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Levels of the enzyme autotaxin (ATX) are elevated in synovial fluid and plasma of osteoarthritic patients, correlating positively with radiographic and symptomatic severity of the disease. Therefore, ATX is studied as potential marker for the progression of osteoarthritis (OA), whereas the chondrocyte-secreted glycoprotein Lubricin has chondroprotective properties. The aim of this study was to evaluate the expression of ATX and Lubricin in healthy and mild OA rat articular cartilage of femur, tibia and patella, and to analyse the effect of a protocol of moderate physical activity on their expressions. Mild OA resulted from anterior cruciate ligament transection and rats exercised on a treadmill for 12 weeks. Computerized staining intensity of immunostaining was used to evaluate ATX and Lubricin expressions. Higher expressions of ATX were found in femur and tibia of OA rats, suggesting that this molecule could participate in the progression of the disease, although not involved in the patella. In the femur, physical activity performed by OA rats was able to lower ATX expression, encouraging the evidence that joint movement is beneficial for the cartilage, although no significant differences in Lubricin expression were detected in femur, tibia and patella. This evidence might shade some light about the role of ATX, Lubricin and physical exercise in OA progression., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Neuroblastoma is the most common extracranial solid childhood tumor, which is believed to originate from primitive neuroblasts giving rise to the sympathetic nervous system. It was previously shown that cyclin D1 (CCDN1) in pediatric neuroblastic tumors (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma) recapitulates its expression during the development of peripheral sympathetic nervous system (PSNS). In the present study, we performed a microarray analysis in order to evaluate the expression of cyclin D1 in neuroblastoma as compared to ganglioneuroma and ganglioneuroblastoma. We first confirmed that comparable levels of cyclin D1 are present in neuroblastoma and fetal neuroblasts. In addition, we observed that neuroblastoma is associated to significantly higher levels of cyclin D1 as compared to both ganglioneuroma and ganglioneuroblastoma. No differences are instead observable between ganglioneuroblastoma and ganglioneuroma. Finally, bioinformatic analysis of cyclin D1-functionally related genes, identified cyclin D2 as an additional marker/etiopathogenic factor in the development of neuroblastoma., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Recent immunohistochemical analyses have showed that cyclin D1 is expressed in soft tissue Ewing's sarcoma/peripheral neuroectodermal tumor (PNET) of childhood and adolescents, while it is undetectable in both embryonal and alveolar rhabdomyosarcoma. In the present paper, microarray analysis provided evidence of a significant upregulation of cyclin D1 in Ewing's sarcoma as compared to normal tissues. In addition, we confirmed our previous findings of a significant over-expression of cyclin D1 in Ewing sarcoma as compared to rhabdomyosarcoma. Bioinformatic analysis also allowed to identify some other genes, strongly correlated to cyclin D1, which, although not previously studied in pediatric tumors, could represent novel markers for the diagnosis and prognosis of Ewing's sarcoma/PNET. The data herein provided support not only the use of cyclin D1 as a diagnostic marker of Ewing sarcoma/PNET but also the possibility of using drugs targeting cyclin D1 as potential therapeutic strategies., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Despite Wilms tumor 1 (WT1) protein was originally considered as a specific immunomarker of Wilms tumor, with the increasing use of immunohistochemistry, there is evidence that other tumors may share WT1 protein expression. This review focuses on the immunohistochemical profile of WT1 protein in the most common malignant tumors of children and adolescents. The variable expression and distribution patterns (nuclear vs cytoplasmic) in the different tumors, dependent on the antibodies used (anti-C or N-terminus WT1 protein), will be emphasized by providing explicative illustrations. Potential diagnostic pitfalls from unexpected WT1 protein expression in some tumors will be discussed in order to avoid diagnostic errors, especially when dealing with small biopsies., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

There is increasing evidence that WT1 protein expression is found not only at nuclear, but also at cytoplasmic, level in several developing and neoplastic tissues. In order to better understand the possible role of WT1 protein in human skeletal myogenesis and oncogenesis of rhabdomyosarcoma, we assessed immunohistochemically its comparative expression in a large series of human developing, adult and neoplastic skeletal muscle tissues. The present study shows that WT1 protein is developmentally expressed in the cytoplasm of human myoblasts from the 6 weeks of gestational age. This expression was maintained in the myotubes of developing muscles of the trunk, head, neck, and extremities, while it was down-regulated in fetal skeletal fibers from 20 weeks of gestational age as well as in adult normal skeletal muscle. Notably, WT1 immunostaining disappeared from rhabdomyomas, whereas it was strongly and diffusely re-expressed in all cases (27/27) of embryonal and alveolar rhabdomyosarcoma. The comparative evaluation of the immunohistochemical findings revealed that WT1 cytoplasmic expression in rhabdomyosarcoma may represent an ontogenetic reversal, and this nuclear transcription factor can also be considered an oncofetal protein which can be exploitable as an additional, highly sensitive immunomarker, together with desmin, myogenin and MyoD1, of this tumor. Moreover, our observations support the rationale for the use of WT1 protein-based target therapy in high risk rhabdomyosarcomas in children and adolescents., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Myogenesis is controlled by an elaborate system of extrinsic and intrinsic regulatory mechanisms in all development stages. The aim of this review is to provide an overview of the different stages of myogenesis and muscle differentiation in mammals, starting from somitogenesis and analysis of the different portions that constitute the mature somite. Particular attention was paid to regulatory genes, in addition to mesodermal stem cells, which represent the earliest elements of myogenesis. Finally, the crucial role of growth factors, molecules of vital importance in contractile regulation, hormones and their function in skeletal muscle differentiation, growth and metabolism, and the role played by central nervous system, are discussed., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

The aim of this review is to focus on the molecular factors that ensure the optimal development and maintenance of the mammary gland thanks to their integration and coordination. The development of the mammary gland is supported, not only by endocrine signals, but also by regulatory molecules, which are able to integrate signals from the surrounding microenvironment. A major role is certainly played by homeotic genes, but their incorrect expression during the spatiotemporal regulation of proliferative, functional and differentiation cycles of the mammary gland, may result in the onset of neoplastic processes. Attention is directed also to the endocrine aspects and sexual dimorphism of mammary gland development, as well as the role played by ovarian steroids and their receptors in adult life., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Cyclin D1 amplification and/or overexpression contribute to the loss of the regulatory circuits that govern G1-S transition phase of the cell cycle, playing pivotal roles in different human malignant tumors, including breast, colon, prostate cancer, lymphoma, melanoma and neuroblastoma. In vitro studies have shown that cyclin D1 is overexpressed in Ewing's sarcoma (EWS)/peripheral Primitive Neuroectodermal Tumor (pPNET), but not in rhabdomyosarcoma cell lines. Only a few immunohistochemical studies are available on cyclin D1 expression in EWS/pPNET, which confirmed its expression only in a limited number of cases. The aim of the present study was a comparative immunohistochemical analysis of the expression and distribution of cyclin D1 in a large series of pediatric/adolescent soft tissue EWS/pPNETs and rhabdomyosarcomas (both embryonal and alveolar subtypes) to assess its potential usefulness in their differential diagnosis. Notably cyclin D1 was strongly and diffusely expressed in all cases (20/20) of EWS/pPNET, while it was lacked in all cases (15/15) of rhabdomyosarcomas. Immunohistochemical overexpression of cyclin D1 in EWS/pPNET is a novel finding which could be exploitable as a diagnostic immunomarker for this tumor. Although highly sensitive, cyclin D1 is not specific for EWS/pPNET, and thus it should not be evaluated alone but in the context of a wide immunohistochemical panel. Accordingly, we first emphasize that when pathologists are dealing with a small round blue cell tumor of soft tissues in pediatric/adolescent patients, a strong and diffuse nuclear expression of cyclin D1 is of complementary diagnostic value to CD99 and FLI-1 in confirming diagnosis of EWS/pPNET and in ruling out rhabdomyosarcoma., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

The pituitary gland and the hypothalamus are morphologically and functionally associated in the endocrine and neuroendocrine control of other endocrine glands. They therefore play a key role in a number of regulatory feedback processes that co-ordinate the whole endocrine system. Here we review the neuroendocrine system, from the discoveries that led to its identification to some recently clarified embryological, functional, and morphological aspects. In particular we review the pituitary gland and the main notions related to its development, organization, cell differentiation, and vascularization. Given the crucial importance of the factors controlling neuroendocrine system development to understand parvocellular neuron function and the aetiology of the congenital disorders related to hypothalamic-pituitary axis dysfunction, we also provide an overview of the molecular and genetic studies that have advanced our knowledge in the field. Through the action of the hypothalamus, the pituitary gland is involved in the control of a broad range of key aspects of our lives: the review focuses on the hypothalamic-pituitary-gonadal axis, particularly GnRH, whose abnormal secretion is associated with clinical conditions involving delayed or absent puberty and reproductive dysfunction., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Several genes playing crucial roles in human development often reproduce a key role also during the onset and progression of malignant tumors. WT1, a transcription factor expressed with a dynamic pattern during human development, has either oncogenic or suppressor tumor properties. A detailed analysis of the immunohistochemical profile of WT1 protein in human developmental tissues could be exploitable as the rational for better understanding its role in cancerogenesis and planning innovative WT1-based therapeutic approaches. This review focuses on the dynamic immunohistochemical expression and distribution of WT1 protein during human ontogenesis, providing illustrations and discussion on the most relevant findings. The possibility that WT1 nuclear/cytoplasmic expression in some tumors mirrors its normal developmental regulation will be emphasized., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Making a correct diagnosis when dealing with a small round blue cell tumor (SRBCT) of children and adolescents may be relatively straightforward if the tumor arises in the typical clinical setting and the classic pathologic features are all recognizable. However it is widely known that diagnostic difficulties may arise because of: (i) many tumors share overlapping morphological and/or immunohistochemical features; (ii) considerable clinical, pathologic, and immunohistochemical variations do exist; (iii) the increasing use of small biopsies in daily practice makes the diagnosis of these neoplasms more challenging. Accordingly, immunohistochemical analyses are currently mandatory in establishing the correct diagnosis. In this regard there is the need to identify more sensitive and specific immunomarkers useful in the distinction of the several tumor entities. Over the last decades, several markers, such as CD99, WT1 protein, desmin, myogenin, NB84, and INI1 have been identified, providing a considerable help in recognition of the most common solid tumors (ESW/pPNET, rhabdomyosarcoma, neuroblastoma, Wilms' tumor, desmoplastic small round cell tumor; malignant rhabdoid tumor) in children and adolescents. However, at the same time, their unusual, unexpected expression can result in a misinterpretation of the immunohistochemical results, especially by pathologists who are not familiar with oncologic pediatric pathology. Therefore the present review focuses on the potential immunohistochemical pitfalls which should be kept in mind by pathologists to prevent diagnostic errors when dealing with SRBCTs., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

The protein cyclin D1 (CD1), which belongs to a family of proteins functioning as regulators of CDKs (cyclin-dependent kinases) throughout the cell cycle, has been immunohistochemically detected in a wide variety of human malignant tumors. The aim of the present study was to investigate immunohistochemically the expression and distribution of CD1 in the developing human peripheral sympathetic nervous system (PSNS) and in childhood peripheral neuroblastic tumors (neuroblastomas, ganglioneuroblastomas, and ganglioneuromas). The above mentioned fetal and neoplastic tissues represent an in vivo model in which undifferentiated neuroblastic cells undergo ganglion cell differentiation. During development, a strong nuclear expression of CD1 was restricted to neuroblasts, disappearing progressively from the maturing ganglion cells with increasing gestational age. In neoplastic tissues, CD1 immunoreactivity was restricted to neuroblastic cell component of all neuroblastomas and ganglioneuroblastomas, whereas it was absent or only focally detectable in maturing/mature ganglion cell component of differentiating neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. We conclude that CD1 is a reliable marker, which can be used routinely to stain neuroblastic cells in both developing and neoplastic tissues. Furthermore, our results indicate that CD1 expression in childhood peripheral neuroblastic tumors recapitulates the changes during normal development of PSNS, as previously reported for Bcl-2 oncoprotein, c-ErbB2, insulin-like growth factor 2, β-2-microglobulin, and cathepsin D. This is consistent with the current view that childhood peripheral neuroblastic tumors exhibit gene expression profiles mirroring those occurring during PSNS development., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Atherosclerosis remains a major cause of mortality. Whereas the histopathological progression of atherosclerotic lesions is well documented, much less is known about the development of unstable or vulnerable plaque, which can rupture leading to thrombus, luminal occlusion and infarct. Apoptosis in the fibrous cap, which is rich in vascular smooth muscle cells (VSMCs) and macrophages, and its subsequent weakening or erosion seems to be an important regulator of plaque stability. The aim of our study was to improve our knowledge on the biological mechanisms that cause plaque instability in order to develop new therapies to maintain atherosclerotic plaque stability and avoid its rupture. In our study, we collected surgical specimens from atherosclerotic plaques in the right or left internal carotid artery of 62 patients with evident clinical symptoms. Histopathology and histochemistry were performed on wax-embedded sections. Immunohistochemical localization of caspase-3, N-cadherin and ADAM-10 was undertaken in order to highlight links between apoptosis, as expressed by caspase-3 immunostaining, and possible roles of N-cadherin, a cell-cell junction protein in VSMCs and macrophages that provides a pro-survival signal reducing apoptosis, and ADAM-10, a "disintegrin and metalloproteases" that is able to cleave N-cadherin in glioblastomas. Our results showed that when apoptosis, expressed by caspase-3 immunostaining, increased in the fibrous cap, rich in VSMCs and macrophages, the expression of N-cadherin decreased. The decreased N-cadherin expression, in turn, was linked to increased ADAM-10 expression. This study shows that apoptotic events are probably involved in the vulnerability of atherosclerotic plaque., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

There is increasing evidence that Wilms' tumor transcription factor-1 (WT1) is expressed in the cytoplasm of neoplastic cells from different benign and malignant tumors. Only a few studies on WT1 cytoplasmic immunolocalization are available in pediatric tumors. The aim of the present study was to investigate immunohistochemically the expression and distribution of WT1 in a large series of soft tissue fibroblastic/myofibroblastic lesions occurring in children and adolescents. Notably WT1 was not expressed in nodular fasciitis and desmoid-type (adult) fibromatosis, while it stained diffusely and strongly in several infantile-type fibromatoses, such as fibrous hamartoma of infancy, myofibroma/myofibromatosis, and lipofibromatosis. Interestingly, WT1 cytoplasmic expression was also found in all cases (10/10) of infantile fibrosarcomas examined. The present study shows that a diffuse WT1 cytoplasmic expression is of complementary diagnostic value to conventional myofibroblastic markers (α-smooth muscle actin; desmin) in confirming diagnosis of young-type fibromatoses or infantile fibrosarcoma and in ruling out both desmoid-type fibromatoses and nodular fasciitis. WT1 cytoplasmic expression in infantile fibrosarcoma is a novel finding which could be exploitable as an immunomarker for this tumor. Although highly sensitive, WT1 cytoplasmic immunostaining is not specific for infantile fibrosarcoma, and thus it should be evaluated in the context of a wide immunohistochemical panel when pathologists are dealing with spindle cell lesions of soft tissues in children and adolescents. Accordingly we recommend that a correct diagnosis of fibroblastic/myofibroblastic soft tissue lesion in pediatric patients is usually achieved on the basis of a careful correlation of morphological and immunohistochemical findings in the appropriate clinical context. The different cellular localization of WT1, namely nuclear, cytoplasmic or nucleo-cytoplasmic, in different benign and malignant tumors supports the hypothesis that this transcription factor plays a complex role in tumorigenesis, likely as a chameleon protein functioning as either a tumor suppressor gene or an oncogene, depending on cellular context., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Wilms' tumor protein (WT1) has been immunohistochemically detected in the cytoplasm of some developing, adult normal and neoplastic human tissues, suggesting its complex regulator activity in transcriptional/translational processes. Among neoplastic tissues, WT1 has been documented in the cytoplasm of benign and malignant vascular tumors and in rhabdomyosarcoma, while there are no available studies about its expression in myofibroblastic tumors. Accordingly, we studied immunohistochemically the potential expression of WT1 in mammary myofibroblastoma (MFB), a prototypical myofibroblastic tumor. A series of 18 cases of mammary MFB, including several morphological variants (classic, fibrotic, myxoid, lipomatous, Schwannian-like, and epithelioid variants), were tested with antibodies against the N-terminal of WT1. The most striking finding was a diffuse and strong WT1 cytoplasmic immunostaining restricted to the "epithelioid cell MFB", a rare and diagnostically challenging variant. Conversely the other variants of MFB, including the classic-type, were negative or only focally positive. The present study shows that mammary epithelioid cell MFB should be added to the list of mesenchymal tumors which express WT1 in the cytoplasm of neoplastic cells. Accordingly, we suggest that the detection of WT1 cytoplasmic immunoreactivity is of complementary diagnostic value to conventional myofibroblastic markers in identifying epithelioid cell myofibroblastoma., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Developmental expression of Wilms' tumor gene (WT1) and protein is crucial for cell proliferation, apoptosis, differentiation and cytoskeletal architecture regulation. Recently, a potential role of WT1 has been suggested in the development of neural tissue and in neurodegenerative disorders. We have investigated immunohistochemically the developmentally regulated expression and distribution of WT1 in the human fetal peripheral sympathetic nervous system (PSNS) and the gastro-enteric nervous system (GENS) from weeks 8 to 28 gestational age. WT1 expression was restricted to the cytoplasm of sympathetic neuroblasts, while it progressively disappeared with advancing morphologic differentiation of these cells along both ganglionic and chromaffin cell lineages. In adult tissues, both ganglion and chromaffin cells lacked any WT1 expression. These findings show that WT1 is a reliable marker of human sympathetic neuroblasts, which can be used routinely in formalin-fixed, paraffin-embedded tissues. The progressive loss of WT1 in both ganglion and chromaffin cells, suggests its potential repressor role of differentiation in a precise temporal window during the development of the human PSNS and GENS., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

The Wilms' tumor (WT1) gene and its protein product are known to exhibit a dynamic expression profile during development and in the adult organism. Apart from a nuclear expression observed in the urogenital system, its precise localization in other developing human tissues is still largely unknown. Accordingly, the aim of this study was to investigate immunohistochemically the temporal and spatial distribution of WT1 in epithelial and mesenchymal developing human tissues from gestational weeks 7-24. For this purpose we used antibodies against the N-terminal of WT1. As might be expected, WT1 nuclear expression was observed in mesonephric/metanephric glomeruli, metanephric blastema, celom-derived membranes (pleura, peritoneum, serosal surfaces) and sex cords. With regard to mesenchymal tissues, a similar nuclear staining was also obtained in the mesenchyme surrounding Müllerian and Wolffian ducts, as well as in the submesothelial mesenchymal cells of all celomatic-derived membranes. The most striking finding was the detection of strong WT1 cytoplasmic immunostaining in developing skeletal and cardiac muscle cells and endothelial cells. The tissue-specific expression of WT1, together with its different nuclear/cytoplasmic localization, both suggest that WT1 protein may have shuttling properties, acting as a protein with complex regulator activity in transcriptional/translation processes during human ontogenesis. The reported cytoplasmic expression of WT1 in human rhabdomyosarcomas and in many vascular tumors strongly suggests an oncofetal expression of this protein. Although not specific, WT1 cytoplasmic expression can be used as a marker of skeletal muscle and endothelial differentiation in an appropriate morphological context., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

We analyzed the expression and distribution of collagen types IV and VI, laminin and fibronectin during the development and regression of the mesonephros in human embryos and fetuses ranging from 6 to 12 weeks of gestation by indirect immunoperoxidase methods. Type IV collagen, laminin and fibronectin were detected along the glomerular, tubular and capsular basement membranes of developing and mature nephrons. Only type IV collagen and fibronectin were found in the mesangium. Type VI collagen formed a delicate interstitial fibrillar network and a continuous basement membrane-like structure along the mesonephric nephrons. Basement membranes (GBM) of developing and mature glomeruli showed a distinct continuous staining for this collagen. The mesangial matrix was rich in type VI collagen. Mesonephric involution started during the 8th week of gestation and coincided with a moderate expansion of mesangial matrix and progressive collapse of the capillary walls, while the tubules became thinner and shorter. Staining for all extracellular matrix glycoproteins studied showed GBM wrinkling, gradual disintegration of some capillary loops and glomerulosclerosis. The sclerotic glomeruli were strongly positive for type IV collagen and less positive for type VI collagen and fibronectin. Laminin was absent. Our results indicate that collagen types IV, VI, laminin and fibronectin may be involved in the development and regression of the human mesonephros.

The expression of alpha 5 beta 1 (alpha 5 beta 1) integrin and its extracellular ligand fibronectin was studied immunohistochemically in 23 cases of Dupuytren's disease using an immunoperoxidase method for light microscopic visualization. All cases consisted of multiple nodules showing a variable degree of cellularity and fibrosis. Depending on the histological appearance of these nodules, each case was assigned to the three following phases: proliferative, involutional and residual. Alpha 5 beta 1 integrin was detected in the highly cellular areas of both proliferative and involutional phases where fibronectin was simultaneously expressed in the extracellular matrix (ECM). Diversely alpha 5 beta 1 and fibronectin disappeared from the hypocellular areas of involutional phase, undergoing fibrotic transformation, and from the fibrotic connective tissue of residual phases. These findings indicate that the expression pattern of alpha 5 beta 1 integrin correlates with the presence in the ECM of the corresponding ligand fibronectin during the different phases of Dupuytren's disease. We suggest that alpha 5 beta 1 integrin, linking fibronectin to stromal cells of both proliferative and involutional phases, may be involved in the contractile processes occurring in Dupuytren's disease.

The expression and distribution of cytokeratins 8, 18, 19, pan-cytokeratin, vimentin, type IV collagen, laminin and fibronectin were investigated immunohistochemically in the Wolffian and Müllerian ducts and perimüllerian mesenchyme of human male fetuses ranging from 8 to 12 weeks of gestation. The epithelial cells of both genital ducts, the coelomic epithelium and the mesenchymal perimüllerian cells coexpressed cytokeratins 18, 19, pancytokeratin and vimentin. Type IV collagen, laminin, and fibronectin were detected in the basement membranes of both genital ducts, the coelomic epithelium and in the interstitium of the perimüllerian mesenchyme. The coelomic basement membrane adjacent to the müllerian duct showed interruptions and perimüllerian cells were in contact with the coelomic epithelium. The cytoskeletal immunophenotype of perimüllerian cells and their relationship with the coelomic epithelium suggested their coelomic origin. During the 12th week of gestation, müllerian duct began to regress with its basement membrane detaching from the surrounding mesenchyme. This coincided with the disappearance of vimentin from the ductal epithelial cells, as well as type IV collagen, laminin and fibronectin from perimüllerian mesenchyme. Thus müllerian ductal basement membrane dissolved. These findings indicate that the human müllerian duct regression is associated with changes in the interactions between Müllerian ductal and perimüllerian mesenchymal cells.