Aquaporins (AQPs) are a membrane protein family involved in the selective transport of water across cell membranes. Recent studies have reported the expression of AQP5 in several tumor types such as gastric, pulmonary, ovarian, pancreatic and colorectal cancer. We have previously reported the expression on tumor cells and the important role of AQP3 on cell growth in tongue cancer. However, little is known about the expression and precise role of AQP5 on squamous cell carcinoma (SCC) of the tongue. We investigated the expression of AQP5 and AQP3 in human oral SCC and adenoid cystic carcinoma (ACC). Overexpression of both AQP5 and AQP3 were immunohistochemically observed on tumor cells in SCC, whereas ACC cells were faintly stained with those antibodies against AQPs. Treatment with pan-AQP inhibitor or specific AQP5-siRNA showed inhibition of cell growth in SCC cell lines via the inhibition of integrins and the mitogen-activated protein kinase pathway. AQPs play important roles in cell growth in SCC rather than ACC.

CTRP3, a paralog of adiponectin, is a member of the C1q and tumor necrosis factor (TNF)-related protein (CTRP) superfamily. It is expressed at high levels in adipose tissue and has recently emerged as a novel adipokine. In the present study, we provide the first evidence for a physiological role of the new adipokine, CTRP3, in the reproductive system. CTRP3 was specifically expressed in interstitial Leydig cells, where testosterone is produced, in the adult mouse testis. CTRP3 increased testosterone production by TM3 mouse Leydig cells in a dose-dependent manner. The increased testosterone production was linked to upregulation of steroidogenic proteins expression, such as steroidogenic acute regulatory (StAR) protein and cholesterol side-chain cleavage cytochrome P450 (P450scc). Moreover, increases in intracellular cyclic AMP (cAMP) concentrations and the phosphorylation of cAMP-response element binding protein (CREB) in CTRP3-stimulated TM3 Leydig cells were observed. Inhibition of this signaling pathway by a specific protein kinase A (PKA) inhibitor, H89, blocked testosterone production in CTRP3-stimulated Leydig cells, suggesting that the stimulatory effect of CTRP3 on testosterone production is associated with activation of the cAMP/PKA signaling pathway. Thus, our results demonstrate a physiological role for CTRP3 in testicular steroidogenesis and provide novel insights in the intracellular mechanisms activated by this protein.

Background/Aims: Severity-based treatment is not homogenously effective for acute cholangitis patients and some are resistant to early treatment. We performed a retrospective cohort study involving acute cholangitis patients and analyzed factors strongly associated with resistance to early treatment. Methodology: The subjects were 94 patients admitted to the Department of Gastroenterology, Showa University Hospital and diagnosed with acute cholangitis. The endpoint was set as the presence or absence of resistance to early treatment. Background and blood test results of the patients immediately after admission were surveyed and significant factors independently contributing to resistance to early treatment were extracted from the surveyed factors employing a logistic regression model. Results: The mean age of the patients was 73.2±11.6 years and 58 were male (61.7%). Jaundice, fever and abdominal pain were observed in 46 (48.9%), 66 (70.2%) and 85 patients (90.4%), respectively. Twenty-eight patients (29.8%) were resistant to early treatment. On multivariate analysis, 3 factors (fever, serum amylase level and systolic blood pressure (below 100mmHg)) were extracted as significant factors independently contributing to resistance to early treatment (p<0.05). Conclusions: If such resistance can be predicted before treatment, appropriate treatment may be selected to shorten the persistence of symptoms, improving the patient's QOL.

Endothelin plays important roles in various physiological functions including vascular constriction. Recent studies reported that the endothelin receptors ETA and ETB are highly expressed in lung and skin tumor tissues. In contrast, there are few reports on endothelin signalling in the proliferation of head and neck cancer. We found that both ETA and ETB endothelin receptors were overexpressed in tumor cells of tongue cancer samples by immunohistochemistry. ETA and ETB were expressed in cultured lingual and esophageal squamous cell carcinoma (SCCs) cell lines. When both cultured cell lines were treated with an ETA selective antagonist (BQ123) or an ETB selective antagonist (BQ788), inhibition of cell growth was observed. Similar results were observed when SCCs were treated with specific siRNA for the suppression of ETA or ETB. Furthermore, inhibition of the mitogen-activated protein (MAP) kinase pathway by the treatments with ET receptor antagonists and siRNA was also observed. These results indicate that endothelin signalling may, in part, play important roles in cell growth in SCCs through the MAP kinase pathway.

We have previously reported the efficacy of the Patient Oriented Clerkship (POC) in the clinical clerkship in Showa University Hospitals, by a trial with old four-year pharmacy program students. In the unique clerkship, each student has a patient in charge, and follows his/her clinical conditions throughout the rotation. The aim of the POC is that having the students learn spontaneously (Active Learning) and actively (Adult Learning) promoted by student's commitment and responsibility by communicating with patients and health professionals in a team. As the POC requires students both Active Learning and Adult Learning, we define the POC as Active Adult Learning (AAL). Having a patient in charge for each student gives them many opportunities to participate in the medical team and foster their problem solving skills. Our previous study eventually showed positive results of the POC in the one-month short clerkship in the four-year program. On the other hand, the effect of the unique hospital clerkship in the new six-year program is not known. We conducted a student survey to clarify the learning effect in the new six-year education system which was revised and 2.5 month clinical clerkship was scheduled according to the model core clerkship curriculum. This report is the first report to show a challenge of the AAL/POC clerkship in the new six-year pharmacy education program.

Background/Aim: Factors predicting the appearance of neutropenia were evaluated in patients with advanced pancreatic cancer undergoing gemcitabine hydrochloride (GEM) therapy. Methodology: The subjects were 92 patients who were diagnosed with unresectable advanced pancreatic cancer and underwent GEM therapy. Mono- and multivariate analyses were performed concerning each evaluated factor. The toxicity index (TI) was also prepared by combining the extracted predictive factors. Results: Severe neutropenia occurred in 26 patients (28.2%). As a result of multivariate analysis, the white blood cell count (WBC), CA19-9 and liver metastasis were extracted as factors independently and significantly contributing to the appearance of severe neutropenia (p<0.05). The TI was prepared by combining these 3 factors and their regression coefficients: TI = 4.777-0.605xWBC (x103/microL)-0.511xlog (CA19-9)-1.285xliver metastasis. Conclusions: The WBC, CA19-9 and liver metastasis before treatment were shown to be related to the appearance of severe neutropenia after GEM therapy.

This study was designed to evaluate detailed philtral morphology involving sex and racial differences and to clarify the objective parameters related to subjective judgments regarding the clarity of the philtrum. Fifty-five Japanese and 20 Mexican normal subjects aged 24 to 40 years were recruited, and three-dimensional facial data were acquired using a noncontacting optical surface scanner. The visual classification of the philtral column morphology in Japanese adults using facial photographs revealed that the predominant philtral column shape was different by sex. The three-dimensional anthropometric data showed significant sex differences, which were reflected in the more pronounced visual impression of the philtrum in men. A comparative study between Japanese and Mexican women also revealed certain racial differences. Furthermore, both the philtral depth and central angle of Cupid's bow were extracted as explanatory variables related to the subjective judgments for the clarity of the philtrum. These results suggest that the comprehensive evaluation of philtral morphologic features by three-dimensional analysis is a useful means of identifying the ideal parameters in philtral construction in cleft surgery.

The orexins (Orexin-A and orexin-B) are neuropeptides which are secreted from neurons in the lateral hypothalamus, which participate in the regulation of feeding behavior. It remains to be determined, however, how the orexins exert their effects on feeding behavior, including masticatory movements. To this end, we analyzed food intake behavior and masticatory muscle activity using video-analysis and electromyography (EMG)-recording methods. The results showed that the cumulative food intake over 4 hrs was larger in rats intraventricularly injected with either orexin-A or orexin-B than saline-injected control rats. The latency to eat and the feeding time for a fixed amount of pellets were shortened by injections of orexins in a dose-dependent manner, with a more potent effect by orexin-A than orexin-B. The shorter feeding time corresponded to a decreased number of chewing cycles. EMG recordings from both the digastric and masseter muscles showed two distinct patterns of bursts corresponding to the gnawing and chewing phases. After the injection of orexin-A, the magnitude of the bursts became larger in both phases in the masseter muscle, the burst duration became longer in the chewing phase in the masseter muscle, and the inter-burst interval became shortened in the gnawing phase in both muscles. Consequently, the burst frequency in the chewing phase was increased in the digastric muscle, and conversely, reduced in the masseter muscle. These results suggest that the orexin-A-induced facilitatory feeding behavior is characterized by a dynamic jaw-opener activity which opens the mouth rapidly and powerful jaw-closer activity for crushing the increased amount of food taken into the mouth. The possible involvement of orexin-A in binge eating disorder is discussed.

HASH(0x2064c5b0)

The T332I mutation in Rho guanine nucleotide exchange factor 10 (ARHGEF10) was previously found in persons with slowed nerve conduction velocities and thin myelination of peripheral nerves. However, the molecular and cellular basis of the T332I mutant is not understood. Here, we show that ARHGEF10 has a negative regulatory region in the N terminus, in which residue 332 is located, and the T332I mutant is constitutively active. An N-terminal truncated ARHGEF10 mutant, ARHGEF10 ΔN (lacking amino acids 1-332), induced cell contraction that was inhibited by a Rho kinase inhibitor Y27632 and had higher GEF activity for RhoA than the wild type. The T332I mutant also showed the phenotype similar to the N-terminal truncated mutant. These data suggest that the ARHGEF10 T332I mutation-associated phenotype observed in the peripheral nerves is due to activated GEF activity of the ARHGEF10 T332I mutant.