TRAIL sensitize MDR cells to MDR-related drugs by down-regulation of P-glycoprotein through inhibition of DNA-PKcs/Akt/GSK-3β pathway and activation of caspases

<p>Abstract</p> <p>Background</p> <p>The development of new modulator possessing high efficacy, low toxicity and high selectivity is a pivotal approach to overcome P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in cancer treatment. In this study, we suggest a new molecular mechanism that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) down-regulates P-glycoprotein (P-gp) through inhibition of DNA-PKcs/Akt/GSK-3β pathway and activation of caspases and thereby sensitize MDR cells to MDR-related drugs.</p> <p>Results</p> <p>MDR variants, CEM/VLB_10-2, CEM/VLB_55-8and CEM/VLB₁₀₀cells, with gradually increased levels of P-gp derived from human lymphoblastic leukemia CEM cells, were gradually more susceptible to TRAIL-induced apoptosis and cytotoxicity than parental CEM cells. The P-gp level of MDR variants was positively correlated with the levels of DNA-PKcs, pAkt, pGSK-3β and c-Myc as well as DR5 and negatively correlated with the level of c-FLIPs. Hypersensitivity of CEM/VLB₁₀₀cells to TRAIL was accompanied by the activation of mitochondrial apoptotic pathway as well as the activation of initiator caspases. In addition, TRAIL-induced down-regulation of DNA-PKcs/Akt/GSK-3β pathway and c-FLIP and up-regulation of cell surface expression of death receptors were associated with the increased susceptibility to TRAIL of MDR cells. Moreover, TRAIL inhibited P-gp efflux function via caspase-3-dependent degradation of P-gp as well as DNA-PKcs and subsequently sensitized MDR cells to MDR-related drugs such as vinblastine and doxorubicin. We also found that suppression of DNA-PKcs by siRNA enhanced the susceptibility of MDR cells to vincristine as well as TRAIL via down-regulation of c-FLIP and P-gp expression and up-regulation of DR5.</p> <p>Conclusion</p> <p>This study showed for the first time that the MDR variant of CEM cells was hypersensitive to TRAIL due to up-regulation of DR5 and concomitant down-regulation of c-FLIP, and degradation of P-gp and DNA-PKcs by activation of caspase-3 might be important determinants of TRAIL-induced sensitization of MDR cells to MDR-related drugs. Therefore, combination of TRAIL and chemotherapeutic drugs may be a good strategy for treatment of cancer with multidrug resistance.</p

Precise Synthesis of Bottlebrush Block Copolymers from ω-End-Norbornyl Polystyrene and Poly(4-tert-butoxystyrene) via Living Anionic Polymerization and Ring-Opening Metathesis Polymerization

A facile and efficient synthetic grafting-through strategy for preparing well-defined bottlebrush block copolymers (BBCPs) was developed through a combination of living anionic polymerization (LAP) and ring-opening metathesis polymerization (ROMP). ω-End-norbornyl polystyrene (NPSt) and poly(4-tert-butoxystyrene) (NPtBOS) were synthesized by LAP using terminator of chlorine moiety containing silane-protecting amine and coupled with a subsequent amidation using norbornyl activated ester. Bottlebrush homopolymers of NPSt were obtained by ROMP with ultrahigh molecular weights (MWs, M_w = 2928 kDa) and narrow molecular weight distributions (MWDs, Đ = 1.07) at high degree of polymerizations (DP_w = 1084). Well-defined BBCPs with ultrahigh MWs (M_w ∼ 3055 kDa) and narrow MWDs (Đ ∼ 1.13) were synthesized through sequential ROMP of NPSt with NPtBOS. The effect of ultrahigh MWs was investigated by self-assembly of the BBCPs in which the phase-separated BBCPs presented periodic lamellar structures and exhibited structural colors from blue to pink

Precise Synthesis of Bottlebrush Block Copolymers from ω-End-Norbornyl Polystyrene and Poly(4-tert-butoxystyrene) via Living Anionic Polymerization and Ring-Opening Metathesis Polymerization

A facile and efficient synthetic grafting-through strategy for preparing well-defined bottlebrush block copolymers (BBCPs) was developed through a combination of living anionic polymerization (LAP) and ring-opening metathesis polymerization (ROMP). ω-End-norbornyl polystyrene (NPSt) and poly(4-tert-butoxystyrene) (NPtBOS) were synthesized by LAP using terminator of chlorine moiety containing silane-protecting amine and coupled with a subsequent amidation using norbornyl activated ester. Bottlebrush homopolymers of NPSt were obtained by ROMP with ultrahigh molecular weights (MWs, M_w = 2928 kDa) and narrow molecular weight distributions (MWDs, Đ = 1.07) at high degree of polymerizations (DP_w = 1084). Well-defined BBCPs with ultrahigh MWs (M_w ∼ 3055 kDa) and narrow MWDs (Đ ∼ 1.13) were synthesized through sequential ROMP of NPSt with NPtBOS. The effect of ultrahigh MWs was investigated by self-assembly of the BBCPs in which the phase-separated BBCPs presented periodic lamellar structures and exhibited structural colors from blue to pink

Experimental Formulation of Photonic Crystal Properties for Hierarchically Self-Assembled POSS–Bottlebrush Block Copolymers

Rodlike “POSS–bottlebrush block copolymers” (POSSBBCPs) containing crystalline polyhedral oligomeric silsesquioxane (POSS) pendants in A block and amorphous polymeric grafts in B block were utilized to create one-dimensional (1D) photonic crystals (PCs). 3-(12-(cis-5-Norbornene-exo-2,3-dicarboximido)dodecanoylamino)propylheptaisobutyl POSS (NB-A16-POSS, MA) and exo-5-norbornene-2-carbonyl-end poly(benzyl methacrylate) (NBPBzMA, MB) were employed in sequential ring-opening metathesis polymerization to afford poly[3-(12-(cis-5-norbornene-exo-2,3-dicarboximido)dodecanoylamino)propylheptaisobutyl POSS]-block-poly(exo-5-norbornene-2-carbonylate-graft-benzyl methacrylate)s, P(NB-A16-POSS)-b-P(NB-g-BzMA)s, with well-modulated block compositions (fA = 34, 50, and 67 wt %) and overall degrees of polymerization (DP = 323–939). The P(NB-A16-POSS)-b-P(NB-g-BzMA)s hierarchically self-assembled to form highly ordered 1D PC films with periodic lamellar arrays that can reflect visible light with particular wavelengths. Their reflectance bandwidths, reflectivities, and ranges of peak reflectance wavelnegth (λ_(peak)) were largely dependent on the block composition. The 1D PC films based on lamellar P(NB-A16-POSS)-b-P(NB-g-BzMA)s demonstrated the capability of formaulation of λ_(peak) as linear functions of initial polymerization parameter ([M]_0/[I]_0)

Sirolimus-eluting stent is superior to paclitaxel-eluting stent for coronary intervention in patients with renal insufficiency: Long-term clinical outcomes

Background: Renal insufficiency (RI) is an independent risk factor for the adverse cardiovascular events. Long-term clinical outcome of percutaneous coronary intervention (PCI) in patients with RI is unknown especially in the era of first generation drug-eluting stents (DES). This study aims at comparing clinical outcomes between sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) based on large scaled registry.Methods: Patients who underwent PCI with DES from January 2004 to December 2009 in the Catholic University of Korea-PCI (COACT) registry were prospectively enrolled. A group of 1,033 patients with RI, defined as estimated glomerular filtration rate under 60 mL/min, were analyzed. Major adverse cardiac events (MACE), including all-cause death, non-fatal myocardial infarction (MI), target lesion revascularization (TLR), and target vessel revascularization (TVR) according to the type of stents were compared.Results: Median follow-up period was 810 days (interquartile range: from 361 to 1,354 days). A group of 612 (59.2%) patients were treated with SES and 421 (40.8%) patients were treated with PES. The PES vs. SES group had significantly higher rate of MACE (35.9% vs. 28.3%, p = 0.01). In multivariate Cox hazard regression analysis, PES vs. SES group had significantly higher rate of MACE (adjusted hazard ratio [AHR] 1.29, 95% confidence interval [CI] 1.02–1.64, p = 0.033), particularly pronounced by all-cause death (AHR 1.34, 95% CI 1.008–1.770; p = 0.044). In further analysis with propensity score matching, overall findings were consistent.Conclusions: In patients with RI, PCI using PES provides poorer clinical outcomes than SES in terms of MACE and all-cause death

Causes and effects of 2008 financial crisis

Beginning in the mid 2007’s the US financial market started to slide into the “worst financial crisis since the Great Depression of the early 1930’s” (Thakor, 2015: p.156). The domino effect of several events and occasions were leading first to a countrywide recession in the USA then later spreading globally. In the following this term paper will deal with the main causes and effects of 2008 financial crisis. Unlike other topics in literature there is no consensus about the question of guilt in this sense. Among economists there are different approaches to explain the main causes of the financial crisis

Five-Year Subjective Outcomes of Obstructive Sleep Apnea Surgery: A Multiinstitutional Study

ObjectivesTo evaluate the effect of obstructive sleep apnea (OSA) surgery on long-term (5-year) subjective outcomes, including sleep disordered breathing (SDB) symptoms and other complications, in patients with OSA.MethodsWe enrolled patients who underwent diagnostic polysomnography for OSA between January 2006 and December 2006 in ten hospitals. Patients either were treated for OSA or were not treated for OSA. All patients completed a brief telephone survey regarding their SDB signs and symptoms (e.g., snoring, apnea, nocturnal arousals, and daytime sleepiness), positive airway pressure (PAP) compliance, and any adverse effects of either the surgery or PAP. A positive subjective outcome for either surgery or no treatment was taken to be the alleviation of apnea, defined as a ≥50% increase in score. A positive subjective outcome (compliance) for PAP was defined as a PAP usage of ≥4 hours per night and ≥5 days per week.ResultsA total of 229 patients were included in this study. Patients were divided into three groups: a surgery group (n=87), a PAP group (n=68), and a control (untreated) group (n=74). The surgery group exhibited significant improvement in all SDB symptoms compared with the control group. The long-term subjective outcomes of the surgery (52.9%) and PAP (54.4%) groups were significantly better than those of the control group (25.0%). The subjective outcome of the surgery group was not significantly different from that of the PAP group. The overall surgical complication rate was 23.0% (20 of 87) in the surgery group, and 55.0% (22 of 40) of all patients with PAP experienced adverse effects.ConclusionThe extent of SDB symptoms was consistently improved in patients with OSA at 5 years postsurgery. Information about the potential long-term subjective outcomes should be provided to patients when considering surgery

Environmental Remediation and Conversion of Carbon Dioxide (CO2) into Useful Green Products by Accelerated Carbonation Technology

This paper reviews the application of carbonation technology to the environmental industry as a way of reducing carbon dioxide (CO2), a green house gas, including the presentation of related projects of our research group. An alternative technology to very slow natural carbonation is the co-called ‘accelerated carbonation’, which completes its fast reaction within few hours by using pure CO2. Carbonation technology is widely applied to solidify or stabilize solid combustion residues from municipal solid wastes, paper mill wastes, etc. and contaminated soils, and to manufacture precipitated calcium carbonate (PCC). Carbonated products can be utilized as aggregates in the concrete industry and as alkaline fillers in the paper (or recycled paper) making industry. The quantity of captured CO2 in carbonated products can be evaluated by measuring mass loss of heated samples by thermo-gravimetric (TG) analysis. The industrial carbonation technology could contribute to both reduction of CO2 emissions and environmental remediation

Association between cord blood 25-hydroxyvitamin D concentrations and respiratory tract infections in the first 6 months of age in a Korean population: a birth cohort study (COCOA)

PurposePrevious studies suggest that the concentration of 25-hydroxyvitamin D [25(OH)D] in cord blood may show an inverse association with respiratory tract infections (RTI) during childhood. The aim of the present study was to examine the influence of 25(OH)D concentrations in cord blood on infant RTI in a Korean birth cohort.MethodsThe levels of 25(OH)D in cord blood obtained from 525 Korean newborns in the prospective COhort for Childhood Origin of Asthma and allergic diseases were examined. The primary outcome variable of interest was the prevalence of RTI at 6-month follow-up, as diagnosed by pediatricians and pediatric allergy and pulmonology specialists. RTI included acute nasopharyngitis, rhinosinusitis, otitis media, croup, tracheobronchitis, bronchiolitis, and pneumonia.ResultsThe median concentration of 25(OH)D in cord blood was 32.0 nmol/L (interquartile range, 21.4 to 53.2). One hundred and eighty neonates (34.3%) showed 25(OH)D concentrations less than 25.0 nmol/L, 292 (55.6%) showed 25(OH)D concentrations of 25.0-74.9 nmol/L, and 53 (10.1%) showed concentrations of ≥75.0 nmol/L. Adjusting for the season of birth, multivitamin intake during pregnancy, and exposure to passive smoking during pregnancy, 25(OH)D concentrations showed an inverse association with the risk of acquiring acute nasopharyngitis by 6 months of age (P for trend=0.0004).ConclusionThe results show that 89.9% of healthy newborns in Korea are born with vitamin D insufficiency or deficiency (55.6% and 34.3%, respectively). Cord blood vitamin D insufficiency or deficiency in healthy neonates is associated with an increased risk of acute nasopharyngitis by 6 months of age. More time spent outdoors and more intensified vitamin D supplementation for pregnant women may be needed to prevent the onset of acute nasopharyngitis in infants