Ocular neovascular diseases are caused by an overproduction of new blood vessels that disrupts eye function. On page 4900, Westenskow et al. uncover a new strategy to block neovascularization and endothelial cell sprouting in the eye. They demonstrate that the Ras pathway is important during angiogenesis and that the regulatory protein p120RasGAP is a key inhibitor in endothelial cells. Moreover, treatments targeting miR-132, a microRNA that targets p120RasGAP, can effectively inhibit angiogenesis. In the cover image, blood vessels in the retina of a 7-day-old mouse are labeled with GS lectin (red) and p120RasGAP staining (green).
Deep brain stimulation (DBS) is an emerging interventional therapy for well-screened patients with specific treatment-resistant neuropsychiatric diseases. Some neuropsychiatric conditions, such as Parkinson disease, have available and reasonable guideline and efficacy data, while other conditions, such as major depressive disorder and Tourette syndrome, have more limited, but promising results. This review summarizes both the efficacy and the neuroanatomical targets for DBS in four common neuropsychiatric conditions: Parkinson disease, Tourette syndrome, major depressive disorder, and obsessive-compulsive disorder. Based on emerging new research, we summarize novel approaches to optimization of stimulation for each neuropsychiatric disease and we review the potential positive and negative effects that may be observed following DBS. Finally, we summarize the likely future innovations in the field of electrical neural-network modulation.
Nolan R. Williams, Michael S. Okun
Schizophrenia is strongly familial yet rarely (if ever) exhibits classical Mendelian inheritance patterns. The advent of large-scale genotyping and sequencing projects has yielded large data sets with higher statistical power in an effort to uncover new associations with schizophrenia. Here, we review the challenges in dissecting the genetics of schizophrenia and provide an update of the current understanding of the underlying genomics. We discuss the breadth of susceptibility alleles, including those that may occur with low frequency and high disease risk, such as the 22q11.2 hemideletion, as well as alleles that may occur with greater frequency but convey a lower risk of schizophrenia, such as variants in genes encoding subunits of the voltage-gated L-type calcium channel. Finally, we provide an overview of the clinical implications for the diagnosis and treatment of schizophrenia based on progress in understanding the underlying genetic basis.
Paola Giusti-Rodríguez, Patrick F. Sullivan
The discovery of citrate anticoagulant in the 1920s and the development of plastic packs for blood collection in the 1960s laid the groundwork for platelet transfusion therapy on a scale not previously possible. A major limitation, however, was the finding that platelet concentrates prepared from blood anticoagulated with citrate were unsuitable for transfusion because of platelet clumping. We found that this could be prevented by simply reducing the pH of platelet-rich plasma to about 6.5 prior to centrifugation. We used this approach to characterize platelet kinetics and sites of platelet sequestration in normal and pathologic states and to define the influence of variables such as anticoagulant and ABO incompatibility on post-transfusion platelet recovery. The “acidification” approach enabled much wider use of platelet transfusion therapy until alternative means of producing concentrates suitable for transfusion became available.
Richard H. Aster
The Chernobyl nuclear disaster has caused a remarkable increase in radiation-induced papillary thyroid carcinoma in children and young adults. In this issue of the
Massimo Santoro, Francesca Carlomagno
Prostate cancer has a range of clinical outcomes, from complete remission in response to treatment to death as a result of aggressive metastasis. Prognosis for individuals with prostate cancer is not readily predictable, and new diagnostics will be useful for treatment strategy determination. In this issue of the
A. Rose Brannon, Charles L. Sawyers
Chronic kidney disease is associated with progressive kidney fibrosis, which disrupts normal kidney function. There is a great need for treatments to reduce renal fibrosis. In this issue of the
Joseph V. Bonventre
Global, sustained production of ROS has deleterious effects on tissue structure and function and gives rise to biochemical and physiological changes associated with organ senescence. Specific, localized ROS metabolites generated by mitochondria and NADPH oxidases also transduce homeostatic information in response to metabolic, mechanical, and inflammatory cues. In this issue of the
Dwight A. Towler
Regulatory T cells (Tregs) control type 2 T helper cell–mediated (Th2-mediated) lung inflammation, but the molecular mechanisms by which Tregs execute this activity remain elusive. In this issue of the
The TGF-β superfamily comprises pleiotropic cytokines that regulate SMAD and non-SMAD signaling. TGF-β–SMAD signal transduction is known to be involved in tissue fibrosis, including renal fibrosis. Here, we found that 1,25-dihydroxyvitamin D3–bound [1,25(OH)2D3-bound] vitamin D receptor (VDR) specifically inhibits TGF-β–SMAD signal transduction through direct interaction with SMAD3. In mouse models of tissue fibrosis, 1,25(OH)2D3 treatment prevented renal fibrosis through the suppression of TGF-β–SMAD signal transduction. Based on the structure of the VDR-ligand complex, we generated 2 synthetic ligands. These ligands selectively inhibited TGF-β–SMAD signal transduction without activating VDR-mediated transcription and significantly attenuated renal fibrosis in mice. These results indicate that 1,25(OH)2D3-dependent suppression of TGF-β–SMAD signal transduction is independent of VDR-mediated transcriptional activity. In addition, these ligands did not cause hypercalcemia resulting from stimulation of the transcriptional activity of the VDR. Thus, our study provides a new strategy for generating chemical compounds that specifically inhibit TGF-β–SMAD signal transduction. Since TGF-β–SMAD signal transduction is reportedly involved in several disorders, our results will aid in the development of new drugs that do not cause detectable adverse effects, such as hypercalcemia.
Ichiaki Ito, Tsuyoshi Waku, Masato Aoki, Rumi Abe, Yu Nagai, Tatsuya Watanabe, Yuka Nakajima, Ichiro Ohkido, Keitaro Yokoyama, Hiroyuki Miyachi, Toshiyuki Shimizu, Akiko Murayama, Hiroyuki Kishimoto, Kazuo Nagasawa, Junn Yanagisawa
Myelodysplastic syndromes (MDS) are age-dependent stem cell malignancies that share biological features of activated adaptive immune response and ineffective hematopoiesis. Here we report that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis. These clonally distinct MDSC overproduce hematopoietic suppressive cytokines and function as potent apoptotic effectors targeting autologous hematopoietic progenitors. Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33. These 2 proteins formed a functional ligand/receptor pair that recruited components to CD33’s immunoreceptor tyrosine-based inhibition motif (ITIM), inducing secretion of the suppressive cytokines IL-10 and TGF-β by immature myeloid cells.
Xianghong Chen, Erika A. Eksioglu, Junmin Zhou, Ling Zhang, Julie Djeu, Nicole Fortenbery, Pearlie Epling-Burnette, Sandra Van Bijnen, Harry Dolstra, John Cannon, Je-in Youn, Sarah S. Donatelli, Dahui Qin, Theo De Witte, Jianguo Tao, Huaquan Wang, Pingyan Cheng, Dmitry I. Gabrilovich, Alan List, Sheng Wei
A dynamic interaction occurs between the lymphoma cell and its microenvironment, with each profoundly influencing the behavior of the other. Here, using a clonogenic coculture growth system and a xenograft mouse model, we demonstrated that adhesion of mantle cell lymphoma (MCL) and other non-Hodgkin lymphoma cells to lymphoma stromal cells confers drug resistance, clonogenicity, and induction of histone deacetylase 6 (HDAC6). Furthermore, stroma triggered a c-Myc/miR-548m feed-forward loop, linking sustained c-Myc activation, miR-548m downregulation, and subsequent HDAC6 upregulation and stroma-mediated cell survival and lymphoma progression in lymphoma cell lines, primary MCL and other B cell lymphoma cell lines. Treatment with an HDAC6-selective inhibitor alone or in synergy with a c-Myc inhibitor enhanced cell death, abolished cell adhesion–mediated drug resistance, and suppressed clonogenicity and lymphoma growth ex vivo and in vivo. Together, these data suggest that the lymphoma-stroma interaction in the lymphoma microenvironment directly impacts the biology of lymphoma through genetic and epigenetic regulation, with HDAC6 and c-Myc as potential therapeutic targets.
Tint Lwin, Xiaohong Zhao, Fengdong Cheng, Xinwei Zhang, Andy Huang, Bijal Shah, Yizhuo Zhang, Lynn C. Moscinski, Yong Sung Choi, Alan P. Kozikowski, James E. Bradner, William S. Dalton, Eduardo Sotomayor, Jianguo Tao
Recurrent mutations in the gene encoding additional sex combs-like 1 (
Daichi Inoue, Jiro Kitaura, Katsuhiro Togami, Koutarou Nishimura, Yutaka Enomoto, Tomoyuki Uchida, Yuki Kagiyama, Kimihito Cojin Kawabata, Fumio Nakahara, Kumi Izawa, Toshihiko Oki, Akie Maehara, Masamichi Isobe, Akiho Tsuchiya, Yuka Harada, Hironori Harada, Takahiro Ochiya, Hiroyuki Aburatani, Hiroshi Kimura, Felicitas Thol, Michael Heuser, Ross L. Levine, Omar Abdel-Wahab, Toshio Kitamura
T helper 9 (Th9) cells are specialized for the production of IL-9, promote allergic inflammation in mice, and are associated with allergic disease in humans. It has not been determined whether Th9 cells express a characteristic transcriptional signature. In this study, we performed microarray analysis to identify genes enriched in Th9 cells compared with other Th subsets. This analysis defined a transcriptional regulatory network required for the expression of a subset of Th9-enriched genes. The activator protein 1 (AP1) family transcription factor BATF (B cell, activating transcription factor–like) was among the genes enriched in Th9 cells and was required for the expression of IL-9 and other Th9-associated genes in both human and mouse T cells. The expression of BATF was increased in Th9 cultures derived from atopic infants compared with Th9 cultures from control infants. T cells deficient in BATF expression had a diminished capacity to promote allergic inflammation compared with wild-type controls. Moreover, mouse Th9 cells ectopically expressing BATF were more efficient at promoting allergic inflammation than control transduced cells. These data indicate that BATF is a central regulator of the Th9 phenotype and contributes to the development of allergic inflammation.
Rukhsana Jabeen, Ritobrata Goswami, Olufolakemi Awe, Aishwarya Kulkarni, Evelyn T. Nguyen, Andrea Attenasio, Daniel Walsh, Matthew R. Olson, Myung H. Kim, Robert S. Tepper, Jie Sun, Chang H. Kim, Elizabeth J. Taparowsky, Baohua Zhou, Mark H. Kaplan
Hans C. Dreyer, Lisa A. Strycker, Hilary A. Senesac, Austin D. Hocker, Keith Smolkowski, Steven N. Shah, Brian A. Jewett
Type 2 diabetes is characterized by insulin resistance and mitochondrial dysfunction in classical target tissues such as muscle, fat, and liver. Using a murine model of type 2 diabetes, we show that there is hypothalamic insulin resistance and mitochondrial dysfunction due to downregulation of the mitochondrial chaperone HSP60. HSP60 reduction in obese, diabetic mice was due to a lack of proper leptin signaling and was restored by leptin treatment. Knockdown of
André Kleinridders, Hans P.M.M. Lauritzen, Siegfried Ussar, Jane H. Christensen, Marcelo A. Mori, Peter Bross, C. Ronald Kahn
Helen Court, Marc Amoyel, Michael Hackman, Kyoung Eun Lee, Ruliang Xu, George Miller, Dafna Bar-Sagi, Erika A. Bach, Martin O. Bergö, Mark R. Philips
The inflammasome is a cytoplasmic multiprotein complex that promotes proinflammatory cytokine maturation in response to host- and pathogen-derived signals. Missense mutations in cryopyrin (
Susannah D. Brydges, Lori Broderick, Matthew D. McGeough, Carla A. Pena, James L. Mueller, Hal M. Hoffman
Anorexia nervosa and bulimia nervosa are common and severe eating disorders (EDs) of unknown etiology. Although genetic factors have been implicated in the psychopathology of EDs, a clear biological pathway has not been delineated. DNA from two large families affected by EDs was collected, and mutations segregating with illness were identified by whole-genome sequencing following linkage mapping or by whole-exome sequencing. In the first family, analysis of twenty members across three generations identified a rare missense mutation in the estrogen-related receptor α (
Huxing Cui, Jarrette Moore, Sunbola S. Ashimi, Brittany L. Mason, Jordan N. Drawbridge, Shizhong Han, Benjamin Hing, Abigail Matthews, Carrie J. McAdams, Benjamin W. Darbro, Andrew A. Pieper, David A. Waller, Chao Xing, Michael Lutter
Tumor vessel dysfunction is a pivotal event in cancer progression. Using an in vivo neovascularization model, we identified G protein–coupled receptor kinase 2 (GRK2) as a key angiogenesis regulator. An impaired angiogenic response involving immature vessels was observed in mice hemizygous for
Verónica Rivas, Rita Carmona, Ramón Muñoz-Chápuli, Marta Mendiola, Laura Nogués, Clara Reglero, María Miguel-Martín, Ramón García-Escudero, Gerald W. Dorn II, David Hardisson, Federico Mayor Jr., Petronila Penela
ROS are implicated in bone diseases. NADPH oxidase 4 (NOX4), a constitutively active enzymatic source of ROS, may contribute to the development of such disorders. Therefore, we studied the role of NOX4 in bone homeostasis.
Claudia Goettsch, Andrea Babelova, Olivia Trummer, Reinhold G. Erben, Martina Rauner, Stefan Rammelt, Norbert Weissmann, Valeska Weinberger, Sebastian Benkhoff, Marian Kampschulte, Barbara Obermayer-Pietsch, Lorenz C. Hofbauer, Ralf P. Brandes, Katrin Schröder
Donor T cells that respond to host alloantigens following allogeneic bone marrow transplantation (BMT) induce graft-versus-host (GVH) responses, but their molecular landscape is not well understood. MicroRNAs (miRNAs) regulate gene (mRNA) expression and fine-tune the molecular responses of T cells. We stimulated naive T cells with either allogeneic or nonspecific stimuli and used argonaute cross-linked immunoprecipitation (CLIP) with subsequent ChIP microarray analyses to profile miR responses and their direct mRNA targets. We identified a unique expression pattern of miRs and mRNAs following the allostimulation of T cells and a high correlation between the expression of the identified miRs and a reduction of their mRNA targets. miRs and mRNAs that were predicted to be differentially regulated in allogeneic T cells compared with nonspecifically stimulated T cells were validated in vitro. These analyses identified wings apart-like homolog (
Yaping Sun, Isao Tawara, Meng Zhao, Zhaohui S. Qin, Tomomi Toubai, Nathan Mathewson, Hiroya Tamaki, Evelyn Nieves, Arul M. Chinnaiyan, Pavan Reddy
Cross-priming of CD8+ T cells and generation of effector immune responses is pivotal for tumor immunity as well as for successful anticancer vaccination and therapy. Dead and dying cells produce signals that can influence Ag processing and presentation; however, there is conflicting evidence regarding the immunogenicity of necrotic cell death. We used a mouse model of sterile necrosis, in which mice were injected with sterile primary necrotic cells, to investigate a role of these cells in priming of CD8+ T cells. We discovered a molecular mechanism operating in Ag donor cells that regulates cross-priming of CD8+ T cells during primary sterile necrosis and thereby controls adaptive immune responses. We found that the cellular peptidases dipeptidyl peptidase 3 (DPP-3) and thimet oligopeptidase 1 (TOP-1), both of which are present in nonimmunogenic necrotic cells, eliminated proteasomal degradation products and blocked Ag cross-presentation. While sterile necrotic tumor cells failed to induce CD8+ T cell responses, their nonimmunogenicity could be reversed in vitro and in vivo by inactivation of DPP-3 and TOP-1. These results indicate that control of cross-priming and thereby immunogenicity of primary sterile necrosis relies on proteasome-dependent oligopeptide generation and functional status of peptidases in Ag donor cells.
Jaba Gamrekelashvili, Tamar Kapanadze, Miaojun Han, Josef Wissing, Chi Ma, Lothar Jaensch, Michael P. Manns, Todd Armstrong, Elizabeth Jaffee, Ayla O. White, Deborah E. Citrin, Firouzeh Korangy, Tim F. Greten
Chronic itch, or pruritus, is associated with a wide range of skin abnormalities. The mechanisms responsible for chronic itch induction and persistence remain unclear. We developed a mouse model in which a constitutively active form of the serine/threonine kinase BRAF was expressed in neurons gated by the sodium channel Nav1.8 (BRAFNav1.8 mice). We found that constitutive BRAF pathway activation in BRAFNav1.8 mice results in ectopic and enhanced expression of a cohort of itch-sensing genes, including gastrin-releasing peptide (
Zhong-Qiu Zhao, Fu-Quan Huo, Joseph Jeffry, Lori Hampton, Shadmehr Demehri, Seungil Kim, Xian-Yu Liu, Devin M. Barry, Li Wan, Zhong-Chun Liu, Hui Li, Ahu Turkoz, Kaijie Ma, Lynn A. Cornelius, Raphael Kopan, James F. Battey Jr., Jian Zhong, Zhou-Feng Chen
Approximately 90% of patients with isolated agammaglobulinemia and failure of B cell development have mutations in genes required for signaling through the pre–B cell and B cell receptors. The nature of the gene defect in the majority of remaining patients is unknown. We recently identified 4 patients with agammaglobulinemia and markedly decreased numbers of peripheral B cells. The B cells that could be detected had an unusual phenotype characterized by the increased expression of CD19 but the absence of a B cell receptor. Genetic studies demonstrated that all 4 patients had the exact same de novo mutation in the broadly expressed transcription factor E47. The mutant protein (E555K) was stable in patient-derived EBV-transformed cell lines and cell lines transfected with expression vectors. E555K in the transfected cells localized normally to the nucleus and resulted in a dominant negative effect when bound to DNA as a homodimer with wild-type E47. Mutant E47 did permit DNA binding by a tissue-specific heterodimeric DNA-binding partner, myogenic differentiation 1 (MYOD). These findings document a mutational hot-spot in E47 and represent an autosomal dominant form of agammaglobulinemia. Further, they indicate that E47 plays a critical role in enforcing the block in development of B cell precursors that lack functional antigen receptors.
Bertrand Boisson, Yong-Dong Wang, Amma Bosompem, Cindy S. Ma, Annick Lim, Tatiana Kochetkov, Stuart G. Tangye, Jean-Laurent Casanova, Mary Ellen Conley
Growth factors and their receptors coordinate neuronal differentiation during development, yet their roles in the pediatric tumor neuroblastoma remain unclear. Comparison of mRNA from benign neuroblastic tumors and neuroblastomas revealed that expression of the type III TGF-β receptor (
Erik H. Knelson, Angela L. Gaviglio, Alok K. Tewari, Michael B. Armstrong, Karthikeyan Mythreye, Gerard C. Blobe
Insulin-independent glucose disposal (referred to as glucose effectiveness [GE]) is crucial for glucose homeostasis and, until recently, was thought to be invariable. However, GE is reduced in type 2 diabetes and markedly decreased in leptin-deficient
Gregory J. Morton, Miles E. Matsen, Deanna P. Bracy, Thomas H. Meek, Hong T. Nguyen, Darko Stefanovski, Richard N. Bergman, David H. Wasserman, Michael W. Schwartz
The prevention and treatment of acute chest syndrome (ACS) is a major clinical concern in sickle cell disease (SCD). However, the mechanism underlying the pathogenesis of ACS remains elusive. We tested the hypothesis that the hemolysis byproduct hemin elicits events that induce ACS. Infusion of a low dose of hemin caused acute intravascular hemolysis and autoamplification of extracellular hemin in transgenic sickle mice, but not in sickle-trait littermates. The sickle mice developed multiple symptoms typical of ACS and succumbed rapidly. Pharmacologic inhibition of TLR4 and hemopexin replacement therapy prior to hemin infusion protected sickle mice from developing ACS. Replication of the ACS-like phenotype in nonsickle mice revealed that the mechanism of lung injury due to extracellular hemin is independent of SCD. Using genetic and bone marrow chimeric tools, we confirmed that TLR4 expressed in nonhematopoietic vascular tissues mediated this lethal type of acute lung injury. Respiratory failure was averted after the onset of ACS-like symptoms in sickle mice by treating them with recombinant hemopexin. Our results reveal a mechanism that helps to explain the pathogenesis of ACS, and we provide proof of principle for therapeutic strategies to prevent and treat this condition in mice.
Samit Ghosh, Olufolake Adetoro Adisa, Prasanthi Chappa, Fang Tan, Kesmic Ann Jackson, David Robert Archer, Solomon Fiifi Ofori-Acquah
Cachexia is a debilitating condition characterized by extreme skeletal muscle wasting that contributes significantly to morbidity and mortality. Efforts to elucidate the underlying mechanisms of muscle loss have predominantly focused on events intrinsic to the myofiber. In contrast, less regard has been given to potential contributory factors outside the fiber within the muscle microenvironment. In tumor-bearing mice and patients with pancreatic cancer, we found that cachexia was associated with a type of muscle damage resulting in activation of both satellite and nonsatellite muscle progenitor cells. These muscle progenitors committed to a myogenic program, but were inhibited from completing differentiation by an event linked with persistent expression of the self-renewing factor Pax7. Overexpression of Pax7 was sufficient to induce atrophy in normal muscle, while under tumor conditions, the reduction of Pax7 or exogenous addition of its downstream target, MyoD, reversed wasting by restoring cell differentiation and fusion with injured fibers. Furthermore, Pax7 was induced by serum factors from cachectic mice and patients, in an NF-κB–dependent manner, both in vitro and in vivo. Together, these results suggest that Pax7 responds to NF-κB by impairing the regenerative capacity of myogenic cells in the muscle microenvironment to drive muscle wasting in cancer.
Wei A. He, Emanuele Berardi, Veronica M. Cardillo, Swarnali Acharyya, Paola Aulino, Jennifer Thomas-Ahner, Jingxin Wang, Mark Bloomston, Peter Muscarella, Peter Nau, Nilay Shah, Matthew E.R. Butchbach, Katherine Ladner, Sergio Adamo, Michael A. Rudnicki, Charles Keller, Dario Coletti, Federica Montanaro, Denis C. Guttridge
The molecular mechanisms that control innate immune cell trafficking during chronic infection and inflammation, such as in tuberculosis (TB), are incompletely understood. During active TB, myeloid cells infiltrate the lung and sustain local inflammation. While the chemoattractants that orchestrate these processes are increasingly recognized, the posttranscriptional events that dictate their availability are unclear. We identified microRNA-223 (miR-223) as an upregulated small noncoding RNA in blood and lung parenchyma of TB patients and during murine TB. Deletion of miR-223 rendered TB-resistant mice highly susceptible to acute lung infection. The lethality of
Anca Dorhoi, Marco Iannaccone, Maura Farinacci, Kellen C. Faé, Jörg Schreiber, Pedro Moura-Alves, Geraldine Nouailles, Hans-Joachim Mollenkopf, Dagmar Oberbeck-Müller, Sabine Jörg, Ellen Heinemann, Karin Hahnke, Delia Löwe, Franca Del Nonno, Delia Goletti, Rosanna Capparelli, Stefan H.E. Kaufmann
Inadequate functional β cell mass underlies both type 1 and type 2 diabetes. β Cell growth and regeneration also decrease with age through mechanisms that are not fully understood. Age-dependent loss of enhancer of zeste homolog 2 (EZH2) prevents adult β cell replication through derepression of the gene encoding cyclin-dependent kinase inhibitor 2a (
Josie X. Zhou, Sangeeta Dhawan, Hualin Fu, Emily Snyder, Rita Bottino, Sharmistha Kundu, Seung K. Kim, Anil Bhushan
The capacity of IL-10 and Tregs in the inflammatory tumor microenvironment to impair anticancer Th1 immunity makes them attractive targets for cancer immunotherapy. IL-10 and Tregs also suppress Th17 activity, which is associated with poor prognosis in several cancers. However, previous studies have overlooked their potential contribution to the regulation of pathogenic cancer-associated inflammation. In this study, we investigated the origin and function of IL-10–producing cells in the tumor microenvironment using transplantable tumor models in mice. The majority of tumor-associated IL-10 was produced by an activated Treg population. IL-10 production by Tregs was required to restrain Th17-type inflammation. Accumulation of activated IL-10+ Tregs in the tumor required type I IFN signaling but not inflammatory signaling pathways that depend on TLR adapter protein MyD88 or IL-12 family cytokines. IL-10 production limited Th17 cell numbers in both spleen and tumor. However, type I IFN was required to limit Th17 cells specifically in the tumor microenvironment, reflecting selective control of tumor-associated Tregs by type I IFN. Thus, the interplay of type I IFN, Tregs, and IL-10 is required to negatively regulate Th17 inflammation in the tumor microenvironment. Therapeutic interference of this network could therefore have the undesirable consequence of promoting Th17 inflammation and cancer growth.
C. Andrew Stewart, Hannah Metheny, Noriho Iida, Loretta Smith, Miranda Hanson, Folkert Steinhagen, Robert M. Leighty, Axel Roers, Christopher L. Karp, Werner Müller, Giorgio Trinchieri
Hirschsprung disease (HSCR) is a partially penetrant oligogenic birth defect that occurs when enteric nervous system (ENS) precursors fail to colonize the distal bowel during early pregnancy. Genetic defects underlie HSCR, but much of the variability in the occurrence and severity of the birth defect remain unexplained. We hypothesized that nongenetic factors might contribute to disease development. Here we found that mycophenolate, an inhibitor of de novo guanine nucleotide biosynthesis, and 8 other drugs identified in a zebrafish screen impaired ENS development. In mice, mycophenolate treatment selectively impaired ENS precursor proliferation, delayed precursor migration, and induced bowel aganglionosis. In 2 different mouse models of HSCR, addition of mycophenolate increased the penetrance and severity of Hirschsprung-like pathology. Mycophenolate treatment also reduced ENS precursor migration as well as lamellipodia formation, proliferation, and survival in cultured enteric neural crest–derived cells. Using X-inactivation mosaicism for the purine salvage gene
Jonathan I. Lake, Olga A. Tusheva, Brittany L. Graham, Robert O. Heuckeroth
Diabetic microvascular complications have been considered to be mediated by a glucose-driven increase in mitochondrial superoxide anion production. Here, we report that superoxide production was reduced in the kidneys of a steptozotocin-induced mouse model of type 1 diabetes, as assessed by in vivo real-time transcutaneous fluorescence, confocal microscopy, and electron paramagnetic resonance analysis. Reduction of mitochondrial biogenesis and phosphorylation of pyruvate dehydrogenase (PDH) were observed in kidneys from diabetic mice. These observations were consistent with an overall reduction of mitochondrial glucose oxidation. Activity of AMPK, the major energy-sensing enzyme, was reduced in kidneys from both diabetic mice and humans. Mitochondrial biogenesis, PDH activity, and mitochondrial complex activity were rescued by treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). AICAR treatment induced superoxide production and was linked with glomerular matrix and albuminuria reduction in the diabetic kidney. Furthermore, diabetic heterozygous superoxide dismutase 2 (
Laura L. Dugan, Young-Hyun You, Sameh S. Ali, Maggie Diamond-Stanic, Satoshi Miyamoto, Anne-Emilie DeCleves, Aleksander Andreyev, Tammy Quach, San Ly, Grigory Shekhtman, William Nguyen, Andre Chepetan, Thuy P. Le, Lin Wang, Ming Xu, Kacie P. Paik, Agnes Fogo, Benoit Viollet, Anne Murphy, Frank Brosius, Robert K. Naviaux, Kumar Sharma
Vascular networks develop from a growing vascular front that responds to VEGF and other guidance cues. Angiogenesis is required for normal tissue function, but, under conditions of stress, inappropriate vascularization can lead to disease. Therefore, inhibition of angiogenic sprouting may prevent neovascularization in patients with blinding neovascular eye diseases, including macular degeneration. VEGF antagonists have therapeutic benefits but also can elicit off-target effects. Here, we found that the Ras pathway, which functions downstream of a wide range of cytokines including VEGF, is active in the growing vascular front of developing and pathological vascular networks. The endogenous Ras inhibitor p120RasGAP was expressed predominately in quiescent VEGF-insensitive endothelial cells and was ectopically downregulated in multiple neovascular models. MicroRNA-132 negatively regulated p120RasGAP expression. Experimental delivery of α-miR-132 to developing mouse eyes disrupted tip cell Ras activity and prevented angiogenic sprouting. This strategy prevented ocular neovascularization in multiple rodent models even more potently than the VEGF antagonist, VEGF-trap. Targeting microRNA-132 as a therapeutic strategy may prove useful for treating multiple neovascular diseases of the eye and for preventing vision loss regardless of the neovascular stimulus.
Peter D. Westenskow, Toshihide Kurihara, Edith Aguilar, Elizabeth L. Scheppke, Stacey K. Moreno, Carli Wittgrove, Valentina Marchetti, Iacovos P. Michael, Sudarshan Anand, Andras Nagy, David Cheresh, Martin Friedlander
Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (
You-Qiang Song, Tatsuki Karasugi, Kenneth M.C. Cheung, Kazuhiro Chiba, Daniel W.H. Ho, Atsushi Miyake, Patrick Y.P. Kao, Kit Ling Sze, Anita Yee, Atsushi Takahashi, Yoshiharu Kawaguchi, Yasuo Mikami, Morio Matsumoto, Daisuke Togawa, Masahiro Kanayama, Dongquan Shi, Jin Dai, Qing Jiang, Chengai Wu, Wei Tian, Na Wang, John C.Y. Leong, Keith D.K. Luk, Shea-ping Yip, Stacey S. Cherny, Junwen Wang, Stefan Mundlos, Anthi Kelempisioti, Pasi J. Eskola, Minna Männikkö, Pirkka Mäkelä, Jaro Karppinen, Marjo-Riitta Järvelin, Paul F. O’Reilly, Michiaki Kubo, Tomoatsu Kimura, Toshikazu Kubo, Yoshiaki Toyama, Hiroshi Mizuta, Kathryn S.E. Cheah, Tatsuhiko Tsunoda, Pak-Chung Sham, Shiro Ikegawa, Danny Chan
Recent controversies surrounding prostate cancer overtreatment emphasize the critical need to delineate the molecular features associated with progression to lethal metastatic disease. Here, we have used whole-genome sequencing and molecular pathological analyses to characterize the lethal cell clone in a patient who died of prostate cancer. We tracked the evolution of the lethal cell clone from the primary cancer to metastases through samples collected during disease progression and at the time of death. Surprisingly, these analyses revealed that the lethal clone arose from a small, relatively low-grade cancer focus in the primary tumor, and not from the bulk, higher-grade primary cancer or from a lymph node metastasis resected at prostatectomy. Despite being limited to one case, these findings highlight the potential importance of developing and implementing molecular prognostic and predictive markers, such as alterations of tumor suppressor proteins PTEN or p53, to augment current pathological evaluation and delineate clonal heterogeneity. Furthermore, this case illustrates the potential need in precision medicine to longitudinally sample metastatic lesions to capture the evolving constellation of alterations during progression. Similar comprehensive studies of additional prostate cancer cases are warranted to understand the extent to which these issues may challenge prostate cancer clinical management.
Michael C. Haffner, Timothy Mosbruger, David M. Esopi, Helen Fedor, Christopher M. Heaphy, David A. Walker, Nkosi Adejola, Meltem Gürel, Jessica Hicks, Alan K. Meeker, Marc K. Halushka, Jonathan W. Simons, William B. Isaacs, Angelo M. De Marzo, William G. Nelson, Srinivasan Yegnasubramanian
Regulatory T (Treg) cells maintain immune homeostasis by limiting autoimmune and inflammatory responses. Treg differentiation, maintenance, and function are controlled by the transcription factor Foxp3. However, the exact molecular mechanisms underlying Treg cell regulation remain elusive. Here, we show that Treg cell–specific ablation of the E3 ubiquitin ligase Itch in mice caused massive multiorgan lymphocyte infiltration and skin lesions, chronic T cell activation, and the development of severe antigen-induced airway inflammation. Surprisingly, Foxp3 expression, homeostasis, and the in vitro and in vivo suppressive capability of Treg cells were not affected by Itch deficiency. We found that the expression of Th2 cytokines by Treg cells was increased in the absence of Itch. Fate mapping revealed that a fraction of Treg cells lost Foxp3 expression independently of Itch. However, Th2 cytokines were excessively augmented in
Hyung-seung Jin, Yoon Park, Chris Elly, Yun-Cai Liu
Exposure to ionizing radiation during childhood markedly increases the risk of developing papillary thyroid cancer. We examined tissues from 26 Ukrainian patients with thyroid cancer who were younger than 10 years of age and living in contaminated areas during the time of the Chernobyl nuclear reactor accident. We identified nonoverlapping somatic driver mutations in all 26 cases through candidate gene assays and next-generation RNA sequencing. We found that 22 tumors harbored fusion oncogenes that arose primarily through intrachromosomal rearrangements. Altogether, 23 of the oncogenic drivers identified in this cohort aberrantly activate MAPK signaling, including the 2 somatic rearrangements resulting in fusion of transcription factor ETS variant 6 (
Julio C. Ricarte-Filho, Sheng Li, Maria E.R. Garcia-Rendueles, Cristina Montero-Conde, Francesca Voza, Jeffrey A. Knauf, Adriana Heguy, Agnes Viale, Tetyana Bogdanova, Geraldine A. Thomas, Christopher E. Mason, James A. Fagin
Therapeutic drugs with ototoxic side effects cause significant hearing loss for thousands of patients annually. Two major classes of ototoxic drugs are cisplatin and the aminoglycoside antibiotics, both of which are toxic to mechanosensory hair cells, the receptor cells of the inner ear. A critical need exists for therapies that protect the inner ear without inhibiting the therapeutic efficacy of these drugs. The induction of heat shock proteins (HSPs) inhibits both aminoglycoside- and cisplatin-induced hair cell death and hearing loss. We hypothesized that exposure to sound that is titrated to stress the inner ear without causing permanent damage would induce HSPs in the cochlea and inhibit ototoxic drug–induced hearing loss. We developed a sound exposure protocol that induces HSPs without causing permanent hearing loss. We used this protocol in conjunction with a newly developed mouse model of cisplatin ototoxicity and found that preconditioning mouse inner ears with sound has a robust protective effect against cisplatin-induced hearing loss and hair cell death. Sound therapy also provided protection against aminoglycoside-induced hearing loss. These data indicate that sound preconditioning protects against both classes of ototoxic drugs, and they suggest that sound therapy holds promise for preventing hearing loss in patients receiving these drugs.
Soumen Roy, Matthew M. Ryals, Astrid Botty Van den Bruele, Tracy S. Fitzgerald, Lisa L. Cunningham
The use of induced pluripotent stem cells (iPSCs) has been postulated to be the most effective strategy for developing patient-specific respiratory epithelial cells, which may be valuable for lung-related cell therapy and lung tissue engineering. We generated a relatively homogeneous population of alveolar epithelial type II (AETII) and type I (AETI) cells from human iPSCs that had phenotypic properties similar to those of mature human AETII and AETI cells. We used these cells to explore whether lung tissue can be regenerated in vitro. Consistent with an AETII phenotype, we found that up to 97% of cells were positive for surfactant protein C, 95% for mucin-1, 93% for surfactant protein B, and 89% for the epithelial marker CD54. Additionally, exposing induced AETII to a Wnt/β-catenin inhibitor (IWR-1) changed the iPSC-AETII–like phenotype to a predominantly AETI-like phenotype. We found that of induced AET1 cells, more than 90% were positive for type I markers, T1α, and caveolin-1. Acellular lung matrices were prepared from whole rat or human adult lungs treated with decellularization reagents, followed by seeding these matrices with alveolar cells derived from human iPSCs. Under appropriate culture conditions, these progenitor cells adhered to and proliferated within the 3D lung tissue scaffold and displayed markers of differentiated pulmonary epithelium.
Mahboobe Ghaedi, Elizabeth A. Calle, Julio J. Mendez, Ashley L. Gard, Jenna Balestrini, Adam Booth, Peter F. Bove, Liqiong Gui, Eric S. White, Laura E. Niklason
Warner C. Greene
Susumu Goyama, Janet Schibler, Lea Cunningham, Yue Zhang, Yalan Rao, Nahoko Nishimoto, Masahiro Nakagawa, Andre Olsson, Mark Wunderlich, Kevin A. Link, Benjamin Mizukawa, H. Leighton Grimes, Mineo Kurokawa, P. Paul Liu, Gang Huang, James C. Mulloy
Natalie J. Thornburg, David P. Nannemann, David L. Blum, Jessica A. Belser, Terrence M. Tumpey, Shyam Deshpande, Gloria A. Fritz, Gopal Sapparapu, Jens C. Krause, Jeong Hyun Lee, Andrew B. Ward, David E. Lee, Sheng Li, Katie L. Winarski, Benjamin W. Spiller, Jens Meiler, James E. Crowe Jr.
Ariel Fernández, Angela Sanguino, Zhenghong Peng, Eylem Ozturk, Jianping Chen, Alejandro Crespo, Sarah Wulf, Aleksander Shavrin, Chaoping Qin, Jianpeng Ma, Jonathan Trent, Yvonne Lin, Hee-Dong Han, Lingegowda S. Mangala, James A. Bankson, Juri Gelovani, Allen Samarel, William Bornmann, Anil K. Sood, Gabriel Lopez-Berestein
Giovanna Maria Pierantoni, Cinzia Rinaldo, Marcella Mottolese, Anna Di Benedetto, Francesco Esposito, Silvia Soddu, Alfredo Fusco
Aurélien Marabelle, Holbrook Kohrt, Idit Sagiv-Barfi, Bahareh Ajami, Robert C. Axtell, Gang Zhou, Ranjani Rajapaksa, Michael R. Green, James Torchia, Joshua Brody, Richard Luong, Michael D. Rosenblum, Lawrence Steinman, Hyam I. Levitsky, Victor Tse, Ronald Levy