Pretreatment levels of the fatty acid handling proteins H-FABP and CD36 predict response to olanzapine in recent-onset schizophrenia patients.

Traditional schizophrenia pharmacotherapy remains a subjective trial and error process involving administration, titration and switching of drugs multiple times until an adequate response is achieved. Despite this time-consuming and costly process, not all patients show an adequate response to treatment. As a consequence, relapse is a common occurrence and early intervention is hampered. Here, we have attempted to identify candidate blood biomarkers associated with drug response in 121 initially antipsychotic-free recent-onset schizophrenia patients treated with widely-used antipsychotics, namely olanzapine (n=40), quetiapine (n=23), risperidone (n=30) and a mixture of these drugs (n=28). Patients were recruited and investigated as two separate cohorts to allow biomarker validation. Data analysis showed the most significant relationship between pre-treatment levels of heart-type fatty acid binding protein (H-FABP) and response to olanzapine (p=0.008, F=8.6, β=70.4 in the discovery cohort and p=0.003, F=15.2, β=24.4 in the validation cohort, adjusted for relevant confounding variables). In a functional follow-up analysis of this finding, we tested an independent cohort of 10 patients treated with olanzapine and found that baseline levels of plasma H-FABP and expression of the binding partner for H-FABP, fatty acid translocase (CD36), on monocytes predicted the reduction of psychotic symptoms (p=0.040, F=6.0, β=116.3 and p=0.012, F=11.9, β=-0.0054, respectively). We also identified a set of serum molecules changed after treatment with antipsychotic medication, in particular olanzapine. These molecules are predominantly involved in cellular development and metabolism. Taken together, our findings suggest an association between biomarkers involved in fatty acid metabolism and response to olanzapine, while other proteins may serve as surrogate markers associated with drug efficacy and side effects.This work was supported by the Stanley Medical Research Institute (SMRI); the European Union FP7 SchizDX research programme (grant reference 223427); the European Union FP7 funding scheme: Marie Curie Actions Industry Academia Partnerships and Pathways (nr. 286334, PSYCH-AID project); by the Virgo consortium, funded by the Dutch Government (project number FES0908); by the Netherlands Genomics Initiative (project number 050-060-452); by the Dutch Fund for Economic Structure Reinforcement, the NeuroBasic PharmaPhenomics project (no. 0908) and by the Engineering and Physical Sciences Research Council UK (EPSRC CASE studentship and Impact Acceleration Award).This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.bbi.2015.10.01

Atomic Hydrogen Properties of AGN Host Galaxies: HI in 16 NUclei of GAlaxies (NUGA) Sources

We present a comprehensive spectroscopic imaging survey of the distribution and kinematics of atomic hydrogen (HI) in 16 nearby spiral galaxies hosting low luminosity AGN, observed with high spectral and spatial resolution (resolution: ~20 arcsec, 5 km/s) using the NRAO Very Large Array (VLA). The sample contains a range of nuclear types, ranging from Seyfert to star-forming nuclei and was originally selected for the NUclei of GAlaxies project (NUGA) - a spectrally and spatially resolved interferometric survey of gas dynamics in nearby galaxies designed to identify the fueling mechanisms of AGN and the relation to host galaxy evolution. Here we investigate the relationship between the HI properties of these galaxies, their environment, their stellar distribution and their AGN type. The large-scale HI morphology of each galaxy is classified as ringed, spiral, or centrally concentrated; comparison of the resulting morphological classification with AGN type reveals that ring structures are significantly more common in LINER than in Seyfert host galaxies, suggesting a time evolution of the AGN activity together with the redistribution of the neutral gas. Dynamically disturbed HI disks are also more prevalent in LINER host galaxies than in Seyfert host galaxies. While several galaxies are surrounded by companions (some with associated HI emission), there is no correlation between the presence of companions and the AGN type (Seyfert/LINER).Comment: 54 pages, 7 figures, accepted for publication in AJ. The full-resolution version is available at http://www.mpia.de/homes/haan/research.htm

Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin

Pathological processes involved in the initiation of rheumatoid synovitis remain unclear. We undertook the present study to identify immune and stromal processes that are present soon after the clinical onset of rheumatoid arthritis ( RA) by assessing a panel of T cell, macrophage, and stromal cell related cytokines and chemokines in the synovial fluid of patients with early synovitis. Synovial fluid was aspirated from inflamed joints of patients with inflammatory arthritis of duration 3 months or less, whose outcomes were subsequently determined by follow up. For comparison, synovial fluid was aspirated from patients with acute crystal arthritis, established RA and osteoarthritis. Rheumatoid factor activity was blocked in the synovial fluid samples, and a panel of 23 cytokines and chemokines measured using a multiplex based system. Patients with early inflammatory arthritis who subsequently developed RA had a distinct but transient synovial fluid cytokine profile. The levels of a range of T cell, macrophage and stromal cell related cytokines ( e. g. IL-2, IL-4, IL-13, IL-17, IL-15, basic fibroblast growth factor and epidermal growth factor) were significantly elevated in these patients within 3 months after symptom onset, as compared with early arthritis patients who did not develop RA. In addition, this profile was no longer present in established RA. In contrast, patients with non-rheumatoid persistent synovitis exhibited elevated levels of interferon-gamma at initiation. Early synovitis destined to develop into RA is thus characterized by a distinct and transient synovial fluid cytokine profile. The cytokines present in the early rheumatoid lesion suggest that this response is likely to influence the microenvironment required for persistent RA

Smoking-associated gene expression alterations in nasal epithelium reveal immune impairment linked to lung cancer risk

BACKGROUND: Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to modifiable lifestyle risk in the form of tobacco smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, 40% of which occur more than 15 years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk remain unclear. We thus set out to examine whether risk stratification in the clinic and in the general population can be improved upon by the addition of genetic data and to explore the mechanisms of the persisting risk in former smokers. METHODS: We analysed transcriptomic data from accessible airway tissues of 487 subjects, including healthy volunteers and clinic patients of different smoking statuses. We developed a computational model to assess smoking-associated gene expression changes and their reversibility after smoking is stopped, comparing healthy subjects to clinic patients with and without lung cancer. RESULTS: We find persistent smoking-associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune- and interferon-related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier. CONCLUSIONS: Our results provide initial evidence for germline-mediated personalized smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality

A Novel, Single Algorithm Approach to Predict Acenocoumarol Dose Based on CYP2C9 and VKORC1 Allele Variants

The identification of CYP2C9 and VKORC1 genes has strongly stimulated the research on pharmacogenetics of coumarins in the last decade. We assessed the combined influence of CYP2C9 *2 and *3, and VKORC1 c.-1639G>A, 497C>G, and 1173C>T variants, on acenocoumarol dosage using a novel algorithm approach, in 193 outpatients who had achieved stable anticoagulation. We constructed an “acenocoumarol-dose genotype score” (AGS, maximum score = 100) based on the number of alleles associated with higher acenocoumarol dosage carried by each subject for each polymorphism. The mean AGS was higher in the high-dose (>28mg/week) compared with the low-dose (<7mg/week) group (mean(SEM) of 84.1±3.4 vs. 62.2±4.8, P = 0.008). An AGS>70 was associated with an increased odds ratio (OR) of requiring high acenocoumarol dosage (OR: 3.347; 95%CI: 1.112–10.075; P = 0.032). In summary, although more research is necessary in other patient cohorts, and this algorithm should be replicated in an independent sample, our data suggest that the AGS algorithm could be used to help discriminating patients requiring high acenocoumarol doses to achieve stable anti-coagulation

Selection-Independent Generation of Gene Knockout Mouse Embryonic Stem Cells Using Zinc-Finger Nucleases

Gene knockout in murine embryonic stem cells (ESCs) has been an invaluable tool to study gene function in vitro or to generate animal models with altered phenotypes. Gene targeting using standard techniques, however, is rather inefficient and typically does not exceed frequencies of 10−6. In consequence, the usage of complex positive/negative selection strategies to isolate targeted clones has been necessary. Here, we present a rapid single-step approach to generate a gene knockout in mouse ESCs using engineered zinc-finger nucleases (ZFNs). Upon transient expression of ZFNs, the target gene is cleaved by the designer nucleases and then repaired by non-homologous end-joining, an error-prone DNA repair process that introduces insertions/deletions at the break site and therefore leads to functional null mutations. To explore and quantify the potential of ZFNs to generate a gene knockout in pluripotent stem cells, we generated a mouse ESC line containing an X-chromosomally integrated EGFP marker gene. Applying optimized conditions, the EGFP locus was disrupted in up to 8% of ESCs after transfection of the ZFN expression vectors, thus obviating the need of selection markers to identify targeted cells, which may impede or complicate downstream applications. Both activity and ZFN-associated cytotoxicity was dependent on vector dose and the architecture of the nuclease domain. Importantly, teratoma formation assays of selected ESC clones confirmed that ZFN-treated ESCs maintained pluripotency. In conclusion, the described ZFN-based approach represents a fast strategy for generating gene knockouts in ESCs in a selection-independent fashion that should be easily transferrable to other pluripotent stem cells

Fundamental role of C1q in autoimmunity and inflammation

C1q, historically viewed as the initiating component of the classical complement pathway, also exhibits a variety of complement-independent activities in both innate and acquired immunity. Recent studies focusing on C1q\u27s suppressive role in the immune system have provided new insight into how abnormal C1q expression and bioactivity may contribute to autoimmunity. In particular, molecular networks involving C1q interactions with cell surface receptors and other ligands are emerging as mechanisms involved in C1q\u27s modulation of immunity. Here, we discuss the role of C1q in controlling immune cell function, including recently elucidated mechanisms of action, and suggest how these processes are critical for maintaining tissue homeostasis under steady-state conditions and in preventing autoimmunity

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): study protocol for a randomized controlled trial

BACKGROUND: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). METHODS/DESIGN: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH2O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure 6430 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. DISCUSSION: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration metho