Tamoxifen stimulates arachidonic acid release from rat liver cells by an estrogen receptor-independent, non-genomic mechanism

BACKGROUND: Tamoxifen is widely prescribed for the treatment of breast cancer. Its success has been attributed to the modulation of the estrogen receptor. I have previously proposed that the release of arachidonic acid from cells may also mediate cancer prevention. METHODS: Rat liver cells were radiolabelled with arachidonic acid. The release of [(3)H] arachidonic acid after various times of incubation of the cells with tamoxifen was measured. RESULTS: Tamoxifen, at micromolar concentrations, stimulates arachidonic acid release. The stimulation is rapid and is not affected by pre-incubation of the cells with actinomycin or the estrogen antagonist ICI-182,780. CONCLUSIONS: The stimulation of AA release by tamoxifen is not mediated by estrogen receptor occupancy and is non-genomic

Genome scan of Diabrotica virgifera virgifera for genetic variation associated with crop rotation tolerance

Crop rotation has been a valuable technique for control of Diabrotica virgifera virgifera for almost a century. However, during the last two decades, crop rotation has ceased to be effective in an expanding area of the US corn belt. This failure appears to be due to a change in the insect's oviposition behaviour, which, in all probability, has an underlying genetic basis. A preliminary genome scan using 253 amplified fragment-length polymorphism (AFLP) markers sought to identify genetic variation associated with the circumvention of crop rotation. Samples of D. v. virgifera from east-central Illinois, where crop rotation is ineffective, were compared with samples from Iowa at locations that the behavioural variant has yet to reach. A single AFLP marker showed signs of having been influenced by selection for the circumvention of crop rotation. However, this marker was not diagnostic. The lack of markers strongly associated with the trait may be due to an insufficient density of marker coverage throughout the genome. A weak but significant general heterogeneity was observed between the Illinois and Iowa samples at microsatellite loci and AFLP markers. This has not been detected in previous population genetic studies of D. v. virgifera and may indicate a reduction in gene flow between variant and wild-type beetles

The Effect of Electrode Configuration on the Unipolar His-Bundle Electrogram

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75654/1/j.1540-8159.1989.tb06148.x.pd

Strong Water Absorption in the Dayside Emission Spectrum of the Planet HD 189733b

Recent observations of the extrasolar planet HD 189733b did not reveal the presence of water in the emission spectrum of the planet. Yet models of such 'Hot Jupiter' planets predict an abundance of atmospheric water vapour. Validating and constraining these models is crucial for understanding the physics and chemistry of planetary atmospheres in extreme environments. Indications of the presence of water in the atmosphere of HD 189733b have recently been found in transmission spectra, where the planet's atmosphere selectively absorbs the light of the parent star, and in broadband photometry. Here we report on the detection of strong water absorption in a high signal-to-noise, mid-infrared emission spectrum of the planet itself. We find both a strong downturn in the flux ratio below 10 microns and discrete spectral features that are characteristic of strong absorption by water vapour. The differences between these and previous observations are significant and admit the possibility that predicted planetary-scale dynamical weather structures might alter the emission spectrum over time. Models that match the observed spectrum and the broadband photometry suggest that heat distribution from the dayside to the night side is weak. Reconciling this with the high night side temperature will require a better understanding of atmospheric circulation or possible additional energy sources.Comment: 11 pages, 1 figure, published in Natur

Multiple uncontrolled conditions and blood pressure medication intensification: an observational study

Abstract Background Multiple uncontrolled medical conditions may act as competing demands for clinical decision making. We hypothesized that multiple uncontrolled cardiovascular risk factors would decrease blood pressure (BP) medication intensification among uncontrolled hypertensive patients. Methods We observed 946 encounters at two VA primary care clinics from May through August 2006. After each encounter, clinicians recorded BP medication intensification (BP medication was added or titrated). Demographic, clinical, and laboratory information were collected from the medical record. We examined BP medication intensification by presence and control of diabetes and/or hyperlipidemia. 'Uncontrolled' was defined as hemoglobin A1c ≥ for diabetes, BP ≥ 140/90 mmHg (≥ 130/80 mmHg if diabetes present) for hypertension, and low density lipoprotein cholesterol (LDL-c) ≥ 130 mg/dl (≥ 100 mg/dl if diabetes present) for hyperlipidemia. Hierarchical regression models accounted for patient clustering and adjusted medication intensification for age, systolic BP, and number of medications. Results Among 387 patients with uncontrolled hypertension, 51.4% had diabetes (25.3% were uncontrolled) and 73.4% had hyperlipidemia (22.7% were uncontrolled). The BP medication intensification rate was 34.9% overall, but higher in individuals with uncontrolled diabetes and uncontrolled hyperlipidemia: 52.8% overall and 70.6% if systolic BP ≥ 10 mmHg above goal. Intensification rates were lowest if diabetes or hyperlipidemia were controlled, lower than if diabetes or hyperlipidemia were not present. Multivariable adjustment yielded similar results. Conclusions The presence of uncontrolled diabetes and hyperlipidemia was associated with more guideline-concordant hypertension care, particularly if BP was far from goal. Efforts to understand and improve BP medication intensification in patients with controlled diabetes and/or hyperlipidemia are warranted.http://deepblue.lib.umich.edu/bitstream/2027.42/78266/1/1748-5908-5-55.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78266/2/1748-5908-5-55.pdfPeer Reviewe

A cross-sectional study of depressive symptoms and diabetes self-care in African Americans and Hispanics/Latinos with diabetes: the role of self-efficacy

Purpose The purpose of this study is to examine the relationship between depressive symptoms and diabetes self-care in African American and Hispanic/Latino patients with type 2 diabetes and whether the association, if any, is mediated by diabetes-related self-efficacy. Methods The sample included self-report baseline data of African American and Hispanic/Latino patients with type 2 diabetes who were aged ≥18 years and enrolled in a diabetes self-management intervention study. Depressive symptoms were assessed with the 9-item Patient Health Questionnaire. The Summary of Diabetes Self-care Activities measured engagement in healthy eating, physical activity, blood glucose checking, foot care, and smoking. The Diabetes Empowerment Scale–Short Form assessed diabetes-related psychosocial self-efficacy. Indirect effects were examined with the Baron and Kenny regression technique and Sobel testing. Results Sample characteristics (n = 250) were as follows: mean age of 53 years, 68% women, 54% African American, and 74% with income <$20 000. Depressive symptoms showed a significant inverse association with the self-care domains of general diet, specific diet, physical activity, and glucose monitoring in the African American group. In Hispanics/Latinos, depression was inversely associated with specific diet. Self-efficacy served a significant mediational role in the relation between depression and foot care among African Americans. Conclusions Self-efficacy mediated the relationship between depression and foot care in the African American group but was not found to be a mediator of any self-care areas within the Hispanic/Latino group. In clinical practice, alleviation of depressive symptoms may improve self-care behavior adherence. Diabetes education may consider inclusion of components to build self-efficacy related to diabetes self-care, especially among African American patients

Time-Course Analysis of Cyanobacterium Transcriptome: Detecting Oscillatory Genes

The microarray technique allows the simultaneous measurements of the expression levels of thousands of mRNAs. By mining these data one can identify the dynamics of the gene expression time series. The detection of genes that are periodically expressed is an important step that allows us to study the regulatory mechanisms associated with the circadian cycle. The problem of finding periodicity in biological time series poses many challenges. Such challenge occurs due to the fact that the observed time series usually exhibit non-idealities, such as noise, short length, outliers and unevenly sampled time points. Consequently, the method for finding periodicity should preferably be robust against such anomalies in the data. In this paper, we propose a general and robust procedure for identifying genes with a periodic signature at a given significance level. This identification method is based on autoregressive models and the information theory. By using simulated data we show that the suggested method is capable of identifying rhythmic profiles even in the presence of noise and when the number of data points is small. By recourse of our analysis, we uncover the circadian rhythmic patterns underlying the gene expression profiles from Cyanobacterium Synechocystis

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14&nbsp;weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48&nbsp;weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Clinical course, costs and predictive factors for response to treatment in carpal tunnel syndrome: The PALMS study protocol

Background Carpal tunnel syndrome (CTS) is the most common neuropathy of the upper limb and a significant contributor to hand functional impairment and disability. Effective treatment options include conservative and surgical interventions, however it is not possible at present to predict the outcome of treatment. The primary aim of this study is to identify which baseline clinical factors predict a good outcome from conservative treatment (by injection) or surgery in patients diagnosed with carpal tunnel syndrome. Secondary aims are to describe the clinical course and progression of CTS, and to describe and predict the UK cost of CTS to the individual, National Health Service (NHS) and society over a two year period. Methods/Design In this prospective observational cohort study patients presenting with clinical signs and symptoms typical of CTS and in whom the diagnosis is confirmed by nerve conduction studies are invited to participate. Data on putative predictive factors are collected at baseline and follow-up through patient questionnaires and include standardised measures of symptom severity, hand function, psychological and physical health, comorbidity and quality of life. Resource use and cost over the 2 year period such as prescribed medications, NHS and private healthcare contacts are also collected through patient self-report at 6, 12, 18 and 24 months. The primary outcome used to classify treatment success or failures will be a 5-point global assessment of change. Secondary outcomes include changes in clinical symptoms, functioning, psychological health, quality of life and resource use. A multivariable model of factors which predict outcome and cost will be developed. Discussion This prospective cohort study will provide important data on the clinical course and UK costs of CTS over a two-year period and begin to identify predictive factors for treatment success from conservative and surgical interventions

Engineered artificial antigen presenting cells facilitate direct and efficient expansion of tumor infiltrating lymphocytes

<p>Abstract</p> <p>Background</p> <p>Development of a standardized platform for the rapid expansion of tumor-infiltrating lymphocytes (TILs) with anti-tumor function from patients with limited TIL numbers or tumor tissues challenges their clinical application.</p> <p>Methods</p> <p>To facilitate adoptive immunotherapy, we applied genetically-engineered K562 cell-based artificial antigen presenting cells (aAPCs) for the direct and rapid expansion of TILs isolated from primary cancer specimens.</p> <p>Results</p> <p>TILs outgrown in IL-2 undergo rapid, CD28-independent expansion in response to aAPC stimulation that requires provision of exogenous IL-2 cytokine support. aAPCs induce numerical expansion of TILs that is statistically similar to an established rapid expansion method at a 100-fold lower feeder cell to TIL ratio, and greater than those achievable using anti-CD3/CD28 activation beads or extended IL-2 culture. aAPC-expanded TILs undergo numerical expansion of tumor antigen-specific cells, remain amenable to secondary aAPC-based expansion, and have low CD4/CD8 ratios and FOXP3+ CD4+ cell frequencies. TILs can also be expanded directly from fresh enzyme-digested tumor specimens when pulsed with aAPCs. These "young" TILs are tumor-reactive, positively skewed in CD8+ lymphocyte composition, CD28 and CD27 expression, and contain fewer FOXP3+ T cells compared to parallel IL-2 cultures.</p> <p>Conclusion</p> <p>Genetically-enhanced aAPCs represent a standardized, "off-the-shelf" platform for the direct ex vivo expansion of TILs of suitable number, phenotype and function for use in adoptive immunotherapy.</p