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Human Challenge Model

Lara M Wierenga, Marieke G N Bos, Elisabeth Schreuders, Ferdi Vd Kamp, Jiska S Peper, Christian K Tamnes, Eveline A Crone
The onset of adolescence in humans is marked by hormonal changes that give rise to secondary sexual characteristics, noted as puberty. It has, however, proven challenging to unravel to what extent pubertal changes may have organizing effects on the brain beyond chronological age, as reported in animal studies. The present longitudinal study aimed to characterize the unique effects of age and puberty on subcortical brain volumes and included three waves of data collection at two-year intervals and 680 T1-weighted MRI scans of 271 participants (54% females) aged between 8 and 29 years old...
March 8, 2018: Psychoneuroendocrinology
Søren Kudsk-Iversen, Naomi Shamambo, M Dylan Bould
The majority of the world's population lacks access to safe, timely, and affordable surgical care. Although there is a health workforce crisis across the board in the poorest countries in the world, anesthesia is disproportionally affected. This article explores some of the key issues that must be tackled to strengthen the anesthesia workforce in low- and lower-middle-income countries. First, we need to increase the overall number of safe anesthesia providers to match a huge burden of disease, particularly in the poorest countries in the world and in remote and rural areas...
April 2018: Anesthesia and Analgesia
Christina H Stuelten, Carole A Parent, Denise J Montell
Metastasis remains the greatest challenge in the clinical management of cancer. Cell motility is a fundamental and ancient cellular behaviour that contributes to metastasis and is conserved in simple organisms. In this Review, we evaluate insights relevant to human cancer that are derived from the study of cell motility in non-mammalian model organisms. Dictyostelium discoideum, Caenorhabditis elegans, Drosophila melanogaster and Danio rerio permit direct observation of cells moving in complex native environments and lend themselves to large-scale genetic and pharmacological screening...
March 16, 2018: Nature Reviews. Cancer
Maria Siemionow, Joanna Cwykiel, Ahlke Heydemann, Jesus Garcia, Enza Marchese, Krzysztof Siemionow, Erzsebet Szilagyi
Duchenne Muscular Dystrophy (DMD) is a progressive and lethal disease caused by mutations of the dystrophin gene. Currently no cure exists. Stem cell therapies targeting DMD are challenged by limited engraftment and rejection despite the use of immunosuppression. There is an urgent need to introduce new stem cell-based therapies that exhibit low allogenic profiles and improved cell engraftment. In this proof-of-concept study, we develop and test a new human stem cell-based approach to increase engraftment, limit rejection, and restore dystrophin expression in the mdx/scid mouse model of DMD...
March 15, 2018: Stem Cell Reviews
Alberto Pilotto, Raffaella Boi, Jean Petermans
Recently, the interest of industry, government agencies and healthcare professionals in technology for aging people has increased. The challenge is whether technology may play a role in enhancing independence and quality of life and in reducing individual and societal costs of caring. Information and communication technologies, i.e. tools aimed at communicating and informing, assistive technologies designed to maintain older peoples' independence and increasing safety, and human-computer interaction technologies for supporting older people with motility and cognitive impairments as humanoid robots, exoskeletons, rehabilitation robots, service robots and companion-type are interdisciplinary topics both in research and in clinical practice...
March 13, 2018: Age and Ageing
Renping Liu, Peihong Wang, Caiqing Wu, Juan Chen, Chengxin Li, Yongtao Xie, Qi Wang, Jianming Liu, Huan He, Jing Zhu
Hedyotis diffusa Willd (HDW) is a constituent of several Chinese medicines used clinically to treat inflammatory diseases, including airway inflammation. The aim of the present study was to investigate whether HDW serves a protective role in suppressing chronic airway inflammation and its underlying mechanisms. A mouse model of chronic smoking was induced via exposure to cigarette smoke (CS) for 30 days, increasing the exposure time for up to 5 min per day and the administration of lipopolysaccharide (LPS)...
April 2018: Experimental and Therapeutic Medicine
Fernanda Ramos-Gomes, Julia Bode, Alyona Sukhanova, Svetlana V Bozrova, Mara Saccomano, Miso Mitkovski, Julia Eva Krueger, Anja K Wege, Walter Stuehmer, Pavel S Samokhvalov, Daniel Baty, Patrick Chames, Igor Nabiev, Frauke Alves
Early detection of malignant tumours and, especially, micrometastases and disseminated tumour cells is still a challenge. In order to implement highly sensitive diagnostic tools we demonstrate the use of nanoprobes engineered from nanobodies (single-domain antibodies, sdAbs) and fluorescent quantum dots (QDs) for single- and two-photon detection and imaging of human micrometastases and disseminated tumour cells in ex vivo biological samples of breast and pancreatic metastatic tumour mouse models expressing human epidermal growth factor receptor 2 (HER2) or carcinoembryonic antigen (CEA)...
March 15, 2018: Scientific Reports
Dezső Ribli, Anna Horváth, Zsuzsa Unger, Péter Pollner, István Csabai
In the last two decades, Computer Aided Detection (CAD) systems were developed to help radiologists analyse screening mammograms, however benefits of current CAD technologies appear to be contradictory, therefore they should be improved to be ultimately considered useful. Since 2012, deep convolutional neural networks (CNN) have been a tremendous success in image recognition, reaching human performance. These methods have greatly surpassed the traditional approaches, which are similar to currently used CAD solutions...
March 15, 2018: Scientific Reports
Alessandra Balduini, Hana Raslova, Christian A Di Buduo, Alessandro Donada, Matthias Ballmaier, Manuela Germeshausen, Carlo L Balduini
Inherited thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by low platelet count resulting in impaired hemostasis. Patients can have spontaneous hemorrhages and/or excessive bleedings provoked by hemostatic challenges as trauma or surgery. To date, ITs encompass 32 different rare monogenic disorders caused by mutations of 30 genes. This review will focus on the major discoveries that have been made in the last years on the diagnosis, treatment and molecular mechanisms of ANKRD26-Related Thrombocytopenia and MYH9-Related Diseases...
March 12, 2018: European Journal of Medical Genetics
Ellen V S Hessel, Yvonne C M Staal, Aldert H Piersma
Developmental neurotoxicity entails one of the most complex areas in toxicology. Animal studies provide only limited information as to human relevance. A multitude of alternative models have been developed over the years, providing insights into mechanisms of action. We give an overview of fundamental processes in neural tube formation, brain development and neural specification, aiming at illustrating complexity rather than comprehensiveness. We also give a flavor of the wealth of alternative methods in this area...
March 12, 2018: Toxicology and Applied Pharmacology
Matthew J Atherton, Kyle B Stephenson, Jake K Nikota, Qian N Hu, Andrew Nguyen, Yonghong Wan, Brian D Lichty
Human papilloma virus (HPV)-associated cancer is a significant global health burden and despite the presence of viral transforming antigens within neoplastic cells, therapeutic vaccinations are ineffective for advanced disease. HPV positive TC1 cells are susceptible to viral oncolysis by MG1-E6E7, a custom designed oncolytic Maraba virus. Epitope mapping of mice vaccinated with MG1-E6E7 enabled the rational design of synthetic long peptide (SLP) vaccines against HPV16 and HPV18 antigens. SLPs were able to induce specific CD8+ immune responses and the magnitude of these responses significantly increased when boosted by MG1-E6E7...
March 12, 2018: Vaccine
Meixiang Zhang, Justine Ngo, Filomena Pirozzi, Ying-Pu Sun, Anthony Wynshaw-Boris
BACKGROUND: Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have been widely used to generate cellular models harboring specific disease-related genotypes. Of particular importance are ESC and iPSC applications capable of producing dorsal telencephalic neural progenitor cells (NPCs) that are representative of the cerebral cortex and overcome the challenges of maintaining a homogeneous population of cortical progenitors over several passages in vitro. While previous studies were able to derive NPCs from pluripotent cell types, the fraction of dorsal NPCs in this population is small and decreases over several passages...
March 15, 2018: Stem Cell Research & Therapy
Alexandra J Harvey, Carmel O'Brien, Jack Lambshead, John R Sheedy, Joy Rathjen, Andrew L Laslett, David K Gardner
Reprogramming somatic cells to a pluripotent cell state (induced Pluripotent Stem (iPS) cells) requires reprogramming of metabolism to support cell proliferation and pluripotency, most notably changes in carbohydrate turnover that reflect a shift from oxidative to glycolytic metabolism. Some aspects of iPS cell metabolism differ from embryonic stem (ES) cells, which may reflect a parental cell memory, or be a consequence of the reprogramming process. In this study, we compared the metabolism of 3 human iPS cell lines to assess the fidelity of metabolic reprogramming...
2018: PloS One
Bárbara da Silva, Ryan K Mathew, Euan S Polson, Jennifer Williams, Heiko Wurdak
Organoid methodology provides a platform for the ex vivo investigation of the cellular and molecular mechanisms underlying brain development and disease. The high-grade brain tumor glioblastoma multiforme (GBM) is considered a cancer of unmet clinical need, in part due to GBM cell infiltration into healthy brain parenchyma, making complete surgical resection improbable. Modeling the process of GBM invasion in real time is challenging as it requires both tumor and neural tissue compartments. Here, we demonstrate that human GBM spheroids possess the ability to spontaneously infiltrate early-stage cerebral organoids (eCOs)...
March 1, 2018: SLAS Discovery
Aleta Pupovac, Berna Senturk, Chiara Griffoni, Katharina Maniura-Weber, Markus Rottmar, Sally L McArthur
3D human skin models provide a platform for toxicity testing, biomaterials evaluation, and investigation of fundamental biological processes. However, the majority of current in vitro models lack an inflammatory system, vasculature, and other characteristics of native skin, indicating scope for more physiologically complex models. Looking at the immune system, there are a variety of cells that could be integrated to create novel skin models, but to do this effectively it is also necessary to understand the interface between skin biology and tissue engineering as well as the different roles the immune system plays in specific health and disease states...
March 15, 2018: Advanced Healthcare Materials
John R Apps, Gabriela Carreno, Jose Mario Gonzalez-Meljem, Scott Haston, Romain Guiho, Julie E Cooper, Saba Manshaei, Nital Jani, Annett Hölsken, Benedetta Pettorini, Robert J Beynon, Deborah M Simpson, Helen C Fraser, Ying Hong, Shirleen Hallang, Thomas J Stone, Alex Virasami, Andrew M Donson, David Jones, Kristian Aquilina, Helen Spoudeas, Abhijit R Joshi, Richard Grundy, Lisa C D Storer, Márta Korbonits, David A Hilton, Kyoko Tossell, Selvam Thavaraj, Mark A Ungless, Jesus Gil, Rolf Buslei, Todd Hankinson, Darren Hargrave, Colin Goding, Cynthia L Andoniadou, Paul Brogan, Thomas S Jacques, Hywel J Williams, Juan Pedro Martinez-Barbera
Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset...
March 14, 2018: Acta Neuropathologica
Beatriz Silva Lima, Mafalda Ascensão Videira
Since the human genome decoding, understanding and identification of genetic disturbances behind many diseases, including cancer, are intensively increasing. Scientific and technological advances in this area trigger the search for therapeutic (curative) approaches targeting the correction of gene disturbances. Gene therapy medicinal products (GTMPs) emerge in this context, bringing new challenges for their characterization. Compared to small molecules, biodistribution is fundamental to identifying target organs and anticipating safety and efficacy, may be integrated into safety and pharmacology studies, and may eventually be anticipated based on specificities of vectors and constructs...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
Roshanak Derakhshandeh, Sonia Sanadhya, Kyu Lee Han, Haiyan Chen, Olga Goloubeva, Tonya J Webb, Rania H Younis
The search for stromal biomarkers in carcinoma patients is a challenge in the field. Semaphorin 4D (Sema4D), known for its various developmental, physiological and pathological effects, plays a role in pro and anti-inflammatory responses. It is expressed in many epithelial tumors including head and neck squamous cell carcinoma (HNSCC). Recently, we found that HNSCC-associated Sema4D modulates an immune-suppressive, tumor-permissible environment by inducing the expansion of myeloid derived suppressor cells. The purpose of this study was to determine the value of Sema4D as a biomarker for the peri-tumoral stromal phenotype in human HNSCC...
February 16, 2018: Oncotarget
Philippe A Gallay, Udayan Chatterji, Aaron Kirchhoff, Angel Gandarilla, Richard B Pyles, Marc M Baum, John A Moss
Introduction: In the absence of a vaccine, there is an urgent need for the identification of effective agents that prevent HIV transmission in uninfected individuals. Non-vaccine Biomedical Prevention (nBP) methods, such as topical or systemic pre-exposure prophylaxis (PrEP), are promising strategies to slow down the spread of AIDS. Methods: In this study, we investigated the microbicidal efficacy of the viral membrane-disrupting amphipathic SWLRDIWDWICEVLSDFK peptide called C5A...
2018: Open Virology Journal
Juliana Serje, Melanie Y Bertram, Callum Brindley, Jeremy A Lauer
Background: Human resources are consistently cited as a leading contributor to health care costs; however the availability of internationally comparable data on health worker earnings for all countries is a challenge for estimating the costs of health care services. This paper describes an econometric model using cross sectional earnings data from the International Labour Organization (ILO) that the World Health Organizations (WHO)-Choosing Interventions that are Cost-effective programme (CHOICE) has used to prepare estimates of health worker earnings (in 2010 USD) for all WHO member states...
2018: Cost Effectiveness and Resource Allocation: C/E
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