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 757 records · Page 42Linked to original sources
PubMed2004

New targets for therapy in breast cancer: small molecule tyrosine kinase inhibitors.

Over the past several years many advances have been made in our understanding of critical pathways involved in carcinogenesis and tumor growth. These advances have led to the investigation of small molecule inhibitors of the ErbB family of receptor tyrosine kinases across a broad spectrum of malignancies. In this article we summarize the rationale for targeting members of the ErbB family in breast cancer, and review the preclinical and clinical data for the agents that are furthest in development. In addition, we highlight directions for future research, such as exploration of the potential crosstalk between the ErbB and hormone receptor signal transduction pathways, identification of predictive markers for tumor sensitivity, and development of rational combination regimens that include the tyrosine kinase inhibitors.

Anticarcinogenic Agents↗
PubMed2005

Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib.

PURPOSE: To evaluate the efficacy and toxicity of combined treatment with two targeted agents, an antibody against vascular endothelial growth factor (bevacizumab) and an epidermal growth factor receptor tyrosine kinase inhibitor (erlotinib), in the treatment of patients with metastatic clear-cell renal carcinoma. PATIENTS AND METHODS: Sixty-three patients with metastatic clear-cell renal carcinoma were treated with bevacizumab 10 mg/kg intravenously every 2 weeks and erlotinib 150 mg orally daily. Patients were reevaluated after 8 weeks of treatment; patients who responded continued treatment until they experienced tumor progression. RESULTS: Fifteen (25%) of 59 assessable patients (95% CI, 16% to 37%) had objective responses to treatment, and an additional 36 patients (61%) had stable disease after 8 weeks of treatment. Only eight patients' (14%) disease had progressed at this time point. The median and 1-year progression-free survivals were 11 months and 43%, respectively. After a median follow-up of 15 months, median survival has not been reached; survival at 18 months was 60%. Treatment was generally well tolerated; only two patients discontinued treatment because of toxicity (skin rash). Grade 1/2 skin rash and diarrhea were the most frequent treatment-related toxicities. CONCLUSION: The combination of bevacizumab and erlotinib is an effective and well-tolerated treatment for patients with advanced renal cell carcinoma. The efficacy of these two drugs in combination suggests that targeting of separate pathways critical to tumor growth and dissemination may achieve results superior to either drug as a single agent. Additional development of this and other combinations of targeted agents is warranted.

Adenocarcinoma, Clear Cell↗
PubMed2003

Developmental and hormonal signals dramatically alter the localization and abundance of insulin receptor substrate proteins in the mammary gland.

Insulin receptor substrates (IRS) are central integrators of hormone, cytokine, and growth factor signaling. IRS proteins can be phosphorylated by a number of signaling pathways critical to normal mammary gland development. Studies in transgenic mice that overexpress IGF-I in the mammary gland suggested that IRS expression is important in the regulation of normal postlactational mammary involution. The goal of these studies was to examine IRS expression in the mouse mammary gland and determine the importance of IRS-1 to mammary development in the virgin mouse. IRS-1 and -2 show distinct patterns of protein expression in the virgin mouse mammary gland, and protein abundance is dramatically increased during pregnancy and lactation, but rapidly lost during involution. Consistent with hormone regulation, IRS-1 protein levels are reduced by ovariectomy, induced by combined treatment with estrogen and progesterone, and vary considerably throughout the estrous cycle. These changes occur without similar changes in mRNA levels, suggesting posttranscriptional control. Mammary glands from IRS-1 null mice have smaller fat pads than wild-type controls, but this reduction is proportional to the overall reduction in body size. Development of the mammary duct (terminal endbuds and branch points) is not altered by the loss of IRS-1, and pregnancy-induced proliferation is not changed. These data indicate that IRS undergo complex developmental and hormonal regulation in the mammary gland, and that IRS-1 is more likely to regulate mammary function in lactating mice than in virgin or pregnant mice.

Adipose Tissue↗
PubMed2005

Prolactin receptor knockdown in the rat paraventricular nucleus by a morpholino-antisense oligonucleotide causes hypocalcemia and stress gastric erosion.

Under acute stress conditions in the rat, there is rapid and transient increase in circulating prolactin (PRL). This leads to an elevated expression of the long form of PRLR (PRLR-L) first in the hypothalamus and the choroid plexus. This increase in PRL is involved in the inhibition of stress-induced hypocalcemia and gastric erosion. In this study we used rat PRL and a PRLR morpholino-antisense oligonucleotide to elucidate the mechanism by which hypothalamic PRLR mediates the inhibition of restraint stress in water (RSW)-induced hypocalcemia and gastric erosion. We found that this effect is largely mediated by PRLRs in the paraventricular nucleus (PVN), medial preoptic nucleus, and ventromedial hypothalamus. We also show that when measured after 7 h of RSW, microinjection of the PRLR antisense oligonucleotide into these areas down-regulates RSW-enhanced expression of PRLR-L protein in the PVN and increases the plasma PRL level, but does not affect plasma levels of another hormone, GH. Furthermore, our experiments demonstrated that under nonstress conditions, knockdown of the PRLR in the PVN significantly lowers circulating Ca2+ levels, but does not affect gastric erosion. These results suggest that PRL acting on the PRLR-L in the PVN is one of the critical pathways for regulating circulating Ca2+ levels under both acute stress and nonstress conditions.

Animals↗
PubMed1999

US neurologists in the 1990's: trends in practice characteristics.

BACKGROUND: The American Academy of Neurology (AAN) conducts periodic surveys of its members to profile and monitor changes in the characteristics of US neurologists and their practices. OBJECTIVE: To assess neurologists' characteristics, geographic distribution, practice arrangements, professional activities, practice volume, procedures performed, sources of revenue, involvement with managed care and capitation, and other selected topics. METHODS: The AAN Member Census survey was sent to US neurologists in the fall of 1996 (response rate = 89%), and the Practice Profile survey was sent to a random sample of 1,986 US neurologists in the summer of 1997 (response rate = 55%) who had completed a Member Census survey. The results of the Practice Profile survey were compared with those of two prior surveys conducted in 1991 to 1992 and 1993 to 1994. RESULTS: The mean age of US neurologists is 48 years, 18% are women, 93% are US citizens, and 24% are international medical graduates. The proportion of neurologists in solo practices, group practices, and medical schools/universities has not changed. The weekly hours worked has remained stable (58 hours), but the time spent in administrative activities has increased (p < 0.001). The average number of patient visits per week to neurologists appears to have increased (p < 0.001), as has the proportion of neurologists performing procedures (p < 0.05). The majority of neurologists have contracts with managed care organizations (82%), and a minority (32%) have capitated payment arrangements. Medicare continues to be the largest source of clinical revenue. Nearly 50% of all respondents have experience in developing clinical practice guidelines or critical pathways, and >20% of respondents employed physician extenders to assist in their practices. CONCLUSION: Neurologists are spending more time in administrative activities, are performing or interpreting more procedures, and are seeing more patients. Neurologists' involvement with capitation is comparable with that in a nationally representative sample of physicians, and they are exploring innovative ways, such as developing practice guidelines and using physician extenders, to improve the quality and efficiency of providing neurologic care.

Adult↗
PubMed2003

Increased Sp1 phosphorylation as a mechanism of hepatocyte growth factor (HGF/SF)-induced vascular endothelial growth factor (VEGF/VPF) transcription.

Hepatocyte growth factor (HGF/SF)-induced expression of vascular endothelial growth factor (VEGF/VPF) has been implicated in paracrine amplification of angiogenesis, contributing to angiogenic responses during inflammation, wound healing, collateral formation and tumor growth. We have shown previously that HGF/SF-mediated VEGF/VPF expression by keratinocytes is primarily dependent on transcriptional activation, and we mapped the HGF/SF-responsive element to a GC-rich region between bp -88 and -65. Sp1-like factors bind to this element constitutively; however the VEGF/VPF promoter is transactivated by HGF/SF in the absence of induced binding activity. In experimental approaches to clarify molecular mechanisms of Sp1-dependent VEGF/VPF gene transcription, neither HGF/SF-dependent changes in nuclear expression nor in relative DNA binding activity of Sp family members to the indicated element were observed. Thus, HGF/SF was hypothesized to induce VEGF/VPF gene transcription via increased transactivation activity of Sp1 owing to biochemical modification. In immunoprecipitation studies, HGF/SF was found to increase the amount of serine-phosphorylated Sp1, revealing a likely mechanism of HGF/SF-induced VEGF/VPF expression, as phosphorylation may enhance the transcriptional activity of Sp1. The contribution of different signaling molecules to HGF/SF-induced VEGF/VPF transcription was demonstrated by the use of chemical inhibition, of expression of kinase-deficient signaling proteins, and by the use of antisense oligonucleotides. Herein, we provide evidence that PI 3-kinase, MEK1/2 and PKC-zeta play a significant role in HGF/SF-induced VEGF/VPF promoter activation. Together, our results elucidate a critical pathway of paracrine amplification of angiogenesis, suggesting that HGF/SF-induced Sp1 phosphorylation may activate VEGF/VPF promoter activity that requires the contribution of distinct signaling molecules.

Animals↗
PubMed2006

Epicardial ablation with cooled tip catheter close to the coronary arteries is effective and safe in the porcine heart if the ventricular potential is being monitored in the epicardium and endocardium.

BACKGROUND: Transthoracic epicardial ablation can be an alternative to conventional treatment for critical pathways of ventricular tachycardia located in the epicardium. However, the usefulness and safety of epicardial ablation close to the coronary arteries (CA) is not clear. The purpose of the present experimental animal study was to analyze the efficacy and safety of epicardial radiofrequency (RF) ablation close to the CA. METHODS AND RESULTS: Of the left ventricle-epicardium ablated sites, 35 lesions (20 with cooling and 15 without cooling) were close to the CA (left anterior descending artery < or = 15 mm) and 33 lesions (23 with cooling and 10 without cooling) were further from the CA. For sites close to the CA, epicardial ablation was effective in 77% (15/20) with cooling and in 40% (6/15) without cooling. There was a significant difference of effective ablation between with cooling and without cooling (p < 0.05). For cooling, epicardial lesion size could be predicted by the change of endocardial ventricular potential using a basket catheter. No damage to major epicardial arteries was detected when the catheter tip was positioned 5 mm away from the CA. CONCLUSIONS: Close to the CA, RF ablation with cooling is more effective than RF without cooling and is safe if the ablation sites are located 5 mm away from the major CA.

Animals↗
PubMed2025

Population genomics of Aedes albopictus across remote Pacific islands for genetic biocontrol considerations.

Remote Pacific islands (RPI) are characterized by ecological isolation, diverse endemic species, and vulnerability to invasive organisms due to globalization-driven connectivity. Among these species, Aedes albopictus, a highly invasive vector of flaviviruses, has spread extensively across the RPI via human-mediated dispersal, posing significant health and economic burdens. While the population structure and the degree of gene flow between mosquito populations can inform the dispersal pathways critical for disease vector management, the population genetics of Ae. albopictus in Northern RPI remains understudied. The present work investigated the population structure and connectivity of Ae. albopictus populations from Guam, Hawaiian Islands, and the Republic of the Marshall Islands (RMI) to inform disease and vector-based biosecurity risks and develop targeted management strategies. This is the first assessment to develop and analyze whole genome sequences of Ae. albopictus for RPI, enabling more accurate estimates of differentiation, admixture, and ancestry. We found distinct genetic clustering between regions, distinct ancestry of populations across RPI, and potential invasions that originated from Hawaii and spread into the RMI, and invasions from North America that spread to Guam. These findings can inform biosecurity protocols to limit the invasion of Ae. albopictus and their associated diseases within Hawaii and around the Pacific. Given the significant degree of genetic differentiation, we found between islets, islands, and regions, the genome data from this study can be used to enable the development of locally confined geographically isolated gene drives. These drives may be used to prevent and control outbreaks of dengue, chikungunya, and Zika, diseases that have had devastating consequences in these remote island communities.

Animals↗
PubMed2026

Inflammasome activation dictates the efficacy of antimycobacterial activity of frontline TB drugs.

Recent developments in tuberculosis (TB) treatment have identified an enormous potential of host-directed therapies (HDT)) in achieving better and faster control of infection. We have previously demonstrated the synergistic effect of sertraline (SRT) with frontline TB drugs in clearing infection in murine tissues. Our attempts to uncover the mechanistic basis of this enhancement, using sertraline as a probe, help identify host signalling pathways critical for controlling Mycobacterium tuberculosis (Mtb). We identify a significant role for sertraline-mediated modulation of mitochondrial physiology and consequent reactive oxygen species (ROS) generation as a secondary signal, leading to greater IL-1&#x3b2; release and K+ efflux from macrophages via NLRP3 inflammasome activation. We thus highlight an important relationship between mitochondrial physiology and inflammasome activation, enabling infected macrophages to better control Mtb.

Animals↗
PubMed2004

Limited impact of a multicenter intervention to improve the quality and efficiency of pneumonia care.

STUDY OBJECTIVES: To evaluate the impact of a multifactorial intervention to improve the quality, efficiency, and patient understanding of care for community-acquired pneumonia. DESIGN: Times series cohort study. SETTING: Four academic health centers in the New York City metropolitan area. PATIENTS OR PARTICIPANTS: All consecutive adults hospitalized for pneumonia during a 5-month period before (n = 1,013) and after (n = 1,081) implementation of an inpatient quality improvement (QI) initiative. INTERVENTIONS: A multidisciplinary team of opinion leaders developed evidence-based treatment guidelines and critical pathways, conducted educational sessions with physicians, distributed pocket reminder cards, promoted standardized orders, and developed bilingual patient education materials. MEASUREMENTS AND RESULTS: The average age was 71.4 years, and 44.1% of cases were low risk, 36.8% were moderate risk, and 19.2% were high risk. The preintervention and postintervention groups were well matched on age, sex, race, nursing home residence, pneumonia severity, initial presentation, and most major comorbidities. The intervention increased the use of guideline-recommended antimicrobial therapy from 78.1 to 83.4% (p = 0.003). There was also a borderline decrease in the proportion of patients being discharged prior to becoming clinically stable, from 27.0 to 23.5% (p = 0.06). However, there were no improvements in the other targeted indicators, including time to first dose of antibiotics, proportion receiving antibiotics within 8 h, timely switch to oral antibiotics, timely discharge, length of stay, or patient education outcomes. CONCLUSIONS: This real-world QI program was able to improve modestly on some quality indicators, but not effect resource use or patient knowledge of their disease. Changing physician and organizational behavior in academic health centers will require the development and implementation of more intensive, system-oriented strategies.

Aged↗
PubMed2004

Inherited disorders of the skin in human and mouse: from development to differentiation.

The last ten years has revealed some of the key players in the development and differentiation of the hair follicle and the epidermis in general. In this review, we discuss how our current understanding of these processes has been made possible by the elucidation of the molecular basis of human inherited diseases and mouse mutants which display defects in the hair and epidermis. For examples, the study of ectodermal dysplasias and the basal cell carcinoma predisposition disease Gorlin syndrome have allowed the determination of signalling hierarchies critical in the formation of the hair follicle. Epidermolytic diseases and hyperkeratoses have focussed attention on the importance of the programs of keratin expression, while ichthyoses provide insight in the final stage of epidermal development, cornification. Finally, the increasing range of diseases and mouse models exhibiting alopecias are revealing the critical pathways in control of the hair follicle cycle.

Alopecia↗
PubMed2002

The use of basiliximab in solid organ transplantation.

The risk of acute rejection is at its highest early post-transplant. The use of various antibodies early after transplant achieves potent immunosuppression to prevent acute rejection, allowing the clinician the opportunity to optimise baseline immunosuppressive management and to delay the use of nephrotoxic agents (calcineurin inhibitors), while the graft reaches a baseline function. Basiliximab (Simulect trade mark, Novartis) is a monoclonal antibody that binds specifically to the alpha-subunit of the human high-affinity interleukin-2 receptor (IL-2r) complex, consequently inhibiting interleukin-2 (IL-2) binding. IL-2 receptors are selectively expressed on the surface of the activated lymphocytes. Administration of basiliximab inhibits IL-2 mediated activation of lymphocytes, a critical pathway involved in allograft rejection. Several clinical studies have shown that basiliximab administration as an induction agent significantly reduces the incidence of acute rejection, even in high risk patients. In addition, basiliximab is well-tolerated with minimal side effects.

Antibodies, Monoclonal↗
PubMed2003

Advances in targeted therapy for chronic myeloid leukemia.

Despite the lack of long-term survival data, the impressive results obtained with imatinib mesylate (Gleevec) therapy and the lack of serious adverse events have significantly altered the management of patients with chronic myeloid leukemia. Nevertheless, a large proportion of patients with more advanced disease will develop resistance to imatinib mesylate monotherapy. To prevent the development of resistance, an understanding of the pathophysiology of chronic myeloid leukemia, including the signaling pathways that are activated by the BCR-ABL fusion protein, and the mechanisms of resistance to imatinib are required. This review summarizes the pathogenesis of chronic myeloid leukemia and the potential therapeutic impact of small molecule inhibitors that target pathways critical to the growth or survival of the leukemic cells in patients with chronic myeloid leukemia.

Animals↗
PubMed2006

2D gel blood serum biomarkers reveal differential clinical proteomics of the neurodegenerative diseases.

This review addresses the challenges of neuroproteomics and recent progress in biomarkers and tests for neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The review will discuss how the application of quantitative 2D gel electrophoresis, combined with appropriate single-variable and multivariate biostatistics, allows for selection of disease-specific serum biomarkers. It will also address how the use of large cohorts of specifically targeted patient blood serum samples and complimentary age-matched controls, in parallel with the use of selected panels of these biomarkers, are being applied to the development of blood tests to specifically address unmet pressing needs in the differential diagnosis of these diseases, and to provide potential avenues for mechanism-based drug targeting and treatment monitoring. While exploring recent findings in this area, the review discusses differences in critical pathways of immune/inflammation and amyloid formation between Parkinson's disease and amyotrophic lateral sclerosis, as well as discernable synergistic relationships between these pathways that are revealed by this approach. The potential for pathway measurement in blood tests for differential diagnosis, disease burden and therapeutic monitoring is also outlined.

Biomarkers↗
PubMed2005

Internal structure of the cerebral hemispheres: an introduction of fiber dissection technique.

The aim of this study is to introduce the fiber dissection technique and its importance in the comprehension of the three-dimensional intrinsic anatomy of the brain. A total of twenty brain hemispheres were dissected. Using Kingler's technique we demonstrated the intrinsic structures of the brain. The supra lateral aspect of the brain as well as the medial aspect were presented. The most important fiber systems were demonstrated. The use and comprehension of new neuroimaging techniques demand a better understanding of this fascinating anatomy. The knowledge acquired with this technique will improve our understanding of critical pathways of the central nervous system.

Brain↗
PubMed1999

Low-molecular-weight heparins for acute coronary syndromes: an emergency medicine perspective.

Patients with chest pain represent one of the largest and most challenging populations for emergency departments to treat. Diagnostic and treatment modalities implemented in the emergency department are associated with significant clinical outcomes and financial implications. Critical pathways are being developed to increase the speed and efficiency with which these patients are managed. Of particular importance is the evolving role of low-molecular-weight heparins, which have both clinical and economic advantages over unfractionated heparins in treating unstable angina and non-Q wave myocardial infarction.

Acute Disease↗
PubMed2006

Chronic inhibition of mammalian target of rapamycin signaling downregulates insulin receptor substrates 1 and 2 and AKT activation: A crossroad between cancer and diabetes?

Overactivation of the mammalian target of rapamycin (mTOR) branch downstream of the phosphatidylinositol 3-kinase-AKT pathway critically modulates insulin and growth factor signaling by insulin receptor substrates (IRS). On the basis of in vitro studies, the mTOR inhibitor rapamycin has been reported to lead to enhanced activation of AKT by relieving this feedback inhibition on IRS function. In view of the critical role of AKT in insulin signaling and tumorigenesis, the in vivo expression and activation of this kinase and of IRS-1 and IRS-2 were explored in PBMC of 30 patients who were treated long term with rapamycin. A marked decrease of basal and insulin-stimulated AKT phosphorylation, which correlated with the increase of patients' insulin resistance, and a significant increase of IRS total protein expression, together with a lower (IRS-2) or absent (IRS-1) increase of insulin-induced tyrosine phosphorylation, were found. Therefore, contrary to the expectations, long-term exposure to rapamycin caused the impairment of IRS signaling and AKT activation, and this would help to explain the antiproliferative effect and the possible deterioration of glucose metabolism that are observed in rapamycin-treated patients. These findings may form a novel basis for improved understanding of the role of mTOR inhibition in human diseases, such as diabetes and cancer.

Adult↗
PubMed2026

Kynurenine metabolism-related gene signature for prognostic stratification in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a major global health burden with high mortality rates and limited therapeutic options. The identification of reliable biomarkers for early diagnosis and prognosis prediction is urgently needed. Kynurenine metabolism, a critical pathway in immune regulation and tumor progression, has been implicated in various cancers. However, its prognostic value in HCC has not been fully elucidated. This study aimed to develop a prognostic risk model based on kynurenine metabolism-related genes (KMRGs) for HCC patients. METHODS: Transcriptomic and clinical data of HCC patients were retrieved from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) databases. A prognostic risk model was established using least absolute shrinkage and selection operator (LASSO) and Cox regression analyses. Survival analysis and functional enrichment analysis were conducted to validate the predictive performance of the model and to investigate the underlying mechanisms. ALDH8A1 was ultimately identified as a target gene based on survival analysis, and its impact on tumor cell migration was assessed using the HCC cell line. RESULTS: A prognostic model based on seven KMRGs was established. The high-risk group exhibited significantly worse overall survival compared to the low-risk group. Functional enrichment analysis in high-risk patients highlighted significant enrichment in core biological processes, including spliceosome assembly and ribonucleoprotein complex biogenesis. Furthermore, a nomogram integrating the risk score and clinical pathological features was developed, demonstrating moderate predictive performance for HCC prognosis. CONCLUSIONS: This study successfully constructed a prognostic risk model based on seven KMRGs, providing a valuable tool for predicting clinical outcomes in HCC patients. These findings highlight the potential role of kynurenine metabolism in HCC progression and offer new insights for future therapeutic strategies.

ALDH8A1↗