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Yu Tung Lo, Neville Wei Yang Teo and Beng Ti Ang

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Chi Long Ho, Chee Meng Wang, Kah Keow Lee, Ivan Ng and Beng Ti Ang

Object

This study addresses the changes in brain oxygenation, cerebrovascular reactivity, and cerebral neurochemistry in patients following decompressive craniectomy for the control of elevated intracranial pressure (ICP) after severe traumatic brain injury (TBI).

Methods

Sixteen consecutive patients with isolated TBI and elevated ICP, who were refractory to maximal medical therapy, underwent decompressive craniectomy over a 1-year period. Thirteen patients were male and 3 were female. The mean age of the patients was 38 years and the median Glasgow Coma Scale score on admission was 5.

Results

Six months following TBI, 11 patients had a poor outcome (Group 1, Glasgow Outcome Scale [GOS] Score 1–3), whereas the remaining 5 patients had a favorable outcome (Group 2, GOS Score 4 or 5). Decompressive craniectomy resulted in a significant reduction (p < 0.001) in the mean ICP and cerebrovascular pressure reactivity index to autoregulatory values (< 0.3) in both groups of patients. There was a significant improvement in brain tissue oxygenation (PbtO2) in Group 2 patients from 3 to 17 mm Hg and an 85% reduction in episodes of cerebral ischemia. In addition, the durations of abnormal PbtO2 and biochemical indices were significantly reduced in Group 2 patients after decompressive craniectomy, but there was no improvement in the biochemical indices in Group 1 patients despite surgery.

Conclusions

Decompressive craniectomy, when used appropriately in protocol-driven intensive care regimens for the treatment of recalcitrant elevated ICP, is associated with a return of abnormal metabolic parameters to normal values in patients with eventually favorable outcomes.

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Hong Zhao, Carol Tang, Kemi Cui, Beng-Ti Ang and Stephen T. C. Wong

Object

The study of tumor cell growth and invasion in cancer biology is often limited by the inability to visualize tumor cell behavior in real time in animal models. The authors provide evidence that glioma cells are heterogeneous, with a subset responsible for increased invasiveness. The use of bioluminescence (BL) imaging to investigate dynamic aspects of glioma progression are discussed.

Methods

Glioblastoma multiforme–initiating cells were generated under conditions typically used to sustain neural stem cells. The invasiveness potential was determined using a Matrigel chamber. The presence of an “invasiveness gene signature” that correlated with patient survival outcome was ascertained through microarray gene expression analysis. To measure invasiveness, the authors devised a method focussed on BL imaging and tested it in vitro and in vivo using a zebrafish xenograft model. Bioluminescence imaging signals were verified using known inhibitors of glioma growth: AEE788, N-[(3,5-Difluorophenyl)acetyl]-L-alanyl-2-phenylglycine-1,1-dimethylethyl ester, and compound E.

Results

The authors' data support the idea that glioblastoma multiforme–initiating cells are heterogeneous and possess an invasive subset; BL imaging was used as a readout method to assess this invasive subset. The in vitro data obtained using a known glioma growth inhibitor, AEE788, showed that BL imaging could detect cellular movement and invasion even before overall cell death was detectable on conventional viability assays. Further work using a zebrafish tumor xenograft model supported the efficacy of BL imaging in monitoring changes in tumor load.

Conclusions

The authors used optically transparent zebrafish and high-resolution confocal imaging to track tumor growth in vivo and demonstrate the efficacy of this model for screening antitumor and antiangiogenic compounds. The integration of zebrafish transgenic technology into human cancer biological studies may aid in the development of cancer models targeting specific organs, tissues, or cell types within tumors. Zebrafish could also provide a cost-effective means for the rapid development of therapeutic agents directed at blocking tumor growth and invasion.

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Zhiquan Damian Lee, David Low Chyi Yeu, Beng Ti Ang, Wai Hoe Ng and Wan Tew Seow

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Constance Chua, Norazean Zaiden, Kooi-Hoong Chong, Siew-Ju See, Meng-Cheong Wong, Beng-Ti Ang and Carol Tang

Object

Cancer progenitor–like cells isolated by Hoechst 33342 dye efflux (termed the “side population” [SP]) have been studied in a variety of cancers, including malignant brain tumors. In this study, the authors investigate the nature of the SP phenotype in 2 glioma cell lines, U87MG and T98G, and their response to temozolomide. The roles of several adenosine triphosphate–binding cassette (ABC) multidrug transporters expressed by SP cells, in particular ABCG2, are also examined.

Methods

Using fluorescence-activated cell sorting, the cells were separated into SP and non-SP fractions and analyzed for progenitor cell–like properties with immunofluorescence staining, quantitative real-time polymerase chain reaction, and their ability to reform glioma mass in an immune-compromised mouse. The response of the SP cells to temozolomide was investigated at the cellular and molecular levels. Small interfering RNA knockdown was used to examine the specific role of the ABCG2 transporter, and the cells' tumorigenic potential was measured using the soft agar clonogenic assay.

Results

Side population cells are characterized by the presence of progenitor cell–like properties: increased expression of nestin, musashi-1, and ABCG2 were observed. In addition, only SP cells were able to reconstitute cellular heterogeneity; these cells were also more invasive than the non-SP cells, and possessed tumorigenic capacity. Temozolomide treatment increased the number of SP cells, and this corresponded to more progenitor-like cells, concurrent with elevated expression of several ABC transporters.

Conclusions

Knockdown of ABCG2 transporters did not abrogate the SP cell response to temozolomide. Upregulation of several other ABC drug transporter genes is proposed to account for this chemoresistance.

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Beng Ti Ang, Elgin Yap, Joyce Lim, Wan Loo Tan, Puay Yong Ng, Ivan Ng and Tseng Tsai Yeo

Object. This study was designed to elucidate the pattern of expression of poly(adenosine diphosphate—ribose) polymerase (PARP) in human pericontusional brain tissue and to correlate these findings with commonly used clinical parameters.

Methods. The expression of PARP was ascertained using immunohistochemical studies in eight specimens of human pericontusional brain tissue obtained when the patients underwent craniotomy for mass effect. The following demographic and clinical parameters were also analyzed for each patient: age, sex, postresuscitation Glasgow Coma Scale score (GCS), computerized tomography findings, intracranial pressure (ICP) recordings during the first 24 hours postsurgery, and the time interval from injury to surgery.

The authors observed that PARP was present in neurons of pericontusional tissue and that it conformed to two patterns of subcellular localization; it was found either in the nucleus exclusively or in both nuclear and cytoplasmic compartments. They showed that a preponderance of cytoplasmic staining in neurons was significantly correlated with a short time interval from trauma to surgery (≤ 4 hours). There was no correlation, however, between the subcellular distribution of PARP and clinical parameters such as admission GCS score and ICP readings obtained intra- and postoperatively.

Conclusions. As in earlier studies in which it has been suggested that caspase-cleaved PARP translocates to the cytoplasm during apoptosis, the authors' results indicate that apoptosis may predominate in the initial time frame after head injury. This information may well influence the timing of administration of antiapoptotic neuronal salvage agents for adjunctive therapy of head injury in the future.