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Cancers
Neuroendocrine lung tumors comprise a range of malignancies that extend from benign tumorlets to ... more Neuroendocrine lung tumors comprise a range of malignancies that extend from benign tumorlets to the most prevalent and aggressive Small Cell Lung Carcinoma (SCLC). They also include low-grade Typical Carcinoids (TC), intermediate-grade Atypical Carcinoids (AC) and high-grade Large Cell Neuroendocrine Carcinoma (LCNEC). Optimal treatment options have not been adequately established: surgical resection when possible is the choice for AC and TC, and for SCLC chemotherapy and very recently, immune checkpoint inhibitors. Some mouse models have been generated based on the molecular alterations identified in genomic analyses of human tumors. With the exception of SCLC, there is a limited availability of (preclinical) models making their development an unmet need for the understanding of the molecular mechanisms underlying these diseases. For SCLC, these models are crucial for translational research and novel drug testing, given the paucity of human material from surgery. The lack of early...
Anticancer Research, Aug 1, 2009
Mol Carcinogen, 2002
Glycogen synthase kinase 3 (GSK-3) is a protein kinase that plays essential roles in the control ... more Glycogen synthase kinase 3 (GSK-3) is a protein kinase that plays essential roles in the control of several developmental, metabolic, and apoptotic processes. Owing to its negative actions on several oncogenic insults, it has been considered a putative functional tumor suppressor. We studied the expression, activity, and localization of GSK-3beta during the process of chemically induced two-stage mouse skin carcinogenesis and also in the tumors generated upon subcutaneous injection of Akt-transformed keratinocytes. We found that GSK-3 activity was downregulated at the later stages of promotion by tyrosine 216 dephosphorylation and serine 9 phosphorylation. The data obtained with Akt-transformed keratinocytes clearly suggested the involvement of Akt in serine 9 phosphorylation of GSK-3beta. Finally, besides functional inactivation, significant basal activity of GSK-3beta was detected in all cases, indicating that this enzyme provides essential functions to malignant keratinocytes.
A pesar de los avances en el conocimiento de las bases molecualres del cancer, la traslacion de e... more A pesar de los avances en el conocimiento de las bases molecualres del cancer, la traslacion de estos hacia una terapia clinica no ha sido suficientemente eficaz. La manipulacion genetica del raton nos permite, actualmente, reproducir de forma muy representativa diferentes tipos de tumores humanos en un contexto in vivo. La aplicacion en estos modelos de metodologias de imagen in vivo y de analisis genomico comparado los convierten en una herramienta preclinica insustituible para el diseno de terapias dirigidas contra dianas moleculares fundamentales que pueden permitir el tratamiento de una forma personalizada y altamente eficiente.
Molecular …, 2008
Functional inactivation of the pRb-dependent pathway is a general feature of human cancer. Howeve... more Functional inactivation of the pRb-dependent pathway is a general feature of human cancer. However, only a reduced spectrum of tumors displays inactivation of the Rb gene. This can be attributed, at least partially, to the possible overlapping functions carried out by the related retinoblastoma family members p107 and p130. We observed that loss of pRb in epidermis, using the Cre/LoxP technology, results in proliferation and differentiation defects. These alterations are partially compensated by the elevation in the levels of p107. Moreover, epidermis lacking pRb and p107, but not pRb alone, develops spontaneous tumors, and double deficient primary keratinocytes are highly susceptible to Ha-ras-induced transformation. Two-stage chemical carcinogenesis experiments in mice lacking pRb in epidermis revealed a reduced susceptibility in papilloma formation and an increase in the malignant conversion. We have now explored whether the loss of one p107 allele, inducing a decrease in the levels of p107 up to normal levels could restore the susceptibility of pRb-deficient skin to two-stage protocol. We observed partial restoration in the incidence, number, and size of tumors. However, there is no increased malignancy despite sustained p53 activation. We also observed a partial reduction in the levels of proapoptotic proteins in benign papillomas. These data confirm our previous suggestions on the role of p107 as a tumor suppressor in epidermis in the absence of pRb.
Journal of Cell Science, 2007
Medicina Clínica
The immunologic, cytogenetic and molecular data from a patient with Sézary syndrome are reported.... more The immunologic, cytogenetic and molecular data from a patient with Sézary syndrome are reported. Immunohistochemical analysis disclosed 90% helper CD4 cells and 10% CD8 cells. One of the most significant cytogenetic abnormalities was a t(7; 14) translocation at the level of the 7p13-15 and 14q11 bands, just where the T-cell receptors are located. At the molecular level, rearrangements of the alpha (in 14q11 chromosome), beta (in the 7q32) and gamma (in the 7p15) receptors were found. The translocation between chromosomes 7 and 14, at the level of the mentioned bands, could be responsible for some of the rearrangements found at the molecular level.
Sangre
Gene rearrangement analysis has been performed in 23 patients with T-cell lymphoproliferative dis... more Gene rearrangement analysis has been performed in 23 patients with T-cell lymphoproliferative diseases: 4 cases with T-gamma lymphocytosis, one case of a Sezary's syndrome, one case of T-cell angioimmunoblastic lymphoma, two cases of T-cell lymphoepitheloid lymphoma, 11 patients with T-cell pleomorphic lymphoma, 3 cases of large anaplastic T-cell lymphoma and one case of T-cell lymphoblastic lymphoma. Rearranged banding patterns have been observed for at least one of the T-cell receptors (TCR) in 19 of the cases, and germ line configuration of the TCR and Ig genes in the other four. Likewise, both Ig and TCR rearrangements have been observed in three cases (one case of T-cell pleomorphic lymphoma, one case of large anaplastic T-cell lymphoma and one case of T-cell lymphoblastic lymphoma). Molecular genetic techniques have been used in order to direct monoclonal proliferations of T cell in the tumoral tissues, to determine the T- or B-cell lineage of the neoplasia and also to outline the molecular characteristics of each group that constitutes the complex classification of T-cell malignancies.
Sangre
Cytogenetic and molecular results in 10 patients with extranodal lymphoma (MALT): 5 low grade and... more Cytogenetic and molecular results in 10 patients with extranodal lymphoma (MALT): 5 low grade and 5 high grade, were compared with the results observed in nodal lymphomas. This study suggests that there are cytogenetic differences between extranodal and nodal low grade lymphomas. Both molecular analysis by conventional Southern blot with probes for the major and minor regions of bcl-2 gene, and PCR analysis with primers from these regions, showed that t (14; 18) is a sporadic event in MALT lymphomas.
Cancer Genetics and Cytogenetics
Revista Clínica Española
A case of Castleman's disease (hialino-vascular subtype) in a female patient 15-years-old... more A case of Castleman's disease (hialino-vascular subtype) in a female patient 15-years-old is considered. Clinically there were isolated lymphadenopathies which relapsed after surgery and absence of general syndrome. Histoimmunological and electron microscopic studies were performed as DNA rearrangement and cytogenetics in order to exclude genetic abnormalities and monoclonality of this disorder. The role of follicular dendritic component in discussed.
Genetics, 2001
The expression of transgene loci in mammals often occurs in a heterocellular fashion resulting in... more The expression of transgene loci in mammals often occurs in a heterocellular fashion resulting in variegated patterns of expression. We have examined the effect of chromosomal integration site, copy number, and transcriptionally activating sequences on the variegation of a keratin 5-lacZ (K5Z) construct in the stratified epithelia of transgenic mice. lacZ expression in these mice is always mosaic, and the beta-gal activity per cell is usually higher in the lines with a higher proportion of expressing cells. Similar constructs, in which cDNAs were exchanged by lacZ sequences, showed no variegation. Also, when a strongly active, nonvariegating construct was coinjected with K5Z, most transgenic lines showed an almost homogeneous lacZ expression. The comparison of transgene arrays of different copies inserted at the same locus (obtained by using a lox/Cre system) showed that the reduction of copy number does not lead to an increase in the proportion of cells that express the transgene. ...
Veterinary Clinical Pathology, 2006
A 9-year-old male Rottweiler was presented to the Veterinary Medical Hospital Montenegro, Porto, ... more A 9-year-old male Rottweiler was presented to the Veterinary Medical Hospital Montenegro, Porto, Portugal with a large mass medial to the left stifle and radiographic signs of bone lysis involving the proximal tibia, fibula, and distal femur. A fine-needle aspiration was obtained from left popliteal lymph node, which was markedly enlarged. Cytologic examination revealed a highly cellular sample consisting of pleomorphic cells with marked anisocytosis and anisokaryosis and other criteria of malignancy. Some cells contained intracytoplasmic, granular, dark brown material, consistent with hemosiderin. Histologic evaluation of the surgically-excised lymph node revealed a neoplastic proliferation of histiocytic cells, with marked pleomorphism; occasional cells were erythrophagocytic. Mitotic figures were frequently observed, and many were atypical. Histologic findings were consistent with malignant histiocytosis. Necropsy examination confirmed the diagnosis of malignant histiocytosis with systemic involvement affecting most organs examined. This case of malignant histiocytosis case had an atypical clinical presentation, mimicking a musculoskeletal disorder. It underlines the importance of cytology as a simple, inexpensive, rapid and noninvasive complementary exam in routine clinical practice that can permit early diagnosis of the disease and timely selection of the most adequate therapy.
Cancers
Neuroendocrine lung tumors comprise a range of malignancies that extend from benign tumorlets to ... more Neuroendocrine lung tumors comprise a range of malignancies that extend from benign tumorlets to the most prevalent and aggressive Small Cell Lung Carcinoma (SCLC). They also include low-grade Typical Carcinoids (TC), intermediate-grade Atypical Carcinoids (AC) and high-grade Large Cell Neuroendocrine Carcinoma (LCNEC). Optimal treatment options have not been adequately established: surgical resection when possible is the choice for AC and TC, and for SCLC chemotherapy and very recently, immune checkpoint inhibitors. Some mouse models have been generated based on the molecular alterations identified in genomic analyses of human tumors. With the exception of SCLC, there is a limited availability of (preclinical) models making their development an unmet need for the understanding of the molecular mechanisms underlying these diseases. For SCLC, these models are crucial for translational research and novel drug testing, given the paucity of human material from surgery. The lack of early...
Anticancer Research, Aug 1, 2009
Mol Carcinogen, 2002
Glycogen synthase kinase 3 (GSK-3) is a protein kinase that plays essential roles in the control ... more Glycogen synthase kinase 3 (GSK-3) is a protein kinase that plays essential roles in the control of several developmental, metabolic, and apoptotic processes. Owing to its negative actions on several oncogenic insults, it has been considered a putative functional tumor suppressor. We studied the expression, activity, and localization of GSK-3beta during the process of chemically induced two-stage mouse skin carcinogenesis and also in the tumors generated upon subcutaneous injection of Akt-transformed keratinocytes. We found that GSK-3 activity was downregulated at the later stages of promotion by tyrosine 216 dephosphorylation and serine 9 phosphorylation. The data obtained with Akt-transformed keratinocytes clearly suggested the involvement of Akt in serine 9 phosphorylation of GSK-3beta. Finally, besides functional inactivation, significant basal activity of GSK-3beta was detected in all cases, indicating that this enzyme provides essential functions to malignant keratinocytes.
A pesar de los avances en el conocimiento de las bases molecualres del cancer, la traslacion de e... more A pesar de los avances en el conocimiento de las bases molecualres del cancer, la traslacion de estos hacia una terapia clinica no ha sido suficientemente eficaz. La manipulacion genetica del raton nos permite, actualmente, reproducir de forma muy representativa diferentes tipos de tumores humanos en un contexto in vivo. La aplicacion en estos modelos de metodologias de imagen in vivo y de analisis genomico comparado los convierten en una herramienta preclinica insustituible para el diseno de terapias dirigidas contra dianas moleculares fundamentales que pueden permitir el tratamiento de una forma personalizada y altamente eficiente.
Molecular …, 2008
Functional inactivation of the pRb-dependent pathway is a general feature of human cancer. Howeve... more Functional inactivation of the pRb-dependent pathway is a general feature of human cancer. However, only a reduced spectrum of tumors displays inactivation of the Rb gene. This can be attributed, at least partially, to the possible overlapping functions carried out by the related retinoblastoma family members p107 and p130. We observed that loss of pRb in epidermis, using the Cre/LoxP technology, results in proliferation and differentiation defects. These alterations are partially compensated by the elevation in the levels of p107. Moreover, epidermis lacking pRb and p107, but not pRb alone, develops spontaneous tumors, and double deficient primary keratinocytes are highly susceptible to Ha-ras-induced transformation. Two-stage chemical carcinogenesis experiments in mice lacking pRb in epidermis revealed a reduced susceptibility in papilloma formation and an increase in the malignant conversion. We have now explored whether the loss of one p107 allele, inducing a decrease in the levels of p107 up to normal levels could restore the susceptibility of pRb-deficient skin to two-stage protocol. We observed partial restoration in the incidence, number, and size of tumors. However, there is no increased malignancy despite sustained p53 activation. We also observed a partial reduction in the levels of proapoptotic proteins in benign papillomas. These data confirm our previous suggestions on the role of p107 as a tumor suppressor in epidermis in the absence of pRb.
Journal of Cell Science, 2007
Medicina Clínica
The immunologic, cytogenetic and molecular data from a patient with Sézary syndrome are reported.... more The immunologic, cytogenetic and molecular data from a patient with Sézary syndrome are reported. Immunohistochemical analysis disclosed 90% helper CD4 cells and 10% CD8 cells. One of the most significant cytogenetic abnormalities was a t(7; 14) translocation at the level of the 7p13-15 and 14q11 bands, just where the T-cell receptors are located. At the molecular level, rearrangements of the alpha (in 14q11 chromosome), beta (in the 7q32) and gamma (in the 7p15) receptors were found. The translocation between chromosomes 7 and 14, at the level of the mentioned bands, could be responsible for some of the rearrangements found at the molecular level.
Sangre
Gene rearrangement analysis has been performed in 23 patients with T-cell lymphoproliferative dis... more Gene rearrangement analysis has been performed in 23 patients with T-cell lymphoproliferative diseases: 4 cases with T-gamma lymphocytosis, one case of a Sezary's syndrome, one case of T-cell angioimmunoblastic lymphoma, two cases of T-cell lymphoepitheloid lymphoma, 11 patients with T-cell pleomorphic lymphoma, 3 cases of large anaplastic T-cell lymphoma and one case of T-cell lymphoblastic lymphoma. Rearranged banding patterns have been observed for at least one of the T-cell receptors (TCR) in 19 of the cases, and germ line configuration of the TCR and Ig genes in the other four. Likewise, both Ig and TCR rearrangements have been observed in three cases (one case of T-cell pleomorphic lymphoma, one case of large anaplastic T-cell lymphoma and one case of T-cell lymphoblastic lymphoma). Molecular genetic techniques have been used in order to direct monoclonal proliferations of T cell in the tumoral tissues, to determine the T- or B-cell lineage of the neoplasia and also to outline the molecular characteristics of each group that constitutes the complex classification of T-cell malignancies.
Sangre
Cytogenetic and molecular results in 10 patients with extranodal lymphoma (MALT): 5 low grade and... more Cytogenetic and molecular results in 10 patients with extranodal lymphoma (MALT): 5 low grade and 5 high grade, were compared with the results observed in nodal lymphomas. This study suggests that there are cytogenetic differences between extranodal and nodal low grade lymphomas. Both molecular analysis by conventional Southern blot with probes for the major and minor regions of bcl-2 gene, and PCR analysis with primers from these regions, showed that t (14; 18) is a sporadic event in MALT lymphomas.
Cancer Genetics and Cytogenetics
Revista Clínica Española
A case of Castleman's disease (hialino-vascular subtype) in a female patient 15-years-old... more A case of Castleman's disease (hialino-vascular subtype) in a female patient 15-years-old is considered. Clinically there were isolated lymphadenopathies which relapsed after surgery and absence of general syndrome. Histoimmunological and electron microscopic studies were performed as DNA rearrangement and cytogenetics in order to exclude genetic abnormalities and monoclonality of this disorder. The role of follicular dendritic component in discussed.
Genetics, 2001
The expression of transgene loci in mammals often occurs in a heterocellular fashion resulting in... more The expression of transgene loci in mammals often occurs in a heterocellular fashion resulting in variegated patterns of expression. We have examined the effect of chromosomal integration site, copy number, and transcriptionally activating sequences on the variegation of a keratin 5-lacZ (K5Z) construct in the stratified epithelia of transgenic mice. lacZ expression in these mice is always mosaic, and the beta-gal activity per cell is usually higher in the lines with a higher proportion of expressing cells. Similar constructs, in which cDNAs were exchanged by lacZ sequences, showed no variegation. Also, when a strongly active, nonvariegating construct was coinjected with K5Z, most transgenic lines showed an almost homogeneous lacZ expression. The comparison of transgene arrays of different copies inserted at the same locus (obtained by using a lox/Cre system) showed that the reduction of copy number does not lead to an increase in the proportion of cells that express the transgene. ...
Veterinary Clinical Pathology, 2006
A 9-year-old male Rottweiler was presented to the Veterinary Medical Hospital Montenegro, Porto, ... more A 9-year-old male Rottweiler was presented to the Veterinary Medical Hospital Montenegro, Porto, Portugal with a large mass medial to the left stifle and radiographic signs of bone lysis involving the proximal tibia, fibula, and distal femur. A fine-needle aspiration was obtained from left popliteal lymph node, which was markedly enlarged. Cytologic examination revealed a highly cellular sample consisting of pleomorphic cells with marked anisocytosis and anisokaryosis and other criteria of malignancy. Some cells contained intracytoplasmic, granular, dark brown material, consistent with hemosiderin. Histologic evaluation of the surgically-excised lymph node revealed a neoplastic proliferation of histiocytic cells, with marked pleomorphism; occasional cells were erythrophagocytic. Mitotic figures were frequently observed, and many were atypical. Histologic findings were consistent with malignant histiocytosis. Necropsy examination confirmed the diagnosis of malignant histiocytosis with systemic involvement affecting most organs examined. This case of malignant histiocytosis case had an atypical clinical presentation, mimicking a musculoskeletal disorder. It underlines the importance of cytology as a simple, inexpensive, rapid and noninvasive complementary exam in routine clinical practice that can permit early diagnosis of the disease and timely selection of the most adequate therapy.