bluuebunny/crossref_metadata_2025 huggingface dataset:
Flavanones from Sedum sarmentosum Bunge Alleviate CCl4‐Induced Liver Fibrosis in Rats by Targeting TGF‐β1/TβR/Smad Pathway In Turn Inhibiting Epithelial Mesenchymal Transition
Authors: Lin Yuancan , Luo Haiying , Wang Xiao , Zheng Minxia , Jin Qianxing , Chen Hongshu , Pan Peilei , Zhang Junjie
Published: February 2018

Objective. The aim of the study is to evaluate the therapeutic effects of flavanones from Sedum sarmentosum Bunge (FSSB) on CCl4‐induced liver fibrosis in rats and the underlying mechanisms of action. Methods. An experimental model of liver fibrosis was established by subcutaneous injection of rats with CCl4 (40% v/v, 3 ml/kg) twice per week for six weeks. FSSB (100, 200, and 400 mg/kg) was intragastrically administered once per day consecutively for five weeks. Results. Our results showed that FSSB significantly attenuated CCl4‐induced liver fibrosis as evidenced by reducing the elevated levels of serum biochemical indexes and improving the histological changes, including decreasing the elevation in serum alanine transaminase (ALT), aspartate transaminase (AST), hyaluronic acid (HA), and laminin (LN) level, reducing infiltration of inflammatory cells and collagen fibers in liver tissue. In addition, compared to the model group, FSSB markedly downregulated the protein and mRNA expression of TGF‐β1, TGF‐β1 receptors I and II (TβRI and TβRII), Smad2, Smad3, and Vimentin in liver tissue, at the mean time upregulating the expression of Smad7 and E‐cadherin. Conclusions. The results suggest that FSSB alleviated CCl4‐induced liver fibrosis probably through inhibition of TGF‐β/TβR/Smad pathway in turn inhibiting epithelial mesenchymal transition.
Acknowledgement Corruption: A New Aspect of Physical Layer Capture in IEEE 802.11 Networks
Authors: Han Jung-Han , Choi Hyoung-Gyu , Han Seung-Jae
Published: February 2018

Even if a collision occurs in IEEE 802.11 network, a transmission may be successfully decoded at the receiver if the signal strength of one transmission is sufficiently stronger than the other transmission. This phenomenon is called “Physical Layer Capture” (PLC). While existing works have considered PLC between data frames, in this paper we investigate the case that an ACK frame collides with the unfinished transmission of other data frames after the occurrence of PLC between data frames. As a result of this collision, the ACK frame may be corrupted and the corresponding data frame needs to be retransmitted. We call this phenomenon “ACK Corruption” (AC). We identify the characteristic of AC via extensive experiments and simulations. Our study reveals that AC can occur in all IEEE 802.11 variants and its chance is dependent upon the relative signal strength between the stations and the MCS setting used. Further, we devise a way to avoid AC occurrence and evaluate its effectiveness.
Mathematical Model for the Fluid-Gas Spontaneous Displacement in Nanoscale Porous Media considering the Slippage and Temperature
Authors: Liu Kang , Lin Zhongyue , Cao Daiyong , Wei Yingchun
Published: February 2018

The fracturing fluid-gas spontaneous displacement during the fracturing process is important to investigate the shale gas production and formation damage. Temperature and slippage are the major mechanisms underlying fluid transport in the micro-/nanomatrix in shale, as reported in the previous studies. We built a fracturing fluid-gas spontaneous displacement model for the porous media with micro-/nanopores, considering two major mechanisms. Then, our spontaneous displacement model was verified by the experimental result of the typical shale samples and fracturing fluids. Finally, the influences of temperature, slip length, and pore size distribution on the spontaneous imbibition process were discussed. Slippage and temperature significantly influenced the imbibition process. Lower viscosity, higher temperature, and longer slip length increased the imbibition speed. Ignoring the temperature change and slippage will lead to significant underestimation of the imbibition process.
A Novel Separated Position and Orientation System Integrated with Inertially Stabilized Platform
Authors: Zhang Yanshun , Feng Shuangji , Wang Zhanqing , Xi Xiaopeng , Li Ming
Published: February 2018

Considering the application requirements of independent imaging payloads design, a novel scheme of separated position and orientation system (POS) is proposed, in which the high-precision inertial sensors of traditional centralized POS fixed on the imaging payloads are mounted on three gimbals of the inertially stabilized platform (ISP), respectively, and make them integrated. Then, the kinematics model of the ISP system is built to transmit the inertial information measured by separated inertial sensors mounted on ISP gimbals and flight body to the imaging payloads, calculating the position and attitude of the imaging payloads to achieve the function of separated POS. Based on the model, a series of simulations indicate that the precision difference between separated system and centralized system is ignorable under the condition of angular motion and variable velocity motion. Besides the effective function equal to traditional centralized system, the separated POS enhances the integration with the ISP. Moreover, it improves the design independence of the imaging payloads significantly.
An Evaluation of Treatment Outcomes in a Cohort of Clients on the DOTS Strategy, 2012–2016
Authors: Tetteh Ato Kwamena , Agyarko Edward , Otchere Joseph , Bimi Langbong , Ayi Irene
Published: February 2018

We present, for the first time, an evaluation of treatment outcomes in a cohort at a TB referral centre in the Central Region of Ghana. Of the 213 clients placed on DOTS, 59.2% (126/213) were sputum smear-positive. An overall cure rate of 90.2% (51.6% cured + 37.6% completed) and a death rate of 8.5% (18/213) were estimated. Of the number of clients who died, 5.7% (12/213) were males (χ2 = 2.891, p=0.699; LR = 3.004, p=0.699). Deaths were only recorded among clients who were > 19 years old (χ2 = 40.319, p=0.099; LR = 41.244, p=0.083). Also, 0.9% (2/213) was lost to follow-up, while 1.4% (3/213) had treatment failure. In total, 13.6% (7.0%, 15/213 males, and 6.6%, 14/213 females) of clients who were placed on DOTS were HIV seropositive. Ages of 40–49 years had the highest number, 13/213 (6.1%), infected with HIV, though the difference among the remaining age groups was not statistically significant (χ2 = 9.621, p=0.142). Furthermore, 7.0% (15/213) had TB/HIV coinfection. Out of them, 9 were cured and 5 died at home, while 1 had treatment failure. Tuberculosis/HIV infection prevention advocacy and interventions that address sociodemographic determinants of unfavourable treatment outcomes are urgently required to augment national efforts towards control.
Coupling Empowerment Based Application of Extension Method for Geothermal Potential Assessment
Authors: Zhang Qing , Ge Weiya , Tian Fujin , Li Yunfeng , Hou Lili , Li Lujuan , Li Jianming
Published: February 2018

Plenty of mathematics researches provide feasibility to calculate the weights of geothermal controlling factors and have been applied in geothermal potential assessment. In order to avoid the disadvantages of subjective and objective weighting calculation methods, an extension theory integrated weighting method was put forward, by combining with the process of AHP and mean variance method. The improved method can reach an agreement on subjective understanding of impact factors’ roles and data-based calculation weights. Then by replacing the point values with intervals, the extension theory was used in classification of geothermal assessment, according to extension judgment matrix. The evaluation results showed perfect performance in classification of impact factors, especially in Wudalianchi area, where 10 out of 11 selected impact factors agreed well with the actual evaluation grades. The study can provide a guidance for primary stage of geothermal investigation including the impact factor selection, weights calculation for impact factors, and the factors’ classification in geothermal assessment.
Risk Evaluation of Endoscopic Retrograde Cholangiopancreatography-Related Contrast Media Allergic-Like Reaction: A Single Centre Experience
Authors: Trottier-Tellier Félix , Harvey Laurence , Baillargeon Jean-Daniel
Published: February 2018

Background and Aims.Few cases of endoscopic retrograde cholangiopancreatography- (ERCP-) related contrast media (CM) adverse reactions have been reported in the current literature. There is a lack of standardisation in practice regarding premedication prophylaxis for at-risk patients undergoing ERCP and there are few data to guide the practitioners. Our goal is to evaluate the risk of CM adverse reaction in a group of patients with a past history of allergic-like reaction to iodine product undergoing ERCP.Methods.A retrospective chart review study was performed of patients who underwent ERCP at our single centre from January 2010 to December 2015.Results.2295 ERCPs were performed among 1766 patients. No anaphylactoid or severe adverse reaction occurred. One (0.04%) ERCP-related CM benign reaction was reported in a patient known for penicillin allergy. Among 127 ERCPs performed on patients with a prior adverse reaction to iodine, 121 procedures were done without and 6 with a premedication prophylaxis. In both groups, no ERCP-related CM reaction occurred.Conclusions.To our knowledge, we report the largest cohort of iodine allergic patients undergoing ERCP ever published. These results suggest that ERCP-related CM adverse reactions are very rare even among patients at risk for CM reaction.
Temperature Sensor Based on an Asymmetric Two-Hole Fiber Using a Sagnac Interferometer
Authors: Domínguez-Cruz René , May-Arrioja Daniel A. , Martínez-Manuel Rodolfo , Lopez-Cortes Daniel
Published: February 2018

We report in this paper a temperature sensor based on an asymmetric two-hole fiber (ATHF) using a Sagnac interferometer (SI) configuration. The operation principle is based on the birefringence change induced by the temperature difference between the air holes and the silica fiber. As a result, the transmitted spectrum of the SI exhibits a sinusoidal profile which is shifted when the temperature is increased. A linear wavelength shift as a function of temperature is observed, and a sensitivity of 2.22 nm/°C was achieved using a 2 m long asymmetric THF, which is in the same order as those previously reported using similar microstructured fibers. The advantage of this system is a linear response, the use of a microstructured fiber with a simpler transverse geometry, and the use of bigger holes which can facilitate the insertion of several materials and improve the sensitivity of the sensor for different applications.
Dietary n-3 PUFA May Attenuate Experimental Colitis
Authors: Charpentier Cloé , Chan Ronald , Salameh Emmeline , Mbodji Khaly , Ueno Aito , Coëffier Moïse , Guérin Charlène , Ghosh Subrata , Savoye Guillaume , Marion-Letellier Rachel
Published: February 2018

Background. Inflammatory bowel diseases (IBD) occurred in genetically predisposed people exposed to environmental triggers. Diet has long been suspected to contribute to the development of IBD. Supplementation with n-3 polyunsaturated fatty acids (PUFA) protects against intestinal inflammation in rodent models while clinical trials showed no benefits. We hypothesized that intervention timing is crucial and dietary fatty acid pattern may influence intestinal environment to modify inflammation genesis. The aim of this study was to evaluate the dietary effect of PUFA composition on intestinal inflammation.Methods. Animals received diet varying in their PUFA composition for four weeks before TNBS-induced colitis. Colon inflammatory markers and gut barrier function parameters were assessed. Inflammatory pathway PCR arrays were determined.Results. n-3 diet significantly decreased colon iNOS, COX-2 expression, IL-6 production, and LTB4 production but tended to decrease colon TNFαproduction (P=0.0617) compared to control diet. Tight junction protein (claudin-1, occludin) expressions and MUC2 and TFF3 mRNA levels were not different among groups. n-9 diet also decreased colon IL-6 production (P<0.05).Conclusions. Dietary n-3 PUFA influence colitis development by attenuating inflammatory markers. Further research is required to better define dietary advice with a scientific rationale.
Testing the Generality of a Passenger Disregarded Train Dwell Time Estimation Model at Short Stops: Both Comparison and Theoretical Approaches
Authors: Li Dewei , Yin Yonghao , He Hong
Published: February 2018

Train dwell time estimation is a critical issue in both scheduling and rescheduling phases. In a previous paper, the authors proposed a novel dwell time estimation model at short stops which did not require the passenger data. This model shows promising results when applied to Dutch railway stations. This paper focuses on testing and improving the generality of the model by two steps: first, the model is tested by applying more independent datasets from another city and comparing the estimation accuracy with the previous Dutch case; second, the model’s generality is tested by a theoretical approach through the analysis of individual model parameters, variables, model scenarios, and model structure as well as work conditions. The validation results during peak hours show that the MAPE of the model is 11.4%, which is slightly better than the results for the Dutch railway stations. A more generalized predictor called “dwell time at the associated station” is used to replace the square root term in the original model. The improved model can estimate train dwell time in all the investigated stations during both peak and off-peak periods. We conclude that the proposed train dwell time estimation model is generic in the given condition.
The In Vitro Antioxidant Activity and Inhibition of Intracellular Reactive Oxygen Species of Sweet Potato Leaf Polyphenols
Authors: Sun Hongnan , Mu Bona , Song Zhen , Ma Zhimin , Mu Taihua
Published: February 2018

The in vitro antioxidant activity and inhibition of intracellular reactive oxygen species (ROS) of the total and individual phenolic compounds from Yuzi No. 7 sweet potato leaves were investigated in this study. Sweet potato leaf polyphenols possessed significantly higher antioxidant activity than ascorbic acid, tea polyphenols, and grape seed polyphenols. Among the individual phenolic compounds, caffeic acid showed the highest antioxidant activity, followed by monocaffeoylquinic acids and dicaffeoylquinic acids, while 3,4,5‐tri‐O‐caffeoylquinic acid showed the lowest value. Sweet potato leaf polyphenols could significantly decrease the level of intracellular ROS in a dose‐dependent manner. The order of the inhibiting effect of individual phenolic compounds on the intracellular ROS level was not in accordance with that of antioxidant activity, suggesting that there was no direct relationship between antioxidant activity and intracellular ROS‐inhibiting effect. Sweet potato leaves could be a good source of biologically active polyphenols with multiple applications in the development of foods, health products, pharmaceuticals, and cosmetics.
Maternal Plasma Metabolomic Profiles in Spontaneous Preterm Birth: Preliminary Results
Authors: Lizewska Barbara , Teul Joanna , Kuc Pawel , Lemancewicz Adam , Charkiewicz Karol , Goscik Joanna , Kacerovsky Marian , Menon Ramkumar , Miltyk Wojciech , Laudanski Piotr
Published: February 2018

Objective.To profile maternal plasma metabolome in spontaneous preterm birth.Method.In this retrospective case-control study, we have examined plasma of patient with preterm birth (between 22 and 36 weeks of pregnancy (n=57)), with threatened preterm labor (between 23 and 36 weeks of pregnancy (n=49)), and with term delivery (n=25). Plasma samples were analysed using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) in positive and negative polarity modes.Results. We found 168 differentially expressed metabolites that were significantly distinct between study groups. We determined 51 metabolites using publicly available databases that could be subdivided into one of the five groups: amino acids, fatty acids, lipids, hormones, and bile acids. PLS-DA models, verified by SVM classification accuracy, differentiated preterm birth and term delivery groups.Conclusions. Maternal plasma metabolites are different between term and preterm parturitions. Part of them may be related with preterm labor, while others may be affected by gestational age or the beginning of labor. Metabolite profile can classify preterm or term delivery groups raising the potential of metabolome as a biomarker to identify high-risk pregnancies. Metabolomic studies are also a tool to detect individual compounds that may be further tested in targeted researches.
Quantitative Relationships between Pulmonary Function and Residual Neuromuscular Blockade
Authors: Fu ShuYing , Lin WenDong , Zhao XiNing , Ge ShengJin , Xue ZhangGang
Published: February 2018

Background. Neuromuscular blockade is a risk factor for postoperative respiratory weakness during the immediate postoperative period. The quantitative relationships between postoperative pulmonary-function impairment and residual neuromuscular blockade are unknown.Methods. 113 patients who underwent elective laparoscopic cholecystectomy were enrolled in this study. They all had a pulmonary-function test (PFT) during the preoperative evaluation. Predictive values based on demographic data were also recorded. The train-of-four ratio (TOFR) was recorded at the same time as the PFT and at every 5 minutes in the qualified 98 patients in the postanesthesia care unit (PACU). We analyzed the degree of PFT recovery when the TOFR had recovered to different degrees.Results. There was a significant difference (P<0.05) between the preoperative baseline value and the postoperative forced vital capacity at each TOFR point, except at a TOFR value of 1.1. There was also a significant difference (P<0.05) between the preoperative baseline value and the postoperative peak expiratory flow at each TOFR point.Conclusions. Postoperative residual neuromuscular blockade was common (75.51%) after tracheal extubation, and pulmonary function could not recover to an acceptable level (85% of baseline value), even if TOFR had recovered to 0.90.Trial Registration. Chinese Clinical Trial Register isChiCTR-OOC-15005838.
Assessment of Knowledge regarding Climate Change and Health among Adolescents in Yogyakarta, Indonesia
Authors: Sulistyawati Sulistyawati , Mulasari Surahma Asti , Sukesi Tri Wahyuni
Published: February 2018

This research was aimed at providing evidence on climate change and health knowledge among adolescents. A cross-sectional study was conducted in Yogyakarta city from June to September 2016. A structured questionnaire was used to collect data among 508 adolescents who were in the second grade of a senior high school. This study revealed that participants had a low and inconsistent understanding regarding climate change and its impact on health. They reported that they prefer to get climate change information via talking with family. In summary, adolescent knowledge regarding climate change and health needs to improve with proper content and appropriate media.
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

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

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

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

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

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

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

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.
Abstract P2-08-02: Novel tumor suppressor regulating the PI3K/AKT pathway in breast cancer
Authors: Chan S , Cardamone MD , Perissi V
Published: February 2018

Breast cancer affects approximately 1 in 8 women over the course of their lifetime. Of the many genes and pathways deregulated by this heterogeneous disease, alterations of members in the PI3K/AKT pathway are present in approximately 20% of all cases, making it one of the more frequently mutated pathways in breast cancer. The PI3K/AKT pathway is well known to be involved in essential cellular processes necessary for cancer development and progression, including altered proliferation, metabolism, and cell survival. Previous studies have made it well known that the activation of AKT is regulated through its phosphorylation, but recent studies have also shown that AKT can also be regulated via ubiquitination, leading to AKT hyperactivation. However, the mechanism and players involved in this process are not well understood. Better understanding of these pathways could inform on better potential therapeutics to target this disease.

Recent work in our lab has identified GPS2, a member of the NCoR/SMRT complex, as a regulator of the insulin-signaling pathway through the inhibition of AKT ubiquitination by Ubc13. As many human cancers frequently have an increase in activated AKT, here we explore the potential of GPS2 as a tumor suppressor in the context of breast cancer and hope to elucidate the mechanism by which AKT ubiquitination regulates its activation.

Citation Format: Chan S, Cardamone MD, Perissi V. Novel tumor suppressor regulating the PI3K/AKT pathway in 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 P2-08-02.
Abstract P2-10-11: A microRNA signature associated with pathological complete response to a novel neoadjuvant therapy regimen in triple negative breast cancer
Authors: Vázquez RG , Camarillo CL , Marchau LM , García ER , Miranda AA , Martínez HM , Parra AC , De la Vega HA , Barrios AG , Cuevas SR
Published: February 2018

Background: Locally advanced triple negative breast cancer (laTNBC) patient's exhibits resistance to neoadjuvant chemotherapy (NC) and poor survival. Distinct therapeutic combinations have been used to reduce high mortality. Recently, novel regimens of NC for laTNBC have achieved pathological complete response (pCR) rates of 10-50%. Evaluation of pCR during oncologic treatment is decisive to identify those patients that response or not response to NC. MicroRNAs (miRNAs) are small non-coding RNAs that represent novel and potential predictive biomarkers useful to identify the patients who will get pCR in cancer.

Methods: Thirty-five patients diagnosed with laTNBC, were invited to participate in this study and enrolled after they signed an informed consent. The 22 patients with pCR and 13 patients without pCR received the experimental NC fluorouracil, adriamycin, cyclophosphamide, cisplatin, paclitaxel (FAC--CDDP/paclitaxel). MiRNA expression profiling was evaluated for 754 miRNAs. A discovery cohort (n=10 pCR and n=8 no-pCR) and a validation cohort (n=12 pCR and n=5 no-pCR). Bioinformatics analysis revealed the affected cellular pathways in pCR group. After a median clinical follow-up of 60 months, statistical analysis was performed to identify miRNAs that could discriminate pCR from no-pCR by using FAC--CDDP/paclitaxel.

Results: MiRNAs expression profiling identified 11 miRNAs that showed significant differences between pCR and no-pCR (p<0.05 and fold change >1.5) groups. Eight miRNAs (miR-9-3p, -30a-3p, -135b, -135b*, -380-5p, -941, -652 and miR-181c*) were upregulated and three miRNAs (miR-770-5p, -584 and miR-143) were downregulated in pCR patients. The altered cellular pathways for the set of miRNAs were PI3K/AKT, FoxO, Ras and ERBB (p<0.05). Four differentially expressed miRNAs (miR-770-5p, miR-143-5p, miR-30a-3p, miR-9-3p) were confirmed in the validation phase. Expression of these miRNAs above the median level was a significant predictor of pCR to experimental NC in laTNBC patients (p<0.001).

Conclusions: These four validated miRNAs could be used as predictors of pCR in response to FAC---CDDP/Paclitaxel treatment in laTNBC patients.

Citation Format: Vázquez RG, Camarillo CL, Marchau LM, García ER, Miranda AA, Martínez HM, Parra AC, De la Vega HA, Barrios AG, Cuevas SR. A microRNA signature associated with pathological complete response to a novel neoadjuvant therapy regimen in triple negative 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 P2-10-11.
Abstract P2-11-08: Risk factors for fibrosis after whole breast radiation therapy in lateral position : A large scale single center experience
Authors: Bronsart E , Dureau S , Xu HP , Costa E , Poortmans P , Chilles A , Berger F , Stilhart A , Fourquet A , Kirova Y
Published: February 2018

Background and Purpose: We previously confirmed the efficacy and safety of our technique of whole breast radiation therapy (WBRT) in isocentric lateral decubitus (ILD) position. The purpose of this work is to evaluate the risk factors for long-term fibrosis in patients treated in ILD position.

Material and methods: We studies 832 consecutive female patients with early stage BC treated by conservative surgery followed by 3D-conformal WBRT at Institut Curie between 2005 and 2010. Fibrosis and deformation were evaluated at the end of the treatment and subsequently every 6 months during at least 5 years, using NCI CTC v3.0 scale. Different fractionation schedules were used: 66Gy in 33 fractions, 50Gy in 25 fractions, 40Gy in 15 fractions, 41.6Gy in 13 fractions and 30Gy in 5 weekly fractions.

Results: Median age is 61.5 years (range: 29 - 90); median follow up is 6.4 years (range: 1.5 - 12.4). During the follow-up, 308 patients (38.9%) had grade 1 fibrosis, and 36 patients (4.3%) only, had grade 2-3 fibrosis. Among patients with grade 1 to 3 fibrosis, the median time to development of fibrosis was 1.6 years (range: 9 days – 8.3 years). In univariate and multivariate analysis, age, cup size and chemotherapy administration had no significant influence on development of breast fibrosis. The hypo fractionated schedule of 30Gy in 5 fractions significantly increased the fibrosis rate (OR=12.5; [2.7; 57.1] p=0.001). On the other hand, 40 Gy/15 fr and 41.6 Gy/13 fr had no significative influence (OR=2.2 [0.5; 11.1] p=0.32) as well as the 66 Gy/33 fr schedule (OR=3.6 [0.8; 15.4] p=0.09) compared to standard scheme of 50 Gy/25 fr. The cosmetic result was good or excellent for 84.8% of cases at the first evaluation. The 30 Gy in 5 fractions schedule significantly influenced the cosmetic result in the multivariate analysis (OR=11.2 [3.1; 43.9]; p<0.001), with increased rates of breast deformation. The risk of breast deformity was also worse for large breast size (OR=2.7 [1.3; 5.8]; p=0.02).

Conclusion: Whole breast radiation therapy in ILD position is well tolerated with good cosmesis and low rates of fibrosis, except for the 30 Gy in 5 weekly fractions schedule. Large breast size has a significantly negative influence on cosmetic results and fibrosis.

Citation Format: Bronsart E, Dureau S, Xu HP, Costa E, Poortmans P, Chilles A, Berger F, Stilhart A, Fourquet A, Kirova Y. Risk factors for fibrosis after whole breast radiation therapy in lateral position : A large scale single center experience [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 P2-11-08.
Abstract P3-14-09: Low rates of chronic breast cancer related lymphedema (BCRL) in a cohort of high-Risk patients undergoing prospective surveillance with bioimpedance spectroscopy (BIS)
Authors: Kaufman D , Shah C , Vicini F
Published: February 2018

Background: We report outcomes using prospective BIS surveillance in a high-risk cohort of patients who all underwent axillary lymph node dissection (ALND).

Methods: From 8/2010 through 12/2016, 206 consecutive patients were evaluated with BIS as part of a prospective surveillance program. 30 underwent ALND and constitute the study population. The program included pre-operative BIS measurement as well as post-operative assessments at regular intervals. Patients with L-Dex readings increasing by more than 10 from baseline were considered to have subclinical BCRL and treated with an over-the-counter (OTC) compression sleeve for 4 weeks. For the purpose of this analysis, additional high-risk features were defined as receipt of axillary radiation, a high body mass index (BMI) or the use of taxane based chemotherapy. Chronic BCRL was defined as the need for complex decongestive physiotherapy (CDP).

Results: Median follow-up was 36 months (range: 4.8-122.1 months). The median number of nodes removed was 18 (range: 5-32) and the median number of positive nodes was two. The median age for the cohort was 57.5 years old with 70% of patients undergoing mastectomy and the remainder breast conserving therapy. With respect to additional high-risk features, 77% also received taxane-based chemotherapy, 62% axillary irradiation, and 48% had an elevated BMI. Overall, 86% of patients had at least one additional high-risk feature, 70% at least two, and 23% had all three additional high-risk features. Seven patients (23%) had an elevated L-Dex score at some point during follow-up and underwent intervention with an OTC sleeve for 4 weeks. To date, no patients have required CDP at any time.

Conclusions: Prospective surveillance with BIS in a high-risk cohort of patients all undergoing ALND (plus additional high-risk features) led to no patients requiring CDP. These excellent findings are consistent with growing data supporting the use of BIS in prospective BCRL surveillance programs.

Citation Format: Kaufman D, Shah C, Vicini F. Low rates of chronic breast cancer related lymphedema (BCRL) in a cohort of high-Risk patients undergoing prospective surveillance with bioimpedance spectroscopy (BIS) [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 P3-14-09.