Since the American Joint Committee on Cancer (AJCC) subdivided the T2 stage of gallbladder carcinoma (GBC) into T2a and T2b, the diagnosis and treatment of those stages have been a subject of heated discussion and controversy. T2 is a stage of GBC that might be treatable. Based on the extent of lymph node metastasis and distant metastasis, T2 GBC can be classified into various pathological stages such as IIA, IIB, IIIB, and IVB, leading to controversy in clinical settings. This review aims to discuss the effectiveness of and controversies concerning S4b+5 resection, the acceptable extent of lymph node dissection, the timing for treatment of incidental gallbladder cancer, and adjuvant therapy. This review also aims to suggest directions for and recommendations regarding clinical research in the future.
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. During the recent years, external-beam radiation therapy (EBRT) has been safely and effectively employed for the management of HCC. We overviewed the current evidence regarding the efficacy and safety of EBRT for HCC according to the different target population. PubMed database was searched for identifying English-language full-text articles regarding EBRT for the treatment of HCC. Search items were "hepatocellular carcinoma AND radiation therapy". Until now, preliminary evidence has suggested the following role of EBRT for HCC. 1) EBRT, especially stereotactic body radiation therapy, is an emerging choice of therapy for small HCC. 2) EBRT combined with non-surgical treatment can achieve an excellent intrahepatic tumor control and a potential survival benefit for huge HCC. 3)Adjunctive EBRT may improve the efficacy of transarterial chemoembolization for HCC with portal vein tumor thrombosis. 4) EBRT can relieve the pain and improve the quality of life for patients with extrahepatic metastases. 5) EBRT may be a bridge to liver transplantation by minimizing the tumor progression. 6) Adjunctive EBRT may reduce the tumor recurrence and improve the survival after resection. In summary, EBRT is a promising choice of treatment of HCC. However, more high-quality evidence is needed to further establish the status of EBRT for the management of HCC.
Cholestasis is a pathological process in which bile drainage is poor for a variety of reasons. Many studies have shown that cholestatic liver injury is a neutrophil-mediated inflammatory response, and oxidative stress induced by neutrophils is the main mechanism of liver cell death. The literature summarizes the bile acid signaling pathway, the neutrophil chemotaxis recruitment process during cholestasis, and the oxidative stress damage produced by neutrophil activation, summarizes the latest research progress. Sphingosine-1-phosphate receptor (S1PR) is a potential therapeutic target for cholestasis that reduces neutrophil aggregation without inhibiting systemic immune status. Early growth response factor 1 (Egr-1) may play a central role in the inflammation induced by cholestasis, and it is also a potential therapeutic target to inhibit the inflammation induced by cholestasis. Strengthening the antioxidant system of hepatocytes to cope with oxidative stress of neutrophils is a feasible treatment for cholestatic liver injury.
End-stage liver disease (ESLD) is among leading causes of death for people living with HIV and HCV. Little is known how liver fibrosis score predicts mortality in HIV/HCV co-infected population under combination antiretroviral therapy (cART). A retrospective cohort study of 691 HIV/HCV co-infected patients receiving cART in Yunnan, China from 2005 to 2016 was carried out to explore the association between Fibrosis-4 index (FIB-4) and all-cause mortality. Cox proportional hazard models were used to estimate the hazard ratios (HRs) for FIB-4 and covariates. After a median follow-up of 4.8 years with a total follow-up time of 3,696 person-years (PY), 131 deaths occurred and the all-cause mortality was 3.5 per 100 PY. The mortality was 2.9 (95% CI: 2.3-3.5)/100 PY for the FIB-4 ≤ 3.25 group and 5.8 (4.2-7.4)/100 PY for the FIB-4 > 3.25 group at baseline. People with FIB-4 changed from mild to advanced group showed HR of 1.81 (95% CI: 1.01-3.25) for death, and with FIB-4 sustaining advanced showed HR of 3.11 (1.75-5.54), both compared to those with FIB-4 remained mild, while lower risk of death was observed among married people (HR = 0.63, 95% CI: 0.41-0.99) compared to unmarried, among those with most recent CD4+ T cell counts between 200 and 350 cells/μL (0.50, 0.30-0.86) and > 350 cells/μL (0.25, 0.15-0.41) compared to CD4 under 200 cells/μL. Advanced and progressive liver fibrosis is a strong predictor of all-cause mortality in HIV/HCV co-infected patients under cART in China.
The small chemical compound 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as an inhibitor of phosphoinositide 3-kinase (PI3K) and reported to inhibit tumor growth. However, its chiral structure and poor solubility prevent its further use. Compound 6-bromo-8-ethoxy-3-nitro-2H-chromene (BENC-511) is an analogue of S14161 produced by structural optimization. A previous study indicated that BENC-511 acted on multiple myeloma and that it had a toxicity by inhibiting the PI3K/protein kinase B (Akt) pathway. However, the effects of BENC-511 on the proliferation and apoptosis of A549 human lung adenocarcinoma cells have not been reported. The current study investigated the effects of BENC-511 on the proliferation and apoptosis of A549 cells in vitro. Results indicated that the compound BENC-511 inhibited the viability of A549 cells in a concentration- and time- dependent manner. BENC-511 suppressed proliferation and colony formation via S phase arrest. BENC-511 decreased the expression of cyclin A, proliferating cell nuclear antigen (PCNA), B-cell lymphoma-2 (Bcl-2), phospho-mammalian target of rapamycin (p-mTOR), and phospho-Akt (p-Akt) and it increased the expression of p21WAF1CIP1(p21), Caspase-3 and Caspase-9. In conclusion, BENC-511 inhibited the proliferation of A549 human lung adenocarcinoma cells via S phase arrest as a result of up-regulation of p21 and reduction of Cyclin A/cyclin-dependent kinase 2 (CDK2)/PCNA complex and it induced apoptosis by reducing the mitochondrial membrane potential via the Akt/Bcl-2/Caspase-9 mitochondrial pathway of apoptosis.
Sufentanil is a type of opioid analgesic and is usually used to facilitate painless labor in combination with the local anesthetic ropivacaine. One aim of the current study was to investigate the effects of sufentanil and ropivacaine on umbilical cord mesenchymal stem cells (UCMSCs). A second aim of this study was to determine whether sufentanil attenuated the cytotoxicity of ropivacaine in vitro. UCMSCs were divided into 3 groups: one was treated with ropivacaine at a concentration of 50, 100, 200, or 400 μg/mL, another was treated with sufentanil at a concentration of 0.5, 5, 50, or 500 nmol/L, and a third was treated with a combination of ropivacaine at a concentration of 200 μg/mL and sufentanil at a concentration of 0.5, 5, 50, or 500 nmol/L. Results indicated that cell proliferation decreased in cells treated with ropivacaine while it increased in cells treated with sufentanil. In addition, sufentanil limited the inhibitory effect of ropivacaine on UCMSC growth in a dose- and time-dependent manner. Combined treatment with ropivacaine at a concentration of 200 μg/mL and sufentanil at a concentration of 500 nmol/L decreased the proportion of dead and apoptotic UCMSCs, and fewer cells were arrested in the S phase compared to cells treated with ropivacaine. Sufentanil inhibited the apoptosis induced by ropivacaine by increasing miR-182-5p, which regulated the expression of mRNA of the pro-apoptotic genes B-cell lymphoma/leukemia 10 (BCL10) and cytochrome c, somatic (CYCS). Sufentanil also increased the expression of mRNA of anti-apoptotic genes. In short, ropivacaine inhibits the cell viability and induces the apoptosis of UCMSCs in vitro while sufentanil attenuates this apoptosis by regulating miR182-5p/BCL10/CYCS.
Immunotherapy might be an effective treatment in extrahepatic cholangiocarcinoma (eCCA), a tumor with extremely limited therapeutic options. Our study is to characterize the programmed death ligand-1 (PD-L1) protein expression and cancer microenvironment profiles in surgically resected eCCA samples. PD-L1 positivity was observed on tumor cells (32.3%) as well as on tumor-associated macrophages (74.2%). PD-L1 expression by eCCA correlated significantly with immune parameters such as intra-tumoral CD3+ tumor infiltrating lymphocytes (TILs) density (P = 0.002), intra-tumoral CD8+ TILs density (P < 0.001), and the expression pattern of human leukocyte antigen (HLA) class I (P < 0.001). Immunofluorescence showed that PD-L1 positive tumor cells were adjacent to PD-1 positive cells and the stroma covered with interferon-γ. Correlation with clinicopathological parameters and survival analyses revealed that PD-L1 positivity in eCCA was related to the absence of venous invasion (P = 0.030), improved overall survival (P = 0.020) and progressionfree survival (P = 0.011). HLA class I molecules defect, which is an important mechanism of immune evasion, was frequently observed in eCCA (50.0%) and was associated with a decreased number of intra-tumoral CD8+ TIL density (P = 0.028). Additionally, the presence of unusually high numbers of tumor-associated macrophages (TAMs) subsets M2 in most of eCCA (74.2%) was noted. Our study indicated that PD-L1 expression in association with intra-tumoral TILs infiltration and HLA class I expression in 32.3% of the eCCA reflects an active immune microenvironment potentially responsive to PD-1/PD-L1 inhibitors. In addition, the combination of macrophage-targeting agents may provide therapeutic synergy for future immunotherapy.
Evaluation of the degree of liver fibrosis is an important basis for the clinical diagnosis and treatment of patients with hepatocellular carcinoma (HCC). It is meaningful to make a preoperative evaluation with non-invasive methods. In the current study, 12 commonly used preoperative serological indicators from 161 HCC patients with different degree of liver fibrosis were collected retrospectively, and 8 of the indicators (ALB, PA, TBil, INR, AST, GGT, ALP, and PT) were ultimately used in matter-element analysis to create a formula. The relationship between those results and the histological sub-classification of the Laennec liver fibrosis scoring system was analyzed. The calculated value of R from this formula will indicate the differing degree of liver fibrosis in a patient: i) the value of 0.802 ≤ R < 1 indicates the early stage of liver cirrhosis, which corresponds to Laennec stages 0-3; ii) the value of 0.752 ≤ R < 0.802 indicates the mild stage of liver cirrhosis, which corresponds to Laennec stage 4A; iii) the value of 0.698 ≤ R < 0.752 indicates the moderate stage of liver cirrhosis, which corresponds to Laennec stage 4B; and iv) the value of 0.444 ≤ R < 0.698 indicates the severe stage of liver cirrhosis, which corresponds to Laennec stage 4C. The hope is that this formula for preoperative evaluation of the degree of liver fibrosis using non-invasive methods would be useful in the clinical diagnosis and treatment of patients with HCC in the future.
Hepatocellular carcinoma (HCC) with bile duct tumor thrombus (BDTT) is rarely seen in clinical practice, and its treatment strategies and prognosis are still a subject of debate. To ascertain the characteristics of and prognosis for HCC with BDTT, 49 patients with HCC with BDTT were studied out of 763 consecutive patients with HCC who underwent surgical treatment from July 2004 to May 2018. The clinical characteristics of and prognosis for those 49 patients were reviewed and analyzed retrospectively. Of the 49 patients, 25 underwent radical resection, 7 underwent thrombectomy through a choledochotomy, and 17 underwent palliative internal and external bile duct drainage. Results indicated that patients who underwent a radical resection had a better prognosis than patients in the other two groups, with a median survival of 19 months vs. 8 months and 3 months (p < 0.001). Moreover, the preoperative bilirubin level (p = 0.025), intraoperative blood loss (p = 0.006), tumor size (p = 0.005), and the presence of portal and hepatic vein tumor thrombi (p = 0.021) were significant prognostic factors associated with long-term survival for patients who underwent radical resection in this study. Radical resection should be performed with adequate preoperative preparation for patients with HCC with BDTT in whom surgery is not contraindicated.
The current study determined the structure of a hemolytic compound found in an extract from the fruiting bodies of the edible mushroom Hypsizygus marmoreus when its pH was lowered. The hemolytic compound was purified using the modified Bligh and Dyer method followed by chromatography using reversed phase and silica gel columns. Structural analyses of the purified hemolytic compound were performed using NMR and ESI-MS. The deduced structure indicated a trans,trans-5,8-docosadienoic acid calcium salt. Although numerous proteinous hemolysins from various mushrooms have been described, the current study is the first to report on a low-molecular-weight hemolytic compound derived from an H. marmoreus extract.
In epigenetics, histone deacetylases (HDACs) are well validated targets for the development of anticancer drugs. In this work, we reported the design and synthesis of a series of twenty two novel (E)-N-hydroxycinnamamide-based HDAC inhibitors with 4-aminopiperidine1-carboxamide as the core structure. Most newly synthesized compounds displayed high inhibition rates toward HDAC at the concentration of 1 μM. Among them, the inhibition rates of compounds LYP-2, LYP-3, LYP-6, and LYP-15 were more than 75%. Furthermore, compounds LYP-2, LYP-3, and LYP-6 potently inhibited the activity of HDAC6 with selectivity over HDAC1. We chose LYP-2 and LYP-6 to test its antiproliferative effect on breast cancer cells MCF-7. Either LYP-2 or LYP-6 alone moderately suppressed the cell growth, but could synergistically enhance the inhibitory effect of bortezomib. These results suggested that combined HDAC6 inhibitor and bortezomib regimen might be an option for breast cancer treatment.
Hypoxia exposure during high-altitude expedition cause psychomotor impairment. Neuroimaging studies indicated that the impairment may be significantly associated with neuron loss and decreased regional homogeneity (ReHo) in several brain regions, suggesting the neural functionality in these regions may be utilized to predict psychomotor impairment under exposure. In this study, 69 subjects come from Shaanxi-Tibet immigrant cohort. Reaction time (RT) tasks were performed to measure the subject's psychomotor function before and after 2-year high-altitude exposure. For each individual, the RT differences between pre-exposure and post-exposure were calculated, which were referred to as "targets" in model establishment. Rs-fMRI data were acquired at the same time with RT tasks. For each individual, the map of ReHo alteration was generated, from which the patterns would be recognized. A pattern recognition procedure was utilized to train and test the predictive models. Two different cross-validation strategies were utilized to evaluate the model performance: leave-one-out cross-validation and four-fold cross-validation. For the models displaying significant R2 and MSE, weight maps were built. As a result, the predictive models were able to decode the changes of simple and recognition reaction time from the alterations of brain activation under the exposure. The regions with highest contributions to the predictions were bilateral putamen and bilateral pallidum, suggesting that predictions were mainly based on the patterns concentrated in these regions. This study was a proof of concept study designed to examine whether individual-level psychomotor impairment under high-altitude exposure could be predicted by a combination of pattern recognition approach and neuroimaging data.
"History, Tradition, and Progress", a grand ceremony in celebration of the 150th Anniversary of the National Center for Global Health and Medicine (NCGM) was held in Tokyo, Japan on December 3, 2018. Hundreds of distinguished guests from home and abroad attended the grand ceremony. The NCGM is a national research and development agency, which is a type of independent administrative entity. The NCGM originated from a temporary army hospital that was established in Tokyo in October 1868. After several rounds of restructuring and reorganization, the facility became the NCGM in April 2015. The NCGM has various departments, including the Center Hospital, Kohnodai Hospital, the Research Institute, the Center for Clinical Sciences, the Bureau of International Health Cooperation, and the National College of Nursing. The NCGM conducts research in various fields such as infectious diseases, immune disorders, diabetes, and metabolic disorders and it provides advanced and comprehensive medical care. The NCGM also comprehensively provides training for personnel in international cooperation and medicine. "As a research and development entity, the NCGM will continue to fulfil those tasks in accordance with Japan's national policies", Dr. Norihiro Kokudo, the president of NCGM, said in his speech of anniversary opening greeting.
Prevention of mother-to-child transmission (PMTCT) program offer a range of services for women of reproductive age living with or at risk of contracting the human immunodeficiency virus (HIV) in order to maintain their health and to protect their infants from acquiring HIV. The program has made significant progress in eliminating HIV. Thanks to the provision of PMTCT services, around 1.4 million HIV infections among children were prevented between 2010 and 2018. PMTCT program in China has developed substantially over the past few years, highlighting the national response to HIV/AIDS. Although huge strides have been made in PMTCT, a number of important issues, such as prevention at each step, monitoring of PMTCT services, and early infant diagnosis, need to be addressed in the future.