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Biomedical subjects

J D Graham

Publications and source records attributed to J D Graham.

At least 19 recordsLinked to original sources
PubMed2006

Tamoxifen treatment promotes phosphorylation of the adhesion molecules, p130Cas/BCAR1, FAK and Src, via an adhesion-dependent pathway.

Reports that the adhesion-associated molecule p130Cas/BCAR1 promotes resistance to tamoxifen suggested that adhesion-mediated signalling may be altered by tamoxifen treatment. We find that p130Cas/BCAR1 phosphorylation is enhanced in tamoxifen-treated estrogen receptor (ER)-positive MCF-7 breast cancer cells. The effects of estrogen and tamoxifen were assessed independently and in combination, and the results demonstrate that tamoxifen antagonizes estrogen regulation of p130Cas/BCAR1 phosphorylation. Phosphorylation correlates with tamoxifen ER antagonist effects, as phosphorylation effects are replicated by the pure antiestrogen ICI 182, 780. Correspondingly, phosphorylation is not changed in ER-negative cells exposed to tamoxifen. We show that deletion of the p130Cas/BCAR1 substrate domain substantially reduces tamoxifen-induced phosphorylation of p130Cas/BCAR1 and confers enhanced sensitivity to tamoxifen. P130Cas/BCAR1 forms a phosphorylation-dependent signalling complex with focal adhesion kinase (FAK) and Src kinase that promotes adhesion-mediated cell survival. Therefore, we examined the kinetics of p130Cas/BCAR1, Src and FAK phosphorylation over a 14-day time course and find sustained phosphorylation of these molecules after 7 days exposure to tamoxifen. Inhibition of Src kinase is shown to reduce tamoxifen-promoted p130Cas/BCAR1 phosphorylation and reduce cell viability. Stimulation of the Src/FAK/p130Cas/BCAR1 adhesion signalling pathway in tamoxifen-treated MCF-7 cells does not cause increased migration; however, there is Src-dependent phosphorylation of the cell survival molecule Akt. Correspondingly, Akt inhibition reduces cell viability in cells treated with tamoxifen. We propose that prolonged activation of adhesion-dependent signalling may confer a survival advantage in response to additional cellular insults or alternatively, may poise cells to develop a migratory phenotype in response to additional cellular cues.

Antineoplastic Agents, Hormonal↗
PubMed2005

A randomised comparison of treosulfan and carboplatin in patients with ovarian cancer: a study by the Scottish Gynaecological Cancer Trials Group (SGCTG).

The management of older and unfit women with advanced ovarian cancer requires post-operative chemotherapy but many of these patients are not suitable for high-dose cisplatin-based regimes. Carboplatin has been an easier alternative and can be given in the ambulatory setting. Historical data suggests that oral alkylating agents to be just effective with similar efficacy. In this study we have compared platinum-based carboplatin to the alkylating agent treosulfan in a population unfit to receive high-dose cisplatin. The trial randomised patients to either intravenous carboplatin or treosulfan as single agent. The trial was stopped prematurely after the interim analysis showed improved survival and response rates in the carboplatin arm. We conclude that carboplatin is a safe and effective drug in a population that is unfit for high-dose cisplatin. Treosulfan showed limited activity but may be considered along with other oral drugs in limited circumstances. With the exception of myelosuppression, toxicity was mild in both arms. Carboplatin remains the gold standard in this older and less fit group of patients.

Aged↗
PubMed2005

Adjuvant bleomycin, vincristine and cisplatin (BOP) for high-risk stage I non-seminomatous germ cell tumours: a prospective trial (MRC TE17).

Adjuvant BEP (bleomycin, etoposide, cisplatin) is effective treatment for high-risk clinical stage I (HRCS1) non-seminomatous germ cell tumours (NSGCT), but the known toxicities of etoposide, and the expansion of the HR group to any patient with vascular invasion (50% of patients), led the Medical Research Council to pilot the BOP regimen. Patients received two courses of BOP 14 days apart: cisplatin 50 mg m(-2) days 1 and 2, vincristine 1.4 mg m(-2) (max. 2 mg) days 2 and 8, bleomycin 30,000 IU days 2 and 8. Primary outcome was relapse rate; quality of life, fertility, hearing and lung function were assessed pre- and post-treatment. In all, 100 patients were required. A total of 115 eligible patients were registered, all received two courses of chemotherapy. Median follow-up is 70 months; two relapses have occurred and the 5-year relapse-free rate is 98.3% (95% confidence interval (CI) 95.5%, 99.9%). As assessed by clinicians during treatment, complete (reversible) alopecia was present in 20% of patients; World Health Organization (WHO) grade 1/2 neurotoxicity was present in 41%/5% of patients during treatment and 22%/1% at 6 months. However, 12% of patients reported 'quite a bit' or 'very much' pain/numbness/tingling in hands/feet 2 years after chemotherapy. Mature follow-up confirms high efficacy for two courses of cisplatin-based adjuvant chemotherapy in HRCS1 NSGCT. Substituting vincristine for etoposide decreases alopecia, but gives a low incidence of significant neuropathy. There are no clearcut advantages to 2 x BOP over 2 x BEP, except for patients who wish to maximise the chance of avoiding significant alopecia.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Cytoskeletal responsiveness to progestins is dependent on progesterone receptor A levels.

Changes in the cell cytoskeleton occur in cell transformation and recent data suggest the involvement of ovarian hormones, which are implicated in cancer development and progression. In human breast and endometrial tumors, there is disrupted expression of progesterone receptor (PR) isoforms and predominance of one isoform, usually PRA. PRA predominance is an early event in carcinogenesis, and in cancers is associated with poor clinical features. Overexpression of PRA in vitro causes altered progestin regulation of cell morphology, suggesting that PRA overexpression may provoke deleterious changes in cell functioning. This study aimed to identify pathways of cytoskeleton regulation responsive to progestins and to determine whether these are perturbed when PRA is overexpressed to the levels seen in cancers. Progestin treatment of PR-positive breast cancer cells caused increased cell surface area whereas after induction of a stably integrated PRA construct, cells became rounded and the cell surface was decreased. The effect of PRA induction on cell rounding was reversed by the anti-progestin RU38486. Altered tropomyosin (Tm) isoforms were implicated in these morphological differences, as there was a PRA-mediated alteration in Tm5 isoform levels, and transfection of Tm5a mimicked progestin-mediated cell rounding in PRA-overexpressing cells. Ezrin was redistributed from the membrane to cytoplasmic locations in the presence of progestin, and discrete focal localization was evident in cells with PRA predominance. Progestin effects on the cytoskeleton in PRA-overexpressing cells provide evidence for novel endocrine regulation of aspects of actin microfilament composition, suggesting that changes in the cytoskeleton known to be associated with cancer development and progression may be regulated in part by altered PRA expression which develops early in carcinogenesis.

Actin Cytoskeleton↗
PubMed2002

Effect of lonophore supplementation on selected serum constituents of sheep consuming locoweed.

The effects of ionophore supplementation on selected serum constituents of sheep consuming locoweed were investigated. Sixteen sheep were allotted by weight to a 2x2 factorial arrangement of treatments: 1) no locoweed, no lasalocid, 2) no locoweed, 0.75 mg lasalocid/kg BW, 3) 0.5 mg swainsonine/kg BW, no lasalocid, 4) 0.5 mg swainsonine/kg BW, 0.75 mg lasalocid/kg BW. Swainsonine was provided by locoweed (Oxytropissericea), and sheep were fed a blue grama based diet at 2.5% BW for a 35 d treatment period. Diets were formulated to be isocaloric and isonitrogenous. Blood samples were collected on d 1, 7,14, 21, 31 and 35 to determine serum swainsonine concentration, alkaline phosphatase, total iron, aspartate aminotransferase, g-glutamyltransferase, and lactate dehydrogenase activity and total cholesterol, and triglyceride concentrations. No lasalocid by locoweed interaction (P > 0.4) was noted for any response variable measured. Average daily gains (P = 0.4) and orts (P = 0.7) were not affected by the treatments. No lasalocid treatment (P = 0.7) or day (P = 0.1) effect of serum swainsonine was observed. A locoweed by day interaction (P < 0.0001) of serum alkaline phosphatase was detected. Alkaline phosphatase levels were elevated (P < 0.01) for locoweed treated sheep at 24 h following initial exposure and remained elevated throughout the trail. Total iron was suppressed (P < 0.08) in locoweed fed sheep. A day effect (P < 0.02) was observed for serum iron. However, no linear, quadratic, or cubic effects of day were noted (P >0.2). A locoweed by day interaction (P < 0.0001) of serum aspartate aminotransferase and g-glutamyltransferase was detected. Aspartate aminotransferase levels were elevated (P < 0.0001) by d 7 for locoweed treated animals and remained elevated throughout the trial. g--Glutamyltransferase levels were suppressed (P < 0.0001) by day 7 for locoweed treated animals and remained suppressed throughout the trial. A locoweed by day interaction (P = 0.06) of serum cholesterol was detected. However, no linear, quadratic, or cubic effects of day were detected (P = 0.2). Lasalocid treatment had no effect on any serum constituent measured. Use of lasalocid in grazing animals should not increase the likelihood of locoweed intoxication.

Alkaline Phosphatase↗
PubMed2001

Predictors of hazardous child seating behavior in fatal motor vehicle crashes: 1990 to 1998.

OBJECTIVE: Motor vehicle crashes are the leading cause of death in children ages 5 to 14. Children seated in the front seats of vehicles are at increased risk of death and injury in crashes, particularly in vehicles with passenger-side air bags. This study identifies factors associated with the seating of children in the front seats of vehicles involved in fatal crashes between 1990 and 1998. METHODS: Using 1990 to 1998 data from the Fatal Analysis Reporting System, a US census of motor vehicle crashes involving a fatality, multivariable logistic regression was used to model the association between child seating behavior and vehicle, driver, and occupant characteristics. RESULTS: The proportion of vehicles carrying children in the front declined from 42% to 31% over the 9-year period. Controlling for driver and vehicle characteristics, the risk of front-seating declined between 1990 and 1998, and this risk was smaller in vehicles carrying only younger children (</=6 years) than in those carrying older children. In the 3 years after the introduction of dual air bags into a significant proportion of the passenger fleet in late 1995, dual air bags were associated with fewer children being seated in the front seat. By the end of 1998, traveling in a vehicle with dual air bags and only children age 6 or younger was associated with a 95% lower chance of a child being seated in the front (odds ratio = 0.05; 95% confidence interval: 0.04-0.08). An important factor in safer seating position was the presence of multiple passengers, especially an older one, and children were at higher risk of front-seating when they traveled alone with the driver. CONCLUSIONS: The 1990s saw a decline in front-seating of children in vehicles involved in fatal crashes among all types of vehicles and drivers. Although this trend is encouraging, children ages 6 to 12 and children traveling alone with the driver remain at higher risk of being seated in the front. These traveling situations should be targeted for behavioral safety interventions to improve child motor vehicle safety.

Accidents, Traffic↗
PubMed2001

Where children sit in cars: the impact of Rhode Island's new legislation.

OBJECTIVES: This study evaluated the impact of Rhode Island's legislation requiring children younger than 6 years to sit in the rear of motor vehicles. METHODS: Roadside observations were conducted in Rhode Island and Massachusetts in 1997 and 1998. Multivariate regression was used to evaluate the proportion of vehicles carrying a child in the front seat. RESULTS: Data were collected on 3226 vehicles carrying at least 1 child. In 1998, Rhode Island vehicles were less likely to have a child in the front seat than in 1997 (odds ratio = 0.6; 95% confidence interval = 0.5, 0.7), whereas no significant changes in child passenger seating behavior occurred in Massachusetts during that period. CONCLUSIONS: Rhode Island's legislation seems to have promoted safer child passenger seating behavior.

Age Factors↗
PubMed2000

Thoughts on tamoxifen resistant breast cancer. Are coregulators the answer or just a red herring?

The antiestrogen tamoxifen is an effective treatment for estrogen receptor positive breast cancers, slowing tumor growth and preventing disease recurrence, with relatively few side effects. However, many patients who initially respond to treatment, later become resistant to treatment. Tamoxifen has both agonist and antagonist activities, which are manifested in a tissue-specific pattern. Development of tamoxifen resistance can be characterized by an increase in the partial agonist properties of the antiestrogen in the breast, resulting in loss of growth inhibition and even inappropriate tumor stimulation. Nuclear receptor function is modulated by transcriptional coregulators, which either enhance or repress receptor activity. Using a mixed antagonist-biased two-hybrid screening strategy, we identified two such proteins: the human homolog of the nuclear receptor corepressor, N-CoR, and a novel coactivator, L7/SPA (Switch Protein for Antagonists). In transcriptional studies N-CoR suppressed the agonist properties of tamoxifen and RU486, while L7/SPA increased agonist effects. We speculated that the relative level of these coactivators and corepressors might determine the balance of agonist and antagonist properties of mixed antagonists such as tamoxifen. Using quantitative RT-PCR we therefore measured the levels of transcripts encoding these coregulators, as well as the corepressor SMRT, and the coactivator SRC-1, in a small cohort of tamoxifen resistant and sensitive breast tumors. The results suggest that tumor sensitivity to mixed antagonists may be governed by a complex set of transcription factors, which we are only now beginning to understand.

Animals↗
PubMed2000

A randomized trial of hypofractionated schedules of palliative radiotherapy in the management of bladder carcinoma: results of medical research council trial BA09.

PURPOSE: To compare the efficacy and toxicity of two hypofractionated radiotherapy schedules for the improvement of local symptoms from muscle-invasive bladder cancer. METHODS AND MATERIALS: A multicenter randomized trial was conducted comparing the efficacy and toxicity of two radiotherapy schedules (35 Gy in 10 fractions and 21 Gy in 3 fractions) for symptomatic improvement in patients considered unsuitable for curative treatment through disease stage or comorbidity. The primary outcome measures were overall symptomatic improvement of bladder-related symptoms at 3 months and changes in bladder- and bowel-related symptoms from pretreatment to end-of-treatment and 3-month assessments. Overall symptomatic improvement was defined prospectively as the improvement in one bladder-related symptom of at least one grade at 3 months, with no deterioration in any other bladder-related symptom. RESULTS: Five hundred patients were recruited, but data on symptomatic improvement at 3 months was only available on 272 patients. Of these, 68% achieved symptomatic improvement (71% for 35 Gy, 64% for 21 Gy), with no evidence of a difference in efficacy or toxicity between the two arms. There was no evidence of a difference in survival between the two schedules (hazard ratio [HR] = 0.99, 95% CI 0.82-1.21, p = 0. 933). CONCLUSION: This is the largest prospective trial to date in the palliative treatment of bladder cancer, and provides baseline data against which other results may be compared. The use of 21 Gy in 3 fractions appears as effective as 35 Gy in 10 fractions, although modest differences in survival, symptomatic improvement rates, and toxicity can not be reliably excluded.

Aged↗
PubMed2000

Estrogen receptors alpha and beta: prevalence of estrogen receptor beta mRNA in human vascular smooth muscle and transcriptional effects.

BACKGROUND: Estrogens have vascular effects through the activation of estrogen receptors (ERs). In addition to ERalpha, the first ER to be cloned, a second subtype called ERbeta has recently been discovered. METHODS AND RESULTS: Using a reverse-transcriptase polymerase chain reaction assay that employs the same primer pair to simultaneously amplify ERalpha and ERbeta transcripts, we found that ERbeta is the ER form that is predominantly expressed in human vascular smooth muscle, particularly in women. The transcriptional effects of the 2 ERs in transfected HeLa cells differed. In response to 17beta-estradiol, ERalpha is a stronger transactivator than ERbeta at low receptor concentrations. However, at higher receptor concentrations, ERalpha activity self-squelches, and ERbeta is a stronger transactivator. Tamoxifen has partial agonist effects with ERalpha but not with ERbeta. CONCLUSIONS: The protective effects of estrogens in the cardiovascular system of women may be due to the genomic effects of ERbeta in vascular tissue.

Estradiol↗
PubMed2000

Child passenger safety: decisions about seating location, airbag exposure, and restraint use.

The installation of passenger-side airbags in new vehicles complicates efforts to maximize child safety in motor vehicle crashes. It has been recommended by both public and private organizations that children sit in the rear seat with proper restraint to achieve maximum safety. Drivers now need to decide whether a child should be restrained, where the child should be seated (front versus rear), and whether the child should be seated in front of a passenger-side airbag. This research was undertaken to determine which choice minimizes the risk of fatality to children. Using data from the U.S. Fatality Analysis Reporting System for calendar years 1989 to 1998, fatal vehicle crashes with child passengers younger than 13 years were analyzed. The effectiveness of passenger-side airbags and rear seating for children, by age category and restraint use, was estimated using the double-pair comparison method. For each of four age categories, the fatality risk of each possible combination of restraint use, seating location, and airbag presence was also estimated using logistic regression. Passenger airbags were associated with an increase in child fatality risk of 31% for restrained children, and 84% for unrestrained children. Passenger airbags did appear to offer protection to restrained 9- to 12-year-old children. Restraint use and rear seating were associated with statistically significant reductions in the odds of a child dying in a crash. In order to minimize child fatality risk, parents should seat children in the rear of the vehicle while using the proper child restraint system, especially in vehicles with passenger airbags. These findings support current public education efforts in the United States.

Accidents, Traffic↗
PubMed2000

Patterns of injury among drivers hospitalized in Level-I Trauma Centers: have frontal airbags made a difference?

This study describes the injuries of drivers discharged from Level-I Trauma Centers between 1995-1997. Differences in the drivers' injuries and outcomes by airbag deployment status and gender were evaluated using Chi 2 and T-tests. Data on 1,065 drivers (66 with airbags, 423 females) were obtained from the Massachusetts Registry of Motor Vehicle and Trauma Registries. Once admitted to trauma centers, drivers with airbags did not differ from drivers without airbags regarding the number, type, clustering, severity or outcome of their injuries. The only exception was that female drivers sustained more fractures to the upper extremities and less injuries to blood vessels and certain traumatic complications (p < 0.05).

Abbreviated Injury Scale↗
PubMed1999

Airbags: an exploratory survey of public knowledge and attitudes.

The present study examines public knowledge and opinion in the United States on issues related to airbag safety. Data were obtained through a national random digit-dial telephone survey of 1005 people living in the contiguous 48 United States. A majority of respondents (1) know that airbags can harm drivers seated too close to the steering wheel; (2) know that rear-facing infant seats should not be placed in the front seat of a car with passenger-side airbags; and (3) know that airbags are saving more lives of women drivers than are being lost. However, most respondents did not know that (1) airbags are killing more children than they are saving; (2) airbags can injure properly belted drivers; and (3) the majority of the lives saved by airbags have been among people who were not wearing safety belts. Knowledge of airbag risks to children and properly belted drivers was significantly associated with a less favorable attitude toward airbags, and with opposition toward the law mandating airbags on all new cars. Drivers of vehicles equipped with airbags held more favorable attitudes toward airbag technology. Further analysis suggests that as the public begins to understand the risks associated with airbags, the current high level of public support for the technology and the mandatory regulation may decline.

Accidents, Traffic↗
PubMed1999

Residential building codes, affordability, and health protection: a risk-tradeoff approach.

Residential building codes intended to promote health and safety may produce unintended countervailing risks by adding to the cost of construction. Higher construction costs increase the price of new homes and may increase health and safety risks through "income" and "stock" effects. The income effect arises because households that purchase a new home have less income remaining for spending on other goods that contribute to health and safety. The stock effect arises because suppression of new-home construction leads to slower replacement of less safe housing units. These countervailing risks are not presently considered in code debates. We demonstrate the feasibility of estimating the approximate magnitude of countervailing risks by combining the income effect with three relatively well understood and significant home-health risks. We estimate that a code change that increases the nationwide cost of constructing and maintaining homes by $150 (0.1% of the average cost to build a single-family home) would induce offsetting risks yielding between 2 and 60 premature fatalities or, including morbidity effects, between 20 and 800 lost quality-adjusted life years (both discounted at 3%) each year the code provision remains in effect. To provide a net health benefit, the code change would need to reduce risk by at least this amount. Future research should refine these estimates, incorporate quantitative uncertainty analysis, and apply a full risk-tradeoff approach to real-world case studies of proposed code changes.

Energy-Generating Resources↗