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Abstract Background Carfilzomib is a selective proteasome inhibitor approved for treating relapsed or refractory multiple myeloma (RRMM). Carfilzomib improves overall survival (OS) and progression‐free survival (PFS); however, treatment with carfilzomib results in a higher incidence of cardiovascular and renal toxicity. More than 70% of patients with RRMM in clinical practice do not meet the eligibility criteria for randomized clinical trials (RCT). OS and PFS are negatively influenced by complications, concomitant medications and prior treatments. Therefore, we assessed the risk factors influencing the OS and time to next treatment (TTNT) in the real world. TTNT has emerged as a relevant alternative clinical endpoint to PFS. Methods A retrospective analysis of a large claims database prepared during the post‐marketing stages in Japan was performed. The patients treated with carfilzomib for the first time were identified. Multivariable Cox proportional hazards regression analysis was performed to evaluate the risk factors influencing OS and TTNT following carfilzomib treatment. Results A total of 732 patients with RRMM who received carfilzomib‐containing chemotherapy between April 2014 and September 2021 were identified. Multivariable Cox regression analysis for OS and TTNT showed a significantly higher hazard ratio (HR) of 1.48 (95% confidence interval [Cl]: 1.10–2.00; p = 0.010) and 1.38 (95% Cl: 1.15–1.65; p

Background: Nearly half of patients with heart failure (HF) have preserved ejection fraction (EF) and the mortality and morbidity of patients with HF with preserved EF (HFpEF) are high. Patients with HFpEF are often elderly and their primary chronic symptom is severe exercise intolerance that results in a reduced quality of life. Thus, improvement of exercise capacity and quality of life presents another important clinical outcome in HFpEF patients. Recent randomized controlled trials (RCTs) and meta-analyses of RCTs reported that sodium–glucose cotransporter 2 (SGLT-2) inhibitors improved cardiovascular (CV) outcomes in patients with HF with reduced EF. Although the effects of SGLT-2 inhibitors in HFpEF patients have been examined in multiple RCTs, results are inconsistent due partly to limited power. We aimed to conduct a meta-analysis of RCTs on the effects of SGLT-2 inhibitors in HFpEF patients. Methods and Results: The search of electronic databases identified 11 RCTs including 10,845 patients. In pooled analyses, SGLT-2 inhibitors reduced the risk of a composite of hospitalization for HF and CV death (hazard ratio [95 % CI] = 0.78 [0.70, 0.87], Pfix

BackgroundAnemia is common in heart failure (HF) patients with chronic kidney disease (CKD) and is associated with worse outcomes. Iron supplementation improves symptoms and is associated with reduced risk of hospitalization for HF in iron-deficiency HF patients. However, iron deficiency is present in MethodsThis meta-analysis will include prospective cohort studies and randomized controlled trials on the effect of HIF-PH inhibitors compared with ESAs in anemic HF patients with CKD. Information of studies will be collected from PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov. The primary outcome will be cardiovascular death. The secondary outcomes will be all-cause death, hospitalization for HF, HF symptoms, exercise capacity, health-related quality of life, and hemoglobin levels.DiscussionThis meta-analysis will evaluate the effect of HIF-PH inhibitors in anemic HF patients with CKD, providing evidence regarding the use of HIF-PH inhibitors in these patients.Systematic review registrationINPLASY202230103.

The survival rate of cardiac arrest patients is less than 10%; therefore, development of a therapeutic strategy that improves their prognosis is necessary. Herein, we searched data collected from medical facilities throughout Japan for drugs that improve the survival rate of cardiac arrest patients. Candidate drugs, which could improve the prognosis of cardiac arrest patients, were extracted using “TargetMine,” a drug discovery tool. We investigated whether the candidate drugs were among the drugs administered within 1 month after cardiac arrest in data of cardiac arrest cases obtained from the Japan Medical Data Center. Logistic regression analysis was performed, with the explanatory variables being the presence or absence of the administration of those candidate drugs that were administered to ≥10 patients and the objective variable being the “survival discharge.” Adjusted odds ratios for survival discharge were calculated using propensity scores for drugs that significantly improved the proportion of survival discharge; the influence of covariates, such as patient background, medical history, and treatment factors, was excluded by the inverse probability-of-treatment weighted method. Using the search strategy, we extracted 165 drugs with vasodilator activity as candidate drugs. Drugs not approved in Japan, oral medicines, and external medicines were excluded. Then, we investigated whether the candidate drugs were administered to the 2,227 cardiac arrest patients included in this study. The results of the logistic regression analysis showed that three (isosorbide dinitrate, nitroglycerin, and nicardipine) of seven drugs that were administered to ≥10 patients showed significant association with improvement in the proportion of survival discharge. Further analyses using propensity scores revealed that the adjusted odds ratios for survival discharge for patients administered isosorbide dinitrate, nitroglycerin, and nicardipine were 3.35, 5.44, and 4.58, respectively. Thus, it can be suggested that isosorbide dinitrate, nitroglycerin, and nicardipine could be novel therapeutic agents for improving the prognosis of cardiac arrest patients.

Aquaporin 9 (AQP9) is a member of the aquaglyceroporin family that transports glycerol, urea and other small solutes as well as water. Compared to the expression and function in epidermal keratinocytes of AQP3, another aquaglyceroporin, our knowledge of epidermal AQP9 remains elusive. In this study, we investigated the expression of AQP9 in the human epidermis and cultured keratinocytes. Immunofluorescence studies revealed that AQP9 expression is highly restricted to the stratum granulosum of the human epidermis, where occludin is also expressed at the tight junctions. Interestingly, the AQP3 staining decreased sharply below the cell layers in which AQP9 is expressed. In cultured normal human epidermal keratinocytes (NHEK), knock-down of AQP9 expression in the differentiated cells induced by RNA interference reduced glycerol uptake, which was not as pronounced as was the case with AQP3 knock-down cells. In contrast, similar reduction of urea uptake was detected in AQP9 and AQP3 knock-down cells. These findings suggested that AQP9 expression in NHEK facilitates at least the transport of glycerol and urea. Finally, we analyzed the effect of retinoic acid (RA), a potent stimulator of keratinocyte proliferation, on AQP3 and AQP9 mRNA expression in differentiated NHEK. Stimulation with RA at 1 μM for 24 h augmented AQP3 expression and down-regulated AQP9 expression. Collectively, these results indicate that AQP9 expression in epidermal keratinocytes is regulated in a different manner from that of AQP3.

We have reported that connexin (Cx) 32 acts as a tumor suppressor gene in renal cancer cells partly due to Her-2 inactivation. Here, we determined if a Her-2/Her-1 inhibitor (PKI-166) can enhance the tumor-suppressive effect of Cx32 in Caki-2 cells from human renal cell carcinoma. The expression of Cx32 in Caki-2 cells was required for PKI-166-induced cytotoxic effect at lower doses. The cyctotoxicity was dependent on the occurrence of apoptosis and partly mediated by Cx32-driven gap junction intercellular communications. These results suggest that PKI-166 further supports the tumor-suppressive effect of the Cx32 gene in renal cancer cells through the induction of apoptosis. Keywords:: connexin 32, PKI-166, renal cancer cell

The presence of atrial natriuretic peptide (ANP) in chondrocytes and parenchymal cells of eel gills is revealed by using homologous eel ligands. The chondrocytes reveal natriuretic peptide receptor (NPR-C) receptors at high levels which are unconnected to the circulatory system. The ANP receptor is limited in the chondrocytes to reveal the importance of NPR-C as a physiological feature, due to the lack of blood vessels in the chondrocyte.

Objective: The aim of this study was to investigate the anti-obesity effects of the polyphenol fisetin in 3T3-L1 preadipocytes and C57BL/6 female mice that were fed a high-fat diet (HFD). Background: Polyphenols, such as sakuranetin, hesperetin, tea catechin, and quercetin, reportedly regulate adipocyte differentiation in 3T3-L1 cells. Furthermore, green tea, apple, and molokheiya polyphenols exhibit anti-obesity activities in HFD-treated obese rats or mice. Fisetin is abundant in plants, fruits, and vegetables and exhibits multiple biological activities, such as the inhibition of prostate cancer growth, neuroprotection, and protection against osteoporosis. In addition, fisetin regulates obesity by targeting mammalian target of rapamycin complex 1 signaling, which is a central mediator of lipid biosynthesis. Materials and methods: (1) in vitro experiments; we investigated the effects of fisetin on intracellular lipid accumulation and glycerol-3-phosphate activity during the differentiation of 3T3-L1 cells. We monitored expression of adipogenetic related-genes in 3T3-L1 cells by real-time polymerase-chain-reaction. (2) in vivo experiments; we examined the effects of fisetin on anti-obesity activities in C57BL/6 female mice that were fed a HFD. Results: Fisetin inhibited intracellular lipid accumulation and glycerol-3-phosphate activity during the differentiation of 3T3-L1 cells in a dose-dependent manner (50-75 μM). In addition, real-time polymerase-chain-reaction revealed that this compound suppressed the expression of peroxisome proliferator-activated receptor γ (PPARγ), adipocyte protein 2, and perilipin mRNAs in 3T3-L1 cells. In contrast, anti-obesity activities, such as reduction of body weight and fat tissue, and improvements in obesity-related blood biochemical parameters and fatty liver, were not observed in HFD-induced mice treated with fisetin (20 mg/kg body weight) by intraperitoneal injections twice per week for 8 weeks. Conclusions: Fisetin exerted anti-adipogenic activities by inhibiting the expression of PPARγ mRNA in 3T3-L1 preadipocytes. However, fisetin (20 mg/kg body weight) did not affect HFD-induced obesity. Our findings indicated that fisetin could be used as an effective remedy in the treatment of the symptoms of obesity. [ABSTRACT FROM AUTHOR]

The effect of subchronic exposure of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), an active metabolite of trichloroethylene (TCE), was investigated in mice, as a part of mechanistic assessment of renal toxicity of TCE. To examine the subchronic effects of DCVC on kidney function, Balb/c male mice were administered DCVC orally and intraperitoneally once a week for 13 weeks at 1, 10 and 30 mg/kg (Main Study) and for 8 weeks at 30 mg/kg (PCR Study). At the terminal sacrifice, mice orally and intraperitoneally administered with 10 and 30 mg/kg showed significantly lower kidney weight and signifi- cantly higher blood urea nitrogen levels than the control group. Pathological examination revealed that a dose of 30 mg/kg delivered by both routes resulted in renal tubular degeneration characterized by tubular necrosis and interstitial fibrosis, and in degradation of the cortex. Degenerative changes were accompanied by the increased expression of tumor necrosis factor-α, interleukin-6 and cyclooxygenase-2 mRNAs in the kidney of mice treated with 30 mg/kg for 8 weeks. These pathohistological observations mostly corresponded to those in short-term toxicity studies on DCVC. DCVC might be a direct cause of renal toxicity, which is suggested from the aggravation in these symptoms with the dose increase. [ABSTRACT FROM AUTHOR]