Ha S. Nguyen

Acid ceramidase is a novel drug target for pediatric brain tumors

Pediatric brain tumors are the most common solid tumors in children and are also a leading culprit of cancer-related fatalities in children. Pediatric brain tumors remain hard to treat. In this study, we demonstrated that medulloblastoma, pediatric glioblastoma, and atypical teratoid rhabdoid tumors express significant levels of acid ceramidase, where levels are highest in the radioresistant tumors, suggesting that acid ceramidase may confer radioresistance. More importantly, we also showed that acid ceramidase inhibitors are highly effective at targeting these pediatric brain tumors with low IC50 values (4.6–50 μM). This data suggests acid ceramidase as a novel drug target for adjuvant pediatric brain tumor therapies. Of these acid ceramidase inhibitors, carmofur has seen clinical use in Japan since 1981 for colorectal cancers and is a promising drug to undergo further animal studies and subsequently a clinical trial as a treatment for pediatric patients with brain tumors.

Acid ceramidase confers radioresistance to glioblastoma cells

Glioblastoma multiforme (GBM) is the most common primary, intracranial malignancy of the central nervous system. The standard treatment protocol, which involves surgical resection, and concurrent radiation with adjuvant temozolomide (TMZ), still imparts a grim prognosis. Ultimately, all GBMs exhibit recurrence or progression, developing resistance to standard treatment. This study demonstrates that GBMs acquire resistance to radiation via upregulation of acid ceramidase (ASAH1) and sphingosine-1-phosphate (Sph-1P). Moreover, inhibition of ASAH1 and Sph-1P, either with humanized monoclonal antibodies, small molecule drugs (i.e. carmofur), or a combination of both, led to suppression of GBM cell growth. These results suggest that ASAH1 and Sph-1P may be excellent targets for the treatment of new GBMs and recurrent GBMs, especially since the latter overexpresses ASAH1.

Management of Adult Traumatic Brain Injury: A Review

Traumatic brain injury (TBI) is a significant source of morbidity and mortality in the adult population. The management of traumatic brain injury depends on its severity. It must be recognized that almost all forms of treatment for TBI are geared towards the minimization of secondary injury, as it is assumed that primary injury is irreversible. The discussion here represents much of what is known up-to-date concerning TBI management, but its treatment continues to evolve once new mechanisms of injury are discovered and those that we know of now are refined. The treating staffs are encouraged to keep up with the current state of the literature to stay informed.

Identification of radiation responsive genes and transcriptome profiling via complete RNA sequencing in a stable radioresistant U87 glioblastoma model

The absence of major progress in the treatment of glioblastoma (GBM) is partly attributable to our poor understanding of both GBM tumor biology and the acquirement of treatment resistance in recurrent GBMs. Recurrent GBMs are characterized by their resistance to radiation. In this study, we used an established stable U87 radioresistant GBM model and total RNA sequencing to shed light on global mRNA expression changes following irradiation. We identified many genes, the expressions of which were altered in our radioresistant GBM model, that have never before been reported to be associated with the development of radioresistant GBM and should be concertedly further investigated to understand their roles in radioresistance. These genes were enriched in various biological processes such as inflammatory response, cell migration, positive regulation of epithelial to mesenchymal transition, angiogenesis, apoptosis, positive regulation of T-cell migration, positive regulation of macrophage chemotaxis, T-cell antigen processing and presentation, and microglial cell activation involved in immune response genes. These findings furnish crucial information for elucidating the molecular mechanisms associated with radioresistance in GBM. Therapeutically, with the global alterations of multiple biological pathways observed in irradiated GBM cells, an effective GBM therapy may require a cocktail carrying multiple agents targeting multiple implicated pathways in order to have a chance at making a substantial impact on improving the overall GBM survival.

Mechanism for the Rapid Spontaneous Resolution of an Acute Subdural Hematoma and Transformation into a Subdural Hygroma

BACKGROUND Spontaneous resolution of acute subdural hematomas (SDHs), occurring as the result of a traumatic injury, is well reported in the literature and rapidly resolving SDHs have been reported as well. Although the mechanism behind the rapid resolution of a SDH has not been well understood, there are postulated mechanisms for this phenomenon. The aim of this report is to present a patient who experienced the rapid resolution of a traumatic SDH, which was replaced by a subdural hygroma. CASE DESCRIPTION This 25-year-old man presented to the hospital with an acute left-sided SDH after a head-on motor vehicle collision. At the time of presentation, the patient had an acute SDH with 11 mm of midline shift. The hematoma resolved spontaneously within 48 hours and was replaced by a thin subdural hygroma. CONCLUSIONS Rapidly resolving SDHs represent a phenomenon that has been well described, although is not entirely understood. The imaging findings of this patient suggest that cerebrospinal fluid washout is a mechanism that promotes acute SDH resolution.

Irradiation of pediatric glioblastoma cells promotes radioresistance and enhances glioma malignancy via genome-wide transcriptome changes

Pediatric glioblastoma (GBM) is a relatively rare brain tumor in children that has a dismal prognosis. Surgery followed by radiotherapy is the main treatment protocol used for older patients. The benefit of adjuvant chemotherapy is still limited due to a poor understanding of the underlying molecular and genetic changes that occur with irradiation of the tumor. In this study, we performed total RNA sequencing on an established stable radioresistant pediatric GBM cell line to identify mRNA expression changes following radiation. The expression of many genes was altered in the radioresistant pediatric GBM model. These genes have never before been reported to be associated with the development of radioresistant GBM. In addition to exhibiting an accelerated growth rate, radioresistant GBM cells also have overexpression of the DNA synthesis-rate-limiting enzyme ribonucleotide reductase, and pro-cathepsin B. These newly identified genes should be concertedly studied to better understand their role in pediatric GBM recurrence and progression after radiation. It was observed that the changes in multiple biological pathways protected GBM cells against radiation and transformed them to a more malignant form. These changes emphasize the importance of developing a treatment regimen that consists of a multiple-agent cocktail that acts on multiple implicated pathways to effectively target irradiated pediatric GBM. An alternative to radiation or a novel therapy that targets differentially expressed genes, such as metalloproteases, growth factors, and oncogenes and aim to minimize oncogenic changes following radiation is necessary to improve recurrent GBM survival.

Surgical Management of Chronic Subdural Hematoma: Short Communication

Chronic subdural hematoma (cSDH) is a common neurosurgical pathology associated with prior traumatic brain injury (TBI) and older age that is often complicated by antiplatelet or anticoagulant therapies. cSDH often results from the liquefaction of a previous acute subdural hematoma that accompanies TBI. The incidence of cSDH will likely increase over the next 25 years, placing a burden on health care costs. As such, a simple, inexpensive treatment option is desirable. In this short communication, we describe recent data and different techniques that are available for treating cSDH.

Management of Pediatric Traumatic Brain Injury: A Mini-Review

Traumatic brain injury (TBI) is a significant source of concern in the pediatric population. It has been estimated that close to 500,000-700,000 pediatric TBI incidents occur within the United States alone, with majority occurring in early childhood ( 15 years). The management of TBI depends on its severity. It is the prevention of worsening of the secondary injury that is often targeted during the medical management. Given that TBI poses such a huge health risk, further understanding is required for adequate management of pediatric patients with TBI; especially due to the fact that their brain is still developing and has not completely matured.

Biomechanics and Management of Lumbar Spinal Stenosis NeurodegenerativeDisease: Mini-Review

Lumbar stenosis is an increasingly common pathology, which causes significant symptoms affecting quality of life, especially in the aging population. The mainstays of treatment employ both conservative and surgical management. Should surgery be required decompression of the lumbar spine via laminectomy or laminotomy has been shown to be effective. The addition of fusion may only benefit in cases with spinal instability. The treatment of lumbar stenosis should include a multifactorial and multidisciplinary approach. Lumbar fusion may lead to an adjacent segment disease as a result of endplate failure by promoting a lumbar alignment with parallel endplates. Upright MRI could be a useful adjunct objective diagnostic option in the future to differentiate symptomatic from asymptomatic patients by evaluating their foraminal geometry.