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Biomedical subjects

Malcolm Smith

Publications and source records attributed to Malcolm Smith.

12 recordsLinked to original sources
PubMed2005

Detection of the p53 regulator murine double-minute protein 2 in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is characterized by hyperplasia of synovial lining tissue, which is involved directly in the damage of cartilage and bone. One of the factors thought to contribute to this synovial lining hyperplasia is dysregulation of, or functional abnormality in, the tumor suppressor protein p53. The protein known as murine double-minute protein 2 (MDM2) is the major negative regulator of p53, and in tumors contributes to increased cell proliferation. The detection of MDM2 in rheumatoid synovium has not previously been described. We investigated whether this protein is detectable in cells and tissues derived from patients with RA. METHODS: Expression of MDM2 protein was examined in fibroblast-like synoviocytes (FLS) by methods including permeabilization flow cytometry, immunofluorescence, and Western blotting, and in synovial tissues using immunohistochemistry. The proliferative capacity of these cells was also examined using 3H/thymidine incorporation. Cell cycle analysis was performed by propidium iodide incorporation. RESULTS: MDM2 was detected in RA FLS and synovial tissues. MDM2 protein was identified in CD14-positive and CD14-negative synovial lining cells and CD14-positive sublining cells. RA FLS exhibited faster proliferative rates and higher levels of MDM2 expression than FLS derived from patients with osteoarthritis (OA). Both OA and RA FLS were found to be in similar phases of the cell cycle at the time of MDM2 protein analysis. CONCLUSION: The abundant expression of MDM2 in RA may be a contributing factor to the hypoapoptotic phenotype of lining tissue through its capacity to downregulate p53 levels and effects. Further studies are required to determine the relationship between this cell-cycle protein profile, tissue hyperplasia, and the functional abnormality of p53 in RA.

Animals↗
PubMed2003

Prevalence and effect of spawner-isolated mortality virus on the hatchery phases of Penaeus monodon and P. merguiensis in Australia.

Spawner-isolated mortality virus (SMV) has been associated with mortalities in broodstock of Penaeus monodon and with mid-crop mortality syndrome on grow-out farms. Epidemiological evidence suggested an association between the SMV status of broodstock and subsequent survival of their progeny, and this paper describes investigations into that association. The faeces of 909 broodstock in 9 different groups were tested by a polymerase chain reaction (PCR) for SMV and positive results were confirmed by an internal dot-blot. Seventy-seven spawners (8.5%) were positive for SMV with prevalence ranging from 0 to 24% among groups. The prevalence in spawners of P. monodon was higher (24%) than in P. merguiensis (4%). Three longitudinal studies were undertaken to compare the survival of progeny from broodstock that were positive to SMV with those that were not. Survival in hatchery tanks of progeny from SMV-positive spawners was lower than those from SMV-negative spawners with reductions of 23% (p = 0.01), 7.3% (p = 0.214) and 18.9% (p = 0.129) in the 3 studies. The conclusions were less consistent when examined during each of the later stages of growth in hatchery pools, nursery and grow-out ponds, with progeny from SMV-postive spawners sometimes having better survival rates. However, survival was better overall in progeny from SMV-negative spawners. Simple linear regression showed survival was negatively related to the proportion of postlarvae from SMV-positive spawners, with a decrease in survival of 5.6% for each 10% increase in the proportion of postlarvae coming from SMV-positive spawners (p = 0.006). Data from 38 ponds showed 6.71% of losses were due to SMV. If these losses were consistent across the entire industry, the annual loss due to SMV would have been approximately AUD 3 million in 1999/2000.

Animals↗
PubMed2003

Regulatory approvals of pediatric oncology drugs: previous experience and new initiatives.

PURPOSE: To review the Food and Drug Administration (FDA) experience with approvals of new drugs for pediatric oncology and to discuss new regulatory initiatives directed at pediatric oncology. METHODS: A retrospective review of FDA archival documents and the published literature. RESULTS: More than 100 drugs have been approved by the Division of Oncology Drug Products of the FDA for the treatment of malignancies. Only 15 have pediatric use information in their labeling, which is less than 50% of the drugs commonly used in the treatment of pediatric malignancies. In the past 20 years, there have been six submissions to the FDA for pediatric oncology indications. To illustrate principles of the approval process, each submission is discussed. CONCLUSION: Potential reasons for a lack of New Drug Application submissions for pediatric oncology include the small pediatric oncology market compared with the adult oncology market and perceived barriers to performing studies in children. Reasons for failure to approve pediatric indications include small numbers of patients, lack of appropriate controls, and failure to demonstrate patient benefit. Approval criteria include the use of controlled trials, prospective data collection, and disease-appropriate end points. Regulatory initiatives to promote pediatric therapeutic development and product labeling are discussed.

Antineoplastic Agents↗
PubMed2002

How sociodemographics, presence of oncology specialists, and hospital cancer programs affect accrual to cancer treatment trials.

PURPOSE: We chose to examine the impact of socioeconomic factors on accrual to National Cancer Institute (NCI)-sponsored cancer treatment trials. PATIENTS AND METHODS: We estimated the geographic and demographic cancer burden in the United States and then identified 24,332 patients accrued to NCI-sponsored cancer treatment trials during a 12-month period. Next, we examined accrual by age, sex, geographic residence, health insurance status, health maintenance organization market penetration, several proxy measures of socioeconomic status, the availability of an oncologist, and the presence of a hospital with an approved multidisciplinary cancer program. RESULTS: Pediatric patients were accrued to clinical trials at high levels, whereas after adolescence, only a small percentage of cancer patients were enrolled onto clinical trials. There were few differences by sex. Black males as well as Asian-American and Hispanic adults were accrued to clinical trials at lower rates than white cancer patients of the same age. Overall, the highest observed accrual was in suburban counties. Compared with the United States population, patients enrolled onto clinical trials were significantly less likely to be uninsured and more like to have Medicare health insurance. Geographic areas with higher socioeconomic levels had higher levels of clinical trial accruals. The number of oncologists and the presence of approved cancer programs both were significantly associated with increased accrual to clinical trials. CONCLUSION: We must work to increase the number of adults who enroll onto trials, especially among the elderly. Ongoing partnership with professional societies may be an effective approach to strengthen accrual to clinical trials.

Adolescent↗
PubMed2002

The role of INI1 and the SWI/SNF complex in the development of rhabdoid tumors: meeting summary from the workshop on childhood atypical teratoid/rhabdoid tumors.

A workshop on childhood atypical teratoid/rhabdoid tumors of the central nervous system, sponsored by the National Cancer Institute and the Pediatric Brain Tumor Foundation of the United States, was held on January 29, 2001 in Bethesda, Maryland. Drs. Malcolm Smith, Jaclyn Biegel, and Roger Packer hosted the meeting. There were 22 participants from 14 institutions. The sessions were designed to review what was known about the biology and clinical behavior of rhabdoid tumors and to begin to develop treatment strategies that might be effective against this clinically aggressive group of malignancies. This report summarizes the biology sessions from the meeting. A detailed summary of the discussions regarding diagnostic studies and the roles for radiation therapy, chemotherapy, and bone marrow or stem cell transplant in the treatment of rhabdoid tumors will be published separately.

Central Nervous System Neoplasms↗
PubMed2002

Current management of U-shaped sacral fractures or spino-pelvic dissociation.

We present a series of four U-shaped sacral fractures, a fracture pattern that is poorly recognised and not included in the standard classifications of these fractures. These fractures are significant as they represent spino-pelvic dissociation, have a high incidence of neurological complications and information regarding current treatment options is sparse. Our four patients underwent early operative stabilisation. Three had ilio-sacral screws inserted, supplemented in one with instrumentation from the lumbar spine to the iliac crest following sacral laminectomy. The other patient had sacral laminectomy with bony stabilisation by instrumentation from the lumbar spine to the iliac crest without ilio-sacral screw fixation. No complications were encountered as a result of fixation and it contributed to the prompt skeletal stabilisation of polytraumatised patients allowing early mobilisation.

Accidents, Traffic↗
PubMedDate not supplied

Atypical teratoid/rhabdoid tumor of the central nervous system: report on workshop.

Childhood atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS) is a recently described entity. Diagnosis is based on distinctive light microscopy and immunohistochemical findings, coupled with molecular genetic analysis. Most AT/RTs demonstrate monosomy 22 or deletions of chromosome band 22q11 with alterations of the hSNF5/INI1 gene. The tumor's incidence is still undefined, but it may comprise as high as 1 in 4 primitive CNS tumors in infants. Treatment is far from optimal, but there are occasional long-term survivors, especially among older children. Therapeutic approached have included surgery, chemotherapy, and radiotherapy. Prospective clinical trials are needed for children with AT/RTs.

Antineoplastic Agents↗
PubMedDate not supplied

An overview of progress in childhood cancer survival.

Survival for children with cancer has continued to improve over the past 20 years, with 5-year survival rates now approaching 80% and with an increasing number of children surviving into adulthood. In recognition of the need to address important issues for survivors of childhood cancer, the National Cancer Institute (NCI) has supported the Childhood Cancer Survivor Study (CCSS) since 1993. The CCSS has established a cohort of over 14,000 5-year survivors of childhood cancer initially diagnosed between 1970 and 1986 and has obtained comprehensive summaries of treatment received by these survivors through abstraction of medical records for chemotherapy, radiation therapy, and surgical procedures. Survivors in the CCSS cohort completed a baseline questionnaire and follow-up questionnaires to provide information about their current status. The CCSS collected buccal cells for DNA isolation from members of the survivor cohort to allow evaluations of the contribution of genetic factors to long-term sequelae of cancer therapy. The CCSS is now poised to expand its contributions through studies designed to gain greater insight into the biological basis for long-term adverse effects of cancer treatment and is enlarging its efforts to include more recently treated cohorts of patients. The experts present at the work group, Moving the Research Agenda Forward for Children With Cancer, offered several possibilities for utilizing CCSS data in expanding research opportunities concerned with cancer survivorship.

Age Distribution↗