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Joseph Califano

Publications and source records attributed to Joseph Califano.

25 records · Page 2Linked to original sources
PubMed2003

A transcriptional progression model for head and neck cancer.

PURPOSE: A genetic progression model for head and neck squamous cell carcinoma (HNSC) has been established and implies the presence of transcriptional dysregulation as a consequence of accumulation of genetic alterations. Although expression array data have been provided for HNSC, the timing of transcriptional dysregulation in the progression from normal mucosa to dyplastic epithelium to invasive HNSC has not been described. Here, we describe a transcriptional progression model of HNSC. EXPERIMENTAL DESIGN: Expression arrays representing >12,000 genes and expressed sequence tags were used to examine malignant lesions (M), premalignant lesions (PM), distant, histopathologically normal mucosa from patients with premalignant or malignant lesions (MN), and normal mucosa from the upper aerodigestive tract of patients with noncancer diagnoses (N). Significance analysis of microarrays, hierarchical clustering, and principal components analysis was used to identify genes with differential expression patterns. RESULTS: Using a false discovery rate of <5% for significance analysis of microarray, the M group revealed 965 up-regulated and 1106 down-regulated genes relative to the N group. The PM group demonstrated 108 up-regulated and 226 down-regulated genes relative to the N group, whereas the M group demonstrated only 5 up-regulated and 13 down-regulated genes relative to the PM group. Both hierarchical cluster analysis and principal components analysis revealed a consistent separation between the N, PM, and M groups, with a closer association between the PM and M groups. To provide independent validation of the microarray data, quantitative reverse transcription-PCR was performed for a significantly up-regulated gene, integrin alpha 6, correlating well with microarray data (linear regression analysis, P < 0.0001). CONCLUSIONS: Similarly to the genetic progression model of HNSC, this transcriptional model shows that the majority of alterations occurs before the development of malignancy and identifies key targets of transcriptional dysregulation during progression from a normal to a premalignant state and from a premalignant to a malignant state.

Carcinoma↗
PubMed2003

DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development.

The p63 gene shows remarkable structural similarity to the p53 and p73 genes. Because of two promoters, the p63 gene generates two types of protein isoforms, TAp63 and DeltaNp63. Each type yields three isotypes (alpha, beta, gamma) because of differential splicing of the p63 COOH terminus. The purpose of this study was to determine whether there is a functional link between the distinct p63 isotypes in their transcriptional regulation of downstream targets and their role in various cellular functions. TAp63alpha and DeltaNp63alpha adenovirus expression vectors were introduced into Saos2 cells for 4 and 24 h, and then gene profiling was performed using a DNA microarray chip analysis. Seventy-four genes (>2-fold change in expression) were identified that overlapped between two independent studies. Thirty-five genes were selected for direct expression testing of which 27 were confirmed by reverse transcription-PCR or Northern blot analysis. A survey of these genes shows that p63 can regulate a wide range of downstream gene targets with various cellular functions, including cell cycle control, stress, and signal transduction. Our study thus revealed p63 transcriptional regulation of many genes in cancer and development while often demonstrating opposing regulatory functions for TAp63alpha and DeltaNp63alpha.

Apoptosis↗
PubMed2003

Anterior cranial base reconstruction using free tissue transfer: changing trends.

INTRODUCTION: A consecutive series of 135 patients undergoing resection for malignant tumors involving the anterior cranial base between 1976 and 1999 was reviewed. PATIENT AND METHODS: In the years from 1976-1991, free-tissue transfer was used in 5 of 76 or 6.6% of cases, whereas free-tissue reconstruction was used in 24 of 59 or 40% of cases in the years 1992-1999. Of those cases reconstructed with free-tissue transfer in 1976-1991, 60% (three of five) underwent a complex resection defined as involving dura, brain, or more than one major structure adjacent to skull base. Of those patients reconstructed with conventional (pericranial or pericranial/galeal) pedicled flaps in this time period, 35% (25 of 71) underwent a complex resection. From 1992-1999, 75% (18 of 24) of patients reconstructed with free-tissue transfer received a complex resection, whereas only 6% (2 of 35) of patients reconstructed by other means received a complex resection. OUTCOMES: For those patients reconstructed by free-tissue transfer, there were no instances of flap loss. Comparison of these two time periods was notable for a similar patient composition in terms of age, histologic findings, and extent of resection. Major complication rates for patients who are reconstructed with free-tissue transfer for anterior cranial base resections (31%) are similar compared with patients who have been reconstructed with conventional pedicled flaps (35%). This was noted despite an increased extent and complexity of resection in those patients who underwent free-tissue transfer reconstruction (72%) compared with those patients reconstructed by more conventional means (26%) p <.001. CONCLUSION: In our institution, the use of vascularized, free-tissue transfer has replaced pedicled flaps as the preferred modality for reconstructing complex anterior cranial base defects involving resection of dura, brain, or multiple major structures adjacent to local skull base, including the orbit, palate, and other structures. Complication rates for patients reconstructed with free-tissue transfer techniques is similar to those patients reconstructed by conventional techniques, despite an increase in complexity of resection in this group.

Adolescent↗
PubMed2002

Multifocal papillary thyroid carcinoma arising in a lingual thyroid: a case report.

We report the first case (to our knowledge) of a multifocal papillary thyroid carcinoma arising in a lingual thyroid. The patient underwent a transcervical, transhyoid approach for excision, followed by radioiodine ablation, with excellent functional and oncologic results. We also discuss the management, diagnosis, and historical background of a malignant neoplasm arising in a lingual thyroid.

Carcinoma, Papillary↗
PubMed2002

DeltaNp63 induces beta-catenin nuclear accumulation and signaling.

The P53 homolog p63 encodes multiple proteins with transactivating, apoptosis-inducing, and oncogenic activities. We showed that p63 is amplified and that DeltaNp63 isotypes are overexpressed in squamous cell carcinoma (SCC) and enhance oncogenic growth in vitro and in vivo. Moreover, p53 associated with DeltaNp63alpha and mediated its degradation. Here, we report that DeltaNp63 associates with the B56alpha regulatory subunit of protein phosphatase 2A (PP2A) and glycogen synthase kinase 3beta (GSK3beta), leading to a dramatic inhibition of PP2A-mediated GSK3beta reactivation. The inhibitory effect of DeltaNp63 on GSK3beta mediates a decrease in phosphorylation levels of beta-catenin, which induces intranuclear accumulation of beta-catenin and activates beta-catenin-dependent transcription. Our results suggest that DeltaNp63 isotypes act as positive regulators of the beta-catenin signaling pathway, providing a basis for their oncogenic properties.

Blood Proteins↗
PubMed2002

Immunohistochemical p53 expression patterns in sarcomatoid carcinomas of the upper respiratory tract.

Sarcomatoid carcinoma of the upper respiratory tract is a phenotypically complex neoplasm that has triggered much thoughtful discussion regarding histogenic origin and morphologic classification. In particular, its putative epithelial lineage and distinction from a pseudosarcomatous reaction are sometimes questioned. Little is known about the genetic alterations underlying sarcomatoid carcinoma. Although about 45% of conventional squamous cell carcinomas of the upper respiratory tract harbor p53 mutations, the p53 status of sarcomatoid carcinomas is not well established. p53 immunohistochemical analysis using the monoclonal antibody D07 was performed on 23 sarcomatoid carcinomas of the upper respiratory tract. Twenty tumors were biphasic, having dual epithelial and spindled components. In four of these biphasic tumors, the epithelial and spindled components were separately analyzed for p53 gene mutations by sequence analysis. p53 immunohistochemistry was also performed on 19 cases of postradiation stromal atypia. Strong and diffuse p53 staining was detected in 18 (78%) of the 23 sarcomatoid carcinomas. When the spindled component was compared with its corresponding epithelial component, identical patterns of p53 protein expression were noted in 19 (95%) of the 20 biphasic tumors. Weak p53 staining was observed in one (5%) of the 19 cases of postradiation stromal atypia. In the four biphasic tumors evaluated by DNA sequence analysis, p53 status was always the same in the paired epithelial and spindle cell components. These findings help further dispel the notion that sarcomatoid carcinoma represents a reactive spindle cell proliferation (pseudosarcoma) or a collision between a carcinoma and a sarcoma (collision tumor). Instead, the epithelial and spindled components share a common pathway of tumorigenesis despite their conspicuous divergence at the phenotypic level.

Adult↗