Restless legs syndrome and cerebrovascular/cardiovascular events: Systematic review and meta-analysis.

OBJECTIVE: We performed a systematic review and meta-analysis to evaluate the proposed association of restless legs syndrome (RLS) with cerebrovascular/cardiovascular outcomes. METHODS: We calculated the corresponding odds ratios on the prevalence of cerebrovascular/cardiovascular risk factors and standardized mean differences on the reported mean age at baseline between RLS patients and controls. We also calculated the corresponding risk ratios and adjusted for potential confounders hazard ratios (HRsadjusted ) on the reported outcomes of interest between RLS patients and controls. RESULTS: We identified 8 eligible studies (644 506 patients, mean age: 60.2 years, 36.2% males; 3.3% with RLS). RLS patients were found to have significantly higher prevalence of hypertension (P = .002), diabetes (P = .003) and hyperlipidemia (P = .010) compared to controls. In the unadjusted analyses of prospective observational studies, RLS patients were found to have significantly higher risk for cerebrovascular ischaemia (P = .01) and all-cause mortality (P = .04) compared to controls during follow-up, while in the adjusted for potential confounders analyses RLS patients were only found to have a higher risk of all-cause mortality (HR adjusted=1.52, 95% CI: 1.17-1.97, P = .002). CONCLUSIONS: The present report does not provide evidence for an increased risk of cerebrovascular and cardiovascular events in RLS patients, which highlights the vast presence of confounding factors.

The diagnostic yield of transesophageal echocardiography in patients with cryptogenic cerebral ischaemia: a meta-analysis.

BACKGROUND AND PURPOSE: The diagnostic utility of transesophageal echocardiography (TEE) in patients with cryptogenic ischaemic stroke (IS) or transient ischaemic attack (TIA) remains controversial. METHODS: A systematic review and meta-analysis was performed according to PRISMA guidelines to estimate the pooled prevalence of potential cardioembolic causes detected by TEE in prospective observational studies of cryptogenic IS/TIA. Cardiac conditions causally associated with cerebral ischaemia were considered to be intramural thrombi and intracardiac tumors according to ASCO phenotyping of IS. RESULTS: Thirty-five eligible studies, comprising 5772 patients (mean age 53.6 years, 56.9% men) were identified. The most common TEE finding was ascending aorta and/or aortic arch atheroma [51.2% (27.4%-74.5%)], followed by patent foramen ovale (PFO) [43.2% (36.3%-50.4%)]. Complex aortic plaques and large PFOs were reported in 14% (10.2%-18.9%) and 19.5% (16.6%-22.8%) of TEE evaluations. The prevalence of atrial septal aneurysm was 12.3% (7.9%-18.7%) and was significantly higher in conjunction with PFO presence (risk ratio 2.04, 95% confidence interval 1.63-2.54, P < 0.001). The prevalence of left atrial thrombus [3.0% (1.1%-8.3%)] and spontaneous echo contrast [3.8% (2.3%-6.2%)] was low. The prevalence of intracardiac tumors was extremely uncommon [0.2% (0%-0.7%)]. Significant heterogeneity was identified (I(2) > 60%) in the majority of analyses. Heterogeneity was not affected by cryptogenic stroke definition (TOAST versus alternative criteria). After dichotomizing available studies using a cut-off of 50 years, PFO was significantly (P = 0.001) more prevalent in younger than in older patients. CONCLUSION: Routine TEE in patients with cryptogenic IS/TIA commonly identifies abnormal findings. However, the prevalence of cardiac conditions considered to be causally associated with cerebral ischaemia (intracardiac thrombi and tumors) is low.

Dynamics of uncrystallized water and protein in hydrated elastin studied by thermal and dielectric techniques.

Dynamics of uncrystallized water and protein was studied in hydrated pellets of the fibrous protein elastin in a wide hydration range (0 to 23wt.%), by differential scanning calorimetry (DSC), thermally stimulated depolarization current technique (TSDC) and dielectric relaxation spectroscopy (DRS). Additionally, water equilibrium sorption-desorption measurements (ESI) were performed at room temperature. The glass transition of the system was studied by DSC and its complex dependence on hydration water was verified. A critical water fraction of about 18wt.% was found, associated with a reorganization of water in the material. Three dielectric relaxations, associated to dynamics related to distinct uncrystallized water populations, were recorded by TSDC and DRS. The low temperature secondary relaxation of hydrophilic polar groups on the protein surface triggered by hydration water for almost dry samples contains contributions from water molecules themselves at higher water fractions (ν relaxation). This particular relaxation is attributed to water molecules in the primary and secondary hydration shells of the protein fibers. At higher temperatures and for water fraction values equal to or higher than 10wt.%, a local relaxation of water molecules condensed within small openings in the interior of the protein fibers was recorded. The evolution of this relaxation (w relaxation) with hydration level results in enhanced cooperativity at high water fraction values, implying the existence of "internal" water confined within the protein structure. At higher temperatures a relaxation associated with water dynamics within clusters between fibers (p relaxation) was also recorded, in the same hydration range.

Apolipoprotein E polymorphisms and ischaemic stroke: a two-center Greek study.

BACKGROUND AND PURPOSE: Apolipropotein E(apoE) is a plasma protein exhibiting three common isoforms (E2, E3, E4). Its involvement in lipoprotein metabolism may have an impact on stroke occurrence. As results in the literature are inconclusive further studies are needed to elucidate its role. Our objective was to study the role of apoE isoforms and the interplay with environmental risk factors in patients with first ischaemic stroke occurrence in the Greek population. METHODS: Three hundred and twenty-nine patients with first-ever ischaemic stroke were included in our study. Strokes of cardioembolic origin and patients with autoimmune or prothrombotic syndromes were excluded. A control group of 361 subjects with no stroke history were also included in our study. Risk factors (hyperlipidemia, hypertension, diabetes mellitus and smoking) were assessed. ApoE alleles were determined in all subjects participating in the study. RESULTS: Genotype ε3/ε3 was found to have a protective role against stroke occurrence compared with other genotypes (odds ratio 0.674, 95% confidence interval 0.480-0.946) especially in the female patient subgroup. In multivariate analysis after adjustment for age, body mass index (BMI), hypertension, dyslipidemia, diabetes mellitus and smoking, the role of genotype was limited and outweighed by risk factors in both genders. No association between apoE alleles and BMI, cholesterol, triglycerides or high-density lipoprotein plasma levels was noted. CONCLUSIONS: Our study was indicative of a protective role of the ε3/ε3 genotype, especially in female patients. However, risk factors such as age, BMI, hypertension, dyslipidemia, diabetes mellitus and smoking have a strong impact on stroke occurrence and outweigh the protective role of the ε3/ε3 genotype.

Glass transition and dynamics in BSA-water mixtures over wide ranges of composition studied by thermal and dielectric techniques.

Protein-water dynamics in mixtures of water and a globular protein, bovine serum albumin (BSA), was studied over wide ranges of composition, in the form of solutions or hydrated solid pellets, by differential scanning calorimetry (DSC), thermally stimulated depolarization current technique (TSDC) and dielectric relaxation spectroscopy (DRS). Additionally, water equilibrium sorption isotherm (ESI) measurements were performed at room temperature. The crystallization and melting events were studied by DSC and the amount of uncrystallized water was calculated by the enthalpy of melting during heating. The glass transition of the system was detected by DSC for water contents higher than the critical water content corresponding to the formation of the first sorption layer of water molecules directly bound to primary hydration sites, namely 0.073 (grams of water per grams of dry protein), estimated by ESI. A strong plasticization of the T(g) was observed by DSC for hydration levels lower than those necessary for crystallization of water during cooling, i.e. lower than about 0.3 (grams of water per grams of hydrated protein) followed by a stabilization of T(g) at about -80°C for higher water contents. The α relaxation associated with the glass transition was also observed in dielectric measurements. In TSDC a microphase separation could be detected resulting in double T(g) for some hydration levels. A dielectric relaxation of small polar groups of the protein plasticized by water, overlapped by relaxations of uncrystallized water molecules, and a separate relaxation of water in the crystallized water phase (bulk ice crystals) were also recorded.

Perimetric and peri-papillary nerve fibre layer thickness findings in multiple sclerosis.

BACKGROUND AND PURPOSE: Several previous studies have employed optical coherence tomography (OCT) of the optic disc and 'white-on-white' automated perimetry to evaluate optic neuritis (ON) associated with multiple sclerosis (MS). This study employed OCT, white-on-white automated perimetry as well as 'blue-on-yellow' automated perimetry to evaluate MS patients with or without episodes of ON. METHODS: The MS group consisted of 56 patients with MS (27 patients with no history of ON in both eyes and 29 patients with at least one ON attack in one or both eyes), whereas the control group consisted of 56 age- and sex-matched healthy subjects. All patients underwent a complete neurological and ophthalmological examination. Peri-papillary retinal nerve fibre layer thickness (RNFLT) was evaluated using OCT. The mean defect and pattern standard deviation for both white-on-white and blue-on-yellow perimetry were also recorded. RESULTS: RNFLT and perimetric scores were significantly lower in MS group without a history of ON and in the unaffected eyes of MS group with unilateral ON, compared with controls. MS group with more than one ON episodes had significantly compromised blue-on-yellow perimetric indices, compared with patients with one ON episode, whereas respective differences for white-on-white perimetry were not statistically significant. CONCLUSIONS: The significantly lower RNFLT and perimetric scores in MS group patients without ON, compared with control group, may possibly be attributed to sub-clinical episodes of ON or to retrograde degeneration of nerve cells from sub-clinical post-chiasmal lesions. Blue-on-yellow perimetry may be advantageous over white-on-white perimetry in evaluating MS-associated functional defects.

Overexpression of E2F-1 in glioma triggers apoptosis and suppresses tumor growth in vitro and in vivo.

The transfer of apoptosis genes to tumors is one of the most promising strategies for cancer gene therapy. We have shown that massive apoptosis occurs when wild-type p53 expression is induced in glioma cells carrying a p53 gene mutation. However, adenovirus-mediated p53 gene transfer is ineffective in causing apoptosis in glioma cells that retain a wild-type p53 genotype. We evaluated the effect of E2F-1 overexpression on the growth of gliomas in vitro and in vivo. In the in vitro study, the adenovirus-mediated transfer of exogenous E2F-1 protein precipitated generalized apoptosis in gliomas. The treatment with Ad5CMV-E2F-1 of nude mice carrying subcutaneous gliomas arrested tumor growth. Our results indicate that E2F-1 has anti-glioma activity in vitro and in vivo.

Molecular mobility in biodegradable poly(ε-caprolactone)/poly(hydroxyethyl acrylate) networks.

Poly(ε-caprolactone)/poly(hydroxyethyl acrylate) networks have been investigated by thermally stimulated depolarization currents (TSDC) and differential scanning calorimetry (DSC). The introduction of hydrophilic units (HEA) in the system aiming at tailoring the hydrophilicity of the system results in a series of copolymer networks with microphase separation into hydrophobic/hydrophilic domains. Polycaprolactone (PCL) crystallization is prevented by the topological constraints HEA units imposed in such heterogeneous domains. Moreover, the mobility of the amorphous PCL chains is enhanced as revealed by the main relaxation process which becomes faster. The glass transition of PHEA-rich domains shifts to lower temperatures, as the total amount of PCL in the copolymer increases, due to the presence of PCL units within the same region. The behaviour of the copolymer networks swollen with different content of water has been investigated to analyze the interaction between water molecules and hydrophobic/hydrophilic domains and provide further insights into the molecular structure of the system.

Immunohistochemical detection of phosphorylated JAK-2 and STAT-5 proteins and correlation with erythropoietin receptor (EpoR) expression status in human brain tumors.

Phosphorylated (activated) forms of Janus Kinase 2 (pJAK-2) and STAT-5 transcription factor (pSTAT-5), which are preferentially expressed after binding of erythropoietin (Epo) to its receptor EpoR, are known to be implicated in the molecular mechanisms controlling brain development. The purpose of this study was to investigate the expression of these proteins (pJAK-2, pSTAT-5, and EpoR) in human brain tumors compared with normal brain. Using specific antibodies and immunohistochemistry on formalin-fixed, paraffin-embedded semi-serial tissue sections a total of 87 human brain tumors and samples from normal brain tissue were studied. pJAK-2/pSTAT-5 nuclear co-expression was detected in 39% of astrocytomas, 43% of oligodendrogliomas, 50% of ependymomas, and in all (100%) of the medulloblastomas examined. In contrast, most of the meningiomas showed weak or no immunoreactivity for pJAK-2/pSTAT-5 proteins. A significant percentage of tumors exhibited pSTAT-5 immunoreactivity, being pJAK-2 immunonegative. EpoR/pJAK-2/pSTAT-5 co-expression was detected in a small percentage of astrocytomas (18%) and ependymomas (33%). Oligodendrogliomas and medulloblastomas were EpoR immunonegative. Tumor vessels exhibited EpoR, pJAK-2, and pSTAT-5 immunoreactivity. In normal brain tissue, EpoR immunoreactivity was detected in neurons and vessels whereas pSTAT-5 and pJAK-2 immunoreactivity was limited to some neurons and a few glial cells, respectively. These results indicate the existence of ligand (other than Epo)-dependent or independent JAK-2 activation that leads to constitutive activation of STAT-5 in most human brain tumors. Given the oncogenic potential of the JAK/STAT pathway, detection of different pJAK-2 and pSTAT-5 expression profiles between groups of tumors may reflect differences in the biological behavior of the various human brain tumors.

Paraoxonase gene polymorphisms and stroke severity.

BACKGROUND: Paraoxonase (PON) is an HDL-associated enzyme that prevents low-density lipoprotein oxidation, playing a major role in the pathogenesis of atherosclerosis. PON genes polymorphisms may affect the corresponding enzyme activity. In this study, we examined the association of ischemic stroke with the three PON genes. METHODS: One hundred and seventy-eight patients hospitalized for ischemic stroke and 181 age- and sex-matched healthy controls were recruited. PON1(Q/R) 192, PON1(M/L) 55, and PON2(S/C) 311 polymorphisms were analyzed. RESULTS: The presence of the PON2 311C allele was significantly increased in patients with severe forms of ischemic stroke according to Modified Rankin Scale (P = 0.02, odds ratio = 2.215). No significant differences in genotype and allele distribution were observed between patients and controls. CONCLUSIONS: The PON2 311C allele was suggested as a possible predisposing factor for severe cases of ischemic stroke. Large-scale multicenter-controlled prospective studies are warranted to further explore the effects of PON polymorphisms on stroke susceptibility and severity.

Significance of aphasia after first-ever acute stroke: impact on early and late outcomes.

BACKGROUND: We assessed the incidence and determinants of aphasia attributable to first-ever acute stroke. We also investigated early and long-term mortality and 1-year dependence in post-stroke patients. METHODS: A 10-year prospective hospital-based study was conducted in the prefecture of Athens, Greece. RESULTS: In total, 2,297 patients were included in the study, of whom 806 (35.1%) had aphasia. The presence of aphasia was independently associated with increasing age (OR: 1.19 per 10-year increase, 95% CI: 1.12-1.21) and atrial fibrillation (OR: 1.35, 95% CI: 1.08-1.67), and inversely associated with Scandinavian Stroke Scale (SSS) score (OR: 0.55 per 10-point increase, 95% CI: 0.52-0.59) and hypertension (OR: 0.77, 95% CI: 0.63-0.96). One-year dependence score (calculated with the modified Rankin score) was higher in aphasic patients compared to non-aphasics (p < 0.001). Moreover, severity of aphasia (estimated with a subscale of SSS) was found as an independent predictor of 1-year dependence. Most of the deaths in the aphasic patients were attributed to infections and neurological damage. Using the Kaplan-Meier limit method, the unadjusted probability of 10-year mortality was demonstrated to increase with the severity of aphasia (log-rank test: 233.9, p < 0.001) and, even after adjustment for several other factors, severity of aphasia remained an independent predictor of 10-year mortality. CONCLUSIONS: Increasing age, atrial fibrillation and severity of stroke were associated with the risk of aphasia after stroke. Severity of aphasia is a strong predictor of long-term mortality and dependence of post-stroke patients.

Descriptive epidemiology of cerebral gliomas in northwest Greece and study of potential predisposing factors, 2005-2007.

BACKGROUND: To investigate the epidemiologic and clinical characteristics (age, sex, tumor location, socioeconomic status) and potential predisposing factors (alcohol, tobacco, mobile phone use, severe head trauma) of cerebral gliomas in a defined area of Northwest Greece. METHODS: The prospective study was conducted in patients with gliomas referred to all 7 hospitals of a study area with a population of 488,435 inhabitants, from June 1, 2005, to May 31, 2007. Incidence rates (IR) were calculated as new cases diagnosed among residents of the study area during the study period per 100,000 inhabitants. A case-control study was carried out in order to study the possible association of the risk of glioma with smoking, alcohol, use of mobile phone, and severe cranial trauma. RESULTS: A total of 56 glioma incident cases were identified with IRs of glioma and glioblastoma (GBM) at 5.73/10(5)/year and 3.69/10(5)/year, respectively. A male to female ratio of 1.25 was obtained in the GBM group. IRs of glioma and GBM for both males and females were higher in the age group 60-79. The most frequent anatomic location was the frontal lobe. 46.5% of the patients originated from the low, 25% from the middle and 28.5% from the high socioeconomic class. There was no significant association between glioma and alcohol consumption, smoking and mobile phone use. A trend for a positive association between the risk of glioma and a history of severe cranial trauma was observed, but this association was not statistically significant. CONCLUSION: The estimated IR of glioma and GBM in this study was higher compared with data from other studies carried out on European, Asian and US populations. Further studies may be needed to assess the possible association of genetic, environmental and lifestyle factors with the high occurrence of gliomas observed in this study.

Short-Range Structure, Thermal and Elastic Properties of Binary and Ternary Tellurite Glasses.

Glasses Al2/3O-TeO2, ZnO-TeO2 and R2/3O-ZnO-TeO2 (R = Al, B) were prepared by melting in Pt crucibles and studied for correlations between structure and thermal as well as mechanical properties, whereby the glass composition is varied to tailor the short-range speciation of tellurite, aluminate, and borate groups. The glass structure was studied by Raman and infrared spectroscopy analyses, and the measured properties include glass-transition temperature (Tg), density (ρ), and ultrasonic longitudinal (VL) and transverse (VT) velocities. In addition, atomic packing density (Cg), elastic moduli, and Poisson's ratio (σ) were evaluated from the measured properties. It was found that Al2/3O leads to cross-linked alumino-tellurite networks by strong Te-O-Al bonds, which cause a profound enhancement in Tg. The influence of ZnO and B2/3O on Tg is relatively smaller due to the weaker cross-linking effects of ZnO4 tetrahedra and of Te···O-B bonds. Short-range bonding characteristics, interatomic bonding energy differences, and atomic packing density were found to have a strong effect on VT and mostly on the VL sound velocity. The combined effects of structure and bonding are nicely expressed in the composition dependence of Poisson's ratio; it exhibits decreasing trends with Al2/3O content in the binary and ternary glasses studied here, but increasing trends with ZnO and B2/3O additions in glasses ZnO-TeO2 and B2/3O-ZnO-TeO2, respectively. The results for Poisson's ratio and atomic packing density for the studied glasses were found to fit nicely in the global σ versus Cg correlation established previously for a range of glasses not including tellurites so far. Finally, the sound velocities and Poisson's ratio of pure TeO2 glass were determined for the first time and found to differ markedly from those in the literature for TeO2 glass melted in alumina crucible; this is because the latter glass is highly doped by Al2O3 leached from the alumina crucible.

Association of estrogen receptor-alpha gene polymorphisms with stroke risk in patients with metabolic syndrome.

OBJECTIVE: The vascular protective effects of estrogens are mediated by their binding to the two known estrogen receptors. In this study, we examine the association of stroke with two common polymorphisms of the ESR1 gene in patients with metabolic syndrome. MATERIALS AND METHODS: DNA from 130 patients hospitalized for ischemic stroke and 240 healthy controls were genotyped for ESR1 PvuII and XbaI polymorphisms. Results - Comparing female and male patients, it was found that CCGG diplotype is more frequent in male patients (P = 0.03). In addition, the AA genotype is associated with the onset of stroke at a younger age in the male patient group (P < 0.05). CONCLUSIONS: These findings suggest that PvuII and XbaI polymorphisms may affect the age at onset of the first stroke and the probability of developing cerebrovascular disease.

p53 enhances the Delta-24 conditionally replicative adenovirus anti-glioma effect.

Previous studies have demonstrated that the conditionally replicative adenovirus Ad5Delta24 is a powerful cytolytic agent against glioma selectively affecting cells with a defective p16/Rb/E2F pathway. The p53 protein is also known to be an apoptotic factor for glioma cells. In this study, we examined the simultaneous delivery of the combination of exogenous p53 and Ad5Delta24 adenovirus in glioma cells. Infecting cells with low doses of adenovirus p53 and Ad5Delta24 resulted in an additive effect on cell death. The cell death induced by both agents was independent of the p53 status of cells. Flow cytometry revealed that the potent anti-tumor effect induced by the mixture of Ad5CMV-p53 and Ad5Delta24 adenoviruses was due to a combination of apoptosis and cell lysis. Our results indicate that Ad5CMV-p53 enhances the oncolytic effect of the Ad5Delta24 adenovirus, and the combination of adenovirus Ad5Delta24 and Ad5CMV-p53 may thus be a potential therapeutic tool for gliomas.

Effects of butyrate, retinol, and retinoic acid on human Y-79 retinoblastoma cells growing in monolayer cultures.

The effects of butyrate, retinol, and retinoic acid were tested on growth and differentiation of human Y-79 retinoblastoma cells in monolayer cultures. Treatment with 4 mM butyrate resulted in marked growth inhibition of cells, due mostly to increased death rate. The effect was greater in serum-supported cultures in which the proliferation rate was high and the effect was less in the serum-free, defined medium in which the cells were differentiated and the growth rate was slow, suggesting a cell-cycle-specific action of this substance. Moreover, butyrate induced morphologic changes in the viable cells; these changes consisted of an elongated appearance of the cells and of retraction of long processes formed in the serum-free-supported cultures. Retinol at 20 microM also affected the cell viability both in serum-containing and in serum-free culture medium. Retinoic acid at 50 microM induced reversible growth inhibition of cells growing in serum-containing medium and cell death in the defined medium-supported cultures. Combination of 0.5 mM butyrate with 50 microM retinoic acid resulted in an enhanced inhibition of growth in an apparently synergistic fashion. These results demonstrated that butyrate, retinol, and retinoic acid suppressed Y-79 cell growth in vitro and could be useful in future studies of these compounds in retinoblastoma tumors in vivo.

Characterization of p53 and p21 functional interactions in glioma cells en route to apoptosis.

BACKGROUND: Alterations of the p53 (also called TP53) gene are one of the most common abnormalities in gliomas. We have previously reported that restoration of wild-type p53 protein function in glioma cells results in programmed cell death (apoptosis). Since p53 functions are mediated by genes that directly control the tumor suppressor effect of the p53 protein, understanding the relationship between p53 and p53-related genes in glioma cells will aid in the design of more rational treatment strategies for brain tumors. PURPOSE: We conducted this study to examine the timing of the p53-mediated events preceding apoptosis. More specifically, we undertook this work to characterize the genetic and cell cycle-related factors that may increase the resistance of glioma cells to p53-induced apoptosis. METHODS: Two human glioma cell lines (U-251 MG and U-373 MG) that express mutant p53 protein and two (U-87 MG and EFC-2) that express wild-type p53 protein were used. Replication-deficient adenovirus was utilized as an expression vector to transfer exogenous p53 and p21 complementary DNAs into the glioma cells; control cells were infected with the viral expression vector alone. To monitor gene transfer and the expression of exogenous genes (as well as the expression of endogenous genes), we used western blot analyses and immunohistochemistry analyses. Flow cytometry studies of cellular DNA content were performed to determine the cell cycle phenotype of the glioma cells before and after treatment. RESULTS: p53-mediated apoptosis was preceded by elevation in the levels of the p21 (cell cycle-related) and Bax (apoptosis-related) proteins. In addition, cell cycle analyses showed that glioma cells were arrested in the G2 phase before undergoing cell death. Transfer of p21 induced a G2 block but did not induce apoptosis. Moreover, coexpression of p21 and p53 prevented glioma cells from undergoing apoptosis. Expression of exogenous p53 in wild-type p53 cells did not induce elevation of Bax levels, arrest in G2 phase, or apoptosis. CONCLUSIONS AND IMPLICATIONS: Our data confirmed the ability of wild-type p53 to induce apoptosis in p53 mutant glioma cells. In addition, our results document that p21 plays a role in protecting cells from p53-mediated programmed cell death and suggest that p53-mediated apoptosis and p21 induction may represent, at least in certain cases, opposite signals. Finally, our data suggest that over expression of p21 in gliomas may be related to resistance to treatments that induce apoptosis.

Germline p53 gene mutations in subsets of glioma patients.

BACKGROUND: Heritable germline mutations of the p53 gene have been described in patients with Li-Fraumeni syndrome, occasionally in nonfamilial malignancies such as multifocal osteosarcoma, in a small subgroup of young patients with two or more primary malignancies, and in patients with sporadic breast carcinoma. We recently reported that multifocal gliomas are frequently associated with other primary malignancies, and we hypothesized that genetic alterations may account for this phenomenon. PURPOSE: We examined the frequency of germline p53 gene mutations in patients with glioma and either multifocality of lesions, history of an additional primary (different) malignancy, or a family history of cancer. METHODS: Lymphocytes from 51 glioma patients were analyzed for germline p53 gene mutations using RNA-polymerase chain reaction analysis, single-strand conformation polymorphism, and gene sequencing techniques. RESULTS: Germline p53 gene mutations were detected in six of 19 patients with multifocal glioma, including two with family history of cancer, one with another primary malignancy, and two with all three risk factors; one of four patients with unifocal glioma, another primary malignancy, and a family history of cancer; and two of 15 patients with unifocal glioma and a family history of cancer but no second malignancies. No mutations were detected in the patient with unifocal glioma and another malignancy or in the 12 control patients with unifocal glioma and no second malignancies or family history of cancer. Patients having mutations were younger than other patients in the same group. CONCLUSIONS: Germline p53 mutations are frequent in patients with multifocal glioma, glioma and another primary malignancy, and glioma associated with a family history of cancer, particularly if these factors are combined. IMPLICATIONS: Relatives at high risk can be identified for genetic counseling, early cancer detection, and possible enrollment in chemoprevention trials.

Cell cycle arrest and inhibition of tumor cell proliferation by the p16INK4 gene mediated by an adenovirus vector.

The p16INK4 (MTS1) gene has many features of a tumor suppressor gene. It maps to 9p21, a region of frequent loss of heterozygosity in a variety of tumor types. It encodes an inhibitor of cyclin-dependent kinase 4, and its homozygous deletion is common in tumor-derived cell lines. To examine its tumor suppressive function and its potential in cancer gene replacement therapy, wild-type p16INK4 was expressed in an adenovirus-derived gene delivery system and introduced into lung cancer cell lines that do not express p16INK4. Expression of the introduced p16INK4 blocked tumor cell entry into S phase of the cell cycle and inhibited tumor proliferation both in vitro and in vivo. These observations strongly support that p16INK4 is a tumor suppressor gene and is a candidate for cancer gene replacement therapy.

Coexpression of neuronal, glial, and major histocompatibility complex class II antigens on retinoblastoma cells.

This study identifies the presence of major histocompatibility complex class II antigens on retinoblastoma cells. In addition, the modulation of HLA-DR by interferon-gamma as well as the preferential expression of this major histocompatibility complex molecule over HLA-DQ is described. Double labeling experiments revealed that HLA-DR antigen is shared concomitantly with cells of glial and neuronal character. Investigations such as these underscore the possibility that expression of major histocompatibility complex class II antigens may function as immunological components in the host or play a role in the cellular differentiation of these tumor cells.