bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regional variation and predictors of over-registration in English primary care in 2014: a spatial analysis
Authors: Burch Patrick , Doran Tim , Kontopantelis Evangelos 
Published: February 2018

BackgroundThere are more people registered with a general practice in England than are estimated to be resident in the country. The reasons behind this are not fully understood. We investigated the levels of over-registration (or under-registration) in English primary care, their regional variability and their association with population and geographical characteristics.MethodsThis was a cross-sectional study using mid-year population estimates for 2014 and general practice populations for the same year. We calculated levels of patient registration with English primary care, in relation to census-derived population estimates, at various geographical levels of interest: regions, clinical commissioning groups and lower super output areas (LSOAs, 2011 census derived geographical areas of 1500 people on average). We used linear regressions to investigate the relationship between levels of registration and area deprivation, urbanicity, ethnicity, age, sex and mean distance to practice.ResultsThe total over-registration rate for England was 3.9% (2 097 101 people) but there was wide regional variability. London had significantly higher levels of over-registration (6.0% and 515 063 people) than other areas in England. Higher levels of over-registration at the LSOA level were associated with greater proportions of non-White British residents, women, elderly people and higher levels of social deprivation.ConclusionOur findings indicate that high mobility and health need may be the underlying causes of over-registrations. The regional variation in over-registration, with London being an outlier, points towards potential inequalities in resourcing of primary care and the ability of the National Health Service to adequately match funding to population need.
High-Capacity Reversible Data Hiding Using Modified Pixel Value Ordering Approach
Authors: Jain Neeraj Kumar , Kasana Singara Singh 
Published: February 2018

The proposed reversible data hiding technique is the extension of Peng et al.’s technique [F. Peng, X. Li and B. Yang, Improved PVO-based reversible data hiding, Digit. Signal Process. 25 (2014) 255–265]. In this technique, a cover image is segmented into nonoverlapping blocks of equal size. Each block is sorted in ascending order and then differences are calculated on the basis of locations of its largest and second largest pixel values. Negative predicted differences are utilized to create empty spaces which further enhance the embedding capacity of the proposed technique. Also, the already sorted blocks are used to enhance the visual quality of marked images as pixels of these blocks are more correlated than the unsorted pixels of the block. Experimental results show the effectiveness of the proposed technique.
TIFR Near Infrared Imaging Camera-II on the 3.6 m Devasthal Optical Telescope
Authors: Baug T. , Ojha D. K. , Ghosh S. K. , Sharma S. , Pandey A. K. , Kumar Brijesh , Ghosh Arpan , Ninan J. P. , Naik M. B. , D’Costa S. L. A. , Poojary S. S. , Sandimani P. R. , Shah H. , Krishna Reddy B. , Pandey S. B. , Chand H. 
Published: February 2018

Tata Institute of Fundamental Research (TIFR) Near Infrared Imaging Camera-II (TIRCAM2) is a closed-cycle Helium cryo-cooled imaging camera equipped with a Raytheon 512[Formula: see text][Formula: see text][Formula: see text]512 pixels InSb Aladdin III Quadrant focal plane array (FPA) having sensitivity to photons in the 1–5[Formula: see text][Formula: see text] wavelength band. In this paper, we present the performance of the camera on the newly installed 3.6[Formula: see text]m Devasthal Optical Telescope (DOT) based on the calibration observations carried out during 2017 May 11–14 and 2017 October 7–31. After the preliminary characterization, the camera has been released to the Indian and Belgian astronomical community for science observations since 2017 May. The camera offers a field-of-view (FoV) of [Formula: see text] on the DOT with a pixel scale of 0.169[Formula: see text]. The seeing at the telescope site in the near-infrared (NIR) bands is typically sub-arcsecond with the best seeing of [Formula: see text] realized in the NIR [Formula: see text]-band on 2017 October 16. The camera is found to be capable of deep observations in the [Formula: see text], [Formula: see text] and [Formula: see text] bands comparable to other 4[Formula: see text]m class telescopes available world-wide. Another highlight of this camera is the observational capability for sources up to Wide-field Infrared Survey Explorer (WISE) W1-band (3.4[Formula: see text][Formula: see text]m) magnitudes of 9.2 in the narrow [Formula: see text]-band ([Formula: see text]; [Formula: see text] 3.59[Formula: see text][Formula: see text]m). Hence, the camera could be a good complementary instrument to observe the bright [Formula: see text]-band sources that are saturated in the Spitzer-Infrared Array Camera (IRAC) ([3.6] [Formula: see text] 7.92 mag) and the WISE W1-band ([3.4] [Formula: see text] 8.1 mag). Sources with strong polycyclic aromatic hydrocarbon (PAH) emission at 3.3[Formula: see text][Formula: see text]m are also detected. Details of the observations and estimated parameters are presented in this paper.
Molecular Pharmacodynamics-Guided Scheduling of Biologically Effective Doses: A Drug Development Paradigm Applied to MET Tyrosine Kinase Inhibitors
Authors: Srivastava Apurva K. , Hollingshead Melinda G. , Govindharajulu Jeevan Prasaad , Covey Joseph M. , Liston Dane , Simpson Melanie A. , Peggins James O. , Bottaro Donald P. , Wright John J. , Kinders Robert J. , Doroshow James H. , Parchment Ralph E. 
Published: February 2018

Abstract
The development of molecularly targeted agents has benefited from use of pharmacodynamic markers to identify “biologically effective doses” (BED) below MTDs, yet this knowledge remains underutilized in selecting dosage regimens and in comparing the effectiveness of targeted agents within a class. We sought to establish preclinical proof-of-concept for such pharmacodynamics-based BED regimens and effectiveness comparisons using MET kinase small-molecule inhibitors. Utilizing pharmacodynamic biomarker measurements of MET signaling (tumor pY1234/1235MET/total MET ratio) in a phase 0–like preclinical setting, we developed optimal dosage regimens for several MET kinase inhibitors and compared their antitumor efficacy in a MET-amplified gastric cancer xenograft model (SNU-5). Reductions in tumor pY1234/1235MET/total MET of 95%–99% were achievable with tolerable doses of EMD1214063/MSC2156119J (tepotinib), XL184 (cabozantinib), and XL880/GSK1363089 (foretinib), but not ARQ197 (tivantinib), which did not alter the pharmacodynamic biomarker. Duration of kinase suppression and rate of kinase recovery were specific to each agent, emphasizing the importance of developing customized dosage regimens to achieve continuous suppression of the pharmacodynamic biomarker at the required level (here, ≥90% MET kinase suppression). The customized dosage regimen of each inhibitor yielded substantial and sustained tumor regression; the equivalent effectiveness of customized dosage regimens that achieve the same level of continuous molecular target control represents preclinical proof-of-concept and illustrates the importance of proper scheduling of targeted agent BEDs. Pharmacodynamics-guided biologically effective dosage regimens (PD-BEDR) potentially offer a superior alternative to pharmacokinetic guidance (e.g., drug concentrations in surrogate tissues) for developing and making head-to-head comparisons of targeted agents. Mol Cancer Ther; 17(3); 698–709. ©2018 AACR.
Abstract BS2-1: Ocogenic and microenvironmental signals driving early dissemination, dormancy and metastasis
Authors: Aguirre-Ghiso JA 
Published: February 2018

Abstract
The mechanisms that produce early-disseminated cancer cells (eDCC) during early stages of breast cancer or that contribute to the development of metastasis from cancer of unknown primary (CUP) are poorly understood. Here we show that HER2+ cancer cells that are present during early stages of cancer before any overt tumors can be detected are highly efficient in systemically disseminating from primary sites. These eDCCs were HER2+/P-p38lo/P-ATF2lo/E-cadherinlo, and were found also in human DCIS samples. Further, eDCC precursors in early lesions activated a Wnt-dependent EMT-like program that was reversed by HER2 or Wnt signaling blockade or p38 activation. Intra-vital imaging of transgenic HER2-CFP mice revealed that eDCC precursors invade the local stroma, intravasate and circulate to target organs, a process that can be stimulated by blocking p38α/β signaling. This process was aided by CD206+/Tie2+ mammary tissue macrophages (MTMs) in a similar way as they regulate mammary branching morphogenesis. We found that macrophages are localized inside the epithelium of early cancer lesions but localize in the stroma of healthy tissue. MTM recruitment depends on upregulation of CCL2 in HER2+ mammary epithelial cells via activation of NFkB. Importantly, samples from patients with DCIS frequently contain intra-epithelial macrophages, correlating with E-Cadherin downregulation. MTMs produce Wnt-1 in response to CCL2 produced by HER2+ early lesion cells and Wnt1 cooperates with the intrinsic oncogene-driven EMT in early cancer cells. Importantly these MTMs contribute to eDCC spread. Surprisingly, although the vast majority of early HER2+ cancer cells are non-tumorigenic, they can spawn eDCCs that remain HER2+/TWIST1+ and dormant in lungs for long periods only to then initiate metastasis. Significantly, depletion of macrophages during early lesion development and before overt tumors appeared, drastically reduced early dissemination and even late metastasis onset. We reveal that during early stages of HER2-driven cancer when dissemination is not thought to occur, HER2 signaling aberrantly activates a side-branching morphogenesis-like program that through macrophage recruitment and cancer cell intrinsic induction of an EMT module causes early dissemination. Our findings reveal that residual cancer may comprise dormant eDCCs with metastasis initiating capacity. We propose our data may lead to changes in our understanding of metastasis onset and how it might be targeted effectively.
Citation Format: Aguirre-Ghiso JA. Ocogenic and microenvironmental signals driving early dissemination, dormancy and metastasis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr BS2-1.
Abstract ES9-2: Tracking progesterone receptor actions in breast cancer progression: Jekyll and Hyde
Authors: Lange CA 
Published: February 2018

Abstract
Recent work on the actions for progesterone receptors (PRs) in breast cancer has raised the profile of PRs as players rather than simply markers of estrogen (E)-responsive luminal disease. Indeed, estrogen receptors (ERs) and PRs are intimate partners at the genome regulatory level rather than having a simple driver/passenger relationship. PRs alter breast cancer cell proliferation in complex ways and can be either growth inhibitory or stimulatory depending on the cell and hormonal context. Additionally, PRs are important drivers of normal mammary stem cell as well as cancer stem cell expansion. Along with ERs, targeting PRs as part of modernized endocrine therapies may provide a rational treatment alternative for women with ER- and PR-positive breast cancers. However, should PR agonists or antagonists be paired with anti-estrogens or estrogen-ablative therapies and when? This lecture will review historical and current literature on the complex topic of PR action in luminal breast cancer, with focus on key knowledge gaps and future steps that could speed translation of exciting research findings into useful clinical therapeutic applications.
Citation Format: Lange CA. Tracking progesterone receptor actions in breast cancer progression: Jekyll and Hyde [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES9-2.
Abstract IS-1: Health System Responses to Women's Cancers in the Americas: Closing Divides to Achieve Universal Health Coverage
Authors: Knaul FM 
Published: February 2018

Abstract
To address the challenges of the increasing cancer burden, low- and middle-income country health systems must function in an integrated manner across the care continuum from prevention to palliative care. Health systems must address disease-specific priorities and systemic challenges synergistically, as envisioned in a diagonal approach to health systems strengthening, which overcomes the barriers between vertical (disease-specific) and horizontal (systemic) approaches by making full use of potential synergies between different programs and allows the development of common delivery platforms that consider shared risk factors across diseases to optimize available resources.
The challenges of meeting the double burden of cancer are epitomized by women's cancers in Latin America: the persistence of preventable cancers like cervical cancer that are especially prevalent among the poor; and the emerging challenge of cancers like breast cancer, that cannot be prevented, but whose impact could be dramatically reduced through early detection and treatment and that affect women of all socio-economic strata. Further, women face specific challenges associated with stigma and discrimination that exacerbate their risks of dying and suffering from cancer, especially those affecting reproductive health. As many Latin American countries continue making strides to ensure health care access for all through universal health coverage, they must aim to effectively meet the challenge of these chronic illnesses across the entire care continuum.
We outline strategies to strengthen health systems through a diagonal approach using the example of how the Mexican health system has responded to the challenge of breast cancer to illustrate effective universal health coverage along the chronic disease continuum and across health systems functions. We also present innovative financing and delivery models, as well as educational interventions that build on overall efforts to strengthen primary care by linking to existing platforms related to reproductive and maternal and child health.
Citation Format: Knaul FM. Health System Responses to Women's Cancers in the Americas: Closing Divides to Achieve Universal Health Coverage [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr IS-1.
Abstract P2-04-03: Epigenomic analysis of cancer stem cell (CSC)-enriched triple-negative breast cancer (TNBC) populations reveals gene regulatory circuitry and novel tumor cell vulnerabilities
Authors: Guenther MG , Lambert AW , Chen MW , Fiore C , Eaton M , Orlando D , Bierie B , Weinberg RA , Fritz CC , Olson ER 
Published: February 2018

Abstract
Tumor-initiating cells (TICs), also termed cancer stem cells (CSCs) are involved in breast cancer chemoresistance, metastasis and disease progression. To pinpoint tumor cell vulnerabilities and transcriptional drivers of therapeutic relevance, we have characterized the triple negative breast cancer (TNBC) CSC transcriptional landscape using epigenome mapping and nucleosome occupancy determination. We identify a set of transcriptional regulators and signaling mediators that enforce the cancer stem cell state and instruct potential therapeutic strategies.
The basal epithelial marker, integrin-β4 (ITGB4), can be used to stratify mesenchymal-like triple-negative breast cancer (TNBC) cells into populations of low and high tumor-initiating ability in vivo. We used ChIP-seq to measure H3K27ac occupancy and map the transcriptional enhancers in SUM159 cells segregated into ITGB4HI (High tumor initiating ability) and ITGB4LOW (Low tumor initiating ability) populations. Gene-enhancer linking and comparative analysis of enhancer usage revealed an epigenomically defined set of genes that are candidate drivers of the CSC cell state, including GSK3β, DNA-binding transcription factors and cellular adhesion proteins. To further define the chromatin architecture and transcriptional regulatory circuitry that underlies CSC state, we deployed ATAC-seq (Assay for Transposase-Accessible Chromatin with high throughput sequencing) within ITGB4HI and ITGB4LOW populations. By pairing nucleosome occupancy and transcription factor kinetics, we created enhancer-linked transcriptional regulatory circuitry of these tumor-initiating cells.
Together, the isolation of partially mesenchymal ITGB4HI CSCs, coupled with enhancer mapping and distillation of transcriptional regulatory circuitry from these cells enable the identification of cancer vulnerabilities and therapeutic opportunities for high-risk patients with TNBC.
Citation Format: Guenther MG, Lambert AW, Chen MW, Fiore C, Eaton M, Orlando D, Bierie B, Weinberg RA, Fritz CC, Olson ER. Epigenomic analysis of cancer stem cell (CSC)-enriched triple-negative breast cancer (TNBC) populations reveals gene regulatory circuitry and novel tumor cell vulnerabilities [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-04-03.
Abstract P2-07-04: Molecular regulators of resistance and relapse in chemorefractory triple-negative breast cancers
Authors: Hancock BA , Chen Y-H , Solzak JP , Ahmad MN , Wedge DC , Brinza D , Scafe C , Veitch J , Gottimukkala R , Short W , Atale RV , Ivan M , Badve SS , Schneider BP , Miller KD , Radovich M 
Published: February 2018

Abstract
Triple-Negative Breast Cancer (TNBC) accounts for approximately one-fifth of breast cancer incidence but disproportionately high mortality. Two-thirds of early-stage TNBCs are resistant to pre-surgical chemotherapy and highly prone to relapse within 3 years. Morever, no advanced therapies are indicated for patients with these cancers. We have embarked on a comprehensive genomic analysis of chemoresistant TNBC to gain an in-depth understanding of molecular entities driving chemoresistance and relapse. By collecting somatic mutation and copy number, RNA-sequencing, and outcome data in the context of a phase II post-neoadjuvant clinical trial, we have uncovered several molecular mechanisms behind these aggressive cancers. Through the analysis of matched pairs sampled before and after chemotherapy, we have discovered multiple means by which tumors are able to overcome the effects of chemotherapy including clonal evolution of high-level oncogene amplification, repression of the in situ immune system, and upregulation of the stem cell-related MEK-ERK and JAK-STAT pathways. Investigation into factors related to prognosis revealed important correlations between relapse and immune and JAK-STAT signaling. Finally, using a novel method of demarcating loss-of-function of p53, which we have termed graduated inactivation, we discovered additional associations between p53 loss and relapse, mortality, and MYC signalling.
Citation Format: Hancock BA, Chen Y-H, Solzak JP, Ahmad MN, Wedge DC, Brinza D, Scafe C, Veitch J, Gottimukkala R, Short W, Atale RV, Ivan M, Badve SS, Schneider BP, Miller KD, Radovich M. Molecular regulators of resistance and relapse in chemorefractory triple-negative breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-07-04.
Abstract P2-08-01: Loss of function of Brca1 or Gata3 induces basal-like breast cancer
Authors: Pei X-H , Chan HL , Zhang L , Wang C , Robbins DJ , Capobianco T , Bai F 
Published: February 2018

Abstract
BACKGROUND:
Breast cancer is mainly divided into estrogen receptor (ER)-positive luminal and ER-negative basal-like tumors. Luminal-type tumors are associated with better survival and respond to hormone therapies whereas basal-like tumors are more aggressive and associated with a poor prognosis. Mammary epithelia are mainly composed of luminal and basal cells that are maintained by luminal and basal progenitors, respectively. The maintenance of luminal cell fate is orchestrated by networks of transcription factors, including BRCA1 and GATA3. Functional loss of BRCA1 by germline or somatic mutation or by promoter methylation is associated with more than one third of basal-like breast cancers. GATA3 expression is reduced in basal-like breast cancers and cancers that metastasize. Overexpression of GATA3 in cancer cells inhibits tumor formation. Deletion of Brca1 or Gata3 in mice results in early lethality or growth defects. How BRCA1 and GATA3 suppress breast cancer remains elusive.
METHODS:
We generated mice lacking Brca1 or Gata3 in mammary epithelia. Due to the proliferative defects and induction of p18Ink4c (p18), an inhibitor of CDK4/6, in mammary epithelial cells of these mice, we then generated mice lacking Brca1 or Gata3 in p18 deficient mammary epithelia. We determined spontaneous mammary tumor development in mutant mice and the mechanisms underlying the role of Brca1 and Gata3 in suppressing tumorigenesis and progression.
RESULTS:
Depletion of Brca1 or Gata3 led to growth defects of mammary epithelial cells, which was rescued by loss of p18. Depletion of Brca1 or Gata3 in a p18 null background induced heterogeneous mammary tumors with less luminal and more basal-like features and accelerated metastasis. Deletion of Brca1 eliminated Gata3 expression in human and mouse mammary tissues and cells. How Brca1 interacts with Gata3 to control mammary tumor development and progression is currently under investigation.
CONCLUSION: Our results suggest that loss of function of either Brca1 or Gata3 induces basal-like mammary tumors in p18 deficient background.
Citation Format: Pei X-H, Chan HL, Zhang L, Wang C, Robbins DJ, Capobianco T, Bai F. Loss of function of Brca1 or Gata3 induces basal-like breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-08-01.