Identification and validation of a new set of five genes for prediction of risk in early breast cancer.

Molecular tests predicting the outcome of breast cancer patients based on gene expression levels can be used to assist in making treatment decisions after consideration of conventional markers. In this study we identified a subset of 20 mRNA differentially regulated in breast cancer analyzing several publicly available array gene expression data using R/Bioconductor package. Using RTqPCR we evaluate 261 consecutive invasive breast cancer cases not selected for age, adjuvant treatment, nodal and estrogen receptor status from paraffin embedded sections. The biological samples dataset was split into a training (137 cases) and a validation set (124 cases). The gene signature was developed on the training set and a multivariate stepwise Cox analysis selected five genes independently associated with DFS: FGF18 (HR = 1.13, p = 0.05), BCL2 (HR = 0.57, p = 0.001), PRC1 (HR = 1.51, p = 0.001), MMP9 (HR = 1.11, p = 0.08), SERF1a (HR = 0.83, p = 0.007). These five genes were combined into a linear score (signature) weighted according to the coefficients of the Cox model, as: 0.125FGF18 - 0.560BCL2 + 0.409PRC1 + 0.104MMP9 - 0.188SERF1A (HR = 2.7, 95% CI = 1.9-4.0, p < 0.001). The signature was then evaluated on the validation set assessing the discrimination ability by a Kaplan Meier analysis, using the same cut offs classifying patients at low, intermediate or high risk of disease relapse as defined on the training set (p < 0.001). Our signature, after a further clinical validation, could be proposed as prognostic signature for disease free survival in breast cancer patients where the indication for adjuvant chemotherapy added to endocrine treatment is uncertain.

High prevalence of BK polyomavirus sequences in human papillomavirus-16-positive precancerous cervical lesions.

High- and low-grade cervical lesions were analyzed for the presence of polyomavirus (PYV) and human papillomavirus (HPV) sequences. In precancerous cervical lesions, the overall prevalence of PYV sequences was 44% (41/93). Specifically, among the PYV-positive samples, 83% (34/41) tested positive for BK polyomavirus (BKV) sequences, whereas 17% (7/41) were positive for JC-virus. None of the samples were positive for simian virus 40. The presence of BKV DNA in high-grade squamous intraepithelial lesions was confirmed by in situ PCR. BKV sequences were detected more frequently in high-grade squamous intraepithelial lesions, together with the genotype HPV-16. The association of BKV with precancerous cervical lesions suggests that this polyomavirus participates with HPV-16 in the cell transformation process. Alternatively, BKV might multiply better in HPV-16-positive cells from precancerous cervical lesions than in HPV-16-negative cells.

[Gastrointestinal stromal tumour in emergency surgery]. / GIST intestinali nell'emergenza chirurgica.

Although rare, gastrointestinal stromal tumours (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract. We present our experience with the treatment of 8 patients affected by gastrointestinal stromal tumours of the ileum and colon. These cases were characterised by acute bleeding, intestinal obstruction or diffuse abdominal pain, and all of them underwent an emergency surgical treatment. We performed six partial resections of the ileum, one right hemicolectomy and one left hemicolectomy. Three patients died after surgical procedures for disease relapse, one died 10 years later due to other complications, and the others are still alive.

Co-expression of HSV2 and Chlamydia trachomatis in HPV-positive cervical cancer and cervical intraepithelial neoplasia lesions is associated with aberrations in key intracellular pathways.

OBJECTIVE: Oncogenic human papillomaviruses (HPVs) are the etiological agents of cervical cancer. Different cofactors might be needed for malignant transformation, but they still remain elusive. METHODS: To delineate the role of Chlamydia trachomatis (CT) and herpes simplex virus type 2 (HSV2) in HPV-positive cervical intraepithelial neoplasia (CIN) lesions and cervical carcinoma a series of 149 cervical cancer and CIN biopsies were analyzed for CT and HSV2 DNA by PCR, and HPV genotyped by InnoLipa. Monitoring of aberrations in key intracellular pathways due to CT/HSV2 and HPV co-expression were analyzed with 13 biomarkers. RESULTS: Of the 149 samples tested, 136 were HPV DNA positive; 32/136 contained also CT DNA and 29 HSV2 DNA. Detection of CT was significantly (p = 0.0001) related to multiple-type HPV infections, while HSV2 was of borderline significance (p = 0.053). Of the 13 biomarkers tested, cytoplasmic and nuclear NF-kappaB and VEGF-C were significantly increased in CT+/HPV+ lesions; p = 0.023, p = 0.045, and p = 0.020 as well as survivin, p = 0.026. Survivin was the only marker that was overexpressed also in HSV2+/HPV+ lesions, p = 0.027. CONCLUSIONS: CT infection favors the entry and persistence of multiple HR-HPV types, which leads to viral integration, inhibition of apoptosis, overexpression of E6/E7 oncogenes and cell transformation.

Detection of oncogenic DNA viruses in colorectal cancer.

BACKGROUND: As a part of our search for oncogenic viruses as potential etiological agents in human malignancies, our studies on human papillomaviruses (HPV) were extended to analysis of the 3 polyomaviruses (SV40, BKV and JCV) in colorectal carcinomas. PATIENTS AND METHODS: Archival tumour samples from 71 patients with colorectal cancer were analyzed for the sequences of SV40, BKV, JCV and HPV using PCR-based techniques. HPV genotypes were determined using sequencing and reverse blot hybridization (InnoLipa). RESULTS: Amplification of BKV and JCV with the primer pair PEP-1 and PEP-2 and subsequent restriction digestion of the amplified products with BamH I disclosed BKV in 6/66 (9%) of the samples, whereas none contained JCV. SV40 was amplified in 10/66 (15.1%) samples and confirmed by sequencing analysis. In pair-wise analysis for co-infections, the samples were significantly different in their BKV-JCV and JCV-SV40 status, in contrast to their BKV-SV40 co-infection status. HPV DNA was detected in 22/66 (33.3%) of the samples analysed with either the MY09/11 or SPF primer mix. Of these 22 HPV infections, 7 were single-type infections and 15 contained multiple HPV types. HPV detection or type distribution showed no relationship to the gender of the patients or histological grade of the tumour. HPV status was not significantly related to detection of BKV, JCV or SV40. Similarly, in pair-wise analysis for co-infections, the samples were significantly different in their status of HPV-BKV (p=0.0006), HPV-JCV (p=0.0001), and HPV-SV40 (p=0.019), implicating that HPV and the 3 polyomaviruses are rarely detected concomitantly in the same samples. CONCLUSION: Taking the known molecular mechanisms of action of these individual viruses, there is a chance that these viruses could alter the mechanisms of cell cycle control and inhibit apoptosis, thus potentially causing chromosomal instability and promoting colorectal oncogenesis.

[Gastric mesenchymal tumours (GIST)]. / Tumori mesenchimali gastrici (GIST): aspetti clinici e revisione critica delle metodologie diagnostiche.

The incidence of gastrointestinal stromal tumours (GIST) has increased in recent years. A number of authors have attempted to define the actual nature of these tumours. Immunohistochemistry highlighting the positivity of tyrosine-kinase (CD117/c-Kit) has revealed the difference between gastrointestinal stromal tumours and other mesenchymal tumours and, therefore, the possibility of medical rather than surgical therapy. We retrospectively reviewed 19 patients affected by primary gastric GIST, who underwent surgery in recent years with subsequent follow-up. Gastroscopy and gastrointestinal tract radiography were used not only to obtain the diagnosis but also to establish the size, density, contours, ulceration, regional lymphadenopathy, mesenteric infiltration and the presence of metastases. The aim of this study was to evaluate the roles of endoscopy and radiology in this pathology and the advantages and limitations of each individual technique.

Single or multiple HPV types in cervical cancer and associated metastases.

Almost all cervical cancers are human papillomavirus (HPV)-positive. Some aspects of HPV carcinogenesis, such as factors involved in the transformation process and the mono- or polyclonal origin of the carcinogenic process, need to be defined. The latter aspect is addressed in our study. Cervical samples were collected from 102 patients with squamous cell carcinoma. The HPV positivity was established by PCR analysis performed using consensus and specific primers for the L1 and E6/E7 regions, respectively. Eighty-seven samples were positive for the L1 gene and 5 for the E6/E7 genes. Overall, 92 samples contained segments of HPV-DNA (90.2%). HPV-16 was most frequently found either alone or associated with other genotypes (63%). All genotypes identified as a single infection, except HPV-73, belonged to the high-risk HPV group. Among multiple infections, the HPV-31+54 couple was the most frequent. The presence of two genotypes in a primary tumor raises the question of their distribution in a single tumor cell. We attempted to answer this question by comparing the HPV patterns in primary tumors and metastases, considering that metastases derive from cell clones released from the primary tumor. The HPV patterns of primary tumors and metastases overlapped in most patients, even when primary tumors contained a double genotype, thus suggesting that single tumor cells may contain multiple HPV genotypes.

Preparação para a aposentadoria: relato de uma intervenção clínica na abordagem da psicologia positiva / Preparation for retirement: report of a clinical intervention in a positive psychology approach / Preparación para lajubilación: relato de una intervención clinica en el enfoque de la psicología positiva

O processo de aposentadoria representa um momento crítico dentro do processo de desenvolvimento. O objetivo deste estudo de caso foi o de descrever e analisar uma experiência de atenção psicológica desenvolvida em um Programa de Preparação de Aposentadoria (PPA) de uma universidade pública federal voltada especificamente para profissionais da educação básica, a partir da abordagem da Psicologia Positiva. Foram realizados 13 encontros individuais com uma professora de 45 anos de idade, nos quais foram trabalhadas as questões envolvendo o reconhecimento de limites, a necessidade de organização e planejamento, bem como a reflexão sobre atividades laborais gratificantes. Concluiu-se que o acompanhamento psicológico na preparação para a aposentadoria não pode se dar de modo dissociado da compreensão crítica acerca das atuais condições de trabalho, motivo pelo qual o adoecimento pelo trabalho pode e deve ser um disparador para que se pense em estratégias de ampliação dos conceitos de saúde e bem-estar.

The retirement process represents a turning-point of development procedure. The main goals of this report were to analyze and describe a psychology attention experience. Developed by a public university, the Retirement Preparation Program uses positive psychology throughout the retirement period of basic education employees. A 45 years old teacherprovided basics information for this report by participating in 13 individual meetings. During those sessions, topics such as, limits recognition, planning and organization necessities, and the reflection of rewarding work activities were discussed. The psychology attention on a preparation of retirement has been concluded as an activity directly related to the work conditions. Often, those work conditions are reasons for illness so, that fact should be a step for a change in concepts of health and wellness.

El proceso de jubilación representa un momento crítico en el proceso de desarrollo. El objetivo de este estudio fue describir y analizar una experiencia de atención psicológica desarrollado en un Programa de Preparación la Jubilación de una universidad pública federal dedicada específicamente para profesionales de lo enseñanza primaria, desde el enfoque de la Psicología Positiva. Fue realizado 13 encuentros individuales con una profesora de 45 años, con la que trabajaron temas relacionados con el reconocimiento de los límites, la necesidad de organización y planificación, así como la reflexión sobre las actividades de trabajo gratificantes. Se concluyó que el acompañamiento psicológico en la preparación para la jubilación no puede ocurrir disoció del comprensión crítica de las condiciones de trabajo actuales, razón por lo que la enfermedad en el trabajo puede y debe ser un disparador para hacer pensar en estrategias de expansión de los conceptos de salud y bienestar.

Mulheres profissionais do sexo e o consumo excessivo de álcool / Female sex workers and the excessive consumption of alcohol

A prostituição é considerada uma das profissões mais antigas existentes, porém ainda é muito discriminada (por motivos como promiscuidade, pecado e ameaça à saúde) e apresenta fatores de risco, dentre eles, o consumo excessivo de bebidas alcoólicas. O objetivo desta pesquisa foi investigar o consumo de álcool por profissionais do sexo feminino, indagando sobre os principais fatores ambientais envolvidos, a trajetória de vida e relações sociais das profissionais. Foram realizadas entrevistas com seis participantes, todas profissionais do sexo numa cidade do Triângulo Mineiro/MG. Os principais resultados apontam que o ambiente de trabalho e o elevado consumo de bebidas alcoólicas pelas profissionais do sexo estão relacionados à comissão que elas recebem por este consumo, porém com consequências para a própria saúde que nem sempre são reconhecidos. Além disso, as participantes dissociam suas identidades entre a do mundo do trabalho e das demais relações sociais como estratégia de enfrentamento das dificuldades no mundo do trabalho

Prostitution is one of the oldest professions and is highly discriminated (promiscuity, sin and health threat), presenting risk factors like excessive consumption of alcoholic beverages. The objective of this research was to investigate the consumption of alcohol by females sexual workers at Triângulo Mineiro (Brazil). Six brazilians females sexual workers were interviewed. The main results indicate that the work environment and high alcoholic beverages consumption were correlated ­ because of the commission they receive for this consumption; and they know that alcohol causes several health consequences. In addition, the participants dissociate their identities from work and other social relations as a strategy for coping with difficulties in the world of work

Identification of the novel KI and WU polyomaviruses in human tonsils.

BACKGROUND: Three novel polyomaviruses have been recently discovered: KI, WU and MC polyomaviruses. Their role in human pathology is debated while tissue tropism and site of latency remain unknown. OBJECTIVE: To test the hypothesis that KI, WU and MC polyomaviruses can infect human tonsils. STUDY DESIGN: Archival paraffin-embedded tonsils from 91 patients affected by different tonsil diseases were screened by polymerase chain reaction to detect viral DNA of KIV, WUV, MCV, BKV and JCV. Phylogenetic and evolutionary analysis of the identified polyomaviruses was carried out. RESULTS: Of the 91 tested specimens, 11 contained KIV DNA (12%), 4 WUV DNA (4.4%), 5 BKV DNA (5.5%). MCV and JCV were not detected. Phylogenetic analysis showed that KIVs identified in tonsils fall into a clade distinct from that containing KIVs isolated from respiratory secretions, respiratory tissue and feces. Moreover, four positively selected sites (4.5% of t-Ag sites) were found under strong positive selection (omega=11.4), with posterior probabilities above 0.99. All the sites were located in the N-terminal region of the small t antigen. CONCLUSIONS: The results suggest that the novel KI and WU polyomaviruses can infect human tonsils. Future studies are needed to define their role in tonsil diseases.

Over-expression of topoisomerase IIalpha is related to the grade of cervical intraepithelial neoplasia (CIN) and high-risk human papillomavirus (HPV), but does not predict prognosis in cervical cancer or HPV clearance after cone treatment.

OBJECTIVE: One of the pathways leading to cervical cancer is a loss of normal cell cycle control. Topoisomerase IIalpha and IIbeta are important nuclear proteins controlling the G2/M checkpoint, and shown to be over-expressed in many human cancers. Their links to oncogenic human papillomavirus (HPV) types and their prognostic value in cervical cancer are practically unexplored. MATERIAL AND METHODS: As part of our HPV-PathogenISS study, a series of 150 squamous cell carcinomas (SCC) and 152 CIN lesions were examined using immunohistochemical (IHC) staining for topoisomerase IIalpha (topo IIalpha), and tested for HPV using PCR with three primer sets (MY09/11, GP5/GP6, SPF). Follow-up data were available from all SCC patients, and 67 CIN lesions had been monitored with serial PCR for HPV clearance/persistence after cone treatment. RESULTS: Topo IIalpha expression increased with increasing grade of CIN (p = 0.0001), with the most dramatic up-regulation upon progression from CIN2 to CIN3 and peaking in SCC (OR 16.23; 95%CI 7.89-33.38). Topo IIalpha up-regulation was also significantly associated with HR-HPV detection in univariate analysis (OR = 3.07; 95%CI 1.70-5.52), but was confounded by the histological grade (Mantel-Haenszel common OR = 1.622; 95%CI 0.782-3.365), and by entering both p16(INK4a) (9) and Survivin (33) in the multivariate regression model. Topo IIalpha did not predict clearance/persistence of HR-HPV after treatment of CIN, and it was not a prognostic factor in cervical cancer in either univariate or multivariate analysis. CONCLUSIONS: Over-expression of topo IIalpha is significantly associated with progression from CIN2 to CIN3, being a late marker of cell proliferation. Its close association with HR-HPV is plausibly explained by the fact that E7 oncoproteins of these HR-HPV (but not LR-HPV) block the normal pRb-mediated inhibition of topo IIalpha by degrading the wild-type Rb.