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PubMed2001

Monitoring the care of lung cancer patients: linking audit and care pathways.

Clinical audit plays an important role in monitoring the provision of care for patients whatever their condition. Care pathways define the steps and expected course of events in the care of patients with a specific clinical problem over a set time scale. This paper describes a study undertaken in a multisite cancer unit to develop a tool for monitoring the progress of lung cancer patients through a care pathway and auditing key standards within the pathway. Important issues associated with the development of this tool are highlighted. The process of developing this tool involved the following steps: a review of the literature dealing with the management of lung cancer patients; interviews with key personnel in primary, secondary, tertiary and palliative care; development of a paper-based series of forms representing key steps in the patient's care pathway; 3-month trial of the paper-based tool; analysis of completion rates and interviews with form users to evaluate effectiveness; and recommendations for creating an electronic record using the experience and lessons learned from the paper version. The paper forms developed through this multistage process were found to be acceptable to users and have the potential to provide accurate information at key points for audit throughout the patient's time within the health-care system for their lung cancer condition. The flexibility of this methodology allows it to be adapted readily to a variety of clinical situations and conditions.

Cancer Care Facilities↗
PubMed2005

Does dysregulation of key epigenetic and biochemical pathways occur in postulated vasoactive neuropeptide autoimmune disorders?

Autoimmune dysfunction of certain vasoactive neuropeptides (VNs) has been postulated as a contributing cause of sudden infant death syndrome (SIDS), chronic fatigue syndrome (CFS), Gulf War syndrome (GWS) and other fatigue-related disorders. This family of VNs includes pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP). The postulated mechanism is compromise of adenylate cyclase activation, a vital and unique step in cyclic AMP production from ATP, through autoimmune dysfunction of VNs, their receptors or their genes possibly involving cytosine-phosphate-guanine (CpG) fragments. CpG fragments are immunomodulatory dinucleotides serving as 'friend or foe' recognition systems to differentiate bacterial and viral (hypomethylated CpG) from mammalian (methylated CpG) DNA. However hypomethylation disorders affecting these fragments in mammals may convert them to dysfunctional states by promoting autoimmune inflammatory reactions. Epigenetic mechanisms acting on gene promoter regions may contribute to the development of VN autoimmune fatigue-related disorders through CpG fragments located in vital segments of VN/receptor genes by causing signalling defects with profound implications for VN function. Neurotransmitter dysfunction particularly glutamatergic transmission could also result with disruption of neuronal cellular biochemical functions such as ammonia regulation. Endosomal acidity and mitochondrial membrane potential modifiers such as chloroquine, together with immunoregulatory therapies, may have therapeutic implications in protecting against these apparent autoimmune disorders. This paper examines specific epigenetic and biochemical mechanisms possibly mediated by VN or receptor genes resulting in postulated VN autoimmune fatigue-related disorders. These mechanisms may have implications for treatment and prevention options for VN autoimmune disorders. VN autoimmune processes have implications for military medicine where radiological, chemical and biological agents may play an important role in pathogenesis.

Autoimmune Diseases↗
PubMed2002

LIS1, CLIP-170's key to the dynein/dynactin pathway.

CLIP-170 is a plus-end tracking protein which may act as an anticatastrophe factor. It has been proposed to mediate the association of dynein/dynactin to microtubule (MT) plus ends, and it also binds to kinetochores in a dynein/dynactin-dependent fashion, both via its C-terminal domain. This domain contains two zinc finger motifs (proximal and distal), which are hypothesized to mediate protein-protein interactions. LIS1, a protein implicated in brain development, acts in several processes mediated by the dynein/dynactin pathway by interacting with dynein and other proteins. Here we demonstrate colocalization and direct interaction between CLIP-170 and LIS1. In mammalian cells, LIS1 recruitment to kinetochores is dynein/dynactin dependent, and recruitment there of CLIP-170 is dependent on its site of binding to LIS1, located in the distal zinc finger motif. Overexpression of CLIP-170 results in a zinc finger-dependent localization of a phospho-LIS1 isoform and dynactin to MT bundles, raising the possibility that CLIP-170 and LIS1 regulate dynein/dynactin binding to MTs. This work suggests that LIS1 is a regulated adapter between CLIP-170 and cytoplasmic dynein at sites involved in cargo-MT loading, and/or in the control of MT dynamics.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2005

R-ras as a key player for signaling pathway of plexins.

Axon guidance represents an important step in the formation of neuronal networks. Axons are guided by various guidance factors, such as semaphorins, slits, ephrins, and netrins. Plexins are cell surface receptors for the repulsive molecules of the semaphorin family. Cytoplasmic regions of plexins are responsible for initiating cellular signal transduction, resulting in axon repulsion. Recent advances have shed light on the signal transduction mechanism of plexins and the mechanisms by which it leads to a repulsive response. Plexin-B1 possesses an intrinsic guanine triphosphate (GTP)ase activating protein activity for R-Ras, a member of Ras family of small GTPases that has been implicated in promoting cell adhesion and neurite outgrowth through integrin activation. Stimulation of Plexin-B1 by Sema4D induces collapse of the growth cone through downregulation of R-Ras activity. This article summarizes current understanding of the signaling mechanisms of plexins.

Animals↗
PubMed2006

Pharmacogenomics of beta2-agonist: key focus on signaling pathways.

Asthma is one of the most common respiratory diseases, where inhalation and exhalation are obstructed due to narrowing of the airways by broncho-constriction or by inflammation. Among all the available anti-asthma therapies, beta2-agonists are the most effective bronchodilators available, and give rapid relief of asthma symptoms. Evidence suggests that the degree of beta2-agonist response varies greatly between patients and genetic factors have a major role in it. Despite several studies on the beta2-agonist pharmacogenetics, significant gaps in knowledge still remain and need to be resolved before the pharmacotyping of beta2-agonist responsiveness comes to clinical practice. As we know, beta2-agonists show their influence by targeting beta2-adrenergic receptors, leading to the activation of beta2-adrenergic receptors and its downstream cascade. Signaling through beta2-adrenergic receptors mediates numerous airway functions by regulating broncho-constriction and dilation pathways. Therefore, it is an important prerequisite to understand these pathways, which will assist in defining the variability in therapeutic responses for beta2-agonists. Owing to the complexity of the action of a beta2-agonist and its therapeutic response, a broader genomics approach will help in optimizing therapy for the individual patient. This might be achieved by considering and focusing on receptor/s at which the drug binds directly, signal transduction cascades or downstream proteins and proteins involved in the relaxation and constriction of the airway smooth muscle. Considering that a drug response may involve a large number of proteins, it seems unlikely that a single polymorphism or haplotype in a single gene would explain a high degree of drug response variability in a consistent fashion. Thus, it shows that a polygenic approach will be more appropriate. In order to follow this, the mode of action of the beta2-agonist and its downstream signaling cascade should essentially be assessed to resolve the beta2-agonist enigma.

Adrenergic beta-Agonists↗
PubMed2026

Multimodal Analysis Reveals Aberrant Expression of SUMO2 and Its Significant Association With Key Mechanisms of Metabolic Pathways in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. However, the role of small ubiquitin-like modifier 2 (SUMO2), a core member of the small ubiquitin-like modifier (SUMO) family, regarding its expression patterns and metabolism-related functions in HCC remains inadequately understood. METHODS: A multidimensional analytical framework was applied, integrating immunohistochemistry (153 HCC vs. 21 non-HCC samples), proteomics (159 paired samples), bulk transcriptomics (3240 HCC vs. 2267 non-HCC samples), single-cell RNA sequencing (RNA-seq) (10 HCC vs. 8 non-HCC samples), spatial transcriptomics, and external CRISPR/Cas9 functional genomics data. Systematic analyses included standardized mean difference (SMD), pathway enrichment, pseudotime trajectory inference, in silico knockout, cell-cell communication, metabolic flux scoring, immune infiltration, clinical correlation, drug sensitivity prediction, and molecular docking. RESULTS: At the protein level, immunohistochemistry (nuclear positivity) and external proteomic data collectively demonstrated consistent SUMO2 overexpression in HCC. Consistent upregulation was also observed at the mRNA level across large-scale cohorts. Single-cell RNA-seq and spatial transcriptomics localized SUMO2 enrichment to malignant hepatocytes and tumor-dominant regions. CRISPR-mediated SUMO2 knockout suppressed proliferation in multiple HCC cell lines. Mechanistically, high SUMO2 expression was significantly associated with metabolic reprogramming involving glycolysis/gluconeogenesis, pyruvate metabolism, and the tricarboxylic acid cycle. SUMO2-high malignant hepatocyte subpopulations exhibited enhanced activity of the macrophage migration inhibitory factor signaling axis and enhanced iron-sensor interactions. Further, the immune infiltration analysis revealed a negative correlation between SUMO2 expression and M1 macrophages and a positive correlation between follicular helper T cells and regulatory T cells. Clinically, elevated SUMO2 levels were found to be associated with adverse prognostic features. Furthermore, high SUMO2 expression was associated with increased sensitivity to dasatinib, and molecular docking simulations predicted potential binding between SUMO2 and dasatinib, with a Vina score of -8.5 kcal/mol. CONCLUSIONS: SUMO2 is aberrantly expressed at the protein, mRNA, single-cell, and spatial transcriptomic levels in HCC and is significantly associated with metabolic reprogramming and altered migration inhibitory factor (MIF)-mediated intercellular communication, suggesting its potential as a novel biomarker for diagnosis and treatment.

Humans↗
PubMed2003

Viral modulators of cell death provide new links to old pathways.

By observing how viruses facilitate their parasitic relationships with host cells, we gain insights into key regulatory pathways of the cell. Not only are mitochondria key players in the regulation of programmed cell death, but many viral regulators of cell death also alter mitochondrial functions either directly or indirectly. Although cytomegalovirus vMIA and Epstein-Barr virus BHRF1 seem to have opposite effects on mitochondrial morphology, they both inhibit cell death. Drosophila Reaper, a regulator of developmental cell death, acts on IAP (inhibitor of apoptosis) proteins to activate caspases, but can regulate mitochondrial permeability in vitro. Despite its pivotal role in Drosophila, homologues of Reaper in other species were not previously known. Recently, amino acid sequence similarity was recognized between Drosophila Reaper and a protein known to be important for the replication and virulence of mosquito-borne bunyaviruses that cause human encephalitis. Thus, viral mechanisms for regulating apoptosis are diverse and not fully elucidated but promise to provide new insights.

Animals↗
PubMed2006

Gestational diabetes and the adenosine/L-arginine/nitric oxide (ALANO) pathway in human umbilical vein endothelium.

Altered endothelial cell function is a key factor associated with vascular disorders and is critical in the fetal growth and development. Pregnancies affected by diseases such as gestational diabetes are associated with human umbilical vein endothelial dysfunction, a finding that has been associated with a high incidence of vascular complications during the adult life. Limited information is available addressing cellular mechanisms associated with altered human umbilical vein endothelial function in gestational diabetes. One of the key signalling pathways associated with altered vascular physiology is the synthesis of the vasodilator nitric oxide (NO) from the cationic amino acid L-arginine by the endothelium (i.e. the endothelial L-arginine/NO pathway). The activity of this signalling pathway is modulated by D-glucose, adenosine, insulin, and ATP, among other molecules, and is upregulated (transcriptional, post-transcriptional and post-translational levels) in gestational diabetes. This review focuses on the cellular and molecular mechanisms involved with elevated adenosine levels in fetal umbilical vein blood and the endothelial L-arginine/NO pathway activity in gestational diabetes. We suggest that a lower capacity of adenosine transport by the fetal endothelium in gestational diabetes leads to extracellular accumulation of this nucleoside and its higher bio-availability activates endothelial P1 type purinoceptors. A functional association between A2a purinoceptor subtype signalling and the activity of the l-arginine transport mediated by human cationic amino acid transporters and endothelial NO synthase activity (i.e. 'ALANO pathway') is proposed, revealing in part the mechanisms that account for human umbilical vein endothelial cell dysfunction programmed through the development of the fetus in gestational diabetes.

Adenosine↗
PubMed2006

Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes.

To investigate the role of brain insulin action in the pathogenesis and treatment of diabetes, we asked whether neuronal insulin signaling is required for glucose-lowering during insulin treatment of diabetes. Hypothalamic signaling via the insulin receptor substrate-phosphatidylinositol 3-kinase (IRS-PI3K) pathway, a key intracellular mediator of insulin action, was reduced in rats with uncontrolled diabetes induced by streptozotocin (STZ-DM). Further, infusion of a PI3K inhibitor into the third cerebral ventricle of STZ-DM rats prior to peripheral insulin injection attenuated insulin-induced glucose lowering by approximately 35%-40% in both acute and chronic insulin treatment paradigms. Conversely, increased PI3K signaling induced by hypothalamic overexpression of either IRS-2 or protein kinase B (PKB, a key downstream mediator of PI3K action) enhanced the glycemic response to insulin by approximately 2-fold in STZ-DM rats. We conclude that hypothalamic insulin signaling via the IRS-PI3K pathway is a key determinant of the response to insulin in the management of uncontrolled diabetes.

Animals↗
PubMed2026

Transcriptomic signatures of mind-body transformations therapy in breast cancer: Downregulation of the interferon signaling pathway.

BACKGROUND: Growing evidence has shown that Mind-Body Transformations-Therapies (MBT-T) are able to modulate chronic inflammation, a well-known driver of cancer progression and drug resistance. In our previous work, we showed that a specific MBT-T protocol was able to reduce the release of various pro-inflammatory cytokines and chemokines in the sera of patients with breast cancer that completed adjuvant chemotherapy. Despite these clinical observations, the underlying molecular pathways through which this therapy exerts its effects remain unclear. This study aims to address this gap by characterizing genome-wide transcriptional profiles in patients undergoing a novel MBT-T protocol. METHODS: In this proof-of-concept study, patients with breast cancer were randomized into two groups: Group 1 (CTL), receiving standard follow-up care, and Group 2 (MBT-T), receiving standard follow-up plus biweekly MBT-T for 4 months. Blood samples were collected at different timepoints during the treatment. After RNA extraction from whole blood, gene expression was analyzed on twenty-one patients (CTL, n = 7; MBT-T, n = 14) using the nCounter® Human Inflammation Panel (249 genes). RESULTS: Patients undergoing MBT-T showed a significant global downregulation of inflammatory gene expression compared to the control group. The analysis revealed that the Interferon (IFN) signaling pathway was the most significantly suppressed, by downregulation of key genes such as IFIT1, IFIT3, IFI44, MX1 and OASL in the MBT-T group. CONCLUSIONS: MBT-T acts as a biological modulator capable of downregulating key inflammatory pathways at the transcriptional level. These findings provide a genomic basis for the clinical benefits of mind-body interventions in oncology.

Breast cancer↗
PubMed1999

Different protein turnover of interleukin-6-type cytokine signalling components.

Interleukin (IL)-6 and IL-6-type cytokines signal through the gp130/Jak/STAT signal transduction pathway. The key components involved are the signal transducing receptor subunit gp130, the Janus kinases Jak1, Jak2 and Tyk2, STAT1 and STAT3 of the family of signal transducers and activators of transcription, the protein tyrosine phosphatase SHP2 and the suppressors of cytokine signalling SOCS1, SOCS2 and SOCS3. Whereas considerable information has been accumulated concerning the time-course of activation for the individual signalling molecules, data on the availability of the proteins involved in IL-6-type cytokine signal transduction are scarce. Nevertheless, availability of these molecules, determined by the balance of protein synthesis and degradation, also influences IL-6-type cytokine signal transduction. Here, we present a comprehensive set of data on the half-lives of the key molecules involved in the IL-6 signal transduction pathway. The turnover rates for the various proteins differ substantially. Three groups of signalling proteins can be discriminated: whereas the feedback inhibitors SOCS1, SOCS2 and SOCS3 are very short-lived, STAT1, STAT3 and SHP2 have an extremely slow turnover rate. Interestingly, the half-life of STAT3beta, a splice variant of STAT3alpha, is reduced to almost 50% of the half-life of STAT3alpha. The Janus kinases Jak1, Jak2, Tyk2 and gp130 show intermediate half-lives. Our data imply that signalling components activated by post-translational modifications are long-lived whereas the activity of very short-lived proteins is regulated mainly at the transcriptional level.

Antigens, CD↗
PubMed2004

Keypathophysiologic pathways in age-related macular disease.

PURPOSE: To review current knowledge of key pathogenetic pathways in age-related macular disease (AMD). METHODS: Experimental evidence and clinical observations are reviewed. RESULTS: A number of common downstream pathophysiologic pathways appear to be relevant in AMD manifestations irrespective of primary heterogeneous etiologies. These include sequelae of oxidative damage, retinal pigment epithelium (RPE) cell dysfunction with accumulation of lipofuscin and impairment of lysosomal functions, deposition of subsequently incompletely degraded material at the basal RPE cell side and alterations in Bruch's membrane extracellular matrix, immunologic responses to extracellular material (drusen) with subsequent growth of drusen, induction of choroidal neovascularization as a result of imbalance between anti-angiogenetic and proangiogenetic factors as well as cell death (geographic atrophy) without prior neovascular events. CONCLUSIONS: Understanding is expanding regarding the sequence of events that lead to early and late lesions in AMD. Therapeutic approaches that focus on the molecular mechanisms are more likely to succeed than currently available treatment options as exemplified by the management of choroidal neovascularisations.

Animals↗
PubMed2006

Key cancer cell signal transduction pathways as therapeutic targets.

Growth factor signals are propagated from the cell surface, through the action of transmembrane receptors, to intracellular effectors that control critical functions in human cancer cells, such as differentiation, growth, angiogenesis, and inhibition of cell death and apoptosis. Several kinases are involved in transduction pathways via sequential signalling activation. These kinases include transmembrane receptor kinases (e.g., epidermal growth factor receptor EGFR); or cytoplasmic kinases (e.g., PI3 kinase). In cancer cells, these signalling pathways are often altered and results in a phenotype characterized by uncontrolled growth and increased capability to invade surrounding tissue. Therefore, these crucial transduction molecules represent attractive targets for cancer therapy. This review will summarize current knowledge of key signal transduction pathways, that are altered in cancer cells, as therapeutic targets for novel selective inhibitors. The most advanced targeted agents currently under development interfere with function and expression of several signalling molecules, including the EGFR family; the vascular endothelial growth factor and its receptors; and cytoplasmic kinases such as Ras, PI3K and mTOR.

Antineoplastic Agents↗
PubMed2006

Regulation of gene transcription by mitogen-activated protein kinase signaling pathways.

Mitogen-activated protein kinase (MAPK) signaling pathways are key mediators of eukaryotic transcriptional responses to extracellular signals. These pathways control gene expression in a number of ways including the phosphorylation and regulation of transcription factors, co-regulatory proteins and chromatin proteins. MAPK pathways therefore target multiple components of transcriptional complexes at gene promoters and can regulate DNA binding, protein stability, cellular localization, transactivation or repression, and nucleosome structure. Recent work has uncovered further complexities in the mechanisms by which MAPKs control gene expression including their roles as integral components of transcription factor complexes and their interplay with other post-translational modification pathways. In this review I discuss these advances with particular focus on how MAPK signals are integrated by transcription factor complexes to provide specific transcriptional responses and how this relates to cellular function.

Acetylation↗
PubMed2002

Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy.

The mammalian target of rapamycin (mTOR) modulates key signaling pathways that promote uncontrolled proliferation of glioblastoma multiforme (GBM). Because rapid tumor proliferation may contribute to the clinical radioresistance of GBM tumors, the combination of rapamycin, a selective mTOR inhibitor, and radiation was studied in vitro and in vivo in a GBM model. In monolayer cultures of U87 and SKMG-3 cells, rapamycin had no impact on radiation sensitivity. In contrast, rapamycin significantly enhanced the efficacy of fractionated radiation of established U87 xenografts in nude mice. Similar effects were seen in U87 spheroids treated with rapamycin and radiation, which suggests that the sensitizing effects of this drug are dependent on disruption of mTOR signaling pathways specifically within tumor cells. Inhibition of these signaling pathways can lead to inhibition of G(1)-specific cyclin-dependent kinase activities, and this could contribute to the sensitizing effects of rapamycin. Consistent with this idea, roscovitine, a specific cyclin-dependent kinase inhibitor, also enhanced the efficacy of fractionated radiation in U87 spheroids. These data demonstrate that inhibition of tumor proliferation does not diminish the efficacy of fractionated radiation and suggest that disruption of key signal transduction pathways may significantly enhance the effectiveness of radiation therapy in malignant gliomas.

Animals↗
PubMed2003

[Relationship between key enzyme activities of inosine-producing pathway and inosine accumulation].

The specific activities of key enzymes relating to the pathway of inosine synthesis of three different bacterial strains including high-yield, low-yield and wild strains were determined and compared systematically. A close relationship between inosine production and the specific activities of key enzymes was found. According to the enzyme characteristics of high-yield strain, suggestions on further strain improvement by modification of genetic engineering were proposed. Enzymology study is believed to be an effective way to make screening of high-yield strains more efficient.

Adenylosuccinate Synthase↗