Myocardial fibrosis after acute myocardial infarction (AMI) is one of the main causes of myocardial remodeling and heart function abnormalities. Bone morphogenetic protein-7 (BMP-7) has been reported to play essential roles in anti-fibrosis. In this study, we demonstrated the role of exogenous BMP-7 on myocardial fibrosis and heart function recovery after AMI. A rat model of AMI was established via ligation of the left anterior descending coronary artery (LAD). Twenty rats were grouped into sham group which underwent chest open operation, but did not receive LAD ligation. Another 40 rats underwent LAD ligation were randomly grouped into saline-treated group (n = 20) and BMP-7-treated group (n = 20) which received saline treatment or exogenous BMP-7 treatment for 14 days, respectively. Two weeks after LAD ligation, the survival rate of BMP-7-treated AMI group was significantly improved compared to the saline group. Moreover, the cardiac function was preserved as shown by echocardiography examination, and the infarcted size was limited upon BMP-7 treatment. In addition, we investigated the role of TGF-β1 signaling pathway in BMP-7-mediated cardioprotective effects by analyzing the expression levels of TGF-β1, Smad 2 and Smad 3 in the infarct zone, border zone, and non-infarct zone. Western blot and quantitative PCR results suggested that BMP-7 attenuated myocardial fibrosis through counteracting TGF-β1 signaling pathway, thereby exerting cardioprotective effects. In conclusion, our data provide a potential therapeutic direction for preserving cardiac function and improving prognosis of AMI patients.
In Japan, traditional gender roles of women, especially the role of motherhood, may cause early career resignations in female physicians and a shortage of female researchers. Besides this gender issue, a general physician shortage is affecting basic science fields. Our previous study suggested that female physicians could be good candidates for the basic sciences because such work offers good work-life balance. However, the attractiveness for female physicians of working in the basic sciences, including work-life balance, is not known. In a 2012 nationwide cross-sectional questionnaire survey, female physicians holding tenured positions in the basic sciences at Japan’s medical schools were asked an open-ended question about positive aspects of basic sciences that clinical medicine lacks, and we analyzed 58 respondents’ comments. Qualitative analysis using the Kawakita Jiro method revealed four positive aspects: research attractiveness, priority on research productivity, a healthy work-life balance, and exemption from clinical duties. The most consistent positive aspect was research attractiveness, which was heightened by medical knowledge and clinical experience. The other aspects were double-edged swords; for example, while the priority on research productivity resulted in less gender segregation, it sometimes created tough competition, and while exemption from clinical duties contributed to a healthy work-life balance, it sometimes lowered motivation as a physician and provided unstable income. Overall, if female physicians lack an intrinsic interest in research and seek good work-life balance, they may drop out of research fields. Respecting and cultivating students’ research interest is critical to alleviating the physician shortage in the basic sciences.
Rotator cuff tears (RCTs) are a common shoulder problem in the elderly that can lead to both muscle atrophy and fatty infiltration due to less physical load. Satellite cells, quiescent cells under the basal lamina of skeletal muscle fibers, play a major role in muscle regeneration. However, the myogenic potency of human satellite cells in muscles with fatty infiltration is unclear due to the difficulty in isolating from small samples, and the mechanism of the progression of fatty infiltration has not been elucidated. The purpose of this study was to analyze the population of myogenic and adipogenic cells in disused supraspinatus (SSP) and intact subscapularis (SSC) muscles of the RCTs from the same patients using fluorescence-activated cell sorting. The microstructure of the muscle with fatty infiltration was observed as a whole mount condition under multi-photon microscopy. Myogenic differentiation potential and gene expression were evaluated in satellite cells. The results showed that the SSP muscle with greater fatty infiltration surrounded by collagen fibers compared with the SSC muscle under multi-photon microscopy. A positive correlation was observed between the ratio of muscle volume to fat volume and the ratio of myogenic precursor to adipogenic precursor. Although no difference was observed in the myogenic potential between the two groups in cell culture, satellite cells in the disused SSP muscle showed higher intrinsic myogenic gene expression than those in the intact SSC muscle. Our results indicate that satellite cells from the disused SSP retain sufficient potential of muscle growth despite the fatty infiltration.
Sleep disturbance is a common symptom after natural disasters. Although musculoskeletal pain also increases after natural disasters, its relation to sleep disturbance is not clear. The purpose of this study was to determine the influence of musculoskeletal pain on new-onset sleep disturbance among survivors after the Great East Japan Earthquake (GEJE). A prospective cohort study was conducted with the survivors of the GEJE at two and three years after the earthquake. New-onset sleep disturbance was defined as sleep disturbance absent at two years and present at three years after the earthquake. The sites of musculoskeletal pain included low back, shoulder, knee, and hand or foot. The number of musculoskeletal pain sites at two years after the earthquake was divided into three categories (0, 1, and 2 or more). Univariate and multivariate logistic regression models were used to calculate the odds ratio (OR) and 95% confidence interval (95%CI) for new-onset sleep disturbance according to the number of musculoskeletal pain sites. A total of 1,102 survivors were included in this study and 14.6% of the participants reported new-onset sleep disturbance. Using “0” as a reference, the adjusted ORs (95% CI) for new-onset sleep disturbance were 2.43 (1.55-3.80) in “1” and 2.96 (1.88-4.64) in “2 or more”, respectively (P for trends < 0.001). In conclusion, this is the first study showing higher incidence of sleep disturbance among survivors with musculoskeletal pain after the GEJE. Care for musculoskeletal pain is important to prevent sleep disturbance after natural disasters.
The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in immune checkpoint therapy for cancer. Nivolumab, an anti-PD-1 monoclonal antibody, blocks PD-1 and can restore anti-cancer immune responses by disrupting the signal that inhibits T-cell activation. Nivolumab may induce endocrine-related adverse events, including hypophysitis, autoimmune thyroiditis, and type 1 diabetes mellitus. Here we report a 68-year-old female patient with advanced renal cell carcinoma who was treated with nivolumab. She had positive anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies with slightly elevated thyroid-stimulating hormone (9.048 μU/mL), and was diagnosed as chronic thyroiditis with subclinical hypothyroidism before nivolumab therapy. She developed painless thyroiditis after the first cycle of the therapy (Day 14). At the 7th cycle of nivolumab therapy (Day 98), hyperglycemia (473 mg/dL) was noted, whereas glycated hemoglobin level was 6.9%. Islet-related autoantibodies were all negative. The glucagon tolerance test showed complete depletion of insulin. Human leukocyte antigen typing showed haplotype DRB1*09:01-DQB1*03:03, which was reported to be closely associated with type 1 diabetes mellitus in Japan. Fulminant type 1 diabetes mellitus was diagnosed, and she was immediately treated with multiple daily injections of insulin. Fulminant type 1 diabetes mellitus is characterized by rapid-onset diabetic ketoacidosis, and negative islet-related autoantibodies, and was proposed as a novel subtype of non-autoimmune diabetes. Preceding painless thyroiditis with positive thyroid autoantibodies observed in the present case, however, raises the possibility that autoimmune mechanisms are involved in the pathogenesis of nivolumab-induced fulminant type 1 diabetes mellitus.
Hematopoietic stem cells can self-renew and differentiate into all blood cell types. The transcription factor GATA-2 is expressed in hematopoietic stem and progenitor cells and is essential for cell proliferation and differentiation. Heterozygous germline GATA2 mutations induce GATA-2 deficiency syndrome, characterized by monocytopenia, a predisposition to myelodysplasia and acute myeloid leukemia, and a profoundly reduced dendritic cell (DC) population, which is associated with increased susceptibility to viral infections. Because patients with GATA-2 deficiency syndrome could retain a wild-type copy of GATA-2, boosting residual wild-type GATA-2 activity may represent a novel therapeutic strategy for the disease. Here, we sought to establish a screening system to identify GATA-2 activators using human U937 monocytic cells as a potential model of the DC progenitor. Enforced GATA-2 expression in U937 cells induces CD205 expression, a marker of DC differentiation, indicating U937 cells as a surrogate of human primary DC progenitors. Transient luciferase reporter assays in U937 cells reveals a high promoter activity of the −0.5 kb GATA-2 hematopoietic-specific promoter (1S promoter) fused with two tandemly connected GATA-2 +9.9 kb intronic enhancers. We thus established U937-derived cell lines stably expressing tandem +9.9 kb/−0.5 kb 1S-luciferase. Importantly, forced GATA-1 expression, a repressor for GATA-2 expression, in the stable clones caused significant decreases in the luciferase activities. In conclusion, our system represents a potential tool for identifying novel regulators of GATA-2, thereby contributing to the development of novel therapeutic approaches.
Critical limb ischemia (CLI) is the most severe complication of peripheral arterial disease (PAD). Understanding the molecular mechanisms underlying tissue repair after CLI is necessary for preventing PAD progression. Y-box binding protein-1 (YB-1) regulates the expression of many genes in response to environmental stresses. We aimed to determine whether YB-1 is involved in ischemic muscle regeneration. A mouse ischemic hind-limb model was generated; namely, the femoral, saphenous, and popliteal arteries in the left hind limb were ligated. The right hind limb, with skin incisions alone, served as control. Hind limbs (n = 3-5 for each time point) were examined on day 0 (before the operation) and on postoperative days 1, 2, 7, 10, and 14, and the biceps femoris, adductor, rectus femoris, and gracilis muscles were subjected to histopathological and immunohistochemical analyses. In ischemic limbs, myogenesis, triggered by an increase in myotubes, began on day 7; thereafter, regenerated muscles gradually increased in volume. RT-PCR analysis showed that YB-1 mRNA levels were increased in the limbs after ischemic injury, peaked on day 2, and subsequently decreased. On day 7, expression levels of MyoD and alpha-smooth muscle actin (αSMA) mRNAs were significantly higher in ischemic muscles than in control muscles. Immunohistochemical analysis revealed increased YB-1 immunoreactivity in myoblasts and myotubes on day 7, which was decreased by day 14. The immunoreactive αSMA and smooth muscle myosin heavy chain were transiently increased in myotubes. This is the first report showing the increased expression of YB-1 during muscle regeneration after ischemic injury.
Alcohol consumption is a risk factor for breast cancer in Western countries, but few studies have evaluated the risk for Japanese women, who have a relatively low alcohol intake. This case-control study investigated the association of alcohol consumption with breast cancer risk according to estrogen-receptor and progesterone-receptor (ER/PgR) status in Japanese women. From female patients aged 30 years and over admitted to a single hospital in Japan between 1997 and 2011, 1,256 breast cancer cases (669 ER+/PgR+, 162 ER+/PgR−, 21 ER−/PgR+, 305 ER−/PgR−, and 99 missing) and 2,933 controls were selected. Alcohol-related measures were assessed using a self-administered questionnaire. Unconditional logistic regression analysis was performed. Alcohol-related measures were not associated with breast cancer risk among the women overall. Moreover, no association was observed between ever drinking and the risk of a concordant receptor subtype (ER+/PgR+ or ER−/PgR−). Conversely, ever drinking was inversely associated with the risk of discordant subtype (ER+/PgR−, odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.41-0.95; ER−/PgR+, OR = 0.44, 95% CI: 0.14-1.42). For ER+/PgR−, an inverse association with the amount of alcohol consumed per day was observed (P for trend = 0.04), and this inverse association was limited to premenopausal women. Alcohol consumption may have differential effects on concordant and discordant receptor subtypes of breast cancer. In view of the low frequency of discordant subtype in Japanese women and their relatively low alcohol intake, our findings may provide a clue for elucidating the etiology of breast cancer rather than for preventing discordant subtype.
Retracted Review article: Nucleophagy in Human Disease: Beyond the Physiological Role. [Tohoku J. Exp. Med., 2018, 244 (1), 75-81. doi: 10.1620/tjem.244.75.]
The above Review article was published online on January 27, 2018. Soon after its publication (on February 1, 2018), Dr. Nian Fu and Prof. Linxi Chen informed the Editor-in-Chief, The Tohoku Journal of Experimental Medicine (TJEM), about serious violation of publication ethics. Indeed, Dr. Nian Fu and Prof. Linxi Chen were astonished to find their names as coauthors of this Review article, because they were not involved in the submission process of this Review article and they do not know any of other coauthors. In addition, the Review article is similar to their unpublished manuscript.
After a thorough investigation in accordance with the recommendations of the Committee on Publication Ethics (COPE), the Editor-in-Chief of TJEM decided to retract this Review article. The reasons for Retraction are summarized below: forged authors and an unexpected case of plagiarism.
Forged authors: Dr. Nian Fu and Prof. Linxi Chen were added as co-authors of the Review article without their knowledge. In fact, the signature provided by Prof. Linxi Chen is apparently different from the signature of a coauthor, named Linxi Chen, on the AUTHORS’ RESPONSIBILITY FORM, provided by the corresponding author of the Review article. More critically, the signature provided by Dr. Nian Fu is completely different from the signature of Nian Fu, because the Chinese characters are different between the two signatures. In addition, the replies from three authors (Ming Zhou, Hongwen Ji and Yong Xia) clearly indicate that they misunderstand the identity of Dr. Nina Fu. We also attempted to contact two authors, named Nian Fu and Linxi Chen, via e-mail. As expected, the forged authors did not respond to our inquiries, despite that their e-mail addresses appear to be active.
An unexpected case of plagiarism: This Review article is similar to the unpublished manuscript prepared by Dr. Nian Fu and Prof. Linxi Chen. Moreover, two figures used in the Review article are identical to the preliminary figures of their unpublished manuscript. According to Dr. Nian Fu, a local agency for language editing had transferred their unpublished manuscript to a third party. Unfortunately, the check system of TJEM is not effective for plagiarism of unpublished materials. We believe that the corresponding author of the Review article included the names of the original two authors to avoid the criticism of plagiarism. Eventually, the corresponding author agreed to retract the Review article.
We apologize for any inconvenience caused by this retraction to readers. We also hope that the publication of the plagiarized Review article will not trouble Dr. Nian Fu and Prof. Linxi Chen too much.