In vivo activation of PEGylated long circulating lipid nanoparticle to achieve efficient siRNA delivery and target gene knock down in solid tumors.

We developed a lipid nanoparticle formulation (LNPK15) to deliver siRNA to a tumor for target gene knock down. LNPK15 is highly PEGylated with 3.3% 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-(polyethylene glycol-2000) (PEG-DSPE) and shows a long duration: the half-lives of siRNA in LNPK15 were 15.

Meteorological effects on severe hemoptysis: A hospital-based observational study.

Background: Although some meteorological factor are likely to contribute to the onset of hemoptysis, few studies have investigated this issue, with none conducted in the Asia-Pacific region. Therefore, the present study aimed to evaluate the associations of meteorological factors with the occurrence of hemoptysis. Differences in the frequency of hemoptysis among several calendar variables were also assessed.

Accumulation of Liver Lipids Induced by Vitamin B Deficiency Was Effectively Ameliorated by Choline and, to a Lesser Extent, Betaine.

Despite previous studies suggesting that choline and betaine ameliorate lipid accumulation in rat livers, the relative effectiveness of the two nutrients is unclear. We examined the efficacy of dietary supplementation with choline or betaine in ameliorating lipid accumulation induced by vitamin B (B) deficiency in the rat liver. Male Wistar rats were fed control, B-deficient, choline-supplemented B-deficient, betaine-supplemented B-deficient, or both choline and betaine-supplemented B-deficient diets (all containing 9 g of l-methionine (Met)/kg) for 35 d.

A comparative study for detecting CYP3A induction by CYP3A probe drugs and endogenous markers in cynomolgus monkeys.

CYP3A probe drugs such as midazolam and endogenous markers, and plasma 4β-hydroxycholesterol (4β-OHC) and urinary 6β-hydroxycortisol-to-cortisol ratios (6β-OHC/C) have been used as markers of CYP3A induction in cynomolgus monkeys, as with humans. However, there is limited information on their sensitivity and ability to detect CYP3A induction, as most studies were evaluated only at a high dose of the inducer, rifampicin (RIF; 20 mg/kg). In the present study, the CYP3A induction by RIF over a range doses of 0.

Studies of CDK 8/19 inhibitors: Discovery of novel and selective CDK8/19 dual inhibitors and elimination of their CYP3A4 time-dependent inhibition potential.

In this article, synthetic studies around a pyridylacrylamide-based hit compound (1), utilizing structure-based drug design guided by CDK8 docking models, is discussed. Modification of the pendant 4-fluorophenyl group to various heteroaromatic rings was conducted aiming an interaction with the proximal amino acids, and then replacement of the morpholine ring was targeted for decreasing potential of time-dependent CYP3A4 inhibition. These efforts led to the compound 4k, with enhanced CDK8 inhibitory activity and no apparent potential for time-dependent CYP3A4 inhibition (CDK8 IC: 2.

Design and synthesis of selective CDK8/19 dual inhibitors: Discovery of 4,5-dihydrothieno[3',4':3,4]benzo[1,2-d]isothiazole derivatives.

To develop a novel series of CDK8/19 dual inhibitors, we employed structure-based drug design using docking models based on a library compound, 4,5-dihydroimidazolo[3',4':3,4]benzo[1,2-d]isothiazole 16 bound to CDK8. We designed various [5,6,5]-fused tricyclic scaffolds bearing a carboxamide group to maintain predicted interactions with the backbone CO and NH of Ala100 in the CDK8 kinase hinge region. We found that 4,5-dihydrothieno[3',4':3,4]benzo[1,2-d]isothiazole derivative 29a showed particularly potent enzymatic inhibitory activity in both CDK8/19 (CDK8 IC: 0.

Fibronectin adsorption on osteoconductive hydroxyapatite and non-osteoconductive α-alumina.

The osteoconductivity mechanism of hydroxyapatite (HAp) has not been elucidated. It is hypothesized that specific proteins adsorb on HAp, promoting its osteoconductivity. To verify this hypothesis, we compared the adsorption behavior of fibronectin (Fn) on HAp powder and on α-alumina (α-Al2O3) powder, a material with no osteoconductivity.

Checkpoint Kinase 1 Activation Enhances Intestinal Epithelial Barrier Function via Regulation of Claudin-5 Expression.

Several stressors are known to influence epithelial tight junction (TJ) integrity, but the association between DNA damage and TJ integrity remains unclear. Here we examined the effects of daunorubicin and rebeccamycin, two anti-tumor chemicals that induce DNA damage, on TJ integrity in human intestinal epithelial cells. Daunorubicin and rebeccamycin dose-dependently enhanced transepithelial electrical resistance (TER) and decreased flux of the 4 kDa FITC-dextran in Caco-2 cell monolayer.

IgE Abs to Der p 1 and Der p 2 as diagnostic markers of house dust mite allergy as defined by a bronchoprovocation test.

Background: Limited information is available regarding the clinical usefulness of measuring the levels of IgE to allergen components from house dust mites (HDMs) in the diagnosis of genuine HDM allergy.

Methods: To evaluate the diagnostic usefulness of measuring levels of serum IgE antibodies (Abs) to allergen components from Dermatophagoides pteronyssinus (DP) as a predictor of immediate asthmatic response (IAR) to bronchoprovocation, we studied 55 DP-sensitized asthmatic patients who underwent a bronchoprovocation test using crude DP extract. The levels of IgE Abs to crude DP, nDer p 1, rDer p 2, and rDer p 10 in patients who showed IAR (n = 41) were compared with those in patients who showed no IAR (n = 14).

[Comparison of exhaled nitric oxide levels measured by two offline methods and the NO breath® method in Japan].

Background: The fraction of exhaled nitric oxide (FeNO) is a useful marker of eosinophilic airway inflammation in asthmatics. Clinical application of FeNO measurement in Japan is expected increase because the procedure is now covered through health insurance. However, the measurement system used is known to affect FeNO results, and it remains unknown whether results from offline methods correlate with those from traditional online methods, such as NO breath®.

Effect of dalteparin, a low-molecular-weight heparin, as adjunctive therapy in patients with Kawasaki disease: a retrospective study.

Background: Dalteparin, a low-molecular-weight heparin, has anticoagulant and anti-angiogenic activity. This study investigated whether dalteparin reduced coronary artery lesion (CAL) prevalence, and resistance to intravenous immunoglobulin (IVIG) therapy in Kawasaki disease (KD).

Methods: This retrospective study comprised two parts.

Development of vascular smooth muscle contractility by endothelium-derived transforming growth factor β proteins.

It is well established that the release of vasodilators and vasoconstrictors from vascular endothelium regulates vascular smooth muscle contraction. In this report, we investigate the role of the endothelium in the development and maintenance of constitutive vascular contractility. For that purpose, contractile activity of cultured bovine aortic smooth muscle cells (BASMCs) embedded in collagen gels was monitored by changes in gel diameter.

Cough variant and cough-predominant asthma are major causes of persistent cough: a multicenter study in Japan.

Objective: Persistent cough is a frequent cause of doctor and hospital visits, and its incidence may be increasing. However, diagnosis of the cause of cough remains difficult. Because different causes of cough have different treatments, accurate diagnosis of the cause of cough is critical.

Age-specific characteristics of inpatients with severe asthma exacerbation.

Background: The characteristics of inpatients with severe asthma exacerbation remain unclear. It is considered that the characteristics of inpatients with severe asthma vary depending on age. However, these are rarely investigated.

Oxidative addition of a strained C-C bond onto electron-rich rhodium(I) at room temperature.

The C-C bond of cyclobutanones undergoes oxidative addition to a T-shape rhodium(I) complex possessing a PBP pincer ligand at room temperature. The remarkable propensity of the rhodium complex for oxidative addition is attributed to the highly electron-donating nature of the boron ligand as well as the unsaturation on the rhodium center.

Glycemic control after addition of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes showing inadequate response to thrice-a-day treatment with α-glucosidase inhibitors.

Objective: We investigated the effect of addition of alogliptin, while continuing the α-glucosidase inhibitor (αGI) administration at the same or reduced dose, or discontinuing the drug, on the glycemic control in type 2 diabetic patients showing inadequate response to αGI treatment.

Research Design And Methods: A prospective, randomized, controlled, multicenter interventional study trial. Subjects were randomly assigned to treatment with alogliptin alone (Intake 0 group), or alogliptin in addition to an αGI administered once-/twice-/thrice-daily (Intake 1, 2 and 3 groups).

Acute encephalopathy with pandemic (H1N1) 2009 virus infection.

Objectives: In April 2009, a novel influenza A (H1N1) pdm virus was identified in Mexico and spread quickly around the world. However, the clinical features of acute encephalopathy associated with 2009 pandemic influenza have not yet been elucidated.

Methods: We treated 8 patients (3 boys and 5 girls) aged 4 to 11 years (average age, 8 y 3 months) with influenza virus-associated encephalopathy, who presented at our 2 hospitals between July 2009 and March 2010.

Rapid effectiveness of minocycline or doxycycline against macrolide-resistant Mycoplasma pneumoniae infection in a 2011 outbreak among Japanese children.

Background: Mycoplasma pneumoniae is a major pathogen causing community-acquired pneumonia in children and young adults. Outbreaks typically occur at intervals of several years. In 2011, a widespread outbreak was associated with macrolide-resistant M.

Isolation of a PBP-pincer rhodium complex stabilized by an intermolecular C-H σ coordination as the fourth ligand.

A little help from my friends: a highly reactive, 16-electron square-planar rhodium complex was isolated. This species displays an intermolecular interaction between the rhodium and the C-H bond of another molecule as the fourth ligand to form an infinite network in the crystal lattice. The complex undergoes oxidative addition to the O-H bond of phenol or a primary alkyl alcohol to give the corresponding hydrido-phenoxido Rh(III) complex or carbonyl Rh(I) complex, respectively.

A 4-year-old girl with clinically mild encephalopathy with a reversible splenial lesion associated with rotavirus infection.

Rotavirus is a common cause of severe gastroenteritis in children. It is known that rotavirus gastroenteritis may be accompanied by neurological manifestations, including encephalitis/encephalopathy and seizures. We report a case of a 4-year-old girl with clinically mild encephalopathy with a reversible splenial lesion associated with rotavirus infection.

[Analysis of inpatients with pneumonia due to influenza (H1N1) 2009--clinical aspects based on the presence or absence of respiratory complications].

We retrospectively analyzed the clinical aspects of inpatients with pneumonia caused by influenza (H1N1) 2009 after classifying them into two groups based on the presence or absence of respiratory complications. The study population--121 (5.6%) of 1,777 subjects diagnosed with influenza (H1N1) 2009 using a rapid influenza diagnostic kit or real-time reverse-transcription PCR-were hospitalized from August 2009 to May 2010 as detailed from admission to discharge in hospital medical charts.

Persistent airflow obstruction in young adult asthma patients.

Background: Lung function determined by spirometry and the severity of dyspnea correlate weakly in asthma patients. We attempted to determine the risk factors in asthma patients having persistent airway obstruction despite of having only mild subjective symptoms, and to examine the possibility of improving FEV1 by treating asthma on the basis of the bronchodilator change in FEV1.

Methods: We examined asthma patients in their 20s and who visited Sagamihara National Hospital for the first time over a period of four years, by reviewing their clinical records.

TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimens.

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. TAK-960 [4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl) benzamide] is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1).