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Biomedical subjects

David Peters

Publications and source records attributed to David Peters.

At least 19 recordsLinked to original sources
PubMed2006

Peptides selected for binding to clotted plasma accumulate in tumor stroma and wounds.

Screening of a phage library for peptides that bind to clotted plasma in the presence of liquid plasma yielded two cyclic decapeptides, CGLIIQKNEC (CLT1) and CNAGESSKNC (CLT2). When injected intravenously into mice bearing various types of tumors, fluorescein-conjugated CLT peptides accumulated in a fibrillar meshwork in the extracellular compartment of the tumors, but were not detectable in other tissues of the tumor-bearing mice. The tumor homing of both peptides was strongly reduced after coinjection with unlabeled CLT2, indicating that the two peptides recognize the same binding site. The CLT peptide fluorescence colocalized with staining for fibrin(ogen) present in the extravascular compartment of tumors, but not in other tissues. The CLT peptides did not home to tumors grown in fibrinogen-null mice or in mice that lack plasma fibronectin. The CLT peptides also accumulated at the sites of injury in arteries, skeletal muscle, and skin. We conclude that the CLT peptides recognize fibrin-fibronectin complexes formed by clotting of plasma proteins that have leaked into the extravascular space in tumors and other lesions. These peptides may be useful in targeting diagnostic and therapeutic materials into tumors and injured tissues.

Animals↗
PubMed2005

Stress-dependent and -independent expression of the myogenic regulatory factors and the MARP genes after eccentric contractions in rats.

The relationship between muscle mechanical conditions and gene expression was investigated by varying both stress and contraction mode imposed upon rat dorsiflexors (n= 25), activating them at high or low frequencies (150 Hz or 40 Hz) either eccentrically or isometrically. Muscle physiological, immunohistochemical and gene expression changes were then measured 24 h after the exercise bout. Peak stress was the best predictor of muscle injury, independent of contraction mode (i.e. eccentric or isometric). When peak stresses were matched, no physiological or immunohistochemical differences were detected between isometric and eccentric contractions. The expression of certain myogenic regulatory and muscle ankyrin repeat protein (MARP) genes (myoD, myogenin, MLP and CARP) depended both on peak muscle stress achieved during contraction and contraction mode. In contrast, Arpp/Ankrd2 was dramatically upregulated only by eccentric contractions, but not by isometric contractions, even though the stress level of the eccentric contractions varied over a three-fold range and overlapped with that of the isometric group. The role that Arpp/Ankrd2 upregulation plays in the biological response to eccentric contraction remains to be determined, as does the control mechanism whereby the expression of certain genes (such as myoD, myogenin, MLP and CARP) is sensitive to muscle stress while another (Arpp/Ankrd2) is sensitive only to contraction mode.

Animals↗
PubMed2005

Angiostatic peptides use plasma fibronectin to home to angiogenic vasculature.

A group of angiogenesis inhibitors are derived from fragments of extracellular matrix or blood proteins. Endostatin, antithrombin, and anastellin are members of this group of substances. The plasma adhesion proteins fibronectin and vitronectin serve as cofactors for these three antiangiogenic proteins. Anginex is a synthetic 33-amino acid peptide that was originally modeled to reproduce the beta-sheet structure of antiangiogenic proteins. Here, we show that anginex initiates fibronectin polymerization and is inactive in mice that lack plasma fibronectin. Anginex shares these characteristics with anastellin. Fluorescein-labeled anginex and anastellin specifically localized in angiogenic vessels in vivo. This localization was dependent on plasma fibronectin and inhibited by an Arg-Gly-Asp peptide. Thus, anginex shares with several physiological angiogenesis inhibitors a dependence on plasma adhesion proteins. The role of the adhesion protein interaction apparently is to form integrin-binding complexes that deliver the antiangiogenic proteins to sites of angiogenesis. This functional convergence of several antiangiogenic factors has important implications for antiangiogenic therapies.

Angiogenesis Inhibitors↗
PubMed2005

Genome-wide transcriptional analysis of carboplatin response in chemosensitive and chemoresistant ovarian cancer cells.

We have recently described an ex vivo chemoresponse assay for determining chemosensitivity in primary cultures of human tumors. In this study, we have extended these experiments in an effort to correlate chemoresponse data with gene expression patterns at the level of transcription. Primary cultures of cells derived from ovarian carcinomas of individual patients (n=6) were characterized using the ChemoFx assay and classified as either carboplatin sensitive (n=3) or resistant (n=3). Three representative cultures of cells from each individual tumor were then subjected to Affymetrix gene chip analysis (n=18) using U95A human gene chip arrays. Data were analyzed using the dCHIP software package. We identified a significant number of genes whose expression patterns were altered between carboplatin chemosensitive and chemoresistant cells, in normal culture conditions and in the presence of carboplatin for either 2 or 72 hours. Among these differentially expressed genes, we found a significant proportion to be associated with apoptosis, cell-cell communication, cell adhesion, DNA repair, and cell proliferation. In general, the molecular phenotype displayed by chemoresistant cells was reflective of an extended life span in culture in the presence of carboplatin and the genes that define this phenotype are potential biomarkers for the prognostic management of ovarian cancer patients.

Antineoplastic Agents↗
PubMed2004

The ribbon of hydrogen bonds in globular proteins. IV. The example of the papain family.

A study of the role of the hydrogen-bonding side chains in the ribbon of hydrogen bonds in globular proteins, using the papain family as an example, suggests that these side chains may be divided into three categories depending on their position in the molecule. In the first category, they form part of the local ribbon, in the second they form part of the ribbon at a site remote along the main chain, and in the third they play no role in the formation of the ribbon. The second case is particularly interesting because it provides a natural mechanism for the formation of the tertiary structure of the globular proteins. The results suggest that the robustness of the globular proteins towards mutations arises from the fact that many mutations that involve hydrogen-bonding side chains either leave the hydrogen bonding of the ribbon essentially unchanged or their hydrogen bonding plays no part in the formation of the ribbon in the first place. The results show that it is possible to obtain the ribbon of hydrogen bonds for a family of proteins whose data set's are of intermediate quality by studying the ribbons of several members of such a family and then taking an average over the different partial ribbons to create a standard ribbon of hydrogen bonds for the family as a whole. This method is used here to derive the standard ribbon for the papain family with papain itself, actinidin, and human liver cathepsin B as the representatives of the family. All three members of the family fit the standard ribbon with an accuracy of 85-91%. This result opens up the use of this technique for the study of a large number of globular proteins whose recorded data sets are of intermediate quality.

Cathepsin B↗
PubMed2004

Evidence of systematic expressed sequence tag IMAGE clone cross-hybridization on cDNA microarrays.

We present evidence of a potentially serious source of error intrinsic to all spotted cDNA microarrays that use IMAGE clones of expressed sequence tags (ESTs). We found that a high proportion of these EST sequences contain 5'-end poly(dT) sequences that are remnants from the oligo(dT)-primed reverse transcription of polyadenylated mRNA templates used to generate EST cDNA for sequence clone libraries. Analysis of expression data from two single-dye cDNA microarray experiments showed that ESTs whose sequences contain repeats of consecutive 5'-end dT residues appeared to be strongly coexpressed, while expression data of all other sequences exhibited no such pattern. Our analysis suggests that expression data from sequences containing 5' poly(dT) tracts are more likely to be due to systematic cross-hybridization of these poly(dT) tracts than to true mRNA coexpression. This indicates that existing data generated by cDNA microarrays containing IMAGE clone ESTs should be filtered to remove expression data containing significant 5' poly(dT) tracts.

Adipocytes↗
PubMed2004

Altered arterial homeostasis and cerebral aneurysms: a review of the literature and justification for a search of molecular biomarkers.

DESPITE THE CATASTROPHIC consequence of ruptured intracranial aneurysms, very little is understood regarding their pathogenesis, and there are no reliable predictive markers for identifying at-risk individuals. Given that intracranial aneurysms have a strong but complex genetic component and well-characterized modifiable risk factors, it seems likely that the most valuable approach to developing minimally invasive diagnostic and prognostic tools will involve a multifactorial model that includes both genetic and environmental risk factors. Unfortunately, the genetic basis of intracranial aneurysms is poorly described, and reports describing the association of nonrandom deoxyribonucleic acid sequence variation with intracranial aneurysms have been limited to a handful of ad hoc studies that have focused on a variety of markers in small populations. One reason for this lack of coordinated analysis of the genetic basis of intracranial aneurysms is that the molecular pathogenesis and pathobiological characteristics of the disease are poorly described, so candidate marker selection has been problematic. Few studies have addressed the molecular pathological basis of intracranial aneurysms or the possible mechanisms of intracranial aneurysm formation. In this regard, candidate gene selection strategies have relied almost exclusively on limited knowledge of monogenic disorders such as Ehlers-Danlos syndrome and Marfan's syndrome, in which intracranial aneurysm is a feature of a spectrum of syndromic phenotypes. Without exception, these approaches have not affected the clinical identification and/or management of intracranial aneurysms significantly. Therefore, it is imperative that coordinated large-scale efforts in genetics, molecular biology, and genetic epidemiology are implemented to overcome these obstacles and drive developments in the field. In this review, we summarize the current screening modalities for intracranial aneurysms, review the current state of understanding relating to the genetic basis of intracranial aneurysms, and suggest a broader theory of aneurysm pathogenesis to form the foundation of a coordinated molecular search for biological markers that may be associated with aneurysm formation and rupture.

Cerebral Arteries↗
PubMed2004

Altered arterial homeostasis and cerebral aneurysms: a molecular epidemiology study.

OBJECTIVE: We hypothesized that patients with intracranial cerebral aneurysms (IAs) harbor a molecular defect in the process responsible for maintaining arterial integrity (arterial homeostasis). In this study, we undertook a preliminary assessment of differential expression of key molecules involved with each phase of homeostasis: arterial flow modulation, arterial tear and repair, and the ensuing extracellular matrix. METHODS: Key molecules from each phase of the arterial homeostatic process were selected: prostacyclin-stimulating factor, implicated with arterial flow modulation; PNUT and RAI, involved with tissue repair and arterial remodeling; and Type III collagen and fibronectin, which are key constituents of the extracellular matrix. A small sample of the IA dome was harvested at the time of surgical repair from both ruptured and unruptured domes. Pericranial vascular tissue was harvested from a sample of the superficial temporal artery (STA) or occipital artery from aneurysmal and nonaneurysmal patients undergoing craniotomy for unrelated conditions. Statistical analysis examining expression of each marker was performed initially using dichotomous analysis (presence or absence of expression), followed by an assessment of quantitative differences in expression. Initial analysis was restricted to the pair consisting of dome and STA harvested from each individual patient. This was followed by a pooled analysis in which all domes and STAs were respectively pooled. RESULTS: A total of 86 tissue samples were studied, including 24 IA domes, STA samples from 43 aneurysmal patients, and STA samples from 19 nonaneurysmal patients. We found that the degree of prostacyclin-stimulating factor and RAI expression was reduced in ruptured aneurysm domes when compared with STAs from IA patients (odds ratio, 0.26; 95% confidence interval [CI], 0.08-0.89; and odds ratio, 0.18; 95% CI, 0.03-0.94, respectively). Type III collagen expression also was reduced among ruptured domes when compared with STA (P = 0.042). These differences were found to be independent of the effects of smoking with adjusted odds ratios of 0.25 (95% CI, 0.08-0.77) and 0.18 (95% CI, 0.04-0.79), respectively, for prostacyclin-stimulating factor and RAI. No statistically significant differences were noted among the unruptured domes. CONCLUSION: These preliminary data suggest an impaired ability to express proteins responsible for flow modulation and arterial repair within the ruptured domes when compared with control pericranial tissue. The study generates a hypothesis of impaired arterial homeostasis with a reduced ability to modulate hemodynamic flow with perhaps increased microinjury. This is exacerbated further by an impaired molecular ability to repair the vessel wall, culminating in aneurysm rupture. The study has limitations based on the use of pericranial tissue as the control and the relatively small sample size. Nevertheless, this study suggests that altered arterial homeostasis warrants further investigation in hopes of better understanding IA pathogenesis.

Adult↗
PubMed2003

Asynchronous functional, cellular and transcriptional changes after a bout of eccentric exercise in the rat.

Thirty eccentric contractions (ECs) were imposed upon rat dorsiflexors (n = 46) by activating the peroneal nerve and plantarflexing the foot ~40 deg, corresponding to a sarcomere length change over the range 2.27-2.39 microm for the tibialis anterior and 2.52-2.66 microm for the extensor digitorum longus. Animals were allowed to recover for one of 10 time periods ranging from 0.5 to 240 h, at which time muscle contractile properties, immunohistochemical labelling and gene expression were measured. Peak isometric torque dropped significantly by ~40 % from an initial level of 0.0530 +/- 0.0009 Nm to 0.0298 +/- 0.0008 Nm (P < 0.0001) immediately after EC, and then recovered in a linear fashion to control levels 168 h later. Immunohistochemical labelling of cellular proteins revealed a generally asynchronous sequence of events at the cellular level, with the earliest event measured being loss of immunostaining for the intermediate filament protein, desmin. Soon after the first signs of desmin loss, infiltration of inflammatory cells occurred, followed by a transient increase in membrane permeability, manifested as inclusion of plasma fibronectin. The quantitative polymerase chain reaction (QPCR) was used to measure transcript levels of desmin, vimentin, embryonic myosin heavy chain (MHC), myostatin, myoD and myogenin. Compared to control levels, myostatin transcripts were significantly elevated after only 0.5 h, myogenic regulatory factors significantly elevated after 3 h and desmin transcripts were significantly increased 12 h after EC. None of the measured parameters provide a mechanistic explanation for muscle force loss after EC. Future studies are required to investigate whether there is a causal relationship among desmin loss, increased cellular permeability, upregulation of the myoD and desmin genes, and, ultimately, an increase in the desmin content per sarcomere of the muscle.

Animals↗
PubMed2003

Immunotoxin-treated rhesus monkeys: a model for renal allograft chronic rejection.

BACKGROUND: Unlike acute and hyperacute rejection, chronic rejection (CR) still constitutes a poorly understood process. The onset is insidious, occurs in a period of months to years and, because the pathophysiology is not well understood, is untreatable. A reliable large-animal model for renal allograft CR is needed and has not been reported in the literature yet. METHODS: CR biopsy changes were studied in major histocompatibility complex-mismatched renal allografts performed in nine rhesus monkeys that received CD3 T-lymphocyte depletion therapy with immunotoxin on the day of the transplantation (n=7) or 7 days before transplant (n=2). RESULTS: Mean graft survival time was 613.77 days. Biopsy changes of CR were identified as soon as 84 days after transplant (mean, 336 days; range, 84-896 days). Most of the experimental animals had severe interstitial fibrosis, tubular atrophy, chronic transplant glomerulopathy, and chronic vascular rejection changes at the time of necropsy. A significant positive correlation between the severity of CR and the degree of CD68+ macrophage infiltrate of renal parenchyma and the degree of anemia and serum creatinine level elevations were also observed. CONCLUSIONS: Our findings are similar to those seen in human renal chronic allograft nephropathy, but in contrast, our model excludes all the nonimmune factors associated with chronic allograft nephropathy, including donor disease, injury from prolonged preservation, drug toxicity, and underlying recipient disease. Immunotoxin-treated rhesus monkeys emerge as an outstanding animal model for assisting us in understanding the pathophysiology of CR.

Animals↗
PubMed2003

Effectiveness of home-based cardiac rehabilitation for special needs patients.

BACKGROUND: The benefits of cardiac rehabilitation programmes have been well documented including reductions in mortality, improved physical performance, and improved quality of life. However, a large number of special needs patients often fail to access these programmes. Of particular concern are elderly patients with chronic illness and disability. AIMS: To evaluate the effectiveness of a home-based cardiac rehabilitation programme in improving health outcomes and rehabilitation access for special-needs patients. DESIGN: Using a one-group pre and post-test quasi-experimental design 40 elderly patients recently discharged from hospital following a cardiac event completed the Short Form Health Survey, the Angina Quiz, and the Exercise Assessment Questionnaire prior to undertaking home-based rehabilitation. The rehabilitation programme consisted of four community nursing contacts over a 9-week period primarily aimed at individual patient education and carer support. ANALYSIS: Descriptive statistics provided analysis for demographic data. Repeated measures multivariate analysis of variance (manova) were computed to examine changes in health-state and practices. RESULTS: Significant positive changes were found for measures of quality of life, knowledge of angina, and exercise tolerance. Additionally, the higher levels of participation and completion by older women was encouraging. Development of carer competence through an improved knowledge base and nursing support was also evident. LIMITATIONS: While theoretically defensible positive outcomes were found these results need to be replicated in a larger study. Similarly, the limitations imposed by a single group pretest, post-test design suggest that claims of generalizability need to be limited to the specific variables measured in this study. CONCLUSION: The study demonstrated medium term positive health outcomes. These positive findings suggest that home-based rehabilitation using larger samples of older patients with comorbidities, and using randomized comparative group designs, may be a fruitful area in future research.

Aftercare↗
PubMed2003

Working with the private sector for child health.

Private sector providers are the most commonly consulted source of care for child illnesses in many countries, offering significant opportunities to expand the reach of essential child health services and products. Yet collaboration with private providers presents major challenges - the suitability and quality of the services they provide is often questionable and governments' capacity to regulate them is limited. This article assesses the actual and potential contributions of the private sector to child health, and classifies and evaluates public sector strategies to promote and rationalize the contributions of private sector actors. Governments and international organizations can use a variety of strategies to collaborate with and influence private sector actors to improve child health - including contracting, regulating, financing and social marketing, training, coordinating and informing the public. These mutually reinforcing strategies can both improve the quality of services currently delivered in the private sector, and expand and rationalize the coverage of these services. One lesson from this review is that the private sector is very heterogeneous. At the country level, feasible strategies depend on the potential of the different components of the private sector and the capacity of governments and their partners for collaboration. To date, experience with private sector strategies offers considerable promise for children's health, but also raises many questions about the feasibility and impact of these strategies. Where possible, future interventions should be designed as experiments, with careful assessment of the intervention design and the environment in which they are implemented.

Child Health Services↗