Congressional Committee explores alternative medicine and women's cancers.
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Breast Neoplasms↗
Biomedical subjects
S Erickson
Publications and source records attributed to S Erickson.
Molecular mechanisms underlying interferon-alpha-induced G0/G1 arrest: CKI-mediated regulation of G1 Cdk-complexes and activation of pocket proteins.
One prominent effect of IFNs is their cell growth-inhibitory activity. The mechanism behind this inhibition of proliferation is still not fully understood. In this study, the effect of IFN-alpha treatment on cell cycle progression has been analysed in three lymphoid cell lines, Daudi, U-266 and H9. Examination of the growth-arrested cell populations shows that Daudi cells accumulate in a G0-like state, whereas U-266 cells arrest later in G1. H9 cells are completely resistant to IFN-alpha's cell growth-inhibitory effects. The G0/G1-phase arrest is preceded by a rapid induction of the cyclin-dependent kinase inhibitors (CKIs), p21 and p15. In parallel, the activities of the G1 Cdks are significantly reduced. In addition to p21/p15 induction, IFN-alpha regulates the expression of another CKI, p27, presumably by a post-transcriptional mechanism. In the G1 Cdk-complexes, there is first an increased binding of p21 and p15 to their respective kinases. At longer exposure times, when Cdk-bound p15 and p21 decline, p27 starts to accumulate. Furthermore, we found that IFN-alpha not only suppresses the phosphorylation of pRb, but also alters the phosphorylation and expression of the other pocket proteins p130 and p107. These data suggest that induction of p21/p15 is involved in the primary IFN-alpha response inhibiting G1 Cdk activity, whereas increased p27 expression is part of a second set of events which keep these Cdks in their inactive form. Moreover, elevated levels of p27 correlated with a dissociation of cyclin E/Cdk2-p130 or p107 complexes to yield cyclin E/Cdk2-p27 complexes. In resistant H9 cells, which possess a homozygous deletion of the p15/p16 genes and lack p21 protein expression, IFN-alpha causes no detectable changes in p27 expression and, furthermore, no effects are observed on either pocket proteins in this cell line. Taken together, these data suggest that the early decline in G1 Cdk activity, subsequent changes in phosphorylation of pocket proteins, and G1/G0 arrest following IFN-alpha treatment, is not primarily due to loss of the G1 kinase components, but result from the inhibitory action of CKIs on these complexes.
Burkitt Lymphoma↗
Simultaneous identification of medial and lateral bucket-handle tears: the Jack and Jill lesion.
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Adult↗
Interferon-alpha inhibits proliferation in human T lymphocytes by abrogation of interleukin 2-induced changes in cell cycle-regulatory proteins.
IFN-alpha exerts prominent regulatory functions on the immune system. One such effect is the inhibition of proliferation of in vitro stimulated T lymphocytes. The exact physiological function of this activity is not known, but it has been implicated in the antiviral effects of IFN, its antitumor action in T-cell malignancies, and the regulation of the in vivo T-cell response. Here, we have investigated the mechanism underlying the IFN-alpha-mediated growth inhibition of normal human PHA- and IL-2-stimulated T lymphocytes by an analysis of how IFN-alpha treatment influences known molecular events that normally accompany the transition from quiescence to proliferation in these cells. IFN-alpha treatment was found to profoundly block S-phase entry of stimulated T lymphocytes. This correlated with a strong inhibition of IL-2-induced changes in G1-regulatory proteins, including the prevented up-regulation of G1 cyclins and cyclin-dependent kinases as well as an abrogation of mitogen-induced reduction of p27Kip1 levels. This latter effect was due to a maintained stability of the p27Kip1 protein in the IFN-alpha-treated cells. In line with these findings, phosphorylation of the pocket proteins was abrogated in IFN-alpha-treated cells. Furthermore, our data indicate that IFN-alpha has selective effects on the pathways that emerge from the IL-2 receptor because IFN-alpha treatment does not block IL-2-induced up-regulation of c-myc or Cdc25A.
Blotting, Northern↗
Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence.
Little is known about the molecular background to senescence in T-lymphocytes. In fibroblast systems replicative senescence has been shown to correlate with a number of changes in the expression of the proteins normally regulating progression through the G1 phase of the cell cycle, and recently the Ink4 inhibitor p16 was implicated as a central regulator of replicative senescence in human fibroblasts. It has, however, been claimed that p16 is not expressed in T-lymphocytes. In the present study we have analysed G1 regulating proteins in ageing human T-lymphocytes. We show that PHA and IL-2 stimulated T-lymphocytes cease to proliferate after around 20 population doublings, these cells can not thereafter be restimulated to growth, and were also found to exhibit markers for senescence. We found that T-lymphocytes accumulate p16 and p15 protein during successive population doublings and display high levels of these proteins as they enter into replicative senescence. There was also an increased binding of p16 to the Cdk6 kinase in senescent cells, and a decreased Cdk6 as well as Cdk2 kinase activity. The levels of other G1 regulating proteins were also altered in the senescent cells, such as slightly elevated levels of p21/WAF1, and downregulation of Cdk2 and cyclinD3. The levels of p27/ Kip1 is down regulated in proliferating cells but rise to approximately 15% of the levels in un-stimulated quiescent cells. As a high proportion of T-cell childhood acute lymphoblastic leukaemias have deletions of both p15 and p16, our data suggest that inactivation of these genes makes it possible for leukemic cells to avoid senescence.
CD28 Antigens↗
Evaluation of the gemini infusion pump for the safe delivery of peripheral blood progenitor cells (stem cells).
The purpose of this in vitro study was to determine whether the Gemini PC-2TX infusion pump could safely deliver peripheral stem cells (PSC) for an autologous PSC transplant. For purposes of hypothesis testing, it was assumed that there would be no significant difference in CD34+ cell counts and colony-forming units-granulocyte, macrophage (CFU-GM) when the PSCs were administered by an IMED PC-2TX infusion pump as opposed to an intravenous push method. The American Red Cross collected 50-ml samples of PSCs from four donors by apheresis. These cells were tested for CD34+ using flow cytometry and for functional progenitor cells using a CFU-GM assay. The cells were cryopreserved after testing. For our study, samples were tested simultaneously at a single facility. Each sample was individually thawed and a baseline thaw sample collected; 10 ml of the donor specimen was pushed through a syringe into a specimen container (intravenous push sample). The remainder of the specimen was infused through the IMED Gemini PC-2TX pump into a specimen container (intravenous pump sample). All samples were assayed for CD34+ cell counts and CFU-GM. Data analyses were conducted using the t-test for paired samples, with values of P < 0.05 considered significant. Results failed to demonstrate a statistically significant difference between the CD34+ or CFU-GM results of the intravenous push and intravenous pump specimens. Additionally, we failed to find a statistically significant difference when we compared the intravenous push and the intravenous pump specimens with the baseline thaw sample. The results of this study support the hypothesis that the Gemini PC-2TX infusion pump can safely deliver PSCs for the purposes of stem cell transplantation.
Antigens, CD34↗
The impact of an individual tutorial session on MEDLINE use among obstetrics and gynaecology residents in an academic training programme: a randomized trial.
Over the past decade, on-line databases have become increasingly popular among health care professionals. As a group, these 'end-users' report utilizing databases to keep abreast of medical progress, to conduct research and to address specific patient care issues. Throughout the literature, medical professionals ('content experts') have proved to be less effective searchers than librarians ('search experts'). The potential implications of this discrepancy are worrysome. For any given clinical scenario, for example, published reports may reach contradictory conclusions. A poorly skilled searcher may not retrieve enough articles to appreciate this fact. Optimizing searching skills is therefore a worthwhile goal. As a first step, many medical schools introduce students to on-line databases, most notably MEDLINE. Residency is an ideal time to continue this training. A recognized obstacle to provide residents with formal MEDLINE instruction is time constraint. We therefore conducted this study to ascertain the impact an individual 1-hour tutorial session would have on MEDLINE utilization among obstetrics and gynecology residents training at an academic medical centre. Outcome measures included MEDLINE search frequency, duration, recall, precision and searcher satisfaction. Search recall measures the searcher's ability to retrieve articles deemed relevant to the question at hand. Search precision gauges the searchers' ability to eliminate irrelevant articles. Although the sessions were well received, we were unable to demonstrate an improvement in the outcome measures analysed. Further research is therefore indicated so that cost-effective educational strategies can be recommended for wide-scale use.
Double-Blind Method↗
Osseous anatomy of the pterygopalatine fossa.
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Diagnostic Imaging↗
Induction of Cip/Kip and Ink4 cyclin dependent kinase inhibitors by interferon-alpha in hematopoietic cell lines.
One prominent effect of IFNs is their cell growth inhibitory activity. The exact molecular mechanism behind this inhibition of proliferation remains to be elucidated. Possible effectors for IFN-induced growth inhibition are the recently discovered cyclin-dependent kinase inhibitors. The effect of IFN-alpha treatment on the members of the Ink4 and Cip/Kip families of Cdk inhibitors was investigated in three hematopoietic cell lines Daudi, U-266 and H9. Two of these cell lines, Daudi and U-266, respond to IFN-alpha by G1 arrest, whereas the H9 cell line is not growth arrested by IFN-alpha. We show that a p53-independent upregulation of p21 mRNA occurs following IFN-alpha treatment in all three cell lines. In Daudi and U-266 cells, the mRNA induction is accompanied by an increase in p21 protein, followed by an increased binding of p21 to Cdk2 and a subsequent decrease in Cdk2 activity, temporally coinciding with G1 arrest. In both these cell lines, there was also an increased binding of p21 to Cdk4. In contrast, p21 protein was not expressed in H9 cells, despite high levels of p21 mRNA following IFN-alpha treatment. In U-266 cells, IFN-alpha increased not only p21 but also p15 mRNA and protein levels, followed by an increased association of p15 with Cdk4. Furthermore, IFN-alpha treatment caused a four- to sixfold induction of the p16 E1beta transcript in U-266 cells. Expression levels of the other Ink4 and Cip/Kip Cdk inhibitors were not induced by IFN treatment in any of the cell lines. We conclude that IFN-alpha can act as a potent regulator of Cdk-inhibitor expression, correlating with decreased Cdk activity and cell growth inhibition. One mechanism for resistance to IFN may be loss of the ability of cells to upregulate these proteins.
Blood Proteins↗
Defense reactions and coping strategies in normal adolescents.
In exploring the relationship between defense reactions and coping strategies in a non-clinic sample of adolescents (N = 81), we assessed: defense structure by the Bond Defense Style Questionnaire (DSQ); coping behaviors by the Coping Responses Inventory-Youth Form (CRI-Youth); and general adjustment by Global Assessment of Functioning (GAF) ratings. Defense reactions and coping strategies were modestly associated and made independent contributions in predicting the GAF. Mature and immature defenses and avoidance coping comprised the optimal combination in predicting the GAF, accounting for 20% of GAF variance. It is therefore important to assess both unconscious and conscious processes when assessing general functioning in normal adolescents.
Adaptation, Psychological↗
Managed care and the cystic fibrosis patient.
Since the first published report of mortality in cystic fibrosis in 1969, the median survival among cystic fibrosis patients has risen from 14 to 31 years. The reasons for this improved survival are complex and include earlier diagnosis; improved control of pulmonary infection; aggressive nutritional intervention; and enhanced monitoring of patients in peer-reviewed, accredited centers for cystic fibrosis care, teaching, and research. Emphasis on the importance of research on changing and improved treatment has been effectively communicated to patients and families. As a result, a group of highly educated medical consumers has been created. During the last decade, another focus of rapid change has appeared, that of cost containment in the medical profession, creating the field of managed care. Practicing medical professionals perceive the need for reduction in excessive spending in medicine and have taken a variety of approaches to balance better the value and cost of medical care while maintaining superb quality. Physicians and consumers continue to have concerns about the potential negative impact of managed care on a relatively rare, specialized, and chronic illness such as cystic fibrosis if managed care concepts are applied without proper understanding of the disease. A great concern is that managed care in cystic fibrosis may cause reversal of trends in improved quality and length of survival. The increased length of survival places an increasing demand on the already stressed system of health care financing. Understanding the changing area of managed care is therefore of paramount importance to clinicians involved in cystic fibrosis care. The Cystic Fibrosis Foundation has presented symposia on managed care at each of the last three annual meetings, including the North American Cystic Fibrosis Meeting, October 1996. The following issues were addressed by speakers and panel discussants, with portions excerpted for this review: trends in managed care, measures and guidelines useful in managed care, Medicaid managed care and cystic fibrosis, and practical aspects of using pathways in caring for patients with cystic fibrosis.
Critical Pathways↗
How does interferon exert its cell growth inhibitory effect?
The interferons (IFNs) have become accepted therapy in a range of haematological and non-haematological malignancies. The mechanism behind IFN's antitumour action is, however, unclear. Interferons (IFNs) are capable of modulating a variety of cellular responses. One prominent effect of IFNs is their cell growth inhibitory activity, which has also been suggested to be of major importance in their antitumour action. In the present review we will discuss the cellular events leading to a decreased number of cells following IFN treatment, the molecular mechanisms underlying these phenomena, and the importance of these effects in a clinical perspective.
Apoptosis↗
Induction of apoptosis and inhibition of cell growth are independent responses to interferon-alpha in hematopoietic cell lines.
IFNs are capable of modulating a variety of cellular responses, including cell growth and apoptosis. The prospective connections between these two biological responses are not fully understood, and the molecular mechanisms underlying the effects of IFNs on these processes are not completely defined. We have investigated the relationship between IFN-alpha-induced apoptosis and cell cycle arrest in three hematopoietic cell lines, Daudi, U-266, and H9. It was found that IFN-alpha was a rapid and potent inducer of apoptosis in H9 and U-266 cells, whereas IFN-alpha-induced cell cycle arrest in Daudi cells is not associated with the onset of apoptosis. In H9 cells, apoptosis occurs without a preceding cell cycle block, whereas in U-266 cells, apoptosis occurs subsequent to G1 arrest. Cell cycle arrest per se, induced by serum starvation or treatment with aphidicolin, had only minor effects on the viability of these cell lines and did not abrogate the apoptosis-inducing capacity of IFN-alpha. Additionally, IFN-alpha-induced apoptosis occurred in cells from all cell cycle phases. Thus, we conclude that IFN-alpha-induced apoptosis seems to occur independent of cell growth inhibition. There were no changes in Bcl-2 or Bax protein levels that could account for the apoptosis-inducing effects of IFN-alpha in these cell lines. Moreover, examination of p53 status suggests that IFN-alpha-induced apoptosis in the U-266 and H9 cell lines occurs through a p53-independent pathway.
Apoptosis↗
Clinical pathways and case management in anesthesia practice: new tools and systems for the evolving healthcare environment.
Clinical care pathways and case management are strategies utilized by increasing numbers of hospitals to meet the challenges of capitated reimbursement and managed care. A clinical pathway is an outcome-focused tool used to define a multidisciplinary plan of care. A case manager coordinates patient care across an episode of illness or hospitalization. These tools and systems have great potential for use by nurse anesthetists in ensuring that high-quality anesthesia care is delivered in a cost-effective manner.
Anesthesia↗
Magnetic resonance imaging scanning in the diagnosis of zone II flexor tendon rupture.
This study was undertaken to determine the usefulness of magnetic resonance imaging (MRI) in the diagnosis of flexor tendon rupture in patients who had prior surgery. Magnetic resonance imaging scans were performed on 11 digits (16 tendons) with the clinical diagnosis of flexor tendon rupture. Clinical suspicion correlated with MRI and surgical findings. Clinical examination yielded a 60% accuracy in diagnosis. MRI differentiated rupture from adhesions with a 100% accuracy rate. The MRI scan is a valuable tool in diagnosing tendon ruptures and may help reduce the incidence of unnecessary tendon explorations.
Adolescent↗
Role transition: from clinical nurse specialist to clinical nurse specialist/case manager.
Changes in the healthcare environment provide the impetus to look closely at the way in which patient care is delivered. Complex health problems, requiring the expertise of multiple healthcare specialists, coupled with complex hospital systems, result in fragmented care that is confusing to patients and their families. Case management by nurses working closely with physicians in hospitals is one strategy that can reduce fragmentation of care. Case management also facilitates the delivery of cost-effective patient-focused care. Because of his her expertise, the clinical nurse specialist (CNS) is an ideal choice for the role of case manager. The authors describe the role transition of nurses from CNS to CNS case manager over a 2-year period and identify the key system supports required to ensure successful evolution into this expanded role.
Career Mobility↗
In vitro propagated dendritic cells from prostate cancer patients as a component of prostate cancer immunotherapy.
T cell-mediated cancer immunotherapy requires efficient antigen-presenting cells. Dendritic cells (DCs) are arguably the most efficient antigen-presenting cells studied to date. Individuals with prostate cancer often undergo various therapies which may compromise their immune system, including the state of their DC precursors. We report the in vitro propagation of DCs from peripheral blood of patients with prostate cancer, most of whom are in clinical stages D1 or D2 and have undergone radiation therapy. After 7 days in culture, the number of DCs recovered were 20-50-fold higher than those isolated directly from peripheral blood. This number is comparable to findings of previous studies with healthy individuals. Cultured patients' DCs were capable of presenting tetanus toxoid to autologous T cells in vitro. Furthermore, T cells from 2 of 4 patients proliferated when cultured with their DCs and the lysate of a human prostate cancer cell line (LNCaP), demonstrating the potential role of autologous DCs in prostate cancer immunotherapy studies.
Aged↗
Potential diagnostic implications of breakpoints in the long arm of chromosome 8 in lipoblastoma.
We report a case of lipoblastoma in a 17-month-old male patient with a pseudodiploid karyotype of 46,XY,der(14)t(8;14)(q11.2;q24). The tumor cells show two normal chromosome 8 homologs in addition to the extra 8q11.2-->qter segment, making it trisomic for the region 8q11.2-->qter, and monosomic for 14q24-->qter. Reports of chromosome studies in lipoblastoma are rare; however, a breakpoint in the long arm of chromosome 8q11-13 appears to be emerging as a consistent finding.
Chromosome Aberrations↗