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Maurizio Chiriva-Internati,
Nicoletta Gagliano,
Elena Donetti,
Francesco Costa,
Fabio Grizzi, Barbara Franceschini,
Elena Albani,
Paolo E Levi-Setti,
Magda Gioia,
Marjorie Jenkins,
Everardo Cobos,
W Martin Kast
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ABSTRACT: Sperm protein 17 (Sp17) is a highly conserved mammalian protein characterized in rabbit, mouse, monkey, baboon, macaque, human testis and spermatozoa. mRNA encoding Sp17 has been detected in a range of murine and human somatic tissues. It was also recognized in two myeloma cell lines and in neoplastic cells from patients with multiple myeloma and ovarian carcinoma. These data all indicate that Sp17 is widely distributed in humans, expressed not only in germinal cells and in a variety of somatic tissues, but also in neoplastic cells of unrelated origin.
Sp17 expression was analyzed by immunocytochemistry and transmission electron microscopy on spermatozoa.
Here, we demonstrate the ultrastructural localization of human Sp17 throughout the spermatozoa flagellar fibrous sheath, and its presence in spermatozoa during in vitro states from their ejaculation to the oocyte fertilization.
These findings suggest a possible role of Sp17 in regulating sperm maturation, capacitation, acrosomal reaction and interactions with the oocyte zona pellucida during the fertilization process. Further, the high degree of sequence conservation throughout its N-terminal half, and the presence of an A-kinase anchoring protein (AKAP)-binding motif within this region, suggest that Sp17 might play a regulatory role in a protein kinase A-independent AKAP complex in both germinal and somatic cells.
Journal of Translational Medicine 08/2009; 7:61. · 3.41 Impact Factor
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ABSTRACT: Prostate cancer is the fifth most frequent cancer in the world. However, none of the actual prognostic factors provide a valid index for predicting patient outcome. Here, we evaluate the two-dimensional vascularity in primary prostate tumors and surrounding non-tumoral parenchyma by means of fractal geometry, and assess any correlations between the results and some clinical and pathological parameters of prostate carcinoma. Prostate sections from 27 carcinoma patients were treated with CD34 antibodies. Two >10mm(2) areas of tumoral and surrounding non-tumoral parenchyma were digitized using an image analysis system that automatically quantified the fractal dimension of the vascular surface. Data were correlated with patient's age, PSA level, clinical and pathological stage, Gleason score, tumor volume, vascular invasion, surgical margins, and biochemical relapse. Two groups of patients were distinguished on the basis of whether the fractal dimension of their tumoral vascular surface was higher (group 1) or lower (group 2) than that of the surrounding non-tumoral parenchyma. Statistically significant between-group differences were found in terms of serum PSA levels (p=0.0061), tumor volume (p=0.0017), and biochemical relapse (p=0.031). The patients in group 2 had a poorer outcome. Our findings suggest a group of prostate cancer patients with a poor outcome, and the vascular surface fractal dimension as a helpful geometrical index in clinical practice.
Pathology - Research and Practice 03/2009; 205(7):438-44. · 1.21 Impact Factor
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ABSTRACT: Hepatocellular carcinoma (HCC) remains one of the major public health problems throughout the world. Although originally associated with tumorigenic processes, liver angiogenesis has also been observed in the context of different liver inflammatory, fibrotic, and ischemic conditions. Here we investigate the fractal dimension as a quantitator of non-Euclidean two-dimensional vascular geometry in a series of paired specimens of primary HCC and surrounding non-tumoral tissue, and discuss why this parameter might provide additional information regarding cancer behavior. The application of fractal geometry to the measurement of liver vascularity and the availability of a computer-aided quantitative method can eliminate errors in visual interpretation, and make it possible to obtain closer-to-reality numerals that are compulsory for any measurement process.
Journal of Zhejiang University SCIENCE B 05/2007; 8(4):217-20. · 1.10 Impact Factor
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ABSTRACT: Despite advances in our cellular and molecular knowledge, hepatocellular carcinoma (HCC) remains one of the major public health problems throughout the world. It is now known to be highly heterogeneous: it encompasses various pathological entities and a wide range of clinical behaviors, and is underpinned by a complex array of gene alterations that affect supra-molecular processes.Four families of HCC tumour markers have been recently proposed: a) onco-fetal and glycoprotein antigens; b) enzymes and iso-enzymes; c) cytokines and d) genes. A category of tumour-associated antigens called cancer-testis (CT) antigens has been identified and their encoding genes have been extensively investigated. CT antigens are expressed in a limited number of normal tissues as well as in malignant tumors of unrelated histological origin, including the liver. Given that cancers are being recognized as increasingly complex, we here review the role of CT antigens as liver tumour biomarkers and their validation process, and discuss why they may improve the effectiveness of screening HCC patients and help in determining the risk of developing HCC.
Journal of Translational Medicine 02/2007; 5:3. · 3.41 Impact Factor
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Hepatology 01/2007; 44(6):1701-2. · 11.66 Impact Factor
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ABSTRACT: Mast cells (MCs) are multifunctional effector cells of the immune system. MCs were originally thought to be involved in IgE-associated immediate hypersensitivity and allergic disorders, but it is now known that they contain or elaborate an array of mediators with a multitude of effects on many other cells. A number of studies have found that MCs are involved in various liver diseases. Although still controversial, they seem to be involved in the liver's fibrotic response to chronic inflammation and parasitic infection. Hepatic fibrosis is the most frequent liver response to toxic, infectious, or metabolic agents. During the establishment of this pathological condition, there is an increase in the components of the basement membrane that leads to continuous basement membrane-like structures being raised within Disse's space and a decrease in the number of sinusoid endothelial fenestrae. This leads to a complex process called "sinusoidal capillarization." At the cellular level, liver fibrogenesis is initiated by hepatocyte necrosis, which induces the recruitment of a large number of inflammatory cells, including MCs, which can be considered the primary effectors of the process changing sinusoidal endothelial cells into capillary-type endothelial cells. We review the roles played by MCs in hepatic chronic diseases and describe a biopsy section of hepatic tissue taken from a patient with chronic C virus-related hepatitis showing diffuse sinusoidal capillarization and a high density of MCs. This observation has led us to hypothesize a relationship between these highly specialized cells and sinusoidal capillarization.
Digestive Diseases and Sciences 01/2007; 51(12):2248-56. · 2.12 Impact Factor
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ABSTRACT: To assess the sampling variability of computer-aided, fractal-corrected measures of fibrosis in liver biopsies.
Samples were derived from six to eight different parts of livers removed from 12 patients with clinically and histologically proven cirrhosis undergoing orthotopic liver transplantation. Sirius red-stained sections with a thickness of 2 mum were digitized using a computer-aided image analysis system that automatically measures the surface of fibrosis, as well as its outline perimeter, fractal surface and outline dimensions, wrinkledness, and Hurst coefficient.
We found a high degree of inter-sample variability in the measurements of the surface [coefficient of variation (CV) = 43% +/- 13%] and wrinkledness (CV = 28% +/- 9%) of fibrosis, but the inter-sample variability of Hurst's exponent was low (CV = 14% +/- 2%).
This study suggests that Hurst's exponent might be used in clinical practice as the best histological estimate of fibrosis in the whole organ, and evidences the fact that biopsy sections, which are fundamental for the qualitative diagnosis of chronic hepatitis, play a key role in the quantitative estimate of architectural changes in liver tissue.
World Journal of Gastroenterology 01/2007; 12(47):7660-5. · 2.47 Impact Factor
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Journla of Immunotherapy 10/2006; 29(6):680-681. · 3.27 Impact Factor
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ABSTRACT: To provide the accurate alternative metrical means of monitoring the effects of new antiviral drugs on the reversal of newly formed collagen.
Digitized histological biopsy sections taken from 209 patients with chronic C virus hepatitis with different grade of fibrosis or cirrhosis, were measured by means of a new, rapid, user-friendly, fully computer-aided method based on the international system meter rectified using fractal principles.
The following were described: geometric perimeter, area and wrinkledness of fibrosis; the collation of the Knodell, Sheuer, Ishak and METAVIR scores with fractal-rectified metric measurements; the meaning of the physical composition of fibrosis in relation to the magnitude of collagen islets; the intra- and inter-biopsy sample variability of these parameters; the"staging" of biopsy sections indicating the pathway covered by fibrosis formation towards its maximum known value; the quantitative liver tissue architectural changes with the Hurst exponent.
Our model provides the first metrical evaluations of the geometric properties of fibrosis and the quantitative architectural changes of the liver tissue. The representativeness of histological sections of the whole liver is also discussed in the light of the results obtained with the Hurst coefficient.
World Journal of Gastroenterology 05/2006; 12(14):2187-94. · 2.47 Impact Factor
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Fabio Grizzi,
Paolo Gaetani, Barbara Franceschini,
Antonio Di Ieva,
Piergiuseppe Colombo,
Giorgia Ceva-Grimaldi,
Angelo Bollati,
Eldo E Frezza,
E Cobos,
Riccardo Rodriguez y Baena,
Nicola Dioguardi,
Maurizio Chiriva-Internati
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ABSTRACT: Human sperm protein 17 (Sp17) is a highly conserved protein that was originally isolated from a rabbit epididymal sperm membrane and testis membrane pellet. It has recently been included in the cancer/testis (CT) antigen family, and shown to be expressed in multiple myeloma and ovarian cancer. We investigated its immunolocalisation in specimens of nervous system (NS) malignancies, in order to establish its usefulness as a target for tumour-vaccine strategies.
The expression of Sp17 was assessed by means of a standardised immunohistochemical procedure [(mAb/antigen) MF1/Sp17] in formalin-fixed and paraffin embedded surgical specimens of NS malignancies, including 28 neuroectodermal primary tumours (6 astrocytomas, 16 glioblastoma multiforme, 5 oligodendrogliomas, and 1 ependymoma), 25 meningeal tumours, and five peripheral nerve sheath tumours (4 schwannomas, and 1 neurofibroma).
A number of neuroectodermal (21%) and meningeal tumours (4%) were found heterogeneously immunopositive for Sp17. None of the peripheral nerve sheath tumours was immunopositive for Sp17. The expression pattern was heterogeneous in all of the positive samples, and did not correlate with the degree of malignancy.
The frequency of expression and non-uniform cell distribution of Sp17 suggest that it cannot be used as a unique immunotherapeutic target in NS cancer. However, our results do show the immunolocalisation of Sp17 in a proportion of NS tumour cells, but not in their non-pathological counterparts. The emerging complex function of Sp17 makes further studies necessary to clarify the link between it and immunopositive cells.
BMC Cancer 02/2006; 6:23. · 3.01 Impact Factor
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Klaus Bumm,
Fabio Grizzi, Barbara Franceschini,
Michael Koch,
Heinrich Iro,
Jochen Wurm,
Giorgia Ceva-Grimaldi,
Arno Dimmler,
Everado Cobos,
Nicola Dioguardi,
Uttam K Sinha,
W Martin Kast,
Maurizio Chiriva-Internati
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ABSTRACT: Esthesioneuroblastomas (ENBs) are rare malignant tumors of the nasal vault, the origin, diagnosis, and management of which are still subjects of discussion. That there is no related prognostic factor or generally recognized therapeutic regimen highlights the need for further analyses of its underlying biologic features and investigations of new marker proteins that allow more reliable clinical testing. We here show that sperm protein 17 (Sp17) is expressed in the ciliated cells of the normal olfactory epithelium and in a proportion of primary ENB lesions. We found an association between Sp17 expression and metastases at relapse (P = .035), chromogranin expression (P = .014), and a female sex prevalence. A statistically nonsignificant relation was found between Sp17 and S-100, synaptophysin, and neurofilament expression. No correlation was also found between Sp17 expression and the proliferative capacity of the lesion that was evaluated by Ki-67 immunohistochemistry. The results of this study show the usefulness of Sp17 as a means of discriminating 2 subsets of primary ENB lesions and seem to suggest the existence of 2 distinct cell pathways in their origin and development.
Human Pathlogy 01/2006; 36(12):1289-93. · 2.88 Impact Factor
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Fabio Grizzi,
Paolo Gaetani, Barbara Franceschini,
Di Ieva Antonio,
Piergiuseppe Colombo,
Giorgia Ceva-Grimaldi,
Angelo Bollati,
Eldo Frezza,
E Cobos,
Riccardo Baena,
Nicola Dioguardi,
Maurizio Chiriva-Internati
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ABSTRACT: Abstract
Background
Human sperm protein 17 (Sp17) is a highly conserved protein that was originally isolated from a rabbit epididymal sperm membrane and testis membrane pellet. It has recently been included in the cancer/testis (CT) antigen family, and shown to be expressed in multiple myeloma and ovarian cancer. We investigated its immunolocalisation in specimens of nervous system (NS) malignancies, in order to establish its usefulness as a target for tumour-vaccine strategies.
Methods
The expression of Sp17 was assessed by means of a standardised immunohistochemical procedure [(mAb/antigen) MF1/Sp17] in formalin-fixed and paraffin embedded surgical specimens of NS malignancies, including 28 neuroectodermal primary tumours (6 astrocytomas, 16 glioblastoma multiforme, 5 oligodendrogliomas, and 1 ependymoma), 25 meningeal tumours, and five peripheral nerve sheath tumours (4 schwannomas, and 1 neurofibroma),.
Results
A number of neuroectodermal (21%) and meningeal tumours (4%) were found heterogeneously immunopositive for Sp17. None of the peripheral nerve sheath tumours was immunopositive for Sp17. The expression pattern was heterogeneous in all of the positive samples, and did not correlate with the degree of malignancy.
Conclusion
The frequency of expression and non-uniform cell distribution of Sp17 suggest that it cannot be used as a unique immunotherapeutic target in NS cancer. However, our results do show the immunolocalisation of Sp17 in a proportion of NS tumour cells, but not in their non-pathological counterparts. The emerging complex function of Sp17 makes further studies necessary to clarify the link between it and immunopositive cells.
BMC Cancer. 01/2006;
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ABSTRACT: Modeling the complex development and growth of tumor angiogenesis using mathematics and biological data is a burgeoning area of cancer research. Architectural complexity is the main feature of every anatomical system, including organs, tissues, cells and sub-cellular entities. The vascular system is a complex network whose geometrical characteristics cannot be properly defined using the principles of Euclidean geometry, which is only capable of interpreting regular and smooth objects that are almost impossible to find in Nature. However, fractal geometry is a more powerful means of quantifying the spatial complexity of real objects.
This paper introduces the surface fractal dimension (Ds) as a numerical index of the two-dimensional (2-D) geometrical complexity of tumor vascular networks, and their behavior during computer-simulated changes in vessel density and distribution.
We show that Ds significantly depends on the number of vessels and their pattern of distribution. This demonstrates that the quantitative evaluation of the 2-D geometrical complexity of tumor vascular systems can be useful not only to measure its complex architecture, but also to model its development and growth.
Studying the fractal properties of neovascularity induces reflections upon the real significance of the complex form of branched anatomical structures, in an attempt to define more appropriate methods of describing them quantitatively. This knowledge can be used to predict the aggressiveness of malignant tumors and design compounds that can halt the process of angiogenesis and influence tumor growth.
BMC Cancer 03/2005; 5:14. · 3.01 Impact Factor
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ABSTRACT: Despite the fact that all anatomical forms are characterised by non-polyhedral volumes, rough surfaces and irregular outlines,
it has been suggested that sophisticated computer-aided analytical systems based on the Euclidean principles of regularity,
smoothness and linearity can be used in human quantitative anatomy. However, the new fractal geometry is a more powerful means
of quantifying the spatial complexity of real objects. The present study introduces the surface fractal dimension as a numerical
index of the complex architecture of the corneal stroma, and investigates its behaviour during computer-simulated changes
in keratocyte density and distribution, and in the heterogeneous composition of the extracellular matrix. We found that the
surface fractal dimension depends on keratocyte density and distribution, as well as on the different concentrations of the
constituents making up the extracellular matrix. Our results show that the surface fractal dimension could be widely used
in ophthalmology not only because of its ability to quantify drug-correlated architectural changes, but also because it can
stage corneal stroma alterations and predict disease evolution.
12/2004: pages 223-230;
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International Journal of Cancer 11/2004; 111(6):972-3; author reply 974. · 5.44 Impact Factor
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Fabio Grizzi,
Maurizio Chiriva-Internati, Barbara Franceschini,
Klaus Bumm,
Piergiuseppe Colombo,
Michele Ciccarelli,
Elena Donetti,
Nicoletta Gagliano,
Paul L Hermonat,
Robert K Bright,
Magda Gioia,
Nicola Dioguardi,
W Martin Kast
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ABSTRACT: It was once believed that sperm protein 17 (Sp17) was expressed exclusively in the testis and that its sole function was to bind to the oocyte during fertilization. However, immunohistochemistry of the human respiratory airways and reproductive systems show that it is abundant in ciliated cells but not in human cells with stereocilia and microvilli. The high degree of sequence conservation throughout its N-terminal half, and the presence of an A-kinase anchoring protein (AKAP)-binding motif within this region, suggest that Sp17 plays a regulatory role in a PKA-independent AKAP complex in both male germinal and ciliated somatic cells.
Journal of Histochemistry and Cytochemistry 05/2004; 52(4):549-54. · 2.72 Impact Factor
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ABSTRACT: To introduce a new mathematical method based on the principles of fractal geometry analysis that permits more realistic quantification of some of the physical (morphologic) aspects of irregular bodies appearing under microscopy.
The principles of the method were tested on microscopic images of irregular collagen deposition in liver tissue. The method uses an ad hoc rectified meter implemented in a computer-assisted planar image analysis system that has been adapted to give metric measures of irregular outlines and surfaces that can be used to produce an index capable of quantifying the typical wrinkledness of biologic objects. Prototypical example measures of liver fibrosis were made on biopsy specimens showing chronic hepatitis C virus-related disease. Measurements were also made of the microscopic images of the abnormal deposition of lipid droplets in hepatocytes, a case of amyloid deposition in an osteoarthromuscular structure and a cytologic specimen of human dendritic cells.
The proposed computer-aided method permits rapid measurements of the image of a whole biopsy section digitized at high magnification. The snapshot measurement of liver fibrosis deposition offered by a biopsy pattern is a valid means of more rigorously identifying the staging of the process.
This method can measure liver fibrosis during chronic liver disease as well as any other irregular biologic structure that cannot be correctly quantified using traditional Euclidean-based metric methodologies.
Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology 01/2004; 25(6):312-20. · 0.41 Impact Factor
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ABSTRACT: Sperm protein 17 (Sp17) is a highly conserved mammalian protein whose primary function is still poorly understood. Immunohistochemistry (IHC) in the human testis reveals the presence of Sp17 in some spermatocytes and abundantly in spermatids. All spermatogonia, Sertoli cells, and Leydig cells appear to be immunonegative for Sp17, whereas some interstitial cells are immunopositive. IHC recognized two distinct populations (immunopositive or not for Sp17) in the ejaculated spermatozoa. Although it will be necessary to clarify why some ejaculated spermatozoa do not contain Sp17, its distribution suggests that this protein may be associated with some phases of germinal cell differentiation.
Journal of Histochemistry and Cytochemistry 10/2003; 51(9):1245-8. · 2.72 Impact Factor
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Blood 10/2003; 102(6):2308-9. · 9.90 Impact Factor
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ABSTRACT: To investigate the density of mast cells (MCs) in human hepatocellular carcinoma (HCC), and to determine whether the MCs density has any correlations with histopathological grading, staging or some baseline patient characteristics.
Tissue sections of 22 primary HCCs were histochemically stained with toluidine blue, in order to be able to quantify the MCs in and around the neoplasm using a computer-assisted image analysis system. HCC was staged and graded by two independent pathologists. To identify the sinusoidal capillarisation of each specimen 3 ?m thick sections were histochemically stained with sirius red, and semi-quantitatively evaluated by two independent observers. The data were statistically analysed using Spearman's correlation and Student's t-test when appropriate.
MCs density did not correlate with the age or sex of the patients, the serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, or the stage or grade of the HCC. No significant differences were found between the MCs density of the patients with and without hepatitis C virus infection, but they were significantly higher in the specimens showing marked sinusoidal capillarisation.
The lack of any significant correlation between MCs density and the stage or grade of the neoplastic lesions suggests that there is no causal relationship between MCs recruitment and HCC. However, as capillarisation proceeds concurrently with arterial blood supply during hepatocarcinogenesis, MCs may be considered of primary importance in the transition from sinusoidal to capillary-type endothelial cells and the HCC growth.
World Journal of Gastroenterology 08/2003; 9(7):1469-73. · 2.47 Impact Factor
