. Results suggest that interventions targeting high-risk workers should be developed and implemented by public health agencies to prevent the spread of H10N8. Additionally policies that encourage farmers’ market workers to receive influenza vaccine should be developed, adopted, and enforced.
Gestational diabetes mellitus (GDM) is a frequent medical condition during pregnancy. Early diagnosis and treatment of GDM are crucial for both the mother and the baby. In the present study, we aimed to identify specific biomarkers to assist in the early detection of GDM and give some clues to the possible causes of GDM by comparing serum peptide profile differences between GDM patients and healthy controls. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used in combination with weak cation exchange magnetic bead (WCX-MB). Levels of four peptides (4418.9, 2219.7, 2211.5, and 1533.4 Da) were significantly different. Interestingly, three of them (4418.9, 2211.5, and 1533.4 Da) were identified when GDM patients with two degrees of glucose intolerance were compared. Additionally, peptides 2211.5 and 1533.4 Da showed a decreasing trend as glucose intolerance increased, while peptide 4418.9 Da exhibited the reverse tendency. In conclusion, our study provides novel insights into the altered serum peptide profile of GDM patients. The specific candidate biomarkers may contribute to the development of GDM.
Platelet-derived growth factor receptor alpha (PDGFRα) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biological significance of PDGFRα and PDGFRα blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer.
Expression of PDGFRα was examined in uterine cancer clinical samples and cell lines, and biological effects of PDGFRα inhibition were evaluated using in vitro (cell viability, apoptosis, and invasion) and in vivo (orthotopic) models of uterine cancer.
PDGFRα was highly expressed and activated in uterine cancer samples and cell lines. Treatment with 3G3 resulted in substantial inhibition of PDGFRα phosphorylation and of downstream signaling molecules AKT and MAPK. Cell viability and invasive potential of uterine cancer cells were also inhibited by 3G3 treatment. In orthotopic mouse models of uterine cancer, 3G3 monotherapy had significant antitumor effects in PDGFRα-positive models (Hec-1A, Ishikawa, Spec-2), but not in PDGFRα-negative model (OVCA432). Greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in the PDGFRα-positive models. The anti-tumor effects of therapy were related to increased apoptosis and decreased proliferation and angiogenesis.
These findings identify PDGFRα as an attractive target for therapeutic development in uterine cancer.
PDGFRα; 3G3; uterine cancer
The reproductive development and maturation of female schistosomes are crucial since their released eggs are responsible for the host immunopathology and transmission of schistosomiasis. However, little is known about the nutrients required by female Schistosoma japonicum during its sexual maturation. We evaluated the promoting effect of several nutrients (calf serum, red blood cells (RBCs), ATP and hypoxanthine) on the reproductive development of pre-adult females at 18 days post infection (dpi) from mixed infections and at 50 dpi from unisexual infections of laboratory mice in basic medium RPMI-1640. We found RBCs, rather than other nutrients, promoted the female sexual maturation and egg production with significant morphological changes. In 27% of females (18 dpi) from mixed infections that paired with males in vitro on day 14, vitelline glands could be positively stained by Fast Blue B; and in 35% of females (50 dpi) from unisexual infections on day 21, mature vitelline cells were observed. Infertile eggs were detected among both groups. To analyze which component of mouse RBCs possesses the stimulating effect, RBCs were fractionated and included in media. However, the RBC fractions failed to stimulate development of the female reproductive organs. In addition, bovine hemoglobin hydrolysate, digested by neutral protease, was found to exhibit the promoting activity instead of untreated bovine hemoglobin. The other protein hydrolysate, lactalbumin hydrolysate, exhibited a similar effect with bovine hemoglobin hydrolysate. Using quantitative RT-PCR, we found the expression levels of four reproduction-related genes were significantly stimulated by RBCs. These data indicate that RBCs provide essential nutrients for the sexual maturation of female S. japonicum and that the protein component of RBCs appeared to constitute the key nutrient. These findings would improve laboratory culture of pre-adult schistosomes to adult worms in medium with well-defined components, which is important to investigate the function of genes related to female sexual maturation.
The prevalence of obesity is high in older adults. Alcalase potato protein hydrolysate (APPH), a nutraceutical food, might have greater benefits and be more economical than hypolipidemic drugs. In this study, serum lipid profiles and heart protective effects were evaluated in high fat diet (HFD) induced hyperlipidemia in aging rats treated with APPH (15, 45 and 75 mg/kg/day) and probucol (500 mg/kg/day). APPH treatments reduced serum triacylglycerol (TG), total cholesterol (TC), and low density lipoprotein (LDL) levels to the normal levels expressed in the control group. Additionally, the IGF1R-PI3K-Akt survival pathway was reactivated, and Fas-FADD (Fas-associated death domain) induced apoptosis was inhibited by APPH treatments (15 and 45 mg/kg/day) in HFD aging rat hearts. APPH (75 mg/kg/day) rather than probucol (500 mg/kg/day) treatment could reduce serum lipids without affecting HDL expression. The heart protective effect of APPH in aging rats with hyperlipidemia was through lowering serum lipids and enhancing the activation of the compensatory IGF1R-PI3K-Akt survival pathway.
hyperlipidemia; alcalase potato protein hydrolysate; aging
The ovate family protein named MaOFP1 was identified in banana (Musa acuminata L.AAA) fruit by a yeast two-hybrid (Y2H) method using the banana MADS-box gene MuMADS1 as bait and a 2 day postharvest (DPH) banana fruit cDNA library as prey. The interaction between MuMADS1 and MaOFP1 was further confirmed by Y2H and Bimolecular Fluorescence Complementation (BiFC) methods, which showed that the MuMADS1 K domain interacted with MaOFP1. Real-time quantitative PCR evaluation of MuMADS1 and MaOFP1 expression patterns in banana showed that they are highly expressed in 0 DPH fruit, but present in low levels in the stem, which suggests that simultaneous but different expression patterns exist for both MuMADS1 and MaOFP1 in different tissues and developing fruits. Meanwhile, MuMADS1 and MaOFP1 expression was highly stimulated and greatly suppressed, respectively, by exogenous ethylene. In contrast, MaOFP1 expression was highly stimulated while MuMADS1 was greatly suppressed by the ethylene competitor 1-methylcyclopropene (1-MCP). These results indicate that MuMADS1 and MaOFP1 are antagonistically regulated by ethylene and might play important roles in postharvest banana fruit ripening.
AIM: To investigate the correlation between Kirsten rat sarcoma viral oncogene homolog (KRAS) status and the therapeutic effects of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) in metastatic colorectal cancer (mCRC).
METHODS: Randomized controlled trials (RCTs) were identified and the association between KRAS mutation and clinical outcome in mCRC patients treated with anti-EGFR MoAbs was investigated. Ten RCTs were included in this meta-analysis. Progression-free survival and overall survival were used to assess the strength of the relationship between KRAS mutation and clinical outcome.
RESULTS: In first-line treatment, survival benefit was confined to patients with wild-type KRAS. Chemotherapy regimens and angiogenesis inhibitor treatment influenced the results of the analysis. Wild-type KRAS mCRC patients did not seem to benefit from oxaliplatin-based chemotherapy (PFS: HR = 0.88, 95%CI: 0.70-1.10; OS: HR = 0.93, 95%CI: 0.82-1.04). Clinical benefit in mCRC patients was limited to therapeutic regimens which included anti-EGFR MoAbs and fluorouracil-based therapy (PFS: HR = 0.77, 95%CI: 0.69-0.86; OS: HR = 0.85, 95%CI: 0.75-0.95). When anti-EGFR MoAbs were used as second- or further-line treatment, clinical benefit was still confined to patients with wild-type KRAS.
CONCLUSION: KRAS status is a potential predictive marker of clinical benefit due to anti-EGFR MoAb therapy in mCRC patients.
Colorectal neoplasm; Kirsten rat sarcoma viral oncogene homolog; Cetuximab; Panitumumab; Meta-analysis
Neural synapses are intercellular asymmetrical junctions that transmit biochemical and biophysical information between a neuron and a target cell. They are very tight, dynamic, and well organized by many synaptic adhesion molecules, signaling receptors, ion channels, and their associated cytoskeleton that bear forces. Mechanical forces have been an emerging factor in regulating axon guidance and growth, synapse formation and plasticity in physiological and pathological brain activity. Therefore, mechanical forces are undoubtedly exerted on those synaptic molecules and modulate their functions. Here we review current progress on how mechanical forces regulate receptor-ligand interactions, protein conformations, ion channels activation, and cytoskeleton dynamics and discuss how these regulations potentially affect synapse formation, stabilization, and plasticity.
Lung cancer rates in Xuanwei are the highest in China. In-home use of smoky coal was associated with lung cancer risk, and the association of smoking and lung cancer risk strengthens after stove improvement. Here, we explored the differential association of tobacco use and lung cancer risk by the intensity, duration, and type of coal used.
Materials and Methods
We conducted a population-based case–control study of 260 male lung cancer cases and 260 age-matched male controls. Odds ratios (OR) and 95% confidence interval (CI) for tobacco use was calculated by conditional logistic regression.
Use of smoky coal was significantly associated with an increased risk of lung cancer risk, and tobacco use was weakly and non-significantly associated with lung cancer risk. When the association was assessed by coal use, the cigarette-lung cancer risk association was null in hazardous coal users and elevated in less hazardous smoky coal users and non-smoky coal users. The risk of lung cancer per cigarette per day decreased as annual use of coal increased (>0-3 tons: OR: 1.09; 95% CI: 1.03-1.17; >3 tons: OR: 0.99; 95% CI: 0.95-1.03). Among more hazardous coal users, attenuation occurs at even low levels of usage (>0-3 tons: OR: 1.02; 95% CI: 0.91-1.14; >3 tons: OR: 0.94; 95% CI: 0.97-1.03).
We found evidence that smoky coal attenuated the tobacco and lung cancer risk association in males that lived in Xuanwei, particularly among users of hazardous coal where even low levels of smoky coal attenuated the association. Our results suggest that the adverse effects of tobacco may become more apparent as China's population continues to switch to using cleaner fuels for the home, underscoring the urgent need for smoking cessation in China and elsewhere.
Coal; tobacco; lung cancer; indoor air pollution; China; global health; epidemiology
EphA2 is an attractive therapeutic target due to its diverse roles in cancer growth and progression. Dasatinib is a multi-kinase inhibitor that targets EphA2 and other kinases. However, reliable predictive markers and a better understanding of the mechanisms of response to this agent are needed.
The effects of dasatinib on human uterine cancer cell lines were examined using a series of in vitro experiments, including MTT, Western blot, and plasmid transfection. In vivo, an orthotopic mouse model of uterine cancer was utilized to identify the biological effects of dasatinib. Molecular markers for response prediction and the mechanisms relevant to response to dasatinib were identified by using RPPA, immunoprecipitation, and double immunofluorescence staining.
We show that high levels of CAV-1, EphA2 phosphorylation at S897 and the status of PTEN are key determinants of dasatinib response in uterine carcinoma. A set of markers essential for dasatinib response was also identified and includes CRaf, pCRafS338, pMAPKT202/Y204 (MAPK pathway), pS6S240/244, p70S6kT389 (mTOR pathway) and pAKTS473. A novel mechanism for response was discovered whereby high expression level of CAV-1 at the plasma membrane disrupts the BRaf/CRaf heterodimer and thus inhibits the activation of MAPK pathway during dasatinib treatment.
Our in vitro and in vivo results provide a new understanding of EphA2 targeting by dasatinib and identify key predictors of therapeutic response. These findings have implications for ongoing dasatinib-based clinical trials.
Dasatinib; EphA2; Caveolin-1 (CAV-1); Uterine Cancer
Cultured mammalian cells exhibit elevated glycolysis flux and high lactate production. In the industrial bioprocesses for biotherapeutic protein production, glucose is supplemented to the culture medium to sustain continued cell growth resulting in the accumulation of lactate to high levels. In such fed-batch cultures, sometimes a metabolic shift from a state of high glycolysis flux and high lactate production to a state of low glycolysis flux and low lactate production or even lactate consumption is observed. While in other cases with very similar culture conditions, the same cell line and medium, cells continue to produce lactate. A metabolic shift to lactate consumption has been correlated to the productivity of the process. Cultures that exhibited the metabolic shift to lactate consumption had higher titers than those which didn’t. However, the cues that trigger the metabolic shift to lactate consumption state (or low lactate production state) are yet to be identified. Metabolic control of cells is tightly linked to growth control through signaling pathways such as the AKT pathway. We have previously shown that the glycolysis of proliferating cells can exhibit bistability with well-segregated high flux and low flux states. Low lactate production (or lactate consumption) is possible only at a low glycolysis flux state. In this study, we use mathematical modeling to demonstrate that lactate inhibition together with AKT regulation on glycolysis enzymes can profoundly influence the bistable behavior, resulting in a complex steady-state topology. The transition from the high flux state to the low flux state can only occur in certain regions of the steady state topology, and therefore the metabolic fate of the cells depends on their metabolic trajectory encountering the region that allows such a metabolic state switch. Insights from such switch behavior present us with new means to control the metabolism of mammalian cells in fed-batch cultures.
Biodegradable porous scaffolds have been investigated as an alternative approach to current metal, ceramic, and polymer bone graft substitutes for lost or damaged bone tissues. Although there have been many studies investigating the effects of scaffold architecture on bone formation, many of these scaffolds were fabricated using conventional methods, such as salt leaching and phase separation, and were constructed without designed architecture. To study the effects of both designed architecture and material on bone formation, we designed and fabricated three types of porous scaffold architecture from two biodegradable materials, poly (L-lactic acid) (PLLA) and 50:50Poly (lactic-co-glycolic acid) (PLGA) using image based design and indirect solid freeform fabrication techniques, seeded them with bone morphogenic protein-7 transduced human gingival fibroblasts and implanted them subcutaneously into mice for 4 and 8 weeks. Micro-computed tomography data confirmed that the fabricated porous scaffolds replicated the designed architectures. Histological analysis revealed that the 50:50PLGA scaffolds degraded and did not maintain their architecture after 4 weeks. The PLLA scaffolds maintained their architecture at both time points and showed improved bone ingrowth which followed the internal architecture of the scaffolds. Mechanical properties of both PLLA and 50:50PLGA scaffolds decreased, but PLLA scaffolds maintained greater mechanical properties than 50:50PLGA after implantation. The increase of mineralized tissue helped to support mechanical properties of bone tissue and scaffold constructs from 4 to 8 weeks. The results indicated the importance of choice of scaffold materials and computationally designed scaffolds to control tissue formation and mechanical properties for desired bone tissue regeneration.
To evaluate the immunotoxicity of trichloroethylene (TCE), we conducted a cross-sectional molecular epidemiology study in China of workers exposed to TCE. We measured serum levels of IL-6, IL-10, and TNF-α, which play a critical role in regulating various components of the immune system, in 71 exposed workers and 78 unexposed control workers. Repeated personal exposure measurements were taken in workers before blood collection using 3 M organic vapor monitoring badges. Compared to unexposed workers, the serum concentration of IL-10 in workers exposed to TCE was decreased by 70% (P = 0.001) after adjusting for potential confounders. Further, the magnitude of decline in IL-10 was >60% and statistically significant in workers exposed to <12 ppm as well as in workers with exposures ≥ 12 ppm of TCE, compared to unexposed workers. No significant differences in levels of IL-6 or TNF-α were observed among workers exposed to TCE compared to unexposed controls. Given that IL-10 plays an important role in immunologic processes, including mediating the Th1/Th2 balance, our findings provide additional evidence that TCE is immunotoxic in humans.
trichloroethylene; immunotoxicity; IL-10; TNF-α; IL-6; occupational exposure