Predictive DNA damage signaling for low­dose ionizing radiation.

Numerous studies have attempted to develop biological markers for the response to radiation for broad and straightforward application in the field of radiation. Based on a public database, the present study selected several molecules involved in the DNA damage repair response, cell cycle regulation and cytokine signaling as promising candidates for low­dose radiation­sensitive markers. The HuT 78 and IM­9 cell lines were irradiated in a concentration­dependent manner, and the expression of these molecules was analyzed using western blot analysis. Notably, the activation of ataxia telangiectasia mutated (ATM), checkpoint kinase 2 (CHK2), p53 and H2A histone family member X (H2AX) significantly increased in a concentration­dependent manner, which was also observed in human peripheral blood mononuclear cells. To determine the radioprotective effects of cinobufagin, as an ATM and CHK2 activator, an in vivo model was employed using sub­lethal and lethal doses in irradiated mice. Treatment with cinobufagin increased the number of bone marrow cells in sub­lethal irradiated mice, and slightly elongated the survival of lethally irradiated mice, although the difference was not statistically significant. Therefore, KU60019, BML­277, pifithrin­α, and nutlin­3a were evaluated for their ability to modulate radiation­induced cell death. The use of BML­277 led to a decrease in radiation­induced p­CHK2 and γH2AX levels and mitigated radiation­induced apoptosis. On the whole, the present study provides a novel approach for developing drug candidates based on the profiling of biological radiation­sensitive markers. These markers hold promise for predicting radiation exposure and assessing the associated human risk.

Cumulative exposure to hypertriglyceridemia and risk of type 2 diabetes in young adults.

AIM: This study aimed to examine whether cumulative exposure to hypertriglyceridemia is associated with an increased risk of developing type 2 diabetes in young adults. METHODS: The study included 1,840,251 participants aged 20-39 years who had undergonefourconsecutiveannualhealth checkups and had no history of type 2 diabetes. Participants werecategorized into five groups (exposure score 0-4) based on the frequencies of hypertriglyceridemia diagnosis over a four-year period. The primary outcome was newly diagnosed type 2 diabetes. Exploratory analyses were performed for the different subgroups. RESULTS: During a follow-up period of 6.53 years, 40,286 participants developed type 2 diabetes. The cumulative incidence of type 2 diabetes significantly increased with higher exposure scores for hypertriglyceridemia (log-rank test, P < 0.001). The multivariable-adjusted hazard ratios for incident diabetes were 1.674 (95 % CI, 1.619, 1.732), 2.192 (95 % CI, 2.117, 2.269), 2.637 (95 % CI, 2.548, 2.73), and 3.715 (95 % CI, 3.6, 3.834) for participants with scores of 1-4, respectively, compared with those with an exposure score of 0. CONCLUSIONS: In this large-scale prospective cohort study of young adults, cumulative exposure to hypertriglyceridemia was significantly associated with an increased risk of type 2 diabetes, independent of lifestyle-related factors.

Type 2 Diabetes and Its Association With Psychiatric Disorders in Young Adults in South Korea.

Importance: Because type 2 diabetes (T2D) has become increasingly prevalent among young adults, the study of the association of T2D with psychiatric disorders in young adults is important for early detection and timely intervention. Objective: To determine whether a diagnosis of a psychiatric disorder is associated with increased risk of developing T2D in young adults. Design, Setting, and Participants: This large-scale prospective cohort study used data collected by the South Korean National Health Insurance Service between 2009 and 2012, representing 97% of the South Korean population. Young adults aged 20 to 39 years with and without diagnoses of psychiatric disorders were included in the study. Young adults with missing data and those with a history of T2D were excluded from the study. The cohort was followed up to monitor development of T2D until December 2018. Data were analyzed from March 2021 to February 2022. Exposure: Diagnosis of 1 of 5 psychiatric disorders, including schizophrenia, bipolar disorder, depressive disorder, anxiety disorder, and sleep disorder. Main Outcomes and Measures: The primary outcome was newly diagnosed T2D during a follow-up period of 7.59 years. The incidence rate of T2D was calculated as the number of new cases per 1000 person-years during the follow-up period. The Cox proportional hazards regression model was used to estimate the hazard ratios (HRs) and 95% CIs for T2D incidence. Exploratory analyses were performed for subgroups stratified by age and sex. Results: In total, 6 457 991 young adults (mean [SD] age, 30.74 [4.98] years; 3 821 858 men [59.18%]) were followed up, including 658 430 individuals with psychiatric disorders. The cumulative incidence of T2D differed significantly between individuals with and without psychiatric disorders (log-rank test, P < .001). Incidence rates of T2D for individuals with and without psychiatric disorders were 2.89 and 2.56 per 1000 person-years, respectively. Individuals with a diagnosis of any psychiatric disorder showed a higher risk of developing T2D than those without a diagnosis (adjusted HR, 1.20; 95% CI, 1.17-1.22). The adjusted HRs for T2D were 2.04 (95% CI, 1.83-2.28) for individuals with schizophrenia, 1.91 (95% CI, 1.73-2.12) for individuals with bipolar disorder, 1.24 (95% CI, 1.20-1.28) for individuals with depressive disorder, 1.13 (95% CI, 1.11-1.16) for individuals with anxiety disorder, and 1.31 (95% CI, 1.27-1.35) for individuals with sleep disorder. Conclusions and Relevance: In this large-scale prospective cohort study of young adults, 5 psychiatric disorders were significantly associated with an increased risk of developing T2D. Young adults with schizophrenia and bipolar disorder in particular were at a higher risk of T2D. These results have important implications for early detection of and timely intervention in T2D for young adults with psychiatric disorders.

Cumulative exposure to metabolic syndrome in a national population-based cohort of young adults and sex-specific risk for type 2 diabetes.

BACKGROUND: Metabolic syndrome is associated with type 2 diabetes and its prevalence is increasing worldwide in young adults. We aimed to determine whether cumulative exposure to metabolic syndrome is associated with type 2 diabetes risk in young adults. METHODS: Data of 1,376,540 participants aged 20-39 years without a history of type 2 diabetes and who underwent four annual health check-ups were collected. In this large-scale prospective cohort study, we evaluated the incidence rates and hazard ratios (HRs) of diabetes according to cumulative frequencies of metabolic syndrome over 4 years of consecutive annual health check-ups (burden score 0-4). Subgroup analyses were performed by sex and age. RESULTS: During 5.18 years of follow-up, 18,155 young adults developed type 2 diabetes. The incidence of type 2 diabetes increased with burden score (P < 0.0001). The multivariable-adjusted HRs for type 2 diabetes were 4.757, 10.511, 18.288, and 31.749 in participants with a burden score of 1 to 4, respectively, compared to those with 0. In subgroup analyses, the risk of incident diabetes was greater in women than men and in the 20-29 years age group than the 30-39 years age group. The HRs were 47.473 in women and 27.852 in men with four burden scores. CONCLUSION: The risk of type 2 diabetes significantly increased with an increase in the cumulative burden of metabolic syndrome in young adults. Additionally, the association between cumulative burden and diabetes risk was stronger in women and the 20s age group.

Poliovirus receptor inhibition in breast cancer cells induces antitumor immunity via T cell activation.

Radiotherapy (RT) is a commonly used treatment option for patients with cancer because it can effectively control tumor growth and kill tumor cells. However, the impact of RT goes beyond direct tumor cell killing because it can change the tumor microenvironment by altering surrounding tissues and infiltrating cells and modulating the expression of immune checkpoints. Poliovirus receptor (PVR, cluster of differentiation (CD)155), a member of the nectin-like molecule family, is overexpressed in many human cancers. However, its role in the tumor growth and T-cell immune responses of triple-negative breast cancer (TNBC) remains unclear. In the present study, we observe that radiation exposure increases PVR expression in MDA-MB-231 and BT549 cells. Silencing PVR not only inhibited the proliferation of breast cancer cells but also significantly enhanced the cytotoxicity of cytotoxic T lymphocytes (CTLs) compared with the control or RT groups. Treatment of T cells with PVR decreased CD8+ T cells, increased CD4+ T cells, and induced PVR ligands such as T cell immunoreceptor with immunoglobulin and ITIM domain, CD226, and CD96. However, after treatment with PVR, CTL responses decreased and secretion of interferon-γ, tumor necrosis factor-α, interleukin (IL)-2, IL-6, and IL-10 was significantly inhibited. In contrast, PVR knockdown increased the production of these cytokines, illustrating the immunosuppressive function of PVR. Suppression of PVR using an anti-PVR antibody inhibited 4T1 tumor growth by increasing immune cell infiltration. These results provide new insights into the role of PVR in TNBC and highlight its potential as a target for T cell-mediated immunotherapy in breast cancer.

Inertia-Acoustophoresis Hybrid Microfluidic Device for Rapid and Efficient Cell Separation.

In this paper, we proposed an integrated microfluidic device that could demonstrate the non-contact, label-free separation of particles and cells through the combination of inertial microfluidics and acoustophoresis. The proposed device integrated two microfluidic chips which were a PDMS channel chip on top of the silicon-based acoustofluidic chip. The PDMS chip worked by prefocusing the particles/cells through inducing the inertial force of the channel structure. The connected acoustofluidic chips separated particles based on their size through an acoustic radiation force. In the serpentine-shaped PDMS chip, particles formed two lines focusing in the channel, and a trifugal-shaped acoustofluidic chip displaced and separated particles, in which larger particles focused on the central channel and smaller ones moved to the side channels. The simultaneous fluidic works allowed high-efficiency particle separation. Using this novel acoustofluidic device with an inertial microchannel, the separation of particles and cells based on their size was presented and analyzed, and the efficiency of the device was shown. The device demonstrated excellent separation performance with a high recovery ratio (up to 96.3%), separation efficiency (up to 99%), and high volume rate (>100 µL/min). Our results showed that integrated devices could be a viable alternative to current cell separation based on their low cost, reduced sample consumption and high throughput capability.

Receptor interacting protein 1 knockdown induces cell death in liver cancer by suppressing STAT3/ATR activation in a p53-dependent manner.

The survival and death of eukaryotic cells are tightly controlled by a variety of proteins in response to the cellular environment. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a receptor-interacting Ser/Thr kinase that has recently been reported as an important regulator of cell survival, apoptosis, and necroptosis; however, its role in liver cancer remains unclear. In this study, we examined the effect of siRNA-mediated RIPK1 knockdown on the survival and death of liver cancer cells. Treatment with siRIPK1 decreased the growth rate of liver cancer cells and increased apoptotic, but not necrotic cell death, which was higher in wild-type p53 (wt-p53) cells than in mutant-type p53 (mt-p53) cells. In addition, RIPK1 knockdown increased p53 expression and G1 phase arrest in wt-p53 cells. Although suppressing p53 did not alter RIPK1 expression, it did attenuate siRIPK1-induced cell death. Interestingly, RIPK1 knockdown also increased the generation of reactive oxygen species and DNA damage by inhibiting signal transduced and activator of transcription 3 (STAT3) and ATM and RAD3-related (ATR) in wt-p53 cells but not in mt-p53 cells. Moreover, STAT3 or ATR inhibition in p53 mutant cells restored siRIPK1-mediated cell death. Together, the results of this study suggest that RIPK1 suppression induces apoptotic cell death by inhibiting the STAT3/ATR axis in a p53-dependent manner. Furthermore, these findings suggest that RIPK1, alone or in combination, may be a promising target for treating liver cancer.

PCW-1001, a Novel Pyrazole Derivative, Exerts Antitumor and Radio-Sensitizing Activities in Breast Cancer.

As pyrazole and its derivatives have a wide range of biological activities, including anticancer activity, the design of novel pyrazole derivatives has emerged as an important research field. This study describes a novel pyrazole derivative that exerts antitumor and radiosensitizing activities in breast cancer both in vitro and in vivo. We synthesized a novel pyrazole compound N,N-dimethyl-N'-(3-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)phenyl)azanesulfonamide (PCW-1001) and showed that it inhibited several oncogenic properties of breast cancer both in vitro and in vivo. PCW-1001 induced apoptosis in several breast cancer cell lines. Transcriptome analysis of PCW-1001-treated cells showed that it regulates genes involved in the DNA damage response, suggesting its potential use in radiotherapy. Indeed, PCW-1001 enhanced the radiation sensitivity of breast cancer cells by modulating the expression of DNA damage response genes. Therefore, our data describe a novel pyrazole compound, PCW-1001, with antitumor and radiosensitizer activities in breast cancer.

BHMPS Inhibits Breast Cancer Migration and Invasion by Disrupting Rab27a-Mediated EGFR and Fibronectin Secretion.

Our previous work demonstrated that (E)-N-benzyl-6-(2-(3, 4-dihydroxybenzylidene) hydrazinyl)-N-methylpyridine-3-sulfonamide (BHMPS), a novel synthetic inhibitor of Rab27aSlp(s) interaction, suppresses tumor cell invasion and metastasis. Here, we aimed to further investigate the mechanisms of action and biological significance of BHMPS. BHMPS decreased the expression of epithelial-mesenchymal transition transcription factors through inhibition of focal adhesion kinase and c-Jun N-terminal kinase activation, thereby reducing the migration and invasion of breast cancer. Additionally, knockdown of Rab27a inhibited tumor migration, with changes in related signaling molecules, whereas overexpression of Rab27a reversed this phenomenon. BHMPS effectively prevented the interaction of Rab27a and its effector Slp4, which was verified by co-localization, immunoprecipitation, and in situ proximity ligation assays. BHMPS decreased the secretion of epidermal growth factor receptor and fibronectin by interfering with vesicle trafficking, as indicated by increased perinuclear accumulation of CD63-positive vesicles. Moreover, administration of BHMPS suppressed tumor growth in Rab27a-overexpressing MDA-MB-231 xenograft mice. These findings suggest that BHMPS may be a promising candidate for attenuating tumor migration and invasion by blocking Rab27a-mediated exocytosis.

Effects of feeding starch sugar by-products on in situ rumen disappearance rate, growth performance, and carcass characteristics of late finishing Hanwoo steers.

OBJECTIVE: The aim of this study was to determine the effects of feeding starch sugar by-products (SSBs) on in situ disappearance rate, performance, and carcass characteristics of Hanwoo steers in the late finishing stage. METHODS: To determine the in situ disappearance rate, nylon bags filled with 5 g of SSB were inserted into the ventral sac of two cannulated Holsteins cows and incubated for 0, 2, 4, 8, 16, 24, and 48 h. A total of 30 Hanwoo steers were fed the experimental diets, which were basal diet (control) and 7% SSB on an as-fed basis (4.35% dry matter [DM]), formulated according to requirements of the Korean Feeding Standard for Hanwoo. The experiment was conducted over 80 days using a completely randomized block design. RESULTS: Soluble fraction a of DM and organic matter (OM) was 44.20% and 64.60% DM, fraction b was 23.00% and 19.40% DM, and c values (the rate of degradation of fraction b) were 0.04 and 0.04/h, respectively. The effective degradability of DM at rumen solid outflow rates of 0.02, 0.05, and 0.08/h was 59.83, 54.75, and 52.16, respectively, and for OM was 77.78, 73.52, and 71.34, respectively. Initial and final body weight, average daily gain, DM intake, and gain:feed did not differ significantly between control and SSB groups during the entire experimental period. Carcass traits of Hanwoo steers with SSB supplementation were not significantly different between treatments except for dressing percentage, which was greater with SSB treatment. The content of saturated fatty acid (SFA) was greater and that of unsaturated fatty acids (UFA) was lower in the SSB group than in the control group. The ratio of UFA to SFA was significantly lower in the SSB group than in the control group. CONCLUSION: A total mixed ration containing less than 4.0% DM of SSBs can be used in Hanwoo steers without a decrease in productivity and carcass traits.

Mean and Variability of Lipid Measurements and Risk for Development of Subclinical Left Ventricular Diastolic Dysfunction.

BACKGROUND: Subclinical left ventricular diastolic dysfunction (LVDD) is an emerging consequence of increased insulin resistance, and dyslipidemia is one of the few correctable risk factors of LVDD. This study evaluated the role of mean and visit-to-visit variability of lipid measurements in risk of LVDD in a healthy population. METHODS: This was a 3.7-year (interquartile range, 2.1 to 4.9) longitudinal cohort study including 2,817 adults (median age 55 years) with left ventricular ejection fraction >50% who underwent an annual or biannual health screening between January 2008 and July 2016. The mean, standard deviation (SD), coefficient of variation (CV), variability independent of the mean (VIM), and average real variability of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apoB), non-HDL-C, and triglycerides were obtained from three to six measurements during the 5 years preceding the first echocardiogram. RESULTS: Among the 2,817 patients, 560 (19.9%) developed LVDD. The mean of no component of lipid measurements was associated with risk of LVDD. CV (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.10 to 1.67), SD (HR, 1.27; 95% CI, 1.03 to 1.57), and VIM (HR, 1.26; 95% CI, 1.03 to 1.55) of LDL-C and all the variability parameters of apoB were significantly associated with development of LVDD. The association between CV-LDL and risk of LVDD did not have significant interaction with sex, increasing/decreasing trend at baseline, or use of stain and/or lipid-modifying agents. CONCLUSION: The variability of LDL-C and apoB, rather than their mean, was associated with risk for LVDD.

A novel function of HRP-3 in regulating cell cycle progression via the HDAC-E2F1-Cyclin E pathway in lung cancer.

To improve the poor survival rate of lung cancer patients, we investigated the role of HDGF-related protein 3 (HRP-3) as a potential biomarker for lung cancer. The expression of endogenous HRP-3 in human lung cancer tissues and xenograft tumor models is indicative of its clinical relevance in lung cancer. Additionally, we demonstrated that HRP-3 directly binds to the E2F1 promoter on chromatin. Interestingly, HRP-3 depletion in A549 cells impedes the binding of HRP-3 to the E2F1 promoter; this in turn hampers the interaction between Histone H3/H4 and HDAC1/2 on the E2F1 promoter, while concomitantly inducing Histone H3/H4 acetylation around the E2F1 promoter. The enhanced Histone H3/H4 acetylation on the E2F1 promoter through HRP-3 depletion increases the transcription level of E2F1. Furthermore, the increased E2F1 transcription levels lead to the enhanced transcription of Cyclin E, known as the E2F1-responsive gene, thus inducing S-phase accumulation. Therefore, our study provides evidence for the utility of HRP-3 as a biomarker for the prognosis and treatment of lung cancer. Furthermore, we delineated the capacity of HRP-3 to regulate the E2F1 transcription level via histone deacetylation.

Thyroid Hormone Profile and Its Prognostic Impact on the Coronavirus Disease 2019 in Korean Patients.

BACKGROUND: Data on the association between coronavirus disease 2019 (COVID-19) and thyroid have been reported, including overt thyrotoxicosis and suppression of thyroid function. We aimed to evaluate the thyroid hormone profile and its association with the prognosis of COVID-19 in Korean patients. METHODS: The clinical data of 119 patients with COVID-19, admitted in the Myongji Hospital, Goyang, South Korea, were retrospectively evaluated. The thyroid hormone profiles were analyzed and compared based on disease severity (non-severe disease vs. severe to critical disease). Clinical outcomes were analyzed according to the tertiles of thyroid hormones. RESULTS: Of the 119 patients, 76 (63.9%) were euthyroid, and none presented with overt thyroid dysfunction. Non-thyroidal illness syndrome was the most common manifestation (18.5%), followed by subclinical thyrotoxicosis (14.3%) among patients with thyroid dysfunction. Thyroid stimulating hormone (TSH) and triiodothyronine (T3) levels were significantly lower in patients with severe to critical disease than in those with non-severe disease (P<0.05). Patients in the lowest T3 tertile (<0.77 ng/mL) had higher rates of mechanical ventilation, intensive care unit admission, and death than those in the middle and highest (>1.00 ng/mL) T3 tertiles (P<0.05). COVID-19 patients in the lowest T3 tertile were independently associated with mortality (hazard ratio, 5.27; 95% confidence interval, 1.09 to 25.32; P=0.038) compared with those in the highest T3 tertile. CONCLUSION: Thyroid dysfunction is common in COVID-19 patients. Changes in serum TSH and T3 levels may be important markers of disease severity in COVID-19. Decreased T3 levels may have a prognostic significance in COVID-19 related outcome.

Discovery and Characterization of a Novel MASTL Inhibitor MKI-2 Targeting MASTL-PP2A in Breast Cancer Cells and Oocytes.

Although microtubule-associated serine/threonine kinase-like (MASTL) is a promising target for selective anticancer treatment, MASTL inhibitors with nano range potency and antitumor efficacy have not been reported. Here, we report a novel potent and selective MASTL inhibitor MASTL kinase inhibitor-2 (MKI-2) identified in silico through a drug discovery program. Our data showed that MKI-2 inhibited recombinant MASTL activity and cellular MASTL activity with IC50 values of 37.44 nM and 142.7 nM, respectively, in breast cancer cells. In addition, MKI-2 inhibited MASTL kinase rather than other AGC kinases, such as ROCK1, AKT1, PKACα, and p70S6K. Furthermore, MKI-2 exerted various antitumor activities by inducing mitotic catastrophe resulting from the modulation of the MASTL-PP2A axis in breast cancer cells. The MKI-2 treatment showed phenocopies with MASTL-null oocyte in mouse oocytes, which were used as a model to validate MKI-2 activity. Therefore, our study provided a new potent and selective MASTL inhibitor MKI-2 targeting the oncogenic MAST-PP2A axis in breast cancer cells.

Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor.

More than 80% of colorectal cancer patients have adenomatous polyposis coli (APC) mutations, which induce abnormal WNT/ß-catenin activation. Tankyrase (TNKS) mediates the release of active ß-catenin, which occurs regardless of the ligand that translocates into the nucleus by AXIN degradation via the ubiquitin-proteasome pathway. Therefore, TNKS inhibition has emerged as an attractive strategy for cancer therapy. In this study, we identified pyridine derivatives by evaluating in vitro TNKS enzyme activity and investigated N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(2-cyanophenyl)piperidine-4-carboxamide (TI-12403) as a novel TNKS inhibitor. TI-12403 stabilized AXIN2, reduced active ß-catenin, and downregulated ß-catenin target genes in COLO320DM and DLD-1 cells. The antitumor activities of TI-12403 were confirmed by the viability of the colorectal cancer cells and its lack of visible toxicity in DLD-1 xenograft mouse model. In addition, combined 5-FU and TI-12403 treatment synergistically inhibited proliferation to a greater extent than that in a single drug treatment. Our observations suggest that TI-12403, a novel selective TNKS1 inhibitor, may be a suitable compound for anticancer drug development.

Urinary Free Metanephrines for Diagnosis of Pheochromocytoma and Paraganglioma.

BACKGROUND: Pheochromocytoma and paraganglioma (PPGL) is diagnosed through biochemical confirmation of excessive catecholamines in urine and plasma. Recent technological developments have allowed us to measure urinary free metanephrines; however, the diagnostic accuracy of these new methods and the diagnostic cutoff values have not been evaluated. METHODS: This is a retrospective study of 595 subjects, including 71 PPGL cases and 524 controls. PPGL was based on pathological confirmation. Subjects with no evidence of PPGL over 2 years were included in the control group. RESULTS: Urinary free metanephrines yielded similar area under the curve (AUC) to urinary fractionated metanephrines and plasma free metanephrines. However, urinary free normetanephrine yielded a better AUC than did urinary fractionated normetanephrine. The optimal cutoff for urinary free metanephrine and normetanephrine corrected for urinary creatinine yielded 97.2% sensitivity and 98.1% specificity. CONCLUSION: Urinary free metanephrines are a reliable method for diagnosing PPGL in Asian populations compared with existing biochemical methods.

Primary aldosteronism subtyping in the setting of partially successful adrenal vein sampling.

BACKGROUND AND AIMS: Frequent failure of adrenal vein (AV) cannulation is a major obstacle to the universal use of adrenal vein sampling (AVS) for subtyping primary aldosteronism (PA). This study aimed to confirm and modify the value of a previously reported AVS parameter for PA subtyping in the case of cannulation failure on one side. METHODS: Successfully catheterized AVS studies in 157 patients (121 patients as a derivation cohort and 36 patients as a validation cohort) from two tertiary hospitals were retrospectively reviewed. The AV/inferior vena cava (IVC) index was defined by dividing the aldosterone/cortisol ratio (ACR) of AV by the ACR of the IVC. Cutoff values for lateralized PA were obtained from two methods: scatterplots and the values corresponding to Youden's index in receiver operating characteristic (ROC) curves, on the assumption of catheterization failure on one side. RESULTS: Due to multiple samplings in a single AVS procedure, 252 left AV/IVC ratios (LIRs) and 272 right AV/IVC ratios (RIRs) were calculated. Scatterplot cutoffs of LIR >5.4 or <0.5 predicted unilateral PA with a sensitivity of 42.1% and a specificity of 98.6%. Scatterplot cutoffs of RIR <0.5 or >7.0 showed a sensitivity of 55.1% and a specificity of 98.6%. ROC curve cutoffs of LIR ⩽0.8 or >3.1 predicted unilateral PA with a sensitivity of 82.5% and a specificity of 69.6%. ROC curve cutoffs of RIR ⩽0.8 or >3.9 resulted in 87.4% sensitivity and 80.7% specificity. CONCLUSION: In the case of unilateral AVS failure, the AV/IVC index may help in diagnosing PA subtype.

Association of Urinary N-Acetyl-ß-D-Glucosaminidase with Cardiovascular Autonomic Neuropathy in Type 1 Diabetes Mellitus without Nephropathy.

BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is a common microvascular complication of diabetes and related to albuminuria in diabetic nephropathy (DN). Urinary N-acetyl-ß-D-glucosaminidase (uNAG) is a renal tubular injury marker which has been reported as an early marker of DN even in patients with normoalbuminuria. This study evaluated whether uNAG is associated with the presence and severity of CAN in patients with type 1 diabetes mellitus (T1DM) without nephropathy. METHODS: This cross-sectional study comprised 247 subjects with T1DM without chronic kidney disease and albuminuria who had results for both uNAG and autonomic function tests within 3 months. The presence of CAN was assessed by age-dependent reference values for four autonomic function tests. Total CAN score was assessed as the sum of the partial points of five cardiovascular reflex tests and was used to estimate the severity of CAN. The correlations between uNAG and heart rate variability (HRV) parameters were analyzed. RESULTS: The association between log-uNAG and presence of CAN was significant in a multivariate logistic regression model (adjusted odds ratio, 2.39; 95% confidence interval [CI], 1.08 to 5.28; P=0.031). Total CAN score was positively associated with loguNAG (ß=0.261, P=0.026) in the multivariate linear regression model. Log-uNAG was inversely correlated with frequency-domain and time-domain indices of HRV. CONCLUSION: This study verified the association of uNAG with presence and severity of CAN and changes in HRV in T1DM patients without nephropathy. The potential role of uNAG should be further assessed for high-risk patients for CAN in T1DM patients without nephropathy.

Anti-leukemic Activity of AIU2008 in FLT3-ITD-positive Acute Myeloid Leukemia.

BACKGROUND/AIM: FMS-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase involved in signal transduction underlying survival, proliferation, and differentiation of hematopoietic cells. An internal tandem duplication (ITD) in FLT3 in the juxtamembrane domain is a common mutation causing human acute myeloid leukemia (AML) and activates constitutive signaling. MATERIALS AND METHODS: We evaluated the novel FLT3 inhibitor 5-(4-fluorophenyl)-N-(naphthalen-1-yl)oxazol-2-amine (AIU2008) for the treatment of AML. RESULTS: AIU2008 was designed by modifying FLT3 inhibitor 7c, and showed improved anti-leukemic efficacy in FLT3-ITD-positive AML cells. Specifically, AIU2008 inhibited cell growth and apoptotic death. In addition, AIU2008 down-regulated DNA repair genes involved in homologous recombination and non-homologous end joining. It contributed to the synergistic inhibition of AML cell growth in combination treatment with PARP inhibitors. CONCLUSION: AIU2008 is a promising FLT3 targeting agent, and may be used in combination with PARP inhibitors for the treatment of AML.

East Asian diet-mimicking diet plan based on the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet in adults with type 2 diabetes: A randomized controlled trial.

AIMS/INTRODUCTION: Using an investigational diet plan based on the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet comprised of substitute ingredients that mimic the average East Asian diet, this study assessed the glycemic benefits in comparison with a food exchange system-based diet in established type 2 diabetes patients. MATERIALS AND METHODS: This was a 12-week, open-label randomized clinical trial carried out among 60 Korean adults with type 2 diabetes having a median body mass index of 23.5 kg/m2 . Glycemic benefits in the investigational diet (group A) were compared with those obtained with a food exchange system-based diet, either in the form of ready meals provided to participants (group B) or not (group C). The primary end-point was changes in glycated hemoglobin from baseline to week 12. RESULTS: Changes in glycated hemoglobin (%) from baseline to week 12 were -0.97 ± 0.97 in group A (vs group B, P = 0.085 in the full analysis set, and P = 0.028 in the per-protocol set; vs group C, P = 0.030 in the full analysis set and P = 0.020 in the per-protocol set), -0.51 ± 0.65 in group B (vs group C, P > 0.05 in the full analysis set and the per-protocol set), and -0.36 ± 0.74 in group C. Decreases from baseline in body mass index, waist circumference and blood pressure were greater in group A than in group C. CONCLUSION: With the provision of ready meals, the glycemic benefits of the investigational diet plan were demonstrable over a self-prepared food exchange system-based diet in Korean adults with established type 2 diabetes.