Adjuvant therapy with Jianpi Huayu decoction improves overall and recurrence-free survival after hepatectomy for hepatocellular carcinoma: a retrospective propensity score-matching study.

Hepatocellular carcinoma (HCC) patients experience high rates of recurrence following hepatectomy. Many herbal preparations used in traditional Chinese medicine have been shown to improve the postoperative condition of cancer patients. This retrospective study examined the efficacy and safety of Jianpi Huayu decoction (JPHYD) as adjuvant therapy for HCC following hepatectomy. HCC patients received postoperative management according to Chinese Society of Clinical Oncology recommendations, either alone (Control group) or in addition to daily JPHYD (1 week in hospital and 3 months after release). To reduce selection bias, we performed 1:1 propensity score matching between the Control and JPHYD groups. The main endpoint was recurrence-free survival (RFS), and secondary endpoints included overall survival (OS) and adverse event frequency. A total of 207 patients meeting inclusion criteria were enrolled, 127 in the Control group and 80 in the JPHYD group. Patients were then propensity score-matched, yielding each group of 80. Recurrence-free survival rate was significantly higher in the JPHYD group than in the Control group at 1 year (67.9% vs. 38.1%), 2 years (39.1% vs. 26.2%), and 3 years (31.3% vs. 26.2%) following hepatectomy (HR 0.5666 [95%CI, 0.3655 to 0.8784]; p = 0.0066). Additionally, OS was significantly higher in the JPHYD group than the Control group at 1 year (94.3% vs. 81.9%), 2 years (76.4% vs. 58.8%), and 3 years (66.3% vs. 51.4%) following hepatectomy (HR 0.5199 [95%CI, 0.2849 to 0.9490]; p = 0.027). Adverse events frequencies did not differ between the two groups. In conclusion, JPHYD can safely improve RFS and OS following hepatectomy for HCC.

Regioselective C-H chalcogenylation and halogenation of arenes and alkenes under metal-free conditions.

The reactions of direct Csp2-H chalcogenylation and halogenation of N-arylpyrrolidone under the action of PIFA without a directing group and under metal-free conditions were reported in this paper. Diphenyl selenide/sulfur and selenium phenyl halides were used as reaction reagents to obtain chalcogenylated and halogenated N-arylpyrrolidone products, respectively. The mechanistic studies indicated that a radical pathway was likely involved in these reactions. Preliminary antitumor tests showed that these compounds have moderate to potent activities against human acute leukemia cells K562 in vitro, which may be used as lead compounds for subsequent research.

Synthesis and antitumor activity of a series of novel N-aryl-5-(2,2,2-trifluoroethoxy)-1,5-dihydro-2H-pyrrol-2-ones derivatives.

With the help of the establishment of novel reaction methodology, a series of N-Aryl-5-(2,2,2-trifluoroethoxy)-1,5-dihydro-2H-pyrrol-2-one conjugates were designed and synthesized in 2-4 steps, and subsequent anticancer activity of these compounds was evaluated. Preliminary results showed that these compounds have moderate to potent activities against human acute leukemia cells K562, human lung cancer A549, human breast cancer MDA-MB-231, and human cervical cancer HeLa cancer cell lines. Among them, compounds 2d and 2k were the most potent against K562 cell line with IC50 values of 0.07 and 0.52 µM, respectively, and the toxicity of 2d to the normal of hepatocytes (LO2) cell line was low (the survival rate 81 %). Flow cytometry analysis showed that 2d arrested K562 cells in the G2/M phase potently, even much better than Combretastatin A4 (CA4). In addition, the results demonstrated the involvement of the caspase-dependent or independent pathways of apoptosis, evidenced by the upregulation of FADD, pro-caspase 3, cleaved-caspase 3, HTRA2/Omi, SMAC/Diablo and the ratio of Bax/Bcl-2.The biological effects founding of 2d in this work point to prospective uses against acute leukemia.

Serum Biomarkers for Autoimmune Hepatitis Type 1: the Case for CD48 and a Review of the Literature.

In autoimmune hepatitis (AIH), the persisting inflammation contributes to fibrosis progression, for which conventional biochemical markers manifest relatively unsatisfactory prediction. Herein, we assessed the value of serum CD48 (sCD48) as an indicator for inflammation and fibrosis in AIH type 1. The levels of sCD48 were detected first in an exploratory cohort using ELISA. In this cohort, compared with healthy controls (4.90 ng/mL, P < 0.0001), primary biliary cholangitis (7.32 ng/mL, P < 0.0001), and non-alcoholic fatty liver disease (7.76 ng/mL, P < 0.0001), sCD48 levels were elevated in AIH (12.81 ng/mL) and correlated with histological inflammation and fibrosis. Further using multivariate logistic regression analysis, sCD48 was identified as an independent predictor for both significant inflammation (G3-4) and advanced fibrosis (S3-4). Two predictive scores, based on sCD48, were constructed for diagnosing significant inflammation and advanced fibrosis (sCD48-AIH-SI and sCD48-AIH-AF, respectively). Using these data as a premise, predictive abilities were subsequently evaluated and verified in a validation cohort. In the exploratory cohort, the area under the receiver operating characteristic curve of sCD48 and sCD48-AIH-SI, for significant inflammation, were 0.748 and 0.813, respectively. Besides, during treatment follow-up, sCD48 levels gradually decreased from immunosuppression initiation to re-evaluation biopsy, in parallel with aspartate transaminase, total sera IgG, and fibrosis-4 score. For AIH patients in a re-evaluation biopsy cohort, sCD48 could predict significant fibrosis (S2-4). Further using immunohistochemistry, hepatic CD48 expression was elevated in AIH patients and decreased after treatment. In conclusion, sCD48 and sCD48-based predictive scores predict histological inflammation and fibrosis in AIH-1. Detecting sCD48 might help in the clinical management of AIH.

Design, synthesis, and evaluation of a novel series of mono-indolylbenzoquinones derivatives for the potential treatment of breast cancer.

Breast cancer is one of the most common cancers in the world, and pro-apototic drugs activating the apoptotic pathway are a strategy for anticancer therapy. To explore new antineoplastic agents, a series of novel mono-indolylbenzoquinone derivatives have been designed and synthesized. Compared with the lead bis-indolylbenzoquinones, most of the novel mono-indolylbenzoquinone derivatives have significantly increased their activity against A549, HeLa, and especially, MDA-MB-231 cell lines. Among them, 10d has the lowest IC50 value of 70 nM on MDA-MB-231 cells. Moreover, its oral toxicity is extremely low with an LD50 value of 374 mg/kg and no obvious liver and kidney damage to mice. 10d down-regulated Bcl-2, up-regulated Bax, and increased the release of cytochrome C, caspase3 and 9. 10d also up-regulated the expression of p53, catalase, and HTRA2/Omi. Therefore, 10d may exert its anticancer activity by activating apoptotic pathway and p53 expression. In vivo, 10d suppressed breast cancer 4T1 tumor growth with 36% inhibition ratio of tumor by intraperitoneal injection in mice. Furthermore, a cross-linked cyanoacrylate (CA)-based local sustained-release drug delivery systems (LSRDDSs) improved 10d anticancer activity to 49.8% inhibition of tumor growth. Taken together, 10d could be a promising drug candidate for clinical development to treat metastatic breast cancer.

Role of miR­34 in gastric cancer: From bench to bedside (Review).

Gastric cancer (GC) is a prevalent digestive system malignancy that is associated with a poor prognosis specifically for advanced­stage patients. MicroRNAs (miRNAs) are small, non­coding RNAs that have been reported to play roles as oncogenes or tumour suppressors in all types of cancer, including GC, by post­transcriptionally regulating cancer­related genes. Recently, miR­34a and miR­34b/c, members of the microRNA­34 (miR­34) family, were identified to be direct transcriptional targets of the onco­suppressor p53. In this review, we report that miR­34 is epigenetically downregulated or silenced in GC tissues and cell lines, changes which may result from mutations in p53 or DNA methylation and histone modifications of the miR­34 promoter regions. Moreover, miR­34 has been identified as a tumour­suppressor in GC. p53­induced miR­34 regulates several different target genes and signalling pathways, inducing apoptosis, senescence, and cell cycle arrest and repressing GC cell proliferation, migration and metastasis, thus contributing to the suppression of carcinogenesis and GC cancer progression. Furthermore, miR­34 is a novel prognostic and predictive biomarker in GC, and restoring miR­34 expression by delivering miR­34 mimics may be a promising therapeutic strategy for the treatment of GC.

Novel role of microRNA-126 in digestive system cancers: From bench to bedside.

MicroRNAs (miRNAs) are ubiquitously expressed, small, non-coding RNAs that regulate the expression of approximately 30% of the human genes at the post-transcriptional level. miRNAs have emerged as crucial modulators in the initiation and progression of various diseases, including numerous cancer types. The high incidence rate of cancer and the large number of cancer-associated cases of mortality are mostly due to a lack of effective treatments and biomarkers for early diagnosis. Therefore there is an urgent requirement to further understand the underlying mechanisms of tumorigenesis. MicroRNA-126 (miR-126) is significantly downregulated in a number of tumor types and is commonly identified as a tumor suppressor in digestive system cancers (DSCs). miR-126 downregulates various oncogenes, including disintegrin and metalloproteinase domain-containing protein 9, v-crk sarcoma virus CT10 oncogene homolog and phosphoinositide-3-kinase regulatory subunit 2. These genes are involved in a number of tumor-associated signaling pathways, including angiogenesis, epithelial-mensenchymal transition and metastasis pathways. The aim of the current review was to summarize the role of miR-126 in DSCs, in terms of its dysregulation, target genes and associated signaling pathways. In addition, the current review has discussed the potential clinical application of miR-126 as a biomarker and therapeutic target for DSCs.

MicroRNAs and the PTEN/PI3K/Akt pathway in gastric cancer (Review).

Gastric carcinogenesis arises from complicated interactions among host, environmental and bacterial factors, which cause genetic and epigenetic dysregulation of oncogenic and tumor­suppressive genes. MicroRNAs (miRNAs), a class of small non­coding RNAs that post­transcriptionally regulate ~30% human genes, may serve as oncogenes or tumor­suppressors in malignancies, including gastric cancer (GC). Although miRNA dysregulation commonly exists in GC, exact roles miRNAs serve in the pathogenesis and promotion of this tumor remain undetermined. Recently, results of previous studies regarding mechanisms underlying miRNAs generally converged on pathways critical in cellular processes, including cell proliferation, apoptosis and invasion, among which phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3­kinase (PI3K)/protein kinase B (Akt) signaling is a fundamental one, with frequent oncogenic alterations in GC. Therefore, in the present review, the disorder and function of miRNAs and PTEN/PI3K/Akt signaling in GC are discussed. Additionally, how miRNAs transduce their effects by regulating this pathway, particularly in GC stem cells and the tumor microenvironment, and two novel hypotheses significant in carcinogenesis, tumor progression and recurrence, are discussed. Furthermore, the roles of miRNAs and the PTEN/PI3K/Akt pathway in target therapies against this lethal disease are outlined.

Variations in Volatile Oil Yield and Composition of "Xin-yi" (Magnolia biondii Pamp. Flower Buds) at Different Growth Stages.

Dried flower buds of Magnolia biondii Pamp. are the main ingredient in "Xin-yi" in China, and the volatile oils of M. biondii flower buds are the principal medicinal component. Gas chromatographymass spectrometry (GC-MS) and microscopic techniques were employed to detect the volatile yields of M. biondii flowers at various growth stages. The volatile oil yields of M. biondii flowers differed significantly at different growth stages and were closely related to flower dry weight, oil cell density and degree of oil accumulation. In February 2016, flower buds had the highest dry weight, the maximum percentage of oil cells at the oil saturation stage and the highest density of oil cells, which coincided with the highest oil yield. In March 2016, flower buds had a lower dry weight, a higher percentage of oil cells at the oil-degrading stage and the lowest oil cell density, resulting in decreased oil yields. The total amounts of the major medicinal components in the M. biondii flower also showed regular changes at different growth stages. In January and February of 2016, M. biondii flowers had a higher dry weight, volatile oil yield and total content of medicinal ingredients, which was the best time for harvesting high-quality medicinal components. Our study reveals that volatile oil content and chemical composition are closely related to the growth stage of M. biondii flower buds. The results provide a scientific morphology and composition index for evaluating the medicinal value and harvesting of high-quality M. biondii medicinal herbs.

MicroRNA-200a inhibits epithelial-mesenchymal transition in human hepatocellular carcinoma cell line.

OBJECTIVE: Our study investigated the role of microRNA (miR)-200a and its molecular targets in hepatocellular carcinoma (HCC) cells. METHODS: An inhibitor of miR-200a was transiently transfected into the hepatocellular carcinoma cell line, MHCC-97L. The effect of this transfection on mRNA levels of epithelial-mesenchymal transition (EMT)-related genes was measured by fluorescence-based quantitative real-time polymerase chain reaction (qRT-PCR). Further, protein levels of EMT-related genes, cell proliferation and apoptosis-related markers were assessed by Western blot analysis in these transfected cells. MTT and wound-healing assay were used to evaluate the proliferation and migration of MHCC-97L cells in presence and in absence of miR-200a inhibitor. RESULTS: Compared with miR-NC control group, qRT-PCR results in anti-miR-200a group revealed a significant reduction in the mRNA levels of E-cadherin, with a concomitant increasing in vimentin mRNA level (all P < 0.05). Western blot results showed higher E-cadherin and Caspase-3 protein expressions in anti-miR-200a group compared to miR-NC group (P < 0.05). In addition, vimentin and Ki-67 protein expression was found sharply decreased in anti-miR-200a group compared to miR-NC group (P < 0.05). Consistent with this, wound-healing and MTT assay showed that migration and proliferation capacity of MHCC-97L cells in anti-miR-200a group is significantly increased compared with miR-NC group (both P < 0.05). CONCLUSION: Our study reveals an important role of miR-200a in inhibiting EMT, proliferation and migration in HCC cells, suggesting the possibility of miR-200a-based therapeutics in HCC.

Correlation of hedgehog signal activation with chemoradiotherapy sensitivity and survival in esophageal squamous cell carcinomas.

OBJECTIVE: To investigate the significance of hedgehog signaling pathway in chemoradiotherapy sensitivity and its effect on the prognosis of esophageal squamous cell carcinoma. METHODS: In the present study, we used the method of immunohistochemistry to examine the expression status of two hedgehog components, PTCH1 and glioma-associated oncogene GLI-1, in 100 pre-treated biopsy specimens of esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy. RESULTS: We find that high levels of PTCH1 and GLI-1 were detected in 76.0 and 72.0% of esophageal squamous cell carcinoma, respectively. Significant associations of high PTCH1 and GLI-1 expression with large tumor size (both P = 0.01), locoregional progression (P= 0.001 and 0.003, respectively) and the lack of complete response to chemoradiotherapy (P= 0.008 and 0.01, respectively) were observed. Univariate analysis revealed that high PTCH1 and GLI-1 expression was associated with poor locoregional progression-free survival, distant progression-free survival and overall survival. Furthermore, esophageal squamous cell carcinoma patients with high PTCH1 and GLI-1 expression have the shorter survival time than the subgroups with negative and low PTCH1 and GLI-1 expression. In multivariate analysis, PTCH1 and GLI-1 expression status were both evaluated as independent prognostic factors for locoregional progression-free survival, distant progression-free survival and overall survival. CONCLUSIONS: These findings suggest an important role for the activation of hedgehog signaling in esophageal squamous cell carcinoma progression and that PTCH1 and GLI-1 expression may be significantly associated with esophageal squamous cell carcinoma resistance to chemoradiotherapy.