Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This recent symposium featured speakers from several clinical and research disciplines. Among the findings: peptic ulcer disease is a significant predisposing risk factor (odds ratio = 3.9) for pancreatic cancer; as many as 50% of all intraductal papillary mucinous neoplasms are associated with invasive adenocarcinomas; alteration of gene expression via methylation of a gene promotor region constitutes a potentially reversible method of tumor suppressor gene inactivation; > 400 transcriptional alterations of gene expression have been identified for pancreatic cancer; some common molecular markers such as p53 and HER-2/neu may be related to morphologic alterations of in situ neoplasia and to transcriptional alterations of gene expression rather than mutational events; epidermal growth factor (EGF), transforming growth factor beta (TGF-beta), and related molecules may modulate gene transcription via "autocrine" or "paracrine" mechanisms; several cytokines, amylin (islet amyloid polypeptide), and other cachexia factors are responsible for paraneoplastic peripheral insulin resistance, ineffective utilization of glucose, and profound cachexia. In the clinical diagnostic arena: the World Health Organization established a standard nomenclature for intraductal papillary mucinous neoplasms, mucinous cystic tumors, intraductal mucinous hyperplasias, and solid pseudopapillary tumors; focal glandular differentiation may be commonly identified within pancreatic endocrine neoplasms (islet cell tumors) while not necessarily implying an unfavorable prognosis typical of ductal adenocarcinomas; positron emission tomography scanning may be used for evaluation of early tumor response to novel chemotherapeutic regimens; helical computed tomography (CT) is the state of the art in preoperative imaging for pancreatic cancer; neoadjuvant 5-fluorouracil (5-FU)-based chemoradiation in 39 "resectable" patients provided a median survival of 19 months, actuarial 4-year survival of 19%, and improved local tumor control; gemcitabine has shown promise in alleviating tumor-related symptoms with a significantly better "clinical benefit response" than single agent 5-FU (23.8 vs. 4.8%, p = 0.0022) based on change in pain intensity, daily analgesic consumption, performance status, and weight; a significant survival advantage was demonstrated in patients treated with conventional therapies whose tumors expressed p21WAF-1, an important inhibitor of cell cycle progression and downstream molecule of p53 and TGF-beta; a p21-adenovirus (rAD-p21) gene therapy resulted in significant growth inhibition of pancreatic cancer cell lines in tissue culture, and development of a successful SCID mouse-human pancreatic adenocarcinoma xenograft model provided an animal model for preclinical trials of rAD-p21.
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PMID:Current concepts in pancreatic cancer: symposium summary. 982 Nov 73

Cachexia is associated with poor prognosis in patients with chronic disease. Tumor necrosis factor-alpha (TNFalpha) plays a pivotal role in mediating cachexia and has been demonstrated to inhibit skeletal muscle differentiation in vitro. It has been proposed that TNFalpha-mediated activation of NFkappaB leads to down regulation of MyoD, however the mechanisms underlying TNFalpha effects on skeletal muscle remain poorly understood. We report here a novel pathway by which TNFalpha inhibits muscle differentiation through activation of caspases in the absence of apoptosis. TNFalpha-mediated caspase activation and block of differentiation are dependent upon the expression of PW1, but occur independently of NFkappaB activation. PW1 has been implicated previously in p53-mediated cell death and can induce bax translocation to the mitochondria. We show that bax-deficient myoblasts do not activate caspases and differentiate in the presence of TNFalpha, highlighting a role for bax-dependent caspase activation in mediating TNFalpha effects. Taken together, our data reveal that TNFalpha inhibits myogenesis by recruiting components of apoptotic pathways through PW1.
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PMID:TNFalpha inhibits skeletal myogenesis through a PW1-dependent pathway by recruitment of caspase pathways. 1184 11

Death induction by Walker 256 tumor cachexia in non-tumor-infiltrating lymphocytes was investigated. Lymphocytes from cachectic tumor-bearing rats presented a higher proportion of cells with ruptured membranes, indicating necrotic cell death. The cachexia induced by Walker 256 tumor also increased by 3.6-fold the percentage of cells with fragmented DNA, suggestive of apoptotic cell death. The mitochondria involvement was examined by analysis of mitochondria transmembrane potential using rhodamine 123. Lymphocytes from cachectic tumor-bearing rats presented a more pronounced depolarization of mitochondrial transmembrane potential in comparison with cells from the control group. The expression of important proapoptotic (Bcl-xs, Bax, p53, caspase-3) and antiapoptotic genes (Bcl-2 and Bcl-xL) was also altered by tumor cachexia. These results suggest that the immunosuppression induced by Walker 256 tumor cachexia is at least in part a result of lymphocyte death. Evidence was found for the involvement of mitochondria and important proapoptotic genes in the process of lymphocyte death by Walker 256 tumor cachexia.
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PMID:Cachexia induced by Walker 256 tumor growth causes rat lymphocyte death. 1537 80

Muscle wasting (cachexia) is an incurable complication associated with chronic infection and cancers that leads to an overall poor prognosis for recovery. Tumor necrosis factor-alpha (TNFalpha) is a key inflammatory cytokine associated with cachexia. TNFalpha inhibits myogenic differentiation and skeletal muscle regeneration through downstream effectors of the p53 cell death pathway including PW1/Peg3, bax, and caspases. We report that p53 is required for the TNFalpha-mediated inhibition of myogenesis in vitro and contributes to muscle wasting in response to tumor load in vivo. We further demonstrate that PW1 and p53 participate in a positive feedback regulatory loop in vitro. Consistent with this observation, we find that the number of PW1-expressing stem cells in skeletal muscle declines significantly in p53 nullizygous mice. Furthermore, gene transfer of a dominant-negative form of PW1 into muscle tissue in vivo blocks myofiber atrophy in response to tumor load. Taken together, these results show a novel role for p53 in mediating muscle stem cell behavior and muscle atrophy, and point to new targets for the therapeutic treatment of muscle wasting.
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PMID:Muscle cachexia is regulated by a p53-PW1/Peg3-dependent pathway. 1718 69

Conditionally replicating adenovirus (CRAd) has demonstrated to be safe in clinical studies. We generated a triple-regulated p53-armed CRAd, SG600-p53, in which the partially deleted E1a and E1b genes are regulated under the human telomerase reverse transcriptase promoter and the hypoxia response element. SG600-p53 was proven to be effective both in vitro and in vivo. In this study, the preclinical safety profiles of SG600-p53 in animal models were investigated. SG600-p53 had no adverse effects on mouse behavioral and nervous systems at 1.0 x 10(11) viral particles (VP)/kg, 2.0 x 10(11) VP/kg and 4.0 x 10(11) VP/kg doses, and on cat cardiovascular and respiratory systems at 2.0 x 10(10) VP/kg, 4.0 x 10(10) VP/kg, and 8.0 x 10(10) VP/kg doses. In acute toxicity test in mice, the maximum tolerated dose (2.5 x 10(13) VP/kg) induced cachexia, decreased activity, and eye closure in 9/20 mice which could be self-resolved within 30 min. Sensitized by five repeated ip injections at 1.0 x 10(10) VP/kg each ip and excitated by one iv injection at 1.0 x 10(11) VP/kg, guinea pigs did not show any sign of systemic anaphylaxis. In repeat-dose toxicological studies, the no-observable-adverse-effect levels of SG600-p53 in rats (1.0 x 10(11) VP/kg) and cynomolgus monkeys (5.0 x 10(11) VP/kg) were 12-fold and 60-fold of the proposed clinical dose, respectively. Intramuscular injections of SG600-p53 in cynomolgus monkeys caused inflammation at injection sites, which was alleviative at the end of observation period. The anti-virus antibody was produced in animal sera and decreased gradually 4 weeks later. No histopathological changes were found by bone marrow examination. Our data in different animal models suggest that SG600-p53 is a safe antitumor therapeutic agent.
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PMID:Toxicology profiles of a novel p53-armed replication-competent oncolytic adenovirus in rodents, felids, and nonhuman primates. 1870 61

Skeletal muscles of subjects with advanced cancer undergo progressive wasting, referred to as cachexia. Cachexia is an important area for medical research because strategies proposed until now have yielded little benefit. We have recently identified necdin as a key player in fetal and postnatal physiological myogenesis and in muscle regeneration. Here we show that necdin is selectively expressed in muscles of cachetic mice and prove that its expression is causally linked to a protective response of the tissue against tumor-induced wasting, inhibition of myogenic differentiation and fiber regeneration. Necdin carries out this role mainly via interference with TNFalpha signaling at various levels, including regulation of expression of TNFR1 and p53, and regulation of the activity of caspase 3 and caspase 9. These data suggest that inhibition of muscle wasting using necdin is a feasible approach to treat cachexia in neoplastic patients.
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PMID:Necdin is expressed in cachectic skeletal muscle to protect fibers from tumor-induced wasting. 1933 47

The author reports a case of CD34-positive malignant myxoid sarcoma in the retroperitoneum with a dilemma of differential diagnosis in multiple biopsy specimens of different locations. A 79-year-old man was diagnosed with right renal pelvic carcinoma and nephrectomy was performed. The carcinoma was urothelial carcinoma (2 cm in diameter) without invasion. The patient was followed up, and a large retroperitoneal tumor was found two years after the operation. Multiple needle biopsies were performed. The patient then showed a hepatic metastasis, and died of cachexia one year after the detection of the retroperitoneal tumor. The needle biopsy specimens showed spindle cell sarcoma in the myxomatous stroma (80%) and in the non-myxomatous stroma (20%). Immunohistochemically, the tumor cells were positive for vimentin, CD34, CD99, bcl-2 and p53 protein. They were negative for cytokeratins, desmin, alpha-smooth muscle actin, S100 protein, melanosome, CEA, neuron specific enolase, CD68, factor VIII-related antigen, CD31, KIT, and PDGFRA. Ki67 labeling was 30%. A genetic analysis for KIT gene (exons 9, 11, 13 and 17) and PDGFRA gene (exons 12 and 18) showed no mutations. Although the differential diagnosis is problematic and difficult, the present case is probably dedifferentiated liposarcoma. The needle biopsy diagnosis of sarcomas is difficult and limited because sarcomas show heterogeneous histologies with regard to locations in the same tumor.
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PMID:CD34-positive myxoid sarcoma of the retroperitoneum: a dilemma in differential diagnosis of multiple biopsy specimens. 2055 46

Carcinogenic potential of argemone oil (AO) and butter yellow (BY), the adulterants encountered in edible oil, in gall bladder of Swiss albino mice was undertaken to investigate the potential aetiological factors of gall bladder carcinoma (GBC) in the Indo-Gangetic basin. Twice weekly intraperitoneal (ip) administration of AO (5 ml/kg body wt) and BY (25 mg/kg body wt) to Swiss albino male and female mice for 30 and 60 days indicated that females were more vulnerable to these adulterants in terms of responses to inflammatory markers. Subsequent experiments with dietary exposure of AO (1%) and BY (0.06%) for 6 months in female mice showed symptoms related to cachexia, jaundice and anaemia. High levels of total cholesterol, low density lipoprotein (LDL), TG, bilirubin and low level of high density lipoprotein (HDL) as well as gallstone formation was shown by AO exposure only, leading to the development of adenocarcinoma. BY exposure resulted in adenoma and hyperplasia without stone formation. The cyclooxygenase (COX-2) overexpression was found to be related to prostaglandin E2 (PGE2) production in AO treated mice but not in BY exposed animals, thereby indicating a differential pathway specific carcinogenicity. PGE2 stimulates the secretion of secreted mucins (MUC5AC), which is involved in stone formation following AO exposure. Enhanced secretion of membrane bound mucins (MUC4) in BY and AO exposed mice resulted in the activation of ErbB2 and downstream signalling such as p-AKT, p-ERK and p-JNK, which ultimately affects the target proteins, p53 and p21 leading to adenoma and adenocarcinoma, respectively. The study suggests that AO and BY are responsible for producing GBC in mice along with stone formation in the AO exposed animals.
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PMID:Edible oil adulterants, argemone oil and butter yellow, as aetiological factors for gall bladder cancer. 2207 Nov 30

Human anaplastic thyroid cancer (ATC) is a lethal disease with an advanced clinical presentation and median survival of 3 months. The BRAF(V600E) oncoprotein is a potent transforming factor that causes human thyroid cancer cell progression in vitro and in vivo; therefore, we sought to target this oncoprotein in a late intervention model of ATC in vivo. We used the human ATC cell line 8505c, which harbors the BRAF(V600E) and TP53(R248G) mutations. Immunocompromised mice were randomized to receive the selective anti-BRAF(V600E) inhibitor, PLX4720, or vehicle by oral gavage 28 d after tumor implantation, 1 wk before all animals typically die due to widespread metastatic lung disease and neck compressive symptoms in this model. Mice were euthanized weekly to evaluate tumor volume and metastases. Control mice showed progressive tumor growth and lung metastases by 35 d after tumor implantation. At that time, all control mice had large tumors, were cachectic, and were euthanized due to their tumor-related weight loss. PLX4720-treated mice, however, showed a significant decrease in tumor volume and lung metastases in addition to a reversal of tumor-related weight loss. Mouse survival was extended to 49 d in PLX4720-treated animals. PLX4720 treatment inhibited cell cycle progression from 28 d to 49 d in vivo. PLX4720 induces striking tumor regression and reversal of cachexia in an in vivo model of advanced thyroid cancer that harbors the BRAF(V600E) mutation.
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PMID:Late intervention with anti-BRAF(V600E) therapy induces tumor regression in an orthotopic mouse model of human anaplastic thyroid cancer. 2220 62

Cutaneous metastasis of renal cell carcinoma (RCC) is very rare. The author herein report two cases of RCC with cutaneous metastasis. Case 1: is a 75-year-old man with right lumbago. Imaging modalities including CT and MRI revealed a right renal tumor. Nephrectomy was performed. Pathological diagnosis of the renal tumor was RCC of clear cell type (Fuhrman's grade II). He denied follow-up. Nine years later, he (at the age of 84 years), a neck skin tumor emerged. Clinical diagnosis was hemangioma. Imaging modalities including CT and MRI showed several tumors in both lungs. The resection of the neck tumor was performed. The tumor was composed of clear cell type arranged in a trabecular pattern. Immunohistochemically, the tumor cells were positive for pancytokeratins, cytokeratin 18, CD10, Ki-67 (labeling=13%), but negative for CD34, factor-VIII-related antigen, CEA, EMA, melanosome (HMB45), S100 protein, p53, and HepPar-1. Metastatic RCC was diagnosed. Despite interferon therapy, he died of 6 months after the second admission. Case 2 is a 66-year-old man with gross hematuria. Imaging modalities revealed left renal tumor. A nephrectomy was performed. The pathological diagnosis was RCC of clear cell type (grade II). The tumor was invasive into the renal pelvis. He was treated by chemoradiation, but metastases of lungs, skin (thigh), and lib emerged, and died of cachexia 9 months after the admission. Necropsy of the skin tumor was performed. The skin tumor was composed of clear cells arranged in a trabecular pattern. Immunohistochemically, the tumor cells were positive for pancytokeratins (AE1/3, CAM5.2), CD10, p53, and Ki-67 (labeling=20%), but negative for CD34, factor-VIII-related antigen, CEA, melanosome (HMB45), S100 protein, and HepPar-1. A diagnosis of RCC (grade II) was diagnosed.
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PMID:Cutaneous metastasis of renal cell carcinoma: a report of two cases. 2240 81


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