Polyaniline Induced Trivalent Ni in Laser-Fabricated Nickel Oxides for Efficient Oxygen Evolution Reaction.

Although it is generally acknowledged that transition metals at high oxidation states represent superior oxygen evolution reaction (OER) activity, the preparation and stability of such a high-valence state are still a challenge, which requires relatively harsh reaction conditions and is unstable under ambient conditions. Herein, we report the formation of trivalent nickel (Ni3+) in laser-fabricated nickel oxides induced by polyaniline (PANI) under electrochemical activation via a significant charge transfer between Ni and N, as confirmed by X-ray photoelectron spectroscopy and density functional theory calculations. Thereafter, the presence of Ni3+ and the improved conductivity by PANI effectively increase the electrochemical OER activity of the samples together with excellent long-term stability. This work provides new insights for the rational manufacture of high-valence metal for electrochemical reactions.

Inflammation and cancer: paradoxical roles in tumorigenesis and implications in immunotherapies.

Chronic inflammation caused by persistent infections and metabolic disorders is thought to contribute to the increased cancer risk and the accelerated cancer progression. Oppositely, acute inflammation induced by bacteria-based vaccines or that is occurring after cancer selectively inhibits cancer progression and metastasis. However, the interaction between inflammation and cancer may be more complex than the current explanations for the relationship between chronic and acute inflammation and cancer. In this review, we described the impact of inflammation on cancer on the basis of three perspectives, including inflammation with different durations (chronic and acute inflammation), different scopes (systemic and local inflammation) and different occurrence sequences (inflammation occurring after and before cancer). In addition, we also introduced bacteria/virus-based cancer immunotherapies. We perceive that inflammation may be a double-edged sword with cancer-promoting and cancer-suppressing functions in certain cases. We expect to further improve the understanding of the relationship between inflammation and cancer and provide a theoretical basis for further research on their complex interaction.

LS-007 inhibits melanoma growth via inducing apoptosis and cell cycle arrest and regulating macrophage polarization.

LS-007, an inhibitor of cyclin-dependent kinase 9 (CDK9), exhibits potential antitumor activity against chronic lymphocytic leukemia and ovarian cancer, but its effect on melanoma and tumor microenvironment (TME) has not been reported yet. This study aimed to investigate the role of LS-007 in B16F10 melanoma and relevant mechanisms. LS-007 significantly inhibited viability and induced apoptosis of B16F10 cells in a dose-dependent manner, which were accompanied with the increased ratio of Bax to Bcl-2 and decreased Mcl-1 mRNA level. Western blot analysis showed that LS-007 increased the expression of cleaved caspase-3 and poly ADP-ribose polymerase (PARP). Furthermore, flow cytometry analysis and qRT-PCR results showed that LS-007 treatment resulted in cell cycle arrest by changing cell cycle-related gene expression. Notably, in vivo evaluation showed that LS-007 significantly decreased the weight and volume of tumor and the expression of Ki67, promoted the expression of iNOS and inhibited the expression of CD206, suggesting that LS-007 might inhibit tumor growth by suppressing polarization of macrophages into tumor-associated macrophages (TAMs) in the TME. The increase in M1/M2 treated with LS-007 detected by flow cytometry hinted that macrophages were polarized towards an antitumor phenotype. In addition, LS-007 induced higher apoptotic rate of B16F10 cells when co-cultured B16F10 with BMDMs. LS-007 has inhibitory effects on B16F10 cells in vivo and in vitro via inducing apoptosis, cell cycle arrest, and changing macrophage function in the TME.

Local and systemic inflammation triggers different outcomes of tumor growth related to infiltration of anti-tumor or pro-tumor macrophages.

BACKGROUND: Previous evidence suggests inflammation may be a double-edged sword with cancer-promoting and cancer suppressing function. In this study, we explore the impact of local and systemic inflammation on cancer growth. METHODS: Female BALB/C mice were subcutaneously implanted with foreign body (plastic plates) to build up a local inflammation and intraperitoneally injected with PolyIC or lipopolysaccharides (LPS) to build up a systemic inflammation, followed by subcutaneous injection of 5  × 10 5 colon cancer cells. Immunohistochemistry and enzyme linked immunosorbent assay were utilized to detect the Ki67 and interleukin (IL) 6, IL-1ß, and monocyte chemoattractant protein-1 expression in the tumor tissues and serum, respectively. The distributions of immune cells and expression of toll-like receptors (TLRs) were evaluated by flow cytometry (FCM) and quantitative real time-polymerase chain reaction. RESULTS: The results showed that local inflammation induced by foreign body implantation suppressed tumor growth with decreased tumor weight ( P   =  0.001), volume ( P   =  0.004) and Ki67 index ( P   <  0.001). Compared with the control group, myeloid-derived suppressive cells sharply decreased ( P   =  0.040), while CD4 + T cells slightly increased in the tumor tissues of the group of foreign body-induced local inflammation ( P   =  0.035). Moreover, the number of M1 macrophages ( P   =  0.040) and expression of TLRs, especially TLR3 ( P  < 0.001) and TLR4 ( P  < 0.001), were significantly up-regulated in the foreign body group. Contrarily, tumor growth was significantly promoted in LPS or PolyIC-induced systemic inflammation ( P   =  0.009 and 0.006). FCM results showed M1 type macrophages ( P   =  0.017 and 0.006) and CD8 + T cells ( P   =  0.031 and 0.023) were decreased, while M2 type macrophages ( P  = 0.002 and 0.007) were significantly increased in tumor microenvironment of LPS or PolyIC-induced systemic inflammation group. In addition, the decreased expression of TLRs was detected in LPS or PolyIC group. CONCLUSIONS: The foreign body-induced local inflammation inhibited tumor growth, while LPS or PolyIC- induced systemic inflammation promoted tumor growth. The results suggested that the different outcomes of tumor growth might be attributed to the infiltration of anti-tumor or pro-tumor immune cells, especially M1 or M2 type macrophages into tumor microenvironment.

Cancer-associated fibroblasts promote tumor progression by lncRNA-mediated RUNX2/GDF10 signaling in oral squamous cell carcinoma.

Cancer-associated fibroblasts (CAF) are the most abundant stromal cells in tumor and exert a pro-tumoral effect in cancer progression. Numerous evidence shows long non-coding RNA (lncRNA) abnormally regulates gene expression in various cancers. However, little is known about the role of lncRNA in the interaction between CAF and cancer cells. Here, we first identify an uncharacterized lncRNA, LOC100506114, which is significantly upregulated in CAF and is involved in the functional transformation of normal fibroblasts (NF) and CAF. Expression of LOC100506114 enhances the expression of fibroblast activation protein alpha and α-smooth muscle actin in NF and promotes malignant characteristics of NF and CAF in vivo and in vitro. The profile of gene co-expression analysis shows that growth differentiation factor 10 (GDF10) is positively correlated with the expression of LOC100506114. CAF promote stromal fibroblast activation and the proliferation and migration of tumor cells by secreting GDF10. Our data demonstrate that lncRNA plays a critical role in the interplay of stromal fibroblasts and tumor cells in oral squamous cell carcinoma.

SPION-MSCs enhance therapeutic efficacy in sepsis by regulating MSC-expressed TRAF1-dependent macrophage polarization.

BACKGROUND: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The liver has a crucial role in sepsis and is also a target for sepsis-related injury. Macrophage polarization between the M1 and M2 types is involved in the progression and resolution of both inflammation and liver injury. Iron oxide-based synthetic nanoparticles (SPIONs) can be used as antibacterial agents to regulate the inflammatory response. Mesenchymal stromal/stem cells (MSCs) have been widely used in the treatment of autoimmune diseases, sepsis, and other diseases. However, to date, both the effects of SPIONs on MSCs and the fate of SPION-labelled MSCs in sepsis and other diseases are still unclear. METHODS: Mice were subjected to caecal ligation and puncture (CLP) or lipopolysaccharide (LPS) induction to develop sepsis models. The CLP or LPS models were treated with MSCs or SPION-labelled/pretreated MSCs (SPION-MSCs). Bone marrow (BM)-derived macrophages and RAW 264.7 cells were cocultured with MSCs or SPION-MSCs under different conditions. Flow cytometry, transmission electron microscopy, western blotting, quantitative real-time PCR, and immunohistochemical analysis were performed. RESULTS: We found that SPIONs did not affect the basic characteristics of MSCs. SPIONs promoted the survival of MSCs by upregulating HO-1 expression under inflammatory conditions. SPION-MSCs enhanced the therapeutic efficacy of liver injury in both the CLP- and LPS-induced mouse models of sepsis. Moreover, the protective effect of SPION-MSCs against sepsis-induced liver injury was related to macrophages. Systemic depletion of macrophages reduced the efficacy of SPION-MSC therapy. Furthermore, SPION-MSCs promoted macrophages to polarize towards the M2 phenotype under sepsis-induced liver injury in mice. The enhanced polarization towards M2 macrophages was attributed to their phagocytosis of SPION-MSCs. SPION-MSC-expressed TRAF1 was critical for promotion of macrophage polarization and alleviation of sepsis in mice. CONCLUSION: MSCs labelled/pretreated with SPIONs may be a novel therapeutic strategy to prevent or treat sepsis and sepsis-induced liver injury. HIGHLIGHTS: 1. SPIONs enhance the viability of MSCs by promoting HO-1 expression. 2. SPION-labelled/pretreated MSCs effectively improve sepsis by regulating macrophage polarization to M2 macrophages. 3. SPION-labelled/pretreated MSCs regulate macrophage polarization in a manner dependent on MSC-expressed TRAF1 protein.

Chitosan-Poly(Acrylic Acid) Nanoparticles Loaded with R848 and MnCl2 Inhibit Melanoma via Regulating Macrophage Polarization and Dendritic Cell Maturation.

PURPOSE: Since immune cells in the tumor microenvironment (TME) can affect the development and progression of tumors, strategies modulating immune cells are considered to have an important therapeutic effect. As a TLR7/8 agonist, R848 effectively activates the innate immune cells to exert an anti-tumor effect. Mn2+ has been reported to strongly promote the maturation of antigen-presenting cells (APCs), thereby enhancing the cytotoxicity of CD8+ T cells. Thus, we tried to investigate whether chitosan-poly(acrylic acid) nanoparticles (CS-PAA NPs) loaded with R848 and MnCl2 (R-M@CS-PAA NPs) could exert an anti-tumor effect by regulating the function of immune cells. METHODS: R-M@CS-PAA NPs were prepared, and their basic characteristics, anti-tumor effect, and potential mechanisms were explored both in vitro and in vivo. RESULTS: R-M@CS-PAA NPs easily released MnCl2 and R848 at low pH. In B16F10 mouse melanoma model, R-M@CS-PAA NPs exerted the most significant anti-melanoma effect compared with the control group and CS-PAA NPs loaded with R848 or MnCl2 alone. FITC-labeled R-M@CS-PAA NPs were displayed to be accumulated at the tumor site. R-M@CS-PAA NPs significantly increased the infiltration of M1 macrophages and CD8+ T cells but reduced the number of suppressive immune cells in the TME. Moreover, in vitro experiments showed that R-M@CS-PAA NPs polarized macrophages into the M1 phenotype to inhibit the proliferation of B16F10 cells. R-M@CS-PAA NPs also enhanced the killing function of CD8+ T cells to B16F10 cells. Of note, R-M@CS-PAA NPs not only promoted the maturation of APCs such as dendritic cells and macrophages by STING and NF-кB pathways, but also enhanced the ability of dendritic cells to present ovalbumin to OT-I CD8+ T cells to enhance the cytotoxicity of OT-I CD8+ T cells to ovalbumin-expressing B16F10 cells. CONCLUSION: These data indicate that the administration of R-M@CS-PAA NPs is an effective therapeutic strategy against melanoma.

Ferumoxytol-ß-glucan Inhibits Melanoma Growth via Interacting with Dectin-1 to Polarize Macrophages into M1 Phenotype.

Background: Regulating the polarization of macrophages to antitumor M1 macrophages is a promising strategy for overcoming the immunosuppression of the tumor microenvironment for cancer therapy. Ferumoxytol (FMT) can not only serve as a drug deliver agent but also exerts anti-tumor activity. ß-glucan has immuno-modulating properties to prevent tumor growth. Thus, a nanocomposite of FMT surface-coated with ß-glucan (FMT-ß-glucan) was prepared to explore its effect on tumor suppression. Methods: Male B16F10 melanoma mouse model was established to explore the antitumor effect of FMT-ß-glucan. The viability and apoptotic rates of B16F10 cells were detected by cell counting kit-8 and Annexin-V/PI experiments. The levels of M1 markers were quantified by quantitative reverse transcription-polymerase chain reaction and enzyme linked immunosorbent assay. Phagocytic activity and intracellular reactive oxygen species (ROS) in macrophages were evaluated by the neutral red uptake assay and flow cytometry, respectively. Small interfering RNA (siRNA) transfection was applied to knock down the Dectin-1 gene in RAW 264.7 cells. Results: FMT-ß-glucan suppressed tumor growth to a greater extent and induced higher infiltration of M1 macrophages than the combination of FMT and ß-glucan (FMT+ß-glucan) in vivo. In vitro, supernatant from FMT-ß-glucan-treated RAW 264.7 cells led to lower cell viability and induced more apoptosis of B16F10 cells than that from the FMT+ß-glucan group. Moreover, FMT-ß-glucan boosted the expression of M1 type markers, and increased phagocytic activity and ROS in RAW 264.7 cells. Further research indicated that FMT-ß-glucan treatment promoted the level of Dectin-1 on the surface of RAW 264.7 cells and that knockdown of Dectin-1 abrogated the phosphorylation levels of several components in MAPK and NF-κB signaling. Conclusion: The nanocomposite FMT-ß-glucan suppressed melanoma growth by inducing the M1 macrophage-activated tumor microenvironment.

17ß-Estradiol promotes LC3B-associated phagocytosis in trained immunity of female mice against sepsis.

Sepsis is a common serious clinical infectious disease accompanied by more severe injuries and higher mortality rates in men than women. The much higher level of 17ß-estradiol (E2) in female is one of the significant reasons for better sepsis resistance ability. Trained immunity is a novel way to fight against infection by improving innate immunity. However, whether ß-glucan-induced trained immunity can promote macrophage phagocytosis to clear infections in early sepsis has not been clarified. And whether E2 involved in this process needs further investigation. Symptoms among male, female and ovariectomized (OVX) C57BL/6 mice in early sepsis were detected. The effect of trained immunity on macrophage LC3B-associated phagocytosis (LAP) and the mechanism of E2 functioned in this process have also been explored. We demonstrated compared with male mice, female has significantly more mild symptoms and more reactive oxygen species (ROS) production and stronger NADPH oxidase 2 (NOX2) expression in the macrophage of major organs. In contrary, these characteristics are disappeared in OVX mice. Furthermore, in macrophage cell lines and primary bone marrow- derived macrophages (BMDMs), ß-glucan-induced trained immunity can increase ROS production by activating NOX2 to promote macrophage LAP. E2 can up-regulate RUBICON through estrogen receptor α (ERα) to further facilitate macrophage LAP. These results indicated that trained immunity can improve sepsis resistance ability by stimulating macrophage LAP. E2 can boost ROS production and RUBICON expression to further promote macrophage LAP, which can provide a new perspective to recognize the mechanism of trained immunity in gender differences when responding to sepsis.

Ganoderma lucidum fruiting body extracts inhibit colorectal cancer by inducing apoptosis, autophagy, and G0/G1 phase cell cycle arrest in vitro and in vivo.

Although previous studies have found that Ganoderma lucidum extracts have the ability to directly resist tumor proliferation and reduce metastasis and invasion, the effect of the extracts of Ganoderma lucidum fruiting body (GLE) on cancer is not clarified. This study intends to investigate the anticancer role of GLE on HCT116 colorectal cancer cells in vitro and in vivo. The effects of GLE on the proliferation, apoptosis, autophagy and cell cycle arrest of HCT116 cells were detected by cell counting kit-8 (CCK-8), flow cytometry, electron microscope, quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assay. Xenografted mouse models were used to evaluate the tumor growth inhibition effect of GLE in vivo. GLE could significantly inhibit the viability of four tumor cell lines (A549, SW1990, SKOV3 and HCT116) and HCT116 cells were more sensitive to GLE treatment with a half inhibitory concentration of 106 µg/mL. GLE treatment induced apoptosis of HCT116 cells by downregulating of the ratio of Bcl-2 to Bax and increasing cleaved caspase-3 and poly ADP-ribose polymerase (PARP) protein expression. Autophagy of HCT116 cells also increased after GLE treatment, as shown by observation of autophagosomes formation and altered protein expressions in the mTOR pathway. In addition, GLE treatment led to G0/G1 cell cycle arrest as evidenced by flow cytometry analysis and changes in cell-cycle-related gene expressions at the mRNA levels. Of note, in vivo evaluation indicated that GLE significantly inhibited tumor weight and tumor volume and decreased Ki67 expression. In summary, GLE has potential to be developed as an anticancer agent against colorectal cancer, and further evaluation is needed.

Ferumoxytol Attenuates the Function of MDSCs to Ameliorate LPS-Induced Immunosuppression in Sepsis.

Sepsis-induced immunosuppression is recognized as one of the main features responsible for therapeutic failures. Myeloid-derived suppressor cells (MDSCs), which are mainly characterized by their suppressive properties, have been reported to be expanded in sepsis. Ferumoxytol (FMT), an FDA-approved iron supplement, has been shown to possess immune-modulatory properties in tumors. However, it is unclear whether FMT alters the functions of MDSCs to reduce late-sepsis immunosuppression. Here, we showed an immunomodulatory effect of FMT on MDSCs to ameliorate lipopolysaccharide (LPS)-induced immunosuppression in the late stage of sepsis. Separation of cells with internalized FMT and detection of the intracellular iron content showed that MDSCs could uptake FMT. Low doses of FMT had no effects on the cell viability of MDSCs, but FMT inhibited the expansion of MDSCs in vitro. Moreover, FMT significantly downregulated the expression levels of Arg-1, S100A8, S100A9, and p47phox as well as ROS production in MDSCs. FMT decreased the percentage of granulocytic MDSCs (G-MDSCs) and promoted the differentiation of MDSCs into macrophages. Furthermore, FMT reduced white blood cell recruitment and alveolar wall thickening in the lungs and areas of necrosis in the liver as well as some biochemical markers of liver dysfunction. FMT decreased the percentage of G-MDSCs and monocytic MDSCs (M-MDSCs) in the spleens of LPS-induced septic mice. Of note, FMT reduced the T cell immunosuppressive functions of both G-MDSCs and M-MDSCs. Expectedly, FMT also significantly reduced Arg-1 and p47phox gene expression in splenic CD11b+Gr-1+ cells isolated from LPS-challenged mice. These data indicate that FMT decreased the immunosuppressive functions of MDSCs by decreasing Arg-1 and ROS production, suggesting that FMT may reduce long-term immunosuppression in the late stage of sepsis.

SPIONs enhances IL-10-producing macrophages to relieve sepsis via Cav1-Notch1/HES1-mediated autophagy.

BACKGROUND: Sepsis is a life-threatening condition caused by dysregulated host responses to infection. Macrophages, which recognize microbial infections through identification of bacterial markers such as lipopolysaccharide (LPS), are crucial to the pathogenesis of sepsis-associated liver injury. However, the understanding of the SPIONs-mediated modulation of macrophage responses in LPS-induced sepsis and liver injury is limited. MATERIALS AND METHODS: Superparamagnetic iron oxide nanoparticles (SPIONs) of γ-Fe2O3 nanoparticles were prepared, and their morphology and magnetic properties were characterized. RESULTS: Using a murine model of LPS-induced sepsis and liver injury, we found that SPIONs alleviated LPS-induced sepsis, preventing infiltration of inflammatory cells into the liver. SPIONs also increased the level of interleukin-10 (IL-10) in liver macrophages, while SPIONs's effect on LPS-induced sepsis was abrogated in IL-10-/- mice, indicating that the protective effect of SPIONs is dependent on IL-10+ macrophages. Moreover, SPIONs activated macrophage autophagy to increase IL-10 production, which was markedly attenuated by autophagy inhibition. Furthermore, SPIONs upregulated the expression of Caveolin-1 (Cav1) in macrophages, which plays a role in cellular uptake of metallic nanoparticles. Interestingly, activation of Cav1 and Notch1/HES1 signaling was involved in SPIONs-induced autophagy in both RAW 264.7 cells and bone marrow-derived macrophages (BMDMs). Our data reveal a novel mechanism for SPIONs -induced autophagy in macrophages, which occurs through activation of the Cav1-Notch1/HES1 signaling pathway, which promotes the production of IL-10 in macrophages, leading to inhibition of inflammation in LPS-induced sepsis and liver injury. CONCLUSION: Our results suggest that SPIONs may represent a potential therapeutic agent for the treatment of sepsis and sepsis-induced liver injury.

FABP1 Polymorphisms Contribute to Hepatocellular Carcinoma Susceptibility in Chinese Population with Liver Cirrhosis: A Case-Control Study.

Purpose: Single nucleotide variations in the liver fatty acid binding protein (L-FABP, FABP1) gene lead to changes in cellular signaling pathways and lipid metabolism. FABP1 polymorphisms were associated with some liver diseases, like steatotic hepatocellular carcinoma. However, the association between FABP1 rs1545224 and rs2241883 polymorphisms and hepatitis B virus-related liver cirrhosis (LC) and hepatocellular carcinoma (HCC) has not been reported. We performed this study to explore their relationship. Methods: One thousand individuals (250 healthy controls, 250 chronic HBV (CHB), 250 LC, and 250 HCC patients) were recruited. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were applied to assess the difference in allele and genotype frequencies. Cochran-Armitage trend test was used to evaluate the cumulative effect. Significant difference would be defined when the P value was less than 0.05. Results: The distribution of rs1545224 GG, AG and AA genotypes in healthy controls or CHB carriers was not significant when compared to LC or HCC patients (P>0.05). LC patients carrying at least one A allele are more likely to develop HCC in contrast with those with G allele (P<0.05). After adjustment for confounders, meaningful results were only seen in the comparison between rs1545224 AG+AA genotype carriers and GG genotype carriers among the LC patients (P<0.05). Rs2241883 polymorphism did not influence the risk of developing LC or HCC in healthy and CHB individuals, nor did it influence the risk of HCC in LC patients (P>0.05). Conclusions: Taken together, FABP1 rs1545224 polymorphism might increase HCC risk in LC patients, indicating that FABP1 rs1545224 polymorphism may be related to the process of developing HCC in Chinese patients with LC.

The role of microRNA-608 polymorphism on the susceptibility and survival of cancer: a meta-analysis.

The role of rs4919510 polymorphism in microRNA-608 (miR-608) and cancer susceptibility and prognosis remain controversial and debatable. We conducted a meta-analysis of twenty-four eligible publications on the association of rs4919510 polymorphism with cancer risk and/or prognosis. Odds ratios, hazard ratios, and 95% confidence interval were used to investigate the association between this polymorphism and susceptibility, overall survival, and recurrence-free survival of cancer. Overall, eighteen case-control studies and nine cohort studies evaluated the susceptibility and prognostic value of rs4919510 polymorphism in cancer, respectively. Pooled analysis showed that rs4919510 polymorphism was not associated with cancer risk in all five genetic models. When stratifying by different cancer sites, rs4919510 polymorphism was detected to have a significant association with a decreased risk of colorectal cancer in homozygous model (P = 0.006) and recessive model (P = 0.001), subgroup analysis also emerged a weakened correlation between rs4919510 polymorphism and an increased risk of papillary thyroid cancer in heterozygote model (P = 0.04). Furthermore, the prognosis of rs4919510 variant in cancer patients showed that rs4919510 GG genotype was significant association with poor recurrence-free survival in homozygous models (P = 0.04). The meta-analysis suggested that the microRNA-608 rs4919510 polymorphism maybe associate with a significantly decreased risk for colorectal cancer. Further investigations on larger populations are required to evaluate and confirm this relationship.

PEP06 polypeptide 30 exerts antitumour effect in colorectal carcinoma via inhibiting epithelial-mesenchymal transition.

BACKGROUND AND PURPOSE: PEP06, a polypeptide modified from endostatin, was investigated for its antitumour effects on colorectal cancer (CRC) and the possible mechanisms of this antitumour activity were examined in in vitro and in vivo models. EXPERIMENTAL APPROACH: After PEP06 treatment, cell proliferation and migration assays were performed in CRC cells. Epithelial-mesenchymal transition (EMT) progression was determined by Western blotting, immunofluorescent staining and immunohistochemistry in vitro and in a residual xenograft model. MiRNAs regulated by PEP06 were identified by miRNA microarray and verified by in situ hybridization and quantitative real-time PCR. The interactions between PEP06 and integrin αvß3 were determined with Biacore SA biochips. The cellular function of miR-146b-5p was validated by gain-of-function and loss-of-function approaches. A mouse model of lung metastasis was used to determine the effect of PEP06 on metastatic growth. KEY RESULTS: PEP06 did not affect cell viability but reduced migration and EMT in SW620 and HCT116 cells. PEP06 significantly repressed the expression of miR-146b-5p in these two cell lines through binding to integrin αvß3. MiR-146b-5p was shown to increase EMT by targeting Smad4, and the miR-146b-5p-Smad4 cascade regulated EMT in CRC. PEP06 also suppressed CRC pulmonary metastasis, increased survival of mice and hampered residual tumour growth by inhibiting EMT through down-regulating miR-146b-5p. CONCLUSIONS AND IMPLICATIONS: PEP06 is a polypeptide that inhibits the growth and metastasis of colon cancer through its RGD motif binding to integrin αvß3, thereby down-regulating miR-146b-5p to inhibit EMT in vitro and in vivo. It might have potential as a therapeutic for CRC.

Association between body mass index and breast cancer risk: evidence based on a dose-response meta-analysis.

INTRODUCTION: Breast cancer is the most common cancer in women worldwide. The association between body mass index (BMI) and breast cancer risk has been paid more attention in the past few years, but the findings are still controversial. To obtain a more reliable conclusion, we performed a dose-response meta-analysis on 12 prospective cohort studies comprising 22,728,674 participants. METHODS: Linear and nonlinear trend analyses were conducted to explore the dose-response relationship between BMI and breast cancer risk. The summary relative risk (SRR) and 95% confidence intervals (CIs) were used to evaluate the cancer risk. RESULTS: The overall results showed a weak positive association between a 5-unit increase in BMI and breast cancer risk, indicating that a 5 kg/m2 increase in BMI corresponded to a 2% increase in breast cancer risk (SRR: 1.02, 95% CI: 1.01-1.04, p<0.001). Notably, further subgroup meta-analysis found that higher BMI could be a protective factor of breast cancer risk for premenopausal women (SRR: 0.98, 95% CI: 0.96-0.99, p<0.001). In addition, the dose-response result demonstrated that there was a linear association between BMI and breast cancer risk (Pnonlinearity=0.754). CONCLUSION: In summary, this dose-response meta-analysis of prospective cohort studies showed that every 5 kg/m2 increase in BMI corresponded to a 2% increase in breast cancer risk in women. However, higher BMI could be a protective factor in breast cancer risk for premenopausal women. Further studies are necessary to verify these findings and elucidate the pathogenic mechanisms.

Pooling-analysis on hMLH1 polymorphisms and cancer risk: evidence based on 31,484 cancer cases and 45,494 cancer-free controls.

To elucidate the veritable relationship between three hMLH1 polymorphisms (rs1800734, rs1799977, rs63750447) and cancer risk, we performed this meta-analysis based on overall published data up to May 2017, from PubMed, Web of knowledge, VIP, WanFang and CNKI database, and the references of the original studies or review articles. 57 publications including 31,484 cancer cases and 45,494 cancer-free controls were obtained. The quality assessment of six articles obtained a summarized score less than 6 in terms of the Newcastle-Ottawa Scale (NOS). All statistical analyses were calculated with the software STATA (Version 14.0; Stata Corp, College Station, TX). We found all the three polymorphisms can enhance overall cancer risk, especially in Asians, under different genetic comparisons. In the subgroup analysis by cancer type, we found a moderate association between rs1800734 and the risk of gastric cancer (allele model: OR = 1.14, P = 0.017; homozygote model: OR = 1.33, P = 0.019; dominant model: OR = 1.27, P = 0.024) and lung cancer in recessive model (OR = 1.27, P = 0.024). The G allele of rs1799977 polymorphism was proved to connect with susceptibility of colorectal cancer (allele model: OR = 1.21, P = 0.023; dominate model: OR = 1.32, P <0.0001) and prostate cancer (dominate model: OR = 1.36, P <0.0001). Rs63750447 showed an increased risk of colorectal cancer, endometrial cancer and gastric cancer under all genetic models. These findings provide evidence that hMLH1 polymorphisms may associate with cancer risk, especially in Asians.

Prognostic role and clinical significance of trophoblast cell surface antigen 2 in various carcinomas.

INTRODUCTION: Trophoblast cell surface antigen 2 (TROP2) has been linked to disease prognosis in various human cancers and plays a critical role in tumor development, progression, and metastasis. A number of relevant studies have been published on this topic. A meta-analysis of the latest literature to evaluate the value of TROP2 as a predictive prognosticator of cancer was performed. METHODS: Several online databases were searched, and relevant articles were retrieved. Overall and subcategory meta-analyses were performed, and results were collated. RESULTS: Twenty-seven articles, including 29 studies, were included, involving 4,852 cancer patients, and results showed that the above-baseline expression of TROP2 was significantly associated with poorer overall survival (OS) (pooled hazard ratio [HR]: 1.84, 95% confidence interval [CI]: 1.45-2.35), disease-free survival (DFS) (pooled HR: 2.77, 95% CI: 1.73-4.42), and progression-free survival (PFS) (pooled HR: 1.71, 95% CI: 1.25-2.35). The following clinical characteristics were also significantly linked with TROP2 overexpression: moderate/poor differentiation (pooled HR: 3.03, 95% CI: 1.99-4.63), distant metastasis (pooled HR: 2.46, 95% CI: 1.05-5.75), lymph node metastasis (pooled HR: 2.47, 95%: CI 1.72-3.56), and advanced TNM stage (pooled HR: 2.02, 95% CI: 1.38-2.95). CONCLUSION: TROP2 overexpression was predictive of poor prognosis in human cancers and may be an independent prognostic predictive biomarker. Further studies should be performed to confirm the significance of TROP2 in clinical practice.

IL-18 polymorphisms contribute to hepatitis B virus-related cirrhosis and hepatocellular carcinoma susceptibility in Chinese population: a case-control study.

IL-18 polymorphisms influence the transcriptional activity of the IL-18 gene and associated with various diseases. However, their relationships with hepatitis B virus-related liver diseases had not reached a consensus. So we conducted this case-control study with a view to clarifying the association. We included four groups: healthy controls, chronic hepatitis B virus (CHB) carriers, liver cirrhosis (LC) and hepatocellular carcinoma (HCC) groups with each group of 250 persons. Odd ratios (ORs) and 95% confidence intervals (95%CIs) with or without adjustment were calculated. Haplotype analysis was also performed. The results showed people carrying rs187238 CG genotype had a lower risk of LC (CG vs. CC: OR = 0.59, 95%CI = 0.38-0.91, P = 0.02), while GG genotype carriers had a higher risk of HCC (GG vs. CC+CG: OR = 4.73, 95%CI = 1.01-22.1, P = 0.03) than those with CC and CG genotypes in healthy group. Rs187238 GG genotype increased the risk from CHB to LC status (GG vs. CC: OR = 4.81, 95%CI = 1.03-22.6; GG vs. CC+CG: OR = 4.73, 95%CI = 1.01-22.1), meanwhile the trend also existed by controlling confounding factors (GG vs. CC: OR = 6.25, 95%CI = 1.09-35.8; GG vs. CC+CG: OR = 5.91, 95%CI = 1.04-33.7). Haplotype Crs187238Trs1946518 moderately decreased the risk of CHB carriers developing into HCC (OR = 0.69, 95%CI = 0.50-0.96, P = 0.03) after adjustment. In conclusion, IL-18 rs187238 GG genotype may increase the risk of HCC in healthy population and the risk of LC in CHB carriers.

Pooling-analysis for diagnostic and prognostic value of MiRNA-100 in various cancers.

Many studies manifested miRNA-100 was deregulated in various cancers, which indicated that miRNA-100 might be a potential biomarker of cancer diagnosis and prognosis. However, the role of miRNA-100 was still uncertain. We searched for qualified studies using PubMed, EMBASE, Web of Science, Cochrane library and CNKI databases. The diagnostic effect was evaluated by the pooled sensitivity, specificity, and other indexes. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) were calculated to assess the prognostic value. This meta-analysis included 7 and 19 studies about diagnosis and prognosis, respectively. The results of pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) were 0.75 (95%CI: 0.71-0.78), 0.74 (95%CI: 0.69-0.78), 2.61 (95%CI: 1.81-3.76), 0.33 (95%CI: 0.24-0.45), 8.46 (95%CI: 4.85-14.77), respectively. And, the area under SROC curve (AUC) was 0.8141. We also found that lower expression of miRNA-100 in cancer tissues could significantly predict poorer prognosis in overall cancer (HR = 0.59, 95%CI: 0.39-0.90), especially in genital system tumors (HR = 0.42, 95%CI: 0.27-0.66, P = 0.431), bladder cancer (HR = 0.21, 95%CI: 0.06-0.73, P = 0.143) and esophageal squamous cell carcinoma (HR = 0.26, 95%CI: 0.13-0.52, P = 0.164). Our studies concluded that miRNA-100 has a certain value in diagnosis and it may indicate a poor prognosis of cancers.