Aldosterone plays pivotal roles in renin-angiotensin-aldosterone system in order to maintain the equilibrium of liquid volume and electrolyte metabolism. Aldosterone action is mediated by both mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Its excessive actions directly induced tissue injuries in its target organs such as myocardial and vascular fibrosis in addition to chronic kidney diseases. Excessive aldosterone actions were also reported to be involved in unbalanced electrolyte metabolism in inflammatory bowel disease and development of pulmonary diseases. Hyperaldosteronism is tentatively classified into primary and secondary types. Primary aldosteronism is more frequent and has been well known to result in secondary hypertension with subsequent cardiovascular damages. Primary aldosteronism is also further classified into distinctive subtypes and among those, aldosterone-producing adenoma is the most frequent one accounting for the great majority of unilateral primary aldosteronism cases. In bilateral hyperaldosteronism, aldosterone-producing diffuse hyperplasia and aldosterone-producing micronodules or nodules are the major subtypes. All these aldosterone-producing lesions were reported to harbor somatic mutations including KCNJ5, CACNA1D, ATP1A1 and ATP2B3, which were all related to excessive aldosterone production. Among those mutations above, somatic mutation of KCNJ5 is the most frequent in aldosterone-producing adenoma and mostly composed of clear cells harboring abundant aldosterone synthase expression. In contrast, CACNA1D-mutated aldosterone-producing micronodules or aldosterone-producing nodules were frequently detected not only in primary aldosteronism patients but also in the zona glomerulosa of normal adrenal glands, which could eventually lead to an autonomous aldosterone production resulting in normotensive or overt primary aldosteronism, but their details have remained unknown.
Tripartite motif-containing 44 (TRIM44) was reported to be involved in the tumorigenesis of several tumors, but its function in laryngeal squamous cell carcinoma has not been investigated yet. In the present study, we aimed to elucidate the function of TRIM44 in laryngeal squamous cell carcinoma, and identify the compounds which could inhibit TRIM44 expression. Our results showed that TRIM44 was upregulated in tumor tissues and cell lines of laryngeal squamous cell carcinoma. Knockdown of TRIM44 significantly inhibited cell growth of laryngeal squamous cell carcinoma by suppressing TLR4, phosphorylated AKT and phosphorylated NF-κB p65 expression in vitro. Moreover, TRIM44 knockdown inhibited tumor growth in nude mice, which further suggested that TRIM44 exerted oncogenic activity in laryngeal squamous cell carcinoma. Interestingly, it was found that nuciferine significantly inhibited the mRNA levels of TRIM44 after screening a small natural compound library. Our further studies showed nuciferine markedly downregulated the protein levels of TRIM44 and its substrate TLR4 in a concentration-dependent manner in laryngeal squamous cell carcinoma cells. Moreover, the activation of downstream kinases of TLR4 such as AKT signaling pathway was also inhibited by nuciferine. Additionally, nuciferine markedly inhibited cell survival of laryngeal squamous cell carcinoma in a concentration-dependent manner. In contrast, TRIM44 overexpression significantly reduced the cytotoxicity of nuciferine in laryngeal squamous cell carcinoma cells. In conclusion, this study indicated that inhibiting TRIM44 would be a useful strategy for the treatment of laryngeal squamous cell carcinoma, and nuciferine could be a potential chemical applicated in the therapy of laryngeal squamous cell carcinoma.
Many cultures are witnessing high-risk births due to the increasing trend of delayed childbearing. This has resulted in a higher proportion of children requiring long-term medical care (CLTM). The number of home-visit nursing stations available for pediatric patients should increase to provide care for CLTM at home. Through a questionnaire-based cross-sectional survey of 338 home-visit nursing station managers, this study aimed to identify the determinants of the acceptance of CLTM by analyzing the characteristics of the stations, managers, staff, and registered children, and the volume of home visits. Chi-squared tests and logistic regressions were applied to determine the independence of the variables of acceptance and analyze their significance, respectively. The response rate was 14.6%, the number of pediatric patients registered in the past was 914, and the average number of registered pediatrics was 2.7. The results indicate a correspondence between the increase in home visits by nursing staff and the number of CLTM accepted for home-visit nursing services after discharge from neonatal intensive care units. Additionally, stations whose managers have three or more years of pediatric care experience accept more CLTM, and their employees are better equipped to facilitate these acceptances. Nonetheless, the number of facilities with pediatric departments has declined; thus, nurses will face increasing difficulty gaining pediatric work experiences. Therefore, enhanced seminars and training on pediatric medical care for managers and nurses, as well as strengthened collaboration/coordination with pediatric wards, clinics, and multidisciplinary occupations should be implemented as countermeasures. Our findings illustrate issues and strategies for acceptance.
Although several molecular targeted therapy and immunotherapy have been developed, cutaneous melanoma prognosis is still not satisfying. Cul4b promotes the progression of several malignant tumors by regulating cell proliferation. However, its prognostic role in malignant cutaneous melanoma has not been evaluated. In this study, immunohistochemistry was performed to assess the expression of Cul4b in a consecutive patient cohort. The prognostic role of Cul4b was estimated with univariate and multivariate analysis. Cul4b was knocked down in melanoma cell line to evaluate its role in promoting cell proliferation. The results revealed that Cul4b was highly expressed in some of the cutaneous malignant melanoma patients and high expression of Cul4b was associated with poor melanoma-specific overall survival and poor disease-free survival. Cul4b expression was associated with Breslow categories, Clark level, and Ki67 expression. Univariate and multivariate analysis revealed that Cul4b is an independent prognosis risk factor of cutaneous melanoma. Downregulation of Cul4b inhibited the proliferation ability of melanoma cells and downregulated the expression of CDKN2A. These results suggest that Cul4b plays an essential role in cutaneous melanoma progression and may serve as a promising treatment target.
Binge drinking is a common and risky behavior among college students. In Japan, however, research on the prevalence of binge drinking and alcohol-related consequences, and the relationship between them, is currently scant. The aim of this study is to examine the status of binge drinking and alcohol-related problems, and the relationship between them, among Japanese college students. We conducted a cross-sectional survey of college students who participated in a health seminar or lecture including alcohol-related contents from December 2018 to January 2019. Drinking patterns and alcohol-related consequences were assessed using the Brief Young Adult Alcohol Consequences Questionnaire (B-YAACQ) and demographic data. A total of 382 students participated in the seminar, of whom 280 agreed to cooperate in this study and 249 had drinking experience. A total of 88 men (67.7%) and 42 women (32.2%) were classified as binge drinkers. Binge drinkers more significantly experienced various consequences, such as hangover, feeling remorse and embarrassing behavior and some of them were suspected of physical dependence. Furthermore, logistic analysis revealed that among men, the B-YAACQ scores of binge drinkers were 2.01-fold higher those of non-binge drinkers. The findings of this study indicated that binge drinking may cause not only physical consequences but also mental and social problems, especially among men. It is important to tell college students these risks properly not to engage in binge drinking.
Whether trastuzumab use beyond disease progression is beneficial in second-line treatment for patients with unresectable human epidermal growth factor receptor 2 (HER2)-positive gastric cancer remains to be elucidated. We conducted this phase II study to assess whether trastuzumab plus docetaxel was effective for patients with previously treated advanced HER2-positive gastric cancer. This trial was a single-arm, open-label, multicenter, phase II study, conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE). Patients aged 20 years or older who had advanced HER2-positive gastric cancer and were refractory to trastuzumab, fluoropyrimidine, and cisplatin were enrolled. Patients were treated with 6 mg/kg trastuzumab and 60 mg/m2 docetaxel every 3 weeks. The primary endpoint was the overall response rate. The threshold overall response rate was estimated to be at 15%. Secondary endpoints were progression-free survival, 6-month survival rate, overall survival, and toxicities. A total of 27 patients were enrolled from 7 hospitals. The median age was 67 years. Partial response was seen in 3 patients among the 26 evaluated patients. The overall response rate was at 11.5% (90% confidence interval 1.2%-21.8%). The median progression-free survival was 3.2 months, the 6-month survival rate was 85%, and the median overall survival was 11.6 months. Febrile neutropenia was observed in 14.8%. The most frequently observed grade 3 non-hematologic toxicity was anorexia (14.8%). The primary endpoint was not achieved. The results support a current consensus that the continuation of trastuzumab in second-line therapy for gastric cancer is not a recommended option.
Discontinuation of denosumab is associated with the risk of rebound in bone turnover and rebound-associated spontaneous clinical vertebral fractures. This case report presents an 86-year-old woman with rheumatoid arthritis who experienced rebound-associated spontaneous clinical vertebral fractures at 9 months after denosumab discontinuation. Following 5-year bisphosphonate treatment, the patient had 9 injections of 60-mg denosumab every 6 months. Because of tooth extraction, denosumab treatment was discontinued, and raloxifene was administered. At 9 months after the last denosumab injection, the patient experienced severe low back pain. Magnetic resonance imaging (MRI) and radiograph demonstrated clinical fracture at the fourth lumbar vertebra. MRI performed at 3 months after first fracture showed two additional fractures at the second and third lumbar vertebrae. Teriparatide was administered for management of rebound-associated spontaneous clinical, multiple vertebral fractures. Teriparatide was effective for accelerating the fracture healing and suppressing the occurrence of new fractures. However, 2-year treatment of teriparatide did not have suppressive effect of rebound in bone turnover and general bone loss. This case suggested that teriparatide was effective for suppression of new rebound-associated spontaneous clinical vertebral fractures, but not effective in prevention of general bone loss after denosumab discontinuation.