bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanistic Differences between Nucleic Acid Chaperone Activities of the Gag Proteins of Rous Sarcoma Virus and Human Immunodeficiency Virus Type 1 Are Attributed to the MA Domain
Authors: Rye-McCurdy Tiffiny D. , Nadaraia-Hoke Shorena , Gudleski-O'Regan Nicole , Flanagan John M. , Parent Leslie J. , Musier-Forsyth Karin 
Published: May 2014

ABSTRACT

Host cell tRNAs are recruited for use as primers to initiate reverse transcription in retroviruses. Human immunodeficiency virus type 1 (HIV-1) uses tRNA
Lys3
as the replication primer, whereas Rous sarcoma virus (RSV) uses tRNA
Trp
. The nucleic acid (NA) chaperone function of the nucleocapsid (NC) domain of HIV-1 Gag is responsible for annealing tRNA
Lys3
to the genomic RNA (gRNA) primer binding site (PBS). Compared to HIV-1, little is known about the chaperone activity of RSV Gag. In this work, using purified RSV Gag containing an N-terminal His tag and a deletion of the majority of the protease domain (H6.Gag.3h), gel shift assays were used to monitor the annealing of tRNA
Trp
to a PBS-containing RSV RNA. Here, we show that similar to HIV-1 Gag lacking the p6 domain (GagΔp6), RSV H6.Gag.3h is a more efficient chaperone on a molar basis than NC; however, in contrast to the HIV-1 system, both RSV H6.Gag.3h and NC have comparable annealing rates at protein saturation. The NC domain of RSV H6.Gag.3h is required for annealing, whereas deletion of the matrix (MA) domain, which stimulates the rate of HIV-1 GagΔp6 annealing, has little effect on RSV H6.Gag.3h chaperone function. Competition assays confirmed that RSV MA binds inositol phosphates (IPs), but in contrast to HIV-1 GagΔp6, IPs do not stimulate RSV H6.Gag.3h chaperone activity unless the MA domain is replaced with HIV-1 MA. We conclude that differences in the MA domains are primarily responsible for mechanistic differences in RSV and HIV-1 Gag NA chaperone function.

IMPORTANCE
Mounting evidence suggests that the Gag polyprotein is responsible for annealing primer tRNAs to the PBS to initiate reverse transcription in retroviruses, but only HIV-1 Gag chaperone activity has been demonstrated
in vitro
. Understanding RSV Gag's NA chaperone function will allow us to determine whether there is a common mechanism among retroviruses. This report shows for the first time that full-length RSV Gag lacking the protease domain is a highly efficient NA chaperone
in vitro
, and NC is required for this activity. In contrast to results obtained for HIV-1 Gag, due to the weak nucleic acid binding affinity of the RSV MA domain, inositol phosphates do not regulate RSV Gag-facilitated tRNA annealing despite the fact that they bind to MA. These studies provide insight into the viral regulation of tRNA primer annealing, which is a potential target for antiretroviral therapy.
Reversible Nerve Damage and Corneal Pathology in Murine Herpes Simplex Stromal Keratitis
Authors: Yun Hongmin , Rowe Alexander M. , Lathrop Kira L. , Harvey Stephen A. K. , Hendricks Robert L. 
Published: May 2014

ABSTRACTHerpes simplex virus type 1 (HSV-1) shedding from sensory neurons can trigger recurrent bouts of herpes stromal keratitis (HSK), an inflammatory response that leads to progressive corneal scarring and blindness. A mouse model of HSK is often used to delineate immunopathogenic mechanisms and bears many of the characteristics of human disease, but it tends to be more chronic and severe than human HSK. Loss of blink reflex (BR) in human HSK is common and due to a dramatic retraction of corneal sensory nerve termini in the epithelium and the nerve plexus at the epithelial/stromal interface. However, the relationship between loss of BR due to nerve damage and corneal pathology associated with HSK remains largely unexplored. Here, we show a similar retraction of corneal nerves in mice with HSK. Indeed, we show that much of the HSK-associated corneal inflammation in mice is actually attributable to damage to the corneal nerves and accompanying loss of BR and can be prevented or ameliorated by tarsorrhaphy (suturing eyelids closed), a clinical procedure commonly used to prevent corneal exposure and desiccation. In addition, we show that HSK-associated nerve retraction, loss of BR, and severe pathology all are reversible and regulated by CD4+T cells. Thus, defining immunopathogenic mechanisms of HSK in the mouse model will necessitate distinguishing mechanisms associated with the immunopathologic response to the virus from those associated with loss of corneal sensation. Based on our findings, investigation of a possible contribution of nerve damage and BR loss to human HSK also appears warranted.IMPORTANCEHSK in humans is a potentially blinding disease characterized by recurrent inflammation and progressive scarring triggered by viral release from corneal nerves. Corneal nerve damage is a known component of HSK, but the causes and consequences of HSK-associated nerve damage remain obscure. We show that desiccation of the corneal surface due to nerve damage and associated loss of BR severely exacerbates and prolongs inflammation-induced pathology in mice. Preventing corneal desiccation results in a milder and more transient HSK with variable scarring that mirrors HSK seen in most humans. We further show that nerve damage is reversible and regulated by CD4+T cells. Thus, we provide a mouse model that more closely resembles typical human HSK and suggest nerve damage is an important but largely overlooked factor in human disease.
Findings on interval colonoscopies: an auditable performance indicator for colonoscopy quality?
Authors: Vaughan-Shaw P G , Aung M , Sahnan K , Rai P , Goodman A 
Published: May 2014

ObjectiveAn important marker of colonoscopy quality is detection of pathology and incidence of missed pathology. Back-to-back colonoscopies cannot ethically be performed for quality assurance alone yet may be required for clinical reasons. This study aims to investigate the incidence of new findings in colonoscopies repeated within a 12 month period and considers the role of such an analysis in the assessment of colonoscopy quality.DesignAll colonoscopies performed over a 3-year period at an endoscopy training unit were studied. Colonoscopies repeated within a 12-month period were analysed.Results5747 colonoscopies were performed over the study period. 137 repeat colonoscopies were included with median interval from initial colonoscopy of 174 days. 19 (14%) repeat colonoscopies yielded new findings including one cancer, 234 days following a normal colonoscopy. Additional polyps were identified in 13 colonoscopies indicating a missed polyp rate of 9%. In these, a median number of two polyps per colonoscopy with median size 5.5 mm were found. There was no morbidity associated with repeat colonoscopy in this series. New findings on repeat colonoscopy appeared more likely following initial colonoscopy by non-consultant non-training grade endoscopists (23% vs 11%, p=0.09) yet small numbers involved preclude meaningful comparison.ConclusionsAnalysis of clinically indicated repeat colonoscopies and rate of detection of new pathology may offer utility in colonoscopy quality assurance and would offer a direct assessment of the most important aspect of colonoscopy quality.
Primary stentriever versus combined stentriever plus aspiration thrombectomy approaches: in vitro stroke model comparison
Authors: Mokin Maxim , Ionita Ciprian N , Setlur Nagesh Swetadri Vasan , Rudin Stephen , Levy Elad I , Siddiqui Adnan H 
Published: May 2014

BackgroundArtificial stroke models can be used for testing various thrombectomy devices.ObjectiveTo determine the value of combined stentriever–aspiration thrombectomy compared with the stentriever-alone approach.MethodsWe designed an in vitro model of the intracranial circulation with a focus on the middle cerebral artery (MCA) that closely resembles the human intracranial circulation. After introducing fresh clot in the MCA, we used conventional biplane angiography and microangiographic fluoroscopy to compare recanalization rates and occurrence of emboli in new, unaffected territory for thrombectomy approaches in which a stentriever (Solitaire flow restoration stentriever, Covidien) was used alone or in combination with continuous manual aspiration through a Navien catheter (Covidien).ResultsIn a total of 22 experiments (11 for each approach), successful clot delivery to the MCA was achieved in all cases. Successful angiographic recanalization (thrombolysis in cerebral infarction score of 2b–3) was achieved more frequently with the combined stentriever–aspiration approach than with the stentriever-alone approach (in 10 vs 4 experiments, p=0.023). Emboli in new territory occurred in three experiments with the stentriever-alone approach, and none were seen with the combined approach (p=0.21).ConclusionsThe combined stentriever–aspiration approach to thrombectomy leads to better angiographic recanalization rates than use of the stentriever alone. Further experiments are needed to test the value of balloon-guide catheters and aspiration performed using other types of catheters and modes of aspiration.
Hindlimb lameness and gait abnormalities in bitches with pyometra
Authors: Klainbart S. , Ranen E. , Glikman G. , Kelmer E. , Bdolah‐Abram T. , Aroch I. 
Published: May 2014

The objective of this study was to assess the frequency of gait abnormalities and lameness (GAL) in bitches with pyometra, and their association with clinical and laboratory findings. The study included 79 bitches diagnosed with pyometra and 35 negative control intact bitches presented with other soft tissue surgical disorders. Dogs with a history of chronic lameness due to orthopaedic or neurological origin were excluded. A history of GAL was more frequent in the pyometra group (47 per cent) compared with the control group (20 per cent) (P=0.007). In the pyometra group, bitches presenting GAL had (P<0.04) higher frequencies of closed‐cervix pyometra, anorexia and vomiting, as well as higher serum creatinine concentration and muscle enzymes activity, compared with those in without GAL. GAL signs resolved postovariohysterectomy in all but one bitch. The results suggest that GAL signs occur frequently in bitches with pyometra, especially in closed‐cervix disease. Therefore, pyometra should be considered among the differential diagnoses when GAL occurs, especially when the clinical signs are non‐specific and the reproductive history is unclear.
Use of a GnRH agonist implant as alternative for surgical neutering in pet ferrets
Authors: van Zeeland Y. R. A. , Pabon M. , Roest J. , Schoemaker N. J. 
Published: May 2014

In the current study, the duration of effectiveness, owner satisfaction and side effects of a gonadotrophin releasing hormone‐agonist (deslorelin) implant were investigated during a two‐year follow‐up study in which 61 male and 69 female entire pet ferrets were given a 4.7 mg deslorelin implant as alternative to surgical neutering. In 27 participating non‐oestrous jills, a double‐blind placebo controlled study was performed to investigate whether a single low dose of medroxyprogesterone (2 mg orally) four days preceding placement of the implant could prevent oestrus induction. The duration of effectiveness of the implant ranged from 301 days to over 1339 days (mean 1012±38 days), with no sex difference present. Over 90 per cent of owners were pleased with the effects of the implant. Minor local side effects were noted in less than 20 per cent of ferrets, which all resolved within a week without treatment. Oestrus was induced in 77 per cent of jills receiving medroxyprogesterone and 50 per cent of jills receiving the placebo, indicating that administration of a low‐dose progestogen cannot prevent postimplant oestrus. Based on the minimum duration of effectiveness, it is advised to place a new implant on a yearly basis to guarantee continuous gonadal suppression, although biannual replacement may be sufficient in the majority of ferrets.
Long-term evolution of the surface environment of the Campine area, northeastern Belgium: first assessment
Authors: Beerten K. , De Craen M. , Leterme B. 
Published: May 2014

Abstract
In this paper we describe the characteristics of the surface environment of the Boom Clay in the Campine area (outcrop and subcrop zone), which is regarded as a potential host formation for disposal of radioactive waste. A good description and understanding of the relationship between surface variables – the geomorphology, hydrography, vegetation, soils, land use and hydrology – is needed to evaluate the past evolution and assess the future evolution of the surface environment. Changing climatic conditions (glacials and interglacials), global sea-level variations and tectonic movements (uplift and subsidence) may cause the surface environment to change profoundly over long timescales. Starting from the present status, the palaeogeographical and palaeohydrological evolution of the Campine area is described in the framework of the Quaternary geological history of the area. Finally, a first assessment of possible future conditions of the surface environment is given, based on the integration of the palaeorecord and several published modelling studies.
An Integrated Computational Model of the Bone Microenvironment in Bone-Metastatic Prostate Cancer
Authors: Araujo Arturo , Cook Leah M. , Lynch Conor C. , Basanta David 
Published: May 2014

Abstract
Bone metastasis will impact most men with advanced prostate cancer. The vicious cycle of bone degradation and formation driven by metastatic prostate cells in bone yields factors that drive cancer growth. Mechanistic insights into this vicious cycle have suggested new therapeutic opportunities, but complex temporal and cellular interactions in the bone microenvironment make drug development challenging. We have integrated biologic and computational approaches to generate a hybrid cellular automata model of normal bone matrix homeostasis and the prostate cancer-bone microenvironment. The model accurately reproduces the basic multicellular unit bone coupling process, such that introduction of a single prostate cancer cell yields a vicious cycle similar in cellular composition and pathophysiology to models of prostate-to-bone metastasis. Notably, the model revealed distinct phases of osteolytic and osteogenic activity, a critical role for mesenchymal stromal cells in osteogenesis, and temporal changes in cellular composition. To evaluate the robustness of the model, we assessed the effect of established bisphosphonate and anti-RANKL therapies on bone metastases. At approximately 100% efficacy, bisphosphonates inhibited cancer progression while, in contrast with clinical observations in humans, anti-RANKL therapy fully eradicated metastases. Reducing anti-RANKL yielded clinically similar results, suggesting that better targeting or dosing could improve patient survival. Our work establishes a computational model that can be tailored for rapid assessment of experimental therapies and delivery of precision medicine to patients with prostate cancer with bone metastases. Cancer Res; 74(9); 2391–401. ©2014 AACR.
SWI/SNF Factors Required for Cellular Resistance to DNA Damage Include ARID1A and ARID1B and Show Interdependent Protein Stability
Authors: Watanabe Reiko , Ui Ayako , Kanno Shin-ichiro , Ogiwara Hideaki , Nagase Takahiro , Kohno Takashi , Yasui Akira 
Published: May 2014

AbstractThe SWI/SNF chromatin-remodeling family contains various protein complexes, which regulate gene expression during cellular development and influence DNA damage response in an ATP- and complex-dependent manner, of which details remain elusive. Recent human genome sequencing of various cancer cells revealed frequent mutations in SWI/SNF factors, especially ARID1A, a variant subunit in the BRG1-associated factor (BAF) complex of the SWI/SNF family. We combined live-cell analysis and gene-suppression experiments to show that suppression of either ARID1A or its paralog ARID1B led to reduced nonhomologous end joining activity of DNA double-strand breaks (DSB), decreased accumulation of KU70/KU80 proteins at DSB, and sensitivity to ionizing radiation, as well as to cisplatin and UV. Thus, in contrast to transcriptional regulation, both ARID1 proteins are required for cellular resistance to various types of DNA damage, including DSB. The suppression of other SWI/SNF factors, namely SNF5, BAF60a, BAF60c, BAF155, or BAF170, exhibits a similar phenotype. Of these factors, ARID1A, ARID1B, SNF5, and BAF60c are necessary for the immediate recruitment of the ATPase subunit of the SWI/SNF complex to DSB, arguing that both ARID1 proteins facilitate the damage response of the complex. Finally, we found interdependent protein stability among the SWI/SNF factors, suggesting their direct interaction within the complex and the reason why multiple factors are frequently lost in parallel in cancer cells. Taken together, we show that cancer cells lacking in the expression of certain SWI/SNF factors, including ARID1A, are deficient in DNA repair and potentially vulnerable to DNA damage. Cancer Res; 74(9); 2465–75. ©2014 AACR.
Prospective Population-Based Study of the Association between Serum 25-Hydroxyvitamin-D Levels and the Incidence of Specific Types of Cancer
Authors: Skaaby Tea , Husemoen Lise Lotte Nystrup , Thuesen Betina Heinsbæk , Pisinger Charlotta , Jørgensen Torben , Roswall Nina , Larsen Sofus Christian , Linneberg Allan 
Published: May 2014

Abstract
Background: Observational studies have suggested an inverse association between vitamin D status and cancer. We investigated the prospective associations between vitamin D status and the total and specific type of cancer in three cohorts from the general Danish population.
Methods: A total of 12,204 individuals 18 to 71 years old were included. The level of 25-hydroxyvitamin D was measured at baseline, and information about cancer was obtained from the Danish Cancer Registry.
Results: During the 11.3-year median follow-up time, there were 1,248 incident cancers. HRs [95% confidence intervals (CI)] per 10 nmol/L higher baseline vitamin D level were: for all cancers (HR = 1.02; 95% CI, 0.99–1.04), all cancers excluding non-melanoma skin cancer, NMSC (HR = 1.00; 95% CI, 0.97–1.03), head and neck cancer (HR = 0.97; 95% CI, 0.84–1.12), colorectal cancer (HR = 0.95; 95% CI, 0.88–1.02), cancer of bronchus and lung (HR = 0.98; 95% CI, 0.91–1.05), breast cancer (HR = 1.02; 95% CI, 0.96–1.09), cancer of the uterus (HR = 1.10; 95% CI, 0.95–1.27), prostate cancer (HR = 1.00; 95% CI, 0.93–1.08), cancer of the urinary organs (HR = 1.01; 95% CI, 0.90–1.14), NMSC (HR = 1.06; 95% CI, 1.02–1.10), and malignant melanoma (HR = 1.06; 95% CI, 0.95–1.17).
Conclusions: Apart from a significantly higher risk for NMSC with higher vitamin D status, we found no statistically significant associations between vitamin D status and total or specific cancers.
Impact: Our results do not indicate that there is an impact of vitamin D on total cancer incidence. Cancer Epidemiol Biomarkers Prev; 23(7); 1220–9. ©2014 AACR.
Disruption of Follicular Dendritic Cells–Follicular Lymphoma Cross-talk by the Pan-PI3K Inhibitor BKM120 (Buparlisib)
Authors: Matas-Céspedes Alba , Rodriguez Vanina , Kalko Susana G. , Vidal-Crespo Anna , Rosich Laia , Casserras Teresa , Balsas Patricia , Villamor Neus , Giné Eva , Campo Elías , Roué Gaël , López-Guillermo Armando , Colomer Dolors , Pérez-Galán Patricia 
Published: May 2014

AbstractPurpose: To uncover the signaling pathways underlying follicular lymphoma–follicular dendritic cells (FL–FDC) cross-talk and its validation as new targets for therapy.Experimental Design: FL primary cells and cell lines were cocultured in the presence or absence of FDC. After 24 and 48 hours, RNA was isolated from FL cells and subjected to gene expression profiling (GEP) and data meta-analysis using DAVID and GSEA softwares. Blockade of PI3K pathway by the pan-PI3K inhibitor BKM120 (buparlisib; Novartis Pharmaceutical Corporation) and the effect of PI3K inhibition on FL–FDC cross-talk were analyzed by means of ELISA, RT-PCR, human umbilical vein endothelial cell tube formation, adhesion and migration assays, Western blot, and in vivo studies in mouse FL xenografts.Results: GEP of FL–FDC cocultures yields a marked modulation of FL transcriptome by FDC. Pathway assignment by DAVID and GSEA software uncovered an overrepresentation of genes related to angiogenesis, cell adhesion, migration, and serum-response factors. We demonstrate that the addition of the pan-PI3K inhibitor BKM120 to the cocultures was able to downregulate the expression and secretion of proangiogenic factors derived from FL–FDC cocultures, reducing in vitro and in vivo angiogenesis. Moreover, BKM120 efficiently counteracts FDC-mediated cell adhesion and impedes signaling and migration induced by the chemokine CXCL12. BKM120 inhibits both constitutive PI3K/AKT pathway and FDC- or CXCL12-induced PI3K/AKT pathway, hampers FDC survival signaling, and reduces cell proliferation of FL cells in vitro and in mouse xenografts.Conclusions: These data support the use of BKM120 in FL therapy to counteract microenvironment-related survival signaling in FL cells. Clin Cancer Res; 20(13); 3458–71. ©2014 AACR.
Chloroquine Targets Pancreatic Cancer Stem Cells via Inhibition of CXCR4 and Hedgehog Signaling
Authors: Balic Anamaria , Sørensen Morten Dræby , Trabulo Sara Maria , Sainz Bruno , Cioffi Michele , Vieira Catarina R. , Miranda-Lorenzo Irene , Hidalgo Manuel , Kleeff Joerg , Erkan Mert , Heeschen Christopher 
Published: May 2014

Abstract
Pancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs as a putative source for disease relapse. Thus, to identify potentially more effective treatment regimens, we screened established and new compounds for their ability to eliminate CSCs in primary pancreatic cancer (stem) cells in vitro and corresponding patient-derived pancreatic cancer tissue xenografts in vivo. Intriguingly, we found that in vitro treatment with the antimalarial agent chloroquine significantly decreased CSCs, translating into diminished in vivo tumorigenicity and invasiveness in a large panel of pancreatic cancers. In vivo treatment in combination with gemcitabine was capable of more effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloroquine was not related to inhibition of autophagy, but was due to inhibition of CXCL12/CXCR4 signaling, resulting in reduced phosphorylation of ERK and STAT3. Furthermore, chloroquine showed potent inhibition of hedgehog signaling by decreasing the production of Smoothened, translating into a significant reduction in sonic hedgehog-induced chemotaxis and downregulation of downstream targets in CSCs and the surrounding stroma. Our study demonstrates that via to date unreported effects, chloroquine is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer. Mol Cancer Ther; 13(7); 1758–71. ©2014 AACR.