The evidence base for circulating tumour DNA blood-based biomarkers for the early detection of cancer: a systematic mapping review

Background: The presence of circulating cell-free DNA from tumours in blood (ctDNA) is of major importance to those interested in early cancer detection, as well as to those wishing to monitor tumour progression or diagnose the presence of activating mutations to guide treatment. In 2014, the UK Early Cancer Detection Consortium undertook a systematic mapping review of the literature to identify blood-based biomarkers with potential for the development of a non-invasive blood test for cancer screening, and which identified this as a major area of interest. This review builds on the mapping review to expand the ctDNA dataset to examine the best options for the detection of multiple cancer types. Methods: The original mapping review was based on comprehensive searches of the electronic databases Medline, Embase, CINAHL, the Cochrane library, and Biosis to obtain relevant literature on blood-based biomarkers for cancer detection in humans (PROSPERO no. CRD42014010827). The abstracts for each paper were reviewed to determine whether validation data were reported, and then examined in full. Publications concentrating on monitoring of disease burden or mutations were excluded. Results: The search identified 94 ctDNA studies meeting the criteria for review. All but 5 studies examined one cancer type, with breast, colorectal and lung cancers representing 60% of studies. The size and design of the studies varied widely. Controls were included in 77% of publications. The largest study included 640 patients, but the median study size was 65 cases and 35 controls, and the bulk of studies (71%) included less than 100 patients. Studies either estimated cfDNA levels non-specifically or tested for cancer-specific mutations or methylation changes (the majority using PCR-based methods). Conclusion: We have systematically reviewed ctDNA blood biomarkers for the early detection of cancer. Pre-analytical, analytical, and post-analytical considerations were identified which need to be addressed before such biomarkers enter clinical practice. The value of small studies with no comparison between methods, or even the inclusion of controls is highly questionable, and larger validation studies will be required before such methods can be considered for early cancer detection

Resolving the neural circuits of anxiety

Although anxiety disorders represent a major societal problem demanding new therapeutic targets, these efforts have languished in the absence of a mechanistic understanding of this subjective emotional state. While it is impossible to know with certainty the subjective experience of a rodent, rodent models hold promise in dissecting well-conserved limbic circuits. The application of modern approaches in neuroscience has already begun to unmask the neural circuit intricacies underlying anxiety by allowing direct examination of hypotheses drawn from existing psychological concepts. This information points toward an updated conceptual model for what neural circuit perturbations could give rise to pathological anxiety and thereby provides a roadmap for future therapeutic development.National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (NIH Director’s New Innovator Award DP2-DK-102256-01)National Institute of Mental Health (U.S.) (NIH) R01-MH102441-01)JPB Foundatio

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

S

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics

The Kuramoto model in complex networks

181 pages, 48 figures. In Press, Accepted Manuscript, Physics Reports 2015 Acknowledgments We are indebted with B. Sonnenschein, E. R. dos Santos, P. Schultz, C. Grabow, M. Ha and C. Choi for insightful and helpful discussions. T.P. acknowledges FAPESP (No. 2012/22160-7 and No. 2015/02486-3) and IRTG 1740. P.J. thanks founding from the China Scholarship Council (CSC). F.A.R. acknowledges CNPq (Grant No. 305940/2010-4) and FAPESP (Grants No. 2011/50761-2 and No. 2013/26416-9) for financial support. J.K. would like to acknowledge IRTG 1740 (DFG and FAPESP).Peer reviewedPreprin

Phytogeographical patterns of dry forests sensu stricto in northern Minas Gerais State, Brazil

The Deciduous Complex that occurs in northern Minas Gerais State, Brazil, raises questions about the floristic affinities of these formations in relation to neighboring phytogeographical domains. Little is known about the identity of the seasonal forest formations that comprise this complex, or about its relationships to abiotic components, such as soils, topography and climate. This study aimed to recognize the patterns of floristic similarity of all studied fragments of dry forest of northern Minas Gerais with soil and climate attributes, based on the available database. Cluster analysis indicated the existence of two floristic groups that had clear associations with either the Koppen's BSh (semi-arid) or Aw (seasonal tropical) climates. Likewise, the subdivisions of these groups showed clear associations with the dominant soil classes in the region. The Red-Yellow Latosol is the dominant soil classes in the BSh climatic domain, seconded by alluvial areas associated with Fluvic Neosols. The Aw domain comprised a much varied set of soils: Nitosols, Argisols, Cambisols and Litholic Neosols, most derived from the Bambuí limestone/slate formation. The ecotonal nature of northern Minas Gerais State provides a complex interaction between the flora of neighboring phytogeographical domains. This, allied to pedogeomorphological factors, allowed a better understanding of the effects of late Quaternary climate changes for the Deciduous Complex evolution. We conclude that the Latosols under present-day semi-arid climates (BSh) are relicts of former wetter climates, during which humid forest (semideciduous) expansion took place. Later, these semideciduous forests were subjected to a much drier climate, when selection for deciduousness led to the present-days Deciduous Complex scenario

Modulation of macrophage cytokine profiles during solid tumor progression: susceptibility to Candida albicans infection

<p>Abstract</p> <p>Background</p> <p>In order to attain a better understanding of the interactions between opportunist fungi and their hosts, we investigated the cytokine profile associated with the inflammatory response to <it>Candida albicans </it>infection in mice with solid Ehrlich tumors of different degrees.</p> <p>Methods</p> <p>Groups of eight animals were inoculated intraperitoneally with 5 × 10⁶<it>C. albicans </it>7, 14 or 21 days after tumor implantation. After 24 or 72 hours, the animals were euthanized and intraperitoneal lavage fluid was collected. Peritoneal macrophages were cultivated and the levels of IFN-γ, TNF-α, IL-12, IL-10 and IL-4 released into the supernatants were measured by ELISA. Kidney, liver and spleen samples were evaluated for fungal dissemination. Tumor-free animals and animals that had only been subjected to <it>C. albicans </it>infection were used as control groups.</p> <p>Results</p> <p>Our results demonstrated that the mice produced more IFN-γ and TNF-α and less IL-10, and also exhibited fungal clearance, at the beginning of tumor evolution. With the tumor progression, this picture changed: IL-10 production increased and IFN-γ and TNF-α release decreased; furthermore, there was extensive fungal dissemination.</p> <p>Conclusion</p> <p>Our results indicate that solid tumors can affect the production of macrophage cytokines and, in consequence, affect host resistance to opportunistic infections.</p

Cardiorespiratory evaluation in pre and post operative moments of laparoscopic cholecystectomy

PURPOSE: To analyze the changes in both respiratory function and cardiopulmonary exercise tests results in patients subjected to laparoscopic cholecystectomy. METHODS: Fifty patients were evaluated (76% women) and the average age was 47.8±14.2 years. All individuals underwent the measurement of spirometry, manovacuometry, 6-minute walk test (6MWT) and stair-climbing test (SCT). All tests were performed at the first (PO1), fifth (PO5) and thirtieth (PO30) postoperative days. RESULTS: BMI average was 28.8±4.8 kg/m2. Sample comprised 68% non-smokers, 20% current smokers, and 12% former smokers. There was no incidence of postoperative complication whatsoever. There was a significant decrease in spirometric values at PO1, but values were similar to the ones of PRE at PO30. Manovacuometry showed alterations at PO1 displaying values that were similar to the ones of PRE at PO30. 6MWT was significantly shorter at until PO5, but at PO30 values were similar to ones of PRE. As for SCT, values were significantly compromised at PO5 and PO30 since they were similar to the ones of PRE. CONCLUSION: Patients submitted to laparoscopic cholecystectomy present a decrease in cardiorespiratory function on the first postoperative moments but there is a rapid return to preoperative conditions.Sao Paulo State University Botucatu School of MedicineUNESP Botucatu School of MedicineSao Paulo State University Botucatu School of MedicineUNESP Botucatu School of Medicin

Comparison of direct machine parameter optimization versus fluence optimization with sequential sequencing in IMRT of hypopharyngeal carcinoma

Background: To evaluate the effects of direct machine parameter optimization in the treatment planning of intensity-modulated radiation therapy (IMRT) for hypopharyngeal cancer as compared to subsequent leaf sequencing in Oncentra Masterplan v1.5. Methods: For 10 hypopharyngeal cancer patients IMRT plans were generated in Oncentra Masterplan v1.5 (Nucletron BV, Veenendal, the Netherlands) for a Siemens Primus linear accelerator. For optimization the dose volume objectives (DVO) for the planning target volume (PTV) were set to 53 Gy minimum dose and 59 Gy maximum dose, in order to reach a dose of 56 Gy to the average of the PTV. For the parotids a median dose of 22 Gy was allowed and for the spinal cord a maximum dose of 35 Gy. The maximum DVO to the external contour of the patient was set to 59 Gy. The treatment plans were optimized with the direct machine parameter optimization ("Direct Step & Shoot", DSS, Raysearch Laboratories, Sweden) newly implemented in Masterplan v1.5 and the fluence modulation technique ("Intensity Modulation", IM) which was available in previous versions of Masterplan already. The two techniques were compared with regard to compliance to the DVO, plan quality, and number of monitor units (MU) required per fraction dose. Results: The plans optimized with the DSS technique met the DVO for the PTV significantly better than the plans optimized with IM (p = 0.007 for the min DVO and p 0.05). Plan quality, target coverage and dose homogeneity inside the PTV were superior for the plans optimized with DSS for similar dose to the spinal cord and lower dose to the normal tissue. The mean dose to the parotids was lower for the plans optimized with IM. Treatment plan efficiency was higher for the DSS plans with (901 +/- 160) MU compared to (1151 +/- 157) MU for IM (p-value < 0.05). Renormalization of the IM plans to the mean of the dose to 95% of the PTV (D(95)) of the DSS plans, resulted in similar target coverage and dose to the parotids for both strategies, at the cost of a significantly higher dose to the normal tissue and maximum dose to the target. The relative volume of the PTV receiving 107% or more of the prescription dose V(107) increased to 35.5% +/- 20.0% for the IM plan as compared to a mean of 0.9% +/- 0.9% for the DSS plan. Conclusion: The direct machine parameter optimization is a major improvement compared to the fluence modulation with subsequent leaf sequencing in Oncentra Masterplan v1.5. The resulting dose distribution complies better with the DVO and better plan quality is achieved for identical specification of DVO. An additional asset is the reduced number of MU as compared to IM