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Abstract There has been no reliable marker for predicting oncological outcomes in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy (NACRT). We retrospectively analyzed 73 patients with LARC who underwent curative surgery after NACRT. The modified Glasgow prognostic score (mGPS) was assessed after NACRT, and clinical outcomes were compared between the high (mGPS = 1 or 2; n = 23) and low (mGPS = 0; n = 50) groups. Body mass index was significantly higher in the low mGPS group. The 5-year disease-free survival (DFS) rate was significantly worse in the high mGPS group than that in the low mGPS group (36.7% vs. 76.6%, p = 0.002). Univariate and multivariate analyses of DFS revealed that mGPS was the most significant predictor (p

BackgroundIn Japan, preoperative adjuvant chemotherapy followed by surgical resection is the standard treatment for patients with locally advanced esophageal squamous cell carcinoma. However, the risk of recurrence after surgical resection remains high. Although a randomized controlled trial evaluating the efficacy of nivolumab, a fully human monoclonal anti-programmed death 1 antibody, as postoperative adjuvant therapy after neoadjuvant chemoradiotherapy and surgery established its superior efficacy as adjuvant therapy, the efficacy for patients who received preoperative adjuvant chemotherapy has not been demonstrated. This study aims to elucidate the efficacy and safety of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection.MethodsThis study is a multi-institutional, single-arm, Phase II trial. We plan to recruit 130 esophageal squamous cell carcinoma patients, who have undergone preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. If the patient did not have a pathological complete response, nivolumab is started as a postoperative adjuvant therapy within 4-16 weeks after surgery. The nivolumab dose is 480 mg/day every four weeks. Nivolumab is administered for up to 12 months. The primary endpoint is disease-free survival; the secondary endpoints are overall survival, distant metastasis-free survival, and incidence of adverse events.DiscussionTo our knowledge this study is the first trial establishing the efficacy of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. In Japan, preoperative adjuvant chemotherapy followed by surgery is a well-established standard treatment for resectable, locally advanced esophageal squamous cell carcinoma. Therefore, developing an effective postoperative adjuvant therapy has been essential for improving oncological outcomes.

Abstract The risk factors for delayed gastric emptying (DGE) following gastrectomy are unclear. This study aimed to investigate the risk factors for DGE and the severity of DGE. We retrospectively evaluated 412 patients who underwent gastrectomy for gastric cancer between 2011 and 2019. The cases were classified into the DGE (n = 27) and non-DGE (n = 385) groups; the DGE group was further classified into two subgroups based on nasogastric tube insertion as an indicator of severity. For determining the relationship between resected stomach volume and DGE, we calculated the area of each surgical specimen using the ImageJ software. Female sex (odds ratio [OR] 2.55; 95% confidence interval [CI] 1.09–5.93; P = 0.03), diabetes (OR 2.38; 95% CI 1.02–5.57; P = 0.03), and distal gastric tumors (OR 2.61; 95% CI 1.10–6.19; P = 0.02) were identified as independent risk factors by multivariate analysis. The duration of hospital stay was longer in the DGE group than in the non-DGE group (29 vs. 15 days, P

Although a therapeutic response to neoadjuvant chemoradiotherapy (NACRT) is important to improve oncological outcomes after surgery in patients with locally advanced rectal cancer, there is no reliable predictor for this. The Wnt/β-catenin signal is known to be crucial for the tumorigenesis of colorectal cancer. This study aimed to investigate the association of Wnt/β-catenin signal activation with a pathological response to NACRT. The immunohistochemical expression of nuclear and membranous β-catenin was analyzed in biopsy samples obtained from 60 patients with locally advanced rectal cancer who received curative surgery following NACRT. The association of Wnt/β-catenin signal activation with their clinical outcomes was investigated. Notably, the body mass index of these patients was significantly higher in the low nuclear β-catenin expression group. Moreover, patients in the high nuclear β-catenin expression group tended to have more advanced disease and a higher rate of positive vascular invasion than those in the low expression group. Furthermore, the rate of good histological responses was significantly higher in the low nuclear β-catenin expression group (72% vs. 37.1%, p < 0.01). Overall, relapse-free survival tended to be better in patients with low nuclear/high membranous β-catenin expression (n = 9) than in other individuals (n = 51) (p = 0.093 and p = 0.214, respectively). Activation of the Wnt/β-catenin signal pathway represented by nuclear β-catenin accumulation was significantly associated with a poor response to NACRT in patients with rectal cancer. Analysis of nuclear β-catenin accumulation before starting treatment might help predict the therapeutic response to NACRT.

We investigated the antidiabetic effects of E3030, which is a potent dual activator of peroxisome proliferator-activated receptor (PPAR) α and PPARγ, in an animal model of diabetes, C57BL/KsJ-db/db mice (db/db mice), and the lipidemic effects of E3030 in beagle dogs, whose PPARα and PPARγ transactivation responses to E3030 were similar to those of humans. E3030 activated human PPARα, mouse PPARα, dog PPARα, human PPARγ, mouse PPARγ, and dog PPARγ with EC50 values of 65, 920, 87, 34, 73, and 34 nM, respectively, in the chimeric GAL4-PPAR receptor transactivation reporter assay. In db/db mice orally administered E3030 decreased blood glucose, triglyceride (TG), non-esterified fatty acids (NEFA), and insulin levels and increased blood adiponectin levels during a 14-day experimental period. Significant effects on blood glucose and adiponectin levels were observed at a dose of 3 mg/kg or greater. Furthermore, significant effects on blood TG, NEFA, and insulin levels were observed at doses of 1 mg/kg or more. An oral glucose tolerance test (OGTT) performed on Day 15 showed that E3030 at 3 mg/kg improved glucose tolerance in this model. Fourteen days of oral treatment with E3030 at a dose of 0.03 mg/kg or greater showed remarkable TG- and non high-density lipoprotein (non-HDL) cholesterol–lowering effects in beagle dogs. These results were similar to those observed for the PPARα agonist fenofibrate. E3030 also reduced apo C-III levels on Days 7 and 14, and elevated lipoprotein lipase (LPL) levels on Day 15. These results indicate that the TG- and non-HDL cholesterol-lowering actions of E3030 involve combined effects on reduction of apo C-III and elevation of LPL, resulting in increased lipolysis. The experimental results in animals suggest that E3030 has potential for use in the treatment of various aspects of metabolic dysfunction in type 2 diabetes, including dyslipidemia, hyperglycemia, hyperinsulinemia, and impaired glucose disposal. Keywords:: E3030, peroxisome proliferator-activated receptor (PPAR) α, PPARγ, PPARα/γ agonist

It is important to understand the mechanisms that regulate macrophage activation to establish novel therapies for inflammatory diseases, such as sepsis; a systemic inflammatory response syndrome generally caused by bacterial lipopolysaccharide (LPS). In this study, we investigated the involvement of extracellular ATP-mediated autocrine signaling in LPS-induced macrophage activation. We show here that ATP release via exocytosis, followed by activation of P2Y11 receptor, is a major pathway of the macrophage activation, leading to release of cytokines. Treatment of human monocyte THP-1 cells with LPS induced rapid ATP release from cells, and this release was blocked by knockdown of SLC17A9 (vesicular nucleotide transporter, VNUT), which is responsible for exocytosis of ATP. ATP-enriched vesicles were found in cytosol of THP-1 cells. These data suggest the involvement of vesicular exocytosis in the release of ATP. Knockdown of SLC17A9, the P2Y11 antagonist NF157 or knockdown of P2Y11 receptor significantly suppressed both M1-type polarization and IL-6 production in THP-1 cells, indicating an important role of activation of P2Y11 receptor by released ATP in macrophage activation. Next, the effect of NF157 on LPS-induced immune activation was examined in vivo. Administration of LPS to mice caused increase of serum IL-1ß, IL-6, IL-12 and TNF-alpha levels at 3-24 h after the administration. Pre-treatment of LPS-treated mice with NF157 suppressed both elevation of proinflammatory cytokines in serum and M1 polarization of peritoneal/spleen macrophages. Moreover, post-treatment with NF157 at 30 min after administration of LPS also suppressed the elevation of serum cytokines levels. We conclude that vesicular exocytosis of ATP and autocrine, positive feedback through P2Y11 receptors is required for the effective activation of macrophages. Consequently, P2Y11 receptor antagonists may be drug candidates for treatment of inflammatory diseases such as sepsis.

Background/Aim: The relationship between gastric cancer and oral health has been reported in several studies. This study aimed to determine the relationship between the postoperative prognosis of gastric cancer and oral health using preoperative tooth loss as a simple index. Patients and Methods: We conducted a single-center retrospective cohort study. Patients were divided into two groups according to the number of tooth losses. The survival curve was constructed using the Kaplan--Meier method. We also performed univariate and multivariate analyses of overall survival based on Cox proportional hazard regression to determine prognostic factors. Results: A total of 191 patients were divided into two groups: those with seven or more tooth losses and those with less than seven tooth losses. The three-year overall survival rate was 71.5% in the group with seven or more tooth losses and 87.0% in the group with less than seven tooth losses. The group with seven or more tooth losses had a significantly lower overall survival rate compared to the group with less than seven tooth losses (p=0.0014). However, in multivariate analysis, tooth loss was not identified as an independent prognostic factor whereas age, clinical T stage, CEA level, and serum albumin level were independent poor prognostic factors. Conclusion: Preoperative tooth loss was not a prognostic factor for gastric cancer after gastrectomy, but tooth loss may be a simple and useful method for evaluating frailty in patients. [ABSTRACT FROM AUTHOR]

Background/Aim: Neoadjuvant chemotherapy (NAC) for advanced gastric cancer (GC) and esophagogastric junction cancer (EGC) is expected to effectively control the tumor; however, histological tumor response and immune function markers as prognostic factors for NAC remain unknown. This study assessed the prognostic significance of histological response and immune function markers in patients undergoing NAC for GC and EGC. Patients and Methods: Forty-two patients who underwent NAC followed by surgical resection for operable advanced GC or EGC from January 2007 to December 2019 were divided into two groups based on histological response. Overall survival (OS), tumor response, and immune function markers, such as the neutrophil/lymphocyte ratio (NLR), were the outcomes analyzed. Results: The 5-year OS for Grade 2b-3 (n=10, responder group) according to the Japanese Gastric Cancer Classification was 72.0% with a favorable prognosis, compared with 33.3% for Grade 0-1a (n=18), and 46.8% for Grade 1b-2a (n=14) in the nonresponder group. There was no significant difference in the background between the two groups regarding clinical status or immune function markers. In a multivariate analysis of immune function markers, the NLR value before NAC was significantly associated with prognosis (p=0.048). Patients with an NLR value <3.4 had a favorable OS (p=0.03). Conclusion: Histological response scores for Grade 2b or higher may help predict a favorable prognosis for patients undergoing NAC for advanced GC and EGC. The outcomes may be further improved by considering NLR values. [ABSTRACT FROM AUTHOR]

To improve heat recovery and electrical power generation at municipal solid waste incinerators, a new flue gas treatment system, which includes a ceramic filter for dust removal at 300°C and a selective catalytic reduction (SCR) process for nitrogen oxide (NOx) decomposition, has been proposed. In this study, we added urea to this system as an inhibitor of polychlorinated dibenzo-p-dioxin/dibenzofuran (PCDD/Fs) and polychlorinated biphenyl (PCB) formation, as well as a NOx reducing agent, and examined the resulting PCDD/Fs, PCB, and NOx concentrations. First, we confirmed that PCB concentrations decreased by 87% in the presence of 1% urea and 5% oxygen (compared with no urea and 10% oxygen) in a lab-scale test. Bench-scale tests were then performed. In the presence of 1% urea, the rates of PCB and PCDD/Fs inhibition ranged from 11% to 36%. Considering the residence time of fly ash on the ceramic filter, the overall inhibitory efficiency in the bench-scale test concurred with the result of the lab-scale test. Nitrogen monoxide (NO) was simultaneously reduced at almost ideal stoichiometric proportions between NO and urea. The toxic equivalency (TEQ) concentration in flue gas at the outlet of the SCR met the regulation value (0.1 ng-TEQ/Nm3). [ABSTRACT FROM AUTHOR]

Heat stress (HS) induces activation of high-affinity sodium-dependent glucose transporter (SGLT1) in porcine renal LLC-PK1 cells. In this study, we investigated the roles of SGLT1 activation in reorganization of zonula occludens-1 (ZO-1), a cytosolic tight junction (TJ) protein, after HS. HS (42C, 3 h) caused decrease in transepithelial electrical resistance (TER). Subsequent incubation at 37C for 12 h increased TER above pre-HS level. The treatment of phloridzin, a potent SGLT1 inhibitor, or the replacement of glucose with a nonmetabolizable glucose analog blocked the recovery of TER and increased the transepithelial flux of FITC-dextran (4,000 Da). Immunofluorescent staining of ZO-1 showed that HS diffused ZO-1 from cell contact to cytosolic sites. Furthermore, the fraction of ZO-1 was distributed from the Triton X-100 insoluble to the Triton X-100 soluble pool. After incubation at 37C for 12 h, cell contact and ZO-1 extractability with Triton X-100 returned to pre-HS conditions, but the recovery was completely prevented by phloridzin. Tyrosine kinases activity was increased by HS that was inhibited by phloridzin. Genistein and CGP77675, tyrosine kinases inhibitors, blocked the recovery of TER and increased the transepithelial flux of FITC-dextran. Furthermore, these inhibitors prevented the recovery of cell contact and ZO-1 extractability with Triton X-100 as same as phloridzin. These findings suggested that the activation of SGLT1 reorganized ZO-1 mediated by elevation of tyrosine kinases activity after heat injury. 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Resident macrophages in the liver (Kupffer cells) produce various cytokines and chem-okines, and have important roles in hepatitis and liver fibrosis. The cells are activated by various factors, for example lipopolysaccharide (LPS), which is an endotoxin and is high in the blood of patients with liver cirrhosis. Involvement of P2 receptors in the release of proinflammatory cytokines from Kupffer cells is little. In this study, we investigated purinergic signaling in the release of pro-inflammatory cytokines, such as IL-6 and TNF-α, from liver Kupffer cells of C57BL/6 mice (KUP5 cells). KUP5cells were isolated from C57BL/6 mice and cultivated with Dulbecco's modified Eagle's medium. The cells were stimulated with LPS. LPS-induced IL-6 production by KUP5 cells was suppressed significantly by pretreatments with non-selective P2 antagonist suramin, P2Y13 antagonist MRS2211, and ecto-nucleotidase, whereas P2Y receptor agonists, significantly increased the IL-6 production. P2Y133 knockdown reduced LPS-induced IL-6 production, but by less than 50%. These results would suggest that P2Y receptors including P2Y13 and others, may involves in LPS-induced IL-6 production in Kupffer cells, leading to the liver inflammation. Therefore, we first showed the importance of purinergic signaling via P2Y receptors in the activation of Kupffer cells and liver injury, which is worthwhile in drug development for liver diseases. [ABSTRACT FROM AUTHOR]