NUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity. Despite the impact of homozygous CRIM1 on thiopurine toxicity, several patients with wild-type ...NUDT15, TPMT, and CRIM1 experience thiopurine toxicity, therapeutic failure, and relapse of acute lymphoblastic leukemia (ALL). Novel pharmacogenetic interactions associated with thiopurine intolerance from hematological toxicities were investigated using whole-exome sequencing for last-cycle 6-mercaptopurine dose intensity percentages (DIP) tolerated by pediatric ALL patients (N = 320). IL6 rs13306435 carriers (N = 19) exhibited significantly lower DIP (48.0 ± 27.3%) than non-carriers (N = 209, 69.9 ± 29.0%; p = 0.0016 and 0.0028 by t test and multiple linear regression, respectively). Among 19 carriers, 7 with both heterozygous IL6 rs13306435 and CRIM1 rs3821169 showed significantly decreased DIP (24.7 ± 8.9%) than those with IL6 (N = 12, 61.6 ± 25.1%) or CRIM1 (N = 94, 68.1 ± 28.4%) variants. IL6 and CRIM1 variants showed marked inter-ethnic variability. Four-gene-interplay models revealed the best odds ratio (8.06) and potential population impact relative risk (5.73), population attributable fraction (58%), number needed to treat (3.67), and number needed to genotype (12.50). Interplay between IL6 rs13306435 and CRIM1 rs3821169 was suggested as an independent and/or additive genetic determinant of thiopurine intolerance beyond NUDT15 and TPMT in pediatric ALL.
Although serum bile acid concentrations are approximately 10 µM in healthy subjects, the crosstalk between the biliary system and vascular repair has never been investigated. In this study, ...tauroursodeoxycholic acid (TUDCA) induced dissociation of CD34(+) hematopoietic stem cells (HSCs) from stromal cells by reducing adhesion molecule expression. TUDCA increased CD34(+) /Sca1(+) progenitors in mice peripheral blood (PB), and CD34(+) , CD31(+) , and c-kit(+) progenitors in human PB. In addition, TUDCA increased differentiation of CD34(+) HSCs into EPC lineage cells via Akt activation. EPC invasion was increased by TUDCA, which was mediated by fibroblast activating protein via Akt activation. Interestingly, TUDCA induced integration of EPCs into human aortic endothelial cells (HAECs) by increasing adhesion molecule expression. In the mouse hind limb ischemia model, TUDCA promoted blood perfusion by enhancing angiogenesis through recruitment of Flk-1(+) /CD34(+) and Sca-1(+) /c-kit(+) progenitors into damaged tissue. In GFP(+) bone marrow-transplanted hind limb ischemia, TUDCA induced recruitment of GFP(+) /c-kit(+) progenitors to the ischemic area, resulting in an increased blood perfusion ratio. Histological analysis suggested that GFP(+) progenitors mobilized from bone marrow, integrated into blood vessels, and differentiated into VEGFR(+) cells. In addition, TUDCA decreased cellular senescence by reducing levels of p53, p21, and reactive oxygen species and increased nitric oxide. Transplantation of TUDCA-primed senescent EPCs in hind limb ischemia significantly improved blood vessel regeneration, as compared with senescent EPCs. Our results suggested that TUDCA promoted neovascularization by enhancing the mobilization of stem/progenitor cells from bone marrow, their differentiation into EPCs, and their integration with preexisting endothelial cells.
Genetic and chemical engineering approaches are used to employ P22 viral capsids as nanoplatforms for developing an efficient delivery vehicle. Catechol ligands are chemically attached to the ...interior surface of P22 viral capsid for subsequent encapsulation of an anticancer drug, bortezomib (BTZ), through boronic acid‐diol complexation. For targeted delivery, hepatocellular carcinoma (HCC)‐targeting peptide (SP94, SFSIIHTPILPL) is synthesized and chemically conjugated to the exterior surface of the P22 viral capsid nanocomposites. Effective targeted delivery of synthesized P22 viral capsid nanocomposites is demonstrated by fluorescent cell imaging and the efficacy of delivered P22 viral capsid nanocomposites is evaluated using a cell viability assay.
P22 viral capsid‐based multifunctional delivery nanocomposites are constructed using both genetic and chemical manipulations. P22 viral capsid nanocomposites show an excellent capability to encapsulate an anti‐cancer drug, BTZ, through boronic acid‐diol complexation and to deliver it to the target hepatocellular carcinoma cells with the aid of the targeting ligands on their surface.
Invasive fungal diseases (IFDs) increase the mortality rate of patients with neutropenia who receive chemotherapy or have previously undergone hematopoietic stem cell transplantation (HSCT). ...Micafungin is a broad-spectrum echinocandin with minimal toxicity and low drug interactions. We therefore investigated the efficacy and safety of prophylactic micafungin in pediatric and adolescent patients who underwent autologous HSCT.
This was a phase II, prospective, single-center, open-label, and single-arm study. From November 2011 to February 2017, 125 patients were screened from Seoul National University Children's Hospital, Korea, and 112 were enrolled. Micafungin was administered intravenously at a dose of 1 mg/kg/day (maximum 50 mg/day) from day 8 of autologous HSCT until neutrophil engraftment. Treatment success was defined as the absence of proven, probable, or possible IFD up to 4 weeks after therapy.
The study protocol was achieved without premature interruption in 110 patients (98.2%). The reasons interrupting micafungin treatment included early death (
= 1) and patient refusal (
= 1). Treatment success was achieved in 109 patients (99.1%). Only one patient was diagnosed with probable IFD. No patients were diagnosed with possible or proven IFD. In the full analysis set, 21 patients (18.8%) experienced 22 adverse events (AEs); however, all AEs were classified as "unlikely" related to micafungin. No patient experienced grade IV AEs nor discontinued treatment, and none of the deaths were related to micafungin.
Our study demonstrated that micafungin is a safe and effective option for antifungal prophylaxis in pediatric patients who underwent autologous HSCT, with promising efficacy without significant AEs.
Stemphol (STP) is a novel druggable phytotoxin triggering mixed apoptotic and non-apoptotic necrotic-like cell death in human acute myeloid leukemia (AML). Use of several chemical inhibitors ...highlighted that STP-induced non-canonical programmed cell death was Ca2+-dependent but independent of caspases, poly (ADP-ribose) polymerase-1, cathepsin, or calpains. Similar to thapsigargin, STP led to increased cytosolic Ca2+ levels and computational docking confirmed binding of STP within the thapsigargin binding pocket of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA). Moreover, the inositol 1,4,5-trisphosphate receptor is implicated in STP-modulated cytosolic Ca2+ accumulation leading to ER stress and mitochondrial swelling associated with collapsed cristae as observed by electron microscopy. Confocal fluorescent microscopy allowed identifying mitochondrial Ca2+ overload as initiator of STP-induced cell death insensitive to necrostatin-1 or cycloheximide. Finally, we observed that STP-induced necrosis is dependent of mitochondrial permeability transition pore (mPTP) opening. Importantly, the translational immunogenic potential of STP was validated by HMGB1 release of STP-treated AML patient cells. STP reduced colony and in vivo tumor forming potential and impaired the development of AML patient-derived xenografts in zebrafish.
•Stemphol induces cell death by disrupting calcium homeostasis.•Stemphol induces necrosis by mediating mPTP opening.•Stemphol triggers immunogenic cell death markers ER stress and HMGB1 release.•Stemphol impairs development of leukemia patient-derived zebrafish xenografts.
Background and aims:
The pathophysiology of hippocampal enlarged perivascular spaces (H-EPVS) and its relationship to cognitive impairment is largely unknown. This study aimed to investigate the ...relationship between H-EPVS and cognition in non-dementic elderly population.
Methods:
A total of 109 subjects were prospectively enrolled. The eligibilities for inclusion were age from 55 to 85 years and Mini-Mental Status Examination score of ≥26. The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Montreal Cognitive Assessment, transcranial Doppler (TCD), and brain magnetic resonance imaging results were evaluated. H-EPVS was categorized in a three-degree scale: degree 0 (no), degree 1 (1,2), and degree 2 (>2). The associations between H-EPVS and TCD parameters/cognitive test profiles were analyzed.
Results:
The mean age was 65.2 years, and 52.3% subjects were men. H-EPVS was found to be associated with age (degree 2 vs. degree 1 vs. degree 0, 69.20 ± 6.93 vs. 65.70 ± 5.75 vs. 63.80 ± 5.43;
p
= 0.030) and ADAS-Cog memory score (degree 2 vs. degree 1 vs. degree 0, 14.88 ± 4.27 vs. 12.49 ± 4.56 vs. 11.4 ± 4.23;
p
= 0.037). However, the pulsatility index was not related to the degree of H-EPVS. Multivariate analysis revealed medial temporal atrophy (MTA) scale score was independently associated with ADAS-Cog memory score (MTA scale sum ≥4,
p
= 0.011) but not with the degree of H-EPVS. MTA scale score showed correlation with H-EPVS (
r
= 0.273,
p
= 0.004).
Conclusions:
Aging was associated with the development of H-EPVS in non-dementic elderly population. Memory function was found to be associated with MTA but not with the degree of H-EPVS.
Background:
Because the suicide mortality depends on the lethality of suicide methods, the identification and prediction of suicide methods are important for suicide prevention.
Methods:
Examination ...data of suicide decedents were collected based on police reports. Suicide decedents were divided into groups according to the suicide methods (hanging, gas poisoning, pesticide poisoning, jumping, drug poisoning, and drowning) they used. Predictive factors for each suicide method in comparison to other suicide methods were identified.
Results:
Among 23,647 subjects, hanging was the most common method of suicide. Regarding gas poisoning, the history of previous suicide attempt was a risk factor and being age of 65 or older was a protective factor. Being age of 65 or older showed a highly strong association with suicide by pesticide poisoning. Being age of 18 or younger and the presence of schizophrenia were associated with jumping. A history of psychiatric outpatient treatment was a risk factor for drug poisoning. Regarding suicide by drowning, schizophrenia was a risk factor, while being age of 65 or older was a protective factor.
Limitations:
Only eight out of a total of 17 regions in South Korea were examined and included in the data of this study. Also, the methods of suicide were defined as one method that directly caused the death, which could undermine other less fatal methods used.
Conclusions:
There were differences in predictive factors according to the method of suicide. Predicting the method of suicide in people at high risk for suicide stands to be an important strategy for suicide prevention in clinical settings.
Arsenic, cadmium, lead, and mercury contents of Ganoderma lucidum, Phellinus linteus, Umbilicaria esculenta, Trametes versicolor, Agaricus blazei, Hericium erinaciium, Paecilomyces japonica, ...Fuscoporia obliqua, Sarcodon imbricatu and Hypsizygus marmoreus mushroom samples from the South Korean market were analyzed using validated methods. Method validation was performed, and the limits of detection and quantification were determined to be 0.38-0.66 and 1.21-2.09 μg/kg, respectively. The recoveries of the target metals ranged from 91.3% to 103.5%. The contents of As, Cd, Hg, and Pb were significantly different among the ten mushroom species, and the ranged from 0.006 to 3.9, 0.025 to 5.8, 0.01 to 0.21, and 0.004 to 12.3 mg/kg dry weight, respectively. Additionally, the estimated daily exposures to these metals from consumption of mushroom used in this work were found to be safe in accordance with the provisional tolerable weekly intake. Considering the results in this study, it could be mentioned that the consumption of the ten mushrooms species from Korea presented no noticeable health risk to the general public.
The number of patients receiving peritoneal dialysis has increased worldwide. Herein, we report the first case to our knowledge of continuous ambulatory peritoneal dialysis (CAPD) peritonitis caused ...by Micrococcus aloeverae, which was initially reported to be caused by Micrococcus luteus in the dialysate culture report but later identified by 16S ribosomal ribonucleic acid (rRNA) gene sequencing as M. aloeverae. A 59-year-old woman visited the emergency room due to abdominal pain. She was hospitalized with CAPD peritonitis. The patient initially responded to empirical antibiotic treatment comprising intraperitoneal cefazolin (15 mg/kg/day) and ceftazidime (1 g/day); however, the leukocyte count of dialysate effluent increased again. M. luteus was isolated four times from peritoneal dialysate cultures. We treated the patient with intraperitoneal administration of vancomycin (2 g loading, followed by 1 g every 7 days) but needed to switch from CAPD to temporary hemodialysis. We analyzed the 16S rRNA sequence to confirm the exact causative organism, and the results revealed that the organism was M. aloeverae. Because M. aloeverae and M. luteus have sequence similarity, 16S rRNA sequencing is a useful method to distingush them.
PURPOSE. To determine the anatomic variations in the peripapillary retinal nerve fiber layer (RNFL) thickness distribution and the relationship between these anatomic variations and other ocular ...variables. METHODS. A complete ophthalmic examination, including measurement of visual acuity, refraction, and axial length, was performed on 269 subjects with no ophthalmic abnormalities. Further, fundus photographs and optic disc cube scans of the subjects' eyes were obtained with a fundus camera and spectral domain OCT (Cirrus HD-OCT; Carl Zeiss Meditec, Inc., Dubin, CA), respectively. The distance between the foveola and the center of the optic nerve head was measured. The correlations of the angles of the peaks in the RNFL thickness profile with the axial length, spherical equivalent of refractive error (SE), and distance between the foveola and optic disc center were analyzed by simple linear regression. RESULTS. Considerable interindividual variations were found in the angles of the peaks in the RNFL thickness profile. Further, the angles in the eyes in each individual showed significant differences. The angles of the superior and inferior first peak correlated significantly with the SE, axial length, and distance between the foveola and optic disc center. CONCLUSIONS. Subjects with increased distance between the foveola and optic disc center are likely to have a temporal shift in peak RNFL thickness. RNFL profiles with horizontally deviated peak RNFL thickness differ considerably from the normative data provided with the HD-OCT system. The variations in RNFL thickness profiles should be taken into account.
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