- correlation of antitumor activity of heat shock protein 90 (HSP90) inhibitors with a pharmacokinetics/pharmacodynamics analysis using NCI-N87 xenograft mice.

The antitumor activity (e.g. IC) of anticancer drugs is important for selecting candidate compounds for drug efficacy study in the early stage of drug discovery.

Coronary ostial stenosis detected by transesophageal echocardiography after aortic valve replacement: a case report.

Background: Coronary ostial stenosis is a life-threatening complication of aortic valve replacement (AVR). Clinical symptoms usually appear within the first 6 months after AVR (Funada and Mizuno et al., Circ J 70:1312-7, 2006), and perioperative onset is very rare.

Unexpected Collection of Pulmonary Venous Blood from a Pulmonary Artery Catheter: A Case Report.

Background: Pressure and waveform at the catheter tip are continuously monitored during catheterization of pulmonary artery to ensure accurate catheter placement. We present a case in which pulmonary venous blood was unexpectedly collected from the pulmonary artery catheter despite pulmonary artery pressure and waveform detection at the catheter tip, and describe the measures taken to correct the catheter placement.

Case Presentation: A 74-year-old male underwent mitral valve plasty for cardiac failure caused by mitral valve regurgitation.

Factors Causing Post-Anesthetic High Respiratory Resistance in Patients Undergoing Transurethral Resection of Bladder Tumors.

Background: In this study, we investigated the causes of high respiratory resistance that is observed after general anesthesia. We focused on respiratory resistance at 5 Hz (R5), which were measured preoperatively and postoperatively.

Methods: Our prospective observational study enrolled 68 patients who underwent transurethral resection of bladder tumors from April to October 2015.

High expression of the Notch ligand Jagged-1 is associated with poor prognosis after surgery for colorectal cancer.

The importance of Notch signaling in colorectal cancer (CRC) carcinogenesis and progression has previously been presented. Increased expression of Jagged-1 (JAG1), a Notch ligand, in CRC has been revealed, but the detailed prognostic significance of JAG1 in CRC has not been determined. Protein expression of JAG1 was examined using immunohistochemistry in 158 CRC specimens.

[Anesthetic Management of One-stage Intravenous Leiomyomatosis Resection Extending to the Right Ventricle].

We report a case of 71-year-old female with intravenous leiomyomatosis (IVL) extending to the right ventricle. She was operated on successfully by one-stage approach involving thoracotomy and laparotomy. The important question was whether to perform IVL extraction first, or hysterectomy first; performing hysterectomy before IVL extraction may increase the risk of postoperative infection such as mediastinitis, as well as the risk of intraperitoneal hemorrhage during cardiopulmonary bypass (CPB) and tumor embolism.

[Postoperative Management and Cost-effectiveness of Epidural Anesthesia in Patients undergoing Abdominal Aortic Replacement Surgery].

Background: The use of epidural anesthesia for ablominal aortic replacement surgery may be problematic because of the amount of heparin used during the procedure, which places the patient at increased risk of epidural hematoma. We evaluated its benefits, risks, postoperative outcomes and costs.

Methods: We retrospectively collected data on 93 patients who underwent Y-graft infra-renal abdominal aortic replacement at our institution between 2008 and 2010.

Effect of differences in extubation timing on postoperative care following abdominal aortic replacement surgery: a comparison study.

Background: Abdominal aortic replacement requires an extensive incision and strict blood pressure control, making rapid extubation of the tracheal tube and pain management difficult. The effects of extubation timing on the postoperative course and medical costs in the intensive care unit (ICU) were analyzed.

Methods: Patients who underwent elective abdominal aortic replacement were evaluated retrospectively.

[Discrepancy in the length of smoking cessation between surgeon's and anesthesiologist's records in relation to hypoxia during one-lung ventilation].

Background: Smoking cessation before pulmonary surgery is essential for preventing respiratory complications associated with operation and anesthesia. We compared patients' smoking habits and length of smoking cessation based on respiratory surgeon's and anesthesiologist's records.

Methods: We retrospectively surveyed 68 patients who underwent elective operation under one-lung ventilation (OLV) with respect to the Brinkmann index, smoking cessation period, and incidence of hypoxia during OLV.

[One-lung ventilation using dexmedetomidine in an emphysema patient with pneumothorax due to metastatic lung cancer].

We report a case of double-lumen tube intubation and intraoperative one-lung ventilation under spontaneous breathing with continuous dexmedetomidine administration. A 61-year-old man developed pneumothorax due to multiple metastatic cancer, had multiple bilateral bullae, and underwent bullae resection under general anesthesia. An epidural catheter was placed at T8-9.

[Successful double-lumen tube insertion using Pentax-AWS Airwayscope with an infant-sized intlock in a rheumatoid arthritis patient with restricted mouth opening and head tilting].

Successful tracheal intubation with a double-lumen tube was achieved using Pentax-AWS Airwayscope (AWS) with an infant-size Intlock in a patient with restricted mouth opening and head tilting. A 78-year-old woman with rheumatoid arthritis was scheduled for extended thymectomy under general anesthesia, with anticipated difficult airway. Sufficient mask ventilation with the jaw-thrust maneuver was achieved.

Design and synthesis of 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazines as novel Hsp90 inhibitors.

A novel series of 2-amino-1,3,5-triazines bearing a tricyclic moiety as heat shock protein 90 (Hsp90) inhibitors is described. Molecular design was performed using X-ray cocrystal structures of the lead compound CH5015765 and natural Hsp90 inhibitor geldanamycin with Hsp90. We optimized affinity to Hsp90, in vitro cell growth inhibitory activity, water solubility, and liver microsomal stability of inhibitors and identified CH5138303.

Assessing the impact of HER2 status on the antitumor activity of an HSP90 inhibitor in human tumor xenograft mice using pharmacokinetic-pharmacodynamic modeling.

The purpose of this study is to assess the impact of human epidermal growth factor receptor 2 (HER2) status on the antitumor activity of CH5164840, an orally available heat shock protein 90 (HSP90) inhibitor, using pharmacokinetic-pharmacodynamic modeling. Athymic mice, each implanted with one of eight human tumor xenografts, were treated with CH5164840 once daily at doses of 3.13 to 50 mg/kg.

Enhanced antitumor activity of erlotinib in combination with the Hsp90 inhibitor CH5164840 against non-small-cell lung cancer.

Inhibition of heat shock protein 90 (Hsp90) can lead to degradation of multiple client proteins, which are involved in tumor progression. Epidermal growth factor receptor (EGFR) is one of the most potent oncogenic client proteins of Hsp90. Targeted inhibition of EGFR has shown clinical efficacy in the treatment of patients with non-small-cell lung cancer (NSCLC).

Design and synthesis of novel macrocyclic 2-amino-6-arylpyrimidine Hsp90 inhibitors.

Macrocyclic compounds bearing a 2-amino-6-arylpyrimidine moiety were identified as potent heat shock protein 90 (Hsp90) inhibitors by modification of 2-amino-6-aryltriazine derivative (CH5015765). We employed a macrocyclic structure as a skeleton of new inhibitors to mimic the geldanamycin-Hsp90 interactions. Among the identified inhibitors, CH5164840 showed high binding affinity for N-terminal Hsp90α (K(d)=0.

Effects of Selected Anionic β-Cyclodextrins on Persistence of Blood Glucose Lowering by Insulin Glargine after Subcutaneous Injection to Rats.

Insulin glargine is a synthetic long-acting insulin product used for patients with diabetes mellitus. In this study, to obtain the further desirable blood-glucose lowering profile of insulin glargine, we investigated the effects of β-cyclodextrin sulfate (Sul-β-CyD) and sulfobutylether β-cyclodextrin (SBE7-β-CyD) on physicochemical properties of insulin glargine and pharmacokinetics/pharmacodynamics of insulin glargine after subcutaneous injection to rats. Sul-β-CyD and SBE7-β-CyD increased solubility of insulin glargine.

Preclinical antitumor activity of the novel heat shock protein 90 inhibitor CH5164840 against human epidermal growth factor receptor 2 (HER2)-overexpressing cancers.

Heat shock protein 90 (Hsp90), a molecular chaperone that plays a significant role in the stability and maturation of client proteins, including oncogenic targets for cell transformation, proliferation, and survival, is an attractive target for cancer therapy. We identified the novel Hsp90 inhibitor, CH5164840, and investigated its induction of oncogenic client protein degradation, antiproliferative activity, and apoptosis against an NCI-N87 gastric cancer cell line and a BT-474 breast cancer cell line. Interestingly, CH5164840 demonstrated tumor selectivity both in vitro and in vivo, binding to tumor Hsp90 (which forms active multiple chaperone complexes) in vitro, and being distributed effectively to tumors in a mouse model, which, taken together, supports the decreased levels of phosphorylated Akt by CH5164840 that we observed in tumor tissues, but not in normal tissues.

Lead generation of heat shock protein 90 inhibitors by a combination of fragment-based approach, virtual screening, and structure-based drug design.

Heat shock protein 90 (Hsp90) is a molecular chaperone which regulates maturation and stabilization of its substrate proteins, known as client proteins. Many client proteins of Hsp90 are involved in tumor progression and survival and therefore Hsp90 can be a good target for developing anticancer drugs. With the aim of efficiently identifying a new class of orally available inhibitors of the ATP binding site of this protein, we conducted fragment screening and virtual screening in parallel against Hsp90.

Effect of sulfobutyl ether-β-cyclodextrin on bioavailability of insulin glargine and blood glucose level after subcutaneous injection to rats.

Insulin glargine is the first long-acting basal insulin analogue used for subcutaneous administration once daily in patients with type 1 or type 2 diabetes mellitus. To obtain the further bioavailability and the sustained glucose lowering effect of insulin glargine, in the present study, we investigated the effect of sulfobutyl ether-β-cyclodextrin (SBE4-β-CyD), with the degree of substitution of sulfobutyl ether group of 3.9, on pharmaceutical properties of insulin glargine and the release of insulin glargine after subcutaneous injection to rats.

An improved synthesis of benzocycloalkanone derivatives.

A convenient and improved annulation method for the synthesis of bicyclic ketones was developed. A 2,2-dimethyl-6-(2-phenylsulfonyl)ethylcyclohexanone was converted into a sulfonylester by the addition of ethyl acetate and subsequent dehydration. A Dieckmann type condensation of the sulfonylester followed by desulfonylation afforded the 8,8-dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-2-one in good yield.

Quantitative analysis of influenza virus RNP interaction with RNA cap structures and comparison to human cap binding protein eIF4E.

Influenza virus polymerase uses capped RNA primers for transcription initiation in infected cells. This unique mechanism involves the specific binding of the polymerase to capped mRNA precursors in the nucleus of infected cells. These host RNAs are then cleaved by a polymerase associated endonuclease at a position 10-15 nucleotides downstream of the cap structure.

The yeast Chs4 protein stimulates the trypsin-sensitive activity of chitin synthase 3 through an apparent protein-protein interaction.

Inducible overexpression of the CHS4 gene under the control of the GAL1 promoter increased Chs3p (chitin synthase 3) activity in Saccharomyces cerevisiae several fold. Approximately half of the Chs3p activity in the membranes of cells overexpressing Chs4p was extracted using CHAPS and cholesteryl hemisuccinate. The detergent-extractable Chs3p activity appeared to be non-zymogenic because incubation with trypsin decreased enzyme activity in both the presence and absence of the substrate, UDP-N-acetylglucosamine.

The Candida albicans CHS4 gene complements a Saccharomyces cerevisiae skt5/chs4 mutation and is involved in chitin biosynthesis.

The Candida albicans CHS4 gene encoding chitin synthase 4 has been isolated using the Saccharomyces cerevisiae CHS4/SKT5 gene as a probe. The gene contains a 2061 bp open reading frame capable of encoding a protein of 687 amino acids (76053 Da). No intron was observed in the gene.

Isolation of CaSLN1 and CaNIK1, the genes for osmosensing histidine kinase homologues, from the pathogenic fungus Candida albicans.

Recent studies have revealed that fungi possess a mechanism similar to bacterial two-component systems to respond to extracellular changes in osmolarity. In Saccharomyces cerevisiae, Sln1p contains both histidine kinase and receiver (response regulator) domains and acts as an osmosensor protein that regulates the downstream HOG1 MAP kinase cascade. SLN1 of Candida albicans was functionally cloned using an S.