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At least 595 records · Page 33Linked to original sources
PubMed1998

Mouse models dissect the role of p53 in cancer and development.

Mice lacking one or two copies of the p53 gene have provided invaluable insight into the process of tumorigenesis. The importance of apoptosis in suppression of tumorigenesis in vivo became evident from analysis of these mice. Moreover, the timing and kinds of tumors that develop in these mice are altered by the presence of additional inherited mutations, by strain differences, and by food intake. Developmental abnormalities are also visible in mice with loss of p53 and with overexpression of p53 suggesting that p53 levels are critical for normal cellular processes. While mice do not necessarily recapitulate all the tumor types found in inherited cancers, they offer the unique opportunity to decipher the critical pathways in tumorigenesis. These findings can then be applied to humans.

Animals↗
PubMed1996

The use of mechanistically defined chemical mixtures (MDCM) to assess mixture component effects on the percutaneous absorption and cutaneous disposition of topically exposed chemicals. II. Development of a general dermatopharmacokinetic model for use in risk assessment.

We present a conceptual approach to a general comprehensive mathematical model to quantify percutaneous absorption of topically applied chemicals in complex mixtures on the basis of biophysical parameters estimated or measured using in vitro and ex vivo perfused skin preparations. This model addresses mechanistically defined chemical mixtures (MDCM) which consist of components selected because of their potential to modulate by various mechanisms the absorption of a marker toxic penetrant. This model accounts for observed toxicodynamic general and specific effects of chemicals, acting single or in concert, on the absorption of any or all components in a defined mixture. We have also included experimental data from an isolated perfused porcine skin flap study with topically applied parathion as the marker penetrant and acetone or DMSO as solvent, with methyl nicotinate as a potential rubefacient, sodium laurel sulfate as a surfactant, and stannous chloride as a reducing agent in order to provide an illustration of the application and performance of the model. This model supports the MDCM concept that defining and then simulating those components of a complex mixture that could have a significant impact on the absorption of a marker toxic compound would be a useful screening approach in the risk assessment of topical chemical mixtures. It may also be used to identify critical pathways where chemical mixture component interactions significantly modify the absorption of the penetrant of interest.

Animals↗
PubMed2006

Integrating the diagnosis of childhood malignancies.

Significant progress has been made in understanding the molecular basis of pediatric malignancies. Mechanisms of pediatric acute leukemia induction include hyperdiploidy, aberrant expression of proto-oncogenes, and activation of transcription factors or kinases by aberrant fusion genes. Molecular analysis of these alterations has facilitated the recognition of distinct groups with different sensitivity to therapy, and identified potential targets for antileukemic agents. Similar analysis of pediatric soft tissue and bone tumors also resulted in the identification of specific fusion genes, and their characterization has contributed greatly to understand their biology. Molecular assays for these rearrangements have become important tools in classifying these tumors, providing important prognostic data. However, the understanding of mechanisms involved in the pathogenesis of many other pediatric malignancies, including some embryonal tumors--believed to arise due to perturbation of the normal developmental program--is still vastly incomplete. The Department of Pathology at Texas Children's Hospital is one of the Children's Oncology Group (COG) reference centers for pediatric liver tumors. We have been particularly interested in the biology of hepatoblastoma, the most common type of pediatric liver tumor. Although a number of cytogenetic and molecular abnormalities have been described for this type of embryonal tumor, its pathogenesis is still poorly understood. In an attempt to explore the role of different signaling pathways in this disease, we analyzed the expression patterns of different histologic subtypes of hepatoblastoma using cDNA microarray analysis, qualitative reverse transcription, polymerase chain reaction (QRT-PCR), and immunohistochemistry. Wnt signaling pathway, critical both in development and in neoplasia, appears to be particularly relevant in these tumors. Mutations of the beta-catenin gene are present in over 90% of hepatoblastomas, leading to activating transcription of a number of target genes. The pattern of beta-catenin expression and type of mutation in groups of tumors are crucial to understand the corresponding differences in their gene expression profiles. Our findings are consistent with a relationship between poor histologic phenotype and beta-catenin activation, indicating the potential utility of targeted gene expression assays to identify molecular events related to the pathogenesis and prognosis of hepatoblastomas. Integration of clinical, morphologic, phenotypic, cytogenetic, and molecular data has become the basis of novel prognostic prediction and therapeutic strategies in pediatric leukemia. Similarly, integration of new genetic and molecular data with clinical, and other diagnostic information will be crucial for accurate classification of pediatric tumors, risk stratification, and successful development of new therapies for pediatric oncologic patients.

Child↗
PubMed1992

Environmental cadmium in Europe.

The present article reviews information from the latest 10 years concerning fate and exposure of cadmium in the environment, on ecotoxicological effects, and on critical pathways leading to human and environmental exposure. It emphasizes the situation within the Community of European Countries by referring to limit values used in the EEC and some of its member states for emissions to water, air and soil. Estimates have been made on total emission balances for the Netherlands, Denmark, and for the EEC as a whole. The balances show that 70-90% of all cadmium circulating in the Community is disposed of as waste in solid waste deposits. Production and use patterns are presently changing, as indicated by reduced consumption in recent years of cadmium for plating, stabilizers and pigments in several countries as a result of regulations. However, significant increases in consumption for cadmium-containing batteries have occurred, resulting globally in increasing trends for the total consumption and production. Cadmium in sediments is more mobile than described earlier. Aquatic organisms can be classified in order of decreasing accumulation: algae greater than molluscs greater than crustaceans greater than fish. There is no evidence of biomagnification of cadmium within marine or fresh water food webs. Cadmium may enter into plants via roots or by foliar adsorption following atmospheric deposition. Biomagnification in terrestrial food chains is not observed. The uptake into plants is plant specific. Within plants significant variations are seen with concentrations generally decreasing in the order: roots greater than leaves greater than fruiting parts greater than seeds. A compilation of cadmium in air, in the aquatic environment and in soil is given. A downward trend during the 1970s to mid-1980s seems to be evidenced from various Northern European studies on cadmium air concentrations as well as for deposition rates of cadmium. In rivers, the dissolved cadmium concentrations are generally found to be relatively low (10-500 ng/L). In seawater, cadmium concentrations are found at 0.5-10 ng/L in oceanic or open marine areas, while elevated concentrations are reported in more closed marine areas and especially in coastal zones close to polluted estuaries. In fresh water, lake sediments concentrations 3-30 times higher than the background concentrations are reported in the surface layers of sediments. A significant decrease in such pollution has been observed within the recent 10 years. For marine sediments, enrichment factors of two are found in sediments from open areas and locally even 5-10 times.(ABSTRACT TRUNCATED AT 400 WORDS)

Cadmium↗
PubMed2003

Chemoprevention of lung cancer: new directions.

The refractoriness of advanced lung cancer to current treatment modalities requires new approaches to reduce the public health burden associated with this disease. One strategy that is currently being tested is chemoprevention, which aims to prevent the development of cancer in populations that are at high risk for cancer due to a variety of genetic or environmental factors. The key to the success of this approach, however, requires the identification of appropriately targeted efficacious, non-toxic agents as well as the methodologies to efficiently test them. Given the lack of success of previous phase III definitive lung cancer chemoprevention trials, there is a need for smaller scale phase II trials with molecular, imaging, or histologic endpoints to demonstrate preliminary safety and efficacy. The identification of molecular pathways critical to lung carcinogenesis offers the opportunity to develop targeted therapies for prevention. Means of optimizing the risk/benefit ratio associated with treatment include regional drug delivery that minimizes systemic toxicities and combination therapies. Identification of the most appropriate cohorts, such as former smokers without ongoing DNA damage due to carcinogen exposure, may uncover benefits that are hidden in a mixed population. Equally important is the identification of appropriate study endpoints that are predictive of patient outcomes such as cancer incidence. Further understanding of lung cancer biology will be critical to the success of future clinical trials.

Antineoplastic Agents↗
PubMed1996

Emergency Department Observation Units: Has the Time Come?

Background: Economic pressures for efficiency in health care have led to the need for new strategies for the care of patients with acute chest pain. Methods: Chest pain observation units have been developed in many hospitals and are widely considered to have the potential to provide rapid and safe evaluations for low-risk patients with acute chest pain. Critical pathways are also an increasingly used strategy for the management of this patient population. Results: Available data suggest that chest pain observation units can decrease 6 month resource utilization compared with patients admitted to traditional sites of care. However, the potential exists for these units to increase resource utilization by encouraging admissions to the hospital of patients who otherwise would have been discharged directly home. Conclusions: Chest pain observation units appear to be an important innovation for the care of patients with a low risk for acute myocardial infarction. Use of guidelines for the se units may permit true increases in efficiency without compromising quality.

Journal Article↗
PubMed2003

Development and differentiation of the intestinal epithelium.

The gastrointestinal tract develops from a simple tube to a complex organ with patterns of differentiation along four axes of asymmetry. The organ is composed of all three germ layers signaling to each other during development to form the adult structure. The gut epithelium is a constitutively developing tissue, constantly differentiating from a stem cell in a progenitor pool throughout the life of the organism. Signals from the adjacent mesoderm and between epithelial cells are required for normal orderly development/differentiation, homeostasis, and apoptosis. Embryonically important patterning factors are used during adult stages for these processes. Such critical pathways as the hedgehog, bone morphogenetic protein, Notch, Sox, and Wnt systems are used both in embryologic and adult times of gut development. We focus on and review the roles of these factors in gut epithelial cell development and differentiation.

Adult↗
PubMed2006

Insights into the genetic basis of congenital heart disease.

Cardiovascular malformations are the most common type of birth defect and result in significant mortality worldwide. The etiology for the majority of these anomalies remains unknown. Advances in the characterization of the molecular pathways critical for normal cardiac development have led to the identification of numerous genes necessary for this complex morphogenetic process. This work has aided the discovery of an increasing number of single genes being implicated as the cause of human cardiovascular malformations. This review summarizes normal cardiac development and outlines the recent discoveries of the genetic causes of congenital heart disease.

Aorta↗
PubMed2005

Hospitalization after open colectomy: expectations and practice in general surgery.

PURPOSE: There is increasing pressure to reduce the length of stay (LOS) in hospital after colectomy. To assess the impact of unintended variations on LOS, actual discharge management was compared with the expectations expressed by general surgeons. METHODS: We retrospectively examined 262 patients who underwent elective open colectomy. The effects of patient demographics, surgical variables, and functional recovery on postoperative LOS were assessed in univariate and multivariate models. We also used a structured questionnaire to assess the expectations of surgeons regarding criteria affecting patient discharge. RESULTS: The median LOS was 11 days, which was univariately correlated with morbidity, bowel movement, oral feeding, mobilization, surgeon, rectal procedures, comorbidity, type of analgesia, blood transfusion, and colorectal cancer. According to the multivariate analysis, morbidity (P < 0.001), colorectal cancer (P = 0.026), rectal procedure (P = 0.037), and analgesia (P = 0.04) were correlated with LOS. The surgeons we interviewed believed that discharge should be based on the return of bowel movement and the absence of morbidity. By discharging our patients on postoperative day 5 or 6, these criteria would have been respected in 84% and 88%, respectively. CONCLUSION: Prolonged hospitalization after colectomy persists when critical pathways are not observed and there is a lack of institutional pressure to reduce to the LOS. Many factors affect the delay in patient discharge, possibly reflecting unwanted variation rather than the surgeons' expectations.

Aged↗
PubMed2004

A method for cross-sector priority setting. Gaps and hypotheses in malaria research: Tanzania.

This study proposes a new priority setting method for identifying critical information gaps in a multisector system. The method uses graph-theoretical concepts and principles of systems theory in characterizing the underlying information structure of the system. Its application is illustrated in the context of malaria control in Tanzania, drawing on the findings of a workshop held in October 2003 in Dar es Salaam. The workshop identified two critical pathways, EVHA and EVHPA, which warrant better understanding. The first suggests that the malaria research should generate information on the effects of environmental changes (E) on vector ecology (V) and then on the effects of V on human health (H) and then on the effects of H on agriculture (A). Interpreted likewise, the second pathway additionally points to the need for information on the effects of socioeconomic conditions (P) on A.

Health Priorities↗
PubMed2006

Heterochromatin assembly: a new twist on an old model.

The organization of eukaryotic genomes requires a harmony between efficient compaction and accessibility. This is achieved through its packaging into chromatin. Chromatin can be subdivided into two general structural and functional compartments: euchromatin and heterochromatin. Euchromatin comprises most of the expressed genome, while heterochromatin participates intimately in the production of structures such as centromeres and telomeres essential for chromosome function. Studies in the fission yeast Schizosaccharomyces pombe have begun to highlight the genetic pathways critical for the assembly and epigenetic maintenance of heterochromatin, including key roles played by the RNAi machinery, H3 lysine 9 methylation and heterochromatin protein 1 (HP1). Recent studies have also identified a novel E3 ubiquitin ligase universally required for H3 K9 methylation. Here we outline these studies and propose several models for the role of this E3 ligase in heterochromatin assembly.

Animals↗
PubMed2005

Anti-angiogenic therapy in pediatric neuro-oncology.

In order to grow, tissues require additional nutrients and oxygen as well as removal of waste products. Tumors achieve this by up-regulating angiogenic cytokines and/or down-regulating natural inhibitory proteins that allow neovascularization to proceed. Brain tumors continue to account for significant morbidity and mortality, in spite of significant advances in neurosurgical and radiation techniques and new chemotherapy combinations. As such, there is a real and immediate need for novel biologic therapies that can target these tumors. A number of new drugs that target different aspects of the angiogenic cascade have been identified and are now in clinical trials in children with primary brain tumors. In many of these pre-clinical and clinical studies, anti-angiogenic therapy has been well tolerated, has lacked many of the traditional toxicities of radiation and chemotherapy, does not require blood-brain barrier penetration, and targets a critical pathway in central nervous system tumor development. This review will discuss what angiogenesis is, how pediatric brain tumors regulate angiogenesis to obtain a vascular supply, what types of inhibitors are available, how different classes of inhibitors work, the types of resistance possible, how rapidly these inhibitors may work, and what surrogate markers of activity are available to follow response.

Angiogenesis Inhibitors↗
PubMed2003

New targeted therapies in gastrointestinal cancers.

Despite surgical, radiotherapeutic, and chemotherapeutic advances, a large proportion of gastrointestinal (GI) cancers remain incurable. An improved understanding of the molecular pathogenesis of cancer has promulgated the development of novel agents designed to target critical pathways involved in cancer development and progression. The crucial role of the epidermal growth factor receptor (EGFR) in tumor proliferation and the overexpression of EGFR in several GI cancers provides the rationale for targeting and interrupting this key signaling network. EGFR blockade through monoclonal antibodies (C225 and ABX-EGF) and tyrosine kinase inhibitors (ZD1839 and OSI-774) has translated into promising evidence of clinical benefit. Ras-mediated signal transduction has been targeted using inhibitors of farnesyl transferase (R115777 and SCH66336) to block the post-translation modification of Ras. Inhibitors of vascular growth factor receptor (bevacizumab and PTK787) and matrix metalloproteinase target the effects of the host environment. Cyclooxygenase-2 inhibitors in colorectal cancer and STI571 in GI stromal tumors represent novel therapies of interest for these specific GI cancers. Evidence suggests that novel agents can be administered alone or in combination with standard therapies with little additional toxicity. The results of ongoing and future research efforts will clarify the optimal use and survival benefit of targeted therapies for patients with GI malignancies.

Adult↗
PubMed2006

The emerging role for type 5 phosphodiesterase inhibition in heart failure.

Patients with heart failure (HF) due to left ventricular (LV) systolic dysfunction have abnormal endothelium-dependent, nitric oxide-cyclic guanosine monophosphate-mediated vasodilation in the pulmonary and skeletal muscle vasculature. Therefore, inhibition of type 5 phosphodiesterase (PDE5), the principle enzyme responsible for cyclic guanosine monophosphate catabolism in the lungs and skeletal muscle, has been targeted in an effort to counteract vasoconstriction that contributes to increased right and LV afterload in HF. The efficacy of PDE5 inhibition in the treatment of pulmonary arterial hypertension has led to the investigation of its potential utility in the treatment of HF patients with secondary pulmonary hypertension. Moreover, recent preclinical studies suggest direct myocardial effects of PDE5 inhibition that may counteract beta-adrenergic, hypertrophic, and pro-apoptotic signaling, three critical pathways in the development of LV dysfunction. This review outlines both the underlying rationale and the results of initial studies of the therapeutic effects of PDE5 inhibition in HF.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2003

Genetics of the kidney and hypertension.

Success in the search for genes that cause or contribute to hypertension susceptibility has been limited to a few rare Mendelian forms of hypertension (glucocorticoid remediable aldosteronism, apparent mineralocorticoid excess, and Liddle's syndrome). Our well-reasoned efforts to assess candidate genes in critical pathways known to be involved in blood pressure regulation have not been as productive in complex genetic cases of hypertension. These cases involve both genetic and environmental determinants. The most frequently used approach to the identification of hypertension genes involves genetic association studies, which are population based and compare cases and controls. Linkage analyses are also used but require family data. While much effort is spent identifying new markers and candidate genes, it is important to periodically determine which findings of linkage or association are confirmed in order to advance our quest to identify hypertension genes. In this review, the status of the assessment of the HSD11B2 gene is reviewed. In addition, data supporting the need to assess the mitochondrial genome, the other human genome, in hypertension susceptibility are reviewed.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed1994

Playing by the numbers: how collecting outcomes data changed by life.

The Northern New England Cardiovascular Study Group has been using clinical epidemiology to analyze outcomes data in patients undergoing cardiac surgical procedures to answer three questions: (1) for the surgeon: how am I doing?, (2) for the patient: what are my chances?, and (3) for society: can outcomes data be voluntarily collected and organized in a way to improve care delivery? The Dartmouth-Hitchcock Medical Center cardiac surgery program has combined this regional outcomes data with the internal development of critical pathways; with evaluations of patient expectations, patient satisfaction, and patient functional health; and with innovative techniques of data display in an effort to improve the cardiac surgical outcomes in patients at the center. The length of stay has declined, and both the mortality rate and readmission rate have remained stable.

Clinical Protocols↗
PubMed1986

Definition of two distinct mechanisms of action of antiestrogens on human breast cancer cell proliferation using hydroxytriphenylethylenes with high affinity for the estrogen receptor.

Treatment of MCF 7 human breast cancer cells with three high affinity hydroxylated antiestrogens (Kd for the estrogen receptor = 0.11-0.45 nM) resulted in biphasic inhibition of cell growth. Administration of 0.1-1.0 nM of each drug caused a concentration-dependent decrease in cell number to a maximum of 30-40% of control but no further change was observed as the drug concentration was increased to 1 microM. Between 1.0 and 10 microM, however, a further concentration-dependent decrease in cell proliferation was observed. Among these compounds relative potencies paralleled their affinities for estrogen receptor in the 0.1-10 nM range but at micromolar concentrations this relationship did not hold. It is concluded that antiestrogens inhibit cell proliferation by two distinct mechanisms one of which involves the estrogen receptor and the other a mechanism yet to be defined. The parallel changes in cell cycle kinetic parameters accompanying growth inhibition in both concentration ranges i.e. accumulation of cells in the G1 phase at the expense of S phase cells, suggests that both mechanisms may converge on common pathways critical to cell cycle progression.

Binding, Competitive↗
PubMed1994

Glucose metabolism in separated embryos and investing membranes during organogenesis in the rat.

Glucose metabolism provides an essential energy source in the mammalian embryo. We used the rat embryo culture system to investigate the activity of several critical pathways for glucose metabolism during early organogenesis, before (day 10 of gestation) and during (day 11) the establishment of the chorioallantoic circulation and closure of the neural tube. We studied glucose metabolism in the intact conceptus, the separated embryo, and its investing membranes, including the visceral yolk sac, allantois, and amnion. Short-term incubations were performed for 4 hours in culture media containing U-14C-, 14C-1-, or 14C-6-labeled D-glucose on day 10 and day 11 of gestation, and the rates of glucose utilization by glycolysis and oxidative metabolism, including the pentose phosphate pathway (PPP), were measured. Glycolytic metabolism, estimated by the accumulation of lactate, was high on day 10 in the intact conceptus, embryo, and membranes (92 +/- 6, 63 +/- 5, and 99 +/- 8 nmol/micrograms protein/4 h, respectively) and decreased by two thirds by day 11 in each tissue. Of note, the rate of glycolysis was greater in membranes than in the embryo on both days (P < .01). On the other hand, oxidative metabolism, reflected in the production of 14CO2, was relatively low on day 10 (0.78 +/- 0.04, 0.73 +/- 0.05, and 0.6 +/- 0.06 nmol/micrograms protein/4 h for intact conceptus, embryo, and membranes, respectively) and increased significantly in each tissue by day 11 (P < .01 for each).

Animals↗