The emerging tumor microbe microenvironment: From delineation to multidisciplinary approach-based interventions.

Intratumoral microbiota has become research hotspots, and emerges as a non-negligent new component of tumor microenvironments (TME), due to its powerful influence on tumor initiation, metastasis, immunosurveillance and prognosis despite in low-biomass. The accumulations of microbes, and their related components and metabolites within tumor tissues, endow TME with additional pluralistic features which are distinct from the conventional one. Therefore, it's definitely necessary to comprehensively delineate the sophisticated landscapes of tumor microbe microenvironment, as well as their functions and related underlying mechanisms. Herein, in this review, we focused on the fields of tumor microbe microenvironment, including the heterogeneity of intratumor microbiota in different types of tumors, the controversial roles of intratumoral microbiota, the basic features of tumor microbe microenvironment (i.e., pathogen-associated molecular patterns (PAMPs), typical microbial metabolites, autophagy, inflammation, multi-faceted immunomodulation and chemoresistance), as well as the multidisciplinary approach-based intervention of tumor microbiome for cancer therapy by applying wild-type or engineered live microbes, microbiota metabolites, antibiotics, synthetic biology and rationally designed biomaterials. We hope our work will provide valuable insight to deeply understand the interplay of cancer-immune-microbial, and facilitate the development of microbes-based tumor-specific treatments.

Physical- and Chemical-Dually ROS-Responsive Nano-in-Gel Platforms with Sequential Release of OX40 Agonist and PD-1 Inhibitor for Augmented Combination Immunotherapy.

Combination immunotherapy synergizing the PD-1 blockade with OX40 agonism has become a research hotspot, due to its enormous potential to overcome the restricted clinical objective response suffered by monotherapy. Questions of timing and sequence have been important aspects of immunotherapies when considering immunologic mechanisms; however, most of the time the straightforward additive approach was taken. Herein, our work is the first to investigate an alternative timing of aOX40 and aPD-1 treatment in melanoma-bearing mice, and it demonstrates that sequential administration (aOX40 first, then aPD-1 following) provided superior antitumor benefits than concurrent treatment. Based on that, to further avoid the limits suffered by solution forms, we adopted pharmaceutical technologies to construct an in situ-formed physical- and chemical-dually ROS-responsive nano-in-gel platform to implement sequential and prolonged release of aPD-1 and aOX40. Equipped with these advantages, the as-prepared (aPD-1NCs&aOX40)@Gels elicited augmented combination immunity and achieved great eradication of both primary and distant melanoma tumors in vivo.

Splenic Artery Embolization for Splenic Artery Steal Syndrome After Living Donor Liver Transplantation: A Case Report.

Splenic artery steal syndrome (SASS) has been considered a life-threatening complication to liver transplant recipients. Herein we timely diagnosed a case of SASS with deteriorating liver function. SASS was screened by routine Doppler ultrasonography (DUS) and multidetector computed tomography and was ultimately diagnosed by selective celiac trunk angiography. The patient was rescued by splenic artery embolization. In this case, routine DUS was useful to screen SASS. Signs of high-resistance hepatic artery waveform and low diastolic flow were highly suspected of SASS. This case also indicated that portal hyperperfusion was a cause of graft dysfunction in SASS. The study was in accordance with the Helsinki Congress and the Declaration of Istanbul, no prisoners were used, and participants were neither paid nor coerced in this study. Furthermore, we reviewed the recent literatures on the advances in the diagnosis and treatment of SASS. These studies suggest that splenic artery embolization may be a safe and effective technique to treat SASS. In addition, identification of recipients at high risk of SASS with preoperative computed tomography scans and DUS is recommended. Banding or ligation the splenic artery may be useful to prevent SASS and other potential complications after liver transplantation.

Achieving sustainability: Determinants of conscious green purchasing behavior during the COVID-19 pandemic.

The COVID-19 pandemic has spread worldwide, resulting in crises in public health and sustainable development. Aimed at understanding the determinants of conscious green purchasing behavior (GPB), this paper developed a comprehensive framework linking the moderating effect of negative environmental affective reactions (NEAR) to COVID-19 based on the S-O-R paradigm. Using randomly selected urban residents from China's Yangtze River Delta and Bohai Rim regions, the empirical study was conducted using 559 valid responses. The results show that media and peers are the major social forces activating altruistic and egoistic motivations, while family influence was not significant. Dual motivations significantly mediated the relationships of unconditional and conditional GPB with media exposure and peer influence. Contrary to expectations, NEAR negatively moderated the formation process of conscious GPB. The findings indicate that the influence of peers on conscious GPB through dual motivations is stronger compared to media. Negative affective reactions to COVID-19 were also found to inhibit the impact of peer influence on altruistic and egoistic motivations, as well as the path of altruistic motivation on unconditional GPB. The results of this study have important theoretical and practical implications for enterprise marketing and environmental campaigns, and narrowing the green attitude-behavior gap.

Hepatic sinusoidal obstruction syndrome induced by tacrolimus following liver transplantation: Three case reports.

BACKGROUND: Hepatic sinusoidal obstruction syndrome (HSOS) is a rare complication in solid organ transplant recipients, especially in liver transplantation recipients. However, the consequences of HSOS occurrence are pernicious, which could result in severe liver or renal failure, and even death. In addition to previously reported azathioprine and acute rejection, tacrolimus is also considered as one predisposing factor to induce HSOS after liver transplantation, although the underlying mechanism remains unclear. CASE SUMMARY: In this study, we reported three cases of tacrolimus-related HSOS after liver transplantation. The diagnosis of HSOS was firstly based on the typical symptoms including ascites, painful hepatomegaly and jaundice. Furthermore, the features of patchy enhancement on portal vein and delayed phase of abdominal enhanced computed tomography were suspected of HSOS and ultimately confirmed by liver biopsy and histological examination in two patients. A significant decrease in ascites and remission of clinical symptoms of abdominal distention and pain were observed after withdrawal of tacrolimus. CONCLUSION: Tacrolimus-induced HSOS is a scarce but severe complication after liver transplantation. It lacks specific symptoms and diagnostic criteria. Timely diagnosis of HSOS is based on clinical symptoms, radiological and histological examinations. Discontinuation of tacrolimus is the only effective treatment. Transplantation physicians should be aware of this rare complication potentially induced by tacrolimus.

lncENST Suppress the Warburg Effect Regulating the Tumor Progress by the Nkx2-5/ErbB2 Axis in Hepatocellular Carcinoma.

The therapeutic efficacy of radiofrequency ablation (RFA) against liver cancer is often limited by proliferation and metastasis of residual tumor cells. These phenomena are closely associated with the Warburg effect, wherein ErbB2 is activated. While RFA inhibits the Warburg effect of residual tumor cells at the early stage, the specific mechanisms remain unclear. We explored the regulatory relationship between the long noncoding RNA ENST00000570843.1 (lncENST) and ErbB2 using lentiviral transfection of lncENST and ErbB2 overexpression/interference vectors in in vitro and in vivo models of hepatocellular carcinoma in the presence of sublethal heat at 50°C. ErbB2-mediated Warburg effect was suppressed by lncENST, as manifested by reduced glucose uptake and lactic acid production in SMMC-7721 cells. lncENST also increased tumor apoptosis and inhibited tumor progression in nude Balb/c mice for up to 28 days after RFA. Additionally, we predicted through bioinformatic analysis that the promoter of ErbB2 binds to the transcription factor Nkx2-5, resulting in a negative regulatory effect. This speculation was confirmed by chromatin immunoprecipitation of the Nkx2-5 protein and ErbB2, indicating that ErbB2 transcription was curbed by Nkx2-5. We propose that lncENST downplays the Warburg effect in residual tumor cells by downregulating ErbB2 via Nkx2-5 activation. This study is aimed at providing molecular targets that can prevent residual tumor cell proliferation after RFA, with clinical significance in hepatocellular carcinoma treatment.

Sequential Portal Vein Embolization and Percutaneous Radiofrequency Ablation for Future Liver Remnant Growth: A Minimally Invasive Alternative to ALPPS Stage-1 in Treatment of Hepatocellular Carcinoma.

Background: To evaluate the feasibility and efficacy of sequential portal vein embolization (PVE) and radiofrequency ablation (RFA) (PVE+RFA) as a minimally invasive variant for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) stage-1 in treatment of cirrhosis-related hepatocellular carcinoma (HCC). Methods: For HCC patients with insufficient FLR, right-sided PVE was first performed, followed by percutaneous RFA to the tumor as a means to trigger FLR growth. When the FLR reached a safe level (at least 40%) and the blood biochemistry tests were in good condition, the hepatectomy was performed. FLR dynamic changes and serum biochemical tests were evaluated. Postoperative complications, mortality, intraoperative data and long-term oncological outcome were also recorded. Results: Seven patients underwent PVE+RFA for FLR growth between March 2016 and December 2019. The median baseline of FLR was 353 ml (28%), which increased to 539 (44%) ml after 8 (7-18) days of this strategy (p < 0.05). The increase of FLR ranged from 40% to 140% (median 47%). Five patients completed hepatectomy. The median interval between PVE+RFA and hepatectomy was 19 (15-27) days. No major morbidity ≥ III of Clavien-Dindo classification or in-hospital mortality occurred. One patient who did not proceed to surgery died within 90 days after discharge. After a median follow-up of 18 (range 3-50) months, five patients were alive. Conclusion: Sequential PVE+RFA is a feasible and effective strategy for FLR growth prior to extended hepatectomy and may provide a minimally invasive alternative for ALPPS stage-1 for treatment of patients with cirrhosis-related HCC.

Moderated Mediation Mechanism to Determine the Effect of Gender Heterogeneity on Green Purchasing Intention: From the Perspective of Residents' Values.

This study determines gender differences in the generation logic for green purchasing intention within the framework of bounded morality and bounded self-interest and determines the causes of the attitude-behavior gap from a new perspective. Empirical analysis of 977 sample data points is used to test the influencing mechanism of gender heterogeneity on green purchasing intention through altruistic values (ALVs) and egoistic values (EGVs). Meanwhile, the moderated mediation effects are also analyzed. The results show that gender heterogeneity negatively affects ALVs and positively affects EGVs for women as the reference group. The mediation effect of ALVs and EGVs is significant, and there are significant gender differences in the formation of values and green purchasing intention. As expected, women demonstrate higher levels of proenvironmental intention than men. Media exposure (ME) significantly moderates the mediation models. It negatively moderates the mediation effect of ALVs and positively moderates the mediation effect of EGVs. The results reveal the complex formation mechanism for green purchasing intention. It can conclude that the gender differences in terms of green purchasing, the different guiding roles of dual values, and the moderated mechanism of ME are key elements in accurate guidance of green consumption and the effective modification of the attitude-behavior gap.

Low expression of organic anion-transporting polypeptide 1B3 predicts a poor prognosis in hepatocellular carcinoma.

OBJECTIVE: To detect the expression level of organic anion-transporting polypeptide 1B3 (OATP1B3) in hepatocellular carcinoma (HCC) and to determine the relationship between OATP1B3 expression, clinicopathological features, and prognosis. METHODS: Immunohistochemical (IHC) staining was performed to detect the expression of OATP1B3 in 131 HCC specimens and in 89 adjacent nontumorous tissues. Moreover, the expression levels of OATP1B3 in 30 pairs of tumor and matched adjacent nontumorous tissues were detected by quantitative real-time polymerase chain reaction, and 34 pairs of tumor and matched adjacent nontumorous tissues were detected by Western blotting. The χ2 test was applied to analyze the correlation between OATP1B3 expression and the clinical parameters of HCC patients. The prognostic value of OATP1B3 in HCC patients was estimated by Kaplan-Meier survival analysis and the Cox stepwise proportional hazards model. RESULTS: Compared with that in adjacent nontumorous tissues (25.8%, 23/89), OATP1B3 expression was significantly downregulated in tumor tissues (59.5%, 78/131) (P < 0.0001). Moreover, OATP1B3 expression was markedly correlated with tumor size, recurrence, tumor differentiation, and tumor node metastasis (TNM) stage (P < 0.05 for each). However, age, sex, tumor capsule status, HBsAg, cirrhosis, tumor number, vascular invasion, and serum alpha fetoprotein were not associated with OATP1B3 expression. The overall survival (OS) and disease-free survival (DFS) of HCC patients who had high expression of OATP1B3 were significantly longer than those of patients with low expression (33.0% vs 12.9%, P = 0.001; 18.8% vs 5.3%, P < 0.0001). Cox multivariate analysis showed that OATP1B3, invasion, and TNM stage (P < 0.05 for each) were independent prognostic factors of OS in HCC patients and that OATP1B3 and TNM stage (both P < 0.05) were independent prognostic factors of DFS in HCC patients. CONCLUSIONS: The expression of OATP1B3 in HCC patients was significantly lower than that in adjacent nontumorous tissues. OATP1B3 expression may be a potential prognostic marker in HCC patients.

Targeting autophagy enhances heat stress-induced apoptosis via the ATP-AMPK-mTOR axis for hepatocellular carcinoma.

PURPOSE: Radiofrequency ablation (RFA) is widely accepted as a curative treatment for small hepatocellular carcinoma (HCC). However, insufficient RFA (IRFA) can lead to rapid local recurrence. The underlying mechanisms remain poorly understood. This study aimed to elucidate the role and regulatory mechanisms of autophagy in the recurrence of HCC after IRFA. MATERIALS AND METHODS: SMMC7721 and Huh7 cells were exposed to sublethal heat stress to stimulate the transition zone of IRFA treatment. The levels of autophagy were measured by western blot, immunofluorescence and transmission electron microscopy. Functional assays, such as CCK-8, EdU incorporation and flow cytometry, were performed to determine the role of heat-induced autophagy. The involved signaling pathways were explored by western blot. Finally, the antitumor effects of chloroquine (CQ) on heat-treated HCC cells were evaluated via an in vivo xenograft tumor model. RESULTS: Sublethal heat stress induced autophagy in a temperature- and time-dependent manner in HCC cells. Furthermore, the inhibition of autophagy by CQ or siRNA targeting the autophagy-related genes Beclin-1 and Atg5 enhanced heat-induced apoptosis. The combination of CQ and heat treatment significantly suppressed tumor growth both in vitro and in vivo. Mechanistically, we reported for the first time that the ATP-AMPK-mTOR signaling pathway was involved in heat-induced autophagy. CONCLUSIONS: Heat stress induced protective autophagy against heat-induced apoptosis in HCC via the ATP-AMPK-mTOR axis, suggesting that targeting autophagy may be a promising strategy for improving the efficacy of RFA treatment for HCC.

[Clinical effect and mechanism of hemoperfusion in treatment of children with severe abdominal Henoch-Schönlein purpura].

OBJECTIVE: To study the clinical effect and mechanism of hemoperfusion (HP) in the treatment of children with severe abdominal Henoch-Schönlein purpura (HSP). METHODS: A total of 24 children with severe abdominal HSP were divided into two groups: conventional treatment and HP (n=12 each). Ten healthy children who underwent physical examination were enrolled as the control group. Before and after treatment, chemiluminescence was used to measure the serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α); thiobarbituric acid colorimetry was used to measure the plasma level of malondialdehyde (MDA); the hydroxylamine method was used to measure the plasma level of superoxide dismutase (SOD); chemical colorimetry was used to measure the plasma level of total anti-oxidant capability (T-AOC). RESULTS: Compared with the control group, the conventional treatment and HP groups had significantly higher IL-6, TNF-α, and MDA levels and significantly lower SOD and T-AOC levels before treatment (P<0.05), but there were no significant differences between the conventional treatment and HP groups (P>0.05). After treatment, the conventional treatment and HP groups had significant reductions in IL-6, TNF-α, and MDA levels and significant increases in SOD and T-AOC levels (P<0.05). The HP group had significantly greater changes than the conventional treatment group; however, there were still significant differences in these indices between the HP and control groups (P<0.05). Compared with the HP group, the conventional treatment group had a significantly lower percentage of children with disappearance of digestive tract symptoms at 4 days after treatment and significantly longer time to disappearance of rash and digestive tract symptoms (P<0.05). Compared with the conventional treatment group, the HP group had a significantly lower amount of glucocorticoid used during treatment and a significantly lower percentage of children who experienced hematuria and/or proteinuria within 6 months of the disease course (P<0.05). There were no significant differences between the two groups in length of hospital stay and recurrence rates of rash and abdominal pain within 6 months of the disease course. CONCLUSIONS: HP can reduce the amount of glucocorticoid used during treatment and the incidence rate of kidney injury in children with severe abdominal HSP, possibly by eliminating IL-6, TNF-α, and MDA.

Insufficient radiofrequency ablation promotes hepatocellular carcinoma cell progression via autophagy and the CD133 feedback loop.

Insufficient radiofrequency ablation (iRFA) often leads to residual hepatocellular carcinoma (HCC) progression. However, the mechanism is still poorly understood. In the present study, we demonstrated that LC3B protein expression levels were significantly increased in the residual hepatocellular carcinoma cells after radiofrequency ablation (RFA) treatment in vivo. Moreover, iRFA promoted autophagy, autophagosome formation and autophagic flux in Huh-7 and SMMC7721 cell lines in vitro. In addition, iRFA induced HCC cell viability and invasion. However, blockade of autophagy by the autophagosome inhibitor 3-methyladenine (3-MA) suppressed iRFA-induced cell viability and invasion. Furthermore, we revealed that the expression of liver cancer stem cell marker CD133 was also significantly increased in the residual hepatocellular carcinoma cells after RFA treatment in vivo, and was positively correlated with LC3B protein expression. iRFA also promoted CD133 protein expression in Huh-7 and SMMC7721 cell lines in vitro. CD133 was localized to autophagosomes, and was suppressed by 3-MA or chloroquine (CQ) after iRFA treatment. CD133 downregulation also suppressed iRFA-induced cell viability, invasion and autophagy. Collectively, our results indicated that RFA may promote residual HCC cell progression by autophagy and CD133 feedback loop.

Radiofrequency ablation using a multiple-electrode switching system for hepatocellular carcinoma within the Milan criteria: long-term results.

PURPOSE: To assess the long-term outcome of 516 consecutive patients treated with multiple-electrode switching system (MESS) radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) that met the Milan criteria. MATERIALS AND METHODS: We performed 522 MESS RFAs on 516 patients from December 2006 to June 2011. A total of 956 tumours that met the Milan criteria with an average diameter of 2.64 cm (range, 0.9-4.6 cm) were treated with MESS RFA. Ultrasonic contrast and serum α-fetoprotein (AFP) were measured every 2 months during the first postoperative year and every 4 months thereafter. Enhanced computed tomography was performed every 6 months. Survival was estimated using the Kaplan-Meier method. Follow-up was censored at 60 months. Multivariate analysis was performed using the Cox proportional hazards model. RESULTS: For the 956 HCC tumours, the complete ablation rate with MESS was 98.83% (510/516). During a median of 34 months (IQR, 23-52 months) of follow-up, 171 patients died and 4 were lost to follow-up (15, 30, 38 and 42 months). The cumulative incidence of local tumour progression at 1, 3 and 5 years was 0.39%, 4.96% and 6.66%, respectively, and the 1-, 3- and 5-year overall survival was 99.42%, 83.97% and 68.42%, respectively. Tumour size >30 mm was the only parameter that was predictive of local tumour progression (p < .0001). Risk factors associated with overall survival included prothrombin time >14 s, serum AFP levels >200 ng/mL and tumour abutting vessel diameter <5 mm. The complication rate was 1.74%. CONCLUSION: MESS RFA is a safe and effective method for HCC treatment. This approach results in a high local progression-free survival for HCC tumours that meet the Milan criteria.

Long noncoding RNA expression profiles in sub-lethal heat-treated hepatoma carcinoma cells.

BACKGROUND: Sub-lethal heat treatment characterizes a transition zone of radiofrequency ablation (RFA) which explains hepatocellular carcinoma (HCC) residual cancer occurrence in this area after RFA treatment. The biochemistry of residual cancer cell recurrence is poorly understood, but long noncoding RNAs (lncRNAs) may have aberrant expression that is associated with diverse cancers. Thus, we measured lncRNA gene expression in sub-lethally heat-treated HCC cells using microarray. METHOD: Differentially expressed lncRNA and mRNA were measured with an Agilent Human lncRNA + mRNA Array V4.0 (4 × 180 K format) containing 41,000 lncRNAs and 34,000 mRNAs. Bioinformatics analysis was used to assess differentially expressed lncRNA and mRNA. Seven lncRNA and seven mRNA were validated by qRT-PCR analysis in HCC cells. RESULTS: Genome-wide lncRNA and mRNA expression data in sub-lethal heat-treated SMMC-7721 HCC cells 558 lncRNA and 250 mRNA were significantly up-regulated and 224 lncRNA and 1031 mRNA down-regulated compared to normal cultured SMMC-7721 cells. We demonstrated for the first time that ENST00000570843.1, ENST00000567668.1, ENST00000582249.1, ENST00000450304.1, TCONS_00015544, ENST00000602478.1, TCONS_00001266 and ARC, IL12RB1, HSPA6 were upregulated, whereas STAT3, PRPSAP1, MCU, URB2 were down-regulated in sub-lethally heat-treated HCC cells. CONCLUSIONS: lncRNA expression data in sub-lethally heat-treated HCC cells will provide important insights about lncRNAs' contribution to HCC recurrence after RFA treatment.

[Application of continuous blood purification combined with hemoperfusion in the treatment of hemolytic-uremic syndrome in children].

OBJECTIVE: To observe the therapeutic effect of continuous blood purification (CBP) combined with hemoperfusion (HP) in children with hemolytic-uremic syndrome (HUS) and to investigate its possible mechanism. METHODS: Eight children with HUS received CBP combined with HP on the basis of internal medicine treatment in the acute stage. Before and after treatment, serum levels of interleukin-6 (IL-6), IL-8 and tumor necrosis factor-α (TNF-α) were measured by chemiluminescence method, and levels of blood urea nitrogen (BUN), serum creatinine (SCr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), creatine kinase MB (CKMB), hemoglobin (Hb), platelet (PLT) and C-reactive protein (CRP) were measured. Eight healthy children undergoing physical examination were used as controls. RESULTS: The 8 children with HUS all survived after CBP combined with HP and showed improved conditions. They had increased Hb and PLT levels and decreased serum levels of IL-6, IL-8, TNF-α, BUN, SCr, ALT, CK and CRP after treatment (P<0.05). CONCLUSIONS: CBP combined with HP can quickly remove pathogenic factors, continually eliminate inflammatory mediators and toxins, and reverse multiple organ dysfunction, and is one of effective methods for treating HUS in children.