Overexpression of NT-3 in the hippocampus suppresses the early phase of the adult neurogenic process.

The dentate gyrus (DG) of the hippocampus regulates stress-related emotional behaviors and ensures neurogenesis throughout life. Neurotrophin-3 (NT-3) is a neurotrophic factor that regulates neuronal differentiation, survival, and synaptic formation in both the peripheral and central nervous systems. NT-3 is expressed in the adult DG of the hippocampus; several chronic stress conditions enhance NT-3 expression in rodents. However, functional modulation of the adult DG by NT-3 signaling remains unclear. To directly investigate the impact of NT-3 on DG function, NT-3 was overexpressed in the hippocampal ventral DG by an adeno-associated virus carrying NT-3 (AAV-NT-3). Four weeks following the AAV-NT-3 injection, high NT-3 expression was observed in the ventral DG. We examined the influence of NT-3 overexpression on the neuronal responses and neurogenic processes in the ventral DG. NT-3 overexpression significantly increased the expression of the mature DG neuronal marker calbindin and immediate early genes, such as Fos and Fosb, thereby suggesting DG neuronal activation. During neurogenesis, the number of proliferating cells and immature neurons in the subgranular zone of the DG significantly decreased in the AAV-NT-3 group. Among the neurogenesis-related factors, Vegfd, Lgr6, Bmp7, and Drd1 expression significantly decreased. These results demonstrated that high NT-3 levels in the hippocampus regulate the activation of mature DG neurons and suppress the early phase of neurogenic processes, suggesting a possible role of NT-3 in the regulation of adult hippocampal function under stress conditions.

A case of synchronous serous ovarian cancer and uterine serous endometrial intraepithelial carcinoma.

BACKGROUND: Serous endometrial intraepithelial carcinoma (SEIC) is now considered to represent an early stage of uterine serous carcinoma (USC). It is an intraepithelial lesion but has been reported to cause extrauterine metastases. We report a case of SEIC with serous ovarian carcinoma and lymph node metastasis. CASE PRESENTATION: A 57-year-old post-menopausal woman (gravida 3, para 2, SA1) was referred to our hospital with lower abdominal pain. An ultrasound and MRI showed that the ovary had swollen to 8 cm in size and had a solid lesion. The uterus was normal. The patient underwent exploratory laparoscopy on the suspicion of torsion of the ovarian tumor. Intraoperative findings showed a right ovarian tumor, but no ovarian tumor torsion was observed. A small amount of bloody ascites was found in the Douglas fossa, and bleeding was observed from the tumor itself. A right salpingo-oophorectomy was then performed. Histopathological results revealed a high-grade serous carcinoma. Forty days after the first surgery, we performed a staging laparotomy: a total abdominal hysterectomy, left salpingo-oophorectomy, systematic pelvic and paraaortic lymphadenectomy, and a partial omentectomy. A complete cytoreduction was achieved. In the pathological examination, the invasion of the serous carcinoma was observed in the left ovarian ligament, and lymph node metastasis was found in the paraaortic lymph nodes. Atypical columnar cells formed irregular papillary lesions which had proliferated in the endometrium, and this was diagnosed as SEIC. The final diagnosis was serous ovarian cancer, FIGO stage IIIA1(ii), pT2bN1M0, with SEIC. CONCLUSION: We report a case of SEIC with synchronous serous carcinoma of the adnexa uteri. Both were serous carcinomas and, thus, it was difficult to identify the primary lesion. The distinction between metastatic cancer and two independent primary tumors is important for an accurate diagnosis and tumor staging. Histological diagnostic criteria remain controversial, and further development of a method for differentiating between both diseases is required.

A Case of Significant Response to Olaparib in a Patient with Primary Peritoneal Carcinosarcoma Diagnosed by Laparoscopic Surgery.

Primary peritoneal carcinosarcomas which arise from extragenital locations are extremely rare. Carinosarcomas contain both carcinomatous and sarcomatous elements and can be mainly detected in the female genital tract. We herein report a case of primary peritoneal carcinosarcoma diagnosed by laparoscopic surgery and treated with olaparib. A 62-year-old woman referred to our hospital due to abdominal distension. From imaging findings, we suspected advanced primary peritoneal carcinoma, and laparoscopic surgery was thereafter performed. The pathological diagnosis was carcinosarcoma, and the patient received chemotherapy with docetaxel and carboplatin. After three cycles of chemotherapy, the interval debulking surgery was attempted but resulted in suboptimal results. Because the bilateral ovaries were observed with a normal size and normal findings, we considered that the most likely diagnosis was primary peritoneal carcinosarcoma. After the additional chemotherapy and a 6-month observation period, the tumor relapsed. The patient received chemotherapy again, and the peritoneal carcinosarcoma was judged to be a platinum-sensitive tumor. Oral administration of olaparib was thus initiated. Although a dose reduction was needed due to anemia, olaparib was effective, and the patient could continue the drug for another 7 months. This is the first report of primary peritoneal carcinosarcoma treated with olaparib and shows that it could be a treatment option for platinum-sensitive tumors.

Anterior cleft palate due to Cbfb deficiency and its rescue by folic acid.

Core binding factor ß (Cbfb) is a cofactor of the Runx family of transcription factors. Among these transcription factors, Runx1 is a prerequisite for anterior-specific palatal fusion. It was previously unclear, however, whether Cbfb served as a modulator or as an obligatory factor in the Runx signaling process that regulates palatogenesis. Here, we report that Cbfb is essential and indispensable in mouse anterior palatogenesis. Palatal fusion in Cbfb mutants is disrupted owing to failed disintegration of the fusing epithelium specifically at the anterior portion, as observed in Runx1 mutants. In these mutants, expression of TGFB3 is disrupted in the area of failed palatal fusion, in which phosphorylation of Stat3 is also affected. TGFB3 protein has been shown to rescue palatal fusion in vitro TGFB3 also activated Stat3 phosphorylation. Strikingly, the anterior cleft palate in Cbfb mutants is further rescued by pharmaceutical application of folic acid, which activates suppressed Stat3 phosphorylation and Tgfb3 expression in vitro With these findings, we provide the first evidence that Cbfb is a prerequisite for anterior palatogenesis and acts as an obligatory cofactor in the Runx1/Cbfb-Stat3-Tgfb3 signaling axis. Furthermore, the rescue of the mutant cleft palate using folic acid might highlight potential therapeutic targets aimed at Stat3 modification for the prevention and pharmaceutical intervention of cleft palate.

A novel PTCH1 mutation in basal cell nevus syndrome with rare craniofacial features.

Basal cell nevus syndrome (BCNS) is a rare, multisystem, autosomal dominant disorder that is characterized by various phenotypes, including multiple basal cell carcinomas of the skin, odontogenic keratocysts of the jaws, and occasionally cleft lip and/or palate. In this report, we describe a 6-year-old Japanese girl with a novel heterozygous nonsense mutation in PTCH1 who exhibited rare craniofacial phenotypes, such as oligodontia and a short-tooth root.

Multidetector CT findings suggesting a perforation site in the gastrointestinal tract: analysis in surgically confirmed 155 patients.

PURPOSE: The aim of this study was to investigate how accurately we could diagnose the level of gastrointestinal (GI) tract perforation using multidetector computed tomography (MDCT). MATERIALS AND METHODS: We reviewed 155 patients with surgically confirmed GI tract perforation. MDCT scans were obtained with eight-detector CT; 5 mm thick axial images and 2.5 mm thick coronal multiplanar reconstruction (MPR) images were generated for all patients. Contrast enhancement was performed in 44 of the 155 patients. Two board-certified radiologists reviewed the images for direct findings (free air, ruptured GI tract wall) and indirect findings (inflammatory changes, fluid collection, focal thickening of the GI tract wall) and attempted to identify the perforation site in each patient. RESULTS: Free air was seen in more than 95% of the patients with perforation at sites other than the appendix; free air was seen in 44% of patients with appendicitis. On contrast-enhanced CT performed in 44 patients, rupture of the wall of the GI tract was directly visualized in 14 (32%) on axial images only and in 23 (52%) on axial or MPR images, respectively. The perforation site was correctly diagnosed in 90% of the patients when the radiologists referred to both direct and indirect findings. CONCLUSION: MDCT was valuable for identifying the presence and level of GI tract perforation.

Role of membrane-bound heparin-binding epidermal growth factor-like growth factor (HB-EGF) in renal epithelial cell branching.

UNLABELLED: Role of membrane-bound heparin-binding epidermal growth factor-like growth factor (HB-EGF) in renal epithelial cell branching. BACKGROUND: The developing metanephros is characterized by growth and differentiation of the ureteric bud and the surrounding mesenchymal tissue. These processes can be influenced by several growth factors, including epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha). We examined whether another member of the EGF family of growth factors, heparin-binding epidermal growth factor (HB-EGF), might act as a morphogen in renal epithelial tubulogenesis. METHODS: Expression of HB-EGF mRNA and immunoreactive protein were examined in fetal, neonatal and adult rat kidneys. For in vitro studies of tubulogenesis, a rat renal epithelial cell line (NRK52E) stably transfected with proHB-EGF (NRKproHB-EGF) was treated with TPA for 30 minutes, washed with 2 mol/L NaCl to remove soluble HB-EGF trapped by cell surface heparan sulfate proteoglycan and replated onto plastic dishes in the absence of fetal calf serum. In further experiments, NRKproHB-EGF were suspended in a type I collagen gel in serum-free media. RESULTS: Northern blot analysis indicated that HB-EGF was strongly expressed in embryonic rat kidney (embryonic days 18-20) and was still increased in the neonatal kidney (day 10), compared to the low basal levels in adult kidney. Immunohistochemical analysis confirmed that immunoreactive HB-EGF expression in the fetal rat kidney was localized predominantly to the ureteric bud. When NRKproHB-EGF were plated onto plastic substrata, they became progressively flattened and enlarged and exhibited filopoidia. By 10 hours after plating, NRKproHB-EGF began to migrate and subsequently developed cell-cell contact and fully established tubular-like structures. Immunoelectron microscopy revealed that the initial recovery of cellular proHB-EGF was localized predominantly to areas of cell-cell attachment. No tubule-like structures were observed in similarly treated NRK52E cells transfected with the vector alone. In collagen gels, NRKproHB-EGF developed short tubule-like structures in the absence of TPA treatment, but with simultaneous TPA treatment, longer and more arborized structures developed. MMP-1 mRNA and immunoreactive protein increased in the TPA-treated cells, suggesting that protein kinase C-mediated collagenase activity was important for the observed tubulogenesis. However, inhibition of EGF receptor tyrosine kinase with AG 1478 significantly blunted the TPA-induced tubulogenesis by NRKproHB-EGF grown in collagen gels. CONCLUSIONS: These results indicate that membrane-bound HB-EGF can mediate both epithelial cell branching and cell motility. Localization of proHB-EGF to the site of cell-cell contact and development of tubule-like structures in collagen gels suggests that proHB-EGF may be an important morphogen for renal epithelial cells.