Inhibition of HDAC8 Reduces the Proliferation of Adult Neural Stem Cells in the Subventricular Zone.

In the adult mammalian brain, neurons are produced from neural stem cells (NSCs) residing in two niches-the subventricular zone (SVZ), which forms the lining of the lateral ventricles, and the subgranular zone in the hippocampus. Epigenetic mechanisms contribute to maintaining distinct cell fates by suppressing gene expression that is required for deciding alternate cell fates. Several histone deacetylase (HDAC) inhibitors can affect adult neurogenesis in vivo. However, data regarding the role of specific HDACs in cell fate decisions remain limited. Herein, we demonstrate that HDAC8 participates in the regulation of the proliferation and differentiation of NSCs/neural progenitor cells (NPCs) in the adult mouse SVZ. Specific knockout of Hdac8 in NSCs/NPCs inhibited proliferation and neural differentiation. Treatment with the selective HDAC8 inhibitor PCI-34051 reduced the neurosphere size in cultures from the SVZ of adult mice. Further transcriptional datasets revealed that HDAC8 inhibition in adult SVZ cells disturbs biological processes, transcription factor networks, and key regulatory pathways. HDAC8 inhibition in adult SVZ neurospheres upregulated the cytokine-mediated signaling and downregulated the cell cycle pathway. In conclusion, HDAC8 participates in the regulation of in vivo proliferation and differentiation of NSCs/NPCs in the adult SVZ, which provides insights into the underlying molecular mechanisms.

Albumin-Globulin Ratio Is an Independent Prognostic Factor for Gastric Cancer Patients who Received Curative Treatment.

BACKGROUND/AIM: The albumin-globulin ratio (AGR) is a useful biomarker for predicting postoperative complications and a poor prognosis in patients with various types of cancer and can be evaluated without invasive testing or surgery. In this study, we aimed to evaluate the usefulness of the AGR in predicting the short- and long-term prognoses of patients with gastric cancer who underwent radical resection at our institution. PATIENTS AND METHODS: This study is a retrospective cohort analysis in which eligible patients were selected from the medical records of patients who underwent radical resection for gastric cancer at Yokohama City University from 2000 to 2020 and their medical records were reviewed. A total of 240 patients with gastric cancer were classified into high-AGR (>1.57) and low-AGR (≤1.57) groups and their overall survival (OS), recurrence-free survival (RFS), and postoperative complication rates were compared. RESULTS: Of the total 240 patients, 87 were classified into the high AGR group and 153 were classified into the low AGR group; the incidence of postoperative complications in the two groups did not differ to a statistically significant extent (34.4% vs. 39.2%, p=0.491). The long-term findings showed that the 5-year OS and RFS rates were significantly better in the high AGR group [84.0% vs. 64.8% (p=0.005), 80.0% vs. 61.9% (p=0.015), respectively]. CONCLUSION: Preoperative low AGR is a risk factor for OS and DFS in patients with gastric cancer who undergo surgery. The AGR may be a useful biomarker that can be applied as a prognostic indicator for patients with gastric cancer.

CRP-albumin-lymphocyte (CALLY) Index Is an Independent Prognostic Factor for the Esophageal Cancer Patients Who Received Curative Treatment.

BACKGROUND/AIM: Perioperative inflammation and the nutritional status affect both short- and long-term oncological outcomes in various malignancies. We clarified the clinical impacts of the CRP-albumin-lymphocyte (CALLY) index in patients with esophageal cancer who received curative treatment. PATIENTS AND METHODS: The present study included 180 patients who underwent curative treatment for esophageal cancer between 2005 and 2020. The prognosis and clinicopathological parameters were compared between a high-fibrinogen group and a low-fibrinogen group. RESULTS: The 3- and 5-year overall survival rates were 50.0% and 42.6%, respectively, in the CALLY index-low group, and 75.9% and 66.6% in the CALLY index-high group. The differences between the two groups were statistically significant (p<0.001). Univariate and multivariate analyses demonstrated that the CALLY index was an independent prognostic factor [hazard ratio=2.310, 95% confidence interval=1.416-3.767, p<0.001]. Similar results were observed in recurrence-free survival. When comparing the details of postoperative surgical complications, there was a significant difference in the incidence of anastomotic leakage. The incidence of anastomotic leakage was 40.2% in the CALLY index-low group, while it was 27.5% in the CALLY index-high group (p=0.030). CONCLUSION: The pretreatment CALLY index is one of the independent prognostic factors for esophageal cancer. The CALLY index might become a promising biomarker for the treatment and management of esophageal cancer.

Prognostic Nutritional Index as a Predictor of Prognosis in Postoperative Patients With Gastric Cancer.

BACKGROUND/AIM: The prognostic nutritional index (PNI) has been reported as an immunonutritional index that can easily evaluate nutritional status and immunocompetence from blood tests. The purpose of this study was to investigate the usefulness of PNI as a prognostic factor in postoperative gastric cancer patients. PATIENTS AND METHODS: In this retrospective cohort study, we evaluated 258 patients with pStage I-III gastric cancer who underwent radical resection at Yokohama City University Hospital, from 2015 to 2021. To examine the association with prognosis, we analyzed clinicopathological factors including PNI (<47/≥47), age (<75/≥75), sex (male/female), depth (pT1/≥pT2), lymph node metastasis (pN+/pN-), lymphatic invasion (ly+/ly-), vascular invasion (v+/v-), histological type (enteric/spread) and postoperative complications. RESULTS: In univariate analysis, PNI (p<0.001), depth of tumor invasion (p<0.001), lymph node involvement (p<0.001), age (p=0.002), lymphatic invasion (p<0.001), vascular invasion (p<0.001), and postoperative complications (p=0.003) were associated with overall survival. In multivariate analysis, PNI (HR=2.100, 95% confidence interval 1.225-3.601, p=0.007), tumor invasion, lymph node metastasis, and postoperative complications were shown as poor prognostic factors for overall survival. CONCLUSION: PNI is an independent prognostic factor for overall and recurrence-free survival in postoperative gastric cancer patients. PNI could be implemented in clinical practice to identify patients at higher risk for poor outcomes.

Prognostic Value of the Perioperative Systemic Inflammation Score for Patients With Curatively Resected Gastric Cancer.

BACKGROUND/AIM: The systemic inflammation score (SIS) is a promising tool for the evaluation of prognosis. The present study aimed to evaluate the clinical impact of the preoperative SIS status in gastric cancer (GC) patients who underwent curative resection. PATIENTS AND METHODS: This study retrospectively analyzed 258 patients with primary gastric cancer who received curative treatment at Yokohama City University. The SIS was evaluated before surgery as determined by the lymphocyte-to-monocyte ratio (cut-off value=4.44) and serum albumin level (cut-off value=4.0 g/dl). RESULTS: A high SIS was identified as an independent predictor of overall survival [hazard ratio (HR)=1.784, p<0.05] and multivariate analysis showed marginal significance for recurrence-free survival (HR=1.710, p<0.05). CONCLUSION: The preoperative SIS score was correlated with both the OS and RFS of GC patients, as well as the clinical course of adjuvant chemotherapy. Thus, the SIS score is a promising prognostic factor for GC.

Clinical Impact of Platelet-to-albumin Ratio on Esophageal Cancer Patients Who Receive Curative Treatment.

BACKGROUND/AIM: Perioperative nutrition and inflammation affect the oncological outcomes of various malignancies. We evaluated the clinical impact of the preoperative platelet-to-albumin ratio (PAR) in resectable esophageal cancer patients who received curative treatment. PATIENTS AND METHODS: This study included 168 patients who underwent curative surgery followed by perioperative adjuvant chemotherapy for esophageal cancer between 2005 and 2018. The risk factors for overall survival (OS) and recurrence-free survival (RFS) were identified. RESULTS: Based on the 3- and 5-year OS rates, we set the cut-off value for the PAR at 80×103 in the present study. Among 168 patients, 134 (79.8%) were defined as the PAR-low and 34 (20.2%) as the PAR-high group. The 3- and 5-year OS rates were 60.2% and 51.7% in the PAR-low group and 30.2% and 18.9% in the PAR-high group, respectively. There were significant differences in OS (p=0.005). The PAR was therefore selected for the final multivariate analysis model [hazard ratio=1.997, 95% confidence interval (CI)=1.230-3.241, p=0.037]. On comparing the perioperative clinical course between the PAR-high and PAR-low groups, there were marginally significant differences in the postoperative surgical complications and intraoperative blood loss between the groups. CONCLUSION: The PAR had clinical influence on the long-term oncological outcomes of esophageal cancer patients and might thus be a promising prognostic factor for esophageal cancer patients.

The Platelet-to-Lymphocyte Ratio Is an Independent Prognostic Factor for Patients With Esophageal Cancer Who Receive Curative Treatment.

BACKGROUND: Perioperative systemic inflammation affects the long-term oncological outcomes of patients with malignancies. We evaluated the clinical impact of the preoperative platelet-to-lymphocyte ratio (PLR) in patients with resectable esophageal cancer who received curative treatment. PATIENTS AND METHODS: This study included 168 patients who underwent curative surgery followed by perioperative adjuvant chemotherapy for esophageal cancer between 2005 and 2018. The risk factors for overall survival (OS) and recurrence-free survival (RFS) were identified. RESULTS: Based on the 3- and 5-year OS rates, we set the cut-off value of the PLR at 150 in the present study. Among 168 patients, 78 patients (46.4%) were categorized into the PLR-low group and 90 patients (53.6%) were categorized into the PLR-high group. The 3- and 5-year OS rates were 64.4% and 53.8%, respectively, in the PLR-low group, and 46.9% and 38.1% in the PLR-high group; the difference in OS was significant (p=0.046). PLR was therefore selected for the final multivariate analysis model (hazard ratio=1.553, 95% confidence interval=1.026-2.350, p=0.037). When the perioperative clinical course was compared between the two groups, the incidence of grade 2 or more anastomotic leakage after surgery was significantly lower in the PLR-low group at 26.9% compared to 43.3% in the PLR-high group (p=0.027). CONCLUSION: The PLR had a clinical impact on the long-term oncological outcomes of patients with esophageal cancer treated with curative intent. Therefore, the PLR might be a promising prognostic factor for patients with esophageal cancer.

Aminothioneine, a product derived from golden oyster mushrooms (Pleurotus cornucopiae var. citrinopileatus), activates Ca2+ signal-mediated brain-derived neurotrophic factor expression in cultured cortical neurons.

Ameliorating reduced brain-derived neurotrophic factor (BDNF) expression or maintaining high BDNF levels in the brain has been suggested to improve brain function in neurological diseases and prevent aging-related brain dysfunction. In this study, we found that a food-derived product, Aminothioneine® (AT), which is prepared from the extract of golden oyster mushrooms (Pleurotus cornucopiae var. citrinopileatus), increased Bdnf mRNA expression levels in primary rat cortical neuron cultures. Ergothioneine (ET) comprises more than 1% in AT and is an active constituent of AT, and ET has been reported to increase neurotrophin-4/5, but not BDNF, expression levels in neural stem cells. ET also did not affect Bdnf mRNA expression in cultured cortical neurons, suggesting that AT contains other active constituents that induce Bdnf mRNA expression in neurons. AT-induced Bdnf mRNA expression was completely blocked by d-(-)-2-Amino-5-phosphonopentanoic acid but partially blocked by nicardipine, U0126, and FK506. This result suggested that N-methyl-d-aspartate receptor-derived Ca2+ signals, including those mediated by extracellular signal-regulated kinase/mitogen-activated protein kinase and calcineurin, are the main contributors to Bdnf mRNA induction. In addition, AT increased cAMP-response element-binding protein (CREB) phosphorylation and the nuclear localization of CREB-regulated transcriptional coactivator 1 in neurons. Thus, AT can increase Bdnf mRNA expression via Ca2+ signal-induced CREB-dependent transcription in neurons. Because AT is a food-derived product, increasing and/or maintaining BDNF levels in the brain by daily intake of the product could be possible, which may be beneficial for neurological and aging-related disorders.