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Science Translational Medicine

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https://www.readbyqxmd.com/read/30404864/wnt1-is-an-lrp5-independent-bone-anabolic-wnt-ligand
#1
Julia Luther, Timur Alexander Yorgan, Tim Rolvien, Lorenz Ulsamer, Till Koehne, Nannan Liao, Daniela Keller, Nele Vollersen, Stefan Teufel, Mona Neven, Stephanie Peters, Michaela Schweizer, Andreas Trumpp, Sebastian Rosigkeit, Ernesto Bockamp, Stefan Mundlos, Uwe Kornak, Ralf Oheim, Michael Amling, Thorsten Schinke, Jean-Pierre David
WNT1 mutations in humans are associated with a new form of osteogenesis imperfecta and with early-onset osteoporosis, suggesting a key role of WNT1 in bone mass regulation. However, the general mode of action and the therapeutic potential of Wnt1 in clinically relevant situations such as aging remain to be established. Here, we report the high prevalence of heterozygous WNT1 mutations in patients with early-onset osteoporosis. We show that inactivation of Wnt1 in osteoblasts causes severe osteoporosis and spontaneous bone fractures in mice...
November 7, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30404863/enhanced-detection-of-circulating-tumor-dna-by-fragment-size-analysis
#2
Florent Mouliere, Dineika Chandrananda, Anna M Piskorz, Elizabeth K Moore, James Morris, Lise Barlebo Ahlborn, Richard Mair, Teodora Goranova, Francesco Marass, Katrin Heider, Jonathan C M Wan, Anna Supernat, Irena Hudecova, Ioannis Gounaris, Susana Ros, Mercedes Jimenez-Linan, Javier Garcia-Corbacho, Keval Patel, Olga Østrup, Suzanne Murphy, Matthew D Eldridge, Davina Gale, Grant D Stewart, Johanna Burge, Wendy N Cooper, Michiel S van der Heijden, Charles E Massie, Colin Watts, Pippa Corrie, Simon Pacey, Kevin M Brindle, Richard D Baird, Morten Mau-Sørensen, Christine A Parkinson, Christopher G Smith, James D Brenton, Nitzan Rosenfeld
Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for noninvasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0...
November 7, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30404862/calcified-nodules-in-retinal-drusen-are-associated-with-disease-progression-in-age-related-macular-degeneration
#3
Anna C S Tan, Matthew G Pilgrim, Sarah Fearn, Sergio Bertazzo, Elena Tsolaki, Alexander P Morrell, Miaoling Li, Jeffrey D Messinger, Rosa Dolz-Marco, Jianqin Lei, Muneeswar G Nittala, Srinivas R Sadda, Imre Lengyel, K Bailey Freund, Christine A Curcio
Drusen are lipid-, mineral-, and protein-containing extracellular deposits that accumulate between the basal lamina of the retinal pigment epithelium (RPE) and Bruch's membrane (BrM) of the human eye. They are a defining feature of age-related macular degeneration (AMD), a common sight-threatening disease of older adults. The appearance of heterogeneous internal reflectivity within drusen (HIRD) on optical coherence tomography (OCT) images has been suggested to indicate an increased risk of progression to advanced AMD...
November 7, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30404861/-68-ga-dota-ggnle-cycmsh-hex-targets-the-melanocortin-1-receptor-for-melanoma-imaging
#4
Jianquan Yang, Jingli Xu, Rene Gonzalez, Thomas Lindner, Clemens Kratochwil, Yubin Miao
Melanocortin-1 receptor (MC1R) is a molecular target for melanoma imaging and therapy because of its overexpression on rodent and human melanoma cells. Here, we evaluated the MC1R targeting and specificity of 68 Ga-DOTA-GGNle-CycMSHhex and Cy5.5-GGNle-CycMSHhex using murine and human melanoma cells, and murine and xenografted tumors. 68 Ga-DOTA-GGNle-CycMSHhex was used first in human as an imaging probe to evaluate the possibility of radionuclide therapy in patients with advanced-stage melanoma. 68 Ga-DOTA-GGNle-CycMSHhex and Cy5...
November 7, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30404860/one-size-does-not-fit-all-size-based-plasma-dna-diagnostics
#5
REVIEW
Ellen Heitzer, Michael R Speicher
Understanding the biological properties of plasma cell-free DNA may expand its applications in oncology (Mouliere et al , this issue).
November 7, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30381411/antisense-oligonucleotides-targeting-mutant-ataxin-7-restore-visual-function-in-a-mouse-model-of-spinocerebellar-ataxia-type-7
#6
Chenchen Niu, Thazah P Prakash, Aneeza Kim, John L Quach, Laryssa A Huryn, Yuechen Yang, Edith Lopez, Ali Jazayeri, Gene Hung, Bryce L Sopher, Brian P Brooks, Eric E Swayze, C Frank Bennett, Albert R La Spada
Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by cerebellar and retinal degeneration, and is caused by a CAG-polyglutamine repeat expansion in the ATAXIN-7 gene. Patients with SCA7 develop progressive cone-rod dystrophy, typically resulting in blindness. Antisense oligonucleotides (ASOs) are single-stranded chemically modified nucleic acids designed to mediate the destruction, prevent the translation, or modify the processing of targeted RNAs. Here, we evaluated ASOs as treatments for SCA7 retinal degeneration in representative mouse models of the disease after injection into the vitreous humor of the eye...
October 31, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30381410/epidermal-electronics-for-noninvasive-wireless-quantitative-assessment-of-ventricular-shunt-function-in-patients-with-hydrocephalus
#7
Siddharth R Krishnan, Tyler R Ray, Amit B Ayer, Yinji Ma, Philipp Gutruf, KunHyuck Lee, Jong Yoon Lee, Chen Wei, Xue Feng, Barry Ng, Zachary A Abecassis, Nikhil Murthy, Izabela Stankiewicz, Juliet Freudman, Julia Stillman, Natalie Kim, Grace Young, Camille Goudeseune, John Ciraldo, Matthew Tate, Yonggang Huang, Matthew Potts, John A Rogers
Hydrocephalus is a common and costly neurological condition caused by the overproduction and/or impaired resorption of cerebrospinal fluid (CSF). The current standard of care, ventricular catheters (shunts), is prone to failure, which can result in nonspecific symptoms such as headaches, dizziness, and nausea. Current diagnostic tools for shunt failure such as computed tomography (CT), magnetic resonance imaging (MRI), radionuclide shunt patency studies (RSPSs), and ice pack-mediated thermodilution have disadvantages including high cost, poor accuracy, inconvenience, and safety concerns...
October 31, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30381409/safe-and-effective-superoxide-dismutase-1-silencing-using-artificial-microrna-in-macaques
#8
Florie Borel, Gwladys Gernoux, Huaming Sun, Rachel Stock, Meghan Blackwood, Robert H Brown, Christian Mueller
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease caused by degeneration of motor neurons leading to rapidly progressive paralysis. About 10% of cases are caused by gain-of-function mutations that are transmitted as dominant traits. A potential therapy for these cases is to suppress the expression of the mutant gene. Here, we investigated silencing of SOD1 , a gene commonly mutated in familial ALS, using an adeno-associated virus (AAV) encoding an artificial microRNA (miRNA) that targeted SOD1 In a superoxide dismutase 1 (SOD1)-mediated mouse model of ALS, we have previously demonstrated that SOD1 silencing delayed disease onset, increased survival time, and reduced muscle loss and motor and respiratory impairments...
October 31, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30381408/the-vermiform-appendix-impacts-the-risk-of-developing-parkinson-s-disease
#9
Bryan A Killinger, Zachary Madaj, Jacek W Sikora, Nolwen Rey, Alec J Haas, Yamini Vepa, Daniel Lindqvist, Honglei Chen, Paul M Thomas, Patrik Brundin, Lena Brundin, Viviane Labrie
The pathogenesis of Parkinson's disease (PD) involves the accumulation of aggregated α-synuclein, which has been suggested to begin in the gastrointestinal tract. Here, we determined the capacity of the appendix to modify PD risk and influence pathogenesis. In two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, we observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset...
October 31, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30381407/inflammasome-inhibition-prevents-%C3%AE-synuclein-pathology-and-dopaminergic-neurodegeneration-in-mice
#10
Richard Gordon, Eduardo A Albornoz, Daniel C Christie, Monica R Langley, Vinod Kumar, Susanna Mantovani, Avril A B Robertson, Mark S Butler, Dominic B Rowe, Luke A O'Neill, Anumantha G Kanthasamy, Kate Schroder, Matthew A Cooper, Trent M Woodruff
Parkinson's disease (PD) is characterized by a profound loss of dopaminergic neurons in the substantia nigra, accompanied by chronic neuroinflammation, mitochondrial dysfunction, and widespread accumulation of α-synuclein-rich protein aggregates in the form of Lewy bodies. However, the mechanisms linking α-synuclein pathology and dopaminergic neuronal death to chronic microglial neuroinflammation have not been completely elucidated. We show that activation of the microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome is a common pathway triggered by both fibrillar α-synuclein and dopaminergic degeneration in the absence of α-synuclein aggregates...
October 31, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30355802/erratum-for-the-research-article-pi3k-inhibition-results-in-enhanced-estrogen-receptor-function-and-dependence-in-hormone-receptor-positive-breast-cancer-by-a-bosch-z-li-a-bergamaschi-h-ellis-e-toska-a-prat-j-j-tao-d-e-spratt-n-t-viola-villegas-p-castel-g-minuesa
#11
https://www.readbyqxmd.com/read/30355801/-clostridioides-difficile-uses-amino-acids-associated-with-gut-microbial-dysbiosis-in-a-subset-of-patients-with-diarrhea
#12
Eric J Battaglioli, Vanessa L Hale, Jun Chen, Patricio Jeraldo, Coral Ruiz-Mojica, Bradley A Schmidt, Vayu M Rekdal, Lisa M Till, Lutfi Huq, Samuel A Smits, William J Moor, Yava Jones-Hall, Thomas Smyrk, Sahil Khanna, Darrell S Pardi, Madhusudan Grover, Robin Patel, Nicholas Chia, Heidi Nelson, Justin L Sonnenburg, Gianrico Farrugia, Purna C Kashyap
The gut microbiota plays a critical role in pathogen defense. Studies using antibiotic-treated mice reveal mechanisms that increase susceptibility to Clostridioides difficile infection (CDI), but risk factors associated with CDI in humans extend beyond antibiotic use. Here, we studied the dysbiotic gut microbiota of a subset of patients with diarrhea and modeled the gut microbiota of these patients by fecal transplantation into germ-free mice. When challenged with C. difficile , the germ-free mice transplanted with fecal samples from patients with dysbiotic microbial communities showed increased gut amino acid concentrations and greater susceptibility to CDI...
October 24, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30355800/antibiotics-induce-sustained-dysregulation-of-intestinal-t-cell-immunity-by-perturbing-macrophage-homeostasis
#13
Nicholas A Scott, Anna Andrusaite, Peter Andersen, Melissa Lawson, Cristina Alcon-Giner, Charlotte Leclaire, Shabhonam Caim, Gwenaelle Le Gall, Tovah Shaw, James P R Connolly, Andrew J Roe, Hannah Wessel, Alberto Bravo-Blas, Carolyn A Thomson, Verena Kästele, Ping Wang, Daniel A Peterson, Allison Bancroft, Xuhang Li, Richard Grencis, Allan McI Mowat, Lindsay J Hall, Mark A Travis, Simon W F Milling, Elizabeth R Mann
Macrophages in the healthy intestine are highly specialized and usually respond to the gut microbiota without provoking an inflammatory response. A breakdown in this tolerance leads to inflammatory bowel disease (IBD), but the mechanisms by which intestinal macrophages normally become conditioned to promote microbial tolerance are unclear. Strong epidemiological evidence linking disruption of the gut microbiota by antibiotic use early in life to IBD indicates an important role for the gut microbiota in modulating intestinal immunity...
October 24, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30355799/suppression-of-stromal-derived-dickkopf-3-dkk3-inhibits-tumor-progression-and-prolongs-survival-in-pancreatic-ductal-adenocarcinoma
#14
Liran Zhou, Hongmei Husted, Todd Moore, Mason Lu, Defeng Deng, Yan Liu, Vijaya Ramachandran, Thiruvengadam Arumugam, Christof Niehrs, Huamin Wang, Paul Chiao, Jianhua Ling, Michael A Curran, Anirban Maitra, Mien-Chie Hung, Jeffrey E Lee, Craig D Logsdon, Rosa F Hwang
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and it is unclear whether its stromal infiltrate contributes to its aggressiveness. Here, we demonstrate that Dickkopf-3 (DKK3) is produced by pancreatic stellate cells and is present in most human PDAC. DKK3 stimulates PDAC growth, metastasis, and resistance to chemotherapy with both paracrine and autocrine mechanisms through NF-κB activation. Genetic ablation of DKK3 in an autochthonous model of PDAC inhibited tumor growth, induced a peritumoral infiltration of CD8+ T cells, and more than doubled survival...
October 24, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30355798/systems-biology-based-drug-repositioning-identifies-digoxin-as-a-potential-therapy-for-groups-3-and-4-medulloblastoma
#15
Lei Huang, Sarah Garrett Injac, Kemi Cui, Frank Braun, Qi Lin, Yuchen Du, Huiyuan Zhang, Mari Kogiso, Holly Lindsay, Sibo Zhao, Patricia Baxter, Adesina Adekunle, Tsz-Kwong Man, Hong Zhao, Xiao-Nan Li, Ching C Lau, Stephen T C Wong
Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Although outcomes have improved in recent decades, new treatments are still needed to improve survival and reduce treatment-related complications. The MB subtypes groups 3 and 4 represent a particular challenge due to their intragroup heterogeneity, which limits the options for "rational" targeted therapies. Here, we report a systems biology approach to drug repositioning that integrates a nonparametric, bootstrapping-based simulated annealing algorithm and a 3D drug functional network to characterize dysregulated driver signaling networks, thereby identifying potential drug candidates...
October 24, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30355797/in-situ-identification-of-gram-negative-bacteria-in-human-lungs-using-a-topical-fluorescent-peptide-targeting-lipid-a
#16
Ahsan R Akram, Sunay V Chankeshwara, Emma Scholefield, Tashfeen Aslam, Neil McDonald, Alicia Megia-Fernandez, Adam Marshall, Bethany Mills, Nicolaos Avlonitis, Thomas H Craven, Annya M Smyth, David S Collie, Calum Gray, Nik Hirani, Adam T Hill, John R Govan, Timothy Walsh, Christopher Haslett, Mark Bradley, Kevin Dhaliwal
Respiratory infections in mechanically ventilated patients caused by Gram-negative bacteria are a major cause of morbidity. Rapid and unequivocal determination of the presence, localization, and abundance of bacteria is critical for positive resolution of the infections and could be used for patient stratification and for monitoring treatment efficacy. Here, we developed an in situ approach to visualize Gram-negative bacterial species and cellular infiltrates in distal human lungs in real time. We used optical endomicroscopy to visualize a water-soluble optical imaging probe based on the antimicrobial peptide polymyxin conjugated to an environmentally sensitive fluorophore...
October 24, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30333241/in-utero-priming-of-highly-functional-effector-t-cell-responses-to-human-malaria
#17
Pamela M Odorizzi, Prasanna Jagannathan, Tara I McIntyre, Rachel Budker, Mary Prahl, Ann Auma, Trevor D Burt, Felistas Nankya, Mayimuna Nalubega, Esther Sikyomu, Kenneth Musinguzi, Kate Naluwu, Abel Kakuru, Grant Dorsey, Moses R Kamya, Margaret E Feeney
Malaria remains a significant cause of morbidity and mortality worldwide, particularly in infants and children. Some studies have reported that exposure to malaria antigens in utero results in the development of tolerance, which could contribute to poor immunity to malaria in early life. However, the effector T cell response to pathogen-derived antigens encountered in utero, including malaria, has not been well characterized. Here, we assessed the frequency, phenotype, and function of cord blood T cells from Ugandan infants born to mothers with and without placental malaria...
October 17, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30333240/avidity-based-binding-to-her2-results-in-selective-killing-of-her2-overexpressing-cells-by-anti-her2-cd3
#18
Dionysos Slaga, Diego Ellerman, T Noelle Lombana, Rajesh Vij, Ji Li, Maria Hristopoulos, Robyn Clark, Jennifer Johnston, Amy Shelton, Elaine Mai, Kapil Gadkar, Amy A Lo, James T Koerber, Klara Totpal, Rodney Prell, Genee Lee, Christoph Spiess, Teemu T Junttila
A primary barrier to the success of T cell-recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, we developed an anti-HER2/CD3 T cell-dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells...
October 17, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30333239/health-and-societal-implications-of-medical-and-technological-advances
#19
REVIEW
Victor J Dzau, Celynne A Balatbat
Scientific and technological breakthroughs are transforming the future of medicine and health, but they inevitably carry risks and have societal implications that need to be addressed proactively.
October 17, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/30333238/a-dysbiotic-microbiome-triggers-t-h-17-cells-to-mediate-oral-mucosal-immunopathology-in-mice-and-humans
#20
Nicolas Dutzan, Tetsuhiro Kajikawa, Loreto Abusleme, Teresa Greenwell-Wild, Carlos E Zuazo, Tomoko Ikeuchi, Laurie Brenchley, Toshiharu Abe, Charlotte Hurabielle, Daniel Martin, Robert J Morell, Alexandra F Freeman, Vanja Lazarevic, Giorgio Trinchieri, Patricia I Diaz, Steven M Holland, Yasmine Belkaid, George Hajishengallis, Niki M Moutsopoulos
Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, we demonstrate an expansion of resident memory T helper 17 (TH 17) cells in human periodontitis. Phenocopying humans, TH 17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral TH 17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)-dependent manner, periodontitis-associated expansion of TH 17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23...
October 17, 2018: Science Translational Medicine
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