Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats

Background & Aims: Regenerating gene (Reg) has been isolated from rat regenerating pancreatic islets, and Reg protein is mitogenic to islet cells. We have recently shown that Reg gene and Reg protein are expressed in gastric enterochromaffin-like (ECL) cells. This study aimed to clarify whether gastrin enhances Reg protein production in ECL cells and whether Reg protein is mitogenic to gastric mucosal cells. Methods:Reg gene expression in response to acute and chronic hypergastrinemia was investigated in rats. Immunohistochemical studies, Northern blotting, and in situ hybridization were performed to investigate the expression of Reg protein and Reg gene. The direct effect of gastrin on Reg gene expression was investigated using isolated ECL cells, and the trophic effect of Reg protein on cultured gastric epithelial cells was assessed by [³H]thymidine uptake. Results: Both chronic hypergastrinemia and short-term gastrin administration stimulated Reg gene expression and Reg protein production in fundic mucosa. Reg gene expression was also augmented in isolated ECL cells after incubation with rat gastrin. Reg protein was mitogenic to cultured rat gastric epithelial cells. Conclusions: Gastrin stimulates the production of Reg protein in gastric ECL cells, which may be involved in the gastrin-induced gastric mucosal cell growth.GASTROENTEROLOGY 1998;115:1483-1493     

Cabergoline administration prevents development of moderate to severe ovarian hyperstimulation syndrome and it contributes to reduction in ovarian volume

PurposeThe aim of this study was to determine the prophylactic effects of cabergoline on ovarian hyperstimulation syndrome (OHSS) after oocyte retrieval.MethodsA total of 187 women underwent controlled ovarian stimulation using gonadotropin releasing hormone (GnRH) agonist long protocol or flexible GnRH antagonist protocol for in vitro fertilization. They responded excessively to ovulation induction, and fresh embryo transfers were canceled. Sixty‐one patients in the intervention group were administered oral cabergoline (0.5 mg) three times after oocyte retrieval (day 0, 2, and 4 following the oocyte retrieval). Ultrasonography and blood examination were performed on the seventh day following oocyte retrieval. The main outcomes measured were the incidence of OHSS, estimated ovarian volumes, ascites, hematocrits, and white blood cell counts.ResultsThe incidence of moderate to severe OHSS was lower after cabergoline administration (9.8 vs. 23.0 %, p = 0.03). The ovarian volumes reduced after intervention (96.2 vs. 145.5 cm³, p = 0.008). The reduction was evident in the patients with agonist long protocol (92.1 vs. 167.5 cm³, p = 0.0005). No significant differences were observed for other factors.ConclusionsCabergoline has a favorable effect on the prevention of moderate to severe OHSS affiliated with ovarian volume reduction.     

Being breastfed in infancy and adult breast cancer risk among Japanese women

Objective  

Being breastfed in infancy has been hypothesized to influence subsequent breast cancer risk. In a hospital-based case–control study, we investigated the relationship between having been breastfed and breast cancer risk, both overall and separately among female subjects with different birth years.     

Validity of endoscopic classification of nonerosive reflux disease

BACKGROUND: Minimal changes, such as erythema without sharp demarcation or whitish turbidity of the lower esophageal mucosa, have recently been used for endoscopic classification of nonerosive reflux disease (NERD) in Japan. This study examined the usefulness of such changes in characterizing the pathophysiology of NERD. METHODS: Physicians specializing in esophageal endoscopy performed endoscopy on 115 patients with NERD. Based on the presence or absence of minimal changes, patients were categorized as displaying NERD with minimal changes (grade M, n = 49) or with no minimal changes or mucosal breaks (grade N, n = 66). Clinical features, quality of life (QOL) scores, and ambulatory 24-h esophageal pH values were compared between groups. Ambulatory 24-h esophageal pH values were monitored in 31 patients (14 grade M and 17 grade N patients) who gave consent out of 115 patients. RESULTS: In ambulatory 24-h esophageal pH monitoring, 57.1% (8/14) of grade M patients had pH < 4 more than 4% of the time (abnormal acid reflux) compared with 11.8% (2/17) in the grade N group, a significant difference (P = 0.018). QOL scores did not differ significantly between grades and were significantly lower in both groups compared with the general Japanese population. No significant differences were observed in patient background between the grade M and grade N groups. CONCLUSIONS: Frequency of abnormal acid reflux with NERD is higher in patients with minimal changes than in patients without such changes. Minimal changes are most likely attributable to gastric acid reflux.     

Phase I/II Study of Cisplatin plus Nab‐Paclitaxel with Concurrent Thoracic Radiotherapy for Patients with Locally Advanced Non‐Small Cell Lung Cancer

Lessons Learned

• The combination of cisplatin plus nab‐paclitaxel with concurrent thoracic radiotherapy in unresectable stage III non‐small cell lung cancer is a promising therapeutic strategy.
• Further investigation is warranted.

BackgroundWe conducted a phase I/II trial of cisplatin plus nab‐paclitaxel with concurrent thoracic radiotherapy for locally advanced non‐small cell lung cancer (NSCLC) to determine the recommended dose (RD) of nab‐paclitaxel and to evaluate the safety and efficacy of this regimen.MethodsIn the phase I study, escalating doses of weekly nab‐paclitaxel were administered together with cisplatin at 75 mg/m² every 3 weeks and concurrent radiotherapy. In the phase II study, nab‐paclitaxel was administered at the RD.ResultsIn the phase I study, whereas no dose‐limiting toxicity (DLT) was observed with nab‐paclitaxel at 50 or 60 mg/m², one of six patients experienced DLT (esophagitis of grade 3) at 70 mg/m², determined as the RD. Twenty‐four patients at RD were evaluable for safety and efficacy in phase II. Common toxicities included esophagitis (87.5%) and leukopenia (79.2%). Pneumonitis and treatment‐related deaths were not observed, but 20 patients (83.3%) experienced radiation pneumonitis, with one case of grade 3 and four of grade 2, after completion of concurrent chemoradiotherapy. The 2‐year overall survival and progression‐free survival rates were 73.9% and 56.5% (95% confidence interval [CI], 34.3%–74.7%), respectively.ConclusionConcurrent chemoradiation with nab‐paclitaxel at 70 mg/m² and cisplatin at 75 mg/m² every 3 weeks showed encouraging feasibility and activity for locally advanced NSCLC.     

SHP2 mediates gp130-dependent cardiomyocyte hypertrophy via negative regulation of skeletal alpha-actin gene

Morphological and biochemical phenotypes of cardiomyocyte hypertrophy are determined by neurohumoral factors. Stimulation of G protein-coupled receptor (GPCR) results in uniform cell enlargement in all directions with an increase in skeletal α-actin (α-SKA) gene expression, while stimulation of gp130 receptor by interleukin-6 (IL-6)-related cytokines induces longitudinal elongation with no increase in α-SKA gene expression. Thus, α-SKA is a discriminating marker for hypertrophic phenotypes; however, regulatory mechanisms of α-SKA gene expression remain unknown. Here, we clarified the role of SH2-containing protein tyrosine phosphatase 2 (SHP2) in α-SKA gene expression. In neonatal rat cardiomyocytes, endothelin-1 (ET-1), a GPCR agonist, but not leukemia inhibitory factor (LIF), an IL-6-related cytokine, induced RhoA activation and promotes α-SKA gene expression via RhoA. In contrast, LIF, but not ET-1, induced activation of SHP2 in cardiomyocytes, suggesting that SHP2 might negatively regulate α-SKA gene expression downstream of gp130. Therefore, we examined the effect of adenovirus-mediated overexpression of wild-type SHP2 (SHP2^WT), dominant-negative SHP2 (SHP2^C/S), or β-galactosidase (β-gal), on α-SKA gene expression. LIF did not upregulate α-SKA mRNA in cardiomyocytes overexpressing either β-gal or SHP2^WT. In cardiomyocytes overexpressing SHP2^C/S, LIF induced upregulation of α-SKA mRNA, which was abrogated by concomitant overexpression of either C3-toxin or dominant-negative RhoA. RhoA was activated after LIF stimulation in the cardiomyocytes overexpressing SHP2^C/S, but not in myocytes overexpressing β-gal. Furthermore, SHP2 mediates LIF-induced longitudinal elongation of cardiomyocytes via ERK5 activation. Collectively, these findings indicate that SHP2 negatively regulates α-SKA expression via RhoA inactivation and suggest that SHP2 implicates ERK5 in cardiomyocyte elongation downstream of gp130.