Selective inhibition of HDAC6 promotes bladder cancer radiosensitization and mitigates the radiation-induced CXCL1 signalling.

Background: Although trimodality therapy resecting tumours followed by chemoradiotherapy is emerged for muscle-invasive bladder cancer (MIBC), chemotherapy produces toxicities. Histone deacetylase inhibitors have been identified as an effective strategy to enhance cancer radiotherapy (RT).

Methods: We examined the role of HDAC6 and specific inhibition of HDAC6 on BC radiosensitivity by performing transcriptomic analysis and mechanism study.

Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts.

The tumorous niche may drive the plasticity of heterogeneity and cancer stemness, leading to drug resistance and metastasis, which is the main reason of treatment failure in most cancer patients. The aim of this study was to establish a tumor microenvironment (TME)-based screening to identify drugs that can specifically target cancer stem cells (CSCs) and cancer-associated fibroblasts (CAFs) in the TME. Lung cancer patient-derived cancer cell and CAFs were utilized to mimic the TME and reproduce the stemness properties of CSCs and develop a high-throughput drug screening platform with phenotypical parameters.

DNA methylome and transcriptome landscapes of cancer-associated fibroblasts reveal a smoking-associated malignancy index.

Unlike the better-studied aberrant epigenome in the tumor, the clinicopathologic impact of DNA methylation in the tumor microenvironment (TME), especially the contribution from cancer-associated fibroblasts (CAFs), remains elusive. CAFs exhibit profound patient-to-patient tumorigenic heterogeneity. We asked whether such heterogeneity may be exploited to quantify the level of TME malignancy.

Landscape of Mitochondria Genome and Clinical Outcomes in Stage 1 Lung Adenocarcinoma.

Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and their associations with cancer development and progression are not yet clearly characterized.

Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity.

The type 2 transmembrane serine protease matriptase is involved in many pathophysiological processes probably via its enzymatic activity, which depends on the dynamic relationship between zymogen activation and protease inhibition. Matriptase shedding can prolong the life of enzymatically active matriptase and increase accessibility to substrates. We show here that matriptase shedding occurs via a de novo proteolytic cleavage at sites located between the SEA domain and the CUB domain.

Circulating MicroRNA-125b Predicts the Presence and Progression of Uremic Vascular Calcification.

Objective: Vascular calcification (VC) is a major cause of mortality in patients with end-stage renal diseases. Biomarkers to predict the progression of VC early are in urgent demand.

Approach And Results: We identified circulating, cell-free microRNAs as potential biomarkers using in vitro VC models in which both rat and human aortic vascular smooth muscle cells were treated with high levels of phosphate to mimic uremic hyperphosphatemia.

A panel of three markers hyper- and hypomethylated in urine sediments accurately predicts bladder cancer recurrence.

Purpose: The high risk of recurrence after transurethral resection of bladder tumor of nonmuscle invasive disease requires lifelong treatment and surveillance. Changes in DNA methylation are chemically stable, occur early during tumorigenesis, and can be quantified in bladder tumors and in cells shed into the urine. Some urine markers have been used to help detect bladder tumors; however, their use in longitudinal tumor recurrence surveillance has yet to be established.

Reprogramming of the human intestinal epigenome by surgical tissue transposition.

Extracellular cues play critical roles in the establishment of the epigenome during development and may also contribute to epigenetic perturbations found in disease states. The direct role of the local tissue environment on the post-development human epigenome, however, remains unclear due to limitations in studies of human subjects. Here, we use an isogenic human ileal neobladder surgical model and compare global DNA methylation levels of intestinal epithelial cells pre- and post-neobladder construction using the Infinium HumanMethylation450 BeadChip.

Single- and multiple-dose study to determine the safety, tolerability, and pharmacokinetics of ceftaroline fosamil in combination with avibactam in healthy subjects.

This study was conducted to determine the safety, tolerability, and pharmacokinetics of intravenous doses of ceftaroline fosamil administered in combination with the novel non-β-lactam β-lactamase inhibitor avibactam in healthy adults. In the single-dose, open-label arm, 12 subjects received single 1-h intravenous infusions of ceftaroline fosamil alone (600 mg), avibactam alone (600 mg), and ceftaroline fosamil in combination with avibactam (600/600 mg) separated by 5-day washout periods. In the multiple-dose, placebo-controlled, double-blind arm, 48 subjects received intravenous infusions of ceftaroline fosamil/avibactam at 600/600 mg every 12 h (q12h), 400/400 mg q8h, 900/900 mg q12h, 600/600 mg q8h, or placebo for 10 days.

DNA methylation screening identifies driver epigenetic events of cancer cell survival.

Cancer cells typically exhibit aberrant DNA methylation patterns that can drive malignant transformation. Whether cancer cells are dependent on these abnormal epigenetic modifications remains elusive. We used experimental and bioinformatic approaches to unveil genomic regions that require DNA methylation for survival of cancer cells.

Curcumin inhibits lung cancer cell invasion and metastasis through the tumor suppressor HLJ1.

Curcumin (diferuloylmethane) is an active component of the spice turmeric and has a diversity of antitumor activities. In this study, we found that curcumin can inhibit cancer cell invasion and metastasis through activation of the tumor suppressor DnaJ-like heat shock protein 40 (HLJ1). Human lung adenocarcinoma cells (CL1-5) treated with curcumin (1-20 mumol/L) showed a concentration-dependent reduction in cell migration, invasion, and metastatic ability, and this was associated with increased HLJ1 expression.

Systemic exposure and urinary cortisol effects of fluticasone propionate formulated with hydrofluoroalkane in 4- to 11-year-olds with asthma.

The systemic exposure of fluticasone propionate with hydrofluoroalkane propellant compared with chlorofluoro-carbon propellant and the effect of fluticasone propionate hydrofluoroalkane on 24-hour urinary cortisol in children aged 4 to 11 years with asthma were evaluated. Study 1 was an open-label, 2-way crossover study in which 16 subjects were randomized to 7.5 days each of fluticasone propionate hydrofluoroalkane 88 mug twice a day or fluticasone propionate chlorofluorocarbon 88 mug twice a day.

Zymogen activation, inhibition, and ectodomain shedding of matriptase.

Matriptase is a member of an expanding group of type II transmembrane serine proteases. Recently, much has been learned about the biochemistry, cellular biology, normal tissue physiology, and human pathology of this protease, and of its inhibitor, termed the hepatocyte growth factor inhibitor-1 (HAI-1). This review examines the recent literature that has characterized the regulation of matriptase and HAI-1 with an emphasis on the molecular mechanisms governing its zymogen activation, inhibition by HAI-1, and ectodomain shedding.

Titanium dioxide nanoparticles induce emphysema-like lung injury in mice.

Titanium dioxide nanoparticles (nanoTiO2) have been widely used as a photocatalyst in air and water cleaning. However, these nanoparticles inhalation can induce pulmonary toxicity and its mechanism is not fully understood. In this study we investigated the pulmonary toxicity of nanoTiO2 and its molecular pathogenesis.

In vitro and in vivo comparison of two diclofenac sodium sustained release oral formulations.

The aim of this study was to investigate the effect of formulation on the pharmacokinetics of diclofenac in two sustained release formulations (formulation A and Voltaren SR) after oral delivery. The dissolution of diclofenac from sustained release formulation was pH-dependent. While drug released from both formulations increased with increased pH, the release kinetics of these two formulations was different.

Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats.

Cyclosporin, an immunosuppressant with a narrow therapeutic window, is a substrate for both CYP3A4 and P-glycoprotein (Pgp). Quercetin is an inhibitor of CYP3A4 and a modulator of Pgp. This study aimed to measure the effect of quercetin on the absorption and disposition of cyclosporin in pigs and rats.

Possible degradative process of cholecystokinin analogs in rabbit jejunum brush-border membrane vesicles.

Our recent work on the intestinal metabolism and absorption of cholecystokinin analogs, sulfated C-terminal octapeptide (CCK8; Asp-Tyr(SO(3)H)-Met-Gly-Trp-Met-Asp-Phe(NH(2)) = DY(SO(3)H)MGWMDF(NH(2))) and tetrapeptide (CCK4; Trp-Met-Asp-Phe(NH(2)) = WMDF(NH(2))), was extended to investigate the degradative process of these analogs using rabbit jejunum brush-border membrane vesicles and to find a better enzyme-inhibitor system for intestinal absorption of peptide drugs. Various enzyme inhibitors and a lower pH buffer were applied to discover the major enzyme(s) involved in each process. Metabolic pathways showing degradative processes were proposed for both analogs.

Effects of distension of urinary bladder on coronary conduit and resistance vessels in hyperlipidemic patients.

Background: Distension of the urinary bladder reflexly causes a change of coronary vasomotor response. The effect of such distension on the coronary circulation in hyperlipidemic patients, a condition with impaired endothelial function, remains unknown.

Hypothesis: We tested the hypothesis whether urinary bladder distension caused an exaggerated vasomotor response of epicardial and resistance vasoconstriction in hyperlipidemic patients.

Effect of pravastatin on proteinuria in patients with well-controlled hypertension.

Proteinuria is an important risk factor for cardiovascular and renal morbidity and mortality. The effects of 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitor (statin) therapy on proteinuria in normolipidemic patients with well-controlled hypertension have not been studied. A total of 63 normolipidemic (total cholesterol <240 mg/dL) and proteinuric (300 to 3000 mg/d) patients with well-controlled blood pressure (<140/90 mm Hg) were randomized to receive either placebo (n=32) or pravastatin (10 mg/d; n=31) after a 3-month placebo period.

Intestinal metabolism and absorption of cholecystokinin analogs in rats.

Intestinal metabolism and poor permeability were known to be major barriers for oral absorption of large peptide drugs. Dimensionless wall permeability values of C-terminal octa- and tetra-peptides cholecystokinin analogs (CCK8 and CCK4) were estimated and found out to be greater than 1, suggesting no permeability-limited absorption for CCK analogs. Thus, a strategy employing enzyme inhibitors and a specific delivery site to improve the absorption was developed and tested with CCK8, followed by identification of metabolites of the analogs and their participating enzymes in rabbit brush-border membrane vesicles.

Differential effects of sarcolemmal and mitochondrial K(ATP) channels activated by 17 beta-estradiol on reperfusion arrhythmias and infarct sizes in canine hearts.

We have demonstrated the effects of estrogen on modulation of ATP-sensitive K(+) channels; however, the subcellular location of these channels is unknown. The purpose of the present study was to investigate the role of the sarcolemmal and mitochondrial ATP-sensitive K(+) channels in a canine model of myocardial infarction after stimulation with 17 beta-estradiol. Anesthetized dogs were subjected to 60 min of the left anterior descending coronary artery occlusion followed by 3 h of reperfusion.