Cerebellar Purkinje cells (PCs) express a large amount of the ␥ isoform of protein kinase C (PKC␥) and a modest level of PKC␣. The PKC␥ is involved in the pruning of climbing fiber (CF) synapses from developing PCs, and PKC␣ plays a critical role in long-term depression (LTD) at parallel fiber (PF)-PC synapses. Moreover, the PKC signaling in PCs negatively modulates the nonselective transient receptor potential cation channel type 3 (TRPC3), the opening of which elicits slow EPSCs at PF-PC synapses. Autosomal dominant spinocerebellar ataxia type 14 (SCA14) is caused by mutations in PKC␥. To clarify the pathology of this disorder, mutant (S119P) PKC␥ tagged with GFP was lentivirally expressed in developing and mature mouse PCs in vivo, and the effects were assessed 3 weeks after the injection. Mutant PKC␥-GFP aggregated in PCs without signs of degeneration. Electrophysiology results showed impaired pruning of CF synapses from developing PCs, failure of LTD expression, and increases in slow EPSC amplitude. We also found that mutant PKC␥ colocalized with wild-type PKC␥, which suggests that mutant PKC␥ acts in a dominant-negative manner on wild-type PKC␥. In contrast, PKC␣ did not colocalize with mutant PKC␥. The membrane residence time of PKC␣ after depolarization-induced translocation, however, was significantly decreased when it was present with the mutant PKC␥ construct. These results suggest that mutant PKC␥ in PCs of SCA14 patients could differentially impair the membrane translocation kinetics of wild-type ␥ and ␣ PKCs, which would disrupt synapse pruning, synaptic plasticity, and synaptic transmission.

Background Duodenal endoscopic submucosal dissection (ESD) remains technically challenging, with a high risk of severe adverse events. Because exposure of the duodenal post-ESD mucosal defect to pancreatic juice and bile acid reportedly induces delayed perforation and bleeding, we examined whether defect closure using an over-the-scope clip (OTSC) system was useful for preventing postoperative adverse events. Methods From April 2016 to February 2017, a total of 50 consecutive patients with superficial non-ampullary duodenal epithelial tumors (SNADETs) larger than 10 mm, with no more than semi-circumferential spread, were prospectively enrolled in this study. All of the lesions were treated by experienced ESD operators and the post-ESD mucosal defect was closed using OTSCs. Results All of the SNADETs were completely removed by ESD, with an R0 resection rate of 88.0 %. The mean procedure and closure times were 67.3 ± 58.8 minutes and 9.8 ± 7.2 minutes, respectively. Although complete defect closure was achieved in 94.0 % of the patients (47/50), two patients required surgical conversion. Delayed perforation occurred in only one patient (2.1 %), who did not have successful closure of the defect, as misplacement of the OTSC exposed the muscle layer. Meanwhile, delayed bleeding occurred in three patients (6.3 %); however, the bleeding was easily controlled using endoscopic coagulation. The mean duration of postoperative hospitalization was 5.5 ± 7.2 days. Conclusions Prophylactic defect closure using OTSCs may be effective in reducing severe adverse events after duodenal ESD.

In 42% of the osteosarcomas, the tumor cells expressed ErbB-2. Expression of ErbB-2 was strongly correlated with early pulmonary metastasis and poor survival rate for the patient. These data suggest that ErbB-2 plays a significant role in aggressive tumor growth and in the promotion of metastatic potential in osteosarcomas. ErbB-2 in the osteosarcoma tissues would be a useful prognostic marker for patients.

BACKGROUND The prognosis for patients with osteosarcoma has improved over the past 20 years, mainly due to developments in chemotherapy. Some proteins have been reported to show drug resistance. Theoretically, overexpression of some of these proteins makes treatment difficult, leading to poorer outcome. METHODS Specimens taken from conventional osteosarcomas of the extremity bones from 60 patients younger than 30 years were used. In all cases, preoperative oncostatic chemotherapy was undertaken after biopsy. If available, biopsy specimens were also used for sequential comparison. Among resistance‐related proteins, expression of metallothioneins (MTs), glutathione‐S‐transferase π (GST π), heat shock protein 27 (Hsp27), and lung resistance‐related protein (LRP) was evaluated immunohistochemically in paraffin sections. The log rank test was used for univariate analysis and the Cox regression model for multivariate analysis. RESULTS At biopsy, only overexpression of Hsp27 was associated with poor prognosis. At surgery, a relationship was observed between poor prognosis and overexpression of GST π, Hsp27, and LRP. Groups overexpressing one protein tended to overexpress another. Overexpression of these proteins in surgical specimens also correlated with histologic response to preoperative chemotherapy and clinical stage. In multivariate analysis, Hsp27 overexpression at biopsy was an independent prognostic factor. CONCLUSIONS Inherent overexpression of Hsp27 is independently related to poor outcome in osteosarcoma patients. Overexpression of GST π, Hsp27, and LRP at surgery might be associated with failure of preoperative chemotherapy. Control of the expression of these proteins may improve the outcome for patients with osteosarcoma. Cancer 1997; 79:2336‐44. © 1997 American Cancer Society.

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