tbuckley/cabot-search huggingface dataset:
Abstract 433: Glycogen accumulation in aggressive breast cancers during hypoxic exposure
Authors: Megan Altemus, Joel Yates, ZhiFen Wu, LiWei Bao, Sofia Merajver
Journal: Cancer Research (2017)

Abstract Isolation of specific metabolic alterations in aggressive triple negative and inflammatory breast cancers represents a compelling avenue for the development of treatments for these diseases. The ability of cancer to utilize diverse metabolic pathways to modulate increased survival and proliferation is well established. Indeed, we have previously described a series of metabolic adaptations in the triple negative inflammatory breast cancer cell line SUM149 and demonstrated a role for the small GTPase RhoC in the metabolic phenotype of the cell line. In this work we seek to describe a survival mechanism for cancer cells that are subjected to hypoxic environments. Hypoxic survival or growth is often necessitated at the center of a growing tumor mass or if the tumor is growing in the lymphatic system, as is often the case for inflammatory breast cancers. Here we investigate the regulation of glycogen levels in breast cancer and normal-like cell lines in atmospheric and 1% oxygen environments. Reserves of glucose are typically stored in liver and muscle cells as the polysaccharide glycogen. Elevated levels of glycogen have previously been observed in various cancers, and recent studies have implicated the importance of glycogen metabolism in promoting cancer cell survival. We hypothesize that aggressive breast cancers utilize modifications of the glycogen synthesis and degradation pathways to provide nutritional flexibility as they proliferate and invade into diverse environments. MCF10A, SUM149, and SUM190 cell lines demonstrate a greater than 10-fold increase in glycogen accumulation when subjected to hypoxic growth conditions. MDA-MB-231 cells also increase glycogen storage, though at levels on the order of 2-3 times higher in hypoxia when compared to normoxic growth. Conditioned media for all cell lines in normoxic and hypoxic conditions were analyzed for glucose and lactate levels to determine changes in metabolite consumption. The data presented indicate an unexpected accumulation of glycogen in response to hypoxic conditions. Studies to determine the mechanisms through which these changes occur and why they are important for continued survival and growth of the cancer cells are ongoing and will be presented. Citation Format: Megan Altemus, Joel Yates, ZhiFen Wu, LiWei Bao, Sofia Merajver. Glycogen accumulation in aggressive breast cancers during hypoxic exposure [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 433. doi:10.1158/1538-7445.AM2017-433
Abstract 4613: Cytotoxicity of selenium trastuzumab and bevacizumab immunoconjugates against triple negative breast cancer cells
Authors: Soni Khandelwal, Lauren Gollahon, Julian Spallholz, Mallory Boylan, Maria Del Mar Garcia-Hernandez
Journal: Cancer Research (2017)

Abstract Breast cancer (BC) is the second leading cause of death among women with an estimated 246,660 new cases of invasive breast cancer expected to be diagnosed this year. Of the different subtypes, 15-20% are classified as triple negative breast cancer (TNBC) because they lack three key receptors; progesterone, estrogen and HER2. These receptors are considered essential for “targeted therapies”. Thus, systemic chemotherapy is the only TNBC drug treatment option. In this study, two clinical monoclonal antibodies; Herceptin® and Avastin® were covalently labeled with redox selenium and used to treat two TNBC cell lines (MDA-MB-231 and MDA-MB-468) in culture. TNBC cell lines were treated with vehicle control, increasing concentrations of selenium as Selenite (ranging from 2 to 20 µg); Se-Herceptin® or Se-Avastin® and compared to native antibodies with equal concentrations of protein. Cell counts and viability were analyzed using Beckman ViCell Counter and Trypan Blue exclusion over a seven day period. Selenite, Se-Avastin® and Se-Herceptin® were observed to be more cytotoxic over dose and time to both TNBC cell lines in comparison to control cells and cells treated with native antibodies alone. Morphological changes were observed under phase contrast microscopy in all selenium treated cell lines. In contrast, visible alterations in morphology were absent in native Herceptin® and Avastin® treated cells compared to control cells. We believe this is the first report of selenium Antibody-Drug Conjugates (ADCs) being demonstrated as cytotoxic to these TNBC cell lines, suggesting a potential strategy to design more effective treatments of TNBC resistant to chemotherapy. Citation Format: Soni Khandelwal, Lauren Gollahon, Julian Spallholz, Mallory Boylan, Maria Del Mar Garcia-Hernandez. Cytotoxicity of selenium trastuzumab and bevacizumab immunoconjugates against triple negative breast 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 4613. doi:10.1158/1538-7445.AM2017-4613
Abstract 3266: Oral rinse point of care test to predict head and neck cancer
Authors: Michael J. Donovan, Kris Curtis, Greg Ginn, Elizabeth J. Franzmann
Journal: Cancer Research (2017)

Abstract Background: Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cause of cancer mortality throughout the world affecting some 50,000 people in the US and 600,000 worldwide each year. The ability to detect the disease in a potentially malignant phase and earlier stage could have significant impact on overall outcome. Previous studies have demonstrated that a combined salivary CD44, a tumor-initiating marker, and total protein assay was able to aid in the diagnosis of HNSCC. We sought to understand the performance characteristics of these biomarkers in a prospective population using a qualitative, point-of-care assay (POC) which consists of a cassette with a colorimetric read-out based on a pre-determined threshold for both CD44 and total protein. We also performed results from same samples with a quantitative lab-based test. Methods: Saline oral rinse specimens (~5ml) from 134 patients (84 HNSCC cases; 50 controls) were obtained from biorepositories. Samples were thawed, gently swirled, placed in a standard collection cup. 600ul were removed for lab assay prior to POC test. The tapered end of the POC cassette was submerged in rinse for 20’; levels of CD44 and total protein (TP) were evaluated by two operators. POC test results were compared between operators and with lab test results using Cohen’s kappa coefficient and McNemar’s test, sensitivity(Se), specificity(Sp), NPV and PPV. Results: 95% HNSCC patients (cases) were mean 60 years of age, 60% male, 97% white and 74% smokers vs. 43 years, 28%, 96% and 0% respectively, for controls. POC was positive with either CD44 or TP above threshold. Weighted kappa yielded 75% and 72% for CD44 and TP respectively between operators. With a prevalence of 9.27: POC: NPV 94%, PPV 10%; variable TP cut-off produced Se71-84% and Sp30%-50%. McNemar and Kappa for both lab CD44 and TP vs POC indicated moderate agreement; independently both POC and lab produced NPV &amp;gt;90%. Conclusions: Concordance of the POC assay between operators and moderate agreement with a quantitative lab assay provides supportive evidence for clinical application of the POC assay as an aid in the diagnosis for HNSCC. Additional studies are underway to confirm these observations. Citation Format: Michael J. Donovan, Kris Curtis, Greg Ginn, Elizabeth J. Franzmann. Oral rinse point of care test to predict head and neck 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 3266. doi:10.1158/1538-7445.AM2017-3266
Abstract 1381: Human CRL4DDB2E3 ubiquitin ligase regulates post-repair chromatin restoration of epigenetic marker H3K56Ac through recruitment of histone chaperon CAF-1
Authors: Qianzheng Zhu, Nidhi Sharma, Jinshan He, Gulzar Wani, Altaf A. Wani
Journal: Cancer Research (2017)

Abstract Epigenetic marker acetylated histone H3 lysine 56 (H3K56Ac) diminishes as an early DNA damage response but is restored in chromatin after DNA repair. Here, we report that human CRL4DDB2 ubiquitin ligase regulates the DNA repair-driven chromatin restoration of H3K56Ac by monitoring the recruitment of histone chaperon CAF-1. We show that the H3K56Ac accumulates at DNA damage sites. The post-repair H3K56Ac restoration depends on CAF-1 and CBP/p300 function. The CRL4DDB2 components DDB1, DDB2 and CUL4A are required not only for maintaining the H3K56Ac level in chromatin, but also for restoring H3K56Ac following the repair of DNA photolesions and strand breaks. Depletion of CUL4A decreases the recruitment of CAF-1 p60 and p150 to ultraviolet radiation (UVR)- and phleomycin-induced DNA damage. Inhibition of neddylation renders CRL4DDB2 inactive and concomitantly diminishes the recruitment of CAF-1 and prevents post-repair H3K56Ac restoration. Additionally, a PCNA-interacting protein (PIP) motif is shown to exist within DDB2. The mutation in the PIP box of DDB2 compromises its capability to maintain the H3K56Ac level but does not affect CRL4DDB2-mediated XPC ubiquitination. These results suggest a novel role of CRL4DDB2 in regulating post-repair chromatin restoration, which differs from its canonical role in the process of nucleotide excision repair. Citation Format: Qianzheng Zhu, Nidhi Sharma, Jinshan He, Gulzar Wani, Altaf A. Wani. Human CRL4DDB2 E3 ubiquitin ligase regulates post-repair chromatin restoration of epigenetic marker H3K56Ac through recruitment of histone chaperon CAF-1 [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 1381. doi:10.1158/1538-7445.AM2017-1381
Abstract 3965: Epithelial membrane protein-2 is a novel regulator of immune editing in breast cancer
Authors: Jessica Tsui, Negin Ashki, Yuling Chang, Deven Patel, Jasmine Sjarif, Madhuri Wadehra
Journal: Cancer Research (2017)

Abstract Cancer immuno-editing is a process that describes the interaction between immune cells and tumor cells. This interaction can result in elimination of a developing tumor, tumor dormancy, or tumor cells that are capable of surviving in an immune-competent host. We have recently uncovered a novel mechanism of immunoediting by the tetraspan protein Epithelial membrane protein or EMP2. We propose that EMP2 serves as a bridge between innate and adaptive immunity via tumor mediated type I interferon expression. Most tumor cells evade the immune system through suppression or ignorance. EMP2 levels promote type I interferon expression which was found to correlate with PDL1 expression in a number of cell lines. Concordantly, in vivo, in multiple breast cancer cell lines, EMP2 promoted tumor growth. In contrast, reduction in EMP2 levels correlated with a reduction in tumor size and a corresponding increase in tumor associated macrophages. Given that tumors with lower levels of EMP2 grow poorly, we hypothesized that targeting EMP2 may provide a therapeutic benefit. Recently, we have developed a panel of novel IgG1 monoclonal antibodies to EMP2 and tested their ability to treat both xenograft and syngeneic mouse models. Our results show that anti-EMP2 IgG1 significantly reduces tumor load in both models in part through the recruitment of M1 macrophages. To explore this observation more fully, experiments using murine syngeneic models were employed. Anti-EMP2 therapy elicits a robust ADCC response, producing an immune infiltrate rich in macrophages, NK cells, and lymphocytes. In addition, we show that CD8 cells show reduced exhaustion in the presence of anti-EMP2 antibodies. Conclusions: EMP2 is a protein upregulated in a number of cancers in women including breast, ovarian, and endometrial tumors. Our work collectively show that EMP2 is a novel immune regulator where its expression creates an immunosuppressive tumor microenvironment. We thus predict that targeting EMP2 may improve therapeutic outcomes for cancers in women. Citation Format: Jessica Tsui, Negin Ashki, Yuling Chang, Deven Patel, Jasmine Sjarif, Madhuri Wadehra. Epithelial membrane protein-2 is a novel regulator of immune editing in 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 3965. doi:10.1158/1538-7445.AM2017-3965
Abstract 103: Blockage of Cdc7/CDK9 signaling sensitizes triple negative breast cancer to EGFR-targeted therapy
Authors: Ronan P. McLaughlin, Jichao He, Vera van der Noord, Jevin Redel, Marcel Smid, Lambert Dorssers, John Martens, John Foekens, Yinghui Zhang, Bob van de Water
Journal: Cancer Research (2017)

Abstract The treatment of Triple-Negative Breast Cancer (TNBC) still represents a profound clinical challenge, the disease being disproportionately responsible for breast cancer-associated deaths. As a consequence, the identification of targeted agents, which synergize with current therapeutic options, is paramount. Resistance to EGFR-tyrosine kinase inhibitors (TKIs), despite frequent EGFR overexpression and reliance on downstream signalling pathways in TNBC, remains endemic. Recent data has also suggested that kinase-inhibition of EGFR in itself is insufficient, given the kinase-independent functions of the protein in transcriptional regulation and DNA-repair may permit prolonged EGFR-mediated signalling in the presence of inhibitors. We performed a kinase inhibitor drug screen (378 kinase inhibitors targeting ~40 different cancer-related kinases) to identify synergistic activity with EGFR inhibition in TNBC. We demonstrate that the dual cdc7/CDK9 inhibitor PHA-767491 synergizes with multiple EGFR-TKIs (Erlotinib, Gefitinib and Lapatinib) in vitro to overcome resistance to EGFR-targeted therapy in various TNBC cell lines. Combined inhibition of EGFR and cdc7/CDK9 resulted in reduced cell proliferation, accompanied by induction of apoptosis and G2-M cell cycle-arrest. Combination therapy inhibited crucial components of the DNA-replicative machinery and also proteins involved in CDK9-mediated transcriptional elongation. Moreover, higher expression of cdc7 and POLR2A was found to be significantly correlated with poorer survival rates in breast cancer patients. Additionally, this synergistic combination effectively inhibited the growth of cells isolated from patient-derived TNBC xenografts under ex vivo culture conditions, highlighting the utility of targeting common transcriptional nodes in cancers addicted to growth factor-mediated signalling pathways. Citation Format: Ronan P. McLaughlin, Jichao He, Vera van der Noord, Jevin Redel, Marcel Smid, Lambert Dorssers, John Martens, John Foekens, Yinghui Zhang, Bob van de Water. Blockage of Cdc7/CDK9 signaling sensitizes triple negative breast cancer to EGFR-targeted therapy [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 103. doi:10.1158/1538-7445.AM2017-103
Court overturns optometrist’s conviction for gross negligence manslaughter
Authors: Clare Dyer
Journal: BMJ (2017)

The Court of Appeal has quashed an optometrist’s conviction for gross negligence manslaughter, in a judgment that clarifies the law and could help reduce the number of such cases brought against doctors.

The court confirmed that, for a gross negligence manslaughter prosecution to succeed, an obvious and serious risk of death must have been foreseeable at the time the breach of duty occurred.

The optometrist, Honey Rose, performed a routine eye examination on an 8 year old boy, Vincent Barker, but failed to properly examine the back of his eyes, which would have disclosed swollen optic discs. He died five months later from acute …
Abstract 4503: Role of ER-associated degradation in rhabdomyosarcoma
Authors: Sara Sannino, Christopher J. Guerriero, Jeffrey L. Brodsky
Journal: Cancer Research (2017)

Abstract Due to their higher proliferation rate, most cancers experience impaired ATP generation, hypoxia, hypoglycemia, and increased genetic mutations that may perturb cellular and protein homeostasis. Persistent stress conditions induce the unfolded protein response (UPR) as well as increased expression of molecular chaperones, such as Hsp70, to modulate cell fate. Our recent studies demonstrate how perturbing cytosolic Hsp70 activity with a small molecule modulator, MAL3-101, induces rhabdomyosarcoma cell (RMS13) death, patient-derived cells of one of the most common soft-tissue cancers in children. MAL3-101 addition activates PERK- and CHOP-dependent RMS13 cell death in a dose dependent manner (Sabnis et al., PNAS, 2016). To identify the mechanism that links UPR-triggered cell death and cytosolic Hsp70 inhibition, an isogenic MAL3-101-resistant cell line was generated (MAR4C). Even though both RMS13 and MAR4C cells were equally sensitive to a diverse panel of therapeutic compounds, we now find that they have different efficiencies of ER-associated degradation (ERAD), a quality control pathway that degrades misfolded proteins in the secretory pathway and that lessens proteotioxic stress. Specifically, MAR4C cells remove both soluble and membrane associated ERAD substrates faster than RMS13 cells and possess increased levels of ubiquitinated proteins upon proteasomal inhibition. These data suggest that higher ERAD efficiency is required for MAR4C cell survival upon Hsp70 inhibition and highlight an unexpected link between cytosolic Hsp70 inhibition and the ERAD pathway in cancer cells. Moreover, RNAseq analysis suggests that select redox-related ER quality control chaperones are differentially expressed between MAR4C and RMS13 cells, and lower levels of the BiP and PDI chaperones and Peroxiredoxin 4 are found in MAR4C cells. Because new therapeutic agents as well as reliable biomarkers are critically needed in rhabdomyosarcoma and other cancers, this study sheds light on one mechanism of cancer pathogenesis and suggests that different cancer subtypes modulate ER quality protein quality uniquely. Citation Format: Sara Sannino, Christopher J. Guerriero, Jeffrey L. Brodsky. Role of ER-associated degradation in rhabdomyosarcoma [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 4503. doi:10.1158/1538-7445.AM2017-4503
Magnitude, numerosity, and development of number: Implications for mathematics disabilities
Authors: Nancy C Jordan, Luke Rinne, Ilyse M Resnick
Journal: Behavioral and Brain Sciences (2017)

Abstract Leibovich et al. challenge the prevailing view that non-symbolic number sense (e.g., sensing number the same way one might sense color) is innate, that detection of numerosity is distinct from detection of continuous magnitude. In the present commentary, the authors' viewpoint is discussed in light of the integrative theory of numerical development along with implications for understanding mathematics disabilities.
Abstract 3686: Time to Peak Flow-Mediated Dilation as a Measure of Vascular Endothelial Function is both Variable and not Repeatable: Implications for the Accurate Assessment of Endothelial Function
Authors: Mary Clare Luca, Andrew Liuni, Tommaso Gori, Monica Lisi, Saverio Dragoni, Giuseppe Di Stolfo, John D Parker
Journal: Circulation (2008)

BACKGROUND: The measurement of flow-mediated dilation (FMD) is the most common method to noninvasively assess endothelial function. Traditionally, the evaluation of peak diameter has been made with...
Abstract 2290: Perceived stressfulness of life events impacts breast cancer risk
Authors: Avital Fischer, Argios Ziogas, Hoda Anton-Culver
Journal: Cancer Research (2017)

Abstract Background: Breast cancer is the most prevalent malignancy and the second most common cause of cancer mortality among women. Approximately 60% of variability in breast cancer risk remains unexplained. It is imperative to perform further research focusing on identifying preventable risk factors for breast cancer. The relationship between psychological stress and breast cancer risk is unclear. Psychological stress arises when environmental demands are appraised as going beyond one’s coping abilities. Higher perceived stress has been linked to increased cortisol levels and HPA perturbations. The purpose of this study is to understand the relationship between stressfulness appraisal of salient life events and breast cancer risk. Methods: A case-control design was used and included 664 female cases identified through the Cancer Surveillance Program of Orange County, CA and 203 female population-based controls. Participants completed a risk factor questionnaire that included a life event section. Participants were asked to determine if events occurred and if they were considered to be significantly stressful or not. Multivariate unconditional logistic regression was used to calculate ORs while adjusting for known breast cancer covariates. Results: Cumulative adverse life events perceived as stressful were associated with increased breast cancer risk in a dose response fashion (OR=1.63, 95% CI=1.00-2.66, Ptrend=0.045). Conversely, cumulative adverse life events not reported as stressful did not have a significant impact on breast cancer risk (OR=2.04, 95% CI=0.77-5.43). History of personal illness was directly related to increased breast cancer risk, when perceived as stressful (OR=2.84, 95% CI=1.96-4.11) or non-stressful (OR=3.47, 95% CI=1.34-8.94). Interestingly, abortion and relocation were observed to have a protective effect on breast cancer risk only when reported as being stressful (OR=0.54, 95% CI=0.32-0.92; OR=0.63, 95% CI=0.43-0.93 respectively). Conclusions: This study broadens our understanding of the relationship between major life events and breast cancer risk and underscores the importance of stressfulness appraisal. Our results indicate the importance of incorporating assessments of perceived stressfulness in future epidemiological investigations focusing on the assessment of life events and breast cancer risk. Note: This abstract was not presented at the meeting. Citation Format: Avital Fischer, Argios Ziogas, Hoda Anton-Culver. Perceived stressfulness of life events impacts breast cancer risk [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 2290. doi:10.1158/1538-7445.AM2017-2290