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Zinc-fingers and homeoboxes 1 (ZHX1) is a nuclear transcription repressor and known to be involved in cell differentiation and tumorigenesis. However, the pathophysiological roles of ZHX1 have not been characterized in glioblastoma. We examined ZHX1 expression in glioblastoma patients' tissues and analyzed overall survival of the patients based on expression level of ZHX1. We also examined the effects of ZHX1 on proliferation and motility of glioblastoma cells. In silico analysis and immunohistochemical studies showed that the messenger RNA and protein expressions of ZHX1 were higher in the tissues of glioblastoma patients than in normal brain tissues, and that its overexpression was associated with reduced survival. In vitro, the downregulation of ZHX1 decreased the proliferation, migration, and invasion of glioblastoma cells, whereas its upregulation had the opposite effects. In addition, we showed ZHX1 could contribute to glioblastoma progression via the regulations of TWIST1 and SNAI2. Taken together, this study demonstrates that ZHX1 plays crucial roles in the progression of glioblastoma, and its findings suggest that ZHX1 be viewed as a potential prognostic maker and therapeutic target of glioblastoma.

Zinc fingers and homeoboxes (ZHX) is a transcription repressor family that contains three members; ZHX1, ZHX2, and ZHX3. Although ZHX family members have been associated with the progression of cancer, their values as prognostic factors in cancer patients have been poorly examined. Renal cell carcinoma (RCC) is a highly heterogeneous, aggressive cancer that responds variably to treatment. Thus, prognostic molecular markers are required to evaluate disease progression and to improve the survival. In clear cell RCC (ccRCC), ZHX1 and ZHX3 expression were found to be down-regulated but ZHX2 was up-regulated, and the expressions of ZHX1 and ZHX3 were significantly associated with pathological stage. Furthermore, Kaplan-Meier and multivariate regression analysis showed that reduction in the mRNA expression of ZHX1 was associated with poorer survival. Taken together, the present study shows loss of ZHX1 is correlated with ccRCC progression and suggests it is an independent prognostic marker in ccRCC., Competing Interests: The authors have declared that no competing interests exist.

In this study, we investigated various highly porous extracellular matrix (ECM)-based cryogels for cartilage tissue engineering. For the fabrication of ECM-based cryogels, either methacrylated chondroitin sulfate (MeCS) or methacrylated hyaluronic acid (MeHA) were cross-linked along with poly (ethylene glycol) diacrylates (PEGDA) via free radical polymerization under freezing conditions. This procedure induces ice crystallization (used as a porogen) prior polymer crosslinking in which, after complete cryopolymerization, a thawing process transforms the ice crystals into a unique interconnected macroporous structure within ECM-cryogels. The developed ECM-cryogels exhibited an average macroporosity of 75% and supported the infiltration of chondrocyteds. When rabbit chondrocytes were cultured on ECM-cryogels, MeCS-based cryogels stimulated aggrecan gene expression and GAG accumulation, whereas MeHA-based cryogels stimulated type II collagen gene expression and collagen accumulation. These results demonstrate that design of ECM-based cryogels can play an important role in promoting specific ECM proteins secretion for cartilage tissue engineering., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Zinc-fingers and homeoboxes 1 (ZHX1) is a transcription repressor that has been associated with the progressions of hepatocellular carcinoma, gastric cancer, and breast cancer. However, the functional roles of ZHX1 in cholangiocarcinoma (CCA) have not been determined. We investigated the expression and roles of ZHX1 during the proliferation, migration, and invasion of CCA cells. In silico analysis and immunohistochemical studies showed amplification and overexpression of ZHX1 in CCA tissues. Furthermore, ZHX1 knockdown using specific siRNAs decreased CCA cell proliferation, migration, and invasion, whereas ZHX1 overexpression promoted all three characteristics. In addition, results suggested EGR1 might partially mediate the effect of ZHX1 on the proliferation of CCA cells. Taken together, these results show ZHX1 promotes CCA cell proliferation, migration, and invasion, and present ZHX1 as a potential target for the treatment of CCA., Competing Interests: The authors have declared that no competing interests exist.

Abnormal DNA methylation is an epigenetic mechanism that promotes gastric carcinogenesis. While the abnormal methylation at promoter regions has been characterized for many genes, the function of DNA methylation marks at distal regulatory regions in gastric cancer remains poorly described. Here, we performed RNA-seq, MBD-seq, and H3K27ac ChIP-seq on gastric tissues and cell lines to understand the epigenetic changes in the distal as well as the proximal regulatory regions. In total, 257,651 significant DMRs (Differentially methylated regions) were identified in gastric cancer, and the majority of these DMRs were located in the intergenic, intronic, and non-coding RNA regions. We identified the aberrant expression of many genes and lncRNAs due to changes in DNA methylation. Furthermore, we profiled the molecular subtype-specific methylation patterns in gastric cancer to characterize subtype-specific regulators that undergo DNA methylation changes. Our findings provide insights for understanding methylation changes at distal regulatory regions and reveal novel epigenetic targets in gastric cancer., Competing Interests: The authors declare no conflicts of interest.

In this study, we present a method for assembling biofunctionalized paper into a multiform structured scaffold system for reliable tissue regeneration using an origami-based approach. The surface of a paper was conformally modified with a poly(styrene-co-maleic anhydride) layer via initiated chemical vapor deposition followed by the immobilization of poly-l-lysine (PLL) and deposition of Ca(2+). This procedure ensures the formation of alginate hydrogel on the paper due to Ca(2+) diffusion. Furthermore, strong adhesion of the alginate hydrogel on the paper onto the paper substrate was achieved due to an electrostatic interaction between the alginate and PLL. The developed scaffold system was versatile and allowed area-selective cell seeding. Also, the hydrogel-laden paper could be folded freely into 3D tissue-like structures using a simple origami-based method. The cylindrically constructed paper scaffold system with chondrocytes was applied into a three-ring defect trachea in rabbits. The transplanted engineered tissues replaced the native trachea without stenosis after 4 wks. As for the custom-built scaffold system, the hydrogel-laden paper system will provide a robust and facile method for the formation of tissues mimicking native tissue constructs.

Neuronal loss caused by neurodegenerative diseases, traumatic brain injury and stroke results in cognitive dysfunctioning. Implantation of neural stem/precursor cells (NPCs) can improve the brain function by replacing lost neurons. Proper synaptic integration following neuronal differentiation of implanted cells is believed to be a prerequisite for the functional recovery. In the present study, we characterized the functional properties of immortalized neural progenitor HiB5 cells implanted into the rat hippocampus with chemically induced lesion. The implanted HiB5 cells migrated toward CA1 pyramidal layer and differentiated into vGluT1-positive glutamatergic neurons with morphological and electrophysiological properties of endogenous CA1 pyramidal cells. Functional synaptic integration of HiB5 cell-derived neurons was also evidenced by immunohistochemical and electrophysiological data. Lesion-caused memory deficit was significantly recovered after the implantation when assessed by inhibitory avoidance (IA) learning. Remarkably, IA learning preferentially produced long-term potentiation (LTP) at the synapses onto HiB5 cell-derived neurons, which occluded paring protocol-induced LTP ex vivo. We conclude that the implanted HiB5 cell-derived neurons actively participate in learning process through LTP formation, thereby counteracting lesion-mediated memory impairment.

Various types of histone methylation have been associated with cancer progression. Depending on the methylation site in histone proteins, its effects on transcription are different. DPY30 is a common member of SET1/MLL histone H3K4 methyltransferase complexes. However, its expression and roles in gastric cancer have been poorly characterized. To determine whether DPY30 has pathophysiological roles in gastric cancer, its expression and roles were examined. Immunohistochemistry and real time PCR showed up-regulation of DPY30 expression in some gastric cancer cell lines and patients' tissues. Its knockdown by siRNA decreased the proliferation, migration, and invasion of gastric cancer cells, whereas its overexpression showed the opposite effects. These results indicate that DPY30 has critical roles in the proliferation, migration, and invasion of gastric cancer cells, and suggest DPY30 might be a therapeutic target in gastric cancer.

MED30 is an essential member of the mediator complex that forms a hub between transcriptional activators and RNA polymerase II. However, the expressions and roles of MED30 have been poorly characterized in cancer. In this study, we examined the functional roles of MED30 during gastric cancer progression. It was found that MED30 was overexpressed in gastric cancer tissues and cell lines. Moreover, MED30 overexpression increased the proliferation, migration, and invasion of gastric cancer cells, whereas MED30 knockdown inhibited these effects. Furthermore the knockdown significantly inhibited tumorigenicity in SCID mice. MED30 also promoted the expressions of genes related to epithelial-mesenchymal transition and induced a fibroblast-like morphology. This study shows MED30 has pathophysiological roles in the proliferation, migration, and invasion of gastric cancer cells and suggests that MED30 should be viewed as a potent therapeutic target for malignant gastric carcinoma.

Background: Gastric cancer stem cells (GCSCs) have been successfully isolated from patients. However, the molecular mechanisms underlying the self-renewal of GCSCs and their relationship with the microenvironment are poorly characterized., Methods: GCSCs and cancer-associated fibroblasts (CAFs) were cultured directly from gastric cancer patients. The self-renewal of GCSCs was assayed by sphere formation assay and in vivo tumorigenicity. Expression of neuregulin1 (NRG1) was examined by immunohistochemistry, real-time PCR and western blotting., Results: CAFs increased the self-renewal of GCSCs by secreting NRG1. NRG1 activated NF-κB signaling and this activation regulated GCSC self-renewal. Moreover, NF-κB-active GCSCs were tumorigenic, however NF-κB-inactive GCSCs were not. The overexpression of NRG1 in stromal cells and cancer cells was observed in the tumor tissues of gastric cancer patients and was associated with clinical stage lymph node metastasis and survival in gastric cancer patients. In addition, we also found that NRG1 can regulate the proliferation and invasion of gastric cancer cells., Conclusions: These results indicate that NRG1, which can be secreted by CAFs or cancer cells, promotes progression of gastric cancer by regulating the self-renewal of GCSCs and its overexpression is associated with a prognosis of gastric cancer.

Cancer stem cells (CSCs) have been shown to mediate tumorigenicity, chemo-resistance, radio-resistance and metastasis, which suggest they be considered therapeutic targets. Because their differentiated daughter cells are no longer tumorigenic, to induce the differentiation of CSCs can be one of strategies which can eradicate CSCs. Here we show that ATOH1 can induce the differentiation of gastric cancer stem cells (GCSCs). Real time PCR and western blot analysis showed that ATOH1 was induced during the differentiation of GCSCs. Furthermore, the lentivirus-induced overexpression of ATOH1 in GCSCs and in gastric cancer cell lines significantly induced differentiation, reduced proliferation and sphere formation, and reduced in vivo tumor formation in the subcutaneous injection and liver metastasis xenograft models. These results suggest ATOH1 be considered for the development of a differentiation therapy for gastric cancer.

Matrix metalloproteinase 2 (MMP2) plays critical roles in various diseases, such as atherosclerosis and cancer, and has been suggested to contribute to the instability of atherosclerotic plaque. To visualize MMP2 in pathologic tissues, we developed an aptamer targeting MMP2 protein by performing eight rounds of modified DNA systematic evolution of ligands by exponential enrichment (SELEX). The aptamer showed high affinity for MMP2 (Kd = 5.59 nM), precipitated MMP2, and detected MMP2 protein in pathological tissues such as atherosclerotic plaque and gastric cancer tissues. Furthermore, a MMP2 aptamer-conjugated fluorescent nanoprobe successfully visualized atherosclerotic plaques in apolipoprotein E (ApoE) knockout mice. These results suggest that the devised MMP2 aptamer could be useful for the development of various diagnostic tools.

Background: Wilms' tumor 1-associating protein (WTAP) is a nuclear protein that has been associated with the regulation of proliferation and apoptosis. Although its dynamic expression and physiological functions in vascular cells have been reported, its expression and roles in cholangiocarcinoma cells are poorly characterized., Methods: To examine the expression of WTAP in patient tissues, we performed immunohistochemistry. To examine motility of cholangiocarcinoma cells, we employed Boyden chamber, wound healing and Matrigel invasion assays, and a liver xenograft model., Results: Immunohistochemistry in patient tissues showed WTAP overexpression in cholangiocarcinoma tissues and correlation of WTAP expression with metastasis of cholangiocarcinoma cells. Overexpression or knockdown of WTAP significantly increased or decreased the motility of cholangiocarcinoma cells. Moreover, WTAP overexpression or knockdown significantly increased or decreased tumorigenicity of cholangiocarcinoma cells in an orthotopic xenograft model. Furthermore, microarray study showed that WTAP induce the expressions of MMP7, MMP28, cathepsin H and Muc1., Conclusion: WTAP is overexpressed in cholangiocarcinoma and regulates motility of cholangiocarcinoma cells.

The gastric epithelium is continuously regenerated by gastric stem cells, which give rise to various kinds of daughter cells, including parietal cells, chief cells, surface mucous cells, mucous neck cells, and enteroendocrine cells. The self-renewal and differentiation of gastric stem cells need delicate regulation to maintain the normal physiology of the stomach. Recently, it was hypothesized that cancer stem cells drive the cancer growth and metastasis. In contrast to conventional clonal evolution hypothesis, only cancer stem cells can initiate tumor formation, self-renew, and differentiate into various kinds of daughter cells. Because gastric cancer can originate from gastric stem cells and their self-renewal mechanism can be used by gastric cancer stem cells, we review here how critical signaling pathways, including hedgehog, Wnt, Notch, epidermal growth factor, and bone morphogenetic protein signaling, may regulate the self-renewal and differentiation of gastric stem cells and gastric cancer stem cells. In addition, the precancerous change of the gastric epithelium and the status of isolating gastric cancer stem cells from patients are reviewed.

Glioblastoma is a diffusely growing malignant brain tumor and among the most aggressive of all tumors. Wilms' tumor 1-associating protein (WTAP) is a nuclear protein that has been associated with regulation of proliferation and apoptosis. Although its dynamic expression and physiological functions in vascular cells have been reported, those in other cells are largely unknown. Here, we show for the first time that WTAP is overexpressed in glioblastoma. Moreover we found that WTAP regulates migration and invasion of glioblatoma cells. Specific knockdown by siRNA or overexpression by cDNA regulated migration and invasion of cancer cells. In xenograft study, WTAP overexpression made cancer cells more tumorigenic. In the investigation for its underlying mechanism, we found that the activity of epidermal growth factor receptor can be regulated by WTAP. These results reveal a novel function of WTAP and suggest its clinical application., (© 2012 Japanese Cancer Association.)

Background: Lamina-associated polypeptides 2 (LAP2) is a nuclear protein that connects the nuclear lamina with chromatin. Although its critical roles in genetic disorders and hematopoietic malignancies have been described, its expression and roles in digestive tract cancers have been poorly characterized., Methods: To examine the expression of LAP2 in patient tissues, we performed immunohistochemistry and real-time PCR. To examine motility of cancer cells, we employed Boyden chamber, wound healing and Matrigel invasion assays. To reveal its roles in metastasis in vivo, we used a liver metastasis xenograft model. To investigate the underlying mechanism, a cDNA microarray was conducted., Results: Immunohistochemistry in patient tissues showed widespread expression of LAP2 in diverse digestive tract cancers including stomach, pancreas, liver, and bile duct cancers. Real-time PCR confirmed that LAP2β is over-expressed in gastric cancer tissues. Knockdown of LAP2β did not affect proliferation of most digestive tract cancer cells except pancreatic cancer cells. However, knockdown of LAP2β decreased motility of all tested cancer cells. Moreover, overexpression of LAP2β increased motility of gastric and pancreatic cancer cells. In the liver metastasis xenograft model, LAP2β increased metastatic efficacy of gastric cancer cells and mortality in tested mice. cDNA microarrays showed the possibility that myristoylated alanine-rich C kinase substrate (MARCKS) and interleukin6 (IL6) may mediate LAP2β-regulated motility of cancer cells., Conclusions: From the above results, we conclude that LAP2 is widely overexpressed in diverse digestive tract cancers and LAP2β regulates motility of cancer cells and suggest that LAP2β may have utility for diagnostics and therapeutics in digestive tract cancers.

Cancer stem cells have been hypothesized to drive the growth and metastasis of tumors. Because they need to be targeted for cancer treatment, they have been isolated from many solid cancers. However, cancer stem cells from primary human gastric cancer tissues have not been isolated as yet. For the isolation, we used two cell surface markers: the epithelial cell adhesion molecule (EpCAM) and CD44. When analyzed by flow cytometry, the EpCAM(+)/CD44(+) population accounts for 4.5% of tumor cells. EpCAM(+)/CD44(+) gastric cancer cells formed tumors in immunocompromised mice; however, EpCAM(-)/CD44(-), EpCAM(+)/CD44(-) and EpCAM(-)/CD44(+) cells failed to do so. Xenografts of EpCAM(+)/CD44(+) gastric cancer cells maintained a differentiated phenotype and reproduced the morphological and phenotypical heterogeneity of the original gastric tumor tissues. The tumorigenic subpopulation was serially passaged for several generations without significant phenotypic alterations. Moreover, EpCAM(+)/CD44(+), but not EpCAM(-)/CD44(-), EpCAM(+)/CD44(-) or EpCAM(-)/CD44(+) cells grew exponentially in vitro as cancer spheres in serum-free medium, maintaining the tumorigenicity. Interestingly, a single cancer stem cell generated a cancer sphere that contained various differentiated cells, supporting multi-potency and self-renewal of a cancer stem cell. EpCAM(+)/CD44(+) cells had greater resistance to anti-cancer drugs than other subpopulation cells. The above in vivo and in vitro results suggest that cancer stem cells, which are enriched in the EpCAM(+)/CD44(+) subpopulation of gastric cancer cells, provide an ideal model system for cancer stem cell research.

Purpose: To evaluate the prognostic outcome of cardiac computed tomography (CT) for prediction of major adverse cardiac events (MACEs) in low-risk patients suspected of having coronary artery disease (CAD) and to explore the differential prognostic values of coronary artery calcium (CAC) scoring and coronary CT angiography., Materials and Methods: Institutional review committee approval and informed consent were obtained. In 4338 patients who underwent 64-section CT for evaluation of suspected CAD, both CAC scoring and CT angiography were concurrently performed by using standard scanning protocols. Follow-up clinical outcome data regarding composite MACEs were procured. Multivariable Cox proportional hazards models were developed to predict MACEs. Risk-adjusted models incorporated traditional risk factors for CAC scoring and coronary CT angiography., Results: During the mean follow-up of 828 days ± 380, there were 105 MACEs, for an event rate of 3%. The presence of obstructive CAD at coronary CT angiography had independent prognostic value, which escalated according to the number of stenosed vessels (P < .001). In the receiver operating characteristic curve (ROC) analysis, the superiority of coronary CT angiography to CAC scoring was demonstrated by a significantly greater area under the ROC curve (AUC) (0.892 vs 0.810, P < .001), whereas no significant incremental value for the addition of CAC scoring to coronary CT angiography was established (AUC = 0.892 for coronary CT angiography alone vs 0.902 with addition of CAC scoring, P = .198)., Conclusion: Coronary CT angiography is better than CAC scoring in predicting MACEs in low-risk patients suspected of having CAD. Furthermore, the current standard multisection CT protocol (coronary CT angiography combined with CAC scoring) has no incremental prognostic value compared with coronary CT angiography alone. Therefore, in terms of determining prognosis, CAC scoring may no longer need to be incorporated in the cardiac CT protocol in this population., (© RSNA, 2011.)

Glioblastoma is the most common type of astrocytoma in the brain. Due to its high invasiveness and chemoresistance, patients with advanced stage of glioblastoma have a poor prognosis. SNAI1, an important regulator of epithelial-mesenchymal transition, has been associated with metastasis in various carcinoma cells. However, its roles in glioblastoma cells have been poorly characterized. To examine roles of SNAI1 in glioblastoma cells, we knockdowned SNAI1 expression using siRNA. SNAI1 siRNA increased the expression level of E-cadherin and decreased that of vimentin. In the water-soluble tetrazolium salt (WST-1) assay, SNAI1 siRNA inhibited the proliferation of U87-MG and GBM05 glioblastoma cells. Moreover, in the Boyden chamber assay and Matrigel invasion assay, SNAI1 siRNA inhibited serum-induced migration and invasion of glioblastoma cells. These results suggested that SNAI1 is involved in the proliferation and migration of glioblastoma cells.

Hedgehog (Hh) signaling is an essential pathway in embryonic development of prostate. Hh also plays roles in the proliferation of progenitor cells and cancer cells of adult prostate. However, how Hh signaling contributes to carcinogenesis of prostate is poorly understood. Stathmin1 is a microtubule-regulating protein that plays an important role in the assembly and disassembly of the mitotic spindle. Stathmin1 is expressed in normal developing mouse prostate and in prostate cancer. The expression pattern of stathmin1 is similar to that of Shh in prostate development and cancer, suggesting a connection between these two proteins. In this study, we examined the relationship between stathmin1 and Hh signaling. Here, we show that stathmin1 expression is regulated by Hh signaling in prostate cancer cells. Cyclopamine, a specific inhibitor of Hh signaling, reduced the expression of stathmin1 in prostate cancer cells. However, the Shh peptide induced stathmin1 expression. Overexpression of Gli1 further confirmed the relationship. Co-expression of stathmin1 and Patched 1, a receptor for Hh signaling was observed in prostate cancer tissues. Cyclopamine and stathmin1 siRNA both decreased proliferation of prostate cancer cells but did not produce an additive effect, suggesting a common pathway. These results suggest that Hh signaling regulates proliferation of prostate cancer cells by controlling stathmin1 expression.

Background: Stathmin1 is a microtubule-regulating protein that has an important role in the assembly and disassembly of the mitotic spindle. The roles of stathmin1 in carcinogenesis of various cancers, including prostate and breast cancer, have been explored. However, its expression and roles in gastric cancer have not yet been described., Methods: Stathmin1 expression in paraffin-embedded tissue sections from 226 patients was analysed by immunohistochemistry. Roles of stathmin1 were studied using a specific small interfering RNA (siRNA)., Results: The expression of stathmin1 was positively correlated with lymph node metastasis, TNM stages and vascular invasion, and negatively with recurrence-free survival, in the diffuse type of gastric cancer. The median recurrence-free survival in patients with a negative and positive expression of stathmin1 was 17.0 and 7.0 months, respectively (P=0.009). When the expression of stathmin1 was knocked down using siRNA, the proliferation, migration and invasion of poorly differentiated gastric cancer cells in vitro were significantly inhibited. Moreover, stathmin1 siRNA transfection significantly slowed the growth of xenografts in nude mice., Conclusion: These results suggest that stathmin1 can be a good prognostic factor for recurrence-free survival rate and is a therapeutic target in diffuse-type gastric cancer.

Background: Caffeine is the most commonly consumed psycho-stimulant in the world. The effects of caffeine on the body have been extensively studied; however, its effect on the structure of the brain has not been investigated to date., Results: In the present study we found that the long-term consumption of caffeine can induce ventriculomegaly; this was observed in 40% of the study rats. In the caffeine-treated rats with ventriculomegaly, there was increased production of CSF, associated with the increased expression of Na(+), K(+)-ATPase and increased cerebral blood flow (CBF). In contrast to the chronic effects, acute treatment with caffeine decreased the production of CSF, suggesting 'effect inversion' associated with caffeine, which was mediated by increased expression of the A1 adenosine receptor, in the choroid plexus of rats chronically treated with caffeine. The involvement of the A1 adenosine receptor in the effect inversion of caffeine was further supported by the induction of ventriculomegaly and Na+, K+-ATPase, in A1 agonist-treated rats., Conclusion: The results of this study show that long-term consumption of caffeine can induce ventriculomegaly, which is mediated in part by increased production of CSF. Moreover, we also showed that adenosine receptor signaling can regulate the production of CSF by controlling the expression of Na(+), K(+)-ATPase and CBF.

Gastric cancer is the second most common cause of cancer deaths worldwide. The underlying molecular mechanisms of its carcinogenesis are relatively poorly characterized. Hedgehog (Hh) signaling, which is critical for development of various organs including the gastrointestinal tract, has been associated with gastric cancer. The present study was undertaken to reveal the underlying mechanism by which Hh signaling controls gastric cancer cell proliferation. Treatment of gastric cancer cells with cyclopamine, a specific inhibitor of Hh signaling pathway, reduced proliferation and induced apoptosis of gastric cancer cells. Cyclopamine treatment induced cytochrome c release from mitochondria and cleavage of caspase 9. Moreover, Bcl-2 expression was significantly reduced by cyclopamine treatment. These results suggest that Hh signaling regulates the survival of gastric cancer cells by regulating the expression of Bcl-2.

Ischemia-induced cerebral injury evolves over a longer period than previously believed through post-ischemic inflammation. Retinoic acid (RA) has been shown to exert cytoprotective effects on several cells, but its effects on ischemia-induced cerebral injury have been poorly characterized. The aim of the present study was to examine the effects of all-trans-RA on ischemia-induced cerebral injury and elucidate the underlying mechanism. All-trans-RA treatment reduced the size of the ischemia-induced cerebral infarct. To elucidate the underlying mechanism, ischemia-induced cerebral inflammation was studied by examination of expressions of interleukin 1beta (IL-1beta) and ED-1. RA treatment significantly reduced the cerebral inflammation. Moreover, cerebral ischemic induction of cyclooxygenase-2 (COX-2) and CCAAT/enhancer binding protein beta (C/EBPbeta), which binds to the COX-2 promoter, was also inhibited by RA. These results suggest that RA can reduce ischemia-induced cerebral injury by an anti-inflammatory action, which may be effected via inhibition of C/EBPbeta-mediated COX-2 induction.

Background: Hedgehog signaling plays critical roles during embryonic development. It is also involved in tissue regeneration and carcinogenesis in various adult tissues. Moreover, it regulates the maintenance of cancer stem cells and adult stem cells. Although hedgehog signaling is important in gastric carcinogenesis, its role in gastric regeneration has not been previously examined. In the present study, we evaluated the expression and roles of hedgehog signaling during gastric regeneration., Methods: Gastric ulcers were induced by serosal application of an acetic acid solution in mice. Sham-operated mice served as controls. The proliferation of gastric progenitor cells was studied using bromodeoxyuridine (BrdU). The expression of hedgehog signaling molecules and the differentiation of gastric progenitor cells were examined by immunohistochemical staining and Western blotting., Results: One day after the induction of gastric ulcer, the proliferation of gastric progenitor cells increased; however, the expression of hedgehog signaling molecules, including sonic hedgehog (Shh), Indian hedgehog (Ihh), desert hedgehog (Dhh), and patched (Ptch1) decreased at the ulcer margin. From 5 days after the induction of gastric ulcer, newly generated gastric glands and their differentiation were observed at the ulcer margin. The expression of hedgehog signaling molecules gradually increased in the newly generated gastric glands of the ulcer margin. Cyclopamine, a specific inhibitor of hedgehog signaling, significantly inhibited the differentiation of mucous cells and parietal cells during the gastric regeneration process., Conclusion: The above results suggest that hedgehog signaling is involved in the differentiation of gastric progenitor cells during the gastric ulcer repair process.

Background: Oculomotor dysfunctions are among the most common abnormalities found in the brain-injured population. The purpose of the current study was to determine retrospectively the effectiveness of conventional optometric vision therapy for oculomotor disorders of vergence and version in a sample of ambulatory, visually symptomatic, predominantly adult outpatients who had either mild traumatic brain injury (TBI) or cerebrovascular accident (CVA)., Methods: A computer-based query for acquired brain injury patients examined between the years of 2000 and 2003 was conducted in our clinic. This yielded 160 individuals with mild TBI and 60 with CVA. Of these patients, only those for whom vision therapy was prescribed and who completed an optometric vision therapy program for remediation of their oculomotor dysfunctions were selected. This included 33 with TBI and 7 with CVA. The criterion for treatment success was denoted by marked/total improvement in at least 1 primary symptom and at least 1 primary sign., Results: Ninety percent of those with TBI and 100% of those with CVA were deemed to have treatment success. These improvements remained stable at retesting 2 to 3 months later., Conclusion: Nearly all patients in the current clinic sample exhibited either complete or marked reduction in their oculomotor-based symptoms and improvement in related clinical signs, with maintenance of the symptom reduction and sign improvements at the 2- to 3-month follow-up. These findings show the efficacy of optometric vision therapy for a range of oculomotor abnormalities in the primarily adult, mild brain-injured population. Furthermore, it shows considerable residual neural plasticity despite the presence of documented brain injury.

Neurogenesis can be induced by pathological conditions such as cerebral ischemia. However the molecular mechanisms or modulating reagents of the reactive neurogenesis after the cerebral ischemia are poorly characterized. Retinoic acid (RA) has been shown to increase neurogenesis by enhancing the proliferation and neuronal differentiation of forebrain neuroblasts. Here, we examined whether RA can modulate the reactive neurogenesis after the cerebral ischemia. In contrast to our expectation, RA treatment decreased the reactive neurogenesis in subventricular zone (SVZ), subgranular zone (SGZ) and penumbral region. Furthermore, RA treatment also decreased the angiogenesis and gliosis in penumbral region.

Caffeine is one of the most extensively consumed psychostimulants in the world. However, compared to short-term effects of caffeine, the long-term effects of caffeine consumption on learning and memory are poorly characterized. The present study found that long-term consumption of low dose caffeine (0.3 g/L) slowed hippocampus-dependent learning and impaired long-term memory. Caffeine consumption for 4 weeks also significantly reduced hippocampal neurogenesis compared to controls. From these results, we concluded that long-term consumption of caffeine could inhibit hippocampus-dependent learning and memory partially through inhibition of hippocampal neurogenesis.

Background: The purpose of this retrospective study was to determine the frequency of occurrence of oculomotor dysfunctions in a sample of ambulatory outpatients who have acquired brain injury (ABI), either traumatic brain injury (TBI) or cerebrovascular accident (CVA), with associated vision symptoms., Methods: Medical records of 220 individuals with either TBI (n = 160) or CVA (n = 60) were reviewed retrospectively. This was determined by a computer-based query spanning the years 2000 through 2003, for the frequency of occurrence of oculomotor dysfunctions including accommodation, version, vergence, strabismus, and cranial nerve (CN) palsy., Results: The majority of individuals with either TBI (90%) or CVA (86.7%) manifested an oculomotor dysfunction. Accommodative and vergence deficits were most common in the TBI subgroup, whereas strabismus and CN palsy were most common in the CVA subgroup. The frequency of occurrence of versional deficits was similar in each diagnostic subgroup., Conclusion: These new findings should alert the clinician to the higher frequency of occurrence of oculomotor dysfunctions in these populations and the associated therapeutic, rehabilitative, and quality-of-life implications.

Primary Objective: To determine retrospectively the relative risk of ocular disease in a selected, visually-symptomatic sample of clinic patients having traumatic brain injury (TBI; n=160) vs. cerebrovascular accident (CVA; n=60), with all initially presenting at the clinic with symptoms and/or signs of vision dysfunction., Methods and Procedures: To review retrospectively 220 medical records of individuals with TBI (n=160) vs. CVA (n=60), as determined by a computer-based query spanning the years 2000-2003, to ascertain the frequency of occurrence of ocular disease in the two major sub-groups of acquired brain injury., Main Outcomes and Results: Conditions with high relative risk unique to TBI included corneal abrasion, blepharitis, chalazion/hordeolum, dry eye, traumatic cataract, vitreal prolapse and optic atrophy. This is distinct from those ophthalmic conditions unique to CVA, which included sub-conjunctival haemorrhage and ptosis., Conclusion: These new findings should alert clinicians to the potential increased frequency of occurrence of specific ocular diseases in a selected, visually-symptomatic population with TBI and their associated rehabilitative and quality-of-life implications.