Generative adversarial networks for imputing missing data for big data clinical research.

BACKGROUND: Missing data is a pervasive problem in clinical research. Generative adversarial imputation nets (GAIN), a novel machine learning data imputation approach, has the potential to substitute missing data accurately and efficiently but has not yet been evaluated in empirical big clinical datasets. OBJECTIVES: This study aimed to evaluate the accuracy of GAIN in imputing missing values in large real-world clinical datasets with mixed-type variables. The computation efficiency of GAIN was also evaluated. The performance of GAIN was compared with other commonly used methods, MICE and missForest. METHODS: Two real world clinical datasets were used. The first was that of a cohort study on the long-term outcomes of patients with diabetes (50,000 complete cases), and the second was of a cohort study on the effectiveness of a risk assessment and management programme for patients with hypertension (10,000 complete cases). Missing data (missing at random) to independent variables were simulated at different missingness rates (20, 50%). The normalized root mean square error (NRMSE) between imputed values and real values for continuous variables and the proportion of falsely classified (PFC) for categorical variables were used to measure imputation accuracy. Computation time per imputation for each method was recorded. The differences in accuracy of different imputation methods were compared using ANOVA or non-parametric test. RESULTS: Both missForest and GAIN were more accurate than MICE. GAIN showed similar accuracy as missForest when the simulated missingness rate was 20%, but was more accurate when the simulated missingness rate was 50%. GAIN was the most accurate for the imputation of skewed continuous and imbalanced categorical variables at both missingness rates. GAIN had a much higher computation speed (32 min on PC) comparing to that of missForest (1300 min) when the sample size is 50,000. CONCLUSION: GAIN showed better accuracy as an imputation method for missing data in large real-world clinical datasets compared to MICE and missForest, and was more resistant to high missingness rate (50%). The high computation speed is an added advantage of GAIN in big clinical data research. It holds potential as an accurate and efficient method for missing data imputation in future big data clinical research. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03299010 ; Unique Protocol ID: HKUCTR-2232.

Anti-tumoral effect of arsenic compound, sodium metaarsenite (KML001), in non-Hodgkin's lymphoma: an in vitro and in vivo study.

Arsenic compounds have been used in traditional medicine for several centuries. KML001 (sodium metaarsenite; NaAsO2) is an orally bio-available arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in lymphoid neoplasms. The aim of this study is to evaluate the anti-proliferative effect of KML001 in non-Hodgkin's lymphoma and to compare its efficacy with As2O3. KML001 inhibited cellular proliferation in all tested lymphoma cell lines as well as JurkatR cells (adriamycin-resistant Jurkat cells) in a dose-dependent manner, while As2O3 was not effective. Cell cycle regulatory protein studies have suggested that KML001 induces G1 arrest via p27-induced inhibition of the kinase activities of CDK2, 4, and 6. Treatment of KML001 induced apoptosis in Jurkat and JurkatR cells. The apoptotic process was associated with down-regulation of Bcl-2 (antiapoptotic molecule), up-regulation of Bax (proapoptotic molecule), and inhibition of caspase-3, -8, and -9. In addition, cell signaling including the STAT, PI3K/Akt, MAPK, and NF-κB signal pathways were inhibited in KML001-treated Jurkat and JurkatR cells. Furthermore, targeting the telomere by KML001 was observed in the Jurkat and JurkatR cells. The In vivo anti-tumoral activity of KML001 was confirmed in a xenograft murine model. Interestingly, partial responses were seen in two lymphoma patients treated with 10 mg/day (follicular lymphoma for 16 weeks and mantle cell lymphoma for 24 weeks) without severe toxicities. These findings suggest that KML001 may be a candidate agent for the treatment of de novo, refractory, and relapsed non-Hodgkin's lymphoma patients.

Inhibitory effects of eupatilin on tumor invasion of human gastric cancer MKN-1 cells.

Extracts of the whole herb of Artemisia asiatica Nakai (Asteraceae) are used in traditional oriental medicine to treat inflammation. Eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone) is one of the pharmacologically active components found in A. asiatica, and has been shown to possess anti-tumoral effects in some malignancies, including gastric cancer. However, its anti-metastatic effect in gastric cancer is hardly known. In this study, anti-metastatic effect of eupatilin was investigated in the human gastric cancer cell line, MKN-1. Eupatilin inhibited MKN-1 growth in a dose- and a time-dependent manner, and induced apoptosis with a concomitant increase of caspase-3 activity. ELISA demonstrated that release of pro-inflammatory cytokines (IL-1ß, TNF-α, IL-6, and IL-8) was significantly reduced by eupatilin. And p-AKT and p-ERK (p44/42) was reduced. Expression level of ß-catenin and integrin was reduced and p-GSKß was increased. In transcription reporter system, the activity of the transcriptional factor, NF-κB, was reduced by eupatilin and the expression of p65 was down-regulated when MKN-1 cells were treated with eupatilin. Moreover, a zymography study revealed that this reduction in invasive potential resulted from a reduction in type IV collagenolytic (gelatinolytic) activity. The expressions of metalloproteinases (MMP-2 and MMP-9) were also reduced in MKN-1 cells treated with eupatilin. In vitro invasion assay, eupatilin inhibited MKN-1 penetrating reconstituted basement membrane barriers. These results suggest that eupatilin inhibits the MKN-1 gastric cancer cell proliferation via activation of caspase-3 and the metastatic potential of gastric cancer cells via down-regulation of NF-κB activity followed by reduction of pro-inflammatory cytokine-mediated MMPs expressions.

Anti-leukemic effect of 2-pyrone derivatives via MAPK and PI3 kinase pathways.

Substituted 2-pyrones are important structural sub-units present in a number of natural products having broad range of biological activity. However, little is known about the anti-cancer effect of 2-pyrone derivatives including leukemia. Therefore, this present study was undertaken to investigate the effect of 2-pyrone derivatives in human acute myeloid leukemia (AML). Among 23 synthesized derivatives, 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (code name; pyrone 9) showed the most potent antileukemic activity with 5 × 10(-6) M to 5 × 10(-5) M of IC(50) in various AML cell lines as well as primary leukemic blasts from AML patients, while normal peripheral blood mononuclear cells was not affected by pyrone 9. Flow cytometric analysis indicated that pyrone 9 induced the G1 and G2 phase dual arrest of the cell cycle in HL-60 cells. To address the mechanism of the antileukemic effect of pyrone 9, we examined the effect of pyrone 9 on cell cycle-related proteins in HL-60 cell. The levels of CDK2, CDK4, CDK6, CDK1, cyclin B1 and cyclin E were decreased; in contrast, cyclin A was not altered. In addition, pyrone 9 not only increased the p27 level but also enhanced its binding to with CDK2, CDK4 and CDK6 which resulted in the reduction of CDK2-, CDK4- and CDK6-associated kinase activities. Pyrone 9 also induced the apoptosis in HL-60 cells. The apoptotic process of HL-60 cells was associated with increased Bax, decreased Bcl-2 and activation of caspase-8, -9, -3 and PARP. Antileukemic effect of pyrone 9 was associated with activation of mitogen-activated protein kinase (MAPK) pathway, as evidenced by activation of p-ERK and p38 MAPK. In addition, pyrone 9 was influenced PI3 kinase pathway. Expressions of p-Akt (ser473), p-Raf, and p-PDK were down-regulated; in contrast, those of PTEN and p-PTEN were up-regulated. Furthermore, pyrone 9 suppressed NF-κB pathway signaling. To gain insights into the antileukemic activity of pyrone 9 in vivo, BALB/c mouse leukemic model was established using intraperitoneal inoculation of syngeneic WEHI-3BD(+) mouse leukemic cells. Pyrone 9 inhibited in vitro and in vivo the growth of WEHI-3BD(+) cells, and ultimately, prolonged the survival of pyrone 9-treated mice. These findings suggest that the pyrone 9 inhibits the cell proliferation of human AML cell line, HL-60, through MAPK and PI3 kinase pathway as well as induction of cell cycle arrest. In particular, pyrone 9 prolonged the survival of pyrone 9-treated leukemic mice.

Development of a machine learning model for the prediction of the short-term mortality in patients in the intensive care unit.

PURPOSE: The aim of this study was to develop and evaluate a machine learning model that predicts short-term mortality in the intensive care unit using the trends of four easy-to-collect vital signs. MATERIALS AND METHODS: The primary training cohort included 1968 patients at the Veterans Health Service Medical Center. The external validation cohort comprised 409 patients at Seoul National University Hospital. Datasets of heart rate, systolic blood pressure, diastolic blood pressure, and peripheral capillary oxygen saturation (SpO2) measured every hour for 10 h were used. The performances of mortality prediction models generated using five machine learning algorithms, Random Forest (RF), XGboost, perceptron, convolutional neural network, and Long Short-Term Memory, were calculated and compared using area under the receiver operating characteristic curve (AUROC) values and an external validation dataset. RESULTS: The machine learning model generated using the RF algorithm showed the best performance. Its AUROC was 0.922, which is much better than the 0.8408 of the Acute Physiology and Chronic Health Evaluation II. The machine learning model developed using SpO2 showed the best performance (AUROC, 0.89). CONCLUSIONS: This simple yet powerful new mortality prediction model could be useful for early detection of probable mortality and appropriate medical intervention, especially in rapidly deteriorating patients.

A fiberoptic orotracheal intubation successfully performed using a modified Guedel airway in a sedated emergency patient - A case report.

BACKGROUND: Fiberoptic intubation is a powerful and safe technique to deal with airway difficulty, but it requires a lot of training to be able to perform correctly. There are various specialized oral airways for fiberoptic intubation, but none of them have perfect functionality. CASE: A 75-year-old male (body weight 71.6 kg, height 159.3 cm, body mass index 28.22 kg/m2) was diagnosed with acute appendicitis, and it was decided to do a laparoscopic appendectomy. After the induction of general anesthesia, it was impossible to insert the direct laryngoscope deep enough for vocal cord visualization without damaging the teeth because of limited mouth opening. We successfully performed fiberoptic intubation with a newly modified Guedel airway via a longitudinal channel on the convex side and a distal opened lingual end. CONCLUSIONS: Our modified Guedel airway can be useful in assisting fiberoptic intubation in unexpectedly difficult airway situations.

A novel urinary mRNA signature using the droplet digital polymerase chain reaction platform improves discrimination between prostate cancer and benign prostatic hyperplasia within the prostate-specific antigen gray zone.

Purpose: The aim of this study was to identify a noninvasive urinary marker for prostate cancer (PCa) diagnosis and to validate the clinical performance of this novel urinary mRNA signature using the droplet digital polymerase chain reaction (ddPCR) approach. Materials and Methods: A gene expression microarray (HT-12, Illumina Inc., USA) was used to identify genes differentially expressed between 16 PCa and 8 benign prostatic hyperplasia (BPH) tissues; ddPCR (QX200; Bio-Rad Laboratories, USA) was carried out to quantify the expression of selected genes in urine. The urinary molecular PCa risk score (UMPCaRS) was calculated by using the sum of three upregulated genes as the numerator and the sum of three downregulated genes as the denominator. The diagnostic utility of the UMPCaRS was validated by using a screening set (10 PCa and 10 BPH samples) and a validation set (131 PCa and 105 BPH samples). Results: Three upregulated genes (PDLIM5, GDF-15, THBS4) and three downregulated genes (UPK1A, SSTR3, NPFFR2) were selected from the microarray and subjected to ddPCR. The UMPCaRS for PCa in the screening and validation sets was significantly higher than that for BPH. For the validation set, the diagnostic accuracy of the UMPCaRS was comparable with that of prostate-specific antigen (PSA). Importantly, in the "PSA gray zone" (3-10 ng/mL), the AUC for the UMPCaRS was 0.843 and that for PSA was 0.628 (p<0.001). Conclusions: The data demonstrate that the UMPCaRS is useful for discriminating between PCa and BPH in the "PSA gray zone".

Antileukemic effect of a synthetic vitamin D3 analog, HY-11, with low potential to cause hypercalcemia.

1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] is capable of inhibiting the proliferation of acute myelogenous leukemia (AML). However, toxicity of hypercalcemia has limited the use of 1,25(OH)2D3 in clinical trials. We have evaluated 11 synthesized vitamin D3 analogs for their ability to inhibit clonal growth of HL-60 myeloid leukemic cells. Among the 11 vitamin D3 analogs, HY-11 (code name) showed the most potent antileukemic activity with 2.5x10(-6) M of IC50, however, it did not affect the cellular growth of normal peripheral blood mononuclear cells until 10(-6) M. Flow cytometric analysis indicated that HY-11 induced the G1 arrest in a dose-dependent manner, which was mediated via inactivation of CDK4 and CDK6 in association with up-regulation of CDKI (cyclin-dependent kinase inhibitor), p27 and Rb protein. Induction of apoptosis was mediated via caspase-3 pathway in HY-11-treated HL-60. In addition, HY-11 enhanced the expression of TGF-beta1, TGF-beta receptor type I and II and vitamin D3 receptor (VDR). VDR expression was increased by TGF-beta1, suggesting that TGF-beta1 might be involved in the antiproliferative effect of HY-11 on HL-60 cells by autocrine and paracrine regulation. Serum calcium levels were within normal limit when HY-11 was given intraperitoneally (i.p.) every other day for 5 weeks to BALB/c mice at the doses of 10(-7), 10(-6)and 10(-5) M. HY-11 inhibited the growth of WEHI-3BD+ mouse leukemic cells in vitro, and syngeneic BALB/c mice that received WEHI-3BD+ mouse leukemic cells and HY-11 had a significantly longer survival without producing hypercalcemia compared to control group. In summary, HY-11 is a vitamin D3 analog that inhibited the proliferation of human AML cell line, HL-60, through induction of cell cycle arrest, triggering apoptosis as well as modulation of TGF-beta1 and its receptors. In particular, HY-11 significantly increased the survival of mice that had myeloid leukemia without producing hypercalcemia.

Advanced glycation end product (AGE)-induced proliferation of HEL cells via receptor for AGE-related signal pathways.

This study investigated whether advanced glycation end products (AGE) and RAGE (receptor for AGE) are involved in the proliferation of leukemia cells. AGE strongly induced the proliferation of primary acute myeloid leukemia (AML) cells and cell lines. MAP kinase, PI3K and JAK/STAT pathways were involved in cellular proliferation of HEL cells by AGE. RAGE antisense S-ODN effectively inhibited cell growth, induced apoptosis and reversed AGE-induced expression of targeting molecules in HEL cells. The study demonstrated for the first time that AGE directly induced human AML cell proliferation via the MAPK, PI3K and JAK/STAT pathways.

Postoperative delirium in elderly patients with critical limb ischemia undergoing major leg amputation: a retrospective study.

BACKGROUND: Critical limb ischemia has been identified as a risk factor for the incidence of postoperative delirium in elderly patients. Limb amputation is the last option in critical limb ischemia treatments. We investigated the incidence and predisposing factors of postoperative delirium in patients undergoing major leg amputation. METHODS: From January 2012 to December 2016, 121 patients aged over 60 years who had undergone major leg amputation were enrolled in this study. Various factors related to the patients' outcomes were assessed, including demographic, preoperative laboratory, anesthetic, surgical, and postoperative indicators. RESULTS: Twenty two patients were excluded and 99 patients were assigned to either the delirium group or no delirium group. Forty of them (40%) developed a delirium during 30 days postoperatively. Univariate analysis implied that end-stage renal disease on hemodialysis, alcohol consumption, C-reactive protein, staying in an intensive care unit (ICU), duration of an ICU stay, occurrence of complications, and mortality during six months, were the factors that accounted for significant differences between the two groups. In multivariate analysis, three factors were significantly related to the development of delirium: mortality during six months (odds ratio [OR] = 13.86, 95% CI [2.10-31.90]), alcohol (OR = 8.18, 95% CI [1.13-16.60]), and hemodialysis (OR = 4.34, 95% CI [2.06-93.08]). CONCLUSIONS: Approximately 40% of the elderly patients suffered from postoperative delirium in major leg amputation. Identifying those with risk factors for postoperative delirium and intervening at the early stage will be of great benefit in major leg amputations for the elderly population.

Radioprotective effects of various cytokines in peripheral blood mononuclear cells and C3H mice.

The purpose of this study was to investigate the radioprotective effect of HGFs (GM-CSF, IL-3 and SCF) in irradiated human peripheral blood mononuclear cells (PBMCs) in vitro, and the survival effect of lethally irradiated C3H mice in vivo. The irradiation of human PBMCs using a (137)Cs irradiator showed a dose-dependent inhibition of cell growth up to a dose of 5 Gy. This cell growth inhibition induced apoptosis, which was associated with the down-regulation of Bcl-2, up-regulation of Bax, depolarization of mitochondrial transmembrane potential (Delta psi m), and caspase-3 and -9 activation. Following gamma-irradiation at 2 Gy, IL-3 (10 ng/ml) alone or combined with SCF (50 ng/ml) reduced the apoptotic portion of human PBMCs by 15 and 20% of the cell population, respectively, showing no activation of caspase-3 compared to the control group. To examine the in vivo effect of gamma-irradiation and cytokines, we investigated the survival rate and recovery of peripheral blood cells in C3H mice. C3H mice subjected to total body irradiation (TBI) at a dose of 7 Gy (lethal dose 83% at 30 days) showed time-dependent decreases in RBC, WBC and platelet counts, with the nadir occurring at 12 to 15 days. However, treatment with recombinant murine (rm) SCF (2 microg/day s.c.), rmIL-3 (2 microg/day s.c.), or rmG-CSF (2.5 microg/day s.c.) 24 h before and after irradiation did not promote hematologic recovery or survival in the lethally irradiated C3H mice. These findings indicate that the combined treatment of IL-3 and SCF prevents the apoptosis induced in PBMCs by gamma-irradiation in vitro, but it does not afford any in vivo radioprotective effect in lethally irradiated C3H mice.

Anti-leukemic effect of sodium metaarsenite (KML001) in acute myeloid leukemia with breaking-down the resistance of cytosine arabinoside.

Sodium metaarsenite (NaAs2O3: code name KML001) is an orally bioavailable arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in acute myeloid leukemia (AML). We investigated the anti-leukemic effect of KML001 in AML, and determined the mode of action of KML001. KML001 inhibited the cellular proliferation in all AML cell lines and primary AML blasts as well as HL-60R (cytosine arabinoside-resistant HL-60) cells, while As2O3 was not effective in primary AML blasts and AML cell lines including HL-60R cells. KML001 induced G1 arrest and apoptosis in HL-60 and HL-60R cells. KML001 inhibited the activation of STAT (signal transducer and activator of transcription) 1, 3, 5, NF-κB, AKT and PI3K, while phosphorylated PTEN was upregulated. In addition, activation of ERK, p38 and JNK was observed in KML001-induced growth inhibition of HL-60 and HL-60R cells. Furthermore, KML001 induced telomeric terminal restriction fragment (TRF) length shortening in a time-dependent manner in HL-60 and HL-60R cells. Real­time PCR with RNA extracted from KML001-treated HL-60 and HL-60R cells showed a significant reduction of catalytic subunit of telomerase, hTERT, in a time-dependent manner. Additionally, γ-H2AX, a sensitive molecular marker of DNA damage, in HL-60 and HL-60R cells was induced by KML001. These results suggest that KML001 inhibits the proliferation of AML cells including cytosine arabinoside-resistant AML cells via various mechanisms such as cell cycle arrest, induction of apoptosis, inhibition of JAK/STAT and PI3K pathways, activation of MAPK pathway and telomere targeting.

Epidural anesthesia for permanent spinal cord stimulation with a cylindrical type lead: a case series.

Spinal cord stimulation (SCS) in trials involving external stimulation are easily conducted under local anesthesia. However, implantation of a permanent SCS system is painful, and can be intolerable in some patients. Epidural anesthesia can be used to perform the SCS implantation without discomfort if the patient can localize the area of paresthesia. However, little is known about epidural anesthesia for SCS. This paper reports 23 cases of permanent SCS with a cylindrical type lead implanted under the epidural anesthesia. Epidural anesthesia was sufficient in 22 patients without discomfort and significant complications. The remaining patient experienced incomplete epidural anesthesia and required additional analgesics to blunt the pain. All the leads were placed consistent with the patient's report of paresthesia area under epidural anesthesia. Thus, epidural anesthesia is an effective and safe method for the optimal placement of SCS to minimize the discomfort for patients without impairing patients' response to the intraoperative stimulation test.

Association between the use of gel pads under patients' knees and the incidence of peroneal neuropathy following liver transplantation.

INTRODUCTION: There have been intermittent reports of peroneal neuropathy (PN) occurring after liver transplantation. Although PN may not be viewed as a serious complication by liver transplant (LT) recipients who require the transplant for survival, PN can significantly reduce quality of life. The incidence of PN appears to have increased after the use of gel pads was introduced. These gel pads, which are placed under patients' knees during surgery, are used to reduce lower back strain and prevent contact between the peroneal nerve at the fibular head and the hard surface of the operating table. The aim of the present study was to investigate the association, if any, between the use of gel pads and the incidence of PN. METHODS: The medical records of 261 adult LT recipients were retrospectively reviewed. The recipients were divided into gel pad (n = 167) and non-gel pad (n = 94) groups. The incidence and possible risk factors of PN were compared between the two groups. RESULTS: The overall incidence of PN was 8.0% (21/261). The occurrence of PN was significantly higher in the gel pad group than in the non-gel pad group (10.8% vs. 3.2%; p < 0.05). Other possible risk factors were comparable between the two patient groups. CONCLUSION: As the use of gel pads may increase the incidence of PN, we recommend against the use of gel pads under the knees of LT recipients.

Treatment of digit ulcers in a patient with Buerger's disease by using cervical spinal cord stimulation -a case report-.

Buerger's disease (thromboangiitis obliterans) is known as a segmental inflammatory vasculitis that involves the small-sized and medium-sized arteries, veins, and nerves. Most effective treatment for Buerger's disease is smoking cessation. Except for the cessation of tobacco use, surgical revascularization is available in severe ischemia and a distal target vessel. Amputation has been used as the last treatment option of the disease up to the present. Increasing limb survival and decreasing amputation rate is important. This case describes the use of spinal cord stimulation (SCS) in patient with Buerger's disease and its effect is not only the complete healing of ulcers but also amputation is not performed.

Chloroquine enhances the chemotherapeutic activity of 5-fluorouracil in a colon cancer cell line via cell cycle alteration.

Autophagy is a conserved catabolic process that degrades cytoplasmic proteins and organelles for recycling. The role of autophagy in tumorigenesis is controversial because autophagy can be either protective or damaging to tumor cells, and its effects may change during tumor progression. A number of cancer cell lines have been exposed to chloroquine, an anti-malarial drug, with the aim of inhibiting cell growth and inducing cell death. In addition, chloroquine inhibits a late phase of autophagy. This study was conducted to investigate the anti-cancer effect of autophagy inhibition, using chloroquine together with 5-fluorouracil (5-FU) in a colon cancer cell line. Human colon cancer DLD-1 cells were treated with 5-FU (10 µΜ) or chloroquine (100 µΜ), or a combination of both. Autophagy was evaluated by western blot analysis of microtubule-associated protein light chain3 (LC3). Proliferative activity, alterations of the cell cycle, and apoptosis were measured by MTT assays, flow cytometry, and western blotting. LC3-II protein increased after treatment with 5-FU, and chloroquine potentiated the cytotoxicity of 5-FU. MTT assays showed that 5-FU inhibited proliferation of the DLD-1 cells and that chloroquine enhanced this inhibitory effect of 5-FU. The combination of 5-FU and chloroquine induced G1 arrest, up-regulation of p27 and p53, and down-regulation of CDK2 and cyclin D1. These results suggest that chloroquine may potentiate the anti-cancer effect of 5-FU via cell cycle inhibition. Chloroquine potentiates the anti-cancer effect of 5-FU in colon cancer cells. Supplementation of conventional chemotherapy with chloroquine may provide a new cancer therapy modality.

Anti-leukemic effect of a synthetic compound, (±) trans-dihydronarciclasine (HYU-01) via cell-cycle arrest and apoptosis in acute myeloid leukemia.

(±) trans-Dihydronarciclasine, isolated from Chinese medicinal plant Zephyranthes candida, has been shown to possess quite potent anti-tumoral effect against selected human cancer cell lines. However, little is known about the anti-tumoral effect of (±) trans-dihydronarciclasine in acute myeloid leukemia (AML). This study was performed to investigate the effect of a novel synthetic (±) trans-dihydronarciclasine (code name; HYU-01) in AML. The HYU-01 inhibited the proliferation of various AML cell lines including HL-60 as well as primary leukemic blasts in a dose-dependent manner. To investigate the mechanism of the anti-proliferative effect of HYU-01, cell-cycle analysis was attempted in HL-60 cells, resulting in G1 arrest. The expression levels of CDK2, CDK4, CDK6, cyclin E, and cyclin A were decreased in a time-dependent manner. In addition, HYU-01 up-regulated the expression of the p27, and markedly enhanced the binding of p27 with CDK2, 4, and 6, ultimately resulting in the decrease of their kinase activities. Furthermore, HYU-01 induced the apoptosis through the induction of proapoptotic molecules and reduction of antiapoptotic molecules in association with the activation of caspase-3, -8, and -9. These results suggest that HYU-01 may inhibit the proliferation of HL-60 cells, via apoptosis, as well as G1 block in association with the induction of p27.

Effect of pretreatment with gabapentin on withdrawal movement associated with intravenous rocuronium injection.

BACKGROUND: The major disadvantage of rocuronium is the withdrawal movement associated with its injection. The analgesic effect of perioperative gabapentin has been evaluated. We investigated the effects of gabapentin on the withdrawal movement induced by rocuronium injection. METHODS: 86 ASA physical status I or II patients, aged 18-69 years who were scheduled to undergo elective surgery with general anesthesia were enrolled. Patients were randomly allocated into two groups to receive either gabapentin 600 mg or placebo 2 hours prior to surgery. The patient's response to rocuronium injection was graded using a 4-point scale. RESULTS: The incidence of withdrawal movement after rocuronium administration was significantly lower in the gabapentin group (55.0% in the control group vs 28.6% in the gabapentin group). The number of patients with generalized response indicating severe pain, was 9 (22.5%) in the control group and 3 (7.1%) in the gabapentin group. CONCLUSIONS: Pretreatment with a single oral dose of gabapentin 600 mg reduced the incidence and severity of withdrawal movement after rocuronium administration.

Enhancer of zeste homolog 2 expression is associated with tumor cell proliferation and metastasis in gastric cancer.

The enhancer of zeste homolog 2 (EZH2), a member of the polycomb group of proteins, plays an important role in cell proliferation and cell cycle regulation. EZH2 is overexpressed in aggressive forms of prostate, breast, bladder, and endometrial cancers. However, the role of EZH2 expression in gastric cancer has not been fully determined. This study was conducted to investigate the correlation between EZH2 and cell cycle-related molecules, and the clinical value of EZH2 expression in gastric cancer. We analyzed EZH2 expression using Western blotting in AGS, MKN-28, SNU-16, SNU-484, SNU-601, and SNU-638 gastric cancer cell lines. After transfection of EZH2 siRNA into MKN-28 cells, the change in cell cycle-related molecules was assessed by Western blot analysis. Expression of EZH2, Ki-67, and p53 was determined by immunohistochemical staining of tissue microarrays from specimens of 137 cases of resected gastric cancer. We found high expressions of EZH2 in all of the tested gastric cancer cell lines. RNA interference of EZH2 induced upregulation of p53 and HDAC1 and downregulation of cyclin D1 and cyclin E. High EZH2 expression was observed in 60.6% of gastric cancers and in 6.7% of non-neoplastic gastric tissues (p < 0.01); 40.1% were positive for p53 in gastric cancers. High EZH2 expression was correlated with Ki-67 and p53 expressions and was significantly associated with distant metastases and non-signet ring cells. Our results suggest that high EZH2 expression is associated with tumor cell proliferation and metastasis in gastric cancer.

Anesthetic experience of methemoglobinemia detected during general anesthesia for gastrectomy of advanced gastric cancer -A case report-.

Methemoglobinemia is an uncommon but potentially fatal disorder. Most cases have no adverse clinical consequence and require no treatment, but methemoglobinemia is often overlooked as a cause of low oxygen saturation, and often mistaken for the more common causes of hypoxia by anesthesiologists despite simple bedside tests that indicate the presence of this treatable abnormality. We present a 68-year-old female patient who underwent gastrectomy for advanced gastric cancer with bleeding. In the preoperative period, the patient showed cyanosis and oxygen saturation was 85% by pulse oximeter, but oxygen saturation by arterial blood gas analysis was 100%. After tracheal intubation, the methemoglobin level was 18.3%. Ascorbic acid and methylene blue were administered. During preanesthetic evaluation, the patient had not informed the anesthesiologist that she had been taking dapsone.