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•Antiproliferative 3-deaoxysphingomyelin analogs were developed.•Cytotoxicity evaluation against cell lines representing four major types of cancers.•Alkyl chain influence the ...activity more than pyrrolidine ring stereochemistry.•Concentration dependent mechanism of action for this class of compounds.•Akt phorphorylation inhibition might be the mechanism of action at low concentration.
Sphingomyelins and glycerophospholipids are structurally related phospholipids. Nevertheless, glycerophospholipids analogs are known as antitumor agents while sphingomyelin analogs were reported as cytoprotective agents. Herein, we have addressed the development of 3-deoxysphingomyelin analogs as cytotoxic agents possessing modified sphingobases. Thus, pyrrolidine-based 3-deoxysphingomyelin analogs were synthesized and evaluated against a panel of cell lines representing four major types of cancers. Compounds 3d, 4d and 6d elicited better GI50 values than the FDA approved drug miltefosine. Investigation of their impact on Akt phosphorylation as a possible mechanism for the antiproliferative activity of this class of compounds revealed that these compounds might elicit a concentration-dependent mechanism via inhibition of Akt phosphorylation at the lower concentration. Molecular docking predicted their binding modes to Akt to involve polar head binding to the Pleckstrin homology domain and hydrophobic tail extension into a hydrophobic pocket connecting the Pleckstrin homology domain and the kinase domain. As a whole, the described work suggests compounds 3d, 4d and 6d as promising pyrrolidine-based 3-deoxysphingomyelin analogs for development of novel cancer therapies.
Summary
Introduction: Myeloproliferative neoplasm (MPN) is known to be a major risk factor of splanchnic vein thrombosis (SVT). Recent studies revealed that a significant proportion of patients with ...SVT harbor a gain‐of‐function mutation in the JAK2 gene (V617F) with or without MPN. In this study, the authors investigated the prevalence of MPN and JAK2 V617F mutation in Korean patients with SVT.
Methods: The study subjects were 26 patients diagnosed as having SVT based on Doppler ultrasound and/or computed tomography from January 2008 to January 2010 (16 men and 10 women; mean age 44 years, range 15–75 years). The clinical and laboratory data were reviewed. The JAK2 V617F mutation was detected by allele‐specific polymerase chain reaction and direct sequencing analyses using DNA from peripheral blood leukocytes.
Results: Among 26 study patients, 12 had portal vein thrombosis, five had hepatic vein thrombosis, three had mesenteric, and two had splenic vein thrombosis. Four patients had thrombosis involving more than one splanchnic vein. Two patients (7.7%; 2/26) had overt MPN (essential thrombocythemia). JAK2 V617F was detected in three patients (11.5%) including the two patients with overt MPN. Thus, the prevalence of the JAK2 V617F mutation in patients with SVT but without overt MPN was 4.2% (1/24).
Conclusion: The prevalence of overt MPN and that of JAK2 V617F were lower in Korean patients with SVT than in previous reports. Data from a larger number of patients with long‐term follow‐up are needed to reveal the clinical relevancy of JAK2 V617F in Korean patients with SVT.
Spatial decision support systems have already proved their value in helping to reduce infectious diseases but to be effective they need to be designed to reflect local circumstances and local data ...availability. We report the first stage of a project to develop a spatial decision support system for infectious diseases for Karnataka State in India. The focus of this paper is on malaria incidence and we draw on small area data on new cases of malaria analysed in two-monthly time intervals over the period February 2012 to January 2016 for Kalaburagi taluk, a small area in Karnataka. We report the results of data mapping and cluster detection (identifying areas of excess risk) including evaluating the temporal persistence of excess risk and the local conditions with which high counts are statistically associated. We comment on how this work might feed into a practical spatial decision support system.
The prevalence of voiding dysfunction was 47.4% by the question of "do you usually experience a feeling of incomplete bladder emptying" from Korean version of PFDI (pelvic floor distress inventory), ...33.7% by the value of less than 10th centile of peak flow rate of uroflowmetry by Liverpool nomogram, 20.2% by the cutoff values of less than 12 ml per second of maximum flow rate and greater than 25cmH20 of detrusor pressure at maximum flow rate in the pressure flow study and 11.6% by the elevated post-void residual urine volume more than 50 ml in 95 women who visited urogynaecology clinic with lower urinary tract symptoms. Each method had low positive predictive values for high post-void residuals (subjective symptom 0.16, uroflowmetry 0.29, pressure flow study 0.28). The prevalence of voiding dysfunction is fairly high and none of the questionnaire and objective bladder emptying tests is sufficient for the diagnosis of urinary retention.
Mesenchymal stem cells (MSCs), which evoke only minimal immune reactivity, may have anti-inflammatory and immunomodulatory effects. In this study, we conducted a comparative analysis of the ...immunomodulatory properties of MSCs derived from adult human tissues including bone marrow (BM), adipose tissues (AT), umbilical cord blood (CB), and cord Wharton’s jelly (WJ). Using a multiple cytokine detection assay, we showed that there were no significant differences in levels of secreted factors from non-stimulated MSCs. We compared the immunosuppressive effect of BM-MSCs, AT-MSCs, CB-MSCs, and WJ-MSCs on phytohemagglutinin-induced T-cell proliferation. AT-MSCs, CB-MSCs, and WJ-MSCs effectively suppressed mitogen-induced T-cell proliferation as effectively as did BM-MSCs. Levels of interferon (IFN)-γ and tumor necrosis factor (TNF)-α secreted from activated T-cells increased over time, but these levels were significantly reduced when cocultured with each type of MSCs. In addition, the expression of hepatocyte growth factor, IL-10, transforming growth factor-β
1, cyclooxygenase (COX)-1, and COX-2 were unchanged in MSCs treated with IFN-γ and/or TNF-α, while indoleamine 2,3-dioxygenase (IDO) expression increased. IFN-γ and/or TNF-α produced by activated T-cells were correlated with induction of IDO expression by MSCs, which, in turn, suppressed T-cell proliferation. These findings suggest that MSCs derived from AT, CB, or WJ could be substituted for BM-MSCs for treatment of allogeneic conflicts.
IV administration of tPA is accepted as a standard treatment for acute cerebral ischemia, but the clinical outcomes cannot be guaranteed in patients who are not recanalized after IV-tPA and in those ...who are not eligible for IV-tPA. In this study, outcomes from groups of patients treated with additional IA thrombolytic therapy with the use or omission of IV-tPA administration were compared.
IA thrombolytic therapy (thrombolytic agents combined with mechanical intervention) was attempted in those patients who were not eligible for IV-tPA and who showed continuous major vessel occlusion after IV-tPA. Sixty-three patients were divided into 2 groups: a tPA group (n = 29, IA thrombolysis after IV-tPA) and a non-tPA group (n = 34, IA thrombolysis without IV-tPA). These groups were subdivided according to match or mismatch DWI/PWI after MR imaging. Treatment results were compared by recanalization rate, clinical outcome, mortality, and ICH rate.
The recanalization rate was 79.3% in the tPA group and 55.9% in the non-tPA group (χ(2) test, P < .05). Subgroup analysis between DWI/PWI mismatch in the tPA group and DWI/PWI mismatch in the non-tPA group also showed no statistical difference in recanalization rate, favorable clinical outcome, and mortality (χ(2) test, P > .05), but the significant ICH rate was high in the tPA group (χ(2) test, P < .05).
Additional IA thrombolytic treatment after full-dose IV-tPA administration might be an acceptable treatment option for patients with DWI/PWI mismatch.
Yoo E‐H, Woo H, Ki C‐S, Lee HJ, Kim D‐K, Kang I‐S, Park P, Sung K, Lee CS, Chung T‐Y, Moon JR, Han H, Lee S‐T, Kim J‐W. Clinical and genetic analysis of Korean patients with Marfan syndrome: possible ...ethnic differences in clinical manifestation.
Marfan syndrome (MFS) is an autosomal dominant disorder of the fibrous connective tissue caused by mutations in the fibrillin‐1 (FBN1) gene. Although clinical and genetic analyses have been performed in various populations, there have been few studies in Korea. The aim of this study was to investigate the clinical characteristics and genetic background of Korean patients with MFS. In 39 Korean patients with MFS who met the Ghent criteria, the most common clinical finding was aortic dilatation and/or dissection (94.9%), whereas only 35.9% of patients had ectopia lentis. The majority of MFS patients had fewer than four of the skeletal findings required to fulfill the major skeletal Ghent criterion for MFS. Only 21% of Korean patients had major skeletal abnormalities and most cases showed only minor skeletal involvement. FBN1 gene mutations were detected in 35 out of 39 patients (89.7%), which is similar to rates presented in the previous reports. These results suggest that some clinical features in Korean patients with MFS differed from those reported in Western MFS patients.
Hyper-Kamiokande consists of two identical water-Cherenkov detectors of total 520 kt, with the first one in Japan at 295 km from the J-PARC neutrino beam with 2.5 degrees off-axis angles (OAAs), and ...the second one possibly in Korea at a later stage. Having the second detector in Korea would benefit almost all areas of neutrino oscillation physics, mainly due to longer baselines. There are several candidate sites in Korea with baselines of 1000-1300 km and OAAs of 1 degrees-3 degrees. We conducted sensitivity studies on neutrino oscillation physics for a second detector, either in Japan (JD x 2) or Korea (JD + KD), and compared the results with a single detector in Japan. Leptonic charge-parity (CP) symmetry violation sensitivity is improved, especially when the CP is non-maximally violated. The larger matter effect at Korean candidate sites significantly enhances sensitivities to non-standard interactions of neutrinos and mass ordering determination. Current studies indicate the best sensitivity is obtained at Mt. Bisul (1088 km baseline, 1.3 degrees OAA). Thanks to a larger (1000 m) overburden than the first detector site, clear improvements to sensitivities for solar and supernova relic neutrino searches are expected.
Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late‐onset dementia, including Alzheimer's disease (AD), indicates a ...potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World‐Wide FINGERS (WW‐FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW‐FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline—from at‐risk asymptomatic states to early symptomatic stages—in different geographical, cultural, and economic settings. WW‐FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies.
Respiratory syncytial virus (RSV) is a major health problem in young children, and host response to severe disease favors a Th2 immune response. To investigate the genetic basis for RSV disease ...severity, linked variants of 3 Th2 cytokine genes, IL4, IL13 and IL5 (which are clustered on chromosome 5q31.1) were characterized in 105 children who were hospitalized with severe RSV infection and 315 Korean control subjects in a pilot study. A common IL4 haplotype defined at 5 loci, which includes the −589T promoter variant, previously shown to be associated with increased interleukin (IL)–4 transcriptional activity and predisposition to asthma, was overrepresented in patients with severe RSV disease (odds ratio, 1.63; P=.02). These results support the hypothesis that severe RSV disease might be related to increased Th2 response, which is perhaps mediated by overexpression of IL-4, and provide preliminary evidence for a genetic link between severe RSV disease and subsequent wheezing
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