Lowered cAMP and cGMP signalling in the brain during levodopa-induced dyskinesias in hemiparkinsonian rats: new aspects in the pathogenetic mechanisms.

Dysregulation of dopamine receptors is thought to underlie levodopa-induced dyskinesias in experimental models of Parkinson's disease. It is unknown whether an imbalance of the second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), is involved in the alterations of levodopa/dopamine signal transduction. We examined cAMP and cGMP signalling in the interconnected cortico-striatal-pallidal loop at the peak of levodopa-induced dyskinesias in rats with 6-hydroxydopamine lesions in the substantia nigra.

Increased expression of transketolase-like-1 in papillary thyroid carcinomas smaller than 1.5 cm in diameter is associated with lymph-node metastases.

Background: Patients with small papillary thyroid carcinoma (PTC) may have a high incidence of regional lymph-node (LN) metastases at presentation, and these are considered to be an independent risk factor for tumor recurrence. A mutated transketolase transcript (TKTL1) has been found up-regulated in different human malignancies, and strong TKTL1 protein expression has been associated with aggressiveness and poor patient survival in several epithelial cancers.

Methods: TKTL1 protein expression was analyzed in 256 consecutive cases of PTCs View Article and Find Full Text PDF

L-dopa modulates motor cortex excitability in Alzheimer's disease patients.

In Alzheimer's disease (AD), transcranial magnetic stimulation (TMS) studies have shown abnormalities of motor cortical excitability, such as a decreased intra-cortical inhibition (ICI) and changes in resting motor threshold (rMT). We studied the effects of L-dopa on rMT and ICI in a cohort of moderate AD patients after paired-pulse TMS. Results were compared with a control group of healthy subjects.

Isoindolo[2,1-a]quinoxaline derivatives, novel potent antitumor agents with dual inhibition of tubulin polymerization and topoisomerase I.

Isoindoloquinoxalines 4 and 5 were obtained by refluxing 2-(2'-aminoaryl)-1-cyanoisoindoles 3a- e in acetic or formic acid. All derivatives were screened by the National Cancer Institute (Bethesda, MD) for the in vitro one dose primary anticancer assay against a 3-cell line panel. Compounds 4a- e, screened against a panel of about 60 human tumor cell lines, showed remarkable antineoplastic activity; they had GI 50 values in the low micromolar or submicromolar range and reached, in the case of 4c, nanomolar concentrations on 88% of the 59 tested cell lines.

In vivo electrophysiology of dopamine-denervated striatum: focus on the nitric oxide/cGMP signaling pathway.

Within the striatum, the gaseous neurotransmitter nitric oxide (NO) is produced by a subclass of interneurons containing the neuronal NO synthase (nNOS). NO promotes the second messenger cGMP through the activation of the soluble guanyl cyclase (sGC) and plays a crucial role in the integration of glutamate (GLU) and DA transmission. The aim of this study was to characterize the impact of 6-hydroxyDA (6-OHDA) lesion of the rat nigrostriatal pathway on NO/cGMP system.

Associations between Notch-2, Akt-1 and HER2/neu expression in invasive human breast cancer: a tissue microarray immunophenotypic analysis on 98 patients.

Objective: We aimed to investigate the existence of associations between well-established and newly recognized biological and phenotypic features of breast cancer involved in tumor progression and prognosis.

Methods: Ninety-eight cases of invasive breast cancer were assessed for the immunohistochemical expression of estrogen and progesterone receptors, Ki-67, HER2, Akt-1, and Notch-2, using the tissue microarray technique. Data regarding tumor histotype, histological grade, tumor size and lymph node status were collected for each patient and included in the analysis.

Clonal diversity in carcinomas: its implications for tumour progression and the contribution made to it by epithelial-mesenchymal transitions.

The progression of tumours to malignancy is commonly considered to arise through lineal evolution, a process in which mutations conferring pro-oncogenic cellular phenotypes are acquired by a succession of ever-more dominant clones. However, this model is at odds with the persistent polyclonality observed in many cancers. We propose that an alternative mechanism for tumour progression, called interclonal cooperativity, is likely to play a role at stages of tumour progression when mutations cause microenvironmental changes, such as occur with epithelial-mesenchymal transitions (EMTs).

Adult polyglucosan body disease: proton magnetic resonance spectroscopy of the brain and novel mutation in the GBE1 gene.

Adult polyglucosan body disease (APBD) is characterized by the accumulation of insoluble glucose polymers within the central and peripheral nervous systems. A common missense mutation in the glycogen branching enzyme (GBE1) gene has been identified in Ashkenazi patients with APBD. We report on a non-Jewish patient with APBD on whom we performed proton magnetic resonance spectroscopic imaging of the brain.

Sub-cellular localization of manganese in the basal ganglia of normal and manganese-treated rats An electron spectroscopy imaging and electron energy-loss spectroscopy study.

We have studied at the ultrastructural level the presence of manganese (Mn) in rat basal ganglia, which are target regions of the brain for Mn toxicity. The rats underwent a moderate level of Mn exposure induced per os for 13 weeks. Mn was detected by means of electron spectroscopy imaging (ESI) and electron energy-loss spectroscopy (EELS) analyses on perfusion fixed samples embedded in resin.

Manganese intoxication decreases the expression of manganoproteins in the rat basal ganglia: an immunohistochemical study.

Manganese (Mn) is a cofactor for some metalloprotein enzymes, including Mn-superoxide dismutase (Mn-SOD), a mitochondrial enzyme predominantly localized in neurons, and glutamine synthetase (GS), which is selectively expressed in astroglial cells. The detoxifying effects of GS and Mn-SOD in the brain, involve catabolizing glutamate and scavenging superoxide anions, respectively. Mn intoxication is characterized by impaired function of the basal ganglia.

3,5-bis(3'-indolyl)pyrazoles, analogues of marine alkaloid nortopsentin: synthesis and antitumor properties.

A series of 10 bis-indolylpyrazoles of type 9, 10 were obtained by cyclization of diketones 8 using hydrazine monohydrate or methylhydrazine in refluxing acetic acid/THF. Derivatives 9a,c,d were selected, by the National Cancer Institute (NCI, Bethesda, USA), to be evaluated against the full panel of about 60 human tumor cell lines derived from nine human cancer cell types and showed antiproliferative activity in the micromolar range. In particular, 9d, the most active compound was effective against all the tested cell lines with a GI(50) mean value of 3.

Different expression of thymidylate synthase in primary tumour and metastatic nodes in breast cancer patients.

Background: To date an accurate evaluation of predictive markers in breast cancer is mainly conducted at the primary site, although the main goal of the adjuvant therapy is the control of micrometastases. Adjuvant therapy drugs need a high proliferative cell rate to be effective. The proliferating activity can be evaluated by the Ki-67 marker and even by thymidylate synthase (TS), a cell cycle enzyme present in proliferating cells.

BRAF V600E mutation and p27 kip1 expression in papillary carcinomas of the thyroid

Background: BRAF(V600E) mutation and p27(kip1) expression have been introduced as novel indicators that may predict prognosis in different tumors, as well as in papillary thyroid carcinomas.

Methods: Tissue samples from 214 consecutive patients who underwent total or near-total thyroidectomy with histological diagnosis of papillary thyroid carcinoma (PTC)
Results: The BRAF(V600E) mutation was detected in 88 of the tumors examined, with significant differences between groups with and without lymph node (LN) metastases; the mean age of patients with BRAF(V600E) mutation was significantly higher than that of patients without mutations.

Which kind of vascular access for hemodialysis in pediatric patients?

The choice of vascular access in hemodialysis pediatric patients can be challenging, due to the small diameter of vessels. In the last 19 years, 38 arteriovenous fistulas (AVF) for hemodialysis have been created on 21 patients; 25 of them were radio-cephalic AVF. The evaluation of the vessels was, in the majority of cases, done by clinical criteria.

PSA reduction (after antibiotics) permits to avoid or postpone prostate biopsy in selected patients.

Microscopic foci of prostatitis may induce prostate-specific antigen (PSA) increase. PSA reduction after antibiotics might identify those patients in whom biopsy can be avoided. Ninety-nine patients received ciprofloxacin for 3 weeks, of whom 59 showed PSA reduction.

P2Y1 receptor switches to neurons from glia in juvenile versus neonatal rat cerebellar cortex.

Background: In the CNS, several P2 receptors for extracellular nucleotides are identified on neurons and glial cells to participate to neuron-neuron, glia-glia and glia-neuron communication.

Results: In this work, we describe the cellular and subcellular presence of metabotropic P2Y1 receptor in rat cerebellum at two distinct developmental ages, by means of immunofluorescence-confocal and electron microscopy as well as western blotting and direct membrane separation techniques. At postnatal day 21, we find that P2Y1 receptor in addition to Purkinje neurons, is abundant on neuronal specializations identified as noradrenergic by anatomical, morphological and biochemical features.

Nanostructured lipid carriers-containing anticancer compounds: preparation, characterization, and cytotoxicity studies.

This article describes the development of nanostructured lipid carriers (NLC) as colloidal carriers for two antitumor compounds that possess a remarkable antineoplastic activity. But their limited stability and low solubility in water could give a very low parenteral bioavailability. Results revealed an enhancement of the cytotoxicity effect of drug-loaded NLC on human prostate cancer (PC-3) and human hepatocellular carcinoma (HuH-6, HuH-7) cell lines with respect to that of both free drugs.

Synthesis and antitumor properties of 2,5-bis(3'-indolyl)thiophenes: analogues of marine alkaloid nortopsentin.

A series of 11 bis-indolylthiophenes of type 8-10 were obtained by cyclization of diketones 4 and 7 using Lawesson's reagent. Derivatives 8c, 9c, 9d, and 10c were selected to be evaluated in the full panel of about 60 human tumor cell lines derived from nine human cancer cell types and showed antiproliferative activity generally in the micromolar range. The most sensitive cell lines were: CCRF-CEM, MOLT-4, HL60 (TB), and RPMI-8226 of the leukemia subpanel, HT29 and HCC-2998 cell lines of the colon sub-panel, NCI-H522 of the non-small cell lung cancer sub-panel, LOX IMVI of the melanoma sub-panel, and UO-31 of the renal cancer sub-panel.

Lymph node metastases displaying lower Ki-67 immunostaining activity than the primary breast cancer.

Unlabelled: The aim of the study was to verify by Ki-67 immunostaining if any difference exists in the cell proliferating fraction between primary breast tumors (PTs) and matching positive axillary lymph nodes (ALNs).

Patients And Methods: Immunohistochemistry with the monoclonal antibody against Ki-67 was performed in 160 node-positive breast carcinomas and in their respective lymph node metastases.

Results: An increase of Ki-67 immunoreactive cells in ALN compared with that of PTs was observed in 84% of cases (ALN: mean 17%, PTs: mean 8%; p < 0.

Beneficial effects of rolipram in a quinolinic acid model of striatal excitotoxicity.

Activity of c-AMP responsive element-binding protein (CREB) is decreased in Huntington's disease (HD). Such decrease was also described by our group in the quinolinic acid lesion model of striatal excitotoxicity. The phosphodiesterase type IV inhibitor rolipram increases CREB phosphorylation.

CSF markers in Alzheimer disease patients are not related to the different degree of cognitive impairment.

Standard markers in cerebrospinal fluid (CSF), as soluble amyloid beta 1-42 (Abeta1-42) and total tau protein (t-tau), may contribute to dementia subtypes diagnostic accuracy. Yet, their sensitivity to assess the different degree of cognitive deficit is not fully clarified. Our study analyses Abeta1-42 and t-tau CSF levels in different cohorts of Alzheimer's disease (AD) patients, distinguished as early AD (mild cognitively impaired subjects recently converted to AD), mild AD (MMSE<23; > or =18), and moderately advanced AD (MMSE<18).

Difference in Ki67 and thymidylate synthase expression in primary tumour compared with metastatic nodes in breast cancer patients.

Breast cancer is a heterogeneous disease, so therapeutic predictive biological markers need to be identified. To date an accurate evaluation of predictive markers is mainly done at the primary site; however, the main goal of adjuvant therapy for breast cancer is the control of micrometastases. The aim of this study is to assess as therapeutic and/or prognostic marker, the proliferation status of primary tumors and involved nodes as measured by Ki67 and thymidylate synthase (TS) expression, in 30 breast cancer node positive patients.

Isoindolo[2,1-c]benzo[1,2,4]triazines: a new ring system with antiproliferative activity.

A series of isoindolo-benzo-triazines of type 4 was obtained by diazotization of 2-(2-aminoaryl)-1-cyanoisoindoles 3a-j. All the synthesized derivatives were screened by the National Cancer Institute (NCI, Bethesda, USA), for in vitro antitumor activity against a 3-human cancer cell line panel consisting of MCF7 (breast), NCI-H460 (lung), and SF-268 (CNS). Derivatives 4a, f, i, j were selected to be evaluated in the full panel of about 50 human tumor cell lines derived from nine human cancer cell types and showed antiproliferative activity generally in the micromolar range.

Distribution of TRPC1 receptors in dendrites of rat substantia nigra: a confocal and electron microscopy study.

Transient receptor potential channels (TRPC) are plasma membrane, non-selective cationic channels and have been proposed as candidates involved in the regulation of cellular Ca2+ influx. The expression, at mRNA level, of several TRPCs has been demonstrated recently in dopaminergic neurons of the substantia nigra (SN). The aim of the present study was to characterize the expression of TRPC1, at a protein level, in the substantia nigra neurons and non-excitable cells of Wistar rats.