Association between Antacid Exposure and Risk of Interstitial Lung Diseases.

BACKGROUND: The mechanisms leading to lung fibrosis are still under investigation. This study aimed to demonstrate whether antacids could prevent the development of interstitial lung disease (ILD). METHODS: This population-based longitudinal cohort study was conducted between January 2006 and December 2010 in South Korea. Eligible subjects were ≥40 years of age, exposed to proton pump inhibitors (PPI)±histamine-2 receptor antagonists (H-2 blockers) or H-2 blockers only, and had no history of ILD between 2004 and 2005. Exposure to antacids was defined as the administration of either PPI or H-2 receptor antagonists for >14 days, whereas underexposure was defined as antacid treatment administered for less than 14 days. Newly developed ILDs, including idiopathic pulmonary fibrosis (IPF), were counted during the 5-year observation period. The association between antacid exposure and ILD development was evaluated using adjusted Cox regression models with variables, such as age, sex, smoking history, and comorbidities. RESULTS: The incidence rates of ILD with/without antacid use were 43.2 and 33.8/100,000 person-years, respectively and those of IPF were 14.9 and 22.9/100,000 person-years, respectively. In multivariable analysis, exposure to antacid before the diagnosis of ILD was independently associated with a reduced development of ILD (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.45 to 0.71; p<0.001), while antacid exposure was not associated with development of IPF (HR, 0.88; 95% CI, 0.72 to 1.09; p=0.06). CONCLUSION: Antacid exposure may be independently associated with a decreased risk of ILD development.

Association between the use of statins and risk of interstitial lung disease/idiopathic pulmonary fibrosis: time-dependent analysis of population-based nationwide data.

BACKGROUND: We aimed to study whether statin use is associated with lowering the development of interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). METHODS: The study population was the Korean National Health Insurance Service-Health Screening Cohort. ILD and IPF cases were identified using diagnosis codes (J84.1 for ILD and J84.1A as a special code for IPF) based on the International Classification of Diseases, 10th Revision. The study participants were followed up from 1 January 2004 to 31 December 2015. Statin use was defined by the cumulative defined daily dose (cDDD) per 2-year interval and participants were categorised into never-users, <182.5, 182.5-365.0, 365.0-547.5 and ≥547.5 by cDDD. A Cox regression was used to fit models with time-dependent variables of statin use. RESULTS: Incidence rates for ILD with and without statin use were 20.0 and 44.8 per 100 000 person-years, respectively, and those for IPF were 15.6 and 19.3 per 100 000 person-years, respectively. The use of statins was independently associated with a lower incidence of ILD and IPF in a dose-response manner (p-values for trend <0.001). ILD showed respective adjusted hazard ratios (aHRs) of 1.02 (95% CI 0.87-1.20), 0.60 (95% CI 0.47-0.77), 0.27 (95% CI 0.16-0.45) and 0.24 (95% CI 0.13-0.42) according to the increasing category of statin use compared with never-users. IPF showed respective aHRs of 1.29 (95% CI 1.07-1.57), 0.74 (95% CI 0.57-0.96), 0.40 (95% CI 0.25-0.64) and 0.21 (95% CI 0.11-0.41). CONCLUSION: A population-based cohort analysis found that statin use is independently associated with a decreased risk of ILD and IPF in a dose-response manner.

Association between use of antacid medications (proton pump inhibitors and histamine-2 receptor antagonists) and the incidence of lung cancer: A population-based cohort analysis.

This study investigated the association between antacid administration and lung cancer incidence in a real-world setting. This was a nationwide, retrospective cohort study. The cohort comprised random samples (n = 1,031,392) from the entire South Korean population in 2002. The duration of antacid administration between January 2006 and December 2010 was recorded for each participant. Newly developed lung cancers were counted during the 5-year observation period (January 1, 2006 to December 31, 2010). A total of 437,370 participants aged ≥ 40 years were included, of whom 301,201 (68.9%) had antacid exposure before the diagnosis of lung cancer. A total of 1230 (0.28%) antacid-exposed patients developed lung cancer. Among patients with no antacid exposure or underexposure (n = 136,171), 597 (0.44%) developed lung cancer. In the multivariable analysis, antacid exposure before the diagnosis of lung cancer was independently associated with a reduced incidence of lung cancer (hazard ratio: 0.64; 95% confidence interval: 0.55-0.74; P < .001). Antacid use might be independently associated with a decreased risk of lung cancer development in this cohort study.

Prognostic outcome of treatment modalities for epidermal growth factor receptor-mutated advanced lung cancer.

BACKGROUND/AIMS: The treatment of epidermal growth factor receptor (EGFR)-mutated lung cancer cases has shown remarkable development in the past two decades. However, there have been limited studies comparing the prognostic effects of EGFR-tyrosine kinase inhibitor (TKI) and other treatment modalities. Therefore, we compared the survival outcomes of patients treated with EGFR-TKIs versus those treated with other treatment modalities. METHODS: Patient data were collected from the Korean National Health Insurance Database, National Health Insurance Service- National Sample Cohort 2002 to 2015, which was released by the Korean National Health Insurance Service in 2015. The lung cancer group included patients (n = 2,003) initially diagnosed with lung cancer between January 2010 and December 2013. The main outcome was all-cause mortality. A Cox proportional hazard regression analysis was used to calculate the relative risk of mortality. RESULTS: Among the newly diagnosed lung cancer cases, 1,004 (50.1%) were included in the analysis. A 15.1-month median survival benefit was observed in the EGFR-TKI group than that of the multimodality therapy group. The risk of mortality was as follows: EGFR-TKI treatment group (n = 142; hazard ratio [HR], 5.29; 95% confidence interval [CI], 3.57 to 7.86) and multimodality therapy group (n = 326; HR, 7.42; 95% CI, 5.19 to 10.63) compared to surgery only (n = 275). CONCLUSION: Patients with advanced lung cancer harbouring EGFR mutations treated with EGFR-TKIs showed better median survival and lower risk of mortality than those in the multimodality therapy group. In the case of EGFR-mutated advanced lung cancer, there is room for downstaging in the TNM classification.

Fermented kimchi rejuvenated precancerous atrophic gastritis via mitigating Helicobacter pylori-associated endoplasmic reticulum and oxidative stress.

Dietary intervention to prevent Helicobacter pylori (H. pylori)-gastric cancer might be ideal by long-term intervention, rejuvenating action, and no risk of bacterial resistance. Stimulated with finding that kimchi prevented H. pylori-gastric cancer, we compared the efficacy of cancer preventive kimchi (cpkimchi) and standard recipe kimchi (skimchi) and the efficacy between fermented kimchi and non-fermented kimchi (kimuchi) in H. pylori-initiated gastric cancer model and explored novel mechanisms hinted from RNAseq transcriptome analysis. Animal models assessing gastric pathology on 24 and 36 weeks after H. pylori initiated, salt diet-promoted gastric mutagenesis model showed fermented cpkimchi afforded the best outcome of either rejuvenating atrophic gastritis or inhibiting tumorigenesis compared to skimchi and kimuchi. Highest inhibition of atrophic gastritis was achieved with cpkimchi, while significantly lower in kimuchi. Transcriptomic analysis showed ameliorated-endoplasmic reticulum (ER) stress, -oxidative stress, and -apoptosis as major rejuvenating action of cpkimchi. Homogenates from animal model showed that elevated expressions of p-PERK, IRE, ATF6, p-elf, and XBP1 in control group, while significantly decreased with dietary intake of only cpkimchi. Significantly increased expressions of HO-1 and γ-GCS were only noted with cpkimchi. Conclusively, long-term dietary intervention of fermented cpkimchi can be potential way preventing H. pylori-associated carcinogenesis via rejuvenation of atrophic gastritis.

Transcriptome profiling implicated in beneficiary actions of kimchi extracts against Helicobacter pylori infection.

Dietary intervention to prevent Helicobacter pylori (H. pylori)-gastric cancer might be ideal because of no risk of bacterial resistance, safety, and rejuvenating action of atrophic gastritis. We have published data about the potential of fermented kimchi as nutritional approach for H. pylori. Hence recent advances in RNAseq analysis lead us to investigate the transcriptome analysis to explain these beneficiary actions of kimchi. gastric cells were infected with either H. pylori or H. pylori plus kimchi. 943 genes were identified as significantly increased or decreased genes according to H. pylori infection and 68 genes as significantly changed between H. pylori infection and H. pylori plus kimchi (p<0.05). Gene classification and Medline database showed DLL4, FGF18, PTPRN, SLC7A11, CHAC1, FGF21, ASAN, CTH, and CREBRF were identified as significantly increased after H. pylori, but significantly decreased with kimchi and NEO1, CLDN8, KLRG1, and IGFBP1 were identified as significantly decreased after H. pylori, but increased with kimchi. After KEGG and STRING-GO analysis, oxidative stress, ER stress, cell adhesion, and apoptosis genes were up-regulated with H. pylori infection but down-regulated with kimchi, whereas tissue regeneration, cellular anti-oxidative response, and anti-inflammation genes were reversely regulated with kimchi (p<0.01). Conclusively, transcriptomes of H. pylori plus kimchi showed significant biological actions.

Fecal microbiota changes with fermented kimchi intake regulated either formation or advancement of colon adenoma.

Gut bacteria might contribute in early stage of colorectal cancer through the development and advancement of colon adenoma, by which exploring either beneficial bacteria, which are decreased in formation or advancement of colon adenoma and harmful bacteria, which are increased in advancement of colon adenoma may result in implementation of dietary interventions or probiotic therapies to functional means for prevention. Korean fermented kimchi is one of representative probiotic food providing beneficiary microbiota and exerting significant inhibitory outcomes in both APC/Min+ polyposis model and colitis-associated cancer. Based on these backgrounds, we performed clinical trial to document the changes of fecal microbiota in 32 volunteers with normal colon, simple adenoma, and advanced colon adenoma with 10 weeks of fermented kimchi intake. Each amplicon is sequenced on MiSeq of Illumina and the sequence reads were clustered into Operational Taxonomic Units using VSEARCH and the Chao Indices, an estimator of richness of taxa per individual, were estimated to measure the diversity of each sample. Though significant difference in α or ß diversity was not seen between three groups, kimchi intake significantly led to significant diversity of fecal microbiome. After genus analysis, Acinobacteria, Cyanobacteria, Clostridium sensu, Turicibacter, Gastronaeophillales, H. pittma were proven to be increased in patients with advanced colon adenoma, whereas Enterococcua Roseburia, Coryobacteriaceau, Bifidobacterium spp., and Akkermansia were proven to be significantly decreased in feces from patients with advanced colon adenoma after kimchi intake. Conclusively, fermented kimchi plentiful of beneficiary microbiota can afford significant inhibition of either formation or advancement of colon adenoma.

Cesarean delivery may be protective against neoplasms of the uterine cervix in women of childbearing age.

Parity has been reported as a risk factor for cervical cancer. However, no study has investigated the risk of neoplasms of the uterine cervix according to the delivery type. We carried out a retrospective cohort study using nationwide data from the Korean Health Insurance Review and Assessment Database to investigate whether cesarean delivery might be associated with less development of neoplasms of the uterine cervix than a vaginal delivery in women of childbearing age. Women aged 20-44 years, who had undergone vaginal or cesarean deliveries in 2009 were included as subjects. Two individual datasets for carcinoma in situ (CIS) and cancer of the cervix were followed for 8 years until either disease outcomes or 31 December 2016. In total, 260 438 and 132 232 women had undergone vaginal only and cesarean only deliveries, respectively. There were 1505 and 423 new cases of CIS and cervical cancer, respectively, with median follow-up durations of 89.9 and 90.0 months for vaginal delivery and cesarean delivery, respectively. The unadjusted CIS risk ratio for cesarean delivery compared with vaginal delivery was 0.90 [95% confidence interval, (CI), 0.80-1.00]. After adjusting for categorical age, residential area, facility types, and number of visits to obstetrics and gynecology clinics, it was 0.83 (95% CI, 0.75-0.93). The unadjusted and adjusted risk ratios for cervical cancer for cesarean delivery were 0.98 (95% CI, 0.80-1.20) and 0.87 (95% CI, 0.71-1.08), respectively. Cesarean delivery may be more protective against CIS than vaginal delivery in women of childbearing age.

Dietary intake of probiotic kimchi ameliorated IL-6-driven cancer cachexia.

Cancer cachexia is a syndrome accompanying weight loss, skeletal muscle atrophy, and loss of adipose tissue in patients with advanced cancer. Since interleukin-6 (IL-6) is one of core mediators causing cancer cachexia and kimchi can modulate IL-6 response, we hypothesized dietary intake of kimchi can ameliorate cancer cachexia. In this study, we studied preemptive administration of kimchi can ameliorate mouse colon carcinoma cells colon (C26) adenocarcinoma-induced cancer cachexia and explored anti-cachexic mechanisms of kimchi focused on the changes of muscle atrophy, cachexic inflammation, and catabolic catastrophe. As results, dietary intake of kimchi significantly attenuated the development of cancer cachexia, presented with lesser weight loss, higher muscle preservation as well as higher survival from cancer cachexia in mice. Starting from significant inhibition of IL-6 and its signaling, kimchi afforded significant inhibition of muscle specific ubiquitin-proteasome system including inhibition of atrogin-1 and muscle ring finger protein-1 (MuRF-1) with other muscle related genes including mitofusin-2 (Mfn-2) and PGC-1α. Significant inhibition of lipolysis gene such as adipose triglyceride lipase (ATGL) and hormone-sensitive ligase (HSL) accompanied with significant induction of fatty acid synthase (FAS) and sterol response element binding protein 1 (SREBP1) was achieved with kimchi. As gene regulation, IL-6 and their receptor as well as Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were significantly attenuated with kimchi. In conclusion, dietary intake of cancer preventive kimchi can be an anticipating option to ameliorate cancer cachexia via suppressive action of IL-6 accompanied with decreased muscle atrophy and lipolysis.

Lung Cancer development and mortality in interstitial lung disease with and without connective tissue diseases: a five-year Nationwide population-based study.

BACKGROUND: Connective tissue disease associated with interstitial lung disease (CTD-ILD) and interstitial lung disease (ILD) alone have same pathological and imaging backgrounds. However, the differences between lung cancer development and the mortality risk between these two conditions are unclear. Incidence of primary lung cancer and all-cause mortality were studied between interstitial lung disease patients with and without connective tissue disease. METHODS: Data were extracted from the Korean National Health Insurance Research Database in 2009. A total of 12,787 cases of ILD without idiopathic pulmonary fibrosis and 2491 cases of CTD-ILD were diagnosed in 2009. The cohort was followed up until June 30, 2014. Incident lung cancers and all-cause mortality were ascertained. RESULTS: The overall incidence of lung cancer was 165.7 and 161.8 per 10,000 person-years in the CTD-ILD and ILD-only, respectively (rate ratio, 1.08; 95% confidence interval, 0.89-1.30). CTD-ILD patients in the 40-49 and 50-59 years old age groups had lung cancer incidence rates of 92.5 and 139.2, which were 2.0 and 1.7 times higher than those in the ILD-only, respectively. All-cause mortality was significantly higher in the CTD-ILD group compared to ILD-only group in patients aged 50-79 years. All-cause mortality of women in the 50-59, 60-69 and 70-79 age groups was 2.0, 1.8, and 1.4 times higher in the CTD-ILD group than in the ILD-only group, respectively. CONCLUSIONS: CTD-ILD patients aged < 60 years had a higher lung cancer incidence than ILD-only patients in the same age group. Furthermore, CTD-ILD patients aged 50-79 years had higher all-cause mortality than ILD-only patients in the same age group.

Targeted molecular ablation of cancer stem cells for curing gastrointestinal cancers.

INTRODUCTION: Abundance of the ATPase-binding cassette (ABC) transporters and deranged self-renewal pathways characterize the presence of cancer stem cells (CSCs) in gastrointestinal cancers (GI cancers), which play crucial roles in tumorigenesis, chemotherapy resistance, tumor recurrence, and cancer metastasis. Therefore, in order to ensure high cure rates, chemoquiescence, CSCs should be ablated. Recent advances in either understanding CSCs or biomarker identification enable scientists to develop techniques for ablating CSCs and clinicians to provide cancer cure, especially in GI cancers characterized by inflammation-driven carcinogenesis. Areas covered: A novel approach to ablate CSCs in GI cancers, including esophageal, gastric, and colon cancers, is introduced along with explored underlying molecular mechanisms. Expert commentary: Though CSC ablation is still in the empirical stages and not in clinical practice, several strategies for ablating CSCs in GI cancers had been published, proton-pump inhibitors (PPIs) that regulate the membrane-bound ABC transporters, which underlie drug resistance; chloroquine (CQ) that inhibits autophagy, which is responsible for tumor survival; Hedgehog/Wnt/Notch inhibitors that influence the underlying stem-cell growth, and some natural products including Korean red ginseng, cancer-preventive kimchi, Artemisia extract, EGCG from green tea, and walnut extracts.

A Comparison of Implants Used in Double Door Laminoplasty : Allogeneic Bone Spacer versus Hydroxyapatite Spacer.

OBJECTIVE: The aim of this study was to compare the clinical and radiological outcomes associated with the use of hydroxyapatite (HA) spacer and allogeneic bone (AB) spacer in laminoplasty. METHODS: From January 2006 to July 2014, 79 patients with cervical spondylotic myelopathy or ossification of the posterior longitudinal ligament underwent cervical laminoplasty. The radiologic parameters were obtained from plain radiography and three-dimensional computed tomography. All images were taken before and after surgery. Cervical lordosis, spinal canal dimension, fusion between lamina and spacer, and resorption of spacer were checked. Clinical outcomes were assessed using visual analog scale and Japanese Orthopedic Association. RESULTS: Double-door laminoplasty was performed on 280 levels : 182 in the HA group and 98 in the AB group. The mean follow-up was 23.1 months (range : 4-69 months). Similar fusion rates were found in these groups (p=0.3). The resorption rate between lamina and spacer was lower in the HA group (p<0.001). During the immediate postoperative period, the canal dimension of both groups increased compared with the results in the preoperative period. However, the canal dimension of the AB group decreased over time compared with that of the HA group (p<0.001). CONCLUSION: Double-door laminoplasty improved the clinical outcomes of both groups. However, the spinal canal dimension in the AB group showed a greater degree of reduction than in the HA group at the final postoperative follow-up. Therefore, we suggest that surgeons consider the use of larger-sized AB spacers in double-door laminoplasties.

Diagnostic usefulness of a peribulbar eosinophilic infiltrate in alopecia areata.

IMPORTANCE: The histopathologic diagnosis of alopecia areata (AA) may be difficult in the chronic stage in which the presence of a peribulbar lymphocytic infiltrate is not definite. An eosinophilic infiltrate has been reported as a relatively common histopathologic finding and a helpful diagnostic feature in AA. OBJECTIVE: To investigate the frequency and diagnostic usefulness of an eosinophilic infiltrate around the hair bulbs or within the fibrous tracts during the chronic stage of AA. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review was conducted at Chungbuk National University Hospital. A total of 162 scalp biopsy specimens of AA were analyzed. MAIN OUTCOMES AND MEASURES: The frequency of a peribulbar eosinophilic infiltrate in AA. RESULTS: In 30 of 162 specimens (18.5%) of AA in all stages, eosinophils were found around the hair bulbs with variable density but were not identified in the fibrous tracts of any specimen. Eosinophils around the hair bulbs were detected in 24 of 78 specimens (30.8%) of the acute stage of AA in which a peribulbar lymphocytic infiltrate was present, and eosinophils were densely infiltrated in 6 of these specimens (7.7%). In contrast, in the chronic stage of AA in which a peribulbar lymphocytic infiltrate was sparse or absent, eosinophils around the hair bulbs were found in only 6 of 84 specimens (7.1%); furthermore, eosinophils were sparsely present in all specimens. Pigmentary incontinence around the hair follicles was found in 58 of 84 specimens (69.0%), follicular miniaturization in 52 (61.9%), and shift to the catagen or telogen phase in 46 (54.8%). CONCLUSIONS AND RELEVANCE: An eosinophilic infiltrate around the hair bulbs or within the fibrous tracts is not a common finding in the histopathologic characteristics of AA, especially in the chronic stage of the disease. Thus, the diagnostic usefulness of the eosinophilic infiltrate is limited to few cases of AA in the chronic stage. Other histopathologic findings, such as pigmentary incontinence around the hair follicles, follicular miniaturization, and shift to the catagen or telogen phase, are more useful diagnostic features in the cases of AA not showing a definite peribulbar lymphocytic infiltrate.

Primary localized cutaneous nodular amyloidosis following local trauma.

Primary localized cutaneous nodular amyloidosis (nodular amyloidosis) is a rare and distinct type of amyloidosis, in which amyloid L deposition is limited to the skin and typically manifested as a tumefactive nodule on the acral sites. However, the definite cause of nodular amyloidosis is still unknown. Although it is relatively well known that the amyloid deposits in nodular amyloidosis originate from immunoglobulin light chains secreted by local plasma cells, traumatic injury to the skin has rarely been recognized as a triggering factor of nodular amyloidosis. Herein, we present a case of a 50-year-old male patient with primary localized cutaneous nodular amyloidosis, which occurred after local trauma, and discuss the relationship between traumatic damage and dermal amyloid L deposition.

Aurintricarboxylic acid translocates across the plasma membrane, inhibits protein tyrosine phosphatase and prevents apoptosis in PC12 cells.

Aurintricarboxylic acid (ATA) prevents apoptosis in a diverse range of cell types including PC12 cells. It is known to stimulate tyrosine phosphorylation of signaling proteins including Shc proteins, phosphatidylinositol 3-kinase, phospholipase C-g and mitogen-activated protein kinases (MAPKs). However, it has been unclear how ATA increases the phosphorylation of these proteins as it was believed to be membrane impermeable. We found that ATA translocates across the plasma membrane of PC12 cells and have confirmed that it is a potent inhibitor of protein tyrosine phosphatases (PTP ases). Other PTPase inhibitors also prevented apoptosis independent of ATA. These observations indicate that ATA exerts its anti-apoptotic effect on PC12 cells at least in part by inhibiting certain PTPase(s).