bluuebunny/crossref_metadata_2025_split huggingface dataset:
Process evaluations of primary care interventions addressing chronic disease: a systematic review
Authors: Liu Hueiming , Mohammed Alim , Shanthosh Janani , News Madeline , Laba Tracey-Lea , Hackett Maree L , Peiris David , Jan Stephen 
Published: August 2019

ObjectiveProcess evaluations (PEs) alongside randomised controlled trials of complex interventions are valuable because they address questions of for whom, how and why interventions had an impact. We synthesised the methods used in PEs of primary care interventions, and their main findings on implementation barriers and facilitators.DesignSystematic review using the UK Medical Research Council guidance for PE as a guide.Data sourcesAcademic databases (MEDLINE, SCOPUS, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, EMBASE and Global Health) were searched from 1998 until June 2018.Eligibility criteriaWe included PE alongside randomised controlled trials of primary care interventions which aimed to improve outcomes for patients with non-communicable diseases.Data extraction and synthesisTwo independent reviewers screened and conducted the data extraction and synthesis, with a third reviewer checking a sample for quality assurance.Results69 studies were included. There was an overall lack of consistency in how PEs were conducted and reported. The main weakness is that only 30 studies were underpinned by a clear intervention theory often facilitated by the use of existing theoretical frameworks. The main strengths were robust sampling strategies, and the triangulation of qualitative and quantitative data to understand an intervention’s mechanisms. Findings were synthesised into three key themes: (1) a fundamental mismatch between what the intervention was designed to achieve and local needs; (2) the required roles and responsibilities of key actors were often not clearly understood; and (3) the health system context—factors such as governance, financing structures and workforce—if unanticipated could adversely impact implementation.ConclusionGreater consistency is needed in the reporting and the methods of PEs, in particular greater use of theoretical frameworks to inform intervention theory. More emphasis on formative research in designing interventions is needed to align the intervention with the needs of local stakeholders, and to minimise unanticipated consequences due to context-specific barriers.PROSPERO registration numberCRD42016035572.
Practice induces a qualitative change in the memory representation for visuomotor learning
Authors: Huberdeau David M. , Krakauer John W. , Haith Adrian M. 
Published: August 2019

Adaptation of our movements to changes in the environment is known to be supported by multiple learning processes that operate in parallel. One is an implicit recalibration process driven by sensory-prediction errors; the other process counters the perturbation through more deliberate compensation. Prior experience is known to enable adaptation to occur more rapidly, a phenomenon known as “savings,” but exactly how experience alters each underlying learning process remains unclear. We measured the relative contributions of implicit recalibration and deliberate compensation to savings across 2 days of practice adapting to a visuomotor rotation. The rate of implicit recalibration showed no improvement with repeated practice. Instead, practice led to deliberate compensation being expressed even when preparation time was very limited. This qualitative change is consistent with the proposal that practice establishes a cached association linking target locations to appropriate motor output, facilitating a transition from deliberate to automatic action selection. NEW & NOTEWORTHY Recent research has shown that savings for visuomotor adaptation is attributable to retrieval of intentional, strategic compensation. This does not seem consistent with the implicit nature of memory for motor skills and calls into question the validity of visuomotor adaptation of reaching movements as a model for motor skill learning. Our findings suggest a solution: that additional practice adapting to a visuomotor perturbation leads to the caching of the initially explicit strategy for countering it.
Abstract 100: Novel selective PI3Kγ inhibitor AZD3458 promotes anti-tumor immune responses and reverts resistance to immunotherapy in checkpoint blockade refractory preclinical models
Authors: Carnevalli Larissa S. , Carrol Danielle , Moschetta Michele , Gutierrez Pablo Morentin , Gardelli Cristina , Taylor Molly A. , Montoya Antonio , Hughes Adina , King Matthew , Klinowska Teresa , Barry Simon T. 
Published: August 2019

Abstract
The PI3Kγ isoform is a key regulator of immune cell proliferation, survival, migration and activation. PI3Kγ inhibitors have the potential to treat a variety of diseases including respiratory, inflammatory, metabolic disorders and cancer. In the context of cancer PI3Kγ inhibition re-polarizes macrophages to an immuno-stimulatory phenotype activating a T-cell mediated tumor immune response. Selective PI3Kγ inhibitors have potential as monotherapy and in combination with checkpoint inhibition to overcome resistance and to enhance efficacy of checkpoint inhibitors. AZD3458 is a highly selective PI3Kγ clinical candidate kinase inhibitor with a cellular IC50 of 8nM with a 100-fold selectivity over PI3Kδ. In vitro, AZD3458 inhibits pAKTS308/S473 in human macrophages and mouse CD11b activation at 32nM and 30nM free IC50, respectively. At these concentrations AZD3458 reverses macrophage polarization increasing IL12/IL-10 ratio and does not impact T cell proliferation and function analysed by gene expression profiling, cytokine quantification and flow cytometry. Oral administration of AZD3458 (20mg/Kg BID) remodeled the tumor microenvironment in 4T1 orthotopic breast tumor model. AZD3458 decreased tumor associated macrophages by 20% compared to vehicle and reduced overall protein expression of immunosuppressive markers CD206 and PD-L1 measured by flow cytometry. In addition, AZD3458 reduced MDSC/neutrophil activation and promoted cytotoxic T-cell activation in vivo, measured by GzmB and Perforin mRNA and protein expression. Consistent to the observed tumor remodeling, combination with checkpoint inhibitors α-PD-1 or α-PD-L1 antibodies (10mg/kg 3x week) had greater anti-tumor effects than checkpoint inhibitor alone in 4T1, LLC, CT-26 and MC-38 mouse syngeneic models. These data demonstrate that AZD3458 can reverse myeloid suppressive tumor microenvironment and revert tumor resistance to immunotherapy in myeloid-enriched immunosuppressive tumor types.
Citation Format: Larissa S. Carnevalli, Danielle Carrol, Michele Moschetta, Pablo Morentin Gutierrez, Cristina Gardelli, Molly A. Taylor, Antonio Montoya, Adina Hughes, Matthew King, Teresa Klinowska, Simon T. Barry. Novel selective PI3Kγ inhibitor AZD3458 promotes anti-tumor immune responses and reverts resistance to immunotherapy in checkpoint blockade refractory preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 100.
Abstract 1003: Modulating estrogen related receptors (ERRs) activity in breast cancer using endogenous ligands
Authors: Ghanbari Faegheh , Mader Sylvie , Philip Anie 
Published: August 2019

Abstract
Estrogen-receptor related receptors which consists of ERRα, ERRβ and ERRγ belong to the orphan nuclear receptor subfamily of NR3B (nuclear receptor subfamily 3, group B). The ERRs have been shown to actively modulate estrogenic responses, and to play an essential role in pregnancy, and are implicated in breast cancer progression. Despite intensive efforts, no endogenous ligand has been identified for ERRs so far. The discovery of ligands that bind these orphan receptors will allow the manipulation of this pathway and may lead to novel strategies for the treatment of cancer and other diseases. In this study we show two endogenous ligands of ERRs: 1) estradienolone (ED), a novel endogenous steroid during pregnancy which acts as an inverse agonist of ERRs, 2) cholesterol as an agonist of ERRs. Our recent results show that ED acts as an inverse agonist of ERRα and ERRγ by directly interacting with these receptors, and inhibiting their transcriptional activity. We also demonstrate that ED has strong anti-mitogenic properties. ED inhibits the growth of both estrogen receptor-positive (MCF-7) and estrogen receptor-negative (MDA-MB-231) breast cancer cells in a dose dependent manner, while of displaying a little effect on normal epithelial breast cells. In addition, we show that the effect of cholesterol or lovastatin (a drug known to inhibit cholesterol synthesis) in triple negative breast cancer (MDA-MB 231) requires ERRα. These data suggest that both ED-ERR and cholesterol-ERR interactions may represent novel physiologically relevant ERR pathways in the human.
Citation Format: Faegheh Ghanbari, Sylvie Mader, Anie Philip. Modulating estrogen related receptors (ERRs) activity in breast cancer using endogenous ligands [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1003.
Abstract 1005: Tamoxifen treatment induces the epigenetic changes in breast cancer stem cells
Authors: Palaniyandi Kanagarj , Gnasampandapandian Dhanavathy , Ramachandran Ilangovan , Sambandam Yuvaraj , Chandrakesan Parthasarathy 
Published: August 2019

Abstract
Purpose: Breast cancer is diagnosed in younger women population and is the leading cause of cancer-related deaths in India. Tamoxifen (TOM) is one of the most effective and widely used first-line endocrine therapy for ER+ breast cancer. However, breast cancer patients often develop TOM resistance and enhanced with caner stem cell (CSC)-like phenotypes. These TOM-resistance (TR) breast cancer phenotypes are highly aggressive and they do not respond to most of the chemotherapies. It is therefore essential to understand the mechanism that resulted in the development of TR in breast cancer. The current study was designed to investigate the epigenetic changes associated mechanism that induces the development of hormone-resistance in breast CSCs.
Experimental Procedure: In this study, we used ALDEFLOUR assay, flow cytometry, mammosphere culture, western blot, Chromatin-immunoprecipitation, and RT-PCR analyses.
Results: Our study showed that breast CSC-like population possesses higher TR cancer cell phenotypes than non-CSCs. We generated MCF7-derived mammospheres (CSCs) utilizing MammoCult media. However, when treated with TOM (1µM)-we observed an increased number of mammospheres (CSCs) than vehicle control. We found a strong interplay between TR and epigenetic changes, in particular, the changes observed in histone demethylase, which is believed to be one of the crucial links that involved in the development of therapy resistance and enhanced CSC population. Furthermore, TR breast CSCs derived from MCF7 cells display an increased expression of the NOTCH-1 protein. Induced overexpression of NOTCH in MCF7 cells increased the number of mammosphere formation ability than control cells. Finally, overexpression of NOTCH-1 also led to transcriptional up-regulation of cyclin genes A, B, and D.
Conclusion: We observed a crucial interplay between TR and breast CSCs. TR associated epigenetic alteration enhanced the expression of NOTCH1, which resulted in increased mitotic signals in the tumor cells including CSCs. Thus, these new phenotypes of breast CSCs with TR characteristics need more understanding for the development of effective combinatorial and adjuvant therapies.
Note: This abstract was not presented at the meeting.
Citation Format: Kanagarj Palaniyandi, Dhanavathy Gnasampandapandian, Ilangovan Ramachandran, Yuvaraj Sambandam, Parthasarathy Chandrakesan. Tamoxifen treatment induces the epigenetic changes in breast cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1005.
Abstract 1010: Extracellular matrix signaling modulates estrogen receptor activity in breast cancer
Authors: DiGiacomo Josh W. , Godet Inês , Rodriguez Michael Trautmann , Ye I Chae , Gilkes Daniele M. 
Published: August 2019

Abstract
The tumor microenvironment plays a crucial role in cancer progression. In breast cancer, the extracellular matrix (ECM) is especially important as it contributes to mammographic breast density. Women with higher mammographic breast densities are at a greater risk for the development of breast cancer. Despite this, much knowledge of the ECM’s effects on breast cancer progression remains elusive. To better understand how ECM signaling affects breast cancer, we utilize fibroblast-deposited, decellularized ECM scaffolds. Scaffolds are produced for in vitro use by culturing a confluent layer of fibroblast cells over six days followed by decellularization with a detergent solution. RNA sequencing analysis of MCF7 human breast cancer cells cultured on ECM scaffolds versus uncoated dishes revealed differential expression of hundreds of genes. Most notably, genes within hallmark sets for early and late responses to estrogen were significantly enriched when cells were cultured on ECM. We confirm the expression of estrogen-responsive genes in breast cancer cells cultured on ECM even in the complete absence of estrogen, and also note that the estrogen receptor (ER) itself is downregulated at both the RNA and protein-level, consistent with results of estrogen stimulation. Treatment of breast cancer cells with ER inhibitors hydroxytamoxifen and fulvestrant reduces ECM-induced expression of estrogen-responsive genes. Likewise, culturing breast cancer cells on ECM enhances phosphorylation of Erk. Inhibition of phospho-Erk also reduces the expression of the same estrogen-responsive genes in cells cultured on ECM. Through luciferase, conditioned media, and estrogen-starvation assays, we demonstrate that ECM signaling activates estrogen receptor signaling in an estrogen-independent, nonclassical mechanism. In addition, we show that ER positive cells cultured on ECM are more resistant to ER-targeted therapeutics, but not other chemotherapeutic agents like paclitaxel or doxorubicin. Ultimately, we describe a pathway in which ECM can induce estrogen-independent activation of the ER as well as resistance to estrogen-targeted therapies in breast cancer. Clinical research into the effects of mammographic breast density beyond breast cancer predisposition is sparse, and this work provides incentive for investigators to better understand the relationship between breast fibrosis and clinical outcome.
Citation Format: Josh W. DiGiacomo, Inês Godet, Michael Trautmann Rodriguez, I Chae Ye, Daniele M. Gilkes. Extracellular matrix signaling modulates estrogen receptor activity in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1010.
Abstract 1036: WISP-1 promotes epithelial-mesenchymal transition in oral squamous cell carcinoma via the miR-153-3p/Snail axis
Authors: Chang An-Chen , Tang Chih-Hsin 
Published: August 2019

Abstract
Oral squamous cell carcinoma (OSCC) is the most common oral malignancy and approximately 50% of patients with OSCC present with regional regional lymph node metastasis. The first step in the ‘invasion-metastasis cascade’ is the phenomenon of epithelial-to-mesenchymal transition (EMT), whereby epithelial cells of the primary tumor lose their apical-basal polarity and transition to a mesenchymal phenotype, gaining the ability to migrate and invade basement membrane and blood vessels. WNT1-inducible signaling pathway protein-1 (WISP-1/CCN4) is an extracellular matrix-related protein that belongs to the CCN family, capable of stimulating bone remodeling and tumor progression. Our previous research showed that WISP-1 promotes cell migration and VEGF-C-dependent lymphangiogenesis in OSCC cells. This investigation further examined the role of WISP-1 in regulating EMT. First, we analyzed data from the cancer genome atlas (TCGA) database, to determine the clinical importance of WISP-1 in oral cancer. We found that WISP-1 expression was significantly associated with clinical disease stage and regional lymph node metastasis. Moreover, we found higher levels of WISP-1 expression in serum samples obtained from 62 patients with OSCC compared with samples from healthy controls. Treatment of the OSCC cell line SCC4 with WISP-1 increased EMT by downregulating expression of the epithelial marker E-cadherin and upregulating the mesenchymal marker Snail. We also observed that WISP-1 regulated the expression of EMT markers via the FAK, ILK and AKT signal transduction pathways. Computational analysis confirmed that microRNA (miR)-29c directly targets the 3′ untranslated region (3′ UTR) of Snail. Treatment of SCC4 cells with WISP-1 inhibited miR-29c expression, while miR-29c mimic prevented WISP-1-induced enhancement of Snail expression, revealing an inverse correlation between miR-29c and Snail expression during WISP-1 treatment. Our findings provide insight into WISP-1-mediated regulation of EMT in OSCC.
Citation Format: An-Chen Chang, Chih-Hsin Tang. WISP-1 promotes epithelial-mesenchymal transition in oral squamous cell carcinoma via the miR-153-3p/Snail axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1036.
Abstract 1049A: Deregulation of MITF in the context of inactive MC1R leads to melanocyte transformation
Authors: Alver Tine Norman , Lavelle Timothy J. , Heintz Karen-Marie , Wernhoff Patrik , Nygaard Vegard , Øy Geir F. , Bøe Sigurd L. , Urbanucci Alfonso , Hovig Eivind J. 
Published: August 2019

Abstract
MC1R, the cAMP pathway and the response to solar UV are all elements involved in the growth, differentiation and survival of melanocytes and in malignant melanoma. Here we present a model of melanomagenesis based on the forced expression of MITF-M in the context of MC1R-inactivating variants in a way not dependent on sun exposure. We demonstrate that lentiviral transduction of MITF-M alone leads to consistent transformation of the Hermes4C cell line with inactive MC1R, but not the Hermes3C cell line having a wild type background. Hermes 4c cells transduced with MITF-M are able to form tumors in mice. We mapped MITF binding to chromatin and found that 4C cells displayed enhanced MITF chromatin binding compared to 3C. Expression analysis revealed that the altered binding pattern leads to enhanced transcription of epithelial to mesenchymal transition genes and consequent repression of key melanocyte-specific genes e.g. involved in pigmentation in the background of inactive MC1R. We observed a marked deregulation of AXL and EGFR, which is accompanied by downregulation of PTEN and increased phosphorylation of ERK and PI3K-AKT pathway. In conclusion, we show that MITF-M is a molecular switch in the context of MC1R-inactivating variant which leads to cell reprogramming and melanomagenesis.
Citation Format: Tine Norman Alver, Timothy J. Lavelle, Karen-Marie Heintz, Patrik Wernhoff, Vegard Nygaard, Geir F. Øy, Sigurd L. Bøe, Alfonso Urbanucci, Eivind J. Hovig. Deregulation of MITF in the context of inactive MC1R leads to melanocyte transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1049A.
Abstract 1061: Animal models of prostate cancer
Authors: Ponthan Frida , Brown Matthew , Playle Emma , Booth Catherine 
Published: August 2019

Abstract
Background: Prostate cancer is the most common male malignancy and the second most common cause of cancer-related deaths in the United Kingdom and the United States. It’s a heterogeneous disease caused by different genetic mutations where the majority of prostate cancers are indolent and slow growing. However, some tumours are aggressive with the ability to invade local structures and metastasise leading to poor clinical outcome. One of the most important aspects in anti-cancer drug development is the availability of robust preclinical models which allow the efficacy of novel therapies to be examined. We have developed a reproducible, well growing and robust subcutaneous model of LNCaP with an effective response to both conventional standard of care (SOC) chemotherapy and androgen receptor inhibitors.
Materials and Methods: Cells were subcutaneously implanted on the flank of NSG mice and treated with an anti-androgen with or without conventional chemotherapy starting after 15-20 days when the mean tumour volume was 150-200mm3. Animal weight and tumour volume was measured 3x weekly. Androgen receptor (AR) expression was analysed with immunohistochemistry and gene expression analysis before and after treatment.
Results: The LNCaP cell line grew well in vivo with 100% take rate. Vehicle treated tumours doubled in size over the first 6 days of treatment and were 4.5x the mean starting volume by day 17 post-treatment start, when the group was removed from the study. Significant tumour growth inhibition was observed in response to both conventional and anti-androgen receptor treatment consistent with the maintained AR expression confirmed by gene expression analysis.
Conclusion: This high take rate responsive model represents a significant improvement in subcutaneous xenograft models of prostate cancer, and allows the comparison of AR responsive therapies, alone or in combination with conventional SOC or irradiation. Current protocols employing luciferase transfected cells has also enabled evaluation of metastatic disease.
Citation Format: Frida Ponthan, Matthew Brown, Emma Playle, Catherine Booth. Animal models of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1061.