bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell transcriptome analysis identifies distinct cell types and intercellular niche signaling in a primary gastric organoid model
Authors: Chen Jiamin , Lau Billy T , Andor Noemi , Grimes Sue M , Handy Christine , Wood-Bouwens Christina , Ji Hanlee P 
Published: October 2017

ABSTRACTThe diverse cellular milieu of the gastric tissue microenvironment plays a critical role in normal tissue homeostasis and tumor development. However, few cell culture model can recapitulate the tissue microenvironment and intercellular signalingin vitro. Here we applied an air-liquid interface method to culture primary gastric organoids that contains epithelium with endogenous stroma. To characterize the microenvironment and intercellular signaling in this model, we analyzed the transcriptomes of over 5,000 individual cells from primary gastric organoids cultured at different time points. We identified epithelial cells, fibroblasts and macrophages at the early stage of organoid formation, and revealed that macrophages were polarized towards wound healing and tumor promotion. The organoids maintained both epithelial and fibroblast lineages during the course of time, and a subset of cells in both lineages expressed the stem cell markerLgr5. We identified thatRspo3was specifically expressed in the fibroblast lineage, providing an endogenous source of the R-spondin to activate Wnt signaling. Our studies demonstrate that air-liquid-interface-derived organoids provide a novel platform to study intercellular signaling and immune responsein vitro.
The impact of surveillance and control on highly pathogenic avian inuenza outbreaks in poultry in Dhaka division, Bangladesh
Authors: Hill Edward M. , House Thomas , Dhingra Madhur S. , Kalpravidh Wantanee , Morzaria Subhash , Osmani Muzaffar G. , Brum Eric , Yamage Mat , Kalam Md. A. , Prosser Diann J. , Takekawa John Y. , Xiao Xiangming , Gilbert Marius , Tildesley Michael J. 
Published: October 2017

AbstractIn Bangladesh, the poultry industry is an economically and socially important sector, but it is persistently threatened by the effects of H5N1 highly pathogenic avian influenza. Thus, identifying the optimal control policy in response to an emerging disease outbreak is a key challenge for policy-makers. To inform this aim, a common approach is to carry out simulation studies comparing plausible strategies, while accounting for known capacity restrictions. In this study we perform simulations of a previously developed H5N1 influenza transmission model framework, fitted to two separate historical outbreaks, to assess specific control objectives related to the burden or duration of H5N1 outbreaks among poultry farms in the Dhaka division of Bangladesh. In particular, we explore the optimal implementation of ring culling, ring vaccination and active surveillance measures when presuming disease transmission predominately occurs from premises-to-premises, versus a setting requiring the inclusion of external factors. Additionally, we determine the sensitivity of the management actions under consideration to differing levels of capacity constraints and outbreaks with disparate transmission dynamics. While we find that reactive culling and vaccination policies should pay close attention to these factors to ensure intervention targeting is optimised, across multiple settings the top performing control action amongst those under consideration were targeted proactive surveillance schemes. Our findings may advise the type of control measure, plus its intensity, that could potentially be applied in the event of a developing outbreak of H5N1 amongst originally H5N1 virus-free commercially-reared poultry in the Dhaka division of Bangladesh.
Dynamic evolution of the major transcription factor DNA binding domain, and protein-protein interaction families during the evolution of the avian lineage
Authors: Graham Allie M. , Presnell Jason S. 
Published: October 2017

ABSTRACTTranscription factors are characterized by their domain architecture, including DNA binding and protein-protein interaction domain combinations, which regulate their binding specificity, as well as their ability to effect a change on gene expression of their downstream targets. Transcription factors are central to organismal development, thus they potentially are instrumental in producing phenotypic diversity. Transcription factor abundance was estimated via 49 major DNA binding domain families, as well as 34 protein-protein interaction domain families, in 48 bird genomes, which were then compared with 6 available reptile genomes, in an effort to assess the degree to which these domains are potentially connected to increased phenotypic diversity in the avian lineage. We hypothesized that there would be increased abundance in multiple transcription factor domain families, as well as domains associated with protein-protein interactions, that would correlate with the increased phenotypic diversity found in birds; instead, this data shows a general loss/contraction of major domain families, with the largest losses in domain families associated with multiple developmental (feather, body-plan, immune) and metabolic processes. Ultimately, the results of this analyses represent a general characterization of domain family composition in birds, thus the specific domain composition of TF families should be probed further, especially those with the largest reductions seen in this study.
miR-128 inhibits telomerase activity by targeting TERT mRNA
Authors: Guzman Herlinda , Sanders Katie , Idica Adam , Bochnakian Aurore , Jury Douglas , Daugaard Iben , Zisoulis Dimitrios G , Pedersen Irene Munk 
Published: October 2017

ABSTRACTTelomerase is a unique cellular reverse transcriptase essential for maintaining telomere stability and required for the unlimited proliferation of cancer cells. The limiting determinant of telomerase activity is the catalytic component TERT, and TERT expression is closely correlated with telomerase activity and cancer initiation and disease progression. For this reason the regulation of TERT levels in the cell is of great importance. microRNAs (miRs) function as an additional regulatory level in cells, crucial for defining expression boundaries, proper cell fate decisions, cell cycle control, genome integrity, cell death and metastasis. We performed an anti-miR library screen to identity novel miRs, which participate in the control of telomerase. We identified the tumor suppressor miR (miR-128) as a novel endogenous telomerase inhibitor and determined that miR-128 significantly reduces the mRNA and protein levels of Tert in a panel of cancer cell lines. We further evaluated the mechanism by which miR-128 regulates TERT and demonstrated that miR-128 interacts directly with the coding sequence of TERT mRNA in both HeLa cells and teratoma cells. Interestingly, the functional miR-128 binding site in TERT mRNA, is conserved between TERT and the other cellular reverse transcriptase encoded by Long Interspaced Elements-1 (LINE-1 or L1), which can also contribute to the oncogenic phenotype of cancer. This finding supports the novel idea that miRs may function in parallel pathways to inhibit tumorigenesis, by regulating a group of enzymes (RT) by targeting conserved binding sites in the coding region of both enzymes.NOVELTY AND IMPACTTelomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA sequences and almost universally provides the molecular basis for unlimited proliferative potential. Expression of human telomerase alone is sufficient for the immortalization of diverse cell types. We have identified the tumor suppressor microRNA (miR-128) as a novel regulator of telomerase, which directly targets the coding sequence (CDS) of TERT mRNA and significantly represses Tert protein expression in a panel of cancer cell lines.
A 30-minute nucleic acid amplification point-of-care test for genitalChlamydia trachomatisinfection in women: a prospective, multi-centre study of diagnostic accuracy
Authors: Harding-Esch EM , Cousins EC , Chow S-LC , Phillips LT , Hall CL , Cooper N , Fuller SS , Nori AV , Patel R , Thomas-William S , Whitlock G , Edwards SJE , Green M , Clarkson J , Arlett B , Dunbar JK , Lowndes CM , Sadiq ST 
Published: October 2017

ABSTRACTBackgroundRapid Point-Of-Care Tests (POCTs) forChlamydia trachomatis(CT) may reduce onward transmission and reproductive sexual health (RSH) sequelae by reducing turnaround times between diagnosis and treatment. The io®single module system (Atlas Genetics Ltd) runs clinical samples through a microfluidic CT cartridge, delivering results in 30 minutes. We evaluated its performance on female genital samples in four UK Genito-Urinary Medicine (GUM)/RSH clinics.MethodsProspective diagnostic accuracy study, using BD ProbeTec CT/GC assay as the routine clinic nucleic acid amplification test (NAAT) as the initial comparator test, and the QIAgen Artus CT assay to resolve discrepancies. In these instances, the reference standard was defined as the resolved result when two out of three assay results concurred. Female participants aged ≥16 provided additional-to-routine self-collected vulvovaginal swabs. Samples were tested fresh with the io®CT assay within 7 days of collection, or were frozen at −80°C for later testing. Participant clinical, demographic and behavioural characteristics were collected to assess risk factors associated with CT infection.ResultsOf 785 participants recruited, final analyses were conducted on 709 (90.3%). CT prevalence was 7.2% (51/709) overall. Sensitivity, specificity, positive and negative predictive values of the io®CT assay were, respectively, 96.1% (95% Confidence Interval (CI): 86.5-99.5), 97.7% (95%CI: 96.3-98.7), 76.6% (95%CI: 64.3-86.2) and 99.7% (95%CI: 98.9-100). There was no significant difference in performance measures between fresh and frozen samples, or between symptomatic and asymptomatic participants (p>0.05). The only risk factor associated with CT infection was being a sexual contact of an individual with CT.ConclusionsThe io®CT-assay is the only 30-minute, fully automated, high-performing NAAT currently CE-marked for CT diagnosis in women, making it a highly promising diagnostic to enable specific treatment, initiation of partner notification and appropriately intensive health promotion at the point of care. Future research is required to evaluate acceptability by clinicians and patients in GUM/RSH clinics, impact on clinical pathways and patient management, and cost-effectiveness.
Repurposing non-cancer Drugs in Oncology – How many drugs are out there?
Authors: Pantziarka Pan , Sukhatme Vidula , Meheus Lydie , Sukhatme Vikas , Bouche Gauthier 
Published: October 2017

AbstractBackgroundDrug repurposing can speed up access to new therapeutic options for cancer patients. With more than 2000 drugs approved worldwide and 6 relevant targets per drug on average, the potential is quantitatively important. In this paper, we have attempted to quantify the number of non-cancer drugs supported by either preclinical or clinical cancer data.MethodsA PubMed search was performed to identify non-cancer drugs which could be repurposed in one or more cancer types. Drugs needed at least one peer-reviewed article showing an anticancer effect in vitro, in vivo or in humans.ResultsA total of 235 eligible non-cancer drugs were identified (Table 1). Main charateirstics of the drugs are summarized in Table 2. 67 (29%) are on the WHO list of essential medicines and 176 (75%) are off-patent. 133 (57%) had human data in cancer patient(s). Four were listed in clinical guidelines, namely thalidomide, all-trans retinoic acid, zoledronic acid and non-steroidal anti-inflammatory drugs (NSAID). Several drugs have shown a survival benefit in randomized trials such as cimetidine (colorectal cancer), progesterone (breast cancer) or itraconazole (lung cancer). Several other drugs induced responses in rare tumours, like clarithromycin, timolol or propranolol.ConclusionWe have found that the number of off-patent repurposing opportunities is large and increasing. Joint non-commercial clinical development (academics, governments, charities) may bring new therapeutic options to patients at low cost, especially in indications for which the industry has no incentive to invest in.
Simulations for Designing and Interpreting Intervention Trials in Infectious Diseases
Authors: Elizabeth Halloran M. , Auranen Kari , Baird Sarah , Basta Nicole E. , Bellan Steve , Brookmeyer Ron , Cooper Ben , DeGruttola Victor , Hughes James , Lessler Justin , Lofgren Eric T. , Longini Ira M. , Onnela Jukka-Pekka , Özler Berk , Seage George , Smith Thomas A. , Vespignani Alessandro , Vynnycky Emilia , Lipsitch Marc 
Published: October 2017

AbstractHere we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly in emerging infectious disease, that more accurately reflects the dynamics of the transmission process. Interventions in infectious diseases can have indirect effects on those not receiving the intervention as well as direct effects on those receiving the intervention. Combinations of interventions can have complex interactions at the population level. These often cannot be adequately addressed with standard study designs and analytic methods. Simulations can help to accurately represent transmission dynamics in an increasingly complex world which is critical for proper trial design and interpretation. Some ethical aspects of a trial can also be quantified using simulations. After a trial has been conducted, simulations can be used to explore possible explanations for the observed effects. A great deal is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods and the conduct of clinical trials.
Melanoma proteomics unravels major differences related to mutational status
Authors: Trilla-Fuertes Lucía , Gámez-Pozo Angelo , Prado-Vázquez Guillermo , Zapater-Moros Andrea , Díaz-Almirón Mariana , Fortes Claudia , López-Vacas Rocío , Márquez-Rodas Iván , Soria Ainara , Fresno Vara Juan Ángel , Espinosa Enrique 
Published: October 2017

AbstractThe aim of the study was to explore the molecular differences between melanoma tumor subtypes, based on BRAF and NRAS mutational status. Fourteen formalin-fixed, paraffin- embedded melanoma samples were analyzed using a high-throughput proteomics approach, coupled with probabilistic graphical models and Flux Balance Analysis, to characterize these differences. Proteomics analyses showed differences in expression of proteins related with fatty acid metabolism, melanogenesis and extracellular space between BRAF mutated and BRAF non-mutated melanoma tumors. Additionally, probabilistic graphical models showed differences between melanoma subgroups at biological processes such as melanogenesis or metabolism. On the other hand, Flux Balance Analysis predicts a higher tumor growth rate in BRAF mutated melanoma samples. In conclusion, differential biological processes between melanomas showing a specific mutational status can be detected using combined proteomics and computational approaches.
Application of benchmark analysis for mixed contaminant exposures: Mutual adjustment of two perfluoroalkylate substances associated with immunotoxicity
Authors: Budtz-Jøergensen Esben , Grandjean, Philippe 
Published: October 2017

AbstractBackgroundDevelopmental exposure to perfluorinated substances is associated with deficient IgG antibody responses to childhood vaccines as an indication of depressed immune system functions. As this outcome may represent a critical effect of these substances, calculation of benchmark dose (BMD) results would be useful for standards setting to protect exposed populations against adverse effects. However, in the mixed exposure setting of most epidemiological evidence, the two major and inter-related substances associated with this adverse effect have shown similar benchmark results that raise concerns about possible confounding.MethodsWith the aim of better characterizing the immunotoxicity impact of the two major perfluorinated substances in the mixed exposures, we carried out BMD calculations on prospective data from two prospective birth cohort studies from the Faroe Islands with a total of 1,146 children. Exposure data included serum concentrations of perfluorooctane sulfonate and perfluorooctanoate at birth and at age 5 years and, as outcome parameters, the serum concentrations of specific IgG antibodies against tetanus and diphtheria at ages 5 and 7. We calculated the BMDs and their lower confidence bounds (BMDLs) and included mutual adjustment for the two compounds.ResultsThe BMDLs for the two immunotoxicants were of similar magnitude before and after adjustment. Both substances showed lower results for a logarithmic dose-response model, which also provided a slightly better fit than a linear dose model for both antibodies. We also used a broken curve shape that allowed a different slope below the median exposure. Postnatal exposure as represented by the age 5 serum concentration, showed a stronger association with the antibody outcomes than the prenatal exposure. Due to the correlation between the two immunotoxicants, the mutual adjustment resulted in elevated BMD results andpvalues. However, the BMDL values were virtually unchanged.ConclusionsAdjustment for co-exposure to another immunotoxicant increased the variance and the BMD values, but affected the BMDL values only to a negligible extent. These calculations are in accordance with an interpretation that, when two toxicants appear to affect an outcome to an almost equal degree and none of them is known to be solely responsible, the exposures should both be considered responsible and attract equal regulatory attention until further evidence shows otherwise.
The VT GAL4, LexA, and split-GAL4 driver line collections for targeted expression in theDrosophilanervous system
Authors: Tirian Laszlo , Dickson Barry J. 
Published: October 2017

AbstractIn studying the cellular interactions within complex tissues, it is extremely valuable to be able to reproducibly and flexibly target transgene expression to restricted subsets of cells. This approach is particularly valuable in studying the nervous system, with its bewildering diversity of neuronal cell types. We report here the generation of over 18,000 driver lines (the VT collection) that exploit the GAL4, LexA, and split-GAL4 systems to express transgenes in distinct and highly specific cell types inDrosophila. We document the expression patterns of over 14,000 of these lines in the adult male brain.
Data mining of digitized health records in a resource-constrained setting reveals that timely immunophenotyping is associated with improved breast cancer outcomes
Authors: López-Pineda Arturo , Rodríguez-Moran Mario F. , Álvarez-Aguilar Cleto , Fuentes Valle Sarah M. , Acosta-Rosales Román , Bhatt Ami S. , Sheth Shruti N. , Bustamante Carlos D. 
Published: October 2017

AbstractBackgroundOrganizations that issue guidance on breast cancer recommend the use of immunohistochemistry (IHC) for providing appropriate and precise care. However, little focus has been directed to the identification of maximum allowable turnaround times for IHC, which is necessary given the diversity of hospital settings in the world. Much less effort has been committed to the development of digital tools that allow hospital administrators to monitor service utilization histories of their patients.MethodsIn this retrospective cohort study, we reviewed electronic and paper medical records of all suspected breast cancer patients treated at one secondary-care hospital of the Mexican Institute of Social Security (IMSS), located in western Mexico. We then followed three years of medical history of those patients with IHC testing.ResultsIn 2014, there were 402 breast cancer patients, of which 30 were tested for some IHC biomarker (ER, PR, HER2). The subtyping allowed doctors to adjust (56.7 %) or confirm (43.3 %) the initial therapeutic regimen. The average turnaround time was 56 days. Opportune IHC testing was found to be beneficial when it was available before or during the first rounds of chemotherapy.ConclusionsThe use of data mining tools applied to health record data revealed that there is an association between timely immunohistochemistry and improved outcomes in breast cancer patients. Based on this finding, inclusion of turnaround time in clinical guidelines is recommended. As much of the health data in the country becomes digitized, our visualization tools allow a digital dashboard of the hospital service utilization histories.
In the Absence of Apoptosis, Myeloid Cells Arrest When Deprived of Growth Factor, But Remain Viable by Consuming Extracellular Glucose
Authors: Dong Li , Reljic Boris , Cheung Jen G. , Ng Elizabeth S. , Lindqvist Lisa M. , Elefanty Andrew G. , Vaux David L. , Tran Hoanh 
Published: October 2017

AbstractWithdrawal of the growth factor interleukin 3 from IL3-dependent myeloid cells causes them to undergo Bax/Bak1-dependent apoptosis, whereas factor-deprivedBax-/-Bak1-/-cells remain viable, but arrest and shrink. It was reported that withdrawal of IL3 fromBax-/-Bak1-/-cells caused decreased expression of the glucose transporter Glut1, leading to reduced glucose uptake, so that arrested cells required Atg5-dependent autophagy for long-term survival. In other cell types, a decrease in Glut1 is mediated by the thioredoxin-interacting protein Txnip, which is induced in IL3-dependent myeloid cells when growth factor is removed. We mutatedAtg5andTxnipby CRISPR/Cas9 and found that Atg5-dependent autophagy was not necessary for the long-term viability of cycling or arrestedBax-/-Bak1-/-cells, and that Txnip was not required for the decrease in Glut1 expression in response to IL3 withdrawal. Surprisingly, Atg5-deficientBax/Bak1double mutant cells survived for several weeks in medium supplemented with 10% fetal bovine serum (FBS), without high concentrations of added glucose or glutamine. When serum was withdrawn, the provision of an equivalent amount of glucose present in 10% FBS (~0.5 mM) was sufficient to support cell survival for more than a week, in the presence or absence of IL3. Thus,Bax-/-Bak1-/-myeloid cells deprived of growth factor consume extracellular glucose to maintain long-term viability, without a requirement for Atg5-dependent autophagy.