Search

Background Autophagy is a conserved catabolic process, which plays an important role in regulating tumor cell motility and degrading protein aggregates. Chemotherapy-induced autophagy may lead to tumor distant metastasis and even chemo-insensitivity in the therapy of hepatocellular carcinoma (HCC). Therefore, a vast majority of HCC cases do not produce a significant response to monotherapy with autophagy inhibitors. Results In this work, we developed a biomimetic nanoformulation (TH-NP) co-encapsulating Oxaliplatin (OXA)/hydroxychloroquine (HCQ, an autophagy inhibitor) to execute targeted autophagy inhibition, reduce tumor cell migration and invasion in vitro and attenuate metastasis in vivo. The tumor cell-specific ligand TRAIL was bioengineered to be stably expressed on HUVECs and the resultant membrane vesicles were wrapped on OXA/HCQ-loaded PLGA nanocores. Especially, TH-NPs could significantly improve OXA and HCQ effective concentration by approximately 21 and 13 times in tumor tissues compared to the free mixture of HCQ/OXA. Moreover, the tumor-targeting TH-NPs released HCQ alkalized the acidic lysosomes and inhibited the fusion of autophagosomes and lysosomes, leading to effective blockade of autophagic flux. In short, the system largely improved chemotherapeutic performance of OXA on subcutaneous and orthotopic HCC mice models. Importantly, TH-NPs also exhibited the most effective inhibition of tumor metastasis in orthotopic HCCLM3 models, and in the HepG2, Huh-7 or HCCLM3 metastatic mice models. Finally, we illustrated the enhanced metastasis inhibition was attributed to the blockade or reverse of the autophagy-mediated degradation of focal adhesions (FAs) including E-cadherin and paxillin. Conclusions TH-NPs can perform an enhanced chemotherapy and antimetastatic effect, and may represent a promising strategy for HCC therapy in clinics. Graphical Abstract

Background. The hypercoagulable status, which forms a vicious cycle with hematogenous metastasis, is a common systemic alteration in cancers. As modeling is a key approach in research, a model which is suitable for studying how the hypercoagulable status promotes hematogenous metastasis in breast cancer is urgently needed. Methods. Based on the tumor-bearing period (TBP) and postoperative incubation period (PIP), 4T1-breast cancer models were constructed to evaluate coagulation and tumor burden to generate multiple linear regression-based lung metastasis prediction formula. Platelets and 4T1 cells were cocultured for 30 min or 24 h in vitro to evaluate the early and late phases of their crosstalk, and then the physical characteristics (concentration and size) and procoagulant activity of the coculture supernatants were assayed. Results. The multiple linear regression model was constructed as log 10 photon number = 0.147 TBP + 0.14 PIP + 3.303 ( TBP ≤ 25 and PIP ≤ 17 ) to predict lung metastasis. Coculture of platelets and 4T1 cells contributed to the release of extracellular vesicles (EVs) and the development of the hypercoagulable status. Conclusions. In vivo and in vitro hypercoagulable status models were developed to explore the mechanism of hypercoagulable status which is characterized by platelet activation and promotes hematogenous metastasis in breast cancer.

Background: Nanoparticle albumin-bound paclitaxel (nab-PTX) has exhibited clinical efficacy in breast cancer treatment, but toxicities can be yielded more at the same time. We did this meta-analysis aiming to unambiguously compare nab-PTX with conventional solvent-based paclitaxel (sb-PTX) in breast cancer patients of all stages. Method: Pubmed, Embase and Cochrane Library were searched for head-to-head randomized controlled trials of nab-PTX and sb-PTX in breast cancer. Risk ratio (RR) with 95% confidence interval was used for dichotomous variables while Hazard ratio (HR) was used for time-to-event outcomes. Results: Our review finally included 9 studies with 3508 patients. Nab-PTX showed a benefit on objective response rate (ORR) (RR=1.22 [1.04-1.43], P=0.01) as well as non-inferiority compared with sb-PTX in disease control rate (DCR) (RR=1.01 [0.98-1.04], P=0.44), overall survival (OS) (HR=0.99 [0.93-1.05], P=0.81) and disease free survival/progression free survival (DFS/PFS) (HR=0.92 [0.81-1.05], P=0.21). However, when it comes to toxicities (fatigue, nausea or vomiting, peripheral sensory neuropathy and adverse event related discontinuation), results favored sb-PTX (RR=2.89 [1.07-7.8], 3.15 [1.78-5.59], 2.11 [1.32-3.37], 2.02 [1.61-2.53]; P

Targeting EGFR, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), brings lights to the treatment of non-small cell lung cancer (NSCLC). Although T790M mutation responded as one of the main reasons of acquired resistance, still 15% of the resistance patients can't be explained by the known mechanisms. The purpose of this research was to identify some new mechanisms of gefitinib acquired resistance, and to predict small molecules drugs which may reverse drug resistance by integrated bioinformatics analysis. The GSE34228 data package containing the microarray data of acquired gefitinib-resistant cell line (PC9GR) and gefitinib-sensitive cell line (PC9) from the GEO database were downloaded, and gene co-expression networks by weighted gene co-expression network analysis (WGCNA) were constructed to identified key modules and key genes related to gefitinib resistance. Furthermore, the significantly differentially expressed genes (DEGs) between the two cell types were screened out, and a protein-protein interaction (PPI) network to obtain the key genes of DEGs was accordingly constructed. Through the above two methods, 4 hub genes, PI3, S100A8, AXL and PNPLA4 were mined as the most relevant to gefitinib resistance. Among them, PI3, S100A8 were down-regulated in PC9GR cell samples, while AXL, PNPLA4 were up-regulated. The gene set enrichment analysis (GSEA) for single gene showed that the four hub genes were mainly correlated with cell proliferation and cycle. Besides, small molecule drugs with the potential to overcome resistance, such as Emetine and cephaeline, were screened by CMap database. Consistent with this, in vitro experiments results have shown that emetine and cephaeline can increase the sensitivity of drug-resistant cells to gefitinib, and the mechanism may be related to the regulation of PI3 and S100A8. In conclusion, 4 hub genes were found to be related to the occurrence of gefitinib resistance in non-small cell lung cancer, and several small molecule drugs were screened out as potential therapeutic agents to overcome gefitinib resistance, which may lead a new way for the treatment of NSCLC of acquired resistance to gefitinib.

The anti-angiogenic drug Bevacizumab (Bev) is engaged in neoadjuvant therapy for non-metastatic breast cancer (NMBC). However, whether neoadjuvant Bev providing a greater benefit to patients is debatable. Our study aimed to review Bev's role in Neoadjuvant therapy (NAT) in NMBC and identify predictive markers associated with its efficacy by systemic review and meta-analysis. Eligible trials were retrieved from the Pubmed, Embase, and Cochrane Library, and random or fixed effects models were applied to synthesize data. Power of pCR to predict DFS or OS was evaluated by nonlinear mixed effect model. In NMBC, Bev significantly improved the rate of patients achieving pCR, but this benefit discontinued in DFS or OS. Biomarkers such as PAM50 intrinsic subtype, VEGF overexpression, regulation of VEGF signaling pathway, hypoxia-related genes, BRCA1/2 mutation, P53 mutation and immune phenotype can be used to predict Bev-inducing pCR and/or DFS/OS. Unfortunately, although patients with pCR survived longer than those without pCR when ignoring the use of Bev, but patients achieving pCR with Bev might survive shorter than those achieving pCR without Bev. Subgroup analyses found Bev prolonged patients' OS when given pre- and post-surgery. Lastly, adding Bev increased adverse effects. Overall, Bev offered limited effect for patients with NMBC in an unscreened population. However, in biomarkers - identified subgroup, Bev could be promising to ameliorate the prognosis of specific patients with NMBC.

Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth and metastasis. We have utilized mice over-expressing (Hpa-tg) heparanase to reveal the role of host heparanase in tumor initiation, growth and metastasis. While in wild type mice tumor development in response to DMBA carcinogenesis was restricted to the mammary gland, Hpa-tg mice developed tumors also in their lungs and liver, associating with reduced survival of the tumor-bearing mice. Consistently, xenograft tumors (lymphoma, melanoma, lung carcinoma, pancreatic carcinoma) transplanted in Hpa-tg mice exhibited accelerated tumor growth and shorter survival of the tumor-bearing mice compared with wild type mice. Hpa-tg mice were also more prone to the development of metastases following intravenous or subcutaneous injection of tumor cells. In some models, the growth advantage was associated with infiltration of heparanase-high host cells into the tumors. However, in other models, heparanase-high host cells were not detected in the primary tumor, implying that the growth advantage in Hpa-tg mice is due to systemic factors. Indeed, we found that plasma from Hpa-tg mice enhanced tumor cell migration and invasion attributed to increased levels of pro-tumorigenic factors (i.e., RANKL, SPARC, MIP-2) in the plasma of Hpa-Tg vs. wild type mice. Furthermore, tumor aggressiveness and short survival time were demonstrated in wild type mice transplanted with bone marrow derived from Hpa-tg but not wild type mice. These results were attributed, among other factors, to upregulation of pro-tumorigenic (i.e., IL35(+)) and downregulation of anti-tumorigenic (i.e., IFN-γ(+)) T-cell subpopulations in the spleen, lymph nodes and blood of Hpa-tg vs. wild type mice and their increased infiltration into the primary tumor. Collectively, our results emphasize the significance of host heparanase in mediating the pro-tumorigenic and pro-metastatic interactions between the tumor cells and the host tumor microenvironment, immune cells and systemic factors.

Objective: To study the effect and mechanism of Huayu Wan (化瘀丸, HYW) in combination of chemotherapy of tumor treatment. Methods: HYW serum was added in Lewis cells to assess its impact on fluorescent doxorubicin delivery in vitro. Then, Lewis tumor cells was implanted in C57BL/6 mice via xenograft transplantation. Tumor growth was measured and signal intensity corresponding to blood flow was assessed by laser doppler perfusion imaging (LDPI). Finally, the effect of HYW on the effificacy of doxorubicin was studied. Results: HYW can improve the transfer of fluorescent doxorubicin into cells. The blood flow signal in the tumor tissues of the HYW group was higher than that of the control group (P

The current criteria for defining the recurrence risks of stage II colorectal cancer (CRC) are not robust; therefore, we aimed to explore novel gene signatures to predict recurrence risks and to reveal the underlying mechanisms of stage II CRC. First, the gene expression profiles of 124 patients with stage II CRC from The Cancer Genome Atlas (TCGA) database were obtained to screen differentially expressed genes (DEGs). A total of 202 DEGs, including 128 upregulated and 74 downregulated, were identified in the recurrence group (n = 24) compared to the nonrecurrence group (n = 100). Furthermore, the top 5 DEGs (ZNF561, WFS1, SLC2A1, MFI2, and PTGR1) were identified by random forest variable hunting, and four (ZNF561, WFS1, SLC2A1, and PTGR1) were selected to create a four‐gene recurrent model (GRM), with an area under the curve (AUC) of 0.882 according to the receiver operating characteristic curve, and the robust diagnostic effectiveness of the GRM was further validated with another gene expression profiling dataset (GSE12032), with an AUC of 0.943. The diagnostic effectiveness of the GRM regarding recurrence was associated with poor disease‐free survival in all stages of CRC. In addition, gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed 18 enriched functions and 6 enriched pathways. Four genes, ABCG2, CACNA1F, CYP19A1, and TF, were identified as hub genes by the protein‐protein interaction network, which further validated that these genes were correlated with a poor pathologic stage and overall survival in all stages of CRC. In conclusion, the GRM can effectively classify stage II CRC into groups of high and low risks of recurrence, thereby making up for the prognostic value of the traditional clinicopathological risk factors defined by the National Comprehensive Cancer Network guidelines. The hub genes may be useful therapeutic targets for recurrence. Thus, the GRM and hub genes could offer clinical value in directing individualized and precision therapeutic regimens for stage II CRC patients., This study finds indicators for predicting postoperative recurrence in patients with stage II colorectal cancer (CRC). Moreover, the gene recurrent model and hub genes potentially offer clinical values in directing individualized and precision therapeutic regimen be selection for stage II CRC.

Hepatocellular carcinoma (HCC) is characterized by poor prognosis and high mortality. The treatment of HCC is closely related to the stage, and the early-stage of HCC patients usually accompanies a more long-term survival rate after clinical treatment. Hence, there are critical needs to develop effective imaging agents with superior diagnostic precision for HCC detection at an early stage. Recently, mesoporous silica nanoparticles (MSNs) based imaging agents have gained extensive attentions in HCC detection, which can serve as a multifunctional nanoplatform with controllable size and facile surface functionalization. This perspective summarizes recent advances in MSNs based imaging agents for HCC detection by the incorporation of several clinical imaging modalities. Multi-modal imaging system has been developed for higher spatial resolution and sensitivity. Even though some limitations and challenges need to be overcome, we envision the development of novel MSNs based imaging agents will offer great potential applications in clinical HCC detection.

Purpose To surmount the critical issues of clinical hepatectomy and achieve a precise surgical navigation of hepatocellular carcinoma after long-term transcatheter arterial embolization (TAE).Methods A facile and green pure-nanomedicine formulation technology was developed to construct carrier-free indocyanine green nanoparticles (nanoICG). The nanoICG was dispersed into lipiodol via a super-stable homogeneous lipiodol formulation technology (SHIFT nanoICG) for TAE combined with near-infrared fluorescence-guided precise hepatectomy.Results We demonstrate that SHIFT nanoICG integrates excellent anti-photobleaching capacity, great optical imaging properties, and specific tumoral deposition to recognize tumor regions, featuring sufficient physical stability for fluorescence-guided precise hepatectomy. Importantly, SHIFT nanoICG is capable of visualizing all lesions in rabbit-bearing VX2 orthotopic hepatocellular carcinoma models, even the tiny focus to 0.6 × 0.4 mm.Conclusion Our findings indicate that SHIFT nanoICG provides a promising avenue to address the clinical issue of hepatectomy and has excellent potential for a translational pipeline.

Background Benign anastomotic stricture remains among the most prevalent complications following surgery for colorectal cancer, albeit its incidence is very low. Objective This study is aimed at identifying risk factors of anastomotic stricture as well as generating an effective nomogram for the stricture. Design: This is a retrospective study. Setting: This study was conducted from January, 2015 to December, 2019 in a single tertiary center with colorectal cancer. Patients: A total of 117 colorectal patients after surgery without recurrence including 39 with anastomotic stricture (the distance between anastomotic site and anal margin

The development of multiple drug resistance (MDR) to chemotherapy and subsequent treatment failures are major obstacles in cancer therapy. An attractive option for combating MDR is inhibiting the expression of P-glycoprotein (P-gp) in tumor cells. Here, we report a novel chemosensitizing agent, XMD8-92, which can down-regulate P-gp. To enhance the specificity of MDR chemotherapy, a promising nanotheranostic micelle system based on poly(ethylene glycol)-blocked-poly(L-leucine) (PEG-b-Leu) was developed to simultaneously carry the anticancer drug doxorubicin, chemosensitizing agent XMD8-92, and superparamagnetic iron oxide nanoparticles (SPIOs). Featured with MDR environmentally responsive dual-targeting capability, controllable drug delivery, and efficient magnetic resonance (MR) imaging characteristics, the prepared nanotheranostics (DXS@NPs) showed outstanding in vitro cytotoxicity on MDR cells (SCG 7901/VCR) with only 53% of cells surviving compared to 90% of DOX-treated cells. Furthermore, efficient tumor inhibition and highly reduced systemic toxicity were exhibited by MDR tumor-bearing mice treated with DXS@NPs. Overall, the environmentally responsive dual-targeting nanotheranostics represent a promising approach for overcoming cancer MDR.

Reinforced concrete structures experience severe durability degradation when subjected to alkali–silica reaction (ASR) and chloride attack. A special electrochemical rehabilitation treatment, containing lithium compound anolyte, has been developed to drive lithium ions into concrete composites and remove chlorides simultaneously, for mitigating both the ASR-induced cracks and the chloride-induced reinforcing steel-bar/fiber corrosion. In this study, the efficiency of the impregnation of lithium ions and the removal of chloride ions through a specific electrochemical treatment is numerically evaluated, which results into the distribution profiles of all typical ionic species. A heterogeneous numerical model, which treats concrete as a three-phase composite, is presented to examine the response of inner structures, especially the interaction between active aggregates and lithium ions that are supposed to mitigate ASR. The ionic interaction between different species, binding and the electrochemical reaction at electrodes are also considered. Through a detailed modelling of multi-phase and multi-species, a systemic parametric analysis based on a series of significant factors during electrochemical treatment (e.g., current density, treatment time, temperature, cathode position and concentration of lithium solution) reveals some important tendencies of ionic electromigration in concrete structures, which are supposed to guide the field applications.

Ultra-small superparamagnetic iron oxide nanoparticles (USPIO-NPs) are widely used as clinical magnetic resonance imaging contrast agents for hepatic diseases diagnosis. USPIO-NPs often damage the hepatocytes and affect the function of liver but its mechanism of action remains unclear. In the present study, USPIO-NPs caused higher cytotoxicity and lactate dehydrogenase (LDH) leakage in hepatic L02 cells than SPIO-NPs. Subsequently, USPIO-NPs affected more genes’ expression than SPIO-NPs analyzed through microarray and bioinformatics analysis. The affected genes were involved in several biological processes, including calcium ion homeostasis, inflammatory response-related leukocyte chemotaxis, and migration. In addition, the level of endoplasmic reticulum (ER) calcium ion was increased by USPIO-NPs. USPIO-NPs also upregulated the genes related to acute-phase inflammation, including IL1B, IL6, IL18, TNFSF12, TNFRSF12, SAA1, SAA2, JAK1, STAT5B, and CXCL14. Furthermore, interleukin-6 (IL-6) secretion was elevated by USPIO-NPs as detected using ELISA. On the other hand, USPIO-NPs changed the morphology of ER and triggered the ER stress and unfolded protein response PERK/ATF4 pathway. Furthermore, blocking ER stress with inhibitor or ATF4 small interfering RNA counteracted IL-6-related acute-phase inflammation and cytotoxicity caused by USPIO-NPs. Taken together, we found that the USPIO-NPs could trigger stronger IL-6-related acute-phase inflammation than SPIO-NPs in hepatocytes. We demonstrated, for the first time, that IL-6-related acute-phase inflammation caused by NPs was regulated by PERK/ATF4 signaling. The PERK/ATF4 pathway explored in this study could be a candidate for diagnostic and therapeutic target against NPs-induced liver injury and cytotoxicity, which would be helpful for USPIO-NPs medical application.

Background： Atoh1, also named Math1, is essential for the development of inner ear hair cells. Many studies have confirmed that the absence of Atoh1 resulted in a total loss of inner ear hair cells, which indicates that Atoh1 plays very similar roles in the development of hair cells in the cochlea and vestibule. Objective： The aim of this study was to evaluate whether Atoh1 plays different roles in the cochlea and vestibule.We generated Atoh1-null mice by inbreeding Atoh1We found that no inner ear hair cells were detected in Atoh1-null mice. However, a different cell status was found in the mutant cochlea and vestibule on the last embryonic day (E18.5). In the Atoh1-null cochlea, the epithelial cells that should develop into hair cells were totally absent, while in the Atoh1-null vestibule, most of the epithelial cells that should develop into hair cells still survived.Our data indicate that Atoh1 may have similar but partially different functions in the development of hair cells in the cochlea and vestibule.

Objective To investigate the effect of transcranial direct current stimulation (tDCS) combined with conventional comprehensive rehabilitation on dysphagia after brainstem stroke. Materials and methods Forty brainstem stroke patients were randomly divided into tDCS group and conventional comprehensive treatment group, including 20 patients in each group. Both groups were given routine swallowing function training, and tDCS group added transcranial direct current stimulation (tDCS). The Dysphagia Outcome and Severity Scale (DOSS) and Functional Dysphagia Scale (FDS) were evaluated respectively before and after 8 weeks of continuous treatment with VFSS. The white blood cell (WBC), c-reactive protein, prealbumin (PAB), albumin (Alb), and hemoglobin (Hb) were also compared between the two groups before and after 8 weeks of continuous treatment. Results After 8 consecutive weeks of treatment, the score of DOSS scale and FDS scale in both groups was improved (P < 0.05), WBC and CRP were decreased (P < 0.05), and Alb and Hb were improved (P < 0.05), and PAB had no differences (P=0.474). The tDCS group was superior to conventional comprehensive group in improving the swallowing function and nutritional indexes (P < 0.05). Conclusions tDCS therapy combined with routine training can improve the swallowing function and nutritional status of patients, and reduce infection.

Visualizing siRNA delivery through medical imaging methods has drawn much attentions in recent gene therapy studies. Among them, iron oxide-based magnetic resonance imaging (MRI) is regarded as one of the most promising imaging modalities for its high spatial resolution as well as deep penetration and real-time properties. In this chapter, a detailed protocol of an amphiphilic superparamagnetic iron oxide (SPIO) nanovehicle-based siRNA delivery is described, mainly focusing on SPIO/siRNA complexes formation and characterization, in vitro and in vivo siRNA delivery, MRI study of the delivery and transfection efficiency evaluation.

The conventional immunoadjuvants in vaccine have weak effect on stimulating antigen presentation and activating anti-tumor immunity. Unexpectedly, we discovered that non-pathogenic Sendai virus (SeV) could activate antigen-presenting cells (APCs) represented by dendritic cells (DCs). Here, we designed an injectable SeV-based hydrogel vaccine (SHV) to execute multi-channel recruitment and stimulation of DCs for boosting the specific immune response against tumors. After the release of the NIR-triggered antigens from tumor cells, dendritic cells around the vaccine efficiently transport the antigens to lymph nodes and present them to T lymphocytes, thereby inducing systemic anti-tumor immune memory. Our findings demonstrated that the SHV with excellent universality, convenience and flexibility has achieved better immune protection effects in inhibiting the occurrence of melanoma and breast cancer. In conclusion, the SHV system might serve as the next generation of personalized anti-tumor vaccines with enhanced features over standard vaccination regimens, and represented an alternative way to suppress tumorigenesis., Graphical abstract Schematic diagram of SeV-based hydrogel vaccine (SHV) in preventing tumorigenesis. A highly biocompatible hydrogel as a matrix material was employed to fix tumor cells with temperature sensitivity for supplying all tumor antigens. Photosensitizer (ICG) was used to release tumor antigen precisely under near-infrared laser trigger. Tumor cells ruptured under near-infrared radiation, causing DNA fragmentation to activate STING pathway and secrete type I interferon (IFN). And the Sendai virus (SeV) as an immunoadjuvant efficiently recruited and activated DCs to further activate immunity. DCs then presented tumor antigens to the lymph nodes for maturing T cells and inducing the formation of immune memory cells. When the same tumor cells re-invade, the immune memory cells of mice immunized with the SHV will be efficiently stimulated to kill these invading tumor cells.Image 1, Highlights • SeV served as immuneadjuvant can activate APCs through TLR7/8 and TLR3 pathways. • Non-pathogenic SeV in the injectable hydrogel vaccine recruit and activate DCs. • Tumor cells acted as an “antigen library” to release all antigens by NIR-trigger. • Fragmented DNA from tumor cells after photothermal damage activated STING pathway. • The synergy effect of SHV and aOX40 greatly enhanced anti-tumor immune memory.

A rapid and sensitive stability indicating HPLC method has been developed and validated for the determination of buprenorphine (BPN) in transdermal patch. Chromatographic separation was achieved isocratically on an XBridge(superscript TM) Shield RP18 column with a mobile phase of acetonitrile/0.063 M ammonium bicarbonate buffer (pH 9.5) (58:42, v/v) at the flow rate of 1.5 mL/min with UV absorbance monitoring at 230 nm. The system performance was evaluated and the result showed that BPN and degradation products were separated. Buprenorphine was subjected to neutral, acidic and basic hydrolysis as well as chemical oxidation to evaluate the specificity. The calibration curve of buprenorphine was linear in the range of 30~70 μg/mL (r=0.9999, n=5). The values of RSD (%) for the intra-day and inter-day precision ranged from 0.04 to 0.22 and 0.65 to 0.88%, respectively. The average of the recovery percentage ranged from 98.86 to 99.36%. The detection limit (DL) and quantitation limit (QL) for buprenorphine were 0.008 and 0.024 μg/mL, separately. The robustness of this method was also evaluated on the small fluctuations of pH in the mobile phase, the mobile phase compositions, and the flow rate. The results of stability studies showed the hydrolysis reaction of buprenorphine followed zero-order kinetics model in acidic and basic environment and followed first-order kinetics model in the presence of hydrogen peroxide. This analytical method was successfully applied to the determination of buprenorphine in transdermal patch and can be used for routine quality control work.

Ginger is one of the most frequently used ingredients in Chinese folk medicine and cooking. Ginger rhizome is used in treating/relieving appetite loss and motion sickness in western world. 6-Gingerol has been used as a marker substance of ginger . An HPLC analytical procedure of 6-gingerol was described. The correlation coefficients were greater than 0.999. The described HPLC procedure in this report has been validated and can be used to check 6-gingerol stability. It is also suitable for the preformulat ion study of ginger. The stabilities of ginger solution at different pHs were studied. The 6-gingerol contents in different preparations wer e evaluated.

This study was aimed to develop the new transdermal formulation to improve the permeability of buprenorphine. The apparent partition coefficients of buprenorphine were measured using the buffers at pH 1.2 to 10.0 as aqueous phase. The solubility of buprenorphine was 12.97 μg/mL in the 0.1 M phosphate buffer at pH 6.8. The influences of vehicles at different pH, adhesives, and permeation enhancers on the penetration of buprenorphine through nude mouse skin were investigated using the static Franz diffusion cells. The permeation parameter J(subscript ss) of buprenorphine increased along with the reduction of the pH of receptor fluid, and the vehicle at pH 6.8 was used in the following skin permeation studies. The pressure sensitive adhesives (PSA) including polyisobutylene (PIB), polystyrene-block-polyisoprene-block-polystyrene (SIS), and acrylic adhesives were evaluated. The permeability of buprenorphine was higher in the PIB or SIS adhesives than that in the acrylic adhesives under the condition without enhancer. When combined the enhancers with propylene glycol (PG) to improve the penetration of buprenorphine, the permeation-enhancing effects of enhancers were in the following order: lauric acid ＞ linolenic acid ＞ menthol ＞ oleic acid ＞ N-methyl-2-pyrrolidone (NMP) ＞ laurocapram ＞ glabridin. Finally, a matrix-type transdermal delivery system for buprenorphine was formulated using acrylic adhesive, PG, and lauric acid. The Jss parameter was 2.68±0.20 μg/cm^2/h and buprenorphine permeated across the nude mouse skin was 31.68%.

In this study, metalla-aromatic agents (MA) and a cluster of superparamagnetic iron oxide nanoparticles (SPIOs) were loaded inside a micellar carrier (Alkyl-PEI2k-PEG), resulting in MA/SPIOs@Alkyl-PEI2k-PEG nanoparticles (MASAs). The prepared MASAs with a photothermal transduction efficiency of 26.6% were also demonstrated as a potential photodynamic sensitizer to generate ROS effectively. Under the guidance of MRI/photoacoustic imaging, combined photothermal and photodynamic therapy achieved a synergistic anti-tumor effect, significantly improving the therapeutic efficacy of MASAs both in vitro and in vivo. This work shows that the developed MASAs are a potential theranostic agent for dual-modal imaging-guided cancer phototherapy.

Triple‑negative breast cancer (TNBC), which is characterized by inherently aggressive behavior and lack of recognized molecular targets for therapy, poses a serious threat to women's health worldwide. However, targeted treatments have yet to be made available. A crosstalk between tumor cells and platelets (PLT) contributing to growth, angiogenesis and metastasis has been reported in numerous cancers. Heparanase (Hpa), the only mammalian endoglycosidase that cleaves heparan sulfate, has been demonstrated to contribute to the growth, angiogenesis and metastasis of numerous cancers. Hypoxia affects the growth, angiogenesis and metastasis of nearly all solid tumors, and the ability of Hpa to promote invasion is enhanced in hypoxia. However, whether Hpa can strengthen the crosstalk between tumor cells and PLT, and whether enhancing the biological function of Hpa in TNBC promotes malignant progression, have yet to be fully elucidated. The present study, based on bioinformatics analysis and experimental studies in vivo and in vitro, demonstrated that Hpa enhanced the crosstalk between TNBC cells and PLT to increase the supply of oxygen and nutrients, while also conferring tolerance of TNBC cells to oxygen and nutrient shortage, both of which are important for overcoming the stress of hypoxia and nutritional deprivation in the tumor microenvironment, thereby promoting malignant progression, including growth, angiogenesis and metastasis in TNBC. In addition, the hypoxia‑inducible factor‑1a (HIF-1a)/vascular endothelial growth factor‑a (VEGF- a)/phosphorylated protein kinase B (p-)Akt axis may be the key pathway involved in the effects of Hpa on the biological processes mentioned above. Therefore, improving local hypoxia, anti‑Hpa treatment and inhibiting PLT activation may improve the prognosis of TNBC.

Ethnopharmacological relevance The Scutellaria barbata and Hedyotis diffusa (SH) herb pair is extensively used in Traditional Chinese Medicine for efficacy enhancement in cancer treatment in China and Asian countries. Superior clinical efficacy observations based on high dosages (≥60 g) motivated us to explore appropriate dosages and the underlying mechanisms of action. Aim of the study To explore the efficacy and potential mechanisms of actions of SH through in vitro and in vivo experiments and network pharmacology. Materials and methods SH lyophilized powder (SHLP) was prepared from decoctions and the active ingredients were identified using high performance liquid chromatography (HPLC). Proliferation and migration experiments in vitro and tumor growth in vivo were performed to evaluate the effects of SHLP on breast cancer. Corresponding potential target genes for SHLP components and breast cancer were extracted from established databases and the Protein-Protein Internetwork of shared genes were constructed using STRING database. Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotation clusters were acquired and the top 30 pathways were presented. At last, as one of pathways indicated by enriched results, apoptosis was validated with flow cytometric analysis and caspase-3, 8, 9 activities. Results Seventy-five ingredients were identified from SHLP by HPLC. High SHLP doses inhibited proliferation and migration of three types of breast cancer cells in vitro and tumor growth in nude mice. After target genes extraction and intersection, the top 30 KEGG clusters were enriched, including PI3K-Akt, cell cycle and other related pathways like VEGF, Micro-RNAs and NF-κB, besides, key genes in apoptosis were mapped. In the last, apoptosis was validated by flow cytometric analysis and caspase-3, 8, 9 activities after SHLP treatment. Conclusion High SHLP dosages inhibited breast cancer in vitro and in vivo, enriched by network pharmacology and confirmed by flow cytometric analysis and caspase activation, with apoptosis was identified as one of the mechanisms of action of SHLP. SHLP administration with higher doses is recommended for clinical usage.

Rice blast, caused by Magnaporthe oryzae, is one of the most devastating diseases of rice worldwide. The aim of the present study was to elucidate the virulence structure of M. oryzae populations in Fujian Province, China, over the period 2006–2015. For this purpose, 456 M. oryzae isolates collected from diverse cultivars from eight rice cropping regions in Fujian were screened for the presence of 11 known avirulence genes: Avr-Pik, Avr-Pita1, Avr-Pita2, Avr-Pita3, PWL2, Avr1-CO39, ACE1, Avr-Piz-t, Avr-Pia, Avr-Pii and Avr-Pikm, with gene-specific molecular markers. The results showed that Avr-Pik and Avr-Pita3 occurred at the highest frequency (94.5% and 91.7%, respectively), while Avr1-CO39 and Avr-Pii were not detected. Further, the remaining avirulence genes occurred at frequencies ranging from 5.9% to 89.0%. Temporal population dynamics revealed that Avr-Pik was uniformly distributed in all 10 years, at frequencies of more than 87.5%. Spatial distribution analysis showed avirulence genes were...

To assess the effectiveness of Yishen Jiangu Granules (益肾健骨颗粒, YSJGG) on aromatase inhibitor-associated musculoskeletal symptoms (AIMSS). A single-arm, open-label study was conducted in 34 postmenopausal women with breast cancer who experienced AIMSS. Patients were treated with YSJGG for 12 weeks (12.4 g orally twice daily). The primary outcome was a change in the mean worst pain score of Brief Pain Inventory-Short Form (BPI-SF) over 12 weeks, and the second outcomes included changes in pain severity and pain-related interference of BPI-SF and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH), the Functional Assessment of Cancer Therapy-Breast (FACT-B), bone mineral density (BMD) and blood indices such as calcium (Ca), phosphate (P), and alkaline phosphatase (ALP). Of 37 women recruited, 30 initiated the therapy and 24 were evaluable at 12 weeks. The primary outcome (BPI-SF worst pain scores) achieved a 2.17-point reduction compared with baseline (5.75±1.87 vs 3.58±2.15, P

The tumor microenvironment (TME) is featured with aberrant vasculatures, specific physiological parameters, viscoelastic extracellular matrix and stromal cells, which are important factors in tumor initiation, development and metastasis. The components in TME form physical/biological barriers for drug delivery and therapy, and also contribute to resistance to treatment and immunosuppression. The advances in nanobiotechnology have offered a myriad of nanoparticles for targeting and treating tumors through the passive or active targeting strategies. However, the barriers in TME always limit the drug delivery and therapeutic efficacy of nanoparticles. To cope with this, recent strategies have employed nanoparticles to target and remodel tumor microenvironment, while a variety of nanoparticles have been developed with different functions for this score. In this review, we have described the typical features of tumor microenvironment along with their roles in tumor progression, and then focused on recent progresses in development and application of nanoparticles to target and remodel TME for enhanced cancer therapy.

The development of tumor-targeting nanocarriers is critical important for effective treatment. The synthetic polyesters have demonstrated high potential for developing nanocarriers for cancer theranostics. Especially, the biocompatible and biodegradable polyester micelles have held great promise for cancer therapy and diagnosis, while some candidates have been translated into clinical applications or under clinical trial. In this review, we have provided the state-of-the-art of polyester micelles for drug delivery and cancer theranostics. In addition, we have summarized several major types of polyesters used in the biomedical fields, the current clinical achievements of polyester micelles and recent progresses of multi-functional polyester micelles for tumor molecular imaging and therapeutic applications.

Soil properties are often assumed to be static over time in hydrological studies, especially in hydrological modelling. Although it is well appreciated that soil structure and its impact on hydraulic properties are time-variable, particularly on cultivated land, very few studies have focused on quantifying the influence of such changes on soil hydrology, especially at the short term (i.e. seasonal). This study explored the value of incorporating such short-term time-variable soil properties in hydrological models. It is based on soil hydraulic properties from temporal field data under no-till done by direct seeding and under conventional cultivation done by ploughing to 0.2 m and harrowing. It uses a controlled tillage experiment in Scotland, on a soil with very good structural stability that experiences gentle rainfall in a temperate oceanic climate (Koppen Cfb). Water retention data were collected from intact soil cores sampled at 0.025, 0.095 and 0.275 m depth at three times between April and August 2013; (i) immediately following tillage, (ii) at barley crop establishment 1 month later and (iii) after harvest. Soil structure varied over time, with no-till soils gaining porosity and ploughed soils losing porosity. We hypothesised that no-till soils would have less seasonal temporal variability, but found it to be comparable to ploughed soils, albeit with pore structure changes following different trends. These changes were reflected in Van Genuchten fitting parameters, which if accounted for in 1-D HYDRUS modelling, had a marked impact on modelled soil water content over time if contrasted to predictions assuming a static pore structure. Using data from multiple sampling events, as opposed to one sampling event, resulted in up to a 44 % difference in soil water content predictions and increased the temporal variability by a factor of 1.5. Hence, our results have demonstrated that it is important to account for short-term temporal variability in soil physical properties in soil water modelling studies, and should not be ignored as a default, particularly on cultivated agricultural soils.

Abiotic stress, such as water deficit, is one of the most devastating factors hindering sustainable agricultural crop output today...

A proper animal model is crucial for a better understanding of diseases. Animal models established by different methods (subcutaneous injections, xenografts, genetic manipulation, chemical reagents induction, etc.) have various pathological characters and play important roles in investigating certain aspects of diseases. Although no single model can totally mimic the whole human disease progression, orthotopic organs disease models with a proper stromal environment play an irreplaceable role in understanding diseases and screening for potential drugs. In this article, we describe how to implant breast cancer cells into the mammary fat pad in a simple, less invasive, and easy-to-handle way, and follow the metastasis to distant organs. With the proper features of primary tumor growth, breast and nipple pathological changes, and a high occurrence of other organs' metastasis, this model maximumly mimics human breast cancer progression. Primary tumor growth in situ, long-distant metastasis, and the tumor microenvironment of breast cancer can be investigated by using this model.

In recent decades, the advancements in nanotechnology, nanochemistry, and surface modification have inspired the booming development of multifunctional and stimuli-sensitive nanocarriers, which enable effective delivery therapeutic cargos to disease sites, then spontaneously response to local pathological factors or external physical stimuli. Such nanocarriers could improve drug delivery and mediate tumor-specific release spatiotemporally in an on-demand fashion, offering powerful weapons for an effective cancer therapy. Moreover, the external stimuli show promise performance in some therapy modalities, including photothermal, photodynamic, magnetic hyperthermia, and sonodynamic therapy besides chemotherapy or gene therapy. Meanwhile, the concept of image-guided therapy has been proposed. By coencapsulating imaging contrast agents into nanocarriers, real-time monitoring of drug delivery, release, and effectiveness could be achieved for better planning and adjusting therapy strategy during treatment. In this chapter, we summary recent advances in stimuli-responsive nanocarriers for image-guided therapy, including introduction of various imaging modalities and their role in image-guided therapy, and different kinds of stimuli-responsive systems (exogenous or endogenous factors responsive) applied in image-guided therapy.

Background Nanoparticle albumin-bound paclitaxel (nab-PTX) has exhibited clinical efficacy in breast cancer treatment, but toxicities can be yielded more at the same time. We did this meta-analysis aiming to unambiguously compare nab-PTX with conventional solvent-based paclitaxel in breast cancer patients of all stages. Method Pubmed, EMBASE, Cochrane Library, Chinese Biomedical database, Chinese National Knowledge Infrastructure, Chinese Science and Technology Periodical database, and WangFang database were searched for head-to-head randomized controlled trials of nab-PTX and solvent-based paclitaxel in breast cancer. Other sources will also be searched like Google Scholar and gray literatures. Two researchers will independently search the database and extract data from the articles. Risk of bias will be assessed using the Cochrane Collaboration's tool. Objective tumor response rate, chemotherapy completion rate after 4 or 6 cycles, and toxicity will be primary outcomes. Disease control rate, overall survival, and progression-free survival/disease-free survival will be included in secondary outcomes. Risk ratio with 95% confidence interval was used for dichotomous variables while hazard ratio was used for time-to-event outcomes. The following 3 data sets will all be considered when synthesizing the data: intention-to-treat population, those who actually received taxanes treatment, and those who were actually assessed. All the analyses were done using Review Manager Software 5.3. Any disagreements in study selection, data collection, and analysis will be resolved by a third investigator. Results and conclusion This study is aim to evaluate the efficacy and safety of nab-PTX compared with PTX in breast cancer treatment as well as to find the best dose or schedule and identify the benefit population. This meta-analysis could provide evidence for clinicians to make a better choice between nab-PTX and PTX in different specific contexts. Prospero registration number CRD42019117912.

Ethnopharmacological relevance Astragalus mongholicus, Solanum nigrum Linn, Lotus plumule, Ligusticum are widely used traditional herbal medicines for cancer treatment in China. They were typical drugs selected from Gubenyiliu II and series of formula (GYII), which were developed on the foundation of YIQIHUOXUEJIEDU theory. In the present study, four active ingredients (Astragaloside IV, α-solanine, neferine, and 2,3,5,6-tetramethylpyrazine) derived from medicines above were applied in combination as SANT. Aim of the study Triple-negative breast cancer (TNBC) is a serious threat to women's health worldwide. Heparanase (HPSE) is often up-regulated in breast cancer with the properties of facilitating tumorigenesis and influencing the autophagy process in cancer cells. This study aimed at evaluating the anti-tumor potential of SANT in treating HPSE related TNBC both in-vitro and in-vivo. Materials and methods In this study, we explored the correlation between HPSE expression and survival of breast cancer patients in databases. We performed MTS, trans-well and wound scratch assays to assess the impact of SANT on cell proliferation and migration. Confocal microscopy observation and western blots were applied to verify the autophagy flux induced by SANT. Mice models were employed to evaluate the efficacy and safety of SANT in-vivo by tumor weights and volumes or serum index, respectively. To analyze the underlying mechanisms of SANT, we conducted human autophagy PCR array and angiogenesis proteome profiler on tumor tissues. Results Patients with elevated HPSE expression were associated with a poor outcome in both RFS (P = 1.7e-12) and OS (P = 0.00016). SANT administration significantly inhibited cancer cells’ proliferation and migration, enhanced autophagy flux, and slightly reduced the active form of HPSE in-vitro. SANT also suppressed tumor growth and angiogenesis in-vivo. Human autophagy PCR array results indicated that SANT increased the ATG16L1, ATG9B, ATG4D gene expressions while decreased TMEM74 and TNF gene expressions.Angiogenesis proteome profiler results showed SANT reduced protein level of HB-EGF, thrombospondin-2, amphiregulin, leptin, IGFBP-9, EGF, coagulation factor III, and MMP-9 (pro and active form) in tumor, raised the protein expression of serpin E1 and platelet factor 4. Conclusions These findings indicated that herbal compounds SANT may be a promising candidate in anti-cancer drug discovery. It also provides novel strategies for using natural compounds to achieve optimized effect.

So far, there is very little literature on how pre-transplant pulmonary infection developed in horizontal laminar flow unit (HLFU) affects outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT).A retrospective analysis was performed on allo-HSCT recipients who were diagnosed with pre-transplant pulmonary infection developed in HLFU between January 2012 and December 2012. Various tests were analyzed to evaluate the overall survival (OS) and pulmonary infection rate after allo-HSCT.Among 317 patients who received allo-HSCT from related donors, 7 cases of human leukocyte antigen (HLA)-haploidentical transplantation reported a fever, cough, and other symptoms before transplantation. Chest radiography findings showed pulmonary infection, and the C-reactive protein (CRP) level was higher than normal, which confirmed pulmonary infection (incidence rate 2.21%). The Breslow test suggested that the early survival rate was lower in the group with pre-transplant pulmonary infection than in the group without pre-transplant pulmonary infection (OS: 28.4 vs. 42.4 months; P=0.023); the early survival rate was lower in patients with a pulmonary infection accompanied by bilateral pleural effusion than in patients without pleural effusion (OS: 1.5 vs. 36.3 months; P=0.010). In the first month after transplantation, the difference in the CD4CD45RO+CD45RA- and CD4CD45RO-CD45RA+ between the groups with and without pre-transplant pulmonary infection was statistically significant (P0.05). Patients with pre-transplant pulmonary infection who survived3 years had a higher rate of pulmonary infection in the first 2 months after allo-HSCT than those without pre-transplant pulmonary infection [100% (5/5 patients) vs. 38.1% (118/310); χ(2)=5.542, P=0.019].Development of pre-transplant pulmonary infection in the HLFU in patients with hematological malignancies who receive HLA-haploidentical HSCT is associated with an increased risk of recurrent pulmonary infection in the early period after transplantation; however, there is no impact on patients' long-term survival rate.

Metastasis is the leading lethal factor severely restraining the effectiveness of clinical treatment. TGF-beta is the key regulator for metastasis and influences paradoxically on cancer progression. The known TGF-beta blockers exert little selectivity on its functions, indiscriminately causing the anti-metastatic and pro-growth effects. Under such circumstances, specifically rebalancing the oncological function of TGF-beta provides a crucial oncotarget against metastasis. In our study, we established the screening platform targeting cell motility and identified a potential flavonoid, Chamaejasmenin B (ICJ), extracted from Stellera chamaejasme L..It suppressed the migration and invasion in breast cancer cells in vitro. Moreover, by dynamical quantification of breast cancer progression in small-animal imaging system, ICJ was proved to be a potent inhibitor of metastasis with minimal toxic side effects. Mechanism study further revealed that ICJ efficiently blocked TGF-beta induced EMT, disrupted the interaction between β3 integrin-TβRII complex and, consequently, resulted in the selective inhibition of FAK:Src:p38 pathway. Meanwhile, specific blockage of this pathway largely attenuated the anti-metastatic function of ICJ. Importantly, in contrast with the antagonistic effects on TGF-beta induced metastasis, ICJ obviously sensitized its cytostatic activity, suggesting that it was not a pan-blocker but a rebalancer for the functional output of TGF-beta. Collectively, by targeting TGF-beta Paradox, we experimentally provided a promising candidate for metastatic intervention.

Aim The aim of this study was to explore the efficacy of a new sonographic morphology score (SMS) to differentiate malignant from benign ovarian tumors. Methods Data on 84 ovarian tumors in patients hospitalized in our hospital between 2013 and 2014 were retrospectively analyzed. We established a new sonographic morphology score for ovarian tumors based on volume and structure scores. The efficacy of the new SMS was compared with that of Ueland's index (the old SMS). Receiver–operator curves (ROC) of the two SMS were constructed, and the areas under the curve were calculated and compared. The ROC of the new SMS was also compared with those for the patients' CA-125 and CA-72-4 levels. Results The area under the ROC of the new SMS for ovarian tumors was 0.836, while for the old SMS for ovarian tumors it was 0.709. By Z-test (Z = 2.452, P = 0.0384), there was a significant difference between the new SMS and the old SMS in the diagnosis of ovarian tumors. There was no significant difference in the area under the ROC between the new SMS and CA-125 and CA-72-4 in the diagnosis of ovarian tumors. With a cut-off value of 6, the sensitivity, specificity, positive prognostic value, and negative prognostic value of the new SMS were 0.797, 0.85, 0.944, and 0.567, respectively. Conclusion The new SMS may be used to differentiate malignant ovarian carcinomas from benign tumors except in the case of ovarian thecoma.

The initially formed defects in the mold of continuous casting are likely to be expanded and propagated in the subsequent processing. Based on the principle of material mechanics, a mathematic model is proposed to describe the development of the solidifying shell at meniscus for continuous casting steel slab of low-carbon ([C] = 0.04%) that with the cross-section of 1200 mm × 200 mm. The influence of mechanical stress induced by the mold oscillation on the growth state of meniscus shell and the primary dendrites is evaluated in combination with a non-sinusoidal oscillation mode of mold. The results suggest that the stress caused by the shell bending tends to exceed the critical fracture strength of initial solidifying shell at high temperature. The initial surface crack is formed easily when the upward oscillation velocity of mold exceeds 1.6 m min−1 and is located at 1.9–5.6 mm below meniscus. The subsurface crack is formed when the downward velocity oversteps 6 m min−1 during the negative strip time and is produced in the distance from 3.1 to 4.3 mm below meniscus. The growth direction of primary dendrite changed regularly along with the mold oscillation.

There exists an emergency clinical demand to overcome TRAIL/Apo2L (tumor necrosis factor-related apoptosis-inducing ligand) resistance, which is a major obstacle attributed to insufficient level or mutation of TRAIL receptors. Here, we developed an iron oxide cluster-based nanoplatform for both sensitization and MR image-guided evaluation to improve TRAIL/Apo2L efficacy in colorectal cancer, which has an inadequate response to TRAIL/Apo2L or chemotherapy. Specifically, NanoTRAIL (TRAIL/Apo2L-iron oxide nanoparticles) generated ROS (reactive oxygen species)-triggered JNK (c-Jun N-terminal kinase) activation and induced subsequent autophagy-assisted DR5 upregulation, resulting in a significant enhanced antitumor efficacy of TRAIL/Apo2L, which confirmed in both TRAIL-resistant HT-29, intermediately resistant SW-480 and sensitive HCT-116 cells. Furthermore, in a subcutaneous colorectal cancer mouse model, the in vivo tumor retention of NanoTRAIL can be demonstrated by MR T2 weighted contrast imaging, and NanoTRAIL significantly suppressed tumor growth and prolonged the survival time without observable adverse effects compared with control and TRAIL/Apo2L monotherapy. Importantly, in the study of colorectal cancer patient-derived xenograft models, we found that the NanoTRAIL treatment could significantly improve the survival outcome with consistent ROS-dependent autophagy-assisted DR5 upregulation and tumor apoptosis. Our results describe a transformative design that can be applied clinically to sensitize Apo2L/TRAIL-resistant patients using FDA-approved iron oxide nanoparticles.

Background: Nausea and vomiting are the most common complications following chemotherapy and usually lead to decreased quality of life. Acupuncture therapy is an effective method for chemotherapy-induced nausea and vomiting (CINV), the effects and safety have been observed by many clinicians and demonstrated in a systematic review, which was included in the Cochrane Library in 2014. After several years, new studies have occurred and an updated systematic evaluation is needed. This protocol describes a method for performing a systematic review and meta-analysis to further evaluate the beneficial effects and safety of acupuncture for CINV. Methods: A searching strategy will be carried out mainly in eight databases in English and Chinese, Cochrane Central Register of Controlled Trials, PubMed, Embase, China National Knowledge Infrastructure, the Chinese Scientific Journal Database, the Wanfang database, China Doctoral Dissertations Full-text Database, and China Master's Theses Full-text Database. Only randomized controlled trials related to acupuncture for CINV will be included to enhance the effectiveness. The effective percentage will be used as primary outcome. Changes in the symptoms of nausea and vomiting, like severity, duration, and frequency as well as quality of life will be assessed as secondary outcome. Side effects and adverse events will be used as safety evaluations. To ensure the quality of the systematic evaluation, study selection, data extraction, and quality assessment will be independently performed by 2 authors, and the third author will deal with any disagreement. The Review Manager V.5.3.3 s will be used to perform the data synthesis and subgroup analysis. Results: There are additional studies, further explanations and more subgroup analyses compared with the previous systematic analysis to determine the effects and safety of acupuncture for CINV. Conclusion: The result of this systematic review may offer clinicians stronger evidence to assist patient in relieving CINV. Ethics and dissemination: There is no need to acquire ethical approval for individuals come from literatures instead of recruiting directly. The findings of this review will be reported in peer-reviewed publications and/or presented at relevant conferences Trial registration number: CRD42016045223.

The VAD (vincristine-doxorubicin-dexamethasone) regimen has been used for decades to treat multiple myeloma (MM). Based on reports that vascular endothelial growth factor- (VEGF-) mediated angiogenesis is critical for MM pathogenesis, the antiangiogenic compound thalidomide has been added to VAD (T-VAD). However, it remains unclear whether T-VAD is more efficacious than VAD for serum VEGF reduction or if the difference influences clinical outcome. Pubmed, Cochrane library, China Biomedical Literature (CBM) database, China National Knowledge Infrastructure (CNKI) database, Vip database, and Wanfang database were searched for relevant studies published up to June 2017. RevMan5.2 was used for methodological quality evaluation and data extraction. Thirteen trials (five randomized, seven nonrandomized, and one historically controlled) involving 815 cases were included. Serum VEGF was significantly higher in MM cases than non-MM controls (MD=353.01, [95%CI 187.52–518.51], P

BACKGROUND: Mammalian cells express a single functional heparanase, an endoglycosidase that cleaves heparan sulfate and thereby promotes tumor metastasis, angiogenesis, and inflammation. Malignant mesothelioma is highly aggressive and has a poor prognosis because of the lack of markers for early diagnosis and resistance to conventional therapies. The purpose of this study was to elucidate the mode of action and biological significance of heparanase in mesothelioma and test the efficacy of heparanase inhibitors in the treatment of this malignancy. METHODS: The involvement of heparanase in mesothelioma was investigated by applying mouse models of mesothelioma and testing the effect of heparanase gene silencing (n = 18 mice per experiment; two different models) and heparanase inhibitors (ie, PG545, defibrotide; n = 18 per experiment; six different models). Synchronous pleural effusion and plasma samples from patients with mesothelioma (n = 35), other malignancies (12 non–small cell lung cancer, two small cell lung carcinoma, four breast cancer, three gastrointestinal cancers, two lymphomas), and benign effusions (five patients) were collected and analyzed for heparanase content (enzyme-linked immunosorbent assay). Eighty-one mesothelioma biopsies were analyzed by H-Score for the prognostic impact of heparanase using immunohistochemistry. All statistical tests were two-sided. RESULTS: Mesothelioma tumor growth, measured by bioluminescence or tumor weight at termination, was markedly attenuated by heparanase gene silencing (P = .02) and by heparanase inhibitors (PG545 and defibrotide; P < .001 and P = .01, respectively). A marked increase in survival of the mesothelioma-bearing mice (P < .001) was recorded. Heparanase inhibitors were more potent in vivo than conventional chemotherapy. Clinically, heparanase levels in patients’ pleural effusions could distinguish between malignant and benign effusions, and a heparanase H-score above 90 was associated with reduced patient survival (hazard ratio = 1.89, 95% confidence interval = 1.09 to 3.27, P = .03). CONCLUSIONS: Our results imply that heparanase is clinically relevant in mesothelioma development. Given these preclinical and clinical data, heparanase appears to be an important mediator of mesothelioma, and heparanase inhibitors are worthy of investigation as a new therapeutic modality in mesothelioma clinical trials.

Endothelial progenitor cell (EPC)-based therapy has brought potential benefits to stroke patients as an important restorative therapeutics. However, its efficacy is limited by poor migration and survival ability. Here, we found out that hif-prolyl hydroxylase 2 (PHD2) silencing could enhance the migration and survival ability of EPCs which could improve the therapy efficacy for ischemic stroke. We successfully developed a siRNA delivery system, which could achieve siRNA delivery and EPCs tracking with magnetic resonance imaging (MRI) simultaneously. Besides, combining MRI and bioluminescence imaging (BLI), we successfully observed full temporal profile of EPCs dynamics in vivo. Furthermore, we found out that PHD2 silencing in EPCs elevated the expression of C-X-C chemokine receptor type 4 (CXCR4) and hypoxia-inducible factor 1α (HIF-1α), which enhanced the migration and survival ability of EPCs respectively. Significantly decreased infarct volume, functional deficits and increased fractional anisotrophy (FA) value, fiber counts were observed in the siPHD2-EPCs (EPCs transfected with siRNA targeting PHD2) group. What's more, higher level of BNDF, CD31, DCX, NeuN and MBP were also observed in the siPHD2-EPCs group. Altogether, our study provides an effective method to improve EPC-based therapy efficacy for ischemic stroke.

Background: Ischemic stroke caused severe damages to patients, mostly treatments for ischemic stroke focused recovery on the peri-infarct areas. In this study, we found that focal ischemic stroke caused damages to whole brain, endothelial progenitor cells (EPCs) treatment could significantly promote the recovery of the whole brain after ischemic stroke. Methods: EPCs were infected with lentivirus carrying luc2 and eGFP cassette for bioluminescence imaging (BLI) and labeled with Alkyl-PEI-SPIO for magnetic resonance imaging (MRI). 5×10^5 EPCs were transplanted intracardially 24 hours after photothrombotic ischemic stroke onset. BLI, MRI and behavior test were carried out at different time points. Expression of BDNF, VEGF in the ipsilateral and contralateral hemisphere and infarct volume were analyzed 7 days after EPCs transplantation. Expression of myelin basic protein (MBP) and NeuN in the ipsilateral and contralateral hemisphere were detected 14 days after EPCs transplantation. Findings: EPCs transplantation significantly increased the expression of BDNF, MBP and NeuN in both ipsilateral and contralateral hemisphere, while no significant differences were found in VEGF expression. Also, in vivo MRI results showed that fiber counts and FA values in both ipsilateral and contralateral corpus callosum increased 14 days after EPCs transplantation. No significant differences were found in the infarct volume 7 days after EPCs transplantation. mNSS scores and foot-faults test indicated better functional recovery 14 days after EPCs transplantation. Interpretation: Studies should focus on the whole brain recovery after stroke onset. EPCs treatment offered a powerful therapy method for whole brain recovery after ischemic stroke which may associated with elevated BDNF expression. Funding Statement: This work was supported by the National Key Basic Research Program of China (NOs. 2013CB733800 and 2013CB733803), the National Natural Science Foundation of China (NOs. 81230034 and 81520108015), the National Natural Science Foundation of Jiangsu Province (NO. BK20130057), the National Science Foundation for Youths of China (NOs. 81601544 and 81501522), the Fundamental Research Funds for the Central Universities (NO. 2242018k30004). C. Wang acknowledged the financial support from the China Scholarship Council for his joint PhD scholarship (NO. 201706090204). The funder had no role in the study design, data analysis, write-up or in the writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Declaration of Interest: The authors have no conflicts of interest to disclose. Ethics Approval Statement: This study was approved by the Institutional Animal Care and Use Committee (IACUC) of Southeast University (approval ID: SYXK-2010.4987). BALB/c nude female mice (8 weeks, 20-23 g, Comparative Medicine Centre of Yangzhou University [SCXK (SU) 2012-0004], Yangzhou, China) were used in this study. Briefly, EPCs were isolated from newborns with all mothers’ informed consent and with the approval of the local hospital ethics committee.