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Biomedical subjects

Robert Brown

Publications and source records attributed to Robert Brown.

At least 37 records · Page 2Linked to original sources
PubMed2005

CpG island methylation of DNA damage response genes in advanced ovarian cancer.

We have determined the methylation frequencies of 24 CpG islands of genes associated with DNA damage responses or with ovarian cancer in 106 stage III/IV epithelial ovarian tumors. We have analyzed this data for whether there is evidence of a CpG island methylator phenotype or associations of CpG island methylation with response to chemotherapy in advanced ovarian cancer. Frequent methylation was observed for OPCML, DCR1, RASSF1A, HIC1, BRCA1, and MINT25 (33.3%, 30.7%, 26.4%, 17.3%, 12.3%, and 12.0%, respectively), whereas no methylation was observed for APAF-1, DAPK, FANCF, FAS, P14, P21, P73, SOCS-3, and SURVIVIN. The remaining genes showed only a low frequency of methylation, <10%. Unsupervised gene shaving identified a nonrandom pattern of methylation for OPCML, DCR1, RASSF1A, MINT25, HIC1, and SFRP1, supporting the concept of concordant methylation of these genes in ovarian cancer. Methylation of at least one of the group of genes involved in DNA repair/drug detoxification (BRCA1, GSTP1, and MGMT) was associated with improved response to chemotherapy (P = 0.013). We have examined the frequency of a polymorphism in the DNA methyltransferase gene DNMT3b6, which has been previously reported to affect gene transcription and cancer risk. The genetic polymorphism in the DNMT3b6 gene promoter (at position -149) is not significantly associated with the concordant methylation observed, but is weakly associated with the overall frequency of methylation at the genes examined (P = 0.04, n = 56). This supports the hypothesis that genetic factors affecting function of DNMT genes may underlie the propensity of tumors to acquire aberrant CpG island methylation.

Adult↗
PubMed2005

Multi-organ transplantation: is there a protective effect against acute and chronic rejection?

BACKGROUND: Heart-lung transplantation (Tx) is known to offer a protective effect against acute cardiac rejection. This study was undertaken to evaluate acute and chronic heart and/or lung rejection in the setting of multiple-transplanted organs from the same donor compared with single-organ transplantation. METHODS: Acute (treated rejection episodes of heart or lungs) and chronic (allograft vasculopathy in hearts and bronchiolitis obliterans syndrome [BOS] in lungs) rejection events were analyzed in 348 heart transplant (H) recipients, 24 heart-lung (HL) recipients, 82 double-lung (L) recipients and 8 heart-kidney (HK) recipients >18 years of age, who were transplanted between 1990 and 2002. RESULTS: Survival at 3 years differed among groups as follows: HK, 100%; H, 82%; HL, 74%; and L, 70%. The probability of acute rejection within the first 3 months was higher in H recipients than in HL (81% vs 22%; p < 0.0001) or HK (81% vs 12%; p = 0.00009) recipients. Acute cardiac rejection occurred more frequently during the first 2 years in isolated H recipients compared with HL (2.8 vs 0.27 episodes; p < 0.0001) and HK (2.8 vs 0.54; p < 0.001) recipients. Acute lung rejection occurred more frequently in the first 2 years in L than HL (2.4 vs 1.0 episodes; p = 0.02) recipients. Chronic cardiac rejection (allograft vasculopathy) was more likely within 3 years after H compared with HL (32% vs 16%; p = 0.04) or HK (32% vs 0%; p = 0.14). The onset of chronic lung rejection (BOS) within 3 years was similar in HL and L recipients (39% vs 40%; p = 0.9). CONCLUSIONS: Recipients of multiple organs from a single donor undergo less acute rejection of the heart or lungs compared with isolated heart or lung transplant recipients. Cardiac allograft vasculopathy is decreased significantly when cardiac transplantation is combined with a lung allograft. A lower incidence of cardiac allograft vasculopathy is observed when cardiac transplantation is combined with a renal allograft, and may prove statistically significant when more cases have been accumulated. These phenomena may result from immune modulation of the recipient by simultaneous transplant of disparate tissues or introduction of immune-modulating hematopoietic elements.

Acute Disease↗
PubMed2005

Highly stable phenanthridinium frameworks as a new class of tunable DNA binding agents with cytotoxic properties.

A new class of cytotoxic heteroaromatic cations is presented, based on the dihydro-imidazo-phenanthridinium framework (DIP), that have affinity for DNA and cytotoxicity toward cancerous cells. The DIP framework is particularly tunable due to the flexible synthetic methodology. Furthermore, the central moiety has proved to be very stable to hydrolysis and reduction compared to other phenanthridinium-based agents.

Antineoplastic Agents↗
PubMed2005

Multiple markers for melanoma progression regulated by DNA methylation: insights from transcriptomic studies.

The incidence of melanoma is increasing rapidly, with advanced lesions generally failing to respond to conventional chemotherapy. Here, we utilized DNA microarray-based gene expression profiling techniques to identify molecular determinants of melanoma progression within a unique panel of isogenic human melanoma cell lines. When a poorly tumorigenic cell line, derived from an early melanoma, was compared with two increasingly aggressive derivative cell lines, the expression of 66 genes was significantly changed. A similar pattern of differential gene expression was found with an independently derived metastatic cell line. We further examined these melanoma progression-associated genes via use of a tailored TaqMan Low Density Array (LDA), representing the majority of genes within our cohort of interest. Considerable concordance was seen between the transcriptomic profiles determined by DNA microarray and TaqMan LDA approaches. A range of novel markers were identified that correlated here with melanoma progression. Most notable was TSPY, a Y chromosome-specific gene that displayed extensive down-regulation in expression between the parental and derivative cell lines. Examination of a putative CpG island within the TSPY gene demonstrated that this region was hypermethylated in the derivative cell lines, as well as metastatic melanomas from male patients. Moreover, treatment of the derivative cell lines with the DNA methyltransferase inhibitor, 2'-deoxy-5-azacytidine (DAC), restored expression of the TSPY gene to levels comparable with that found in the parental cells. Additional DNA microarray studies uncovered a subset of 13 genes from the above-mentioned 66 gene cohort that displayed re-activation of expression following DAC treatment, including TSPY, CYBA and MT2A. DAC suppressed tumor cell growth in vitro. Moreover, systemic treatment of mice with DAC attenuated growth of melanoma xenografts, with consequent re-expression of TSPY mRNA. Overall, our data support the hypothesis that multiple genes are targeted, either directly or indirectly, by DNA hypermethylation during melanoma progression.

Animals↗
PubMed2005

Mechanical signals and IGF-I gene splicing in vitro in relation to development of skeletal muscle.

It has been shown that the insulin-like growth factor (IGF-I) gene is spliced in response to mechanical signals producing forms of IGF-I which have different actions. In order to study how mechanical signals influence this gene splicing in developing muscle, C2C12 cells were grown in three-dimensional (3D) culture and subjected to different regimens of mechanical strain. IGF-IEa which initiates the fusion of myoblasts to form myotubes was found to be constitutively expressed in myoblasts and myotubes (held under endogenous tension) and its expression upregulated by a single ramp stretch of 1-h duration but reduced by repeated cyclical stretch. In contrast, mechano growth factor (MGF), which is involved in the proliferation of mononucleated myoblasts that are required for secondary myotube formation and to establish the muscle satellite (stem) cell pool, showed no significant constitutive expression in static cultures, but was upregulated by a single ramp stretch and by cycling loading. The latter types of force simulate those generated in myoblasts by the first contractions of myotubes. These data indicate the importance of seeking to understand the physiological signals that determine the ratios of splice variants of some growth factor/tissue factor genes in the early stages of development of skeletal muscle.

Alternative Splicing↗
PubMed2005

Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy.

Monitoring of intracranial pressure (ICP) in acute liver failure (ALF) is controversial as a result of the reported complication risk (approximately 20%) and limited therapeutic options for intracranial hypertension. Using prospectively collected information from 332 patients with ALF and severe encephalopathy, we evaluated a recent experience with ICP monitoring in the 24 centers constituting the U.S. ALF Study Group. Special attention was given to the rate of complications, changes in management, and outcome after liver transplantation (LT). ICP monitoring was used in 92 patients (28% of the cohort), but the frequency of monitoring differed between centers (P < 0.001). ICP monitoring was strongly associated with the indication of LT (P < 0.001). A survey performed in a subset of 58 patients with ICP monitoring revealed intracranial hemorrhage in 10.3% of the cohort, half of the complications being incidental radiological findings. However, intracranial bleeding could have contributed to the demise of 2 patients. In subjects listed for LT, ICP monitoring was associated with a higher proportion of subjects receiving vasopressors and ICP-related medications. The 30-day survival post-LT was similar in both monitored and nonmonitored groups (85% vs. 85%). In conclusion, the risk of intracranial hemorrhage following ICP monitoring may have decreased in the last decade, but major complications are still present. In the absence of ICP monitoring, however, patients listed for LT appear to be treated less aggressively for intracranial hypertension. In view of the high 30-day survival rate after LT, future studies of the impact of intracranial hypertension should also focus on long-term neurological recovery from ALF.

Adult↗
PubMed2005

Dyspnea during daily activities in chronic spinal cord injury.

OBJECTIVE: To assess factors associated with breathlessness in chronic spinal cord injury (SCI) during daily activities. DESIGN: Cross-sectional survey. SETTINGS: Veterans Affairs SCI service and the community. PARTICIPANTS: Four hundred forty-one participants 1 or more years post-SCI, and without acute illness, were recruited between 1994 and 2003 and were categorized according to their ability to walk unassisted, walk with an aid, or to move about by either hand-propelled wheelchair or motorized wheelchair (MWC). INTERVENTIONS: Assessment of injury extent, respiratory symptoms, cigarette smoking, comorbid medical conditions, and spirometry. MAIN OUTCOME MEASURES: Breathlessness during talking, eating, or dressing. RESULTS: Breathlessness was more common in MWC users (20/85 users, 24%) than in nonusers (20/356, 6%). The main activity associated with breathlessness in 15 MWC users was talking (18%). In MWC users, the risk of breathlessness was related to lifetime cigarette smoking (odds ratio [OR]=1.02; 95% confidence interval [CI], 1.00-1.03 per pack year), and reports of chronic cough (OR=7.8; 95% CI, 2.0-32.7), and wheeze (OR=3.5; 95% CI, 1.04-13.6). SCI level, percentage of predicted forced vital capacity and forced expiratory volume in 1 second, and maximal inspiratory pressures were not related to breathlessness. CONCLUSIONS: Breathlessness during selected daily activities (most commonly talking) was greatest in SCI participants who were most impaired with regard to mobility and was associated with reports of coughing, wheezing, and cigarette smoking.

Activities of Daily Living↗
PubMed2005

The case for selective re-issuance of medical certificates to allow pilots who have received a heart transplant to resume flying.

BACKGROUND: Cardiac transplant recipients have been regarded as not medically fit to fly an airplane. Recently, the Federal Aviation Administration decided to re-examine this policy and, in response, this study was undertaken to determine the risk of death from any cause and sudden-onset death in heart transplant recipients during the 12 months after an annual evaluation. METHODS: Of 6,510 patients undergoing primary orthotopic cardiac transplantation enrolled in the Cardiac Transplant Research Database (CTRD), 4,978 patients survived for at least 1 year and formed the basis of this study. Risk factors for death from any causes and sudden-onset death (a composite of causes of death that could conceivably result in a pilot's incapacitation) were determined during the 12-month period after an anniversary evaluation. Patients were re-entered into the analysis at each evaluation, resulting in a total of 23,575 anniversary evaluations. RESULTS: The presence of coronary allograft vasculopathy (CAV), left ventricular systolic dysfunction, history of rejection, malignancy, infection and pre-transplant insulin-dependent diabetes were associated with an increased risk of death from any cause and sudden-onset death during the 12-month period after an evaluation. Based on the absence of these risk factors, a group of heart transplant recipients could be defined with a 12-month risk of death from any cause of 1.0% and of sudden-onset death of 0.3% (which is identical to the mortality rate of a matched population from the U.S. life-table). CONCLUSION: Using these identified risk factors, a group of heart transplant recipients can be defined that are potentially medically certifiable to fly without compromising aviation safety.

Adolescent↗
PubMed2005

Demethylation of the MCJ gene in stage III/IV epithelial ovarian cancer and response to chemotherapy.

OBJECTIVE: Methylation of a CpG island within the Methylation controlled DNAJ (MCJ) gene results in loss of expression in normal and neoplastic cells. Normal ovarian surface epithelial cells are methylated at the MCJ CpG island and do not express the MCJ gene. Furthermore, re-expression of the MCJ gene, in ovarian cancer cell lines, has been correlated with increased sensitivity to several important chemotherapeutic drugs. The objective of this study was to determine the extent of MCJ promoter methylation in epithelial ovarian cancer patients and address the possible role of MCJ methylation levels in response to chemotherapy in ovarian cancer patients. METHODS: The methylation status of 35 CpG sites within the MCJ CpG island was determined by sequencing of sodium bisulfite modified tumor DNA in 41 patients with stage III/IV epithelial ovarian tumors. Levels of methylation of the MCJ CpG island were then compared with response to therapy and overall survival in the patients. RESULTS: The analysis identified frequent loss of MCJ methylation in ovarian tumors, with only a subset retaining high methylation levels. While 93% (38/41) of tumors examined showed some level of MCJ methylation, only 17% (7/41) retained very high levels (>90% methylation). The presence of such high levels of CpG island methylation correlated significantly with poor response of patients' tumors to therapy (P = 0.027) and poor overall survival (P = 0.023, hazard ratio = 2.9). CONCLUSIONS: These results suggest that MCJ methylation may be useful as a marker of response to chemotherapy in ovarian cancer and are consistent with previous in vitro data linking loss of MCJ expression with drug resistance.

Base Sequence↗
PubMed2005

Bilateral oculosympathetic paresis associated with loss of nocturnal melatonin secretion in patients with spinal cord injury.

BACKGROUND: Lesions along the sympathetic pathway to the eye produce oculosympathetic paresis (OSP, Horner's syndrome). The oculosympathetic pathway descends from the hypothalamus through the cervical spinal cord and ascends to the superior cervical ganglion (SCG), which innervates sympathetic targets in the ipsilateral face and eye. This pathway appears to closely co-localize with a similar retino-pineal neural pathway from the hypothalamus through the cervical spinal cord and SCG to the pineal gland. As such, lesions along this shared pathway, such as occur in neurologically complete injury to the cervical spinal cord (tetraplegia), would be predicted to result in simultaneous OSP and loss of pineal melatonin production. Loss of melatonin production may contribute to the pervasive sleep disruption observed in patients with tetraplegia. METHODS: We assessed the presence of OSP by photographic documentation of ptosis and pupillary dilation response to cocaine eye drops in 5 individuals with neurologically complete damage to their upper thoracic or lower cervical spinal cord. We correlated these results with an analysis of the pattern of melatonin production in these same individuals. RESULTS: Bilateral OSP was present in individuals with cervical spinal cord injury; each also lacked significant production of melatonin. No evidence of OSP was observed in the 2 individuals with thoracic spinal cord injury below the level of the oculosympathetic pathway. Both had normal circadian rhythms of melatonin production, with timing and amplitude of the rhythm within normal parameters. CONCLUSION: The presence of bilateral oculosympathetic paresis can be predictive of the complete loss of the nocturnal production of melatonin.

Adult↗
PubMed2005

Utilization of extended donor criteria liver allografts maximizes donor use and patient access to liver transplantation.

OBJECTIVE: The objective of this study was to evaluate the effect of systematic utilization of extended donor criteria liver allografts (EDC), including living donor allografts (LDLT), on patient access to liver transplantation (LTX). SUMMARY BACKGROUND DATA: Utilization of liver allografts that do not meet traditional donor criteria (EDC) offer immediate expansion of the donor pool. EDC are typically allocated by transplant center rather than regional wait-list priority (RA). This single-institution series compares outcomes of EDC and RA allocation to determine the impact of EDC utilization on donor use and patient access to LTX. METHODS: The authors conducted a retrospective analysis of 99 EDC recipients (49 deceased donor, 50 LDLT) and 116 RA recipients from April 2001 through April 2004. Deceased-donor EDC included: age >65 years, donation after cardiac death, positive viral serology (hepatitis C, hepatitis B core antibody, human T-cell lymphotrophic), split-liver, hypernatremia, prior carcinoma, steatosis, and behavioral high-risk donors. Outcome variables included patient and graft survival, hospitalization, initial graft function, and complication categorized as: biliary, vascular, wound, and other. RESULTS: EDC recipients were more frequently diagnosed with hepatitis C virus or hepatocellular carcinoma and had a lower model for end-stage liver disease (MELD) score at LTX (P < 0.01). Wait-time, technical complications, and hospitalization were comparable. Log-rank analysis of Kaplan-Meier survival estimates demonstrated no difference in patient or graft survival; however, deaths among deceased-donor EDC recipients were frequently the result of patient comorbidities, whereas LDLT and RA deaths resulted from graft failure (P < 0.01). EDC increased patient access to LTX by 77% and reduced pre-LTX mortality by over 50% compared with regional data (P < 0.01). CONCLUSION: Systematic EDC utilization maximizes donor use, increases access to LTX, and significantly reduces wait-list mortality by providing satisfactory outcomes to select recipients.

Adolescent↗
PubMed2005

The impact of pre-operative loco-regional therapy on outcome after liver transplantation for hepatocellular carcinoma.

No prior studies have shown that pre-operative loco-regional therapy for hepatocellular carcinoma (HCC) improves survival following orthotopic liver transplantation (OLT). We performed subgroup analyses according to pathologic HCC stage among 168 patients who underwent OLT to test the hypothesis that pre-operative loco-regional therapy confers a survival advantage in a subgroup at intermediate risk for HCC recurrence. Patients with pathologic T3 HCC meeting the proposed UCSF expanded criteria (single lesion not exceeding 6.5 cm or two to three lesions none > 4.5 cm with total tumor diameter within 8 cm) had a similar 5-year recurrence-free survival as patients with pathologic T2 HCC (88.5% vs. 93.8%; p = 0.56). In the subgroup with pathologic T2 or T3 HCC, the 5-year recurrence-free survival was 93.8% for the 85 patients who received pre-operative loco-regional therapy, versus 80.6% for the other 41 patients without treatment (p = 0.049). The treatment benefit, according to 5-year recurrence-free survival, appeared greater for pathologic T3 (85.9% vs. 51.4%; p = 0.05) than T2 HCC (96.4% versus 87.1%; p = 0.12). In conclusion, although the lack of a randomized controlled design precludes drawing firm conclusions, our results suggest that pre-operative loco-regional therapy may confer a survival benefit after OLT in the subgroup with pathologic T2 and T3 HCC.

Adult↗
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↗