Novel Agents Targeting the IGF-1R/PI3K Pathway Impair Cell Proliferation and Survival in Subsets of Medulloblastoma and Neuroblastoma.

The receptor tyrosine kinase (RTK)/phosphoinositide 3-kinase (PI3K) pathway is fundamental for cancer cell proliferation and is known to be frequently altered and activated in neoplasia, including embryonal tumors. Based on the high frequency of alterations, targeting components of the PI3K signaling pathway is considered to be a promising therapeutic approach for cancer treatment. Here, we have investigated the potential of targeting the axis of the insulin-like growth factor-1 receptor (IGF-1R) and PI3K signaling in two common cancers of childhood: neuroblastoma, the most common extracranial tumor in children and medulloblastoma, the most frequent malignant childhood brain tumor. By treating neuroblastoma and medulloblastoma cells with R1507, a specific humanized monoclonal antibody against the IGF-1R, we could observe cell line-specific responses and in some cases a strong decrease in cell proliferation. In contrast, targeting the PI3K p110α with the specific inhibitor PIK75 resulted in broad anti-proliferative effects in a panel of neuro- and medulloblastoma cell lines. Additionally, sensitization to commonly used chemotherapeutic agents occurred in neuroblastoma cells upon treatment with R1507 or PIK75. Furthermore, by studying the expression and phosphorylation state of IGF-1R/PI3K downstream signaling targets we found down-regulated signaling pathway activation. In addition, apoptosis occurred in embryonal tumor cells after treatment with PIK75 or R1507. Together, our studies demonstrate the potential of targeting the IGF-1R/PI3K signaling axis in embryonal tumors. Hopefully, this knowledge will contribute to the development of urgently required new targeted therapies for embryonal tumors.

Risco de quedas em idosos: revisão integrativa pelo diagnóstico da North American Nursing Diagnosis Association

Foi objetivo desta pesquisa analisar a produção científica de fatores de risco para quedas, a partir do diagnóstico da North American Nursing Diagnosis Association, na literatura científica brasileira e estrangeira, de 2005 a 2010. Revisão integrativa, na qual foram utilizados os descritores: acidente por quedas e idoso, nas bases de dados da Cumulative Index to Nursing and Allied Health Literature e Literatura Latino-Americana e do Caribe em Ciências da Saúde, sendo selecionados 32 artigos para análise de conteúdo. Os resultados são apresentados conforme os fatores de riscos indicados na North American Nursing Diagnosis Association, sendo eles: fatores de riscos ambientais, como recinto com móveis e objetos/tapetes espalhados pelo chão, pouca iluminação, piso escorregadio; fatores de riscos cognitivos, tais como estado mental rebaixado; fatores de riscos em adultos, como idade acima de 65 anos; fatores de riscos fisiológicos, como equilíbrio prejudicado, dificuldades visuais, incontinência, dificuldade na marcha, neoplasia; fatores de riscos para uso de alguns medicamentos. A análise dos fatores de risco de quedas nos idosos evidência a necessidade de desenvolvimento de novas estratégias modificadoras dos ambientes e componentes intrínsecos.

Neutrophil-derived APRIL concentrated in tumor lesions by proteoglycans correlates with human B-cell lymphoma aggressiveness.

A PRoliferation-Inducing TNF Ligand (APRIL) costimulates B-cell activation. When overexpressed in mice, APRIL induces B-cell neoplasia, reminiscent of human B-cell chronic lymphoid leukemia (B-CLL). We analyzed APRIL expression in situ in human non-Hodgkin lymphomas. APRIL up-regulation was only observed in high-grade B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma (BL). Up-regulation was seen in 46% and 20% of DLBCL and BL, respectively. In DLBCL, neutrophils, constitutively producing APRIL and infiltrating the tumor tissue, were the main cellular source of APRIL. Rare DLBCL cases showed a predominance of histiocytes or mesenchymal cells as APRIL source. APRIL secreted by neutrophils accumulated on tumor cells via proteoglycan binding. In addition to proteoglycans, DLBCL tumor cells expressed the APRIL signaling receptor, TACI and/or BCMA, indicating that these tumor cells are fully equipped to respond to APRIL. A retrospective clinical analysis revealed a significant correlation between high expression of APRIL in tumor lesions and decreased overall patient survival rate. Hence, APRIL produced by inflammatory cells infiltrating lymphoma lesions may increase tumor aggressiveness and affect disease outcome.

Promoção da adesão à prevenção do cancro da próstata. Intervenções de Enfermagem no centro de Saúde de Ribeira de Craquinha

O Cancro da Próstata é a neoplasia maligna que mais comummente afeta os homens em Cabo Verde, ocupando o terceiro lugar entre das causas de mortalidade por cancro entre os homens. Essa prevalência acompanha a tendência mundial de aumento das doenças crónicas não transmissíveis motivado pela adoção de estilos de vida não-saudáveis e por comportamentos de não procura de saúde. O aumento da incidência e da morbidade do cancro da próstata, sobretudo nos últimos anos, constitui um sério problema de saúde pública em Cabo Verde. Vários são os fatores que poderão estar por trás desses números, destacando-se de entre eles a resistência por parte dos homens em aderir à prevenção e à deteção precoce do cancro da próstata, quer por insuficiência de informações, quer por preconceitos presentes na nossa sociedade relacionados com a questão. O presente trabalho pretende abordar a problemática a jusante, isto é, pretende realçar a necessidade da enfermagem desenvolver estratégias para a promoção da adesão à prevenção, detetando precocemente o cancro da próstata. Por esta razão, este estudo propõe-se identificar os obstáculos que impedem os homens a aderir ao diagnóstico precoce do cancro da próstata na comunidade de Ribeira de Craquinha. A atuação da Enfermagem junto à comunidade na realização de trabalhos preventivos e promocionais de saúde torna-se imprescindível quando a questão é atingir os objetivos que permeiam os níveis de prevenção primária. Para alcançar o objetivo utilizou-se a metodologia qualitativa do tipo exploratório com uma abordagem fenomenológica utilizando como instrumento de recolha de dados a entrevista estruturada que foi aplicada a quatro (4) enfermeiros do centro da Ribeira de Craquinha. Os resultados evidenciaram que os profissionais de saúde devem dar mais atenção à saúde do homem e apostar mais nas estratégias para a consciencialização na prevenção do cancro da próstata. Também ao longo dos resultados constatamos que os homens por vergonha de expor o seu corpo aos profissionais de saúde, muito pouco procuram o sistema de saúde.

Estudio prospectivo de la cefalea en pacientes con hemopatías malignas

Objetivo: describir las cefaleas en pacientes ingresados con neoplasias hematológicas, identificar los factores asociados a cefaleas secundarias graves. Estudio observacional prospectivo. Se incluyen 30 casos de cefalea correspondientes a 23 pacientes. Ocho cefaleas son primarias y 22 secundarias. Diez de estas, son secundarias a patología grave o potencialmente grave: encefalopatía hipertensiva, neoplasia intracraneal, hemorragia intracraneal, infección cefálica, trombosis venosa, fiebre tumoral e hipertensión sin encefalopatía. El riesgo de que una cefalea sea secundaria a patología grave es mayor en los casos que presentan esa cefalea por primera vez y en los que coincide con el debut de la enfermedad hematológica.

Epithelial to mesenchymal transition in the pathogenesis of uterine malignant mixed Müllerian tumours: the role of ubiquitin proteasome system and therapeutic opportunities.

Malignant mixed Müllerian tumours (malignant mixed mesodermal tumours, MMMT) of the uterus are metaplastic carcinomas with a sarcomatous component and thus they are also called carcinosarcomas. It has now been accepted that the sarcomatous component is derived from epithelial elements that have undergone metaplasia. The process that produces this metaplasia is epithelial to mesenchymal transition (EMT), which has recently been described as a neoplasia-associated programme shared with embryonic development and enabling neoplastic cells to move and metastasise. The ubiquitin proteasome system (UPS) regulates the turnover and functions of hundreds of cellular proteins. It plays important roles in EMT by being involved in the regulation of several pathways participating in the execution of this metastasis-associated programme. In this review the specifi c role of UPS in EMT of MMMT is discussed and therapeutic opportunities from UPS manipulations are proposed.

La thrombose veineuse profonde chez l'adolescent [Venous thromboembolic disease in adolescents]

Deep vein thrombosis in children and adolescents is a quite rare event. Risk factors most often associated with DVT in this particular population are: central vein catheters, neoplasia, vascular malformations and oral contraception. Diagnosis and management of DVT in adolescents does not differ greatly from that of adults. Compression ultrasound is the initial exam of choice. Hospitalization is often not necessary and treatment can be started by using low molecular weight heparin followed by oral anti-vitamin K antagonists. Thrombophilia screening is not routinely recommended and should be reserved for those patients for whom results would change therapeutical management.

Adenocarcinoma of the pancreas: Comparative single centre analysis between ductal and mucinous type.

1. Background¦Adenocarcinomas of the pancreas are exocrine tumors, originate from ductal system, including two morphologically distinct entities: the ductal adenocarcinoma and mucinous adenocarcinoma. Ductal adenocarcinoma is by far the most frequent malignant tumor in the pancreas, representing at least about 90% of all pancreas cancers. It is associated with very poor prognosis, due to the fact that actually there are no any biological markers or diagnostic tools for identification of the disease at an early stage. Most of the time the disease is extensive with vascular and nerves involvement or with metastatic spread at the time of diagnosis (1). The median survival is less than 5% at 5 years, placing it, at the fifth leading cause of death by cancer in the world (2). The mucinous form of pancreatic adenocarcinoma is less frequent, and seems to have a better prognosis with about 57% survival at 5 years (1)(3)(4).¦Each morphologic type of pancreatic adenocarcinoma is associated with particular preneoplastic lesions. Two types of preneoplastic lesions are described: firstly, pancreatic intra-epithelial neoplasia (PanIN) which affects the small and peripheral pancreatic ducts, and the intraductal papillary-mucinous neoplasm (IPMN) interested the main pancreatic ducts and its principal branches. Both of preneoplastic lesions lead by different mechanisms to the pancreatic adenocarcinoma (1)(2)(3)(4)(5)(6)(7)(8)(9)(10).¦The purpose of our study consists in a retrospective analysis of various clinical and histo-morphological parameters in order to assess a difference in survival between these two morphological types of pancreatic adenocarcinomas.¦1.2 Material and methods¦We conducted a retrospective analysis including 35 patients, (20 men and 15 women), beneficed the surgical treatment for pancreas adenocarcinoma at the Surgical Department of University Hospital in Lausanne. The patients involved in our study have been treated between 2003 and 2008, permitting at least 5-years mean follow up. For each patient the following parameters were analysed: age, gender, type of operation, type of preneoplastic lesions, TNM stage, histological grade of the tumor, vascular invasion, lymphatic and perineural invasion, resection margins, and adjuvant treatment.¦The results from these observations were included in a univariate and multivariate statistical analysis and compared with overall survival, as well as specific survival for each morphologic subtype of adenocarcinoma.¦As a low number of mucinous adenocarcinomas (n=5) was insufficient to conduct a pertinent statistical analysis, we compared the data obtained from adenocarcinomas developed on PanIN with adenocarcinomas developed on IPMN including both, ductal or mucinous types.¦1.3 Result¦Our results show that adenocarcinomas developed on pre-existing IPMN including both morphologic types (ductal and mucinous form) are associated with a better survival and prognosis than adenocarciomas developed on PanIN.¦1.4 Conclusion¦This study reflects that the most relevant parameter in survival in pancreatic adenocarcinoma seems to be the type of preneoplastic lesion. The significant difference in survival was noted between adenocarcinomas developing on PanIN as compared to adenocarcinomas developed on IPMN precursor lesions. Ductal adenocarcinomas developped on IPMN present significantly longer survival than those developed on PanIN lesions (P value= 0,01). Therefore we can suggest that the histological type of preneoplastic lesion rather than the histological type of adenocarcinoma should be the determinant prognosis factor in survival of pancreatic adenocarcinoma.

Notch regulation of lymphocyte development and function.

Notch proteins regulate a broad spectrum of cell fate decisions and differentiation processes during fetal and postnatal development. Mammals have four Notch receptors that bind five different ligands. The function of Notch signaling during lymphopoiesis and T cell neoplasia, based on gain-of-function and conditional loss-of-function approaches for the Notch1 receptor, indicates Notch1 is essential in T cell lineage commitment. Recent studies have addressed the involvement of other Notch receptors and ligands as well as their downstream targets, demonstrating additional functions of Notch signaling in embryonic hematopoiesis, intrathymic T cell development, B cell development and peripheral T cell function.

Clonal deletion and the fate of autoreactive thymocytes that survive negative selection.

Clonal deletion of autoreactive thymocytes is important for self-tolerance, but the intrathymic signals that induce clonal deletion have not been clearly identified. We now report that clonal deletion during negative selection required CD28-mediated costimulation of autoreactive thymocytes at the CD4(+)CD8(lo) intermediate stage of differentiation. Autoreactive thymocytes were prevented from undergoing clonal deletion by either a lack of CD28 costimulation or transgenic overexpression of the antiapoptotic factors Bcl-2 or Mcl-1, with surviving thymocytes differentiating into anergic CD4(-)CD8(-) double-negative thymocytes positive for the T cell antigen receptor αβ subtype (TCRαβ) that 'preferentially' migrated to the intestine, where they re-expressed CD8α and were sequestered as CD8αα(+) intraepithelial lymphocytes (IELs). Our study identifies costimulation by CD28 as the intrathymic signal required for clonal deletion and identifies CD8αα(+) IELs as the developmental fate of autoreactive thymocytes that survive negative selection.

Axillary Sentinel Lymph Node Biopsy for Breast Cancer and Melanoma Patients after Previous Axillary Surgery: A Systematic Review

Objective: Sentinel lymph node biopsy (SLNB) is a validated staging technique for breast carcinoma. Some women are exposed to have a second SLNB due to breast cancer recurrence or a second neoplasia (breast or other). Due to modi- fied anatomy, it has been claimed that previous axillary surgery represents a contra-indication to SLNB. Our objective was to analyse the literature to assess if a second SLNB is to be recommended or not. Methods: For the present study, we performed a review of all published data during the last 10 years on patients with previous axilla surgery and second SLNB. Results: Our analysis shows that second SLNB is feasible in 70%. Extra-axillary SNs rate (31%) was higher after radical lymph node dissection (ALND) (60% - 84%) than after SLNB alone (14% - 65%). Follow-up and com- plementary ALND following negative and positive second SLNB shows that it is a reliable procedure. Conclusion: The review of literature confirms that SLNB is feasible after previous axillary dissection. Triple technique for SN mapping is the best examination to highlight modified lymphatic anatomy and shows definitively where SLNB must be per- formed. Surgery may be more demanding as patients may have more frequently extra-axillary SN only, like internal mammary nodes. ALND can be avoided when second SLNB harvests negative SNs. These conclusions should however be taken with caution because of the heterogeneity of publications regarding SLNB and surgical technique.

Calprotectine fécale: outil diagnostique dans les maladies inflammatoires chroniques de l'intestin [Fecal calprotectin: a diagnostic tool for inflammatory bowel disease].

Fecal calprotectin (FC) is a valid biomarker to discriminate with a good sensitivity and specificity the presence of mucosal lesions of the gastrointestinal tube (e.g. ulcers in the context of inflammatory bowel disease (IBD)) from functional disorders (e.g. irritable bowel syndrome). FC is not specific for IBD and can be elevated also in gastrointestinal infections, ischemic colitis or neoplasia. An elevated FC should stimulate further investigations, notably an endoscopic workup. The level of FC correlates with the endoscopic score in Crohn's disease and ulcerative colitis. The correlation of FC and the endoscopic severity is better than the one of CRP or blood leukocytes. Thus, FC can also be used in the follow-up of IBD patients.

A novel mucosal orthotopic murine model of human papillomavirus-associated genital cancers.

Cervical cancer results from infection with high-risk type human papillomaviruses (HPV). Therapeutic vaccines aiming at controlling existing genital HPV infections and associated lesions are usually tested in mice with HPV-expressing tumor cells subcutaneously implanted into their flank. However, effective vaccine-induced regression of these ectopic tumors strongly contrasts with the poor clinical results of these vaccines produced in patients with HPV-associated genital neoplasia. To assess HPV therapeutic vaccines in a more relevant setting, we have, here, established an orthotopic mouse model where tumors in the genital mucosa (GM) develop after an intravaginal instillation of HPV16 E6/E7-expressing tumor cells transduced with a luciferase-encoding lentiviral vector for in vivo imaging of tumor growth. Tumor take was 80-90% after nonoxynol-9 induced damage of the epithelium. Tumors remained localized in the genital tract, and histological analysis showed that most tumors grew within the squamous epithelium of the vaginal wall. Those tumors induced (i) E7-specific CD8 T cells restricted to the GM and draining lymph nodes, in agreement with their mucosal location and (ii) high Foxp3+ CD4+ infiltrates, similarly to those found in natural non-regressing HPV lesions. This novel genital HPV-tumor model by requiring GM homing of vaccine-induced immune responses able to overcome local immuno-suppression may be more representative of the situation occurring in patients upon therapeutic vaccination.

Simpson-Golabi-Behmel syndrome type 1 in a 27-week macrosomic preterm newborn: the diagnostic value of rib malformations and index nail and finger hypoplasia.

The Simpson-Golabi-Behmel syndrome type 1 (SGBS1, OMIM #312870) is an X-linked overgrowth condition comprising abnormal facial appearance, supernumerary nipples, congenital heart defects, polydactyly, fingernail hypoplasia, increased risk of neonatal death and of neoplasia. It is caused by mutation/deletion of the GPC3 gene. We describe a macrosomic 27-week preterm newborn with SGBS1 who presents a novel GPC3 mutation and emphasize the phenotypic aspects which allow a correct diagnosis neonatally in particular the rib malformations, hypoplasia of index finger and of the same fingernail, and 2nd-3rd finger syndactyly.

Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues

MicroRNAs (miRNAs) are short non-coding RNA molecules playing regulatory roles by repressing translation or cleaving RNA transcripts. Although the number of verified human miRNA is still expanding, only few have been functionally described. However, emerging evidences suggest the potential involvement of altered regulation of miRNA in pathogenesis of cancers and these genes are thought to function as both tumours suppressor and oncogenes. In our study, we examined by Real-Time PCR the expression of 156 mature miRNA in colorectal cancer. The analysis by several bioinformatics algorithms of colorectal tumours and adjacent non-neoplastic tissues from patients and colorectal cancer cell lines allowed identifying a group of 13 miRNA whose expression is significantly altered in this tumor. The most significantly deregulated miRNA being miR-31, miR-96, miR-133b, miR-135b, miR-145, and miR-183. In addition, the expression level of miR-31 was correlated with the stage of CRC tumor. Our results suggest that miRNA expression profile could have relevance to the biological and clinical behavior of colorectal neoplasia.