Macrophage Cell Activation with Acute Apical Abscess Contents Determined by Interleukin-1 Beta and Tumor Necrosis Factor Alpha Production

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Efeitos anti-inflamatório e antitumoral dos constituintes de Qualea grandiflora no tumor de Ehrlich

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

PHF21B as a candidate tumor suppressor gene in head and neck squamous cell carcinomas

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Differential Expression of ADAM23, CDKN2A (P16), MMP14 and VIM Associated with Giant Cell Tumor of Bone

Though benign, giant cell tumor of bone (GCTB) can become aggressive and can exhibit a high mitotic rate, necrosis and rarely vascular invasion and metastasis. GCTB has unique histologic characteristics, a high rate of multinucleated cells, a variable and unpredictable growth potential and uncertain biological behavior. In this study, we sought to identify genes differentially expressed in GCTB, thus building a molecular profile of this tumor. We performed quantitative real-time polymerase chain reaction (qPCR), immunohistochemistry and analyses of methylation to identify genes that are putatively associated with GCTB. The expression of the ADAM23 and CDKN2A genes was decreased in GCTB samples compared to normal bone tissue, measured by qPCR. Additionally, a high hypermethylation frequency of the promoter regions of ADAM23 and CDKN2A in GCTB was observed. The expression of the MAP2K3, MMP14, TIMP2 and VIM genes was significantly higher in GCTB than in normal bone tissue, a fact that was confirmed by qPCR and immunohistochemistry. The set of genes identified here furthers our understanding of the molecular basis of GCTB.

The neuroimmune changes induced by cohabitation with an Ehrlich tumor-bearing cage mate rely on olfactory information

Cohabitation for 14 days with Ehrlich tumor-bearing mice was shown to increase locomotor activity, to decrease hypothalamic noradrenaline (NA) levels, to increase NA turnover and to decrease innate immune responses and decrease the animals' resistance to tumor growth. Cage mates of a B16F10 melanoma-bearer mice were also reported to show neuroimmune changes. Chemosignals released by Ehrlich tumor-bearing mice have been reported to be relevant for the neutrophil activity changes induced by cohabitation. The present experiment was designed to further analyze the effects of odor cues on neuroimmune changes induced by cohabitation with a sick cage mate. Specifically, the relevance of chemosignals released by an Ehrlich tumor-bearing mouse was assessed on the following: behavior (open-field and plus maze); hypothalamic NA levels and turnover; adrenaline (A) and NA plasmatic levels; and host resistance induced by tumor growth. To comply with such objectives, devices specifically constructed to analyze the influence of chemosignals released from tumor-bearing mice were employed. The results show that deprivation of odor cues released by Ehrlich tumor-bearing mice reversed the behavioral, neurochemical and immune changes induced by cohabitation. Mice use scents for intraspecies communication in many social contexts. Tumors produce volatile organic compounds released into the atmosphere through breath, sweat, and urine. Our results strongly suggest that volatile compounds released by Ehrlich tumor-injected mice are perceived by their conspecifics, inducing the neuroimmune changes reported for cohabitation with a sick companion. (C) 2011 Elsevier Inc. All rights reserved.

Transmission of clear cell tumor in a graft liver from cadaveric donor: Case report

Neoplasms in children after organ transplantation are related to the type and intensity of immunosuppression and the donorrecipient serostatus, especially in relation to the EpsteinBarr virus. The patient was a two-yr-old female child with biliary atresia who underwent a liver transplantation from a female cadaver donor. Two adults received kidney transplants from the same donor. Nine months after transplantation, one of the adult recipients developed an urothelial tumor in the kidney graft. Imaging tests were repeated monthly in the liver-transplanted child and revealed no abnormalities. However, one yr and two months after the transplantation, the patient developed episodes of fever. At that time, imaging and liver biopsy showed a clear cell tumor of urothelial origin in the graft and the disease was limited to the liver. The patient underwent liver retransplantation, and she is currently free of tumor recurrence. Although rare, the occurrence of tumors in the post-transplant period from cadaver donors, without previously diagnosed tumors, is one of the many problems encountered in the complex world of organ transplantation.

Central Granular Cell Odontogenic Tumor of the Maxilla

The central granular cell odontogenic tumor (CGCOT) is a rare benign odontogenic neoplasm composed of varying amounts of large eosinophilic granular cells and apparently inactive odontogenic epithelium. It tends to occur as a small asymptomatic swelling in the posterior region of the mandible with nonaggressive appearance. We report an unusual case of CGCOT in the maxillary region with clinical features of malignancy. The patient underwent surgical treatment, and the 2-year follow-up revealed no signs of recurrence. Central granular cell odontogenic tumor is a very rare condition with few cases reported, especially in the maxillary region. This case highlights the possibility of aggressive behavior by these lesions.

Expression of Mast Cell Proteases Correlates with Mast Cell Maturation and Angiogenesis during Tumor Progression

Tumor cells are surrounded by infiltrating inflammatory cells, such as lymphocytes, neutrophils, macrophages, and mast cells. A body of evidence indicates that mast cells are associated with various types of tumors. Although role of mast cells can be directly related to their granule content, their function in angiogenesis and tumor progression remains obscure. This study aims to understand the role of mast cells in these processes. Tumors were chemically induced in BALB/c mice and tumor progression was divided into Phases I, II and III. Phase I tumors exhibited a large number of mast cells, which increased in phase II and remained unchanged in phase III. The expression of mouse mast cell protease (mMCP)-4, mMCP-5, mMCP-6, mMCP-7, and carboxypeptidase A were analyzed at the 3 stages. Our results show that with the exception of mMCP-4 expression of these mast cell chymase (mMCP-5), tryptases (mMCP-6 and 7), and carboxypeptidase A (mMC-CPA) increased during tumor progression. Chymase and tryptase activity increased at all stages of tumor progression whereas the number of mast cells remained constant from phase II to III. The number of new blood vessels increased significantly in phase I, while in phases II and III an enlargement of existing blood vessels occurred. In vitro, mMCP-6 and 7 are able to induce vessel formation. The present study suggests that mast cells are involved in induction of angiogenesis in the early stages of tumor development and in modulating blood vessel growth in the later stages of tumor progression.

Mechanistic study of cell death induction by O 6-methylating agents, focusing on the role of homologous recombination as a molecular target for sensitization of tumor cells to chemotherapeutic alkylating agents

Chemotherapeutic SN1‑methylating agents are important anticancer drugs. They induce several covalent modifications in the DNA, from which O6‑methylguanine (O6MeG) is the main toxic lesion. In this work, different hypotheses that have been proposed to explain the mechanism of O6MeG‑triggered cell death were tested. The results of this work support the abortive processing model, which states that abortive post‑replicative processing of O6MeG‑driven mispairs by the DNA mismatch repair (MMR) machinery results in single‑strand gaps in the DNA that, upon a 2nd round of DNA replication, leads to DNA double‑strand break (DSB) formation, checkpoint activation and cell death. In this work, it was shown that O6MeG induces an accumulation of cells in the 2nd G2/M‑phase after treatment. This was accompanied by an increase in DSB formation in the 2nd S/G2/M‑phase, and paralleled by activation of the checkpoint kinases ATR and CHK1. Apoptosis was activated in the 2nd cell cycle. A portion of cells continue proliferating past the 2nd cell cycle, and triggers apoptosis in the subsequent generations. An extension to the original model is proposed, where the persistence of O6MeG in the DNA causes new abortive MMR processing in the 2nd and subsequent generations, where new DSB are produced triggering cell death. Interestingly, removal of O6MeG beyond the 2nd generation lead to a significant, but not complete, reduction in apoptosis, pointing to the involvement of additional mechanisms as a cause of apoptosis. We therefore propose that an increase in genomic instability resulting from accumulation of mis‑repaired DNA damage plays a role in cell death induction. Given the central role of DSB formation in toxicity triggered by chemotherapeutic SN1‑alkylating agents, it was aimed in the second part of this thesis to determine whether inhibition of DSB repair by homologous recombination (HR) or non‑homologous end joining (NHEJ) is a reasonable strategy for sensitizing glioblastoma cells to these agents. The results of this work show that HR down‑regulation in glioblastoma cells impairs the repair of temozolomide (TMZ)‑induced DSB. HR down‑regulation greatly sensitizes cells to cell death following O6‑methylating (TMZ) or O6‑chlorethylating (nimustine) treatment, but not following ionizing radiation. The RNAi mediated inhibition in DSB repair and chemo‑sensitization was proportional to the knockdown of the HR protein RAD51. Chemo‑sensitization was demonstrated for several HR proteins, in glioma cell lines proficient and mutated in p53. Evidence is provided showing that O6MeG is the primary lesion responsible for the increased sensitivity of glioblastoma cells following TMZ treatment, and that inhibition of the resistance marker MGMT restores the chemo‑sensitization achieved by HR down‑regulation. Data are also provided to show that inhibition of DNA‑PK dependent NHEJ does not significantly sensitized glioblastoma cells to TMZ treatment. Finally, the data also show that PARP inhibition with olaparib additionally sensitized HR down‑regulated glioma cells to TMZ. Collectively, the data show that processing of O6MeG through two rounds of DNA replication is required for DSB formation, checkpoint activation and apoptosis induction, and that O6MeG‑triggered apoptosis is also executed in subsequent generations. Furthermore, the data provide proof of principle evidence that down‑regulation of HR is a reasonable strategy for sensitizing glioma cells to killing by O6‑alkylating chemotherapeutics.

Synergistic induction of cell death in liver tumor cells by TRAIL and chemotherapeutic drugs via the BH3-only proteins Bim and Bid

Although death receptors and chemotherapeutic drugs activate distinct apoptosis signaling cascades, crosstalk between the extrinsic and intrinsic apoptosis pathway has been recognized as an important amplification mechanism. Best known in this regard is the amplification of the Fas (CD95) signal in hepatocytes via caspase 8-mediated cleavage of Bid and activation of the mitochondrial apoptosis pathway. Recent evidence, however, indicates that activation of other BH3-only proteins may also be critical for the crosstalk between death receptors and mitochondrial triggers. In this study, we show that TNF-related apoptosis-inducing ligand (TRAIL) and chemotherapeutic drugs synergistically induce apoptosis in various transformed and untransformed liver-derived cell lines, as well as in primary human hepatocytes. Both, preincubation with TRAIL as well as chemotherapeutic drugs could sensitize cells for apoptosis induction by the other respective trigger. TRAIL induced a strong and long lasting activation of Jun kinase, and activation of the BH3-only protein Bim. Consequently, synergistic induction of apoptosis by TRAIL and chemotherapeutic drugs was dependent on Jun kinase activity, and expression of Bim and Bid. These findings confirm a previously defined role of TRAIL and Bim in the regulation of hepatocyte apoptosis, and demonstrate that the TRAIL-Jun kinase-Bim axis is a major and important apoptosis amplification pathway in primary hepatocytes and liver tumor cells.

Telomerase-specific GV1001 peptide vaccination fails to induce objective tumor response in patients with cutaneous T cell lymphoma

There is currently no curative therapy for cutaneous T cell lymphoma (CTCL). New therapies are therefore needed. Telomerase, the enzyme that allows for unrestricted cell divisions of cancer cells, is a promising target for cancer therapy. The telomerase-specific peptide vaccination GV1001 has shown promising results in previous studies. Since telomerase is expressed in malignant cells of CTCL, GV1001 vaccination in CTCL is a promising new therapeutic approach.

Recurrent giant cell tumor of long bones: analysis of surgical management

Treatment of giant cell tumor of bone (GCT) often is complicated by local recurrence. Intralesional curettage is the standard of care for primary GCTs. However, there is controversy whether intralesional curettage should be preferred over wide resection in recurrent GCTs.

Giant cell tumor of bone: risk factors for recurrence

Many surgeons treat giant cell tumor of bone (GCT) with intralesional curettage. Wide resection is reserved for extensive bone destruction where joint preservation is impossible or when expendable sites (eg, fibular head) are affected. Adjuvants such as polymethylmethacrylate and phenol have been recommended to reduce the risk of local recurrence after intralesional surgery. However, the best treatment of these tumors and risk factors for recurrence remain controversial.