Citations

Abstract In the current study, we examined a panel of serially passaged glioblastoma xenografts, in the context of an intracranial tumor therapy response model, to identify associations between glioblastoma molecular characteristics and tumor sensitivity to the epidermal growth factor receptor (EGFR) kinase inhibitor erlotinib. From an initial evaluation of 11 distinct glioblastoma xenografts, two erlotinib-sensitive tumors were identified, each having amplified EGFR and expressing wild-type PTEN. One of these tumors expressed truncated EGFRvIII, whereas the other expressed full-length EGFR. Subsequent cDNA sequence analysis revealed the latter tumor as expressing an EGFR sequence variant with arginine, rather than leucine, at amino acid position 62; this was the only EGFR sequence variant identified among the 11 xenografts, other than the aforementioned vIII sequence variant. EGFR cDNAs were then examined from 12 more xenografts to determine whether additional missense sequence alterations were evident, and this analysis revealed one such case, expressing threonine, rather than alanine, at amino acid position 289 of the extracellular domain. This glioblastoma was also amplified for EGFR, but did not display significant erlotinib sensitivity, presumably due to its lacking PTEN expression. In total, our study identified two erlotinib-sensitive glioblastoma xenografts, with the common molecular characteristics shared by each being the expression of wild-type PTEN in combination with the expression of amplified and aberrant EGFR. [Mol Cancer Ther 2007;6(3):1167–74]

The purpose of this study was to identify common personality traits in males with traumatic spinal cord injury (SCI). One hundred and five participants with SCI completed the NEO Personality Inventory (NEO-PI). The participants averaged 41.1 years of age and 17.9 years since injury onset. Compared with the NEO-PI normative sample, the SCI sample scored significantly lower on the Conscientiousness factor and the Activity and Assertiveness facet scales. They scored significantly higher on the Excitement-Seeking scale. These results suggest that males with SCI are less determined, have lower energy levels, are socially retiring, and that they tend to seek stimulation. These findings may reflect the contribution of both preinjury personality traits and adaptation to the limitations imposed by SCI.

This study investigated the psychometric properties of the Mattis Dementia Rating Scale (DRS), including its internal consistency, sensitivity to age and education effects, pattern of change scores, convergent validity and predictive utility. Age and education effects and stability were assessed in a sample of 280 cognitively normal persons over age 55. All other features were assessed in a sample of 274 persons with cognitive impairment, including 221 newly diagnosed dementia patients and 53 patients with mild cognitive impairment. Both samples were drawn from the Mayo Clinic Alzheimer's Disease Patient Registry. Within the normal sample, Pearson correlation coefficients for DRS Total score with age, education and intelligence were all significant, p < .0001; MAYO Full Scale IQ (FSIQ) shared approximately 20% variance with DRS Total score. Internal consistency was greater than .7 for Construction, Conceptualization, Memory, and Total score, greater than .65 for Attention and less than .5 for Initiation and Perseveration. DRS subscales cores for Memory, Attention, and Conceptualization were significantly correlated with appropriate indices from the WAIS-R or Wechsler Memory Scale-Revised, as assessed in the Mayo Older Americans Normative Studies, providing convergent validity for these DRS scales. Importantly, proportional hazards modeling revealed initial DRS Total score to be a significant predictor of longitudinal institutionalization and mortality outcomes.

Ongoing communication with cancer patients about their treatment preferences is important. A survey assessing treatment preferences was distributed to 100 cancer patients who were newly diagnosed, 100 in remission after therapy, and 60 who had failed therapy/ relapsed; 100 cancer caregivers, and 100 noncancer patients attending the cancer center for benign hematologic problems. Almost 59% of respondents preferred treatment even if the chance of cure was less than 10%. Among subjects who did not have cancer, less than 50% wanted treatment under these circumstances, whereas over 70% of cancer patients who had failed treatment or relapsed wanted treatment ( P = .0994). Multiple logistic regression analysis revealed that the adjusted odds of preferring aggressive treatment were less for those without cancer and those with newly diagnosed cancer than for respondents who had failed treatment or were in relapse. The preference for aggressive cancer treatment is related to medical condition.

The trafficking of leukocytes from the blood to sites of inflammation is the cumulative result of receptor-ligand-mediated signaling events associated with the leukocytes themselves as well as with the underlying vascular endothelium. Our data show that Gα i signaling pathways in the vascular endothelium regulate a critical step required for leukocyte diapedesis. In vivo studies using knockout mice demonstrated that a signaling event in a non-lymphohematopoietic compartment of the lung prevented the recruitment of proinflammatory leukocytes. Intravital microscopy showed that blockade was at the capillary endothelial surface and ex vivo studies of leukocyte trafficking demonstrated that a Gα i -signaling event in endothelial cells was required for transmigration. Collectively, these data suggest that specific Gα i2 -mediated signaling between endothelial cells and leukocytes is required for the extravasation of leukocytes and for tissue-specific accumulation.

We evaluated the effects of chronic hyperglycemia on L5 dorsal root ganglion (DRG) neurons using immunohistochemical and electrophysiologic techniques for evidence of oxidative injury. Experimental diabetic neuropathy was induced by streptozotocin. To evaluate the pathogenesis of the neuropathy, we studied peripheral nerve after 1, 3, and 12 months of diabetes. Electrophysiologic abnormalities were present from the first month and persisted over 12 months. 8-Hydroxy-2′-deoxyguanosine labeling was significantly increased at all time points in DRG neurons, indicating oxidative injury. Caspase-3 labeling was significantly increased at all three time points, indicating commitment to the efferent limb of the apoptotic pathway. Apoptosis was confirmed by a significant increase in the percentage of neurons undergoing apoptosis at 1 month (8%), 3 months (7%), and 12 months (11%). These findings support the concept that oxidative stress leads to oxidative injury of DRG neurons, with mitochondrium as a specific target, leading to impaired mitochondrial function and apoptosis, manifested clinically as a predominantly sensory neuropathy.

Chronic hyperglycemia results in a predominantly sensory neuropathy. Recent studies suggest that dorsal root ganglion (DRG) neurons comprise a specific target and may be responsible for the important complication of diabetic sensory neuropathy, since hyperglycemia for longer than 6 months results in a vacuolar ganglionopathy with associated radiculopathy and distal sensory neuropathy. We undertook morphometric analysis of L5 DRG neurons in seven diabetic rats and six age- and sex-matched littermates. Nerve conduction studies were also performed, and neuropathy was confirmed. Diabetes was induced with streptozotocin; duration of diabetes was 12 months. The DRG count for control rats was 15,304 ± 991 neurons. Two of seven diabetic DRG counts were reduced, but the group mean count at 14,847 ± 1,524 was not significantly reduced. The number of small neurons (type B) considerably exceeded that of large neurons (type A), at a ratio of 71:29. The percentage of large cells was significantly reduced in diabetic compared with control rats (P = 0.01). The large-diameter population can be subdivided into two groups; with this subdivision, the number of neurons &lt;50 μm was not reduced in samples from diabetic rats, but the neurons of largest size (≥50 μm) were significantly reduced (by 41%).

The peripheral nerve of experimental diabetic neuropathy (EDN) is reported to be ischemic and hypoxic, with an increased dependence on anaerobic metabolism, requiring increased energy substrate stores. When glucose stores become reduced, fiber degeneration has been reported. We evaluated glucose uptake, nerve energy metabolism, the polyol pathway, and protein kinase C (PKC) activity in EDN induced by streptozotocin. Control and diabetic rats received lipoic acid (0, 10, 25, 50, 100 mg/kg). Duration of diabetes was 1 month, and alpha-lipoic acid was administered intraperitoneally 5 times per week for the final week of the experiment. Nerve glucose uptake was reduced to 60, s 37, and 30% of control values in the sciatic nerve, L5 dorsal root ganglion, and superior cervical ganglion (SCG), respectively, in rats with EDN. Alpha-lipoic acid supplementation had no effect on glucose uptake in normal nerves at any dose, but reversed the deficit in EDN, with a threshold between 10 and 25 mg/kg. Endoneurial glucose, fructose, sorbitol, and myo-inositol were measured in sciatic nerve. Alpha-lipoic acid had no significant effect on either energy metabolism or polyol pathway of normal nerves. In EDN, endoneurial glucose, fructose, and sorbitol were significantly increased, while myo-inositol was significantly reduced. Alpha-lipoic acid had a biphasic effect: it dose-dependently increased fructose, glucose, and sorbitol, peaking at 25 mg/kg, and then fell beyond that dose, and it dose-dependently increased myo-inositol. Sciatic nerve cytosolic PKC was increased in EDN. ATP, creatine phosphate, and lactate were measured in sciatic nerve and SCG. Alpha-lipoic acid prevented the reduction in SCG creatine phosphate. We conclude that glucose uptake is reduced in EDN and that this deficit is dose-dependently reversed by alpha-lipoic acid, a change associated with an improvement in peripheral nerve function.

Retinopathy is an important sequela of diabetes mellitus, but clinical risk factors for this condition have rarely been assessed in a geographically defined population. In this population-based study, the 1135 Rochester, Minnesota, residents with diabetes mellitus initially diagnosed between 1945 and 1969 (incidence cohort) were followed through their complete medical records in the community to January 1, 1982. Because most of the cases of diabetic retinopathy in Rochester residents developed in patients with non-insulin-dependent diabetes mellitus (NIDDM), risk factors for diabetic retinopathy were examined in this group (N = 1031). A proportional hazards model identified the following risk factors for diabetic retinopathy in NIDDM: elevated initial fasting blood glucose level, marked obesity, and earlier age at onset of diabetes. Stratified analyses indicated that duration of diabetes was also significantly associated with an increased risk of retinopathy. Two secular trends, increasing detection of “mild” NIDDM and decreasing risk of diabetic retinopathy, had a major effect on retinopathy risk assessment. These data also suggest that insulin therapy is not an independent risk factor for diabetic retinopathy.