Background: Cholecystitis is an important risk factor for gallbladder cancer, but the bile microbiome and its association with gallbladder disease has not been investigated fully.We aimed to analyze the bile microbiome in normal conditions, chronic cholecystitis, and gallbladder cancer, and to identify candidate bacteria that play an important role in gallbladder carcinogenesis. Methods: We performed metagenome sequencing on bile samples of 10 healthy individuals, 10 patients with chronic cholecystitis, and 5 patients with gallbladder cancer, and compared the clinical, radiological, and pathological characteristics of the participants. Results: No significant bacterial signal was identified in the normal bile. The predominant dysbiotic bacteria in both chronic cholecystitis and gallbladder cancer were those belonging to the Enterobacteriaceae family. Klebsiella increased significantly in the order of normal, chronic cholecystitis, and gallbladder cancer. Patients with chronic cholecystitis and dysbiotic microbiome patterns had larger gallstones and showed marked epithelial atypia, which are considered as precancerous conditions. Conclusion We investigated the bile microbiome in normal, chronic cholecystitis, and gallbladder cancer. We suggest possible roles of Enterobacteriaceae, including Klebsiella, in gallbladder carcinogenesis. Our findings reveal a possible link between a dysbiotic bile microbiome and the development of chronic calculous cholecystitis and gallbladder cancer.

Background: Cholecystitis is an important risk factor for gallbladder cancer, but the bile microbiome and its association with gallbladder disease has not been investigated fully.We aimed to analyze the bile microbiome in normal conditions, chronic cholecystitis, and gallbladder cancer, and to identify candidate bacteria that play an important role in gallbladder carcinogenesis. Methods: We performed metagenome sequencing on bile samples of 10 healthy individuals, 10 patients with chronic cholecystitis, and 5 patients with gallbladder cancer, and compared the clinical, radiological, and pathological characteristics of the participants. Results: No significant bacterial signal was identified in the normal bile. The predominant dysbiotic bacteria in both chronic cholecystitis and gallbladder cancer were those belonging to the Enterobacteriaceae family. Klebsiella increased significantly in the order of normal, chronic cholecystitis, and gallbladder cancer. Patients with chronic cholecystitis and dysbiotic microbiome patterns had larger gallstones and showed marked epithelial atypia, which are considered as precancerous conditions. Conclusion We investigated the bile microbiome in normal, chronic cholecystitis, and gallbladder cancer. We suggest possible roles of Enterobacteriaceae, including Klebsiella, in gallbladder carcinogenesis. Our findings reveal a possible link between a dysbiotic bile microbiome and the development of chronic calculous cholecystitis and gallbladder cancer.

Purpose: Some patients who have undergone surgery due to lumbar disc herniation still complain of leg pain and other abnormal sensations. Therefore, the study examined the effects of the neurodynamics on pain and other abnormal nerve sensations in post-operated patients with lumbar disc herniation. Methods: The participants of this study comprised 20 adults (10 males and 10 females) who were diagnosed with lumbar disc herniation. The subjects were classified into two groups of 10 patients each in the lower extremity neurodynamics (LEN) and lumbar stabilization exercise (LSE) groups. Each intervention was applied twice a day for one week and was composed of two different exercise patterns; one was applied by a therapist, and the other was performed by the patients themselves. The data were analyzed using assessment methods of Digital Infrared Thermal Imaging (DITI), Toronto clinical neuropathy scoring system (TCNSS), Sympathetic Skin Response (SSR) test, and Oswestry Disability Index (ODI) scale. Results: Significant differences in TCNSS, DITI, ODI scale were observed between the LEN and LSE group (p<0.01). On the other hand, there was no significant difference in the SSR test between pre and post-treatment (p>0.05). Conclusion The results indicated that neurodynamics treatment is effective in pain reduction and abnormal sensations, such as leg muscle cramps, in post-operated patients with lumbar disc herniation.

Purpose: Some patients who have undergone surgery due to lumbar disc herniation still complain of leg pain and other abnormal sensations. Therefore, the study examined the effects of the neurodynamics on pain and other abnormal nerve sensations in post-operated patients with lumbar disc herniation. Methods: The participants of this study comprised 20 adults (10 males and 10 females) who were diagnosed with lumbar disc herniation. The subjects were classified into two groups of 10 patients each in the lower extremity neurodynamics (LEN) and lumbar stabilization exercise (LSE) groups. Each intervention was applied twice a day for one week and was composed of two different exercise patterns; one was applied by a therapist, and the other was performed by the patients themselves. The data were analyzed using assessment methods of Digital Infrared Thermal Imaging (DITI), Toronto clinical neuropathy scoring system (TCNSS), Sympathetic Skin Response (SSR) test, and Oswestry Disability Index (ODI) scale. Results: Significant differences in TCNSS, DITI, ODI scale were observed between the LEN and LSE group (p<0.01). On the other hand, there was no significant difference in the SSR test between pre and post-treatment (p>0.05). Conclusion The results indicated that neurodynamics treatment is effective in pain reduction and abnormal sensations, such as leg muscle cramps, in post-operated patients with lumbar disc herniation.

Purpose: Mesenchymal epithelial transition (MET) is a proto-oncogene that encodes a heterodimerictransmembrane receptor tyrosine kinase for the hepatocyte growth factor. Aberrant METsignaling has been described in several solid tumors—especially non-small cell lung cancer—and is associated with tumor progression and adverse prognosis. As MET is a potentialtherapeutic target, information regarding its prevalence and clinicopathological relevanceis crucial. Materials and Methods: We investigated MET expression and gene amplification in 113 gallbladder cancers usingtissue microarray. Immunohistochemistry was used to evaluate MET overexpression, andsilver/fluorescence in situ hybridization (ISH) was used to assess gene copy number. Results: MET overexpression was found in 37 cases of gallbladder carcinoma (39.8%), and geneamplification was present in 17 cases (18.3%). MET protein expression did not correlatewith MET amplification. MET amplification was significantly associated with aggressive clinicopathologicalfeatures, including high histological grade, advanced pT category, lymphnode metastasis, and advanced American Joint Committee on Cancer stage. There was nosignificant correlation between any clinicopathological factors and MET overexpression. Nodifference in survival was found with respect to MET overexpression and amplification status. Conclusion Our data suggested that MET might be a potential therapeutic target for targeted therapyin gallbladder cancer, because MET amplification was found in a subset of tumors associatedwith adverse prognostic factors. Detection of MET amplification by ISH might be a usefulpredictive biomarker test for anti-MET therapy.

BACKGROUND: The heterogeneity of histological findings in preclinical diet-induced nonalcoholic fatty liver disease (NAFLD) animal models is highly challenging. Here, we aimed to evaluate the feasibility and stability of repeated liver biopsy in NAFLD animal models. METHODS: Heterogeneity of diet-induced NAFLD was evaluated at different time points in 52 high-fat diet (HFD), 35 methionine choline-deficiency diet (MCD), and 166 western diet (WD) induced NAFLD mice. Serial liver biopsies (left lateral, right medial, and left medial lobes) were performed monthly for up to 3 months. Mortality rates and changes in food intake, body weight, and liver enzymes were assessed. RESULTS: At 12 weeks, of the HFD animals, 14% and 30% did not develop steatosis and lobular inflammation, respectively; of the MCD animals, 7% did not develop lobular inflammation; and of the WD animals, 14% and 51% did not develop steatosis and lobular inflammation, respectively. The mortality rate of repeated liver biopsy was 1.62% (2/123 mice died). Repeated liver biopsy can be used to trace disease progression. Although body weight, food intake, and liver enzymes slightly changed after biopsy, all recovered within a week. Repeated liver biopsy did not affect the degrees of inflammation and steatosis of the other liver lobes. CONCLUSION: The diet-induced NAFLD models were quite heterogeneous. Our results suggest that the repeated liver biopsy before treatment was applicable and stable in this NAFLD animal study.
Animals ; Biopsy* ; Body Weight ; Diet ; Diet, High-Fat ; Diet, Western ; Disease Progression ; Eating ; Inflammation ; Liver* ; Methionine ; Mice ; Models, Animal ; Mortality ; Non-alcoholic Fatty Liver Disease* ; Population Characteristics

Sjögren's syndrome (SS) is a chronic heterogeneous disease that mainly affects exocrine glands, leading to sicca syndromes such as xerostomia. Despite the second highest prevalence rate among systemic autoimmune diseases, its pathophysiology remains largely unknown. Here we report that SKG mice, a cardinal model of Th17 cell-mediated arthritis, also develop a secondary form of SS-like disorder upon systemic exposure to purified curdlan, a type of β-glucan. The reduced production of saliva was not caused by focal immune cell infiltrates but was associated with IgG deposits in salivary glands. Sera from curdlan-injected SKG mice contained elevated titers of IgG (predominantly IgG1), autoantibody to the muscarinic type 3 receptor (M3R) and inhibited carbachol-induced Ca2+ signaling in salivary acinar cells. These results suggest that the Th17 cells that are elicited in SKG mice promote the production of salivary gland-specific autoantibodies including anti-M3R IgG; the antibodies are then deposited on acinar cells and inhibit M3R-mediated signaling required for salivation, finally leading to hypofunction of the salivary glands. This type II hypersensitivity reaction may explain the origin of secondary SS occurring without focal leukocyte infiltrates.
Acinar Cells ; Animals ; Antibodies ; Arthritis ; Autoantibodies ; Autoimmune Diseases ; Exocrine Glands ; Hypersensitivity ; Immunoglobulin G ; Leukocytes ; Mice ; Prevalence ; Saliva ; Salivary Glands ; Salivation ; Sjogren's Syndrome ; Th17 Cells ; Xerostomia

BACKGROUND: Lung cancer is the most common cause of cancer-related death, and adenocarcinoma is the most common histologic subtype. MicroRNA is a small non-coding RNA that inhibits multiple target gene expression at the post-transcriptional level and is commonly dysregulated in malignant tumors. The purpose of this study was to analyze the expression of microRNA-374a (miR-374a) in lung adenocarcinoma and correlate its expression with various clinicopathological characteristics.METHODS: The expression level of miR-374a was measured in 111 formalin-fixed paraffin-embedded lung adenocarcinoma tissues using reverse transcription-quantitative polymerase chain reaction assays. The correlation between miR-374a expression and clinicopathological parameters, including clinical outcome, was further analyzed.RESULTS: High miR-374 expression was correlated with advanced pT category (chi-square test, p=.004) and pleural invasion (chi-square test, p=.034). Survival analysis revealed that patients with high miR-374a expression had significantly shorter disease-free survival relative to those with low miR-374a expression (log-rank test, p=.032).CONCLUSIONS: miR-374a expression may serve as a potential prognostic biomarker for predicting recurrence in early stage lung adenocarcinoma after curative surgery.
Adenocarcinoma ; Disease-Free Survival ; Gene Expression ; Humans ; Lung Neoplasms ; Lung ; MicroRNAs ; Polymerase Chain Reaction ; Recurrence ; RNA, Small Untranslated

BACKGROUND/AIMS: For the clinical application of stem cell therapy, functional enhancement is needed to increase the survival rate and the engraftment rate. The purpose of this study was to investigate functional enhancement of the paracrine effect using stem cells and hepatocyte-like cells and to minimize stem cell homing by using a scaffold system in a liver disease model. METHODS: A microporator was used to overexpress Foxa2 in adipose tissue-derived stem cells (ADSCs), which were cultured in a poly(lactic-co-glycolic acid) (PLGA) scaffold. Later, the ADSCs were cultured in hepatic differentiation medium for 2 weeks by a 3-step method. For in vivo experiments, Foxa2-overexpressing ADSCs were loaded in the scaffold, cultured in hepatic differentiation medium and later were implanted in the dorsa of nude mice subjected to acute liver injury (thioacetamide intraperitoneal injection). RESULTS: Foxa2-overexpressing ADSCs showed greater increases in hepatocyte-specific gene markers (alpha fetoprotein [AFP], cytokeratin 18 [CK18], and albumin), cytoplasmic glycogen storage, and cytochrome P450 expression than cells that underwent the conventional differentiation method. In vivo experiments using the nude mouse model showed that 2 weeks after scaffold implantation, the mRNA expression of AFP, CK18, dipeptidyl peptidase 4 (CD26), and connexin 32 (CX32) was higher in the Foxa2-overexpressing ADSCs group than in the ADSCs group. The Foxa2-overexpressing ADSCs scaffold treatment group showed attenuated liver injury without stem cell homing in the thioacetamide-induced acute liver injury model. CONCLUSIONS: Foxa2-overexpressing ADSCs applied in a scaffold system enhanced hepatocyte-like differentiation and attenuated acute liver damage in an acute liver injury model without homing effects.
Animals ; Cytochrome P-450 Enzyme System ; Cytoplasm ; Dipeptidyl Peptidase 4 ; Fetal Proteins ; Glycogen ; Keratin-18 ; Liver Diseases ; Liver Failure, Acute ; Liver ; Mesenchymal Stromal Cells ; Methods ; Mice ; Mice, Nude ; RNA, Messenger ; Stem Cells ; Survival Rate

Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disorder that affects mainly salivary and lacrimal glands, but its cause remains largely unknown. Clinical data indicating that SS occurs in a substantial proportion of patients with lupus points to common pathogenic mechanisms underlying the two diseases. To address this idea, we asked whether SS develops in the lupus-prone mouse strain sanroque (SAN). Owing to hyper-activation of follicular helper T (Tfh) cells, female SAN mice developed lupus-like symptoms at approximately 20 wk of age but there were no signs of SS at that time. However, symptoms typical of SS were evident at approximately 40 wk of age, as judged by reduced saliva flow rate, sialadenitis, and IgG deposits in the salivary glands. Increases in serum titers of SS-related autoantibodies and numbers of autoantibody-secreting cells in cervical lymph nodes (LNs) preceded the pathologic manifestations of SS and were accompanied by expansion of Tfh cells and their downstream effector cells. Thus, our results suggest that chronic dysregulation of Tfh cells in salivary gland-draining LNs is sufficient to drive the development of SS in lupus-prone mice.
Animals ; Autoantibodies ; Autoimmunity ; Disease Models, Animal ; Female ; Humans ; Immunoglobulin G ; Lacrimal Apparatus ; Lupus Erythematosus, Systemic ; Lymph Nodes ; Mice ; Saliva ; Salivary Glands ; Sialadenitis