O fabrico e uso da pólvora no Brasil colonial: o papel de alpoim na primeira metade do século XVIII

Gunpowder played a significant role in colonial Brazil. This reached a climax in the eighteenth century, when the country's large gold output enticed the greed of many. The French invasion of Rio de Janeiro in 1711 made the city's defense even more pressing to the metropolis. Brigadier Alpoim symbolized this reaction. He was a leading Luso-Brazilian engineer of that century, whose multiple activities set him apart in colonial life. These activities included a pioneer role in teaching the manufacture and use of gunpowder, about which he wrote extensively during the first half of the eighteenth century. His work is thus among the first to treat chemical technology in the colony at such an early age.

Invasive populations of Senecio pterophorus are neither more productive nor more plastic than the native populations

Successful plant invaders may have specific morphological and physiological traits that promote invasion in a new habitat. The Evolution of Increased Competitive Ability (EICA) hypothesis predicts that plants released from natural enemies in the introduced habitats are more competitive and perform better than plants from the native populations. An increased phenotypic plasticity may also favour invasion because it allows plants to function under a wider range of environments. In this study we used Senecio pterophorus (Asteraceae) to test whether introduced plant populations are 1)more competitive and 2) more plastic compared with the native populations. We conducted a common garden experiment using plants from the native range (South Africa, Eastern Cape), an expanded range (South Africa, Western Cape) and two introduced ranges (Australia and Europe) under different conditions of water availability. Contrary to the EICA and the increased plasticity hypotheses, plants from the invasive and expanded populations grew less and responded less to watering than those from their native range. These results may be caused by a depleted competition as well as the presence of genetic bottlenecks in the newly invaded areas.

Orthotopic PC-3 Tumor Xenografts in Studies on Prostate Cancer Growth and Metastasis

Prostate cancer is generally a slowly developing disease. However, some cancers develop into an aggressive, metastasic and consequently life-threatening state. The mechanisms of prostate cancer spread are still mainly unidentified but hormones and growth factors are known to been involved. The forming of new blood vessels i.e. angiogenesis is crucial for tumor growth. Blood vessels and lymphatic vessels are also prominent routes for metastasis. Both angiogenic and lymphangiogenic factors are overexpressed in prostate cancer. We established an in vivo model to study the factors effecting human prostate cancer growth and metastasis. Tumors were produced by the orthotopic inoculation of PC-3 prostate cancer cells into the prostates of immunodeficient mice. Like human prostate tumors, these tumors metastasized to prostate-draining lymph nodes. Treatment of the mice with the bisphosphonate alendronate known to decrease prostate cancer cell invasion in vitro inhibited metastasis and decreased tumor growth. Decreased tumor growth was associated with decreased angiogenesis and increased apoptosis of tumor cells. To elucidate the role of angiogenesis in prostate cancer progression, we studied the growth of orthotopic PC-3 tumors overexpressing fibroblast growth factor b (FGF8b) known to be expressed in human prostate cancer. FGF8b increased tumor growth and angiogenesis, which were both associated with a characteristic gene expression pattern. To study the role of lymphangiogenesis, we produced orthotopic PC-3 tumors overexpressing vascular endothelial growth factor C (VEGF-C). Blocking of VEGF-C receptor (VEGFR3) completely inhibited lymph node metastasis whereas overexpression of VEGF-C increased tumor growth and angiogenesis. VEGF-C also increased lung metastases but, surprisingly, decreased spread to lymph nodes. This suggests that the expanded vascular network was primarily used as a route for tumor spreading. Finally, the functionality of the capillary network in subcutaneous FGF8b-overexpressing PC-3 tumors was compared to that of tumors overexpressing VEGF. Both tumors showed angiogenic morphology and grew faster than control tumors. However, FGF8b tumors were hypoxic and their perfusion and oxygenation was poor compared with VEGF tumors. This suggests that the growth advantage of FGF8b tumors is more likely due to stimulated proliferation than effective angiogenesis. In conclusion, these results show that orthotopic prostate tumors provide a useful model to explore the mechanisms of prostate cancer growth and metastasis.

The Integrin Tail: A Tale of Cell Motility and Division

Integrin transmembrane receptor functions are regulated by adaptor molecules binding to their alpha and beta subunit intracellular domains, or tails, thus affecting integrin traffic and adhesion during e.g. cell motility. Interestingly, many cellular proteins function in both cell motility and cell division, thus raising the possibility that integrins might be involved in regulating the cell cycle. A thorough understanding of cell division is essential in cell biology and in human malignancies. It is well established that failures to complete cell cycle can give rise to genetically unstable cells with tumorigenic properties. Transformed cells promote the disruption of intercellular adhesions such as tight junctions, and this correlates with the onset of cell motility, invasion and unfavorable prognosis in cancer. In this study, we analyzed integrin regulation, mediated by adaptor binding to the  subunit tail, during cell motility and cell division. We revealed a novel molecular mechanism by which Rab21, through association with the integrin alpha subunits, drives integrin endosomal traffic during mitotic phases. In addition, we found indications for this finding in vivo, as RAB21 gene deletions were mapped in ovarian and prostate cancer samples. Importantly, the multinucleated phenotype of cultured ovarian cancer cells could be reverted by Rab21 overexpression. In this thesis work, we also show how the tight junction protein ZO-1 unexpectedly interacts with the 5 integrin cytoplasmic domain in the lamellipodia to promote cell motility and at the cleavage furrow to support separation of the daughter cells. The alpha5-ZO-1 complex formation was dependent on PKC which regulates ZO-1 phosphorylation and its subcellular localization. In addition, by an in situ detection method, we showed that a subset of metastatic human lung cancers expressed the alpha5beta-ZO-1 complex. Taken together, we were able to identify new molecular pathways that regulate integrin functions in an alpha tail-mediated fashion. These findings firmly suggest that genetic alterations in integrin traffic may lead to progression of tumorigenesis as a result of failed cell division. Also, the interplay of integrins and ZO-1 in forming spatially regulated adhesive structures broadens our view of crosstalk between pathways and distinct adhesive structures that can be involved in cancer cell biology.

Anchor or Accelerate – A Study on Cancer Cell Adhesion and Motility

Cell migration and adhesion to the extracellular matrix (ECM) are crucial in many biological and pathological processes such as morphogenesis, tissue repair, inflammatory responses, survival, and cancer. Cell-matrix adhesion is mediated by the integrin family of transmembrane receptors, which not only anchor cells to their surroundings, but also transmit bidirectional signalling at the cell surface and couple the ECM to the cytoskeleton. Another group of adhesion receptors are the syndecan proteoglycans, which engage the ECM and possess signalling activity in response to a variety of ligands. Cell migration is a complex process that requires spatial and temporal coordination of adhesion, cell contractility, intracellular traffic of integrins, and matrix turnover by matrix metalloproteinases (MMPs). Thus, integrins and syndecans, as well as MMPs, play essential roles in cancer cell migration and invasion. The understanding of the cooperation of syndecans and integrins was broadened in this thesis study. The results reveal that syndecan-1 functions in concert with 21 integrin in cell adhesion to collagen, whereas syndecan-4 is essential in 21 integrin-mediated matrix contraction. Finally, oncogenic K-Ras was shown to regulate 21 integrin, membrane-type 1 MMP, and syndecan-1 and -4 expression and their cooperation in cell invasion. Epithelial-mesenchymal transition (EMT) is fundamental during embryogenesis and organ development. Activation of EMT processes, including the upregulation of mesenchymal intermediate filament protein vimentin, has also been implicated in the acquisition of a malignant phenotype by epithelial cancer cells. Members of the protein kinase C (PKC) superfamily are involved in cell migration and various integrindependent cellular functions. One aim of this work was to shed light on the role of vimentin in the regulation of integrin traffic and cell motility. In addition, the mechanism by which vimentin participates in EMT was investigated. The results show that integrin recycling and motility are dependent on the PKC–mediated phosphorylation of vimentin. In addition, vimentin was found to be a positive regulator of EMT and regulate the expression of several migratory genes. Specifically, vimentin governs the expression of receptor tyrosine kinase Axl, which is implicated in tumour growth and metastasis. Taken together, the findings described in this thesis reveal novel aspects of the complex interplay between distinct cellular components: integrins, syndecans, and the vimentin cytoskeleton, which all contribute to the regulation of human cancer cell adhesion, migration, and invasion.

Novel Players in the Integrin Signaling Orchestra: TCPTP and MDGI

Metastases are the major cause of cancer deaths. Tumor cell dissemination from the primary tumor utilizes dysregulated cellular adhesion and upregulated proteolytic degradation of the extracellular matrix for progeny formation in distant organs. Integrins are transmembrane adhesive receptors mediating cellcell and cellmatrix interactions that are crucial for regulating cell migration, invasion, proliferation, and survival. Consequently, increased integrin activity is associated with augmented migration and invasion capacity in several cancer types. Heterodimeric integrins consist of an alpha - and beta-subunit that are held together in a bent conformation when the receptor is inactive, but extension and separation of subdomains is observed during receptor activation. Either inside-out or outside-in activation of receptors is possible through the intracellular molecule binding to an integrin cytoplasmic domain or extracellular ligand association with an integrin ectodomain, respectively. Several regulatory binding partners have been characterized for integrin cytoplasmic beta-domains, but the regulators interacting with the cytoplasmic alpha-domains have remained elusive. In this study, we performed yeast two-hybrid screens to identify novel binding partners for the cytoplasmic integrin alpha-domains. Further examination of two plausible candidates revealed a significant coregulatory role of an integrin alpha-subunit for cellular signaling processes. T-cell protein tyrosine phosphatase (TCPTP) showed a specific interaction with the cytoplasmic tail of integrin alpha1. This association stimulated TCPTP phosphatase activity, leading to negative regulation of epidermal growth factor receptor (EGFR) signaling and diminished anchorage-independent growth. Another candidate, mammary-derived growth inhibitor (MDGI), exhibited binding to several different integrin cytoplasmic alpha-tails through a conserved GFFKR sequence. MDGI overexpression in breast cancer cells altered EGFR trafficking and caused a remarkable accumulation of EGFR in the cytoplasm. We further demonstrated in vivo that MDGI expression induced a novel form of anti-EGFR therapy resistance. Moreover, MDGI binding to α-tails retained integrin in an inactive conformation attenuating integrin-mediated adhesion, migration, and invasion. In agreement with these results, sustained MDGI expression in breast cancer patients correlated with an increased 10-year distant disease-free survival. Taken together, the integrin signaling network is far from a complete view and future work will doubtless broaden our understanding further.

Functional Study of Oncogenic Transcription Factor ERG and its Signaling in Prostate Cancer

TMPRSS2–ERG is the most frequent type of genomic rearrangement present in prostate tumors, in which the 5- prime region of the TMPRSS2 gene is fused to the ERG oncogene. TMPRSS2, containing androgen response elements (AREs), is regulated by androgens in the prostate. The truncated TMPRSS2-ERG fusion transcript is overexpressed in half of the prostate cancer patients. The formation of TMPRSS2-ERG transcript is an early event in prostate carcinogenesis and previous in vivo and in vitro studies have shown ectopic ERG expression to be associated with increased cell invasion. However, the molecular function of ERG and its role in cell signaling is poorly understood. In this study, genomic rearrangement of ERG with TMPRSS2 was studied by using comparative genomic hybridization (CGH) in prostate cancer samples. The biological processes associated with the ERG oncogene expression in prostate epithelial cells were studied, and the results were compared with findings observed in clinical prostate tumor samples. The gene expression data indicated that increased WNT signaling and loss of cell adhesion were a characteristic of TMPRSS2- ERG fusion positive prostate tumor samples. Up- regulation of WNT pathway genes were present in ERG positive prostate tumors, with frizzled receptor 4 (FZD4) presenting with the highest association with ERG overexpression, as verified by quantitative reverse transcription-PCR, immunostaining, and immunoblotting in TMPRSS2-ERG positive VCaP prostate cancer cells. Furthermore, ERG and FZD4 silencing increased cell adhesion by inducing active β1-integrin and E-cadherin expression in VCaP cells. Furthermore, we found a novel inhibitor, 4-(chloromethyl) benzoyl chloride which inhibited the WNT signaling and induced similar phenotypic effects as observed after ERG or FZD4 down regulation in VCaP cells. In conclusion, this work deepens our understanding on the complex oncogenic mechanisms of ERG in prostate cancer that may help in developing drugs against TMPRSS2-ERG positive tumors.

Molecular markers for progression of squamous cell carcinoma of the skin

Incidence of nonmelanoma skin cancer (NMSC) is increasing. Ultraviolet (UV) –light is a major risk factor for the development of cutaneous SCC. Cutaneous SCCs that develop to chronic ulcers are known to progress and metastasize more easily than UV-induced SCCs. Matrix metalloproteinases (MMPs) are a group of proteolytic enzymes which are suggested to have a role in cancer growth and invasion. The molecular background for progression of cutaneous SCC was examined by immunohistochemistry (IHC) using tissue samples of recessive dystrophic epidermolysis bullosa (RDEB) –associated SCC, sporadic UV-induced SCC, and SCC precursors. IHC studies using tissue microarray (TMA) technique revealed overexpression of MMP-7 and MMP-13 in SCC tumor cells. MMP-7 expression was enhanced especially in the SCC tumor cells of the RDEB –associated SCCs. Studies with SCC cell lines showed that tumor cell derived MMP-7 activated heparin binding epidermal growth factor –like growth factor (HB-EGF) which enhanced the growth of SCC tumor cells. Further, it was shown that type VII collagen (COL7) is expressed in sporadic SCC tumor cells. Interestingly, it was shown that SCC –associated MMP-13 is capable of cleaving COL7 in vitro. COL7 cleavage may have a role in the progression of cutaneous SCC. Studies on serine proteinase inhibitor gene family using SCC tumor cell gene array, quantitative real-time PCR, SCC cell lines, normal human epidermal keratinocytes and IHC of TMA samples showed that serine proteinase inhibitor clade A, member 1 (serpinA1, alpha-1-antitrypsin) is expressed and produced by human SCC tumor cells but not by normal keratinocytes. Moreover, serpinA1 expression was shown to correlate with the progression of cutaneous SCC using transformed HaCaT-cell lines and mouse chemically induced skin SCC model. SerpinA1 may serve as a novel biomarker for the progression of cutaneous SCC. This study elucidated putative mechanisms of the progression of cutaneous SCC and revealed novel biomarker candidates for the progression of SCC of the skin.

The regulation and function of collagenase-3 (MMP-13) in cutaneous wound healing and squamous cell carcinoma

Matrix metalloproteinase-13 (MMP-13) is a potent proteolytic enzyme, whose expression has been previously associated with fetal bone development and postnatal bone remodeling and with adult gingival wound healing. MMP-13 is also known to be involved in the growth and invasion of various cancers including squamous cell carcinoma (SCC) of the skin. The aim of this study was to further elucidate the function and regulation of MMP-13 in wound repair and cancer. In this study, it was shown that fetal skin fibroblasts express MMP-13 in response to transforming growth factor-β in a p38 MAP kinase dependent manner. In addition, MMP-13 was found to be expressed in vivo by wound fibroblasts in human fetal skin grafted on SCID mice. Adenovirally delivered expression of MMP-13 enhanced collagen matrix contraction by fibroblasts in vitro in association with altered cytoskeletal structure, enhanced proliferation and survival. These results indicate that MMP-13 is involved in cell-mediated collagen matrix remodeling and suggest a role for MMP-13 in superior matrix remodeling and scarless healing of fetal skin wounds. Using an MMP-13 deficient mouse strain, it was shown that MMP-13 is essential for the normal development of experimental granulation tissue in mice. MMP-13 was implicated in the regulation of myofibroblast function and angiogenesis and the expression of genes involved in cellular proliferation and movement, immune response, angiogenesis and proteolysis. Finally, epidermal mitogen, keratinocyte growth factor (KGF) was shown to suppress the malignant properties of skin SCC cells by downregulating the expression of several target genes with potential cancer promoting properties, including MMP-13, and by reducing SCC cell invasion. These results provide evidence that MMP-13 potently regulates cell viability, myofibroblast function and angiogenesis associated with wound healing and cancer. In addition, fibroblasts expressing MMP-13 show high collagen reorganization capacity. Moreover, the results suggest that KGF mediates the anti-cancer effects on skin SCC

Conduta terapêutica atual no adenocarcinoma da cárdia e da junção esofagogástrica

Adenocarcinomas of the cardia and gastroesophageal junction are peculiar entities with three different origins, which differ somewhat from other adenocarcinomas of the stomach in their clinical presentation and pathogenesis, and have a poorer prognosis. In this article the authors reviewed definitions, incidence and epidemiology, etiologic factors, genetic implications, clinical presentation, diagnosis, staging and treatment, with emphasis on the surgical approach, discussing the current management of these cancers. The prognostic factors related specifically to the cardia cancers are: esophageal invasion greater than 3cm, microscopic residual tumor and wall penetration (>T2). Preoperative workup should include computed tomography, and endoscopic ultrasonography and laparoscopy when available. Preoperative recognition of T3/ T4/N2 lesions should indicate inclusion in neo-adjuvant protocols whenever possible. The authors present the results of 46 resected cases of adenocarcinomas of the cardia and GE junction of the Instituto Nacional do Câncer- Brazil (1981-1995). Cure was intended in 29 and palliation in 17 patients. The most common type of resection was total gastrectomy with abdominal esophagectomy (28 cases). Morbidity (major and minor) occurred in 50% of the patients. The main causes were of respiratory origin and fistulas (19.6% each). Death occurred in 44% of the patients with fistula. Postoperative death until the 30th day occurred in 17.24% of the curative cases and in 23.52% of the palliative ones. The median survival time was 68.5 months for stage I, 25 months for stage II, 31 months for stage III and 12.5 months for stage IV diseases. The median survival time was 8 months for palliation and 28.5 months for cure. No long-term survival was obtained with the palliative group, whereas 25% survived five years of more in the curative group. The authors conclude that the surgical approach should be the one the surgeon feels more comfortable with. Complete removal of the disease proved by frozen section, splenectomy and D2 lymphadenectomy should be the standard therapy with curative intent.

Tumor do apêndice vermiforme

Appendiceal tumors are rare and usually presented as acute appendicitis. They are incidentally discovered at an emergency surgery, in which case the decision-making is very difficult. The purpose of this report is discuss to the most appropriate management for appendiceal tumors. A retrospective analysis of one case treated at HU-UEL was undertaken and the literature was reviewed. The conclusion is that frozen section should be done whenever the appendiceal findings are atypical. For appendiceal carcinoids greater than 2 cm and adenocarcinomas, a right hemicolectomy is recommended. Appendectomy is apropriate for patients whose carcinoid tumors are 1 cm in diameter or less and for carcinoid tumors between 1 cm and 2 cm without extensive lymphatic permeation and mesenteric invasion. Every case should be searched for synchronous tumors.

Utilização da veia esplênica para restabelecer o fluxo sangüíneo mesentérico-porta após ressecção de veia mesentérica superior durante duodenopancreatectomia

Superior mesenteric vein invasion has historically been considered a contraindication for pancreatic cancer resection. Several studies have shown that in selected cases vascular resection can be performed safely. Many techniques have been used to reconstruct the venous flow. We describe one case of mesenteric superior vein resection and reconstrution of mesenteric-portal venous flow using the splenic vein during a pancreatoduodenectomy for pancreatic adenocarcinoma. The patient presented an extensive involvement of the superior mesenteric vein. A segmental resection with an end-to-end anastomosis of this vein and the splenic vein was accomplished after splenectomy. The patient had histologically confirmed negative margins. There was no hospital complications. These results show that the splenic vein can be an option for venous flow reconstruction when a segmental vascular resection is required during at pancreaticoduodenectomy.

Cirurgia de tikhoff-linberg para tratamento de condrossarcoma localmente avançado da região escápulo-umeral

Chondrosarcoma is a rare malignant neoplasia that most of the time affects young adults. Its location is preferentially the pelvic and scapular girdle and surgery is its treatment of choice. There are no role for chemo or radiation therapy, because of their low index of response. We describe a case of a 45 year-old male patient with an extensive low grade right umerus chondrosarcoma. In spite of the local extension, there was no invasion of the shoulder neurovascular structures. Treatment proposed was the Tikhoff-Linberg procedure, and the operation was performed with success, with no complications. Free margins were obtained. The patient is now on two years follow-up with no evidence of recurrent disease and is able to drive, fish and carry packs. He can not abduct his arm, but he could not do that even before surgery, due to severe pain. We believe this is an excellent conservative approach to such tumors, that otherwise would require a forequarter amputation, and strongly recommend the technique.

A biologia molecular no prognóstico do carcinoma da tireóide

This overview examines some selected genetic mechanisms of cancer development. Strong evidence has been accumulated suggesting that alteration in either the struture or activity of proto-oncogene contributes to the development and for the maintenance of the malignant phenotype. Many factors are known to interfere with both normal and pathological controls of growth and differentiation of thyroid cells. Among them, some are oncogenes, like those encoding g-proteins (ras, gsp, TSH-R), encoding thyrosino kinases receptors (RET, trk, c-met, c-erb, BRAF) and encoding nuclear proteins (c-myc, e-fós). Others are anti-oncogenes (p53, p15, RB), by loss of the growth suppression ativity of the suppressive gene. Cancer cell invasion and metastasis are the major causes of morbidity and mortality in cancer patients. Many genes are involved in the mechanism of invasion and metastasis of thyroid tumors, like Nis, b-catenina, E-caderina, galectina-3, GLUT, telomerase, VEGT, nm-23. All these oncogenes, antioncogenes and tumor invasion and metastasis-related genes are analysed. Several clinical and prognostic factors have been proposed to identify patients at risk for the development of metastasis and death. The role of molecular genetics in this issue is discussed. However, other studies are needed to validate molecular alterations as an independent prognostic factor in thyroid cancer.

Hemoptise como manifestação de aneurisma de aorta torácica descendente

Aortotracheal fistula is a rare condition that is invariably fatal if not diagnosed and surgically treated. Patients usually present with small intermittent hemoptysis. The findings using computerized tomography (CT) are usually diagnostic. CT should be considered in the initial investigation of patients suspected to have such a disease. A 62-year-old woman with a aneurysm of the descending thoracic aorta presented with new-onset back pain and hemoptysis. The hemoptysis was thought to be the result of invasion of the bronchial tree by the aneurysm.