Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer: Updated Overall Survival Outcomes From Phase III PRODIGY.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The phase III PRODIGY study demonstrated that neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 chemotherapy (CSC) improved progression-free survival (PFS) compared with surgery followed by adjuvant S-1 (SC) for patients with resectable locally advanced gastric cancer (LAGC) with clinical T2-3N+ or T4Nany disease. The primary end point was PFS. Overall survival (OS) was the secondary end point. We herein report the long-term follow-up outcomes, including OS, from this trial. A total of 238 and 246 patients were randomly assigned to the CSC and SC arms, respectively, and were treated (full analysis set). As of the data cutoff (September 2022), the median follow-up duration of the surviving patients was 99.5 months. Compared with SC, CSC significantly increased the OS (adjusted hazard ratio [HR], 0.72; stratified log-rank P = .027) with an 8-year OS rate of 63.0% and 55.1% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (HR, 0.70; stratified log-rank P = .016). In conclusion, neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, prolonged the OS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1. It should be considered one of the standard treatment options for patients with LAGC in Asia.

Timely Pulmonary Tuberculosis Diagnosis Based on the Epidemiological Disease Spectrum: Population-Based Prospective Cohort Study in the Republic of Korea.

BACKGROUND: Timely pulmonary tuberculosis (PTB) diagnosis is a global health priority for interrupting transmission and optimizing treatment outcomes. The traditional dichotomous time-divided approach for addressing time delays in diagnosis has limited clinical application because the time delay significantly varies depending on each community in question. OBJECTIVE: We aimed to reevaluate the diagnosis time delay based on the PTB disease spectrum using a novel scoring system that was applied at the national level in the Republic of Korea. METHODS: The Pulmonary Tuberculosis Spectrum Score (PTBSS) was developed based on previously published proposals related to the disease spectrum, and its validity was assessed by examining both all-cause and PTB-related mortality. In our analysis, we integrated the PTBSS into the Korea Tuberculosis Cohort Registry. We evaluated various time delays, including patient, health care, and overall delays, and their system-associated variables in line with each PTBSS. Furthermore, we reclassified the scores into distinct categories of mild (PTBSS=0-1), moderate (PBTBSS=2-3), and severe (PBTBSS=4-6) using a multivariate regression approach. RESULTS: Among the 14,031 Korean patients with active PTB whose data were analyzed from 2018 to 2020, 37% (n=5191), 38% (n=5328), and 25% (n=3512) were classified as having a mild, moderate, and severe disease status, respectively, according to the PTBSS. This classification can therefore reflect the disease spectrum of PTB by considering the correlation of the score with mortality. The time delay patterns differed according to the PTBSS. In health care delays according to the PTBSS, greater PTB disease progression was associated with a shorter diagnosis period, since the condition is microbiologically easy to diagnose. However, with respect to patient delays, the change in elapsed time showed a U-shaped pattern as PTB progressed. This means that a remarkable patient delay in the real-world setting might occur at both apical ends of the spectrum (ie, in both mild and severe cases of PTB). Independent risk factors for a severe PTB pattern were age (adjusted odds ratio 1.014) and male sex (adjusted odds ratio 1.422), whereas no significant risk factor was found for mild PTB. CONCLUSIONS: Timely PTB diagnosis should be accomplished. This can be improved with use of the PTBSS, a simple and intuitive scoring system, which can be more helpful in clinical and public health applications compared to the traditional dichotomous time-only approach.

Personalized probiotic strategy considering bowel habits: impacts on gut microbiota composition and alleviation of gastrointestinal symptoms via Consti-Biome and Sensi-Biome.

Personalized probiotic regimens, taking into account individual characteristics such as stool patterns, have the potential to alleviate gastrointestinal disorders and improve gut health while avoiding the variability exhibited among individuals by conventional probiotics. This study aimed to explore the efficacy of personalized probiotic interventions in managing distinct stool patterns (constipation and diarrhea) by investigating their impact on the gut microbiome and gastrointestinal symptoms using a prospective, randomized, double-blind, placebo-controlled clinical trial design. This research leverages the multi-strain probiotic formulas, Consti-Biome and Sensi-Biome, which have previously demonstrated efficacy in alleviating constipation and diarrhea symptoms, respectively. Improvement in clinical symptoms improvement and compositional changes in the gut microbiome were analyzed in participants with predominant constipation or diarrhea symptoms. Results indicate that tailored probiotics could improve constipation and diarrhea by promoting Erysipelotrichaceae and Lactobacillaceae, producers of short-chain fatty acids, and regulating inflammation and pain-associated taxa. These findings suggest the potential of tailored probiotic prescriptions and emphasize the need for personalized therapeutic approaches for digestive disorders. Clinical trial registration: https://cris.nih.go.kr/cris/index/index.do, identifier KCT0009111.

Multistrain Probiotics Alleviate Diarrhea by Modulating Microbiome-Derived Metabolites and Serotonin Pathway.

Diarrhea, a common gastrointestinal symptom in health problems, is highly associated with gut dysbiosis. The purpose of this study is to demonstrate the effect of multistrain probiotics (Sensi-Biome) on diarrhea from the perspective of the microbiome-neuron axis. Sensi-Biome (Lactiplantibacillus plantarum, Bifidobacterium animalis subsp. lactis, Lactobacillus acidophilus, Streptococcus thermophilus, Bifidobacterium bifidum, and Lactococcus lactis) was administered in a 4% acetic acid-induced diarrhea rat model at concentrations of 1 × 108 (G1), 1 × 109 (G2), and 1 × 1010 CFU/0.5 mL (G3). Diarrhea-related parameters, inflammation-related cytokines, and stool microbiota analysis by 16S rRNA were evaluated. A targeted and untargeted metabolomics approach was used to analyze the cecum samples using liquid chromatography and orbitrap mass spectrometry. The stool moisture content (p < 0.001), intestinal movement rate (p < 0.05), and pH (p < 0.05) were significantly recovered in G3. Serotonin levels were decreased in the multistrain probiotics groups. The inflammatory cytokines, serotonin, and tryptophan hydroxylase expression were improved in the Sensi-Biome groups. At the phylum level, Sensi-Biome showed the highest relative abundance of Firmicutes. Short-chain fatty acids including butyrate, iso-butyrate, propionate, and iso-valeric acid were significantly modified in the Sensi-Biome groups. Equol and oleamide were significantly improved in the multistrain probiotics groups. In conclusion, Sensi-Biome effectively controls diarrhea by modulating metabolites and the serotonin pathway.

Lactobacillus acidophilus KBL409 Ameliorates Atopic Dermatitis in a Mouse Model.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with repeated exacerbations of eczema and pruritus. Probiotics can prevent or treat AD appropriately via modulation of immune responses and gut microbiota. In this study, we evaluated effects of Lactobacillus acidophilus (L. acidophilus) KBL409 using a house dust mite (Dermatophagoides farinae)-induced in vivo AD model. Oral administration of L. acidophilus KBL409 significantly reduced dermatitis scores and decreased infiltration of immune cells in skin tissues. L. acidophilus KBL409 reduced in serum immunoglobulin E and mRNA levels of T helper (Th)1 (Interferon-γ), Th2 (Interleukin [IL]-4, IL-5, IL-13, and IL-31), and Th17 (IL-17A) cytokines in skin tissues. The anti-inflammatory cytokine IL-10 was increased and Foxp3 expression was up-regulated in AD-induced mice with L. acidophilus KBL409. Furthermore, L. acidophilus KBL409 significantly modulated gut microbiota and concentrations of short-chain fatty acids and amino acids, which could explain its effects on AD. Our results suggest that L. acidophilus KBL409 is the potential probiotic for AD treatment by modulating of immune responses and gut microbiota of host.

Strain-Specific Anti-Inflammatory Effects of Faecalibacterium prausnitzii Strain KBL1027 in Koreans.

Faecalibacterium prausnitzii is one of the most dominant commensal bacteria in the human gut, and certain anti-inflammatory functions have been attributed to a single microbial anti-inflammatory molecule (MAM). Simultaneously, substantial diversity among F. prausnitzii strains is acknowledged, emphasizing the need for strain-level functional studies aimed at developing innovative probiotics. Here, two distinct F. prausnitzii strains, KBL1026 and KBL1027, were isolated from Korean donors, exhibiting notable differences in the relative abundance of F. prausnitzii. Both strains were identified as the core Faecalibacterium amplicon sequence variant (ASV) within the healthy Korean cohort, and their MAM sequences showed a high similarity of 98.6%. However, when a single strain was introduced to mice with dextran sulfate sodium (DSS)-induced colitis, KBL1027 showed the most significant ameliorative effects, including alleviation of colonic inflammation and restoration of gut microbial dysbiosis. Moreover, the supernatant from KBL1027 elevated the secretion of IL-10 cytokine more than that of KBL1026 in mouse bone marrow-derived macrophage (BMDM) cells, suggesting that the strain-specific, anti-inflammatory efficacy of KBL1027 might involve effector compounds other than MAM. Through analysis of the Faecalibacterium pan-genome and comparative genomics, strain-specific functions related to extracellular polysaccharide biosynthesis were identified in KBL1027, which could contribute to the observed morphological disparities. Collectively, our findings highlight the strain-specific, anti-inflammatory functions of F. prausnitzii, even within the same core ASV, emphasizing the influence of their human origin.

In Vitro Evaluation of Probiotic Properties of Two Novel Probiotic Mixtures, Consti-Biome and Sensi-Biome.

Changes in the gut microbiome cause recolonization by pathogens and inflammatory responses, leading to the development of intestinal disorders. Probiotics administration has been proposed for many years to reverse the intestinal dysbiosis and to enhance intestinal health. This study aimed to evaluate the inhibitory effects of two newly designed probiotic mixtures, Consti-Biome and Sensi-Biome, on two enteric pathogens Staphylococcus aureus and Escherichia coli that may cause intestinal disorders. Additionally, the study was designed to evaluate whether Consti-Biome and Sensi-Biome could modulate the immune response, produce short-chain fatty acids (SCFAs), and reduce gas production. Consti-Biome and Sensi-Biome showed superior adhesion ratios to HT-29 cells and competitively suppressed pathogen adhesion. Moreover, the probiotic mixtures decreased the levels of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-6 and IL-1ß. Cell-free supernatants (CFSs) were used to investigate the inhibitory effects of metabolites on growth and biofilms of pathogens. Consti-Biome and Sensi-Biome CFSs exhibited antimicrobial and anti-biofilm activity, where microscopic analysis confirmed an increase in the number of dead cells and the structural disruption of pathogens. Gas chromatographic analysis of the CFSs revealed their ability to produce SCFAs, including acetic, propionic, and butyric acid. SCFA secretion by probiotics may demonstrate their potential activities against pathogens and gut inflammation. In terms of intestinal symptoms regarding abdominal bloating and discomfort, Consti-Biome and Sensi-Biome also inhibited gas production. Thus, these two probiotic mixtures have great potential to be developed as dietary supplements to alleviate the intestinal disorders.

Time delays and risk factors in the management of patients with active pulmonary tuberculosis: nationwide cohort study.

Estimating the time delay and identifying associated factors is essential for effective tuberculosis control. We systemically analysed data obtained from the Korea Tuberculosis Cohort in 2019 by classifying delays as presentation and healthcare delays of pulmonary tuberculosis (PTB). Of 6593 patients with active PTB, presentation and healthcare delays were recorded in 4151 and 5571 patients, respectively. The median presentation delay was 16.0 (5.0-40.0) days. Multivariable logistic regression analysis showed that longer presentation delays were associated with neuropsychiatric disease [adjusted odds ratio (OR) 2.098; 95% confidence interval (CI) 1.639-2.687; p < 0.001] and heavy alcohol intake (adjusted OR 1.505; 95% CI 1.187-1.907; p < 0.001). The median healthcare delay was 5.0 (1.0-14.0) days. A longer healthcare delay was associated with malignancy (adjusted OR 1.351; 95% CI 1.069-1.709; p = 0.012), autoimmune disease (adjusted OR 2.445; 95% CI 1.295-4.617; p = 0.006), and low bacterial burden manifested as an acid-fast bacillus smear-negative and tuberculosis polymerase chain reaction-negative status (adjusted OR 1.316; 95% CI 1.104-1.569; p = 0.002). Active case-finding programmes need to focus on patients with heavy alcoholism or neuropsychiatric diseases. To ensure early PTB detection, healthcare providers must carefully monitor patients with malignancy, autoimmune disease, or a high index of suspicion for PTB.

Additional Usefulness of Bronchoscopy in Patients with Initial Microbiologically Negative Pulmonary Tuberculosis: A Retrospective Analysis of a Korean Nationwide Prospective Cohort Study.

Purpose: Bronchoscopy is widely used for microbiological diagnosis of patients with minimal sputum production. However, the usefulness of bronchoscopy in patient groups who benefit from subsequent microbiological confirmation has not been established. Patients and Methods: We retrospectively analyzed Korean tuberculosis (TB) cohort data from September 2018 to October 2019 to evaluate the usefulness of bronchoscopy in patients with microbiologically negative pulmonary TB (based on initial sputum polymerase chain reaction and culture results). The primary outcome was the proportion of microbiological diagnoses made after bronchoscopy. Secondary outcomes were the predictors of microbiological confirmation and the percentage of additional resistance detection after bronchoscopy. Results: A total of 5194 patients were diagnosed with pulmonary TB, 937 of whom were microbiologically negative for pulmonary TB based on the initial sputum findings. Of these, 319 patients underwent bronchoscopy, and further microbiological confirmation was achieved in 157 (49.1%) patients. The predictors of microbiological confirmation after bronchoscopy were age >65 years, female sex, and low body mass index (BMI). The rate of additional resistance detection was 10.5% (multidrug resistant/rifampin-resistant 3.8%; isoniazid-resistant 5.7%). Conclusion: Bronchoscopy can be used for the detection of resistant pathogens. Bronchoscopy should be considered for microbiologically negative pulmonary TB in women aged >65 years and with low BMI for subsequent microbiological confirmation.

Impact of the Deep Neuromuscular Block on Oncologic Quality of Laparoscopic Surgery in Obese Gastric Cancer Patients: A Randomized Clinical Trial.

BACKGROUND: Obesity can hinder laparoscopic procedures and impede oncological safety during laparoscopic cancer surgery. Deep neuromuscular block (NMB) reportedly improves laparoscopic surgical conditions, but its oncological benefits are unclear. We aimed to evaluate whether deep NMB improves the oncologic quality of laparoscopic cancer surgery in obese patients. STUDY DESIGN: We conducted a double-blinded, parallel-group, randomized, phase 3 trial at 9 institutions in Korea. Clinical stage I and II gastric cancer patients with a BMI at or above 25 kg m -2 were eligible and randomized 1:1 ratio to the deep or moderate NMB groups, with continuous infusion of rocuronium (0.5-1.0 and 0.1-0.5 mg kg -1 h -1, respectively). The primary endpoint was the number of retrieved lymph nodes (LNs). The secondary endpoints included the surgeon's surgical rating score (SRS) and interrupted events. RESULTS: Between August 2017 and July 2020, 196 patients were enrolled. Fifteen patients were excluded, and 181 patients were finally included in the study. There was no significant difference in the number of retrieved LNs between the deep (N = 88) and moderate NMB groups (N = 93; 44.6 ± 17.5 vs 41.5 ± 16.9, p = 0.239). However, deep NMB enabled retrieving more LNs in patients with a BMI at or above 28 kg/m2 than moderate NMB (49.2 ± 18.6 vs 39.2 ± 13.3, p = 0.026). Interrupted events during surgery were lower in the deep NMB group than in the moderate NMB group (21.6% vs 36.6%; p = 0.034). The SRS was not influenced by NMB depth. CONCLUSION: Deep NMB provides potential oncologic benefits by retrieving more LNs in patients with BMI at or above 28 kg/m2 during laparoscopic gastrectomy.

Survival impact of compliance in extra-perigastric lymphadenectomy for gastric cancer: 20 years of real-world data from a single institution.

BACKGROUND: Compliance in lymphadenectomy was first introduced as part of quality control in a Dutch clinical trial. Although a few studies have investigated compliance, no studies have evaluated the survival impact at individual lymph node stations. METHODS: In total, 2,932 patients who underwent radical gastrectomy between 1996 and 2014 at the Korea University Guro Hospital in Seoul, South Korea were retrospectively reviewed. We compared survival outcomes among the compliance, noncompliance, and metastatic groups. RESULTS: The highest compliance among extra-perigastric stations was recorded for #8a (86.6%), followed by #7 (76.6%) and #9 (68.3%). Stations #11 and #12 showed low compliance rates of 28.9% and 31.0%, respectively. Compliance at #7, #8a, and #9 was related to better 5-year relapse-free survival rates (74.5%, 72.8%, and 71.3%, respectively) than noncompliance (61.9% [hazard ratio, 1.72; 95% confidence interval, 1.40-2.11], 61.0% [hazard ratio, 1.6; 95% confidence interval 1.26-2.04], 65.3% [hazard ratio, 1.25; 95% confidence interval 1.04-1.51], respectively). At #11 and #12, there were no significant differences in relapse-free survival between compliance (69.1% and 70.2%, respectively) and noncompliance (67.4% [hazard ratio, 0.85; 95% confidence interval 0.53-1.36], 65.1% [hazard ratio, 1.13; 95% confidence interval 0.71-1.81], respectively). In multivariable analysis, stations #7 and #8 alone showed an increased hazard ratio of relapse-free survival in the noncompliance group relative to the compliance group. CONCLUSION: We showed a survival benefit of compliance during lymphadenectomy for gastric cancer. Although further prospective trials to validate our results are warranted, compliance could be adopted in real-world practice to achieve better survival among patients with gastric cancer.

PRODIGY: A Phase III Study of Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 Versus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer.

PURPOSE: Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier: NCT01515748) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC. PATIENTS AND METHODS: Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 every 6 weeks for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1-14 every 3 weeks for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary objective was progression-free survival (PFS) with CSC versus SC. Two sensitivity analyses were performed: intent-to-treat and landmark PFS analysis. RESULTS: Between January 18, 2012, and January 2, 2017, 266 patients were randomly assigned to CSC and 264 to SC at 18 Korean study sites; 238 and 246 patients, respectively, were treated (full analysis set). Follow-up was ongoing in 176 patients at data cutoff (January 21, 2019; median follow-up 38.6 months [interquartile range, 23.5-62.1]). CSC improved PFS versus SC (adjusted hazard ratio, 0.70; 95% CI, 0.52 to 0.95; stratified log-rank P = .023). Sensitivity analyses confirmed these findings. Treatments were well tolerated. Two grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant treatment. CONCLUSION: PRODIGY showed that neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.

Alleviation of DSS-induced colitis via Lactobacillus acidophilus treatment in mice.

Gut microbiota play a major role in host physiology and immunity. Inflammatory bowel diseases (IBDs), the important immune-related diseases, can occur through immune system malfunction originating due to dysregulation of the gut microbiota. The aim of this study was to investigate the capabilities and mechanisms of Lactobacillus acidophilus (L. acidophilus) KBL402 and KBL409 treatment in the alleviation of colitis using the in vivo dextran sodium sulfate (DSS)-induced colitis mice model. Various colitis symptoms of mice, including disease activity index score [4.55 ± 0.99 (P < 0.001) and 5.12 ± 0.94 (P < 0.001), respectively], colon length [6.18 ± 0.43 mm (P < 0.001) and 6.62 ± 0.47 mm (P < 0.001), respectively], and colon histological score [(5.33 ± 1.03 (P < 0.001) and 4.00 ± 0.89 (P < 0.01), respectively)], were significantly restored with L. acidophilus KBL402 or KBL409 administration (1 × 109 colony-forming units) for 8 days. Moreover, inflammatory cytokines, chemokines, and myeloperoxidase were downregulated in mice with L. acidophilus treatment. Upregulation of anti-inflammatory cytokine IL-10 or regulatory T cells were discovered with L. acidophilus KBL402 (12.90 ± 7.87 pg mL-1) (P < 0.05) or L. acidophilus KBL409 treatment (10.63 ± 2.70%) (P < 0.05), respectively. Expressions of inflammation-related micro-RNAs (miRs) were also significantly altered in mice with L. acidophilus. Finally, L. acidophilus treatment could restore the diversity of the gut microbiota. Mice with L. acidophilus KBL402 treatment showed a high relative abundance of the genus Akkermansia (0.022 ± 0.017) and Prevotella (0.010 ± 0.006) (P < 0.01). Butyrate and propionate, the major short-chain fatty acids, in the ceca of DSS + KBL402-treated mice were significantly higher than in that of the mice with DSS-induced colitis (0.03 ± 0.02 ng mg-1 and 0.03 ± 0.01 ng mg-1, respectively) (P < 0.05). Our study suggests that L. acidophilus KBL402 and KBL409 could be useful for the prevention or treatment of IBDs in various ways including the modulation of immune responses and miR expression, restoration of the gut microbiota, and production of metabolites.

Intraperitoneal Paclitaxel Combined with S-1 Plus Oxaliplatin for Advanced Gastric Cancer with Peritoneal Metastasis: a Phase I Study.

PURPOSE: We designed a new regimen by combining intraperitoneal (IP) paclitaxel (PTX) with systemic S-1 plus oxaliplatin (SOX) for the treatment of advanced gastric cancer with peritoneal metastasis. This dose-escalation study aimed to determine the maximum tolerated dose (MTD) and recommended dose (RD) of IP PTX administered weekly to patients. MATERIALS AND METHODS: Eight cycles of IP PTX plus SOX regimen were administered to the patients. S-1 was administered orally twice daily at a dose of 80 mg/m2/day for 14 consecutive days, followed by 7 days of rest. Intravenous oxaliplatin was administered at a fixed dose of 100 mg/m2 on day 1, while IP PTX was administered on days 1 and 8. The initial dose of IP PTX was 40 mg/m2, and the dose escalation was set in units of 20 mg/m2 up to 80 mg/m2. Dose-limiting toxicities (DLTs) were defined as grade 3 non-hematologic toxicities, grade 4 leukopenia, grade 3 febrile neutropenia, and grade 3 thrombocytopenia. RESULTS: Nine patients were included in the study. No DLTs were observed in any of the enrolled patients. Therefore, the MTD was not reached, and the RD of IP PTX was determined to be 80 mg/m2. Four patients (44%) showed a decreased peritoneal cancer index score on second-look laparoscopic examination. CONCLUSIONS: The present study determined the dose for further clinical trials of IP PTX to be 80 mg/m2, when combined with a systemic SOX regimen.

Combination of LMT-28 and Metformin Improves Beneficial Anti-Inflammatory Effect in Collagen-Induced Arthritis.

OBJECTIVES: The interleukin-6 (IL-6)-mediated signaling pathway plays an essential role in the development of rheumatoid arthritis. LMT-28 suppresses the activation of the IL-6-mediated signaling by direct targeting of gp130. Although LMT-28 and metformin both possess anti-inflammatory activity, the beneficial effect of LMT-28 and metformin combination on a collagen-induced arthritis (CIA) model has not yet been investigated. This study aimed to investigate the anti-inflammatory effect and mechanism of a combination of LMT-28 and metformin in a CIA model. METHODS: In MH7A cells, cell proliferation and the IL-6-mediated signaling pathway following administration of LMT-28 and metformin combination was analyzed through MTT assay and Western blotting. The level of T helper 17 (Th17) cell differentiation from CD4+ T cells was analyzed in mouse splenocytes and human peripheral blood mononuclear cells. Arthritis score, incidence rate, inflammatory cytokine, and T-cell subsets were measured in CIA mice following administration of LMT-28 and metformin combination. RESULTS: Combination treatment with LMT-28 and metformin diminished proliferation of MH7A cells and IL-6-mediated gp130, STAT3, and ERK signaling more than in individual treatments. Furthermore, the differentiation of CD4+ T cells into Th17 cells was attenuated more by combination treatment with LMT-28 and metformin than individual treatments. The combination of LMT-28 and metformin ameliorated the arthritic score better than individual treatments. The combination significantly reduced tumor necrosis factor and IL-6 levels in the sera and had an anti-inflammatory effect on the distribution of Treg/Th17 cells in the lymph nodes. CONCLUSION: Combination treatment with LMT-28 and metformin significantly ameliorates arthritic symptoms in CIA by suppressing Th17 differentiation and IL-6 signaling.

Lactobacillus paracasei KBL382 administration attenuates atopic dermatitis by modulating immune response and gut microbiota.

Administration of probiotics has been linked to immune regulation and changes in gut microbiota composition, with effects on atopic dermatitis (AD). In this study, we investigated amelioration of the symptoms of AD using Lactobacillus paracasei KBL382 isolated from the feces of healthy Koreans. Mice with Dermatophagoides farinae extract (DFE)-induced AD were fed 1 × 109 CFU d-1 of L. paracasei KBL382 for 4 weeks. Oral administration of L. paracasei KBL382 significantly reduced AD-associated skin lesions, epidermal thickening, serum levels of immunoglobulin E, and immune cell infiltration. L. paracasei KBL382-treated mice showed decreased production of T helper (Th)1-, Th2-, and Th17-type cytokines, including thymic stromal lymphopoietin, thymus, and activation-regulated chemokine, and macrophage-derived chemokine, and increased production of the anti-inflammatory cytokine IL-10 and transforming growth factor-ß in skin tissue. Intake of L. paracasei KBL382 also increased the proportion of CD4+ CD25+ Foxp3+ regulatory T cells in mesenteric lymph nodes. In addition, administration of L. paracasei KBL382 dramatically changed the composition of gut microbiota in AD mice. Administration of KBL382 significantly ameliorates AD-like symptoms by regulating the immune response and altering the composition of gut microbiota.

Lactobacillus paracasei treatment modulates mRNA expression in macrophages.

Macrophage metabolic pathways show changes in response to various external stimuli. Especially, increased lipopolysaccharide, an important bacterial component and Toll-like receptor 4 agonist, can induce activity in various macrophage metabolic pathways, including energy production and biosynthesis, as well as high immune responses due to increase in differentiated M1 macrophages. In this study, we confirmed that Lactobacillus paracasei (L. paracasei) KBL382, KBL384 and KBL385, isolated from the feces of healthy Koreans, can modulate various enzymes and membrane transporters related to glycolysis or macrophage polarization including hypoxia-inducible factor 1-alpha (HIF1A), inducible nitric oxide synthase (iNOS) and arginase in stimulated macrophages at the mRNA level, using the in vitro rodent bone-marrow-derived macrophage (BMDM) model. All L. paracasei exhibited significant down-regulatory effects on mRNAs for glycolysis-related enzymes, including lactate dehydrogenase A, solute carrier family 2 member 1, and triosephosphate isomerase. Moreover, L. paracasei treatment could lead to significant reductions in HIF1A or iNOS mRNA, and induced arginase mRNA in the BMDM model. Therefore, further extensive studies should be performed to support the application of L. paracasei, such as in probiotics or therapeutics, in controlling abnormal immune responses related to macrophage.

TLQP-21 mediated activation of microglial BV2 cells promotes clearance of extracellular fibril amyloid-ß.

ß-Amyloid (Aß) plaque in the brains of patients with Alzheimer's disease (AD) is mainly caused by impaired clearance of Aß by glial cells, including microglia and astrocytes. Because microglia play an important protective role in the central nervous system, many efforts have been made to identify agents that effectively improve microglial Aß phagocytosis. This study found that TLQP-21, which is cleaved from VGF (VGF nerve growth factor inducible) precursor protein, enhanced Aß phagocytosis and degradation by microglial BV2 cells. TLQP-21 also improved microglial phagocytic activity and promoted fibrillar amyloid-ß (fAß) uptake by microglial BV2 cells via a C3AR1-dependent mechanism. Moreover, TLQP-21 stimulated Aß degradation by enhancing lysosome activity, thereby enhancing fAß clearance. These results suggest that treatment with TLQP-21 may be a novel therapeutic strategy to efficiently enhance microglial Aß clearance in AD.

Administration of Lactobacillus fermentum KBL375 Causes Taxonomic and Functional Changes in Gut Microbiota Leading to Improvement of Atopic Dermatitis.

Gut microbiota play an important role in immune responses and energy metabolism. In this study, we evaluated whether administration of Lactobacillus fermentum (L. fermentum) KBL375 isolated from healthy Korean feces improves the atopic dermatitis using the house dust mite (Dermatophagoides farinae)-induced atopic dermatitis (AD) mouse model. Administration of L. fermentum KBL375 significantly decreased dermatitis score, ear and dorsal thickness, and serum immunoglobulin E level in AD-induced mice. Significant reductions in mast cells and eosinophils were discovered in skin tissues from L. fermentum KBL375-treated mice. T helper 2 cell-related cytokines interleukin (IL)-4, IL-5, IL-13, and IL-31 significantly decreased, and anti-inflammatory cytokine IL-10 or transforming growth factor-ß increased in skin tissues from L. fermentum KBL375-treated mice. In addition to phenotypic changes in skin tissues, L. fermentum KBL375 treatment induced an increase in the CD4+CD25+Foxp3+ cell population in mesenteric lymph nodes. Taxonomic and functional analyses of gut microbiota showed significantly higher cecum bacterial diversities and abundances including genus Bilophila, Dorea, and Dehalobacterium in L. fermentum KBL375-treated mice. Metabolic analysis of the cecum also showed significant changes in the levels of various amino acids including methionine, phenylalanine, serine, and tyrosine, as well as short chain fatty acids such as acetate, butyrate, and propionate in AD-induced mice due to L. fermentum KBL375 treatment. These altered metabolites in AD-induced mice returned to the levels similar to those in control mice when treated with L. fermentum KBL375. Therefore, L. fermentum KBL375 could be useful for AD treatment by modulating the immune system and inducing various metabolites.

Characteristics of proximal early gastric cancer differentiating distal early gastric cancer.

Previous studies reported substantial differences between proximal and distal gastric cancer, however, most of the cases included in these studies were advanced gastric cancers (AGCs). The aim of this study was to investigate the unique characteristics of proximal early gastric cancer (EGC) by comparing with distal EGC. From March 2007 to March 2016, proximal and distal EGC patients who underwent endoscopic or surgical resection at our institution were matched 1:3 according to age and sex. We retrospectively analyzed the clinical and histopathological information. A total of 368 patients were enrolled including 92 (25%) in the proximal and 276 (75%) in the distal group. The proportion of patients who underwent surgery (56.5 vs. 20.3%, p<0.001), undifferentiated type (38.0 vs. 19.6%, p<0.001), tumor size (29.5 ±19.4 vs. 20.3 ±16.8 mm, p<0.001) and submucosal (SM) invasion (60.9 vs. 25.7%, p<0.001) were significantly higher in the proximal group than in the distal group. In multivariate analysis, the proximal location of EGC was a significant risk factor for SM invasion in the total population (odds ratio [OR], 3.541; 95% confidence interval [CI], 2.053-6.110; p<0.001), and in subgroup with EGC < 30mm (n = 279) (OR, 5.940; 95% CI, 2.974-11.862; p<0.001). In conclusion, careful therapeutic decision of proximal EGC is essential due to the different histopathological characteristics such as large tumor size and higher potential for SM invasion.