Machine Learning-Based Proteomics Reveals Ferroptosis in COPD PatientDerived Airway Epithelial Cells Upon Smoking Exposure

Background@#Proteomics and genomics studies have contributed to understanding the pathogenesis of chronic obstructive pulmonary disease (COPD), but previous studies have limitations. Here, using a machine learning (ML) algorithm, we attempted to identify pathways in cultured bronchial epithelial cells of COPD patients that were significantly affected when the cells were exposed to a cigarette smoke extract (CSE). @*Methods@#Small airway epithelial cells were collected from patients with COPD and those without COPD who underwent bronchoscopy. After expansion through primary cell culture, the cells were treated with or without CSEs, and the proteomics of the cells were analyzed by mass spectrometry. ML-based feature selection was used to determine the most distinctive patterns in the proteomes of COPD and non-COPD cells after exposure to smoke extract.Publicly available single-cell RNA sequencing data from patients with COPD (GSE136831) were used to analyze and validate our findings. @*Results@#Five patients with COPD and five without COPD were enrolled, and 7,953 proteins were detected. Ferroptosis was enriched in both COPD and non-COPD epithelial cells after their exposure to smoke extract. However, the ML-based analysis identified ferroptosis as the most dramatically different response between COPD and non-COPD epithelial cells, adjusted P value = 4.172 × 10−6 , showing that epithelial cells from COPD patients are particularly vulnerable to the effects of smoke. Single-cell RNA sequencing data showed that in cells from COPD patients, ferroptosis is enriched in basal, goblet, and club cells in COPD but not in other cell types. @*Conclusion@#Our ML-based feature selection from proteomic data reveals ferroptosis to be the most distinctive feature of cultured COPD epithelial cells compared to non-COPD epithelial cells upon exposure to smoke extract.

The Korean Dysphagia Society (KDS) Position Statement for Oropharyngeal Dysphagia / 대한연하장애학회지

Oropharyngeal dysphagia is a clinical condition caused by various underlying diseases and is characterized by difficulty in swallowing. Diagnosis and treatment of oropharyngeal dysphagia require multidisciplinary consultations. This position statement for oropharyngeal dysphagia was developed by The Korean Dysphagia Society (KDS) to outline its position on oropharyngeal dysphagia. The clinical practice guideline, position statements, a recent meta-analysis, a systematic review, and randomized controlled trials for oropharyngeal dysphagia were all performed. An expert Delphi survey was also done to achieve a consensus of opinion on this position statement. This position statement for oropharyngeal dysphagia aims to help make evidence-based decisions in clinical practice, improve clinical evaluation and manage oropharyngeal dysphagia in Korea.

Treatment of gestational diabetes diagnosed by the IADPSG criteria decreases excessive fetal growth

The Impact of Autophagy on the Cigarette Smoke Extract-Induced Apoptosis of Bronchial Epithelial Cells / 결핵및호흡기질환

BACKGROUND: Previous studies report that apoptosis and autophagy are involved in the pathogenesis of emphysema, and macroautophagy is one of the processes regulating the apoptosis pathway. However, few studies have evaluated whether chaperone-mediated autophagy (CMA) contributes to the regulation of apoptosis. In this study, we investigated the impact of autophagy, including both macroautophagy and CMA, on the apoptosis in bronchial epithelial cells. METHODS: Cigarette smoke extract (CSE) was injected intratracheally into C57BL/6 mice, and emphysema and apoptosis were evaluated in the lungs. After treatment with CSE, apoptosis, macroautophagy, and CMA were measured in BEAS2-B cells, and the impact of autophagy on the apoptosis was evaluated following knockdown of autophagy-related genes by short interfering RNAs (siRNAs). RESULTS: Intratracheal CSE injection resulted in the development of emphysema and an increase in apoptosis in mice. CSE increased the apoptosis in BEAS2-B cells, and also elevated the expression of proteins related to both macroautophagy and CMA in BEAS2-B cells. The knockdown experiment with siRNAs showed that macroautophagy increases apoptosis in BEAS2-B cells, while CMA suppresses apoptosis. CONCLUSION: The intratracheal injection of CSE induces pulmonary emphysema and an increase in apoptosis in mice. CSE also induces apoptosis, macroautophagy, and CMA of bronchial epithelial cells. Macroautophagy and CMA regulate apoptosis in opposite directions.

Clinical Experiences of Uncommon Motor Neuron Disease: Hirayama Disease

Hirayama disease, juvenile muscular atrophy of the distal upper limb, is a rare disease predominantly affecting the anterior horn cells of the cervical spinal cord in young men. This cervical myelopathy is associated with neck flexion. It should be suspected in young male patients with a chronic history of weakness and atrophy involving the upper extremities followed by clinical stability in few years. Herein, we report 2 cases of Hirayama disease on emphasis of diagnostic approach and describe the pathognomonic findings at flexion magnetic resonance imaging.

The Anti-Inflammatory Effect of Arginine-Vasopressin on Lipopolysaccharide-Induced IkappaBalpha/Nuclear Factor-kappaB Cascade / 대한구급학회지

BACKGROUND: Arginine vasopressin (AVP) is widely used as a vasopressor agent. Some recent studies have suggested that AVP may exert an immunomodulatory effect. However, the mechanism about the anti-inflammatory effect of AVP is not well known. We investigated the effect of AVP on the ihibitor of kappa B (IkappaBalpha)/nuclear factor-kappa B (NF-kappaB) pathway in RAW 264.7 cells. METHODS: Cultured RAW 264.7 cells were pretreated with AVP and stimulated with lipopolysaccharide (LPS). To evaluate the effect of AVP on inflammatory cytokines, the concentration of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were assessed by an enzyme-linked immunosorbent assay technique. The expression of IkappaBalpha and nuclear translocation of NF-kappaB p65 were measured by Western blotting, and IkappaB kinase (IKK) activity was analyzed by an in vitro immune complex kinase assay. To confirm the AVP effect on IkappaBalpha/NF-kappaB cascade and via V2 receptor, we added tolvaptan (V2 receptor antagonist) after AVP pretreatment. RESULTS: The increase of IL-6 and TNF-alpha in LPS-stimulated RAW 264.7 cells was suppressed by a treatment with AVP. Pretreatment of AVP inhibited increasing of IKK activity and IkappaBalpha degradation induced by LPS in RAW 264.7 cells. Furthermore, LPS induced and NF-kappaB transcription was inhibited by AVP pretreatment. The observed changes in IKK activity, IkappaBalpha degradation and NF-kappaB transcription by AVP was abolished by tolvaptan treatment. CONCLUSIONS: Our results suggest that AVP showed anti-inflammatory effect on LPS-induced IkappaBalpha/NF-kappaB cascade in mouse macrophages via V2 receptors.

Immune thrombocytopenia associated with sarcoidosis / 영남의대학술지

Sarcoidosis is a systemic disease of unknown cause involving multiple organs and is characterized by noncaseating granuloma. Immune thrombocytopenia (ITP) is an autoimmune disease characterized by increased peripheral platelet destruction due to the presence of an antibody to the platelet and abnormal platelet production. There is no known pathogenesis that occurs concurrently with ITP and sarcoidosis. However, considering together of 2 known pathogenesis, abnormal immune response triggers either ITP or sarcoidosis. The disease that develops first stimulates secondary disease. After development of secondary disease, they stimulate each other. A few cases of ITP associated with sarcoidosis are well documented in English; however, the disease has rarely been reported in Korea. Here, we report on a case of ITP with sarcoidosis in a 29-year-old man. He suffered from easy bruising. The chest X-ray and the contrast-enhanced computed tomography scan showed bihilar lymphadenopathy and reticulonodular infiltrates. Bone marrow study and fluoroscopy-guided percutaneous needle biopsy were performed and the patient was diagnosed with sarcoidosis and ITP. He was put on 400 mg/kg of intravenous immunoglobulin for 5 days and administered oral steroids and further follow-up will be carried out. He has shown a good response without significant bleeding event. However, administration of more oral steroid and additional follow-up is required than for single disease, whether sarcoidosis or ITP.

The Anti-Inflammatory Effect of Arginine-Vasopressin on Lipopolysaccharide-Induced IkappaBalpha/Nuclear Factor-kappaB Cascade / 대한중환자의학회지

BACKGROUND: Arginine vasopressin (AVP) is widely used as a vasopressor agent. Some recent studies have suggested that AVP may exert an immunomodulatory effect. However, the mechanism about the anti-inflammatory effect of AVP is not well known. We investigated the effect of AVP on the ihibitor of kappa B (IkappaBalpha)/nuclear factor-kappa B (NF-kappaB) pathway in RAW 264.7 cells. METHODS: Cultured RAW 264.7 cells were pretreated with AVP and stimulated with lipopolysaccharide (LPS). To evaluate the effect of AVP on inflammatory cytokines, the concentration of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were assessed by an enzyme-linked immunosorbent assay technique. The expression of IkappaBalpha and nuclear translocation of NF-kappaB p65 were measured by Western blotting, and IkappaB kinase (IKK) activity was analyzed by an in vitro immune complex kinase assay. To confirm the AVP effect on IkappaBalpha/NF-kappaB cascade and via V2 receptor, we added tolvaptan (V2 receptor antagonist) after AVP pretreatment. RESULTS: The increase of IL-6 and TNF-alpha in LPS-stimulated RAW 264.7 cells was suppressed by a treatment with AVP. Pretreatment of AVP inhibited increasing of IKK activity and IkappaBalpha degradation induced by LPS in RAW 264.7 cells. Furthermore, LPS induced and NF-kappaB transcription was inhibited by AVP pretreatment. The observed changes in IKK activity, IkappaBalpha degradation and NF-kappaB transcription by AVP was abolished by tolvaptan treatment. CONCLUSIONS: Our results suggest that AVP showed anti-inflammatory effect on LPS-induced IkappaBalpha/NF-kappaB cascade in mouse macrophages via V2 receptors.

A Case of Type 1 Neurofibromatosis Associated with Multiple Metastatic Gastrointestinal Stromal Tumors / 영남의대학술지

Type 1 neurofibromatosis (von Recklinghausen's disease, NF-1) is an autosomal-dominant neurocutaneous-disorder characterized by systemic cafe'-au-lait spots, multiple cutaneous neurofibromas, axillary or inguinal freckling, and Lisch nodules (pigmented iris hamartomas). Approximately 10-25% of NF1 patients have gastrointestinal neoplasms. Gastrointestinal stromal tumor (GIST) in patients with neurofibromatosis is most commonly found in the small bowel and the stomach, and approximately 60% of such patients have multiple tumors or multiple tumor sites. Although, the increased incidence of GIST in patients with neurofibromatosis is well documented in pathology literature in English, but has rarely been documented in Korea. Here, we report a case of multiple GISTs in a 48-year-old woman accompanied by NF1. She was admitted to Yeungnam University Hospital with complaints of melena and dyspnea. A contrast-enhanced computed tomography (CT) scan revealed that multiple soft tissue masses were occupying the entire peritoneal cavity. An ultrasonogram- guided biopsy was performed and the tumors were found to have been composed of tumor cells that were positive for c-kit protein. The patient was put on Imatinib mesylate treatment, and further follow-up will be carried out.

Long-Term Complete Remission in an Acute Myeloid Leukemia Patient with Isolated Central Nervous System Relapse after Allogeneic Hematopoietic Stem Cell Transplantation / 영남의대학술지

Allogeneic hematopoietic stem cell transplantation (HSCT) is considered the optimal curative treatment for acute myeloid leukemia (AML), but some patients develop bone marrow relapse due to remnant leukemia, and few patients develop extramedullary relapse without bone marrow relapse. Isolated extramedullary relapse (IMER) is defined as extramedullary relapse without bone marrow relapse. IMER has been reported in various sites, including the skin, soft tissue, and central nervous system(CNS). Isolated CNS relapse is relatively rare and is associated with poor prognosis due to the absence of an optimal treatment for it. Reported herein is a case involving an adult AML woman who suffered from isolated extramedullary relapse in the CNS after allogeneic HSCT. She was treated with intrathecal chemotherapy and whole-brain and spine radiotherapy, followed by systemic chemotherapy. She is currently well, with no evidence of leukemia recurrence for over six years.

Treatment of Hemangiopericytoma-Associated Hypoglycemia with Glucocorticoid Therapy / 영남의대학술지

Non-islet cell tumor-induced hypoglycemia (NICTH) is associated with mesenchymal tumor types, including hemangiopericytoma, fibrosarcoma, mesothelioma, and neurofibroma, as well as carcinoma of the liver, adrenal glands, and kidneys. Non-islet cell tumors induce hypoglycemia by overproducing an abnormal form of insulin-like growth factor II (IGF II). Complete removal of the tumor or reduction of the tumor mass is a successful therapeutic strategy in cases of NICTH. However, if the tumor re-grows, curative resection is nearly impossible, and hypoglycemia occurs repeatedly. Glucocorticoids are effective in terms of long-term relief from hypoglycemia through promotion of gluconeogenesis in the liver, tumor suppression, production of 'big'-IGF-II, and correction of the attendant biochemical abnormalities involving the growth hormone (GH)-IGF axis. We found that administration of corticosteroid therapy to a patient suffering from NICTH resulted in improvement of hypoglycemia associated symptoms.

Clinical Practice Guideline for Stroke Rehabilitation in Korea

The clinical practice guideline for the stroke rehabilitation was formulated through both extensive review of published literature and consensus meeting of the specialists. The purposes of this study were to provide optimum practical guideline for acute and subacute stroke rehabilitation and to enhance the quality of stroke rehabilitation team in Korea. This guideline contains evidences and recommendations on the organization of post-stroke rehabilitation team, timing, evaluation, and intensity of rehabilitation, detailed management of dysphagia, neurogenic bladder and bowel, movement, shoulder problem, cognition, neglect, language, mood and complications commonly encountered in the acute and subacute period of stroke rehabilitation. Clinicians who are working in the field of stroke rehabilitation can adopt this guideline for their practice and give the feedback for further revision.

PS-341-Induced Apoptosis is Related to JNK-Dependent Caspase 3 Activation and It is Negatively Regulated by PI3K/Akt-Mediated Inactivation of Glycogen Synthase Kinase-3beta in Lung Cancer Cells / 결핵및호흡기질환

BACKGROUND: PS-341 is a novel, highly selective and potent proteasome inhibitor, which showed cytotoxicity against some tumor cells. Its anti-tumor activity has been suggested to be associated with modulation of the expression of apoptosis-associated proteins, such as p53, p21(WAF/CIP1), p27(KIP1), NF-kappa, Bax and Bcl-2. c-Jun N-terminal kinase (JNK) and glycogen synthase kinase-3beta(GSK-3beta are important modulators of apoptosis. However, their role in PS-341-induced apoptosis is unclear. This study was undertaken to elucidate the role of JNK and GSK-3beta in the PS-341-induced apoptosis in lung cancer cells. METHOD: NCI-H157 and A549 cells were used in the experiments. The cell viability was assayed using the MTT assay and apoptosis was evaluated by proteolysis of PARP. The JNK activity was measured by an in vitro immuno complex kinase assay and by phosphorylation of endogenous c-Jun. The protein expression was evaluated by Western blot analysis. Dominant negative JNK1 (DN-JNK1) and GSK-3betawere overexpressed using plasmid and adenovirus vectors, respectively. RESULT: PS-341 reduced the cell viability via apoptosis, activated JNK and increased the c-Jun expression. Blocking of the JNK activation by overexpression of DN-JNK1, or pretreatment with SP600125, suppressed the apoptosis induced by PS-341. The activation of caspase 3 was mediated by JNK activation. Blocking of the caspase 3 activation suppressed PS-341-induced apoptosis. PS-341 activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, but its blockade enhanced the PS-341-induced cell death via apoptosis. GSK-3betawas inactivated by PS-341 via the PI3K/Akt pathway. Overexpression of constitutively active GSK-3beta enhanced PS-341-induced apoptosis; in contrast, this was suppressed by dominant negative GSK-3beta(DN-GSK-3beta. Inactivation of GSK-3beta by pretreatment with lithium chloride or the overexpression of DN-GSK-3beta suppressed both the JNK activation and c-Jun up-regulation induced by PS-341. CONCLUSION: The JNK/caspase pathway is involved in PS-341-induced apoptosis, which is negatively regulated by the PI3K/Akt-mediated inactivation of GSK-3beta in lung cancer cells.

Effect of Uteroglobin on cPLA2, COX-2 Expression and ERK Activation in NSCLC Cells / 결핵

BACKGROUND: Uteroglobin is a protein produced by the normal bronchial epithelium and its expression level is lower in non-small cell lung cancer tissues and cell lines. It mainly functions as an anti-inflammatory, and when it is overexpressed in cancer cells, the neoplastic phenotype is antagonized. cPLA2 and COX-2, which are also associated with inflammation, were reported to be related to cancer. The relationship between cPLA2, COX-2 and uteroglobin is unclear. The relationship between uteroglobin and ERK, which is related to cell growth, is also not unclear. This study investigated the changes in the cPLA2 and COX-2 expression levels and the ERK activities after the overexpression of uteroglobin in non-small cell lung cancer cell lines. METHODS: The A549 and NCI-H460 cell lines were infected by adenovirus-null and adenovirus- uteroglobin. The cChange in the cPLA2, COX-2 expression level and ERK activity after uteroglobin overexpression was measured by Western blot. The change in MMP activity was measured by zymography. RESULTS: Western blot revealed decreased expression levels of cPLA2, and COX-2, and increased pERK levels in nonsmall cell lung cancer cells after uteroglobin overexpression. Zymography revealed no changes in the MMP-2 activity and lower MMP-9 activity. U0126, which is a specific inhibitor of ERK-activating kinase MEK-1/-2, prevented the decrease in the MMP-9 activity CONCLUSIONS: A decrease in cPLA2 expression, COX-2 expression, MMP-9 activity and a increase in ERK activity may be related to the anticancer effects of uteroglobin in nonsmall cell lung cancer cells.

Characteristics of Developmentally Delayed Infants and Young Children Who Demonstrated Normal Myelination by Brain MRI / 소아과

PURPOSE: To evaluate the clinical characteristics of infants and young children who had developmental delay without delayed myelination and dysmyelination. METHODS: We retrospectively reviewed 59 cases of developmental disability between July 1996 and June 2001 at Inha University Hospital. Twenty-eight patients showed normal myelination(Group I), while thirty-one patients showed delayed myelination(Group II) by brain MRI. The following clinical records and diagnostic procedures were performed; birth history, head size, neurological examination, developmental assortment test, brain stem auditory evoked potential, visual evoked potential, electroencephalogram, chromosomal study, metabolic screening tests, and clinical psychologic tests. RESULTS: There were no significant differences of sex, age, gestational period, birth weight, etiology, and seizures between group I and II. The incidences of cerebral palsy and abnormal background activity of EEG in group II were significantly higher than those in group I. In group I, mental retardations or speech disorders were higher than motor handicaps. In group II, motor handicaps were higher than mental retardations or speech disorders. In both groups, cases accompanied with seizures, have a tendency of intractability. CONCLUSION: Characteristics of developmentally delayed patients with normal myelination by brain MRI were not significantly different from characteristics of patients with delayed myelination. Even though infants and young children with the developmental delay showed normal findings by brain MRI, they are likely to be accompanied by severe development retardation.

The Mechanism of Proteasome Inhibitor-Induced Apoptosis in Lung Cancer Cells / 결핵

BACKGROUND: Proteasome inhibitors can promote either cell survival or programmed cell death, depending on both the specific type and proliferative status of the cell. However, it is not well known whether inhibition of proteasome activity is related to apoptosis in lung cancer cells. In addition, the exact mechanisms responsible for apoptosis induced by proteasome inhibition are not well understood. In the present study, we have examined the effect of proteasome inhibition on lung cancer cells and tried to test the mechanisms that may be associated with the apoptosis of these cells. METHODS: We examined the effect of proteasome inhibition with MG132 or PS-341 on cell survival in A549 and NCI-H157 lung cancer cells using MTT assay, and analyzed the cleavage of PARP by Western blot analysis to find evidence of apoptosis. Next, we evaluated the activation of caspase 3 by Western blot analysis and the activity of JNK by immunocomplex kinase assay. We also examined the changes in anti-apoptotic pathways like ERK and cIAP1 by Western blot analysis after inhibition of proteasome function. RESULTS: We demonstrated that MG132 reduced cell survival by inducing apoptosis in A549 and NCI-H157 cells. Proteasome inhibition with MG132 or PS-341 was associated with activation of caspase 3 and JNK, reduced expression of activated ERK, and downregulation of cIAP1. CONCLUSION: Apoptosis induced by proteasome inhibition may be associated with the activation of pro-apoptotic pathways like caspase 3 and JNK and the inactivation of anti-apoptotic pathways in lung cancer cells.

The Relationship Between the NF-kappa B Activity and Anti-inflammatory Action of Surfactant in the Acute Lung Injury of Rats / 결핵

BACKGROUND: The therapeutic effects of surfactants on acute lung injury derive not only from their recruiting action on collapsed alveoli but also from their anti-inflammatory action in the alveolar space. This study evaluated the anti-inflammatory action of a surfactant in an acute lung injury model of rats by measuring the WBC count, IL-1beta and IL-6 level of bronchoalveolar lavage(BAL) fluid. In addition, neutrophils were recollected from the BAL fluid and the NF-kappa B activity of the neutrophilic nuclear protein was evaluated. METHODS: Male Sprague-Dawley rats weighing approximately 300 gram were divided into 3 groups, which consisted of 6 rats respectively. In the control group, normal saline(3ml/kg) was instilled into the trachea twice with 30 minute interval. In two other groups, acute lung injury was induced by the intra-tracheal instillation of LPS(5mg/kg). Thirty minutes later, either a surfactant(ST group; 30mg/kg) or normal saline(NT group: 3ml/kg) was instilled via the trachea. Twenty-four hours after the LPS instillation, the BAL fluid was retrieved to measure the WBC count and cytokine(IL-1beta and IL-6) levels. The neutrophils were isolated from the BAL fluid and the nuclear protein was extracted to evaluate the NF-kappa Bactivity using a eletrophoretic mobility shift assay(EMSA). RESULTS: The WBC count of the BAL fluid of the ST group(3,221+/-1,914 X 10(3)/micro liter) was higher than that of the control group(356+/-275X10(3)/micro liter)(p<0.05) and lower than that of the NT group(5,561+/-1,757 X 10(3)/micro liter)(p<0.05)). The BAL fluid level of IL-1beta from the NT group(2,064+/-1,082pg/ml) was higher than those of the ST group(360+/-234pg/ml)(p<0.05) and the control group(0pg/ml)(p<0.05). The BAL fluid concentration of IL-6 from the NT group(3,621+/-567pg/ml) was also higher than those of the ST group(1,754+/-1,340pg/ml)(p<0.05) and control group(49+/-62pg/ml)(p<0.05). The NF-kappa B activity of the neutrophilic nuclear protein in the ST group and NT group was similar. CONCLUSIONS: The surfactant attenuates the alveolar inflammation in the acute lung injury of rats model. However, its anti-inflammatory action does no't appear to be mediated by the inhibition of NF-kappa B activity.

Clinical Approach for Visual Achievement in Amblyopia Treatment

We retrospectively studied 60 amblyopic patients who had been treated for 12 months or more. They were divided into three age groups; below 5.5 years, 5.5 years to 8 years and 8 years or more, and visual improvements were compared with three age groups. The visual improvements were 5 line increase in both of below 5.5 year group and 5.5 year to 8 year age group and 3 line increase in 8 year and older group. In all three age groups, two-thirds of the improvements were achieved during the first three months of treatment There was no difference in visual improvement according to amblyopic type(strabismic, anisometropic, strabismic and anisometropic amblyopia). Treatment failures seemed to be the later onset of treatment, eccentric fixation and large anisometropic difference.

Histiocytic Medullary Reticulosis / 영남의대학술지

The term histiocytic medullary reticulosis first was introduced by Scott and Robb-Smith. It is a clinicopathologic syndrome characterized by wasting, fever, lymphadenopathy, hepatosplenomegaly, pancytopenia, and is often accompanied by jaundice, purpura. Cardinal pathologic feature are systemized proliferation of atypical, neoplastic, erythrophagocytic D. We are here reporting one case which considered compatible for HMR, with a few elementary reviewed literatures.