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Biomedical subjects

S Scott

Publications and source records attributed to S Scott.

At least 91 records · Page 5Linked to original sources
PubMed1999

A novel four-drug ablative regimen with hemopoietic stem cell rescue for patients with breast cancer: a phase II study.

High-dose chemotherapy and autologous hemopoietic stem cell transplantation (HSCT) may provide durable progression-free survival in some patients with stage IV breast cancer (S4Brca). We have studied a new four-drug intensive preparative regimen with HSCT in a group of 158 women with S4Brca to define the risk and potential benefit of this regimen in this patient population. From May 1988 through May 1997, 158 women with S4Brca at a single center were treated with cisplatin, etoposide, thiotepa, and cyclophosphamide (PETCy) plus autologous HSCT Eligible patients were also treated with posttransplant involved-field radiation therapy. Patients with estrogen-receptor positive tumors not previously treated with tamoxifen also received this therapy for 5 years following transplantation. All patients experienced significant toxicity requiring blood-product support and parenteral nutrition. Eighteen patients (11%) died of regimen-related toxic events. With a median follow-up of 540 days for surviving patients, a retrospective Kaplan-Meier analysis projects an overall survival of 38+/-8.5% (95% CI) at 890 days with a maximum follow-up of 8.8 years. For 52 patients in sensitive relapse, the median event-free survival time is 767 days, with 46.2+/-15.3% (95% CI) predicted to be alive at 884 days with a maximal follow-up of almost 9 years. Nearly one-half of patients in this study with S4Brca in sensitive relapse have experienced durable remissions following PETCy ablation and HSCT. Although toxicity is significant, the PETCy regimen produces a favorable balance between efficacy (event-free survival) and treatment failure (relapse + regimen-related toxic death) compared with published results. These data suggest that within the high-dose range for preparative therapy, a steep dose-response may exist for breast cancer. Trials comparing the dose intensity of preparative regimens are warranted.

Adult↗
PubMed1999

Synergistic operation of the CAR2 (Ornithine transaminase) promoter elements in Saccharomyces cerevisiae.

Dal82p binds to the UIS(ALL) sites of allophanate-induced genes of the allantoin-degradative pathway and functions synergistically with the GATA family Gln3p and Gat1p transcriptional activators that are responsible for nitrogen catabolite repression-sensitive gene expression. CAR2, which encodes the arginine-degradative enzyme ornithine transaminase, is not nitrogen catabolite repression sensitive, but its expression can be modestly induced by the allantoin pathway inducer. The dominant activators of CAR2 transcription have been thought to be the ArgR and Mcm1 factors, which mediate arginine-dependent induction. These observations prompted us to investigate the structure of the CAR2 promoter with the objectives of determining whether other transcription factors were required for CAR2 expression and, if so, of ascertaining their relative contributions to CAR2's expression and control. We show that Rap1p binds upstream of CAR2 and plays a central role in its induced expression irrespective of whether the inducer is arginine or the allantoin pathway inducer analogue oxalurate (OXLU). Our data also explain the early report that ornithine transaminase production is induced when cells are grown with urea. OXLU induction derives from the Dal82p binding site, which is immediately downstream of the Rap1p site, and Dal82p functions synergistically with Rap1p. This synergism is unlike all other known instances of Dal82p synergism, namely, that with the GATA family transcription activators Gln3p and Gat1p, which occurs only in the presence of an inducer. The observations reported suggest that CAR2 gene expression results from strong constitutive transcriptional activation mediated by Rap1p and Dal82p being balanced by the down regulation of an equally strong transcriptional repressor, Ume6p. This balance is then tipped in the direction of expression by the presence of the inducer. The formal structure of the CAR2 promoter and its operation closely follow the model proposed for CAR1.

5' Untranslated Regions↗
PubMed1999

Angiotensin II signaling in vascular smooth muscle cells under high glucose conditions.

The mechanisms responsible for the accelerated cardiovascular disease in diabetes, as well as the increased hypertrophic effects of angiotensin II (Ang II) under hyperglycemic conditions, are not very clear. We examined whether the culture of vascular smooth muscle cells (VSMC) under hyperglycemic conditions to simulate the diabetic state can lead to increased activation of key growth- and stress-related kinases, such as the mitogen-activated protein kinases (MAPKs), in the basal state and in response to Ang II. Treatment of porcine VSMC for short time periods (0.5 to 3 hours) with high glucose (HG; 25 mmol/L) markedly increased the activation of the extracellular signal-regulated kinase (ERK1/2) and c-Jun/N-terminal kinase (JNK) relative to cells cultured in normal glucose (NG; 5.5 mmol/L). p38 MAPK also was activated by HG, and this effect remained sustained for several hours. Ang II treatment increased the activity of all 3 families of MAPKs. Ang II-induced ERK activation was potentiated nearly 2-fold in cells treated with HG for 0.5 hour. However, Ang II-induced JNK was not altered. In VSMC cultured for 24 hours with HG, Ang II and HG displayed an additive response on p38 MAPK activity. MAPKs can lead to activation of transcription factors such as activator protein-1 (AP-1). HG alone significantly increased AP-1 DNA-binding activity. Furthermore, Ang II and HG combined had additive effects on AP-1 activity. These results suggest that increased activation of specific MAPKs and downstream transcription factors, such as AP-1, may be key mechanisms for the increased VSMC growth potential of HG alone and of Ang II under HG conditions.

Angiotensin II↗
PubMed1998

Nociception activates Elk-1 and Sap1a following expression of the ORL1 receptor in Chinese hamster ovary cells.

Nociceptin stimulation of the ORL1 receptor expressed in Chinese hamster ovary (CHO) cells results in the activation of the extracellular signal regulated kinases ERK1 and ERK2. ERK1/ERK2 activation is inhibited by pertussis toxin, the MEK inhibitor PD 98059 and by transient expression of alpha-transducin, indicating that ORL1 up-regulation of these kinases occurs as a consequence of the release of the G-protein betagamma complex following the activation of pertussis-toxin sensitive Galphai-family G-proteins. Using specific reporter genes we demonstrate that the transcription factors Elk-1 and Sapla are activated in a pertussis toxin-sensitive manner as a consequence of ORL1 upregulation of ERK1/ERK2 to induce changes in gene expression. The activation of these transcription factors is also inhibited following treatment with PD 98059 and following coexpression of alpha-transducin.

Animals↗
PubMed1998

An anti-sense construct of full-length ATM cDNA imposes a radiosensitive phenotype on normal cells.

The cloning of a full-length cDNA for the gene (ATM) mutated in the human genetic disorder ataxia-telangiectasia (A-T) has been described recently. This cDNA, as well as a fragment representing a functional region from ATM, are capable of rescuing various aspects of the radiosensitive phenotype in A-T cells. We have subcloned full-length ATM cDNA in the opposite orientation in an EBV-based vector under the control of an inducible promoter to determine whether this anti-sense construct might sensitize control lymphoblastoid cells to ionizing radiation. The effectiveness of expression of this construct in control cells was monitored by loss of ATM protein which was evident over a period 6-12 h after induction. Under these conditions radiosensitivity was enhanced approximately threefold in control cells, approaching the degree of radiosensitivity observed in A-T cells. Expression of the anti-sense construct also increased the number of radiation-induced chromosomal breaks and led to the appearance of radioresistant DNA synthesis in these cells. Abrogation of the G1/S checkpoint was evident from the loss of the p53 response and that of its downstream effector, p21/WAF1, post-irradiation. The extent of accumulation of transfected cells in G2/M phase at 24 h post-irradiation was similar to that observed in A-T cells and the induction of stress-activated protein kinase by ionizing radiation was prevented by antisense ATM cDNA expression. These data demonstrate that full-length ATM anti-sense cDNA, by reducing the amount of ATM protein, is effective in imposing a series of known defects characteristic of the A-T phenotype. This inducible system provides an experimental model to further investigate mechanisms underlying radiosensitivity and cell cycle control.

Ataxia Telangiectasia↗
PubMed1998

Human metabotropic glutamate receptor 2 couples to the MAP kinase cascade in chinese hamster ovary cells.

We have examined the functional coupling of the human metabotropic glutamate receptor type 2 (mGluR2) with the regulation of the mitogen activated protein kinase (MAP kinase) signal transduction cascade. We demonstrated that L-glutamate stimulation of the human mGluR2 receptor transiently expressed in chinese hamster ovary (CHO) cells leads to a rapid increase in the activity of p42/p44 MAP kinase (also known as the extracellular signal regulated kinases, ERK1 and ERK2). Activation of p42/p44 MAP kinase has been demonstrated in a peptide phosphorylation assay and through the demonstration of a shift in electrophoretic mobility of p42 MAP kinase following activation. In both assay systems L-glutamate stimulation of MAP kinase was inhibited by pertussis toxin and by the MEK (MAP/ERK activating kinase) inhibitor PD 98059. We conclude that L-glutamate stimulation of the mGluR2 receptor in CHO cells mediated regulation of p42/p44 MAP kinase following the activation of pertussis toxin-sensitive G alpha(i) G-proteins via a distinct protein kinase signalling pathway that utilizes MEK.

Animals↗
PubMed1998

Regulation of LPS-mediated induction of C/EBP delta gene expression in livers of young and aged mice.

The C/EBP family of transcription factors plays a major role in the regulation of families of stress response genes, in particular, the acute phase response genes. We have examined expression of the C/EBP delta gene during the bacterial lipopolysaccharide mediated induction of the acute phase response in livers of young (4 months) and aged (24-28 months) male C57B1/6 mice by Northern, Western, and Southwestern analyses. C/EBP delta mRNA is present at a low constitutive level, is induced by lipopolysaccharide, and reaches the same induced level in young and aged mice. Aged mice, however, show a higher constitutive, uninduced mRNA pool level and a delay in recovery to uninduced levels after lipopolysaccharide treatment. C/EBP delta mRNA is observable 30 min after lipopolysaccharide in total RNA, cytoplasmic and polysomal fractions. Specific full length 28-kDa nascent peptides are detectable in polysomes 90 min after lipopolysaccharide. mRNA and nascent peptides cosediment with large polysomes and C/EBP delta mRNA is shifted to larger polysomes in lipopolysaccharide treated aged mice, consistent with an increased rate of initiation. Specific DNA-binding activity of C/EBP delta protein in nuclear extracts was examined by electromobility shift and antibody supershift assay. The levels of C/EBP delta binding-activity, are consistent with the changes in mRNA levels in young lipopolysaccharide treated livers. These studies support our hypothesis that aged mice exhibit a state of chronic inflammation or stress in the absence of a stressor.

Acute-Phase Reaction↗
PubMed1998

Autoinducer of virulence as a target for vaccine and therapy against Staphylococcus aureus.

Staphylococcus aureus causes pathologies ranging from minor skin infections to life-threatening diseases. Pathogenic effects are largely due to production of bacterial toxin, which is regulated by an RNA molecule, RNAIII. The S. aureus protein called RAP (RNAIII activating protein) activates RNAIII, and a peptide called RIP (RNAIII inhibiting peptide), produced by a nonpathogenic bacteria, inhibits RNAIII. Mice vaccinated with RAP or treated with purified or synthetic RIP were protected from S. aureus pathology. Thus, these two molecules may provide useful approaches for the prevention and treatment of diseases caused by S. aureus.

Amino Acid Sequence↗
PubMed1998

Causes of recurrence after laparoscopic hernioplasty. A multicenter study.

BACKGROUND: To determine if there are common factors beyond the learning curve that lead to recurrence after laparoscopic hernioplasty, we analyzed failures seen in seven centers specializing in laparoscopic hernia repair. METHOD: We performed a retrospective review of patients who had a laparoscopic hernioplasty (Tapp or Tep) between 1990 and 1996 at centers specializing in laparoscopic repairs (>500 repairs at each center). RESULTS: In all, 7661 patients had 10,053 hernias repaired by the transabdominal preperitoneal or the totally extraperitoneal approach; they were followed for 1 month to 6 years. In patients followed for >/=6 months with a median follow-up of 36 months, 35 repairs failed (0.4%), and all but one of these patients underwent a remedial operation. Twenty-nine had a laparoscopic repair, four had a combined laparoscopic and anterior repair, and one had an anterior repair alone. The cause of failure was determined in all 34 patients. The mechanism of recurrence was inadequate lateral fixation of the mesh in 11 cases, inadequate lateral fixation compounded by too small a mesh in three cases, missed lipoma of the cord in four cases, inadequate fixation of the mesh medially to Cooper's ligament in eight cases (seven of which were associated with too small a mesh), a missed hernia in four cases, and a hernia through a keyhole in the mesh in five cases. As surgeons gained experience, the incidence of recurrence due to missed hernias or too small a mesh decreased. CONCLUSIONS: This large multicenter study demonstrated that the incidence of recurrence after laparoscopic hernioplasty performed by experienced surgeons was extremely low and that some causes could be corrected by experience, whereas others will require changes in technique or equipment.

Hernia, Inguinal↗
PubMed1998

The interacting effects of prices and weather on population cycles in a preindustrial community.

The exogenous cycles and population dynamics of the community at Penrith, Cumbria, England, have been studied (1557-1812) using aggregative analysis, family reconstitution and time series analysis. This community was living under marginal conditions for the first 200 years and the evidence presented is of a homeostatic regime where famine, malnutrition and epidemic disease acted to regulate the balance between resources and population size. This provides an ideal historic population for an investigation of the direct and indirect effects of malnutrition. Throughout the period studied, a short wavelength oscillation in grain prices was apparently the major external factor that drove exogenous cycles in mortality, birth rate, and migration. In particular, the different responses of children to variations in food supply are emphasised; fluctuations in poor nutrition correlated significantly with the variations in mortality rates for infants (probably indirectly during pregnancy and directly during the first year of life) and for young children (via susceptibility to lethal infectious diseases). Migratory movements contributed to the maintenance of homeostasis in the population dynamics. A medium wavelength cycle in low winter temperatures was associated with a rise in adult mortality which, in turn, promoted an influx of migrants into this saturated habitat. A model incorporating these interacting associations between vital events and exogenous cycles is presented: grain prices were an important density-dependent factor and constituted the major component of the negative feedback of this population and drove the exogenous, short wavelength mortality cycles. Cycles of births and immigration provide a positive feedback for the build-up of susceptibles and the initiation of smallpox epidemics and increased population size.

Commerce↗
PubMed1998

The effects of population density and malnutrition on the dynamics of whooping cough.

Liverpool, a seaport in NW England, suffered severely from lethal infectious diseases in the second half of the 19th century: the population was densely crowded and malnourished and life expectancy was low. Time-series analysis shows that the epidemics of whooping cough (i) had an interepidemic interval of 2.9 years, 1863-85, which lengthened to 3.4 years, 1885-1900 (ii) were strongly coherent with wheat prices (P < 0.001) and (iii) also correlated with cycles of seasonal weather conditions. It is suggested from mathematical modelling that the epidemics in this compromised population were maintained (i.e. the system was driven) by an oscillation of malnutrition and by seasonal weather conditions. A model that incorporates both the dynamics of whooping cough and the demographic characteristics of the population is presented. It has been shown to replicate the dynamics of the epidemics and has been used to predict the changes with time of (i) the force of the infection and (ii) the proportion of those infected with whooping cough who died.

Disease Outbreaks↗
PubMed1998

ATM associates with and phosphorylates p53: mapping the region of interaction.

The human genetic disorder ataxia-telangiectasia (AT) is characterized by immunodeficiency, progressive cerebellar ataxia, radiosensitivity, cell cycle checkpoint defects and cancer predisposition. The gene mutated in this syndrome, ATM (for AT mutated), encodes a protein containing a phosphatidyl-inositol 3-kinase (PI-3 kinase)-like domain. ATM also contains a proline-rich region and a leucine zipper, both of which implicate this protein in signal transduction. The proline-rich region has been shown to bind to the SH3 domain of c-Abl, which facilitates its phosphorylation and activation by ATM. Previous results have demonstrated that AT cells are defective in the G1/S checkpoint activated after radiation damage and that this defect is attributable to a defective p53 signal transduction pathway. We report here direct interaction between ATM and p53 involving two regions in ATM, one at the amino terminus and the other at the carboxy terminus, corresponding to the PI-3 kinase domain. Recombinant ATM protein phosphorylates p53 on serine 15 near the N terminus. Furthermore, ectopic expression of ATM in AT cells restores normal ionizing radiation (IR)-induced phosphorylation of p53, whereas expression of ATM antisense RNA in control cells abrogates the rapid IR-induced phosphorylation of p53 on serine 15. These results demonstrate that ATM can bind p53 directly and is responsible for its serine 15 phosphorylation, thereby contributing to the activation and stabilization of p53 during the IR-induced DNA damage response.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1998

Towards a psycho-social theoretical framework for sexual health promotion.

Numerous interventions have been designed to promote safer sexual behaviour amongst young people. However, relatively few have proved effective, which is, at least partially, due to the lack of development of theoretically based programmes. An understanding of the origins and control of sexual behaviour can be derived from basic social science research. Unless this is applied to the design of behaviour-change programmes they are unlikely to target the most important determinants of young people's sexual behaviour and are, therefore, unlikely to be effective. This paper outlines some of the key theoretical insights which have been drawn upon in the development of a new sex education programme currently being tested in Scottish schools. The theoretical basis is intentionally eclectic, combining social psychological cognitive models with sociological interpretations, since we are not concerned to advance any particular theory but to find which are most useful in promoting sexual health. First, the social influences on sexual behaviour are considered, and then the way in which these translate into individual perceptions and beliefs. Finally, the paper attempts to develop a theoretical understanding of sexual interaction and the social contexts of sexual behaviour.

Adolescent↗