bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of hypoxia‐inducible factors in carotid body (patho) physiology
Authors: Semenza Gregg L. , Prabhakar Nanduri R. 
Published: January 2018

AbstractHypoxia‐inducible factors mediate adaptive responses to reduced O2 availability. In patients with obstructive sleep apnoea, repeated episodes of hypoxaemia and reoxygenation (intermittent hypoxia) are sensed by the carotid body (CB). The ensuing CB chemosensory reflex activates the sympathetic nervous system and increased secretion of catecholamines by the adrenal medulla, resulting in hypertension and breathing abnormalities. In the CB, intermittent hypoxia induces the formation of reactive oxygen species (ROS) and increased intracellular Ca2+ levels, which drive increased expression of hypoxia‐inducible factor (HIF) 1α and a decrease in the levels of HIF‐2α. Intermittent hypoxia increases HIF‐1α‐dependent expression of Nox2, encoding the pro‐oxidant enzyme NADPH oxidase 2, and decreased HIF‐2α‐dependent expression of Sod2, encoding the anti‐oxidant enzyme superoxide dismutase 2. These changes in gene expression drive persistently elevated ROS levels in the CB, brainstem, and adrenal medulla that are required for the development of hypertension and breathing abnormalities. The ROS generated by dysregulated HIF activity in the CB results in oxidation and inhibition of haem oxygenase 2, and the resulting reduction in the levels of carbon monoxide leads to increased hydrogen sulfide production, triggering glomus cell depolarization. Thus, the pathophysiology of obstructive sleep apnoea involves the dysregulation of O2‐regulated transcription factors, gasotransmitters, and sympathetic outflow that affects blood pressure and breathing.
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Characterization of the
In Vitro
Chlamydia pecorum Response to Gamma Interferon
Authors: Islam M. Mominul , Jelocnik Martina , Huston Wilhelmina M. , Timms Peter , Polkinghorne Adam 
Published: January 2018

ABSTRACT

Chlamydia pecorum
is an important intracellular bacterium that causes a range of diseases in animals, including a native Australian marsupial, the koala. In humans and animals, a gamma interferon (IFN-γ)-mediated immune response is important for the control of intracellular bacteria. The present study tested the hypotheses that
C. pecorum
can escape IFN-γ-mediated depletion of host cell tryptophan pools. In doing so, we demonstrated that, unlike
Chlamydia trachomatis
,
C. pecorum
is completely resistant to IFN-γ in human epithelial cells. While the growth of
C. pecorum
was inhibited in tryptophan-deficient medium, it could be restored by the addition of kynurenine, anthranilic acid, and indole, metabolites that could be exploited by the gene products of the
C. pecorum
tryptophan biosynthesis operon. We also found that expression of
trp
genes was detectable only when
C. pecorum
was grown in tryptophan-free medium, with gene repression occurring in response to the addition of kynurenine, anthranilic acid, and indole. When grown in bovine kidney epithelial cells, bovine IFN-γ also failed to restrict the growth of
C. pecorum
, while
C. trachomatis
was inhibited, suggesting that
C. pecorum
could use the same mechanisms to evade the immune response
in vivo
in its natural host. Highlighting the different mechanisms triggered by IFN-γ, however, both species failed to grow in murine McCoy cells treated with murine IFN-γ. This work confirms previous hypotheses about the potential survival of
C. pecorum
after IFN-γ-mediated host cell tryptophan depletion and raises questions about the immune pathways used by the natural hosts of
C. pecorum
to control the widespread pathogen.
Purification of Highly Active Alphavirus Replication Complexes Demonstrates Altered Fractionation of Multiple Cellular Membranes
Authors: Pietilä Maija K. , van Hemert Martijn J. , Ahola Tero 
Published: January 2018

ABSTRACT
Positive-strand RNA viruses replicate their genomes in membrane-associated structures; alphaviruses and many other groups induce membrane invaginations called spherules. Here, we established a protocol to purify these membranous replication complexes (RCs) from cells infected with Semliki Forest virus (SFV). We isolated SFV spherules located on the plasma membrane and further purified them using two consecutive density gradients. This revealed that SFV infection strongly modifies cellular membranes. We removed soluble proteins, the Golgi membranes, and most of the mitochondria, but plasma membrane, endoplasmic reticulum (ER), and late endosome markers were retained in the membrane fraction that contained viral RNA synthesizing activity, replicase proteins, and minus- and plus-strand RNA. Electron microscopy revealed that the purified membranes displayed spherule-like structures with a narrow neck. This membrane enrichment was specific to viral replication, as such a distribution of membrane markers was only observed after infection. Besides the plasma membrane, SFV infection remodeled the ER, and the cofractionation of the RC-carrying plasma membrane and ER suggests that SFV recruits ER proteins or membrane to the site of replication. The purified RCs were highly active in synthesizing both genomic and subgenomic RNA. Detergent solubilization destroyed the replication activity, demonstrating that the membrane association of the complex is essential. Most of the newly made RNA was in double-stranded replicative molecules, but the purified complexes also produced single-stranded RNA as well as released newly made RNA. This indicates that the purification established here maintained the functionality of RCs and thus enables further structural and functional studies of active RCs.

IMPORTANCE
Similar to all positive-strand RNA viruses, the arthropod-borne alphaviruses induce membranous genome factories, but little is known about the arrangement of viral replicase proteins and the presence of host proteins in these replication complexes. To improve our knowledge of alphavirus RNA-synthesizing complexes, we isolated and purified them from infected mammalian cells. Detection of viral RNA and
in vitro
replication assays revealed that these complexes are abundant and highly active when located on the plasma membrane. After multiple purification steps, they remain functional in synthesizing and releasing viral RNA. Besides the plasma membrane, markers for the endoplasmic reticulum and late endosomes were enriched with the replication complexes, demonstrating that alphavirus infection modified cellular membranes beyond inducing replication spherules on the plasma membrane. We have developed here a gentle purification method to obtain large quantities of highly active replication complexes, and similar methods can be applied to other positive-strand RNA viruses.
Retinal vascular alterations in reticular pseudodrusen with and without outer retinal atrophy assessed by optical coherence tomography angiography
Authors: Cicinelli Maria Vittoria , Rabiolo Alessandro , Sacconi Riccardo , Lamanna Francesca , Querques Lea , Bandello Francesco , Querques Giuseppe 
Published: January 2018

PurposeTo investigate the intraretinal structural and vascular alterations in patients featuring reticular pseudodrusen (RPD), RPD with outer retinal atrophy (ORA), and drusen.DesignObservational cross-sectional study.MethodsClinical practice study including 68 eyes of 57 patients (22 eyes of 17 patients with RPD; 24 eyes of 21 patients with RPD+ORA; 22 eyes of 19 patients with drusen). Each patient underwent spectral-domain optical coherence tomography (OCT) and OCT angiography (OCT-A). Measurement of retinal layers’ thickness was obtained by the automated segmentation protocol of the Spectralis OCT (Heidelberg Eye Explorer V.1.9.10.0). The superficial capillary plexus (SCP) and the deep capillary plexus (DCP) vessel density, as well as the size of the foveal avascular zone were calculated on 3×3 OCT-A. Main outcome was to compare vessel density at the SCP and DCP among the groups and controls.ResultsAt the SCP, the vessel density was lower in RPD and RPD+ORA patients with respect to controls (P=0.02 and P=0.003, respectively). At the DCP, meaningful disparity was found between the study groups and the healthy subjects in the vessel density (P<0.001, P=0.04 and P=0.001 for RPD, RDP+ORA and drusen, respectively). The ganglion cell layer (GCL) was thinner in all patients affected either by RPD, RPD+ORA or drusen compared with healthy subjects (P=0.02, P=0.03 and P=0.004, respectively).ConclusionSignificant retinal vascular loss is a common feature of patients with non-exudative age-related macular degeneration, more pronounced in those featuring RPD and RPD+ORA. It is associated with retinal thinning, localised particularly at the GCL, compared with controls.
Cell of origin affects tumour development and phenotype in pancreatic ductal adenocarcinoma
Authors: Lee Alex Y L , Dubois Claire L , Sarai Karnjit , Zarei Soheila , Schaeffer David F , Sander Maike , Kopp Janel L 
Published: January 2018

ObjectivePancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumour thought to arise from ductal cells via pancreatic intraepithelial neoplasia (PanIN) precursor lesions. Modelling of different genetic events in mice suggests both ductal and acinar cells can give rise to PDAC. However, the impact of cellular context alone on tumour development and phenotype is unknown.DesignWe examined the contribution of cellular origin to PDAC development by inducing PDAC-associated mutations, KrasG12D expression and Trp53 loss, specifically in ductal cells (Sox9CreER;KrasLSL-G12D;Trp53flox/flox (‘Duct:KPcKO’)) or acinar cells (Ptf1aCreER;KrasLSL-G12D;Trp53flox/flox (‘Acinar:KPcKO’)) in mice. We then performed a thorough analysis of the resulting histopathological changes.ResultsBoth mouse models developed PDAC, but Duct:KPcKO mice developed PDAC earlier than Acinar:KPcKO mice. Tumour development was more rapid and associated with high-grade murine PanIN (mPanIN) lesions in Duct:KPcKO mice. In contrast, Acinar:KPcKO mice exhibited widespread metaplasia and low-grade as well as high-grade mPanINs with delayed progression to PDAC. Acinar-cell-derived tumours also had a higher prevalence of mucinous glandular features reminiscent of early mPanIN lesions.ConclusionThese findings indicate that ductal cells are primed to form carcinoma in situ that become invasive PDAC in the presence of oncogenic Kras and Trp53 deletion, while acinar cells with the same mutations appear to require a prolonged period of transition or reprogramming to initiate PDAC. Our findings illustrate that PDAC can develop in multiple ways and the cellular context in which mutations are acquired has significant impact on precursor lesion initiation, disease progression and tumour phenotype.
Public misperception that very low nicotine cigarettes are less carcinogenic
Authors: Byron M Justin , Jeong Michelle , Abrams David B , Brewer Noel T 
Published: January 2018

ObjectiveThe USA is considering a very low nicotine content (VLNC) cigarette standard. We sought to characterise the prevalence and correlates of the incorrect belief that VLNC cigarettes are less carcinogenic than current cigarettes, as this could reduce motivation to quit.MethodsParticipants were a nationally representative sample of 650 adult smokers in the USA. In 2015–2016, before the VLNC proposal became public, these smokers took part in an online survey. We used multivariate weighted analyses to calculate ORs and percentages and a χ2 test to examine the association between variables.ResultsOverall, 47.1% of smokers believed that smoking VLNC cigarettes for 30 years would be less likely to cause cancer than smoking current cigarettes. This misperception was more common among smokers who were aged above 55 (56.6%) and black (57.4%). Additionally, 23.9% of smokers reported they would be less likely to quit if the USA adopted a VLNC standard. Thinking that VLNC cigarettes would be less carcinogenic was associated with smokers reporting they would be less likely to quit (P<0.01).ConclusionsMany smokers had the misperception that smoking VLNC cigarettes is less likely to cause cancer, and some stated that they would be less likely to quit. A VLNC standard may be more effective if accompanied by a communication campaign that emphasises the continued dangers of smoking VLNC cigarettes due to the many toxic chemicals in smoke.
Tumor–Stroma IL1β-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemoresistance, and Poor Prognosis in Pancreatic Cancer
Authors: Zhang Daoxiang , Li Lin , Jiang Hongmei , Li Qiong , Wang-Gillam Andrea , Yu Jinsheng , Head Richard , Liu Jingxia , Ruzinova Marianna B. , Lim Kian-Huat 
Published: January 2018

Abstract
Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but success in the clinic has thus far been limited. Preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAF) carries a risk of accelerating PDAC progression, underscoring the need to concurrently target key signaling mechanisms that drive the malignant attributes of both CAF and PDAC cells. We previously reported that inhibition of IL1 receptor–associated kinase 4 (IRAK4) suppresses NFκB activity and promotes response to chemotherapy in PDAC cells. In this study, we report that CAF in PDAC tumors robustly express activated IRAK4 and NFκB. IRAK4 expression in CAF promoted NFκB activity, drove tumor fibrosis, and supported PDAC cell proliferation, survival, and chemoresistance. Cytokine array analysis of CAF and microarray analysis of PDAC cells identified IL1β as a key cytokine that activated IRAK4 in CAF. Targeting IRAK4 or IL1β rendered PDAC tumors less fibrotic and more sensitive to gemcitabine. In clinical specimens of human PDAC, high stromal IL1β expression associated strongly with poor overall survival. Together, our studies establish a tumor–stroma IL1β-IRAK4 feedforward signal that can be therapeutically disrupted to increase chemotherapeutic efficacy in PDAC.
Significance: Targeting the IL1β-IRAK4 signaling pathway potentiates the effect of chemotherapy in pancreatic cancer. Cancer Res; 78(7); 1700–12. ©2018 AACR.
Myeloma Cells Are Activated in Bone Marrow Microenvironment by the CD180/MD-1 Complex, Which Senses Lipopolysaccharide
Authors: Kikuchi Jiro , Kuroda Yoshiaki , Koyama Daisuke , Osada Naoki , Izumi Tohru , Yasui Hiroshi , Kawase Takakazu , Ichinohe Tatsuo , Furukawa Yusuke 
Published: January 2018

AbstractMultiple myeloma (MM) cells acquire dormancy and drug resistance via interaction with bone marrow stroma cells (BMSC) in a hypoxic microenvironment. Elucidating the mechanisms underlying the regrowth of dormant clones may contribute to further improvement of the prognosis of MM patients. In this study, we find that the CD180/MD-1 complex, a noncanonical lipopolysaccharide (LPS) receptor, is expressed on MM cells but not on normal counterparts, and its abundance is markedly upregulated under adherent and hypoxic conditions. Bacterial LPS and anti-CD180 antibody, but not other Toll-like receptor ligands, enhanced the growth of MM cells via activation of MAP kinases ERK and JNK in positive correlation with expression levels of CD180. Administration of LPS significantly increased the number of CD180/CD138 double-positive cells in a murine xenograft model when MM cells were inoculated with direct attachment to BMSC. Knockdown of CD180 canceled the LPS response in vitro and in vivo. Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the CD180 gene. Both cell adhesion and hypoxia activated transcription of the CD180 gene by increasing Ikaros expression and its binding to the promoter region. Pharmacological targeting of Ikaros by the immunomodulatory drug lenalidomide ameliorated the response of MM cells to LPS in a CD180-dependent manner in vitro and in vivo. Thus, the CD180/MD-1 pathway may represent a novel mechanism of growth regulation of MM cells in a BM milieu and may be a therapeutic target of preventing the regrowth of dormant MM cells.Significance: This study describes a novel mechanism by which myeloma cells are regulated in the bone marrow, where drug resistance and dormancy can evolve after treatment, with potential therapeutic implications for treating this often untreatable blood cancer. Cancer Res; 78(7); 1766–78. ©2018 AACR.
Nitric Oxide Production by Myeloid-Derived Suppressor Cells Plays a Role in Impairing Fc Receptor–Mediated Natural Killer Cell Function
Authors: Stiff Andrew , Trikha Prashant , Mundy-Bosse Bethany , McMichael Elizabeth , Mace Thomas A. , Benner Brooke , Kendra Kari , Campbell Amanda , Gautam Shalini , Abood David , Landi Ian , Hsu Vincent , Duggan Megan , Wesolowski Robert , Old Matthew , Howard John Harrison , Yu Lianbo , Stasik Nancy , Olencki Thomas , Muthusamy Natarajan , Tridandapani Susheela , Byrd John C. , Caligiuri Michael , Carson William E. 
Published: January 2018

AbstractPurpose: mAbs are used to treat solid and hematologic malignancies and work in part through Fc receptors (FcRs) on natural killer cells (NK). However, FcR-mediated functions of NK cells from patients with cancer are significantly impaired. Identifying the mechanisms of this dysfunction and impaired response to mAb therapy could lead to combination therapies and enhance mAb therapy.Experimental Design: Cocultures of autologous NK cells and MDSC from patients with cancer were used to study the effect of myeloid-derived suppressor cells (MDSCs) on NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in vitro. Mouse breast cancer models were utilized to study the effect of MDSCs on antibody therapy in vivo and test the efficacy of combination therapies including a mAb and an MDSC-targeting agent.Results: MDSCs from patients with cancer were found to significantly inhibit NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in a contact-independent manner. In addition, adoptive transfer of MDSCs abolished the efficacy of mAb therapy in a mouse model of pancreatic cancer. Inhibition of iNOS restored NK-cell functions and signal transduction. Finally, nonspecific elimination of MDSCs or inhibition of iNOS in vivo significantly improved the efficacy of mAb therapy in a mouse model of breast cancer.Conclusions: MDSCs antagonize NK-cell FcR-mediated function and signal transduction leading to impaired response to mAb therapy in part through nitric oxide production. Thus, elimination of MDSCs or inhibition of nitric oxide production offers a strategy to improve mAb therapy. Clin Cancer Res; 24(8); 1891–904. ©2018 AACR.
The Expanding World of N-MYC–Driven Tumors
Authors: Rickman David S. , Schulte Johannes H. , Eilers Martin 
Published: January 2018

Abstract
Enhanced and deregulated expression of N-MYC, a member of the MYC family of transcription factors, drives the development of multiple tumors, including tumors of the nervous and hematologic systems and neuroendocrine tumors in other organs. This review summarizes the cell-of-origin, biological features, associated signaling pathways, and current treatment strategies for N-MYC–driven tumors. We also highlight biological differences within specific tumor types that are driven by the different MYC proteins.
Significance: N-MYC is a driver of multiple tumor types that are derived through a mechanism that involves direct differentiation within the same lineage (e.g., in the case of neuroblastoma, medulloblastoma, and acute myeloid leukemia) and is often associated with a poor prognosis. Emerging data suggest that N-MYC also drives other tumor types through a mechanism that promotes a lineage switch and that this switch may be exploited for therapeutic purposes. Cancer Discov; 8(2); 150–63. ©2018 AACR.
Combination Gemcitabine and WT1 Peptide Vaccination Improves Progression-Free Survival in Advanced Pancreatic Ductal Adenocarcinoma: A Phase II Randomized Study
Authors: Nishida Sumiyuki , Ishikawa Takeshi , Egawa Shinichi , Koido Shigeo , Yanagimoto Hiroaki , Ishii Jun , Kanno Yoshihide , Kokura Satoshi , Yasuda Hiroaki , Oba Mari Saito , Sato Maho , Morimoto Soyoko , Fujiki Fumihiro , Eguchi Hidetoshi , Nagano Hiroaki , Kumanogoh Atsushi , Unno Michiaki , Kon Masanori , Shimada Hideaki , Ito Kei , Homma Sadamu , Oka Yoshihiro , Morita Satoshi , Sugiyama Haruo 
Published: January 2018

Abstract
We investigated the efficacy of a Wilms' tumor gene 1 (WT1) vaccine combined with gemcitabine (GEMWT1) and compared it with gemcitabine (GEM) monotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) in a randomized phase II study. We randomly assigned HLA-A*02:01– or HLA-A*24:02–positive patients with advanced PDAC to receive GEMWT1 or GEM. We assessed WT1-specific immune responses via delayed-type hypersensitivity (DTH) to the WT1 peptide and a tetramer assay to detect WT1-specific cytotoxic T lymphocytes (WT1-CTL). Of 91 patients enrolled, 85 were evaluable (GEMWT1: n = 42; GEM: n = 43). GEMWT1 prolonged progression-free survival [PFS; hazard ratio (HR), 0.66; P = 0.084] and improved overall survival rate at 1 year (1-year OS%; GEMWT1: 35.7%; GEM: 20.9%). However, the difference in OS was not significant (HR: 0.82; P = 0.363). These effects were particularly evident in metastatic PDAC (PFS: HR 0.51, P = 0.0017; 1-year OS%: GEMWT1 27.3%; GEM 11.8%). The combination was well tolerated, with no unexpected serious adverse events. In patients with metastatic PDAC, PFS in the DTH-positive GEMWT1 group was significantly prolonged, with a better HR of 0.27 compared with the GEM group, whereas PFS in the DTH-negative GEMWT1 group was similar to that in the GEM group (HR 0.86; P = 0.001). DTH positivity was associated with an increase in WT1-CTLs induced by the WT1 vaccine. GEM plus the WT1 vaccine prolonged PFS and may improve 1-year OS% in advanced PDAC. These clinical effects were associated with the induction of WT1-specific immune responses. Cancer Immunol Res; 6(3); 320–31. ©2018 AACR.