Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Critical Pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 811 records · Page 45Linked to original sources
PubMed2001

Ablation of p21waf1cip1 expression enhances the capacity of p53-deficient human tumor cells to repair UVB-induced DNA damage.

During periods of genotoxic stress, the cyclin-dependent kinase inhibitor p21waf1cip1 (hereafter referred to as p21) is transcriptionally up-regulated by the p53 tumor suppressor and subsequently plays a key role in cellular growth arrest. Investigations have also indicated that p21 may regulate nucleotide excision repair, a critical pathway that removes carcinogenic DNA damage induced by UV light and other mutagens. In this study, we examined whether low levels of endogenous p21 expression can modulate nucleotide excision repair in p53-deficient human tumor cells after UVB exposure. For this purpose, we used the well-characterized p53-/-p21+/+ adenocarcinoma cell strain DLD1 and its isogenic counterpart carrying a homozygous knockout for p21 (p53-/-p21-/- DLD1). Because p53-/-p21+/+ DLD1 expresses very low levels of endogenous p21 protein that are not up-regulated after mutagen exposure, this strain has been considered functionally p21-deficient in the cellular response to DNA damage. Nonetheless, the ligation-mediated PCR technology was used here to demonstrate, at nucleotide resolution, that p53-/-p21+/+ DLD1 excises UVB-induced cyclobutane pyrimidine dimers from the c-jun proto-oncogene at a significantly lower rate than the isogenic p53-/-p21-/- derivative. The higher efficiency of DNA repair in UVB-exposed p53-/-p21-/- DLD1 cells is accompanied by increased clonogenic survival and reduced levels of apoptosis, relative to the p53-/-p21+/+ counterpart. Our results show that ablation of p21 expression can significantly enhance the capacity of p53-deficient human tumor cells to repair UVB-induced DNA damage.

Adenocarcinoma↗
PubMed2001

[Guideline development for general medicine: the problem of dichotomized algorithm development].

Development of clinical guidelines in Germany is based on two divergent principles. One is the clinical position of individuality and clinical experience. The other is the strong adherence to the principles of evidence-based medicine and the scientific method, as demonstrated by the clear, algorithmic methodology of critical pathway development. We discuss the pros and cons of both concepts and try to find some sort of practical middle ground between the two extremes.

Algorithms↗
PubMed2002

Promoter hypermethylation of multiple genes in nasopharyngeal carcinoma.

PURPOSE: The methylation profile of nasopharyngeal carcinoma (NPC) has been investigated by a candidate gene approach. EXPERIMENTAL DESIGN: Four NPC cell lines, 4 NPC xenografts, 33 NPC primary tumors, and 6 samples of normal nasopharyngeal epithelium were subjected to methylation-specific PCR for analysis of promoter methylation of eight cancer-related genes. These eight genes were RASSF1A, RARbeta2, DAP-kinase, p16, p15, p14, MGMT, and GSTP1. The correlation between methylation status of these genes and clinical features such as stage, local-regional recurrence, distant metastasis, and survival has been analyzed. RESULTS: The incidence of promoter methylation in NPC samples was 84% for RASSF1A, 80% for RARbeta2, 76% for DAP-kinase, 46% for p16, 17% for p15, 20% for p14, 20% for MGMT, and 3% for GSTP1. No methylation of these genes was detected in the six normal nasopharyngeal epithelium samples. All NPC tumor samples in this study displayed aberrant methylation in at least one of these eight genes. No significant correlation between methylation status of these genes and clinical parameters of the patients was found. CONCLUSIONS: A high frequency of aberrant methylation of the 5' CpG island of the RASSF1A, RARbeta2, DAP-kinase, and p16 genes in the present study was noted. Our findings suggest that methylation of the genes in the critical pathways is common in NPC.

Apoptosis Regulatory Proteins↗
PubMed2002

[Therapy of Philadelphia chromosome positive acute lymphatic leukemia (Ph+ ALL) with an inhibitor of abl-tyrosine kinase (Glivec)].

BACKGROUND: Ph+/bcr-abl positive ALL has the worst prognosis of all subgroups of ALL; only a small minority of patients are cured with currently established treatment regimens. The central pathogenetic role of the constitutively activated and deregulated abl-tyrosine kinase that is a direct consequence of the bcr-abl rearrangement opens the possibility of treating this disease using a molecularly targeted approach. The recent development of the selective abl-tyrosine kinase inhibitor Glivec (formerly STI571) opens the opportunity of blocking the signal transduction pathways critically involved in bcr-abl induced leukemogenesis. TREATMENT RESULTS AND CONCLUSIONS: Glivec exerts a significant anti-leukemic effect in patients with Ph+ ALL, with a remarkably favorable toxicity profile. This enables transfer of a subset of the responding patients to a potentially curative allogeneic stem cell transplantation. Despite promising initial therapeutic effects, treatment with Glivec alone is not able to achieve cures in the majority of patients with relapsed or refractory Ph+ ALL. The earlier administration of Glivec in patients with "de novo" ALL as well as combining it with other treatment modalities is likely to improve treatment results. The identification of specific resistance mechanisms towards Glivec should provide valuable information regarding the development of clinical strategies to circumvent resistance. Glivec can already be considered an important element in the treatment of Ph+ ALL, although the most effective ways of employing this novel agent remain to be established.

Antineoplastic Agents↗
PubMed2001

Hypertension exacerbates coronary artery disease in transgenic hyperlipidemic Dahl salt-sensitive hypertensive rats.

BACKGROUND: The mechanisms underlying the known interaction of two complex polygenic traits, hypertension and hyperlipidemia, resulting in exacerbation of coronary artery disease have not been elucidated. Identification of critical pathways underlying said exacerbation could identify mechanism-based targets for intervention and prevention. MATERIALS AND METHODS: To investigate hypertension- atherosclerosis interaction, we studied the inbred transgenic atherosclerosis-polygenic hypertension Dahl salt-sensitive (S) rat model (Tg53), which over-expresses human cholesteryl ester transfer protein (hCETP) in the liver, and exhibits coronary artery disease and decreased survival compared with control non-transgenic Dahl S rats. Using serial-section histopathological and immunohistochemical analyses, we analyzed the coronary artery disease phenotype of Tg53 rats at end-stage marked by cardio-respiratory compromise as the experimental equivalent of acute coronary syndromes, and determined the effects of reduction of blood pressure through low salt diet (0.008% NaCl) on the coronary artery disease phenotype and survival. RESULTS: End-stage Tg53 rats exhibit coronary artery lesions in the proximal right coronary artery system which exhibit "culprit plaque" features such as plaque inflammation, matrix degradation, apoptosis, neovascularization, thrombosis and hemorrhage recapitulating said features and heterogeneity of human coronary "culprit plaques". Comparative analysis of 6 month vs end-stage lesions reveals distinct lesion development profiles of proximal coronary lesions which quickly progress from eccentric non-occlusive foam-cell rich lesions at 6 months to occlusive "culprit plaques", compared with more distal coronary lesions which exhibit occlusive thick-cap atheroma that remain relatively unchanged from 6 months to end stage. Reduction of hypertension through a low-salt (0.008% NaCl) diet increased survival (P < 0.0001) of Tg53 rats and significantly attenuated the coronary artery disease phenotype detected at 10 months of age marked by diminished apoptosis, neovascularization, matrix degradation compared with end-stage lesions detected at <8 months of age. CONCLUSIONS: End stage coronary lesions in the Tg53 rats recapitulate many, albeit not all, features of "culprit plaques" in humans supporting proposed paradigms of plaque vulnerability implicating lesion macrophage enrichment, apoptosis, matrix degradation and pathological neovascularization. Comparative time course analysis of coronary lesions reveals that plaques which develop into end-stage "culprit plaques" are distinct from "stable plaques" by location and early lesion morphology, suggesting distinct lesion development and progression pathways. The significant effects of low-salt diet-induced decrease in hypertension on right coronary disease phenotype provides compelling evidence that polygenic hypertension accelerates coronary plaque progression and complication independent of cardiac hypertrophy, and more importantly provides paradigmatic support for public health policy.

Animals↗
PubMed2002

Adenoviral transfer of the melanoma differentiation-associated gene 7 (mda7) induces apoptosis of lung cancer cells via up-regulation of the double-stranded RNA-dependent protein kinase (PKR).

Adenoviral-mediated overexpression of the melanoma differentiation-associated gene 7 (Ad-mda7) induces apoptosis in a wide range of cancer cells, although themechanism is not well understood. We report that Ad-mda7 induces andactivates the double-stranded RNA-dependent protein kinase (PKR), which leads to phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2alpha) and the induction of apoptosis in lung cancer cells. Treatment with 2-aminopurine (2-AP), a serine/threonine kinase inhibitor, inhibits PKR activation, eIF2alpha phosphorylation, and apoptosis induction by Ad-mda7. Additionally, PKR null but not wild-type fibroblasts are resistant to Ad-mda7-induced apoptosis. These results suggest that the activation of PKR and its downstream targets may be a critical pathway for Ad-mda7-mediated apoptosis.

2-Aminopurine↗
PubMed2002

Restoration of T cell-specific V(D)J recombination in DNA-PKcs(-/-) mice by ionizing radiation: The effects on survival, development, and tumorigenesis.

DNA-dependent protein kinase (DNA-PK) is a DNA-activated nuclear serine/threonine protein kinase. DNA-PK consists of a heterodimeric Ku subunit (composed of a 70 and 86 kD subunit) which binds DNA ends and targets the catalytic subunit DNA-PKcs to DNA strand breaks. DNA-PK plays a major role in the repair of double-strand breaks (DSB) induced in DNA after exposure to ionizing radiation. To better understand the nature of DNA repair defect associated with DNA-PKcs deficiency, we have established DNA-PKcs(-/-) mouse embryo fibroblast cell lines and DNA-PKcs(-/-) null mice, and investigated the response of these mutant cells and mice to DNA damage. DNA-PKcs(-/-) cells are hypersensitive to gamma-irradiation, as evidenced by their low survival as assayed by colony formation efficiencies. Consistent with the radiation hypersensitive phenotype of the cell lines, DNA-PKcs(-/-) mice also display an extreme radiosensitivity, characterized by enhanced mortality after gamma-irradiation. Treatment of newborn DNA-PKcs(-/-) mice with sublethal doses of ionizing radiation restores T cell receptor (TCR) beta recombination and T cell maturation. However, radiation does not restore B cell development. All these mice eventually developed thymic lymphoma. These observations suggest an interrelationship between DSB repair, V(D)J recombination and lymphomagenesis, and provide an in vivo model to elucidate the critical pathways between the regulation of DNA DSB repair, V(D)J recombination, and the molecular mechanism of lymphoid neoplasia.

Animals↗
PubMed2002

Effects of perillyl alcohol on melanoma in the TPras mouse model.

This study evaluates the chemopreventive effects of topically applied perillyl alcohol on the development of melanoma in TPras transgenic mice. Our strategy was to target critical pathways in the development of melanoma, in particular, the ras pathway. Ras has been shown in our experimental mouse model, as well as others, to be important in the development and maintenance of melanomas. Perillyl alcohol (POH), a naturally occurring monoterpene, inhibits the isoprenylation of small G protein, including Ras. POH (10 mM) was applied to the shaved dorsal skin of TPras mice starting 1 week before five treatments of dimethylbenz[a]anthracene (50 microg) and was continued for 38 weeks. We observed a delay in the appearance of tumors and a 25-35% reduction in melanoma incidence. POH treatment of melanoma cells in vitro reduced the levels of detectable Ras protein and inhibits the activation of downstream targets, mitogen-activated protein kinases and Akt. POH only minimally induced apoptosis in this system. Pretreatment but not post-treatment of the melanoma cells with POH, however, markedly reduced levels of UV-induced reactive oxygen species. These studies suggest that POH inhibition of the Ras signaling pathway may be an effective target for chemoprevention of melanoma.

Animals↗
PubMed2002

[Recommendations for the management of acute chest pain. Report of the Belgian Interdisciplinary Group on Acute Cardiology].

The Belgium Interdisciplinary Working Group on Acute Cardiology (BIWAC), including cardiologists, intensivists and urgentists was formed to give consensus regarding the management of acute chest pain in the prehospital and the early hospital phases. General recommendations and critical pathways are proposed to improve the treatment of the patients with acute coronary syndromes.

Acute Disease↗
PubMed2002

[Recommendations for management of acute chest pain. Report of the Belgium Interdisciplinary Working Group on Acute Cardiology].

The Belgium Interdisciplinary Working group on Acute Cardiology, including cardiologists, intensivists and urgentists was formed to provide consensus regarding the management of acute chest pain in the prehospital and the early hospital phase. General recommendations and critical pathways are proposed to improve the treatment of the patients with acute coronary syndromes.

Acute Disease↗
PubMed2002

Information model and terminology model issues related to goals.

Goal statements are a significant component of structures that support the process of health care delivery such as practice guidelines, standards of care, critical pathways, disease management plans, patient education plans, and nursing care plans. Although these structures are increasingly computer-based, there has been little attention to the formal representation of goal statements. This is a necessary prerequisite for enabling semantic interoperability. Existing and evolving information model and terminology model standards offer some approaches that may be applicable to goal statements, however, a number of issues require resolution

Goals↗
PubMed2003

Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors.

Genome-wide copy number profiles were characterized in 41 primary bladder tumors using array-based comparative genomic hybridization (array CGH). In addition to previously identified alterations in large chromosomal regions, alterations were identified in many small genomic regions, some with high-level amplifications or homozygous deletions. High-level amplifications were detected for 192 genomic clones, most frequently at 6p22.3 (E2F3), 8p12 (FGFR1), 8q22.2 (CMYC), 11q13 (CCND1, EMS1, INT2), and 19q13.1 (CCNE). Homozygous deletions were detected in 51 genomic clones, with four showing deletions in more than one case: two clones mapping to 9p21.3 (CDKN2A/p16, in nine cases), one at 8p23.1 (three cases), and one at 11p13 (two cases). Significant correlations were observed between copy number gain of clones containing CCNE1 and gain of ERBB2, and between gain of CCND1 and deletion of TP53. In addition, there was a significant complementary association between gain of CCND1 and gain of E2F3. Although there was no significant relationship between copy number changes and tumor stage or grade, the linked behavior among genomic loci suggests that array CGH will be increasingly important in understanding pathways critical to bladder tumor biology.

Chromosomes, Human, Pair 9↗
PubMed2003

Reflexivity in nursing: where is the patient? Where is the nurse?

Drawing upon forty years of nursing experience, in this paper we are reflexive about four issues relative to nursing clinical practices: seeking technological solutions to health and ill-health; moving from the nurse-patient relationship to the patient-healer relationship; utilising critical pathways; and, supporting evidence-based nursing. We examine current nursing practices and ask probing questions to generate debate. Most of all, we encourage nurses to engage in reflexivity and not to lose sight of their selves (knowledge, expertise and skills), and their patients' voices and subjectivity, in their contribution to health care.

Australia↗
PubMed2003

Prevalence, clinical characteristics, resource utilization and outcome of patients with acute chest pain in the emergency department. A multicenter, prospective, observational study in north-eastern Italy.

BACKGROUND: The evaluation and triage of patients with suspected myocardial ischemia in the emergency department is challenging and costly. In Italy there are no prospective data neither about the prevalence, clinical characteristics, and outcome of patients with chest pain in the emergency room, nor about the costs of their triage. Therefore, this study was undertaken to evaluate the diagnostic accuracy and costs of the actual emergency department triage modalities of patients with acute chest pain. METHODS: We analyzed the clinical data from a multicenter, prospective study of all patients with chest pain who presented to the emergency department of three hospitals in North-Eastern Italy from April to October 1999. RESULTS: Of 12,375 new medical admissions at the three emergency departments during the study period, 495 (prevalence 4%, mean age 62 +/- 16 years, 50% females) were for chest pain. Thirty-seven percent of the patients with chest pain were hospitalized with a suspected acute coronary syndrome, while 63% were directly discharged from the emergency department. The diagnosis of acute coronary syndrome was confirmed in 79% of hospitalized patients. Among the patients discharged directly from the emergency department 68% were immediately sent back home (69 +/- 60 min from admission) and 32% required a brief clinical observation lasting 10 +/- 6 hours and including serial electrocardiographic and myocardial injury marker assessment. The average cost of the emergency department triage was 189 +/- 237 [symbol: see text]/patient. The 1-month follow-up of the patients directly discharged from the emergency department revealed a 2.5% incidence of acute coronary syndromes (3 acute myocardial infarctions), but no deaths. CONCLUSIONS: Data obtained from our multicenter observational study suggest that present triage modalities for patients with chest pain in the emergency department based on patient history, clinical data, electrocardiography, and myocardial injury marker assessment could be improved in terms of accuracy and efficacy. Our data provide the clinical and economical framework for the designation of trials of new accelerated critical pathways for chest pain evaluation in the emergency department.

Acute Disease↗
PubMed2003

Inhibition of lysophosphatidic acid acyltransferase beta disrupts proliferative and survival signals in normal cells and induces apoptosis of tumor cells.

Lysophosphatidic acid acyltransferase beta (LPAAT-beta) is an intrinsic membrane protein that catalyzes the synthesis of phosphatidic acid (PA) from lysoPA. Given that PA is a cofactor in a number of signaling cascades that are constitutively active in tumors, we evaluated the role of PA produced by LPAAT-beta in Xenopus oocyte meiotic maturation assays and an isoform-specific inhibitor of LPAAT-beta in mammalian cell assays. We found that ectopic overexpression of LPAAT-beta cooperates in activation of the Ras/Raf/Erk pathway in Xenopus oocytes and that inhibition of LPAAT-beta inhibits signaling in both the Ras/Raf/Erk and PI3K/Akt pathways. When LPAAT-beta activity is suppressed by CT32228 (N-(4-bromo-phenyl)-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine-2,4-diamine), an isoform-specific noncompetitive inhibitor, tumor cells undergo mitotic catastrophe while most normal cells simply arrest or become quiescent. The data presented here suggest that PA produced by LPAAT-beta plays an important role in signaling pathways critical to tumor cell survival.

Acyltransferases↗
PubMedDate not supplied

The nursing case management computerized system: meeting the challenge of health care delivery through technology.

Does nursing case management compute? In this article, the author attempts to explain how computerizing the team plan of care and critical pathways decreases paperwork, makes it easier to develop standardized team care plans, enhances quality improvement trending, and is flexible enough to update the plan of care according to the patient's changing needs. The Nurse Case Management Computerized System puts the patient care team plan into an interactive computer program. The computer does the work of presenting the nurse with care plan options and printing a hard copy ready to implement. Use of the computer program enhances the health care team's ability to individualize the team plan of care while maintaining patient care standards. The system is also used to collect patient care data automatically and to trend for quality improvement.

Humans↗
PubMed2003

[Network for the treatment of acute myocardial infarction in the province of Mantova: results after 2 years of work].

BACKGROUND: Since June 2001, in the province of Mantova, we have been carrying out a program for the management of acute myocardial infarction based on early assessment of the patients' risk profile, on telematic connection among care centers and on optimization of in- and out-of-hospital critical pathways for the access to care. METHODS: Our network provides connection among the following centers: advanced life support ambulances, 7 hospitals, 3 coronary care units, 1 cath lab on call 24 hours a day for primary angioplasty, 1 thoracic surgery division. This program, through its strong telematic platform, allows early assessment of myocardial infarction, and provides primary angioplasty to all high-risk patients, being fibrinolytic treatment reserved only to the low-risk patients admitted in peripheral hospitals. RESULTS: Two hundred and twenty patients with acute myocardial infarction were treated with angioplasty; 179 (81%) patients underwent primary angioplasty, 26 (12%) patients facilitated angioplasty and 15 patients (7%) rescue angioplasty; 121 patients (55%) were first admitted in the Mantova hospital, 65 patients (30%) were referred to Mantova from peripheral hospitals and 34 patients (15%) were directly transported to the cath lab by advanced life support ambulances. Procedural success was obtained in 98% of cases, with 05% intraprocedural mortality. In-hospital mortality was 55%, while mortality of cardiogenic shock patients was 36%. Recurrence of acute myocardial infarction occurred in 1% and major bleeding in 2.2% of patients. One patient with cardiogenic shock died during transport. Mean door-to-balloon time was 73 min with 39% reduction in the second period of recruitment after telematic connection. CONCLUSIONS: This program, developed in the setting of a provincial network for the management of acute myocardial infarction, provided primary angioplasty to all high-risk patients, with a high procedural success rate. Within a few months, time to treatment was minimized by the employment of telematic facilities.

Adult↗
PubMed2003

The specialty of colon and rectal surgery: its impact on patient care and role in academic medicine.

The specialty of colon and rectal surgery, a specialty of general surgery, has evolved from the field of proctology. Clinical care has demonstrated decreased number of patients requiring intestinal stomas, improved quality of life in patients with benign anorectal disorders, and more favorable results in patients afflicted with primary and recurrent colorectal cancer. Basic science investigations have spawned from clinical questions such as the molecular biology of colorectal cancer, use of cyclooxygenase inhibitors and polyp regression, and novel cytokine antagonists in inflammatory bowel disease. Medical students are exposed to surgeons with expertise in anorectal anatomy and physiology, mechanisms of carcinogenesis and the importance of screening for detection of colorectal cancer, and novel therapies for inflammatory bowel disease. Surgical residents benefit by having a colorectal surgeon on the faculty by repetitive exposure to anorectal surgery, low pelvic anastomoses, stoma creation and closure, and surgery involving the small intestine. Senior colorectal surgeons will develop critical pathways for the healthcare delivery of patients afflicted with colorectal disease. The specialty of colorectal surgery will continue to translate into improved patient care and positively impact in academic medicine by providing expertise into student and resident training and generate highly sophisticated clinical and basic science investigations.

Colon↗