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Biomedical subjects

Robert Brown

Publications and source records attributed to Robert Brown.

At least 19 recordsLinked to original sources
PubMed2004

The dl1520 virus is found preferentially in tumor tissue after direct intratumoral injection in oral carcinoma.

PURPOSE: dl1520 (also known as Onyx-015) is an E1B-deleted adenovirus designed to selectively lyse p53-deficient cancer cells. Clinical trials involving patients with recurrent squamous cell carcinoma of the head and neck have shown clinical efficacy, but no direct evidence as to the tumor or p53 selectivity of the virus was demonstrated. We wanted to determine whether dl1520 is selective for survival and replication within tumor tissue after direct injection and whether this is determined by p53 status of the tissues. We also wanted to ascertain whether the virus has any macroscopic effect on normal tissue. EXPERIMENTAL DESIGN: An open-label Phase II trial was devised in which a fixed dose of the virus was administered to 15 patients via a direct intertumoral injection before surgery for untreated oral squamous cell carcinoma. The agent was also delivered into an area of adjacent normal buccal mucosa. Specimens of the excised tumor and of biopsies of the injected normal tissue were assessed for viral presence and p53 status. RESULTS: We demonstrated that the virus replicates selectively in tumor as opposed to normal tissue after this direct injection. It was not possible to determine whether this selectivity was p53 related. It was found that dl1520 triggers an early rise in apoptosis levels in injected normal tissues. No adverse effects of viral injection were noted. CONCLUSIONS: This is the first report of injection of dl1520 into previously untreated squamous cell cancer. The data support the concept that dl1520 is replication deficient in normal, compared with cancerous, tissues and has potential as a selective anticancer agent against tumor tissues.

Adenoviridae↗
PubMed2004

The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients.

Aberrant epigenetic regulation, such as CpG island methylation and associated transcriptional silencing of genes, has been implicated in a variety of human diseases, including cancer. Methylation of genes involved in apoptosis, including the DNA mismatch repair (MMR) gene hMLH1, can occur in tumor models of resistance to chemotherapeutic drugs. However, the relevance for acquired resistance to chemotherapy of patients' tumors remains unsubstantiated. Plasma DNA from cancer patients, including those with ovarian cancer, often contains identical DNA changes as the tumor and provides a means to monitor CpG island methylation changes. We have examined plasma DNA of patients with epithelial ovarian cancer enrolled in the SCOTROC1 Phase III clinical trial for methylation of the hMLH1 CpG island before carboplatin/taxoid chemotherapy and at relapse. Methylation of hMLH1 is increased at relapse, and 25% (34 of 138) of relapse samples have hMLH1 methylation that is not detected in matched prechemotherapy plasma samples. Furthermore, hMLH1 methylation is significantly associated with increased microsatellite instability in plasma DNA at relapse, providing an independent measure of function of the MMR pathway. Acquisition of hMLH1 methylation in plasma DNA at relapse predicts poor overall survival of patients, independent from time to progression and age (hazard ratio, 1.99; 95% confidence interval, 1.20-3.30; P = 0.007). These data support the clinical relevance of acquired hMLH1 methylation and concomitant loss of DNA MMR after chemotherapy of ovarian cancer patients. DNA methylation changes in plasma provide the potential to define patterns of methylation during therapy and identify those patient populations who would be suitable for novel epigenetic therapies.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Palliation of allograft vasculopathy with transluminal angioplasty: a decade of experience.

OBJECTIVES: The goal of this study was to examine the outcomes of percutaneous coronary interventions (PCI) and the predictors for restenosis after cardiac transplantation. BACKGROUND: The role of PCI as definitive therapy for allograft coronary disease (ACD) remains contentious. METHODS: Between January 1, 1990 and December 31, 2000, 62 patients (1.5 to 15.5 years after transplant) underwent 151 procedures resulting in PCIs of 219 lesions. Follow-up after PCI angiography was usually obtained at three and six months, then yearly. Repeat PCI was routinely done to lesions with >60% restenosis. RESULTS: The primary procedural success was 97%. Repeat PCI occurred in 74 of 219 lesions (34%); PCI-related mortality was 2.6% (4 of 151). The freedom from re-PCI (of same vessel site) was 75% at six months, 65% at one year, and 57% at four years. The freedom from restenosis was 95% at one month, 81% at three months, and 57% at six months. Multivariate predictors of freedom from restenosis were the use of stents, higher anti-proliferative immunosuppressant dose, and an era effect. In the setting of one-vessel disease at first PCI, the two-year freedom for ACD death or graft loss was 74%, compared with 75% for two-vessel and 27% for three-vessel disease (p = 0.009). CONCLUSIONS: Despite the increasing effectiveness of PCI for localized ACD, the survival after development of advanced ACD remains poor. Stents appear to increase effectiveness of PCI for ACD, but other factors in the current era contribute to improved outcomes.

Angioplasty, Balloon, Coronary↗
PubMed2004

Critical evaluation of p53 as a prognostic marker in ovarian cancer.

The tumour suppressor gene encoding p53 has been shown from experimental studies to have a crucial role in how cells respond to DNA damage. p53 has important functions in apoptosis, cell-cycle arrest and DNA repair, largely mediated by its activity on gene transcription. However, despite this wealth of in vitro data, its role in how tumours respond to DNA damage induced by chemotherapeutic drugs remains controversial. In this review, we highlight some of the problems surrounding design and analysis of studies of p53 as a prognostic marker of clinical outcome, using ovarian cancer as an example. We aim to build on the knowledge of the published literature in ovarian cancer to identify criteria for clinical studies that should give a more definitive estimate of the role of p53 in clinical drug resistance. A search of three public databases using keywords combined with Boolean operators identified 64 clinical publications investigating the relationship of p53 to clinical outcome following chemotherapy in ovarian cancer. Although 43% of 215 published analyses from the 64 papers reported a significant correlation between p53 status and a clinical endpoint relevant to chemoresistance, only six analyses fulfil minimum criteria and none of these finds a statistically significant correlation of p53 with chemotherapy-resistance endpoints. The results from published clinical studies suggest a more complex role of p53 mutation in the mechanism of resistance in ovarian cancer than is suggested by in vitro studies.

Antineoplastic Agents↗
PubMed2004

Molecular and cellular cognition; the unraveling of memory retrieval.

While the study of molecular and cellular cognition has begun to elucidate the mechanisms of acquisition, consolidation, and storage of memories, the understanding of retrieval has lagged behind. In this issue of Cell, use molecular genetic approaches combined with pharmacology to demonstrate that beta-adrenergic receptor function regulates retrieval of certain forms of memory.

Animals↗
PubMed2004

Effect of a 10-week strength training program and recovery drink on body composition, muscular strength and endurance, and anaerobic power and capacity.

OBJECTIVE: We investigated whether postexercise consumption of a supplement containing whey protein, amino acids, creatine, and carbohydrate combined with a strength training program promotes greater gains in fat-free mass (FFM), muscle strength and endurance, and anaerobic performance compared with an isocaloric, carbohydrate-only control drink combined with strength training. METHODS: The study was double blind and randomized, and the experimental supplement was compared with a carbohydrate-only control. Forty-one males (n = 20 in control group, n = 21 in the supplement group; mean age, 22.2 y) participated in a 4 d/wk, 10-wk periodized strength training program. Subjects had to complete at least 70% of the workouts. Before and after 10 wk of strength training, subjects were tested for body composition by using hydrostatic weighing and skinfold thicknesses, one repetition maximum strength and muscular endurance for the bench press and 45-degree leg press, and anaerobic performance using a 30-s Wingate test. Thirty-three subjects (80.5%) completed the training program (n = 15 in control group, n = 18 in the supplement); these 33 subjects also completed all post-training test procedures. Data were analyzed with two-way analysis of variance with repeated measures on time. P <== 0.05 was set as statistically significant. All statistical analyses, including calculation of effect size and power, were completed with SPSS 11.0. RESULTS: Across groups, FFM increased during 10 wk of strength training. Although there was no statistically significant time x group interaction for FFM, there was a trend toward a greater increase in FFM for the supplement group (+3.4 kg) compared with the control group (+1.5 kg; P = 0.077). The effect size (eta(2) = 0.100) was moderately large. Percentage of body fat declined and fat mass was unchanged; there were no differences between groups. One repetition maximum strength for the bench press and 45-degree leg press increased, but there were no differences between groups. Muscular endurance expressed as the number of repetitions completed with 85% of the one repetition maximum was unchanged; external work, which was estimated as repetitions completed x resistance used, increased for the 45-degree leg press but not for the bench press over the 10-wk training period; there were no time x group interactions for either measurement. Anaerobic power and capacity improved, but there were no differences between groups for these variables or for fatigue rate. CONCLUSIONS: Consumption of a recovery drink after strength training workouts did not promote greater gains in FFM compared with consumption of a carbohydrate-only drink; however, a trend toward a greater increase in FFM in the supplement group suggests the need for longer-term studies. Performance variables such as muscle strength and endurance and anaerobic performance were not improved when compared with the carbohydrate-only group.

Adolescent↗
PubMed2004

Alcohol use associated with cervical spinal cord injury.

OBJECTIVES: To determine whether alcohol use at time of spinal cord injury (SCI) is more common with cervical injury than with lower levels of spinal injury. METHODS: Veterans and nonveterans with SCI were assessed at a Veteran's Affairs Medical Center from 1994 through 2002 and completed a health questionnaire that included information on alcohol use at time of traumatic injury. RESULTS: Of 362 men, 45% had neurologically complete or incomplete cervical injuries. Participants with cervical injury were more likely to have used alcohol when injured (62/162, 38%) compared with participants without cervical injury (45/200, 23%). Adjusting for age at injury and accident type, participants with cervical SCI had an increased relative odds of having used alcohol at injury compared with participants without cervical SCI (2.06, 95% confidence interval = 1.24-3.43). CONCLUSION: Alcohol use at time of SCI is a risk factor for cervical injury. This finding is of public health concern and should be included in alcohol educational programs.

Adolescent↗
PubMed2004

High-throughput gene discovery in the rat.

The rat is an important animal model for human diseases and is widely used in physiology. In this article we present a new strategy for gene discovery based on the production of ESTs from serially subtracted and normalized cDNA libraries, and we describe its application for the development of a comprehensive nonredundant collection of rat ESTs. Our new strategy appears to yield substantially more EST clusters per ESTs sequenced than do previous approaches that did not use serial subtraction. However, multiple rounds of library subtraction resulted in high frequencies of otherwise rare internally primed cDNAs, defining the limits of this powerful approach. To date, we have generated >200,000 3' ESTs from >100 cDNA libraries representing a wide range of tissues and developmental stages of the laboratory rat. Most importantly, we have contributed to approximately 50,000 rat UniGene clusters. We have identified, arrayed, and derived 5' ESTs from >30,000 unique rat cDNA clones. Complete information, including radiation hybrid mapping data, is also maintained locally at http://genome.uiowa.edu/clcg.html. All of the sequences described in this article have been submitted to the dbEST division of the NCBI.

Animals↗
PubMed2004

Demethylation of DNA by decitabine in cancer chemotherapy.

Genes involved in all aspects of tumor development and growth can become aberrantly methylated in tumor cells, including genes involved in apoptosis and cell cycle regulation. Decitabine, 2'-deoxy-5-azacytidine, can inhibit DNA methyltransferases and reverse epigenetic silencing of aberrantly methylated genes. Nucleoside DNA methyltransferase inhibitors, such as decitabine, have been reported to have antitumor activity, especially against hematologic malignancies. Such demethylating agents have been proposed to reactivate tumor suppressor genes aberrantly methylated in tumor cells, leading to inhibition of tumor growth. An important consequence of this is that, unlike conventional cytotoxic agents, it may be best to use such drugs at concentrations lower than the maximum tolerated dose and in a manner dependent on their demethylating activity. Furthermore, synergistic activity with other types of investigational epigenetic therapies and existing chemotherapies opens the possibility of rational combinations and scheduling of these agents based on their biologic activity.

Antimetabolites, Antineoplastic↗
PubMed2004

Dual repair modulation reverses Temozolomide resistance in vitro.

Temozolomide is an alkylating agent that mediates its cytotoxic effects via O(6)-methylguanine (O(6)-meG) adducts in DNA and their recognition and processing by the postreplication mismatch repair system (MMR). O(6)-meG adducts can be repaired by the DNA repair protein O(6)-alkylguanine-DNA-alkyltransferase (MGMT), which therefore constitutes a major resistance mechanism to the drug. Resistance to Temozolomide can also be mediated by loss of MMR, which is frequently mediated by methylation of the hMLH1 gene promoter. Methylation of hMLH1 can be reversed by treatment of cells with 5-aza-2'-deoxycytidine, while the MGMT pseudosubstrate O(6)-(4-bromothenyl)guanine (PaTrin-2) can deplete MGMT activity. Using a drug-resistant cell line which expresses MGMT and has methylated hMLH1, we show that while either of these treatments can individually sensitize cells to Temozolomide, the combined treatment leads to substantially greater sensitization. The increased sensitization is not observed in matched MMR proficient cells.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX.

MSH2 and MLH1 have a central role in correcting mismatches in DNA occurring during DNA replication and have been implicated in the engagement of apoptosis induced by a number of cytotoxic anticancer agents. The function of MLH1 is not clearly defined, although it is required for mismatch repair (MMR) and engagement of apoptosis after certain types of DNA damage. In order to identify other partners of MLH1 that may be involved in signalling MMR or apoptosis, we used human MLH1 in yeast two-hybrid screens of normal human breast and ovarian cDNA libraries. As well as known partners of MLH1 such as PMS1, MLH3 and MBD4, we identified the carboxy terminus of the human c-MYC proto-oncogene as an interacting sequence. We demonstrate, both in vitro by yeast two-hybrid and GST-fusion pull-down experiments, as well as in vivo by coimmunoprecipitation from human tumour cell extracts, that MLH1 interacts with the c-MYC protein. We further demonstrate that the heterodimeric partner of c-MYC, MAX, interacts with a different MMR protein, MSH2, both in vitro and in vivo. Using an inducible c-MYC-ER fusion gene, we show that elevated c-MYC expression leads to an increased HGPRT mutation rate of Rat1 cells and an increase in the number of frameshift mutants at the HGPRT locus. The effect on HGPRT mutation rate is small (2-3-fold), but is consistent with deregulated c-MYC expression partially inhibiting MMR activity.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Effect of NT-4 and BDNF delivery to damaged sciatic nerves on phenotypic recovery of fast and slow muscles fibres.

We investigated whether neurotrophin-4 (NT-4) and brain-derived neurotrophic factor (BDNF) affected the reinnervation of slow and fast motor units. Neurotrophin-impregnated or plain fibronectin (FN) conduits were inserted into a sciatic nerve gap. Fast extensor digitorum longus (EDL) and slow soleus muscles were collected 4 months postsurgery. Muscles were weighed and fibre type proportion and mean fibre diameters were derived from muscle cross-sections. All fibre types in muscles from FN animals were severely atrophied and this correlated well with type 1 fibre loss and atrophy in soleus and type 2b loss and atrophy in EDL. Treatment with NT-4 reversed soleus but not EDL mass loss above the FN group by significantly restoring type 1 muscle fibre proportion and diameters towards those of normal unoperated animals. BDNF did not increase muscle mass but did have minor effects on fibre type and diameter. Thus, NT-4 significantly improved slow motor unit recovery, and provides a basis for therapies intended to aid the functional recovery of muscles after denervating injury.

Animals↗
PubMed2003

Aberrant DNA methylation in ovarian cancer: is there an epigenetic predisposition to drug response?

Epigenetic regulation of gene expression has been observed in a variety of tumor types. We have used microarray technology to evaluate the predisposition of drug response by aberrant methylation in ovarian cancer. Results indicate that loss of gene activity due to hypermethylation potentially confers a predisposition in certain cancer types and is an early event in disease progression. Methylation profiles of ovarian cancer might be useful for early cancer detection and prediction of chemotherapy outcome in a clinical context.

Antineoplastic Agents↗
PubMed2003

Spirometry testing standards in spinal cord injury.

STUDY OBJECTIVES: Because muscle paralysis makes it uncertain whether subjects with spinal cord injury (SCI) can perform spirometry in accordance with American Thoracic Society (ATS) standards, determinants of test failure were examined. DESIGN: Cross-sectional study. SETTING: Veterans Affairs (VA) medical center. PARTICIPANTS: Veterans with SCI at VA Boston Healthcare System and nonveterans recruited by mail and advertisement. MEASUREMENTS AND RESULTS: Two hundred thirty of 278 subjects (83%) were able to produce three expiratory efforts lasting > or = 6 s and without excessive back-extrapolated volume (EBEV). In 217 of 230 subjects (94%), FVC and FEV(1) were each reproducible in accordance with 1994 ATS standards. In the remaining 48 subjects, efforts with smooth and continuous volume-time tracings and acceptable flow-volume loops were identified. These subjects had a lower percentage of predicted FVC, FEV(1), and maximum expiratory and inspiratory pressures compared to the others, and a greater proportion had neurologically complete cervical injury (42% compared to 16%). In 19 subjects (40%), some expiratory efforts were not sustained maximally for > or = 6 s but had at least a 0.5-s plateau at residual volume (short efforts). In eight subjects (17%), some efforts were not short but had EBEV. In the remaining 21 subjects (44%), some efforts were short, some had EBEV, and some had both. If these efforts were not rejected, 262 of 278 subjects (94%) would have produced three acceptable efforts, and in 257 subjects (92%), the efforts were reproducible. CONCLUSIONS: Subjects with SCI with the most impaired respiratory muscles and abnormal pulmonary function are able to perform spirometry reproducibly despite not meeting usual ATS acceptability standards. Exclusion of these subjects would lead to bias in studies of respiratory function in SCI. The modification of spirometry testing standards to include efforts with EBEV and with a 0.5-s plateau if < 6 s would reduce the potential for bias.

Adult↗
PubMed2003

Clinical ventilator adjustments that improve speech.

STUDY OBJECTIVES: We sought to improve speech in tracheostomized individuals receiving positive-pressure ventilation. Such individuals often speak with short phrases, long pauses, and have problems with loudness and voice quality. SUBJECTS: We studied 15 adults with spinal cord injuries or neuromuscular diseases receiving long-term ventilation. INTERVENTIONS: The ventilator was adjusted using lengthened inspiratory time (TI), positive end-expiratory pressure (PEEP), and combinations thereof. RESULTS: When TI was lengthened (by 8 to 35% of the ventilator cycle), speaking time increased by 19% and pause time decreased by 12%. When PEEP was added (5 to 10 cm H(2)O), speaking time was 25% longer and obligatory pauses were 21% shorter. When lengthened TI and PEEP were combined (with or without reduced tidal volume), their effects were additive, increasing speaking time by 55% and decreasing pause time by 36%. The combined intervention improved speech timing, loudness, voice quality, and articulation. Individual differences in subject response to the interventions were substantial in some cases. We also tested high PEEP (15 cm H(2)O) in three subjects and found speech to be essentially identical to that produced with a one-way valve. CONCLUSIONS: These simple interventions markedly improve ventilator-supported speech and are safe, at least when used on a short-term basis. High PEEP is a safer alternative than a one-way valve.

Adult↗