Biomedical subjects

James A Martin

Publications and source records attributed to James A Martin.

23 records · Page 2Linked to original sources

PubMed2002

Effects of telomerase and viral oncogene expression on the in vitro growth of human chondrocytes.

Senescent chondrocytes accumulate with aging in articular cartilage, a process that interferes with cartilage homeostasis and increases the risk of cartilage degeneration. We showed previously that chondrocyte telomere length declines with donor age, which suggests that the aging process is telomere dependent. From these results we hypothesized that telomerase should delay the onset of senescence in cultured chondrocytes. Population doubling limits (PDL) were determined for chondrocytes expressing telomerase. We found that telomerase alone did not extend PDL beyond controls that senesced after 25 population doublings. The human papillomavirus 16 oncogenes E6 and E7 were transduced into the same cell population to investigate this telomere-independent form of senescence further. Chondrocytes expressing E6 and E7 grew longer than the telomerase cDNA (hTERT) cells but still senesced at 55 population doublings. In contrast, chondrocytes expressing telomerase with E6 and E7 grew vigorously past 100 population doublings. We conclude that although telomerase is necessary for the indefinite extension of chondrocyte life span, telomere-independent senescence limits PDL in vitro and may play a role in the age-related accumulation of senescent chondrocytes in vivo.

Cells, Cultured↗

PubMed2002

Attributional style in schizophrenia: an investigation in outpatients with and without persecutory delusions.

The attributional style of outpatients with schizophrenia with and without persecutory delusions was investigated. Thirty individuals with schizophrenia were divided into persecutory-deluded and non-persecutory-deluded groups based on a score of 5 or higher on the suspiciousness item from the Expanded Brief Psychiatric Rating Scale (BPRS-E). The two resulting groups, and a nonclinical control group, were administered a battery of attributional measures, and their attributional responses were coded by both the subjects themselves and a pair of independent raters. The results showed evidence of a self-serving bias for subjects with persecutory delusions; however, this bias was not unique to those with persecutory delusions, and it disappeared when independent raters evaluated subjects' causal statements on a reliable measure of attributional style. Subjects with persecutory delusions tended to show a stronger bias toward blaming others rather than situations for negative outcomes, and there was a linear association between persecutory ideation and a self-serving attributional style. Finally, there were significant discrepancies between the attributional ratings of the persecutory-deluded subjects and those of independent judges. Implications for future research are discussed.

Adult↗

PubMed2002

Human chondrocyte senescence and osteoarthritis.

Although osteoarthritis (OA) is not an inevitable consequence of aging, a strong association exists between age and increasing incidence of OA. We hypothesized that this association is due to in vivo articular cartilage chondrocyte senescence which causes an age-related decline in the ability of the cells to maintain articular cartilage, that is, increasing age increases the risk of OA because chondrocytes lose their ability to replace their extracellular matrix. To test this hypothesis, we measured senescence markers in human articular cartilage chondrocytes from 27 donors ranging in age from one to 87 years. The markers included expression of the senescence-associated enzyme beta-galactosidase, mitotic activity measured by 3H-thymidine incorporation, and telomere length. beta-galactosidase expression increased with age (r=0.84, p=0.0001) while mitotic activity and mean telomere length declined (r=-0.774, p=0.001 and r=-0.71, p=0.0004, respectively). Decreasing telomere length was strongly correlated with increasing expression of beta-galactosidase and decreasing mitotic activity. These findings help explain the previously reported age related declines in chondrocyte synthetic activity and responsiveness to anabolic growth factors and indicate that in vivo articular cartilage chondrocyte senescence is responsible, at least in part, for the age related increased incidence of OA. The data also imply that people vary in their risk of developing OA because of differences in onset of chondrocyte senescence; and, the success of chondrocyte transplantation procedures performed to restore damaged articular surfaces in older patients could be limited by the inability of older chondrocytes to form new cartilage. New efforts to prevent the development or progression of OA might include strategies that delay the onset of chondrocyte senescence or replace senescent cells.

Aging↗

PubMed2002

Chondrocyte senescence and telomere regulation: implications in cartilage aging and cancer (a brief review).

Recent studies on osteoarthritis and the cartilage aging in our laboratory demonstrate that chronologic age correlates with molecular changes in human chondrocytes that affect cell cycle control and replicative life span. These findings indicate that age-related changes in chondrocytes may explain the heightened risk for development of primary osteoarthritis (OA) with increasing age. Concomitant studies of human chondrosarcoma suggest that these aging mechanisms may also play a role in preventing the malignant transformation of chondrocytes. The convergence at the molecular level of these seemingly dissimilar biologic processes provides an excellent opportunity to deepen our understanding of the fundamental processes underlying cartilage neoplasia, cartilage aging, and osteoarthritis.

Cartilage↗

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↗