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At least 1,423 records · Page 79Linked to original sources
PubMed2005

Resveratrol reduces oxidation and proliferation of human retinal pigment epithelial cells via extracellular signal-regulated kinase inhibition.

Epidemiological evidence suggests that moderate wine consumption and antioxidant-rich diets may protect against age-related macular degeneration (AMD), the leading cause of vision loss among the elderly. Development of AMD and other retinal diseases, such as proliferative vitreoretinopathy (PVR), is associated with oxidative stress in the retinal pigment epithelium (RPE), a cell layer responsible for maintaining the health of the retina by providing structural and nutritional support. We hypothesize that resveratrol, a red wine polyphenol, may be responsible, in part, for the health benefits of moderate red wine consumption on retinal disease. To test this hypothesis, the antioxidant and antiproliferative effects of resveratrol were examined in a human RPE cell line (designated ARPE-19). Cell proliferation was determined using the bromodeoxyuridine (BrdU) assay, intracellular oxidation was assessed by dichlorofluorescein fluorescence, and activation of the mitogen-activated protein kinase (MAPK) cascade was measured by immunoblotting. Treatment with 50 and 100 micromol/L resveratrol significantly reduced proliferation of RPE cells by 10% and 25%, respectively (P<0.05). This reduction in proliferation was not associated with resveratrol-induced cytotoxicity. Resveratrol (100 micromol/L) inhibited basal and H2O2-induced intracellular oxidation and protected RPE cells from H2O2-induced cell death. The observed reduction in cell proliferation was associated with inhibition of mitogen activated protein kinase/ERK (MEK) and extracellular signal-regulated kinase (ERK 1/2) activities at concentrations of resveratrol as low as 5 micromol/L. These results suggest that resveratrol can reduce oxidative stress and hyperproliferation of the RPE.

Antioxidants↗
PubMed2000

Glycosylphosphatidylinositol-anchored proteins are not required for crosslinking-mediated endocytosis or transfection of avidin bioconjugates into biotinylated cells.

Even though glycosylphosphatidylinositol (GPI)-anchored proteins lack direct structural contact with the intracellular space, these ubiquitously expressed surface receptors activate signaling cascades and endocytosis when crosslinked by extracellular ligands. Such properties may be due to their association with membrane microdomains composed of glycosphingolipids, cholesterol and some signaling proteins. In this study, we hypothesize that GPI proteins may be required for crosslinking-mediated endocytosis of extracellular bioconjugates. To test this hypothesis, we first biotinylated the surface membranes of native K562 erythroleukemia cells versus K562 cells incapable of surface GPI protein expression. We then compared the entry of fluorescently labeled avidin or DNA condensed on polyethylenimine-avidin bioconjugates into the two biotinylated cell populations. Using fluorescence microscopy, nearly 100% efficiency of fluorescent avidin endocytosis was demonstrated in both cell types over a 24 h period. Surprisingly, plasmid DNA transfer was slightly more efficient among the biotinylated GPI-negative cells as measured by the expression of green fluorescence protein. Our findings that GPI proteins are not required for the endocytosis of avidin bioconjugates into biotinylated cells suggest that endocytosis associated with general membrane crosslinking may be due to overall reorganization of the membrane domains rather than GPI protein-specific interactions.

Avidin↗
PubMed2001

Atmospheric water vapour processor designs for potable water production: a review.

Atmospheric water vapour processing (AWVP) technology is reviewed. These processors are machines which extract water molecules from the atmosphere, ultimately causing a phase change from vapour to liquid. Three classes of machines have been proposed. The machines either cool a surface below the dewpoint of the ambient air, concentrate water vapour through use of solid or liquid desiccants, or induce and control convection in a tower structure. Patented devices vary in scale and potable water output from small units suitable for one person's daily needs to structures as large as multi-story office buildings capable of supplying drinking water to an urban neighbourhood. Energy and mass cascades (flowcharts) are presented for the three types of water vapour processors. The flowcharts assist in classifying designs and discussing their strengths and limitations. Practicality and appropriateness of the various designs for contributing to water supplies are considered along with water cost estimates. Prototypes that have been tested successfully are highlighted. Absolute humidity (meteorological normals) ranges from 4.0 g of water vapour per cubic metre of surface air in the atmosphere (Las Vegas, Nevada, USA) to 21.2 g m-3 (Djibouti, Republic of Djibouti). Antofagasta, Chile has a normal absolute humidity of 10.9 g m-3. A 40% efficient machine in the vicinity of Antofagasta requires an airflow of 10 m3 s-1 to produce 3767 l of water per day. At a consumption of 50 l per person per day, 75 people could have basic water requirements for drinking, sanitation, bathing, and cooking met by a decentralized and simplified water supply infrastructure with attendant economic and societal benefits.

Air↗
PubMed2002

Deciphering the transcriptional histone acetylation code for a human gene.

We report the results of experiments designed to test the histone code hypothesis. We found that only a small subset of lysines in histones H4 and H3 are acetylated in vivo by the GCN5 acetyltransferase during activation of the IFN-beta gene. Reconstitution of recombinant nucleosomes bearing mutations in these lysine residues revealed the cascade of gene activation via a point-by-point interpretation of the histone code through the ordered recruitment of bromodomain-containing transcription complexes. Acetylation of histone H4 K8 mediates recruitment of the SWI/SNF complex whereas acetylation of K9 and K14 in histone H3 is critical for the recruitment of TFIID. Thus, the information contained in the DNA address of the enhancer is transferred to the histone N termini by generating novel adhesive surfaces required for the recruitment of transcription complexes.

Acetylation↗
PubMed2003

Library screening for synthetic agonists and antagonists of a Pseudomonas aeruginosa autoinducer.

The autoinducer (AI) that initiates the quorum sensing (QS) signaling cascade in Pseudomonas aeruginosa is an acyl-homoserine lactone (acyl-HSL). We initiated a study of the requirements for binding of the AI to its protein effector LasR by synthesizing a library of analogs with the HSL moiety replaced with different amines and alcohols. We tested each compound for both agonist and antagonist activity using a QS-controlled reporter gene assay and found several new agonists and antagonists. A representative antagonist was further tested for its ability to inhibit virulence factors. This data progresses our understanding of the LasR-AI interaction toward the rational design of therapeutic inhibitors of QS.

4-Butyrolactone↗
PubMed1989

Optimized inhalation aerosols. I. The effects of spherical baffle size and position upon the output of several pressurized nonaqueous suspension formulations.

Baffles contained in conventional actuators may be a convenient alternative to some of the extension devices used presently with metered-dose inhalers (MDIs). Actuators were modified to determine whether baffles could be used to decrease the output of large "nonrespirable" droplets. These actuators were tested using a series of nonaqueous suspension aerosols containing 0.1 to 2.0% micronized disodium fluorescein (DF) as the model drug, stabilized by sorbitan trioleate in a constant blend of fluorocarbons 11, 12, and 114. A 25-microliter metering volume was used throughout. Aerosol output was characterized by cascade impaction. Baffle size and position had pronounced effects on actuator retention and aerosol output. Increasing baffle size resulted in increased retention in the actuator. The total output of the MDI in the "respirable" range (aerodynamic diameter, Dae, less than 5.5 microns) was greater in the unbaffled actuator than in all baffled actuators. However, all baffles increased the respirable fraction (DF with Dae less than 5.5 microns: total DF leaving the actuator), R, when compared to their unbaffled controls. For example, for a 0.1% DF, 0.14% surfactant formulation, R was increased from 0.40 (unbaffled) to 0.71 by incorporation of a 0.6-cm-diameter sphere 1.3 cm from the jet of the actuator. In these cases, aerosol segregation occurred due to droplet inertia in the high velocity gas flows. Increasing the respirable fraction at the expense of the total respirable output may obviate undesirable clinical effects.

Aerosols↗
PubMed2003

[Immunopathogenesis of psoriasis].

Psoriasis is a chronic inflammatory disease of the skin and the joints. Multiple factors contribute to the initiation of psoriasis. They include specific genetic characteristics such as major histocompatibility antigens and psoriasis susceptibility genes, as well as trigger factors, namely streptococcal infections. Today, psoriasis is considered as a T-lymphocyte mediated autoimmune disease, even though the putative autoantigen remains unknown. Bacterial proteins with similarity to structural proteins of keratinocytes are potential target antigens. As in other autoimmune diseases, inflammatory cytokines of the innate immune system initiate a cascade that activates inflammation locally in the skin, in the circulation and most likely also in lymph nodes. IFN-gamma-producing CD4+ Th1-lymphocytes seem to be of central importance in the pathogenesis of psoriasis as they critically influence differentiation and functioning of antigen presenting cells, mast cells, neutrophils and endothelial cells. This inflammatory cascade simultaneously provokes neoangiogenesis in the dermis and proliferation of keratinocytes. Based on this hypothesis, cytokines or anticytokine antibodies that either inhibit T-cell mediated inflammation or transform disease-inducing, pro-inflammatory Th1-lymphocytes into a phenotype with anti-inflammatory properties were tested in psoriasis. As both approaches improved psoriasis, they strongly support the current concept that views psoriasis as a Th1-lymphocyte mediated disease.

Arthritis, Psoriatic↗
PubMed2001

Support for an infection-induced apoptotic pathway in human fetal membranes.

OBJECTIVE: Lipopolysaccharide and tumor necrosis factor alpha levels are both elevated in the amniotic fluid of women during infection-associated preterm labor and premature rupture of fetal membranes. Our laboratory has shown that apoptosis is associated with premature rupture of fetal membranes but is not associated with preterm labor. The exact pathway that leads to apoptosis-mediated premature rupture of fetal membranes is still unclear. Because infection and increased inflammatory cytokine response are associated with the majority of cases of premature rupture of fetal membranes, we examined the roles of bacterial lipopolysaccharide and tumor necrosis factor alpha in inducing the proapoptotic caspase pathway in fetal membranes. STUDY DESIGN: Amniochorionic membranes collected from women undergoing elective repeat cesarean delivery at term were placed in an organ explant system. At the end of a 48-hour incubation period, membranes were stimulated with lipopolysaccharide (50 ng/mL) and recombinant tumor necrosis factor (50 ng/mL). Total ribonucleic acid extracted from these samples was subjected to reverse transcription and two separate sets of multiple polymerase chain reaction. One set studied the expression of Fas, Fas ligand, caspase 8, Fas-associated death domain, and tumor necrosis factor receptor-associated death domain genes and the second set studied the expression of caspase 2, 4, 6, 7, and 10. Caspase 2, 3, and 9 expression was also studied by reverse transcriptase-polymerase chain reaction. RESULTS: Multiple polymerase chain reactions and reverse transcriptase-polymerase chain reactions documented the induction of Fas and caspase 2, 3, 7, 8, and 9 genes in amniochorion after lipopolysaccharide and tumor necrosis factor stimulation compared with the nonstimulated controls. Neither lipopolysaccharide nor tumor necrosis factor induced Fas ligand expression in human fetal membranes. Caspase 3, 4, and 6, Fas-associated death domain, and tumor necrosis factor receptor-associated death domain expressions were constitutive in all the tissues tested; however, tumor necrosis factor receptor-associated death domain expression appeared stronger in tumor necrosis factor-stimulated tissues. CONCLUSION: The presence of the signal docking proteins tumor necrosis factor receptor-associated death domain and Fas-associated death domain and the induction of caspase cascade initiators (caspase 2, 8, and 10) and effector caspases (caspase 3, 6, 7, and 9) by lipopolysaccharide and tumor necrosis factor suggest that tumor necrosis factor-tumor necrosis factor receptor-mediated apoptosis may occur in the human fetal membrane.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Mitochondrial permeability transition is a central coordinating event of apoptosis.

In a number of experimental systems, the early stage of the apoptotic process, i.e., the stage that precedes nuclear disintegration, is characterized by the breakdown of the inner mitochondrial transmembrane potential (delta psi m). This delta psi m disruption is mediated by the opening of permeability transition (PT) pores and appears to be critical for the apoptotic cascade, since it is directly regulated by Bcl-2 and since mitochondria induced to undergo PT in vitro become capable of inducing nuclear chromatinolysis in a cell-free system of apoptosis. Here, we addressed the question of which apoptotic events are secondary to mitochondrial PT. We tested the effect of a specific inhibitor of PT, bongkrekic acid (BA), a ligand of the mitochondrial adenine nucleotide translocator, on a prototypic model of apoptosis glucocorticoid-induced thymocyte death. In addition to abolishing the apoptotic delta psi m disruption, BA prevents a number of phenomena linked to apoptosis: depletion of nonoxidized glutathione, generation of reactive oxygen species, translocation of NF kappa B, exposure of phosphatidylserine residues on the outer plasma membrane, cytoplasmic vacuolization, chromatin condensation, and oligonucleosomal DNA fragmentation. BA is also an efficient inhibitor of p53-dependent thymocyte apoptosis induced by DNA damage. These data suggest that a number of apoptotic phenomena are secondary to PT. In addition, we present data indicating that apoptotic delta psi m disruption is secondary to transcriptional events. These data connect the PT control point to the p53- and ICE/ Ced 3-regulated control points of apoptosis and place PT upstream of nuclear and plasma membrane features of PCD.

Animals↗
PubMed2026

Integrative multi-omics and single-cell analysis identifies EGFR pathway activation and metabolic reprogramming as potential synthetic lethal vulnerabilities in resistance to the FGFR inhibitor AZD4547.

BACKGROUND: Although fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) have demonstrated clinical promise, the inevitable emergence of acquired resistance remains a critical bottleneck, severely compromising their long-term clinical efficacy. The pan-cancer molecular landscape and heterogeneous mechanisms driving this resistance, ranging from genetic alterations to dynamic network rewiring, remain poorly understood. METHODS: We integrated large-scale pharmacogenomic profiling of the FGFR inhibitor AZD4547 from the GDSC2 and PRISM databases with single-cell RNA sequencing to dissect the multi-omics landscape of FGFRi resistance across 312 cell lines from 8 cancer types. This multi-omics framework was further extended by machine learning modeling and systematic synthetic lethality screening to uncover actionable therapeutic targets. In vitro viability assays and western blot analysis were subsequently conducted to experimentally evaluate the predicted FGFR-EGFR synthetic lethality. RESULTS: Our dual-database analysis unveiled a multi-dimensional atlas of FGFRi resistance. We identified cancer-specific genomic drivers, such as ELF4 amplification in glioblastoma, alongside key transcriptomic markers including UCP2 and FSCN1, highlighting a shift towards metabolic reprogramming and epithelial-mesenchymal transition (EMT). Single-cell analysis unveiled that resistance is linked to the heterogeneous enrichment of baseline subpopulations characterized by distinct metaprograms, including cell-cycle dysregulation. Furthermore, a random forest model built on a LASSO-derived transcriptomic signature was constructed, demonstrating promising predictive capability for AZD4547 sensitivity (mean test-set AUC&#x2009;=&#x2009;0.73, 95% CI [0.63, 0.80]); the signature generalized well to erdafitinib but showed limited transferability to some other FGFR inhibitors (e.g. pemigatinib, BGJ398). Most notably, our synthetic lethal screening revealed a convergent reliance on compensatory RTK signaling (specifically EGFR pathway enrichment) and downstream MAPK/PI3K cascades in resistant phenotypes, providing converging computational evidence for EGFR pathway activation as an adaptive bypass mechanism. This predicted synthetic lethality was experimentally supported in two FGFR-dependent cell line models (RT112 and CCLP1), in which combined FGFR-EGFR inhibition produced marked synergistic antiproliferative effects. CONCLUSIONS: This study establishes a comprehensive multi-omics atlas of resistance to the FGFR inhibitor AZD4547, delineating convergent mechanisms of metabolic reprogramming and EGFR-mediated bypass signaling. Our findings characterize the resistance as a dynamic network rewiring and nominate rational combination strategies to overcome this therapeutic bottleneck. While FGFR-EGFR co-inhibition is experimentally supported, metabolic co-targeting remains a computationally derived, hypothesis-generating strategy.

Benzamides↗
PubMed1991

The H2O2-generating system modulates protein iodination and the activity of the pentose phosphate pathway in dog thyroid.

Iodide oxidation and binding to proteins require a thyroperoxidase and an ill defined H2O2-generating system. The NADP+ supply and, thus, NADPH oxidation are the limiting steps of the pentose phosphate pathway. The purpose of this work was to test the hypothesis that H2O2 generation is a limiting step of iodination and NADPH oxidation and, therefore, of the pentose phosphate pathway. H2O2 produced by dog thyroid slices was measured with the homovanillic fluorescence assay. Our data show that H2O2 generation is stimulated by both the cAMP cascade [as activated by TSH, forskolin and (Bu)2cAMP] and the Ca2(+)-phosphatidylinositol cascade (as activated by carbamylcholine, ionomycin, and 12-O-tetradecanoylphorbol-13-acetate). We used several physiological and pharmacological agents that modulate iodide organification. In all cases there was a strict parallelism between effects on H2O2 generation, iodide binding to proteins, and pentose phosphate pathway activity. Moreover, in TSH- or carbamylcholine-stimulated slices, glucose or Ca2+ depletion, which greatly depressed H2O2 generation, also greatly decreased iodide organification and the activity of the pentose phosphate pathway. The glutathione peroxidase-catalyzed H2O2 reduction in the cytosol, which involves NADPH oxidation and, therefore, increases the NADP supply, also enhances the activity of the pentose phosphate pathway. All of these data strongly support the hypothesis that H2O2 generation in dog thyroid controls iodination of proteins; through the NADPH oxidation resulting from H2O2 production and reduction, hydrogen peroxide also regulates the activity of the pentose phosphate pathway.

Animals↗
PubMed1991

Protective effects of spin-trapping agents on adriamycin-induced cardiotoxicity in isolated rat atria.

Adriamycin (ADR) is known to exert a severe negative inotropic effect on isolated myocardial preparations; a role for free radical generation has been hypothesized. Spin-trapping of free radicals has been extensively exploited in ESR studies, both in cell-free systems and in intact tissues. The interaction between spin-traps and free radicals should in principle stop the reaction cascade leading to cellular damage. Based on this hypothesis, the possible cardioprotective action of three spin-trapping agents, 5,5-dimethyl-l-pyrroline-N-oxide (DMPO), N-tert-butyl-alpha-phenylnitrone (PBN) and alpha-(4-pyridyl 1-oxide) N-tert-butylnitrone (POBN), was tested on isolated rat atria incubated in the presence of ADR; maximal non-cardiotoxic concentrations were used (50, 10 and 50 mM respectively) in order to achieve a maximal spin-trapping effect. A varying degree of protection was observed with the three compounds, directly correlated to their hydrophobicity, as assessed by chloroform/water partition coefficients. It is proposed that ADR-induced free radical generation is responsible for the acute cardiotoxic effects of the drug; this seems to be a site-specific mechanism restricted to one or more hydrophobic cellular compartment/s, since only lipophilic spin-trapping agents are able to prevent the development of the negative inotropic effect of ADR.

Animals↗
PubMed2001

Intracellular signals that control cell proliferation in mammalian balance epithelia: key roles for phosphatidylinositol-3 kinase, mammalian target of rapamycin, and S6 kinases in preference to calcium, protein kinase C, and mitogen-activated protein kinase.

In fish, amphibians, and birds, the loss of hair cells can evoke S-phase entry in supporting cells and the production of new cells that differentiate as replacement hair cells and supporting cells. Recent investigations have shown that supporting cells from mammalian vestibular epithelia will proliferate in limited numbers after hair cells have been killed. Exogenous growth factors such as glial growth factor 2 enhance this proliferation most potently when tested on vestibular epithelia from neonates. In this study, the intracellular signaling pathways that underlie the S-phase entry were surveyed by culturing epithelia in the presence of pharmacological inhibitors and activators. The results demonstrate that phosphatidylinositol 3-kinase is a key element in the signaling cascades that lead to the proliferation of cells in mammalian balance epithelia in vitro. Protein kinase C, mammalian target of rapamycin, mitogen-activated protein kinase, and calcium were also identified as elements in the signaling pathways that trigger supporting cell proliferation.

Animals↗
PubMed2001

Differential p53-dependent mechanism of radiosensitization in vitro and in vivo by the protein kinase C-specific inhibitor PKC412.

The cellular response to ionizing radiation is governed by the DNA-damage recognition process but is also modulated by cytoplasmic signal transduction cascades that are part of the cellular stress response. Growth-promoting protein kinase C activity antagonizes irradiation-induced cell death, and, therefore, protein kinase C inhibitors might be potent radiosensitizers. The antiproliferative and radiosensitizing effect of the novel N-benzoylated staurosporine analogue PKC412 was tested in vitro against genetically defined p53-wild type (+/+) and p53-deficient (-/-) murine fibrosarcoma cells and in vivo against radioresistant p53-/- murine fibrosarcoma and human colon adenocarcinoma tumor xenograft (SW480, p53-mutated). PKC412 sensitized both p53+/+ and p53-/- tumor cells in vitro and in vivo for treatment with ionizing radiation but with a different mechanism of radiosensitization depending on the p53 status. In p53+/+, cells combined treatment with PKC412 and ionizing radiation drastically induced apoptotic cell death, whereas no apoptosis induction could be observed in p53-deficient cells in vitro and in histological tumor sections. Combined treatment resulted in an increased G2 cell cycle distribution in p53-/- cells at PKC412 concentrations that did not alter cell cycle distribution when applied alone. In vivo, a minimal treatment regimen during 4 consecutive days of PKC412 (4 x 100 mg/kg) in combination with ionizing radiation (4 x 3 Gy) exerted a substantial tumor growth delay for both p53-disfunctional tumor xenografts and showed that the clinically relevant protein kinase C inhibitor PKC412 is a promising new radiosensitizer with a potentially broad therapeutic window.

Animals↗
PubMed1983

Therapeutic and adjunctive applications of an imidazoline anti-inflammatory agent.

A unique combination of anti-inflammatory and antiulcerogenic activities is described for 2-(2 methyl-4-chlorophenylamino)-2-imidazoline (CDMI). CDMI administered i.p. produced a dose-related decrease in aspirin-induced ulcers which persisted even in the presence of exogenously added HCI. The carrageenin-edema reducing activities of i.p. CDMI and p.o. aspirin were additive. When oral CDMI was combined with oral aspirin or oral indomethacin, the combinations also resulted in additive anti-inflammatory activities (80 and 94% vs. 52% for CDMI, 62% for aspirin and 71% for indomethacin alone). Moreover, gastric ulcerogenicity was reduced by 92% when either aspirin or indomethacin was combined with CDMI. These results indicate that CDMI and related compounds deserve further study as adjuncts to increase the margin of safety of currently used nonsteroidal anti-inflammatory agents. CDMI was also tested against a developing acute inflammatory reaction. When administered at 2 hr post carrageenin, CDMI was as effective as when it was administered 30 min before the carrageenin. These results are discussed as a possible reflection of an action on the lipoxygenase pathways of the arachidonic acid cascade that is not shared by the classical nonsteroidal anti-inflammatory agents.

Animals↗
PubMed1996

Intravenous immune globulin: an alternative therapy in steroid-dependent allergic diseases.

A fundamental feature of asthma is abnormal airway function, now recognized to result from both acute and chronic inflammatory changes. Central to the development of these inflammatory changes may be the activation of T cells and the release of pro-inflammatory cytokines. In the skin, a similar cascade of events may underlie the pathogenesis of atopic dermatitis. Asthma and atopic dermatitis often share several features that may be important in their pathogenesis: T-cell infiltration of the tissues, elevated IgE levels, and a history of known triggers associated with positive immediate skin-test reactions. In both diseases, administration of intravenous immune globulin (IVIG) on a regular basis appears to reduce the need for systemic corticosteroids, reduce symptoms and for asthmatics, reduce hospitalization costs. Although the mechanism of action of IVIG in these disorders remains to be defined, it may be exhibiting significant anti-inflammatory activity. IVIG may be a potent alternative in the treatment of severe, steroid-dependent allergic disorders, reducing steroid dependency.

Adrenal Cortex Hormones↗
PubMed1996

[High-risk surgical patients. Who are they and how should they be treated?].

This review addresses the currently available information that describes the identification of high risk patients undergoing surgery and how they may be treated to improve their outcome. It is clear from this data that high risk patients have a mortality rate of around 30% and that the major cause of death is due to multiple organ failure (MOF) which occurs days or in some cases weeks after the operation. The hypothesis for the onset of MOF is presented and it relates to the breakdown in gut patency which can allow the translocation of initiating inflammatory mediators which sets the MOF cascade in action. Current treatment strategies based on preclinical and clinical data to prevent MOF are discussed which includes the use of catecholamines such as dobutamine and dopexamine (Dopacard). It is concluded that the high risk surgical patient is not well defined and that the most rigorously tested criteria are those developed by Shoemaker. These criteria relate far more to the patients physiological status than the surgery that they are undergoing. The treatment of these patients is far more successful if intervention starts prior to surgery with fluids and vasoactive drugs such as Dopacard where the mortality rate has been shown to be reduced by 75%.

Humans↗
PubMed1997

Tissue-specific expression of human achaete-scute homologue-1 in neuroendocrine tumors: transcriptional regulation by dual inhibitory regions.

Malignancies with neuroendocrine (NE) features such as medullary thyroid cancer (MTC) and small cell lung cancer (SCLC) are prototypic neoplasms arising from peripheral endocrine cells. The mechanisms that regulate the NE phenotype in these tumors and their cellular precursors are not well understood. However, a basic helix-loop-helix transcription factor that is homologous to Drosophila neural fate determination proteins may have a central role. Human achaete-scute homologue-1 (hASH1), a human homologue of the Drosophila achaete-scute complex, is highly expressed in MTC, SCLC, and pheochromocytomas. To determine what mechanisms allow constitutive expression of hASH1 in NE tumors, we cloned human genomic DNA fragments containing the hASH1 gene and characterized its promoter region. We show that hASH1 expression is restricted to NE cell lines by a transcriptionally regulated mechanism. Dual promoters initiate hASH1 transcription, with the predominant site being an evolutionarily conserved initiator (INR) element. Transient transfection studies provide evidence for a generalized enhancer region that has high activity in all cell lines tested. Restriction of hASH1 expression to NE tumor cells depends on two tissue-specific repressor regions, present in the proximal and distal (> 13.5 kb) 5'-flanking region. Understanding the mechanisms of tissue-specific control of hASH1 gene expression provides a useful model to explore regulatory cascades influencing both normal nervous system development and the NE phenotype of tumors such as MTC and SCLC.

Basic Helix-Loop-Helix Proteins↗