Distinct roles of GSK-3α and GSK-3β phosphorylation in the heart under pressure overload

Glycogen synthase kinase-3 (GSK-3) is a master regulator of growth and death in cardiac myocytes. GSK-3 is inactivated by hypertrophic stimuli through phosphorylation-dependent and -independent mechanisms. Inactivation of GSK-3 removes the negative constraint of GSK-3 on hypertrophy, thereby stimulating cardiac hypertrophy. N-terminal phosphorylation of the GSK-3 isoforms GSK-3α and GSK-3β by upstream kinases (e.g., Akt) is a major mechanism of GSK-3 inhibition. Nonetheless, its role in mediating cardiac hypertrophy and failure remains to be established. Here we evaluated the role of Serine(S)21 and S9 phosphorylation of GSK-3α and GSK-3β in the regulation of cardiac hypertrophy and function during pressure overload (PO), using GSK-3α S21A knock-in (αKI) and GSK-3β S9A knock-in (βKI) mice. Although inhibition of S9 phosphorylation during PO in the βKI mice attenuated hypertrophy and heart failure (HF), inhibition of S21 phosphorylation in the αKI mice unexpectedly promoted hypertrophy and HF. Inhibition of S21 phosphorylation in GSK-3α, but not of S9 phosphorylation in GSK-3β, caused phosphorylation and down-regulation of G1-cyclins, due to preferential localization of GSK-3α in the nucleus, and suppressed E2F and markers of cell proliferation, including phosphorylated histone H3, under PO, thereby contributing to decreases in the total number of myocytes in the heart. Restoration of the E2F activity by injection of adenovirus harboring cyclin D1 with a nuclear localization signal attenuated HF under PO in the αKI mice. Collectively, our results reveal that whereas S9 phosphorylation of GSK-3β mediates pathological hypertrophy, S21 phosphorylation of GSK-3α plays a compensatory role during PO, in part by alleviating the negative constraint on the cell cycle machinery in cardiac myocytes.     

Combined pure red cell aplasia and autoimmune hemolytic anemia in systemic lupus erythematosus with anti-erythropoietin autoantibodies

A 42-year-old woman with systemic lupus erythematosus was admitted to our hospital because of severe anemia. Her bone marrow was almost normocellular and erythroblasts were nearly absent. Laboratory data showed elevated levels of lactate dehydrogenase and positive findings on Coombs' tests. On the basis of these findings, her anemia was diagnosed as the overlap of pure red cell aplasia with autoimmune hemolytic anemia. Radioimmunoprecipitation assay revealed that her serum was positive for anti-erythropoietin antibodies before therapy. Furthermore, the autoantibodies inhibited proliferation of an erythropoietin-dependent cell line in a dose-dependent manner. Immunosuppressive treatment improved the anemia accompanied with disappearance of the autoantibodies.     

Impact of extracapsular lymph node involvement on tumor progression in esophageal squamous cell carcinoma after neoadjuvant therapy and effects on lymph nodes induced by chemotherapy and chemoradiotherapy

Background

Neoadjuvant therapy followed by surgery can improve long-term survival and reduce local recurrence in patients with esophageal squamous cell carcinoma (ESCC). Extracapsular lymph node involvement (ECLNI) reflects tumor progression in gastrointestinal malignancies. The aim of this study was to clarify the correlation between ECLNI and clinical outcome in ESCC following neoadjuvant therapy.

Methods

A total of 36 patients with ESCC who underwent neoadjuvant therapy followed by surgery were enrolled in this study (CT: n = 16; CRT: n = 20). The correlation between ECLNI and clinicopathological variables was investigated. In addition, we also evaluated whether differences in pathological response existed between primary tumors and metastatic lymph nodes (LNs), and whether chemotherapy (CT) and chemoradiotherapy (CRT) had different effects on LNs.

Results

Of 36 patients, 22.2 % had detectable ECLNI. ECLNI was significantly correlated with tumor size (>40 mm), LN density (≧20 %), advanced stage, lymphatic invasion, non-R0 resection, and poor pathological response. Patients with ECLNI had a significantly poorer prognosis than those without ECLNI (P = 0.0040). No differences in pathological response were observed between primary tumors and metastatic LNs for each type of therapy. The median number of dissected LNs was 21, 45, and 14 in the surgery alone (n = 22), CT, and CRT groups, respectively (P < 0.05). More severe morphologic changes in LNs appeared to be induced by CRT than by CT.

Conclusion

ECLNI was correlated with poor prognosis in patients with ESCC after neoadjuvant therapy. CT and CRT had different effects on LNs.