Sorafenib is the standard first-line therapeutic treatment for patients with advanced hepatocellular carcinoma (HCC), but its use is hampered by the development of drug resistance. The activation of Akt by sorafenib is thought to be responsible for this resistance. Bufalin is the major active ingredient of the traditional Chinese medicine Chan su, which inhibits Akt activation; therefore, Chan su is currently used in the clinic to treat cancer. The present study aimed to investigate the ability of bufalin to reverse both inherent and acquired resistance to sorafenib. Bufalin synergized with sorafenib to inhibit tumor cell proliferation and induce apoptosis. This effect was at least partially due to the ability of bufalin to inhibit Akt activation by sorafenib. Moreover, the ability of bufalin to inactivate Akt depended on endoplasmic reticulum (ER) stress mediated by inositol-requiring enzyme 1 (IRE1). Silencing IRE1 with siRNA blocked the bufalin-induced Akt inactivation, but silencing eukaryotic initiation factor 2 (eIF2) or C/EBP-homologous protein (CHOP) did not have the same effect. Additionally, silencing Akt did not influence IRE1, CHOP or phosphorylated eIF2α expression. Two sorafenib-resistant HCC cell lines, which were established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition but were sensitive to bufalin. Thus, Bufalin reversed acquired resistance to sorafenib by downregulating phosphorylated Akt in an ER-stress-dependent manner via the IRE1 pathway. These findings warrant further studies to examine the utility of bufalin alone or in combination with sorafenib as a first- or second-line treatment after sorafenib failure for advanced HCC.

Fragile X-related gene 1 (FXR1) is deregulated in a variety of human disorders including cancer. However, there is relatively little evidence concerning the relationship between FXR1 and colorectal cancer. Western blot, immunohistochemistry (IHC), and quantitative real-time PCR (qRT-PCR) were adopted to detect the FXR1 protein and messenger RNA (mRNA) expression, respectively. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the plasma FXR1 expression in our study. MTT assay and colony formation assay were used to examine the proliferation ability of cells in vitro. In addition, Transwell assays were performed to test the migration and invasion abilities of cancer cells. We found that the average plasma FXR1 level in CRC was significantly higher than that in healthy controls (P < 0.001). Moreover, the plasma expression of FXR1 in stage IV patients was dramatically higher than that in stage I, stage II, and stage III patients (P < 0.001). Consistently, FXR1 mRNA expression levels were much higher in cancer tissues than that in normal tissues. Moreover, IHC results showed that cancer tissues possessed higher FXR1 expression (P = 0.027). What's more, plasma FXR1 was a risk factor of colorectal cancer indicated by univariate survival analysis (P = 0.021, HR = 1.685, 95 % CI 1.336-1.927). Multivariate analysis suggested that FXR1 was an independent risk factor of colorectal cancer (P = 0.008, HR = 1.381, 95 % CI 1.119-1.741). Kaplan-Meier analysis showed that the patients with higher plasma FXR1 expression had a poorer outcome (P < 0.001). Besides, FXR1 acted as an oncogene which could increase the proliferation, migration, and invasion of cancer cells. All these data indicate that FXR1 might act as a tumor promoter. Future investigations are warranted to explore whether FXR1 may represent a novel therapeutic target.

Therefore, overexpression of human CD200 in donor pigs could constitute a promising strategy for overcoming xenograft rejection.

Introduction Enhancer of zeste homolog 2 (EZH2) is implicated in hepatocellular carcinoma (HCC), but whether transforming growth factor-β (TGF-β)-metastasis associated 1 (MTA1)-SMAD7-SMAD3-SRY-Box Transcription Factor 4 (SOX4)-EZH2 signaling axis, in which EZH2 participates, is also involved in HCC remained unknown. Methods Data on EZH2 expression in liver hepatocellular carcinoma (LIHC) and its relation with prognosis of HCC patients were predicted and analyzed using online databases. Following transfection with or without TGF-β1, HCC cell viability, migration and invasion were determined with MTT, Scratch and Transwell assays. Relative expressions of epithelial-to-mesenchymal transition (EMT)-related factors (N-Cadherin, Vimentin, and E-Cadherin) and TGF-β-MTA1-SMAD7-SMAD3-SOX4-EZH2 signaling axis factors (TGF-β, MTA1, SMAD7, phosphorylated-SMAD3, SOX4 and EZH2) were calculated via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot. Results EZH2 was upregulated in HCC, which was related to poor prognosis. Silencing EZH2 suppressed EZH2 expression and HCC cell viability, migration, and invasion, and increased E-Cadherin expression yet decreased N-Cadherin and Vimentin expression, whereas EZH2 overexpression did conversely. Also, silencing EZH2 reversed the effects of TGF-β1 on promoting viability, migration, and invasion, as well as N-Cadherin and Vimentin expressions, yet suppressing E-Cadherin expression in HCC cells. In addition, TGF-β1 promoted TGF-β, MTA1, SOX4 and EZH2 expressions and p-SMAD3/SMAD3 ratio yet suppressed SMAD7, whereas silencing EZH2 solely reversed the effects of TGF-β1 on EZH2 expression in HCC cells. Conclusion The present study provides a theoretical basis for TGF-β-MTA1-SMAD7-SMAD3-SOX4-EZH2 signaling cascade in viability, migration, invasion, and EMT of HCC cells. Inhibiting these signals may represent a therapeutic pathway for the treatment of metastatic HCC.

Human B-1 cells have been proposed to be CD20+CD27+CD43+CD1c− B cells found in the umbilical cord and adult peripheral blood, but their regulatory mechanisms have not been well elucidated. Previously, we reported that mouse CD49dhigh CD4+ T cells could enhance the secretion of natural antibodies by B-1 cells. In this study, we aimed to investigate the presence and helper functions of the human equivalents of murine CD49dhigh CD4+ T cells. Here, we showed that human CD49dhigh CD4+ T cells found in the peritoneal cavity (PEC), spleen, and peripheral blood can enhance the production of IgM antibodies by B-1 cells. As revealed in mouse, CD49dhigh CD4+ T cells were more abundant in the PEC and showed a higher tendency to form conjugates with B cells than CD49dlow CD4+ T cells. Moreover, CD49dhigh CD4+ T cells showed a Th1-like memory phenotype, characterized by high expression of CD44 and CXCR3; low expression of CD62L and CCR7; rapid production of IFN-γ, tumor necrosis factor-α, and IL-2 upon stimulation with phorbol myristate acetate and ionomycin; and rapid proliferation upon stimulation with anti-CD3 and anti-CD28 antibodies. These cells also expressed high levels of PD-1, ICOS, and CD5, suggesting that they are undergoing chronic stimulation. Remarkably, CD49dhigh CD4+ T cells specifically helped B-1 cells, but not follicular memory B cells (CD27+ CD43−CD1c−) or marginal zone B cells (CD27+CD43−CD1c+), produce IgM and IgG antibodies. In parallel, the titer of human anti-blood group A IgM was positively correlated with the frequency of CD49dhigh CD4+ T cells. In conclusion, we identified human CD49dhigh CD4+ T cells with a Th1-like memory phenotype that secrete Th1 proinflammatory cytokines and help B-1 cells secrete antibodies, thereby aiding in primary defense. We suggest that these CD49dhigh CD4+ T cells are a unique type of B-cell helper T cells distinct from follicular helper T cells.

Objectives: Regulatory B cells (Bregs) are a new B cell subset that suppresses immune responses. Recently, both anti-CD45RB and anti-Tim-1 treatments have been found to regulate immune responses by inducing Bregs; however, the role of Bregs in renal ischemia-reperfusion injury (IRI) has not been shown. Methods: We investigated impacts of Bregs and anti-CD45RB on IRI and its mechanisms using mouse models of bilateral renal IRI. Results: Adoptive transfer of Bregs prior to or following IRI attenuated renal IRI. Anti-CD45RB treatment with or without anti-Tim-1 prior to IRI increased the renal infiltration of CD19 + Tim-1 + Bregs and regulatory T cells. Anti-CD45RB decreased serum creatinine levels, pathologic injury score, and tubular apoptosis. Levels of IL-1β, IL-6, MCP-1, IFN-γ, and IL-17 were decreased, whereas IL-10 was increased in the CD45RB group. Following IRI, anti-CD45RB with or without anti-Tim-1 also induced Bregs, thereby improving renal function and tubular regeneration. In RAG1 knockout mice with B cell transfer, TCRα knockout mice, and wild-type mice with T cell depletion, anti-CD45RB increased Bregs and attenuated IRI. However, anti-CD45RB did not attenuate IRI in RAG1 knockout mice with T cell transfer or μMT mice and induced only mild improvement in wild-type mice with B cell depletion. Furthermore, B cells from IL-10 knockout mice did not show anti-CD45RB-mediated renal protection against IRI, in contrast to those from wild-type mice. Conclusions: Anti-CD45RB treatment attenuated acute renal injury and facilitated renal recovery after IRI through induction of IL-10 + Bregs. The present study suggests anti-CD45RB as a potential therapeutic strategy in renal IRI.

Staged hepatectomy, particularly associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a recently developed advanced surgery for resecting liver tumors. However, large wound surfaces, incomplete drainage and high rates of mortality are vital limitations of ALPPS. The present case study describes a patient with liver cancer who underwent ALPPS surgery combined with negative pressure wound therapy. A 46-year-old male patient was hospitalized due to right upper abdominal pain. Computed tomography and magnetic resonance cholangiopancreatography scan results indicated gallbladder cancer, accompanied by multiple liver metastases. Resection of the right trisegment and partial resection of metastatic nodules in the left outer lobe were performed. Vacuum sealing drainage was pre-implanted at liver cross-sections with drainage tubes to drain the bile. The patient exhibited improved wound healing compared with conventional ALPPS.

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