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Noy S.,Technion - Israel Institute of Technology | Noy S.,University of Manitoba | Vlodavsky E.,Surgical Pathology Unit | Klorin G.,Rambam Health Care Campus | And 5 more authors.
Analytical and Quantitative Cytology and Histology | Year: 2011

OBJECTIVE: To use novel digital and morphometric methods to identify variables able to better predict the recurrence of intracranial meningiomas. STUDY DESIGN: Histologic images from 30 previously diagnosed meningioma tumors that recurred over 10 years of follow-up were consecutively selected from the Rambam Pathology Archives. Images were captured and morphometrically analyzed. Novel algorithms of digital pattern recognition using Fourier transformation and fractal and nuclear texture analyses were applied to evaluate the overall growth pattern complexity of the tumors, as well as the chromatin texture of individual tumor nuclei. The extracted parameters were then correlated with patient prognosis. RESULTS: Kaplan-Meier analyses revealed statistically significant associations between tumor morphometric parameters and recurrence times. Tumors with less nuclear orientation, more nuclear density, higher fractal dimension, and less regular chromatin textures tended to recur faster than those with a higher degree of nuclear order, less pattern complexity, lower density, and more homogeneous chromatin nuclear textures (p < 0.01). CONCLUSION: To our knowledge, these digital morphometric methods were used for the first time to accurately predict tumor recurrence in patients with intracranial meningiomas. The use of these methods may bring additional valuable information to the clinician regarding the optimal management of these patients. © Science Printers and Publishers, Inc. Source


Guetta J.,Legacy Heritage Clinical Research Institute | Klorin G.,Legacy Heritage Clinical Research Institute | Tal R.,Legacy Heritage Clinical Research Institute | Berger G.,Legacy Heritage Clinical Research Institute | And 10 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2012

In the last two decades, the role of the alveolar active sodium transport was extensively studied and was found to play a crucial role in regulating alveolar fluid clearance (AFC), and thus in keeping the airspaces free of edema. The recent development of highly selective nonpeptide vasopressin-receptor antagonists gives us a rare chance to explore the role of vasopressin in the pathogenesis of lung edema. Therefore, the present study examined the involvement of vasopressin in modulating the ability of the lung to clear edema. Vasopressin enhanced the rate of lung edema clearance by 30% as compared with untreated control rats (from 0.49 ± 0.02 to 0.64 ± 0.02 ml/h), whereas V2 receptor antagonists significantly decreased the ability of the lung to clear water (from 0.64 ± 0.02 to 0.31 ± 0.06 ml/h; P < 0.0001). In contrast, V1 receptor antagonist did not change the rate of AFC. The administration of ouabain (a Na,K-ATPase inhibitor) and amiloride (a Na+ channel blocker) inhibited the stimulatory effects of vasopressin (from 0.64 6 0.02 to 0.22 ± 0.02 ml/h [P < 0.0001] and from 0.64 ± 0.017 to 0.23 ± 0.02 ml/h [P < 0.0001], respectively). Vasopressin significantly increased Na,K-ATPase protein abundance in the basolateral membranes of the alveolar epithelial cells via V2 receptor activation. We report a novel role of the vasopressin pathway in AFC. This observation indicates a beneficial role of vasopressin in AFC by up-regulating active sodium transport. Copyright © 2012 by the American Thoracic Society. Source


Farber L.,Institute of Pathology | Farber L.,Technion - Israel Institute of Technology | Efrati E.,B Rappaport Institute For Research In The Medical Science | Elkin H.,B Rappaport Institute For Research In The Medical Science | And 8 more authors.
Virchows Archiv | Year: 2011

KRAS mutation status has a significant role determining anti-epidermal growth factor receptor (anti-EGFR) treatment response in colon carcinoma patients. Malignant transformation is a dynamic process and therefore, it is conceivable that, at a certain point, the tumor cells' mass might be heterogeneous for particular mutations. Therefore, the fraction of tumor cells carrying a particular mutation may be more relevant for treatment than the simple determination of presence or absence of mutation. The purpose of this study is to assess whether or not KRAS mutation status is heterogeneous and, if so, to what extent in colon carcinoma samples. Deoxyribonucleic acid was extracted from formalin-fixed paraffin-embedded samples of colon carcinoma and analyzed for the presence of KRAS mutation. The relative fraction of mutated versus wild-type KRAS alleles was evaluated by real-time polymerase chain reaction. Additionally, the relative fraction of cancer cells in the tissue sample was evaluated using computer assisted morphometric analysis. Using this data, we calculated the fraction of mutation containing cells in the samples. Colon carcinoma (169 cases) were analyzed, and a KRAS mutation was found in 75 cases (44%), of which 42 were available for morphometric analysis. In 41 (97.6%) of these cases, the fraction of mutation containing tumor cells was 50% or higher, indicating the absence of significant KRAS mutation status heterogeneity. There was a strong positive correlation (R = 0.66, P < 0.0001) between the fraction of mutated KRAS alleles and the fraction of cancer cells in the samples. The strong positive correlation between the fraction of mutated KRAS alleles and the fraction of cancer cells in the samples indicate homogeneity of KRAS mutation status in colorectal carcinoma. © 2011 Springer-Verlag. Source


Efrati E.,Technion - Israel Institute of Technology | Elkin H.,Technion - Israel Institute of Technology | Elkin H.,Institute of Pathology | Peerless Y.,Institute of Pathology | And 8 more authors.
Cancer Biomarkers | Year: 2010

Introduction: KRAS mutations in colon carcinomas are associated with lack of response to anti-EGFR monoclonal antibody treatment. Therefore, patients must undergo genetic testing to be eligible for treatment. Several methods for KRAS mutation analysis exist, but many are not sensitive enough to detect a mutation in samples with low fraction of malignant cells. In the present study, we developed a KRAS mutations detection method that is both simple and sensitive. Methods: Using a locked nucleic acid (LNA) containing oligonucleotide, we developed a PCR clamping method that preferentially amplifies the mutated over wild type KRAS. We evaluated the sensitivity of this method using serial dilutions of plasmids containing wild-type and mutated KRAS fragments. Additionally, KRAS mutation status was evaluated on 60 archived tissue samples of colon carcinoma, and compared to direct sequencing and high resolution melting (HRM) methods. Results: The PCR clamping method could detect as little as 1% mutated DNA in the sample analyzed. Of the 29 KRAS mutations identified by the PCR clamping method, only 23 (79%) were identified by standard direct sequencing. The results of PCR clamping correlated with HRM results. Conclusions: LNA based PCR clamping method is a simple and highly sensitive method for the detection of KRAS mutations. © 2010/2011 - IOS Press and the authors. All rights reserved. Source

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