[Show abstract][Hide abstract] ABSTRACT: Background:
The human immunodeficiency virus type-1 (HIV-1) nucleocapsid protein (NC) is an essential and multifunctional protein involved in multiple stages of the viral life cycle such as reverse transcription, integration of proviral DNA, and especially genome RNA packaging. For this reason, it has been considered as an attractive target for the development of new anti-HIV drugs. Although a number of inhibitors of NC have been reported thus far, the search for NC-specific and functional inhibitor(s) with a good antiviral activity continues.
In this study, we report the identification of A1752, a small molecule with inhibitory action against HIV-1 NC, which shows a strong antiviral efficacy and an IC50 around 1 μM. A1752 binds directly to HIV-1 NC, thereby inhibiting specific chaperone functions of NC including Psi RNA dimerization and complementary trans-activation response element (cTAR) DNA destabilization, and it also disrupts the proper Gag processing. Further analysis of the mechanisms of action of A1752 also showed that it generates noninfectious viral particles with defects in uncoating and reverse transcription in the infected cells.
These results demonstrate that A1752 is a specific and functional inhibitor of NC with a novel mode of action and good antiviral efficacy. Thus, this agent provides a new type of anti-HIV NC inhibitor candidate for further drug development.
[Show abstract][Hide abstract] ABSTRACT: Background:
The incidence of herpes zoster is substantial during bortezomib treatment in patients with multiple myeloma (MM).
This study aimed to elucidate the effect of chemotherapy with or without bortezomib in MM patients on their herpes zoster incidence and varicella zoster virus (VZV)-specific cell-mediated immunity (CMI).
Peripheral blood mononuclear cells were collected at baseline and after 1 month of bortezomib-based or thalidomide-based chemotherapy and then analyzed using VZV-specific interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assay. The clinical data from these patients were analyzed in relation to the ELISPOT results.
Of 58 patients analyzed, 39 patients received bortezomib and the other 19 patients, thalidomide. Among them, 5 patients developed herpes zoster during chemotherapy; all 5 were being treated with the bortezomib-based regimen and were not receiving prophylactic anti-viral agents. The median onset of herpes zoster was 32 days (range, 15-95 days) from the initiation of chemotherapy. Among patients who received bortezomib therapy, acyclovir prophylaxis significantly reduced the risk for herpes zoster (100-day cumulative incidence, 0% vs. 49.5%; p<0.001). Spot-forming cell (SFC) counts in the IFN-γ ELISPOT assay decreased from baseline after bortezomib (p=0.011) or thalidomide (p=0.096) treatment. Patients with baseline SFCs greater than 20/10(6) mononuclear cells exhibited significantly higher incidence of herpes zoster (100-day cumulative incidence, 34.8% vs. 0%; p=0.040).
Bortezomib treatment significantly reduced VZV-specific CMI, and high baseline SFC counts in patients receiving this treatment without acyclovir prophylaxis were associated with a significantly increased risk for herpes zoster.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 10/2015; 73. DOI:10.1016/j.jcv.2015.10.018 · 3.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Decursin, a bioactive phytochemical isolated from Angelica gigas Nakai (danggwi), has shown preclinical anticancer efficacy in various cancer models. However, the antitumor effect of decursin in melanoma models remains undefined. The antitumor activities of decursin were investigated in B16F10 cells in vitro and in vivo. In this study, we show that treatment with decursin inhibited cell proliferation in a dose-dependent manner in B16F10 cells, but not in normal cells. Decursin also induced apoptosis in B16F10 cells, as determined by annexin V-staining assay and transferase-mediated nick-end labeling (TUNEL) staining assay. Decursin increased the phosphorylation of p38 as well as the expression of Bax while decreasing the phosphorylation of extracellular signaling-regulated kinase (ERK) and the expression of Bcl-2 in B16F10 cells. Moreover, decursin activated caspase-3 in B16F10 cells and xenograft tumor tissue. Together, these findings support further investigations into the potential use of decursin in the treatment of melanoma cells.
[Show abstract][Hide abstract] ABSTRACT: Background/objectives:
The effect of aspirin and clopidogrel in a fixed-dose combination (FDC) on platelet function was compared with separate formulations in patients that had undergone percutaneous coronary intervention (PCI) with drug-eluting stent (DES).
This was a phase IV, prospective, multicenter, single-arm, non-inferiority study. Patients that had taken aspirin 100mg and clopidogrel 75mg once daily as separate formulations for >6months after PCI with DES were enrolled, and then switched to an aspirin/clopidogrel FDC once-daily for 4weeks. Platelet reactivity was determined using the VerifyNow® P2Y12 assay at baseline (immediately prior to switching) and 4weeks later.
A total of 648 patients (the full-analysis population; age, 63.6±9.0years; male, 76.5%) finished the study, and 565 (the per-protocol population) completed without protocol violations. In the per-protocol population, the % inhibitions of P2Y12 and ARU were not significantly different between baseline and after 4weeks of FDC treatment (29.2±20.0% to 29.0±19.9%, P=0.708; 445.1±69.2 to 446.2±63.0, P=0.799, respectively) and the difference in P2Y12 inhibition observed did not exceed the predetermined limit of non-inferiority (95% CI, -0.9 to 1.3). In the full-analysis population, the % inhibitions of P2Y12, PRU, and ARU were not significantly changed after 4weeks of FDC treatment.
This study demonstrates that the efficacy of platelet inhibition by an aspirin/clopidogrel FDC was not inferior to that of separate aspirin and clopidogrel formulations in patients that had undergone PCI with DES.
International journal of cardiology 09/2015; 202. DOI:10.1016/j.ijcard.2015.09.024 · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The propagation of human pluripotent stem cells (hPSCs) in conditioned medium derived from human cells in feeder-free culture conditions has been of interest. Nevertheless, an ideal humanized ex vivo feeder-free propagation method for hPSCs has not been developed; currently, additional exogenous substrates including basic fibroblast growth factor (bFGF), a master hPSC-sustaining factor, is added to all of culture media and synthetic substrata such as Matrigel or laminin are used in all feeder-free cultures. Recently, our group developed a simple and efficient protocol for the propagation of hPSCs using only conditioned media derived from the human placenta on a gelatin-coated dish without additional exogenous supplementation or synthetic substrata specific to hPSCs. This protocol has not been reported previously and might enable researchers to propagate hPSCs efficiently in humanized culture conditions. Additionally, this model obviates hPSC contamination risks by animal products such as viruses or unknown proteins. Furthermore, this system facilitates easy mass production of hPSCs using the gelatin coating, which is simple to handle, dramatically decreases the overall costs of ex vivo hPSC maintenance.
[Show abstract][Hide abstract] ABSTRACT: This article considers the unrelated parallel machine scheduling problem with sequence- and machine-dependent setup times and machine-dependent processing times. Furthermore, the machine has a production availability constraint to each job. The objective of this problem is to determine the allocation policy of jobs and the scheduling policy of machines to minimize the total completion time. To solve the problem, a mathematical model for the optimal solution is derived, and hybrid genetic algorithms with three dispatching rules are proposed for large-sized problems. To assess the performance of the algorithms, computational experiments are conducted and evaluated using several randomly generated examples.
[Show abstract][Hide abstract] ABSTRACT: One of the most important operational management problems of a cross docking system is the truck scheduling problem. Cross docking is a logistics management concept in which products delivered to a distribution center by inbound trucks are immediately sorted out, routed and loaded into outbound trucks for delivery to customers. The truck scheduling problem in a multi-door cross docking system considered in this paper comprises the assignment of trucks to dock doors and the determination of docking sequences for all inbound and outbound trucks in order to minimize the total operation time. A mathematical model for optimal solution is derived, and the genetic algorithms (GAs) and the adaptive genetic algorithms (AGAs) as solution approaches with different types of chromosomes are proposed. The performance of the meta-heuristic algorithms are evaluated using randomly generated several examples.
Asia Pacific Journal of Operational Research 06/2015; 32(03):1550016. DOI:10.1142/S0217595915500165 · 0.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We compared the efficacy of high-dose cytarabine alone to that of intermediate-dose cytarabine combined with anthracyclines as consolidation therapy. Patients enrolled in the Korea University acute myeloid leukemia (AML) registry received remission induction chemotherapy with the same standard induction regimen (idarubicin and cytarabine 3 + 7). Postremission therapy was performed for three or four cycles according to one of the following regimens: high-dose cytarabine (3 g/m(2)) or combination of intermediate-dose cytarabine (1 g/m(2)) with anthracyclines (idarubicin or mitoxantrone). Among the 443 AML patients enrolled in the registry, 145 patients received consolidation chemotherapy. The median overall survival (OS) and relapse-free survival (RFS) in the high-dose cytarabine group were significantly longer than those in the anthracycline combination group (OS, not reached vs. 16.6 months, p = 0.045; RFS, 38.6 months vs. 11.0 months, p = 0.011). The median duration of neutropenia was longer in the anthracycline combination group than in the high-dose cytarabine group (8 vs. 10 days, p = 0.001). This study suggests that high-dose cytarabine consolidation may produce superior outcomes than combination treatment with intermediate-dose cytarabine and anthracyclines and that the addition of anthracyclines during AML consolidation has limited value as compared to cytarabine intensification.
Annals of Hematology 05/2015; 94(9). DOI:10.1007/s00277-015-2389-9 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We compared the efficacy and safety of valsartan and rosuvastatin combination therapy with each treatment alone in hypercholesterolemic hypertensive patients.
Patients who met inclusion criteria were randomized to receive 1 of the following 2-month drug regimens: valsartan 160 mg plus rosuvastatin 20 mg, valsartan 160 mg plus placebo, or rosuvastatin 20 mg plus placebo. The primary efficacy variables were change in sitting diastolic blood pressure (sitDBP) and sitting systolic blood pressure (sitSBP), and percentage change in low-density lipoprotein-cholesterol (LDL-C) in the combination, valsartan, and rosuvastatin groups. Adverse events (AEs) during the study were analyzed.
A total of 354 patients were screened and 123 of them were finally randomized. Changes of sitDBP by least squares mean (LSM) were -11.1, -7.2, and -3.6 mm Hg, respectively, and was greater in the combination, as compared to both valsartan (p=0.02) and rosuvastatin (p<0.001). Changes of sitSBP by LSM were -13.2, -10.8, and -4.9 mm Hg, and was greater in the combination, as compared to rosuvastatin (p=0.006) and not valsartan (p=0.42). Percentage changes of LDL-C by LSM were -52, -4, and -47% in each group, and was greater in the combination, as compared to valsartan (p<0.001), similar to rosuvastatin (p=0.16). Most AEs were mild and resolved by the end of the study.
Combination treatment with valsartan and rosuvastatin exhibited an additive blood pressure-lowering effect with acceptable tolerability, as compared to valsartan monotherapy. Its lipid lowering effect was similar to rosuvatatin monotherapy.
Korean Circulation Journal 05/2015; 45(3):225-33. DOI:10.4070/kcj.2015.45.3.225 · 0.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The first edition of the Korean treatment guidelines for chronic myelogenous leukemia (CML) was published in 2006. We intend to update those guidelines to include the use of next-generation tyrosine kinase inhibitors (TKIs).
[Show abstract][Hide abstract] ABSTRACT: In this paper, we consider a single machine scheduling problems integrating with deterioration effect and rate-modifying activities (RMAs). The scheduling problem assumes that the machine may have multiple RMAs and each job has the processing time with deterioration effect increased depending upon the gap between recent RMA and starting time of the job. In practical industrial applications, the determination of the number and position of RMAs is a critical issue, because the RMAs recover deteriorated processing time of jobs bringing back to normal processing time. In this paper, we simultaneously determine the schedule of time-dependent deteriorating jobs and the number and positions of RMAs to minimize the makespan. To solve the problem, a mathematical model is derived to obtain the optimal solution and hybrid meta-heuristic algorithms are proposed for the problem. The performance of the algorithms is compared using randomly generated examples.
Journal of Advanced Mechanical Design Systems and Manufacturing 01/2015; 9(1):JAMDSM0007-JAMDSM0007. DOI:10.1299/jamdsm.2015jamdsm0007 · 0.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Despite the advances in acute myeloid leukemia (AML) treatment, the prognosis of elderly patients remains poor and no definitive treatment guideline has been established. In the present study, we aimed to evaluate the effectiveness of intensive chemotherapy in elderly AML patients and to determine which subgroup of patients would be most responsive to the therapy.
We retrospectively analyzed 84 elderly patients: 35, 19, and 30 patients were administered intensive chemotherapy, low-dose chemotherapy, and supportive care, respectively.
Among those who received intensive chemotherapy, there were 17 cases of remission after induction chemotherapy; treatment-related mortality was 22.9%. The median overall survival was 7.9 months. Multivariate analysis indicated that the significant prognostic factors for overall survival were performance status, fever before treatment, platelet count, blast count, cytogenetic risk category, and intensive chemotherapy. Subgroup analysis showed that intensive chemotherapy was markedly effective in the relatively younger patients (65-70 years) and those with de novo AML, better-to-intermediate cytogenetic risk, no fever before treatment, high albumin levels, and high lactate dehydrogenase levels.
Elderly AML patients had better outcomes with intensive chemotherapy than with low-intensity chemotherapy. Thus, appropriate subgroup selection for intensive chemotherapy is likely to improve therapeutic outcome.
[Show abstract][Hide abstract] ABSTRACT: Here we report a new chemical inhibitor against HIV-1 with a novel structure and mode of action. The inhibitor, designated as A1836, inhibited HIV-1 replication and virus production with a 50% inhibitory concentration (IC50) of 2.0 µM in an MT-4 cell-based and cytopathic protection antiviral assay, while its 50% cytotoxic concentration (CC50) was much higher than 50 µM. Examination of the effect of A1836 on in vitro HIV-1 reverse transcriptase (RT) and integrase showed that neither were molecular targets of A1836. The characterization and re-infection assay of the HIV-1 virions generated in the presence of A1836 showed that the synthesis of early RT products in the cells infected with the virions was inhibited dose-dependently, due in part to abnormal protein formation within the virions, thus resulting in an impaired infectivity. These results suggest that A1836 might be a novel candidate for the development of a new type of HIV-1 inhibitor.
[Show abstract][Hide abstract] ABSTRACT: Basic fibroblast growth factor (bFGF) is a crucial factor sustaining human pluripotent stem cells (hPSCs). We designed this study to search the substitutive factors other than bFGF for the maintenance of hPSCs by using human placenta-derived conditioned medium without exogenous bFGF (hPCCM-), containing CXCR2 ligands including IL-8 and GROα, which was developed on the basis of our previous studies. Firstly, we confirmed that IL-8 and/or GROα play independent roles to preserve the phenotype of hPSCs. And, we tried CXCR2 blockage of hPSCs in hPCCM- and verified the significant decrease of pluripotency-associated genes expression and the proliferation of hPSCs. Interestingly, CXCR2 suppression of hPSCs in mTeSR™1 containing exogenous bFGF decreased the proliferation of hPSCs with maintaining pluripotency characteristics. Lastly, we found that hPSCs proliferated robustly for more than 35 passages in hPCCM- on a gelatin substratum. As well, the higher CXCR2 expression of hPSCs cultured in hPCCM- than those in mTeSR™1 was observable. Our findings suggest that, CXCR2 and its related ligands might be novel factors comparable to bFGF supporting the characteristics of hPSCs and hPCCM- might be useful for the maintenance of hPSCs as well as for the accurate evaluation of CXCR2 role on hPSCs without the confounding influence of exogenous bFGF.
Stem Cells and Development 11/2014; 24(8). DOI:10.1089/scd.2014.0381 · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lymphoma, especially non-Hodgkin's lymphoma is extremely rare in pregnancy. A 24-year-old pregnant woman was diagnosed with diffuse large B-cell lymphoma (DLBCL), a subgroup of non-Hodgkin's lymphoma, at 24 weeks' gestation, and was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. After 4 cycles of R-CHOP, she delivered a healthy baby via cesarean section at 34 weeks and 5 days' gestation because of preterm contraction-related fetal distress. The patient was administered the remaining 2 cycles of R-CHOP after delivery. Follow-up magnetic resonance imaging and computed tomography showed complete remission. Here, we report a rare case of DLBCL successfully treated with R-CHOP chemotherapy during pregnancy, we also performed a systematic review of literature for similar cases. There were 3 earlier reports of R-CHOP treatment for DLBCL. All cases, including our case, resulted in preterm birth. Together, these findings suggest that R-CHOP chemotherapy for DLBCL in pregnancy may be associated with preterm birth.