Cell regulation.
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Cell Physiological Phenomena↗
Biomedical subjects
A Hall
Publications and source records attributed to A Hall.
Glutathione-S-transferase activity and isoenzyme levels measured by two methods in ovarian cancer, and their value as markers of disease outcome.
A study has been carried out to investigate the cellular distribution and levels of glutathione-S-transferase isoenzymes (GST), acidic (pi), basic (alpha) and neutral (mu), in ovarian tumour biopsies, and to measure GST activity in the same tumour specimens. Two methods of assessing isoenzyme levels (immunohistochemistry and Western blot) were compared. Well-known important clinicopathological features were correlated with response to treatment, overall survival and progression-free survival for each of 97 patients from whom biopsies had been obtained. The glutathione-S-transferase isoenzyme levels were also correlated with overall and progression-free survival, and with the important clinicopathological features. As expected, there was a significant correlation between FIGO stage, histological grade of tumour, amount of residual disease after staging laparotomy, response to chemotherapy, and both overall and progression-free survival. Glutathione-S-transferase isoenzyme levels (acidic, basic and neutral) measured by Western blot were not found to be significantly correlated with any of the clinicopathological parameters tested. Using the immunohistochemistry method of detection there was a correlation between the GST acidic isoenzyme level and the amount of residual disease remaining after initial debulking surgery (higher levels were detected in the group with no residual disease, P=0.034), and also between the GST acidic isoenzyme level and the type of chemotherapy regimen used. Higher levels of the acidic isoenzyme were present in tumour biopsies taken from the patient group who had received a combination regimen (cyclophosphamide, carboplatin, ifosfamide and doxorubicin). The neutral and basic GST isoenzyme levels were not significantly correlated with any of the clinicopathological parameters. None of the GST isoenzyme levels were significantly correlated with response to treatment, overall survival or progression-free survival (using either method of detection). Similarly, glutathione transferase activity showed no significant correlation with prognosis or survival.
Adult↗
What is molecular epidemiology?
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Humans↗
Previous enteric adenovirus infection does not protect against subsequent symptomatic infection: longitudinal follow-up of eight infants.
Eight infants followed longitudinally were found to have enteric adenovirus (EAdv) infections: in 5 infants with diarrhea and in 3 with no accompanying diarrhea. Sequential stool samples prior to EAdv infections were tested for adenovirus antigen, anti-adenoviral IgA and neutralizing antibodies to serotypes 40, 41 and 2 in order to ascertain whether protection from symptoms was due to prior infection. No difference was found in the number of adenoviral infections among infants prior to their EAdv infections with or without accompanying diarrhea. However, in 3 of the 5 infants in whom EAdv infection was accompanied by diarrhea and 2 of 3 control infants, previous EAdv infections had occurred as detected by serotype-specific antibody rises.
Adenoviridae Infections↗
Respiratory health in a total very low birthweight cohort and their classroom controls.
AIMS: To compare the respiratory health and function at 8 to 9 years of age of a total population based cohort of 300 very low birthweight (VLBW) children with that of two classroom controls (n = 590) matched for age and sex. STUDY DESIGN: Cohort study with controls. SETTING: Schools throughout Scotland. RESULTS: The VLBW children were more likely than their peers to use an inhaler, to be absent from school, and to be admitted to hospital because of respiratory illness. They were significantly shorter than their classroom controls, but even after adjusting for differences in height, the VLBW children had reduced forced vital capacity (FVC); this was associated with a history of prolonged ventilation (> 28 days) and pneumothorax in the neonatal period. There were no significant differences between the groups in forced expiratory volume in one second (FEV1)/FVC but twice as many (7.9% v 3.7%) of the VLBW children had ratios < 70%, denoting obstructive airways disease. Poor expiratory function was associated with neonatal respiratory distress syndrome, prolonged ventilation, and the need for > 40% oxygen. Exercise induced airway narrowing was increased in VLBW children (odds ratio = 2.0; 95% confidence interval 1.2 to 3.4) and was very little changed by adjustment for inhaler use and exposure to cigarette smoke. CONCLUSIONS: As in other low birthweight cohorts, respiratory morbidity was increased. Unlike previous studies, FVC was more affected than expiratory function in this VLBW population. Our findings support the hypothesis that poorer lung function is associated with very low birth weight, but not with intrauterine growth retardation.
Asthma, Exercise-Induced↗
Selective reduction of pregnancy: a legal analysis.
This article examines the technique and legality of induced abortion of one or more fetuses in a multiple pregnancy, where the aim is the destruction of some but not all of the fetuses present (selective reduction of pregnancy). It concludes that since the legal status of the procedure in English law is unclear, it may be a criminal offence to perform selective reduction even where there is an ostensible clinical need. Moreover if the procedure is carried out negligently, and any infant damaged as a result is subsequently born alive, he or she may have a civil claim against the practitioner who carried out the procedure.
Abortion, Legal↗
Spinal cord oligodendrocytes develop from ventrally derived progenitor cells that express PDGF alpha-receptors.
Platelet-derived growth factor alpha-receptors (PDGFR alpha) are expressed by a subset of neuroepithelial cells in the ventral half of the embryonic day 14 (E14) rat spinal cord. The progeny of these cells subsequently proliferate and migrate into the dorsal parts of the cord after E16. Here, we show that E14 ventral cells are able to generate oligodendrocytes in culture but that dorsal cells acquire this ability only after E16, coinciding with the appearance of PDGFR alpha-immunoreactive cells in the starting population. PDGFR alpha-positive cells in optic nerve and spinal cord cultures co-labelled with antibody markers of oligodendrocyte progenitors. When PDGFR alpha-positive cells were purified from embryonic rat spinal cords by immunoselection and cultured in defined medium, they all differentiated into oligodendrocytes. Very few oligodendrocytes developed in cultures of embryonic spinal cord cells that had been depleted of PDGFR alpha-expressing cells by antibody-mediated complement lysis. These data demonstrate that all PDGFR alpha-positive cells in the embryonic rat spinal cord are oligodendrocyte progenitors and that most or all early-developing oligodendrocytes are derived from these ventrally-derived precursors.
Animals↗
Diabetes as a risk factor for coronary disease.
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Adult↗
Regulation of the actin cytoskeleton, integrins and cell growth by the Rho family of small GTPases.
The Rho family of small GTP binding proteins play a key part in regulating the actin cytoskeleton and cell adhesion through integrin receptors. In addition, these proteins regulate signal transduction pathways essential for normal cell growth. Many of the molecules that regulate Rho have oncogenic activity, suggesting that members of the Rho family may have an important role in tumour formation.
Actins↗
Comparison of peripheral Ia and corticomotoneuronal composite EPSPs in human motoneurons.
The effects of excitatory inputs arising from Ia afferent and corticomotoneuronal volleys on repetitively firing flexor carpi radialis (FCR) motoneurons were compared in normal human subjects. Peripheral (Ia) volleys were produced by transcutaneous electrical stimulation of the median nerve and by mechanical taps to the FCR tendon. Transcranial magnetic stimulation (TMS) was used to activate the corticomotoneuronal pathway. The duration of the excitatory response peaks measured from peri-stimulus time histograms (PSTHs) and the time course of the response trajectories were both taken to reflect the shapes of the underlying composite excitatory postsynaptic potentials (EPSP)s acting upon that motoneuron. The duration of excitatory response peaks for the H-reflex and the first sub-peak (SP1) of the motor unit's response to TMS were similar and were typically less than those arising from tendon taps. The response trajectories, which measure the excitability of the motoneuron during different phases of the afterhyperpolarization, overlapped for H-reflex and SP1 responses, but were different for tendon tap inputs. Our results indicate that the SP1 response of a motoneuron to TMS input and its response to near-synchronous Ia afferent activation are mediated by composite EPSPs with similar rise times. We suggest that a similar spatial distribution of synaptic boutons for both Ia and corticomotoneuronal input to motoneurons innervating FCR is likely.
Adult↗
p190-B, a new member of the Rho GAP family, and Rho are induced to cluster after integrin cross-linking.
p120GAP forms distinct complexes with two phosphoproteins, p62 and p190. Here we have cloned a cDNA encoding a protein with 51% amino acid identity to p190 (hereafter designated p190-A) and have designated it p190-B. The N-terminal portion of p190-B contained several motifs characteristic of a GTPase domain, while its C terminus contained a Rho GAP domain. A recombinant Rho GAP domain polypeptide showed GAP activity for RhoA, Rac1, and G25K/CDC42Hs. Immunoprecipitation and immunofluorescence studies demonstrated that p190-B protein was expressed in a variety of cells and was localized diffusely in the cytoplasm and in fibrillar patterns that co-localized with the alpha 5 beta 1 integrin receptor for fibronectin. Adhesion of fibronectin-coated latex beads to cells resulted in recruitment of significant amounts of p190-B and Rho to the plasma membrane beneath the site of bead binding. In contrast, beads coated with polylysine or concanavalin A were unable to recruit p190-B or Rho. Additionally, anti-beta 1 or anti-alpha 5 integrin antibody-coated beads were also able to recruit large amounts of p190-B and Rho. These results identify a novel second member of the p190 family and establish the existence of a novel transmembrane link between integrins and a new protein p190-B and Rho.
Amino Acid Sequence↗
A conserved binding motif defines numerous candidate target proteins for both Cdc42 and Rac GTPases.
Rho, Rac, and Cdc42 are small GTPases that regulate the formation of a variety of actin structures and the assembly of associated integrin complexes, but little is known about the target proteins that mediate their effects. Here we have used a motif-based search method to identify putative effector proteins for Rac and Cdc42. A search of the GenBankTM data base for similarity with the minimum Cdc42/Rac interactive binding (CRIB) region of a potential effector protein p65PAK has identified over 25 proteins containing a similar motif from a range of different species. These candidate Cdc42/Rac-binding proteins include family members of the mixed lineage kinases (MLK), a novel tyrosine kinase from Drosophila melanogaster (DPR2), a human protein MSE55, and several novel yeast and Caenorhabditis elegans proteins. Two murine p65PAK isoforms and a candidate protein from C. elegans, F09F7.5, interact strongly with the GTP form of both Cdc42 and Rac, but not Rho in a filter binding assay. Three additional candidate proteins, DPR2, MSE55, and MLK3 showed binding to the GTP form of Cdc42 and weaker binding with Rac, and again no interaction with Rho. These results indicate that proteins containing the CRIB motif bind to Cdc42 and/or Rac in a GTP-dependent manner, and they may, therefore, participate in downstream signaling.
Amino Acid Sequence↗
Hepatitis B vaccination policy in drug treatment services.
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Health Policy↗
Rac GTPase interacts with GAPs and target proteins through multiple effector sites.
Rac, a small GTPase in the ras superfamily, regulates at least two biological processes in animal cells: (i) the polymerization of actin and the assembly of integrin complexes to produce lamellipodia and ruffles; and (ii) the activity of an NADPH oxidase in phagocytic cells. NADPH oxidase activation is mediated through a rac effector protein, p67phox, and using chimeras made between rac and the closely related GTPase, rho, we have identified two distinct effector sites in rac, one N-terminal and one C-terminal, both of which are required for activation of p67phox. The same two effector sites are essential for rac-induced actin polymerization in fibroblasts. p65PAK, a ubiquitous serine/threonine kinase, interacts with rac at both the N- and C-terminal effector sites, but the GTPase-activating protein, bcr interacts with rac at a different region. This makes p65PAK, but not bcr, a candidate effector of rac-induced lamellipodium formation.
3T3 Cells↗
An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1.
Members of the Rho family of small guanosine triphosphatases (GTPases) regulate the organization of the actin cytoskeleton; Rho controls the assembly of actin stress fibers and focal adhesion complexes, Rac regulates actin filament accumulation at the plasma membrane to produce lamellipodia and membrane ruffles, and Cdc42 stimulates the formation of filopodia. When microinjected into quiescent fibroblasts, Rho, Rac, and Cdc42 stimulated cell cycle progression through G1 and subsequent DNA synthesis. Furthermore, microinjection of dominant negative forms of Rac and Cdc42 or of the Rho inhibitor C3 transferase blocked serum-induced DNA synthesis. Unlike Ras, none of the Rho GTPases activated the mitogen-activated protein kinase (MAPK) cascade that contains the protein kinases c-Raf1, MEK (MAPK or ERK kinase), and ERK (extracellular signal-regulated kinase). Instead, Rac and Cdc42, but not Rho, stimulated a distinct MAP kinase, the c-Jun kinase JNK/SAPK (Jun NH2-terminal kinase or stress-activated protein kinase). Rho, Rac, and Cdc42 control signal transduction pathways that are essential for cell growth.
3T3 Cells↗
Rac mediates growth factor-induced arachidonic acid release.
Growth factor-induced stress fiber formation involves signal transduction through Rac and Rho proteins and production of leukotrienes from arachidonic acid metabolism. In exploring the relationship between these pathways, we found that Rac is essential for EGF-induced arachidonic acid production and subsequent generation of leukotrienes and that Rac V12, a constitutively activated mutant of Rac, generates leukotrienes in a growth factor-independent manner. Leukotrienes generated by EGF or Rac V12 are necessary and sufficient for stress fiber formation. Furthermore, leukotriene-dependent stress fiber formation requires Rho proteins. We have therefore identified elements of a pathway from growth factor receptors that includes Rac, arachidonic acid production, arachidonic acid metabolism to leukotrienes, and leukotriene-dependent Rho activation. This appears to be the major pathway by which Rac influences Rho-dependent cytoskeleton rearrangements.
3T3 Cells↗
Isolation of salmonellae from seals from UK waters.
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Animals↗