Comparing Immuno-oncology Combination Therapy With Tyrosine Kinase Inhibitor Monotherapy for Advanced Renal Cell Carcinoma.

Background/aim: Immuno-oncology (IO) improves the prognosis of advanced renal cell carcinoma (RCC). Since research has so far been limited to clinical trials, we herein focused on the effects of IO-tyrosine kinase inhibitor (TKI) combination therapy in real-world clinical settings.

Patients And Methods: We conducted a retrospective study on 125 patients with advanced RCC who received IO-TKI combination therapy or TKI monotherapy.

Effect of acetic acid inactivation of SARS-CoV-2.

Effective measures are needed to prevent the spread and infectivity of SARS-CoV-2 that causes COVID-19. Chemical inactivation may help to prevent the spread and transmission of this and other viruses. Hence, we tested the SARS-CoV-2 antiviral activity of acetic acid, the main component of vinegar, in vitro.

Yellow Pea Pasta Enhances the Saltiness and Suppression of Postprandial Blood Glucose Elevation.

Salt and carbohydrates, two causes of elevated blood glucose, are essential components for survival; however, excessive intake of either is a known health risk. In a previous study, we reported the usefulness of pasta prepared from yellow pea (YPP) as a functional staple food that is beneficial for blood sugar control. In this study, we investigated the usefulness of YPP in reducing health risks by examining its effects on saltiness, postprandial satisfaction, and second meal.

Safety Evaluation of the Excessive Intake of Ceramide-Containing Acetic Acid Bacteria - A Randomized, Double-Blind, Placebo-Controlled Study Over a 4-week Period.

Ceramide plays an important role in maintaining the skin barrier function. Aging and atopic dermatitis are known to reduce the levels of ceramide. Application of exogenous ceramide to the skin can restore the barrier function.

Safety and Efficacy of Oral Intake of Ceramide-Containing Acetic Acid Bacteria for Improving the Stratum Corneum Hydration: A Randomized, Double-Blind, Placebo-Controlled Study over 12 Weeks.

The barrier function of the skin protects it from external stresses to which it is constantly exposed, such as dryness, ultraviolet rays, and chemicals. Lipids, in particular a type of sphingolipid known as ceramides, play a central role in the barrier function of the skin by preventing dryness. The number of ceramides in the skin is known to decrease with age, which has led to the development of a large number of anti-aging cosmetic products that contain ceramides.

Structural instability of IκB kinase β promotes autophagic degradation through enhancement of Keap1 binding.

IKKβ, an essential kinase of NF-κB signaling, is composed of an N-terminal kinase domain (KD) and a C-terminal scaffolding domain, containing a ubiquitin-like domain (ULD). The Hsp90 chaperon has special responsibility for folding of protein kinases including IKKβ. Here, we found that Hsp90 inhibition induced IKKβ degradation, which is partially mediated by Keap1.

Ripply3 is required for the maintenance of epithelial sheets in the morphogenesis of pharyngeal pouches.

During tissue development, the morphogenesis of epithelial sheets is regulated by many factors, including mechanical force, although the underlying mechanisms remain largely unknown. In the pharyngeal region of the vertebrate embryo, endodermal epithelium is reiteratively folded outward to form pharyngeal pouches, making partitions between the pharyngeal arches. Ripply3, encoding a member of the Ripply family of adaptor proteins, is required for the pouch formation posterior to the 2nd pharyngeal pouch.

Distinct B subunits of PP2A regulate the NF-κB signalling pathway through dephosphorylation of IKKβ, IκBα and RelA.

PP2A is composed of a scaffolding subunit (A), a catalytic subunit (C) and a regulatory subunit (B) that is classified into four families including B, B', B'' and B'''/striatin. Here, we found that a distinct PP2A complex regulates NF-κB signalling by dephosphorylation of IKKβ, IκBα and RelA/p65. The PP2A core enzyme AC dimer and the holoenzyme AB'''C trimer dephosphorylate IKKβ, IκBα and RelA, whereas the ABC trimer dephosphorylates IκBα but not IKKβ and RelA in cells.

Tumour resistance in induced pluripotent stem cells derived from naked mole-rats.

The naked mole-rat (NMR, Heterocephalus glaber), which is the longest-lived rodent species, exhibits extraordinary resistance to cancer. Here we report that NMR somatic cells exhibit a unique tumour-suppressor response to reprogramming induction. In this study, we generate NMR-induced pluripotent stem cells (NMR-iPSCs) and find that NMR-iPSCs do not exhibit teratoma-forming tumorigenicity due to the species-specific activation of tumour-suppressor alternative reading frame (ARF) and a disruption mutation of the oncogene ES cell-expressed Ras (ERAS).

LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a disorder characterized by hepatic lipid accumulation followed by the inflammation-induced death of hepatocytes and fibrosis. In this process, oxidative stress contributes to the induction of several inflammatory cytokines including TNF-α andIL-1β in macrophages, while, in hepatocytes, NF-κB reportedly induces the expressions of cell survival genes for protection from apoptosis. Recently, it was reported that the new ubiquitin ligase complex termed linear ubiquitin chain assembly complex (LUBAC), composed of SHARPIN (SHANK-associated RH domain-interacting protein), HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1), and HOIP (HOIL-1L interacting protein), forms linear ubiquitin on NF-κB essential modulator (NEMO) and thereby induces NF-κB pathway activation.

Pin1 Inhibitor Juglone Exerts Anti-Oncogenic Effects on LNCaP and DU145 Cells despite the Patterns of Gene Regulation by Pin1 Differing between These Cell Lines.

Background: Prostate cancer initially develops in an androgen-dependent manner but, during its progression, transitions to being androgen-independent in the advanced stage. Pin1, one of the peptidyl-prolyl cis/trans isomerases, is reportedly overexpressed in prostate cancers and is considered to contribute to accelerated cell growth, which may be one of the major factors contributing to their androgen-independent growth. Thus, we investigated how Pin1 modulates the gene expressions in both androgen-dependent and androgen-independent prostate cancer cell lines using microarray analysis.

DPP-IV inhibitor anagliptin exerts anti-inflammatory effects on macrophages, adipocytes, and mouse livers by suppressing NF-κB activation.

Dipeptidyl peptidase IV (DPP-IV) expression in visceral adipose tissue is reportedly increased in obese patients, suggesting an association of DPP-IV with inflammation. In this study, first, lipopolysaccharide (LPS)- or palmitate-induced elevations of inflammatory cytokine mRNA expressions in RAW264.7 macrophages were shown to be significantly suppressed by coincubation with a DPP-IV inhibitor, anagliptin (10 μM), despite low DPP-IV expression in the RAW264.

Par14 protein associates with insulin receptor substrate 1 (IRS-1), thereby enhancing insulin-induced IRS-1 phosphorylation and metabolic actions.

Pin1 and Par14 are parvulin-type peptidyl-prolyl cis/trans isomerases. Although numerous proteins have been identified as Pin1 substrates, the target proteins of Par14 remain largely unknown. Par14 expression levels are increased in the livers and embryonic fibroblasts of Pin1 KO mice, suggesting a compensatory relationship between the functions of Pin1 and Par14.

Integrator complex plays an essential role in adipose differentiation.

The dynamic process of adipose differentiation involves stepwise expressions of transcription factors and proteins specific to the mature fat cell phenotype. In this study, it was revealed that expression levels of IntS6 and IntS11, subunits of the Integrator complex, were increased in 3T3-L1 cells in the period when the cells reached confluence and differentiated into adipocytes, while being reduced to basal levels after the completion of differentiation. Suppression of IntS6 or IntS11 expression using siRNAs in 3T3-L1 preadipocytes markedly inhibited differentiation into mature adipocytes, based on morphological findings as well as mRNA analysis of adipocyte-specific genes such as Glut4, perilipin and Fabp4.

Role of Pin1 protein in the pathogenesis of nonalcoholic steatohepatitis in a rodent model.

Nonalcoholic steatohepatitis (NASH) is a disorder characterized by simultaneous fat accumulation and chronic inflammation in the liver. In this study, Pin1 expression was revealed to be markedly increased in the livers of mice with methionine choline-deficient (MCD) diet-induced NASH, a rodent model of NASH. In addition, Pin1 KO mice were highly resistant to MCD-induced NASH, based on a series of data showing simultaneous fat accumulation, chronic inflammation, and fibrosis in the liver.

IL-1 receptor antagonist blocks the lipopolysaccharide-induced inhibition of gastric motility in freely moving conscious rats.

Background And Aims: Endotoxin/lipopolysaccharide (LPS) alters gastrointestinal functions. However, little is known as to whether LPS could change gastric antral contractility in freely moving conscious animals. We tried to clarify this problem and the associated mechanisms.

Antihypertensive efficacy of the losartan/hydrochlorothiazide combination and its effect on plasma B-type natriuretic peptide in hypertensive patients uncontrolled by angiotensin II type 1 receptor antagonist-based therapy: a multicentre prospective observational study.

Background And Objectives: Although strict blood pressure (BP) control is effective in the prevention of cardiovascular events, it is often insufficient in many hypertensive patients. B-type natriuretic peptide (BNP) has been shown to be associated with cardiovascular events. We investigated the effects of the losartan/hydrochlorothiazide combination on BP and plasma BNP in hypertensive patients uncontrolled by an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB])-based therapy.

Valsartan, independently of AT1 receptor or PPARγ, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes.

Macrophages are integrated into adipose tissues and interact with adipocytes in obese subjects, thereby exacerbating adipose insulin resistance. This study aimed to elucidate the molecular mechanism underlying the insulin-sensitizing effect of the angiotensin II receptor blocker (ARB) valsartan, as demonstrated in clinical studies. Insulin signaling, i.

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 associates with insulin receptor substrate-1 and enhances insulin actions and adipogenesis.

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is a unique enzyme that associates with the pSer/Thr-Pro motif and catalyzes cis-trans isomerization. We identified Pin1 in the immunoprecipitates of overexpressed IRS-1 with myc and FLAG tags in mouse livers and confirmed the association between IRS-1 and Pin1 by not only overexpression experiments but also endogenously in the mouse liver. The analysis using deletion- and point-mutated Pin1 and IRS-1 constructs revealed the WW domain located in the N terminus of Pin1 and Ser-434 in the SAIN (Shc and IRS-1 NPXY binding) domain of IRS-1 to be involved in their association.

Impact of glycemic control on the clinical outcome in diabetic patients with percutaneous coronary intervention--from the FU-registry.

Background: It is not yet clear whether glycemic control affects the clinical outcome of percutaneous coronary intervention (PCI) in diabetic patients.

Methods And Results: This study compared the effects of glycemic control on the clinical outcome in 2 groups of patients with diabetes mellitus (DM) who underwent PCI: a poor-glycemic-control group, who showed greater than 6.9% HbA(1c) at the time of PCI (Pre-HbA(1c)) (`≥6.

4F2hc stabilizes GLUT1 protein and increases glucose transport activity.

Glucose transporter 1 (GLUT1) is widely distributed throughout various tissues and contributes to insulin-independent basal glucose uptake. Using a split-ubiquitin membrane yeast two-hybrid system, we newly identified 4F2 heavy chain (4F2hc) as a membrane protein interacting with GLUT1. Though 4F2hc reportedly forms heterodimeric complexes between amino acid transporters, such as LAT1 and LAT2, and regulates amino acid uptake, we investigated the effects of 4F2hc on GLUT1 expression and the associated glucose uptake.

Angiographic late lumen loss at the site of overlap of multiple Cypherâ„¢ sirolimus-eluting stents: ALSOCE study.

Objectives: It has been reported that the overlap of sirolimus-eluting stents (SESs) is associated with greater in-stent late lumen loss and more angiographic restenosis. The purpose of this study was to evaluate whether the site of such overlap shows increased or decreased late lumen loss as assessed by quantitative coronary angiogram.

Methods And Results: We compared 7-month angiographic late lumen loss at the site of overlap in patients with multiple overlapping stents (overlap SES group, n=48) to that in patients with single stents (single SES group, n=144).