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Science Translational Medicine

Pamela Summers-Trio, Allison Hayes-Conroy, Burton Singer, Ralph I Horwitz
Medicine-based evidence integrates a patient's biology and biography to improve individual medical care and to help eliminate the translational gap between research and the clinic.
February 13, 2019: Science Translational Medicine
Ruth Saunders, Himanshu Kaul, Rachid Berair, Sherif Gonem, Amisha Singapuri, Amanda J Sutcliffe, Latifa Chachi, Michael S Biddle, Davinder Kaur, Michelle Bourne, Ian D Pavord, Andrew J Wardlaw, Salman H Siddiqui, Richard A Kay, Bindi S Brook, Rod H Smallwood, Christopher E Brightling
Increased airway smooth muscle mass, a feature of airway remodeling in asthma, is the strongest predictor of airflow limitation and contributes to asthma-associated morbidity and mortality. No current drug therapy for asthma is known to affect airway smooth muscle mass. Although there is increasing evidence that prostaglandin D2 type 2 receptor (DP2 ) is expressed in airway structural and inflammatory cells, few studies have addressed the expression and function of DP2 in airway smooth muscle cells. We report that the DP2 antagonist fevipiprant reduced airway smooth muscle mass in bronchial biopsies from patients with asthma who had participated in a previous randomized placebo-controlled trial...
February 13, 2019: Science Translational Medicine
Anne-Laure Papa, Amanda Jiang, Netanel Korin, Michelle B Chen, Erin T Langan, Anna Waterhouse, Emma Nash, Jildaz Caroff, Amanda Graveline, Andyna Vernet, Akiko Mammoto, Tadanori Mammoto, Abhishek Jain, Roger D Kamm, Matthew J Gounis, Donald E Ingber
Platelets are crucial for normal hemostasis; however, their hyperactivation also contributes to many potentially lethal pathologies including myocardial infarction, stroke, and cancer. We hypothesized that modified platelets lacking their aggregation and activation capacity could act as reversible inhibitors of platelet activation cascades. Here, we describe the development of detergent-extracted human modified platelets (platelet decoys) that retained platelet binding functions but were incapable of functional activation and aggregation...
February 13, 2019: Science Translational Medicine
Sunil Singhal, Jason Stadanlick, Michael J Annunziata, Abhishek S Rao, Pratik S Bhojnagarwala, Shaun O'Brien, Edmund K Moon, Edward Cantu, Gwenn Danet-Desnoyers, Hyun-Jeong Ra, Leslie Litzky, Tatiana Akimova, Ulf H Beier, Wayne W Hancock, Steven M Albelda, Evgeniy B Eruslanov
Data from mouse tumor models suggest that tumor-associated monocyte/macrophage lineage cells (MMLCs) dampen antitumor immune responses. However, given the fundamental differences between mice and humans in tumor evolution, genetic heterogeneity, and immunity, the function of MMLCs might be different in human tumors, especially during early stages of disease. Here, we studied MMLCs in early-stage human lung tumors and found that they consist of a mixture of classical tissue monocytes and tumor-associated macrophages (TAMs)...
February 13, 2019: Science Translational Medicine
Felipe J Núñez, Flor M Mendez, Padma Kadiyala, Mahmoud S Alghamri, Masha G Savelieff, Maria B Garcia-Fabiani, Santiago Haase, Carl Koschmann, Anda-Alexandra Calinescu, Neha Kamran, Meghna Saxena, Rohin Patel, Stephen Carney, Marissa Z Guo, Marta Edwards, Mats Ljungman, Tingting Qin, Maureen A Sartor, Rebecca Tagett, Sriram Venneti, Jacqueline Brosnan-Cashman, Alan Meeker, Vera Gorbunova, Lili Zhao, Daniel M Kremer, Li Zhang, Costas A Lyssiotis, Lindsey Jones, Cameron J Herting, James L Ross, Dolores Hambardzumyan, Shawn Hervey-Jumper, Maria E Figueroa, Pedro R Lowenstein, Maria G Castro
Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1R132H ) are younger at diagnosis and live longer. IDH1 mutations co-occur with other molecular lesions, such as 1p/19q codeletion, inactivating mutations in the tumor suppressor protein 53 (TP53 ) gene, and loss-of-function mutations in alpha thalassemia/mental retardation syndrome X-linked gene ( ATRX ). All adult low-grade gliomas (LGGs) harboring ATRX loss also express the IDH1R132H mutation. The current molecular classification of LGGs is based, partly, on the distribution of these mutations...
February 13, 2019: Science Translational Medicine
Bruno Saleme, Vikram Gurtu, Yongneng Zhang, Adam Kinnaird, Aristeidis E Boukouris, Keshav Gopal, John R Ussher, Gopinath Sutendra
Chemotherapy-induced cardiotoxicity (CIC) is a common clinical problem that compromises effective anticancer therapies. Many chemotherapeutics (including anthracyclines, such as doxorubicin) induce the proapoptotic transcription factor p53 in the tumor and nonspecifically in the heart, promoting heart failure. Although inhibition of p53 shows benefit in preclinical heart failure models, it would not be an attractive adjuvant therapy for CIC, because it would prevent tumor regression. A p53-targeting therapy that would decrease chemotherapy-induced apoptosis in the myocardium and, at the same time, enhance apoptosis in the tumor would be ideal...
February 6, 2019: Science Translational Medicine
Matthew J Watt, Ashlee K Clark, Luke A Selth, Vanessa R Haynes, Natalie Lister, Richard Rebello, Laura H Porter, Birunthi Niranjan, Sarah T Whitby, Jennifer Lo, Cheng Huang, Ralf B Schittenhelm, Kimberley E Anderson, Luc Furic, Poornima R Wijayaratne, Maria Matzaris, Magdalene K Montgomery, Melissa Papargiris, Sam Norden, Maria Febbraio, Gail P Risbridger, Mark Frydenberg, Daniel K Nomura, Renea A Taylor
Metabolism alterations are hallmarks of cancer, but the involvement of lipid metabolism in disease progression is unclear. We investigated the role of lipid metabolism in prostate cancer using tissue from patients with prostate cancer and patient-derived xenograft mouse models. We showed that fatty acid uptake was increased in human prostate cancer and that these fatty acids were directed toward biomass production. These changes were mediated, at least partly, by the fatty acid transporter CD36, which was associated with aggressive disease...
February 6, 2019: Science Translational Medicine
Dorian A Rosen, Scott M Seki, Anthony Fernández-Castañeda, Rebecca M Beiter, Jacob D Eccles, Judith A Woodfolk, Alban Gaultier
Sepsis is an often deadly complication of infection in which systemic inflammation damages the vasculature, leading to tissue hypoperfusion and multiple organ failure. Currently, the standard of care for sepsis is predominantly supportive, with few therapeutic options available. Because of increased sepsis incidence worldwide, there is an urgent need for discovery of novel therapeutic targets and development of new treatments. The recently discovered function of the endoplasmic reticulum (ER) in regulation of inflammation offers a potential avenue for sepsis control...
February 6, 2019: Science Translational Medicine
Alessandro Prestipino, Robert Zeiser
Treatment with immune checkpoint inhibitors targeting programmed death receptor-1 (PD-1) or programmed death ligand-1 (PD-L1) is effective in many cancer types. Tumors harboring specific mutations modulate antitumor immune responses through the PD-1/PD-L1 axis, and this should be taken into account when designing rational combinatory treatments.
February 6, 2019: Science Translational Medicine
Jennifer M Dan, Colin Havenar-Daughton, Kayla Kendric, Rita Al-Kolla, Kirti Kaushik, Sandy L Rosales, Ericka L Anderson, Christopher N LaRock, Pandurangan Vijayanand, Grégory Seumois, David Layfield, Ramsey I Cutress, Christian H Ottensmeier, Cecilia S Lindestam Arlehamn, Alessandro Sette, Victor Nizet, Marcella Bothwell, Matthew Brigger, Shane Crotty
"Strep throat" is highly prevalent among children, yet it is unknown why only some children develop recurrent tonsillitis (RT), a common indication for tonsillectomy. To gain insights into this classic childhood disease, we performed phenotypic, genotypic, and functional studies on pediatric group A Streptococcus (GAS) RT and non-RT tonsils from two independent cohorts. GAS RT tonsils had smaller germinal centers, with an underrepresentation of GAS-specific CD4+ germinal center T follicular helper (GC-TFH ) cells...
February 6, 2019: Science Translational Medicine
Susannah L Hewitt, Ailin Bai, Dyane Bailey, Kana Ichikawa, John Zielinski, Russell Karp, Ameya Apte, Kristen Arnold, Sima J Zacharek, Maria S Iliou, Khushbu Bhatt, Maija Garnaas, Faith Musenge, Ashley Davis, Nikhil Khatwani, Stephen V Su, Graham MacLean, Samuel J Farlow, Kristine Burke, Joshua P Frederick
Many solid cancers contain dysfunctional immune microenvironments. Immune system modulators that initiate responses to foreign pathogens could be promising candidates for reigniting productive responses toward tumors. Interleukin-1 (IL-1) and IL-12 cytokine family members cooperate at barrier tissues after microbial invasion, in human inflammatory diseases, and in antitumoral immunity. IL-36γ, in classic alarmin fashion, acts in damaged tissues, whereas IL-23 centrally coordinates immune responses to danger signals...
January 30, 2019: Science Translational Medicine
Matthew T Wolf, Sudipto Ganguly, Tony L Wang, Christopher W Anderson, Kaitlyn Sadtler, Radhika Narain, Christopher Cherry, Alexis J Parrillo, Benjamin V Park, Guannan Wang, Fan Pan, Saraswati Sukumar, Drew M Pardoll, Jennifer H Elisseeff
Biomaterials in regenerative medicine are designed to mimic and modulate tissue environments to promote repair. Biologic scaffolds (derived from decellularized tissue extracellular matrix) promote a wound-healing (proregenerative) immune phenotype and are used clinically to treat tissue loss, including in the context of tumor resection. It is unknown whether a biomaterial microenvironment that encourages tissue formation may also promote tumor development. We implanted a urinary bladder matrix (UBM) scaffold, which is used clinically for wound management, with syngeneic cancer cell lines in mice to study how wound-healing immune responses affect tumor formation and sensitivity to immune checkpoint blockade...
January 30, 2019: Science Translational Medicine
Lea C Berkhout, Merel J l'Ami, Jill Ruwaard, Margreet H Hart, Pleuni Ooijevaar-de Heer, Karien Bloem, Michael T Nurmohamed, Ronald F van Vollenhoven, Maarten Boers, Daniel F Alvarez, Catherine H Smith, Gerrit J Wolbink, Theo Rispens
Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i...
January 30, 2019: Science Translational Medicine
Niv Zmora, Eliran Soffer, Eran Elinav
Advances in microbiome research are spurring the development of new therapeutics for a variety of diseases, but translational challenges remain.
January 30, 2019: Science Translational Medicine
Laura D Gamble, Stefania Purgato, Jayne Murray, Lin Xiao, Denise M T Yu, Kimberley M Hanssen, Federico M Giorgi, Daniel R Carter, Andrew J Gifford, Emanuele Valli, Giorgio Milazzo, Alvin Kamili, Chelsea Mayoh, Bing Liu, Georgina Eden, Sara Sarraf, Sophie Allan, Simone Di Giacomo, Claudia L Flemming, Amanda J Russell, Belamy B Cheung, Andre Oberthuer, Wendy B London, Matthias Fischer, Toby N Trahair, Jamie I Fletcher, Glenn M Marshall, David S Ziegler, Michael D Hogarty, Mark R Burns, Giovanni Perini, Murray D Norris, Michelle Haber
Amplification of the MYCN oncogene is associated with an aggressive phenotype and poor outcome in childhood neuroblastoma. Polyamines are highly regulated essential cations that are frequently elevated in cancer cells, and the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase 1 (ODC1), is a direct transcriptional target of MYCN. Treatment of neuroblastoma cells with the ODC1 inhibitor difluoromethylornithine (DFMO), although a promising therapeutic strategy, is only partially effective at impeding neuroblastoma cell growth due to activation of compensatory mechanisms resulting in increased polyamine uptake from the surrounding microenvironment...
January 30, 2019: Science Translational Medicine
Guillem Pascual-Pasto, Miriam Bazan-Peregrino, Nagore G Olaciregui, Camilo A Restrepo-Perdomo, Ana Mato-Berciano, Daniela Ottaviani, Klaus Weber, Genoveva Correa, Sonia Paco, Monica Vila-Ubach, Maria Cuadrado-Vilanova, Helena Castillo-Ecija, Gaia Botteri, Laura Garcia-Gerique, Helena Moreno-Gilabert, Marta Gimenez-Alejandre, Patricia Alonso-Lopez, Marti Farrera-Sal, Silvia Torres-Manjon, Dolores Ramos-Lozano, Rafael Moreno, Isabelle Aerts, François Doz, Nathalie Cassoux, Elodie Chapeaublanc, Montserrat Torrebadell, Monica Roldan, Andrés König, Mariona Suñol, Joana Claverol, Cinzia Lavarino, Torres Carmen de, Ligia Fu, François Radvanyi, Francis L Munier, Jaume Catalá-Mora, Jaume Mora, Ramón Alemany, Manel Cascalló, Guillermo L Chantada, Angel M Carcaboso
Retinoblastoma is a pediatric solid tumor of the retina activated upon homozygous inactivation of the tumor suppressor RB1 VCN-01 is an oncolytic adenovirus designed to replicate selectively in tumor cells with high abundance of free E2F-1, a consequence of a dysfunctional RB1 pathway. Thus, we reasoned that VCN-01 could provide targeted therapeutic activity against even chemoresistant retinoblastoma. In vitro, VCN-01 effectively killed patient-derived retinoblastoma models. In mice, intravitreous administration of VCN-01 in retinoblastoma xenografts induced tumor necrosis, improved ocular survival compared with standard-of-care chemotherapy, and prevented micrometastatic dissemination into the brain...
January 23, 2019: Science Translational Medicine
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