Adherence to 24-h Movement Guidelines and Depressive Status During the Coronavirus Disease Outbreak: A Cross-Sectional Japanese Survey

Objectives: The coronavirus disease 2019 (COVID-19) pandemic has affected people’s physical activity, sedentary behavior, and sleep. This study aimed to clarify the association between combining these factors, integrated as adherence to 24-h movement guidelines, and depressive status during the COVID-19 pandemic.Methods: At the end of October 2020, we sent self-administered questionnaires to 1,711 adults aged ≥18. We assessed physical activity, sedentary behavior, sleep duration, adherence to 24-h movement guidelines, depressive status, and confounding factors.Results: Of the 640 valid responses, 90 (14.1%) reported a depressive status. Multivariable odds ratios (95% confidence interval) of depressive status were 0.22 (0.07, 0.71) for all three recommendations of the 24-h movement guidelines and those who met none of the recommendations as reference. The number of guidelines met was associated with depressive status in a dose-response fashion.Conclusion: Meeting the 24-h movement guidelines was associated with a lower prevalence of depressive status during the COVID-19 pandemic. Adults should adhere to these guidelines to maintain their mental health during future quarantine life

JTP-109192, a novel G protein-coupled receptor 119 agonist, prevents atherosclerosis by improving hypercholesterolemia in congenic spontaneously hyperlipidaemic mice

G protein‐coupled receptor 119 (GPR119) expression in pancreatic β‐cells and intestinal L‐cells is a potential therapeutic target for the treatment of type 2 diabetes. Previously, we have reported that the GPR119 agonist JTP‐109192 improves glucose metabolism with single and repeated administration. Conversely, overexpression of the Gpr119 gene reportedly regulates cholesterol transporter expression in animal models, and a natural GPR119 agonist, oleoylethanolamide (OEA), improves atherosclerosis. Therefore, improving dyslipidaemia is considered a possible feature of GPR119 agonists. In the present study, the lipid‐lowering effect of JTP‐109192 was examined in BALB/c background spontaneously hyperlipidaemic (SHL) mice with repeated administration, once daily for 12 weeks. On repeated administration, JTP‐109192 revealed a cholesterol‐lowering effect and improved atherosclerosis following histopathological examination. With further investigation, the cholesterol‐lowering effect and subsequent antiatherosclerotic effect of JTP‐109192 was attributed to changes in intestinal cholesterol metabolism gene expression. Based on these results, JTP‐109192 represents a new potential antihypercholesterolaemic agent for the treatment of dyslipidaemia

Tertiary Lymphoid Tissues Are Microenvironments with Intensive Interactions between Immune Cells and Proinflammatory Parenchymal Cells in Aged Kidneys

三次リンパ組織による腎障害メカニズムの解明: 慢性腎臓病の新たな治療標的候補を同定. 京都大学プレスリリース. 2023-08-08.[Significance Statement] Ectopic lymphoid structures called tertiary lymphoid tissues (TLTs) develop in several kidney diseases and are associated with poor renal prognosis. However, the mechanisms underlying TLT expansion and their effect on renal regeneration remain unclear. The authors report that single-nucleus RNA sequencing and validation experiments demonstrate that TLTs potentially amplify inflammation in aged injured kidneys. Lymphocytes within TLTs promote proinflammatory phenotypes of the surrounding proximal tubules and fibroblasts within the TLTs via proinflammatory cytokine production. These proinflammatory parenchymal cells then interact with immune cells by chemokine or cytokine production. Such cell-cell interactions potentially increase inflammation, expand TLTs, and exacerbate kidney injury. These findings help illuminate renal TLT pathology and suggest potential therapeutic targets. [Background] Ectopic lymphoid structures called tertiary lymphoid tissues (TLTs) develop in several kidney diseases and are associated with poor renal prognosis. However, the mechanisms that expand TLTs and underlie exacerbation of kidney injury remain unclear. [Methods] We performed single-nucleus RNA sequencing (snRNA-seq) on aged mouse kidneys with TLTs after ischemia-reperfusion injury. The results were validated using immunostaining, in situ hybridization of murine and human kidneys, and in vitro experiments. [Results] Using snRNA-seq, we identified proinflammatory and profibrotic Vcam1⁺ injured proximal tubules (PTs) with NFκB and IFN-inducible transcription factor activation. VCAM1⁺ PTs were preferentially localized around TLTs and drove inflammation and fibrosis via the production of multiple chemokines or cytokines. Lymphocytes within TLTs expressed Tnf and Ifng at high levels, which synergistically upregulated VCAM1 and chemokine expression in cultured PT cells. In addition, snRNA-seq also identified proinflammatory and profibrotic fibroblasts, which resided within and outside TLTs, respectively. Proinflammatory fibroblasts exhibited STAT1 activation and various chemokine or cytokine production, including CXCL9/CXCL10 and B cell–activating factor, contributing to lymphocyte recruitment and survival. IFNγ upregulated the expression of these molecules in cultured fibroblasts in a STAT1-dependent manner, indicating potential bidirectional interactions between IFNγ-producing CXCR3⁺ T cells and proinflammatory fibroblasts within TLTs. The cellular and molecular components described in this study were confirmed in human kidneys with TLTs. [Conclusions] These findings suggest that TLTs potentially amplify inflammation by providing a microenvironment that allows intense interactions between renal parenchymal and immune cells. These interactions may serve as novel therapeutic targets in kidney diseases involving TLT formation

Newly Developed Fully Covered Metal Stent for Unresectable Malignant Biliary Stricture

We herein report two patients with unresectable malignant biliary stricture who underwent stenting with a newly developed fully-covered metal stent. In the first case of lower-middle bile duct cancer, a stent was placed through the stenosis. In the second case of middle bile duct stricture due to lymph node metastases from gallbladder cancer, a stent was placed in the bile duct across the stenosis. No procedure-related complications were observed. Unevenness of the outer surface and a low shortening ratio are expected to lessen the occurrence of complications characteristic of covered metal stents such as stent migration and bile duct kinking

Low-Intensity Resistance Training with Moderate Blood Flow Restriction Appears Safe and Increases Skeletal Muscle Strength and Size in Cardiovascular Surgery Patients:A Pilot Study

We examined the safety and the effects of low-intensity resistance training (RT) with moderate blood flow restriction (KAATSU RT) on muscle strength and size in patients early after cardiac surgery. Cardiac patients (age 69.6 +/- 12.6 years, n = 21, M = 18) were randomly assigned to the control (n = 10) and the KAATSU RT group (n = 11). All patients had received a standard aerobic cardiac rehabilitation program. The KAATSU RT group additionally executed low-intensity leg extension and leg press exercises with moderate blood flow restriction twice a week for 3 months. RT-intensity and volume were increased gradually. We evaluated the anterior mid-thigh thickness (MTH), skeletal muscle mass index (SMI), handgrip strength, knee extensor strength, and walking speed at baseline, 5-7 days after cardiac surgery, and after 3 months. A physician monitored the electrocardiogram, rate of perceived exertion, and the color of the lower limbs during KAATSU RT. Creatine phosphokinase (CPK) and D-dimer were measured at baseline and after 3 months. There were no side effects during KAATSU RT. CPK and D-dimer were normal after 3 months. MTH, SMI, walking speed, and knee extensor strength increased after 3 months with KAATSU RT compared with baseline. Relatively low vs. high physical functioning patients tended to increase physical function more after 3 months with KAATSU RT. Low-intensity KAATSU RT as an adjuvant to standard cardiac rehabilitation can safely increase skeletal muscle strength and size in cardiovascular surgery patients.</p

JNK pathway plays a critical role for expansion of human colorectal cancer in the context of BRG1 suppression

Tumor stem cells (TSCs), capable of self-renewal and continuous production of progeny cells, could be potential therapeutic targets. We have recently reported that chromatin remodeling regulator Brg1 is required for maintenance of murine intestinal TSCs and stemness feature of human colorectal cancer (CRC) cells by inhibiting apoptosis. However, it is still unclear how BRG1 suppression changes the underlying intracellular mechanisms of human CRC cells. We found that Brg1 suppression resulted in upregulation of the JNK signaling pathway in human CRC cells and murine intestinal TSCs. Simultaneous suppression of BRG1 and the JNK pathway, either by pharmacological inhibition or silencing of c-JUN, resulted in even stronger inhibition of the expansion of human CRC cells compared to Brg1 suppression alone. Consistently, high c-JUN expression correlated with worse prognosis for survival in human CRC patients with low BRG1 expression. Therefore, the JNK pathway plays a critical role for expansion and stemness of human CRC cells in the context of BRG1 suppression, and thus a combined blockade of BRG1 and the JNK pathway could be a novel therapeutic approach against human CRC

Pancreatic RECK inactivation promotes cancer formation, epithelial-mesenchymal transition, and metastasis

膵癌悪性化の分子機構解明 --RECK発現の低下が膵癌の浸潤・転移を引き起こす--. 京都大学プレスリリース. 2023-09-19.RECK is downregulated in various human cancers; however, how RECK inactivation affects carcinogenesis remains unclear. We addressed this issue in a pancreatic ductal adenocarcinoma (PDAC) mouse model and found that pancreatic Reck deletion dramatically augmented the spontaneous development of PDAC with a mesenchymal phenotype, which was accompanied by increased liver metastases and decreased survival. Lineage tracing revealed that pancreatic Reck deletion induced epithelial-mesenchymal transition (EMT) in PDAC cells, giving rise to inflammatory cancer-associated fibroblast–like cells in mice. Splenic transplantation of Reck-null PDAC cells resulted in numerous liver metastases with a mesenchymal phenotype, whereas reexpression of RECK markedly reduced metastases and changed the PDAC tumor phenotype into an epithelial one. Consistently, low RECK expression correlated with low E-cadherin expression, poor differentiation, metastasis, and poor prognosis in human PDAC. RECK reexpression in the PDAC cells was found to downregulate MMP2 and MMP3, with a concomitant increase in E-cadherin and decrease in EMT-promoting transcription factors. An MMP inhibitor recapitulated the effects of RECK on the expression of E-cadherin and EMT-promoting transcription factors and invasive activity. These results establish the authenticity of RECK as a pancreatic tumor suppressor, provide insights into its underlying mechanisms, and support the idea that RECK could be an important therapeutic effector against human PDAC

Predictive Factors for Inaccurate Diagnosis of Swollen Lymph Nodes in Endoscopic Ultrasound-Guided Fine Needle Aspiration

Background/Aims This study aimed to identify the predictive factors for inaccurate endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) diagnosis of swollen lymph nodes without rapid on-site cytopathological evaluation. Methods Eighty-three consecutive patients who underwent EUS-FNA for abdominal or mediastinal lymph nodes from January 2008 to June 2017 were included from a prospectively maintained EUS-FNA database and retrospectively reviewed. The sensitivity, specificity, and accuracy of EUS-FNA for the detection of neoplastic diseases were calculated. Candidate factors for inaccurate diagnosis (lymph node size and location, needle type, puncture route, number of passes, and causative disease) were evaluated by comparison between accurately diagnosed cases and others. Results The final diagnosis of the punctured lymph node was classified as neoplastic (65 cases: a metastatic lymph node, malignant lymphoma, or Crow-Fukase syndrome) or non-neoplastic (18 cases: a reactive node or amyloidosis). The sensitivity, specificity, and accuracy were 83%, 94%, and 86%, respectively. On multivariate analyses, small size of the lymph node was the sole predictive factor for inaccurate EUS-FNA diagnosis with a significant difference (odds ratios, 19.8; 95% confidence intervals, 3.15–124; p=0.0015). Conclusions The lymph node size of <16 mm was the only independent factor associated with inaccurate EUS-FNA diagnosis of swollen lymph nodes

Expressions of ezrin, ERK, STAT3, and AKT in tongue cancer and association with tumor characteristics and patient survival.

Ezrin, ERK, STAT3, and AKT are proteins that are overexpressed in various types of cancer, although their expressions in tongue cancer has received less focus. This study aimed to address associations between the expression levels of these proteins and with characteristics of the tumor and patient survival. We performed immunohistochemical staining of ezrin, ERK, STAT3, and AKT in tumors from patients with tongue carcinoma in situ (CIS, n = 17) and tongue squamous cell carcinoma (SCC, n = 46). Statistical differences between the SCC versus the CIS cohorts were estimated by calculations of bivariate odds ratios of low versus high expression of the proteins. Fisher\u27s exact tests were used to appraise interassociations between the proteins, as well as expression levels versus patient and tumor characteristics. Survival based on Kaplan-Meier statistics in combination log-rank tests were used to address potential effects of the patient and tumor characteristics versus 5-year survival rate. The relative high: low expression of all four proteins in the two cohorts differed, and particularly ERK was markedly overexpressed in the SCC versus the CIS cohort (odds ratio = 45.3, p < .01). The relative high: low expression each protein versus patient and tumor characteristics; showed associations between AKT expression and T stage (p = .002) plus node metastases (p = .12), and between ERK expression and drinking (p = .01) and smoking history (p = .01). There was no significant difference observed between ERK and the three other molecules, nor any significant difference between the degree of expression of each protein and the 5-year disease-specific survival rate. Ezrin, ERK, STAT3, and AKT appear to be involved in the progress from carcinoma in situ in the tongue into squamous cell carcinoma. ERK in particular is overexpressed, suggesting that ERK may be a novel therapeutic target for preventing tongue cancer

Hearing Loss Controlled by Optogenetic Stimulation of Nonexcitable Nonglial Cells in the Cochlea of the Inner Ear

Light-gated ion channels and transporters have been applied to a broad array of excitable cells including neurons, cardiac myocytes, skeletal muscle cells and pancreatic β-cells in an organism to clarify their physiological and pathological roles. Nonetheless, among nonexcitable cells, only glial cells have been studied in vivo by this approach. Here, by optogenetic stimulation of a different nonexcitable cell type in the cochlea of the inner ear, we induce and control hearing loss. To our knowledge, deafness animal models using optogenetics have not yet been established. Analysis of transgenic mice expressing channelrhodopsin-2 (ChR2) induced by an oligodendrocyte-specific promoter identified this channel in nonglial cells—melanocytes—of an epithelial-like tissue in the cochlea. The membrane potential of these cells underlies a highly positive potential in a K+-rich extracellular solution, endolymph; this electrical property is essential for hearing. Illumination of the cochlea to activate ChR2 and depolarize the melanocytes significantly impaired hearing within a few minutes, accompanied by a reduction in the endolymphatic potential. After cessation of the illumination, the hearing thresholds and potential returned to baseline during several minutes. These responses were replicable multiple times. ChR2 was also expressed in cochlear glial cells surrounding the neuronal components, but slight neural activation caused by the optical stimulation was unlikely to be involved in the hearing impairment. The acute-onset, reversible and repeatable phenotype, which is inaccessible to conventional gene-targeting and pharmacological approaches, seems to at least partially resemble the symptom in a population of patients with sensorineural hearing loss. Taken together, this mouse line may not only broaden applications of optogenetics but also contribute to the progress of translational research on deafness