Clinicomicrobiological risk factors for infective endocarditis in viridans group streptococci bacteraemia.

BACKGROUND: When to perform echocardiography to rule out infective endocarditis (IE) in patients with viridans group streptococci (VGS) bloodstream infections (BSIs) is unclear. OBJECTIVES: We aimed to identify independent risk factors for IE in patients with VGS BSI. METHODS: This retrospective study conducted at Seoul National University Hospital from January 2013 to December 2022 involved patients with VGS and nutritionally variant streptococcal BSI, excluding single positive blood cultures and polymicrobial BSI cases. Independent risk factors were identified by multivariate logistic regression and sensitivity analyses according to echocardiography results, VGS species or the inclusion of possible IE cases. RESULTS: Of 845 VGS BSI cases, 349 were analysed and 86 IE cases were identified (24.6%). In the multivariate analysis, heart valve disease [adjusted odds ratio (aOR), 14.14, 95% CI, 6.14-32.58; P < 0.001], persistent bacteraemia (aOR, 5.12, 95% CI, 2.03-12.94; P = 0.001), age (per year, aOR, 0.98; 95% CI, 0.96-1.00; P = 0.015), solid cancer (aOR, 0.26; 95% CI, 0.13-0.53; P < 0.001) and haematologic malignancy (aOR, 0.04; 95% CI, 0.01-0.41; P = 0.006) were independently associated with IE. Sensitivity analyses yielded consistent results; also, infection by a member of the mitis group was independent risk factor for IE (aOR, 6.50; 95% CI, 2.87-14.68; P < 0.001). CONCLUSIONS: Younger age, heart valve disease, persistent bacteraemia, absence of underlying malignancy and BSI by a member of the mitis group were independent risk factors for IE in patients with VGS BSI. Echocardiographic evaluation could be prudently considered based on these clinicomicrobiological risk factors.

Late Parasitological Failure and Subsequent Isolated Gametocytemia of Uncomplicated Plasmodium falciparum Malaria in a Returned Traveler From Ghana, 2023.

Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the emergency department with high fever, headache, and dizziness. He traveled without antimalarial chemoprophylaxis. Laboratory tests led to the diagnosis of uncomplicated falciparum malaria with an initial density of 37,669 parasites per µL of blood (p/µL). The patient was treated with intravenous artesunate followed by atovaquone/proguanil. He was discharged with improved condition and decreased parasite density of 887 p/µL. However, at follow-up, parasite density increased to 7,630 p/µL despite the absence of any symptoms. Suspecting treatment failure, the patient was administered intravenous artesunate and doxycycline for seven days and then artemether/lumefantrine for three days. Blood smear was negative for asexual parasitemia after re-treatment but positive for gametocytemia until day 101 from the initial diagnosis. Overall, this case highlights the risk of late parasitological failure in patients with imported uncomplicated falciparum malaria.

Simultaneous Analysis of 272 Pesticides in Agricultural Products by the QuEChERS Method and Gas Chromatography with Tandem Mass Spectrometry.

The aim of this study is to develop a rapid and accurate method for simultaneous analysis of multi-residue pesticides and conduct pesticide monitoring in agricultural products produced by the production and distribution stage in Korea. The representative agricultural products were selected as brown rice, soybean, potato, mandarin, and green pepper and developed using gas chromatography with tandem mass (GC-MS/MS) for the analysis of 272 pesticide residues. The experimental samples were extracted by the QuEChERS-EN method and then cleaned up by using d-SPE, including MgSO4 and primary secondary amine (PSA) sorbents. The established method was validated in accordance with Codex CAC-GL/40, and the limit of quantitation (LOQ) was determined to be 0.01 mg/kg. A total of 243 pesticides satisfied the guidelines in five samples at three levels with values of 60 to 120% (recovery) and ≤45% (coefficient of variation, CV). The remaining 29 pesticides did not satisfy the guidelines, and these pesticides are expected to be used as a screening method for the routine inspection of agricultural products. As a result of analyzing 223 agricultural products in South Korea by applying the simultaneous analysis method, none of the detected levels in the samples exceeded the standard values based on maximum residue limits (MRLs). The developed method in this study will be used to inspect residual pesticides in agricultural products, and it is anticipated to contribute to the distribution of safe agricultural products to consumers.

Effect of Abiotic Signals on the Accumulation of Saponarin in Barley Leaves in Hydroponics Under Artificial Lights.

Functional flavonoid production is a new agenda in the agricultural industry, and young barley leaves (YBL) are one of the highlighted crops due to their health-beneficial flavonoid, saponarin. For the year-round cultivation of a high saponarin content of YBL, abiotic signal effects on the biosynthesis and metabolism in YBL need to be understood clearly. In this research, the effects of reactive oxygen species (ROS)-related abiotic signals, such as light, potassium, and sodium, were investigated on the biosynthetic metabolism in YBL cultivation under artificial lights. A higher quantity of blue-rich white light (6500 K of light temperature) irradiation enhanced ROS levels and the related enzyme activities (APX and CAT), as well as photosynthesis and saponarin amount, while red-rich white light (3000 K of light temperature) increased the photosynthesis only. In addition, 1.0 g L-1 K+ treatment in water slightly reduced ROS levels and increased saponarin accumulation in YBL. These blue-rich light and K+ supplemental conditions relatively increased OGT expression and reduced 4-coumaric acid and isovitexin as saponarin precursors. Furthermore, the relative ratio of lutonarin as an oxidized product of saponarin increased in increments of light quantity. Finally, the abiotic conditions for saponarin production were optimized with the mixture solution treatment of 1.0 g L-1 Na+ and 1.0 g L-1 K+ under 500 PPFD of 6500 K light, and the saponarin amount per leaf was 219.5 µg plant-1; it was comparable amount with that under sunlight condition.

The Impact of the Rapid Blood Culture Identification Panel on Antibiotic Treatment and Clinical Outcomes in Bloodstream Infections, Particularly Those Associated with Multidrug-Resistant Micro-Organisms.

We evaluated the impact of the FilmArray blood culture identification (BCID) panel on the time taken to administer effective antibiotics and the clinical outcomes of bloodstream infections. We retrospectively screened patients with bloodstream infections who underwent BCID testing and compared them to a historical control group that received conventional culture testing. A total of 144 and 214 patients who underwent BCID and conventional cultures, respectively, were compared. The 30-day mortality (BCID: 9.7% vs. conventional method: 10.7%, p = 0.755), time to effective antibiotic administration (3 h for both BCID and conventional method, p = 0.789), and time to appropriate antibiotic administration did not differ significantly between the groups. BCID was not significantly associated with 30-day mortality after adjusting for the Pitt bacteremia score and the Charlson comorbidity index (adjusted OR = 0.833, CI; 0.398-1.743). Compared with conventional methods, BCID reduced the time to administration of effective antibiotics in cases of carbapenem-resistant Enterobacterales (CRE) (39 h vs. 93 h, p = 0.012) and vancomycin-resistant enterococci (VRE) (50 h vs. 92 h, p < 0.001) bacteremia. BCID did not affect the clinical outcomes of overall bloodstream infections; however, it contributed to the early administration of effective antibiotics in cases of CRE and VRE bacteremia.

Determination of Modified QuEChERS Method for Chlorothalonil Analysis in Agricultural Products Using Gas Chromatography-Mass Spectrometry (GC-MS/MS).

Chlorothalonil is an organochlorine fungicide that blocks the respiratory process of cells and persists in agricultural products because it is used extensively to prevent fungal diseases. An analytical method of chlorothalonil using the modified QuEChERS method and gas chromatography- mass spectrometry (GC-MS/MS) was developed to analyze the residue in agricultural commodities distributed in Republic of Korea. Acetonitrile, including acetic acid and formic acid, was used to compare the extraction efficiency. The extraction and purification processes were established by comparing three versions of the QuEChERS method and various dispersive solid-phase extraction (d-SPE) combinations. Ultimately, 1% formic acid in acetonitrile with QuEChERS original salts and d-SPE (PSA, C18) were selected for the extraction and clean-up procedures for method validation and establishment. Five agricultural commodities, viz., brown rice, mandarin, soybean, pepper, and potato, were examined to validate the established method, which displayed excellent linearity, with a coefficient of determination of R2 = 0.9939-0.997 in the calibration curve range of 0.002-0.1 mg/kg. The limits of detection (LOD) and quantification (LOQ) were calculated to be 0.003 mg/kg and 0.01, respectively, for the method. The LOQ value satisfied the suitable level for the Positive List System (PLS). The mean recovery of chlorothalonil was 79.3-104.1%, and the coefficient of variation was <17.9% for intra- and inter-day precision at 0.01, 0.1, and 0.5 mg/kg. The matrix effects in the five commodities were confirmed by the ion suppression effects, except for brown rice, in which a medium enhancement effect was observed at 21.4%. Chlorothalonil was detected in eight apples, one watermelon, and one cucumber. Ultimately, chlorothalonil was detected in ten agricultural products. Thus, this analytical method could be used for the routine detection of chlorothalonil in agricultural products, and the data may be used to inform and improve current food policies.

Photochemical advanced oxidative process treatment effect on the pesticide residues reduction and quality changes in dried red peppers.

Pesticide residues in crops are widely monitored, and the residue reduction techniques at the post-harvest stage are important to maintain food safety. In dried crops, pesticide residues can be concentrated after dehydration, which increases concerns regarding residue risk. Therefore, the residue reduction effects of ultraviolet (UV), ozone, and photochemical advanced oxidative process (pAOP) were investigated for dried peppers at the post-harvest stage. UV254 treatment reduced 59.7% of the residue concentration on average, while UV360 showed a reduction of only 13.3% under 9.6 W m-2 of UV exposure for 24 h. Gaseous ozone treatments reduced the residue concentrations up to 57.9% on average. In contrast, the pAOP treatment reduced the concentration up to 97% and was superior to UV or ozone treatment alone. Increased drying temperature under pAOP condition resulted in higher reduction ratios at 40-80 °C. The pAOP conditions with 12 and 24 µmol/mol of ozone and UV254 irradiation for 24-48 h reduced the residue concentrations to 39-67%. Particularly, difenoconazole, fludioxonil, imidacloprid, and thiamethoxam residue concentrations were drastically reduced by over 50% under 12 µmol/mol ozone of the pAOP condition, while carbendazim, fluquinconazole, and pyrimethanil were relatively stable and their concentrations reduced below 50% under 24 µmol/mol ozone of the pAOP treatment. Various drying-related quality parameters of drying peppers such as water-soluble color, capsanthin, capsaicinoids, acid value, peroxide value, and thiobarbituric acid value were slightly altered, but not significantly, under 12 µmol/mol ozone of the pAOP condition, while the peroxide value was significantly altered under the higher ozone conditions. Therefore, pAOP treatment combined with gaseous ozone can be used for reducing residual pesticides in peppers without greatly reducing quality.

A novel FLCN gene mutation causing Birt-Hogg-Dubé syndrome in a Korean family.

Spontaneous pneumothorax is a common manifestation of Birt-Hogg-Dubé (BHD) syndrome, an inherited disorder caused by mutation of the folliculin (FLCN) gene. A 44-year-old female with a history of breast cancer was diagnosed with recurrent pneumothorax. Chest CT showed multiple cysts with left lung pneumothorax, and she received surgery for the diagnosis. Because the patient also had a family history of spontaneous pneumothorax, a FLCN genetic examination was conducted. A novel heterozygous, likely pathogenic variant (NM_144997.5:c.779+2T > C) was detected in the proband, her mother, and aunt. This is the first report of a new mutation of FLCN gene in a BHD syndrome patient.

Fate of endosulfan in ginseng farm and effect of granular biochar treatment on endosulfan accumulation in ginseng.

Endosulfan was widely used as an insecticide in the agricultural sector before its environmental persistence was fully understood. Although its fate and transport in the environment have been studied, the effects of historic endosulfan residues in soil and its bioaccumulation in crops are not well understood. This knowledge gap was addressed by investigating the dissipation and bioaccumulation of endosulfan in ginseng as a perennial crop in fresh and aged endosulfan-contaminated fields. In addition, the effect of granular biochar (GBC) treatment on the bioaccumulation factor (BAF) of endosulfan residue in ginseng was assessed. The 50% dissipation time (DT50) of the total endosulfan was over 770 days in both the fresh and aged soils under mulching conditions. This was at least twofold greater than the reported (6- > 200 days) in arable soil. Among the endosulfan congeners, the main contributor to the soil residue was endosulfan sulfate, as observed from 150 days after treatment. The BAF for the 2-year-old ginseng was similar in the fresh (1.682-2.055) and aged (1.372-2.570) soils, whereas the BAF for the 3-year-old ginseng in the aged soil (1.087-1.137) was lower than that in the fresh soil (1.771-2.387). The treatment with 0.3 wt% GBC extended the DT50 of endosulfan in soil; however, this could successfully suppress endosulfan uptake, and reduced the BAFs by 66.5-67.7% in the freshly contaminated soil and 32.3-41.4% in the aged soil. Thus, this adsorbent treatment could be an effective, financially viable, and sustainable option to protect human health by reducing plant uptake of endosulfan from contaminated soils.

CaV α2δ Autoimmune Encephalitis: A Novel Antibody and its Characteristics.

OBJECTIVE: Discovery of a novel antibody would enable diagnosis and early treatment of autoimmune encephalitis. The aim was to discover a novel antibody targeting a synaptic receptor and characterize the pathogenic mechanism. METHOD: We screened for unknown antibodies in serum and cerebrospinal fluid samples from autoimmune encephalitis patients. Samples with reactivity to rat brain sections and no reactivity to conventional antibody tests underwent further processing for antibody discovery, using immunoprecipitation to primary neuronal cells, mass-spectrometry analysis, an antigen-binding assay on an antigen-overexpressing cell line, and an electrophysiological assay with cultured hippocampal neurons. RESULTS: Two patients had a novel antibody against CaV α2δ (voltage-gated calcium channel alpha-2/delta subunit). The patient samples stained neuropils of the hippocampus, basal ganglia, and cortex in rat brain sections and bound to a CaV α2δ-overexpressing cell line. Knockdown of CaV α2δ expression in cultured neurons turned off the immunoreactivity of the antibody from the patients to the neurons. The patients were associated with preceding meningitis or neuroendocrine carcinoma and responded to immunotherapy. In cultured neurons, the antibody reduced neurotransmitter release from presynaptic nerve terminals by interfering with tight coupling of calcium channels and exocytosis. INTERPRETATION: Here, we discovered a novel autoimmune encephalitis associated with anti-CaV α2δ antibody. Further analysis of the antibody in autoimmune encephalitis might promote early diagnosis and treatment. ANN NEUROL 2021;89:740-752.

Proportion of peripheral regulatory T cells in patients with autoimmune encephalitis.

Purpose: Regulatory T cells (Tregs) play a crucial role in maintaining immune tolerance. Any deficiency or dysfunction of the Tregs can influence the pathogenesis of autoimmune disease. This study aimed to assess the role of Tregs among patients with autoimmune encephalitis (AE) with different autoantibody types and to evaluate their association with clinical features. Methods: This was a cross-sectional observational study involving 29 patients with AE. Peripheral blood was sampled from each patient for flow cytometric analysis. Proportions of CD4+CD25+ and CD4+CD25+Foxp3+ Tregs were calculated and compared between the antibody types (synaptic, paraneoplastic, and undetermined). Associations between the proportion of Tregs and clinical features were also evaluated. Results: Five patients had synaptic autoantibodies, five had paraneoplastic autoantibodies, and the others were of an undetermined type. The proportion of CD4+CD25+ Tregs tended to be higher in those with paraneoplastic antibodies than in those with synaptic antibodies (post-hoc p = 0.028) and undetermined antibody status (post-hoc p = 0.043). A significant negative correlation was found between the proportion of Tregs and the initial modified Rankin score (r = -0.391, p = 0.036). Those who received intravenous immunoglobulin had lower proportions of Tregs than those who did not. Conclusion: The results of the present study suggest that Tregs may play different roles according to the type of AE and may be linked to disease severity.

Chlorfenapyr Residue in Sweet Persimmon from Farm to Table.

The use of the pesticide chlorfenapyr has been increasing over time, with a consequent wider application to crops. However, there is limited information available on the amount and safety of the residues it leaves on crops. The amount of chlorfenapyr residues in sweet persimmon (Diospyros kaki L.) at both the pre- and postharvest stages were investigated in this study by calculating its biological half-life. The half-life at the preharvest stage was 8.8 days, shorter than that found during the storage periods at 4 and 20°C, when the half-lives were 11.0 and 23.9 days, respectively. In addition, peeling and washing after harvesting reduced residue content. The majority of the chlorfenapyr residues in sweet persimmon were found in the peel of the fruit, with the pulp containing less than 25% of the total. Thus, peeling effectively removed chlorfenapyr residues and diminished the residues below the limit of quantification in the pulp. In addition, washing with 1.0% alcohol and 0.2% Tween 20 solutions effectively removed 47.8 and 55.6% of the residues, respectively. Furthermore, a 1.0% alcohol solution showed high reduction efficiency for other hydrophobic pesticides, such as dimethomorph and fluquinconazole, up to 78.0%. Chlorfenapyr residues in sweet persimmon can be effectively reduced via storage or peeling and washing practices or a combination of them.

Maternal immune activation alters brain microRNA expression in mouse offspring.

OBJECTIVE: Maternal immune activation (MIA) is associated with an increased risk of autism spectrum disorder (ASD) in offspring. Herein, we investigate the altered expression of microRNAs (miRNA), and that of their target genes, in the brains of MIA mouse offspring. METHODS: To generate MIA model mice, pregnant mice were injected with polyriboinosinic:polyribocytidylic acid on embryonic day 12.5. We performed miRNA microarray and mRNA sequencing in order to determine the differential expression of miRNA and mRNA between MIA mice and controls, at 3 weeks of age. We further identified predicted target genes of dysregulated miRNAs, and miRNA-target interactions, based on the inverse correlation of their expression levels. RESULTS: Mice prenatally subjected to MIA exhibited behavioral abnormalities typical of ASD, such as a lack of preference for social novelty and reduced prepulse inhibition. We found 29 differentially expressed miRNAs (8 upregulated and 21 downregulated) and 758 differentially expressed mRNAs (542 upregulated and 216 downregulated) in MIA offspring compared to controls. Based on expression levels of the predicted target genes, 18 downregulated miRNAs (340 target genes) and three upregulated miRNAs (60 target genes) were found to be significantly enriched among the differentially expressed genes. miRNA and target gene interactions were most significant between mmu-miR-466i-3p and Hfm1 (ATP-dependent DNA helicase homolog), and between mmu-miR-877-3p and Aqp6 (aquaporin 6). INTERPRETATION: Our results provide novel information regarding miRNA expression changes and their putative targets in the early postnatal period of brain development. Further studies will be needed to evaluate potential pathogenic roles of the dysregulated miRNAs.

LGI1 expression and human brain asymmetry: insights from patients with LGI1-antibody encephalitis.

BACKGROUND: While brain asymmetry has been a fascinating issue in neuroscience, the critical mechanism remains to be elucidated. Based on some index cases with asymmetric 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) uptake in leucine-rich glioma-inactivated 1 (LGI1)-antibody encephalitis, we hypothesized LGI1 expression could be asymmetrically distributed in the human brain. METHODS: We enrolled 13 patients who were diagnosed with LGI1-antibody encephalitis between June 2012 and January 2018 at Seoul National University Hospital. Their pretreatment 18F-FDG-PET images were analyzed to find asymmetry between the left and right hemispheres. Guided by these observations, expression of LGI1 in the human hippocampus and the globus pallidus of both cerebral hemispheres was studied in nine post-mortem human brains. RESULTS: Eleven of the 13 LGI1-antibody encephalitis patients (84.6%) showed asymmetrical FDG high uptake in the hippocampus: nine (81.8%) on the left hippocampus and two (18.2%) on the right. In the basal ganglia, seven patients (53.8%) showed asymmetry: four (57.1%) on the left and three (42.9%) on the right. The asymmetry was not evident in the laterality of faciobrachial dystonic seizures, brain MRI, and EEG. When the expression of LGI1 protein was analyzed in nine post-mortem human brains by western blotting, LGI1 expression was higher on eight left globus pallidus samples (88.89%, P = 0.019) and on four left hippocampal samples (44.44%, P = 0.652), compared to their right hemisphere samples. CONCLUSIONS: Imaging parameters from patients with LGI1-antibody encephalitis and studies of LGI1 protein expression suggest that LGI1 is asymmetrically distributed in the human brain. These observations have implications for our understanding of human brain development.

Loss of Pericytes in Radiation Necrosis after Glioblastoma Treatments.

Radiation necrosis (RN) in brain tumor patients is often symptomatic, persistent without immediate resolution, and confused with tumor recurrence. Cerebral vascular pericytes are essential for endothelial function, vascular integrity, and angiogenesis. In this study, we showed that the loss of pericytes is involved in the pathogenesis of RN. From a brain tumor tissue repository, we identified three patients since 2011 with pathologically confirmed RN after the standard treatment for glioblastoma (GBM). The RN and their preradiation GBM tissues were serially processed for Western blotting using cell-type-specific antibodies against endothelial (CD31, active RhoA), pericyte [platelet-derived growth factor receptor-beta (PDGFR-ß)], alpha-smooth muscle actin (α-SMA), astrocyte (GFAP), myelin sheath protein (MBP), and microglial markers (Iba1). Normal brain tissues from a brain bank were used as normal controls. The expressions of PDGFR-ß and α-SMA were remarkably reduced in the RN, compared to those of GBM. However, the levels of CD31 or RhoA were not different between the two groups, which suggest that there was no change in the number of endothelial cells or their cytoskeletal assembly. The RN tissues showed a decreased ratio of pericyte/endothelial markers and an increased level of Iba1 compared to the GBM and even to the normal brain. The levels of GFAP and MBP were not changed in the RN. In the histopathology, the RN tissues showed a loss of markers (PDGFR-ß), whereas the GBM tissues had abundant expression of the markers. The loss of pericytes and vascular smooth muscle cells, and the unsupported endothelial cells might be the cause of the leaky blood-brain barrier and tissue necrosis.

Both triazolyl ester of ketorolac (15K) and YM155 inhibit the embryonic angiogenesis in ovo (fertilized eggs) via their common PAK1-survivin/VEGF signaling pathway.

15 K is 1,2, 3-triazolyl ester of ketorolac, an old pain-killer, that blocks PAK1 by its R-form and inhibits COX-2 by its S-form. Mainly due to a robust increase in cell-permeability, 15K is over 500 times more potent than ketorolac in both anti-cancer and anti-PAK1 activities in cell culture with IC50 around 24 nM. However, 15K has no anti-AKT activity. Angiogenesis requires at least the kinase PAK1, and perhaps the kinase AKT as well, and is essential for a robust growth of solid tumors. Thus, in this study, we examined the potential antiangiogenic activity of 15K both in ovo and cell culture, prior to its in vivo (xenograft) anti-cancer activity test. The IC50 of 15K against the embryonic angiogenesis in ovo in CAM (chorioallantoic membrane) assay is around 1 nmol/egg. Surprizingly, however, 15K failed to inhibit the tube formation of HUVECs (human umbilical vein endothelial cells) in cell culture even at high as 150 µM. In an attempt to solve this mystery, we tested both in ovo as well as HUVECs-based anti-angiogenic activity of a potent survivin-suppressor called YM155, which blocks PAK1, in addition to AKT. YM155 is slightly more potent than 15K in CAM assay with IC50 around 0.5 nmol/egg, and apparenty inhibits the tube formation of HUVECs with IC50 around 18 nM. According to a few previous findings with the direct PAK1-inhibitor frondoside A (FRA), the tube formation of HUVECs depends solely on PAK1. Thus, the failure of 15K to affect their tube formation is most likely due to their drug (15K)-resistance. Furthermore, unlike FRA, YM155 killed HUVECs with IC50 around 18 nM, clearly indicating that AKT is essential for survival of HUVECs, instead of their tube formation.

Low-dose 1,25-dihydroxyvitamin D(3) combined with arsenic trioxide synergistically inhibits proliferation of acute myeloid leukemia cells by promoting apoptosis.

Arsenic trioxide (As(2)O(3)) has shown substantial efficacy in the treatment of patients with acute promyelocytic leukemia, a specific subtype of acute myeloid leukemia (AML). However, since not all patients can achieve remission after treatment, it is necessary to develop a novel method to overcome this problem. We investigated the anti-leukemic effect of low-dose 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) in combination with As(2)O(3) on the human AML cell lines HL-60 and K562. The cell viability was in reverse proportion to As(2)O(3) or 1,25(OH)(2)D(3) concentration. In both HL-60 and K562 cells, after the combination treatment with As(2)O(3) and 1,25(OH)(2)D(3) at a 10:1 ratio, the combination index (CI) values were <1 in all treatment groups. In the RT-PCR and western blot analysis, the combination treatment decreased Bcl-2 expression and increased Bax and caspase-3 expression more prominently than the single treatment. In the flow cytometric analysis performed in HL-60 cells, the proportion of late apoptotic cells was 4.9% in the control, 30.0% in cells treated with 1.0 µM As(2)O(3), 8.1% in cells treated with 100 nM 1,25(OH)(2)D(3), and 64.3% in cells treated with 1.0 µM As(2)O(3) plus 100 nM 1,25(OH)(2)D(3). In conclusion, low-dose 1,25(OH)(2)D(3) combined with As(2)O(3) synergistically inhibited proliferation of HL-60 and K562 cells. In addition, this combination activated the apoptosis pathway more prominently than the single-drug treatment.

RANTES polymorphisms and the risk of graft-versus-host disease in human leukocyte antigen-matched sibling allogeneic hematopoietic stem cell transplantation.

We investigated the association between RANTES (regulated upon activation, normal T cell expressed and secreted) polymorphisms and clinical outcomes in patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Three RANTES gene polymorphisms, i.e., -403G/A (rs2107538), -28C/G (rs2280788) and In1.1T/C (rs2280789), were genotyped, and the effects of the genotypes and haplotypes of RANTES on clinical outcomes were analyzed. The competing risk regression analysis was used to investigate the relationship between the polymorphisms and the cumulative risk of graft-versus-host disease (GVHD). An AGC haplotype in a recessive model showed significant harmful effects on the cumulative risk of acute GVHD and relapse-free survival (adjusted hazard ratios 2.42 and 2.71, 95% confidence intervals 1.29-4.55 and 1.30-5.64; p = 0.018 and 0.024, respectively), whereas a GCT haplotype did not. RANTES polymorphisms were not significantly associated with overall survival and the risk of chronic GVHD. This study suggests that RANTES polymorphisms might be associated with the occurrence of acute GVHD rather than of chronic GVHD and also of relapse-free survival in the patients treated with allo-HSCT. Further larger prospective investigations are needed to establish the role of RANTES polymorphisms in patients treated with allo-HSCT.

Polymorphisms in genes that regulate cyclosporine metabolism affect cyclosporine blood levels and clinical outcomes in patients who receive allogeneic hematopoietic stem cell transplantation.

In patients who received allogeneic hematopoietic stem cell transplantation (HSCT), we investigated the correlations between single nucleotide polymorphisms (SNPs) in genes that regulate cyclosporine metabolism and clinical outcomes. All patients received sibling-matched HSCT. DNA samples of patients and donors were analyzed for 4 SNPs: MDR1 +1236C>T (rs1128503), +2677G>T>A (rs2032582), +3435C>T (rs1045642), and CYP3A5 +6986G>A (rs776746). A total of 156 patients (median age 40 years) were analyzed. Nineteen patients received HSCT for nonmalignant disease. The CYP3A5 +6986AA genotype was associated with a high cyclosporine blood level after transplantation. However, this genotype was not related to any particular clinical outcome. In contrast, the MDR1 +1236C>T SNP was correlated with specific clinical outcomes. When neither the donor nor the recipient had the CC genotype of MDR1 +1236, patients had lower creatinine levels (P < .001) and less transplantation-related mortality (TRM) (P = .012). These patients also showed longer overall survival (OS) in both univariate (P = .003) and multivariate (P = .003) analyses. Although the CYP3A5 +6986AA genotype was correlated with a high blood cyclosporine concentration, lack of the MDR1 +1236CC genotype in both the donor and recipient was correlated with less TRM and a longer OS in patients who received allogeneic HSCT.