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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]

Mitochondrial morphology and function are coupled in healthy cells, during pathological conditions and (adaptation to) endogenous and exogenous stress. In this sense mitochondrial shape can range from small globular compartments to complex filamentous networks, even within the same cell. Understanding how mitochondrial morphological changes (i.e. “mitochondrial dynamics”) are linked to cellular (patho) physiology is currently the subject of intense study and requires detailed quantitative information. During the last decade, various computational approaches have been developed for automated 2-dimensional (2D) analysis of mitochondrial morphology and number in microscopy images. Although these strategies are well suited for analysis of adhering cells with a flat morphology they are not applicable for thicker cells, which require a three-dimensional (3D) image acquisition and analysis procedure. Here we developed and validated an automated image analysis algorithm allowing simultaneous 3D quantification of mitochondrial morphology and network properties in human endothelial cells (HUVECs). Cells expressing a mitochondria-targeted green fluorescence protein (mitoGFP) were visualized by 3D confocal microscopy and mitochondrial morphology was quantified using both the established 2D method and the new 3D strategy. We demonstrate that both analyses can be used to characterize and discriminate between various mitochondrial morphologies and network properties. However, the results from 2D and 3D analysis were not equivalent when filamentous mitochondria in normal HUVECs were compared with circular/spherical mitochondria in metabolically stressed HUVECs treated with rotenone (ROT). 2D quantification suggested that metabolic stress induced mitochondrial fragmentation and loss of biomass. In contrast, 3D analysis revealed that the mitochondrial network structure was dissolved without affecting the amount and size of the organelles. Thus, our results demonstrate that 3D imaging and quantification are crucial for proper understanding of mitochondrial shape and topology in non-flat cells. In summary, we here present an integrative method for unbiased 3D quantification of mitochondrial shape and network properties in mammalian cells. [ABSTRACT FROM AUTHOR]

Neural stem cells (NSCs) generate new neurons in vivo and in vitro throughout adulthood and therefore are physiologically and clinically relevant. Unveiling the mechanisms regulating the lineage progression from NSCs to newborn neurons is critical for the transition from basic research to clinical application. However, the direct analysis of NSCs and their progeny is still elusive due to the problematic identification of the cells. We here describe the isolation of highly purified genetically unaltered NSCs and transit-amplifying precursors (TAPs) from the adult subependymal zone (SEZ). Using this approach we show that a primary cilium and high levels of epidermal growth factor receptor (EGFR) at the cell membrane characterize quiescent and cycling NSCs, respectively. However, we also observed non-ciliated quiescent NSCs and NSCs progressing into the cell cycle without up-regulating EGFR expression. Thus, the existence of NSCs displaying distinct molecular and structural conformations provides more flexibility to the regulation of quiescence and cell cycle progression [ABSTRACT FROM AUTHOR]

An abstract of the article "Diagnostic capability of CMR for the diagnosis of acute myocarditis in young patients is determined by the presence of elevated cardiac enzymes," by Ina K. Wenzelburger and colleagues is presented.

Background: A targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin- based therapy. Patients and methods: Patients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2- week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety. Results: Three hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75-1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81-1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups. Conclusion: Bevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNAs (miRNAs) constitute a class of small cellular RNAs (typically 21–23nt) that function as post-transcriptional regulators of gene expression. Current estimates indicate that more than one third of the cellular transcriptome is regulated by miRNAs, although they are relatively few in number (less than 2000 human miRNAs). The high relative stability of miRNA in common clinical tissues and biofluids (e.g. plasma, serum, urine, saliva, etc.) and the ability of miRNA expression profiles to accurately classify discrete tissue types and disease states have positioned miRNA quantification as a promising new tool for a wide range of diagnostic applications. Furthermore miRNAs have been shown to be rapidly released from tissues into the circulation with the development of pathology. To facilitate discovery and clinical development of miRNA-based biomarkers, we developed a genome-wide Locked Nucleic Acid (LNA™)-based miRNA qPCR platform with unparalleled sensitivity and robustness. The platform allows high-throughput profiling of miRNAs from important clinical sources without the need for pre-amplification. Using this system, we have profiled thousands of biofluid samples including blood derived plasma and serum. An extensive quality control (QC) system has been implemented in order to secure technical excellence and reveal any unwanted bias coming from pre-analytical or analytical variables. We present our approaches to sample and RNA QC as well as data QC and normalization. Specifically we have developed normal reference ranges for circulating miRNAs in serum and plasma as well as a hemolysis indicator based on microRNA expression. [Copyright &y& Elsevier]

Background and Aims The immune system is a major determinant of the pathophysiological inflammation, which may lead to gastrointestinal mucosal injury in patients with Crohn's disease. Cytokines such as tumour necrosis factor-alpha are well-known mediators of the immune system, and treatment with a chimeric anti-tumour necrosis factor-alpha antibody (infliximab) has been shown to be highly effective in patients with Crohn's disease. Recent evidence indicates that infliximab induces apoptosis in lamina propria T lymphocytes in these patients. To better understand the mechanisms of infliximab's effect on gastrointestinal inflammation, we investigated changes in the serum level of cytokines after treatment in these patients, and the effect of infliximab in inducing the apoptosis of T lymphocytes. Methods Thirteen patients with Crohn's disease were treated with infliximab at a dosage of 5-mg/kg body weight. Clinical response was evaluated using the Crohn's Disease Activity Index, and serum soluble interleukin-2 receptor, interleukin-6, tumour necrosis factor-alpha levels were analysed by enzyme-linked immunosorbent assay at 0 and 2 weeks after treatment. Apoptosis of peripheral and lamina propria T lymphocytes after culture with infliximab was detected by flow cytometry. Results Crohn's Disease Activity Index decreased in 12 of 13 patients, and serum soluble interleukin-2 receptor, interleukin-6 and tumour necrosis factor-alpha levels decreased in most patients after treatment with infliximab. Tumour necrosis factor-alpha level before treatment in the six patients in whom Crohn's Disease Activity Index decreased by more than 70 was <5 ng/mL. Infliximab induced the apoptosis of lamina propria but not of peripheral T lymphocytes. Conclusion These findings suggest that a low level of serum tumour necrosis factor-alpha is an indicator for infliximab treatment. The induction of apoptosis of lamina propria T lymphocytes by infliximab may be an important mechanism of its anti-inflammatory effect in patients with Crohn's disease. [ABSTRACT FROM AUTHOR]

Hayasaki N, Ito M, Suzuki T, Ina K, Ando T, Kusugami K&Goto H(2004)Histopathology45,377–383Neutrophilic phlebitis is characteristic of intestinal Behçet's disease and simple ulcer syndrome: To characterize the histological features of intestinal Behçet's disease and simple ulcer syndrome and to clarify the possible mechanisms involved in their development by analysing the type of inflammatory infiltrates in the diseased intestine and the expression of adhesion molecules on endothelial cells.: Tissue samples from 10 patients diagnosed as having intestinal Behçet's disease or simple ulcer syndrome were studied. Immunohistochemical studies were performed on paraffin-embedded tissue using a labelled streptavidin–biotin method. In all cases, phlebitis was remarkably seen in submucosal inflammatory lesions, but the adjacent arteries were not affected. Inflammatory infiltrates around the affected vessels consisted of neutrophils and mononuclear cells, and neutrophils predominated over CD68+ macrophages and lymphocytes. The majority of mononuclear cells were CD3+ T cells, and CD4+ cells were more frequent than CD8+ T cells. As for adhesion molecule expression, intercellular adhesion molecule-1, but not vascular cell adhesion molecule-1, was expressed in most endothelial cells of the vessels with phlebitis, some of which were also positive for HLA-DR.: Neutrophilic phlebitis may be involved in the pathogenesis of intestinal Behçet's disease and simple ulcer syndrome. [ABSTRACT FROM AUTHOR]

: Failure of Helicobacter pylori eradication occurs frequently despite use of multiple microbial agents. : We aimed to study differences between H. pylori strains isolated before and after eradication failure. : We treated 87 patients with peptic ulcer using triple therapy consisting of omeprazole plus combinations of clarithromycin, amoxicillin, or metronidazole. We studied the status of cagA, vacA, and iceA by PCR, and examined the differences in H. pylori isolates by pulsed-field gel electrophoresis and arbitrary primer polymerase chain reaction. The minimum inhibitory concentration of clarithromycin, amoxicillin, or metronidazole was determined by an agar dilution method. : Eradication therapy failed in 12 patients (14%); H. pylori isolates were obtained from all of these both before and after therapy. After eradication therapy, 10 patients were colonized with the same strain as before therapy, while the other two patients were colonized with different strains from those before therapy. In the former group, one isolate changed from metronidazole-sensitive to -resistant, one changed from clarithromycin- and metronidazole-sensitive to -resistant, and four were resistant to clarithromycin or metronidazole both before and after therapy. The other four isolates remained sensitive to clarithromycin and metronidazole after therapy. In the two patients who yielded apparently different isolates after therapy, they changed from clarithromycin- and metronidazole-sensitive to -resistant. : Eradication of H. pylori by first-line therapy is an important goal in the treatment of H. pylori-positive peptic ulcer, and that appropriate antimicrobial sensitivity testing should be conducted in patients with eradication failure. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-small cell lung cancer (NSCLC) patients harboring oncogenic mutations in the epidermal growth factor receptor (EGFR) inevitably develop resistance to targeted EGFR tyrosine kinase inhibitors (TKI) therapy. To support malignant features associated with cancer development and therapy resistance, the cancer cells adapt their metabolic rate and pathways. As an example, aerobic glycolysis, where the cells use glycolysis in the presence of oxygen, is frequently seen. Here we show that targeting aerobic glycolysis represents a promising strategy in cancer therapeutics. 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. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: Brain tumor segmentations are integral to the clinical management of patients with glioblastoma, the deadliest primary brain tumor in adults. The manual delineation of tumors is time-consuming and highly provider-dependent. These two problems must be addressed by introducing automated, deep-learning-based segmentation tools. This study aimed to identify criteria experts use to evaluate the quality of automatically generated segmentations and their thought processes as they correct them., Materials and Methods: Multiple methods were used to develop a detailed understanding of the complex factors that shape experts' perception of segmentation quality and their thought processes in correcting proposed segmentations. Data from a questionnaire and semistructured interview with neuro-oncologists and neuroradiologists were collected between August and December 2021 and analyzed using a combined deductive and inductive approach., Results: Brain tumors are highly complex and ambiguous segmentation targets. Therefore, physicians rely heavily on the given context related to the patient and clinical context in evaluating the quality and need to correct brain tumor segmentation. Most importantly, the intended clinical application determines the segmentation quality criteria and editing decisions. Physicians' personal beliefs and preferences about the capabilities of AI algorithms and whether questionable areas should not be included are additional criteria influencing the perception of segmentation quality and appearance of an edited segmentation., Conclusion: Our findings on experts' perceptions of segmentation quality will allow the design of improved frameworks for expert-centered evaluation of brain tumor segmentation models. In particular, the knowledge presented here can inspire the development of brain tumor-specific metrics for segmentation model training and evaluation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jayashree Kalpathy-Cramer reports financial support was provided by National Cancer Institute. Jayashree Kalpathy-Cramer reports a relationship with Bayer Corporation that includes funding grants. Jayashree Kalpathy-Cramer reports a relationship with Genentech Inc that includes funding grants. Jayashree Kalpathy-Cramer reports a relationship with General Electric Company that includes funding grants. Jayashree Kalpathy-Cramer reports a relationship with Siloam Vision Llc that includes consulting or advisory. Competing Interests BRR is on the advisory board for ARIA, Butterfly, Inc., DGMIF (Daegu-Gyeongbuk Medical Innovation Foundation), QMENTA, Subtle Medical, Inc., is a consultant for Broadview Ventures, Janssen Scientific, ECRI Institute, GlaxoSmithKline, Hyperfine Research, Inc., Peking University, Wolf Greenfield, Superconducting Systems, Inc., Robins Kaplin, LLC, Millennium Pharmaceuticals, GE Healthcare, Siemens, Quinn Emanuel Trial Lawyers, Samsung, Shenzhen Maternity & Child Healthcare Hospital, and is a founder of BLINKAI Technologies, Inc. JKC has received research funding (to the institution) from Genentech, GE, and Bayer and is a consultant for Siloam Vision Llc., (Copyright © 2024. Published by Elsevier Inc.)

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?

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., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

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.

The glycoprotein Prominin-1 and the carbohydrate Lewis X stage-specific embryonic antigen 1 (LeX-SSEA1) both have been extensively used as cell surface markers to purify neural stem cells (NSCs). While Prominin-1 labels a specialized membrane region in NSCs and ependymal cells, the specificity of LeX-SSEA1 expression and its biological significance are still unknown. To address these issues, we have here monitored the expression of the carbohydrate in neonatal and adult NSCs and in their progeny. Our results show that the percentage of immunopositive cells and the levels of LeX-SSEA1 immunoreactivity both increase with postnatal age across all stages of the neural lineage. This is associated with decreased proliferation in precursors including NSCs, which accumulate the carbohydrate at the cell surface while remaining quiescent. Exposure of precursors to bone morphogenetic protein (BMP) increases LEX-SSEA1 expression, which promotes cell cycle withdrawal by a mechanism involving LeX-SSEA1-mediated interaction at the cell surface. Conversely, interference with either BMP signaling or with LeX-SSEA1 promotes proliferation to a similar degree. Thus, in the postnatal germinal niche, the expression of LeX-SSEA1 increases with age and exposure to BMP signaling, thereby downregulating the proliferation of subependymal zone precursors including NSCs. Stem Cells 2017;35:2417-2429., (© 2017 AlphaMed Press.)

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.

Cancer stem cells (CSCs) are a challenge in cancer treatment due to their therapy resistance. We demonstrated that enhanced Notch signaling in breast cancer promotes self-renewal of CSCs that display high glycolytic activity and aggressive hormone-independent tumor growth in vivo. We took advantage of the glycolytic phenotype and the dependence on Notch activity of the CSCs and designed nanoparticles to target the CSCs. Mesoporous silica nanoparticles were functionalized with glucose moieties and loaded with a γ-secretase inhibitor, a potent interceptor of Notch signaling. Cancer cells and CSCs in vitro and in vivo efficiently internalized these particles, and particle uptake correlated with the glycolytic profile of the cells. Nanoparticle treatment of breast cancer transplants on chick embryo chorioallantoic membranes efficiently reduced the cancer stem cell population of the tumor. Our data reveal that specific CSC characteristics can be utilized in nanoparticle design to improve CSC-targeted drug delivery and therapy.

Gastric cancer is the third leading cause of cancer-related mortality worldwide. Systemic chemotherapy is the main treatment option for advanced gastric cancer when the tumor is inoperable. Despite recent advances in chemotherapeutic agents, the prognosis of unresectable or recurrent gastric cancer remains extremely poor. In Japan, combination therapy including S-1 and cisplatin is the standard first-line treatment for advanced gastric cancer; however, the five-year survival rate remains very low. Lentinan, the backbone of beta-(1,3)-glucan with beta-(1,6) branches, an active ingredient purified from Shiitake mushrooms, has been approved as a biological response modifier for the treatment of gastric cancer. This agent has been used in combination with oral fluoropyrimidines to improve the overall survival of gastric cancer patients. A retrospective chart review on 138 metastatic gastric cancer patients receiving chemotherapy was performed in Nagoya Memorial Hospital from 1 September 2010 to 31 August 2015. 12 patients with liver metastases were treated by lentinan in combination with S-1-based chemotherapy. The rate of objective response was 42% (5/12) and the disease control rate was 83% (10/12) in response to chemo-immunotherapy using lentinan, with a median overall survival of 407 days (95% CI: 207-700 days).

Three strains of a butyrate-producing bacterium were isolated from the rumen contents of grazing sheep and cows. The strains were anaerobic, with Gram-positive cell walls, straight-to-slightly-curved, rod-shaped, non-spore-forming and single flagellate. C 14 : 1 , C 14 : 0 , C 16 : 0 and C 16 : 1 were the predominant fatty acids. The cell-wall peptidoglycan type was A1 γ . The DNA G+C content varied from 41.4 to 42.2 mol%. 16S rRNA gene sequence similarities between the isolates and Eubacterium rectale , Roseburia hominis and Roseburia intestinalis were found to be 96, 95 and 95 %, respectively. The phylogenetic tree showed that the strains constituted a different taxon, separate from other taxa with validly published names and forming a cluster with strains of Eubacterium rectale. On the basis of phenotypic, chemotaxonomic and phylogenetic results (16S RNA, dnaK , groEL , atpA genes), the isolates are considered to represent a novel species of a new genus of the family Lachnospiraceae , for which the name Agathobacter ruminis gen. nov., sp. nov. is proposed (type strain JK623 T  = DSM 29029 T  = LMG 28559 T ). We also propose the transfer of Eubacterium rectale to the new genus as Agathobacter rectalis gen. nov., comb nov. This new genus represents saccharoclastic, chemo-organotrophic and obligatory anaerobic, non-spore-forming rods with Gram-positive membrane. The main fermentation products on peptone yeast glucose (PYG) medium were butyrate, acetate, hydrogen and lactate. The type species of the genus is Agathobacter rectalis gen. nov., comb nov. (Prévot, 1938) with type strain ATCC 33656 T ( = JCM 17463 T ).

The mitochondrial NAD pool is particularly important for the maintenance of vital cellular functions. Although at least in some fungi and plants, mitochondrial NAD is 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 mitochondrial NAD(+) 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., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Histidine decarboxylase (HDC) catalyzes the biosynthesis of histamine from L-histidine and is expressed throughout the mammalian nervous system by histaminergic neurons. Histaminergic neurons arise in the posterior mesencephalon during the early embryonic period and gradually develop into two histaminergic substreams around the lateral area of the posterior hypothalamus and the more anterior peri-cerebral aqueduct area before finally forming an adult-like pattern comprising five neuronal clusters, E1, E2, E3, E4, and E5, at the postnatal stage. This distribution of histaminergic neuronal clusters in the rat hypothalamus appears to be a consequence of neuronal development and reflects the functional differentiation within each neuronal cluster. However, the close linkage between the locations of histaminergic neuronal clusters and their physiological functions has yet to be fully elucidated because of the sparse information regarding the location and orientation of each histaminergic neuronal clusters in the hypothalamus of rats and mice. To clarify the distribution of the five-histaminergic neuronal clusters more clearly, we performed an immunohistochemical study using the anti-HDC antibody on serial sections of the rat hypothalamus according to the brain maps of rat and mouse. Our results confirmed that the HDC-immunoreactive (HDCi) neuronal clusters in the hypothalamus of rats and mice are observed in the ventrolateral part of the most posterior hypothalamus (E1), ventrolateral part of the posterior hypothalamus (E2), ventromedial part from the medial to the posterior hypothalamus (E3), periventricular part from the anterior to the medial hypothalamus (E4), and diffusely extended part of the more dorsal and almost entire hypothalamus (E5). The stereological estimation of the total number of HDCi neurons of each clusters revealed the larger amount of the rat than the mouse. The characterization of histaminergic neuronal clusters in the hypothalamus of rats and mice may provide useful information for further investigations., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)