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Abstract Background Epithelial to mesenchymal transition (EMT) is a well-characterized process of cell plasticity that may involve metabolic rewiring. In cancer, EMT is associated with malignant progression, tumor heterogeneity, and therapy resistance. In this study, we investigated the role of succinate dehydrogenase (SDH) as a potential key regulator of EMT. Methods Associations between SDH subunits and EMT were explored in gene expression data from breast cancer patient cohorts, followed by in-depth studies of SDH suppression as a potential mediator of EMT in cultured cells. Results We found an overall inverse association between EMT and the SDH subunit C (SDHC) when analyzing gene expression in breast tumors. This was particularly evident in carcinomas of basal-like molecular subtype compared to non-basal-like tumors, and a low SDHC expression level tended to have a prognostic impact in those patients. Studies in cultured cells revealed that EMT was induced by SDH inhibition through SDHC CRISPR/Cas9 knockdown or by the enzymatic inhibitor malonate. Conversely, overexpression of EMT-promoting transcription factors TWIST and SNAI2 caused decreased levels of SDHB and C and reduced rates of SDH-linked mitochondrial respiration. Cells overexpressing TWIST had reduced mitochondrial mass, and the organelles were thinner and more fragmented compared to controls. Conclusions Our findings suggest that downregulation of SDHC promotes EMT and that this is accompanied by structural remodeling of the mitochondrial organelles. This may confer survival benefits upon exposure to hostile microenvironment including oxidative stress and hypoxia during cancer progression.

Increased glycolytic activity is a hallmark of cancer initiation and progression and is often observed in non-small cell lung cancer (NSCLC). Pyruvate dehydrogenase (PDH) complex acts as a gatekeeper between glycolysis and oxidative phosphorylation, and activation of PDH is known to inhibit glycolytic activity. As part of a standard therapeutic regimen, patients with NSCLC harboring oncogenic mutations in the epidermal growth factor receptor (EGFR) are treated with EGFR tyrosine kinase inhibitors (EGFR TKIs). Independent of good initial response, development of resistance to this therapy is inevitable. In the presented work, we propose that inhibition of glycolysis will add to the therapeutic effects and possibly prevent development of resistance against both EGFR TKIs and ionizing radiation in NSCLC. Analysis of transcriptome data from two independent NSCLC patient cohorts identified increased expression of pyruvate dehydrogenase kinase 1 (PDHK1) as well as upregulated expression of genes involved in glucose metabolism in tumors compared to normal tissue. We established in vitro models of development of resistance to EGFR TKIs to study metabolism and determine if targeting PDHK would prevent development of resistance to EGFR TKIs in NSCLC cells. The PDHK1 inhibitor dichloroacetate (DCA) in combination with EGFR TKIs and/or ionizing radiation was shown to increase the therapeutic effect in our NSCLC cell models. This mechanism was associated with redirected metabolism towards pyruvate oxidation and reduced lactate production, both in EGFR TKI sensitive and resistant NSCLC cells. Using DCA, the intracellular pool of pyruvate available for lactic fermentation becomes limited. Consequently, pyruvate is redirected to the mitochondria, and reinforces mitochondrial activity. Addition of DCA to cell culture deacidifies the extracellular microenvironment as less lactate is produced and excreted. In our study, we find that this redirection of metabolism adds to the therapeutic effect of EGFR TKI and ionizing radiation in NSCLC.

The mitochondrialNADpool is particularly important for the maintenance of vital cellular functions. Although at least in some fungi and plants, mitochondrialNADis imported from the cytosol by carrier proteins, in mammals, the mechanism of how this organellar pool is generated has remained obscure. A transporter mediating NAD import into mammalian mitochondria has not been identified. In contrast, human recombinant NMNAT3 localizes to the mitochondrial matrix and is able to catalyze NAD+ biosynthesis in vitro. However, whether the endogenous NMNAT3 protein is functionally effective at generating NAD+ in mitochondria of intact human cells still remains to be demonstrated. To modulate mitochondrial NAD+ content, we have expressed plant and yeast mitochondrial NAD+ carriers in human cells and observed a profound increase in mitochondrial NAD+. None of the closest human homologs of these carriers had any detectable effect on mitochondrial NAD+ content. Surprisingly, constitutive redistribution of NAD+ from the cytosol to the mitochondria by stable expression of the Arabidopsis thaliana mitochondrial NAD+ transporter NDT2 in HEK293 cells resulted in dramatic growth retardation and a metabolic shift from oxidative phosphorylation to glycolysis, despite the elevated mitochondrialNAD+ levels. These results suggest that a mitochondrial NAD+ transporter, similar to the known one from A. thaliana, is likely absent and could even be harmful in human cells. We provide further support for the alternative possibility, namely intramitochondrial NAD+ synthesis, by demonstrating the presence of endogenous NMNAT3 in the mitochondria of human cells. [ABSTRACT FROM AUTHOR]

Purpose: Patients with hematological malignancies are at an increased risk of severe infection with coronavirus disease 2019 (COVID-19). However, developing an adequate immune response after vaccination is difficult, especially in patients with lymphoid neoplasms. Since the long-term effects of the BNT162b2 vaccine are unclear, the humoral immune response 5 months after the two vaccinations in patients with hematological disorders was analyzed., Materials and Methods: Samples were collected from 96 patients vaccinated twice with BNT162b2 and treated with at least one line of an antitumor or immunosuppressive drug in our hospital from November 2021 to February 2022. Serum anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) spike (S) antibody titers were analyzed. Patients were age- and sex-matched using propensity matching and compared with a healthy control group. Patients with serum anti-SARS-CoV-2 S antibodies were defined as 'responder' if >50 U/mL. The patients had B-cell non-Hodgkin lymphoma (B-NHL), multiple myeloma, chronic myeloid leukemia, etc., Results: Patients had significantly low antibody levels (median, 55.3 U/mL vs. 809.8 U/mL; p<0.001) and a significantly low response rate (p<0.001). Multivariate analysis showed that patients with B-NHL, aged >72 years, were associated with a low response to vaccination. There were no significant differences between patients with chronic myeloid leukemia and healthy controls., Conclusion: Our study shows that patients with hematological disorders are at risk of developing severe COVID-19 infections because of low responsiveness to vaccination. Moreover, the rate of antibody positivity differed between the disease groups. Further studies are warranted to determine an appropriate preventive method for these patients, especially those with B-NHL., Competing Interests: No potential conflict of interest relevant to this article was reported., (© Korean Vaccine Society.)

In recent years, medical disciplines have moved closer together and rigid borders have been increasingly dissolved. The synergetic advantage of combining multiple disciplines is particularly important for radiology, nuclear medicine, and pathology to perform integrative diagnostics. In this review, we discuss how medical subdisciplines can be reintegrated in the future using state-of-the-art methods of digitization, data science, and machine learning. Integration of methods is made possible by the digitalization of radiological and nuclear medical images, as well as pathological images. 3D histology can become a valuable tool, not only for integration into radiological images but also for the visualization of cellular interactions, the so-called connectomes. In human pathology, it has recently become possible to image and calculate the movements and contacts of immunostained cells in fresh tissue explants. Recording the movement of a living cell is proving to be informative and makes it possible to study dynamic connectomes in the diagnosis of lymphoid tissue. By applying computational methods including data science and machine learning, new perspectives for analyzing and understanding diseases become possible., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: We collaborated with the regional pharmaceutical associations near Nagoya Memorial Hospital and created a communication sheet for pharmaceutical cooperation between the hospital and health insurance pharmacies., Methods: The communication sheet for pharmaceutical cooperation was issued in October 2014. We conducted a questionnaire survey of both cancer patients and community pharmacists 1 year after the implementation of the use of this sheet. Based on the results of the survey, we modified our communication sheet and added a unified reply form in October 2016. We examined the number of replies from community pharmacists from October 2014 to April 2019. We then analyzed how community pharmacists instructed and communicated with cancer patients using the results of both the questionnaire survey and the reply form, which were compared before and after introducing the modified version of the communication sheet., Results: During the 5 years of observation, 743 communication sheets were sent from Nagoya Memorial Hospital to community pharmacists. As a result of pharmaceutical cooperation in using the communication sheet, 96.4% of prescribed medication were immediately prepared in health insurance pharmacies on that day. The communication sheet also enhanced the conversations between cancer patients and pharmacists. The introduction of the unified reply form increased the response rate of community pharmacists from 1.7 to 69.5% ( p  < 0.001). The communication between community pharmacists and cancer patients was significantly hindered by prescriptions without an oral cancer drug and patient age < 65 years old ( p < 0.05). However, this hindrance was reduced by the use of the modified form., Conclusions: The communication sheet for pharmaceutical cooperation is useful for bidirectional information sharing between hospitals and health insurance pharmacies, which may enable pharmacists to provide cancer patients with medication instructions in coordination with hospitals and increase the quality of outpatient pharmacy services., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Aim: This study aimed to examine the relationship between blood coagulability and sense of burden among caregivers of patients with senile dementia of the Alzheimer type., Methods: A cross-sectional study was carried out involving healthy older caregivers who lived with their patients with senile dementia of the Alzheimer type. We evaluated the Zarit Burden Interview score, levels of von Willebrand factor antigen, D-dimer, thrombin-antithrombin III complex, tissue plasminogen activator/plasminogen activator inhibitor type 1 complex, number of chronic diseases, body mass index and number of medications. A linear regression model was used to estimate adjusted associations., Results: Thrombin-antithrombin III complex levels were higher in female caregivers than in male caregivers (P = 0.07). Headaches were significantly more frequent in female caregivers than in male caregivers, as assessed by a visual analog scale (P < 0.01). The number of chronic diseases and body mass index were positively associated with levels of tissue plasminogen activator/plasminogen activator inhibitor type 1 complex (P < 0.05). Similarly, the number of medications was positively associated with levels of D-dimer (P < 0.05). However, the Zarit Burden Interview score was not associated with blood coagulability (P > 0.05)., Conclusions: The present study found that the number of chronic diseases and body mass index were associated with blood coagulability, and that female caregivers were more prone to headaches and higher blood coagulability than male caregivers. These findings highlight the essential nature of health management during caregiving. The impact of caregiver burden on blood coagulability is likely to differ depending on the long-term or short-term psychological stress associated with caregiving conditions. Geriatr Gerontol Int 2019; 19: 804-808., (© 2019 Japan Geriatrics Society.)

Objectives: To report long-term outcome survival analysis of docetaxel-based chemotherapy combined with dexamethasone in castration-resistant prostate cancer patients (Japan-Multinational Trial Organization Pca10-01 trial)., Methods: The Japan-Multinational Trial Organization Pca10-01 phase II trial was a multicenter, prospective single-arm, phase II trial both in non-metastatic and metastatic castration-resistant prostate cancer patients that was organized by The Japan-Multinational Trial Organization. Patients received 75 mg/m 2 of docetaxel (every 21 days) and 0.5 mg of dexamethasone orally twice a day continuing throughout the treatment period. The primary end-point of this additional analysis was overall survival. Secondary end-points were progression-free survival and safety., Results: Between January 2011 and February 2014, a total of 76 chemotherapy-naïve castration-resistant prostate cancer patients were enrolled. The median overall survival time was 42.5 months. The median overall survival time of M1 patients was 40.5 months (M0: not reached). The median progression-free survival time was 13.2 months (M0: 15.7 months and M1: 12.3 months). The multivariate analysis predicting overall survival of M1 patients showed that time to castration-resistant prostate cancer (≥20 months) was an independent parameter (hazard ratio 0.39, P = 0.023). Regarding the safety analysis, 36 out of 74 patients (48.6%) suffered from any grade of adverse events after the protocol treatment, and 18 patients (24.3%) had grade ≥3 adverse events., Conclusions: Docetaxel-based chemotherapy combined with dexamethasone can achieve excellent survival efficacy not only in M0 castration-resistant prostate cancer patients, but also in M1 castration-resistant prostate cancer patients., (© 2019 The Japanese Urological Association.)

Review Question: What is the effect of antenatal parenting education on parenting stress, maternal depressive symptoms and maternal confidence, compared to usual care, for expectant primiparous women in Asian countries?

Aim: Despite the significant advances in chemotherapy, the prognosis of unresectable or recurrent gastric cancer is still very poor. Given that older adults are likely to have a number of concomitant diseases and an impaired major organ function, cancer chemotherapy in elderly patients requires particular caution. We examined what factors are associated with the overall survival of gastric cancer patients undergoing chemotherapy., Methods: A retrospective chart review of gastric cancer patients receiving oral fluoropyrimidines (N=130) was performed at Nagoya Memorial Hospital over 9 years. The overall survival was calculated from the beginning of chemotherapy until death or the most recent date of follow-up. The Kaplan-Meier method was used to plot survival curves, which were compared using the log-rank test. A multivariate analysis was performed using stepwise Cox proportional hazards models. A comprehensive geriatric assessment was conducted for the elderly patients. The chart review was approved by the ethics committee of Nagoya Memorial Hospital., Results: The objective response rate and overall survival did not differ markedly between the patients < 75 years (N=64) and those ≥ 75 years of age (N=28). The addition of lentinan significantly prolonged the survival of the stage 4 gastric cancer patients. In a multivariate analysis of those ≥ 75 years of age, the only independent prognostic factor for the survival was the functional capacity, as measured by the TMIG Index of Competence., Conclusions: This comprehensive geriatric assessment was useful for predicting the longevity of patients with stage 4 gastric cancer ≥ 75 years of age.

Objectives: Previously, one randomized control trial (TAX327) revealed the efficacy of docetaxel-based chemotherapy combined with prednisone. On the other hand, several studies showed a high prostate specific antigen (PSA) response with low-dose dexamethasone in castration-resistant prostate cancer (CRPC) patients. The objective of this study was to evaluate the efficacy and safety of docetaxel-based chemotherapy combined with dexamethasone in CRPC patients., Materials and Methods: This study was a single-arm multi-institutional phase II trial. Patients received 75 mg/m2 of docetaxel, and 0.5 mg of dexamethasone orally twice a day continuing throughout the treatment period. Treatment was planned for 10 cycles, and continued for at least four cycles depending on the observation of PSA flare. The primary endpoint was PSA response defined as a reduction from baseline of at least 50% that continued for at least 3 weeks. Secondary endpoints were safety, PSA flare, time to PSA failure and adherence rate to protocol treatment (10 cycles)., Results: Between January 2011 and February 2014, a total of 76 chemotherapy-naïve CRPC patients were enrolled. Seventy-five patients received docetaxel-based chemotherapy combined with dexamethasone. The median age and PSA level at enrollment were 71 years (53-85) and 23.2 ng/mL (2.9-852), respectively. PSA response rate was 76.8% (90% confidence interval (CI): 66.9-84.9). Of all patients, 30 patients completed 10 cycles of chemotherapy (40%). The incidence rate of PSA flare was 10.7% (eight patients). The median time to PSA failure was 369 days (95% CI: 245-369). The most frequently observed adverse event was hematotoxicity (neutropenia of G2 or greater: 100%)., Conclusions: The present study showed a significantly high PSA response compared with previous reports. Most patients tolerated the protocol treatment well, whereas hematotoxicity was often observed., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Stress-induced inflammatory responses in the portal system are characterized by elevations in serum concentrations of interleukin-6 (IL-6) and endotoxins such as lipopolysaccharides (LPS). LPS translocation from the intestinal to the capillary lumen occurs via LPS endocytosis by the capillary endothelium. Because the capillary endothelium of the small intestinal submucosa is fenestrated, we determined the role of pore modifications within the fenestrated endothelium in relaying inflammatory stress responses in the portal vein. We evaluated changes in the diameter and density of endothelial pores of the lamina propria of intestinal villi induced by continuous light (CL) exposure for 48 h and the correlation between these changes and serum IL-6 concentration in the portal vein in a rat model. We found significant increases in both the pore diameter and density, accompanied by a significant increase in portal IL-6 concentration; these changes were significantly attenuated by pretreatment with propranolol, a beta adrenergic receptor antagonist. In contrast, intravenous noradrenaline administration mimicked CL-induced modifications of the diameter and density of pores and the elevation of portal vein IL-6 concentration. These findings suggested that stress-induced inflammatory responses in the portal system may be a part of the modifications of the endothelial pores triggered by sympathetic activation.