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The SS18-SSX1 fusion gene has been shown to play important roles in the development of synovial sarcoma (SS), but the underlying molecular mechanisms and its downstream target genes are still not clear. Here SHC SH2-domain binding protein 1 (SHCBP1) was identified and validated to be a novel downstream target gene of SS18-SSX1 by using microarray assay, quantitative real-time (qPCR) and western blot. Expression of SHCBP1 was firstly confirmed in SS cell line and SS tissues. The effects of SHCBP1 overexpression or knockdown on SS cell proliferation and tumorigenicity were then studied by cell proliferation, DNA replication, colony formation, flow cytometric assays, and its in vivo tumorigenesis was determined in the nude mice. Meanwhile, the related signaling pathways of SHCBP1 were also examined in SS cells. The results indicated that SHCBP1 was significantly increased in SS cells and SS tissues compared with adjacent noncancerous tissues. The expression of SHCBP1 was demonstrated to be positively correlated with the SS18-SSX1 level. Overexpression and ablation of SHCBP1 promoted and inhibited, respectively, the proliferation and tumorigenicity of SS cells in vitro. SHCBP1 knockdown also significantly inhibited SS cell growth in nude mice, and lowered the MAPK/ERK and PI3K/AKT/mTOR signaling pathways and cyclin D1 expression. Our findings disclose that SHCBP1 is a novel downstream target gene of SS18-SSX1, and demonstrate that the oncogene SS18-SSX1 promotes tumorigenesis by increasing the expression of SHCBP1, which normally acts as a tumor promoting factor.

Lung cancer is one of the most common and a lethal malignancy in the world and non-small cell lung cancer (NSCLC) is the most usual type. H19 long non-coding RNA (lncRNA) plays essential roles in tumor development. But its role in tumor metastasis is still unclear.MACC1 RNAi and Lentivirus-mediated H19-specific shRNA was used to establish H19 stable knocking-down A549 cells. Transwell assays were performed to examine the effect of H19 knocking-down on A549 cells migration and invasion. The downstream signaling proteins targeted by H19 were also examined by western blot. AG1478 and U0126 were used as the inhibitor of EGFR and ERK1/2, respectively.The knockdown of H19 increased the migration and invasion of A549 cells, and knockdown of metastasis-associated in colon cancer 1 (MACC1) decreased the migration and invasion of A549 cells. Furthermore, MACC1 protein targeted by H19 was upregulated as well as the downstream signaling proteins including epidermal growth factor receptor (EGFR), β-catenin, extracellular-signal-regulated kinase 1/2 (ERK1/2). Inhibited the expression of EGFR or ERK1/2 significantly decreased the migration and invasion of tumor cells.Our findings showed that H19 functions as a suppressor of NSCLC and plays an important role in the migration and invasion of NSCLC. More importantly, H19 may regulate NSCLC metastasis through modulating cellular signaling pathway proteins related to cell proliferation and cell adhesion, including MACC1, EGFR, β-catenin and ERK1/2. These results put forward our understanding of the detailed mechanism of H19 lncRNA regulating the process of NSCLC metastasis.

The catalytic activity of materials is highly dependent on their composition and surface structure, especially the density of low-coordinated surface atoms. In this work, we have prepared two-dimensional hexagonal FeS with high-energy (001) facets (FeS-HE-001) via a solution-phase chemical method. Nanosheets (NSs) with exposed high-energy planes usually possess better reaction activity, so FeS-HE-001 was used as a counter electrode (CE) material for dye-sensitized solar cells (DSSCs). FeS-HE-001 achieved an average power conversion efficiency (PCE) of 8.88% (with the PCE of champion cells being 9.10%), which was almost 1.15 times higher than that of the Pt-based DSSCs (7.73%) measured in parallel. Cyclic voltammetry and Tafel polarization measurements revealed the excellent electrocatalytic activities of FeS-HE-001 towards the I 3 – /I– redox reaction. This can be attributed to the promotion of photoelectron transfer, which was measured by electrochemical impedance spectroscopy and scanning Kelvin probe, and the strong I 3 – adsorption and reduction activities, which were investigated using first-principles calculations. The presence of high-energy (001) facets in the NSs was an important factor for improving the catalytic reduction of I 3 – . We believe that our method is a promising way for the design and synthesis of advanced CE materials for energy harvesting.

The titanic acid sheets were prepared by one-step hydrazine hydrate-assisted hydrothermal process. Then the reduced graphite oxide (rGO)@TiO 2 nanosheet composites were finally obtained through ultrasonic exfoliation and following calcination treatment process. rGO@TiO 2 nanosheet composites show excellent hydrogen production performance under AM1.5 light source. The highest hydrogen evolution yield (923.23 μmol) is nearly two times higher than that of pure TiO 2 , mainly due to the special electron structure and more active sites for TiO 2 nanosheet. The introduction of graphene could improve the TiO 2 nanosheet stability and extend visible-light absorption range.

The present study aimed to investigate the expression levels of tumor necrosis factor-α-induced protein 8 (TNFAIP8) in gastric adenocarcinoma. TNFAIP8 expression levels in gastric adenocarcinoma tissue samples (with and without lymph node metastasis), adjacent normal tissue samples and metastatic lymph node tissue samples were detected by immunohistochemistry. The correlation between TNFAIP8 expression levels and clinicopathological data and gastric adenocarcinoma prognosis was analyzed. The results demonstrated that TNFAIP8 expression in gastric adenocarcinoma tissue samples and metastatic lymph node tissue samples markedly increased at a rate of 47.2% (50/106) and 81.7% (49/60), respectively, as compared with the adjacent normal tissue samples in which no TNGFAIP8 expression was detected (0%). This increase in TNFAIP8 expression was statistically significant. TNFAIP8 expression rates in the primary tumors (60%, 36/60) of patients with lymph node metastasis were significantly higher compared with the primary tumors of patients without lymph node metastasis (30.4%, 14/46). TNFAIP8 expression was associated with an increase in the severity of TNM stage, tumor grade, vascular invasion, lymph node metastasis and serum CA72-4 levels. The overall survival rate of patients with gastric adenocarcinoma and high TNFAIP8 expression was poorer compared with patients with low TNFAIP8 expression, and TNFAIP8 expression was negatively correlated with patient prognosis. The results also demonstrated that TNFAIP8 was an independent prognostic marker in gastric adenocarcinoma (relative risk, 1.736; P=0.029). In conclusion, the results of the present study demonstrated that TNFAIP8 expression was associated with the occurrence, development and metastasis of gastric adenocarcinoma, and negatively correlated with the prognosis of patients with gastric adenocarcinoma. TNFAIP8 may therefore serve as a prognostic factor for gastric adenocarcinoma.

Observational studies assessing the association of dietary fat and risk of ovarian cancer yield discrepant results. Pertinent prospective cohort studies were identified by a PubMed search from inception to December 2015. Sixteen independent case-control and nine cohort studies on dietary fat intake were included, with approximately 900,000 subjects in total. Relative risks (RRs) with 95% confidence intervals were pooled using a random effects model. Heterogeneity, sensitivity analysis and publication bias were assessed; subgroup analysis and analysis stratified by EOC histology were conducted. The reported studies showed a significant increase of ovarian cancer risk with high consumption of total-, saturated-, and trans-fats, while serous ovarian cancer was more susceptible to dietary fat consumption than other pathological subtypes. No evidence of positive association between dietary fat intake and ovarian cancer risk was provided by cohort studies. Menopausal status, hormone replacement therapy, body mass index (BMI), and pregnancy times, modified the objective associations. In conclusion, the meta-analysis findings indicate that high consumption of total, saturated and trans-fats increase ovarian cancer risk, and different histological subtypes have different susceptibility to dietary fat.

65 Background: The efficacy of late line treatments for metastatic colorectal cancer (mCRC) is still limited. Antiangiogenic therapy is one of standard treatments in mCRC. Anlotinib is a multitarget tyrosine kinase inhibitor, mainly targets VEGFR1-3. This phase III trial was conducted to evaluate anti-tumor efficacy and safety of anlotinib monotherapy in refractory mCRC. Methods: Aged 18 years or older mCRC patients were enrolled in 33 Chinese hospitals. They had received at least 2 lines of chemotherapy based treatments; had ECOG PS 0-1and adequate bone marrow, liver and renal function. Enrolled patients were 2-to-1 randomly assigned into anlotinib or placebo group and stratified by previous VEGF-targeting therapy (y/n) and time from diagnosis to metastases (

Chimeric antigen receptor (CAR) T cell therapy has made significant progress in the treatment of blood cancers such as leukemia, lymphoma, and myeloma. However, the therapy faces many challenges in treating solid tumors. These challenges include physical barriers, tumor microenvironment immunosuppression, tumor heterogeneity, target specificity, and limited reactive cell expansion in vivo. Conventional CAR T cell therapy has thus far shown weak cell expansion in solid tumor patients and achieved little or no therapeutic responses. Here, we developed CAR T cells based on a novel CoupledCAR® technology to treat solid tumors. In contrast to conventional CAR T cells, CoupledCAR T cells significantly improved the expansion of the CAR T cells in vivo and enhanced the CAR T cells' migration ability and resistance to immunosuppression by the tumor microenvironment. The enhanced migration ability and resistance allow the CAR T cells to infiltrate to tumor tissue sites and increase anti-tumor activities. Specifically, we engineered CoupledCAR T cells with lentiviral vectors encoding an anti-GCC (guanylate cyclase 2C) CAR molecule. Furthermore, anti-GCC CAR T cells showed anti-tumor activities in vitro and in vivo experiments. To verify the safety and efficacy of CoupledCAR T cells for treating solid tumors, we conducted several clinical trials for different solid tumors, including seven patients with colorectal cancer. These seven patients failed multiple rounds of chemotherapy and radiotherapy. In the clinical trial, the patients were infused with autologous anti-GCC CoupledCAR T cells range from 4.9×10^5/kg to 2.9×10^6/kg. All patients using anti-GCC CoupledCAR T cells showed rapid expansion of CoupledCAR T cells and killing of tumor cells. Specifically, we observed that CoupledCAR T cells expanded significantly in the patients and infiltrated tumor tissue sites, demonstrating enhanced anti-tumor activities. PET/CT showed significant tumor shrinkage and SUV max declined, and the ongoing responses were monitored. Patient 3 achieved complete response and the best overall response rate (ORR, include complete remission, complete metabolic response, partial response, and partial metabolic response.) was 71.4% (5/7), complete remission (CR) rate was 14.3% (1/7). The clinical data demonstrated that CoupledCAR T cells effectively expanded, infiltrated tumor tissue sites, and kill tumor cells in patients with colorectal cancer. We used immunotherapy to achieve complete remission in patients with advanced colorectal cancer for the first time. We are recruiting more colorectal cancer patients to further test the safety and efficacy of anti-GCC CoupledCAR T cells. Since our CoupledCAR® technology is a platform technology, we are expanding it to treat other solid tumors using different target tumor markers . Disclosures Xiao: Innovative Cellular Therapeutics: Other: stockholder.

Developing a low-cost counter electrode (CE) catalyst with outstanding catalytic activity for the triiodide (I3−) reduction reaction (IRR) in dye-sensitized solar cells (DSSCs) is highly desirable. Herein, small-sized NiSe2 nanowires (NiSe2-W) were controllable synthesized by introducing the oleic acid (OA) as organic capping ligand into reaction system. Similarly, the monodisperse NiSe2 nanoparticles (NiSe2-P) with the small-sized were prepared by the same synthesis strategy under the absence of OA. The difference in morphologies between NiSe2-W and NiSe2-P can be attributed to the anisotropy and the oriented attachment of OA, and then the possible growth mechanism of them had been proposed. On the basis of the unique 1D nanostructure and chemical composition merits, power conversion efficiency (PCE) of 8.78 % was achieved when the NiSe2-W exploited as the CE catalyst for DSSCs, superior to that of the state-of-the-art Pt-based DSSCs (7.97 %) in parallel. Moreover, the relevant electrochemical measurements revealed that the as-prepared NiSe2-W displayed superior catalytic activity for IRR and good electrochemical durability in the redox electrolyte containing the I3−/I−. Then the NiSe2-W with unqiue 1D structure had been expected to replace Pt for the application of DSSCs, and could be a potential candidate in extensive new energy applications.

Glucoraphanin is a methionine-derived glucosinolate that imparts numerous health-benefits with broad bioactivity. Low amounts in plant tissues and high cost of extraction have limited the production of glucoraphanin. Metabolic engineering in heterologous microorganisms is an attractive approach to achieve efficient production of valuable natural products. In this study, a microbial fermentation process for glucoraphanin production was demonstrated. The engineered bacterial strain stably expressed 10 allogeneic enzymes in E. coli chromosome, including nine heterologous genes from Arabidopsis and Brassica and one from fungus Neurospora crassa, which could produce the specialized glucosinolate compound glucoraphanin with a titer of 0.675 μg/L by fermentation from glucose. The cofactor supplements and individual gene overexpression for glucoraphanin production were also investigated. This work highlights the possibility of supplying specialized plant glucosinolates by microbial fermentation process, instead of chemical extraction. Additionally, the limiting step enzyme, UDP-glucose-thiohydroximate glucosyltransferase, identified in this study also laid a foundation for further optimizing the glucoraphanin-producing cell factory.

4511 Background: Patients (pts) with advanced esophageal squamous cell carcinoma (ESCC) refractory to first-line chemotherapy have limited treatment options. The study aims to evaluate the efficacy and safety of sintilimab, a PD-1 inhibitor, versus chemotherapy in these pts, and explore predictive value of PD-L1 and neutrophil-to-lymphocyte ratio (NLR) on efficacy of sintilimab. Methods: The open-label, multi-center phase 2 trial (NCT03116152) enrolled advanced ESCC pts refractory to first-line chemotherapy, and randomly assigned (1:1) them to receive sintilimab (200mg, Q3W) or chemotherapy (paclitaxel, 175mg/m2, Q3W; or irinotecan, 180mg/m2, Q2W), intravenously. The primary endpoint was overall survival (OS). Explorative endpoint were effects of PD-L1 and NLR on efficacy of sintilimab. Results: From May 16, 2017 to Aug 30, 2018, 190 pts were randomly assigned to sintilimab or chemotherapy (n = 95 per group). With the median follow-up of 7.2 months for sintilimab group and 6.2 months for chemotherapy group, the median OS in sintilimab was significantly higher than chemotherapy (7.2m vs. 6.2m, hazard ratio [HR] 0.70, P = 0.034). The objective response rate (ORR) was greater in sintilimab than chemotherapy with 12.6% vs. 6.3%, and the median duration of response was longer (8.3m vs. 6.2m). Incidences of treatment-related adverse events (TRAEs) of any grade (54.3% vs. 90.8%) and of grade 3-5 (20.2% vs. 39.1%) were both numerically less in sintilimab than in chemotherapy. The ORR in sintilimab versus chemotherapy in pts with tumor PD-L1 tumor proportion score (TPS) ≥1% and with TPS ≥10% were 20.2% vs. 0%, and 35.7% vs. 0%, respectively. In sintilimab group, pts with low NLR ( < 3) had a significant longer median OS (HR 0.54, P = 0.019) than with high NLR. Conclusions: Sintilimab was superior to chemotherapy with a significantly prolonged survival benefit and a favorable safety profile in pts with advanced ESCC refractory to first-line chemotherapy. High tumor PD-L1 expression (TPS ≥1% or ≥10%) might indicate more response benefit to sintilimab for these pts, and low NLR might be a positive predictive factor for sintilimab. Clinical trial information: NCT03116152 .

4613 Background: In the phase 3 study (SANET-ep, NCT02588170), surufatinib significantly prolonged progression free survival compared with placebo in patients with progressive, well-differentiated advanced extrapancreatic neuroendocrine tumors (epNETs) (ESMO 2019 Abs. LBA76). Here, we report the results of health-related quality-of-life (HRQoL) from this study. Methods: Eligible patients were randomized in a 2:1 ratio to receive surufatinib or placebo, 300 mg, orally, once daily, until disease progression or intolerable adverse events. Patient-reported outcome questionnaires, including the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the QLQ-G.I.NET-21, were collected at baseline, Day 15 of the first cycle (28 Days/cycle), and Day 1 of every cycle thereafter and at discontinuation. Time until definitive deterioration (TUDD) was defined as time from randomization to deterioration of 10 points in domain score compared with baseline score (without subsequent observations of deterioration of less than 10 point or any improvement as compared to baseline score), or death due to any cause. TUDD and mean change from baseline based on a longitudinal repeated measures analysis of each domain were analyzed retrospectively. Significance testing was at two-sided 0.05 without adjustment for multiplicity. Results: Of 198 pts randomized (surufatinib n = 129; placebo n = 69), 197 (99.5%) patients completed HRQoL questionnaires at baseline. The questionnaire compliance rate was >90% for most on-treatment assessments. The TUDD was significantly longer in the surufatinib arm versus the placebo arm in the dyspnea domain (hazard ratio [HR] 0.52, p = 0.0103) and social function scale (HR 0.58, p = 0.0222), while the TUDD of diarrhea was significantly shorter in the surufatinib arm compared to placebo (HR 2.68, p = 0.0074). There was no significant difference of TUDD in the remaining domains of QLQ-C30 and G.I.NET-21. There was also no significant difference of the mean change of scores from baseline by repeated measures in the domains between the two arms except diarrhea (increase of 14.0 points [95% CI 9.6, 18.4] in the surufatinib arm versus 2.1 points [95% CI -4.1, 8.4] in the placebo arm, p = 0.0007). Conclusions: Treatment with surufatinib resulted in superior efficacy, acceptable toxicity, while generally maintaining HRQoL, which support surufatinib as a treatment option in this patient population that was previously treated with available therapies for epNETs. Clinical trial information: NCT02588170 .

To investigate the lipase-catalyzed synthesis of high purity sn-1/3 and sn-2 monoacylglycerols (1/3-MAG and 2-MAG) of different fatty acids (FAs). The 1/3-MAGs of three FAs (16:0, 17:0, 16:1) were synthesized using lipase-catalyzed esterification of glycerol with FAs. The 2-MAGs were obtained from the ethanolysis of synthetic triacylglycerols using sn-1,3 regiospecific lipase. The effects of lipase types, substrate ratio, temperature, reaction time and lipase load on the MAG conversion were studied. Under the optimal conditions, high purities (96.74%, 95.44%, 92.96%) with acceptable isolated yields (51.00%, 54.28%, 46.00%) were obtained for 1/3-16:0-MAG, 1/3-17:0-MAG, and 1/3-16:1-MAG, respectively. For 2-16:0-MAG, 2-17:0-MAG, and 2-16:1-MAG, the purities were 92.64, 95.04, and 96.48%, with isolated yields of 50.64, 52.16, and 26.12%, respectively. The molecular structures of the synthetic compounds were confirmed by 1H NMR, and MS and the melting points were characterized by DSC. High purity MAG isomers can be synthesized via lipase-catalyzed reactions to be building blocks for production of functional lipids, the melting points of which are largely governed by the hydrophobic interactions among the alkanyl chains.

Accurate sound localization requires normal binaural input and precise auditory neuronal representation of sound spatial locations. Previous studies showed that unilateral hearing loss profoundly impaired the sound localization abilities. However, the underlying neural mechanism is not fully understood. Here, we investigated how chronic unilateral conductive hearing loss (UCHL) affected the neural tuning to sound source azimuth in the primary auditory cortex (AI). The UCHL was manipulated by the removal of tympanic membrane and malleus in the right ear of young (P14) rats and adult (P57) rats. We recorded the azimuth tuning of neurons in the left AI contralateral to the operated ear in the two groups of rats that experienced 2 months of UCHL, and in the left AI of age-matched control rats. We found that AI neurons in control rats showed predominant preference to sound from contralateral azimuths. However, UCHL weakened the cortical neuronal representation of contralateral azimuths on the operated ear side and strengthened the cortical neuronal representation of ipsilateral azimuths on the intact ear side. This effect was stronger in rats with UCHL at young age than in rats with UCHL in adulthood. Moreover, UCHL degraded the azimuth selectivity and azimuth sensitivity of AI neurons, and this effect was stronger in rats with UCHL in adulthood than in rats with UCHL at young age. These findings highlight a remarkable age-related experience-dependent plasticity of neural tuning to sound source azimuth in AI, and imply a neural mechanism for the impacts of chronic UCHL on sound localization abilities.

The hierarchical electrocatalysts with the superaerophobic property are in favor of removal of gas bubbles and supply of numerous active sites to improve the electrochemical catalytic activity for water splitting. In this work, the self-supported Zn-doped CoNiP (Zn–CoNiP/NF) hierarchical structure that consisted of nanothorns and radial microspheres were prepared with via a facile precursor phosphorization method. Zn-doping could tailor the initial electronic state of CoNiP to improve the hydrogen or oxygen atom binding, which effectively promoted the catalytic kinetics of water splitting. The hierarchical structure not only offered more catalytic active sites for water splitting, but also facilitated gas releasing due to the superaerophobic interface. The hierarchical Zn–CoNiP structure showed a high hydrogen evolution reaction (HER) efficiency in electrolytes with pH 0–14, which yielded low overpotentials of 73 mV in acidic solution and 34 mV in alkaline media at current density of 10 mA cm−2. Furthermore, it also had evidenced by an overpotential of 310 mV for oxygen evolution reaction (OER) at the current density of 50 mA cm−2. Note that the required cell initial voltage was 1.51 V for overall water splitting. These results were comparable or even better than many non-noble catalysts.

The aim of this study was to investigate the mechanism by which KLF6-SV1 promoted lung cancer metastasis through tumor-associated macrophages (TAMs). Plasmid transfection was used to construct cells that upregulated or silenced gene. Tumor-bearing mouse model was established using A549 cells. SP staining was performed to detect the CD163 and CD68. Six-well plates and Transwell chamber were used for co-culture of lung cancer A549 cells and macrophages. CCK-8 and Transwell assay were applied to detected the cell viability and migration respectively. Protein and mRNA were tested by Western blot and quantitative real-time polymerase chain reaction (qRT-PCR).KLF6-SV1 overexpression promoted the expression levels of TWIST1 and CCL2, and also induce macrophage polarization to M2 and epithelial-mesenchymal transition (EMT). In vitro experiments showed that KLF6-SV1 might regulate the migration of lung cancer cells by regulating the expression of TWIST1 and CCL-2. M2 macrophages did not affect the expression of KLF6-SV1, TWIST1 and CCL-2. The co-culture system could up-regulate the EMT of A549 cells.Overexpression of KLF6-SV1 promoted the expression of TWIST1 and CCL2, and up-regulation of TWIST1 expression might promote the infiltration of M2 macrophages, which promoted the involvement of EMT in the metastasis of lung cancer cells.

Objectives: The objective of the study is to investigate the role of basic fibroblast growth factor (bFGF) in sensitivity to cisplatin in non-small cell lung cancer (NSCLC) A549 cells and its effect on the stemness characteristics of NSCLC cells, revealing possible mechanisms of cisplatin resistance. Materials and Methods: After A549 cells were treated with cisplatin, bFGF protein expression was analyzed by Western blot. A549 cells were transfected with bFGF small interfering RNAs (siRNAs), and the knockdown efficiency was confirmed by quantitative reverse transcription polymerase chain reaction and Western blot. After bFGF downregulation, A549 cell proliferation was assessed by Cell Counting Kit-8 assay. The effect of bFGF siRNA on the sensitivity to cisplatin was evaluated by cell viability assays and flow cytometry for cell apoptosis. Colony formation assay was performed to explore whether bFGF affected the stemness characteristics of A549 cells, and OCT-4 protein expression was analyzed by Western blot after bFGF siRNA treatment. Results: Cisplatin treatment enhanced bFGF expression in A549 cells. After A549 cells were transfected with bFGF siRNAs, bFGF expression was significantly decreased compared to that in the negative control siRNA group. In addition, bFGF knockdown inhibited A549 cell proliferation. bFGF siRNA treatment enhanced the inhibitory effect of different concentrations of cisplatin on cell viability and promoted cisplatin-induced apoptosis in A549 cells. Further analyses showed that bFGF siRNA treatment not only significantly decreased colony formation in A549 cells but also downregulated OCT-4 protein expression. Conclusion: bFGF decreased NSCLC sensitivity to cisplatin in vitro, while it enhanced colony formation ability and increased OCT-4 expression of A549 cells, which might account for its involved mechanisms of cisplatin resistance.

Background Anlotinib is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, and stem cell factor receptor (c-Kit). In the phase III ALTER-0303 trial (Clinical Trial Registry ID: NCT 02388919), anlotinib significantly improved overall survival versus placebo in advanced non-small cell lung cancer patients who had received at least two previous chemotherapy and epidermal growth factor receptor/anaplastic lymphoma kinase targeted therapy regimens. This study summarized adverse event management in this trial. Methods Patients were randomized (2:1) to anlotinib or placebo up to progression or intolerable toxicity. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and managed by investigators. Key strategies for preventing and managing the most common adverse events included patient education, supportive care, and dose modification. Results Between February 2015 and August 2016, 294 patients received anlotinib. A total of 170 (57.8%) patients received antihypertensive medications for hypertension, 53 (18.0%) patients received levothyroxine for hypothyroidism, 24 (8.2%) patients received fibrates for hypertriglyceridemia, 11 (3.7%) patients took cortisone cream for hand-foot syndrome, and 38 (12.9%) patients received anti-diarrheal medications for diarrhea. Dose reduction and drug discontinuation were required in 24 (8.16%) and 31 (10.54%) patients in the anlotinib group, respectively. Conclusion Anlotinb-related adverse events could be controlled by patient education, prophylactic measures, early and active intervention, and dose modification.

A sufficient supply of reducing equivalents is essential for obtaining the maximum yield of target products in anaerobic fermentation. The pyruvate dehydrogenase (PDH) complex controls the critical step in pyruvate conversion to acetyl-CoA and NADH. However, in anaerobic Escherichia coli, PDH residing in the dihydrolipoamide dehydrogenase (LPD) component is normally inactive due to inhibition by NADH. In this study, the protein engineering of LPD by structural analysis was explored to eliminate this inhibition. A novel IAA350/351/358VVV triple mutant was successfully verified to be more effective than other LPD mutants reported till date. Notably, PDH activity with the triple mutant at an [NADH]/[NAD+] ratio of 0.15 was still higher than that of the wild-type without NADH addition. The altered enzyme of the PDH complex was also active in the presence of such high NADH levels. This is the first study concerning protein engineering of PDH by structure-guided design. The presence and functional activity of such an NADH-insensitive PDH complex provides a useful metabolic element for fermentation products and has potential for biotechnological application.

Background Mesenchymal stem cells (MSCs) possess powerful immunosuppression capacity. Transforming growth factor-β (TGF-β) is a well-known anti-inflammatory cytokine and plays an important role in various inflammatory processes. We hypothesized that TGF-β could synergize with MSCs in suppressing immune responses, and therefore established a mouse skin graft model to evaluate the effect of MSCs and MSCs combined with TGF-β on transplantation immunity in vivo. Methods Balb/c and C57BL/6 mice were used to establish the skin graft model. The recipients were divided into 3 groups and received intravenous bone marrow mesenchymal stem cells (BMSCs), BMSCs pretreated with TGF-β, and 0.9% saline solution, respectively. Skin graft survival time, pathological detection, the ratio of CD4+CD25+Foxp3+Treg cell of spleens, and the level of IFN-γ, IL-2, IL-10, and TGF-β expression were tested. Results The survival time of skin grafts were prolonged in both BMSC (12.5 ± 1.35 days) and BMSC-TGF-β (10.6 ± 1.90 days) recipients compared to the blank control recipients (8.0 ± 1.05 days). The ratio of CD4+CD25+Foxp3+Treg cell of spleens from BMSC and BMSC-TGF-β recipients was higher than that of the blank control, and the upregulated proliferation in the BMSC group occurred earlier and was prolonged compared to the BMSC-TGF-β group. The expression of IFN-γ and IL-2 was inhibited in both the BMSC and BMSC-TGF-β groups compared to the blank, while the expression of IL-10 and TGF-β was boosted. In contrast to the BMSC group, the BMSC-TGF-β group exhibited a weaker effect on the expression of cytokines. Conclusion TGF-β partially reversed the immunosuppressive effect of MSCs in vivo. This immunoregulatory feature may have potential applications for treating transplant rejection.

Because of its simple structure, high power density and high efficiency, the applications of permanent magnet synchronous machine (PMSM) gain continual expansion, and the low-noise and high-performance PMSM has also become one of the hot research spots. In [1]–[4], the analytical calculation of the air-gap magnetic field of PMSM is studied in detail, and the transient magnetic field distribution of the surface permanent magnet brushless DC machine is obtained. Accordingly, an analytical model of analyzing the radial electromagnetic force wave in fractional-slot PMSM is established, and the influence of stator slotting, etc. on electromagnetic force waves are calculated in [5]. In [6], the vibration characteristics of four different types of interior PMSMs are analyzed by the finite element method (FEM), and the influence of winding configurations on the vibration characteristics is obtained, however, it is difficult to distinguish the source of exciting wave. In this paper, a method of calculating radial electromagnetic force combining analytical method and FEM is proposed. With this method, the influence of slot size is considered, meanwhile, the integral expression of radial electromagnetic force wave is calculated accurately and conveniently. Further, the influences of slot opening width, skewed slot rate, pole arc coefficient, eccentricity on the electromagnetic force wave are analyzed, which lay the theoretical foundation for the weakening of electromagnetic vibration.

Permanent magnet coupler (PMC) acts as a magnetic transmission device, the motivation and torque are transmitted through the interaction between the conductor rotor (CR) and permanent magnet rotor (PMR), the mechanical contact between the motor and load is eliminated. And for the effective suppression of the vibration, high reliability and efficient operation, it has been applied in electric power, petrochemical industry, pumps, blowers, water treatment and other fields [1]–[3]. Many structures of the PMCs had been designed, considering the rotational couplers, configurations as radial and axial magnetic flux represent two possible solutions [4]. For the typical axial flux coupler (i.e., disk type) and radial flux coupler (i.e., cylindrical type), the produced torque was controlled by adjusting the length of air gap or the coupling area between the CR and PMR [5]. However, the magnetic field utilization is lower for disk type, and additional mechanical devices are also needed to adjust the axial relative position between the CR and PMR for both types, the reliability is reduced and the space volume is increased. In [6], a flux adjustable PMC with a movable stator ring, whose slip speed can be adjusted by shifting the movable stator ring along the axial direction, was proposed, and the complicated mechanical devices can be avoided. In this paper, a novel flux adjustable PMC with a double-layer PMR is presented. The magnetic flux is adjusted by circumferentially controlling the relative position of the PMR’s two layers, the axial movement is replaced.

The surface-mounted permanent magnet (SPM) motors with NdFeB magnets, offering high torque density and high efficiency, have been widely applied to various domestic and industrial applications [1]. However, the adoption of NdFeB magnets not only brings high torque density, but also leads to high torque pulsations and high magnet cost. The approaches to suppress torque pulsations in SPM motors have been heavily investigated through drive control or motor design methods [2], [3]. In particular, the suppression of cogging torque has received great attention along with numerous methods, such as skewing [4], auxiliary slots [5], teeth notching [6], and slot-opening shifting [7], etc. However, most of the methods to suppress cogging torque may not result in low torque ripple due to the effects of armature reaction fields. Hence, the approaches to suppress both cogging torque and torque ripple simultaneously are more desired. It is well known that the magnet flux density distribution has a significant effect on torque performance. Accordingly, extensive magnet shaping methods, such as magnet pole shape optimization [8] and sinusoidal magnet poles [9], have been reported to obtain a sinusoidal magnet flux density distribution, thus to reduce torque pulsations. However, these reported methods inevitably lead to manufacturing difficulty and performance degradation. Regarding to the magnet cost saving, the approaches by using ferrite magnets, or hybrid ferrite and NdFeB magnets are investigated, but generally neglecting the issues on torque pulsations [10]. In this paper, an optimal design is proposed for the SPM motor to reduce the cogging torque and toque ripple, and save the magnet cost using multi-grade NdFeB and ferrite magnets. Based on a conventional SPM motor with single-grade NdFeB magnets, the proposed SPM motor is designed with three-grade NdFeB and ferrite magnets, and then optimized to further reduce torque pulsations and save the magnet cost by maintaining the high average torque using the Kriging method and a genetic algorithm. All the motor characteristics are first predicted using the finite element method (FEM) at the same operating conditions. Then the experimental test is performed for the optimized model to validate the optimal design and analysis results.

Line-start permanent magnet synchronous motor (LSPMSM) has been widely used in applications such as pumps, fans and compressors for its high torque and power density, efficiency and power factor [1]–[2]. However, it suffers from the poor starting and synchronization capabilities, and always a compromise between the starting and synchronization capabilities is adopted because of the conflict with each other [3]–[4]. So far, several different rotor configurations, such as squirrel-cage rotor, solid rotor, slotted solid rotor, two-part rotor geometry and so on [5]–[7], and different magnet, cage bars shapes [8]–[9], were presented and discussed to improve the starting and synchronization capabilities. But the starting capability cannot get fundamentally improved for the existence of the braking and pulsating torques. In [10]–[12], the pole changing method was presented, and the drawbacks of PMSM got overcame. However, more switches were used, and the reliability was reduced for the proposed 2/4 pole changing winding. In addition, the turn numbers cannot be adjusted to balance the starting and running performance. In this paper, a 6/8 pole changing LSPMSM is designed based on the novel 6/8 pole changing stator winding. As the different pole numbers between stator winding and rotor PMs during 6-pole starting process, the inherent braking torque and pulsating torque for conventional LSPMSM can get effectively eliminated, and the starting capability can be fundamentally improved. Furthermore, as the effective improvement of the starting capability, the rotor resistance can be optimized to be smaller to improve the synchronization capability simultaneously.

Feline leukemia virus subgroup C receptor 1 (FLVCR1) has been reported to have a crucial role in variety of biological processes, including cell proliferation, cell death, apoptosis, oxidative stress response, cellular differentiation and metabolism. However, little is known about its role in synovial sarcoma (SS). In the current study, FLVCR1 expression was analyzed in two SS cell lines (SW982 and HS-SY-II), and in eight SS tissues and paired adjacent non-tumor tissues using reverse transcription-quantitative polymerase chain reaction, western blot analysis and immunohistochemistry. Lentivirus-mediated short hairpin RNAs were used to knock down FLVCR1 expression in SW982 and HS-SY-II cells. The effects of FLVCR1 knockdown on the cell proliferation, clonogenicity, cell cycle and apoptosis in SS cells were evaluated by MTT, colony formation assay, flow cytometry analysis, western blotting and in vivo tumorigenesis in nude mice. In the current study, gene expression of FLVCR1 was upregulated in SS cell lines (SW982 and HS-SY-II) and SS tissues from patients. The protein levels of FLVCR1 in SS tissues were also significantly higher than in adjacent non-tumor tissues. Furthermore, suppressing the expression of FLVCR1 in SS cells using short hairpin RNA effectively attenuated cell proliferation, colony formation and impaired the cell cycle, and also significantly induced apoptosis and autophagy. In accordance with this, an in vivo tumorigenicity assay in mice demonstrated that suppression of FLVCR1 expression inhibited the growth of SS tumors implanted subcutaneously. Collectively, these results demonstrated that FLVCR1 may act as an oncoprotein, and have key roles in promoting proliferation and tumorigenicity of SS, and this may shed new light on finding novel therapeutic strategies against SS.

MicroRNAs (miRs) have been demonstrated to regulate various biological processes in human cancer, including non-small cell lung cancer (NSCLC). However, little evidence has been provided regarding the exact role of miR-200c in mediating the malignant progression of NSCLC, as well as the underlying mechanism. The present study aimed to investigate the putative role of miR‑200c in the progression of NSCLC. The expression levels of miR‑200c were significantly reduced in NSCLC cell lines compared with in normal lung epithelial cells, as determined by reverse transcription‑quantitative polymerase chain reaction. Overexpression of miR‑200c significantly suppressed cell migration and invasion of A549 NSCLC cells. Results of a luciferase reporter assay further identified zinc finger E‑box‑binding homeobox 2 (ZEB2) as a direct target gene of miR‑200c, and the expression of ZEB2 was shown to be suppressed in A549 cells overexpressing miR‑200c. Furthermore, small interfering RNA‑mediated inhibition of ZEB2 suppressed the migration and invasion of A549 cells. In addition, since ZEB2 is an epithelial‑mesenchymal transition (EMT) regulator, the role of miR‑200c in the regulation of EMT in NSCLC cells was further examined. Results of a western blot analysis indicated that overexpression of miR‑200c upregulated E‑cadherin, and downregulated N‑cadherin and vimentin expression in A549 cells, thus suggesting that EMT was suppressed. Based on these results, the present study suggested that miR‑200c was able to inhibit the metastasis of NSCLC cells by targeting ZEB2. Therefore, miR-200c may be considered as a potential candidate for the treatment of NSCLC.

A comparative transcriptome analysis was conducted to study the expression profiles of the lactic acid-producing strain Bacillus coagulans P38 cultivated in the presence and absence of 2-furfural stress. In response to 7 g l−1 2-furfural stress, the cell growth rate of B. coagulans P38 was reduced, and a total of 740 genes were upregulated and 540 genes downregulated. KEGG pathway enrichment analysis revealed that nine pathways were significantly affected by 2-furfural stress (P

The imbalance of regulatory T cell/T-helper 17 (Treg/Th17) is critical for the pathogenesis of immune thrombocytopenia (ITP) and IL-17A and IL-21 are overexpressed in ITP. The effects and mechanisms of IL-17A and IL-21 in Treg/Th17 imbalance and ITP pathophysiology are not clarified.Peripheral blood mononuclear cells (PBMCs) and CD3(+) T cells from ITP patients and healthy controls were treated with cytokines or antibodies to increase or neutralize IL-17A or IL-21 levels for 72 h. Treg/Th17 differentiation, apoptosis, proliferation and Th17 differentiation-associated transcriptional factors were analyzed.Natural Treg/Th17 decreased in newly diagnosed ITP patients and recovered after remission. IL-17A or IL-21 increased Th17, decreased Tregs and downregulated Treg/Th17 in vitro. Conversely, neutralization of IL-17A or IL-21 decreased Th17, increased Tregs and up-regulated Treg/Th17. The reverse effects of IL-17A or IL-21 were mediated by Th17-associated transcriptional factors. IL-17A or IL-21 enhanced STAT-1, STAT-3, STAT-5 or RAR-related orphan receptor C (RORC), whereas anti-IL-17A or anti-IL-21 mAb downregulated STAT-1, STAT-5 or RORC transcripts in ITP PBMCs. Proliferation showed no significant difference. IL-21 inhibited apoptosis in ITP PBMCs.IL-17A and IL-21 induce Th17 and inhibit Tregs re-differentiation via Th17-associated signaling pathway in ITP patients in vitro. It highlights the potential value of IL-17A or IL-21 blockade as a novel therapeutic target for ITP.

The transcription factor TAp73, a transcriptionally active isoform of p73, has high structure and function similaritieswith its homolog p53, therefore, are thought to be a cancer therapy candidate target. However, there is still a controversy about the tumor suppressor role of TAp73, since it has been found in numerous studies that TAp73 expression is elevated in different cancers. Thus, we take effort to clarify the influence of TAp73 on gastric cancer (GC) chemotherapy. Multiple cell lines of GC such as SNU-1, SNU-3, and AGS were applied to investigate expression of TAp73. Flow cytometry was utilized to detect apoptosis, revealing how TAp73 overexpression affected anticancer drug (ACD). Additionally, we explored how TAp73 overexpression influenced apoptotic cells of neoplastic tissues and tumor size of nude mice in vivo. Our results indicated that TAp73 was down-regulated in GC cells after chemotherapy drugs treatment. Besides, enforced expression of TAp73 affects chemotherapeutic drugs induced GC cell apoptosis, which is dependent on p53. The expression of TAp73 was regulated by its transcription factor, E2F1, in response to chemotherapy drugs. Our in vivo xenograft results also suggested that transfection of TAp73 affects the tumor suppression effect of 5-FU. Consequently, the findings of our study demonstrate that E2F1 and TAp73α are oncogenic and throw light upon the underlying mechanism of their role against apoptosis.

Background Gastric cancer (GC) is one of the most common cancers with high mortality globally. However, the molecular mechanisms of GC are unclear, and the prognosis of GC is poor. Therefore, it is important to explore the underlying mechanisms and screen for novel prognostic markers and treatment targets. Methods The genetic and clinical data of GC patients in The Cancer Genome Atlas (TCGA) was analyzed by weighted gene co-expression network analysis (WGCNA). Modules with clinical significance and preservation were distinguished, and gene ontology and pathway enrichment analysis were performed. Hub genes of these modules were validated in the TCGA dataset and another independent dataset from the Gene Expression Omnibus (GEO) database by t-test. Furthermore, the significance of these genes was confirmed via survival analysis. Results We found a preserved module consisting of 506 genes was associated with clinical traits including pathologic T stage and histologic grade. PDGFRB, COL8A1, EFEMP2, FBN1, EMILIN1, FSTL1 and KIRREL were identified as candidate genes in the module. Their expression levels were correlated with pathologic T stage and histologic grade, also affected overall survival of GC patients. Conclusion These candidate genes may be involved in proliferation and differentiation of GC cells. They may serve as novel prognostic markers and treatment targets. Moreover, most of them were first reported in GC and deserved further research.

Th17 cells are a new subset of CD4(+) T cells involved in the clearance of extracellular pathogens and fungi. Accumulating evidence suggests that Th17 cells and their signature cytokines have a pivotal role in the pathogenesis of multiple autoimmune-mediated inflammatory diseases. Here, we summarize recent research progress on Th17 function in the development and pathogenesis of autoimmune diseases. We also propose to identify new small molecule compounds to manipulate Th17 function for potential therapeutic application to treat human autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, inflammatory bowel disease, and multiple sclerosis.

We investigated the antioxidant content and conducted a cytological examination of the aqueous fluid and lenses of patients with age-related cataracts at different stages. The levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) in the aqueous fluid and lenses were determined by the xanthine oxidase method, the colorimetric method, and the improved reduced glutathione (GSH) depletion method, respectively. SOD, CAT, and GSH-PX content in the aqueous fluid and lenses decreased significantly with increasing lenticular nucleus hardness grading. However, the number of white blood cells, neutrophils, monocytes, lymphocytes, and eosinophils did not vary significantly with varying lenticular nucleus hardness. Antioxidant content examination is an important quantitative indicator for clinical diagnosis and treatment of age-related cataracts. Antioxidant content in the aqueous fluid and lenses decreased significantly with increasing lenticular nucleus hardness grading. Lenses at hardness level V had the lowest content of antioxidants.

We report the synthesis of highly crystalline, small sized, α-NiS nanocrystal inks for the fabrication of a counter electrode for dye-sensitized solar cells. Monodisperse α-NiS nanocrystals (about 7 nm) are obtained via a noninjection, solution-phase chemical synthesis method. During the growth process of α-NiS nanocrystals, the Ni–oleate complex, which is generated in situ from the reaction of nickel chloride and sodium oleate, is decomposed and acts effectively as a growth source in synthesizing monodisperse nanocrystals. By controlling the reaction temperature, the resultant nanocrystal sizes and crystallinity can be well tuned. Compared to conventionally obtained NiS bulk materials, monodisperse α-NiS nanocrystals possess abundant catalytic reaction sites for dye-sensitized solar cells due to their small particle size and high crystallinity. First-principles calculations have been employed for the first time to investigate the adsorption energy of I3− molecules on the (111) surface of α-NiS with equilibrium shape. DSSCs based on monodisperse α-NiS nanocrystal ink with higher crystallinity display a power conversion efficiency of 7.33%, which is comparable to that based on the Pt cathode (7.53%), but significantly higher than that based on the bulk NiS (4.64%) and relatively low-crystalline α-NiS nanocrystals (6.32%). It can be attributed to more reaction catalytic sites due to the surface effect of small α-NiS nanocrystals, and the highest work function level (5.5 eV) that matched the redox shuttle potential. We believe that our method paves a promising way to design and synthesize advanced counter electrode materials for energy harvesting.

Cu

Uridine diphosphate glucuronosyltransferase 1A (UGT1A1), which affects irinotecan metabolism, has been associated with severe adverse reactions in patients with cancer treated with irinotecan. However, neither large-scale analysis of the distribution of UGT1A1 polymorphisms, nor standardized assessment of how UGT1A1 polymorphisms affect irinotecan treatment has been performed in China. The aim of the present study was to investigate the distribution of UGT1A1 polymorphisms (*28 and *6) in 2,093 Chinese patients with cancer who were treated with irinotecan from more than 15 hospitals in Shandong, to examine how the coexistence of UGT1A1*6 and UGT1A1*28 alleles may be able to predict toxicities induced by irinotecan in 105 of the patients, and to search for other relevant risk factors. The distribution of the genotypes was as follows: TA6/TA6 (1,601, 76.5%), TA6/TA7 (463, 22.1%) and TA7/TA7 (29, 1.4%) for UGT1A1*28 (n=2,093); and G/G (286, 66.4%), G/A (124, 28.8%) and A/A (21, 4.9%) for UGT1A1*6 (n=431). The most frequent severe hematological toxicity was neutropenia, and the predominant non-hematological toxicities were diarrhea and cholinergic syndrome. In toxicity comparisons, grade 3–4 leukopenia and neutropenia were significantly higher in TA6/TA7 compared with TA6/TA6 (P

The fabrication of low-cost and earth-abundant electrocatalysts for the hydrogen evolution reaction (HER) over a broad pH range is attractive. In this work, a facile precursor route is developed to synthesize flower-like nickel phosphide microballs with a diameter of approximately 12 μm. With a controlled phosphorization temperature, flower-like nickel phosphide microballs with different crystalline structures (Ni5 P4 and Ni2 P) were obtained easily. Flower-like Ni5 P4 microballs possessed two advantageous features for enhanced HER: fast vectorial electron transfer path along the building block nanoplates and enhanced inherent catalytic activity of each active site for high-energy (0 0 1) facets. The flower-like Ni5 P4 microballs electrocatalyst thus displayed excellent activity for the HER with a low overpotential (η) of 35.4 mV to reach current densities of 10 mA cm-2 and a small Tafel slope of 48 mV dec-1 in acid solution. In addition, it showed excellent activity in 1 m KOH with η=47 mV at 10 mA cm-2 . DFT studies indicated that the free energy of hydrogen adsorbed on the Ni site of Ni5 P4 was 0.152 eV, which is smaller than that of the Ni site of Ni2 P (0.182 eV). Therefore, flower-like Ni5 P4 microballs exhibited better HER activity than Ni2 P, which is consistent with our HER data. This hierarchical structure with exposed high-energy (0 0 1) facets paves the way to design and synthesize low-cost, high-performance catalysts for the HER.

To explore the mechanism of RAP2C participating in spinal cord ischemia-reperfusion injury (SCII).mRNA expressions of miR-204 and RAP2C were measured by qRT-PCR. Protein level of RAP2C was detected by Western blot. Cell apoptosis in AGE1.HN and PC12 cells was detected by Annexin V/propidium iodide assay. The effect of miR-204 knockdown or overexpression on RAP2C expression was observed by luciferase assay.In this experimental research, RAP2C expression in SCII group was lower than control group, while miR-204 expression was higher. In addition, RAP2C expression in AGE1.HN and PC12 cells under hypoxic condition was lower than control group, while miR-204 expression was higher. Hypoxia increased cell apoptosis, and overexpression of RAP2C reversed this effect. In cells treated with hypoxia and miRNA-204 inhibitor, hypoxia upregulated the expression of miR-204, while miRNA-204 inhibitor reversed this effect. Hypoxia downregulated the expression of RAP2C, while miR-204 inhibitor reversed this effect. Moreover, miR-204 could bind to 3'-UTR of RAP2C. And miR-204 inhibitor upregulated the activity and expression of RAP2C, while miR-204 mimic played the opposite role. Finally, hypoxia downregulated RAP2C expression, miR-204 inhibitor upregulated RAP2C expression, while Ad-sh-RAP2C inhibited RAP2C expression. What's more, hypoxia increased the apoptosis rate, miR-204 inhibitor decreased the apoptosis rate, while si-RAP2C increased the apoptosis rate.SCII causes increase of neurocyte apoptosis by inhibiting RAP2C via miR-204.

Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 μg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p

Impurity doping plays a critical role in altering the properties of target nanomaterials in terms of designed morphologies, crystal structures, and functionalities. In this work, we have performed a comprehensive investigation of the effect of Li

Katanin, a microtubule-severing enzyme, consists of two subunits: the catalytic subunit P60, and the regulatory subunit P80. In several species, P80 functions in meiotic spindle organization, the flagella biogenesis, the neuronal development, and the male gamete production. However, the P80 function in higher plants remains elusive. In this study, we found that there are three katanin P80 orthologs (OsKTN80a, OsKTN80b, and OsKTN80c) in Oryza sativa L. Overexpression of OsKTN80a caused the retarded root growth of rice seedlings. Further investigation indicates that the retained root growth was caused by the repressed cell elongation in the elongation zone and the stalled cytokinesis in the division zone in the root tip. The in vivo examination suggests that OsKTN80a acts as a microtubule stabilizer. We prove that OsKTN80a, possibly associated with OsKTN60, is involved in root growth via regulating the cell elongation and division.

e20507 Background: In ALTER 0303, the common adverse reaction (AE) included hypertension (HTN) and hand foot syndrome (HFS). In this subgroup analysis, we aim to assess the relationship between common AEs and clinical benefit in anlotinib cohort. Methods: Eligible patients showed disease progression after second-line or further treatment were randomly assigned in a 2:1 ratio to receive 12 mg/day of anlotinib or placebo. The primary endpoint was overall survival (OS). This subgroup analysis was based on anlotinib cohort. Results: Patients with HTN had significantly improved median OS, median progress-free survival (PFS), objective response (ORR) and disease control rate (DCR) compared with patients without HFS in anlotinib cohort. Similarly, patients with HFS had better clinical outcomes in anlotinib cohort. Not surprisingly, patients occurred both HFS and HTN had more superior medium OS compared with only HFS, only HTN and neither HFS nor HTN. Conclusions: HTN or HFS is associated with better clinical outcomes in advanced NSCLC patients received anlotinib. Clinical trial information: NCT02388919. [Table: see text]

e20503 Background: As a promising multi-target tyrosine kinase inhibitor (TKI), anlotinib hydrochloride significantly improved overall survival (OS) and progression-free survival (PFS) in advanced NSCLC patients in the phase 3 trial (ALTER0303). Here, we demonstrated the efficacy of anlotinib in SCC patients with or without hypertension. Methods: Patients (n = 439) were randomized in a 2:1 ratio to receive anlotinib (12mg daily for 14 days in a 21 day cycle) or placebo. The primary endpoint was OS and second endpoints were PFS, ORR, DCR and QoL. The correlation between hypertension and efficacy (PFS and OS) was analyzed in SCC patients treated with anlotinib. Results: For different ECOG score (0 and 1) SCC patients (n = 46) in the anlotinib arm, the PFS was significantly improved in patients with hypertension in ECOG 1 group (7.00 vs 4.83 months, p = 0.043). There is no statistical difference in other subgroups. Moreover, for the SCC patients in anlotinib arm, PFS was significantly prolonged in patients with hypertension compared to the patients without hypertension (7.23 vs 3.23 months; HR = 0.36; 95% CI, 0.16–0.84; P = 0.001). However, the median OS of the patients with hypertension was numerically but not statistically longer than the patients without hypertension (13.93 vs 6.30 months; HR = 0.56; 95%CI, 0.26-1.22; P = 0.100). Conclusions: In the ALTER0303 trial, anlotinib significantly improved PFS with a potential benefit of OS for SCC patients with hypertension. And ECOG score does not affect the efficacy of anlotinib in SCC patients with or without hypertension. Clinical trial information: NCT02388919. [Table: see text]

In our previous studies, we found that plague vaccines can induce long-term antibody response, but no significant antibody boost was observed when the immunized mice were challenged with virulent Yersinia pestis. However, a booster vaccination of subunit vaccine on week 3 after primary immunization elicited a significantly higher antibody titre than a single dose, whereas no significant antibody titre difference was observed between a single dose and two doses of EV76 vaccination. To address these issues, in this study, we first investigated the kinetics of memory B cells and plasma cells in the mice immunized with EV76 or F1 protein by flow cytometry and then determined antibody titre in five groups of mice immunized with various vaccination strategy. The results showed that memory B cells dropped to a low level at day 56 after primary immunization. In contrast, plasma cells were maintained for more than 98 days. The group with primary immunization of EV76 and booster of F1 antigen developed a higher antibody titre than the group with immunization of F1 antigen and booster of EV76. This result supports a hypothesis that an excess of antigens can neutralize pre-existing antibodies, and then the redundant antigen induces antibody boost. Taken together, a boost of antibody titre after revaccination may be dependent on the existence of memory B cells and an excess of antigen vaccination. In addition, this study showed an ideal immunization strategy that involves first immunization with a live attenuated vaccine, such as EV76, and then with a subunit vaccine.

Purpose To investigate the impact of the cytidine deaminase (CDA) A79C polymorphism on both the response to gemcitabine in non-small cell lung cancer (NSCLC) patients and the risk of hematologic toxicities in patients bearing any kind of cancer taking gemcitabine. Methods The PubMed and Embase databases were searched from the first available article to January 2013. Eligible studies included clinical trials that contained the keywords “gemcitabine” or “cytidine deaminase” and information about response rate of NSCLC patients or hematologic toxicities in patients with any kind of cancer. Relative risk (RR) of different genotypes and 95% confidence intervals (CI) were calculated. Results A total of 7 articles (623 patients from 6 studies) were included. The results showed that patients with wild type CDA (AA and AC) had a significantly lower rate of severe anemia than the homozygote mutant type CC (RR=0.308; 95%CI, 0.113-0.021, p=0.021). However, the rate of severe neutropenia, thrombocytopenia, and the response rate were identical between different CDA genotypes. Conclusion The A79C CDA polymorphism did not show a significant impact on the response rate to gemcitabine in NSCLC patients, while the wild type CDA genotype was indeed correlated to a lower rate of incidence of severe anemia in patients taking gemcitabine.