Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3ß-mediated epileptic seizure activity in mice.

Human WWOX gene resides in the chromosomal common fragile site FRA16D and encodes a tumor suppressor WW domain-containing oxidoreductase. Loss-of-function mutations in both alleles of WWOX gene lead to autosomal recessive abnormalities in pediatric patients from consanguineous families, including microcephaly, cerebellar ataxia with epilepsy, mental retardation, retinal degeneration, developmental delay and early death. Here, we report that targeted disruption of Wwox gene in mice causes neurodevelopmental disorders, encompassing abnormal neuronal differentiation and migration in the brain. Cerebral malformations, such as microcephaly and incomplete separation of the hemispheres by a partial interhemispheric fissure, neuronal disorganization and heterotopia, and defective cerebellar midline fusion are observed in Wwox-/- mice. Degenerative alterations including severe hypomyelination in the central nervous system, optic nerve atrophy, Purkinje cell loss and granular cell apoptosis in the cerebellum, and peripheral nerve demyelination due to Schwann cell apoptosis correspond to reduced amplitudes and a latency prolongation of transcranial motor evoked potentials, motor deficits and gait ataxia in Wwox-/- mice. Wwox gene ablation leads to the occurrence of spontaneous epilepsy and increased susceptibility to pilocarpine- and pentylenetetrazol (PTZ)-induced seizures in preweaning mice. We determined that a significantly increased activation of glycogen synthase kinase 3ß (GSK3ß) occurs in Wwox-/- mouse cerebral cortex, hippocampus and cerebellum. Inhibition of GSK3ß by lithium ion significantly abolishes the onset of PTZ-induced seizure in Wwox-/- mice. Together, our findings reveal that the neurodevelopmental and neurodegenerative deficits in Wwox knockout mice strikingly recapitulate the key features of human neuropathies, and that targeting GSK3ß with lithium ion ameliorates epilepsy.

Hepatoma-derived growth factor supports the antiapoptosis and profibrosis of pancreatic stellate cells.

Pancreatic cancer is refractory and is characterized by extensively surrounding and intratumor fibrotic reactions that are contributed by activated pancreatic stellate cells (PSCs). Herein, we show that CCAAT/enhancer-binding protein δ (CEBPD) responds to transforming growth factor-ß1 (TGF-ß1) through reciprocal loop regulation and that activated hypoxia inducible factor-1α (HIF-1α) further contributes to the upregulation of the hepatoma-derived growth factor (HDGF) gene. Secreted HDGF contributes to the antiapoptosis of PSCs and consequently leads to the synthesis and deposition of extracellular matrix proteins for stabilizing PSC/pancreatic cancer cell (PCC) tumor foci. This result agrees with the observation that severe stromal growth positively correlated with stromal HDGF and CEBPD expression in pancreatic cancer specimens. Collectively, the identification of the TGF-ß1-activated CEBPD/HIF-1α/HDGF axis provides new insights into novel discoveries of HDGF in the antiapoptosis and profibrosis of PSCs and the outgrowth of PCCs.

Continuously tunable and fast-response terahertz metamaterials using in-plane-switching dual-frequency liquid crystal cells.

A metamaterial that is embedded in an in-plane-switching dual-frequency liquid crystal cell is used to develop an electrically controllable terahertz (THz) metamaterial. The resonance peak of the metamaterial can be redshifted and blueshifted as the frequency of an external voltage is switched, and the response times for the redshift and blueshift are 1.044 and 1.376 ms, respectively. A simulation confirms the spectral redshift and blueshift. The variation in peak frequency as a function of applied frequency at the external voltage is presented. Experimental results show that the resonance peak of the metamaterial can be continuously tuned within a frequency range of 15 GHz as the applied frequency is switched between 19 and 22 kHz. Therefore, this metamaterial is a continuously tunable and fast-response THz filter and could be used for THz imaging and THz telecommunications.

CCAAT/enhancer binding protein δ in macrophages contributes to immunosuppression and inhibits phagocytosis in nasopharyngeal carcinoma.

Although tumors tend to be associated with immune cells and inflammation, this immune response often fails to eliminate the cancer and instead promotes cancer progression. Tumor-associated macrophages (TAMs) fail to phagocytose tumor cells, and they also produce signals that suppress the adaptive immune response. We showed that immunosuppressive prostaglandin E2 (PGE2) led to the production and activity of the transcription factor CCAAT/enhancer binding protein δ (C/EBPδ) by stimulating the nucleocytoplasmic shuttling of the RNA binding protein Hu antigen R (HuR), which bound to and stabilized CEBPD mRNA in macrophages. An increase in C/EBPδ abundance in macrophages in response to PGE2 resulted in enhanced production of the immunosuppressive cytokine interleukin-10 (IL-10) and of pentraxin 3 (PTX3), which suppresses the ability of macrophages to phagocytose tumor cells. Furthermore, conditioned medium from C/EBPδ-replete, but not C/EBPδ-deficient, macrophages inhibited the phagocytosis of tumor cells by macrophages, suggesting an autocrine mode of regulation. Immunohistochemical analysis demonstrated that the amount of cytosolic HuR protein correlated with increased C/EBPδ abundance in TAMs in malignant nasopharyngeal carcinoma. Together, these data suggest that the inflammatory PGE2-HuR-C/EBPδ axis in macrophages promotes tumor progression by preventing the phagocytosis of tumor cells and inducing immunosuppressive cytokine production.

Off-pump surgery for multiple coronary artery fistulas with aneurysm.

A 78-year-old woman presented with acute myocardial infarction, anterior wall, Killip III, with congestive heart failure. The finding of coronary angiographic examination was multiple congenital coronary artery fistulas with a huge aneurysm, with fistulas originating from both the right coronary artery and left anterior descending artery. The patient received surgery successfully without cardiopulmonary bypass. The finding of the pathologic examination revealed hyaline change in the aneurysmal vessel wall. In a two-year follow-up, the patient was found to be asymptomatic clinically with improved left ventricular function.