Counterfactual Fairness with Disentangled Causal Effect Variational Autoencoder

The problem of fair classification can be mollified if we develop a method to remove the embedded sensitive information from the classification features. This line of separating the sensitive information is developed through the causal inference, and the causal inference enables the counterfactual generations to contrast the what-if case of the opposite sensitive attribute. Along with this separation with the causality, a frequent assumption in the deep latent causal model defines a single latent variable to absorb the entire exogenous uncertainty of the causal graph. However, we claim that such structure cannot distinguish the 1) information caused by the intervention (i.e., sensitive variable) and 2) information correlated with the intervention from the data. Therefore, this paper proposes Disentangled Causal Effect Variational Autoencoder (DCEVAE) to resolve this limitation by disentangling the exogenous uncertainty into two latent variables: either 1) independent to interventions or 2) correlated to interventions without causality. Particularly, our disentangling approach preserves the latent variable correlated to interventions in generating counterfactual examples. We show that our method estimates the total effect and the counterfactual effect without a complete causal graph. By adding a fairness regularization, DCEVAE generates a counterfactual fair dataset while losing less original information. Also, DCEVAE generates natural counterfactual images by only flipping sensitive information. Additionally, we theoretically show the differences in the covariance structures of DCEVAE and prior works from the perspective of the latent disentanglement

β-Lapachone Significantly Increases the Effect of Ionizing Radiation to Cause Mitochondrial Apoptosis via JNK Activation in Cancer Cells

β-lapachone (β-lap), has been known to cause NQO1-dependnet death in cancer cells and sensitize cancer cells to ionizing radiation (IR). We investigated the mechanisms underlying the radiosensitization caused by β-lap. cells induced ROS generation, triggered ER stress and stimulated activation of ERK and JNK. Inhibition of ROS generation by NAC effectively attenuated the activation of ERK and JNK, induction of ER stress, and subsequent apoptosis. Importantly, inhibition of ERK abolished ROS generation and ER stress, whereas inhibition of JNK did not, indicating that positive feedback regulation between ERK activation and ROS generation triggers ER stress in response to combined treatment. Furthermore, prevention of ER stress completely blocked combination treatment-induced JNK activation and subsequent apoptotic cell death. In addition, combined treatment efficiently induced the mitochondrial translocation of cleaved Bax, disrupted mitochondrial membrane potential, and the nuclear translocation of AIF, all of which were efficiently blocked by a JNK inhibitor. Caspases 3, 8 and 9 were activated by combined treatment but inhibition of these caspases did not abolish apoptosis indicating caspase activation played a minor role in the induction of apoptosis. cells are treated with combination of IR and β-lap, positive feedback regulation between ERK and ROS leads to ER stress causing JNK activation and mitochondrial translocation of cleaved Bax. The resultant decrease in mitochondrial membrane leads to translocation of AIF and apoptosis

Inhibition of Sodium-Glucose Cotransporter-2 during Serum Deprivation Increases Hepatic Gluconeogenesis via the AMPK/AKT/FOXO Signaling Pathway

Background Sodium-dependent glucose cotransporter 2 (SGLT2) mediates glucose reabsorption in the renal proximal tubules, and SGLT2 inhibitors are used as therapeutic agents for treating type 2 diabetes mellitus. This study aimed to elucidate the effects and mechanisms of SGLT2 inhibition on hepatic glucose metabolism in both serum deprivation and serum supplementation states. Methods Huh7 cells were treated with the SGLT2 inhibitors empagliflozin and dapagliflozin to examine the effect of SGLT2 on hepatic glucose uptake. To examine the modulation of glucose metabolism by SGLT2 inhibition under serum deprivation and serum supplementation conditions, HepG2 cells were transfected with SGLT2 small interfering RNA (siRNA), cultured in serum-free Dulbecco’s modified Eagle’s medium for 16 hours, and then cultured in media supplemented with or without 10% fetal bovine serum for 8 hours. Results SGLT2 inhibitors dose-dependently decreased hepatic glucose uptake. Serum deprivation increased the expression levels of the gluconeogenesis genes peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), glucose 6-phosphatase (G6pase), and phosphoenolpyruvate carboxykinase (PEPCK), and their expression levels during serum deprivation were further increased in cells transfected with SGLT2 siRNA. SGLT2 inhibition by siRNA during serum deprivation induces nuclear localization of the transcription factor forkhead box class O 1 (FOXO1), decreases nuclear phosphorylated-AKT (p-AKT), and p-FOXO1 protein expression, and increases phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK) protein expression. However, treatment with the AMPK inhibitor, compound C, reversed the reduction in the protein expression levels of nuclear p-AKT and p-FOXO1 and decreased the protein expression levels of p-AMPK and PEPCK in cells transfected with SGLT2 siRNA during serum deprivation. Conclusion These data show that SGLT2 mediates glucose uptake in hepatocytes and that SGLT2 inhibition during serum deprivation increases gluconeogenesis via the AMPK/AKT/FOXO1 signaling pathway

Endoplasmic Reticulum Stress-Induced JNK Activation Is a Critical Event Leading to Mitochondria-Mediated Cell Death Caused by β-Lapachone Treatment

β-lapachone (β-lap) is a bioreductive agent that is activated by the two-electron reductase NAD(P)H quinone oxidoreductase 1 (NQO1). Although β-lap has been reported to induce apoptosis in various cancer types in an NQO1-dependent manner, the signaling pathways by which β-lap causes apoptosis are poorly understood.β-lap-induced apoptosis and related molecular signaling pathways in NQO1-negative and NQO1-overexpressing MDA-MB-231 cells were investigated. Pharmacological inhibitors or siRNAs against factors involved in β-lap-induced apoptosis were used to clarify the roles played by such factors in β-lap-activated apoptotic signaling pathways. β-lap leads to clonogenic cell death and apoptosis in an NQO1- dependent manner. Treatment of NQO1-overexpressing MDA-MB-231 cells with β-lap causes rapid disruption of mitochondrial membrane potential, nuclear translocation of AIF and Endo G from mitochondria, and subsequent caspase-independent apoptotic cell death. siRNAs targeting AIF and Endo G effectively attenuate β-lap-induced clonogenic and apoptotic cell death. Moreover, β-lap induces cleavage of Bax, which accumulates in mitochondria, coinciding with the observed changes in mitochondria membrane potential. Pretreatment with Salubrinal (Sal), an endoplasmic reticulum (ER) stress inhibitor, efficiently attenuates JNK activation caused by β-lap, and subsequent mitochondria-mediated cell death. In addition, β-lap-induced generation and mitochondrial translocation of cleaved Bax are efficiently blocked by JNK inhibition.Our results indicate that β-lap triggers induction of endoplasmic reticulum (ER) stress, thereby leading to JNK activation and mitochondria-mediated apoptosis. The signaling pathways that we revealed in this study may significantly contribute to an improvement of NQO1-directed tumor therapies

Item non-response imputation in the Korea National Health and Nutrition Examination Survey

OBJECTIVES The Korea National Health and Nutrition Examination Survey (KNHANES) is a public health survey that assesses individuals’ health and nutritional status and monitors the prevalence of major chronic diseases. In general, sampling weights are adjusted for unit non-responses and imputation is conducted for item non-responses. In this study, we proposed strategies for imputing item non-responses in the KNHANES in order to improve the usefulness of data, minimize bias, and increase statistical power. METHODS After applying logical imputation, we adopted 2 separate imputation methods for each variable type: unweighted sequential hot-deck imputation for categorical variables and sequential regression imputation for continuous variables. For variance estimation, multiple imputations were applied to the continuous variables. To evaluate the performance of the proposed strategies, we compared the marginal distributions of imputed variables and the results of multivariable regression analysis for the complete-case data and the expanded data with imputed values, respectively. RESULTS When comparing the marginal distributions, most non-responses were imputed. The multivariable regression coefficients presented similar estimates; however, the standard errors decreased, resulting in statistically significant p-values. The proposed imputation strategies may cope with the loss of precision due to missing data, thus enhancing statistical power in analyses of the KNHANES by providing expanded data with imputed values. CONCLUSIONS The proposed imputation strategy may enhance the utility of data by increasing the number of complete cases and reducing the bias in the analysis, thus laying a foundation to cope with the occurrence of item non-responses in further surveys

Shielding effect of radiation dose reduction fiber during the use of C-arm fluoroscopy: A phantom study

This study evaluated the shielding effect of a newly developed dose-reduction fiber (DRF) made from barium sulfate, in terms of radiation doses delivered to patients' radiosensitive organs and operator during C-arm fluoroscopy and its impact on the quality of images. A C-arm fluoroscopy unit was placed beside a whole-body phantom. Radiophotoluminescent glass dosimeters were attached to the back and front of the whole-body phantom at 20 cm intervals. Radiation doses were measured without DRF and with it applied to the back (position 1), front (position 2) or both sides (position 3) of the phantom. To investigate the impact of DRF on the quality of fluoroscopic images, step-wedge and modulation transfer function phantoms were used. The absorbed radiation doses to the back of the phantom significantly decreased by 25.3-88.8% after applying DRF to positions 1 and 3. The absorbed radiation doses to the front of the phantom significantly decreased by 55.3-93.6% after applying DRF to positions 2 and 3. The contrast resolution values for each adjacent step area fell in the range 0.0119-0.0209, 0.0128-0.0271, 0.0135-0.0339 and 0.0152-0.0339 without and with DRF applied to positions 1, 2 and 3, respectively. The investigated DRF effectively reduces absorbed radiation doses to patients and operators without decreasing the quality of C-arm fluoroscopic images. Therefore, routine clinical use of the DRF is recommended during the use of C -arm fluoroscopy.Y

Effect of metallic tools on scattered radiation dose during the use of C-arm fluoroscopy in orthopaedic surgery

This study investigated the effect of metallic tools on the scattered radiation dose delivered to surgeons' radiosensitive organs while simulating hip surgery using C-arm fluoroscopy. Two phantoms, a pelvis and a Rando phantom, were used to simulate a patient and a surgeon in this study. Photoluminescence dosimeters were inserted into the Rando phantom in the positions of the eye, thyroid and gonad. A drill was positioned above the hip of the pelvis phantom or beside the pelvis phantom of the same height. For each drill location, the scattered radiation dose was measured when the angle to the operator phantom was 45 degrees; this was repeated when the angle was 90 degrees. The scattered radiation doses to the eye, thyroid and gonad when the drill was placed beside the pelvis phantom with 90 degrees angulation to the operator phantom were significantly lower than the reference values and those when the drill was placed beside the pelvis phantom at a 45 degrees angulation to the operator phantom. The scattered radiation doses to the eye and thyroid when the drill was placed above the hip were significantly lower than the references values. Of the four different scenarios, the scattered radiation doses to the eye, thyroid and gonad were lowest when the drill was placed beside the pelvis phantom with 90 degrees angulation. This study showed that the scattered radiation doses to radiosensitive organs were affected by the location and angle of the metallic tools in relation to the operator. Therefore, orthopedic surgeons should consider the effect of metallic tools on the scattered radiation dose during intraoperative use of C-arm fluoroscopy.Y

Clinical Efficacy of Ruxolitinib in Patients with Myelofibrosis: A Nationwide Population-Based Study in Korea

Previous studies have reported the survival benefit after ruxolitinib treatment in patients with myelofibrosis (MF). However, population-based data of its efficacy are limited. We analyzed the effects of ruxolitinib in MF patients with data from the Korean National Health Insurance Database. In total, 1199 patients diagnosed with MF from January 2011 to December 2017 were identified, of which 731 were included in this study. Patients who received ruxolitinib (n = 224) were matched with those who did not receive the drug (n = 507) using the 1:1 greedy algorithm. Propensity scores were formulated using five variables: age, sex, previous history of arterial/venous thrombosis, and red blood cell (RBC) or platelet (PLT) transfusion dependence at the time of diagnosis. Cox regression analysis for overall survival (OS) revealed that ruxolitinib treatment (hazard ratio (HR), 0.67; p = 0.017) was significantly related to superior survival. In the multivariable analysis for OS, older age (HR, 1.07; p < 0.001), male sex (HR, 1.94; p = 0.021), and RBC (HR, 3.72; p < 0.001) or PLT (HR, 9.58; p = 0.001) transfusion dependence were significantly associated with poor survival, although type of MF did not significantly affect survival. Considering evidence supporting these results remains weak, further studies on the efficacy of ruxolitinib in other populations are needed