Immunoregulatory effects of AFP domains on monocyte-derived dendritic cell function

<p>Abstract</p> <p>Background</p> <p>Alpha-fetoprotein (AFP) is a tumor-associated glycoprotein that functions in regulation of both ontogenic and oncogenic growth. Recent study showed that AFP can induce apoptosis or impair monocyte-derived dendritic cell (MDDC) function. However, it is still unclear which AFP domain (D-AFP) plays major role in this function.</p> <p>Results</p> <p>As expected monocytes cultured in the presence of Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) and Interleukin-4 (IL-4) developed into MDDC. Up-regulation of HLA-DR and CD11c as well as loss of CD14 molecules could be observed. Full length AFP (FL-AFP), domain 2 AFP (D2-AFP) and D3-AFP, but not D1-AFP, significantly inhibited the expression of HLA-DR^high/CD11c^highand CD80⁺/CD86^highmolecules. In contrast, CD83 expression was substantially down-regulated in all samples. Expression of CD40 was significantly suppressed by FL-AFP but not by any D-AFPs. Finally, both FL-AFP and D-AFP impaired the MDDC ability to secrete IL-12 (p70).</p> <p>Conclusions</p> <p>D2- and D3- but not D1-AFP extensively suppresses the MDDC function. All the recombinant AFP proteins impaired the ability of MDDC to secrete IL-12.</p

Constraining the Nature of Dark Energy using the SKA

We investigate the potential of the Square Kilometer Array Telescope (SKA) to constrain the sound speed of dark energy. The Integrated Sachs Wolfe (ISW) effect results in a significant power spectrum signal when CMB temperature anisotropies are cross-correlated with galaxies detectable with the SKA in HI. We consider using this measurement, the autocorrelation of HI galaxies and the CMB temperature power spectrum to derive constraints on the sound speed. We study the contributions to the cross-correlation signal made by galaxies at different redshifts and use redshift tomography to improve the signal-to-noise. We use a chi-square analysis to estimate the significance of detecting a sound speed different from that expected in quintessence models, finding that there is potential to distinguish very low sound speeds from the quintessence value.Comment: 8 pages, 8 figures; updated references for publication MNRA

Identifying paediatric nursing-sensitive outcomes in linked administrative health data

There is increasing interest in the contribution of the quality of nursing care to patient outcomes. Due to different casemix and risk profiles, algorithms for administrative health data that identify nursing-sensitive outcomes in adult hospitalised patients may not be applicable to paediatric patients. The study purpose was to test adult algorithms in a paediatric hospital population and make amendments to increase the accuracy of identification of hospital acquitted events. The study also aimed to determine whether the use of linked hospital records improved the likelihood of correctly identifying patient outcomes as nursing sensitive rather than being related to their pre-morbid conditions. Algorithm for nursing-sensitive outcomes used in adult populations have to be amended before application to paediatric populations. Using unlinked individual hospitalisation records to estimate rates of nursing-sensitive outcomes is likely to result in inaccurate rates

Convergent Evidence from Mouse and Human Studies Suggests the Involvement of Zinc Finger Protein 326 Gene in Antidepressant Treatment Response

OBJECTIVES: The forced swim test (FST) is a commonly used model to predict antidepressant efficacy. Uncovering the genetic basis of the model may unravel the mechanism of antidepressant treatment. METHODS: FVB/NJ (FVB) and C57BL/6J (B6) were first identified as the response and non-response strains to fluoxetine (a serotonin-specific reuptake inhibitor antidepressant) treatment in the mouse FST. Simple-interval (SIM) and composite-interval (CIM) mappings were applied to map the quantitative trait loci (QTLs) of the anti-immobility effect of fluoxetine in FST (FST(FLX)) in 865 male B6×FVB-F2 mice. The brain mRNA expressions of the gene with the maximum QTL-linkage signal for FST(FLX) after the FST were compared between B6 and FVB mice and also compared between fluoxetine and saline treatment. The association of the variants in the human homologue of the mouse FST(FLX)-QTL gene with major depressive disorder (MDD) and antidepressant response were investigated in 1080 human subjects (MDD/control = 582/498). RESULTS: One linkage signal for FST(FLX)-QTL was detected at an intronic SNP (rs6215396) of the mouse Zfp326 gene (maximal CIM-LOD = 9.36). The Zfp326 mRNA expression in the FVB thalamus was significantly down-regulated by fluoxetine in the FST, and the higher FVB-to-B6 Zfp326 mRNA expressions in the frontal cortex, striatum and hypothalamus diminished after fluoxetine treatment. Two coding-synonymous SNPs (rs2816881 and rs10922744) in the human homologue of Zfp326, ZNF326, were significantly associated with the 8-week antidepressant treatment response in the MDD patients (Bonferroni-corrected p = 0.004-0.028). CONCLUSIONS: The findings suggest the involvement of the Zfp326 and ZNF326 genes in antidepressant treatment response

A community-integrated home based depression intervention for older African Americans: descripton of the Beat the Blues randomized trial and intervention costs

ABSTRACT: BACKGROUND: Primary care is the principle setting for depression treatment; yet many older African Americans in the United States fail to report depressive symptoms or receive the recommended standard of care. Older African Americans are at high risk for depression due to elevated rates of chronic illness, disability and socioeconomic distress. There is an urgent need to develop and test new depression treatments that resonate with minority populations that are hard-to-reach and underserved and to evaluate their cost and cost-effectiveness. METHODS/DESIGN: Beat the Blues (BTB) is a single-blind parallel randomized trial to assess efficacy of a non-pharmacological intervention to reduce depressive symptoms and improve quality of life in 208 African Americans 55+ years old. It involves a collaboration with a senior center whose care management staff screen for depressive symptoms (telephone or in-person) using the Patient Health Questionnaire (PHQ-9). Individuals screened positive (PHQ-9 ≥ 5) on two separate occasions over 2 weeks are referred to local mental health resources and BTB. Interested and eligible participants who consent receive a baseline home interview and then are randomly assigned to receive BTB immediately or 4 months later (wait-list control). All participants are interviewed at 4 (main study endpoint) and 8 months at home by assessors masked to study assignment. Licensed senior center social workers trained in BTB meet with participants at home for up to 10 sessions over 4 months to assess care needs, make referrals/linkages, provide depression education, instruct in stress reduction techniques, and use behavioral activation to identify goals and steps to achieve them. Key outcomes include reduced depressive symptoms (primary), reduced anxiety and functional disability, improved quality of life, and enhanced depression knowledge and behavioral activation (secondary). Fidelity is enhanced through procedure manuals and staff training and monitored by face-to-face supervision and review of taped sessions. Cost and cost effectiveness is being evaluated. DISCUSSION: BTB is designed to bridge gaps in mental health service access and treatments for older African Americans. Treatment components are tailored to specific care needs, depression knowledge, preference for stress reduction techniques, and personal activity goals. Total costs are $584.64/4 months; or$146.16 per participant/per month. TRIAL REGISTRATION: ClinicalTrials.gov #NCT00511680

Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians

<p>Abstract</p> <p>Background</p> <p><it>CYP2C9 </it>and <it>VKORC1 </it>are two major genetic factors associated with inter-individual variability in warfarin dose. Additionally, genes in the warfarin metabolism pathway have also been associated with dose variance. We analyzed Single Nucleotide Polymorphisms (SNPs) in these genes to identify genetic factors that might confer warfarin sensitivity in Indonesian patients.</p> <p>Methods</p> <p>Direct sequencing method was used to identify SNPs in <it>CYP2C9, VKORC1, CYP4F2, EPHX1, PROC </it>and <it>GGCX </it>genes in warfarin-treated patients. Multiple linear regressions were performed to model the relationship warfarin daily dose requirement with genetic and non-genetic variables measured and used to develop a novel algorithm for warfarin dosing.</p> <p>Results</p> <p>From the 40 SNPs analyzed, <it>CYP2C9 </it>rs17847036 and <it>VKORC1 </it>rs9923231 showed significant association with warfarin sensitivity. In our study population, no significant correlation could be detected between <it>CYP2C9*3, CYP2C9C</it>-65 (rs9332127), <it>CYP4F2 </it>rs2108622, <it>GGCX </it>rs12714145, <it>EPHX1 </it>rs4653436 and <it>PROC </it>rs1799809 with warfarin sensitivity.</p> <p>Conclusions</p> <p><it>VKORC1 </it>rs9923231 AA and <it>CYP2C9 </it>rs17847036 GG genotypes were associated with low dosage requirements of most patients (2.05 ± 0.77 mg/day and 2.09 ± 0.70 mg/day, respectively). <it>CYP2C9 </it>and <it>VKORC1 </it>genetic variants as well as non-genetic factors such as age, body weight and body height account for 15.4% of variance in warfarin dose among our study population. Additional analysis of this combination could allow for personalized warfarin treatment in ethnic Indonesians.</p

FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo

This study aimed to test whether [18F]fluoro-D-glucose (FDG) uptake of tumours measured by positron emission tomography (PET) can be used as surrogate marker to define the optimal biological dose (OBD) of mTOR inhibitors in vivo. Everolimus at 0.05, 0.5, 5 and 15 mg kg−1 per day was administered to gastric cancer xenograft-bearing mice for 23 days and FDG uptake of tumours was measured using PET from day 1 to day 8. To provide standard comparators for FDG uptake, tumour volume, S6 protein phosphorylation, Ki-67 staining and everolimus blood levels were evaluated. Everolimus blood levels increased in a dose-dependent manner but antitumour activity of everolimus reached a plateau at doses ⩾5 mg kg−1 per day (tumour volume treated vs control (T/C): 51% for 5 mg kg−1 per day and 57% for 15 mg kg−1 per day). Correspondingly, doses ⩾5 mg kg−1 per day led to a significant reduction in FDG uptake of tumours. Dose escalation above 5 mg kg−1 per day did not reduce FDG uptake any further (FDG uptake T/C: 49% for 5 mg kg−1 per day and 52% for 15 mg kg−1 per day). Differences in S6 protein phosphorylation and Ki-67 index reflected tumour volume and changes in FDG uptake but did not reach statistical significance. In conclusion, FDG uptake might serve as a surrogate marker for dose finding studies for mTOR inhibitors in (pre)clinical trials

Breast Cancer in Young Women: Poor Survival Despite Intensive Treatment

The general aim of the thesis was to gain increased insight into the long-term prognosis for young women with breast cancer. In a population-based cohort of 22,017 women with breast cancer, we studied prognosis by age. Women aged <35 (n=471), 35–39 (n=858) and 40–49 (n=4789) were compared with women aged 50–69. The cumulative 5-year relative survival ratio (RSR) and the relative excess risk (RER) of mortality were calculated. Women <35 years of age had a worse survival than middle-aged women, partly explained by a later stage at diagnosis. After correction for stage, tumor characteristics and treatment, young age remained an independent risk factor for death. The excess risk of death in young women was only present in stage I-II disease and was most pronounced in women with small tumors. For in-depth studies on a large subpopulation from the original cohort (all 471 women aged <35 and a random sample of 700 women aged 35–69), we collected detailed data from the medical records, re-evaluated slides and produced TMAs from tumor tissue. Breast cancer- specific survival (BCSS), distant disease-free survival (DDFS) and locoregional recurrence- free survival (LRFS) by age were analysed. In a multivariate analysis, age <35 and age 35– 39 years conferred a risk in LRFS but not in DDFS and BCSS. The age-related differences in prognosis were most pronounced in early stage luminal Her2-negative tumors, where low age was an independent prognostic factor also for DDFS (HR 1.87 (1.03–3.44)). To study the importance of proliferation markers for the long-term prognosis in young women, protein expression of Ki-67, cyclin A2, B1, D1 and E1 was analysed in 504 women aged <40 and in 383 women aged ≥40. The higher expression of proliferation markers in young women did not have a strong impact on the prognosis. Proliferation markers are less important in young women, and Ki-67 was prognostic only in young women with Luminal PR+ tumors. Age <40 years was an independent risk factor of DDFS exclusively in this subgroup (adjusted HR 2.35 (1.22-4.50)). The only cyclin adding prognostic value beyond subtype in young women was cyclin E1. In a cohort of 469 women aged <40 and 360 women aged ≥40 we examined whether Her2 status assessed by silver enhanced in situ hybridization (SISH) for all cases, would reveal a proportion of women undiagnosed by routine Her2 testing and whether this would affect their prognosis. With SISH testing for all women, the Her2-positive rate increased from 20.0% to 24.4% (p<0.001), and similarly for women aged <40 and ≥40 years. Young women had Her2+ breast cancer twice as often as middle-aged women. Her2 amplification was present in 4.6% of cases scored 0 with IHC, while the corresponding proportions for scores 1+, 2+ and 3+ were 36.0%, 83.7% and 96.8%, respectively. All Her2 amplified cases, both true positive and false negative, had a significantly worse BCSS than the true negative cases

VAMP3/Syb and YKT6 are required for the fusion of constitutive secretory carriers with the plasma membrane

The cellular machinery required for the fusion of constitutive secretory vesicles with the plasma membrane in metazoans remains poorly defined. To address this problem we have developed a powerful, quantitative assay for measuring secretion and used it in combination with combinatorial gene depletion studies in Drosophila cells. This has allowed us to identify at least three SNARE complexes mediating Golgi to PM transport (STX1, SNAP24/29 and Syb; STX1, SNAP24/29 and YKT6; STX4, SNAP24 and Syb). RNAi mediated depletion of YKT6 and VAMP3 in mammalian cells also blocks constitutive secretion suggesting that YKT6 has an evolutionarily conserved role in this process. The unexpected role of YKT6 in plasma membrane fusion may in part explain why RNAi and gene disruption studies have failed to produce the expected phenotypes in higher eukaryotes