94 results on '"Joon-Khim Loh"'
Search Results
2. Galectin-3 Mediates Tumor Progression in Astrocytoma by Regulating Glycogen Synthase Kinase-3β Activity
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Hung-Pei Tsai, Chien-Ju Lin, Ann-Shung Lieu, Yi-Ting Chen, Tzu-Ting Tseng, Aij-Lie Kwan, and Joon-Khim Loh
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astrocytoma ,galectin-3 ,GSK3B ,Biology (General) ,QH301-705.5 - Abstract
Numerous studies have considered galectin-3 or Glycogen synthase kinase 3 beta (GSK3B) as a potential prognosis marker for various cancers. However, the correlation between the protein expression of galectin-3/GSK3B and the clinical parameters of astrocytoma has not been reported. This study aims to validate the correlation between the clinical outcomes and protein expression of galectin-3/GSK3B in astrocytoma. Immunohistochemistry staining was performed to detect galectin-3/GSK3B protein expression in patients with astrocytoma. The Chi-square test, Kaplan−Meier evaluation, and Cox regression analysis were used to determine the correlation between clinical parameters and galectin-3/GSK3B expression. Cell proliferation, invasion, and migration were compared between a non-siRNA group and a galectin-3/GSK3B siRNA group. Protein expression in galectin-3 or GSK3B siRNA-treated cells was evaluated using western blotting. Galectin-3 and GSK3B protein expression were significantly positively correlated with the World Health Organization (WHO) astrocytoma grade and overall survival time. Multivariate analysis revealed that WHO grade, galectin-3 expression, and GSK3B expression were independent prognostic factors for astrocytoma. Galectin-3 or GSK3B downregulation induced apoptosis and decreased cell numbers, migration, and invasion. siRNA-mediated gene silencing of galectin-3 resulted in the downregulation of Ki-67, cyclin D1, VEGF, GSK3B, p-GSK3B Ser9 (p-GSK3B S9), and β-catenin. In contrast, GSK3B knockdown only decreased Ki-67, VEGF, p-GSK3B S9, and β-catenin protein expression but did not affect cyclin D1 and galectin-3 protein expression. The siRNA results indicated that GSK3B is downstream of the galectin-3 gene. These data support that galectin-3 mediated tumor progression by upregulating GSK3B and β-catenin protein expression in glioblastoma. Therefore, galectin-3 and GSK3B are potential prognostic markers, and their genes may be considered to be anticancer targets for astrocytoma therapy.
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- 2023
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3. BMX, a specific HDAC8 inhibitor, with TMZ for advanced CRC therapy: a novel synergic effect to elicit p53-, β-catenin- and MGMT-dependent apoptotic cell death
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Huey-Jiun Ko, Shean-Jaw Chiou, Cheng-Yu Tsai, Joon-Khim Loh, Xin-Yi Lin, Thu-Ha Tran, Chia-Chung Hou, Tai-Shan Cheng, Jin-Mei Lai, Peter Mu-Hsin Chang, Feng-Sheng Wang, Chun-Li Su, Chi-Ying F. Huang, and Yi-Ren Hong
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HDAC8 inhibitor ,CRC ,TMZ ,MGMT ,β-catenin ,p53 ,Medicine ,Cytology ,QH573-671 - Abstract
Abstract Background Despite advances in treatment, patients with refractory colorectal cancer (CRC) still have poor long-term survival, so there is a need for more effective therapeutic options. Methods To evaluate the HDAC8 inhibition efficacy as a CRC treatment, we examined the effects of various HDAC8 inhibitors (HDAC8i), including BMX (NBM-T-L-BMX-OS01) in combination with temozolomide (TMZ) or other standard CRC drugs on p53 mutated HT29 cells, as well as wild-type p53 HCT116 and RKO cells. Results We showed that HDAC8i with TMZ cotreatment resulted in HT29 arrest in the S and G2/M phase, whereas HCT116 and RKO arrest in the G0/G1 phase was accompanied by high sub-G1. Subsequently, this combination approach upregulated p53-mediated MGMT inhibition, leading to apoptosis. Furthermore, we observed the cotreatment also enabled triggering of cell senescence and decreased expression of stem cell biomarkers. Mechanistically, we found down-expression levels of β-catenin, cyclin D1 and c-Myc via GSK3β/β-catenin signaling. Intriguingly, autophagy also contributes to cell death under the opposite status of β-catenin/p62 axis, suggesting that there exists a negative feedback regulation between Wnt/β-catenin and autophagy. Consistently, the Gene Set Enrichment Analysis (GSEA) indicated both apoptotic and autophagy biomarkers in HT29 and RKO were upregulated after treating with BMX. Conclusions BMX may act as a HDAC8 eraser and in combination with reframed-TMZ generates a remarkable synergic effect, providing a novel therapeutic target for various CRCs. Video Abstract
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- 2022
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4. Deciphering the evolution of composite-type GSKIP in mitochondria and Wnt signaling pathways.
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Cheng-Yu Tsai, Shean-Jaw Chiou, Huey-Jiun Ko, Yu-Fan Cheng, Sin-Yi Lin, Yun-Ling Lai, Chen-Yen Lin, Chihuei Wang, Jiin-Tsuey Cheng, Hsin-Fu Liu, Aij-Li Kwan, Joon-Khim Loh, and Yi-Ren Hong
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Medicine ,Science - Abstract
We previously revealed the origin of mammalian simple-type glycogen synthase kinase interaction protein (GSKIP), which served as a scavenger and a competitor in the Wnt signaling pathway during evolution. In this study, we investigated the conserved and nonconserved regions of the composite-type GSKIP by utilizing bioinformatics tools, site-directed mutagenesis, and yeast two-hybrid methods. The regions were denoted as the pre-GSK3β binding site, which is located at the front of GSK3β-binding sites. Our data demonstrated that clustered mitochondria protein 1 (CLU1), a type of composite-type GSKIP that exists in the mitochondria of all eukaryotic organisms, possesses the protein known as domain of unknown function 727 (DUF727), with a pre-GSK3β-binding site and a mutant GSK3β-binding flanking region. Another type of composite-type GSKIP, armadillo repeat containing 4 (ARMC4), which is known for cilium movement in vertebrates, contains an unintegrated DUF727 flanking region with a pre-GSK3β-binding site (115SPxF118) only. In addition, the sequence of the GSK3β-binding site in CLU1 revealed that Q126L and V130L were not conserved, differing from the ideal GSK3β-binding sequence of simple-type GSKIP. We further illustrated two exceptions, namely 70 kilodalton heat shock proteins (Hsp70/DnaK) and Mitofilin in nematodes, that presented an unexpected ideal GSK3β-binding region with a pre-GSK3β sequence; this composite-type GSKIP could only occur in vertebrate species. Furthermore, we revealed the importance of the pre-GSK3β-binding site (118F or 118Y) and various mutant GSK3β-binding sites of composite-type GSKIP. Collectively, our data suggest that the new composite-type GSKIP starts with a DUF727 domain followed by a pre-GSK3β-binding site, with the subsequent addition of the GSK3β-binding site, which plays vital roles for CLU1, Mitofilin, and ARMC4 in mitochondria and Wnt signaling pathways during evolution.
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- 2022
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5. NBM-BMX, an HDAC8 Inhibitor, Overcomes Temozolomide Resistance in Glioblastoma Multiforme by Downregulating the β-Catenin/c-Myc/SOX2 Pathway and Upregulating p53-Mediated MGMT Inhibition
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Cheng-Yu Tsai, Huey-Jiun Ko, Shean-Jaw Chiou, Yu-Ling Lai, Chia-Chung Hou, Tehseen Javaria, Zi-Yi Huang, Tai-Shan Cheng, Tsung-I Hsu, Jian-Ying Chuang, Aij-Lie Kwan, Tsung-Hsien Chuang, Chi-Ying F. Huang, Joon-Khim Loh, and Yi-Ren Hong
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HDAC8 ,GBM ,TMZ ,MGMT ,connectivity map ,β-catenin ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Although histone deacetylase 8 (HDAC8) plays a role in glioblastoma multiforme (GBM), whether its inhibition facilitates the treatment of temozolomide (TMZ)-resistant GBM (GBM-R) remains unclear. By assessing the gene expression profiles from short hairpin RNA of HDAC8 in the new version of Connectivity Map (CLUE) and cells treated by NBM-BMX (BMX)-, an HDAC8 inhibitor, data analysis reveals that the Wnt signaling pathway and apoptosis might be the underlying mechanisms in BMX-elicited treatment. This study evaluated the efficacy of cotreatment with BMX and TMZ in GBM-R cells. We observed that cotreatment with BMX and TMZ could overcome resistance in GBM-R cells and inhibit cell viability, markedly inhibit cell proliferation, and then induce cell cycle arrest and apoptosis. In addition, the expression level of β-catenin was reversed by proteasome inhibitor via the β-catenin/ GSK3β signaling pathway to reduce the expression level of c-Myc and cyclin D1 in GBM-R cells. BMX and TMZ cotreatment also upregulated WT-p53 mediated MGMT inhibition, thereby triggering the activation of caspase-3 and eventually leading to apoptosis in GBM-R cells. Moreover, BMX and TMZ attenuated the expression of CD133, CD44, and SOX2 in GBM-R cells. In conclusion, BMX overcomes TMZ resistance by enhancing TMZ-mediated cytotoxic effect by downregulating the β-catenin/c-Myc/SOX2 signaling pathway and upregulating WT-p53 mediated MGMT inhibition. These findings indicate a promising drug combination for precision personal treating of TMZ-resistant WT-p53 GBM cells.
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- 2021
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6. Ionizing Radiation Induces Resistant Glioblastoma Stem-Like Cells by Promoting Autophagy via the Wnt/β-Catenin Pathway
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Cheng-Yu Tsai, Huey-Jiun Ko, Chi-Ying F. Huang, Ching-Yi Lin, Shean-Jaw Chiou, Yu-Feng Su, Ann-Shung Lieu, Joon-Khim Loh, Aij-Lie Kwan, Tsung-Hsien Chuang, and Yi-Ren Hong
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GBM ,CSC ,ionizing radiation (IR) ,GSC ,Wnt/β-Catenin ,autophagy ,Science - Abstract
Therapeutic resistance in recurrent glioblastoma multiforme (GBM) after concurrent chemoradiotherapy (CCRT) is a challenging issue. Although standard fractionated radiation is essential to treat GBM, it has led to local recurrence along with therapy-resistant cells in the ionizing radiation (IR) field. Lines of evidence showed cancer stem cells (CSCs) play a vital role in therapy resistance in many cancer types, including GBM. However, the molecular mechanism is poorly understood. Here, we proposed that autophagy could be involved in GSC induction for radioresistance. In a clinical setting, patients who received radiation/chemotherapy had higher LC3II expression and showed poor overall survival compared with those with low LC3 II. In a cell model, U87MG and GBM8401 expressed high level of stemness markers CD133, CD44, Nestin, and autophagy marker P62/LC3II after receiving standard fractionated IR. Furthermore, Wnt/β-catenin proved to be a potential pathway and related to P62 by using proteasome inhibitor (MG132). Moreover, pharmacological inhibition of autophagy with BAF and CQ inhibit GSC cell growth by impairing autophagy flux as demonstrated by decrease Nestin, CD133, and SOX-2 levels. In conclusion, we demonstrated that fractionated IR could induce GSCs with the stemness phenotype by P62-mediated autophagy through the Wnt/β-catenin for radioresistance. This study offers a new therapeutic strategy for targeting GBM in the future.
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- 2021
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7. The Phosphorylation Status of Drp1-Ser637 by PKA in Mitochondrial Fission Modulates Mitophagy via PINK1/Parkin to Exert Multipolar Spindles Assembly during Mitosis
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Huey-Jiun Ko, Cheng-Yu Tsai, Shean-Jaw Chiou, Yun-Ling Lai, Chi-Huei Wang, Jiin-Tsuey Cheng, Tsung-Hsien Chuang, Chi-Ying F. Huang, Aij-Lie Kwan, Joon-Khim Loh, and Yi-Ren Hong
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mitochondria ,Drp1 ,PKA ,phosphorylation ,mitophagy ,centrosomes ,Microbiology ,QR1-502 - Abstract
Mitochondrial fission and fusion cycles are integrated with cell cycle progression. Here we first re-visited how mitochondrial ETC inhibition disturbed mitosis progression, resulting in multipolar spindles formation in HeLa cells. Inhibitors of ETC complex I (rotenone, ROT) and complex III (antimycin A, AA) decreased the phosphorylation of Plk1 T210 and Aurora A T288 in the mitotic phase (M-phase), especially ROT, affecting the dynamic phosphorylation status of fission protein dynamin-related protein 1 (Drp1) and the Ser637/Ser616 ratio. We then tested whether specific Drp1 inhibitors, Mdivi-1 or Dynasore, affected the dynamic phosphorylation status of Drp1. Similar to the effects of ROT and AA, our results showed that Mdivi-1 but not Dynasore influenced the dynamic phosphorylation status of Ser637 and Ser616 in Drp1, which converged with mitotic kinases (Cdk1, Plk1, Aurora A) and centrosome-associated proteins to significantly accelerate mitotic defects. Moreover, our data also indicated that evoking mito-Drp1-Ser637 by protein kinase A (PKA) rather than Drp1-Ser616 by Cdk1/Cyclin B resulted in mitochondrial fission via the PINK1/Parkin pathway to promote more efficient mitophagy and simultaneously caused multipolar spindles. Collectively, this study is the first to uncover that mito-Drp1-Ser637 by PKA, but not Drp1-Ser616, drives mitophagy to exert multipolar spindles formation during M-phase.
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- 2021
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8. Predictive model for 5-year mortality after breast cancer surgery in Taiwan residents
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Su-Hsin Huang, Joon-Khim Loh, Jinn-Tsong Tsai, Ming-Feng Houg, and Hon-Yi Shi
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Breast cancer surgery ,Artificial neural networks ,Multiple logistic regression ,Cox regression ,5-year mortality ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Few studies of breast cancer surgery outcomes have used longitudinal data for more than 2 years. This study aimed to validate the use of the artificial neural network (ANN) model to predict the 5-year mortality of breast cancer patients after surgery and compare predictive accuracy between the ANN model, multiple logistic regression (MLR) model, and Cox regression model. Methods This study compared the MLR, Cox, and ANN models based on clinical data of 3632 breast cancer patients who underwent surgery between 1996 and 2010. An estimation dataset was used to train the model, and a validation dataset was used to evaluate model performance. The sensitivity analysis was also used to assess the relative significance of input variables in the prediction model. Results The ANN model significantly outperformed the MLR and Cox models in predicting 5-year mortality, with higher overall performance indices. The results indicated that the 5-year postoperative mortality of breast cancer patients was significantly associated with age, Charlson comorbidity index (CCI), chemotherapy, radiotherapy, hormone therapy, and breast cancer surgery volumes of hospital and surgeon (all P
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- 2017
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9. GSKIP-Mediated Anchoring Increases Phosphorylation of Tau by PKA but Not by GSK3beta via cAMP/PKA/GSKIP/GSK3/Tau Axis Signaling in Cerebrospinal Fluid and iPS Cells in Alzheimer Disease
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Huey-Jiun Ko, Shean-Jaw Chiou, Yu-Hui Wong, Yin-Hsuan Wang, Yun-Ling Lai, Chia-Hua Chou, Chihuei Wang, Joon-Khim Loh, Ann-Shung Lieu, Jiin-Tsuey Cheng, Yu-Te Lin, Pei-Jung Lu, Ming-Ji Fann, Chi-Ying Huang, and Yi-Ren Hong
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pka/gskip/gsk3β/tau axis ,sh-sy5y ,ips cells ,cerebrospinal fluid ,alzheimer’s disease ,Medicine - Abstract
Based on the protein kinase A (PKA)/GSK3β interaction protein (GSKIP)/glycogen synthase kinase 3β (GSK3β) axis, we hypothesized that these might play a role in Tau phosphorylation. Here, we report that the phosphorylation of Tau Ser409 in SHSY5Y cells was increased by overexpression of GSKIP WT more than by PKA- and GSK3β-binding defective mutants (V41/L45 and L130, respectively). We conducted in vitro assays of various kinase combinations to show that a combination of GSK3β with PKA but not Ca2+/calmodulin-dependent protein kinase II (CaMK II) might provide a conformational shelter to harbor Tau Ser409. Cerebrospinal fluid (CSF) was evaluated to extend the clinical significance of Tau phosphorylation status in Alzheimer’s disease (AD), neurological disorders (NAD), and mild cognitive impairment (MCI). We found higher levels of different PKA−Tau phosphorylation sites (Ser214, Ser262, and Ser409) in AD than in NAD, MCI, and normal groups. Moreover, we used the CRISPR/Cas9 system to produce amyloid precursor protein (APPWT/D678H) isogenic mutants. These results demonstrated an enhanced level of phosphorylation by PKA but not by the control. This study is the first to demonstrate a transient increase in phosphor-Tau caused by PKA, but not GSK3β, in the CSF and induced pluripotent stem cells (iPSCs) of AD, implying that both GSKIP and GSK3β function as anchoring proteins to strengthen the cAMP/PKA/Tau axis signaling during AD pathogenesis.
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- 2019
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10. Thioridazine Enhances P62-Mediated Autophagy and Apoptosis Through Wnt/β-Catenin Signaling Pathway in Glioma Cells
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Cheng-Wei Chu, Huey-Jiun Ko, Chia-Hua Chou, Tai-Shan Cheng, Hui-Wen Cheng, Yu-Hsin Liang, Yun-Ling Lai, Chen-Yen Lin, Chihuei Wang, Joon-Khim Loh, Jiin-Tsuey Cheng, Shean-Jaw Chiou, Chun-Li Su, Chi-Ying F. Huang, and Yi-Ren Hong
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thioridazine ,glioblastoma ,Wnt/β-catenin ,P62 ,autophagy ,apoptosis ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Thioridazine (THD) is a common phenothiazine antipsychotic drug reported to suppress growth in several types of cancer cells. We previously showed that THD acts as an antiglioblastoma and anticancer stem-like cell agent. However, the signaling pathway underlying autophagy and apoptosis induction remains unclear. THD treatment significantly induced autophagy with upregulated AMPK activity and engendered cell death with increased sub-G1 in glioblastoma multiform (GBM) cell lines. Notably, through whole gene expression screening with THD treatment, frizzled (Fzd) proteins, a family of G-protein-coupled receptors, were found, suggesting the participation of Wnt/β-catenin signaling. After THD treatment, Fzd-1 and GSK3β-S9 phosphorylation (inactivated form) was reduced to promote β-catenin degradation, which attenuated P62 inhibition. The autophagy marker LC3-II markedly increased when P62 was released from β-catenin inhibition. Additionally, the P62-dependent caspase-8 activation that induced P53-independent apoptosis was confirmed by inhibiting T-cell factor/β-catenin and autophagy flux. Moreover, treatment with THD combined with temozolomide (TMZ) engendered increased LC3-II expression and caspase-3 activity, indicating promising drug synergism. In conclusion, THD induces autophagy in GBM cells by not only upregulating AMPK activity, but also enhancing P62-mediated autophagy and apoptosis through Wnt/β-catenin signaling. Therefore, THD is a potential alternative therapeutic agent for drug repositioning in GBM.
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- 2019
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11. The alteration of plasma TGF-β1 levels in patients with brain tumors after tumor removal
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Joon-Khim Loh, Ann-Shung Lieu, Yu-Feng Su, Chi-Yun Cheng, Tai-Hsin Tsai, Chih-Lung Lin, Kung-Shing Lee, Shiuh-Lin Hwang, Aij-Lie Kwan, Chih-Jen Wang, Yi-Ren Hong, Shen-Long Howng, and Chung-Ching Chio
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Brain tumor ,Transforming growth factor-beta 1 ,Tumor removal ,Medicine (General) ,R5-920 - Abstract
Transforming growth factor (TGF) β1 may be a candidate for a serologic tumor marker. In this study, the plasma levels of TGF-β1 in patients with brain tumors were measured using enzyme-linked immunosorbent assay before and after tumor removal. Patients were divided into four groups, the control group and the benign, malignant, and metastatic brain tumor groups. All brain tumor groups showed significant increases in the levels of TGF-β1 before tumor removal (6.36 ± 3.94, 17.0 ± 9.7, and 12.2 ± 10.3 ng/ml for the benign, malignant, and metastatic groups, respectively). When compared with the results obtained in the control group (1.12 ± 0.74 ng/ml), significant decreases in TGF-β1 concentrations after total tumor removal were found in both the benign and malignant brain tumor groups (2.55 ± 2.00 and 8.93 ± 5.73 ng/ml, respectively; p = 0.0001 and p = 0.003, respectively). On the other hand, plasma TGF-β1 levels in the metastatic brain tumor group showed a slight but significant increase (14.7 ± 9.3 ng/ml, p = 0.035) after tumor removal. In a case of low-grade astrocytoma, plasma levels of TGF-β1 were found to be 3.6 and 1.1 ng/ml before and after tumor removal, respectively. However, recurrent tumor was noted in this patient 7 months later, and the levels of TGF-β1 were 26.2 and 8.4 ng/ml before and after the second operation, respectively. The data show that plasma TGF-β1 was elevated in the circulation of patients with brain tumors and that significant decreases in TGF-β1 levels were observed after the removal of benign and malignant tumors. The results also suggest that TGF-β1 may be a useful serologic marker for brain tumors.
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- 2012
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12. Eosinophilic granuloma of the occipital bone in an adult: A case report
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Joon-Khim Loh, Yu-Feng Su, Shiuh-Lin Hwang, Chee-Yin Chai, Shen-Long Howng, Ann-Shung Lieu, 羅永欽, 蘇裕峯, 黃旭霖, 蔡志仁, 洪純隆, and 劉安祥
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Eosinophilic granuloma ,Langerhans’ cell histiocytosis ,Skull neoplasm ,Medicine (General) ,R5-920 - Abstract
Eosinophilic granuloma (EG) refers to the most common and benign form of the disorder known as Langerhans’ cell histiocytosis. The disease is typically found in children and adolescents and rarely affects adults. We present a case of EG in the occipital bone in a 36-year-old man, who visited our hospital with the chief complaint of left occipital palpable tumor mass with local tenderness and pain for one month. An X-ray of the skull revealed a rounded osteolytic lesion. A computed tomography scan revealed a shadow of soft tissues in the left occipital site involving the entire thickness of the calvaria, which was indicative of marked destruction of the bone. The soft mass was successfully removed. The margins of the skull lesion were excised, and cranioplasty was performed simultaneously with bone cement. A definitive diagnosis of EG was made by histopathology and immunohistochemical detection of S-100 antigen in the tissue samples. With respect to management, we believe surgery is the best option for most accessible cranial lesions of EG. A cranioplasty with bone cement or autologous bone can be performed in the same session to repair the cranial defect.
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- 2011
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13. Low-Grade Astrocytoma Associated with Abscess Formation: Case Report and Literature Review
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Tai-Hsin Tsai, Yan-Fen Hwang, Shiuh-Lin Hwang, Chen-Hsiang Hung, Cheng-Wei Chu, Boon-Kee Lua, Chih-Lung Lin, Kung-Shing Lee, Joon-Khim Loh, Aij-Lie Kwan, Chih-Jen Wang, Tzuu-Yuan Huang, Shen-Long Howng, and Ann-Shung Lieu
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astrocytoma ,brain abscess ,magnetic resonance spectroscopy ,Medicine (General) ,R5-920 - Abstract
A rare case of low-grade astrocytoma associated with abscess formation occurred in a 52-year-old man presenting with Broca's aphasia. He underwent craniotomy and tumor removal under the impression of brain tumor with necrotic cystic change. Abscess accumulation within the intra-axial tumor was found intraoperatively. Literature related to brain abscess with brain tumor is reviewed, with an emphasis on abscesses with astrocytoma. We discuss the common brain tumors that are associated with abscess, pathogens that coexist with brain tumor, and the pathogeneses of coexisting brain abscess and tumor. It is very important to know how to differentiate between and diagnose a brain abscess and tumor, or brain abscess with tumor, preoperatively from clinical presentation and through the use of computed tomography, conventional magnetic resonance imaging, diffusion-weighted imaging or magnetic resonance spectroscopy.
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- 2008
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14. Analysis of Surgically Treated Intraspinal Tumors in Southern Taiwan
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Yu‐Feng Su, Ann‐Shung Lieu, Chih‐Lung Lin, Kung‐Shing Lee, Yen‐Fen Hwang, Chun‐Po Yen, Chih‐Zen Chang, Joon‐Khim Loh, Tzuu‐Yuan Huang, Shiuh‐Lin Hwang, Aij‐Lie Kwan, Sheng‐Long Howng, and Chih‐Jen Wang
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intraspinal tumor ,spinal metastasis ,statistics ,Taiwan ,Medicine (General) ,R5-920 - Abstract
The medical records of 117 patients with spinal tumors who underwent surgery with pathologic confirmation from January 1999 to April 2004 at Kaohsiung Medical University Hospital were reviewed. Data from this review were compared with those obtained from the same institution 10 years earlier (covering the period 1988‐1995) and from other reported series. There were 69 male and 48 female patients aged from 13 to 87 years old (mean age, 51.9). The most common pathologic findings were metastasis in 45.3% (53/117), nerve sheath tumors in 28.2% (33/117), menin‐giomas in 12% (14/117) and neuroepithelial tumors in 6% (7/117). The peak ages at diagnosis were 41‐50 years and 61–70 years. A slight male predominance was noted for all tumors, except meningiomas. Motor weakness, even paralysis, was the major clinical presentation (64–86%), followed by sensory deficits (50%) and pain (42%). The location of tumors was most often in the thoracic (50.4%; 59/117), lumbosacral (27.4%; 32/117) and cervical spine (22.2%; 26/117) segments. Among the metastatic tumors, the lung (22.6%) and breast (15.1%) were the most common primary sites of origin, followed by unknown origin, the liver (hepatocellular carcinoma), the gastrointestinal tract and the nasopharynx (nasopharyngeal cancer).
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- 2007
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15. Sphenoid Ridge Lymphoplasmacyte-rich Meningioma
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Joon-Khim Loh, Shiuh-Lin Hwang, Kun-Bow Tsai, Aij-Lie Kwan, and Shen-Long Howng
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brain tumor ,meningioma ,Medicine (General) ,R5-920 - Abstract
There are numerous histologic variants of meningioma. Among the more uncommon are intracranial masses composed of meningiomatous and plasma cell-lymphocytic elements. We report a 22-year-old woman with lymphoplasmacyte-rich meningioma who initially presented with dizziness and progressive headache. Neuroradiologic images revealed typical meningiomas of the sphenoid ridge with extensive perifocal edema. Complete macroscopic removal of the tumor was performed. Histologic examination revealed a meningioma with massive infiltrates of plasma cells and lymphocytes. Brain computed tomography on the 6th postoperative day revealed total removal of the tumor with marked reduction of brain edema. Complete resolution of symptoms occurred with no evidence of tumor recurrence during 2 years of follow-up.
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- 2006
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16. Rapid Resolution of Infantile Acute Subdural Hematoma: A Case Report
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Shu-Hung Huang, Ching-Kuo Lin, and Joon-Khim Loh
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acute subdural hematoma ,infant ,head injury ,Medicine (General) ,R5-920 - Abstract
Subdural hematomas in infants are uncommon but usually result from non-accidental trauma or from trauma associated with motor vehicle accidents. This report describes the case of an infant with a traumatic acute subdural hematoma that resolved within 65 hours. A 23-month-old boy fell from a height of approximately 10 m. Brain computed tomography disclosed a left subdural hematoma with midline shift. The associated clots resolved spontaneously within 65 hours of the injury. Although they may mimic more clinically significant subdural hematomas, such collections of clots are likely to be located at least partly within the subarachnoid space. Their recognition may influence decisions regarding both surgical evacuation and the likelihood of non-accidental injury. Clinical and radiographic features distinguishing these “disappearing subdural hematomas” from more typical subdural hematomas are discussed.
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- 2005
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17. Effect of Aspirin and Indomethacin on Prostaglandin E2 Synthesis in C6 Glioma Cells
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Shiuh-Lin Hwang, Kung-Shing Lee, Chih-Lung Lin, Ann-Shung Lieu, Chi-Yun Cheng, Joon-Khim Loh, Yan-Fen Hwang, Yu-Feng Su, and Shen-Long Howng
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prostaglandin E2 ,brain tumor ,aspirin ,indomethacin ,Medicine (General) ,R5-920 - Abstract
Prostaglandin E2 (PGE2) plays an important role in immunosuppression and tumor growth. PGE2 inhibitors such as aspirin and indomethacin suppress experimental tumor growth. Little is known of the relationship between PGE2 synthesis in brain tumors and the dose of aspirin or indomethacin. The present study was undertaken to evaluate the effect of different doses of aspirin and indomethacin on PGE2 synthesis in C6 glioma cells. C6 glioma cells were incubated with different concentrations (2, 4, and 8 μM) of aspirin and indomethacin for 1, 2, 4, 6, 8, 12, and 24 hours. Intracellular PGE2 concentration was measured by enzyme immunoassay. Each concentration of aspirin and indomethacin effectively inhibited PGE2 synthesis. Concentrations of 2, 4, and 8 μM of aspirin significantly inhibited PGE2 production at 6, 4, and 1 hours, respectively, and the inhibition persisted for more than 24 hours (p < 0.05). Concentrations of 2 and 4 μM of indomethacin were effective at 4 and 2 hours (p < 0.05), respectively. However, inhibition was not observed beyond 12 hours (p > 0.05). Indomethacin 8 μM was effective at 1 hour and the inhibition persisted beyond 24 hours (p < 0.05). Our study demonstrates that aspirin and indomethacin inhibit PGE2 synthesis in C6 glioma cells and that low-dose aspirin is as effective as high-dose aspirin. This study may encourage future clinical use of low-dose aspirin in the prevention or treatment of brain tumors.
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- 2004
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18. GSK3beta-mediated Drp1 phosphorylation induced elongated mitochondrial morphology against oxidative stress.
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Chia-Hua Chou, Ching-Chih Lin, Ming-Chang Yang, Chih-Chang Wei, Huei-De Liao, Run-Chin Lin, Wen-Yu Tu, Tsung-Chieh Kao, Ching-Mei Hsu, Jiin-Tsuey Cheng, An-Kuo Chou, Chu-I Lee, Joon-Khim Loh, Shen-Long Howng, and Yi-Ren Hong
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Medicine ,Science - Abstract
Multiple phosphorylation sites of Drp1 have been characterized for their functional importance. However, the functional consequence of GSK3beta-mediated phosphorylation of Drp1 remains unclear. In this report, we pinpointed 11 Serine/Threonine sites spanning from residue 634~736 of the GED domain and robustly confirmed Drp1 Ser693 as a novel GSK3beta phosphorylation site. Our results suggest that GSK3beta-mediated phosphorylation at Ser693 does cause a dramatic decrease of GTPase activity; in contrast, GSK3beta-mediated phosphorylation at Ser693 appears not to affect Drp1 inter-/intra-molecular interactions. After identifying Ser693 as a GSK3beta phosphorylation site, we also determined that K679 is crucial for GSK3beta-binding, which strongly suggests that Drp1 is a novel substrate for GSK3beta. Thereafter, we found that overexpressed S693D, but not S693A mutant, caused an elongated mitochondrial morphology which is similar to that of K38A, S637D and K679A mutants. Interestedly, using H89 and LiCl to inhibit PKA and GSK3beta signaling, respectively, it appears that a portion of the elongated mitochondria switched to a fragmented phenotype. In investigating the biofunctionality of phosphorylation sites within the GED domain, cells overexpressing Drp1 S693D and S637D, but not S693A, showed an acquired resistance to H(2)O(2)-induced mitochondrial fragmentation and ensuing apoptosis, which affected cytochrome c, capase-3, -7, and PARP, but not LC3B, Atg-5, Beclin-1 and Bcl2 expressions. These results also showed that the S693D group is more effective in protecting both non-neuronal and neuronal cells from apoptotic death than the S637D group. Altogether, our data suggest that GSK3beta-mediated phosphorylation at Ser693 of Drp1 may be associated with mitochondrial elongation via down-regulating apoptosis, but not autophagy upon H(2)O(2) insult.
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- 2012
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19. GSKIP modulates cell aggregation through EMT/MET signaling rather than differentiation in SH-SY5Y human neuroblastoma cells
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Cheng-Yu Tsai, Huey-Jiun Ko, Shean-Jaw Chiou, Xin-Yi Lin, Tsung-Hsien Chuang, Jiin-Tsuey Cheng, Yu-Feng Su, Joon-Khim Loh, and Yi-Ren Hong
- Subjects
Cell Biology ,Molecular Biology ,Biochemistry - Abstract
GSK3β interacting protein (GSKIP) is a small A-kinase anchor protein previously reported to mediate the N-cadherin/β-catenin pool for differentiation in SH-SY5Y cells through overexpression of GSKIP to present the neuron outgrowth phenotype. To further investigate how GSKIP functions in neurons, CRISPR/Cas9 technology was utilized to knock out GSKIP (GSKIP-KO) in SH-SY5Y. Several GSKIP-KO clones resulted in an aggregation phenotype and reduced cell growth without retinoic acid (RA) treatment. However, neuron outgrowth was still observed in GSKIP-KO clones treated with RA. The GSKIP-KO clones exhibited an aggregation phenotype through suppression of GSK3β/β-catenin pathways and cell cycle progression rather than cell differentiation. Gene set enrichment analysis indicated that GSKIP-KO was related to epithelial mesenchymal transition/mesenchymal epithelial transition (EMT/MET) and Wnt/β-catenin/cadherin signaling pathways, suppressing cell migration and tumorigenesis through the inhibition of Wnt/β-catenin mediated EMT/MET. Conversely, reintroduction of GSKIP into GSKIP-KO clones restored cell migration and tumorigenesis. Notably, phosphor-β-catenin (S675) and β-catenin (S552) but not phosphor-β-catenin (S33/S37/T41) translocated into the nucleus for further gene activation. Collectively, these results suggested that GSKIP may function as an oncogene to form an aggregation phenotype for cell survival in harsh environments through EMT/MET rather than differentiation in the GSKIP-KO of SH-SY5Y cells. Graphical abstract
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- 2023
20. Compound cellular stress maximizes apoptosis independently of p53 in glioblastoma
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Cheng-Jung Ho, Cheng-Yu Tsai, Wei-Hua Zhu, Yu-Hsuan Pao, Hsin-Wen Chen, Chieh-Ju Hu, Yi-Lin Lee, Tzu-Shuo Huang, Chung-Hwan Chen, Joon-Khim Loh, Yi-Ren Hong, and Chihuei Wang
- Subjects
Bortezomib ,Vorinostat ,Doxorubicin ,Cell Line, Tumor ,Humans ,Apoptosis ,Cell Biology ,Tumor Suppressor Protein p53 ,Glioblastoma ,Molecular Biology ,Developmental Biology ,Research Paper - Abstract
We examined the apoptotic response of two glioblastoma cells, p53 wild type U87 and p53 mutated T98G, to doxorubicin, bortezomib, and vorinostat, which respectively target DNA, 26S proteasome and histone deacetylase, to clarify p53ʹs function in apoptosis. We demonstrated that doxorubicin induced apoptosis in U87 cells but not in T98G cells. The level of p53 was definitively correlated to the extent of DNA damage and apoptosis initiation. Dominant-negative p53 reduced p21 expression, but did not affect doxorubicin-induced apoptosis, so the transcriptional activity of p53 seemed not to participate in doxorubicin-induced apoptosis. However, p53 concentrated into the nucleus during heavy apoptosis. Bortezomib could induce apoptosis in U87 with high sensitivity and T98G cells with low sensitivity. In contrast, vorinostat promoted apoptosis in both U87 and T98G cells and reduced the basal level of p53 in U87 cells, indicating that p53 played no role in the vorinostat-induced apoptosis. To clearly define the role of p53 in bortezomib- and doxorubicin-induced apoptosis, we combined doxorubicin with bortezomib to treat U87 cells to assess this combination’s effect on apoptosis and p53 status. Interestingly, the combination of doxorubicin with bortezomib engendered compound stress, resulting in a synergistic outcome for apoptosis in U87 cells. However, the amounts of p53 in the total count and in the nucleus were much lower with the combination than with doxorubicin alone, suggesting that p53 played no role in either the compound stress, doxorubicin-only or bortezomib-induced apoptosis.
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- 2023
21. Identify Anticancer Effects of Toona Sinensis Leaves through MEK/ERK signaling pathway in Human Glioblastoma Cells
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Cheng Yu Tsai, Tai-Hsin Tsai, Huey-Jiun Ko, Keng-Liang Kuo, Chieh-Hsin Wu, Hui-Yuan Su, Ann-Shung Lieu, Aij-Lie Kwan, Joon-Khim Loh, Chih-Lung Lin, Yi-Ren Hong, and Yu-Feng Su
- Abstract
Introduction: Toona sinensis is a traditional Chinese medicine commonly used in South-East Asia. The aqueous extracts of T. sinensis leaves (TSL) exhibit anticancer effects in various types of cancer. In this study, we assessed the effectiveness of TSL treatment for glioblastoma multiforme (GBM). Methods After treating A172 and U251 GBM with TSL, cell cycle and apoptotic cells were evaluated by flow cytometry, as well as anti-proliferative efficacy by MTT assay. Reactive oxygen species (ROS) and ATP production were quantified by CellROX, Dihydroethidium (DHE) and Tetramethylrhodamine methyl ester (TMRM). Apoptosis and MEK/ERK pathway related protein levels were detected by western blot. Results TSL treatment induced cell cycle arrest at G2/M and apoptosis. It also caused excessive ROS and decreased ATP production via blockage of electron transport chain (ETC) complexes, leading to ROS regulated mitochondrial dysfunction. Under TSL treatment in two GBM cells, the Bax and Puma protein level were elevated whereas Bcl-2 was descended. The mitochondria-mediated apoptosis and caspase-dependent pathway related proteins including cleaved caspase-3, cleaved caspase-9, and cleaved PARP were induced. Finally, U0126 as an inhibitor of MEK/ERK kinase was applied to demonstrate that the MEK/ERK pathway was responsible for the inhibition of ROS-regulated mitochondrial dysfunction and promoted apoptosis. Conclusion TSL treatment suppressed MEK/ERK activation to induce apoptosis through ROS-regulated mitochondrial dysfunction in GBM cells and provide a therapeutic potential in GBM therapy.
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- 2022
22. NBM-BMX, an HDAC8 Inhibitor, Overcomes Temozolomide Resistance in Glioblastoma Multiforme by Downregulating the β-Catenin/c-Myc/SOX2 Pathway and Upregulating p53-Mediated MGMT Inhibition
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Shean Jaw Chiou, Aij Lie Kwan, Cheng Yu Tsai, Chi Ying F. Huang, Tehseen Javaria, Yi Ren Hong, Huey Jiun Ko, Tsung I. Hsu, Zi Yi Huang, Yu Ling Lai, Tsung Hsien Chuang, Chia Chung Hou, Joon Khim Loh, Tai Shan Cheng, and Jian Ying Chuang
- Subjects
p53 ,Cell cycle checkpoint ,QH301-705.5 ,GBM ,Catalysis ,Article ,Histone Deacetylases ,Inorganic Chemistry ,Small hairpin RNA ,Small Molecule Libraries ,Cell Line, Tumor ,medicine ,Temozolomide ,Humans ,Physical and Theoretical Chemistry ,Biology (General) ,Molecular Biology ,QD1-999 ,DNA Modification Methylases ,Spectroscopy ,beta Catenin ,Cell Proliferation ,Chemistry ,Tumor Suppressor Proteins ,Organic Chemistry ,Wnt signaling pathway ,HDAC8 ,General Medicine ,β-catenin ,Xenograft Model Antitumor Assays ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,DNA Repair Enzymes ,Apoptosis ,Drug Resistance, Neoplasm ,Catenin ,Proteasome inhibitor ,Cancer research ,Tumor Suppressor Protein p53 ,TMZ ,MGMT ,connectivity map ,Glioblastoma ,medicine.drug - Abstract
Although histone deacetylase 8 (HDAC8) plays a role in glioblastoma multiforme (GBM), whether its inhibition facilitates the treatment of temozolomide (TMZ)-resistant GBM (GBM-R) remains unclear. By assessing the gene expression profiles from short hairpin RNA of HDAC8 in the new version of Connectivity Map (CLUE) and cells treated by NBM-BMX (BMX)-, an HDAC8 inhibitor, data analysis reveals that the Wnt signaling pathway and apoptosis might be the underlying mechanisms in BMX-elicited treatment. This study evaluated the efficacy of cotreatment with BMX and TMZ in GBM-R cells. We observed that cotreatment with BMX and TMZ could overcome resistance in GBM-R cells and inhibit cell viability, markedly inhibit cell proliferation, and then induce cell cycle arrest and apoptosis. In addition, the expression level of β-catenin was reversed by proteasome inhibitor via the β-catenin/ GSK3β signaling pathway to reduce the expression level of c-Myc and cyclin D1 in GBM-R cells. BMX and TMZ cotreatment also upregulated WT-p53 mediated MGMT inhibition, thereby triggering the activation of caspase-3 and eventually leading to apoptosis in GBM-R cells. Moreover, BMX and TMZ attenuated the expression of CD133, CD44, and SOX2 in GBM-R cells. In conclusion, BMX overcomes TMZ resistance by enhancing TMZ-mediated cytotoxic effect by downregulating the β-catenin/c-Myc/SOX2 signaling pathway and upregulating WT-p53 mediated MGMT inhibition. These findings indicate a promising drug combination for precision personal treating of TMZ-resistant WT-p53 GBM cells.
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- 2021
23. Synthetic Triterpenoid CDDO-Me Inhibits Proliferation, Migration, and Invasion in GBM8401 and GBM8901
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Chien-Ju Lin, Joon-Khim Loh, Chih-Hui Chang, Shih-Hsun Kuo, Chih-Lung Lin, Hung-Pei Tsai, and Aij-Lie Kwan
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0303 health sciences ,Glioblastoma cell ,business.industry ,medicine.disease ,In vitro ,03 medical and health sciences ,0302 clinical medicine ,Triterpenoid ,030220 oncology & carcinogenesis ,Cancer research ,Potency ,Medicine ,Surgery ,business ,030304 developmental biology ,Glioblastoma - Abstract
Objectives: We determined the anticancer potency of CDDO-Me in glioblastoma cell lines and the underlying mechanisms in vitro. Summary: CDDO-Me is a synthetic triterpenoid with more potent anticancer and cancer preventive actions compared with the original triterpenoid CDDO. Methods: Two glioblastoma cell lines, GBM8401 and GBM8901, were utilized to test the effect of CDDO-Me on cell viability, cell migration, and cell invasion using the MTT, wound healing, and transwell migration assays, respectively. Additionally, Western blotting was used to determine the protein expression levels of N-cadherin, cyclin D1, and vascular endothelial growth factor. Results: At nanomolar concentrations, CDDO-Me inhibited proliferation, migration, and invasion in both cell lines. In addition, CDDO-Me exhibited a dose-dependent downregulation in the protein levels of N-cadherin, cyclin D1, and vascular endothelial growth factor in GBM8401 and GBM8901 cells. Conclusions: CDDO-Me exhibited anticancer effects at low nanomolar concentrations and should be considered as a potential chemotherapeutic agent for glioblastoma.
- Published
- 2019
24. AIBp regulates mitotic entry and mitotic spindle assembly by controlling activation of both Aurora-A and Plk1
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Ming-Chang Yang, Joon-Khim Loh, Chihuei Wang, Shen-Long Howng, Ann-Shung Lieu, Chia-Hua Chou, Chung-Lung Cho, Ching-Chih Lin, An-Kuo Chou, Yi-Ren Hong, Ching-Mei Hsu, and Ming-Chang Hong
- Subjects
Regulator ,Mitosis ,Cell Cycle Proteins ,Spindle Apparatus ,Biology ,Protein Serine-Threonine Kinases ,PLK1 ,Spindle pole body ,Proto-Oncogene Proteins ,Humans ,Molecular Biology ,Microtubule nucleation ,Aurora Kinase A ,Cell Biology ,Cell biology ,DNA-Binding Proteins ,enzymes and coenzymes (carbohydrates) ,HEK293 Cells ,Centrosome ,Phosphorylation ,Carrier Proteins ,Multipolar spindles ,Developmental Biology ,Reports ,HeLa Cells - Abstract
We previously reported that Aurora-A and the hNinein binding protein AIBp facilitate centrosomal structure maintenance and contribute to spindle formation. Here, we report that AIBp also interacts with Plk1, raising the possibility of functional similarity to Bora, which subsequently promotes Aurora-A–mediated Plk1 activation at Thr210 as well as Aurora-A activation at Thr288. In kinase assays, AIBp acts not only as a substrate but also as a positive regulator of both Aurora-A and Plk1. However, AIBp functions as a negative regulator to block phosphorylation of hNinein mediated by Aurora-A and Plk1. These findings suggest a novel AIBp-dependent regulatory machinery that controls mitotic entry. Additionally, knockdown of hNinein caused failure of AIBp to target the centrosome, whereas depletion of AIBp did not affect the localization of hNinein and microtubule nucleation. Notably, knockdown of AIBp in HeLa cells impaired both Aurora-A and Plk1 kinase, resulting in phenotypes with multiple spindle pole formation and chromosome misalignment. Our data show that depletion of AIBp results in the mis-localization of TACC3 and ch-TOG, but not CEP192 and CEP215, suggesting that loss of AIBp dominantly affects the Aurora-A substrate to cause mitotic aberrations. Collectively, our data demonstrate that AIBp contributes to mitotic entry and bipolar spindle assembly and may partially control localization, phosphorylation, and activation of both Aurora-A and Plk1 via hNinein during mitotic progression.
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- 2020
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25. GSKIP-Mediated Anchoring Increases Phosphorylation of Tau by PKA but Not by GSK3beta via cAMP/PKA/GSKIP/GSK3/Tau Axis Signaling in Cerebrospinal Fluid and iPS Cells in Alzheimer Disease
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Chihuei Wang, Joon Khim Loh, Yin Hsuan Wang, Yu Te Lin, Huey Jiun Ko, Pei Jung Lu, Ann Shung Lieu, Jiin Tsuey Cheng, Ming-Ji Fann, Shean Jaw Chiou, Yu Hui Wong, Chia Hua Chou, Yi Ren Hong, Yun Ling Lai, and Chi Ying F. Huang
- Subjects
SH-SY5Y ,animal structures ,lcsh:Medicine ,macromolecular substances ,Article ,cerebrospinal fluid ,03 medical and health sciences ,0302 clinical medicine ,GSK-3 ,Amyloid precursor protein ,Medicine ,Protein kinase A ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,Kinase ,lcsh:R ,PKA/GSKIP/GSK3β/Tau axis ,General Medicine ,medicine.disease ,Cell biology ,iPS cells ,biology.protein ,Phosphorylation ,NAD+ kinase ,Alzheimer's disease ,business ,Alzheimer’s disease ,030217 neurology & neurosurgery - Abstract
Based on the protein kinase A (PKA)/GSK3&beta, interaction protein (GSKIP)/glycogen synthase kinase 3&beta, (GSK3&beta, ) axis, we hypothesized that these might play a role in Tau phosphorylation. Here, we report that the phosphorylation of Tau Ser409 in SHSY5Y cells was increased by overexpression of GSKIP WT more than by PKA- and GSK3&beta, binding defective mutants (V41/L45 and L130, respectively). We conducted in vitro assays of various kinase combinations to show that a combination of GSK3&beta, with PKA but not Ca2+/calmodulin-dependent protein kinase II (CaMK II) might provide a conformational shelter to harbor Tau Ser409. Cerebrospinal fluid (CSF) was evaluated to extend the clinical significance of Tau phosphorylation status in Alzheimer&rsquo, s disease (AD), neurological disorders (NAD), and mild cognitive impairment (MCI). We found higher levels of different PKA&ndash, Tau phosphorylation sites (Ser214, Ser262, and Ser409) in AD than in NAD, MCI, and normal groups. Moreover, we used the CRISPR/Cas9 system to produce amyloid precursor protein (APPWT/D678H) isogenic mutants. These results demonstrated an enhanced level of phosphorylation by PKA but not by the control. This study is the first to demonstrate a transient increase in phosphor-Tau caused by PKA, but not GSK3&beta, in the CSF and induced pluripotent stem cells (iPSCs) of AD, implying that both GSKIP and GSK3&beta, function as anchoring proteins to strengthen the cAMP/PKA/Tau axis signaling during AD pathogenesis.
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- 2019
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26. The Phosphorylation Status of Drp1-Ser637 by PKA in Mitochondrial Fission Modulates Mitophagy via PINK1/Parkin to Exert Multipolar Spindles Assembly during Mitosis
- Author
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Jiin Tsuey Cheng, Cheng Yu Tsai, Shean Jaw Chiou, Aij Lie Kwan, Chi Huei Wang, Tsung Hsien Chuang, Huey Jiun Ko, Chi Ying F. Huang, Yun Ling Lai, Joon Khim Loh, and Yi Ren Hong
- Subjects
0301 basic medicine ,lcsh:QR1-502 ,Cyclin B ,Antimycin A ,Cell Cycle Proteins ,Mitochondrion ,Mitochondrial Dynamics ,Biochemistry ,lcsh:Microbiology ,Phosphoserine ,0302 clinical medicine ,Mitophagy ,PKA ,centrosomes ,Aurora Kinase A ,biology ,phosphorylation ,Chemistry ,Cell biology ,mitochondria ,030220 oncology & carcinogenesis ,Mitochondrial fission ,biological phenomena, cell phenomena, and immunity ,Dynamins ,endocrine system ,Ubiquitin-Protein Ligases ,Mitosis ,PINK1 ,Spindle Apparatus ,Drp1 ,Protein Serine-Threonine Kinases ,Models, Biological ,PLK1 ,Article ,Electron Transport ,03 medical and health sciences ,Proto-Oncogene Proteins ,Rotenone ,Humans ,Molecular Biology ,Quinazolinones ,Centrosome ,Cyclin-dependent kinase 1 ,Hydrazones ,Cell Cycle Checkpoints ,Cyclic AMP-Dependent Protein Kinases ,Oxidative Stress ,mitophagy ,030104 developmental biology ,biology.protein ,Protein Kinases ,multipolar spindles ,Multipolar spindles ,HeLa Cells - Abstract
Mitochondrial fission and fusion cycles are integrated with cell cycle progression. Here we first re-visited how mitochondrial ETC inhibition disturbed mitosis progression, resulting in multipolar spindles formation in HeLa cells. Inhibitors of ETC complex I (rotenone, ROT) and complex III (antimycin A, AA) decreased the phosphorylation of Plk1 T210 and Aurora A T288 in the mitotic phase (M-phase), especially ROT, affecting the dynamic phosphorylation status of fission protein dynamin-related protein 1 (Drp1) and the Ser637/Ser616 ratio. We then tested whether specific Drp1 inhibitors, Mdivi-1 or Dynasore, affected the dynamic phosphorylation status of Drp1. Similar to the effects of ROT and AA, our results showed that Mdivi-1 but not Dynasore influenced the dynamic phosphorylation status of Ser637 and Ser616 in Drp1, which converged with mitotic kinases (Cdk1, Plk1, Aurora A) and centrosome-associated proteins to significantly accelerate mitotic defects. Moreover, our data also indicated that evoking mito-Drp1-Ser637 by protein kinase A (PKA) rather than Drp1-Ser616 by Cdk1/Cyclin B resulted in mitochondrial fission via the PINK1/Parkin pathway to promote more efficient mitophagy and simultaneously caused multipolar spindles. Collectively, this study is the first to uncover that mito-Drp1-Ser637 by PKA, but not Drp1-Ser616, drives mitophagy to exert multipolar spindles formation during M-phase.
- Published
- 2021
27. A Case of Leptomeningeal Dissemination of Pilocytic Astrocytoma in a Child
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Joon-Khim Loh, Chee-Yin Chai, Shyh-Shin Chiou, Chih-Hui Chang, Shiuh-Lin Hwang, and Yu-Feng Su
- Subjects
Male ,medicine.medical_specialty ,Vincristine ,medicine.medical_treatment ,Brain tumor ,Astrocytoma ,World Health Organization ,Carboplatin ,Lesion ,03 medical and health sciences ,chemistry.chemical_compound ,Meninges ,0302 clinical medicine ,Meningeal Neoplasms ,medicine ,Humans ,Chemotherapy ,medicine.diagnostic_test ,Pilocytic astrocytoma ,Brain Neoplasms ,business.industry ,Magnetic resonance imaging ,General Medicine ,medicine.disease ,Magnetic Resonance Imaging ,Neurology ,chemistry ,Child, Preschool ,030220 oncology & carcinogenesis ,Histopathology ,Neurology (clinical) ,Radiology ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
We present the case of a 2-year-old boy with progressive left-sided weakness and a cranial magnetic resonance imaging (MRI) scan showing a lesion with a cystic component in the right thalamus and basal ganglia. The lesion was subtotally resected and diagnosed as a pilocytic astrocytoma by histopathology. Tumor seeding along the surgical tract was seen on MRI 16 days and 10 weeks after surgery. The patient received vincristine and carboplatin, and MRI performed 4 months after chemotherapy revealed no additional or residual lesions. This case illustrated that a World Health Organization grade I astrocytoma could disseminate along the surgical tract.
- Published
- 2017
28. p53 Reaction to Cellular Stress Maximizes Apoptosis in Glioblastoma
- Author
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Yi-Ren Hong, Chihuei Wang, Cheng-Jung Ho, Wei-Hua Zhu, Yu-Hsuan Pao, Cheng Wei Chu, Hsin-Wen Chen, Joon Khim Loh, and Ru-Wei Lin
- Subjects
Stress (mechanics) ,Chemistry ,Apoptosis ,Bortezomib ,medicine ,Cancer research ,Doxorubicin ,medicine.disease ,Vorinostat ,oncology_oncogenics ,medicine.drug ,Glioblastoma - Abstract
In prostate cancer, p53 maximizes apoptosis in response to severe DNA damage, not DNA replication stress. Here, we examined the apoptotic response of two glioblastoma cells, p53-wild type U87 and a p53-mutated T98G cell, for the same stresses. We ascertained that p53 intensified apoptosis in response to severe DNA damage, not DNA replication stress in glioblastoma. We further asked if p53-mediated apoptosis can be induced by cellular stress other than severe DNA damage. We analyzed two compounds, bortezomib and vorinostat, respective inhibitors of 26S proteasome and histone deacetylase, to evaluate their capacity to activate p53-mediated apoptosis. The cellular stress incited by bortezomib, not vorinostat, activated p53-mediated apoptosis. Next, we asked if the cellular stress generated by combining the two compounds had a synergistic effect on apoptosis. Our results demonstrated that doxorubicin with bortezomib or CFS-1686, or bortezomib with vorinostat have a significant synergistic effect on apoptosis only in p53-wild type cell. Under high stress, p53 translocates from cytosol into the nucleus to cause apoptosis possibly. Together, p53 maximizes apoptosis for cellular stress caused by severe DNA damage, disruption of protein turnover, and for the stress induced by drug combination including doxorubicin with bortezomib or CFS-1686, and bortezomib with vorinostat.
- Published
- 2019
29. Thioridazine Enhances P62-Mediated Autophagy and Apoptosis Through Wnt/β-Catenin Signaling Pathway in Glioma Cells
- Author
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Yun Ling Lai, Hui Wen Cheng, Chen Yen Lin, Yi Ren Hong, Huey Jiun Ko, Chi Ying F. Huang, Tai Shan Cheng, Jiin Tsuey Cheng, Shean Jaw Chiou, Chihuei Wang, Joon Khim Loh, Cheng Wei Chu, Yu Hsin Liang, Chia Hua Chou, and Chun Li Su
- Subjects
Frizzled ,Programmed cell death ,autophagy ,Cell Survival ,Cell ,Blotting, Western ,P62 ,Catalysis ,Article ,Receptors, G-Protein-Coupled ,lcsh:Chemistry ,Inorganic Chemistry ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Humans ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,Wnt Signaling Pathway ,Spectroscopy ,030304 developmental biology ,0303 health sciences ,Wnt/β-catenin ,Chemistry ,Thioridazine ,Organic Chemistry ,Autophagy ,Cell Cycle ,Wnt signaling pathway ,glioblastoma ,apoptosis ,Catenins ,General Medicine ,Glioma ,3. Good health ,Computer Science Applications ,medicine.anatomical_structure ,lcsh:Biology (General) ,lcsh:QD1-999 ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Beclin-1 ,Signal transduction - Abstract
Thioridazine (THD) is a common phenothiazine antipsychotic drug reported to suppress growth in several types of cancer cells. We previously showed that THD acts as an antiglioblastoma and anticancer stem-like cell agent. However, the signaling pathway underlying autophagy and apoptosis induction remains unclear. THD treatment significantly induced autophagy with upregulated AMPK activity and engendered cell death with increased sub-G1 in glioblastoma multiform (GBM) cell lines. Notably, through whole gene expression screening with THD treatment, frizzled (Fzd) proteins, a family of G-protein-coupled receptors, were found, suggesting the participation of Wnt/β-catenin signaling. After THD treatment, Fzd-1 and GSK3β-S9 phosphorylation (inactivated form) was reduced to promote β-catenin degradation, which attenuated P62 inhibition. The autophagy marker LC3-II markedly increased when P62 was released from β-catenin inhibition. Additionally, the P62-dependent caspase-8 activation that induced P53-independent apoptosis was confirmed by inhibiting T-cell factor/β-catenin and autophagy flux. Moreover, treatment with THD combined with temozolomide (TMZ) engendered increased LC3-II expression and caspase-3 activity, indicating promising drug synergism. In conclusion, THD induces autophagy in GBM cells by not only upregulating AMPK activity, but also enhancing P62-mediated autophagy and apoptosis through Wnt/β-catenin signaling. Therefore, THD is a potential alternative therapeutic agent for drug repositioning in GBM.
- Published
- 2019
30. Meningeal Melanocytoma Associated with Nevus of Ota: Analysis of Twelve Reported Cases
- Author
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Hung-Pei Tsai, Chieh-Hsin Wu, Ann-Shung Lieu, Yu-Feng Su, Chih-Hui Chang, Joon-Khim Loh, Chih-Lung Lin, and Keng-Liang Kuo
- Subjects
Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Meningeal melanocytoma ,Intracranial Neoplasm ,Nevus of Ota ,Lesion ,Neoplasms, Multiple Primary ,03 medical and health sciences ,0302 clinical medicine ,Meningeal Neoplasms ,Medicine ,Humans ,skin and connective tissue diseases ,Melanoma ,business.industry ,Brain Neoplasms ,Neural crest ,Middle Aged ,medicine.disease ,Clinical Practice ,030220 oncology & carcinogenesis ,Melanocytes ,Surgery ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Background Primary melanocytic neoplasms (PMNs) are rare neoplasms, especially within the central nervous system. Meningeal melanocytomas, a subtype of PMN, are even rarer. Nevus of Ota results from the incomplete migration of melanocytes from the neural crest. Synchronous nevus of Ota and meningeal melanocytoma are infrequently encountered in clinical practice. Objective To evaluate and elucidate 12 cases of synchronous meningeal melanocytoma and nevus of Ota, thereby improving the understanding of the relationship between these 2 diseases. Methods We reviewed cases and searched the English-language literature from the PubMed database and collected clinical parameters of 12 cases of synchronously occurring nevus of Ota and meningeal melanocytoma. Results Among the 12 cases, 90.90% and 91.66% of the lesions were located ipsilaterally and supratentorially, respectively. Conclusions Our findings indicated a trend for both types of lesion to be located ipsilaterally and supratentorially. When a patient with nevus of Ota is found to harbor an intracranial neoplasm, the most likely diagnosis is PMN.
- Published
- 2018
31. GSK3β‑mediated Ser156 phosphorylation modulates a BH3‑like domain in BCL2L12 during TMZ‑induced apoptosis and autophagy in glioma cells
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Ming-Chang Yang, Joon Khim Loh, Shean Jaw Chiou, Yi Ren Hong, Yeng-Tseng Wang, Wen‑Sheng Huang, Cheng Wei Chu, Bo‑Xiu Hsiao, and Chia Hua Chou
- Subjects
Models, Molecular ,0301 basic medicine ,autophagy ,Microtubule-associated protein ,Cell ,anti-apoptosis ,Muscle Proteins ,Apoptosis ,DNA methyltransferase ,03 medical and health sciences ,Protein Domains ,GSK-3 ,Cell Line, Tumor ,Temozolomide ,Genetics ,medicine ,Humans ,BH3-like domain ,Protein Interaction Maps ,Phosphorylation ,Antineoplastic Agents, Alkylating ,Glycogen Synthase Kinase 3 beta ,Chemistry ,Autophagy ,Articles ,Glioma ,General Medicine ,Cell cycle ,Cell biology ,Dacarbazine ,030104 developmental biology ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,Cell culture ,BCL2-like 12 ,Beclin-1 ,biological phenomena, cell phenomena, and immunity - Abstract
BH3 domains, classified initially as BCL2 homology domains, participate in both apoptosis and autophagy. Beclin‑1 contains a BH3 domain, which is required for binding to antiapoptotic BCL2 homologs and BCL2‑mediated inhibition of autophagy. BCL2‑like 12 (BCL2L12) also harbors a BH3‑like domain, which is 12 residues long and contains a LXXXAE/D motif. In a yeast two‑hybrid system performed in the present study, BCL2L12 shared similar binding partnerships to antiapoptotic BCL2 homologs, such as Beclin‑1. In addition, this BH3‑like domain was involved in anti‑apoptosis and drug‑induced autophagy in glioma cell lines. Mutations in S156 and hydrophobic L213 to alanine counteracted the antiapoptotic properties of BCL2L12 and downregulated the activation of microtubule associated protein 1 light chain 3B (LC3B), autophagy‑related (ATG)12‑ATG5 conjugates and Beclin‑1, compared with a BCL2L12 wild‑type group. Molecular dynamics simulations revealed that phosphorylation at Ser156 of BCL2L12 (within α‑6 and α‑7 helices) influenced the BH3‑like domain conformation (α‑9 helix), indicating that glycogen synthase kinase (GSK) 3β‑mediated Ser156 phosphorylation modulated a BH3‑like domain in BCL2L12. Altogether, the present findings indicated that BCL2L12 may participate in anti‑apoptosis and autophagy via a BH3‑like domain and GSK3β‑mediated phosphorylation at Ser156. Furthermore, blockade of temozolomide (TMZ)‑induced autophagy by 3‑methyladenine (3‑MA) resulted in enhanced activation of apoptotic markers, as well as tumor suppresor protein p53 (p53) expression in U87MG cells. The present results suggested that p53 and O6‑methylguanine DNA methyltransferase activation, and BCL2, BCL‑extra large, Beclin‑1 and BCL2L12 expression may be used as a detection panel to determine which patients can benefit from TMZ and ABT‑737 combination treatment.
- Published
- 2018
32. The origin of GSKIP, a multifaceted regulatory factor in the mammalian Wnt pathway
- Author
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Chia-Hua Chou, Yu Chung Chuang, Hsin-Fu Liu, Yin-Hsuan Wang, An-Kuo Chou, Ann-Shung Lieu, Jiin-Tsuey Cheng, Chao-Neng Tseng, Chia-Ning Yang, Joon-Khim Loh, Shean-Jaw Chiou, Shen-Long Howng, Bo-Xiu Hsiao, Yi-Ren Hong, and Ming-Chang Yang
- Subjects
0301 basic medicine ,Dynamins ,Models, Molecular ,Protein domain ,Mutant ,Saccharomyces ,GTP Phosphohydrolases ,Evolution, Molecular ,Mitochondrial Proteins ,03 medical and health sciences ,Protein Domains ,Protein kinase A regulatory subunit binding ,Two-Hybrid System Techniques ,Serine ,Humans ,Binding site ,Phosphorylation ,Molecular Biology ,Wnt Signaling Pathway ,Phylogeny ,Binding Sites ,Glycogen Synthase Kinase 3 beta ,030102 biochemistry & molecular biology ,biology ,Chemistry ,Wnt signaling pathway ,Computational Biology ,Cell Biology ,biology.organism_classification ,Cyclic AMP-Dependent Protein Kinases ,Cell biology ,Repressor Proteins ,030104 developmental biology ,HEK293 Cells ,Protein Multimerization ,Microtubule-Associated Proteins ,Function (biology) ,Protein Binding - Abstract
GSK3β interacting protein (GSKIP) is a naturally occurring negative regulator of GSK3β and retains both the Protein Kinase A Regulatory subunit binding (PKA-RII) domain and GSK3β interacting domain. Of these two domains, we found that PKA-RII is required for forming a working complex comprising PKA/GSKIP/GSK3β/Drp1 to influence phosphorylation of Drp1 Ser637. In this study, bioinformatics and experimental explorations re-analyzing GSKIP's biofunctions suggest that the evolutionarily conserved Domain of Unknown Function (DUF727) is an ancestral prototype of GSKIP in prokaryotes, and acquired the C-terminal GSK3β binding site (tail) in invertebrates except for Saccharomyces spp., after which the N-terminal PKA-RII binding region (head) evolved in vertebrates. These two regions mutually influence each other and modulate GSKIP binding to GSK3β in yeast two-hybrid assays and co-immunoprecipitation. Molecular modeling showed that mammalian GSKIP could form a dimer through the L130 residue (GSK3β binding site) rather than V41/L45 residues. In contrast, V41/L45P mutant facilitated a gain-of-function effect on GSKIP dimerization, further influencing binding behavior to GSK3β compared to GSKIP wild-type (wt). The V41/L45 residues are not only responsible for PKA RII binding that controls GSK3β activity, but also affect dimerization of GSKIP monomer, with net results of gain-of-function in GSKIP-GSK3β interaction. In addition to its reported role in modulating Drp1, Ser637 phosphorylation caused mitochondrial elongation; we postulated that GSKIP might be involved in the Wnt signaling pathway as a scavenger to recruit GSK3β away from the β-catenin destruction complex and as a competitor to compete for GSK3β binding, resulting in accumulation of S675 phosphorylated β-catenin.
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- 2017
33. Bcl2L12 with a BH3-like domain in regulating apoptosis and TMZ-induced autophagy: A prospective combination of ABT-737 and TMZ for treating glioma
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Ming-Chang Yang, Jiin-Tsuey Cheng, Yeng-Tseng Wang, An-Kuo Chou, Ann-Shung Lieu, Joon-Khim Loh, Yi-Ren Hong, Shen-Long Howng, Chia-Hua Chou, Yi-Yang Li, and Wen-Sheng Huang
- Subjects
Models, Molecular ,Cancer Research ,bcl-X Protein ,Muscle Proteins ,Apoptosis ,Plasma protein binding ,Biology ,Piperazines ,Nitrophenols ,Protein structure ,Proto-Oncogene Proteins ,Antineoplastic Combined Chemotherapy Protocols ,Autophagy ,Temozolomide ,Tumor Cells, Cultured ,medicine ,Humans ,Sulfonamides ,Oncogene ,Biphenyl Compounds ,Glioma ,Cell cycle ,Peptide Fragments ,Protein Structure, Tertiary ,Cell biology ,Dacarbazine ,Biphenyl compound ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,Drug Resistance, Neoplasm ,Cancer research ,biological phenomena, cell phenomena, and immunity ,Protein Binding ,medicine.drug - Abstract
Bcl2L12 as a new member of the Bcl2 family, which contains a BH2 domain and shares a lower amino acid similarity with other Bcl2 family proteins. Bcl2L12 is reported to be involved in apoptosis regulation, but this role remains controversial in different cancer type. Temozolomide (TMZ) is currently used to intervene glioma multiforme (GBM), but an acquired chemotherapeutic resistance maybe occurred due to undesired autophagy. Previous studies uncovered that Bcl2L12 may interact with Bcl-xL and may harbor a BH3-like domain. Therefore, we investigated whether this BH3-like domain is responsible for the Bcl2L12 anti-apoptotic property. Moreover, we tested whether ABT-737, a BH3 mimetic agent, can be combined with TMZ to treat GBM. We aligned Bcl2L12 with Bcl2 family members, compared interacting pattern of BH3 domain and their protein 3D structure. We identified that Bcl2L12 interacts with Bcl-xL and Bcl2 in yeast two-hybrid system. Bcl2L12192-220 was a minimal region for Bcl2L12-Bcl-xL interaction. Five-point mutations with respect to hydrophobic and charge residues were generated to test whether they are the key residue of BH3-like domain. Our data showed that both h1 (L213) and h2 residue (L217) are essential for Bcl2L12 interacting with Bcl2 family proteins. Ectopically expressed h1 or h2 mutant in U87MG cell line resulted in reactivation of cleaved-PARP, caspase-3 and cytochrome c releasing compared to Bcl2L12 wt group. Implementing ABT-737 combined with TMZ provided a superior effect on apoptosis induction in Bcl2L12 wt group, which effectively reactivated apoptotic markers. Altogether, our findings indicated that Bcl2L12 retains a BH3-like domain, which is important for the Bcl2L12 anti-apoptotic property and TMZ-induced autophagy. Our results basically support the idea of using ABT-737 to counteract the anti-apoptotic role of Bcl2L12 and sensitize drug response of the GBM cells to TMZ.
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- 2015
34. Comparison Study of Clinical Presentation and Surgical Outcome between Children and Adults with Craniopharyngioma: A 22-Year Single-Center Experience in Southern Taiwan
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Yu-Feng Su, Cheng Wei Chu, Aij Lie Kwan, Ann Shung Lieu, Joon Khim Loh, and Chih-Lung Lin
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Pediatrics ,medicine.medical_specialty ,business.industry ,Southern taiwan ,medicine.disease ,Single Center ,Omics ,Craniopharyngioma ,Diabetes insipidus ,Comparison study ,Medicine ,Presentation (obstetrics) ,Medical diagnosis ,business - Abstract
Background: The differences in clinical presentation and surgical outcome between children and adults with craniopharyngioma have not been well-described and there are few data available for Asian population. The aim of this study is to investigate the differences between paediatric and adult patients with craniopharyngioma at a single medical centre in southern Taiwan. Methods: The clinical records of 40 patients with craniopharyngioma who were all surgically treated at Kaohsiung Medical University Hospital from January 1990 to December 2012 were reviewed. The patients were divided into two groups based on age: children (= 20 years) and adults (>20 years). MRI and CT images were obtained pre- and post-operatively. Histopathological examination diagnosed tumors. Statistical analyses were performed to compare the differences in the two groups. Results: Among the patients, 17 were children and 23 were adults. The children group demonstrated more diagnoses of large or giant tumors (p
- Published
- 2017
35. Effect of inhibiting Bcl2L12 expression on autophagy via a BH3-like domain in glioma cells- another role of Bcl2L12 in TMZ-induced autophagy
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Chu, Cheng-Wei, Yang, Ming-Chang, Chia-Hua Chou, Huang, Wen-Sheng, Bo-Xiu Hsiao, Shean-Jaw Chiou, Joon-Khim Loh, and Hong, Yi-Ren
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- 2017
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36. Correlation of Altered Expression of the Autophagy Marker LC3B with Poor Prognosis in Astrocytoma
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Daniel Winardi, Ching Liang Hsieh, Chee Yin Chai, Joon Khim Loh, Chia Li Chung, Hung Pei Tsai, and Yung-Hsiang Chen
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Male ,Pathology ,medicine.medical_specialty ,Article Subject ,medicine.medical_treatment ,Cell ,lcsh:Medicine ,Astrocytoma ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Therapeutic approach ,Antigens, CD ,Autophagy ,Biomarkers, Tumor ,medicine ,Humans ,AC133 Antigen ,neoplasms ,Aged ,Glycoproteins ,Retrospective Studies ,Chemotherapy ,General Immunology and Microbiology ,Brain Neoplasms ,lcsh:R ,Membrane Proteins ,Cancer ,General Medicine ,Prognosis ,medicine.disease ,Radiation therapy ,medicine.anatomical_structure ,Cancer cell ,Neoplastic Stem Cells ,Cancer research ,Beclin-1 ,Female ,Apoptosis Regulatory Proteins ,Peptides ,Microtubule-Associated Proteins ,Research Article - Abstract
Glioblastoma multiforme is one of the most serious malignant brain tumors and is characterized by resistance to chemotherapy and radiation therapy. Recent studies suggest that autophagy may play an important role not only in the regulation of cancer development and progression but also in determining the response of cancer cells to anticancer therapy. The purpose of the present study was to assess the relationship between protein expressions of two autophagy markers, LC3B and Beclin-1, with clinical parameters in astrocytoma patients. Furthermore, the expression of CD133, a marker of the cancer stem-like cells, in astrocytoma patients was also investigated. A total of 106 thin-section slides were retrospectively collected from astrocytoma patients. LC3B, but not Beclin-1, protein expression was found to significantly correlate with resistance to radiation- or chemotherapy. In addition, high intensity of LC3B staining was predictive of poor prognosis. Furthermore, survival time of patients with high-level expression in both CD133 and LC3B was significantly shorter than those with weak expression in both CD133 and LC3B. These results suggest that astrocytoma cancer stem-like cells together with enhanced autophagy may cause resistance to radiation therapy/chemotherapy and that targeting the cancer stem-like cell in astrocytoma may offer a viable therapeutic approach.
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- 2014
37. Progesterone Attenuates Experimental Subarachnoid Hemorrhage-Induced Vasospasm by Upregulation of Endothelial Nitric Oxide Synthase via Akt Signaling Pathway
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Chia-Li Chung, Chih-Zen Chang, Joon-Khim Loh, Chih-Lung Lin, Chia-Mao Chang, Yee-Jean Tsai, and Yu-Feng Su
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Transcriptional Activation ,medicine.medical_specialty ,Subarachnoid hemorrhage ,Article Subject ,lcsh:Medicine ,General Biochemistry, Genetics and Molecular Biology ,Cerebral vasospasm ,Enos ,Internal medicine ,medicine.artery ,medicine ,Basilar artery ,Animals ,Vasospasm, Intracranial ,cardiovascular diseases ,Progesterone ,General Immunology and Microbiology ,biology ,business.industry ,Akt/PKB signaling pathway ,lcsh:R ,Vasospasm ,General Medicine ,Subarachnoid Hemorrhage ,medicine.disease ,biology.organism_classification ,Rats ,nervous system diseases ,Nitric oxide synthase ,Endocrinology ,Gene Expression Regulation ,Vasoconstriction ,cardiovascular system ,biology.protein ,Female ,Nitric Oxide Synthase ,medicine.symptom ,business ,Proto-Oncogene Proteins c-akt ,Research Article ,Signal Transduction - Abstract
Cerebral vasospasm is the leading cause of mortality and morbidity in patients after aneurysmal subarachnoid hemorrhage (SAH). However, the mechanism and adequate treatment of vasospasm are still elusive. In the present study, we evaluate the effect and possible mechanism of progesterone on SAH-induced vasospasm in a two-hemorrhage rodent model of SAH. Progesterone (8 mg/kg) was subcutaneously injected in ovariectomized female Sprague-Dawley rats one hour after SAH induction. The degree of vasospasm was determined by averaging the cross-sectional areas of basilar artery 7 days after first SAH. Expressions of endothelial nitric oxide synthase (eNOS) and phosphorylated Akt (phospho-Akt) in basilar arteries were evaluated. Prior to perfusion fixation, there were no significant differences among the control and treated groups in physiological parameters recorded. Progesterone treatment significantly(P<0.01)attenuated SAH-induced vasospasm. The SAH-induced suppression of eNOS protein and phospho-Akt were relieved by progesterone treatment. This result further confirmed that progesterone is effective in preventing SAH-induced vasospasm. The beneficial effect of progesterone might be in part related to upregulation of expression of eNOS via Akt signaling pathway after SAH. Progesterone holds therapeutic promise in the treatment of cerebral vasospasm following SAH.
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- 2014
38. Leptomeningeal dissemination of pilocytic astrocytoma
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Shiuh-Lin Hwang, Chih-Hui Chang, Chee-Yin Chai, Shyh-Shin Chiou, and Joon-Khim Loh
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medicine.medical_specialty ,Chemotherapy ,Pathology ,medicine.diagnostic_test ,Pilocytic astrocytoma ,business.industry ,medicine.medical_treatment ,Meninges ,Brain tumor ,Magnetic resonance imaging ,medicine.disease ,Tumor seeding ,Surgery ,Lesion ,Right thalamus ,medicine.anatomical_structure ,leptomeningeal dissemination ,medicine ,pilocytic astrocytoma ,medicine.symptom ,business ,brain tumor - Abstract
Summary A unique case of pilocytic astrocytoma (PCA) with leptomeningeal dissemination occurring after surgery in a 2-year-old boy who presented with progressive left-sided weakness is reported. A cranial magnetic resonance imaging (MRI) disclosed a lesion with a cystic component in the right thalamus and basal ganglia. The lesion was subtotally resected and diagnosed by the pathology department to be a PCA. An MRI 16 days after surgery revealed a residual tumor with a tumor seeding along the surgical tract and in the meninges. The patient then underwent chemotherapy and a cranial MRI. Eleven months later the patient did not disclose any residual or additional lesions. The patient continues to do well at the time of this writing. This case illustrates a unique instance of leptomeningeal dissemination through the surgical tract of a resected cerebral PCA in a child.
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- 2013
39. Surgery of spinal cord pilocytic astrocytoma complicated by leptomeningeal dissemination to the brain and spine and rapid progression
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Shiuh-Lin Hwang, Joon-Khim Loh, and Yu-Lin Chou
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Diplopia ,medicine.medical_specialty ,Pathology ,medicine.diagnostic_test ,Pilocytic astrocytoma ,Astrocytic Tumor ,business.industry ,Astrocytoma ,Magnetic resonance imaging ,medicine.disease ,Spinal cord ,Surgery ,law.invention ,Intramedullary rod ,medicine.anatomical_structure ,children ,leptomeningeal dissemination ,law ,medicine ,pilocytic astrocytoma ,medicine.symptom ,business ,Intracranial pressure - Abstract
Summary Pilocytic astrocytoma (PCA) is a common benign astrocytic tumor in children that usually arises in the cerebellum, brainstem, hypothalamic region, or optic pathways. It can also arise in the spinal cord as an intradural intramedullary PCA. In rare cases, it presents with leptomeningeal dissemination, which leads to a poor clinical outcome. We present a rare case of spinal cord pilocytic astrocytoma with leptomeningeal dissemination to the brain and spine with rapid progression. We present a 13-year-old girl with progressive weakness of her right arm. An intramedullary hypervascular neurogenic tumor at the C3–C6 level was identified by magnetic resonance imaging (MRI) and surgical excision was performed. PCA was proven by pathology. The tumor recurred 3 months later and an intramedullary polycystic astrocytoma at the C1–T1 level was confirmed by MRI. Total tumor resection was performed and pathological characteristics again confirmed PCA. However, diplopia with blurred vision was noted 1 month after the last surgery, which was accompanied by signs of increased intracranial pressure (IICP). MRI indicated leptomeningeal enhancement in the brain and tumor seeding along the spinal cord. Chemotherapy and radiotherapy were administered, but the clinical course rapidly deteriorated and the patient died of respiratory distress. Although the prognosis for low-grade astrocytomas is good in most reported studies, this case showed leptomeningeal dissemination with a rapid course that resulted in death. A fatal outcome might be anticipated when encountering difficult intramedullary spinal cord lesions, as in our case.
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- 2013
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40. Plasma levels of transforming growth factor-beta 1 before and after removal of low- and high-grade astrocytomas
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Joon-Khim Loh, Yu-Feng Su, Chih-Jen Wang, Kung-Shing Lee, Tai-Hsin Tsai, Yi-Ren Hong, Ann-Shung Lieu, Aij-Lie Kwan, Chung-Ching Chio, Chi-Yun Cheng, Shiuh-Lin Hwang, Shen-Long Howng, and Chih-Lung Lin
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Immunology ,Urology ,Brain tumor ,Astrocytoma ,Biochemistry ,Transforming Growth Factor beta1 ,Young Adult ,Glioma ,medicine ,Humans ,Immunology and Allergy ,Child ,Prospective cohort study ,Molecular Biology ,Aged ,biology ,Receiver operating characteristic ,business.industry ,Hematology ,Transforming growth factor beta ,Plasma levels ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Survival Analysis ,Cranioplasty ,Treatment Outcome ,ROC Curve ,Case-Control Studies ,Child, Preschool ,biology.protein ,Female ,Neoplasm Grading ,business - Abstract
Transforming growth factor-beta 1 (TGF-β1) has been reported to be a possible marker for a number of tumors, including brain tumors. The aim of this study was to measure the plasma levels of TGF-β1 in patients with low- and high-grade astrocytomas before and after surgery. This prospective study included 14 patients with low-grade astrocytomas and 25 with high-grade astrocytomas who underwent tumor removal and 13 controls (patients who underwent cranioplasty for skull bone defects). Plasma levels of TGF-β1 were measured in all subjects using enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curve analysis showed that when the level of TGF-β1 before tumor removal was ≥ 2.52 ng/ml, astrocytoma was predicted with a sensitivity of 94.9% and specificity of 100%. The mean plasma level of TGF-β1 in both the low-grade and high-grade astrocytoma groups significantly decreased after tumor removal (p0.05); there was no significant change in TGF-β1 plasma level of the controls following surgery. Patients with high-grade astrocytomas had a significantly higher mortality rate than patients with low-grade astrocytomas (p=0.019) and significantly shorter survival (p=0.008). A positive correlation between TGF-β1 level after tumor removal and tumor volume was only found in the high-grade astrocytoma group (γ=0.597, p=0.002). The findings show that plasma TGF-β1 level was increased in patients with low-grade and high-grade astrocytoma, and that the levels significantly decreased after tumor removal in both groups. The results provide additional evidence that TGF-β1 might be useful as a tumor marker for astrocytomas.
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- 2013
41. Differential expression of centrosome-associated proteins in human brain tumors: A possible role of hNinein isoform 6 in cell differentiation
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Ming-Chang Yang, Ann-Shung Lieu, Joon-Khim Loh, Chia-Hua Chou, Ching-Chih Lin, Fang-Yi Lin, Yi-Ren Hong, and Shen-Long Howng
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Gene isoform ,Clinical Biochemistry ,Brain tumor ,Biology ,Biochemistry ,Tubulin ,medicine ,Humans ,Protein Isoforms ,RNA, Messenger ,Centrosome ,Brain Neoplasms ,Pituitary tumors ,Brain ,Nuclear Proteins ,Astrocytoma ,Cell Differentiation ,General Medicine ,Cell cycle ,medicine.disease ,Cell biology ,Reverse transcription polymerase chain reaction ,Cytoskeletal Proteins ,Centrin ,Cancer research ,Molecular Medicine ,Microtubule-Associated Proteins - Abstract
Dysregulated centrosomal expression has been observed in high grade gliomas. Thus, this study aimed to examine the expression of Aurora family kinase and various centrosomal proteins, including centrin, γ-tubulin, and hNinein isoforms, in human brain tumors, including 29 meningiomas, 34 astrocytomas, 6 pituitary adenomas, and 6 metastatic tumors. mRNA expression was evaluated using reverse transcription polymerase chain reaction. The role of hNinein isoform 6 expression in cell differentiation was assessed in BrdU-treated IMR-32 cells. Differential expression of centrosomal proteins of brain tumors and cell lines was observed. Specifically, centrin 2 and centrin 3 expression levels were classified as moderate or abundant in >97% of samples in the meningioma group, 63% of astrocytomas, >83% of metastatic and pituitary tumors. Alternatively, hNinein isoform 6 expression was only detected in normal brain and astrocytoma tumors (17/34); however, it was not expressed in meningioma (0/29), metastatic tumors (0/6) (P < 0.001). Of the six neuroblastoma cell lines analyzed only IMR-32 cells expressed hNinein isoform 6. Furthermore, downregulated expression of hNinein isoform 6 and upregulation of γ-tubulin was correlated to astrocytoma tumor grade (P < 0.001). Increased hNinein isoform 6 mRNA expression was observed in response to BrdU treatment, and its expression was greater in teratomas as compared to embryonic stem cells. Further studies are necessary to determine if hNinein isoform 6 functions as a tumor-suppressor gene in brain tumors. Differential centrosomal protein expression may result in altered centrosome function that is observed the in progression of various brain tumors. © 2012 International Union of Biochemistry and Molecular Biology, Inc.
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- 2012
42. The alteration of plasma TGF-β1 levels in patients with brain tumors after tumor removal
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Chih-Jen Wang, Yu-Feng Su, Chung-Ching Chio, Tai-Hsin Tsai, Chi-Yun Cheng, Kung-Shing Lee, Ann-Shung Lieu, Shiuh-Lin Hwang, Yi-Ren Hong, Aij-Lie Kwan, Chih-Lung Lin, Shen-Long Howng, and Joon-Khim Loh
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pathology ,Adolescent ,Urology ,Brain tumor ,Serology ,Transforming Growth Factor beta1 ,Young Adult ,Biomarkers, Tumor ,medicine ,Humans ,In patient ,Child ,Aged ,Tumor marker ,Medicine(all) ,lcsh:R5-920 ,Brain Neoplasms ,business.industry ,Astrocytoma ,General Medicine ,Plasma levels ,Tumor removal ,Middle Aged ,medicine.disease ,Transforming growth factor-beta 1 ,Female ,business ,lcsh:Medicine (General) ,Transforming growth factor - Abstract
Transforming growth factor (TGF) β1 may be a candidate for a serologic tumor marker. In this study, the plasma levels of TGF-β1 in patients with brain tumors were measured using enzyme-linked immunosorbent assay before and after tumor removal. Patients were divided into four groups, the control group and the benign, malignant, and metastatic brain tumor groups. All brain tumor groups showed significant increases in the levels of TGF-β1 before tumor removal (6.36 ± 3.94, 17.0 ± 9.7, and 12.2 ± 10.3 ng/ml for the benign, malignant, and metastatic groups, respectively). When compared with the results obtained in the control group (1.12 ± 0.74 ng/ml), significant decreases in TGF-β1 concentrations after total tumor removal were found in both the benign and malignant brain tumor groups (2.55 ± 2.00 and 8.93 ± 5.73 ng/ml, respectively; p = 0.0001 and p = 0.003, respectively). On the other hand, plasma TGF-β1 levels in the metastatic brain tumor group showed a slight but significant increase (14.7 ± 9.3 ng/ml, p = 0.035) after tumor removal. In a case of low-grade astrocytoma, plasma levels of TGF-β1 were found to be 3.6 and 1.1 ng/ml before and after tumor removal, respectively. However, recurrent tumor was noted in this patient 7 months later, and the levels of TGF-β1 were 26.2 and 8.4 ng/ml before and after the second operation, respectively. The data show that plasma TGF-β1 was elevated in the circulation of patients with brain tumors and that significant decreases in TGF-β1 levels were observed after the removal of benign and malignant tumors. The results also suggest that TGF-β1 may be a useful serologic marker for brain tumors.
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- 2012
43. GSK3β regulates Bcl2L12 and Bcl2L12A anti-apoptosis signaling in glioblastoma and is inhibited by LiCl
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Ching-Mei Hsu, Joon-Khim Loh, Wei-Jay Chen, Shen-Long Howng, Ming-Chang Yang, Chia-Hua Chou, Yi-Ren Hong, For-Wey Lung, Ching-Chih Lin, Chih-Chang Wei, and An-Kuo Chou
- Subjects
Muscle Proteins ,Apoptosis ,tau Proteins ,Biology ,Glycogen Synthase Kinase 3 ,GSK-3 ,Cell Line, Tumor ,Two-Hybrid System Techniques ,medicine ,Humans ,Protein Isoforms ,Staurosporine ,Phosphorylation ,Molecular Biology ,GSK3B ,Glycogen Synthase Kinase 3 beta ,Brain Neoplasms ,Kinase ,HEK 293 cells ,Cell Biology ,Molecular biology ,Protein Structure, Tertiary ,HEK293 Cells ,Proto-Oncogene Proteins c-bcl-2 ,Ectopic expression ,Signal transduction ,Glioblastoma ,Lithium Chloride ,Protein Binding ,Signal Transduction ,Developmental Biology ,medicine.drug - Abstract
BCL2L12 has been reported to be involved in post-mitochondrial apoptotic events in glioblastoma, but the role of BCL2L12A, a splicing variant of BCL2L12, remains unknown. In this study, we showed that BCL2L12 and BCL2L12A were overexpressed in glioblastoma multiforme (GBM). Large-scale yeast two-hybrid screening showed that BCL2L12 was a GSK3b binding partner in a testis cDNA library. Our data demonstrated that GSK3b interacts with BCL2L12 but not BCL2L12A, whose C terminus lacks a binding region. We found that a BCL2L12(153-191) fragment located outside of the C-terminal BH2 motif is responsible for GSK3b binding. In contrast, no interaction was detected between BCL2L12A and GSK3b. In vitro kinase and l-phosphatase assays showed that GSK3b phosphorylates BCL2L12 at S156, while this site is absent on BCL2L12A. Moreover, our data also showed that the BCL2L12(153-191) fragment directly interrupted GSK3bmediated Tau phosphorylation in a dose-dependent manner. Ectopic expression of GFP-fused BCL2L12 or BCL2L12A in U87MG cells leads to repression of apoptotic markers and protects against staurosporine (STS) insults, indicating an antiapoptotic role for both BCL2L12 and BCL2L12A. In contrast, no anti-apoptotic ability was seen in BCL2L12(S156A). When BCL2L12-expressing U87MG cells were co-administrated with STS and LiCl, cells underwent apoptosis. This effect could be reversed by LiCl. In short, we established a model to demonstrate that GSK3b interacts with and phosphorylates BCL2L12 and might also affect BCL2L12A to modulate the apoptosis signaling pathway in glioblastoma. These findings suggest that LiCl may be a prospective therapeutic agent against GBM.
- Published
- 2012
44. Eosinophilic granuloma of the occipital bone in an adult: A case report
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Ann-Shung Lieu, Yu-Feng Su, Shiuh-Lin Hwang, Chee-Yin Chai, Joon-Khim Loh, and Shen-Long Howng
- Subjects
Adult ,Male ,Eosinophilic granuloma ,medicine.medical_treatment ,Calvaria ,顱骨腫瘤 ,嗜伊紅性肉芽腫 ,medicine ,Humans ,Medicine(all) ,lcsh:R5-920 ,Skull neoplasm ,business.industry ,Occipital bone ,Soft tissue ,Skull Neoplasm ,General Medicine ,Anatomy ,Langerhans’ cell histiocytosis ,medicine.disease ,Bone cement ,Cranioplasty ,蘭格罕細胞組織球增生症 ,Radiography ,Skull ,medicine.anatomical_structure ,Occipital Bone ,business ,lcsh:Medicine (General) - Abstract
Eosinophilic granuloma (EG) refers to the most common and benign form of the disorder known as Langerhans’ cell histiocytosis. The disease is typically found in children and adolescents and rarely affects adults. We present a case of EG in the occipital bone in a 36-year-old man, who visited our hospital with the chief complaint of left occipital palpable tumor mass with local tenderness and pain for one month. An X-ray of the skull revealed a rounded osteolytic lesion. A computed tomography scan revealed a shadow of soft tissues in the left occipital site involving the entire thickness of the calvaria, which was indicative of marked destruction of the bone. The soft mass was successfully removed. The margins of the skull lesion were excised, and cranioplasty was performed simultaneously with bone cement. A definitive diagnosis of EG was made by histopathology and immunohistochemical detection of S-100 antigen in the tissue samples. With respect to management, we believe surgery is the best option for most accessible cranial lesions of EG. A cranioplasty with bone cement or autologous bone can be performed in the same session to repair the cranial defect.
- Published
- 2011
45. GSKIP is homologous to the axin GSK3[beta] interaction domain and functions as a negative regulator of GSK3[beta]
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He-Yen Chou, Shen-Long Howng, Tai-Shan Cheng, Yun-Ling Hsiao, Ann-Shung Lieu, Joon-Khim Loh, Shiuh-Lin Hwang, Ching-Chih Lin, Ching-Mei Hsu, Chihuei Wang, Chu-I Lee, Pei-Jung Lu, Chen-Kung Chou, Chi-Ying Huang, and Yi-Pen Hong
- Subjects
Phosphorylation -- Analysis ,Glycogen -- Research ,Biological sciences ,Chemistry - Abstract
A study was conducted to identify a naturally occurring GSK3[beta] binding protein, GSK3[beta] interaction protein (GSKIP), whose C-terminal region possesses a 25-amino acid region similar to [GID.sub.381-405] of axin. The results indicate that GSKIP is a good GSK3[beta] substrate, and both the full-length protein and a C-terminal fragment of GSKIP could block phosphorylation of primed and nonprimed substrates in different fashions.
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- 2006
46. Factors influencing seizures in adult patients with supratentorial astrocytic tumors
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Ann-Shung Lieu, Kung-Shing Lee, Chih-Zen Chang, T.-Y. Huang, Shen-Long Howng, Joon-Khim Loh, Shiuh-Lin Hwang, T.-H. Kuo, Chun-Po Yen, Chih-Lung Lin, and Chih-Long Lin
- Subjects
Male ,medicine.medical_specialty ,Neurology ,medicine.medical_treatment ,Brain tumor ,Astrocytoma ,Epilepsy ,Postoperative Complications ,Recurrence ,Risk Factors ,medicine ,Humans ,Aged ,Cerebral Hemorrhage ,Retrospective Studies ,business.industry ,Supratentorial Neoplasms ,Odds ratio ,Middle Aged ,medicine.disease ,Anticonvulsant ,Anesthesia ,Disease Progression ,Regression Analysis ,Female ,Surgery ,Neurology (clinical) ,Neurosurgery ,Glioblastoma ,business ,Anaplastic astrocytoma - Abstract
Seizures and epilepsy in adults are important and increasingly common clinical problems. Despite this, the investigation of seizures in adults with astrocytic tumors remains a grey area. The incidence and influencing factors of preoperative and postoperative seizures were evaluated in 101 patients of 45 years or older with supratentorial astrocytic tumors. Preoperative seizures occurred in 14 (14%) patients. Seizures at presentation were significantly correlated with pathological grades of astrocytic tumors (p = 0.0318). The risk of seizures at presentation was greatest in patients with well-differentiated astrocytomas as compared with anaplastic astrocytomas (Odds ratio = 4.364, p = 0.056) or glioblastomas multiforme (Odds ratio = 5.673, p = 0.007). There was no association of preoperative seizures with age, sex, location or site of the tumors. Postoperative seizures occurred in 18 (18%) patients, including 8 (8/14, 57%) recurrent seizures and 10 (10/87, 12%) late-onset seizures. Postoperative seizures were significantly correlated with the presence of preoperative seizures (p = 0.0003). The presence of preoperative seizures was potentially predictive of postoperative seizures when evaluated by logistic regression model (Odds ratio = 6.650). Thirteen (72%) of 18 patients with postoperative seizures were associated with tumor recurrence in 7 cases, hemorrhage in 3 cases and malignant progression in 3 cases. There was no association of postoperative seizures with age, sex, location or site of the tumors, grades of tumors, type of preoperative seizures, duration of preoperative seizures, serum level of anticonvulsant drug, extent of surgery, postoperative radiation or chemotherapy. The patients with preoperative seizures had a higher risk of postoperative seizures and should be carefully monitored. Imaging examination of brain to exclude the possibilities of tumor recurrence or hemorrhage is warrantable in supratentorial astrocytoma patients with postoperative seizures.
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- 2004
47. Acute subdural hematoma in infancy
- Author
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Chih-Lung Lin, Joon-Khim Loh, Aij-Lie Kwan, and Shen-Long Howng
- Subjects
Male ,Child abuse ,medicine.medical_specialty ,medicine.medical_treatment ,Diagnosis, Differential ,Central nervous system disease ,Hematoma ,Risk Factors ,health services administration ,medicine ,Hematoma, Subdural, Acute ,Humans ,Craniotomy ,Neurologic Examination ,medicine.diagnostic_test ,business.industry ,Vascular disease ,Head injury ,Infant, Newborn ,Infant ,Magnetic resonance imaging ,Shaken Baby Syndrome ,medicine.disease ,Magnetic Resonance Imaging ,Surgery ,body regions ,Treatment Outcome ,surgical procedures, operative ,Hematoma, Subdural, Chronic ,Anesthesia ,Etiology ,Female ,Neurology (clinical) ,Tomography, X-Ray Computed ,business ,Follow-Up Studies - Abstract
BACKGROUND Acute subdural hematoma in infants is distinct from that occurring in older children or adults because of differences in mechanism, injury thresholds, and the frequency with which the question of nonaccidental injury is encountered. The purpose of this study is to analyze the clinical characteristics of acute subdural hematoma in infancy, to discover the common patterns of this trauma, and to outline the management principles within this group. METHODS Medical records and films of 21 cases of infantile acute subdural hematoma were reviewed retrospectively. Diagnosis was made by computed tomography or magnetic resonance imaging. Medical records were reviewed for comparison of age, gender, cause of injury, clinical presentation, surgical management, and outcome. RESULTS Twenty-one infants (9 girls and 12 boys) were identified with acute subdural hematoma, with ages ranging from 6 days to 12 months. The most common cause of injury was shaken baby syndrome. The most common clinical presentations were seizure, retinal hemorrhage, and consciousness disturbance. Eight patients with large subdural hematomas underwent craniotomy and evacuation of the blood clot. None of these patients developed chronic subdural hematoma. Thirteen patients with smaller subdural hematomas were treated conservatively. Among these patients, 11 developed chronic subdural hematomas 15 to 80 days (mean = 28 days) after the acute subdural hematomas. All patients with chronic subdural hematomas underwent burr hole and external drainage of the subdural hematoma. At follow-up, 13 (62%) had good recovery, 4 (19%) had moderate disability, 3 (14%) had severe disability, and 1 (5%) died. Based on GCS on admission, one (5%) had mild (GCS 13-15), 12 (57%) had moderate (GCS 9-12), and 8 (38%) had severe (GCS 8 or under) head injury. Good recovery was found in 100% (1/1), 75% (8/12), and 50% (4/8) of the patients with mild, moderate, and severe head injury, respectively. Sixty-three percent (5/8) of those patients undergoing operation for acute subdural hematomas and 62% (8/13) of those patients treated conservatively had good outcomes. CONCLUSIONS Infantile acute subdural hematoma if treated conservatively or neglected, is an important cause of infantile chronic subdural hematoma. Early recognition and suitable treatment may improve the outcome of this injury. If treatment is delayed or the condition is undiagnosed, acute subdural hematoma may cause severe morbidity or even fatality.
- Published
- 2002
48. [Untitled]
- Author
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Shiuh-Lin Hwang, Tzuu-Yuan Huang, Shen-Long Howng, Joon-Khim Loh, and Ann-Shung Lieu
- Subjects
Cancer Research ,medicine.medical_specialty ,Pathology ,Neurology ,business.industry ,medicine.medical_treatment ,Immunosuppression ,Human brain ,medicine.disease ,Central nervous system disease ,medicine.anatomical_structure ,Oncology ,medicine ,lipids (amino acids, peptides, and proteins) ,In patient ,Tumor growth ,Neurology (clinical) ,Tumor removal ,Prostaglandin E2 ,business ,medicine.drug - Abstract
Background. Both experimental and human tumors often synthesize high levels of prostaglandins, most notably prostaglandin E2 (PGE2). This compound may play an important role in tumor growth and immunosuppression. Little is known of the production of PGE2 by brain tumors. The present study was designed to investigate the levels of PGE2 in the plasma of human brain tumors before and after tumor removal.
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- 2002
49. Alteration of Basilar Artery Rho-Kinase and Soluble Guanylyl Cyclase Protein Expression in a Rat Model of Cerebral Vasospasm following Subarachnoid Hemorrhage
- Author
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Hung-Pei Tsai, Pei-Yu Lee, Shu-Chuan Wu, Chih-Jen Wang, Chia-Li Chung, Bin-Nan Wu, Joon-Khim Loh, Neal F. Kassell, and Aij-Lie Kwan
- Subjects
Male ,medicine.medical_specialty ,Subarachnoid hemorrhage ,Article Subject ,Organophosphonates ,lcsh:Medicine ,Receptors, Cytoplasmic and Nuclear ,Tetrazoles ,General Biochemistry, Genetics and Molecular Biology ,Pathogenesis ,Rats, Sprague-Dawley ,Cerebral vasospasm ,Soluble Guanylyl Cyclase ,medicine.artery ,Internal medicine ,medicine ,Basilar artery ,Cyclic AMP ,Cyclic GMP-Dependent Protein Kinases ,Animals ,Vasospasm, Intracranial ,cardiovascular diseases ,Rho-associated protein kinase ,Protein Kinase Inhibitors ,rho-Associated Kinases ,General Immunology and Microbiology ,Behavior, Animal ,Endothelin-1 ,business.industry ,lcsh:R ,General Medicine ,Subarachnoid Hemorrhage ,medicine.disease ,Endothelin 1 ,nervous system diseases ,Disease Models, Animal ,Protein Kinase C-delta ,Protein Transport ,Endocrinology ,Guanylate Cyclase ,Organ Specificity ,Basilar Artery ,business ,Soluble guanylyl cyclase ,Endothelin receptor ,Research Article ,Signal Transduction - Abstract
Background and Purpose. The vasoconstrictor endothelin-1 (ET-1) has been implicated in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). Previous results showed that CGS 26303, an endothelin converting enzyme (ECE) inhibitor, effectively prevented and reversed arterial narrowing in animal models of SAH. In the present study, we assessed the effect of CGS 26303 on neurological deficits in SAH rats. The involvement of vasoactive pathways downstream of ET-1 signaling in SAH was also investigated.Methods. Sprague-Dawley rats were divided into five groups (n=6/group): (1) normal control, (2) SAH, (3) SAH+vehicle, (4) SAH+CGS 26303 (prevention), and (5) SAH+CGS 26303 (reversal). SAH was induced by injecting autologous blood into cisterna magna. CGS 26303 (10 mg/kg) was injected intravenously at 1 and 24 hr after the initiation of SAH in the prevention and reversal protocols, respectively. Behavioral changes were assessed at 48 hr after SAH. Protein expression was analyzed by Western blots.Results. Deficits in motor function were obvious in the SAH rats, and CGS 26303 significantly improved the rate of paraplegia. Expressions of rho-kinase-II and membrane-bound protein kinase C-δand rhoA were significantly increased, while those of soluble guanylyl cyclaseα1andβ1as well as protein kinase G were significantly decreased in the basilar artery of SAH rats. Treatment with CGS 26303 nearly normalized these effects.Conclusions. These results demonstrate that the rhoA/rho-kinase and sGC/cGMP/PKG pathways play pivotal roles in cerebral vasospasm after SAH. It also shows that ECE inhibition is an effective strategy for the treatment of this disease.
- Published
- 2014
50. Association of Aurora A and gamma-tubulin expression in astrocytomas and patient survival
- Author
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Joon-Khim Loh, Aij-Lie Kwan, Hung-Pei Tsai, Ann-Shung Lieu, Cheng-Yu Tsai, Shen-Long Howng, and Chee-Yin Chai
- Subjects
Oncology ,Survival Status ,Adult ,Male ,medicine.medical_specialty ,Pathology ,macromolecular substances ,Astrocytoma ,Resection ,Tubulin ,Internal medicine ,medicine ,Humans ,In patient ,Karnofsky Performance Status ,Aurora Kinase A ,Retrospective Studies ,business.industry ,Brain Neoplasms ,Retrospective cohort study ,Patient survival ,General Medicine ,Middle Aged ,medicine.disease ,Survival Analysis ,Neurology ,Immunohistochemistry ,Disease characteristics ,Female ,Neurology (clinical) ,business - Abstract
The purpose was to evaluate the association of Aurora A and gamma-tubulin expression with disease characteristics and survival in patients with astrocytoma.This is a retrospective study of patients who had surgical specimens that were pathologically diagnosed as astrocytoma. The expression level of Aurora A and gamma-tubulin in tumor tissue was evaluated by immunohistochemistry. Clinical information, Karnofsky performance status scale, and survival status of patients were collected.We found that high protein levels of gamma-tubulin or Aurora A were associated with patients 45 years of age, high tumor grade, more advanced non-fully resectable tumors, and poorer survival status. The survival time for patients whose tumors had high gamma-tubulin and Aurora A expression was about 12 months compared with approximately 41 months for patients with low levels of expression of these proteins. Poor patient performance status following resection was also associated with high levels of gamma-tubulin and Aurora A expression.The expression levels of gamma-tubulin or Aurora A kinase were associated with patients' age, astrocytoma grade, respectability, as well as patient survival and performance. These findings support the idea that these factors may potentially be important prognostic indicators for patients with astrocytomas.
- Published
- 2014
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