Identification of Small GTPases That Phosphorylate IRF3 through TBK1 Activation Using an Active Mutant Library Screen

Interferon regulatory factor 3 (IRF3) integrates both immunological and non-immunological inputs to control cell survival and death. Small GTPases are versatile functional switches that lie on the very upstream in signal transduction pathways, of which duration of activation is very transient. The large number of homologous proteins and the requirement for site-directed mutagenesis have hindered attempts to investigate the link between small GTPases and IRF3. Here, we constructed a constitutively active mutant expression library for small GTPase expression using Gibson assembly cloning. Small-scale screening identified multiple GTPases capable of promoting IRF3 phosphorylation. Intriguingly, 27 of 152 GTPases, including ARF1, RHEB, RHEBL1, and RAN, were found to increase IRF3 phosphorylation. Unbiased screening enabled us to investigate the sequence-activity relationship between the GTPases and IRF3. We found that the regulation of IRF3 by small GTPases was dependent on TBK1. Our work reveals the significant contribution of GTPases in IRF3 signaling and the potential role of IRF3 in GTPase function, providing a novel therapeutic approach against diseases with GTPase overexpression or active mutations, such as cancer.

Clinical efficacy of adjuvant chemotherapy in stage IB (< 4 cm) non-small cell lung cancer patients with high-risk factors

Background/Aims@#Adjuvant chemotherapy is the standard of care for resected stage II-IIIA non-small cell lung cancer (NCSLC). The efficacy of adjuvant chemotherapy in stage IB (< 4 cm) NSCLC with high-risk factors is controversial. @*Methods@#This retrospective multicenter study included 285 stage IB NSCLC patients with high-risk factors according to the 8th edition tumor, node, metastasis (TNM) classification from four academic hospitals. High-risk factors included visceral pleural invasion, vascular invasion, lymphatic invasion, lung neuroendocrine tumors, and micropapillary histology patterns. @*Results@#Of the 285 patients, 127 (44.6%) were included in the adjuvant chemotherapy group and 158 (55.4%) were included in the non-adjuvant chemotherapy group. The median follow-up was 41.5 months. Patients in the adjuvant chemotherapy group had a significantly reduced recurrence rate and risk of mortality than those in the non-adjuvant chemotherapy group (hazards ratio, 0.408; 95% confidence interval, 0.221 to 0.754; p = 0.004 and hazards ratio, 0.176; 95% confidence interval, 0.057 to 0.546; p = 0.003, respectively). Adjuvant chemotherapy should be particularly considered for the high-risk factors such as visceral pleural involvement or vascular invasion. Based on the subgroup analysis, adjuvant chemotherapy should be considered when visceral pleural involvement is present, even if the tumor size is < 3 cm. @*Conclusions@#Adjuvant chemotherapy may be useful for patients with stage IB NSCLC with high-risk factors and is more relevant for patients with visceral pleural involvement or vascular invasion.

Korean Clinical Imaging Guidelines for the Appropriate Use of Chest MRI

MRI has the advantages of having excellent soft-tissue contrast and providing functional information without any harmful ionizing radiation. Although previous technical limitations restricted the use of chest MRI, recent technological advances and expansion of insurance coverage are increasing the demand for chest MRI. Recognizing the need for guidelines on appropriate use of chest MRI in Korean clinical settings, the Korean Society of Radiology has composed a development committee, working committee, and advisory committee to develop Korean chest MRI justification guidelines. Five key questions were selected and recommendations have been made with the evidence-based clinical imaging guideline adaptation methodology.Recommendations are as follows. Chest MRI can be considered in the following circumstances:for patients with incidentally found anterior mediastinal masses to exclude non-neoplastic conditions, for pneumoconiosis patients with lung masses to differentiate progressive massive fibrosis from lung cancer, and when invasion of the chest wall, vertebrae, diaphragm, or major vessels by malignant pleural mesothelioma or non-small cell lung cancer is suspected. Chest MRI without contrast enhancement or with minimal dose low-risk contrast media can be considered for pregnant women with suspected pulmonary embolism. Lastly, chest MRI is recommended for patients with pancoast tumors planned for radical surgery.

Korean Clinical Imaging Guidelines for the Appropriate Use of Chest MRI

MRI has the advantages of having excellent soft-tissue contrast and providing functional information without any harmful ionizing radiation. Although previous technical limitations restricted the use of chest MRI, recent technological advances and expansion of insurance coverage are increasing the demand for chest MRI. Recognizing the need for guidelines on appropriate use of chest MRI in Korean clinical settings, the Korean Society of Radiology has composed a development committee, working committee, and advisory committee to develop Korean chest MRI justification guidelines. Five key questions were selected and recommendations have been made with the evidence-based clinical imaging guideline adaptation methodology.Recommendations are as follows. Chest MRI can be considered in the following circumstances:for patients with incidentally found anterior mediastinal masses to exclude non-neoplastic conditions, for pneumoconiosis patients with lung masses to differentiate progressive massive fibrosis from lung cancer, and when invasion of the chest wall, vertebrae, diaphragm, or major vessels by malignant pleural mesothelioma or non-small cell lung cancer is suspected. Chest MRI without contrast enhancement or with minimal dose low-risk contrast media can be considered for pregnant women with suspected pulmonary embolism. Lastly, chest MRI is recommended for patients with pancoast tumors planned for radical surgery.

Fluorescence Image-Based Evaluation of Gastric Tube Perfusion during Esophagogastrostomy

During esophagectomy and esophagogastrostomy, the prediction of anastomotic leakagerelies on the operating surgeon’s tactile or visual diagnosis. Therefore, anastomoticleaks are relatively unpredictable, and new intraoperative evaluation methods or tools areessential. A fluorescence imaging system enables visualization over a wide region of interest,and provides intuitive information on perfusion intraoperatively. Surgeons can choosethe best anastomotic site of the gastric tube based on fluorescence images in real timeduring surgery. This technology provides better surgical outcomes when used with anoptimal injection dose and timing of indocyanine green.

Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement / 대한내과학회지

Acromegaly is a chronic disorder caused by excessive growth hormone (GH) secretion. In most cases, the excess GH originates from GH-producing pituitary adenomas. Surgery is the preferred first-line treatment for patients with acromegaly, but medical management is considered when the disease persists after surgery or in cases where patients refuse surgery or are poor candidates for surgery. Somatostatin analogues are commonly used to treat acromegaly. The Korean Endocrine Society and the Korean Neuroendocrine Study Group have developed a position statement for the use of somatostatin analogues in the medical treatment of acromegaly. This position statement is based on evidence from the current literature and expert opinions. In the case of discrepancies among expert opinions, the experts voted to determine the recommended approach.

Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement / 대한내과학회지

Acromegaly is a chronic disorder caused by excessive growth hormone (GH) secretion. In most cases, the excess GH originates from GH-producing pituitary adenomas. Surgery is the preferred first-line treatment for patients with acromegaly, but medical management is considered when the disease persists after surgery or in cases where patients refuse surgery or are poor candidates for surgery. Somatostatin analogues are commonly used to treat acromegaly. The Korean Endocrine Society and the Korean Neuroendocrine Study Group have developed a position statement for the use of somatostatin analogues in the medical treatment of acromegaly. This position statement is based on evidence from the current literature and expert opinions. In the case of discrepancies among expert opinions, the experts voted to determine the recommended approach.

Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement

The Korean Endocrine Society (KES) published clinical practice guidelines for the treatment of acromegaly in 2011. Since then, the number of acromegaly cases, publications on studies addressing medical treatment of acromegaly, and demands for improvements in insurance coverage have been dramatically increasing. In 2017, the KES Committee of Health Insurance decided to publish a position statement regarding the use of somatostatin analogues in acromegaly. Accordingly, consensus opinions for the position statement were collected after intensive review of the relevant literature and discussions among experts affiliated with the KES, and the Korean Neuroendocrine Study Group. This position statement includes the characteristics, indications, dose, interval (including extended dose interval in case of lanreotide autogel), switching and preoperative use of somatostatin analogues in medical treatment of acromegaly. The recommended approach is based on the expert opinions in case of insufficient clinical evidence, and where discrepancies among the expert opinions were found, the experts voted to determine the recommended approach.

Meeting report: a close look at oral biofilms and microbiomes / 国际口腔科学杂志·英文版

The "Biofilms, Microbiomes and Oral Diseases: Challenges and Future Perspectives" symposium jointly organized by Penn Dental Medicine and West China School of Stomatology was held on 30 September 2017 at Penn Wharton China Center (PWCC) in Beijing, China. The topics included the pathogenicity of oral biofilms, novel strategies for the control of biofilm-related diseases, oral microbiome and single-cell approaches, and the link between oral diseases and overall health. Researchers from a number of disciplines, representing institutions from China and Penn Dental Medicine, gathered to discuss advances in our understanding of biofilms, as well as future directions for the control of biofilm-related oral and systemic diseases.

A Rare Case of Hyponatremia Caused by Reset Osmostat in a Neonate with Cleft Lip, Cleft Palate, and Imperforate Anus

Hyponatremia is defined as a plasma sodium concentration of < 135 mEq/L. It is a common electrolyte imbalance in newborns. We report the case of a term neonate with cleft lip, cleft palate, imperforate anus, normal male karyotype, and chronic hyponatremia. On the 4th day of life, he showed hyponatremia (plasma sodium concentration 130 mEq/L) with low serum osmolality (275 mOsm/kg), high urine sodium (116.7 mEq/L), and high urine osmolality (412 mOsm/kg). His thyroid and adrenal functions were normal. Despite intravenous and oral sodium supplementation and hydrocortisone treatment, hyponatremia persisted. Brain magnetic resonance imaging showed normal results. He was diagnosed as having reset osmostat, a rare subtype of the syndrome of inappropriate secretion of antidiuretic hormone characterized by a subnormal threshold for antidiuretic hormone secretion, with hypotonic hyponatremia.

Gestational Diabetes Mellitus, Fetal Growth and Vitamin D

Vitamin D is an important secosteroid hormone in skeletal and non-skeletal systems. Vitamin D has relevance to muscle and immune function, hypertension, diabetes mellitus, cancer, and pregnancy because vitamin D receptors (VDR) are present in many non-skeletal tissues. Vitamin D acts on target tissues via the binding of its active form to VDR. As vitamin D affects not only bone metabolism but also glucose metabolism, vitamin D deficiency may affect the development of gestational diabetes mellitus and fetal growth. Although vitamin D deficiency is prevalent during pregnancy, there are conflicting reports on the effect of vitamin D deficiency on pregnancy complications, such as fetal growth restriction and gestational diabetes. This article reviews published papers on the effects of vitamin D on gestational diabetes and fetal growth.

Mindfulness-Based Cognitive Therapy for Depressed Diabetic Patients / 임상당뇨병

Diabetes is a chronic disease that requires long-term management and is accompanied by emotional stress. Psychological difficulties arising from the need for persistent self-management and difficulties due to complications related to the illness also lead to depression. Such depression results in difficulty controlling HbA1C, diet, exercise and medication. Therefore, depression management for diabetic patients is needed. Mindfulness-Based Cognitive Therapy modifies negative thinking patterns through mindfulness meditation that trains individuals to pay attention to what is and to not intentionally judge situations. This helps to ease depression and prevent a return to negative feelings. Thus, Mindfulness-Based Cognitive Therapy could help with blood glucose management and the emotional stability of diabetic patients.

Maternal Thyroid Function during the First Trimester of Pregnancy in Korean Women

BACKGROUND AND OBJECTIVES: Thyroid dysfunction during pregnancy can result in many complications for both mother and infant. Due to the physiologic changes in thyroid stimulating hormone (TSH) level during early pregnancy, it is recommend to use trimester-specific reference ranges for every population. We obtained the reference range of TSH during the first trimester in Korean women according to gestational week. MATERIALS AND METHODS: The study population consisted of pregnant women who had undergone a TSH screening during the first trimester of pregnancy (n=8365) and nonpregnant women (n=1835). RESULTS: Median concentration of serum TSH decreased significantly from the 5th to 8th week of gestation (median TSH concentration: 2.00 mIU/L for 5 weeks; 1.70 mIU/L for 6 weeks; 1.40 mIU/L for 7 weeks; 1.05 mIU/L for 8 weeks). However, there was no significant difference in median concentration of serum TSH from the 8th to 12th weeks of gestation. Using the fixed cut-off value of TSH >3.66 mIU/L, the diagnosis rate of subclinical hypothyroidism was 15.0% for 5 weeks, 10.0% for 6 weeks, 5.9% for 7 weeks, and 3.6% for 8-12 weeks. CONCLUSION: When interpreting the TSH test for pregnancy (maternal thyroid function), we should consider that the TSH level decreases significantly during the early first trimester.

dNP2-ctCTLA-4 inhibits German cockroach extract-induced allergic airway inflammation and hyper-responsiveness via inhibition of Th2 responses

German cockroaches are major household allergens that can trigger allergic airway inflammatory diseases with sensitive T-cell responses. Although the use of immune modulatory biologics, such as antibodies, to mediate allergic responses has recently been examined, only systemic administration is available because of the size limitations on intranasal administration. Here we utilized a cell-permeable peptide, dNP2, to deliver the cytoplasmic domain of cytotoxic T-lymphocyte antigen-4 (ctCTLA-4) through the airway epithelium to modulate Th2 responses in a German cockroach extract (GCE)-induced allergic airway inflammation model. The intranasal delivery efficiency of the dNP2-dTomato protein to the lungs was higher in GCE-induced asthmatic lung parenchymal cells compared to the sham cells. Intranasal administration of the dNP2-ctCTLA-4 protein inhibited airway hyper-responsiveness and reduced airway inflammation and remodeling, including goblet cell metaplasia and collagen deposition around the bronchi. The number of infiltrated cells, including eosinophils, and the levels of IL-4, IL-5, IL-13 and IFN-γ in the lungs were significantly reduced, presumably owing to inhibition of Th2 differentiation. However, intranasal administration of CTLA4-Ig did not inhibit airway inflammation. These results collectively suggest that dNP2-ctCTLA-4 is an efficient intranasally applicable candidate biologic for treating allergic asthma.

The Efficacy of Bisphosphonates for Prevention of Osteoporotic Fracture: An Update Meta-analysis

BACKGROUND: The efficacy of bisphosphonates for osteoporotic fracture has been consistently reported in recent randomized controlled trials (RCTs) enrolling hundreds of patients. The objective of this study was to update knowledge on the efficacy of available bisphosphonates in the prevention of vertebral and non-vertebral fractures. METHODS: An approach “using systematic reviews” on PubMed and Cochrane Library was taken. Twenty-four RCTs investigating the effects of bisphosphonates for the prevention of osteoporotic fracture were included in final analysis. A pairwise meta-analysis was conducted with a random effects model. Subgroup analysis was performed according to the type of bisphosphonate. RESULTS: The use of bisphosphonate decrease the risk of overall osteoporotic fracture (odds ratio [OR] 0.62; P<0.001), vertebral fracture (OR 0.55; P<0.001) and non-vertebral fracture (OR 0.73; P<0.001). Subgroup analysis indicated that zoledronic acid showed the lowest risk reduction (OR 0.61; P<0.001) for overall osteoporotic fractures but no significance was observed for etidronate (OR 0.34; P=0.127). CONCLUSIONS: This update meta-analysis re-confirmed that bisphosphonate use can effectively reduce the risk of osteoporotic fracture. However, there is a lack of evidence regarding etidronate for the prevention of osteoporotic fracture.

Characteristics of Patients Diagnosed with Osteoporosis in South Korea: Results from the National Claim Registry

BACKGROUND: Although osteoporosis is increasing medical issue in the elderly population, attempts to analyze the characteristics of patients diagnosed with osteoporosis are rare in South Korea. We investigated the characteristics of patients diagnosed with osteoporosis using Korea's National Health Insurance claims data, which includes almost Korean population. METHODS: We evaluated the patients who were diagnosed and treated with osteoporosis in medical institute in South Korea, using the national database by the Health Insurance Review & Assessment Service (HIRA). We evaluated the characteristic of patients and state of medical service utilization in 2010. RESULTS: The number of patients who were diagnosed with osteoporosis were 1,733,685, and almost of them (91.1%) were females. Fourteen point three percent of the patients had experienced osteoporosis-related fracture. The most commonly used type of institute and department was hospital and orthopedic surgery. CONCLUSIONS: Considering increasing age population, basic information including characteristic of patients and current state of medical service utilization could be useful to perform appropriate management and treatment for osteoporosis patients in South Korea, using the National Health Insurance claims data.

Effect of 0.05% Cyclosporine A on the Ocular Surface after Photorefractive Keratectomy

PURPOSE: To evaluate the effect of 0.05% cyclosporine A on the ocular surface after photorefractive keratectomy (PRK). METHODS: This retrospective study included 50 patients who underwent PRK. Patients were divided into two groups: 25 patients in group I were treated with topical 0.05% cyclosporine A with conventional medication, and 25 patients in group II were treated with conventional medication. Visual acuity (VA), tear break-up time (BUT), fluorescein staining score (F-stain), Schirmer I test, and ocular surface disease index (OSDI) were evaluated before surgery and 2 weeks, 1 month, 2 months, and 3 months after surgery. RESULTS: F-stain was significantly lower in group I than in group II at 2 weeks and 1 month (p < 0.05). There was no significant difference in uncorrected VA, BUT, Schirmer I test, or OSDI between the groups. However, group I showed a more effective pattern in dry eye. CONCLUSIONS: Combination treatment with 0.05% cyclosporine A was helpful for early ocular surface stability in patients with dry eye after PRK.

The Role of Nuclear Factor-E2-Related Factor 1 in the Oxidative Stress Response in MC3T3-E1 Osteoblastic Cells

BACKGROUND: Reactive oxygen species (ROS) and antioxidants are associated with maintenance of cellular function and metabolism. Nuclear factor-E2-related factor 1 (NFE2L1, Nrf1) is known to regulate the expression of a number of genes involved in oxidative stress and inflammation. The purpose of this study was to examine the effects of NFE2L1 on the response to oxidative stress in osteoblastic MC3T3-E1 cells. METHODS: The murine calvaria-derived MC3T3-E1 cell line was exposed to lipopolysaccharide (LPS) for oxidative stress induction. NFE2L1 effects were evaluated using small interfering RNA (siRNA) for NFE2L1 mRNA. ROS generation and the levels of known antioxidant enzyme genes were assayed. RESULTS: NFE2L1 expression was significantly increased 2.4-fold compared to the control group at 10 µg/mL LPS in MC3T3-E1 cells (P<0.05). LPS increased formation of intracellular ROS in MC3T3-E1 cells. NFE2L1 knockdown led to an additional increase of ROS (20%) in the group transfected with NFE2L1 siRNA compared with the control group under LPS stimulation (P<0.05). RNA interference of NFE2L1 suppressed the expression of antioxidant genes including metallothionein 2, glutamatecysteine ligase catalytic subunit, and glutathione peroxidase 1 in LPS-treated MC3T3-E1 cells. CONCLUSION: Our results suggest that NFE2L1 may have a distinct role in the regulation of antioxidant enzymes under inflammation-induced oxidative stress in MC3T3-E1 osteoblastic cells.

Use of Cell-Penetrating Peptides in Dendritic Cell-Based Vaccination

Cell-penetrating peptides (CPPs) are short amino acids that have been widely used to deliver macromolecules such as proteins, peptides, DNA, or RNA, to control cellular behavior for therapeutic purposes. CPPs have been used to treat immunological diseases through the delivery of immune modulatory molecules in vivo. Their intracellular delivery efficiency is highly synergistic with the cellular characteristics of the dendritic cells (DCs), which actively uptake foreign antigens. DC-based vaccines are primarily generated by pulsing DCs ex vivo with various immunomodulatory antigens. CPP conjugation to antigens would increase DC uptake as well as antigen processing and presentation on both MHC class II and MHC class I molecules, leading to antigen specific CD4+ and CD8+ T cell responses. CPP-antigen based DC vaccination is considered a promising tool for cancer immunotherapy due to the enhanced CTL response. In this review, we discuss the various applications of CPPs in immune modulation and DC vaccination, and highlight the advantages and limitations of the current CPP-based DC vaccination.

Three Cases of Calcifying Pseudoneoplasm which Involve the Epidural Space of the Spine

Calcifying psuedoneoplasm of the spine is a rare non-neoplastic lesion of unknown origin. Radiologic and histologic manifestations are very variable and clinical symptoms include isolated pain, myelopathy, and radiculopathy. Surgical resection is the preferred option of treatment. This report describes three cases of calcifying pseudoneoplasm in the spine. The first case is a 77-year-old female with pain in both legs. The second case is a 67-year-old woman who presented as right leg pain. The third case is a 78-year-old woman with isolated back pain. The involved sites of each of cases were T12, L2-3, and L1, respectively. Surgical resection of the involved masses relieved symptoms.