Identification of an allosteric and Smad3-selective inhibitor of p38αMAPK using a substrate-based approach.

p38α mitogen activated protein kinase (MAPK) plays important roles in multiple cellular functions by phosphorylating a wide variety of substrates, and therefore, p38α MAPK has been considered as an important drug target. In this study, we designed peptide-based inhibitors for p38α MAPK, which can only inhibit the Smad3 phosphorylation specifically, by targeting the KIM binding site of p38α MAPK. Peptide 6 showed a significant inhibitory potency for the Smad3 phosphorylation by p38α MAPK. Peptide 6 showed no ATP dependency, and did not inhibit the phosphorylation of other substrates by p38α MAPK. The discovery of peptide 6 by targeting the KIM binding site likely provide an opportunity for the discovery of a novel class of allosteric and substrate-specific p38α MAPK inhibitors.

[IPSILATERAL SYNCHRONOUS MUCINOUS TUBULAR AND SPINDLE CELL CARCINOMA AND CLEAR CELL PAPILLARY RENAL CELL CARCINOMA: A CASE REPORT AND REVIEW OF THE LITERATURE].

Renal cell carcinoma (RCC), the most common solid lesion of the kidney, accounts for approximately 2%-3% of all malignancies among adults. Clear cell carcinoma and papillary cell carcinoma are the most common types of renal tumors. Some case reports have described synchronous benign and malignant tumors in the same kidney. In particular, angiomyolipoma and RCC in patients with tuberous sclerosis (TSC) and non-TSC have been reported many times in the literature. However, unilateral concordance of malignant renal tumors is very rare; thus, only few cases have been reported in the literature.Here we report the case of a 58-year-old male who had ipsilateral synchronous mucinous tubular and spindle cell carcinoma (MTSCC) and clear cell papillary renal cell carcinoma (CCPRCC). Both cancers are rare and relatively recently defined subtypes of RCC. Additionally, both were successfully treated using partial nephrectomy. MTSCC has been a distinct entity in the World Health Organization classification of kidney tumors since 2004. The classic type of MTSCC is characterized by small elongated tubules lined with clear cuboidal or spindle cells with mucinous stroma. Neoplastic cells always exhibit low-grade histological features. However, unclassified variants of MTSCC, such as mucin-poor, papillary, high-grade, and sarcomatoid variants, have also been reported. MTSCC is considered to have a relatively good prognosis, but some patients with poor prognoses have recently been reported. CCPRCC is a recently recognized entity and represents the fourth most common variant of RCC. It has unique morphological and immunohistochemical features and shows indolent clinical behavior. Microscopically, CCPRCC may mimic other RCCs with clear cell features, such as clear cell RCC, translocation RCC, and papillary RCC, with clear cell changes. In 2006, CCPRCC was described as a subtype of renal tumors in patients with end-stage renal disease. However, currently, CCPRCC has also been shown to occur in kidneys with normal function.To the best of our knowledge, this is the first report of ipsilateral synchronous MTSCC and CCPRCC, which we present with a review of the pertinent literature.

Thrombosis in inferior vena cava due to enlarged renal cysts in autosomal dominant polycystic kidney disease.

We report a rare case of thrombosis in the inferior vena cava (IVC) due to enlarged cysts in autosomal dominant polycystic kidney disease. A 71-year-old woman visited our hospital with a complaint of rapid left lower extremity swelling. Computed tomography (CT) revealed massive thrombosis from the IVC to the bilateral common iliac vein. The extrinsic mechanical stress of renal cysts to the IVC seemed to have induced thrombosis in the vein that resulted in the cause of severe edema in the left lower extremity. Her renal cysts were percutaneously punctured for the relief of compression and she received injection of 99.5% ethanol for prevention against reaccumulation of cyst fluid after IVC filter had been positioned. The edema of her left lower extremity improved temporarily, however, follow-up CT two months after cyst puncture showed reaccumulation of the fluid. Therefore, excision of the responsible cyst wall by open surgery was carried out.

[Two cases of urinary retention secondary to benign inflammatory nervous diseases].

We report two cases of acute urinary retention secondary to benign inflammatory nervous disease. Case 1 is in a 48-year-old male who was diagnosed with aseptic meningitis. Case 2 is in a 67-year-old male who was diagnosed with acute disseminated encephalomyelitis. These two cases differred in specific mechanism of the disease, but both shared symptoms of temporal voiding disturbance due to sacral radiculopathy (Elsberg syndrome). This condition is extremely rare, but should be kept in mind because delayed treatment can lead to permanent impairment.

Vesical endometriosis following the menopause.

We report a rare case of vesical endometriosis in a 65-year-old postmenopausal woman. An abdominal hysterectomy had been performed 34 years previously, and exogenous estrogens had not been administered. The hormone levels were normal for a castrated female subject. The patient was treated surgically with transurethral resection and the following hormonal therapy. Endometriosis of the urinary tract can happen even in postmenopausal women.

An investigation on pharmacy functions and services affecting satisfaction of patients with prescriptions in community pharmacies.

Various functions expected by patient expects are needed with progress in the system for separation of dispensing and prescribing functions. In this investigation, the relationship between patient satisfaction and pharmacy function were analyzed quantitatively. A questionnaire survey was conducted in 178 community pharmacies. Questions on pharmacy functions and services totaled 87 items concerning information service, amenities, safety, personnel training, etc. The questionnaires for patients had five-grade scales and composed 11 items (observed variables). Based on the results, "the percentage of satisfied patients" was determined. Multivariate analysis was performed to investigate the relationship between patient satisfaction and pharmacy functions or services provided, to confirm patient's evaluation of the pharmacy, and how factors affected comprehensive satisfaction. In correlation analysis, "the number of pharmacists" and "comprehensive satisfaction" had a negative correlation. Other interesting results were obtained. As a results of factor analysis, three latent factors were obtained: the "human factor," "patients' convenience," and "environmental factor," Multiple regression analysis showed that the "human factor" affected "comprehensive satisfaction" the most. Various pharmacy functions and services influence patient satisfaction, and improvement in their quality increases patient satisfaction. This will result in the practice of patient-centered medicine.

[Metastatic malignant melanoma of the urinary bladder presenting with hematuria: a case report].

A 65-year-old man complained of macroscopic hematuria and urinary obstruction. A blood clot in the bladder eliminated transurethrally demonstrated a solitary tumor at the dome of the bladder. Transurethral resection of the bladder tumor (TUR-Bt) was performed, and histological diagnosis was malignant melanoma. Physical examination revealed a black-pigmented site on the lateral border of the right foot sole, which was dermatologically diagnosed as malignant melanoma. The vesical site was diagnosed as a metastatic melanoma of the bladder. Metastatic neoplasms of the bladder are rare, ranging from 0.1 to 6.2 percent of all bladder tumors. To our knowledge, approximately forty percent of metastatic neoplasms of the bladder originate from melanoma. Therefore, an atypical nodular lesion encountered during cystoscopy may be metastasis of malignant melanoma and dermatic lesions should be investigated.

[Investigation on patient satisfaction at community pharmacies: analyzing questionnaire survey by structural equation modeling and multiple regression analysis].

Separation of the dispensing function and the prescribing function, Iyaku Bungyo, has been progressing in Japan. We are now witnessing the advent of a new society where patients select pharmacists and their satisfaction is recognized as one of the healthcare outcome indicators. It is necessary to clarify which factors affect patients' satisfaction with the services provided at community pharmacies and how they do so. A survey was conducted among 104 community pharmacies and their patients around the Tokyo metropolitan area in Japan. The questionnaire comprised 11 items (observed variables), each with a five-grade scale. With the transformed data-oriented pharmacy, the percentage of being not unsatisfactory was examined in two multivariate analyses of the relation and structure of patient satisfaction with a community pharmacy. Structural equation modeling (SEM) with factor analysis (FA) was performed using the observed variables and latent factors. Multiple regression analysis was performed with comprehensive satisfaction as an independent variable, examining the factors that affect comprehensive satisfaction with the pharmacy. The result of the FA indicated three latent factors of instruction on the use of drugs, quality of staff, and environment, based on which SEM model was constructed with a relatively high goodness of fit index. The result of multiple regression analyses indicated almost all variables such as satisfaction with reception by the pharmacist affected the comprehensive satisfaction, but privacy did not show a significant effect. These results, notably the relationship between each variables and latent factors, suggested the importance of higher skills of pharmacists, service qualities at pharmacies, and their functions adjusted to the community.

[A case of small cell carcinoma in a diverticulum of the bladder].

We report a case of small cell carcinoma in a diverticulum of the bladder. A 64-year-old Japanese man visited our hospital with the chief complaint of urinary retention. Cystoscopy revealed a papillary tumor arising in a diverticulum on the right lateral wall of the bladder. Partial cystectomy was performed under the diagnosis of bladder cancer in the diverticulum. The histopathological diagnosis was a combination of small cell carcinoma and urothelial carcinoma, of which the former was dominant. It is often difficult to detect tumors in the bladder diverticula and its early penetration is not rare because of the thin wall. Therefore, the prognosis of the bladder cancer in the diverticulum is believed to be generally poor. On the other hand, small cell carcinoma originating in the urinary bladder is also characterized by its extreme rareness and poor prognosis. To our knowledge, this is the second case report of the small cell carcinoma arising in a diverticulum of the urinary bladder in the Japanese literature.

2,4-Bis(octadecanoylamino)benzenesulfonic acid sodium salt as a novel scavenger receptor inhibitor with low molecular weight.

In order to investigate the effect of the fixation of the orientations of the two long chains, three types of novel derivatives of scavenger receptor inhibitor 1 were synthesized, and their biological activities were evaluated. Among the novel derivatives, 2,4-bis(octadecanoylamino)benzenesulfonic acid sodium salt (4d) showed the most potent inhibitory activity against the incorporation of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate-labeled acetyl-LDL (DiI-acetyl-LDL) into macrophages. 2,5-Bis(octadecanoylamino)benzenesulfonic acid sodium salt (4c), a regioisomer of 4d, did not exhibit as potent an inhibitory activity as 4d, meaning that the substitution pattern of two long chains on the benzene ring must be important. Compound 4d exhibited 10 times more potent inhibitory activity against the binding of 125I-labeled acetyl-LDL to the surface of macrophages than compound 1.

Design, synthesis, and evaluation of beta-galactosylceramide mimics promoting beta-glucocerebrosidase activity in keratinocytes.

We have established an efficient synthesis of mimics of beta-galactosylceramide (beta-GalCer) increasing a beta-glucocerebrosidase (beta-GlcCer'ase) activity that associates with the skin barrier function. Among the synthetic beta-GalCer analogues (6a-6e) described herein, compound 6e exhibited a potent effect on the activation of beta-GlcCer'ase function in vitro and reduced the transepidermal water loss (TEWL) level in a UVB-induced barrier disrupted mice model. These findings indicated that compound 6e could be useful for cosmetics and medicines to improve skin barrier function.

Synthesis and structure-activity relationships of 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids as HB-EGF shedding inhibitors.

HB-EGF Shedding inhibitors have been expected to become effective medicines for skin diseases caused by the proliferation of keratinocytes. In order to discover novel HB-EGF shedding inhibitors and clarify their structure-activity relationships, 5,6,7,8-tetrahydronaphthylidine-based hydroxamic acid and 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids have been synthesized. Among the synthesized compounds, the ethoxyethoxy derivative 3o and the methoxypropoxy derivative 3p exhibited much more potent HB-EGF shedding inhibitory activity than CGS 27023A. The structural modification of 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids enabled us to establish the following structure-activity relationships; the existence of the hydroxamic acid, the sulfonamide, and the phenyl moieties are crucial for a potent HB-EGF shedding inhibitory activity, and the stereochemistry of the alpha carbon of hydroxamic acid is also important. In addition, from the comparison of their HB-EGF shedding inhibitory activities with their MMPs inhibitory activities, we found that the S1' pocket of the responsible enzyme for HB-EGF shedding is deep unlike that of MMP-1.

Studies on scavenger receptor inhibitors. Part 1: synthesis and structure-activity relationships of novel derivatives of sulfatides.

Scavenger receptors have been proven to be implicated in the formation of atherosclerotic lesions. A series of novel derivatives of sulfatides were synthesized, and their inhibitory activities against incorporation of DiI-acetyl-LDL into macrophages were evaluated in order to clarify the structure-activity relationships of sulfatides as a scavenger receptor inhibitor and find out novel inhibitors with synthetic easiness. The chemical modification of the substructures of sulfatides led to the establishment of the following structure-activity relationships; (1) the ceramide moiety can be replaced with another structure bearing two long chains, (2) the galactose moiety can be replaced with another structure or be deleted without a large decrease in the inhibitory activity, (3) the sulfate moiety was crucial, and it was the most preferable functional group for a potent inhibitory activity. The inhibitory activity of (S)-2-octadecanoylamino-2-tetradecylcarbamoyl)ethyl sulfate sodium salt (3a) against incorporation of DiI-acetyl-LDL into macrophages was proven to be based on the inhibition against the binding of acetyl-LDL to the surface of macrophages. We discovered novel scavenger receptor inhibitors with synthetic easiness, such as (S)-2-octadecanoylamino-2-(tetradecylcarbamoyl)ethyl sulfate sodium salt (3a) and 2-octadecanoylamino-1-(octadecanoylaminomethyl)ethyl sulfate sodium salt (13q).

Efficacy of 3-D computed tomographic reconstruction in evaluating anatomical relationships of colovesical fistula.

A case of colovesical fistula is reported. The anatomy of the pelvis was determined preoperatively with 3-D computed tomography (CT), and the fistula, including adjacent structures, could clearly be seen. Compared with conventional axial CT imaging, 3-D CT provided better and more complete visualization of the anatomical relationships, which facilitated the surgical procedure and provided a good outcome.

New strategy for antedrug application: development of metalloproteinase inhibitors as antipsoriatic drugs.

Phosphonamide-based inhibitors were synthesized and evaluated for the inhibitory activities against the shedding of epidermal growth factors, amphiregulin and heparin-binding EGF-like growth factor, that would participate in the development of psoriasis. All compounds exhibited excellent inhibitory activities for these EGF sheddings; however, they also inhibited matrix metalloproteinases (MMPs). To avoid adverse effects reported by the clinical development of MMP inhibitors, the antedrug concept was introduced. Among the phosphonamide inhibitors, the 2,2,2-trifluoroethyl ester 8d and 2,2-difluoroethyl ester 8c showed rapid decomposition in human plasma, which is an essential property for the antedrug. Topical applications of these compounds significantly suppressed TPA-induced epidermal hyperplasia in murin skin, a model of psoriasis. These results suggested that the phosphonamide-based inhibitors have a therapeutic potential for the treatment of psoriasis as an antedrug application.