Importance of AST-120 (Kremezin®) Adherence in a Chronic Kidney Disease Patient with Diabetes

We report herein an adult case of chronic kidney disease (CKD) associated with diabetes. The patient had been treated with insulin injection for diabetes 10 years ago. At the time of his first visit to our division for further examinations, we diagnosed him as CKD: cause (C) diabetes; glomerular filtration rate (GFR) (G) G5 (estimated [e] GFR, 10.2 mL/min/1.73 m2; serum creatinine of 4.90 mg/dL); and albuminuria (A) A3 (2.62 g/gCr) by the Japanese Society of Nephrology (JSN) CGA classification. Because he had complained of severe constipation and kidney function, i.e., eGFR was not improved by previous medications, we added on a minimal dosage (2 g/day) of AST-120 (Kremezin®; ordinary dose 6 g/day). After 3 months of AST-120 therapy, eGFR was increased to 17.8 mL/min/1.73 m2 (serum creatinine of 2.90–2.72 mg/dL). Although the patient used some laxative products, he could not continue to take Kremezin and completely stopped 8 months after starting this drug. Kidney function then abruptly declined and progressed to end-stage kidney disease (ESKD). In June 2017, he was introduced to hemodialysis. It appears that the adherence of Kremezin is very important for inhibiting the progression to ESKD for patients with CKD with diabetes

A preclinical research platform to evaluate photosensitizers for transbronchial localization and phototherapy of lung cancer using an orthotopic mouse model

Background: Establishing the efficacy of novel photosensitizers (PSs) for phototherapy of lung cancer requires in vivo study prior to clinical evaluation. However, previously described animal models are not ideal for assessing transbronchial approaches with such PSs. Methods: An ultra-small parallel-type composite optical fiberscope (COF) with a 0.97 mm outer diameter tip. The integration of illumination and laser irradiation fibers inside the COF allows simultaneous white-light and fluorescence imaging, as well as real-time monitoring of tip position during laser phototherapy. An orthotopic lung cancer mouse model was created with three human lung cancer cell lines transbronchially inoculated into athymic nude mice. The COF was inserted transbronchially into a total of 15 mice for tumor observation. For in vivo fluorescence imaging, an organic nanoparticle, porphysome, was used as a PS. Laser excitation through the COF was performed at 50 mW using a 671 nm source. Results: The overall success rate for creating orthotopic lung tumors was 71%. Transbronchial white light images were successfully captured by COF. Access to the left main bronchus was successful in 87% of mice (13/15), the right main bronchus to the cranial lobe bronchus level in 100% (15/15), and to the right basal trifurcation of the middle lobe, caudal lobe and accessory lobe in 93% (14/15). For transbronchial tumor localization of orthotopic lung cancer tumors, PS-laden tumor with the strong signal was clearly contrasted from the normal bronchial wall. Conclusions: The ultra-small COF enabled reliable transbronchial access to orthotopic human lung cancer xenografts in vivo. This method could serve as a versatile preclinical research platform for PS evaluation in lung cancer, enabling transbronchial approaches in in vivo survival models inoculated with human lung cancer cells

Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-κB Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells

Multiple myeloma (MM) is an incurable malignancy often associated with primary and acquired resistance to therapeutic agents, such as proteasome inhibitors. However, the mechanisms underlying the proteasome inhibitor resistance are poorly understood. Here, we elucidate the mechanism of primary resistance to bortezomib and ixazomib in the MM cell lines, KMS-20, KMS-26, and KMS-28BM. We find that low bortezomib and ixazomib concentrations induce cell death in KMS-26 and KMS-28BM cells. However, high bortezomib and ixazomib concentrations induce cell death only in KMS-20 cells. During Gene Expression Omnibus analysis, KMS-20 cells exhibit high levels of expression of various genes, including anti-phospho-fibroblast growth factor receptor 1 (FGFR1), chemokine receptor type (CCR2), and serum and glucocorticoid regulated kinase (SGK)1. The SGK1 inhibitor enhances the cytotoxic effects of bortezomib and ixazomib; however, FGFR1 and CCR2 inhibitors do not show such effect in KMS-20 cells. Moreover, SGK1 activation induces the phosphorylation of NF-κB p65, and an NF-κB inhibitor enhances the sensitivity of KMS-20 cells to bortezomib and ixazomib. Additionally, high levels of expression of SGK1 and NF-κB p65 is associated with a low sensitivity to bortezomib and a poor prognosis in MM patients. These results indicate that the activation of the SGK1/NF-κB pathway correlates with a low sensitivity to bortezomib and ixazomib, and a combination of bortezomib and ixazomib with an SGK1 or NF-κB inhibitor may be involved in the treatment of MM via activation of the SGK1/NF-κB pathway

Pathophysiologic Contributions of Visceral Adiposity to Left Ventricular Diastolic Dysfunction

Background: Visceral fat produces inflammatory cytokines and may play a major role in heart failure with preserved ejection fraction (HFpEF). However, little data exist regarding how qualitative and quantitative abnormalities of visceral fat would contribute to left ventricular diastolic dysfunction (LVDD). Methods: We studied 77 participants who underwent open abdominal surgery for intra-abdominal tumors (LVDD, n = 44; controls without LVDD, n = 33). Visceral fat samples were obtained during the surgery, and mRNA levels of inflammatory cytokines were measured. Visceral and subcutaneous fat areas were measured using abdominal computed tomography. Results: Patients with significant LVDD had greater LV remodeling and worse LVDD than controls. While body weight, body mass index, and subcutaneous fat area were similar in patients with LVDD and controls, the visceral fat area was larger in patients with LVDD than in controls. The visceral fat area was correlated with BNP levels, LV mass index, mitral e′ velocity, and E/e′ ratio. There were no significant differences in the mRNA expressions of visceral adipose tissue cytokines (IL-2, -6, -8, and -1β, TNFα, CRP, TGFβ, IFNγ, leptin, and adiponectin) between the groups. Conclusions: Our data may suggest the pathophysiological contribution of visceral adiposity to LVDD