Search

En la actualidad, el problema de la gestión de información es uno de los problemas más difíciles que enfrenta el Poder Judicial, dada la cultura del secreto que impera en el Perú, y las diversas y preocupantes manifestaciones de corrupción existentes en las distintas entidades públicas de nuestro país en general, y en el Poder Judicial en particular. Este trabajo de investigación buscará establecer cuál es la relación directa que tiene este problema de gestión de información con las manifestaciones de corrupción en el Poder Judicial peruano y en la integridad de los jueces del Perú, afectando la reputación y, por ende, la imagen institucional del Poder Judicial. En este sentido, el trabajo se centrará en las salas penales de la Corte Suprema del Perú.

Following publication of the original article in Stem Cell Research and Therapy [1], it was brought to our attention that panel 5E in Fig. 5 is a duplicate of panel 5F. Please find below the figure with the correct panel E. We apologize for the inconvenience this may have caused.

S100 proteins are low molecular weight proteins ranging in size from 9 to 13 kDa. They form homo- and heterodimers and even oligomers and are expressed in tissue and cell-specific manner [1]. It is well documented, infact, that S100 proteins have a broad range of intracellular and extracellular functions. Intracellular functions include regulation of protein phosphorylation, enzyme activity, calcium homeostasis, regulation of cytoskeletal components and regulation of transcriptional factors, so they are involved in several biological processes including cell cycle regulation, cell growth, cell differentiation, and motility [2]. Extracellularly they act in a cytokine like manner through the receptor for advanced glycation end products (RAGE). In consideration of the critical roles played by S100 proteins in such large spectrum of biological activities, is not surprising that improper expression of S100 members is correlated with many pathologies and especially with cancer. A number of S100 proteins have been shown to interact with oncogenes and various proteins involved in cancer progression, including p53, cytoskeletal proteins, MMPs, and others [3,4]. In this study we aimed to perform a large-scale proteomic investigation on breast cancer patients for the screening of multiple forms of S100 proteins. The 100 surgical tissues of ductal infiltrating breast cancer utilized were collected between 2003 and 2007 in the Breast Unit of the La Maddalena Hospital. Tissue extracts were submitted to proteomic preparations for2D-IPG and protein identification was performed by peptide mass finger printing. The S100 protein members identified in different proteomic maps were: S100A2 (protein S-100L), S100A4 (metastasin), S100A6 (Calcyclin, Prolactin receptor-associated protein), two isoforms, S100A7 (psoriasin), two isoforms, S100A8 (Calgranulin-A), S100A11 (Calgizzarin), three isoforms and S100A13 (S100 calcium-binding protein A13) (Fig. 1). Our results have shown that the majority of S100 proteins were present at very low levels, if not absent, in the nontumoral tissues adjacent to the primary tumor. Moreover, we showed that some S100 protein members were ubiquitously expressed in almost all patients, while others appeared more sporadic among the same group of patients. The Association analysis of S100 members with tumor variables (age, tumor size, nodal status, immuno-cytochemical, presence of HER-2, oestrogen receptors, progesterone receptor, and Ki67), showed no significant correlations of except for S100A6 (isoform b) and S100A13 correlating with Ki67. More interestingly, patients which developed distant metastases after a three year follow-up showed a general tendency of higher S100 protein expression, compared to the disease-free group. The most robust correlation with metastasis regarded primarily the protein S100A4, and secondly the protein S100A7. We believe that this information may substantially contribute to the progress of protein profiling of breast cancer and help to organize subclasses for clinical applications.

Tumor progression and metastasis represent the leading causes of cancer related death. One of the major features that may contribute to neoplastic cell dissemination is the progressive and local degradation of the extracellular matrix (ECM) surrounding the primary tumour. Degradation of the ECM requires the coordinated action of a number of enzymes produced locally by neoplastic cells and/or stromal cells. Five categories of proteinases have been implicated in the invasive process: serine, cysteine, aspartic, threonine proteinases and matrix metalloproteinases (MMPs), also known as matrixins, which play a key role as terminal effectors of the proteolytic cascade. At present 23 members of the matrixin family have been found in humans and classified into subsets of enzymes, according to their molecular domains and preference for the substrates. Since the classic work of Liotta and collaborators [1], much attention has been focused on MMP-2 and MMP-9 because of their ability to degrade type IV collagen, a major constituent of basement membranes. MMP-9 and MMP-2 are secreted by cells as zymogens; both enzymes are activated, by the cleavage of their amino-terminal pro-domains, through distinct pathways operating at the cell-matrix boundary [2]. Tissue detection of MMPs has suggested that augmented secretion and proteolytic activation of MMPs is often associated with tumor metastasis. Several authors have also detected incremented levels of circulating forms MMP-2 and MMP-9 in oncologic patients [3-6]. However, their clinical applications remain controversial. To confirm and extend our previous observations, in this study we analyzed the circulating forms of MMP-9 and MMP-2 in serum samples of 56 selected breast carcinoma patients, in comparison with the enzymatic activities present in tissue extracts from surgical fragments (primary tumor and its paired healthy tissues) of same patients. The activity levels of MMP-2 and MMP-9 were detected by gelatin zymography and quantified by ImageQuant TL. Two bands of activity, corresponding to the proforms of MMP-9 and MMP-2, were detected in the serum samples and tissue extracts of all oncologic patients, but with highly variable levels of intensity. In general the intensity of lytic bands was higher in serum than in the tissue extracts. In addition, most serum samples, and some of the tissue extracts, displayed additional proteolytic bands at higher Mw, corresponding likely to complexed forms of MMP-9 [5]. As previously reported for a pilot number of cases, lytic bands corresponding the activated forms of the two gelatinases were uniquely present in the tumor extracts, and absent in the paired normal tissues, thus confirming the hypothesis that activation of the enzymes is a key step during the invasive growth of the tumor. In order to assess the possible association between MMPs activities and other proteins potentially involved in tumor progression, we correlated the activity levels of both MMPs with the proteomic-based expression levels of the S100 protein members. One of the reasons of interest for this family of proteins is because there is increasing evidence that S100 proteins are often up-regulated in many cancers, including breast cancer, and this is frequently associated with tumour progression. Interestingly we have observed a correlation between the gelatinase activity levels and expression levels of some S100 proteins. In conclusion, our results, which show higher variability of MMP-9 levels suggest its usefulness as a marker evaluable both in the follow-up and in the prognosis of breast cancer patients.

The turn-over of extracellular matrix is a physiological process, that in normal conditions and in wound healing respond to spatial and temporal regulatory mechanisms, involving several cell-matrix interaction pathways. Profound changes occur both at cellular and extracellular level, during the progression of various forms of invasive carcinomas. Collagen alterations and cellular effects. The ultrastructural and biochemical analyses of the collagenous stroma of invasive ductal breast carcinoma have demonstrated the occurrence of extensive fragmentation of pre-existing collagen fibrils and new deposition of thinner fibrils formed mostly by 1(I)3 homotrimer collagen of type I [1-3], which appears preferentially produced by cancer cells [4]. More recently this collagen has been discovered to be resistant to collagenases, due to less efficient unwinding of homotrimers by MMP-1 [5]. When neoplastic cells are exposed to this collagen in an in vitro system, respond by increasing proliferation and migration rates, and display a proteomic [6,7] and genomic differential profiling versus the control cell cultures. Concurrently, we observed an increase of type V collagen, that when used as a substrate for cell culture, induced opposite effects to that exerted by the homotrimer collagen. A similar restraining effect was obtained when cells were induced to express decorin, a small proteoglycan lysine-rich [8]. Experiments conducted in vivo have revealed that the homotrimer collagen, applied on wound beds of treated guinea pigs, promoted keratynocyte migration into the granulation tissue, therefore confirming its propensity to facilitate local cell invasion and metastasis [9]. Fibrobalst influences. Fibroblasts are the major stromal cells with multiple roles, especially toward both the extracellular matrix and the neighbouring cell population, including neoplastic cells. We recently studied the effects exerted by fibroblasts on cancer cell (8701-BC) proteomics, using a trans-well coculture system. Our results clearly indicated that fibroblasts induce considerable proteomic modulations on 8701-BC, mainly in the cytoskeleton proteins and glycolytic enzymes. Additionally, fibroblast-conditioned medium increased neoplastic cell proliferation and invasion with a concurrent upregulation of the c-Myc oncogene. Collectively these results suggest that fibroblast stimulation may enhance the malignant potential of breast cancer cells in vitro [10]. In conclusion, the present information based on multidisciplinary approaches strongly suggest that the local microenvironment around the primary tumor, emanates influences of opposing signals, which may contribute in directing the neoplastic cells towards

HER-2 is a cell membrane protein that belongs to the ErbB family of receptor tyrosine kinases (HER-1, HER-2, HER-3, HER-4). The over-expression of HER-2, which results in the 25-30% of breast cancer patients, is considered a predictive and prognostic marker for breast cancer malignancy and invasiveness and makes HER-2 an excellent therapeutic target. In the last years new therapeutic strategies have been improved in order to better deal tumor diseases an to minimize collateral effects due to classic chemotherapy in patients. In this way, a new approach was the somministration of humanized antibodies directed against tumor-associated molecular targets. Among these ones Herceptin, an anti-neoplastic humanized monoclonal antibody (Herceptin®, Roche, CH), has been shown to be active against breast cancer cells over-expressing HER-2 receptor. Unfortunately the initial response to Herceptin-based regimens is followed by drug-resistance occurring within 1 year in the majority of patients. Thus it becomes critical to understand the molecular mechanisms underlying primary or acquired Herceptin resistance in order to improve the survival of breast cancer patients whose tumors overexpress HER2. On these bases, we focused our attention to investigate the effects caused by Herceptin treatment on SK-BR-3 breast cancer cells, which overexpress HER-2. To obtain drug-resistant cells, SK-BR-3 were treated with 10 µgr/ml of drug, until cells growth rate became synchronous compared to untreated parental cells. Parental and resistant cells were then properly collected and subjected to cell-lysis to obtain protein extracts, while respective conditioned media were harvested to perform analyses of cell-released gelatinolic activities, such as MMP-2 and MMP-9. These investigations are justified by previous observation of our group, showing a certain degree of correlation between gelatinase expression and HER-2 overexpression in vivo [1]. Protein extracts were subjected to IPG-2D electrophoresis, firstly to evaluate proteomic profiles of both resistant and parental cells, secondly to detect differentially expressed proteins in two above mentioned experimental conditions and thirdly to identify new Herceptin-resistance related proteins by means of MALDI-TOF mass spectrometry. The results so far obtained, have shown that prolonged Herceptin treatment induces dramatic changes in malignant resistant cells, such as rearrangement of cytoskeletal structures, evident effects on expression of proteins involved in cytoskeleyton remodelling, metabolic processes, stress responses and cell cycle and proliferation control. We suggest that present data may contribute significantly to the knowledge of the mechanisms underlying Herceptin drug resistance on breast cancer cells. [1]La Rocca, G., Pucci-Minafra, I., Marrazzo, A., Taormina, P. & Minafra, S. 2004. British Journal of Cancer, 90: 1414-1421.

The S-100 family of calcium-binding proteins includes about 20 members of low molecular weight characterized by two consecutive EF hands domains. They make interactions with cellular target proteins in a calcium-dependent manner; therefore they are thought to regulate a variety of physiological functions, such as cell proliferation, signal transduction, cell adhesion, motility as well as cancer metastasis.

Matrix metalloproteases (MMPS) are a family of well-known enzymes which operate prevalently in the extracellular domain, where they fulfil the function of remodeling the extracellular matrix. Within the about 26 family members, encoded by 24 genes in humans, MMP-2 and MMP-9, have been regarded as the primary responsibility for the basement membrane and pericellular ECM rearrangement. In cases of infiltrating carcinomas, which arise from the epithelial tissues of a gland or of an internal organ, a marked alteration of the expression and the activity levels of both MMPs is known to occur. Present investigation represents the continuation and upgrading of our previous studies, now focusing on the occurrence and intensity levels of MMP-2 and -9, and their proteomic correlations, in a cohort of 80 breast cancer surgical tissues