Liver transplantation for advanced-stage primary hepatic yolk sac tumor: A case report and literature review.

RATIONALE: Primary hepatic yolk sac tumors (YSTs) are rare in adults. Liver resection is an acknowledged treatment modality for primary hepatic YST. Liver transplantation may offer a possible cure for unresectable cases. PATIENT CONCERNS: We present a case of a 31-year-old woman with an abdominal mass who had abnormally elevated alpha-fetoprotein (AFP) levels (31,132 ng/mL; normal: 0-7 ng/mL). Contrast-enhanced computed tomography (CT) revealed large tumors located in both lobes of the liver, with arterial enhancement and venous washout. Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT indicated increased 18F-FDG uptake (maximum standardized uptake value, 24.4) in the liver tumors and left middle intra-abdominal nodule. DIAGNOSES: The diagnosis was primary hepatic YST with metastasis to the greater omentum. INTERVENTIONS: The patient underwent orthotopic liver transplantation and intra-abdominal nodule resection after transarterial chemoembolization (TACE) as a bridge. Intraoperatively, an intra-abdominal nodule was confirmed in the greater omentum. Histopathological examination of the liver tumors revealed Schiller-Duval bodies. The tropomyosin receptor kinase (TRK) inhibitor larotrectinib was administered, followed by four cycles of chemotherapy with bleomycin, etoposide, and cisplatin based on the next-generation sequencing results. OUTCOMES: The AFP level decreased to within the normal range. No evidence of tumor collapse was observed during the 34-month follow-up period. LESSONS: This case suggests that multimodal therapy dominated by liver transplantation, including preoperative TACE, postoperative adjuvant chemotherapy, and TRK inhibitors, is an effective treatment modality for unresectable primary hepatic YST.

miR-199a-5p inhibits proliferation and induces apoptosis in hemangioma cells through targeting HIF1A.

MicroRNAs (miRNAs) exhibit a crucial role in the regulation of angiogenesis and tumor progression, of which miR-199a-5p (miR-199a) has been reported to function as a tumor suppressor in multiple malignancies. However, the precise mechanisms underlying miR-199a in hemangiomas (HAs) remain elusive. In this study, we found that miR-199a had low expression level, while proliferating cell nuclear antigen (PCNA) had high expression level in proliferating-phase HAs compared with the involuting-phase HAs and normal tissues. Spearman correlation analysis revealed the negative correlation of miR-199a with PCNA expression in proliferating-phase HAs. In vitro experiments showed that restoration of miR-199a suppressed cell proliferation capability and induced cell apoptosis in HA-derived endothelial cells (HDEC) and CRL-2586 EOMA cells, followed with decreased PCNA expression and increased cleaved caspase-3 expression, but miR-199a inhibitor reversed these effects. Furthermore, HIF1A was identified as a target of miR-199a and had negative correlation with miR-199a expression in proliferating-phase HAs. Overexpression of HIF1A attenuated the anti-proliferation effect of miR-199a mimic in HAs cells. Taken together, our findings demonstrate that miR-199a may inhibit proliferation and induce apoptosis in HAs cells via targeting HIF1A and provide a potential therapeutic target for HAs.

Tim-3 inhibits low-density lipoprotein-induced atherogenic responses in human umbilical vein endothelial cells.

Endothelial injury and dysfunction followed by endothelial activation and inflammatory cell recruitment are factors contributing to the initiation and progression of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) promotes inflammation during atherogenesis and lipid deposition in the arterial wall. We observed that stimulation of human umbilical vein endothelial cells (HUVECs) with ox-LDL activated pro-inflammatory cytokine production and apoptosis, inhibited cell migration, and upregulated T-cell immunoglobulin and mucin domain 3 (Tim-3) expression. Tim-3, in turn, protected HUVECs from ox-LDL-induced apoptosis via the JNK pathway and reversed the inhibition of migration. Tim-3 also inhibited ox-LDL-induced inflammatory cytokine production by suppressing NF-κB activation. In addition, Tim-3 increased production of type 2 T helper cells (Th2) and regulatory T cell (Treg)-associated cytokines. Blocking Tim-3 reversed its effects on the inflammatory response to ox-LDL. Thus, Tim-3 signaling may be a "self-control" mechanism in ox-LDL-triggered inflammation in HUVECs. These results identify Tim-3 as a factor in HUVEC activity and suggest its potential in the treatment of atherosclerosis.

ROCK inhibition as a potential therapeutic target involved in apoptosis in hemangioma.

Gene expression was examined in hemangiomas (HA), benign, birthmark-like tumors occurring in infancy, and confirmed in HA-derived endothelial cells (HDEC), for which cell proliferation and apoptosis were also assessed. Protein and mRNA accumulation of Rho-associated protein kinase (ROCK), vascular endothelial growth factor (VEGF), Ki-67 and proliferating cell nuclear antigen was significantly higher in proliferating phase HAs than in involuting phase HAs. In contrast, p53 and caspase-3 exhibited higher levels of accumulation in involuting than proliferating HAs. Cell apoptotic indexes were low in proliferating phase HAs and increased in involuting phase HAs. HDECs were treated with the ROCK inhibitor Y-27632. Y-27632 induced p53 expression and downregulated VEGF expression, significantly inhibited cell proliferation, and induced cell apoptosis in HA cells. The inhibitor effects were confirmed in HAs from HDEC-injected nude mice. These results indicated that ROCK is involved in p53-mediated apoptosis and VEGF expression in HA cells and suggested that such inhibition may be exploited for future HA therapies.

PD-1 and Tim-3 Pathways Regulate CD8+ T Cells Function in Atherosclerosis.

T cell-mediated immunity plays a significant role in the development of atherosclerosis (AS). There is increasing evidence that CD8+ T cells are also involved in AS but their exact roles remain unclear. The inhibitory receptors programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain 3 (Tim-3) are well known inhibitory molecules that play a crucial role in regulating CD8+ T cell activation or tolerance. Here, we demonstrate that the co-expression of PD-1 and Tim-3 on CD8+ T cells is up-regulated in AS patients. PD-1+ Tim-3+ CD8+ T cells are enriched for within the central T (TCM) cell subset, with high proliferative activity and CD127 expression. Co-expression of PD-1 and Tim-3 on CD8+ T cells is associated with increased anti-atherogenic cytokine production as well as decreased pro-atherogenic cytokine production. Blockade of PD-1 and Tim-3 results in a decrease of anti-atherogenic cytokine production by PD-1+ Tim-3+ CD8+ T cells and in an augmentation of TNF-α and IFN-γ production. These findings highlight the important role of the PD-1 and Tim-3 pathways in regulating CD8+ T cells function in human AS.

Effects of dexamethasone and Salvia miltiorrhiza on multiple organs in rats with severe acute pancreatitis.

OBJECTIVE: To investigate the protective effects and mechanisms of action of dexamethasone and Salvia miltiorrhiza on multiple organs in rats with severe acute pancreatitis (SAP). METHODS: The rats were divided into sham-operated, model control, dexamethasone treated, and Salvia miltiorrhiza treated groups. At 3, 6, and 12 h after operation, the mortality rate of different groups, pathological changes, Bcl-2-associated X protein (Bax) and nuclear factor-κB (NF-κB) protein expression levels in multiple organs (the pancreas, liver, kidneys, and lungs), toll-like receptor 4 (TLR-4) protein levels (only in the liver), intercellular adhesion molecule 1 (ICAM-1) protein levels (only in the lung), and terminal deoxynucleotidy transferase mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) staining expression levels, as well as the serum contents of amylase, glutamate-pyruvate transaminase (GPT), glutamic-oxaloacetic transaminase (GOT), blood urea nitrogen (BUN), and creatinine (CREA) were observed. RESULTS: The mortality rate of the dexamethasone treated group was significantly lower than that of the model control group (P<0.05). The pathological changes in multiple organs in the two treated groups were relieved to different degrees (P<0.05 and P<0.01, respectively), the expression levels of Bax and NF-κB proteins, and apoptotic indexes of multiple organs were reduced (P<0.05 and P<0.01, respectively). The contents of amylase, GPT, GOT, BUN, and CREA in the two treated groups were significantly lower than those in model control groups (P<0.05 and P<0.01, respectively). The expression level of ICAM-1 protein in the lungs (at 3 and 12 h) in the dexamethasone treated group was significantly lower than that in the Salvia miltiorrhiza treated group (P<0.05). The serum contents of CREA (at 12 h) and BUN (at 6 h) of the Salvia miltiorrhiza treated group were significantly lower than those in the dexamethasone treated group (P<0.05). CONCLUSIONS: Both dexamethasone and Salvia miltiorrhiza can reduce the inflammatory reaction, regulate apoptosis, and thus protect multiple organs of rats with SAP.

Methionine-dependence and combination chemotherapy on human gastric cancer cells in vitro.

AIM: To elucidate whether human primary gastric cancer and gastric mucosa epithelial cells in vitro can grow normally in a methionine (Met) depleted environment, i.e. Met-dependence, and whether Met-depleting status can enhance the killing effect of chemotherapy on gastric cancer cells. METHODS: Fresh human gastric cancer and mucosal tissues were managed to form monocellular suspensions, which were then cultured in the Met-free but homocysteine-containing (Met(-)Hcy(+)) medium, with different chemotherapeutic drugs. The proliferation of the cells was examined by cell counter, flow cytometry (FCM) and microcytotoxicity assay (MTT). RESULTS: The growth of human primary gastric cancer cells in Met(-)Hcy(+) was suppressed, manifested by the decrease of total cell counts [1.46 +/- 0.42 (x 10(9).L(-1)) in Met(-)Hcy(+) vs 1.64 +/-0.44(x 10(9).L(-1)) in Met(+)Hcy(-), P<0.01], the decline in the percentage of G(0)G(1) phase cells (0.69 +/- 0.24 in Met(-)Hcy(+) vs 0.80 +/- 0.18 in Met(+)Hcy(-), P<0.01) and the increase of S cells (0.24 +/- 0.20 in Met(-)Hcy(+) vs 0.17 +/- 0.16 in Met(+)Hcy(-), P<0.01); however, gastric mucosal cells grew normally. If Met(-)Hcy(+) medium was used in combination with chemotherapeutic drugs, the number of surviving gastric cancer cells dropped significantly. CONCLUSION: Human primary gastric cancer cells in vitro are Met-dependent; however, gastric mucosal cells have not shown the same characteristics. Met(-)Hcy(+) environment may strengthen the killing effect of chemotherapy on human primary gastric cancer cells.