Ataxia-telangiectasia mutated (ATM), a master kinase of the DNA damage response (DDR), phosphorylates a multitude of substrates to activate signaling pathways after DNA double-strand breaks (DSBs). ATM inhibitors have been evaluated as anticancer drugs to potentiate the cytotoxicity of DNA damage-based cancer therapy. ATM is also involved in autophagy, a conserved cellular process that maintains homeostasis by degrading unnecessary proteins and dysfunctional organelles. In this study, we report that ATM inhibitors (KU-55933 and KU-60019) provoked accumulation of autophagosomes and p62 and restrained autolysosome formation. Under autophagy-inducing conditions, the ATM inhibitors caused excessive autophagosome accumulation and cell death. This new function of ATM in autophagy was also observed in numerous cell lines. Repression of ATM expression using an siRNA inhibited autophagic flux at the autolysosome formation step and induced cell death under autophagy-inducing conditions.Taken together, our results suggest that ATM is involved in autolysosome formation and that the use of ATM inhibitors in cancer therapy may be expanded.

Background: This study was undertaken to compare the sensitivities of mice strains during tumor induction by transcription activator-like effector nucleases (TALEN)-mediated Trp53 mutant gene. Alterations of their tumorigenic phenotypes including survival rate, tumor formation and tumor spectrum, were assessed in FVB/N-Trp53 em2Hwl /Korl and C57BL/6-Trp53 em1Hwl /Korl knockout (KO) mice over 16 weeks. Results: Most of the physiological phenotypes factors were observed to be higher in FVB/N-Trp53 em2Hwl /Korl KO mice than C57BL/6-Trp53 em1Hwl /Korl KO mice, although there were significant differences in the body weight, immune organ weight, number of red blood cells, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count (PLT), total bilirubin (Bil-T) and glucose (Glu) levels in the KO mice relative to the wild type (WT) mice. Furthermore, numerous solid tumors were also observed in various regions of the surface skin of FVB/N-Trp53 em2Hwl /Korl KO mice, but were not detected in C57BL/6-Trp53 em1Hwl /Korl KO mice. The most frequently observed tumor in both the Trp53 KO mice was malignant lymphoma, while soft tissue teratomas and hemangiosarcomas were only detected in the FVB/N-Trp53 em2Hwl /Korl KO mice. Conclusions Our results indicate that the spectrum and incidence of tumors induced by the TALEN-mediated Trp53 mutant gene is greater in FVB/N-Trp53 em2Hwl /Korl KO mice than C57BL/6-Trp53 em1Hwl /Korl KO mice over 16 weeks.

Objective: The present study aimed to explore how the patterns of interaction between stress and positive resources differ according to the severity of depression and which resources play the most important role among the various positive resources. Methods: The study included 1,806 people who had visited a health screening center for a mental health check-up to evaluate the levels of perceived stress, positive resources, and depressive symptoms. The participants were divided into a depressive group (n=1,642, mean age 50.60, female 68%) and a non-depressive group (n=164, mean age 48.42, female 66.6%). We conducted hierarchical regression analyses and simple slope analyses to examine the interaction between perceived stress and positive resources. Results: The interaction between perceived stress and optimism was significantly associated with depression in non-depressive groups. In depressive groups, the interactions between five types of positive resources (optimism, purpose in life, self-control, social support and care) and perceived stress were all significantly related to depression. Conclusion Interventions that promote optimism can be helpful for preventing inevitable stress from leading to depression. A deficiency in positive resources may be a factor in aggravating depression in stressful situations for people reporting moderate to severe depressive symptoms.

Objective: Individual differences in attachment insecurity are important in a broad range of mental health problems. However, few empirical studies have examined the clinical factors that contribute to individual differences in attachment style. This study examines the nature of interrelationships among adult attachment styles, sensitivities of behavioral activation system/behavioral inhibition system (BIS/BAS), and childhood trauma in patients with depressive disorders. Methods: Patients with depressive disorders (n=294) completed self-report questionnaires evaluating adult attachment style, childhood trauma, and BIS/BAS sensitivity. We performed multiple regression analyses to examine the associations between attachment style and other clinical factors, including childhood trauma and BIS/BAS sensitivity. We also conducted hierarchical regression analyses and simple slope analyses to examine the interaction between BIS/BAS sensitivity and childhood trauma. Results: The BAS sensitivity was negatively associated with attachment avoidance. The higher was the BIS/BAS sensitivity, the higher was the level of attachment anxiety. Among childhood trauma, emotional neglect contributed to both dimensions of insecure attachment. The interaction between BAS sensitivity and emotional neglect is significantly associated with attachment anxiety. Conclusion This study used data regarding the interrelationship of childhood trauma and basic motivational systems to contribute to the understanding of adult insecure attachment behaviors, a risk factor for depression.

BACKGROUND: This study aimed to assess the outcome of stem cell transplantation (SCT), including overall survival (OS), failure-free survival (FFS) and graft-versus-host disease (GvHD)-free/failure-free survival (GFFS), and to analyze prognostic factors in children with aplastic anemia (AA).METHODS: From 1991 to 2018, 43 allogeneic SCT recipients were enrolled in the study to investigate the demographic characteristics, survival outcomes and prognostic factors.RESULTS: With the median follow-up of 7.1 years, the estimated 10-year OS, FFS, GFFS were 86.0%, 60.5%, and 51.2%, respectively. Matched related donors (MRD, n = 28) showed better 10-year OS than unrelated donors (n = 15) (96.4% vs. 66.7%; P = 0.006). Engraftment failure was seen in 13 patients (30.2%). Donor-type aplasia was seen in 13.8% (4/29) after fludarabine (Flu)-based conditioning (Flu-group), while in 42.6% (6/14) after cyclophosphamide (Cy)-based regimen (Cy-group) (P = 0.035). Six patients died. The 10-year OS in Cy-group was 92.9% (n = 14, all MRD), while that of Flu-group was 82.1% (n = 29; P = 0.367). But Flu-group tended to have better FFS and GFFS than Cy-group, although Flu-group had less MRDs (41.4% vs. 100%; P = 0.019), and higher proportion of previous immunosuppressive treatment (IST; 62% vs. 21.4%, P = 0.012). In MRD transplants, OS was similar between Flu-group (100%, n = 14) and Cy-group (92.9%, n = 14), while FFS (100.0% vs. 42.9%; P = 0.001) and GFFS (85.7% vs. 35.7%; P = 0.006) were significantly better in Flu-group. Stem cell sources, irradiation in the conditioning, and method of GvHD prophylaxis did not significantly influence the outcome.CONCLUSION: This study reviewed SCT outcomes for pediatric AA with changes of transplant strategies over the last 25 years. The FFS and GFFS were higher in Flu-group than in Cy-group, especially in matched related transplantation. Graft failure including donor-type aplasia remains troublesome even with Flu-based conditioning. Further refinement of transplant strategies to ensure better quality-of-life should be pursued.
Anemia, Aplastic ; Child ; Cyclophosphamide ; Follow-Up Studies ; Graft vs Host Disease ; Humans ; Methods ; Stem Cell Transplantation ; Stem Cells ; Tissue Donors ; Transplants ; Unrelated Donors

BACKGROUND: This study aimed to assess the outcome of stem cell transplantation (SCT), including overall survival (OS), failure-free survival (FFS) and graft-versus-host disease (GvHD)-free/failure-free survival (GFFS), and to analyze prognostic factors in children with aplastic anemia (AA). METHODS: From 1991 to 2018, 43 allogeneic SCT recipients were enrolled in the study to investigate the demographic characteristics, survival outcomes and prognostic factors. RESULTS: With the median follow-up of 7.1 years, the estimated 10-year OS, FFS, GFFS were 86.0%, 60.5%, and 51.2%, respectively. Matched related donors (MRD, n = 28) showed better 10-year OS than unrelated donors (n = 15) (96.4% vs. 66.7%; P = 0.006). Engraftment failure was seen in 13 patients (30.2%). Donor-type aplasia was seen in 13.8% (4/29) after fludarabine (Flu)-based conditioning (Flu-group), while in 42.6% (6/14) after cyclophosphamide (Cy)-based regimen (Cy-group) (P = 0.035). Six patients died. The 10-year OS in Cy-group was 92.9% (n = 14, all MRD), while that of Flu-group was 82.1% (n = 29; P = 0.367). But Flu-group tended to have better FFS and GFFS than Cy-group, although Flu-group had less MRDs (41.4% vs. 100%; P = 0.019), and higher proportion of previous immunosuppressive treatment (IST; 62% vs. 21.4%, P = 0.012). In MRD transplants, OS was similar between Flu-group (100%, n = 14) and Cy-group (92.9%, n = 14), while FFS (100.0% vs. 42.9%; P = 0.001) and GFFS (85.7% vs. 35.7%; P = 0.006) were significantly better in Flu-group. Stem cell sources, irradiation in the conditioning, and method of GvHD prophylaxis did not significantly influence the outcome. CONCLUSION This study reviewed SCT outcomes for pediatric AA with changes of transplant strategies over the last 25 years. The FFS and GFFS were higher in Flu-group than in Cy-group, especially in matched related transplantation. Graft failure including donor-type aplasia remains troublesome even with Flu-based conditioning. Further refinement of transplant strategies to ensure better quality-of-life should be pursued.

The aim of this study was to investigate the influence of light-curing on the translucency change and color-stability of amine(tertiary)-free dual-cured resin cements after accelerated aging. Two curing modes (dual-curing and self-curing) were applied on three dual-cured resin cements (Duo-Link Universal [DLU], Nexus Third Generation [NX3] and RelyX Ultimate [RXU]) in this study. Ten specimens were fabricated for each group. In dual-cured groups only, light-activation was performed with polywave-LED curing unit (Bluphase, Ivoclar Vivadent, Schaan, Liechtenstein), where each sides of the samples were photo-polymerized for 60 seconds. Self-cured groups were kept in the dark storage for 24 hours. The color of the specimens was measured with spectrocolorimeter (NF999, Nippon Denshoku, Japan) after 24 hours of making samples. After the initial color measurements, the specimens were subjected to accelerated aging procedure. Spectrophotometric analysis was carried out on day 7, day 14, day 21 and day 28 of accelerated aging in 60 ℃ of distilled water. The color characteristics, color difference (ΔE*), and translucency parameter (TP) of specimens were calculated according to the CIE L*a*b* color system before and after aging. All the ΔE* values and TP values were analyzed by 2-way analysis of variance. After aging, all groups revealed clinically perceptible color differences (ΔE*>3.3). Differences in ΔE* values of self-cured groups were significantly higher than those of dual-cured groups in NX3 and RXU. But there were no significant differences in ΔE* between dual-cured mode and self-cured mode of DLU. All mean b* values increased after aging. All mean L* values decreased after aging except for self-cured RXU cement. TP values also decreased with aging. TP values of self-cured groups were significantly lower than those of dual-cured groups in NX3 and RXU. Hence, in conclusion, despite the absence of tertiary amine in the dual-cured resin cements, such resin cements should be polymerized with the dual-cure modes to ensure long-term color-stability.
Aging ; Polymers ; Resin Cements ; Water

Gonadotropin-releasing hormone (GnRH) is secreted from the hypothalamus and anti-GnRH antibodies are not formed under normal conditions. However, administration an excess of recombinant GnRH protein results in the formation of anti-GnRH. We evaluated the efficacy of the recombinant Salmonella typhimurium flagellin fljB (STF2)-GnRH vaccine in inducing infertility in 17 intact male cats. The first vaccination and a boosting vaccine was injected for examination. Serum was obtained from blood collected at monthly intervals and anti-GnRH antibodies and testosterone concentrations were determined. Six months after the vaccination, testicular samples are obtained and used for histological examination. Compared with sham control group, the injection groups showed an increase in anti-GnRH antibody titers and testosterone concentrations tended to be reduced in the injection groups and increased in the control group. Histological evaluations and Johnsen's testicular biopsy scores revealed testicular hypoplasia in the 2 injection groups. Consequently, normal sexual maturation with sperm production was observed in the control group. In contrast, the cats that received the GnRH vaccine showed weak (2 of 7 cats) or moderate (4 out of 7 cats) dose-dependent infertility effects. On the basis of the results, the STF2-GnRH vaccine was identified to be effective in inducing infertility in male cats. The results of this study thus indicate the possibility of immunological castration targeting feral cats.
Animals ; Antibodies ; Biopsy ; Castration ; Cats ; Contraception, Immunologic ; Fertility Agents ; Flagellin ; Gonadotropin-Releasing Hormone ; Humans ; Hypothalamus ; Infertility ; Male ; Salmonella typhimurium ; Sexual Maturation ; Spermatozoa ; Testis ; Testosterone ; Vaccination ; Vaccines

A few clues about correlation between endoplasmic reticulum (ER) stress and mulberry (Morus alba) leaves were investigated in only the experimental autoimmune myocarditis and streptozotocin-induced diabetes. To investigate whether a novel extract of mulberry leaves fermented with Cordyceps militaris (EMfC) could suppress ER in fatty liver, alterations in the key parameters for ER stress response were measured in high fat diet (HFD)-induced obese C57L/6 mice treated with EMfC for 12 weeks. The area of adipocytes in the liver section were significantly decreased in the HFD+EMfC treated group as compared to the HFD+Vehicle treated group, while their level was higher in HFD+Vehicle treated group than No treated group. The level of the eukaryotic initiation factor 2 alpha (eIF2α) and inositol-requiring enzyme 1 beta (IRE1α) phosphorylation and CCAAT-enhancer-binding protein homologous protein (CHOP) expression were remarkably enhanced in the HFD+Vehicle treated group. However, their levels were restored in the HFD+EMfC treated group, although some differences were detected in the decrease rate. Similar recovery was observed on the ER stress-induced apoptosis. The level of Caspase-3, Bcl-2 and Bax were decreased in the HFD+EMfC and HFD+orlistat (OT) treated group compared to the HFD+Vehicle treated group. The results of the present study therefore provide first evidence that EMfC with the anti-obesity effects can be suppressed ER stress and ER stress-induced apoptosis in the hepatic steatosis of HFD-induced obesity model.
Adipocytes ; Animals ; Apoptosis ; Caspase 3 ; CCAAT-Enhancer-Binding Proteins ; Cordyceps* ; Diet, High-Fat ; Endoplasmic Reticulum Stress* ; Endoplasmic Reticulum* ; Eukaryotic Initiation Factor-2 ; Fatty Liver ; Liver ; Mice* ; Morus* ; Myocarditis ; Obesity ; Phosphorylation

Regulation of gastrointestinal hormones have been reported in animal models for constipation undergoing laxative therapy when administered herbal products. We undertook to investigate whether the laxative activity of gallotannin-enriched extracts isolated from Galla Rhois (GEGR) affects the regulation of gastrointestinal hormones, by examining the concentration of four hormones and the activation of their receptors in the loperamide (Lop)-induced constipation model. Stool parameters, including number, weight and water content, were significantly recovered in the Lop+GEGR treated group, relative to the Lop+vehicle treated group; however, food intake and water consumption were maintained at a constant level. Also, a similar recovery was detected for thickness of mucosa, muscle and flat luminal surface in the Lop+GEGR treated group. Furthermore, concentration of the four gastrointestinal hormones evaluated, namely, cholecystokinin (CCK), gastrin (GAS), somatostatin (SS) and motilin (MTL), were lower in the Lop+vehicle treated group than the No treated group, but were remarkably enhanced in the Lop+GEGR treated group. Moreover, the downstream signaling pathway of MTL and SS receptors were recovered after GEGR administration. Results of the present study therefore indicate that the laxative effects of GEGR treatment may be tightly related with the regulation of gastrointestinal hormones in the Lop-induced constipation model.
Animals ; Cholecystokinin ; Constipation* ; Drinking ; Eating ; Gastrins ; Gastrointestinal Hormones* ; Loperamide ; Models, Animal ; Motilin ; Mucous Membrane ; Phenobarbital ; Rats* ; Somatostatin ; Water