tbuckley/cabot-search huggingface dataset:
Abstract 1454: Estrogen receptor signaling in FTE of BRCA mutation carriers
Authors: Leah V. Dodds, Omar L. Nelson, Ramlogan Sowamber, Andres Rodrigues, Victoria de Castro, Wendell Henry, Guillermo Morales, Brian Slomovitz, Patricia Shaw, Sophia H. George
Journal: Cancer Research (2017)

Abstract Genetic and reproductive factors predicate epidemiological risk factors underlying epithelial ovarian cancer. The fallopian tube epithelia (FTE), the presumptive etiological site of high-grade serous ovarian cancer (HGSC), is a hormonal responsive tissue. Estrogen is known to promote cell proliferation and its metabolism produces reactive oxygen species that damage DNA and promote tumorigenesis. Estrogen receptor (ER) is rarely mutated, amplified or deleted in HGSC, yet only 10% of patients respond to anti-estrogen treatment, suggesting that intrinsic variables to the ER pathway contribute to this clinical outcome. TP53 mutations occur in almost 100% of HGSCs, indicating that mutated p53 supports a model as an early event in the pathogenesis of HGSC. We hypothesized that in the presence of dysfunctional p53, subsequent promiscuous binding of ER will yield aberrant signaling, ultimately significantly contributing to cellular transformation. Mutant p53 and ER co-localize in FTE cells, suggesting potential synergy. We established cell lines with p53 mutations and treated them with estradiol, an estrogen analog, to observe any changes in response. The genome binding sites of ER-regulated transcription factors were then identified and mapped by whole genome chromatin immunoprecipitation-deep sequencing (ChIP-Seq). The data generated will facilitate the development of gene signatures that will predict response to anti-estrogen therapy in serous ovarian cancer patients, and contribute to the discovery of biomarkers to more accurately identify patients who will benefit from hormonal therapies. Citation Format: Leah V. Dodds, Omar L. Nelson, Ramlogan Sowamber, Andres Rodrigues, Victoria de Castro, Wendell Henry, Guillermo Morales, Brian Slomovitz, Patricia Shaw, Sophia H. George. Estrogen receptor signaling in FTE of BRCA mutation carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1454. doi:10.1158/1538-7445.AM2017-1454
Abstract 5644: The emergence of resistance to tamoxifen in relation to menopausal status, HER-2 status, status of steroid receptor and lymph nodes metastases status
Authors: Sinisa Maksimovic
Journal: Cancer Research (2017)

Abstract Background: The study used data from medical and counselling of patients who were diagnosed with hormonedependent breast cancer. Aim: The objective of the paper is to identify within a group of patients diagnosed with hormone sensitive breast cancer and those who have received adjuvant tamoxifen, and then to isolate the patients with whom the therapeutic effect of tamoxifen stopped. Methods: The study analyzed 153 patients in the period from 2005 to 2011, at the Public Health Institution Hospital, Sveti Vračevi" in Bijeljina. Resistance to tamoxifen was developed by 60 patients (39.2%) and 93 patients (60.8%) did not develop resistance to it. Results: More common emergence of resistance is in the premenopausal group of patients (p&amp;lt;0.001). Statistically significant difference in frequency of resistance to tamoxifen was observed in the group of patients with ER-/PrR+ status of steroid receptors (p&amp;lt;0.001). In relation to HER-2 status of diagnosed cancer, a statistically significant difference in frequency of resistance emergence during tamoxifen therapy in patients with HER2-positive status (p&amp;lt;0.001) was observed. We found that there is a statistically significant difference between patients with metastatic in lymph nodes compared to patients who had no metastases in lymph nodes (X2=39.494; p&amp;lt;0.001). Conclusions: The analysis of menopausal status of patients, status of ER/PgR receptors status, HER-2 status of diagnosed cancer and status of lymph nodes trying to sort out the parameters on the basis of which a group of patients who can be expected to develop resistance to tamoxifen could be differentiated. Note: This abstract was not presented at the meeting. Citation Format: Sinisa Maksimovic. The emergence of resistance to tamoxifen in relation to menopausal status, HER-2 status, status of steroid receptor and lymph nodes metastases status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5644. doi:10.1158/1538-7445.AM2017-5644
Abstract 3329: Combinatorial blockade of ERBB receptors in HER2 low breast cancer
Authors: Mireia Berdiel-Acer, Eileen Reinz, Khalid Abnaof, Sara Burmester, Rainer Will, Ulrike Korf, Stefan Wiemann
Journal: Cancer Research (2017)

Abstract Large number of breast cancer patients clinically classified as HER2 negative, show low/moderate levels of HER2 along with other ERBB receptors. Concomitant blockade of EGFR, ERBB2 and ERBB3 with specific therapeutic antibodies (cetuximab, trastuzumab/pertuzumab and lumretuzumab, respectively) appears as a beneficial approach to improve survival of patients who have failed to previous treatment strategies. Additionally, ERBB3 expression has been reported as a trastuzumab resistance mechanism in HER2 positive subtypes.We have confirmed a specific pattern of ERBB receptors expression in different breast cancer subtypes. Individual and combined blockade of the receptors with therapeutic antibodies has been tested in vitro using a metabolic viability assay (Cell Titer Glo) and their effects in cell cycle status measured by BrdU staining. All four therapeutic antibodies bind to the respective extracellular domains inhibiting downstream signaling pathways. Response to individual treatment is cell dependent and correlates with EGFR expression in the triple negative MDA-MB-468 but not in luminal T47D cancer cell line. Response of T47D cells to lumretuzumab is higher when combined with pertuzumab or trastuzumab, suggesting ERBB2/ERBB3 dimer as the most relevant one, an effect more evident upon ectopic addition of NRG1 (only ligand for ERBB3). Long exposure of MDA-MB468 cells to cetuximab induces ERBB3 expression and increases its sensitivity to cetuximab when combined. As well as, in the HER2+ BT474 cancer cell line resistant to trastuzumab, higher levels of ERBB3 also make cells more sensitive to alternative anti-ERBB therapies. To establish the role of ERBB4 (no specific therapeutic antibody) in the whole ERBB network, stable knock-down regulation (shRNA) has been performed in T47D cells. Although treatment of HER2 overexpressing breast tumors has been successful, targeting other ERBB members in a HER2 moderate/low scenario seems to be a promising approach in combinatorial therapies; even in resistant cell lines. Thus, better characterization of ERBB network should help to pave the way for a personalized treatment of HER2 low breast cancer. [U.K.: Deceased March, 2016] Citation Format: Mireia Berdiel-Acer, Eileen Reinz, Khalid Abnaof, Sara Burmester, Rainer Will, Ulrike Korf, Stefan Wiemann. Combinatorial blockade of ERBB receptors in HER2 low breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3329. doi:10.1158/1538-7445.AM2017-3329
Abstract 435: Regulation of macropinocytosis-dependent cell survival in pancreatic cancer cells
Authors: Sung Eun Kim, Man-Tzu Wang, Frank McCormick
Journal: Cancer Research (2017)

Abstract Cancer cells utilize multiple scavenging mechanisms to support growth in nutrient-poor, hypoxic environments. Signaling pathways to accommodate these mechanisms may not be required for oncogenesis per se but are crucial for cancer cell survival. These processes, known as non-oncogene addiction, can be conferred by specific oncogenes that reprogram metabolism or by the tumor microenvironment. Understanding how these pathways are regulated can provide novel opportunities for therapeutic intervention. Studies showed that KRAS-mutant cancer cells, including pancreatic ductal adenocarcinoma (PDAC), upregulate macropinocytosis, a caveolin- and clathrin-independent endocytic process, to import extracellular protein to support growth upon nutrient depletion. Similarly, high levels of macropinocytic uptake are observed in PDAC murine models and also in human PDAC specimens. This process serves as a scavenging mechanism for cancer cells to survive and proliferate in nutrient-deprived tumor microenvironments. Thus, uncovering the key players of this pathway and the mechanisms underlying their regulation will be important to find potential therapeutic targets. Here, we used the Informer set of small molecules to screen regulators of survival in culture conditions supplemented with either glutamine or extracellular protein. The Informer set drug library consists of small molecules including FDA-approved drugs and clinical candidates that have high selectivity for their targets and regulate many cellular pathways. We find that survival of cells grown in conditions supplemented with glutamine or exogenous protein is differentially regulated by distinct drug subsets. This suggests that different pathways of nutrient uptake, processing, and utilization are used in cells depending on the nutrient source. Further examination to determine the mechanism of pathway inhibition and applicability may unravel potential uses for therapeutics. Citation Format: Sung Eun Kim, Man-Tzu Wang, Frank McCormick. Regulation of macropinocytosis-dependent cell survival in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 435. doi:10.1158/1538-7445.AM2017-435
Coordination of health-service provision in humanitarian crises: a systematic review of suggested models
Authors: Tamara Lotfi, Lama Bou-Karroum, Andrea Darzi, Rayan Hajjar, Ahmad El Rahyel, Jamale El-Eid, Mira Itani, Hneine Brax, Chaza Akik, Mona Osman, Ghayda Hassan, Fadi El-Jardali, Elie A Akl
Journal: The Lancet (2017)
Progress Toward Universal Health Coverage
Authors: Md. Mizanur Rahman, Anup Karan, Md. Shafiur Rahman, Alexander Parsons, Sarah Krull Abe, Ver Bilano, Rabia Awan, Stuart Gilmour, Kenji Shibuya
Journal: JAMA Internal Medicine (2017)

<h3>Importance</h3> Achieving universal health coverage is one of the key targets in the newly adopted Sustainable Development Goals of the United Nations. <h3>Objective</h3> To investigate progress toward universal health coverage in 5 South Asian countries and assess inequalities in health services and financial risk protection indicators. <h3>Design and Settings</h3> In a population-based study, nationally representative household (335 373 households) survey data from Afghanistan (2014 and 2015), Bangladesh (2010 and 2014), India (2012 and 2014), Nepal (2014 and 2015), and Pakistan (2014) were used to calculate relative indices of health coverage, financial risk protection, and inequality in coverage among wealth quintiles. The study was conducted from June 2012 to February 2016. <h3>Main Outcomes and Measures</h3> Three dimensions of universal health coverage were assessed: access to basic services, financial risk protection, and equity. Composite and indicator-specific coverage rates, stratified by wealth quintiles, were then estimated. Slope and relative index of inequality were used to assess inequalities in service and financial indicators. <h3>Results</h3> Access to basic care varied substantially across all South Asian countries, with mean rates of overall prevention coverage and treatment coverage of 53.0% (95% CI, 42.2%-63.6%) and 51.2% (95% CI, 45.2%-57.1%) in Afghanistan, 76.5% (95% CI, 61.0%-89.0%) and 44.8% (95% CI, 37.1%-52.5%) in Bangladesh, 74.2% (95% CI, 57.0%-88.1%) and 83.5% (95% CI, 54.4%-99.1%) in India, 76.8% (95% CI, 66.5%-85.7%) and 57.8% (95% CI, 50.1%-65.4%) in Nepal, and 69.8% (95% CI, 58.3%-80.2%) and 50.4% (95% CI, 37.1%-63.6%) in Pakistan. Financial risk protection was generally low, with 15.3% (95% CI, 14.7%-16.0%) of respondents in Afghanistan, 15.8% (95% CI, 14.9%-16.8%) in Bangladesh, 17.9% (95% CI, 17.7%-18.2%) in India, 11.8% (95% CI, 11.8%-11.9%) in Nepal, and 4.4% (95% CI, 4.0%-4.9%) in Pakistan reporting incurred catastrophic payments due to health care costs. Access to at least 4 antenatal care visits, institutional delivery, and presence of skilled attendant during delivery were at least 3 times higher among the wealthiest mothers in Afghanistan, Bangladesh, Nepal, and Pakistan compared with the rates among poor mothers. Access to institutional delivery was 60 to 65 percentage points higher among wealthy than poor mothers in Afghanistan, Bangladesh, Nepal, and Pakistan compared with 21 percentage points higher in India. Coverage was least equitable among the countries for adequate sanitation, institutional delivery, and the presence of skilled birth attendants. <h3>Conclusions and Relevance</h3> Health coverage and financial risk protection was low, and inequality in access to health care remains a serious issue for these South Asian countries. Greater progress is needed to improve treatment and preventive services and financial security.
Prescription Opioid Analgesics Commonly Unused After Surgery
Authors: Mark C. Bicket, Jane J. Long, Peter J. Pronovost, G. Caleb Alexander, Christopher L. Wu
Journal: JAMA Surgery (2017)

Prescription opioid analgesics play an important role in the treatment of postoperative pain; however, unused opioids may be diverted for nonmedical use and contribute to opioid-related injuries and deaths.To quantify how commonly postoperative prescription opioids are unused, why they remain unused, and what practices are followed regarding their storage and disposal.MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched from database inception to October 18, 2016, for studies describing opioid oversupply for adults after a surgical procedure. The primary outcome-opioid oversupply-was defined as the number of patients with either filled but unused opioid prescriptions or unfilled opioid prescriptions. Two reviewers independently screened studies for inclusion, extracted data, and assessed the study quality.Six eligible studies reported on a total of 810 unique patients (range, 30-250 patients) who underwent 7 different types of surgical procedures. Across the 6 studies, 67% to 92% of patients reported unused opioids. Of all the opioid tablets obtained by surgical patients, 42% to 71% went unused. Most patients stopped or used no opioids owing to adequate pain control, and 16% to 29% of patients reported opioid-induced adverse effects. In 2 studies examining storage safety, 73% to 77% of patients reported that their prescription opioids were not stored in locked containers. All studies reported low rates of anticipated or actual disposal, but no study reported US Food and Drug Administration-recommended disposal methods in more than 9% of patients.Postoperative prescription opioids often go unused, unlocked, and undisposed, suggesting an important reservoir of opioids contributing to nonmedical use of these products, which could cause injuries or even deaths.
Abstract 4810: Loss of Cav-1 is associated with manifestation of stem cell-like properties via Src-mediated phosphorylation in human breast MDA-MB-231 cancer cells
Authors: Hyo-Jin YOON, Do-Hee KIM, Young-Nam CHA, Young-Joon SURH
Journal: Cancer Research (2017)

Abstract A subpopulation of cancer cells, termed cancer stem cells (CSCs), has self-renewal and differentiation potential, which contributes to cancer recurrence and tumor resistance. Caveolin-1 (Cav-1), the major structural protein of flask-shaped plasma membrane invaginations called caveolae, functions as a tumor suppressor or an oncogene depending on the tumor type and the grade. Caveolae participate in various cellular functions, such as vesicle trafficking, cholesterol homeostasis, signal transduction, and tumor progression. In the present study, we investigated the role of Cav-1 on the stemness of human breast cancer (MDA-MB-231) cells. A sphere formation assay has been widely used to enrich for CSCs through serial passaging. A level of Cav-1 protein expression decreased in third-generation mammospheres as compared to parent MDA-MB-231 cells. Under the same experimental conditions, however, there was no concurrent decrease in the Cav-1 mRNA level. Therefore, it is likely that stability of Cav-1 protein is decreased during mammosphere formation. Recently, it has been reported that sustained phosphorylation of Cav-1 promotes its ubiquitination and degradation by the proteasomes. We observed that PP2, an inhibitor of Src, suppressed phosphorylation of Cav-1 in MDA-MB-231-derived mammosphere cells, which in turn increases its protein stability. Breast CSCs are enriched in cells with enhanced expression of phenotypic markers, such as CD44+/CD24-. We found that Cav-1 gene silencing using siRNA enhanced the proportion of CD44+/CD24- MDA-MB-231 cells. In addition, Cav-1 knockdown increased the number and the size of secondary mammospheres, and this was accompanied by enhanced expression of Bmi-1 and Sox-2, which are representative self-renewal markers. Moreover, epithelial-mesenchymal transition (EMT) was decreased by knockdown of Cav-1 in MDA-MB-231 cells. Taken together, these findings suggest that loss of Cav-1 protein stability facilitates the formation of mammospheres through upregulation of self-renewal and EMT markers in breast CSCs. Citation Format: Hyo-Jin YOON, Do-Hee KIM, Young-Nam CHA, Young-Joon SURH. Loss of Cav-1 is associated with manifestation of stem cell-like properties via Src-mediated phosphorylation in human breast MDA-MB-231 cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4810. doi:10.1158/1538-7445.AM2017-4810
Abstract 1887: Untethering heterochromatin: how loss of HP1a enhances cell invasion by altering nuclear envelope integrity
Authors: Tracy K. Hale, Sarah Bond, David Wheeler
Journal: Cancer Research (2017)

Abstract Malignant cell invasion is accompanied by complex changes in nuclear shape and organisation. The onset of invasion correlates with the loss of HP1a in many solid tumours including those of the thyroid, kidney, colon and breast, while in cancer cell lines HP1a suppresses invasive potential. In normal cells HP1a maintains the condensation of transcriptionally silent heterochromatin and sequesters it at the inner periphery of the nuclear envelope; an event critical for the maintenance of nuclear stability and envelope rigidity. This role for HP1a leads us to hypothesise that the un-tethering of heterochromatin from the nuclear periphery that would occur after loss of HP1 causes a remodelling of nuclear envelope that enhances cellular invasion. If true this would explain how the nucleus, the largest and most rigid cellular organelles, becomes malleable enough to squeeze through interstitial spaces in the surrounding tissue during metastatic invasion. In support of this hypothesis we observed a 44% increase in the invasive potential of the poorly invasive MCF7 breast cells when HP1a is knocked down. Lamin A staining and electron microscopy also confirmed that these HP1a knockdown cells had the expected alterations in nuclear morphology and loss of heterochromatin at the nuclear periphery. Furthermore the loss of HP1 was correlated with a decrease in the mechanical stability of the nuclei. The significant enrichment (p-val 6.7x10-8) of nuclear envelope proteins shown by RNAseq analysis of transcripts that are differentially expressed in the MCF7 versus HP1a knock-down cells, suggests this loss of nuclear envelope integrity is associated with alterations to its composition. The most striking change identified in the nuclear envelope of cells lacking HP1a was the loss of two Nesprin1 isoforms. While reintroduction of HP1a in highly invasive MDA-MB-231 cells shows the return of these isoforms to the nuclear envelope. As the Nesprin1 isoforms act as signalling scaffolds connecting to the cytoskeleton or reaching into the nucleus, they represent a means of modulating nuclear malleability. Together these findings suggest that when loss of HP1a increases invasive potential there is a corresponding disruption to the nuclear periphery that is a weakness of these cells that could be exploited. Citation Format: Tracy K. Hale, Sarah Bond, David Wheeler. Untethering heterochromatin: how loss of HP1a enhances cell invasion by altering nuclear envelope integrity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1887. doi:10.1158/1538-7445.AM2017-1887
Should We Perform Catheter Ablation for Asymptomatic Atrial Fibrillation?
Authors: Jonathan M. Kalman, Prashanthan Sanders, Raphael Rosso, Hugh Calkins
Journal: Circulation (2017)

Since the original description of atrial fibrillation ablation, numerous studies have demonstrated the superiority of catheter ablation over pharmacological therapy for maintenance of sinus rhythm in patients with both paroxysmal and persistent atrial fibrillation. However, to date, no randomized studies have been powered to demonstrate a mortality or stroke reduction benefit of rhythm control with catheter ablation over a rate control strategy. The results of such ongoing studies are not expected until 2018 or 2019. Thus, the only indication for atrial fibrillation ablation in recent guidelines has been the presence of symptoms. However, up to 40% of an atrial fibrillation population may be asymptomatic. In 2017, in the absence of randomized studies, are there nevertheless data that support atrial fibrillation ablation in asymptomatic patients?