bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective randomized and crossover comparison of two apheresis machines for peripheral blood stem cell collection: a multicenter study
Authors: Ikeda Kazuhiko , Minakawa Keiji , Muroi Kazuo , Fujiwara Shin‐ichiro , Yamada‐Fujiwara Minami , Fujimori Yoshihiro , Tanosaki Ryuji , Ohto Hitoshi ,   on behalf of the Study Group for Peripheral Blood Stem Cell Collection, Cell Therapy Committee, The Japan Society of Transfusion Medicine and Cell Therapy
Published: August 2016

BACKGROUNDImproving apheresis technology may lead to an efficient and safe peripheral blood stem cell (PBSC) collection. Recently, the Spectra Optia (Optia, Terumo BCT) was introduced as an automated apheresis instrument, but comparisons with other instruments have been few. This is the first randomized multicenter and crossover comparison of the Optia with the automated program of the established apheresis instrument, the Spectra (Spectra‐Auto, Terumo BCT).STUDY DESIGN AND METHODSA total of 233 apheresis procedures performed in 46 autologous patients and 108 allogeneic donors were investigated. Apheresis performed in the first day for all subjects using the Spectra‐Auto (n = 79) and the Optia (n = 75) were evaluated as first‐day analysis. Seventy‐nine subjects, who required another session on the second day, underwent apheresis using the other instrument than the first‐day instrument and were compared with each other in a paired crossover analysis.RESULTSThe two instruments processed similar volumes with comparable run times and volumes of acid‐citrate‐dextrose used. The volumes of collected products were greater in the Optia. Yields of mononuclear cells and CD34+ cells were not different, but collection efficiencies were higher in the Optia (p = 0.008 in CE1 of crossover analysis). Spectra‐Auto–collected products contained more contaminating red blood cells (RBCs), whereas there was a trend of more contaminating platelets (PLTs) in the Optia‐collected products. Slight reductions were noted in the RBC or PLT counts of subjects who underwent apheresis with the Spectra‐Auto or the Optia, respectively.CONCLUSIONThe Optia is safe and more efficient in the PBSC collection compared with the Spectra‐Auto.
Canine bicavitary carcinomatosis with transient needle tract metastasis diagnosed by multiplex immunocytochemistry
Authors: Moore A Russell , Coffey Emily , Leavell Sarah E. , Krafsur Greta , Duncan Colleen , Dowers Kristy , Santangelo Kelly S. 
Published: August 2016

AbstractA 6‐year‐old, male castrated, mixed‐breed dog was referred to the James L. Voss Veterinary Teaching Hospital at Colorado State University for bicavitary effusion. On examination, the dog was tachycardic and tachypneic with bilaterally decreased lung sounds. Thoracic and abdominal ultrasonic examination revealed pleural and peritoneal effusions, which were aspirated and submitted for fluid analysis and cytology. Both cavity fluids were classified as exudates with a large population of vacuolated mononuclear cells. Multiplex immunocytochemistry (ICC) for cytokeratin and vimentin demonstrated exclusively cytokeratin expression, indicating these cells were of epithelial origin. A full diagnostic evaluation was performed, including CBC, clinical chemistry, a pet‐side test for heartworm disease, ehrlichiosis, Lyme disease, and anaplasmosis, imaging modalities of thorax, abdomen, and heart, urinalysis, and fine‐needle aspirations of spleen, liver, and popliteal lymph nodes. The dog was diagnosed with pleural and peritoneal carcinoma with presumed carcinomatosis. A single dose of intracavitary carboplatin was administered before discharge, and over a period of 2 weeks, 5 thoracocenteses were performed. A subcutaneous mass was noted at a thoracocentesis site one week after initial presentation. Cytology of the mass was consistent with carcinoma, and neoplastic seeding of the tumor cells from the thoracocentesis was suspected. The dog was euthanized 15 days after the first visit, and a necropsy was performed. Findings were consistent with carcinomatosis secondary to anaplastic pulmonary carcinoma with transient subcutaneous seeding of neoplastic cells during routine thoracocentesis. This case demonstrates the utility of multiplex ICC in the clinical setting.
Validation of ultrasonography for non‐invasive assessment of diaphragm function in muscular dystrophy
Authors: Whitehead Nicholas P. , Bible Kenneth L. , Kim Min Jeong , Odom Guy L. , Adams Marvin E. , Froehner Stanley C. 
Published: August 2016

Key points
Duchenne muscular dystrophy (DMD) is a severe, degenerative muscle disease that is commonly studied using the mdx mouse. The mdx diaphragm muscle closely mimics the pathophysiological changes in DMD muscles.
mdx diaphragm force is commonly assessed ex vivo, precluding time course studies. Here we used ultrasonography to evaluate time‐dependent changes in diaphragm function in vivo, by measuring diaphragm movement amplitude.
In mdx mice, diaphragm amplitude decreased with age and values were much lower than for wild‐type mice. Importantly, diaphragm amplitude strongly correlated with ex vivo specific force values.
Micro‐dystrophin administration increased mdx diaphragm amplitude by 26% after 4 weeks. Diaphragm amplitude correlated positively with ex vivo force values and negatively with diaphragm fibrosis, a major cause of DMD muscle weakness.
These studies validate diaphragm ultrasonography as a reliable technique for assessing time‐dependent changes in mdx diaphragm function in vivo. This technique will be valuable for testing potential therapies for DMD.
AbstractDuchenne muscular dystrophy (DMD) is a severe, degenerative muscle disease caused by dystrophin mutations. The mdx mouse is a widely used animal model of DMD. The mdx diaphragm muscle most closely recapitulates key features of DMD muscles, including progressive fibrosis and considerable force loss. Diaphragm function in mdx mice is commonly evaluated by specific force measurements ex vivo. While useful, this method only measures force from a small muscle sample at one time point. Therefore, accurate assessment of diaphragm function in vivo would provide an important advance to study the time course of functional decline and treatment benefits. Here, we evaluated an ultrasonography technique for measuring time‐dependent changes of diaphragm function in mdx mice. Diaphragm movement amplitude values for mdx mice were considerably lower than those for wild‐type, decreased from 8 to 18 months of age, and correlated strongly with ex vivo specific force. We then investigated the time course of diaphragm amplitude changes following administration of an adeno‐associated viral vector expressing Flag‐micro‐dystrophin (AAV‐μDys) to young adult mdx mice. Diaphragm amplitude peaked 4 weeks after AAV‐μDys administration, and was 26% greater than control mdx mice at this time. This value decreased slightly to 21% above mdx controls after 12 weeks of treatment. Importantly, diaphragm amplitude again correlated strongly with ex vivo specific force. Also, diaphragm amplitude and specific force negatively correlated with fibrosis levels in the muscle. Together, our results validate diaphragm ultrasonography as a reliable technique for assessing time‐dependent changes in dystrophic diaphragm function in vivo, and for evaluating potential therapies for DMD.
Selective accumulation of biotin in arterial chemoreceptors: requirement for carotid body exocytotic dopamine secretion
Authors: Ortega‐Sáenz Patricia , Macías David , Levitsky Konstantin L. , Rodríguez‐Gómez José A. , González‐Rodríguez Patricia , Bonilla‐Henao Victoria , Arias‐Mayenco Ignacio , López‐Barneo José 
Published: August 2016

Key points
Biotin, a vitamin whose main role is as a coenzyme for carboxylases, accumulates at unusually large amounts within cells of the carotid body (CB).
In biotin‐deficient rats biotin rapidly disappears from the blood; however, it remains at relatively high levels in CB glomus cells. The CB contains high levels of mRNA for SLC5a6, a biotin transporter, and SLC19a3, a thiamine transporter regulated by biotin.
Animals with biotin deficiency exhibit pronounced metabolic lactic acidosis. Remarkably, glomus cells from these animals have normal electrical and neurochemical properties. However, they show a marked decrease in the size of quantal dopaminergic secretory events.
Inhibitors of the vesicular monoamine transporter 2 (VMAT2) mimic the effect of biotin deficiency. In biotin‐deficient animals, VMAT2 protein expression decreases in parallel with biotin depletion in CB cells.
These data suggest that dopamine transport and/or storage in small secretory granules in glomus cells depend on biotin.
AbstractBiotin is a water‐soluble vitamin required for the function of carboxylases as well as for the regulation of gene expression. Here, we report that biotin accumulates in unusually large amounts in cells of arterial chemoreceptors, carotid body (CB) and adrenal medulla (AM). We show in a biotin‐deficient rat model that the vitamin rapidly disappears from the blood and other tissues (including the AM), while remaining at relatively high levels in the CB. We have also observed that, in comparison with other peripheral neural tissues, CB cells contain high levels of SLC5a6, a biotin transporter, and SLC19a3, a thiamine transporter regulated by biotin. Biotin‐deficient rats show a syndrome characterized by marked weight loss, metabolic lactic acidosis, aciduria and accelerated breathing with normal responsiveness to hypoxia. Remarkably, CB cells from biotin‐deficient animals have normal electrophysiological and neurochemical (ATP levels and catecholamine synthesis) properties; however, they exhibit a marked decrease in the size of quantal catecholaminergic secretory events, which is not seen in AM cells. A similar differential secretory dysfunction is observed in CB cells treated with tetrabenazine, a selective inhibitor of the vesicular monoamine transporter 2 (VMAT2). VMAT2 is highly expressed in glomus cells (in comparison with VMAT1), and in biotin‐deficient animals VMAT2 protein expression decreases in parallel with the decrease of biotin accumulated in CB cells. These data suggest that biotin has an essential role in the homeostasis of dopaminergic transmission modulating the transport and/or storage of transmitters within small secretory granules in glomus cells.
HCN channels segregate stimulation‐evoked movement responses in neocortex and allow for coordinated forelimb movements in rodents
Authors: Boychuk Jeffery A. , Farrell Jordan S. , Palmer Laura A. , Singleton Anna C. , Pittman Quentin J. , Teskey G. Campbell 
Published: August 2016

Key points
The present study tested whether HCN channels contribute to the organization of motor cortex and to skilled motor behaviour during a forelimb reaching task.
Experimental reductions in HCN channel signalling increase the representation of complex multiple forelimb movements in motor cortex as assessed by intracortical microstimulation.
Global HCN1KO mice exhibit reduced reaching accuracy and atypical movements during a single‐pellet reaching task relative to wild‐type controls.
Acute pharmacological inhibition of HCN channels in forelimb motor cortex decreases reaching accuracy and increases atypical movements during forelimb reaching.
AbstractThe mechanisms by which distinct movements of a forelimb are generated from the same area of motor cortex have remained elusive. Here we examined a role for HCN channels, given their ability to alter synaptic integration, in the expression of forelimb movement responses during intracortical microstimulation (ICMS) and movements of the forelimb on a skilled reaching task. We used short‐duration high‐resolution ICMS to evoke forelimb movements following pharmacological (ZD7288), experimental (electrically induced cortical seizures) or genetic approaches that we confirmed with whole‐cell patch clamp to substantially reduce Ih current. We observed significant increases in the number of multiple movement responses evoked at single sites in motor maps to all three experimental manipulations in rats or mice. Global HCN1 knockout mice were less successful and exhibited atypical movements on a skilled‐motor learning task relative to wild‐type controls. Furthermore, in reaching‐proficient rats, reaching accuracy was reduced and forelimb movements were altered during infusion of ZD7288 within motor cortex. Thus, HCN channels play a critical role in the separation of overlapping movement responses and allow for successful reaching behaviours. These data provide a novel mechanism for the encoding of multiple movement responses within shared networks of motor cortex. This mechanism supports a viewpoint of primary motor cortex as a site of dynamic integration for behavioural output.
FOXD1–ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells
Authors: Cheng Peng , Wang Jia , Waghmare Indrayani , Sartini Stefania , Coviello Vito , Zhang Zhuo , Kim Sung-Hak , Mohyeldin Ahmed , Pavlyukov Marat S. , Minata Mutsuko , Valentim Claudia L.L. , Chhipa Rishi Raj , Bhat Krishna P.L. , Dasgupta Biplab , La Motta Concettina , Kango-Singh Madhuri , Nakano Ichiro 
Published: August 2016

Abstract
Glioma stem–like cells (GSC) with tumor-initiating activity orchestrate the cellular hierarchy in glioblastoma and engender therapeutic resistance. Recent work has divided GSC into two subtypes with a mesenchymal (MES) GSC population as the more malignant subtype. In this study, we identify the FOXD1–ALDH1A3 signaling axis as a determinant of the MES GSC phenotype. The transcription factor FOXD1 is expressed predominantly in patient-derived cultures enriched with MES, but not with the proneural GSC subtype. shRNA-mediated attenuation of FOXD1 in MES GSC ablates their clonogenicity in vitro and in vivo. Mechanistically, FOXD1 regulates the transcriptional activity of ALDH1A3, an established functional marker for MES GSC. Indeed, the functional roles of FOXD1 and ALDH1A3 are likely evolutionally conserved, insofar as RNAi-mediated attenuation of their orthologous genes in Drosophila blocks formation of brain tumors engineered in that species. In clinical specimens of high-grade glioma, the levels of expression of both FOXD1 and ALDH1A3 are inversely correlated with patient prognosis. Finally, a novel small-molecule inhibitor of ALDH we developed, termed GA11, displays potent in vivo efficacy when administered systemically in a murine GSC-derived xenograft model of glioblastoma. Collectively, our findings define a FOXD1–ALDH1A3 pathway in controling the clonogenic and tumorigenic potential of MES GSC in glioblastoma tumors. Cancer Res; 76(24); 7219–30. ©2016 AACR.
Evidence Implicating Immunological Host Effects in the Efficacy of Metronomic Low-Dose Chemotherapy
Authors: Shaked Yuval , Pham Elizabeth , Hariharan Santosh , Magidey Ksenia , Beyar-Katz Ofrat , Xu Ping , Man Shan , Wu Florence T.H. , Miller Valeria , Andrews David , Kerbel Robert S. 
Published: August 2016

Abstract
Conventional chemotherapy drugs administered at a maximum tolerated dose (MTD) remains the backbone for treating most cancers. Low-dose metronomic (LDM) chemotherapy, which utilizes lower, less toxic, doses given on a close regular basis over prolonged periods, is an alternative and better tolerated potential strategy to improve chemotherapy. LDM chemotherapy has been evaluated preclinically and clinically and has shown therapeutic benefit, in both early and advanced stage metastatic disease, especially when used as a maintenance therapy. However, knowledge about the antitumor mechanisms by which LDM chemotherapy acts remain limited. Here we characterized the effects of LDM and MTD capecitabine therapy on tumor and host cells using high-throughput systems approaches involving mass spectrometry flow cytometry and automated cell imaging followed by in vivo analyses of such therapies. An increase in myeloid and T regulatory cells and a decrease in NK and T cytotoxic cells were found in MTD–capecitabine–treated tumors compared with LDM-capecitbine-treated tumors. Plasma from MTD capecitabine-treated mice induced a more tumorigenic and metastatic profile in both breast and colon carcinoma cells than plasma from mice treated with LDM capecitabine. These results correlated, in part, with in vivo studies using models of human or mouse advanced metastatic disease, where the therapeutic advantage of MTD capecitabine was limited despite a substantial initial antitumor activity found in the primary tumor setting. Overall these results implicate a possible contribution of immunologic host effects in accounting for the therapeutic limitations of MTD compared with LDM capecitabine. Cancer Res; 76(20); 5983–93. ©2016 AACR.
SMYD3-Mediated H2A.Z.1 Methylation Promotes Cell Cycle and Cancer Proliferation
Authors: Tsai Cheng-Hui , Chen Yun-Ju , Yu Chia-Jung , Tzeng Shiou-Ru , Wu I-Chen , Kuo Wen-Hung , Lin Ming-Chieh , Chan Nei-Li , Wu Kou-Juey , Teng Shu-Chun 
Published: August 2016

Abstract
SMYD3 methyltransferase is nearly undetectable in normal human tissues but highly expressed in several cancers, including breast cancer, although its contributions to pathogenesis in this setting are unclear. Here we report that histone H2A.Z.1 is a substrate of SMYD3 that supports malignancy. SMYD3-mediated dimethylation of H2A.Z.1 at lysine 101 (H2A.Z.1K101me2) increased stability by preventing binding to the removal chaperone ANP32E and facilitating its interaction with histone H3. Moreover, a microarray analysis identified cyclin A1 as a target coregulated by SMYD3 and H2A.Z.1K101me2. The colocalization of SMYD3 and H2A.Z.1K101me2 at the promoter of cyclin A1 activated its expression and G1–S progression. Enforced expression of cyclin A1 in cells containing mutant H2A.Z.1 rescued tumor formation in a mouse model. Our findings suggest that SMYD3-mediated H2A.Z.1K101 dimethylation activates cyclin A1 expression and contributes to driving the proliferation of breast cancer cells. Cancer Res; 76(20); 6043–53. ©2016 AACR.
HPV-Related Oropharynx Cancer in the United Kingdom: An Evolution in the Understanding of Disease Etiology
Authors: Schache Andrew G. , Powell Ned G. , Cuschieri Kate S. , Robinson Max , Leary Sam , Mehanna Hisham , Rapozo Davy , Long Anna , Cubie Heather , Junor Elizabeth , Monaghan Hannah , Harrington Kevin J. , Nutting Christopher M. , Schick Ulrike , Lau Andy S. , Upile Navdeep , Sheard Jon , Brougham Kath , West Catharine M.L. , Oguejiofor Ken , Thomas Steve , Ness Andy R. , Pring Miranda , Thomas Gareth J. , King Emma V. , McCance Dennis J. , James Jacqueline A. , Moran Michael , Sloan Phil , Shaw Richard J. , Evans Mererid , Jones Terry M. 
Published: August 2016

AbstractA rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) incidence has occurred throughout the developed world, where it has been attributed to an increasing impact of human papillomavirus (HPV) on disease etiology. This report presents the findings of a multicenter cross-sectional retrospective study aimed at determining the proportion of HPV-positive and HPV-negative OPSCC within the United Kingdom. Archival tumor tissue blocks from 1,602 patients previously diagnosed with OPSCC (2002–2011) were collated from 11 centers. HPV status was determined with three validated commercial tests to provide valid data for 1,474 cases in total. Corresponding national incidence data from the same decade were obtained from UK Cancer registries. The overall proportion of HPV+ OPSCC between 2002 and 2011 was 51.8% [95% confidence interval (CI), 49.3–54.4], and this remained unchanged throughout the decade [unadjusted RR = 1.00 (95% CI, 0.99–1.02)]. However, over the same period, the incidence of OPSCC in the broader UK population underwent a 2-fold increase [age-standardized rate 2002: 2.1 (95% CI, 1.9–2.2); 2011: 4.1 (95% CI, 4.0–4.3)]. Although the number of OPSCCs diagnosed within the United Kingdom from 2002 to 2011 nearly doubled, the proportion of HPV+ cases remained static at approximately 50%. Our results argue that the rapidly increasing incidence of OPSCC in the United Kingdom cannot be solely attributable to the influence of HPV. The parallel increase in HPV+ and HPV− cases we documented warrants further investigation, so that appropriate future prevention strategies for both types of disease can be implemented. Cancer Res; 76(22); 6598–606. ©2016 AACR.
Deep Sequencing Reveals a Novel miR-22 Regulatory Network with Therapeutic Potential in Rhabdomyosarcoma
Authors: Bersani Francesca , Lingua Marcello Francesco , Morena Deborah , Foglizzo Valentina , Miretti Silvia , Lanzetti Letizia , Carrà Giovanna , Morotti Alessandro , Ala Ugo , Provero Paolo , Chiarle Roberto , Singer Samuel , Ladanyi Marc , Tuschl Thomas , Ponzetto Carola , Taulli Riccardo 
Published: August 2016

Abstract
Current therapeutic options for the pediatric cancer rhabdomyosarcoma have not improved significantly, especially for metastatic rhabdomyosarcoma. In the current work, we performed a deep miRNA profiling of the three major human rhabdomyosarcoma subtypes, along with cell lines and normal muscle, to identify novel molecular circuits with therapeutic potential. The signature we determined could discriminate rhabdomyosarcoma from muscle, revealing a subset of muscle-enriched miRNA (myomiR), including miR-22, which was strongly underexpressed in tumors. miR-22 was physiologically induced during normal myogenic differentiation and was transcriptionally regulated by MyoD, confirming its identity as a myomiR. Once introduced into rhabdomyosarcoma cells, miR-22 decreased cell proliferation, anchorage-independent growth, invasiveness, and promoted apoptosis. Moreover, restoring miR-22 expression blocked tumor growth and prevented tumor dissemination in vivo. Gene expression profiling analysis of miR-22–expressing cells suggested TACC1 and RAB5B as possible direct miR-22 targets. Accordingly, loss- and gain-of-function experiments defined the biological relevance of these genes in rhabdomyosarcoma pathogenesis. Finally, we demonstrated the ability of miR-22 to intercept and overcome the intrinsic resistance to MEK inhibition based on ERBB3 upregulation. Overall, our results identified a novel miR-22 regulatory network with critical therapeutic implications in rhabdomyosarcoma. Cancer Res; 76(20); 6095–106. ©2016 AACR.
Ablation of miR-10b Suppresses Oncogene-Induced Mammary Tumorigenesis and Metastasis and Reactivates Tumor-Suppressive Pathways
Authors: Kim Jongchan , Siverly Ashley N. , Chen Dahu , Wang Min , Yuan Yuan , Wang Yumeng , Lee Hyemin , Zhang Jinsong , Muller William J. , Liang Han , Gan Boyi , Yang Xianbin , Sun Yutong , You M. James , Ma Li 
Published: August 2016

Abstract
The invasive and metastatic properties of many human tumors have been associated with upregulation of the miRNA miR-10b, but its functional contributions in this setting have not been fully unraveled. Here, we report the generation of miR-10b–deficient mice, in which miR-10b is shown to be largely dispensable for normal development but critical to tumorigenesis. Loss of miR-10b delays oncogene-induced mammary tumorigenesis and suppresses epithelial–mesenchymal transition, intravasation, and metastasis in a mouse model of metastatic breast cancer. Among the target genes of miR-10b, the tumor suppressor genes Tbx5 and Pten and the metastasis suppressor gene Hoxd10 are significantly upregulated by miR-10b deletion. Mechanistically, miR-10b promotes breast cancer cell proliferation, migration, and invasion through inhibition of the expression of the transcription factor TBX5, leading to repression of the tumor suppressor genes DYRK1A and PTEN. In clinical specimens of breast cancer, the expression of TBX5, HOXD10, and DYRK1A correlates with relapse-free survival and overall survival outcomes in patients. Our results establish miR-10b as an oncomiR that drives metastasis, termed a metastamiR, and define the set of critical tumor suppressor mechanisms it overcomes to drive breast cancer progression. Cancer Res; 76(21); 6424–35. ©2016 AACR.