Enhancing Anti-Cancer Therapy with Selective Autophagy Inhibitors by Targeting Protective Autophagy

Autophagy is a process of eliminating damaged or unnecessary proteins and organelles, thereby maintaining intracellular homeostasis. Deregulation of autophagy is associated with several diseases including cancer. Contradictory dual roles of autophagy have been well established in cancer. Cytoprotective mechanism of autophagy has been extensively investigated for overcoming resistance to cancer therapies including radiotherapy, targeted therapy, immunotherapy, and chemotherapy. Selective autophagy inhibitors that directly target autophagic process have been developed for cancer treatment. Efficacies of autophagy inhibitors have been tested in various pre-clinical cancer animal models. Combination therapies of autophagy inhibitors with chemotherapeutics are being evaluated in clinal trials. In this review, we will focus on genetical and pharmacological perturbations of autophagy-related proteins in different steps of autophagic process and their therapeutic benefits. We will also summarize combination therapies of autophagy inhibitors with chemotherapies and their outcomes in pre-clinical and clinical studies. Understanding of current knowledge of development, progress, and application of cytoprotective autophagy inhibitors in combination therapies will open new possibilities for overcoming drug resistance and improving clinical outcomes.

A Novel VPS33B Variant Identified by Exome Sequencing in a Patient with Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome / 대한소아소화기영양학회지

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare autosomal recessive multisystemic disease that is associated with the liver, kidney, skin, and central nervous and musculoskeletal systems. ARC occurs as a result of mutations in the VPS33B (Vacuolar protein sorting 33 homolog B) or VIPAR (VPS33B interacting protein, apical-basolateral polarity regulator) genes. A female infant presented with neonatal cholestasis with a severe clinical outcome. She was diagnosed with ARC syndrome using targeted exome sequencing (TES). Exome sequencing revealed compound heterozygous mutations, c.707A>T and c.239+5G>A, in VPS33B, where c.707A>T was a novel variant; the resultant functional protein defects were predicted via in silico analysis. c.239+5G>A, a pathogenic mutation that affects splicing, is found in less than 0.1% of the general population. Invasive techniques, such as liver biopsies, did not contribute to a differential diagnosis of ARC syndrome; thus, early TES together with clinical presentations constituted an apparently accurate diagnostic procedure.

Effects of Parity and Breast Feeding Duration on the Risk of Osteoporosis in Postmenopausal Korean Women: A Systematic Review and Meta-Analysis

OBJECTIVES: To summarize the evidence regarding the association of parity and breast feeding duration with the risk of osteoporosis in postmenopausal Korean women. This was because studies have been inconsistent regarding the effect of parity and breast feeding duration on the risk of osteoporosis. METHODS: A systematic literature search of relevant studies published by December 26, 2018 was conducted in PubMed, EMBASE, the Cochrane Library, CINAHL, RISS, KISS, KMbase, and KoreaMed. Outcome estimates of odds ratio (OR) or standardized mean difference were pooled with fixed or random-effect model. In case of heterogeneity, subgroup analysis was conducted. RESULTS: Seven cross-sectional studies (with 3,813 subjects) were included in the analysis. OR for osteoporosis was 1.43 (95% confidence interval [CI] = 1.09–1.88, P = 0.010) in postmenopausal women with higher parity compared to those with less parity. Moreover, OR for osteoporosis was 1.93 (95% CI = 1.28–2.93, P = 0.002) in postmenopausal women with longer durations of breast feeding than in those with shorter durations of breast feeding. CONCLUSIONS: This study revealed that duration of breast feeding increased the risk of osteoporosis in postmenopausal Korean women. More cohort studies with high quality research designs are needed to confirm our results.

Depression and Fear about Maturation in Girls with Precocious Puberty and Depression and Anxiety in Their Mothers

PURPOSE: This study investigated depression and anxiety in girls with precocious puberty and in their mothers. METHOD: This study recruited 75 girls treated with a gonadotropin-releasing hormone agonist (GnRHa) and their mothers from October 2017 to April 2018. The girls completed the Korean Children's Depression Inventory (K-CDI) and Maturity Fear Scale (MFS), and their mothers were surveyed with the Korean Beck Depression Inventory (K-BDI) and Korean Beck Anxiety Inventory (K-BAI). RESULTS: The K-BDI scores showed statistically significant differences according to girl's age (p < 0.016) and household income (p < 0.037). The anxiety scores showed statistically significant differences according to girls' Body Mass Index (BMI) (p < 0.029) and household income (p < 0.005). There was a positive correlation between depression in girls and mothers (r=0.264, p < 0.050). CONCLUSION: Our findings suggest a need for understanding and counseling for depression in both girls??and their mothers during the process of diagnosis and treatment for precocious puberty.

Intractable Atrial Flutter Successfully Treated with Flecainide and Propranolol in a Premature Infant / 이화의대지

Although Atrial flutter (AFL) in newborn infant with normal cardiac anatomy has benign clinical course, an intractable AFL is associated with an increased risk of development of heart failure and sudden death, and is still difficult to manage. It requires multiple external electrical cardioversions, and it shows a poor response to antiarrhythmic drug therapy. We report a case of a premature infant with an intractable AFL, which we successfully treated with oral flecainide and propranolol in spite of recurred AFL. A 1-month-old, 34-week gestation, premature baby presented with an irregular heart beat and irritability. An AFL with 2:1 atrioventricular conduction was documented. Because of the intractable AFL, repeated electrical cardioversion and amiodarone were continued for 14 days. However, amiodarone was discontinued in favour of flecainide and propranolol because of the recurrent AFL and newly developed transient hypothyroidism. During 1-year follow-up period, in which oral flecainide and propranolol were continued, no AFL was observed.

Effect of subcutaneous treatment with human umbilical cord blood-derived multipotent stem cells on peripheral neuropathic pain in rats

In this study, we aim to determine the in vivo effect of human umbilical cord blood-derived multipotent stem cells (hUCB-MSCs) on neuropathic pain, using three, principal peripheral neuropathic pain models. Four weeks after hUCB-MSC transplantation, we observed significant antinociceptive effect in hUCB-MSC–transplanted rats compared to that in the vehicle-treated control. Spinal cord cells positive for c-fos, CGRP, p-ERK, p-p 38, MMP-9 and MMP 2 were significantly decreased in only CCI model of hUCB-MSCs-grafted rats, while spinal cord cells positive for CGRP, p-ERK and MMP-2 significantly decreased in SNL model of hUCB-MSCs-grafted rats and spinal cord cells positive for CGRP and MMP-2 significantly decreased in SNI model of hUCB-MSCs-grafted rats, compared to the control 4 weeks or 8weeks after transplantation (p<0.05). However, cells positive for TIMP-2, an endogenous tissue inhibitor of MMP-2, were significantly increased in SNL and SNI models of hUCB-MSCs-grafted rats. Taken together, subcutaneous injection of hUCB-MSCs may have an antinociceptive effect via modulation of pain signaling during pain signal processing within the nervous system, especially for CCI model. Thus, subcutaneous administration of hUCB-MSCs might be beneficial for improving those patients suffering from neuropathic pain by decreasing neuropathic pain activation factors, while increasing neuropathic pain inhibition factor.

Predictors of High-grade Vesicoureteral Reflux in Children with Febrile Urinary Tract Infections

PURPOSE: This study aimed to investigate clinical and radiological factors that may predict high-grade vesicoureteral reflux (VUR) in patients with febrile urinary tract infection (UTI). METHODS: We retrospectively analyzed medical records of 446 patients diagnosed with febrile UTI from March 2008 to February 2017. All patients underwent renal-bladder ultrasonography (RBUS), 99mTc dimercaptosuccinic acid (DMSA) renal scan, and voiding cystourethrography (VCUG), and were divided in to 3 groups: a high-grade VUR group (n=53), a low-grade VUR group (n=28), and a group without VUR (n=365). RESULTS: The recurrence and non-Escherichia coli infection rates in febrile UTI were significantly higher in the high-grade VUR group than in the other two groups (P<0.05). RBUS showed that hydronephrosis and ureter dilatation were more frequent in the high-grade VUR group than in the other groups (P<0.05). In the high-grade VUR group, a renal cortical defect was more likely to appear as multiple defects, and the difference in bilateral renal scan uptake between both kidneys was larger than in the other two groups (P<0.001). CONCLUSION: Recurrent UTI, non-E. coli UTI, abnormal findings on RBUS such as hydronephrosis and ureter dilatation, and abnormal findings in the DMSA renal scan such as multiple renal cortical defects and greater uptake difference were associated with high-grade VUR. VCUG should be selectively performed when RBUS and/or DMSA renal scan reveal significant abnormalities.

Predictors of High-grade Vesicoureteral Reflux in Children with Febrile Urinary Tract Infections

PURPOSE: This study aimed to investigate clinical and radiological factors that may predict high-grade vesicoureteral reflux (VUR) in patients with febrile urinary tract infection (UTI). METHODS: We retrospectively analyzed medical records of 446 patients diagnosed with febrile UTI from March 2008 to February 2017. All patients underwent renal-bladder ultrasonography (RBUS), 99mTc dimercaptosuccinic acid (DMSA) renal scan, and voiding cystourethrography (VCUG), and were divided in to 3 groups: a high-grade VUR group (n=53), a low-grade VUR group (n=28), and a group without VUR (n=365). RESULTS: The recurrence and non-Escherichia coli infection rates in febrile UTI were significantly higher in the high-grade VUR group than in the other two groups (P<0.05). RBUS showed that hydronephrosis and ureter dilatation were more frequent in the high-grade VUR group than in the other groups (P<0.05). In the high-grade VUR group, a renal cortical defect was more likely to appear as multiple defects, and the difference in bilateral renal scan uptake between both kidneys was larger than in the other two groups (P<0.001). CONCLUSION: Recurrent UTI, non-E. coli UTI, abnormal findings on RBUS such as hydronephrosis and ureter dilatation, and abnormal findings in the DMSA renal scan such as multiple renal cortical defects and greater uptake difference were associated with high-grade VUR. VCUG should be selectively performed when RBUS and/or DMSA renal scan reveal significant abnormalities.

Post-Intensive Care Syndrome Experience among Critical Care Survivors: A Meta-synthesis of Qualitative Research / 중환자간호학회지

PURPOSE: The purpose of this study was to integrate the results of qualitative studies to understand critical care survivors' experience of the post-intensive care syndrome (PICS).METHODS: This was a meta-synthesis of primary studies that used qualitative methods. We reviewed 26 qualitative studies on PICS selected from 8 international and Korean databases and from a manual search. Thomas and Harden's 3 stages (free coding, development of descriptive themes, generation of analytical themes) for thematic synthesis were utilized to analyze the collected qualitative data.RESULTS: Four descriptive themes emerged from the thematic synthesis: weak physical conditions, psycho-emotional changes, the painful-memory of intensive care units, and social vulnerability. The analytical theme for the current study was “unfamiliarity with the vulnerable self.” Critical care survivors had to confront entirely different “selves” after discharge from intensive care units. They had become physically weak, psychologically unstable, and the critical memories continued to create distress. These changes increased their social vulnerability by making them dependent on others, causing family conflicts, and changing interpersonal relationships.CONCLUSIONS: Finding from this qualitative synthesis and other related literature highlight the severity of PICS and the importance of rehabilitative intervention for critical care survivors.

NADPH Oxidase 1 and NADPH Oxidase 4 Have Opposite Prognostic Effects for Patients with Hepatocellular Carcinoma after Hepatectomy

BACKGROUND/AIMS: Nicotinamide adenine dinucleotide phosphate oxidase (NOX)-mediated reactive oxygen species contribute to various liver diseases, including hepatocellular carcinoma (HCC). Uncertainties remain regarding the prognostic relevance of NOX1 and NOX4 protein expression in HCC. METHODS: NOX1 and NOX4 protein expression was examined by using immunohistochemistry in tumor tissue from 227 HCC patients who underwent hepatectomy. RESULTS: High immunoreactivity for NOX1 was observed in 197 (86.8%) of the 227 HCC cases and low immunoreactivity for NOX4 in 112 (49.3%). NOX1 and NOX4 proteins had opposite prognostic effects. High NOX1 expression was an independent predictor of both shorter recurrence-free survival (RFS) (p<0.01) and shorter overall survival (OS) (p=0.01). Low NOX4 expression was an independent predictor of both shorter RFS (p<0.01) and shorter OS (p=0.01). Subgroup analysis showed that, among patients with normal α-fetoprotein levels, patients with tumor size ≤5.0 cm and patients in Barcelona Clinic Liver Cancer stage A, high NOX1 expression had unfavorable effects on RFS, whereas low NOX4 expression had unfavorable effects on both RFS and OS. CONCLUSIONS: These findings demonstrated that NOX1 and NOX4 protein expression had opposite prognostic effects for HCC patients. Moreover, both proteins had prognostic value in HCC patients with normal α-fetoprotein levels or with early-stage HCC.

A Rare Case of Bronchial Epithelial-Myoepithelial Carcinoma with Solid Lobular Growth in a 53-Year-Old Woman / 결핵및호흡기질환

Epithelial-myoepithelial carcinoma (EMC) of lung is a minor subset of salivary type carcinoma of lung of known low grade malignancy. Histologically, two-cell components forming duct-like structure with inner epithelial cell layer and outer myoepithelial cell layer are characteristics of EMC. In salivary gland, dedifferentiation of conventional low grade malignancy has been reported and is thought to be related with poor prognosis. However, precise histomorphology and prognostic factors of pulmonary EMC have not been clarified due to its rarity. Herein, we reported a rare case of EMC presented as endobronchial mass in a 53-year old woman, which showed predominant solid lobular growth pattern and lymph node metastases.