Las estelas fronterizas y falsa-puerta como delimitadoras del espacio físico y simbólico en Egipto

El concepto de "frontera" resulta problemático debido al uso corriente que se le da al término. Está naturalizada la noción de una frontera exclusiva: una barrera que divide un territorio A de un territorio no-A, rigiendo el principio aristotélico del tercero excluido. Para el estudio de sociedades de la antigüedad debemos necesariamente desembarazarnos de tales preconceptos. En el presente trabajo nos proponemos observar la factibilidad de utilizar tal concepto para entender las divisiones (no sólo físicas) en el Antiguo Egipto. Teniendo en cuenta el uso reiterado de estelas en la demarcación del espacio proponemos, a partir del estudio de las mismas, interrogarnos acerca de qué es exactamente lo que ellas delimitan y por qué se las utiliza para ello. Los casos testigo de las estelas que marcan el límite de la ciudad de Akhetatón y las llamadas falsa-puerta nos servirán para ilustrar nuestras tesis. Las primeras, erigidas para ser vistas, decretan un límite físico; las segundas, ocultas dentro de tumbas privadas, hacen las veces de límite entre el mundo de los vivos y el de los muertos. En apariencia diferentes, encierran en realidad una misma función: separar regiones cósmicas, manteniendo al Caos fuera del territorio donde reina el Orden.

Las estelas fronterizas y falsa-puerta como delimitadoras del espacio físico y simbólico en Egipto

El concepto de "frontera" resulta problemático debido al uso corriente que se le da al término. Está naturalizada la noción de una frontera exclusiva: una barrera que divide un territorio A de un territorio no-A, rigiendo el principio aristotélico del tercero excluido. Para el estudio de sociedades de la antigüedad debemos necesariamente desembarazarnos de tales preconceptos. En el presente trabajo nos proponemos observar la factibilidad de utilizar tal concepto para entender las divisiones (no sólo físicas) en el Antiguo Egipto. Teniendo en cuenta el uso reiterado de estelas en la demarcación del espacio proponemos, a partir del estudio de las mismas, interrogarnos acerca de qué es exactamente lo que ellas delimitan y por qué se las utiliza para ello. Los casos testigo de las estelas que marcan el límite de la ciudad de Akhetatón y las llamadas falsa-puerta nos servirán para ilustrar nuestras tesis. Las primeras, erigidas para ser vistas, decretan un límite físico; las segundas, ocultas dentro de tumbas privadas, hacen las veces de límite entre el mundo de los vivos y el de los muertos. En apariencia diferentes, encierran en realidad una misma función: separar regiones cósmicas, manteniendo al Caos fuera del territorio donde reina el Orden.

Las estelas fronterizas y falsa-puerta como delimitadoras del espacio físico y simbólico en Egipto

El concepto de "frontera" resulta problemático debido al uso corriente que se le da al término. Está naturalizada la noción de una frontera exclusiva: una barrera que divide un territorio A de un territorio no-A, rigiendo el principio aristotélico del tercero excluido. Para el estudio de sociedades de la antigüedad debemos necesariamente desembarazarnos de tales preconceptos. En el presente trabajo nos proponemos observar la factibilidad de utilizar tal concepto para entender las divisiones (no sólo físicas) en el Antiguo Egipto. Teniendo en cuenta el uso reiterado de estelas en la demarcación del espacio proponemos, a partir del estudio de las mismas, interrogarnos acerca de qué es exactamente lo que ellas delimitan y por qué se las utiliza para ello. Los casos testigo de las estelas que marcan el límite de la ciudad de Akhetatón y las llamadas falsa-puerta nos servirán para ilustrar nuestras tesis. Las primeras, erigidas para ser vistas, decretan un límite físico; las segundas, ocultas dentro de tumbas privadas, hacen las veces de límite entre el mundo de los vivos y el de los muertos. En apariencia diferentes, encierran en realidad una misma función: separar regiones cósmicas, manteniendo al Caos fuera del territorio donde reina el Orden.

UMA ECOLOGIA REFÉM DO PODER ECONÔMICO: Leitura exegética sócio-econômica de Deuteronômio 5,12-15

Com esse trabalho, visamos discutir a tentativa de estabelecer um equilíbrio entre o ser humano e natureza na área rural de Judá, pouco antes do reinado de Josias (640-609 a.C.). Nesse caso, pode-se perguntar: seria o mandamento de Deuteronômio 5,12-15 um discurso ecológico? A partir dos estudos de Frank Crüsemann e Haroldo Reimer se admite que partes das leis veterotestamentárias eram destinadas ao assim chamado grupo povo da terra de Judá, visando à manutenção de seu poder. O grupo teria assumido a liderança em Judá mediante um golpe político e, articulando-se, desde então, numa política de aliança para se conservar no poder, mesmo não o assumindo diretamente. Nesse contexto de política de alianças deve-se procurar a implementação do mandamento de Deuteronômio 5,12-15. Ele teria sido escrito por anciãos, um grupo junto ao qual o povo da terra teria se aliado para que ordenassem sentenças jurídicas para a acomodação social. Nesse caso, inicialmente o portão da cidade, espaço oficial para discussões, reclamações e propostas de intermediações, deve ter sido o lugar de elaboração de sentenças jurídicas sobre a utilização de técnicas na agricultura. Sendo elas posteriormente levadas ao tribunal do templo para passar pelas mãos dos sacerdotes, outro braço da coalizão. O uso dos animais de porte, cujo peso prejudicava as pequenas propriedades de terra de Judá, deve ter sido um motivo de incessantes conflitos entre pequenos e grandes proprietários de terra. Ressaltamos assim que apenas os homens mais abastados de Judá tinham acesso a esses animais. Esta solução, segundo se entende, liga o rodízio de culturas ao descanso do campo pertencente ao povo da terra de Judá. Liga-se o termo sábado com a vida da elite rural judaíta do período do reinado de Josias. Uma saída encontrada pelas elites de Judá, a qual nos leva a ponderar uma situação similar que ocorre na América Latina, diante da globalização. Se o texto Deuteronômio 5,12-15 é uma ponderação das elites hegemônicas de Judá que buscam o equilíbrio entre ser o humano e a natureza (ecologia), o discurso ecológico contemporâneo poderá ter neste texto um importante interlocutor. Esse discurso pode ocultar interesses econômicos, completamente diferentes, pois se trata de uma estratégia dominadora e não libertadora, objetivando-se, sobretudo, a reprodução social. O Brasil e os demais países da América Latina vêm sofrendo, há algum tempo, com essa distância entre a elite e o resto da sociedade. Nossas elites utilizam-se, há tempos, do discurso ecológico para se manterem no poder dessas sociedades. Por exemplo, vemos nos noticiários uma quantidade de programas e manchetes ligadas à destruição da natureza. Isso é interessante porque, após terem eles mesmo destruído a natureza, passam agora a defendê-la; controlando as reservas naturais, garantindo sua produtividade e seu status quo no sistema econômico atual.(AU)

UMA ECOLOGIA REFÉM DO PODER ECONÔMICO: Leitura exegética sócio-econômica de Deuteronômio 5,12-15

Com esse trabalho, visamos discutir a tentativa de estabelecer um equilíbrio entre o ser humano e natureza na área rural de Judá, pouco antes do reinado de Josias (640-609 a.C.). Nesse caso, pode-se perguntar: seria o mandamento de Deuteronômio 5,12-15 um discurso ecológico? A partir dos estudos de Frank Crüsemann e Haroldo Reimer se admite que partes das leis veterotestamentárias eram destinadas ao assim chamado grupo povo da terra de Judá, visando à manutenção de seu poder. O grupo teria assumido a liderança em Judá mediante um golpe político e, articulando-se, desde então, numa política de aliança para se conservar no poder, mesmo não o assumindo diretamente. Nesse contexto de política de alianças deve-se procurar a implementação do mandamento de Deuteronômio 5,12-15. Ele teria sido escrito por anciãos, um grupo junto ao qual o povo da terra teria se aliado para que ordenassem sentenças jurídicas para a acomodação social. Nesse caso, inicialmente o portão da cidade, espaço oficial para discussões, reclamações e propostas de intermediações, deve ter sido o lugar de elaboração de sentenças jurídicas sobre a utilização de técnicas na agricultura. Sendo elas posteriormente levadas ao tribunal do templo para passar pelas mãos dos sacerdotes, outro braço da coalizão. O uso dos animais de porte, cujo peso prejudicava as pequenas propriedades de terra de Judá, deve ter sido um motivo de incessantes conflitos entre pequenos e grandes proprietários de terra. Ressaltamos assim que apenas os homens mais abastados de Judá tinham acesso a esses animais. Esta solução, segundo se entende, liga o rodízio de culturas ao descanso do campo pertencente ao povo da terra de Judá. Liga-se o termo sábado com a vida da elite rural judaíta do período do reinado de Josias. Uma saída encontrada pelas elites de Judá, a qual nos leva a ponderar uma situação similar que ocorre na América Latina, diante da globalização. Se o texto Deuteronômio 5,12-15 é uma ponderação das elites hegemônicas de Judá que buscam o equilíbrio entre ser o humano e a natureza (ecologia), o discurso ecológico contemporâneo poderá ter neste texto um importante interlocutor. Esse discurso pode ocultar interesses econômicos, completamente diferentes, pois se trata de uma estratégia dominadora e não libertadora, objetivando-se, sobretudo, a reprodução social. O Brasil e os demais países da América Latina vêm sofrendo, há algum tempo, com essa distância entre a elite e o resto da sociedade. Nossas elites utilizam-se, há tempos, do discurso ecológico para se manterem no poder dessas sociedades. Por exemplo, vemos nos noticiários uma quantidade de programas e manchetes ligadas à destruição da natureza. Isso é interessante porque, após terem eles mesmo destruído a natureza, passam agora a defendê-la; controlando as reservas naturais, garantindo sua produtividade e seu status quo no sistema econômico atual.(AU)

A unified theory of carcinogenesis based on order–disorder transitions in DNA structure as studied in the human ovary and breast

Fourier transform-infrared/statistics models demonstrate that the malignant transformation of morphologically normal human ovarian and breast tissues involves the creation of a high degree of structural modification (disorder) in DNA, before restoration of order in distant metastases. Order–disorder transitions were revealed by methods including principal components analysis of infrared spectra in which DNA samples were represented by points in two-dimensional space. Differences between the geometric sizes of clusters of points and between their locations revealed the magnitude of the order–disorder transitions. Infrared spectra provided evidence for the types of structural changes involved. Normal ovarian DNAs formed a tight cluster comparable to that of normal human blood leukocytes. The DNAs of ovarian primary carcinomas, including those that had given rise to metastases, had a high degree of disorder, whereas the DNAs of distant metastases from ovarian carcinomas were relatively ordered. However, the spectra of the metastases were more diverse than those of normal ovarian DNAs in regions assigned to base vibrations, implying increased genetic changes. DNAs of normal female breasts were substantially disordered (e.g., compared with the human blood leukocytes) as were those of the primary carcinomas, whether or not they had metastasized. The DNAs of distant breast cancer metastases were relatively ordered. These findings evoke a unified theory of carcinogenesis in which the creation of disorder in the DNA structure is an obligatory process followed by the selection of ordered, mutated DNA forms that ultimately give rise to metastases.

Dominant transformation by mutated human ras genes in vitro requires more than 100 times higher expression than is observed in cancers

The gene-mutation-cancer hypothesis holds that mutated cellular protooncogenes, such as point-mutated proto-ras, “play a dominant part in cancer,” because they are sufficient to transform transfected mouse cell lines in vitro [Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K. & Watson, J. D. (1994) Molecular Biology of the Cell (Garland, New York)]. However, in cells transformed in vitro mutated human ras genes are expressed more than 100-fold than in the cancers from which they are isolated. In view of the discrepancy between the very low levels of ras transcription in cancers and the very high levels in cells transformed in vitro, we have investigated the minimal level of human ras expression for transformation in vitro. Using point-mutated human ras genes recombined with different promoters from either human metallothionein-IIA or human fibronectin or from retroviruses we found dominant in vitro transformation of the mouse C3H cell line only with ras genes linked to viral promoters. These ras genes were expressed more than 120-fold higher than are native ras genes of C3H cells. The copy number of transfected ras genes ranged from 2–6 in our system. In addition, nondominant transformation was observed in a small percentage (2–7%) of C3H cells transfected with ras genes that are expressed less than 20 times higher than native C3H ras genes. Because over 90% of cells expressing ras at this moderately enhanced level were untransformed, transformation must follow either a nondominant ras mechanism or a non-ras mechanism. We conclude that the mutated, but normally expressed, ras genes found in human and animal cancers are not likely to “play a dominant part in cancer.” The conclusion that mutated ras genes are not sufficient or dominant for cancer is directly supported by recent discoveries of mutated ras in normal animals, and in benign human tissue, “which has little potential to progress” [Jen, J., Powell, S. M., Papadopoulos, N., Smith, K. J., Hamilton, S. R., Vogelstein, B. & Kinzler, K. W. (1994) Cancer Res. 54, 5523–5526]. Even the view that mutated ras is necessary for cancer is hard to reconcile with (i) otherwise indistinguishable cancers with and without ras mutations, (ii) metastases of the same human cancers with and without ras mutations, (iii) retroviral ras genes that are oncogenic without point mutations, and (iv) human tumor cells having spontaneously lost ras mutation but not tumorigencity.

The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin

Angiostatin, a potent naturally occurring inhibitor of angiogenesis and growth of tumor metastases, is generated by cancer-mediated proteolysis of plasminogen. Human prostate carcinoma cells (PC-3) release enzymatic activity that converts plasminogen to angiostatin. We have now identified two components released by PC-3 cells, urokinase (uPA) and free sulfhydryl donors (FSDs), that are sufficient for angiostatin generation. Furthermore, in a defined cell-free system, plasminogen activators [uPA, tissue-type plasminogen activator (tPA), or streptokinase], in combination with one of a series of FSDs (N-acetyl-l-cysteine, d-penicillamine, captopril, l-cysteine, or reduced glutathione] generate angiostatin from plasminogen. An essential role of plasmin catalytic activity for angiostatin generation was identified by using recombinant mutant plasminogens as substrates. The wild-type recombinant plasminogen was converted to angiostatin in the setting of uPA/FSD; however, a plasminogen activation site mutant and a catalytically inactive mutant failed to generate angiostatin. Cell-free derived angiostatin inhibited angiogenesis in vitro and in vivo and suppressed the growth of Lewis lung carcinoma metastases. These findings define a direct mechanism for cancer-cell-mediated angiostatin generation and permit large-scale production of bioactive angiostatin for investigation and potential therapeutic application.

The R1 component of mammalian ribonucleotide reductase has malignancy-suppressing activity as demonstrated by gene transfer experiments

Our recent studies have shown that deregulated expression of R2, the rate-limiting component of ribonucleotide reductase, enhances transformation and malignant potential by cooperating with activated oncogenes. We now demonstrate that the R1 component of ribonucleotide reductase has tumor-suppressing activity. Stable expression of a biologically active ectopic R1 in ras-transformed mouse fibroblast 10T½ cell lines, with or without R2 overexpression, led to significantly reduced colony-forming efficiency in soft agar. The decreased anchorage independence was accompanied by markedly suppressed malignant potential in vivo. In three ras-transformed cell lines, R1 overexpression resulted in abrogation or marked suppression of tumorigenicity. In addition, the ability to form lung metastases by cells overexpressing R1 was reduced by >85%. Metastasis suppressing activity also was observed in the highly malignant mouse 10T½ derived RMP-6 cell line, which was transformed by a combination of oncogenic ras, myc, and mutant p53. Furthermore, in support of the above observations with the R1 overexpressing cells, NIH 3T3 cells cotransfected with an R1 antisense sequence and oncogenic ras showed significantly increased anchorage independence as compared with control ras-transfected cells. Finally, characteristics of reduced malignant potential also were demonstrated with R1 overexpressing human colon carcinoma cells. Taken together, these results indicate that the two components of ribonucleotide reductase both are unique malignancy determinants playing opposing roles in its regulation, that there is a novel control point important in mechanisms of malignancy, which involves a balance in the levels of R1 and R2 expression, and that alterations in this balance can significantly modify transformation, tumorigenicity, and metastatic potential.

Selective increase in specific alternative splice variants of tyrosinase in murine melanomas: A projected basis for immunotherapy

Melanomas tend to become less pigmented in the course of malignant progression. Thus, as proliferation increases, the tumors are decreasingly characterized by the tissue-specific phenotype of normally differentiated melanocytes. To learn whether the decline in melanization is associated with a shift from constitutive to alternative splicing of some pigment gene pre-mRNAs, melanomas were collected from Tyr-SV40E transgenic mice of the standard C57BL/6 strain. The mRNAs of the tyrosinase gene, which has a key role in melanogenesis, were analyzed by quantitative reverse transcriptase–PCR in 34 samples from 16 cutaneous tumors and 9 metastases. The cutaneous tumors included some cases with distinct melanotic and amelanotic zones, which were separately analyzed. All tyrosinase transcripts found in the melanomas were also found in normal skin melanocytes. However, the Δ1b and Δ1d alternatively spliced transcripts, due to deletions within the first exon, were specifically augmented in most of the tumors over their very low levels in skin; the exceptions were some all-amelanotic tumors in which no tyrosinase transcripts were detected. The level of Δ1b rose as high as 11.3% of total tyrosinase mRNAs as compared with 0.6% in skin; Δ1d reached 4.0% as compared with 0.8% in skin. Expression of these splice variants was highest in the melanotic components of zonal primary tumors, relatively lower in their amelanotic components, and still lower in all-amelanotic primary tumors and amelanotic metastases. The increase in Δ1b and Δ1d transcripts may be predicted to increase the levels of unusual peptides, which could have antigenic potential in the tumors, especially in the relatively early phases of malignancy. Analyses of the alternative transcripts of other pigment genes may identify additional candidate antigens, ultimately enabling melanoma cells in all phases of the disease to be represented as a basis for immune intervention.

Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy

Cancer relapse after surgery is a common occurrence, most frequently resulting from the outgrowth of minimal residual disease in the form of metastases. We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade as an adjunctive immunotherapy to reduce metastatic relapse after primary prostate tumor resection. For these studies, we developed a murine model in which overt metastatic outgrowth of TRAMP-C2 (C2) prostate cancer ensues after complete primary tumor resection. Metastatic relapse in this model occurs reliably and principally within the draining lymph nodes in close proximity to the primary tumor, arising from established metastases present at the time of surgery. Using this model, we demonstrate that adjunctive CTLA-4 blockade administered immediately after primary tumor resection reduces metastatic relapse from 97.4 to 44%. Consistent with this, lymph nodes obtained 2 weeks after treatment reveal marked destruction or complete elimination of C2 metastases in 60% of mice receiving adjunctive anti-CTLA-4 whereas 100% of control antibody-treated mice demonstrate progressive C2 lymph node replacement. Our study demonstrates the potential of adjunctive CTLA-4 blockade immunotherapy to reduce cancer relapse emanating from minimal residual metastatic disease and may have broader implications for improving the capability of immunotherapy by combining such forms of therapy with other cytoreductive measures including surgery.

Fibroblast growth factors: An epigenetic mechanism of broad spectrum resistance to anticancer drugs

Based on the observation that removal of tumors from metastatic organs reversed their chemoresistance, we hypothesized that chemoresistance is induced by extracellular factors in tumor-bearing organs. By comparing chemosensitivity and proteins in different tumors (primary vs. metastases) and different culture systems (tumor fragment histocultures vs. monolayer cultures derived from the same tumor), we found elevated levels of acidic (aFGF) and basic (bFGF) fibroblast growth factors in the conditioned medium (CM) of solid and metastatic tumors. These CM induced broad spectrum resistance to drugs with diverse structures and action mechanisms (paclitaxel, doxorubicin, 5-fluorouracil). Inhibition of bFGF by mAb and its removal by immunoprecipitation resulted in complete reversal of the CM-induced chemoresistance, whereas inhibition/removal of aFGF resulted in partial reversal. Using CM that had been depleted of aFGF and/or bFGF and subsequently reconstituted with respective human recombinant proteins, we found that bFGF but not aFGF induced chemoresistance whereas aFGF amplified the bFGF effect. aFGF and bFGF fully accounted for the CM effect, indicating these proteins as the underlying mechanism of the chemoresistance. The FGF-induced resistance was not due to reduced intracellular drug accumulation or altered cell proliferation. We further showed that an inhibitor of aFGF/bFGF (suramin) enhanced the in vitro and in vivo activity of chemotherapy, resulting in shrinkage and eradication of well established human lung metastases in mice without enhancing toxicity. These results indicate elevated levels of extracellular aFGF/bFGF as an epigenetic mechanism by which cancer cells elude cytotoxic insult by chemotherapy, and provide a basis for designing new treatment strategies.

Human renal cell carcinoma expresses distinct binding sites for growth hormone-releasing hormone

Antagonists of growth hormone-releasing hormone (GHRH) inhibit the proliferation of various human cancers in vitro and in vivo by mechanisms that include apparent direct effects through specific binding sites expressed on tumors and that differ from pituitary human GHRH (hGHRH) receptors. In this study, GHRH antagonist JV-1–38 (20 μg/day per animal s.c.) inhibited the growth of orthotopic CAKI-1 human renal cell carcinoma (RCC) by 83% and inhibited the development of metastases to lung and lymph nodes. Using ligand competition assays with 125I-labeled GHRH antagonist JV-1–42, we demonstrated the presence of specific high-affinity (Kd = 0.25 ± 0.03 nM) binding sites for GHRH with a maximal binding capacity (Bmax) of 70.2 ± 4.1 fmol/mg of membrane protein in CAKI-1 tumors. These receptors bind GHRH antagonists preferentially and display a lower affinity for hGHRH. The binding of 125I-JV-1–42 is not inhibited by vasoactive intestinal peptide (VIP)-related peptides sharing structural homology with hGHRH. The receptors for GHRH antagonists on CAKI-1 tumors are distinct from binding sites detected with 125I-VIP (Kd = 0.89 ± 0.14 nM; Bmax = 183.5 ± 2.6 fmol/mg of protein) and also have different characteristics from GHRH receptors on rat pituitary as documented by the insignificant binding of [His1,125I-Tyr10,Nle27]hGHRH(1–32)NH2. Reverse transcription-PCR revealed the expression of splice variants of hGHRH receptor in CAKI-1 RCC. Biodistribution studies demonstrate an in vivo uptake of 125I-JV-1–42 by the RCC tumor tissue. The presence of specific receptor proteins that bind GHRH antagonists in CAKI-1 RCC supports the view that distinct binding sites that mediate the inhibitory effect of GHRH antagonists are present on various human cancers.