Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression

LYRIC/AEG-1 and its altered expression have been linked to carcinogenesis in prostate, brain and melanoma as well as promoting chemoresistance and metastasis in breast cancer. LYRIC/AEG-1 function remains unclear, although LYRIC/AEG-1 is activated by oncogenic HA-RAS, through binding of c-myc to its promoter, which in turn regulates the key components of the PI3-kinase and nuclear factor-kappaB pathways. We have identified the transcriptional repressor PLZF as an interacting protein of LYRIC/AEG through a yeast two-hybrid screen. PLZF regulates the expression of genes involved in cell growth and apoptosis including c-myc. Coexpression of LYRIC/AEG-1 with PLZF leads to a reduction in PLZF-mediated repression by reducing PLZF binding to promoters. We have confirmed that nuclear LYRIC/AEG-1 and PLZF interact in mammalian cells via the N- and C termini of LYRIC/AEG-1 and a region C terminal to the RD2 domain of PLZF. Both proteins colocalize to nuclear bodies containing histone deacetylases, which are known to promote PLZF-mediated repression. Our data suggest one mechanism for cells with altered LYRIC/AEG-1 expression to evade apoptosis and increase cell growth during tumourigenesis through the regulation of PLZF repression.

LYRIC/AEG-1 is targeted to different subcellular compartments by ubiquitinylation and intrinsic nuclear localization signals

PURPOSE: LYRIC/AEG-1 has been reported to influence breast cancer survival and metastases, and its altered expression has been found in a number of cancers. The cellular function of LYRIC/AEG-1 has previously been related to its subcellular distribution in cell lines. LYRIC/AEG-1 contains three uncharacterized nuclear localization signals (NLS), which may regulate its distribution and, ultimately, function in cells.

EXPERIMENTAL DESIGN: Immunohistochemistry of a human prostate tissue microarray composed of 179 prostate cancer and 24 benign samples was used to assess LYRIC/AEG-1 distribution. Green fluorescent protein-NLS fusion proteins and deletion constructs were used to show the ability of LYRIC/AEG-1 NLS to target green fluorescent protein from the cytoplasm to the nucleus. Immunoprecipitation and Western blotting were used to show posttranslational modification of LYRIC/AEG-1 NLS regions.

RESULTS: Using a prostate tissue microarray, significant changes in the distribution of LYRIC/AEG-1 were observed in prostate cancer as an increased cytoplasmic distribution in tumors compared with benign tissue. These differences were most marked in high grade and aggressive prostate cancers and were associated with decreased survival. The COOH-terminal extended NLS-3 (amino acids 546-582) is the predominant regulator of nuclear localization, whereas extended NLS-1 (amino acids 78-130) regulates its nucleolar localization. Within the extended NLS-2 region (amino acids 415-486), LYRIC/AEG-1 can be modified by ubiquitin almost exclusively within the cytoplasm.

CONCLUSIONS: Changes in LYRIC/AEG-1 subcellular distribution can predict Gleason grade and survival. Two lysine-rich regions (NLS-1 and NLS-3) can target LYRIC/AEG-1 to subcellular compartments whereas NLS-2 is modified by ubiquitin in the cytoplasm.

Diogenis Laertii de vitis, dogmatibus et apophthegmatibus clarorum philosophorum, libri. Graece et Latine : cum subjunctis integris annotationibus Is. Casauboni, Th. Aldobrandidni & Mer. Casauboni. Latinam Ambrosii versionem complevit & emendavit, Marcus Meibomius. Seorsum excusas Aeg. Menagii in Diogenem observationes auctiores habet volumen II. Ut & ejusdem syntagma de mulieribus philosophis; et Joachimi Kühnii adDiogenem notas, additae denique sunt priorum editionum praefationes, &indices locupletissimi

UANL

Tʻaegŭk hakpo.

Mode of access: Internet.

AEG Mitteilungen

Title Varies: 1905-12, Mitteilungen der Berliner Elektricitäts-Werke; 1913-16, BEW Mitteilungen

Differential pathologic variables and outcomes across the spectrum of adenocarcinoma of the esophagogastric junction

Background Adenocarcinoma of the esophagogastric junction (AEG) as described by Siewert et al. is classified as one entity in the latest (7th Edition) American Joint Cancer Committee/International Union Against Cancer (AJCC/UICC) manual, compared with the previous mix of esophageal and gastric staging systems. The origin of AEG tumors, esophageal or gastric, and their biology remain controversial, particularly for AEG type II (cardia) tumors. Methods We adapted a large prospective database (n = 520: 180 type I, 182 type II, 158 type III) to compare AEG tumors under the new TNM system Pathological variables associated with prognosis were compared (pT, pN, stage, differentiation, R status, lymphovascular invasion, perineural involvement, number of positive nodes, percent of positive nodes, and tumor length), as well as overall survival. Results Compared with AEG type I tumors, type II and type III tumors had significantly (p\0.05) more advanced pN stages, greater number and percentage of positive nodes, poorer differentiation, more radial margin involvement, and more perineural invasion. In AEG type I, 14/180 patients (8%) had[6 involved nodes (pN3), compared with 16 and 30% of patients classified type II and III, respectively. Median survival was significantly (p = 0.03) improved for type I patients (38 months) compared with those with tumors classified as type II (28 months) and type III (24 months). In multivariate analysis node positivity and pN staging but not AEG site had an impact on survival. Conclusions In this series AEG type I is associated with more favorable pathologic features and improved outcomes compared with AEG type II and III. This may reflect earlier diagnosis, but an alternative possibility, that type I may be a unique paradigm with more favorable biology, requires further study. © Société Internationale de Chirurgie 2010.

Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 x 10(-)(9), odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 x 10(-)(1)(1) (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 x 10(-)(5), permuted threshold for genome-wide significance 7.7 x 10(-)(5). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

No eres la muñeca de nadie.

Mención honorífica de la convocatoria de premios 'Irene: la paz comienza en casa 2006'. Incluye, como anexos, los catálogos diseñados

Intervenção educacional em grupo para promoção do consumo de frutas e hortaliças de Agentes Comunitários de Saúde do município de Porto Feliz-SP

Pós-graduação em Saúde Coletiva - FMB

Sintesi di PNA a libertà conformazionale ridotta

The present work started a research project aimed at the synthesis of conformationally “locked” PNA (Peptide Nucleic Acids) monomers. Compared to classic aeg-PNA, this structural modification would result in an improvement in the pairing properties with natural nucleic acids, due to entropic variations in the process. Specifically, an attempt was made to build a PNA monomer around a β-lactam ring. That ring could be imagined as obtained by linking the methylene groups in α position of both the nucleobase and the carboxyl function. These structural properties would imply pre-organization of the final oligomer, improving the pairing process in biological systems. The first step of this work was the investigation of the Staudinger reaction for the ciclization of the lactam ring, and in particular the activation method of the carboxylic group of the nucleobase derivatives. Use of triazine chloride led to the synthesis of the adenine-based β-lactam-PNA. Attempts to synthesize the same monomer based on cytosine, guanine and thymine were unsuccessful, so alternative methods for carboxylic group activation were investigated. Conversion of carboxylic acids to acyl chlorides led to a partial result: despite the method worked well with analogues of the final reactants, it didn’t worked with substrates needed for lactam based PNAs. Search for a valid activation process continued involving carbonyl diimidazole, Mukayama reagent, and LDA (with methylester derivative of nucelobase) without good results. Last, it was investigated a different synthetic approach by first synthesizing a proper backbone with a chlorine in the β- lactam ring. This chlorine ring should undergo substitution by a nucleobase anion to give the desired PNA monomer. Unluckily also this synthetic route didn’t lead to the desired monomers.

The impact of neural invasion severity in gastrointestinal malignancies: a clinicopathological study.

OBJECTIVES Because neural invasion (NI) is still inconsistently reported and not well characterized within gastrointestinal malignancies (GIMs), our aim was to determine the exact prevalence and severity of NI and to elucidate the true impact of NI on patient's prognosis. BACKGROUND The union internationale contre le cancer (UICC) recently added NI as a novel parameter in the current TNM classification. However, there are only a few existing studies with specific focus on NI, so that the distinct role of NI in GIMs is still uncertain. MATERIALS AND METHODS NI was characterized in approximately 16,000 hematoxylin and eosin tissue sections from 2050 patients with adenocarcinoma of the esophagogastric junction (AEG)-I-III, squamous cell carcinoma (SCC) of the esophagus, gastric cancer (GC), colon cancer (CC), rectal cancer (RC), cholangiocellular cancer (CCC), hepatocellular cancer (HCC), and pancreatic cancer (PC). NI prevalence and severity was determined and related to patient's prognosis and survival. RESULTS NI prevalence largely varied between HCC/6%, CC/28%, RC/34%, AEG-I/36% and AEG-II/36%, SCC/37%, GC/38%, CCC/58%, and AEG-III/65% to PC/100%. NI severity score was uppermost in PC (24.9±1.9) and lowest in AEG-I (0.8±0.3). Multivariable analyses including age, sex, TNM stage, and grading revealed that the prevalence of NI was significantly associated with diminished survival in AEG-II/III, GC, and RC. However, increasing NI severity impaired survival in AEG-II/III and PC only. CONCLUSIONS NI prevalence and NI severity strongly vary within GIMs. Determination of NI severity in GIMs is a more precise tool than solely recording the presence of NI and revealed dismal prognostic impact on patients with AEG-II/III and PC. Evidently, NI is not a concomitant side feature in GIMs and, therefore, deserves special attention for improved patient stratification and individualized therapy after surgery.

A retrospective comparative exploratory study on two methylentetrahydrofolate reductase (MTHFR) polymorphisms in esophagogastric cancer: the A1298C MTHFR polymorphism is an independent prognostic factor only in neoadjuvantly treated gastric cancer patients.

BACKGROUND Methylentetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism and consequently could be an important factor for the efficacy of a treatment with 5-fluorouracil. Our aim was to evaluate the prognostic and predictive value of two well characterized constitutional MTHFR gene polymorphisms for primarily resected and neoadjuvantly treated esophagogastric adenocarcinomas. METHODS 569 patients from two centers were analyzed (gastric cancer: 218, carcinoma of the esophagogastric junction (AEG II, III): 208 and esophagus (AEG I): 143). 369 patients received neoadjuvant chemotherapy followed by surgery, 200 patients were resected without preoperative treatment. The MTHFR C677T and A1298C polymorphisms were determined in DNA from peripheral blood lymphozytes. Associations with prognosis, response and clinicopathological factors were analyzed retrospectively within a prospective database (chi-square, log-rank, cox regression). RESULTS Only the MTHFR A1298C polymorphisms had prognostic relevance in neoadjuvantly treated patients but it was not a predictor for response to neoadjuvant chemotherapy. The AC genotype of the MTHFR A1298C polymorphisms was significantly associated with worse outcome (p = 0.02, HR 1.47 (1.06-2.04). If neoadjuvantly treated patients were analyzed based on their tumor localization, the AC genotype of the MTHFR A1298C polymorphisms was a significant negative prognostic factor in patients with gastric cancer according to UICC 6th edition (gastric cancer including AEG type II, III: HR 2.0, 95% CI 1.3-2.0, p = 0.001) and 7th edition (gastric cancer without AEG II, III: HR 2.8, 95% CI 1.5-5.7, p = 0.003), not for AEG I. For both definitions of gastric cancer the AC genotype was confirmed as an independent negative prognostic factor in cox regression analysis. In primarily resected patients neither the MTHFR A1298C nor the MTHFR C677T polymorphisms had prognostic impact. CONCLUSIONS The MTHFR A1298C polymorphisms was an independent prognostic factor in patients with neoadjuvantly treated gastric adenocarcinomas (according to both UICC 6th or 7th definitions for gastric cancer) but not in AEG I nor in primarily resected patients, which confirms the impact of this enzyme on chemotherapy associated outcome.

Influence of Different Neoadjuvant Chemotherapy Regimens on Response, Prognosis, and Complication Rate in Patients with Esophagogastric Adenocarcinoma.

BACKGROUND Perioperative chemotherapy improves survival in patients with advanced esophagogastric cancer, but the optimal treatment regimen remains unclear. More intensive chemotherapy may improve outcome, but also increase toxicity and complications. METHODS A total of 843 patients were included in this retrospective study and stratified in 4 groups: doublet therapy with cisplatin or oxaliplatin and 5-fluorouracil (groups A/B) or triplet therapy with additional epirubicin or taxane (groups C/D). The influence of the different neoadjuvant chemotherapy regimens on response, prognosis, and complications was assessed. RESULTS Clinical and pathological response were associated with longer overall survival (OS; p < 0.001). No significant differences regarding response or OS were found, but there was a trend toward better outcome in group D (taxane-containing triplet). In the subgroup of 669 patients with adenocarcinomas of the esophagogastric junction (AEG), patients who had received taxane-containing regimens had a significantly longer OS (p = 0.037), but taxane use was not an independent factor in multivariate analysis. Triple therapy with taxanes did not result in a higher complication rate or postoperative mortality. CONCLUSIONS Although no superior neoadjuvant chemotherapy regimen was identified for patients with esophagogastric adenocarcinoma, taxane-containing regimens should be further investigated in randomized trials, especially in patients with AEG tumors.