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Nature Medicine

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https://www.readbyqxmd.com/read/29431745/dkk2-imparts-tumor-immunity-evasion-through-%C3%AE-catenin-independent-suppression-of-cytotoxic-immune-cell-activation
#1
Qian Xiao, Jibo Wu, Wei-Jia Wang, Shiyang Chen, Yingxia Zheng, Xiaoqing Yu, Katrina Meeth, Mahnaz Sahraei, Alfred L M Bothwell, Lieping Chen, Marcus Bosenberg, Jianfeng Chen, Veronika Sexl, Le Sun, Lin Li, Wenwen Tang, Dianqing Wu
Immunotherapy offers new options for cancer treatment, but efficacy varies across cancer types. Colorectal cancers (CRCs) are largely refractory to immune-checkpoint blockade, which suggests the presence of yet uncharacterized immune-suppressive mechanisms. Here we report that the loss of adenomatosis polyposis coli (APC) in intestinal tumor cells or of the tumor suppressor PTEN in melanoma cells upregulates the expression of Dickkopf-related protein 2 (DKK2), which, together with its receptor LRP5, provides an unconventional mechanism for tumor immune evasion...
February 12, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29431744/a-histone-deacetylase-3-dependent-pathway-delimits-peripheral-myelin-growth-and-functional-regeneration
#2
Xuelian He, Liguo Zhang, Luis F Queme, Xuezhao Liu, Andrew Lu, Ronald R Waclaw, Xinran Dong, Wenhao Zhou, Grahame Kidd, Sung-Ok Yoon, Andres Buonanno, Joshua B Rubin, Mei Xin, Klaus-Armin Nave, Bruce D Trapp, Michael P Jankowski, Q Richard Lu
Deficits in Schwann cell-mediated remyelination impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms mediating block of remyelination remain elusive. Here, through small-molecule screening focusing on epigenetic modulators, we identified histone deacetylase 3 (HDAC3; a histone-modifying enzyme) as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 enhanced myelin growth and regeneration and improved functional recovery after peripheral nerve injury in mice...
February 12, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29431743/sorafenib-promotes-graft-versus-leukemia-activity-in-mice-and-humans-through-il-15-production-in-flt3-itd-mutant-leukemia-cells
#3
Nimitha R Mathew, Francis Baumgartner, Lukas Braun, David O'Sullivan, Simone Thomas, Miguel Waterhouse, Tony A Müller, Kathrin Hanke, Sanaz Taromi, Petya Apostolova, Anna L Illert, Wolfgang Melchinger, Sandra Duquesne, Annette Schmitt-Graeff, Lena Osswald, Kai-Li Yan, Arnim Weber, Sonia Tugues, Sabine Spath, Dietmar Pfeifer, Marie Follo, Rainer Claus, Michael Lübbert, Christoph Rummelt, Hartmut Bertz, Ralph Wäsch, Johanna Haag, Andrea Schmidts, Michael Schultheiss, Dominik Bettinger, Robert Thimme, Evelyn Ullrich, Yakup Tanriver, Giang Lam Vuong, Renate Arnold, Philipp Hemmati, Dominik Wolf, Markus Ditschkowski, Cordula Jilg, Konrad Wilhelm, Christian Leiber, Sabine Gerull, Jörg Halter, Claudia Lengerke, Thomas Pabst, Thomas Schroeder, Guido Kobbe, Wolf Rösler, Soroush Doostkam, Stephan Meckel, Kathleen Stabla, Stephan K Metzelder, Sebastian Halbach, Tilman Brummer, Zehan Hu, Joern Dengjel, Björn Hackanson, Christoph Schmid, Udo Holtick, Christof Scheid, Alexandros Spyridonidis, Friedrich Stölzel, Rainer Ordemann, Lutz P Müller, Flore Sicre-de-Fontbrune, Gabriele Ihorst, Jürgen Kuball, Jan E Ehlert, Daniel Feger, Eva-Maria Wagner, Jean-Yves Cahn, Jacqueline Schnell, Florian Kuchenbauer, Donald Bunjes, Ronjon Chakraverty, Simon Richardson, Saar Gill, Nicolaus Kröger, Francis Ayuk, Luca Vago, Fabio Ciceri, Antonia M Müller, Takeshi Kondo, Takanori Teshima, Susan Klaeger, Bernhard Kuster, Dennis Dong Hwan Kim, Daniel Weisdorf, Walter van der Velden, Daniela Dörfel, Wolfgang Bethge, Inken Hilgendorf, Andreas Hochhaus, Geoffroy Andrieux, Melanie Börries, Hauke Busch, John Magenau, Pavan Reddy, Myriam Labopin, Joseph H Antin, Andrea S Henden, Geoffrey R Hill, Glen A Kennedy, Merav Bar, Anita Sarma, Donal McLornan, Ghulam Mufti, Betul Oran, Katayoun Rezvani, Omid Sha, Robert S Negrin, Arnon Nagler, Marco Prinz, Andreas Burchert, Andreas Neubauer, Dietrich Beelen, Andreas Mackensen, Nikolas von Bubnoff, Wolfgang Herr, Burkhard Becher, Gerard Socié, Michael A Caligiuri, Eliana Ruggiero, Chiara Bonini, Georg Häcker, Justus Duyster, Jürgen Finke, Erika Pearce, Bruce R Blazar, Robert Zeiser
Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD+ leukemia cells. This synergized with the allogeneic CD8+ T cell response, leading to long-term survival in six mouse models of FLT3-ITD+ AML...
February 12, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29431742/transcriptional-regulation-of-macrophage-cholesterol-efflux-and-atherogenesis-by-a-long-noncoding-rna
#4
Tamer Sallam, Marius Jones, Brandon J Thomas, Xiaohui Wu, Thomas Gilliland, Kevin Qian, Ascia Eskin, David Casero, Zhengyi Zhang, Jaspreet Sandhu, David Salisbury, Prashant Rajbhandari, Mete Civelek, Cynthia Hong, Ayaka Ito, Xin Liu, Bence Daniel, Aldons J Lusis, Julian Whitelegge, Laszlo Nagy, Antonio Castrillo, Stephen Smale, Peter Tontonoz
Nuclear receptors regulate gene expression in response to environmental cues, but the molecular events governing the cell type specificity of nuclear receptors remain poorly understood. Here we outline a role for a long noncoding RNA (lncRNA) in modulating the cell type-specific actions of liver X receptors (LXRs), sterol-activated nuclear receptors that regulate the expression of genes involved in cholesterol homeostasis and that have been causally linked to the pathogenesis of atherosclerosis. We identify the lncRNA MeXis as an amplifier of LXR-dependent transcription of the gene Abca1, which is critical for regulation of cholesterol efflux...
February 12, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29400714/haploinsufficiency-leads-to-neurodegeneration-in-c9orf72-als-ftd-human-induced-motor-neurons
#5
Yingxiao Shi, Shaoyu Lin, Kim A Staats, Yichen Li, Wen-Hsuan Chang, Shu-Ting Hung, Eric Hendricks, Gabriel R Linares, Yaoming Wang, Esther Y Son, Xinmei Wen, Kassandra Kisler, Brent Wilkinson, Louise Menendez, Tohru Sugawara, Phillip Woolwine, Mickey Huang, Michael J Cowan, Brandon Ge, Nicole Koutsodendris, Kaitlin P Sandor, Jacob Komberg, Vamshidhar R Vangoor, Ketharini Senthilkumar, Valerie Hennes, Carina Seah, Amy R Nelson, Tze-Yuan Cheng, Shih-Jong J Lee, Paul R August, Jason A Chen, Nicholas Wisniewski, Victor Hanson-Smith, T Grant Belgard, Alice Zhang, Marcelo Coba, Chris Grunseich, Michael E Ward, Leonard H van den Berg, R Jeroen Pasterkamp, Davide Trotti, Berislav V Zlokovic, Justin K Ichida
An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear. Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS. We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion...
February 5, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29400713/brown-adipose-tissue-thermogenic-adaptation-requires-nrf1-mediated-proteasomal-activity
#6
Alexander Bartelt, Scott B Widenmaier, Christian Schlein, Kornelia Johann, Renata L S Goncalves, Kosei Eguchi, Alexander W Fischer, Günes Parlakgül, Nicole A Snyder, Truc B Nguyen, Oliver T Bruns, Daniel Franke, Moungi G Bawendi, Matthew D Lynes, Luiz O Leiria, Yu-Hua Tseng, Karen E Inouye, Ana Paula Arruda, Gökhan S Hotamisligil
Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and they are thus an important cell type for the maintenance of proper metabolic health. Although the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER to metabolic challenges in adipocytes are unclear. Here we show that brown adipose tissue (BAT) thermogenic function requires an adaptive increase in proteasomal activity to secure cellular protein quality control, and we identify the ER-localized transcription factor nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1) as a critical driver of this process...
February 5, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29400712/noncanonical-hedgehog-pathway-activation-through-srf-mkl1-promotes-drug-resistance-in-basal-cell-carcinomas
#7
Ramon J Whitson, Alex Lee, Nicole M Urman, Amar Mirza, Catherine Y Yao, Alexander S Brown, Jiang R Li, Gautam Shankar, Micah A Fry, Scott X Atwood, Eunice Y Lee, S Tyler Hollmig, Sumaira Z Aasi, Kavita Y Sarin, Matthew P Scott, Ervin H Epstein, Jean Y Tang, Anthony E Oro
Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity...
February 5, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29400711/pericyte-degeneration-causes-white-matter-dysfunction-in-the-mouse-central-nervous-system
#8
Axel Montagne, Angeliki M Nikolakopoulou, Zhen Zhao, Abhay P Sagare, Gabriel Si, Divna Lazic, Samuel R Barnes, Madelaine Daianu, Anita Ramanathan, Ariel Go, Erica J Lawson, Yaoming Wang, William J Mack, Paul M Thompson, Julie A Schneider, Jobin Varkey, Ralf Langen, Eric Mullins, Russell E Jacobs, Berislav V Zlokovic
Diffuse white-matter disease associated with small-vessel disease and dementia is prevalent in the elderly. The biological mechanisms, however, remain elusive. Using pericyte-deficient mice, magnetic resonance imaging, viral-based tract-tracing, and behavior and tissue analysis, we found that pericyte degeneration disrupted white-matter microcirculation, resulting in an accumulation of toxic blood-derived fibrin(ogen) deposits and blood-flow reductions, which triggered a loss of myelin, axons and oligodendrocytes...
February 5, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29400710/a-novel-chimeric-antigen-receptor-containing-a-jak-stat-signaling-domain-mediates-superior-antitumor-effects
#9
Yuki Kagoya, Shinya Tanaka, Tingxi Guo, Mark Anczurowski, Chung-Hsi Wang, Kayoko Saso, Marcus O Butler, Mark D Minden, Naoto Hirano
The adoptive transfer of T cells engineered with a chimeric antigen receptor (CAR) (hereafter referred to as CAR-T cells) specific for the B lymphocyte antigen CD19 has shown impressive clinical responses in patients with refractory B cell malignancies. However, the therapeutic effects of CAR-T cells that target other malignancies have not yet resulted in significant clinical benefit. Although inefficient tumor trafficking and various immunosuppressive mechanisms can impede CAR-T cell effector responses, the signals delivered by the current CAR constructs may still be insufficient to fully activate antitumor T cell functions...
February 5, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29400709/congenital-zika-virus-infection-as-a-silent-pathology-with-loss-of-neurogenic-output-in-the-fetal-brain
#10
Kristina M Adams Waldorf, Branden R Nelson, Jennifer E Stencel-Baerenwald, Colin Studholme, Raj P Kapur, Blair Armistead, Christie L Walker, Sean Merillat, Jay Vornhagen, Jennifer Tisoncik-Go, Audrey Baldessari, Michelle Coleman, Manjiri K Dighe, Dennis W W Shaw, Justin A Roby, Veronica Santana-Ufret, Erica Boldenow, Junwei Li, Xiaohu Gao, Michael A Davis, Jesica A Swanstrom, Kara Jensen, Douglas G Widman, Ralph S Baric, Joseph T Medwid, Kathryn A Hanley, Jason Ogle, G Michael Gough, Wonsok Lee, Chris English, W McIntyre Durning, Jeff Thiel, Chris Gatenby, Elyse C Dewey, Marian R Fairgrieve, Rebecca D Hodge, Richard F Grant, LaRene Kuller, William B Dobyns, Robert F Hevner, Michael Gale, Lakshmi Rajagopal
Zika virus (ZIKV) is a flavivirus with teratogenic effects on fetal brain, but the spectrum of ZIKV-induced brain injury is unknown, particularly when ultrasound imaging is normal. In a pregnant pigtail macaque (Macaca nemestrina) model of ZIKV infection, we demonstrate that ZIKV-induced injury to fetal brain is substantial, even in the absence of microcephaly, and may be challenging to detect in a clinical setting. A common and subtle injury pattern was identified, including (i) periventricular T2-hyperintense foci and loss of fetal noncortical brain volume, (ii) injury to the ependymal epithelium with underlying gliosis and (iii) loss of late fetal neuronal progenitor cells in the subventricular zone (temporal cortex) and subgranular zone (dentate gyrus, hippocampus) with dysmorphic granule neuron patterning...
February 5, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29377004/antagonism-of-ppar-%C3%AE-signaling-expands-human-hematopoietic-stem-and-progenitor-cells-by-enhancing-glycolysis
#11
Bin Guo, Xinxin Huang, Man Ryul Lee, Sang A Lee, Hal E Broxmeyer
Hematopoietic stem cells (HSCs) quiescently reside in bone marrow niches and have the capacity to self-renew or differentiate to form all of the blood cells throughout the lifespan of an animal. Allogeneic HSC transplantation is a life-saving treatment for malignant and nonmalignant disorders. HSCs isolated from umbilical cord blood (CB) are used for hematopoietic cell transplantation (HCT), but due to the limited numbers of HSCs in single units of umbilical CB, a number of methods have been proposed for ex vivo expansion of human HSCs...
January 29, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29334376/positively-selected-enhancer-elements-endow-osteosarcoma-cells-with-metastatic-competence
#12
James J Morrow, Ian Bayles, Alister P W Funnell, Tyler E Miller, Alina Saiakhova, Michael M Lizardo, Cynthia F Bartels, Maaike Y Kapteijn, Stevephen Hung, Arnulfo Mendoza, Gursimran Dhillon, Daniel R Chee, Jay T Myers, Frederick Allen, Marco Gambarotti, Alberto Righi, Analisa DiFeo, Brian P Rubin, Alex Y Huang, Paul S Meltzer, Lee J Helman, Piero Picci, Henri Versteeg, John Stamatoyannopolus, Chand Khanna, Peter C Scacheri
Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in enhancer activity between primary and metastatic human tumors and between near isogenic pairs of highly lung metastatic and nonmetastatic osteosarcoma cell lines. We term these regions metastatic variant enhancer loci (Met-VELs)...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29334375/a-small-molecule-inhibitor-of-the-ubiquitin-activating-enzyme-for-cancer-treatment
#13
Marc L Hyer, Michael A Milhollen, Jeff Ciavarri, Paul Fleming, Tary Traore, Darshan Sappal, Jessica Huck, Judy Shi, James Gavin, Jim Brownell, Yu Yang, Bradley Stringer, Robert Griffin, Frank Bruzzese, Teresa Soucy, Jennifer Duffy, Claudia Rabino, Jessica Riceberg, Kara Hoar, Anya Lublinsky, Saurabh Menon, Michael Sintchak, Nancy Bump, Sai M Pulukuri, Steve Langston, Stephen Tirrell, Mike Kuranda, Petter Veiby, John Newcomb, Ping Li, Jing Tao Wu, Josh Powe, Lawrence R Dick, Paul Greenspan, Katherine Galvin, Mark Manfredi, Chris Claiborne, Benjamin S Amidon, Neil F Bence
The ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29334374/transitory-presence-of-myeloid-derived-suppressor-cells-in-neonates-is-critical-for-control-of-inflammation
#14
Yu-Mei He, Xing Li, Michela Perego, Yulia Nefedova, Andrew V Kossenkov, Erik A Jensen, Valerian Kagan, Yu-Feng Liu, Shu-Yu Fu, Qing-Jian Ye, Yan-Hong Zhou, Lai Wei, Dmitry I Gabrilovich, Jie Zhou
Myeloid-derived suppressor cells (MDSCs) are pathologically activated and relatively immature myeloid cells that have been implicated in the immunological regulation of many pathologic conditions. Phenotypically and morphologically, MDSCs are similar to neutrophils (PMN-MDSCs) and monocytes (M-MDSCs). However, they have potent suppressive activity and distinct gene expression profiles and biochemical characteristics. No or very few MDSCs are observed in steady-state physiological conditions. Therefore, until recently, accumulation of MDSCs was considered a consequence of pathological processes or pregnancy...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29334373/prevention-of-tuberculosis-in-rhesus-macaques-by-a-cytomegalovirus-based-vaccine
#15
Scott G Hansen, Daniel E Zak, Guangwu Xu, Julia C Ford, Emily E Marshall, Daniel Malouli, Roxanne M Gilbride, Colette M Hughes, Abigail B Ventura, Emily Ainslie, Kurt T Randall, Andrea N Selseth, Parker Rundstrom, Lauren Herlache, Matthew S Lewis, Haesun Park, Shannon L Planer, John M Turner, Miranda Fischer, Christina Armstrong, Robert C Zweig, Joseph Valvo, Jackie M Braun, Smitha Shankar, Lenette Lu, Andrew W Sylwester, Alfred W Legasse, Martin Messerle, Michael A Jarvis, Lynn M Amon, Alan Aderem, Galit Alter, Dominick J Laddy, Michele Stone, Aurelio Bonavia, Thomas G Evans, Michael K Axthelm, Klaus Früh, Paul T Edlefsen, Louis J Picker
Despite widespread use of the bacille Calmette-Guérin (BCG) vaccine, tuberculosis (TB) remains a leading cause of global mortality from a single infectious agent (Mycobacterium tuberculosis or Mtb). Here, over two independent Mtb challenge studies, we demonstrate that subcutaneous vaccination of rhesus macaques (RMs) with rhesus cytomegalovirus vectors encoding Mtb antigen inserts (hereafter referred to as RhCMV/TB)-which elicit and maintain highly effector-differentiated, circulating and tissue-resident Mtb-specific CD4+ and CD8+ memory T cell responses-can reduce the overall (pulmonary and extrapulmonary) extent of Mtb infection and disease by 68%, as compared to that in unvaccinated controls, after intrabronchial challenge with the Erdman strain of Mtb at ∼1 year after the first vaccination...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29334372/pharmacological-blockade-of-asct2-dependent-glutamine-transport-leads-to-antitumor-efficacy-in-preclinical-models
#16
Michael L Schulte, Allie Fu, Ping Zhao, Jun Li, Ling Geng, Shannon T Smith, Jumpei Kondo, Robert J Coffey, Marc O Johnson, Jeffrey C Rathmell, Joe T Sharick, Melissa C Skala, Jarrod A Smith, Jordan Berlin, M Kay Washington, Michael L Nickels, H Charles Manning
The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29334371/cooperative-targeting-of-melanoma-heterogeneity-with-an-axl-antibody-drug-conjugate-and-braf-mek-inhibitors
#17
Julia Boshuizen, Louise A Koopman, Oscar Krijgsman, Aida Shahrabi, Elke Gresnigt- van den Heuvel, Maarten A Ligtenberg, David W Vredevoogd, Kristel Kemper, Thomas Kuilman, Ji-Ying Song, Nora Pencheva, Jens Thing Mortensen, Marnix Geukes Foppen, Elisa A Rozeman, Christian U Blank, Maarten L Janmaat, David Satijn, Esther C W Breij, Daniel S Peeper, Paul W H I Parren
Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29309059/high-dimensional-single-cell-analysis-predicts-response-to-anti-pd-1-immunotherapy
#18
Carsten Krieg, Malgorzata Nowicka, Silvia Guglietta, Sabrina Schindler, Felix J Hartmann, Lukas M Weber, Reinhard Dummer, Mark D Robinson, Mitchell P Levesque, Burkhard Becher
Immune-checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) has been found to be effective for the treatment of metastatic melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable responses. Therefore, predictive biomarkers of a clinical response are urgently needed. Here we used high-dimensional single-cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of patients with stage IV melanoma before and after 12 weeks of anti-PD-1 immunotherapy...
January 8, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29309058/diverse-genetic-driven-immune-landscapes-dictate-tumor-progression-through-distinct-mechanisms
#19
Marco Bezzi, Nina Seitzer, Tomoki Ishikawa, Markus Reschke, Ming Chen, Guocan Wang, Caitlin Mitchell, Christopher Ng, Jesse Katon, Andrea Lunardi, Sabina Signoretti, John G Clohessy, Jiangwen Zhang, Pier Paolo Pandolfi
Multiple immune-cell types can infiltrate tumors and promote progression and metastasis through different mechanisms, including immunosuppression. How distinct genetic alterations in tumors affect the composition of the immune landscape is currently unclear. Here, we characterized the immune-cell composition of prostate cancers driven by the loss of the critical tumor suppressor gene Pten, either alone or in combination with the loss of Trp53, Zbtb7a or Pml. We observed a striking quantitative and qualitative heterogeneity that was directly dependent on the specific genetic events in the tumor and ranged from 'cold', noninflamed tumors to massively infiltrated landscapes-results with important therapeutic implications...
January 8, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29309057/macrophage-extracellular-trap-formation-promoted-by-platelet-activation-is-a-key-mediator-of-rhabdomyolysis-induced-acute-kidney-injury
#20
Koshu Okubo, Miho Kurosawa, Mako Kamiya, Yasuteru Urano, Akari Suzuki, Kazuhiko Yamamoto, Koji Hase, Koichiro Homma, Junichi Sasaki, Hiroaki Miyauchi, Tatsuo Hoshino, Matsuhiko Hayashi, Tanya N Mayadas, Junichi Hirahashi
Rhabdomyolysis is a serious syndrome caused by skeletal muscle injury and the subsequent release of breakdown products from damaged muscle cells into systemic circulation. The muscle damage most often results from strenuous exercise, muscle hypoxia, medications, or drug abuse and can lead to life-threatening complications, such as acute kidney injury (AKI). Rhabdomyolysis and the AKI complication can also occur during crush syndrome, an emergency condition that commonly occurs in victims of natural disasters, such as earthquakes, and man-made disasters, such as wars and terrorism...
January 8, 2018: Nature Medicine
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