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Steven Gitelis

Publications and source records attributed to Steven Gitelis.

18 recordsLinked to original sources
PubMed2006

Severe suppression of Frzb/sFRP3 transcription in osteogenic sarcoma.

Deciphering the molecular basis of cancer is critical for developing novel diagnostic and therapeutic strategies. To better understand the early molecular events involving osteogenic sarcoma (OGS), we have initiated a program to identify potential tumor suppressor genes. Expression profiling of total RNA from ten normal bone cell lines and eleven OGS-derived cell lines by microarray showed 135-fold lower expression of FRZB/sFRP3 mRNA in OGS cells compared to bone cells; this down-regulation of Frzb/sFRP3 mRNA expression was found to be serum-independent. Subsequently, fourteen OGS biopsy specimens showed nine-fold down-regulation of Frzb/sFRP3 mRNA expression compared to expression in eight normal bone specimens as determined by microarray. FRZB /sFRP3 protein level was also found to be at a very low level in 4/4 OGS cell lines examined. Quantitation by RT-PCR indicated approximately 70% and approximately 90% loss of Frzb/sFRP3 mRNA expression in OGS biopsy specimens and OGS-derived cell lines respectively, compared to expression in bone (p<0.0001). Hybridization experiments of a cDNA microarray containing paired normal and tumor specimens from nineteen different organs did not show any significant difference in the level of Frzb/sFRP3 mRNA expression between the normal and the corresponding tumor tissues. Exogenous expression of FRZB/sFRP3 mRNA in two OGS-derived cell lines lacking endogenous expression of the mRNA produced abundant mRNA from the exogenous gene, eliminating degradation as a possibility for very low level of FRZB/sFRP3 mRNA in OGS specimens. Results from PCR-based experiments suggest that the FRZB/sFRP3 gene is not deleted in OGS cell lines, however, karyotyping shows gross abnormalities involving chromosome 2 (location of the FRZB gene) in five of twelve OGS-derived cell lines. Together, these data suggest a tumor-suppressive potential for FRZB/sFRP3 in OGS.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Intrinsic radiation resistance in human chondrosarcoma cells.

Human chondrosarcomas rarely respond to radiation treatment, limiting the options for eradication of these tumors. The basis of radiation resistance in chondrosarcomas remains obscure. In normal cells radiation induces DNA damage that leads to growth arrest or death. However, cells that lack cell cycle control mechanisms needed for these responses show intrinsic radiation resistance. In previous work, we identified immortalized human chondrosarcoma cell lines that lacked p16(ink4a), one of the major tumor suppressor proteins that regulate the cell cycle. We hypothesized that the absence of p16(ink4a) contributes to the intrinsic radiation resistance of chondrosarcomas and that restoring p16(ink4a) expression would increase their radiation sensitivity. To test this we determined the effects of ectopic p16(ink4a) expression on chondrosarcoma cell resistance to low-dose gamma-irradiation (1-5 Gy). p16(ink4a) expression significantly increased radiation sensitivity in clonogenic assays. Apoptosis did not increase significantly with radiation and was unaffected by p16(ink4a) transduction of chondrosarcoma cells, indicating that mitotic catastrophe, rather than programmed cell death, was the predominant radiation effect. These results support the hypothesis that p16(ink4a) plays a role in the radiation resistance of chondrosarcoma cell lines and suggests that restoring p16 expression will improve the radiation sensitivity of human chondrosarcomas.

Acridine Orange↗
PubMed2005

Local and systemic levels of tobramycin delivered from calcium sulfate bone graft substitute pellets.

We asked if tobramycin-loaded calcium sulfate pellets could be used to maintain high local site antibiotic concentrations for an extended period with minimal systemic levels and without adverse effects on vital organs. Calcium sulfate pellets loaded with 10% tobramycin were implanted in contained medullary defects in the proximal humeri of canines. The number of pellets implanted was calculated to yield an equivalent human maximum prescribed dose, and 1.8-fold this dose. These doses converted to approximately 20 mg/kg, and 36 mg/kg, respectively, for the canine. Local and systemic tobramycin levels, pellet resorption, bone response, clinical pathology parameters, and histopathologic responses of potential target organs were analyzed to determine if there was any adverse response for a 28-day period. Serum tobramycin was elevated for less than one day while local levels remained elevated for at least 14 days, and in some animals, 28 days. Tobramycin delivered locally from calcium sulfate pellets had no apparent adverse effect on clinical pathology parameters or on any of the organs that were analyzed. In addition, bone formation and pellet resorption followed patterns typically seen with calcium sulfate materials.

Animals↗
PubMed2004

Acetabular osteoarticular allograft after Ewing's sarcoma resection.

Ewing's sarcoma of the pelvis traditionally has been a difficult problem in orthopaedic oncology. Multiple studies have had inferior outcomes when compared with outcomes of patients with similar stage disease involving only the extremities. A major reason for this discrepancy is the difficulty associated with resection and reconstruction of pelvic tumors. Often the tumors are deemed nonresectable and are treated with chemotherapy and radiation or radiation alone. Patients treated in this manner have lower 5-year survival rates, higher local recurrence rates, and multiple long-term complications. The case of a 4-year-old girl with Ewing's sarcoma of the left hemi-pelvis is reported. Combined with adjuvant chemotherapy, this patient was treated with resection followed by osteoarticular allograft reconstruction. At 2 years followup, the patient was disease-free with an excellent functional outcome.

Acetabulum↗
PubMed2004

Blastomycosis of long bones.

The presentation of blastomycosis clinically and radiographically is nonspecific and often mistaken for a neoplasm. Delay in diagnosis is common. Patients with osseous blastomycosis present with pain and swelling. Radiographs usually show an eccentric lucency in the distal ends of long bones. These patients frequently are referred for a neoplastic workup and a diagnosis is made only after biopsy. We review the cases of five patients diagnosed with a bone tumor who had blastomycosis osteomyelitis. The time to diagnosis from original symptoms was 4.7 months (range, 3-8 months). The average age of the patients was 45.6 years (range, 20-59 years). A Musculoskeletal Tumor Society functional assessment was done. Early radiographs of the current patients ranged from normal to showing faint osteopenia in the involved location. As the disease progressed, the area of lucency appeared with either diffuse or well-marginated borders. Treatment included surgical debridement with antifungals. The mean functional score was 93.3%. All patients are disease-free. Blastomycosis, similar to tuberculosis, often is mistaken for a neoplasm. Blastomycosis osteomyelitis can be treated with excellent results. The key is diagnosis and including endemic fungal infections in the differential diagnosis of bone tumors. In addition, every potential neoplasm should include cultures of specimens obtained at biopsy.

Adult↗
PubMed2004

Results of giant cell tumor of bone treated with intralesional excision.

Treatment of giant cell tumor of bone ranges from intralesional curettage to en bloc resection. We think that intralesional treatment can be done with low recurrence and complication rates and that these patients have good functional results. The results for 40 patients treated by one surgeon with one technique for giant cell tumor of bone between 1985-1999 were reviewed. All patients were treated with intralesional excision of the tumor with adjunctive cautery, phenol, and methylmethacrylate. All patients had been followed up for a minimum of 2 years with the mean followup of 76 months (range, 26-178 months). In addition, recent functional evaluations were done on 23 patients at a mean followup of 90 months (range, 28-175 months). The local recurrence rate was 12.5%. The nononcologic complication rate was 7.5%. Using the Musculoskeletal Tumor Society functional evaluation, 93% of the patients had excellent results. This long-term followup study on patients treated with intralesional excision and methacrylate showed a low recurrence rate similar to those cited in the literature. Additionally, the complication rate was low and the function results were excellent.

Adolescent↗
PubMed2004

Telomerase reverse transcriptase subunit expression is associated with chondrosarcoma malignancy.

Expression of the telomerase reverse transcriptase subunit telomerase reverse transcriptase gene is associated with most human malignancies. Because telomerase reverse transcriptase is rarely expressed in normal tissue, its presence in pathologic specimens is considered a marker of transformed cells. Moreover, high levels of expression have been correlated with poor prognosis in many cancers. Although telomerase activity has been found in chondrosarcomas, its prognostic significance in these malignant cartilage tumors is unknown. Malignancy in cartilage-derived tumors is assessed routinely by histomorphologic grading, but even well differentiated, low-grade lesions can metastasize. This unpredictable behavior greatly complicates the clinical treatment of cartilage tumors, making better prognostic indicators desirable. To address this issue we used immunohistochemistry to compare telomerase reverse transcriptase expression in a collection of 61 tumors consisting of malignant chondrosarcomas of varying grade and benign enchondromas. Associated case histories were reviewed to test the hypothesis that telomerase reverse transcriptase expression levels correlated with subsequent tumor recurrence. We found that the relative abundance of telomerase reverse transcriptase-expressing cells correlated significantly with grade and recurrence. These findings indicate that telomerase reverse transcriptase immunostaining may be a useful adjunct to the conventional three-level grading system.

Biomarkers, Tumor↗
PubMed2004

Functional outcomes of bone graft substitutes for benign bone tumors.

Benign bone tumors are frequently treated surgically by intralesional excision with grafting. Due to the significant morbidity associated with autogenous graft, there is interest in bone graft substitutes. Ninety-eight consecutive patients with benign bone tumors treated by intralesional excision with bone graft substitutes were retrospectively reviewed. Functional scores using the International Symposium of Limb Salvage (ISOLS) system were obtained at most recent follow-up. The mean functional score was 28.3 out of 30 (94%). Three patients suffered fractures that ultimately healed with management. There were no local recurrences. Based on results of this study, bone graft substitutes are a reasonable alternative to autogenous grafting with a successful functional outcome.

Adolescent↗
PubMed2003

Osseous healing using injectable calcium sulfate-based putty for the delivery of demineralized bone matrix and cancellous bone chips.

Three formulations of injectable calcium sulfate-based putties containing demineralized bone matrix (DBM), 50% DBM/50% cancellous bone (CB) chips, and 30% DBM/70% CB were studied in canines. Four humeral defects per dog were implanted with one of each of the putty formulations while the fourth defect was left untreated. After 6 weeks, the dogs were euthanized. Radiographs and histology showed that the area fraction of new bone in the defects was greater for the three putty formulations than the untreated defects. The area of residual cancellous bone graft remaining in the defects was <10% in both CB putties. Residual calcium sulfate was not apparent in any of the histological sections. We conclude that fast-resorbing calcium sulfate-based putties are effective delivery means of bone graft materials for the successful restoration of bony defects.

Animals↗
PubMed2003

Resorption evaluation of a large bolus of calcium sulfate in a canine medullary defect.

New bone formation and resorption of a calcium sulfate bone graft substitute implanted in five canines were evaluated in this study. Healing was assessed radiographically at 2, 6, and 13 weeks. At 13 weeks, the dogs were sacrificed, and the humeri were retrieved. High-resolution contact radiographs of the isolated humeri were obtained and the bones were sectioned for histology. Radiographically, the calcium sulfate appeared to be completely resorbed and replaced by bone at 13 weeks. Histological findings suggest that a residual amount of calcium sulfate remained, which may continue to act as an osteoconductive scaffolding. No adverse inflammatory response was observed.

Animals↗
PubMed2002

The human homolog of yeast SEP1 is a novel candidate tumor suppressor gene in osteogenic sarcoma.

The hSEP1 gene is the human homolog of yeast SEP1. Yeast SEP1 is a multifunctional gene that regulates a variety of nuclear and cytoplasmic functions including homologous recombination, meiosis, telomere maintenance, RNA metabolism and microtubule assembly. The function of hSEP1 is not known. We show loss or reduced expression of hSEP1 messenger RNA (mRNA) in three of four primary osteogenic sarcoma (OGS)-derived cell lines and in eight of nine OGS biopsy specimen. In addition, we find a heterozygous missense mutation (Valine(1484)>Alanine) at a conserved amino acid in the primary OGS-derived cell line U2OS. Importantly, we identified a homozygous missense mutation involving a CG-dinucleotide leading to a change in a conserved amino acid, aspartic acid(1137) >asparagine, in the primary OGS-derived cell line, TE85. hSEP1 mRNA expression was nearly undetectable in TE85 and low in U2OS cell lines. None of these mutations were identified in 20 normal samples consisting of bone, cartilage and fibroblast. The hSEP1 gene is located in chromosome 3 at 3q25-26.1 between markers D3S1309 and D3S1569. An adjacent locus defined by the polymorphic markers D3S1212 and D3S1245 has previously been reported to undergo loss of heterozygosity (LOH) at a >70% frequency in OGS and claimed to harbor an important tumor suppressor gene in osteosarcoma. The homozygous mutation in the hSEP1 mRNA in TE85 cell line suggest that this gene itself is subject to LOH. Taken together, these results suggest that hSEP1 acts as a tumor suppressor gene in OGS.

Base Sequence↗
PubMed2002

The treatment of chronic osteomyelitis with a biodegradable antibiotic-impregnated implant.

The use of local antibiotics from a biodegradable implant for chronic osteomyelitis is an attractive alternative. The implant delivers high tissue levels, obliterates dead space, aids bone repair and does not need to be removed. The purpose of this paper is to review our early clinical experience with custom-made calcium sulfate (Osteoset bone void filler) antibiotic-impregnated implants.

Absorbable Implants↗
PubMed2002

Malignant transformation in human chondrosarcoma cells supported by telomerase activation and tumor suppressor inactivation.

Human chondrosarcomas do not respond to current chemotherapies or radiation therapy, and their size and histological appearance do not reliably predict the risk of local recurrence and metastases, making selection of surgical treatment difficult. Identifying mechanisms responsible for the proliferation and invasive behavior of these tumors would be of immense clinical value. We hypothesized that telomerase expression is one of these mechanisms. We detected telomerase expression in 7 of 16 chondrosarcomas, but cells cultured from telomerase-negative chondrosarcomas acquired strong telomerase activity and lost tumor suppressor activity after their establishment in culture. These changes were associated with accelerated indefinite cell proliferation, morphological transition, and increased invasive activity, indicating that telomerase activation and loss of cell cycle control leads to the emergence of aggressive cells from chondrosarcoma cell populations. These observations may lead to better understanding of the factors responsible for malignant transformation, local recurrence, and metastases of cartilage neoplasms.

Adult↗