Caffeic acid phenethyl ester derivative exerts remarkable anti-hepatocellular carcinoma effect, non-inferior to sorafenib, in vivo analysis.

Caffeic acid phenethyl ester (CAPE) and its derivatives exhibit considerable effects against hepatocellular carcinoma (HCC), with unquestioned safety. Here we investigated CAPE derivative 1' (CAPE 1') monotherapy to HCC, compared with sorafenib. HCC Bel-7402 cells were treated with CAPE 1', the IC50 was detected using CCK-8 analysis, and acute toxicity testing (5 g/kg) was performed to evaluate safety. In vivo, tumor growth after CAPE 1' treatment was evaluated using an subcutaneous tumor xenograft model. Five groups were examined, with group 1 given vehicle solution, groups 2, 3, and 4 given CAPE 1' (20, 50, and 100 mg/kg/day, respectively), and group 5 given sorafenib (30 mg/kg/day). Tumor volume growth and tumor volume-to-weight ratio were calculated and statistically analyzed. An estimated IC50 was 5.6 µM. Acute toxicity tests revealed no animal death or visible adverse effects with dosage up to 5 g/kg. Compared to negative controls, CAPE 1' treatment led to significantly slower increases of tumor volume and tumor volume-to-weight. CAPE 1' and sorafenib exerted similar inhibitory effects on HCC tumors. CAPE 1' was non-inferior to sorafenib for HCC treatment, both in vitro and in vivo. It has great potential as a promising drug for HCC, based on effectiveness and safety profile.

Main Diagnostic Criteria Usually Does Not Work for Autoimmune Pancreatitis Wrongly Presuming Malignancy.

Background: Autoimmune pancreatitis (AIP) usually responds dramatically to steroid therapy. Occasionally, however, misdiagnosed patients have undergone pancreaticoduodenectomy. This study is aimed at providing useful information to improve the accuracy of diagnosis before surgery and thus avoid unnecessary resections in patients with AIP. Methods: From January 2015 to February 2020, a series of patients were enrolled, having undergone pancreaticoduodenectomy for presumed malignancy. AIP diagnoses were confirmed by postoperative pathology. The demographic and clinical data of the AIP patients were evaluated. The main diagnostic criteria (HISORt, Asian, and ICDC) for AIP were applied to assess whether and how unnecessary surgery could have been avoided. Results: A total of 124 cases of pancreaticoduodenectomy were performed for presumed malignancy. Six patients were diagnosed with benign disease and five with AIP. The prevalences of benign disease and AIP were 4.8% and 4%, respectively. Four patients were female and 1 male, with a mean age of 60.0 years old. Jaundice, pain, and weight loss were observed in 100%, 20%, and 40% of AIP patients, respectively. The radiologic features of the AIP patients were a diffusely enlarged gland (40.0%), a focally enlarged gland (40.0%), pancreatic ductal dilatation (60.0%), upstream parenchymal atrophy (20.0%), bile duct thickening (66.0%), and bile duct stricture (40.0%). Based on the diagnostic criteria for AIP, surgery could have been avoided in two cases. Conclusions: IgG4 measurement and integrated use of major diagnostic criteria should be emphasized in every patient eligible for pancreaticoduodenectomies.

Associations between sedentary behaviour patterns and depression among people aged 60 and older in Hebei Province of China.

BACKGROUND: Sedentary behaviours (SBs) are now considered a risk factor for depression. Older adults are sedentary most of the time and are at a high risk of depression. However, not all types of SBs have adverse effects on mental health. Passive SBs (such as watching TV) increase the risk of depression, whereas mentally active SBs (such as using the internet and reading) decrease the risk of depression. The aim of this study was to explore the associations between type of SBs (i.e., passive and mentally active SBs) and depression among people aged 60 years and older in the Hebei Province of China. METHODS: This cross-sectional study used data from the baseline survey of the Community-based Cohort Study on Nervous System Diseases. A total of 2679 older adults aged ≥60 years from the Hebei Province of China were included in this study. The type and time spent on SBs were self-reported. Watching TV was defined as a passive SB, whereas internet use, reading, and social SBs (including communicating with others and playing chess) were defined as mentally active SBs. Depression was evaluated using the Geriatric Depression Scale. The maximal possible score was 30 points, and ≥ 11 points indicated depression. Logistic regression analysis was used to assess the relationship between SBs and depression. Covariates included sex, age, education, employment, smoking, alcohol consumption, sleep duration, domestic work, physical exercise, body mass index (BMI), and chronic diseases. RESULTS: At baseline, the participants who spent two or more hours and 0 h on passive SBs (i.e., TV viewing) had a greater risk of depression (=0 h: adjusted OR = 2.09, 95% CI = 1.18-3.76; 2-3 h: OR = 2.21, 95% CI = 1.16-4.16; > 3 h: OR = 3.59, 95% CI = 1.93-6.68) than the participants who spent 1-2 h on passive SBs. The participants who spent > 1 h on mentally active SBs had a lower risk of depression (adjusted OR = 0.26, 95% CI = 0.06-0.71) than the participants who did not engage in mentally active SBs. Not all mentally active SBs were linked to depression. The participants who engaged in social SBs had a lower risk of depression (adjusted OR: 0.24, 95% CI: 0.06-0.66) than the participants who did not engage in social SBs. CONCLUSIONS: Spending 2 h or more per day on passive SBs (watching TV) was associated with a high risk of depression among people aged 60 years and older in the Hebei Province of China. Mentally active SBs (predominantly social SBs) could reduce the risk of depression. Some participants with depression probably did not watch TV. These findings suggested that spending more time on social SBs (such as communicating with others and playing chess) rather than watching TV may have important public health implications for preventing and managing depression among older Chinese adults. Moreover, society should attend to the mental health of elderly adults who do not watch TV as they may be more prone to suffer from depressive symptoms.

Preoperative Remnant Liver Function Evaluation Using a Routine Clinical Dynamic Gd-EOB-DTPA-Enhanced MRI Protocol in Patients with Hepatocellular Carcinoma.

BACKGROUND: To investigate the clinical feasibility of preoperative routine clinical dynamic Gd-EOB-DTPA-enhanced MRI alone to predict post-hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC). METHODS: 116 patients with HCC who underwent liver resection in Southwest Hospital from 2014 through 2017 were selected in this retrospective cohort study. The remnant function (RF) of the liver RFUR and RFRE15 were calculated by the sum of the uptake rate (UR) or relative enhancement at 15 min (RE15) from dynamic Gd-EOB-DTPA-enhanced MR images in the remnant liver regions, and standardized by standard liver volume (SLV) to generate sRFUR (standardized RFUR) and sRFRE15 (standardized RFRE15). Student's t test or Mann-Whitney U test, logistic regression, and ROC analyses were used to test the associations of preoperative RFUR, sRFUR, RFRE15, sRFRE15, the remnant liver volume (RLV)/SLV, ICG retention rate at 15 min (ICG R15) and sRFICG-K [ICG clearance rate (ICG-K) × RLV/SLV] with PHLF. RESULTS: 28 patients were found to have PHLF, who showed lower RFUR, sRFUR, RFRE15, sRFRE15, RLV/SLV, sRFICG-K, and higher ICG R15 than patients without PHLF (p < 0.001 for all). After adjusting for clinical parameters, RFUR (p = 0.001), sRFUR (p = 0.001), RFRE15 (p = 0.002), or sRFRE15 (p = 0.003) was found to be independently significant indicator in multivariable logistic regression, respectively. RFUR (0.882) and sRFUR (0.882) had larger AUCs than RLV/SLV (0.731, p = 0.008; p = 0.005), ICG R15 (0.765, p = 0.039; p = 0.044) and sRFICG-K (0.767, p = 0.031; p = 0.023). RFRE15 (0.845) and sRFRE15 (0.839) had larger AUCs than RLV/SLV (0.731, p = 0.027; p = 0.025). CONCLUSIONS: The remnant liver function parameters preoperatively estimated from a routine clinical dynamic Gd-EOB-DTPA-enhanced MRI protocol can predict PHLF in patients with HCC, and may be better predictors than conventional methods.

Modulators of histone demethylase JMJD1C selectively target leukemic stem cells.

Leukemic stem cells (LSCs) comprise a very rare cell population that results in the development of acute myeloid leukemia. The selective targeting of drivers in LSCs with small molecule inhibitors holds promise for treatment of acute myeloid leukemia. Recently, we reported the identification of inhibitors of the histone lysine demethylase JMJD1C that preferentially kill MLL rearranged acute leukemia cells. Here, we report the identification of jumonji domain modulator #7 (JDM-7). Surface plasmon resonance analysis showed that JDM-7 binds to JMJD1C and its family homolog JMJD1B. JDM-7 did not significantly suppress cell proliferation in liquid cell culture at higher doses, although it led to a significant decrease in semi-solid colony formation experiments at lower concentrations. Moreover, low doses of JDM-7 did not suppress the proliferation of erythroid progenitor cells. We identified that JDM-7 downregulates the LSC self-renewal gene HOXA9 in leukemia cells. We further found that the structure of JDM-7 is similar to that of tadalafil, a drug approved by the US Food and Drug Administration. Molecular docking and surface plasmon resonance analysis showed that tadalafil binds to JMJD1C. Moreover, similar to JDM-7, tadalafil suppressed colony formation of leukemia cells in semi-solid cell culture at a concentration that did not affect primary umbilical cord blood cells. In summary, we have identified JDM-7 and tadalafil as potential JMJD1C modulators that selectively inhibit the growth of LSCs.

Identification of an acute myeloid leukaemia associated noncoding somatic mutation at 3' end of HOXA cluster.

Noncoding somatic mutations have been demonstrated to play important role in tumourigenesis. Here we show that there exists an acute myeloid leukaemia associated noncoding somatic mutation at 3' terminal of conserved HOXA cluster. The mutation was identified in the bone marrow blasts but not peripheral blood mononuclear cells or buccal cells of two M3 (acute promyelocytic leukaemia, APL) type patients from 45 acute myeloid leukaemia patients. The mutation also existed in a pair of twins one of them developed acute myeloid leukaemia M4 (acute myelomonocytic leukaemia) type. The mutation resides in about 2-kb downstream of HOXA1 gene where a functional retinoic acid response element is located and also bound by histone demethylase KDM3B. Reporter assay showed that the mutation results in the upregulation of transcriptional activity and unresponsiveness to retinoic acid receptor. To sum up, we identified a new acute myeloid leukaemia associated noncoding somatic mutation.

An accessory right hepatic artery derived from the superior mesenteric artery for anterior right liver lobe supply: a case report.

PURPOSE: During the last decades, it has been established that there are numerous individual anatomical variations of the arterial blood supply in human liver. In the present study, we examined the liver vascularization of an intrahepatic cholangiocarcinoma patient. METHODS: For surgical planning, an enhanced CT scan was performed and a three-dimensional model of liver vascularization constructed. RESULTS: The patient was diagnosed as a Michel's type VII hepatic artery variation. An accessory right hepatic artery arose from the superior mesenteric artery and had distributed into the right anterior liver to provide the blood supply of segments V and VIII, which was more medial than the territory of the right hepatic artery coming from the proper hepatic artery. At the same time, an accessory left hepatic artery originated from the left gastric artery. CONCLUSION: We present a case in which an accessory right hepatic artery provided a territory more medial than a right hepatic artery coming from the proper right artery.

Choledochoscopic Examination of a 3-Dimensional Printing Model Using Augmented Reality Techniques: A Preliminary Proof of Concept Study.

BACKGROUND: We applied augmented reality (AR) techniques to flexible choledochoscopy examinations. METHODS: Enhanced computed tomography data of a patient with intrahepatic and extrahepatic biliary duct dilatation were collected to generate a hollow, 3-dimensional (3D) model of the biliary tree by 3D printing. The 3D printed model was placed in an opaque box. An electromagnetic (EM) sensor was internally installed in the choledochoscope instrument channel for tracking its movements through the passages of the 3D printed model, and an AR navigation platform was built using image overlay display. The porta hepatis was used as the reference marker with rigid image registration. The trajectories of the choledochoscope and the EM sensor were observed and recorded using the operator interface of the choledochoscope. RESULTS: Training choledochoscopy was performed on the 3D printed model. The choledochoscope was guided into the left and right hepatic ducts, the right anterior hepatic duct, the bile ducts of segment 8, the hepatic duct in subsegment 8, the right posterior hepatic duct, and the left and the right bile ducts of the caudate lobe. Although stability in tracking was less than ideal, the virtual choledochoscope images and EM sensor tracking were effective for navigation. CONCLUSIONS: AR techniques can be used to assist navigation in choledochoscopy examinations in bile duct models. Further research is needed to determine its benefits in clinical settings.

Oscillatory local field potentials of the nucleus accumbens and the anterior limb of the internal capsule in heroin addicts.

OBJECTIVES: The nucleus accumbens (NAc) is known to regulate the motivation and underlie addictive behaviors, and the anterior limb of the internal capsule (ALIC) is involved in several psychiatric disorders. Our study aimed to explore the functions of NAc and ALIC electrophysiologically. METHODS: The local field potentials (LFPs) of the NAc and ALIC were recorded from 7 heroin addicts treated with deep brain stimulation. Correlation analysis was made between LFP powers in various frequency bands and the subjects' neuropsychological test scores; coherence was calculated for the LFPs in NAc and ALIC. RESULTS: Both the NAc and ALIC exhibited prominent theta and alpha frequency band activity in the LFP power spectra. Additionally, a distinct beta band peak was detected in the power spectra of ALIC LFPs, which may represent the activity of striatal bridge cells. There was a significant negative correlation between the power of the theta frequency band of ALIC LFPs and visual analogue scale (VAS) scores indicative of cravings (Spearman's ρ = -0.758, P = 0.002), and a significant positive correlation was found between the power of the alpha frequency band of NAc LFPs and subjects' scores on the Hamilton depression inventory (ρ = 0.727, P = 0.005). LFPs of the NAc and ALIC exhibited higher coherence values in the theta and alpha frequency bands. CONCLUSIONS: The results suggest that theta power in the ALIC/dorsal striatum and alpha power in the NAc may be associated with drug cravings and depressive symptoms, respectively, in heroin addicts. For these subjects, the neural activities in the dorsal and ventral striatum were mainly coordinated within the low-frequency band. SIGNIFICANCE: The study illustrates the neurophysiologic characteristics of heroin addiction and its comorbidities, providing a potential theoretical basis for optimizing deep brain stimulation (DBS) therapy.

Quantified postsurgical small cell size CTCs and EpCAM+ circulating tumor stem cells with cytogenetic abnormalities in hepatocellular carcinoma patients determine cancer relapse.

Detection of hepatocellular carcinoma circulating tumor cells performed with conventional strategies, is significantly limited due to inherently heterogeneous and dynamic expression of EpCAM, as well as degradation of cytokeratins during epithelial-to-mesenchymal transition, which inevitably lead to non-negligible false negative detection of such "uncapturable and invisible" CTCs. A novel SE-iFISH strategy, improved for detection of HCC CTCs in this study, was applied to comprehensively detect, in situ phenotypically and karyotypically characterize hepatocellular and cholangiocarcinoma CTCs (CD45-/CD31-) in patients subjected to surgical resection. Clinical significance of diverse subtypes of CTC was systematically investigated. Existence of small cell size CTCs (≤5 µm of WBCs) with cytogenetic abnormality of aneuploid chromosome 8, which constituted majority of the detected CTCs in HCC patients, was demonstrated for the first time. The stemness marker EpCAM+ aneuploid circulating tumor stem cells (CTSCs), and EpCAM- small CTCs with trisomy 8, promote tumor growth. Postsurgical quantity of small triploid CTCs (≥5 cells/6 ml blood), multiploid (≥pentasomy 8) CTSCs or CTM (either one ≥ 1) significantly correlated to HCC patients' poor prognosis, indicating that detection of those specific subtypes of CTCs and CTSCs in post-operative patients help predict neoplasm recurrence.

Declining histone acetyltransferase GCN5 represses BMSC-mediated angiogenesis during osteoporosis.

Angiogenesis is disrupted in age-related and postmenopausal osteoporosis. However, the mechanisms of the disorder remain elusive. We confirmed in this study that, in accordance with the decrease of H-type vessels, the proangiogenic potential of bone marrow-derived mesenchymal stem cells (BMSCs) declined during osteoporosis. Screening of the histone acetyltransferase family revealed that GCN5 decreased in BMSCs derived from osteoporotic femur. Further analysis identified that GCN5 plays important roles in regulating the proangiogenic potential of BMSCs. GCN5 promoted BMSC-mediated angiogenesis by enhancing H3K9ac levels on the promoter of Vegf The decrease of GCN5 in osteoporotic BMSCs led to the decline of proangiogenic capacity. Accordingly, overexpression of GCN5 enhanced the proangiogenic potency of osteoporotic BMSCs. Furthermore, recovering GCN5 expression in vivo by lentiviral expression vector significantly attenuated the loss of angiogenesis in ovariectomized mouse femurs. Our study results revealed an epigenetic mechanism controlling BMSC-mediated angiogenesis and provided a novel therapeutic target for osteoporosis treatment.-Jing, H., Liao, L., Su, X., Shuai, Y. Zhang, X., Deng, Z., Jin, Y. Declining histone acetyltransferase GCN5 represses BMSC-mediated angiogenesis during osteoporosis.

Overexpression of microRNA-133b is associated with the increased survival of patients with hepatocellular carcinoma after curative hepatectomy: Involvement of the EGFR/PI3K/Akt/mTOR signaling pathway.

The aim of the present study was carried out to investigate the association of microRNA-133b (miRNA-133b) expression with the prognosis of patients with hepatocellular carcinoma (HCC) after curative hepatectomy. In the present study, the expression of miRNA-133b in HCC tissues was determined to be lower than that noted in the adjacent normal tissues. Overall and disease-free survival of the HCC patients with high miRNA-133b expression was observably extended, compared with the HCC patients with low miRNA­133b expression. Moreover, the overexpression of miRNA-133b inhibited cell proliferation, increased lactate dehydrogenase (LDH) activity, induced apoptosis and promoted caspase­3/-8 activities and Bax/Bcl-2 protein expression in HCC cells, whereas the protein expression of epidermal growth factor receptor (EGFR) was significantly decreased. The overexpression of miRNA-133b significantly suppressed PI3K, phosphorylated (p)-Akt and p-mTOR protein expression in HCC cells. GW2974, an EGFR inhibitor, suppressed the protein expression of EGFR, inhibited cell proliferation, increased LDH activity, induced apoptosis and promoted caspase-3/-8 activities and Bax/Bcl-2 protein expression, downregulated PI3K, p-Akt and p-mTOR protein expression in the transfected HCC cells overexpressing miRNA-133b. Taken together, our results indicate that the overexpression of miRNA-133b is associated with the increased survival of HCC patients after curative hepatectomy. The effects of miRNA-133b in HCC are mediated through the EGFR/PI3K/Akt/mTOR signaling pathway.

Melatonin Treatment Improves Mesenchymal Stem Cells Therapy by Preserving Stemness during Long-term In Vitro Expansion.

Mesenchymal stem cells (MSCs) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro passaging leads to stemness loss of MSCs, resulting in failure of MSCs therapy. Here, we report a melatonin-based strategy to improve cell therapy of in vitro cultured MSCs. Among four small molecules with anti-aging and stem cell-protection properties (rapamycin, resveratrol, quercetin and melatonin), colony forming, proliferation, and osteogenic differentiation assay showed that melatonin was the most efficient to preserve self-renewal and differentiation properties of rat bone marrow MSCs (BMMSCs) after long-term passaging. Functional assays confirmed melatonin treatment did not affect the colony forming, proliferation and osteogenic differentiation of BMMSCs cultured for 1 or 4 passages, but largely prevented the decline of self-renew and differentiation capacity of BMMSCs cultured for 15 passages in vitro. Furthermore, heterotopic osteogenesis assay, critical size calvarial defects repair assay, osteoporosis treatment and experimental colitis therapy assay strongly certified that melatonin preserved the therapeutic effect of long-term passaged BMMSCs on bone regeneration and immunotherapy in vivo. Mechanistically, melatonin functioned by activating antioxidant defense system, inhibiting the pathway of cell senescence, and preserving the expression of gene governing the stemness. Taken together, our findings showed that melatonin treatment efficiently prevented the dysfunction and therapeutic failure of BMMSCs after long-term passaging, providing a practical strategy to improve the application of BMMSCs in tissue engineering and cytotherapy.

Suppression of EZH2 Prevents the Shift of Osteoporotic MSC Fate to Adipocyte and Enhances Bone Formation During Osteoporosis.

During osteoporosis, the shift of mesenchymal stem cell (MSC) lineage commitment to adipocyte leads to the imbalance between bone mass and fat, which increases the risk of fracture. The Enhancer of Zeste homology 2 (EZH2), which methylates histone H3 on lysine 27 (H3K27me3), controls MSC cell lineage commitment. However, whether EZH2 is related to osteoporosis remains elusive. In our study, we found EZH2 expression was significantly increased in osteoporotic MSCs. EZH2 directly increased H3K27me3 levels on promoters of Wnt1, Wnt6, and Wnt10a to silence Wnt gene transcription. The inhibition of Wnt/ß-catenin signaling shifted MSC cell lineage commitment to adipocyte. Knockdown of EZH2 by lentivirus-expressing shRNA rescued the abnormal fate of osteoporotic MSC. By employing the H3K27me3 inhibitor DZNep, we effectively derepressed Wnt signaling and improved osteogenic differentiation of osteoporotic MSCs in vitro. Furthermore, in vivo administration of DZNep successfully increased bone formation and repressed excessive bone marrow fat formation in osteoporotic mice. Noteworthy, DZNep treatment persistently enhanced osteogenic differentiation of endogenous MSCs. In conclusion, our study demonstrated that redundant EZH2 shifted MSC cell lineage commitment to adipocyte, which contributed to the development of osteoporosis. We also provided EZH2 as a novel therapeutic target for improving bone formation during osteoporosis.

Hybrid effects of zirconia nanoparticles with aluminum borate whiskers on mechanical properties of denture base resin PMMA.

The aim of this study was to investigate the hybrid effects of ZrO2 nanoparticles (nano-ZrO2) and aluminum borate whiskers (ABWs) on flexural strength and surface hardness of denture base resin, polymethyl methacrylate (PMMA). Both nano-ZrO2 and ABWs were modified by silane coupling agent (Z6030) before being mixed with PMMA. Various amounts of silanized nano-ZrO2 and ABWs were mixed with PMMA to prepare ZrO2-ABW/PMMA composites. Flexural strength and surface hardness were evaluated using three- point bending test and Vickers hardness test respectively. Fractured surfaces were also observed by scanning electron microscopy (SEM). The mechanical behaviors of silanized ZrO2-ABW/PMMA composites were significantly improved. Flexural strength reached a maximum value of 108.01 ± 5.54 MPa when 2 wt% of nano-ZrO2 was mixed with ABWs at a ZrO2/ABW ratio of 1:2, amounting to an increase of 52% when compared with pure PMMA. Surface hardness achieved a maximum value of 22.50 ± 0.86 MPa when 3 wt% of nano-ZrO2 was mixed with ABWs at the same ZrO2/ABW ratio, which was an increase of 27% when compared with pure PMMA.

Mechanical and thermal properties of denture PMMA reinforced with silanized aluminum borate whiskers.

The aim of this study was to investigate the mechanical and thermal properties of denture polymethyl methacrylate (PMMA) reinforced with aluminum borate whiskers (ABWs). To improve bonding between ABWs and PMMA matrix, the surface of ABWs was modified with a silane coupling agent. Varied contents of silanized ABWs -ranging between 1 and 20 wt%- were mixed into the PMMA resin matrix to prepare ABW/PMMA composites, which were subjected to three-point bending test, Vickers hardness test, and thermal analysis. Silanized ABWs improved the flexural strength, surface hardness, and thermal stability of PMMA. Optimal amount of ABWs in the PMMA matrix was 5 wt%, which provided the ABW/PMMA with maximum reinforcement.