M2-polarized tumor-associated macrophages facilitated migration and epithelial-mesenchymal transition of HCC cells via the TLR4/STAT3 signaling pathway.

BACKGROUND: M2-polarized macrophages are tumor-associated-macrophages (TAMs), which are important contents of tumor-infiltrating immune cells. Toll-like receptor 4 (TLR4) is a molecular biomarker of tumor aggressiveness and poor prognosis. Toll-like receptors (TLRs) have important roles in the immune system and M2-polarized macrophages. However, the effects of TLR4 on M2-polarized macrophages in hepatocellular carcinoma (HCC) are unknown. Here, TLR4 expressed on HCC cells mediates the pro-tumor effects and mechanisms of M2-polarized macrophages. METHODS: THP-1 cells were induced to differentiate into M2-like macrophages through treatments with IL-4, IL-13, and phorbol myristate acetate (PMA). We used the HCC cell lines SMMC-7721 and MHCC97-H cultured in conditioned medium from M2-like macrophages (M2-CM) to investigate the migration potential of HCC cells and epithelial-mesenchymal transition (EMT)-associated molecular genetics. Signaling pathways that mediated M2-CM-promoted HCC migration were detected using western blotting. RESULTS: HCC cells cultured with M2-CM displayed a fibroblast-like morphology, an increased metastatic capability, and expression of EMT markers. TLR4 expression was markedly increased in M2-CM-treated HCC cells. TLR4 overexpression promoted HCC cell migration, and a TLR4-neutralizing antibody markedly inhibited HCC EMT in cells cultured with M2-CM. Furthermore, the TLR4/(signal transducer and activator of transcription 3 (STAT3) signaling pathway contributed to the effects of M2-CM on HCC cells. CONCLUSIONS: Taken together, M2-polarized macrophages facilitated the migration and EMT of HCC cells via the TLR4/STAT3 signaling pathway, suggesting that TLR4 may be a novel therapeutic target. These results improve our understanding of M2-polarized macrophages.

Increased matrix stiffness promotes tumor progression of residual hepatocellular carcinoma after insufficient heat treatment.

Aggravated behaviors of hepatocellular carcinoma (HCC) will occur after inadequate thermal ablation. However, its underlying mechanisms are not fully understood. Here, we assessed whether the increased matrix stiffness after thermal ablation could promote the progression of residual HCC. Heat-treated residual HCC cells were cultured on tailorable 3D gel with different matrix stiffness, simulating the changed physical environment after thermal ablation, and then the mechanical alterations of matrix stiffness on cell phenotypes were explored. Increased stiffness was found to significantly promote the proliferation of the heat-treated residual HCC cells when the cells were cultured on stiffer versus soft supports, which was associated with stiffness-dependent regulation of ERK phosphorylation. Heat-exposed HCC cells cultured on stiffer supports showed enhanced motility. More importantly, vitamin K1 reduced stiffness-dependent residual HCC cell proliferation by inhibiting ERK phosphorylation and suppressed the in vivo tumor growth, which was further enhanced by combining with sorafenib. Increased matrix stiffness promotes the progression of heat-treated residual HCC cells, proposing a new mechanism of an altered biomechanical environment after thermal ablation accelerates HCC development. Vitamin K1 plus sorafenib can reverse this protumor effect.

Low-dose CT combined mammography in diagnosis of overflow breast disease: A protocol of systematic review.

BACKGROUND: Overflow breast disease (OBD), also known as breast nipple discharge, refers fluid or liquid that comes out of nipple. Many patients with breast cancer experience such condition. However, it is not easy to detect it at early stage, especially for pathological OBD. Previous study found low-dose CT combined mammography (LDCTMG) could help in diagnosis of OBD. However, there is no systematic review investigating this issue. Therefore, this study will examine the accuracy of LDCTMG in diagnosis of OBD. METHODS: This study protocol will search literature sources in electronic databases and other sources. The electronic databases will be retrieved in The Cochrane Library, the Cochrane Register of Diagnostic Test Accuracy Studies, PUBMED, EMBASE, Web of Science, CINAHL, CNKI, and WANGFANG from inception to the present. We will also search other sources. All literature sources will be sought without restrictions to the language and publication status. Two researchers will independently carry out study selection, data extraction, and study quality assessment. Statistical analysis will be performed using RevMan 5.3. RESULTS: This study will exert a high-quality synthesis of eligible studies on the analysis of LDCTMG in diagnosis of OBD. CONCLUSIONS: The results of this study may provide evidence to help judge whether LDCTMG is accurate in diagnosis of OBD. STUDY REGISTRATION: INPLASY202050116.

Effect of roux-en Y gastric bypass surgery on patients with type 2 diabetes mellitus: A protocol of systematic review and meta-analysis.

BACKGROUND: Previous studies have reported that roux-en Y gastric bypass surgery (RYGBS) can benefit patients with type 2 diabetes mellitus (T2DM). However, their conclusions are still inconsistent. Thus, this study will aim to assess the effect of RYGBS for patients with T2DM. METHODS: In this study, the electronic databases of MEDLINE, EMBASE, CENTRAL, CINAHL, AMED, and CNKI from inceptions to the present without any limitations to language and publication status. All randomized controlled trials on assessing the effect of RYGBS for patients with T2DM will be included in this study. Two independent authors will carry out study search and selection according to the previous designed inclusion and exclusion criteria. At the same time, 2 authors will independently evaluate the risk of bias assessment by Cochrane risk of bias tool. Any disagreements between 2 authors will be solved by a third author through discussion. RevMan 5.3 software will be utilized for statistical analysis. RESULTS: This study will summarize the most recent studies and will provide a deeper understanding about using the effect of RYGBS for patients with T2DM. CONCLUSIONS: The findings of this study will present the existing evidence for the effect of RYGBS for patients with T2DM. SYSTEMATIC REVIEW REGISTRATION: INPLASY202040127.

Efficacy of laparoscopic sleeve gastrectomy in obese patients with type 2 diabetes mellitus: A protocol of systematic review and meta-analysis.

BACKGROUND: A numerous studies have reported that obese patients (OP) are easily to have type 2 diabetes mellitus (T2DM). Although a variety of managements are available to treat such disorder, their efficacy is still limited. Previous studies have reported that laparoscopic sleeve gastrectomy (LSGT) can benefit OP with T2DM. However, no study specifically and systematically explores this topic. Thus, this study will assess the efficacy and complications of LSGT for the management of OP with T2DM. METHODS: The search strategy will be performed in the electronic databases from inception to the March 31, 2020 without limitations of language and publication time: PUBMED, EMBASE, Cochrane Library, Scopus, Web of Science, CINAHL, AMED, WANGFANG, VIP, and CNKI. Two authors will independently identify the articles, collect the data, and assess the risk of bias using Cochrane risk of bias tool. We will invite a third author to solve any differences between two authors. We will use RevMan 5.3 software to investigate the statistical analysis. RESULTS: This study will supply a high-quality synthesis of randomized controlled trials (RCTs) on the analysis of LSGT for the management of OP with T2DM. CONCLUSIONS: This study will help to build proposals that aim at providing high quality RCTs in the management of LSGT in OP with T2DM. SYSTEMATIC REVIEW REGISTRATION: INPLASY202040128.

Humanistic care and psychological counseling on psychological disorders in medical students after COVID-19 outbreak: A protocol of systematic review.

BACKGROUND: The objective of this study is to investigate the effects of humanistic care and psychological counseling (HCPC) on psychological disorders (PD) in medical students after coronavirus disease 2019 (COVID-19) outbreak. METHODS: We will search randomized controlled trials or case-controlled studies of HCPC on PD in medical students after COVID-19 outbreak in the following electronic databases: PUBMED/MEDLINE, EMBASE, Cochrane Library, CINAHL, AMED, WANGFANG, and CNKI. The time is restricted from the construction of each database to the present. All process of study selection, data collection, and study quality evaluation will be carried out by two independent authors. Any different opinions will be solved by a third author through discussion. We will employ RevMan 5.3 software to conduct statistical analysis. RESULTS: This study will provide a better understanding of HCPC on PD in medical students after COVID-19 outbreak. CONCLUSIONS: This study may offer strong evidence for clinical practice to treat PD in medical students after COVID-19 outbreak. STUDY REGISTRATION: CRD42020193199.

Angiogenesis enhanced by treatment damage to hepatocellular carcinoma through the release of GDF15.

Transarterial chemoembolization (TACE) is the standard treatment for unresectable hepatocellular carcinoma (HCC). Hypoxia-induced angiogenesis by TACE is linked to treatment failure; however, whether the chemotherapeutic damage of TACE to HCC could increase tumor angiogenesis has not been explored. The molecular effects of chemotherapy-damaged HCC cells on the neo-angiogenesis were investigated in vitro and in vivo. The expression of growth differentiation factor 15 (GDF15) was significantly upregulated in HCC cells exposed to chemotherapeutic agents. GDF15 from chemotherapy-damaged HCC cells promoted the in vitro proliferation, migration, and tube formation of endothelial cells. The pro-angiogenic effect of GDF15 was through the activation of Src and its downstream AKT, MAPK, and NF-κB signaling, which was blocked by thalidomide. The use of thalidomide significantly attenuated the in vivo chemotherapy-damaged HCC cells-promoted angiogenesis in nude mice. In conclusion, the chemotherapeutic damage in TACE to HCC could promote tumor angiogenesis via the increased release of GDF15. Thalidomide could reverse these pro-angiogenic effects.

Activated hepatic stellate cells secrete periostin to induce stem cell-like phenotype of residual hepatocellular carcinoma cells after heat treatment.

Some evidences show that residual tumor after thermal ablation will progress rapidly. However, its mechanisms remain unclear. Here, we assessed whether activated HSCs could regulate stem cell-like property of residual tumor after incomplete thermal ablation to promote tumor progression. Human HCC cell lines were exposed to sublethal heat treatment to simulate the peripheral zone of thermal ablation. After residual HCC cells were cultured with conditional medium (CM) from activated HSCs, parameters of the stem cell-like phenotypes were analyzed. Nude mice bearing heat-exposed residual HCC cells and HSCs were subjected to metformin treatment to thwarter tumor progression. CM from activated primary HSCs or LX-2 cells significantly induced the stem cell-like phenotypes of residual HCC cells after heat treatment. These effects were significantly abrogated by neutralizing periostin (POSTN) in the CM. POSTN regulated the stemness of heat-exposed residual HCC cells via activation of integrin ß1/AKT/GSK-3ß/ß-catenin/TCF4/Nanog signaling pathway. Metformin significantly inhibited in vivo progression of heat-exposed residual HCC via suppressing POSTN secretion and decreasing cancer stem cell marker expression. Our data propose a new mechanism of activated HSCs promoting the stemness traits of residual HCC cells after incomplete thermal ablation and suggest metformin as a potential drug to reverse this process.

Over expression of hyaluronan promotes progression of HCC via CD44-mediated pyruvate kinase M2 nuclear translocation.

Hyaluronan is expressed in hepatocellular carcinoma (HCC) as HCC generally arises from a cirrhotic liver in which excessive production and accumulation of HA leads to developing cirrhosis. Though it has been suggested HA is involved in progression of HCC, the mechanisms underlying the connection between HA and HCC progression are unclear. Since increased aerobic glycolysis is a metabolic trait of malignant cells and HA-CD44 can modulate glucose metabolism, we aim to investigate the roles of PKM2, a key enzyme in glucose metabolism, in the HA-CD44 axis facilitated the progress of HCC. We shown PKM2 was required for HA-promoted HCC progression, which was not modulated by PKM2 kinase activity but by nuclear translocation of PKM2. PKM2 translocation was Erk (Thr202/Tyr204) phosphorylation dependent, which functioned at the downstream of HA-CD44 binding. Furthermore, elevated HA expression significantly correlated with PKM2 nuclear location and was an independent factors predicting poor HCC prognosis. In conclusions PKM2 nuclear translocation is required for mediating the described HA biological effects on HCC progression and our results imply that inhibition of HA may have therapeutic value in treating HCC.

Clostridium perfringens infection after transarterial chemoembolization for large hepatocellular carcinoma.

We report an unusual case of Clostridium perfringens liver abscess formation after transcatheter arterial chemoembolization (TACE) for large hepatocellular carcinoma. Severe deterioration in liver and renal function accompanied with hemocytolysis was found on the 2(nd) day after TACE. Blood culture found Clostridium perfringens and abdominal computed tomography revealed a gas-containing abscess in the liver. Following antibiotics administration and support care, the infection was controlled and the liver and renal function turned normal. The 2(nd) TACE procedure was performed 1.5 mo later and no recurrent Clostridium perfringens infection was found.