A new CYP21A1P/CYP21A2 chimeric gene identified in an Italian woman suffering from classical congenital adrenal hyperplasia form

Background  

More than 90% of Congenital Adrenal Hyperplasia (CAH) cases are associated with mutations in the 21-hydroxylase gene (CYP21A2) in the HLA class III area on the short arm of chromosome 6p21.3. In this region, a 30 kb deletion produces a non functional chimeric gene with its 5' and 3' ends corresponding to CYP21A1P pseudogene and CYP21A2, respectively. To date, five different CYP21A1P/CYP21A2 chimeric genes have been found and characterized in recent studies. In this paper, we describe a new CYP21A1P/CYP21A2 chimera (CH-6) found in an Italian CAH patient.     

Uterine and ovarian carcinosarcomas overexpressing Trop-2 are sensitive to hRS7, a humanized anti-Trop-2 antibody

Background

We evaluated the expression of human trophoblastic cell-surface marker (Trop-2) and the potential of hRS7 - a humanized monoclonal anti-Trop-2 antibody - as a therapeutic strategy against treatment-refractory human uterine (UMMT) and ovarian (OMMT) carcinosarcoma cell lines.

Materials and methods

Trop-2 expression was evaluated by immunohistochemistry (IHC) in paraffin-embedded tumor tissues, by real-time polymerase-chain-reaction (RT-PCR) and flow-cytometry in cell lines. Sensitivity to hRS7 antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity was tested using 5-hour chromium-release assays against UMMT and OMMT cells.

Results

Trop-2 expression was elevated in 9 of 26 (35%) UMMT and 8 of 14 (57%) OMMT tissues tested by IHC. Positivity for Trop-2 mRNA by RT-PCR and surface expression by flow cytometry were detected in 2 of 4 cell lines, with high positivity noted in OMMT-ARK-2. OMMT-ARK-2 was highly sensitive to hRS7 ADCC (range: 34.7-41.0%; P < 0.001) with negligible cytotoxicity seen in the absence of hRS7 or in the presence of control antibody (range: 1.1-2.5%). Human IgG did not significantly inhibit ADCC while human complement increased, hRS7-mediated-cytotoxicity against OMMT-ARK-2.

Conclusion

Trop-2 is overexpressed in a proportion of UMMT and OMMT, and hRS7 may represent a novel, potentially highly effective treatment option for patients with treatment-refractory carcinosarcomas overexpressing Trop-2.     

Función familiar y salud mental del cuidador de familiares con dependencia

ObjectiveTo analyse the influence of family function on the caregiver's perceived mental health.DesignCross-sectional study.SettingTwo primary care urban health centres.Participants153 caregivers of dependent people.MeasurementSociodemographic variables of caregiver and dependent relative and psychoactive drugs prescribed to caregiver. Caregiver questionnaires: mental health evaluated with General Health Questionnaire (GHQ-12), family function with adaptation, partnership, growth, affection and resolve (APGAR), and Duke University-University of North Carolina functional social support questionnaire. Care-recipient questionnaires: cognitive disorders with Pfeiffer and functional dependence level with Barthel.ResultsCaregiver's mean age was 63.8 years; 72.5% (n=111) were female; 57.5% have only primary school studies; and 37.1% take psychoactive drugs. More than 40% of the care-receivers have cognitive disorders and 49.7% have total functional impairment. According to the GHQ-12, 27% of the caregivers had mental health disorders; 31.3% of the families were dysfunctional and 32.7% had poor social support. The variables that significantly contributed to the explanation of caregiver's mental health have been: psychoactive drug intake, family function, social support and educational level.ConclusionFamily function is an important predictor of caregiver's mental health.     

On the construction of an inter-subject diffusion tensor magnetic resonance atlas of the healthy human brain

Voxel based morphometry (VBM) has been increasingly applied to detect diffusion tensor (DT) image abnormalities in patients for different pathologies. An important requisite for a robust VBM analysis is the availability of a high-dimensional non-rigid coregistration technique that is able to align both the spatial and the orientational DT information. Consequently, there is a need for an inter-subject DTI atlas as a group specific reference frame that also contains this orientational DT information. In this work, a population based DTI atlas has been developed that incorporates such orientational DT information with high accuracy and precision. The proposed methodology for constructing such an atlas is compared with a subject based DTI atlas, in which a single subject is selected as the reference image. Our results demonstrate that the population based atlas framework is more accurate with respect to the underlying diffusion information.     

Proposal for reclassification of the TNM staging system in patients with locally advanced (pT3-4) renal cell carcinoma according to the cancer-related outcome

OBJECTIVES: The optimal stratification of locally advanced renal cell carcinoma (RCC) is controversial, with the prognostic relevance of ipsilateral adrenal gland invasion and cranial extension of vena cava thrombosis being the most debatable issues. We evaluated the prognosis of patients with locally advanced RCC and identified a new model to stratify their outcome. MATERIALS AND METHODS: We analyzed the data of 227 patients who had undergone partial or radical nephrectomy for pT3-4 RCC at two academic centers between 1986 and 2002. The log-rank test and Cox proportional hazards model were used for univariate and multivariate analysis, respectively. RESULTS: At a median follow-up of 29 mo, we censored 108 (47.6%) cancer-related deaths. On univariate analysis, the 2002 T stage was not statistically significant. According to cancer-related outcome, we identified three subgroups of patients with different prognoses: pT3a(n): tumors with perirenal fat invasion or renal vein thrombosis or thrombosis within the vena cava below the diaphragm; pT3b(n): tumors with renal vein thrombosis or thrombosis within the vena cava below the diaphragm and concomitant perirenal fat invasion; pT4(n): adrenal gland or Gerota fascia invasion or thrombosis within the vena cava above the diaphragm. The three subgroups had significantly different prognoses. The new reclassification was an independent predictive variable on multivariate analysis, as well as the pathologic lymph node stage. CONCLUSIONS: The 2002 version of TNM of locally advanced RCC did not stratify patient outcome. The present study suggests the possibility of reclassifying pT3-4 RCC into three categories capable of predicting cancer-specific survival, regardless of all other prognostic factors.     

Genomic analysis of the 8p11-12 amplicon in familial breast cancer

Amplification of 8p11-12 has been recurrently reported in sporadic breast cancer. These studies define a complex molecular structure with a set of minimal amplified regions, and different putative oncogenes that show a strong correlation between amplification and over-expression such as ZNF703/FLJ14299, SPFH2/C8orf2, BRF2 and RAB11FIP. However, none of these studies were carried out on familial breast malignancies. We have studied the incidence, molecular features and clinical value of this amplification in familial breast tumors associated with BRCA1, BRCA2 and non-BRCA1/2 gene mutations. We detected 9 out of 80 familial tumors with this amplicon by chromosomal comparative genomic hybridization. Next, we used a high-resolution comparative genomic hybridization array covering the 8p11-12 region to characterize this chromosomal region. This approach allowed us to define 2 cores of common amplification that largely overlap with those reported in sporadic tumors. Our findings confirm the molecular complexity of this chromosomal region and indicate that this genomic event is a common alteration in breast cancer, present not only in sporadic but also in familial tumors. Finally, we found correlation between the 8p11-12 amplification and proliferation (Ki-67) and cyclin E expression, which further proves in familial tumors the poor prognosis association previously reported in sporadic breast cancer.     

CD105 is a marker of tumour vasculature and a potential target for the treatment of head and neck squamous cell carcinoma

J Oral Pathol Med (2010) 39 : 361–367 Background: The importance of angiogenesis in solid tumour growth is well recognised. Tumour angiogenesis is considered the result of an imbalance between pro‐ and anti‐angiogenic factors produced by both the malignancy and normal cells. Endoglin (CD105) is a proliferation‐associated, hypoxia‐inducible glycoprotein that seems to be clinically superior to other pan‐endothelial markers in the selective evaluation of tumour angiogenesis. Several studies have revealed CD105 up‐regulation in a wide range of tumour endothelia. Since 2002, endothelial CD105 expression has also been retrospectively investigated in patients with head and neck squamous cell carcinoma (HNSCC). Methods: An exhaustive literature review was performed to investigate available evidence on CD105 expression and its biological role and therapeutic potential in HNSCC. Results: The available evidence supports the hypothesis that CD105 expression in HNSCC may be a valuable parameter for pinpointing patients at greater risk of recurrent malignancy and with a worse prognosis. A high CD105 expression in HNSCC was associated with metastatic lymph nodes in most of the studies. Conclusions: Prospective studies are mandatory to confirm that CD105 expression is a significant prognostic hallmark in HNSCC. The results of prospective studies could be relevant for the adoption of stricter follow‐up protocols and/or alternative therapeutic regimens for patients with a high CD105 expression in HNSCC. Great interest is currently being focused on vascular targeting for therapeutic purposes. Preclinical studies on appropriate animal models resembling HNSCC to investigate the effects of inhibiting CD105 may show the efficacy of combined treatment strategies associating angiogenic‐targeted with conventional therapies for HNSCC.