Antiadhesive effects of GRN163L--an oligonucleotide N3'->P5' thio-phosphoramidate targeting telomerase

We determined previously that a novel human telomerase RNA (hTR) antagonist, GRN163L, inhibited the tumorigenic potential of A549-luciferase (A549-luc) lung cancer cells in vitro and in vivo. Further studies revealed that A549-luc cells were also morphologically altered by GRN163L. A549-luc cells treated before cell attachment with a single dose of GRN163L only weakly attached to the substrate and remained rounded, whereas control mismatch-treated cells exhibited typical epitheloid appearance and adhesion properties. These morphologic changes were independent of hTR expression and telomerase inhibition and were unrelated to telomere length. This effect is dependent on the molecular properties of the lipid moiety, the phosphorothioate backbone, and the presence of triplet-G sequences within the GRN163L structure. Altered adhesion was manifested by a 50% reduction in rapid cellular attachment and a 3-fold decrease in total cell spreading surface area. Administration of a single dose of GRN163L (15 mg/kg) at the time of cell inoculation, using an in vivo model of lung cancer metastasis, resulted in significant reductions in tumor burden at days 13, 20, and 27 of tumor progression. Thus, the potent antimetastatic effects of GRN163L may be related, in part, to the antiadhesive effects of this novel cancer therapeutic conferred via specific structural determinants and that these effects are independent of telomerase inhibition or telomere shortening.     

The role of flexible hollow core carbon dioxide lasers in resection of lumbar intraspinal lipomas

Purpose

The authors assess the role of flexible hollow core CO₂ laser system (Omniguide system) in resection of intraspinal lipomas.

Methods

Eight patients with intraspinal lipomas were operated using an Omniguide laser system over a 22-month period. The age range varied between 6?months and 16?years. All of them had lipoma of the conus medullaris associated with lumbar subcutaneous lipoma. Two of these had previous surgery with resection of the subcutaneous part of the lipoma; in one of them, a partial resection of the conus medullaris lipoma had also been performed. In six, there were no obvious motor or sensory deficits whereas two had gross neurologic deficits, with the deficits occurring in one after the previous decompression. Resection of the conus lipoma, untethering of the spinal cord, and reconstruction of the decompressed conus was performed in all aided with Omniguide laser system. The power settings of the laser system ranged from 4 to 8?W.

Results

Subtotal to near-total resection was achieved in all. None of the patients developed any new motor or sensory deficits. Three had postoperative CSF leaks which initially required reoperation with graft resuturing and subsequently placement of lumboperitoneal shunt. One child with preexisting neurologic deficits improved in power over the next 12?months.

Conclusion

Flexible CO₂ laser system was precise and convenient in decompressing the conus lipomas and untethering of the cord in lumbar spinal lipomas.     

Idiopathic normal-pressure hydrocephalus: evaluation and findings in a multidisciplinary memory clinic

The diagnostic evaluation of patients with possible idiopathic normal-pressure hydrocephalus (INPH) is traditionally performed in the settings of either neurological, neurosurgical or psychiatric departments. The diagnostic procedure and findings in 71 consecutive patients referred with a clinical and radiological suspicion of INPH to our out-patient multidisciplinary memory clinic are evaluated. Primary diagnoses and potential concomitant disorders considered of secondary importance for the symptomatologies were established. Abnormal hydrodynamics, demonstrated by intraventricular pressure monitoring and infusion test were mandatory for the diagnosis of INPH. Mean age was 68 years and mean Mini-Mental State Examination (MMSE) score was 22. DSM IV criteria of dementia were fulfilled in 42%. In half of the referred patients (n=36), the suspicion of INPH was already disproved subsequently to the evaluation programme performed in the outpatient clinic. The main primary diagnosis was cerebrovascular disease (CVD) comprising 27% (n=19) of the referrals, whereas INPH was diagnosed in only 20% (n=14). Shunt improvement rate was 72%. The remaining patients were diagnosed as having one of 26 different conditions. A multiplicity of disorders mimics the INPH syndrome, with CVD being the primary differential diagnosis. Evaluating patients with possible INPH in an outpatient multidisciplinary memory clinic is an effective and rational diagnostic approach.     

Cerebral blood flow response to functional activation

Cerebral blood flow (CBF) and cerebral metabolic rate are normally coupled, that is an increase in metabolic demand will lead to an increase in flow. However, during functional activation, CBF and glucose metabolism remain coupled as they increase in proportion, whereas oxygen metabolism only increases to a minor degree—the so-called uncoupling of CBF and oxidative metabolism. Several studies have dealt with these issues, and theories have been forwarded regarding the underlying mechanisms. Some reports have speculated about the existence of a potentially deficient oxygen supply to the tissue most distant from the capillaries, whereas other studies point to a shift toward a higher degree of non-oxidative glucose consumption during activation. In this review, we argue that the key mechanism responsible for the regional CBF (rCBF) increase during functional activation is a tight coupling between rCBF and glucose metabolism. We assert that uncoupling of rCBF and oxidative metabolism is a consequence of a less pronounced increase in oxygen consumption. On the basis of earlier studies, we take into consideration the functional recruitment of capillaries and attempt to accommodate the cerebral tissue''s increased demand for glucose supply during neural activation with recent evidence supporting a key function for astrocytes in rCBF regulation.     

Proton spectroscopic imaging of the thalamus in treatment-naive pediatric obsessive-compulsive disorder.

BACKGROUND: Neurobiological abnormalities in the thalamus, particularly the dorsomedial nucleus of the thalamus, are believed to be involved in the pathophysiology of obsessive-compulsive disorder. Although obsessive-compulsive disorder commonly arises in childhood and adolescence, no prior study has examined the thalamus in pediatric obsessive-compulsive disorder patients. METHODS: In this study, N-acetyl-aspartate, a putative marker of neuronal viability, creatine/phosphocreatine, and choline levels were measured in the lateral and medical subregions of the left and right thalami using a multislice proton magnetic resonance spectroscopic imaging sequence in 11 treatment-naive, nondepressed obsessive-compulsive disorder outpatients, 8-15 years old, and 11 case-matched control subjects. RESULTS: A significant reduction in N-acetyl-aspartate/choline and N-acetyl-aspartate/(creatine/phosphocreatine + choline) was observed in both the right and left medial thalami in obsessive-compulsive disorder patients compared with control subjects. The N-acetyl-aspartate/choline and N-acetyl-aspartate/(creatine/phosphocreatine + choline) levels did not differ significantly between case-control pairs in either the left or the right lateral thalamus. Reduction in N-acetyl-aspartate levels in the left medial thalamus was inversely correlated with increased obsessive-compulsive disorder symptom severity. CONCLUSIONS: These findings provide new evidence of localized functional neurochemical marker abnormalities in the thalamus in pediatric obsessive-compulsive disorder. Our results must be considered preliminary, however, given the small sample size.     

Magnetic resonance linear accelerator technology and adaptive radiation therapy: An overview for clinicians

Radiation therapy (RT) continues to play an important role in the treatment of cancer. Adaptive RT (ART) is a novel method through which RT treatments are evolving. With the ART approach, computed tomography or magnetic resonance (MR) images are obtained as part of the treatment delivery process. This enables the adaptation of the irradiated volume to account for changes in organ and/or tumor position, movement, size, or shape that may occur over the course of treatment. The advantages and challenges of ART maybe somewhat abstract to oncologists and clinicians outside of the specialty of radiation oncology. ART is positioned to affect many different types of cancer. There is a wide spectrum of hypothesized benefits, from small toxicity improvements to meaningful gains in overall survival. The use and application of this novel technology should be understood by the oncologic community at large, such that it can be appropriately contextualized within the landscape of cancer therapies. Likewise, the need to test these advances is pressing. MR-guided ART (MRgART) is an emerging, extended modality of ART that expands upon and further advances the capabilities of ART. MRgART presents unique opportunities to iteratively improve adaptive image guidance. However, although the MRgART adaptive process advances ART to previously unattained levels, it can be more expensive, time-consuming, and complex. In this review, the authors present an overview for clinicians describing the process of ART and specifically MRgART.