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- Metformin Does not Reduce Markers of Cell Proliferation in Esophageal Tissues of Patients with Barrett's Esophagus. [JOURNAL ARTICLE]
- Clin Gastroenterol Hepatol 2014 Sep 10.
& Aims: Obesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's Esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1) -- a biomarker of insulin pathway activation.Seventy-four subjects with BE (mean age 58.7 years; 58 men [78%0; 52 with BE>2 cm [70%] were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4; n=38) or placebo (n=36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary endpoint.The percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs - 14.7% among subjects given placebo; 1-sided P=.80). Metformin was associated with an almost significant reduction in serum levels of insulin (median -4.7% among subjects given metformin vs 23.6% increase among those given placebo, P=.08) as well as in homeostatic model assessments of insulin resistance (median -7.2% among subjects given metformin vs 38% increase among those given placebo, P=.06). Metformin had no effects on cell proliferation (based on assays for KI67) or apoptosis (based on levels of caspase 3).In a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis. ClinicalTrials.gov number, NCT01447927.
- Monolithic molecularly imprinted polymeric capillary columns for isolation of aflatoxins. [JOURNAL ARTICLE]
- J Chromatogr A 2014 Aug 30.
Monolithic molecularly imprinted polymers extraction columns have been prepared in fused-silica capillaries by UV or thermal polymerization in a two-step process. First, a poly-(trimethylolpropane trimethacrylate) (polyTRIM) core monolith was synthesized either by UV or thermal polymerization. Then it was grafted with the mixture of methacrylic acid (MAA) as a functional monomer, ethylene dimethacrylate (EDMA) as a cross-linking agent, 5,7-dimethoxycoumarin (DMC) as an aflatoxin-mimicking template, toluene as a porogen solvent and 2,2-azobis-(2-methylpropionitrile) (AIBN) as an initiator of the polymerization reaction. Different thermal condition of the photografting and different concentrations of the grafting mixture were tested during polymerization. The extraction capillary columns were evaluated in the terms of their hydrodynamic and chromatographic properties. Retention coefficients for aflatoxin B1 and DMC were used for assessment of the selectivity and imprinting factor. The obtained results indicate that the temperature of photografting and concentration of the grafting mixture are key parameters that determine the quality of the prepared MIPs. From the MIP columns characterized by the highest permeability the column of the highest imprinting factor was applied for isolation of aflatoxins B1, B2, G1 and G2 from the model aqueous sample followed by on-line chromatographic separation. The process was performed using a micro-MISPE-microLC-LIF system of a novel design, which allowed for detection of the eluates from the sample preparation part as well as from the chromatographic separation.
- Inhibition of JNK2 and JNK3 by JNK inhibitor IX induces prometaphase arrest-dependent apoptotic cell death in human Jurkat T cells. [JOURNAL ARTICLE]
- Biochem Biophys Res Commun 2014 Sep 10.
Exposure of human Jurkat T cells to JNK inhibitor IX (JNKi), targeting JNK2 and JNK3, caused apoptotic DNA fragmentation along with G2/M arrest, phosphorylation of Bcl-2, Mcl-1, and Bim, Δψm loss, and activation of Bak and caspase cascade. These JNKi-induced apoptotic events were abrogated by Bcl-2 overexpression, whereas G2/M arrest, cyclin B1 up-regulation, Cdk1 activation, and phosphorylation of Bcl-2 family proteins were sustained. In the concomitant presence of the G1/S blocking agent aphidicolin and JNKi, the cells underwent G1/S arrest and failed to induce all apoptotic events. The JNKi-induced phosphorylation of Bcl-2 family proteins and mitochondrial apoptotic events were suppressed by the Cdk1 inhibitor. Immunofluorescence microscopic analysis revealed that mitotic spindle defect and prometaphase arrest were the underlying factors for the G2/M arrest. These results demonstrate that JNKi-induced mitochondrial apoptosis was caused by microtubule damage-mediated prometaphase arrest, prolonged Cdk1 activation, and phosphorylation of Bcl-2 family proteins in Jurkat T cells.
- The effects of organic solvents on the membrane-induced fibrillation of human islet amyloid polypeptide and on the inhibition of the fibrillation. [JOURNAL ARTICLE]
- Biochim Biophys Acta 2014 Sep 9.
The organic solvent dimethylsulphoxide (DMSO) and 1,1,1,3,3,3-hexafluoro-2-isopropanol (HFIP) have been widely used as a pre-treating agent of amyloid peptides and as a vehicle for water-insoluble inhibitors. These solvents are left in many cases as a trace quantity in bulk and membrane environments with treated amyloid peptides or inhibitors. In the present work, we studied the effects of the two organic solvents on the aggregation behaviors of human islet amyloid polypeptide (hIAPP) and the performances of an all-D-amino-acid inhibitor D-NFGAIL in preventing hIAPP fibrillation both in bulk solution and at phospholipid membrane. We showed that the presence of 1% v/v DMSO or HFIP decreases the rate of fibril formation of hIAPP at lipid membrane rather than accelerates the fibril formation as what happened in bulk solution. We also showed that the presence of 1% v/v DMSO or HFIP impairs the activity of the inhibitor at lipid membrane surface dramatically, while it affects the efficiency of the inhibitor in bulk solution slightly. We found that the inhibitor inserts into lipid membrane more deeply or with more proportion in the presence of the organic solvents than it does in the absence of the organic solvents, which may hinder the binding of the inhibitor to hIAPP at lipid membrane. Our results suggest that the organic solvents should be used with caution in studying membrane-induced fibrillogenesis of amyloid peptides and in testing amyloid inhibitors under membrane environments to avoid incorrect evaluation to the fibrillation process of amyloid peptides and the activity of inhibitors.
- Semi-interpenetrating hybrid membranes containing ADOGEN(®) 364 for Cd(II) transport from HCl media. [JOURNAL ARTICLE]
- J Hazard Mater 2014 Sep 3.:603-611.
Cd(II) transport from 1moldm(-3) HCl media was investigated across semi-interpenetrating hybrid membranes (SIHMs) that were prepared by mixing an organic matrix composed of ADOGEN(®) 364 as an extracting agent, cellulose triacetate as a polymeric support and nitrophenyloctyl ether as a plasticizer with an organic/inorganic network (silane phase, SP) composed of polydimethylsiloxane and a crosslinking agent. The stripping phase used was a 10(-2)moldm(-3) ethanesulfonic acid solution. The effects of tetraorthoethoxysilane, phenyltrimethoxysilane and N',N'-bis[3-tri(methoxysilyl)propyl]ethylendiamine as crosslinking agents on the transport were studied. H3PO4 was used as an acid catalyst during the SP synthesis and optimized for transport performance. Solid-liquid extraction experiments were performed to determine the model that describe the transport of Cd(II) via ADOGEN(®) 364. The transport was found to be chained-carrier controlled with a percolation threshold of 0.094mmolg(-1). The selective recovery of Cd(II) was studied with respect to Ni(II), Zn(II), Cu(II), and Pb(II) at a 1:1 molar ratio, and the optimized membrane system was applied for the recovery of Cd(II) from a real sample consisting of a Ni/Cd battery with satisfactory results. Finally, stability experiments were performed using the same membrane for 14 cycles. The results obtained showed that SIHMs had excellent stability and selectivity, with permeabilities comparable to those of PIMs.
- Antimetastasis and antitumor efficacy promoted by sequential release of vascular disrupting and chemotherapeutic agents from electrospun fibers. [JOURNAL ARTICLE]
- Int J Pharm 2014 Sep 10.
The vasculature in tumor microenvironment plays important roles in the tumor growth and metastasis, and the combination of vascular disrupting agents with chemotherapeutic drugs should be effective in inhibiting tumor progression. But the dosing schedules are essential to achieve a balance between vascular collapse and intratumoral uptake of chemotherapeutic agents. In the current study, emulsion and blend electrospinning were used to create compartmental fibers accommodating both combretastatin A-4 (CA4) and hydroxycamptothecin (HCPT). The release durations of CA4 and HCPT were modulated through the structure of fibers for dual drug loadings and the inoculation of 2-hydroxypropyl-β-cyclodextrin in fiber matrices. Under a noncontact cell coculture in Transwell, the sequential release of CA4 and HCPT indicated a sequential killing of endothelial and tumor cells. In an orthotopic breast tumor model, all the CA4/HCPT-loaded fibers showed superior antitumor efficacy and higher survival rate than fibers with loaded individual drug. Compared with fibrous mats with infiltrated free CA4 and fibers with extended release of CA4 for over 30 days, fibers with sustained release of CA4 for 3-7 days from CA4/HCPT-loaded fibers resulted in the most significant antitumor efficacy, tumor vasculature destruction, and the least tumor metastasis to lungs. A judicious selection of CA4 release durations in the combination therapy should be essential to enhance the tumor suppression efficacy and antimetastasis activity.
- Piceatannol promotes apoptosis via up-regulation of microRNA-129 expression in colorectal cancer cell lines. [JOURNAL ARTICLE]
- Biochem Biophys Res Commun 2014 Sep 8.
Piceatannol, a naturally occurring analog of resveratrol, has been confirmed as an antitumor agent by inhibiting proliferation, migration, and metastasis in diverse cancer. However, the effect and mechanisms of piceatannol on colorectal cancer (CRC) have not been well understood. This study aimed to test whether piceatannol could inhibit growth of CRC cells and reveal its underlying molecular mechanism. MTT assay was used to detect the cell viability in HCT116 and HT29 cells. Flow cytometry analysis was employed to measure apoptosis of CRC cells. Bcl-2, Bax and caspase-3 levels were analyzed by Western blot and miR-129 levels were determined by real-time RT-PCR. Our study showed that piceatannol inhibited HCT116 and HT29 cells growth in a concentration- and time-dependent manner. Piceatannol induced apoptosis by promoting expression of miR-129, and then inhibiting expression of Bcl-2, an known target for miR-129. Moreover, knock down of miR-129 could reverse the reduction of cell viability induced by piceatannol in HCT116 and HT29 cells. Taken together, our study unraveled the ability of piceatannol to suppress colorectal cancer growth and elucidated the participation of miR-129 in the anti-cancer action of piceatannol. Our findings suggest that piceatannol can be considered to be a promising anticancer agent for CRC.
- Emergence of quinupristin/dalfopristin resistance among livestock-associated Staphylococcus aureus ST9 clinical isolates. [JOURNAL ARTICLE]
- Int J Antimicrob Agents 2014 Aug 17.
Quinupristin/dalfopristin (Q/D) is a valuable alternative to vancomycin for the treatment of meticillin-resistant Staphylococcus aureus (MRSA) infections. However, not long after Q/D was approved, bacteria with resistance to this newer antimicrobial agent were reported. To investigate the prevalence of Q/D resistance, a total of 1476 non-duplicate S. aureus isolates, including 775 MRSA, from a Chinese tertiary hospital were selected randomly from 2003 to 2013. Of the 775 MRSA, 3 (0.4%) were resistant to Q/D. All meticillin-susceptible S. aureus were susceptible to Q/D. The prevalence of Q/D resistance among S. aureus was 0.2% (3/1476). The three isolates with Q/D resistance had the same antimicrobial resistance profile, except for cefaclor and chloramphenicol. All three Q/D-resistant MRSA were positive for five streptogramin B resistance genes (ermA, ermB, ermC, msrA and msrB) and two streptogramin A resistance genes (vatC and vgaA) as determined by PCR and DNA sequencing. MRSA WZ1031 belonged to ST9-MRSA-SCCmecV-t899, whilst MRSA WZ414 and WZ480 belonged to ST9-MRSA-SCCmecNT(non-typeable)-t899. ST9 has been reported predominantly in livestock-associated (LA) MRSA in some Asian countries. The three patients with these MRSA isolates were not livestock handlers and did not keep close contact with livestock. The origin of these important LA-MRSA isolates causing human infections is not known. Taken together, Q/D resistance, which was caused by a combination of ermA-ermB-ermC-msrA-msrB-vatC-vgaA, was first found among S. aureus clinical isolates in China. The present study is the first report of the emergence of human infections caused by ST9 LA-MRSA isolates with Q/D resistance.
- A systems science approach to fatigue management in research and health care. [JOURNAL ARTICLE]
- Nurs Outlook 2014 September - October; 62(5):313-321.
The purpose of this article was to highlight innovative analytic approaches in symptom science. Complex systems modeling is discussed using fatigue as an example. Fatigue is a common symptom among individuals of any age. It can be acute or chronic, and it can vary across the day and on weekends compared with weekdays. Fatigue can overlap with other symptoms, has many dimensions, and impacts daily function as well as society at large. With the complexities surrounding symptom science, innovative models are needed to advance our understanding of factors within the person, contextual and situational factors, and workplace or health care system factors that impact the symptom experience. Advances in methodologies, such as complex systems modeling, allow for more innovative methods to study the complexities of the symptom experience, design better ways to intervene and manage symptoms, and ultimately improve outcomes related to symptom management, quality of life, and health care utilization.
- Inhibition of 32Dp210 cells harboring T315I mutation by a novel derivative of emodin correlates with down-regulation of BCR-ABL and its downstream signaling pathways. [JOURNAL ARTICLE]
- J Cancer Res Clin Oncol 2014 Sep 14.
The clinical outcome of chronic myeloid leukemia (CML) patients has been changed dramatically due to the development of imatinib (IM). However, the emergence of IM resistance, commonly associated with point mutations within the BCR-ABL kinase domain, remains a major clinical problem. Here, we investigated the effects of E35, a novel derivative of emodin, on the IM-resistant 32Dp210-T315I cells.Cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide and colony formation assay. Induction of apoptosis was confirmed by DNA fragmentation assay and annexin V/PI staining assay. Real-time quantitative PCR was used to access the BCR-ABL gene expression. Changes of related signaling molecules were detected through Western blot.E35 was found to potently inhibit proliferation of 32Dp210-T315I cells with an average IC50 of 2.4 µM at 48 h. Colony formation was almost fully suppressed in 1.0 μM E35 group. DNA fragmentation and annexin V/PI staining assay exhibited the typical DNA fragmentation and the increased proportion of early apoptotic cells, respectively. The induction of apoptosis was associated with increase of Bax to Bcl-2 expression ratio and activation of caspase cascades involving decrease of pro-caspase 9 and pro-caspase 3 and increase of PARP cleavage. The protein expression of P210(BCR-ABL) and p-P210(BCR-ABL) was down-regulated in the presence of E35, although the mRNA levels remained almost unchanged. Moreover, the activation of the P210(BCR-ABL) downstream signaling pathways including CrkL, Akt/mTOR and MEK/ERK was fully suppressed by E35.Our study indicated that E35 might be a potential antileukemia agent against IM resistance in CML.