Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor.

The Keap1-Nrf2 system is an attractive target for drug discovery regarding various unmet medical needs. Only covalent inhibitors for protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 have been approved or are under clinical trials, but such electrophilic compounds lack selectivity. Therefore, specific non-covalent Keap1-Nrf2 PPI inhibitors are expected to be safer Nrf2 activators.

Expression level of CXCL7 in peripheral blood cells is a potential biomarker for the diagnosis of renal cell carcinoma.

There are no blood biomarkers for the diagnosis of renal cell carcinoma (RCC) in routine clinical use. We focused on the gene expression profile of peripheral blood cells obtained from RCC patients to discover novel biomarkers for RCC diagnosis. Using microarray analysis and quantitative verification, CXCL7 was shown to be significantly upregulated in the peripheral blood cells of RCC patients.

Peripheral blood monocyte count reflecting tumor-infiltrating macrophages is a predictive factor of adverse pathology in radical prostatectomy specimens.

Background: Tumor-infiltrating macrophages, which are thought to be derived from blood monocytes, interact with tumor cells to promote cancer progression. The aim of this study was to assess the association of peripheral blood monocyte count with pathological findings and local tumor-infiltrating macrophages in prostatectomy specimens.

Methods: Preoperative peripheral blood monocyte counts were retrospectively assessed for their associations with pathological findings (pathological T stage, Gleason Score, extraprostatic extension, seminal vesicle invasion, and surgical margin) and biochemical recurrence of 248 patients who underwent radical prostatectomy.

Evaluation of Antigen-Specific IgM and IgG Production during an Peripheral Blood Mononuclear Cell Culture Assay.

The recent attention given to diseases associated with memory B-cell (mBC)-produced antibodies (Abs) suggests the need for a similar assay to evaluate the functions of mBCs. Here, we cultured peripheral blood mononuclear cells (PBMCs) with the intent to collect mBC-derived Abs and maintain their cell-cell contact-dependent interactions with helper T-cells. PBMCs were cultured with interleukin (IL)-21, CpG-oligodeoxynucleotides (ODN), phorbol myristate acetate (PMA), and phytohemagglutinin/leucoagglutinin (PHA-L) in 24-well flat-bottom plates (5 × 10 cells/well).

A Label-Free Fluorescent Array Sensor Utilizing Liposome Encapsulating Calcein for Discriminating Target Proteins by Principal Component Analysis.

A new fluorescent arrayed biosensor has been developed to discriminate species and concentrations of target proteins by using plural different phospholipid liposome species encapsulating fluorescent molecules, utilizing differences in permeation of the fluorescent molecules through the membrane to modulate liposome-target protein interactions. This approach proposes a basically new label-free fluorescent sensor, compared with the common technique of developed fluorescent array sensors with labeling. We have confirmed a high output intensity of fluorescence emission related to characteristics of the fluorescent molecules dependent on their concentrations when they leak from inside the liposomes through the perturbed lipid membrane.

Structural development of 1,2,3,4-tetrahydroisoquinoline-type positive allosteric modulators of prostacyclin receptor (IPPAMs) to improve metabolic stability, and investigation of metabolic fate.

We synthesized a series of 1,2,3,4-tetrahydroisoquinoline-type positive allosteric modulators of prostacyclin receptor (IPPAMs), aiming to improve the metabolic stability of the previously identified hit compound IPPAM-3 (2). Our results indicated that the 3-position of the 2-substituted phenyl ring in this series of IPPAM-3 derivatives is a hot spot for metabolism catalyzed by human hepatic microsomes. This conclusion was confirmed by the finding that 8, in which the 3-position is blocked by a fluorine substituent, exhibited superior metabolic stability (t 21min versus 7min for parent compound 2).

Relationship between molar occlusion and masticatory movement in lateral deviation of the mandible.

Introduction: The relationship between molar occlusion and chewing patterns was examined in subjects with laterally deviated mandibles.

Methods: Twenty-three patients with mandibular deviation from the midline (4 mm or more) and skeletal Class I (0° ≤ANB ≤4°) were divided into 2 groups: normal bite and crossbite. The chewing pattern was classified as normal, reversed, or crossover.

Stereoselective Synthesis of Tabtoxinine-β-lactam by Using the Vinylogous Mukaiyama Aldol Reaction with Acetate-Type Vinylketene Silyl N,O-Acetal and α-Keto-β-lactam.

Stereoselective total synthesis of tabtoxinine-β-lactam has been achieved. The vinylogous Mukaiyama aldol reaction with vinylketene silyl N,O-acetal and α-keto-β-lactam proceeded to afford the adduct possessing a TβL-skeleton with a tert-alcohol in high yield and stereoselectivity. Stereoselective introduction of the amino group has been accomplished by azidation at the α position of the imide followed by hydrogenolysis.

Synthesis of both enantiomers of 1,2,3,4-tetrahydroisoquinoline derivative IPPAM-1 and enantio-dependency of its positive allosteric modulation of prostacyclin receptor.

We present a practical synthesis of both enantiomers of 1,2,3,4-tetrahydroisoquinoline derivative IPPAM-1 (1), which is a positive allosteric modulator (PAM) of prostacyclin receptor (IP) and a candidate for treatment of pulmonary arterial hypertension without the side effects caused by IP agonists. Assay of cAMP production by CHO-K1 cells stably expressing human IP clearly demonstrated that the IPPAM activity resides exclusively on the R-form of 1.

High-pressure carbon monoxide preserves rat kidney grafts from apoptosis and inflammation.

Renal ischemia-reperfusion (I/R) injury is unavoidable in kidney transplantation (KTx) and frequently influences both short- and long-term allograft survival. Carbon monoxide (CO) has attracted attention as a medical gas with anti-inflammatory and anti-apoptotic effects. We investigated a new strategy for organ preservation using ex vivo application of high-pressure CO in an experimental rat KTx model.

Hepatocyte growth factor in physiology and infectious diseases.

Hepatocyte growth factor (HGF) is a pleiotropic cytokine composed of an α-chain and a β-chain, and these chains contain four kringle domains and a serine protease-like structure, respectively. The receptor for HGF was identified as the c-met proto-oncogene product of transmembrane receptor tyrosine kinase. HGF-induced signaling through the receptor Met provokes dynamic biological responses that support morphogenesis, regeneration, and the survival of various cells and tissues, which includes hepatocytes, renal tubular cells, and neurons.

[A CASE OF PROSTATE CANCER WITH SECONDARY HYPOGONADISM].

A 70 year-old man underwent contrast CT, which revealed his swollen left inguinal and pelvic lymph nodes. The lymph nodes reduced in size without any treatments in a follow-up examination. In 2013, the lymph nodes enlarged again, and FDG-PET/CT showed high value at the prostate and multiple lymph nodes.

[A CASE OF SUCCESSFUL RECOVERY OF RENAL ALLOGRAFT FUNCTION FOLLOWING A DIAGNOSIS OF THROMBOTIC MICROANGIOPATHY CLINICALLY MADE IN THE IMMEDIATE POST-TRANSPLANT PERIOD].

A 57-year-old female patient on hemodialysis with chronic renal failure due to chronic glomerular nephritis received deceased donor kidney transplantation. Induction immunosuppressive therapy was combination of tacrolimus, mycophenolate mofetil, everolimus, prednisolone, and basiliximab. She was diagnosed with secondary thrombotic microangiopathy (TMA) by clinical findings such as hemolytic anemia, thrombocytopenia and acute kidney injury not by pathological findings on the 4th post-operative date.

[A Case of Recurrent Renal Cancer in the Autografted Kidney, Treated with Percutaneous Cryoablation].

We report a case of recurrent renal cancer in the autografted kidney, treated with percutaneous cryoablation. A 59-year-old man who had bilateral renal tumors underwent radical left nephrectomy, ex vivo right partial nephrectomy and auto-transplantation at the right ileal fossa in our hospital 11 years ago. Histopathological examination showed clear cell renal cell carcinoma in bilateral kidneys (pT1bN0M0).

Quantitative characterization of T-cell repertoire and biomarkers in kidney transplant rejection.

Background: T-cell-mediated rejection (TCMR) remains a major cause of kidney allograft failure. The characterization of T-cell repertoire in different immunological disorders has emerged recently as a novel tool with significant implications. We herein sought to characterize T-cell repertoire using next generation sequencing to diagnose TCMR.

Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity.

The Keap1-Nrf2 system is involved not only in biological defense but also in malignancy progression and chemoresistance. The ubiquitin-binding protein p62/Sqstm1 (p62), which is highly expressed in several cancers, competes with Nrf2 for Keap1 binding, leading to activation of Nrf2-mediated gene expression and survival of cancer cells. We had previously identified an inhibitor for the Keap1-phosphorylated-p62 (p-p62) protein-protein interaction (PPI), the acetonyl naphthalene derivative K67.

Different growth and metastatic phenotypes associated with a cell-intrinsic change of Met in metastatic melanoma.

A dynamic phenotypic change contributes to the metastatic progression and drug resistance in malignant melanoma. Nevertheless, mechanisms for a phenotypic change have remained to be addressed. Here, we show that Met receptor expression changes in a cell-autonomous manner and can distinguish phenotypical differences in growth, as well as in metastatic and drug-resistant characteristics.

Surgical approach to the thyroarytenoid branch of the inferior laryngeal nerve through the thyroid cartilage.

Purpose: To describe the anatomical course of the intralaryngeal portion of the inferior laryngeal nerve (ILN) and to standardize the surgical access to its thyroarytenoid branch (TAb) through the thyroid cartilage.

Methods: Under surgical microscopy, 33 adult human excised larynges were dissected, to expose the intralaryngeal portion of ILN. The point of entry of TAb, ILN's terminal branch, in the thyroarytenoid (TA) muscle was determined and correlated with thyroid cartilage dimensions.

p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming.

p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC).

[Renal Cell Carcinoma with Metastasis to the Gallbladder : A Case Report].

A 63-year-old male with a past history of left nephrectomy due to clear cell renal cell carcinoma at the age of 57 was admitted for further evaluation. Enhanced abdominal computed tomography revealed that there were several hypervascular tumors in the pancreas and a single hypervascular tumor in the gallbladder. Laparoscopic cholecystectomy was performed to obtain pathological diagnosis.

Muscle Activation Among Supine, Prone, and Side Position Exercises With and Without a Swiss Ball.

Background: Prone, supine, and side position exercises are employed to enhance core stability.

Hypothesis: Overall core muscle activity would be greater in prone position exercises compared with supine and side position exercises.

Study Design: Controlled laboratory study.

Evaluation of intramyocellular and extramyocellular lipids in the paraspinal muscle in patients with chronic low back pain using MR spectroscopy: preliminary results.

Objective:: To analyze the intramyocellular lipids (IMCL) and extramyocellular lipids (EMCL) in the psoas muscle (Pm) and multifidus muscle (Mm) using MR spectroscopy (MRS) in patients with chronic low back pain (CLBP) and asymptomatic volunteers.

Methods:: This prospective study had institutional review board approval, and written informed consent was obtained from all individual participants. 20 patients with CLBP (mean age, 49.

Adherence to Dietary Recommendations in Maintenance Phase Kidney Transplant Patients.

Objectives: Current adherence to dietary recommendations for chronic kidney disease was evaluated in kidney transplant patients in the maintenance phase.

Methods: A total of 268 maintenance phase kidney transplant patients were included in the study. Estimated daily intakes of oral protein and salt were calculated from 24-h urinary excretion of nitrogen and sodium, respectively.

Post-Transplant Anemia Has Strong Influences on Renal and Patient Outcomes in Living Kidney Transplant Patients.

Background: Post-transplant anemia (PTA) is a risk factor for mortality and graft loss in kidney transplant patients.

Methods: In all, 172 patients were included in this study. PTA was defined as hemoglobin <13.