Combination therapy with interleukin-15 and metformin as a synergistic treatment for pancreatic cancer.

OBJECTIVE: To investigate the efficacies and mechanisms of combination therapy with interleukin-15 (IL-15) and metformin (Met) on suppressing pancreatic cell proliferation and protecting Panc02-bearing mice. MATERIALS AND METHODS: MTT assays were applied to assess the inhibitory effects of IL-15 combined Met or Met and IL-15 alone on proliferation of normal HPDE6-C7 and Panc02 cells. After tumor grew up to 150 mm3, the Panc02-bearing xenograft model mice were randomly divided into saline group, IL-15 and Met alone group and combined treatment group (n=8) with the administration of each agent every other day for three weeks, and survival rates were recorded. The changes in tumor size, expression levels of the apoptosis, autophagy as well as Akt/mTOR/STAT3-related factors in tumor tissues were all measured. RESULTS: MTT assays demonstrated significantly inhibiting efficacy of combination therapy with IL-15 and Met on Panc02 cell proliferation compared to other groups (all p<0.05) with combination index<1 showing evident synergistic effect. Moreover, the apoptosis rate of Panc02 cell under combined treatment were 95.5±3.2% and significantly higher than those of others (all p<0.01). In addition, combined administration remarkably inhibited the growth of pancreatic carcinoma, and improved survival rate of Panc02-bearing model with less body weight loss. Furthermore, combined treatment significantly downregulated anti-apoptotic proteins as well as Akt/mTOR/STAT3 signaling pathway and upregulated autophagy related factors, respectively, compared with those of monotherapy groups in both Panc02 cells and tumor tissues. CONCLUSIONS: Combined treatment of IL-15 with Met showed synergistic anti-tumor efficacies on Panc02 cells attributing to promotion on apoptosis, autophagy and inhibition on Akt/mTOR/STAT3 signaling-transduction in Panc02-bearing model mice.

Analysis of the clinicopathological characteristics and prognosis of adenoid cystic carcinoma of the intraoral minor salivary glands: a retrospective study of 40 cases.

The clinicopathological aspects and prognostic factors of 40 patients with adenoid cystic carcinoma (ACC) of the intraoral minor salivary glands, treated between 2007 and 2017 at a single institution, were evaluated retrospectively. Twenty-six were female and 14 were male, and they ranged in age from 26 to 81 years (median 55 years). ACC occurred mainly in the palate, with 54.8% of cases presenting T3-T4 lesions. Curative surgery was performed in all patients, and 62.5% of patients were treated with postoperative adjuvant radiotherapy. In the final analysis, positive surgical margins were noted in 57.5% of cases and perineural invasion in 70%. Follow-up was at least 13 months (range 13-141 months, median 59 months). Nineteen patients (47.5%) developed recurrent disease after initial surgery and nine patients had died at the end of follow-up. The 5- and 10-year overall survival rates were 88.3% and 25.6%, respectively. The 5- and 10-year disease-free survival rates were 75.6% and 34.0%, respectively. Patients with a tumour size >4cm and those with positive surgical margins showed a significantly higher risk of local recurrence. Elective neck dissection is suggested for patients with clinically positive lymph nodes or a locally advanced tumour, especially those undergoing microvascular reconstruction. The survival analysis results are similar to those reported previously in the literature.

Oltipraz attenuates the progression of heart failure in rats through inhibiting oxidative stress and inflammatory response.

OBJECTIVE: To evaluate the effect of oltipraz (OPZ) on isoproterenol-induced heart failure (HF) and heart function. We also explore the underlying molecular mechanism of OPZ. MATERIALS AND METHODS: The rats were randomly divided into four groups, including normal control group, isoproterenol (ISO) group, ISO +100 mg/kg OPZ group, and OPZ group. Hemodynamic parameters, such as left-ventricular systolic pressure, were statistically analyzed. Besides, plasma levels of brain natriuretic peptide (BNP), pro-inflammatory cytokines and antioxidant markers were assessed by using enzyme-linked immunosorbent assay (ELISA). Moreover, histopathological examination was applied to assess the degree of cardiac interstitial fibrosis. RESULTS: OPZ could statistically improve the hemodynamic parameters of the heart function, and could also obviously attenuate cardiac interstitial fibrosis in ISO-induced HF rats when compared with the ISO group. Besides, plasma level of BNP in ISO +100 mg/kg OPZ group dramatically decreased in comparison with that of ISO group. Moreover, compared with ISO group, OPZ treatment significantly reduced the levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). Moreover, OPZ treatment remarkably increased the levels of antioxidant markers such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in ISO-induced HF rats. CONCLUSIONS: OPZ administration may provide experimental evidence for the possible effect of OPZ on isoproterenol-induced heart failure in rats. Moreover, OPZ administration may have potential utility for the treatment of heart failure.

The role of mitochondrial DNA mutations in a Han Chinese population on sepsis pathogenesis.

OBJECTIVE: Individual susceptibility to sepsis has received increasing attention in recent years, and the study of genetic variations has become a hotspot regarding sepsis pathogenesis. We, therefore, investigated the association between mitochondrial genotype and sepsis susceptibility. PATIENTS AND METHODS: One hundred patients admitted with sepsis and registered by five intensive care units (ICUs) in the People's Liberation Army Hospital and the Beijing Aerospace Center Hospital between January 2015 and January 2016 were enrolled as a case group, and 100 healthy persons were recruited as a control group. Patients' general information was obtained, and clinical evaluations and mitochondrial sequence screening were performed. RESULTS: A total of 718 single nucleotide polymorphisms (SNPs) were detected in 708 loci in 100 patients. There were 1754 mutations in 456 loci in the coding region and 567 mutations were found in the RNA region. A total of 34 loci (from 40 cases) were novel mutations. A10398G (52.52%), C5178A (24.24%), C150T (17.17%), G3010A (17.17%), and T16189C (16.16%) were the most frequently observed conserved non-synonymous mutations that were differently expressed between the case and control groups (p<0.05). A5863T and C3270 deletion mutations were located on the genes encoding tRNATyr and tRNALeu, respectively. Small changes in the tRNA gene were likely to result in protein level changes. CONCLUSIONS: We suggest that mitochondrial SNPs may be associated with the pathogenesis of sepsis.

The role of the hippocampus and the function of calcitonin gene-related peptide in the mechanism of traumatic brain injury accelerating fracture-healing.

OBJECTIVE: This research attempts to identify the part the hippocampus plays in accelerated fracture-healing after traumatic brain injury as well as to test functions of calcitonin gene-related peptide (CGRP) during this process. MATERIALS AND METHODS: Experiments were carried out on Male Sprague-Dawley rats that were split into four groups at random: TBI-fracture group, fracture-only group, TBI-only group, and control group. In the first week, blood specimen would be drawn from rats among the groups except those of the control group at three-time points (24, 72 and 168 hours) post-damage. These rats would be assessed from the neurological perspective based on their grades of performance in a sequence of tests 24 hours before and 12 hours after brain injury. Blood samples were also taken from the control group 24 hours before the injury, and whole brain tissues in the injured groups were harvested at 72 and 168 hours post-injury. We compared the serum CGRP concentration, the distribution of CGRP, the CGRP expression, and the expression of CGRP in the hippocampus, the expression of CGRP in the hippocampus, the expression of CGRP in the hippocampus, and the expression of CGRP in the brain by immunohistochemistry, Western blotting, RT- Of CGRP RNA expression levels. RESULTS: Neurological examinations suggested that the functions of the cerebral cortex, cerebellum, and brain stem showed significant differences pre- and post-injury (p < 0.001). ELISA analysis indicated a great density of CGRP in TBI-fracture group at different time points. Furthermore, in the TBI-fracture group, CGRP in both hippocampus and the whole brain showed a noticeable augment in RT-PCR and western blot analysis at 72 and 168 h post-injury, and only in this group, immunohistochemistry analysis indicated that CGRP was present in the hippocampus at 168 hours post-injury. CONCLUSIONS: We observed that the hippocampus and CGRP were responsible for quick bone-healing mechanisms. We suggest a role for the hippocampus in accelerated fracture healing. CGRP expression, as determined by IHC, cannot be observed in other groups, indicating that the hippocampus may be the specific component of the brain that responds to "big stress".

Histone deacetylase inhibitor M344 significantly improves nuclear reprogramming, blastocyst quality, and in vitro developmental capacity of cloned pig embryos.

M344 is a novel histone deacetylase inhibitor. There is no report on the effect of M344 treatment on the development of pig embryos after somatic cell nuclear transfer (SCNT). In the present study, we investigated the effect of M344 on the blastocyst formation rate in cloned embryos, acetylation level of histone H4 lysine 12 (AcH4K12), and the expression of pluripotency-related genes , , and . Our results indicated that treatment with 5 µ M344 for 6 h improved the development of porcine embryos, in comparison with the untreated group (25.1% ± 5.0 vs. 10.9% ± 2.4; < 0.05). Moreover, M344-treated embryos had increased average fluorescence intensity of AcH4K12 at the pseudo-pronuclear stage ( < 0.05). However, no differences exist in Oct4, NANOG, and SOX2 expression in M344-treated and untreated SCNT blastocysts. In evaluating the effect of M344 on in vivo development, 845 M344-treated embryos were transferred into 3 surrogates, 1 of whom became pregnant and developed 3 fetuses. These findings suggested that M344 elevated the level of histone acetylation, facilitated the nuclear programming, and subsequently improved the developmental competence of pig SCNT embryos.

Circulating exosome levels in the diagnosis of steroid-induced osteonecrosis of the femoral head.

OBJECTIVES: Circulating exosomes represent novel biomarkers for multiple diseases. In this study, we investigated whether circulating exosome levels could be used as a diagnostic biomarker for steroid-induced osteonecrosis of the femoral head (ONFH). METHODS: We assessed the serum exosome level of 85 patients with steroid-induced ONFH and 115 healthy donors by Nanosight detection. We then assessed the diagnostic accuracy of serum exosomes by receiver operating characteristic curve analysis. RESULTS: The circulating exosome level of the ONFH group was significantly lower than that of control group. The area under the curve was 0.72, suggesting that the level of serum exosomes has moderate diagnostic accuracy for steroid-induced ONFH. CONCLUSION: Circulating exosome levels are valuable in the diagnosis of steroid-induced ONFH.Cite this article: H-Y. Zhu, Y-C. Gao, Y. Wang, C-Q. Zhang. Circulating exosome levels in the diagnosis of steroid-induced osteonecrosis of the femoral head. Bone Joint Res 2016;5:276-279. DOI: 10.1302/2046-3758.56.BJR-2015-0014.R1.

Relationship between HBV DNA load and levels of serum HBsAg in patients with chronic hepatitis B.

OBJECTIVE: This study aims to investigate the relationship between HBV DNA load and levels of serum HBsAg in patients with chronic hepatitis B (CHB). PATIENTS AND METHODS: Between April 20013 and July 2015, serum samples were collected from 124 CHB patients. Levels of serum HBsAg was determined using chemiluminescent immunoassay and HBV DNA load was measured using quantitative fluorescent RT-PCR (qPCR). Pearson's correlation analysis was performed to analyze the relationship between HBV DNA load and levels of serum HBsAg. RESULTS: Serum HBsAg levels were significantly higher in the group with HBV DNA > 1×103 copies/ml than the group with HBV DNA < 1×103 copies/ml (t=5.983, p=0.000<0.05). One hundred samples with HBV DNA > 1×103 copies/ml were further divided into three subgroups based on HBV DNA load, including group A (levels of serum HBV DNA between 1×103- 1×105 copies/ml), group B (1×105- 1×107 copies/ml) and group C (> 1×107 copies/ml). Levels of serum HBsAg increased with increasing load of HBV DNA. HBsAg levels were the highest in group C and the lowest in group A with significant differences between groups (p<0.05). Pearson's correlation analysis revealed that levels of serum HBV DNA were positively correlated with levels of serum HBsAg (r=0.657, p=0.000<0.05). CONCLUSIONS: HBV DNA load has a certain correlation with levels of serum HBsAg in CHB patients. The combination of HBV DNA load assessment and measurement of serum HBsAg levels can accurately determine HBV infection condition, help with the selection of optimal therapy and predict prognosis.

Novel functional magnetic resonance imaging biomarkers for assessing response to therapy in hepatocellular carcinoma

The established and adapted image biomarkers based on size for tumor burden measurement continue to be applied to hepatocellular carcinoma (HCC) as size measurement can easily be used in clinical practice. However, in the setting of novel targeted therapies and liver directed treatments, simple tumor anatomical changes can be less informative and usually appear later than biological changes. Functional magnetic resonance imaging (MRI) has a potential to be a promising technique for assessment of HCC response to therapy. In this review, we discuss various functional MRI biomarkers that play an increasingly important role in evaluation of HCC response after treatment (AU)

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Cystic fibrosis transmembrane conductance regulator is correlated closely with sperm progressive motility and normal morphology in healthy and fertile men with normal sperm parameters.

Cystic fibrosis transmembrane conductance regulator (CFTR) has been demonstrated to be expressed in mature spermatozoa and correlated with sperm quality. Sperm CFTR expression in fertile men is higher than that in infertile men suffering from teratospermia, asthenoteratospermia, asthenospermia and oligospermia, but it is unknown whether CFTR is correlated with sperm parameters when sperm parameters are normal. In this study, 282 healthy and fertile men with normal semen parameters were classified into three age groups, group (I): age group of 20-29 years (98 cases, 27.1 ± 6.2), group (II): age group of 30-39 years (142 cases, 33.7 ± 2.6) and group (III): age group of more than or equal to 40 years (42 cases, 44.1 ± 4.6). Sperm concentration, total count and progressive motility were analysed by computer-assisted sperm analysis. Sperm morphology was analysed by modified Papanicolaou staining. Sperm CFTR expression was conducted by indirect immunofluorescence staining. There was a significant positive correlation (P < 0.001) between CFTR expression and sperm progressive motility (r = 0.221) and normal morphology (r = 0.202), but there were no correlations between sperm CFTR expression and semen volume, sperm concentration, sperm total count as well as male age (P > 0.05). Our findings show that CFTR expression is associated with sperm progressive motility and normal morphology in healthy and fertile men with normal sperm parameters, but not associated with the number of spermatozoa and male age.

Novel functional magnetic resonance imaging biomarkers for assessing response to therapy in hepatocellular carcinoma.

The established and adapted image biomarkers based on size for tumor burden measurement continue to be applied to hepatocellular carcinoma (HCC) as size measurement can easily be used in clinical practice. However, in the setting of novel targeted therapies and liver directed treatments, simple tumor anatomical changes can be less informative and usually appear later than biological changes. Functional magnetic resonance imaging (MRI) has a potential to be a promising technique for assessment of HCC response to therapy. In this review, we discuss various functional MRI biomarkers that play an increasingly important role in evaluation of HCC response after treatment.

Rapid reuptake of granzyme B leads to emperitosis: an apoptotic cell-in-cell death of immune killer cells inside tumor cells.

A cell-in-cell process refers to the invasion of one living cell into another homotypic or heterotypic cell. Different from non-apoptotic death processes of internalized cells termed entosis or cannibalism, we previously reported an apoptotic cell-in-cell death occurring during heterotypic cell-in-cell formation. In this study, we further demonstrated that the apoptotic cell-in-cell death occurred only in internalized immune killer cells expressing granzyme B (GzmB). Vacuole wrapping around the internalized cells inside the target cells was the common hallmark during the early stage of all cell-in-cell processes, which resulted in the accumulation of reactive oxygen species and subsequent mitochondrial injury of encapsulated killer or non-cytotoxic immune cells. However, internalized killer cells mediated rapid bubbling of the vacuoles with the subsequent degranulation of GzmB inside the vacuole of the target cells and underwent the reuptake of GzmB by killer cells themselves. The confinement of GzmB inside the vacuole surpassed the lysosome-mediated cell death occurring in heterotypic or homotypic entosis processes, resulting in a GzmB-triggered caspase-dependent apoptotic cell-in-cell death of internalized killer cells. On the contrary, internalized killer cells from GzmB-deficient mice underwent a typical non-apoptotic entotic cell-in-cell death similar to that of non-cytotoxic immune cells or tumor cells. Our results thus demonstrated the critical involvement of immune cells with cytotoxic property in apoptotic cell-in-cell death, which we termed as emperitosis taken from emperipolesis and apoptosis. Whereas entosis or cannibalism may serve as a feed-on mechanism to exacerbate and nourish tumor cells, emperitosis of immune killer cells inside tumor cells may serve as an in-cell danger sensation model to prevent the killing of target cells from inside, implying a unique mechanism for tumor cells to escape from immune surveillance.

Production of secoisolariciresinol from defatted flaxseed by bacterial biotransformation.

AIMS: Secoisolariciresinol (SECO) is increasingly recognized for potential clinical application because of its preventive effects against breast and colon cancers, atherosclerosis and diabetes, and its production through biotransformation has been attempted. However, previously reported bacteria all required stringent anaerobic culture conditions, precluding large-scale production. Here, we report the isolation and characterization of bacteria that produce SECO under less stringent anaerobic culture conditions. METHODS AND RESULTS: Using defatted flaxseed as raw material, we isolated a facultative anaerobic bacterium from human faeces that hydrolysed secoisolariciresinol diglucoside-3-hydroxy-3-methyl glutaric acid (SDG-HMGA) oligomers in flaxseed to produce SECO. Both conventional assays and 16S rRNA gene sequence analysis demonstrated its close relatedness with Bacteroides uniformis. The transformation efficiency of SDG in defatted flaxseed to SECO was more than 80% by this bacterial strain. We investigated factors that might influence fermentation, such as redox potential and pH, for large-scale fermentation of defatted flaxseed to produce SECO. CONCLUSIONS: The method to produce SECO through biotransformation of defatted flaxseed with this bacterial strain is highly efficient and economic. SIGNIFICANCE AND IMPACT OF THE STUDY: This bacterial strain can transform SDG to SECO under less stringent anaerobic culture conditions, which will greatly facilitate industry-scale production of SECO.

Novel magnetic chitosan/poly(vinyl alcohol) hydrogel beads: preparation, characterization and application for adsorption of dye from aqueous solution.

Novel magnetic chitosan/poly(vinyl alcohol) hydrogel beads (m-CS/PVA HBs) were prepared by an instantaneous gelation method and characterized by X-ray diffraction (XRD), vibrating sample magnetometry (VSM) and thermogravimetric analysis (TGA). Results of characterization indicated that m-CS/PVA HBs have been prepared successfully without damaging the crystal structure of Fe(3)O(4) and their saturation magnetization were about 21.96 emu g(-1). The adsorption capacity of Congo Red on the m-CS/PVA HBs was 470.1 mg g(-1). The adsorption was well described by pseudo-second-order kinetics and Langmuir equation. Positive value of enthalpy change (ΔH(∘)) (13.32 kJ mol(-1)) showed that the adsorption was endothermic and physical in nature. The values of Gibbs free energy change (ΔG(∘)) were found to be -3.321 kJ mol(-1) at 298 K for m-CS/PVA HBs, indicating the spontaneity of Congo Red adsorption. Therefore, the m-CS/PVA HBs could be employed as a low-cost alternative to other adsorbents in the removal of dyes from aqueous solution.

Development of Composite Adsorbents of Carbon and Intercalated Clay for N2 and O2 Adsorption: A Preliminary Study.

Composite adsorbents of carbon and alumina intercalated montmorillonite were prepared and characterized by adsorption of N2 and O2 at various temperatures. The effects of pyrolysis, temperature, heating rate, subsequent degassing, and doping of cations and anions were investigated. The adsorption capacities of the composite adsorbents developed at higher temperatures (0 and -79 degreesC) are found to be larger than those of normal alumina pillared clays. The experimental results showed that the framework of these adsorbents is made of alumina particles and clay sheets while the pyrolyzed carbon distributes in the space of interlayers and interpillars. The pores between the carbon particles, clay sheets, and alumina pillars are very narrow with very strong adsorption forces, leading to enhanced adsorption capacities at 0 and -79 degreesC. The composite adsorbents exhibit features similar to those of carbonaceous adsorbents. Their pore structures, adsorption capacities, and selectivities to oxygen can be tailored by a controlled degassing procedure. Meanwhile, ions can be doped into the adsorbents to modify their adsorption properties, as usually observed for oxide adsorbents like zeolite and pillared clays. Such flexibility in pore structure tailoring is a potential advantage of the composite adsorbents developed for their adsorption and separation applications. Copyright 1999 Academic Press.

Photocatalytic Properties of Titania Pillared Clays by Different Drying Methods.

Photocatalysts based on titania pillared clays (TiO2 PILCs) have been prepared through a sol-gel method. Different drying methods, air drying (AD), air drying after ethanol extraction (EAD), and supercritical drying (SCD) have been employed and found to have significant effects on the photocatalytic efficiency of the resultant catalysts for the oxidation of phenol in water. Titania pillared clay (TiO2 PILC) obtained by SCD has the highest external and micropore surface area, largest amount and smallest crystallite size of anatase, and exhibited the highest photocatalytic activity. Furthermore, silica titania pillared clay (SiO2-TiO2 PILC) after SCD, titania coated TiO2 PILC (SCD) and SiO2-TiO2 PILC (SCD) were synthesized to study the key factors controlling the photocatalytic activity. It is concluded that the dispersion of nanometer-sized anatase on the surface of the PILC particles and the suspensibility of the particles are the most important factors for high photocatalytic efficiency. Copyright 1999 Academic Press.

Preparation, Characterization, and Catalytic Properties of Clay-Based Nickel Catalysts for Methane Reforming.

Naturally occurring clays and pillared clays are used as supports of nickel catalysts for the methane reforming reaction with carbon dioxide to synthesis gas. The structural and textural characteristics of the supports and catalysts are systematically examined by N2 adsorption/desorption and X-ray diffraction (XRD) techniques. It is found that the pore structures and surface properties of supports greatly affect the catalytic activities of the catalysts prepared. The catalysts supported on the mesoporous clays or pillared clays are obviously superior to those on microporous supports because the mesoporous supports are highly thermal stable compared to the microporous ones. It is found that introducing lanthanum to the supports can improve the catalyst basicity and thus enhance the catalytic activities of these catalysts. Deactivation of catalysts prepared and factors influencing their stability are also discussed. Copyright 1998 Academic Press.