SEARCH · Search PubMed
Results for “In re Eric B.”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.
The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.
Increase of B cell-activating factor of the TNF family (BAFF) after rituximab treatment: insights into a new regulating system of BAFF production.
BACKGROUND: The cytokine B cell-activating factor of the TNF family (BAFF) is involved in the pathogenesis of autoimmune diseases. OBJECTIVE: To access changes in serum protein and mRNA levels of BAFF after rituximab treatment. METHODS: Serum and peripheral blood mononuclear cells (PBMCs) were isolated from five patients (two with lupus, two with Sjögren's syndrome, one with rheumatoid arthritis) before and 12 weeks (range 7-17) after a first course of rituximab infusion. Monocytes and B cells were selected from healthy controls and cocultured for 72 h. BAFF protein and mRNA levels were assessed by ELISA and real-time PCR, respectively. RESULTS: After rituximab treatment, median serum BAFF protein level and BAFF to actin mRNA ratio in PBMCs significantly increased. In monocytes cocultured with autologous B cells, BAFF protein level decreased, whereas the mRNA level was stable. In one closely monitored patient, the mRNA ratio of BAFF to actin in PBMCs increased later than the BAFF serum level. CONCLUSIONS: Two distinct mechanisms are probably involved in the increase in BAFF level after B cell depletion: (1) the decrease in its receptors leading to a release of BAFF; (2) a delayed regulation of BAFF mRNA transcription. This could favour the re-emergence of autoreactive B cells.
Mediator effects in the social development model: an examination of constituent theories.
BACKGROUND: The social development model (SDM) provides an explanatory framework for the progression of antisocial behaviour in children and adolescents. Although previous research has assessed the predictive validity of the model, alternative associations based on the SDM's constituent theories have not been examined. METHOD: Using structural equation modelling, a series of direct paths was examined for mediation by SDM constructs. Data for the study consisted of teacher-, parent- and self-report of 1016 fourth- and fifth-grade students from the Raising Healthy Children project, a longitudinal etiological study with an embedded preventive intervention. RESULTS: Four of the seven paths examined were partially or totally mediated by SDM constructs. Specifically, the relationship between prosocial bonding and adolescent antisocial behaviour, as hypothesized by social control theory, was fully mediated by prosocial beliefs. As hypothesized by social learning theory, students' socioemotional and cognitive skills significantly predicted antisocial behaviour, independent of partial mediation through rewards, bonding and beliefs. As hypothesized by differential association theory, involvement with both prosocial and antisocial persons was directly associated with respective prosocial and antisocial beliefs, independent of partial mediation through rewards and bonding. CONCLUSIONS: These findings suggest additional associations that are not currently specified in the SDM and underscore the importance of re-examining hypotheses from constituent theories when integrating developmental models of antisocial behaviour.
Re: Chronic lymphocytic leukemia resembling metastatic bone disease.
Explore the source record for details and available documents.
Increasing external beam dose for T1-T2 prostate cancer: effect on risk groups.
PURPOSE: The aim of this study was to investigate effect of increasing dose on risk groups for clinical failure (CF: local failure or distant failure or hormone ablation or PSA>or=25 ng/ml) in patients with T1-T2 prostate cancer treated with external beam radiotherapy. METHODS AND MATERIALS: Patients (n=4,537) were partitioned into nonoverlapping dose ranges, each narrow enough that dose was not a predictor of CF, and risk groups for CF were determined using recursive partitioning analysis (RPA). The same technique was applied to the highest of these dose ranges (70-76 Gy, 1,136 patients) to compare risk groups for CF in this dose range with the conventional risk-group classification. RESULTS: Cutpoints defining low-risk groups in each dose range shifted to higher initial PSA levels and Gleason scores with increasing dose. Risk groups for CF in the dose range 70-76 Gy were not consistent with conventional risk groups. CONCLUSIONS: The conventional classification of risk groups was derived in the early PSA era, when total doses<70 Gy were common, and it is inconsistent with risk groups for patients treated to doses>70 Gy. Risk-group classifications must be continuously re-examined whenever the trend is toward increasing total dose.
Abnormal frequency-dependent responses represent the pathophysiologic signature of contractile failure in human myocardium.
BACKGROUND: - The normal increase in isometric developed force (DF) with faster pacing rates, known as the positive force-frequency response/relationship (FFR), is altered in failing myocardium, as shown by its negative response to increased pacing. The objective of this study was to determine if increasing Ca2+ influx with L-type Ca2+ channel (L-CaCh) agonists: BayK 8644 (BayK) and FPL 64176 (FPL) or increased extracellular Ca2+ could increase contractility and normalize the FFR in failing myocardium. METHODS: - Isometric DF was measured in right ventricular trabeculae from failing (n = 28) and non-failing (n = 12) human hearts at various stimulation frequencies (0.5-2.5 Hz) before and after bath application of BayK (250 nM), FPL (100 nM), or high Ca2+ (7.0 mM). Post-rest (PR) experiments were also conducted on several trabeculae. RESULTS: - In trabeculae from failing hearts, the DF decreased with an increase in pacing. Addition of L-CaCh agonists increased DF to similar levels in trabeculae from both failing and non-failing hearts at slow pacing rates, but did not alter the negative FFR in the failing group. During increased rest intervals, the amount of PR potentiation was diminished in trabeculae from failing hearts as compared to the non-failing preparations. CONCLUSION: - This study demonstrates that the abnormal FFR observed in trabeculae from failing hearts is a reliable physiologic signature of the cardiomyopathic state even when DF, at slow stimulation frequencies, is relatively high. These studies further demonstrate that the impaired FFR is not due to an inability to further increase contractility. Rather, our findings suggest that the abnormal FFR and blunted PR potentiation alike are a reflection of an altered functional balance between Ca2+ re-uptake and Ca2+ extrusion.
Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy.
BACKGROUND: Myocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy. METHODS: We studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography. FINDINGS: Stem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7.2 [SD 3.4] vs 33.2 [6.0] cells/mm2, n=4 per group, p<0.02) resulting in greater left-ventricular mass (1.24 [0.29] vs 1.57 [0.27] g) and better cardiac function (shortening fraction 9.2 [4.9] vs 17.2 [4.2]%, n=8 per group, p<0.05). INTERPRETATION: These findings show that SDF-1 is sufficient to induce therapeutic stem-cell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is re-established.
Direct thrombin inhibitors in acute coronary syndromes: effect in patients undergoing early percutaneous coronary intervention.
AIMS: We evaluated the effect of direct thrombin inhibitors (DTIs) in patients undergoing early percutaneous coronary intervention (PCI), using the DTI Trialists' Collaboration database of 35,970 patients from 11 randomized trials of DTIs vs. heparin. METHODS AND RESULTS: We performed a Cox proportional hazards regression analysis with PCI as a time-dependent covariate to assess the independent impact of DTIs according to the performance of early PCI. PCI was performed in 7049 patients in the first 72 h after randomization. In trials in which PCI was not planned, DTIs were associated with a 10% relative risk reduction in death or myocardial infarction at 30 days (HR=0.90, 95% CI: 0.84-0.97). This benefit was found to be greater in patients undergoing early PCI (HR=0.66, 95% CI: 0.48-0.91) than those undergoing non-early PCI (HR=0.94, 95% CI: 0.86-1.03). After adjustment for baseline characteristics and propensity to undergo PCI, the risk of death or myocardial infarction remained lower with DTI (HR=0.62, 95% CI: 0.44-0.89). CONCLUSION: After adjustment for baseline differences and propensity to undergo early PCI, DTIs appeared to be more effective than heparin in reducing death or re-infarction among patients undergoing early PCI.
Production, purification and preliminary X-ray crystallographic studies of adeno-associated virus serotype 4.
Adeno-associated virus (AAV) serotypes 1 to 5 are currently under development as clinical gene delivery vectors for the treatment of human diseases. However, the ubiquitous nature of their cell surface receptors, heparin sulfate (AAV2 and 3) and sialic acids (AAV4 and 5), can preclude specific tissue targeting in vivo. Structural studies of AAV4 were initiated to characterize its capsid surface for re-targeting manipulations. Crystals obtained diffracted synchrotron radiation to 3.2 A resolution. The unit cell is body-centered orthorhombic, I222, with a = 339.6, b = 319.2 and c = 285.0 A. The virus particle orientation and position have been determined.
Autologous cytomegalovirus-specific T cells as effector cells in immunotherapy of B cell chronic lymphocytic leukaemia.
B-cell chronic lymphocytic leukaemia (B-CLL) cells express low levels of co-stimulatory molecules and therefore fail to induce activation and differentiation of tumour-specific T cells. We have shown that patients with B-CLL have considerably expanded numbers of cytomegalovirus (CMV) reactive CD8(+) T cells. This study demonstrated that B-CLL cells loaded with CMV peptide not only promoted the ex vivo expansion of autologous, in vivo-generated virus-specific T cells, but also constituted excellent target cells for these cytotoxic T cells, even without ex vivo re-stimulation. Directing virus-specific T cells to B-CLL may overcome the inadequate immunostimulatory capacity of these cells, which could be exploited for T-cell mediated immunotherapy.
Re: Prognostic significance of a short sequence insertion in the MCL-1 promoter in chronic lymphocytic leukemia.
Explore the source record for details and available documents.
Commentary re: N. J. McCarthy et al., microvessel density, expression of estrogen receptor alpha, MIB-1, p53 and c-erbB-2 in inflammatory breast cancer. Clin. Cancer Res., 8: 3857-3862, 2002.
Explore the source record for details and available documents.
Can cervical cancer screening be stopped at 50? The prevalence of HPV in elderly women.
Although the relation between cervical cancer and the human papillomavirus (HPV) has been established beyond doubt, the introduction of HPV detection in cervical cancer screening is halted, primarily by the high rate of false positivity in relation to morbidity, since the majority of women infected with HPV will not develop lesions. To counteract overconsumption of cervical cancer screening in elderly women, we wanted to test the hypothesis that women of 50 years or older who are HPV-negative and have a cytologically normal smear might be encouraged to refrain from further screening. As a first step, the prevalence of high-risk HPV in a population of 1,936 women of 50 years and older was investigated. After an initial decline, a slightly higher prevalence can be seen with increasing age. There is a decrease in the prevalence of multiple infections with age, paralleled by an increase in single infections, especially of HPV type 16 in the eldest-age group. However, neither the decrease in multiple infections nor the increase in single infections is statistically significant. The data obtained in this study show that, even in the presence of a slight increase in the HPV prevalence in elderly women, approximately 94% of the elderly women can be withdrawn from the cervical cancer screening. However, a follow-up study will be necessary to determine the frequency of (re)infection as well as the course of an HPV infection in elderly women.
Type and position of repeat interruptions as determinants of disease severity and expansion size in Friedreich ataxia.
PURPOSE: In Friedreich ataxia (FRDA) the size of the smaller GAA expansion is a major determinant of disease severity; interruption motifs were identified after the discovery of the pathogenic expansions; however, their impact is only recently investigated. METHODS: 164 patients with FRDA with biallelic expansions and 15 patients without FRDA were analyzed for interruption(s) number, position, and motif. Expansion size and age at onset of ataxia (AAO) were determined for patients with FRDA. RESULTS: Three groups of patients with FRDA were identified by the simultaneous analysis of the precise distance ("depth") between the interruptions (mostly nontriplet) and the 3' end of the expansion (P < .001), the smaller expansion size (P < .001), and AAO (P < .001). Classical FRDA corresponds to absence of interruption or interruption depth < 8 repeats, with AAO often <15 years (area under the curve [AUC] = 0.90; 95% CI, 0.84-0.96); LOFA to interruption depth of 8 to 18 repeats (AUC = 0.97; 95% CI, 0.94-1), with AAO 15 to 34 years (AUC = 1; 95% CI, 1-1); and vLOFA to interruption depth > 18 (AUC = 0.97; 95% CI, 0.92-1), with AAO > 34 years. Multiple (>5) triplet interruptions hamper further expansion. CONCLUSION: This study provides the molecular basis for a novel classification of FRDA that should be recommended for correct diagnosis.
Potential of ancestral sylvatic dengue-2 viruses to re-emerge.
Dengue viruses (DENV) are the most important arboviral pathogens in tropical and subtropical regions throughout the world. DENV transmission includes both a sylvatic, enzootic cycle between nonhuman primates and arboreal mosquitoes of the genus Aedes, and an urban, endemic/epidemic cycle between Aedes aegypti, a mosquito with larval development in peridomestic water containers, and human reservoir hosts. All 4 serotypes of endemic DENV evolved independently from ancestral sylvatic viruses and have become both ecologically and evolutionarily distinct; this process may have involved adaptation to (i) peridomestic mosquito vectors and/or (ii) human reservoir hosts. To test the latter hypothesis, we assessed the ability of sylvatic and endemic DENV-2 strains, representing major genotypes from Southeast Asia, West Africa and the Americas, to replicate in two surrogate human model hosts: monocyte-derived, human dendritic cells (moDCs), and mice engrafted with human hepatoma cells. Although the various DENV-2 strains showed significant inter-strain variation in mean replication titers in both models, no overall difference between sylvatic and endemic strains was detected in either model. Our findings suggest that emergence of endemic DENV strains from ancestral sylvatic strains may not have required adaptation to replicate more efficiently in human reservoir hosts, implying that the potential for re-emergence of sylvatic dengue strains into the endemic cycle is high. The shared replication profiles of the American endemic and sylvatic strains suggest that American strains have maintained or regained the ancestral phenotype.
Not Forgotten: Patient Experiences with Genetic Variant Reclassifications.
PURPOSE: Genetic variant reclassification is increasingly common in clinical genomics, yet limited data describe how patients experience re-contact and variant reclassification in routine clinical care. METHODS: We conducted semi-structured qualitative interviews with 20 adult patients who received a variant reclassification following routine clinical genetic testing. Interviews explored emotional responses, communication experiences, and perceived value of genetic testing. Data were analyzed using Template Analysis, a form of thematic analysis. RESULTS: Three overarching themes were identified. Participants identified a need for improved communication of reclassified results, particularly with respect to timing, modality, and contextualization (Theme 1). Experiences with reclassification also shaped perceptions of the value of genetic testing, with most participants viewing testing as worthwhile despite its evolving nature (Theme 2). Finally, many participants interpreted reclassification as evidence of personalized and ongoing care, reinforcing trust in genetic testing and biomedical research (Theme 3). Participants generally preferred to be informed of reclassified results regardless of reclassification type, although the direction of reclassification influenced emotional responses and preferred modes of communication. Downgrades from variants of uncertain significance to benign or likely benign were widely viewed as meaningful by participants. CONCLUSION: Variant reclassification was experienced as a signal of personalized, ongoing care. Timely, contextualized, patient-centered re-contact practices may reduce uncertainty, strengthen trust, and help patients not feel forgotten.
Usefulness of genetic typing methods to trace epidemiologically Salmonella serotype Ohio.
Different genetic typing procedures were applied in an epidemiological study of Salmonella serotype Ohio. Isolates that generated identical DNA fingerprints (HinclI ribotypes, ERIC and RAPD profiles) were clustered into the same lineage, and the addition of data from plasmid, integron and resistance profiles was used to differentiate types. Results led to the determination of the endemic and the emergent epidemic types at specific times, and to ascertain the clinical and epidemiological impact of each type. In the series analysed (47 clinical isolates and 3 non-clinical isolates) 11 lineages and 32 types were found. Two lineages were considered prevalent and endemic, and during an epidemiological alert (Spain, 1998) a re-emergence and spread of organisms mainly from the most frequent lineage had occurred. The combination of H-ribotype with ERIC profile, as primary markers, and resistance profile with plasmid profile, as secondary markers, was shown to be the most useful tool to trace epidemiologically Ohio.