Does Outcome/Survival of Patients With Myelodysplastic Syndromes Should Be Predicted by Reduced Levels of ADAMTS-13? Results From a Pilot Study

IntroductionVon Willebrand factor (vWF) cleaving protease ADAMTS-13 has a key role for maintaining normal size of vWF. A deficiency or dysfunction of vWF cleaving protease is associated with ultra large vWF multimers and thrombotic microangiopathy. Patients with cancers have reduced levels of vWF cleaving protease. In this pilot study, we have evaluated whether or not deficiencies of ADAMTS-13 were present in myelodysplastic syndromes (MDS). Moreover, we assessed if a reduction in basal levels of ADAMTS-13 may play a role in the prognosis of MDS.Patients and MethodsWe measured and compared the levels of vWF cleaving protease ADAMTS-13 in 100 patients with MDS and 35 healthy controls. Patients were divided into 2 groups according to the International Prognostic Scoring System: group I consisting of 44 patients with low-risk MDS and group II of 56 patients with high-risk MDS. Patients with high-risk and low-risk MDS presented significantly lower levels of ADAMTS-13 than controls (P < .001 and P = .0177, respectively). High-risk patients had significantly lower levels of ADAMTS-13 when compared with the low-risk group (P < .001).ResultsWe found that reduced levels of ADAMTS-13 have a relationship with overall survival (P < .001). Statistical analysis showed that ADAMTS-13 correlates with cytogenetics (P < .001) and a tendency of slight correlation with platelet count and basal levels of ADAMTS-13 (R, 0.35; P value, 0.001). Moreover, we found that levels of ADAMTS-13 have correlation with response to treatment (P < .001).ConclusionsADAMTS-13 in MDS might represent a surrogate marker of prognosis, response to therapy, or disease progression. Further studies are needed.     

Investigation of non-linear Mate1-mediated efflux of trimethoprim in the mouse kidney as the mechanism underlying drug-drug interactions between trimethoprim and organic cations in the kidney

The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with K_i values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with K_m values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CL_R) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CL_R (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CL_R of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates.     

Toxicity of ZnO nanoparticles (NPs) to THP-1 macrophages: interactions with saturated or unsaturated free fatty acids

In a biological microenvironment, free fatty acids (FFA) as ubiquitous biological molecules might interact with nanoparticles (NPs) and consequently change the toxicological responses. However, whether the chemical structures of FFA could influence their interactions with NPs remain unknown. This study investigated the interactions between ZnO NPs and saturated or unsaturated FFA (complexed to BSA), namely stearic acid (SA, C18:0), oleic acid (OA, C18:1), and α-linolenic acid (ALA, C18:3). It was shown that BSA, SA, OA, and ALA increased the atomic force microscope (AFM) heights as well the polydispersity index (PDI) of ZnO NPs. BSA modestly protected THP-1 macrophages from ZnO NP exposure, whereas OA and ALA led to relatively less cyto-protective effects of BSA. Moreover, only co-exposure to ZnO NPs and SA significantly promoted the release of interleukin-8. BSA, SA, OA, and ALA equally changed intracellular ROS and Zn ions associated with ZnO exposure, but co-exposure to ZnO NPs and OA/ALA particularly activated the expression of endoplasmic reticulum stress-apoptosis genes. In combination, these results showed that FFA could influence the colloidal aspects and toxicological signaling pathway of ZnO NPs, which is dependent on the number of unsaturated bonds of FFA.     

高通量血液透析和低通量血液透析不同模式对老年维持性血液透析患者血压的影响

目的 观察高通量血液透析(HFHD)与低通量血液透析(LFHD)的不同模式运用到老年患者维持性血液透析(MHD)中对其血压的影响。方法 选择2015年2月—2017年10月本院治疗的MHD老年患者74例,先为其施LFHD 3个月,再为其辅以3个月的HFHD,3次/周,4 h/次,对比不同透析模式对患者血压的影响。结果 实施HFHD后患者的平均动脉压(MAP)有所降低,在第3 h与第4 h透析后,血压把控优于LFHD(P<0.05)。结论 对于MHD老年患者来说,实施HFHD是优良的透析方法。     

The relationships among monocyte subsets,miRNAs and inflammatory cytokines in patients with acute myocardial infarction

Background

Acute myocardial infarction (AMI) causes irreversible myocardial damage and release of inflammatory mediators, including cytokines, chemokines and miRNAs. We aimed to investigate changes in the levels of cytokines (IL-6, TNF-α and IL-10), miRNAs profiles (miR-146 and miR-155) and distribution of different monocyte subsets (CD14++CD16-, CD14++CD16+, CD14+CD16++) in the acute and post-healing phases of AMI.

Steep Decrease of Gender Difference in DSM-IV Alcohol Use Disorder: A Comparison of Two Nation-wide Surveys Conducted 10 Years Apart in Korea

While decreasing trend in gender differences in alcohol use disorders was reported in Western countries, the change in Asian countries is unknown. This study aims to explore the shifts in gender difference in alcohol abuse (AA) and dependence (AD) in Korea. We compared the data from two nation-wide community surveys to evaluate gender differences in lifetime AA and AD by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Face-to-face interviews using the Composite International Diagnostic Interview (CIDI) were applied to all subjects in 2001 (n=6,220) and 2011 (n=6,022). Male-to-female ratio of odds was decreased from 6.41 (95% CI, 4.81-8.54) to 4.37 (95% CI, 3.35-5.71) for AA and from 3.75 (95% CI, 2.96-4.75) to 2.40 (95% CI, 1.80-3.19) for AD. Among those aged 18-29, gender gap even became statistically insignificant for AA (OR, 1.59; 95% CI, 0.97-2.63) and AD (OR, 1.18; 95% CI, 0.80-2.41) in 2011. Men generally showed decreased odds for AD (0.55; 95% CI, 0.45-0.67) and women aged 30-39 showed increased odds for AA (2.13; 95% CI 1.18-3.84) in 2011 compared to 2001. Decreased AD in men and increased AA in women seem to contribute to the decrease of gender gap. Increased risk for AA in young women suggests needs for interventions.     

Immune checkpoint inhibitor-induced inflammatory arthritis: identification and management

ABSTRACT

Introduction

Immune checkpoint inhibitors (ICIs) have proved to be groundbreaking in the field of oncology. However, immune system overactivation from ICIs has introduced a novel medical entity known as immune-related adverse events (irAEs), that can affect any organ or tissue. ICI-induced inflammatory arthritis (ICI-IIA) is the most common musculoskeletal irAE and can lead to significant morbidity and limitation in anti-cancer therapy.     

Quantitative chemical exchange saturation transfer (qCEST) MRI – omega plot analysis of RF‐spillover‐corrected inverse CEST ratio asymmetry for simultaneous determination of labile proton ratio and exchange rate

Chemical exchange saturation transfer (CEST) MRI is sensitive to labile proton concentration and exchange rate, thus allowing measurement of dilute CEST agent and microenvironmental properties. However, CEST measurement depends not only on the CEST agent properties but also on the experimental conditions. Quantitative CEST (qCEST) analysis has been proposed to address the limitation of the commonly used simplistic CEST‐weighted calculation. Recent research has shown that the concomitant direct RF saturation (spillover) effect can be corrected using an inverse CEST ratio calculation. We postulated that a simplified qCEST analysis is feasible with omega plot analysis of the inverse CEST asymmetry calculation. Specifically, simulations showed that the numerically derived labile proton ratio and exchange rate were in good agreement with input values. In addition, the qCEST analysis was confirmed experimentally in a phantom with concurrent variation in CEST agent concentration and pH. Also, we demonstrated that the derived labile proton ratio increased linearly with creatine concentration (P < 0.01) while the pH‐dependent exchange rate followed a dominantly base‐catalyzed exchange relationship (P < 0.01). In summary, our study verified that a simplified qCEST analysis can simultaneously determine labile proton ratio and exchange rate in a relatively complex in vitro CEST system. Copyright © 2015 John Wiley & Sons, Ltd.     

Design and synthesis of novel organometallic complexes using boronated phenylalanine derivatives as potential anticancer agents

Drug design and discovery studies are important because of the prevalence of diseases without available medical cures. New anticancer agents are particularly urgent because of the high mortality rate associated with cancer. A series of mononuclear gold (III) and platinum (II) complexes based on boronated phenylalanine (BPA) were designed and synthesized using 4,4’-dimethyl-2,2’-dipyridyl (L1) or 1,10-phenanthroline-5,6-dion (L2) ligands to obtain promising anticancer drug candidates. Proton nuclear magnetic resonance, infrared, mass spectrometry, and elemental analyses were utilized for chemical characterizations. Cell viability, cancer cell colony formation, endothelial tube formation, and cytoskeleton staining assays were performed using A549 lung adenocarcinoma and human umbilical vein endothelial cells (HUVECs) to investigate preliminary pharmacological activities. L1-based platinum (II) complex (BPA-L1-Pt) was the most promising complex, and has similar activity with the approved chemotherapy drug cis-platinum. Half maximal inhibitory concentration values for BPA-L1-Pt were 9.15 µM on A549s and 16.61 µM on HUVECs; the values for cis-platinum were 5.24 µM on A549s and 23.14 µM on HUVECs. Consequently, further synthesis studies should be performed to boost the cancer cell selectivity feature of BPA by varying metal and ligand types.