Anti-angiogenic and anti-tumor activities of isoflavonoids from the rhizomes of Belamcanda chinensis

The present study was carried out to clarify whether tectorigenin and tectoridin isolated from the rhizomes of Belamcanda chinensis (Iridaceae) inhibit angiogenesis by the experimental methods in vitro and in vivo. Tectorigenin and tectoridin decreased angiogenesis of both chick embryos in the chorioallantoic membrane assay and basic fibroblast growth factor-induced vessel formation in the mouse Matrigel plug assay. Both compounds also reduced the proliferation of calf pulmonary arterial endothelial (CPAE) cells and found to possess relatively weak gelatinase/collagenase inhibitory activity in vitro. Tectorigenin exhibited a much stronger anti-proliferative activity than its glycoside, tectoridin and was almost equipotent to that of genistein, a reference drug. Tectorigenin, when administered subcutaneously at the dose of 30 mg/kg for 20 days to mice implanted with murine Lewis lung carcinoma (LLC), caused a significant inhibition of tumor volume by 30.8 %. Tectorigenin and tectoridin, when treated i. p. at the same dosage for 10 days to ICR mice bearing sarcoma 180, caused a significant suppression in tumor weight by 44.2 and 24.8 %, respectively.     

Slow injection of nefopam reduces pain intensity associated with intravenous injection: a prospective randomized trial

Purpose

We aimed to investigate the frequency and severity of pain associated with intravenous injection of nefopam and to determine whether a slow rate of administration can effectively reduce such pain.

Methods

We used a solution containing 30 mg nefopam diluted to 20 ml in saline. In all, 102 adult patients undergoing minor surgery were randomly allocated to one of three administration groups: A (60 ml/h, n = 34); B (120 ml/h, n = 34); or C (180 ml/h, n = 34). All patients scored the maximal pain experienced during the 120-s infusion period, using the visual analogue scale (VAS) and the verbal pain score (VPS). Adverse events including phlebitis were recorded.

Results

Eighty-three patients (29 in group A, 27 each in groups B and C) were included in the final analysis. The incidence of injection pain was lower in group A (86.2 %) than in groups B (96.3 %) and C (100 %), but this difference was not statistically significant. The proportion of patients with a tolerable level of pain (VAS 0–3 and VPS 0–1) was significantly higher in group A (79.3 %) versus groups B (7.4 %) and C (3.7 %). The mean VAS scores for groups A, B, and C were 2.2 ± 1.3, 5.1 ± 1.6, and 7.2 ± 1.7, respectively, and these differences were statistically significant.

Conclusions

At the slower rate of infusion (60 ml/h) of the 1.5 mg/ml nefopam solution, injection pain intensity was attenuated to a significantly greater degree than at the faster rates.     

Opposing roles of HDAC6 in liver regeneration and hepatocarcinogenesis

Histone deacetylase 6 (HDAC6), a deacetylase of p53, has emerged as a privileged inhibitory target for cancer therapy because of its deacetylating activity for p53 at K120 and K373/382. However, intricate roles of HDAC6 in hepatocellular carcinogenesis have been suggested by recent evidence, namely that HDAC6 ablation suppresses innate immunity, which plays critical roles in tumor immunosurveillance and antitumor immune responses. Therefore, it is valuable to determine whether HDAC6 ablation inhibits hepatocellular carcinogenesis using in vivo animal models. Here, we firstly showed that HDAC6 ablation increased K320 acetylation of p53, known as pro‐survival acetylation, in all tested animal models but did not always increase K120 and K373/382 acetylation of p53, known as pro‐apoptotic acetylation. HDAC6 ablation induced cellular senescence in primary MEFs and inhibited cell proliferation in HepG2 cells and liver regeneration after two‐thirds partial hepatectomy. However, the genetic ablation of HDAC6 did not inhibit hepatocarcinogenesis, but instead slightly enhanced it in two independent mouse models (DEN + HFD and DEN + TAA). Notably, HDAC6 ablation significantly promoted hepatocarcinogenesis in a multiple DEN treatment hepatocellular carcinoma (HCC) mouse model, mimicking chronic DNA damage in the liver, which correlated with hyperacetylation at K320 of p53 and a decrease in inflammatory cytokines and chemokines. Our data from three independent in vivo animal HCC models emphasize the importance of the complex roles of HDAC6 ablation in hepatocellular carcinogenesis, highlighting its immunosuppressive effects.     

Enhanced antigen uptake by dendritic cells induced by the B pentamer of the type II heat-labile enterotoxin LT-IIa requires engagement of TLR2

The potent mucosal adjuvant properties of the type II heat-labile enterotoxin LT-IIa of Escherichia coli are dependent upon binding of the B pentamer of the enterotoxin (LT-IIa-B₅) to ganglioside receptors on immunocompetent cells. To evaluate the immunomodulatory activities of LT-IIa-B₅, in vitro experiments employing bone marrow-derived dendritic cells (BMDC) were performed. Uptake of OVA-FITC, a model antigen (Ag), was enhanced by treatment of BMDC with LT-IIa-B5, but not by treatment of cells with the B pentamer of cholera toxin (CTB). Expression of co-stimulatory molecules (CD40, CD80, CD86, and MHC-II) and cytokines (IL-12p40, TNF-α, and IFN-γ) was increased in BMDC treated with LT-IIa-B₅. The capacity of LT-IIa-B₅ to enhance Ag uptake and to induce expression of co-stimulatory receptors and cytokines by BMDC was dependent upon expression of TLR2 by the cell. Increased Ag uptake induced by LT-IIa-B₅ was correlated with increased Ag-specific proliferation of CD4⁺ T cells in an in vitro syngeneic DO11.10 CD4⁺ T cell proliferation assay. These experiments confirm that LT-IIa-B₅ exhibits potent immunomodulatory properties which may be exploitable as a non-toxic mucosal adjuvant.     

Personality Types as Predictors of Breast Cancer Screening Compliance in Korean Patients: A Mixed-Method Approach

ObjectiveThe purpose of this study is to identify personality types that can influence breast cancer screening (BCS) compliance among Korean women with breast cancer using a mixed-method approach. MethodsThe participants consisted of 93 women who underwent surgery for breast cancer between July 2010 and March 2012. The demographic and medical characteristics of the participants were evaluated through structured interviews. To identify personality types, in-depth interviews were performed and the transcribed interviews were evaluated using interpretive phenomenological analysis. The participants were categorized into two groups (compliance and non-compliance) based on compliance with the Korean Breast Cancer Society recommendations for BCS. ResultsFive personality types were identified through phenomenological analysis. There were significant differences in the chi-square test results for the BCS compliance and non-compliance groups according to age (p=0.048), cancer stage (p<0.001), and personality types (p=0.018). Logistic regression showed that the odds ratio for compliance with BCS was 9.35 (p=0.01) for individuals with a cautious-organized personality type, 9.38 (p=0.02) for those with a cautious-dependent personality, and 10.58 (p=0.04) for those with a sensitive-downcast personality compared to those with a cautious personality type. ConclusionParticipants with cautious-organized, cautious-dependent, and sensitive-downcast personality types were less likely to follow the BCS recommendations than those with a cautious personality type. This study provides a basis for the future development of an effective questionnaire to investigate the personality types of individuals with breast cancer in order to predict compliance with BCS.     

Impact of everolimus on survival after liver transplantation for hepatocellular carcinoma

Background/AimsThis study aimed to investigate whether everolimus (EVR) affects long-term survival after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC).MethodsThe data from 303 consecutive patients with HCC who had undergone LT from January 2012 to July 2018 were retrospectively reviewed. The patients were divided into two groups: 1) patients treated with EVR in combination with calcineurin inhibitors (CNIs) (EVR group; n=114) and 2) patients treated with CNI-based therapy without EVR (non-EVR group; n=189). Time to recurrence (TTR) and overall survival (OS) after propensity score (PS) matching were compared between the groups, and prognostic factors for TTR and OS were evaluated.ResultsThe EVR group exhibited more aggressive tumor biology than the non-EVR group, such as a higher number of tumors (P=0.003), a higher prevalence of microscopic vascular invasion (P=0.017) and exceeding Milan criteria (P=0.029). Compared with the PS-matched non-EVR group, the PS-matched EVR group had significantly better TTR (P<0.001) and OS (P<0.001). In multivariable analysis, EVR was identified as an independent prognostic factor for TTR (hazard ratio [HR], 0.248; P=0.001) and OS (HR, 0.145; P<0.001).ConclusionsCombined with CNIs, EVR has the potential to prolong long-term survival in patients undergoing LT for HCC. These findings warrant further investigation in a well-designed prospective study.     

Patient-derived cell models as preclinical tools for genome-directed targeted therapy

Background

In this study, we established patient-derived tumor cell (PDC) models using tissues collected from patients with metastatic cancer and assessed whether these models could be used as a tool for genome-based cancer treatment.

Methods

PDCs were isolated and cultured from malignant effusions including ascites and pleural fluid. Pathological examination, immunohistochemical analysis, and genomic profiling were performed to compare the histological and genomic features of primary tumors, PDCs. An exploratory gene expression profiling assay was performed to further characterize PDCs.

Results

From January 2012 to May 2013, 176 samples from patients with metastatic cancer were collected. PDC models were successfully established in 130 (73.6%) samples. The median time from specimen collection to passage 1 (P1) was 3 weeks (range, 0.5–4 weeks), while that from P1 to P2 was 2.5 weeks (range, 0.5–5 weeks). Sixteen paired samples of genomic alterations were highly concordant between each primary tumor and progeny PDCs, with an average variant allele frequency (VAF) correlation of 0.878. We compared genomic profiles of the primary tumor (P0), P1 cells, P2 cells, and patient-derived xenografts (PDXs) derived from P2 cells and found that three samples (P0, P1, and P2 cells) were highly correlated (0.99–1.00). Moreover, PDXs showed more than 100 variants, with correlations of only 0.6–0.8 for the other samples. Drug responses of PDCs were reflective of the clinical response to targeted agents in selected patient PDC lines.

Conclusion(s)

Our results provided evidence that our PDC model was a promising model for preclinical experiments and closely resembled the patient tumor genome and clinical response.