DNMT3B promoter polymorphisms and risk of late onset Alzheimer's disease

The vast majority of Alzheimer's disease (AD) are late-onset forms (LOAD) likely due to the contribution of genetic, environmental, and stochastic factors, superimposed on a physiologically age-related decline of neuronal functions. Increasing evidence indicates epigenetic modifications in LOAD brains, and many of the environmental factors associated with AD risk, such as heavy metals and dietary factors, are able to modify the epigenome. There is also indication that environmentally-induced early life modifications of the genome during embryogenesis and brain development could contribute to the development of the disease later in life. DNA methyltransferase 3b (DNMT3b) is an enzyme involved in de novo methylation of the genome during embryogenesis, expressed in progenitor cells during neurogenesis. In the present study we evaluated two functional DNMT3B promoter polymorphisms, namely -149 C > T (rs2424913) and - 579 G > T (rs1569686), as candidate LOAD risk factors. Our analysis of 376 Italian LOAD patients and 308 matched controls revealed no difference in allele frequencies between the case an the control group (OR = 1.10 (0.88-1.39) for rs2424913, and OR = 1.02 (0.81-1.28) for rs1569686). Also the genotype distributions of both polymorphisms were closely similar between groups, and no significant effect on disease age at onset was observed. Overall, present results do not support a major role for rs2424913 or rs1569686 in LOAD pathogenesis.     

Slug (SNAI2) down-regulation by RNA interference facilitates apoptosis and inhibits invasive growth in neuroblastoma preclinical models

PURPOSE: We assessed the relevance of Slug (SNAI2) for apoptosis resistance and invasion potential of neuroblastoma cells in vitro and in vivo. EXPERIMENTAL DESIGN: We evaluated the effect of imatinib mesylate on invasion and analyzed the genes modulated by imatinib mesylate treatment in neuroblastoma cells. Slug expression, inhibited by imatinib mesylate treatment, was knocked down in neuroblastoma cells by RNA interference, and the effects on invasion and apoptosis were evaluated in vitro. A pseudometastatic model of neuroblastoma in severe combined immunodeficient mice was used to assess the effects of Slug silencing alone or in combination with imatinib mesylate treatment on metastasis development. RESULTS: Microarray analysis revealed that several genes, including Slug, were down-regulated by imatinib mesylate. Slug expression was detectable in 8 of 10 human neuroblastoma cell lines. Two Slug-expressing cell lines were infected with a vector encoding a microRNA to Slug mRNA. Infected cells with reduced levels of Slug were tested for the expression of apoptosis-related genes (p53, Bax, and Bcl-2) identified previously as Slug targets. Bcl-2 was down-regulated in Slug-interfered cells. Slug down-regulation increased sensitivity to apoptosis induced by imatinib mesylate, etoposide, or doxorubicin. Invasion of Slug-silenced cells was reduced in vitro. Animals injected with Slug-silenced cells had fewer tumors than controls and the inhibition of tumor growth was even higher in animals treated with imatinib mesylate. CONCLUSIONS: Slug down-regulation facilitates apoptosis induced by proapoptotic drugs in neuroblastoma cells and decreases their invasion capability in vitro and in vivo. Slug inhibition, possibly combined with imatinib mesylate, may represent a novel strategy for treatment of metastatic neuroblastoma.     

Low-dose aspirin and vascular response in pregnant patients sensitive to angiotensin II.

The angiotensin sensitivity test was performed in 25 high risk pregnant women before and after administration of low-dose aspirin (100 mg/day for 7 days). After aspirin administration there was a significant decrease in AII sensitivity in sensitive patients with no change in nonsensitive patients. Low-dose aspirin favorably affects sensitivity to AII in sensitive patients, thus indicating a reduced vascular reactivity as a consequence of this regimen.     

Predictive value of multiple tumor marker assays in second-look procedures for ovarian cancer

Sera from 51 ovarian cancer patients in clinical remission undergoing a second-look operation were studied. CA 125, CA 15-3, and 90K assays were performed in the week preceding surgery. Twenty-seven patients (53%) had no evidence of disease; 3 (6%) and 21 (41%) had microscopic and macroscopic disease. All patients but two with no evidence of disease had normal CA 125 serum levels, as did the three cases with microscopic disease and 6 patients with macroscopically detectable tumor. Of 17 patients with high CA 125 values, 15 (88%) were found to have persistent disease. Hence, the sensitivity and specificity of a CA 125 assay were 62 and 93%, respectively. CA 15-3 levels were low in all patients with no evidence of disease, in 2 cases with microscopic disease, and in 2 cases with residual tumor greater than 1 cm. All patients with high CA 15-3 titers had a positive second-look. The sensitivity and specificity of assay were 69 and 100%, respectively. With the 90K assay, 4 false-positive and 4 false-negative results were found and the sensitivity and specificity were 69 and 67%, respectively. However, 3 of 4 cases with a false-positive 90K assay had recurrence of disease with 7, 9, and 20 months later. Combination of the three markers increased sensitivity to 79%. These data suggest that more effective surveillance of disease status at second-look is obtained by using a combination of tumor marker assays.     

Usefulness and limits of the ultrasonic examination in the diagnosis and prognosis of early pregnancies with vaginal bleeding

At the Department of Obstetrics and Gynecology of Catholic University in Rome 1257 pregnancies with vaginal bleeding in the first or second trimesters were ultrasonically observed. Pregnancy was found to be in normal development in 538 cases (42.80%); spontaneous abortion was reported in 688 cases (54.73%) and ectopic pregnancy, confirmed at surgery, in 31 cases (2.47%). The duration of bleeding appeared to have a significant effect on the prognosis of the pregnancy. Bleeding for 4 days or more predicted abortion almost significantly more often than a shorter bleeding episode. The spontaneous abortion rate increased with advancing maternal age and decreased with advancing gestational age. After detection of fetal life signs, the pregnancies ended in later abortion only in 9.29% of the cases. In this case there are no significant differences between normal or abnormal ultrasonic examinations. In our experience the ultrasound scanning, in patients with early pregnancy bleeding, is able to differentiate between live gestation or abortion but cannot predict the future.     

Ovarian development of the female child and adolescent: I. Morphology

Ovarian morphology of 180 randomly selected females, aged 8-21, was investigated, utilizing standard sector scanning ultrasound techniques, at -1 year (1 year before menarche), year 0 (menarche) and years +1 to +8 (1-8 years postmenarche). According to strict morphologic criteria, seven ovarian patterns were recognized which varied in dominance with age in reference to menarche. Prior to menarche a multifollicular ovarian pattern (Type 1) dominates which after menarche is substituted by a predominantly active ovarian pattern (Type 5). Approximately 20% of postmenarcheal females do not develop this active pattern. In a relatively persistent percentage of females a microcystic (Type 2) ovarian pattern was recognized throughout all postmenarcheal years, suggestive of a normal transitional pattern from Type 1 to Type 5 ovaries. In contrast, multicystic (Type 3), hyperthecosis (Type 4), polycystic ("Mickey Mouse") (Type 6) and silent (Type 7) ovaries appear to represent abnormal ovarian developments. Based on percentage distributions, it is tempting to speculate that multicystic (Type 3) and/or hyperthecosis (Type 4) ovaries represent precursor ovaries to Type 6 (polycystic) ovaries. Confirmation of this hypothesis would have major clinical importance for the early diagnosis of the polycystic ovarian syndrome.     

Ogilvie syndrome after cesarean section. A clinical contribution

Following the observation of a case of acute pseudo-obstruction of the colon (Ogilvie's syndrome) after cesarean section, the Authors describe their clinical experience in relation to recently published reports. While discussing other features of the syndrome, the importance of radiological monitoring of the colonic stasis and the validity of perendoscopic decompression of the colon as an efficacious therapy are underlined.     

Expression of ras oncogene p21 protein in normal and neoplastic laryngeal tissues: correlation with histopathological features and epidermal growth factor receptors.

Western blotting analysis of the p21 ras oncoprotein was performed in seven normal laryngeal mucosa specimens and 43 primary laryngeal cancers. Varying p21 levels, expressed as optical density (OD), were found in normal mucosa (median 1.94 OD, range 0.90-2.17 OD) and in primary laryngeal tumours (median 1.74 OD, range 0.30-6.37 OD). When p21 expression in laryngeal cancer was compared with the normal counterpart, higher levels were found in neoplastic than in normal laryngeal tissue (median 2.54 OD, range 1.76-6.37 OD, vs median 1.94 OD, range 0.90-2.17 OD) (P = 0.023). Immunohistochemical analysis demonstrated that most of the tumour cells (more than 70%) were immunostained while the stromal component was unreactive. No correlation between p21 expression and tumour location, stage and histopathological grade was observed. The correlation between ras p21 protein expression and epidermal growth factor receptor (EGFR) levels was also investigated. EGFR-positive cases did not show any difference in p21 expression with respect to EGFR-negative cases (median 1.52 OD, range 0.30-6.37 OD, vs median 1.84 OD, range 0.93-3.71 OD). Our findings suggest that overexpression of p21 protein is associated with a malignant phenotype in laryngeal cancer. Further studies should be undertaken to evaluate whether the assessment of p21 protein expression may have clinical significance in laryngeal cancer.     

Analysis of 138 consecutive ovarian cancer patients: Incidence and characteristics of familial cases

Eight families with two or more first-degree relatives affected with ovarian carcinoma were identified among a series of 138 consecutive ovarian cancer patients. History of breast cancer was reported in six of the eight families. Five of 19 patients with familial cancer developed ovarian cancer as a second primary tumor following breast carcinoma, whereas only 6/130 sporadic cases had a previous history of breast cancer. No significant difference was detected in clinical and pathological features between sporadic and familial cases. However, in three high-risk families ovarian cancer tended to develop at a younger age compared with other familial cases and with sporadic occurrences, and nulliparity was less frequent in the familial group. These observations emphasize the need to take into account multiple factors-in addition to positive family history-for the evaluation of genetic predisposition to ovarian carcinoma.