tbuckley/cabot-search huggingface dataset:
Adherence to hormone treatment for breast cancer and beliefs about treatment and screening.
Authors: Jenny J Lin, Kathie-Ann P. Joseph, Kezhen Fei, Rebeca Franco, Nina Bickell
Journal: Journal of Clinical Oncology (2012)

e11004 Background: Beliefs about medications, more than knowledge, have been found to affect medication adherence. For breast cancer patients, at least 5 years of daily adjuvant hormonal therapy (HT) improves survival but it is often difficult for women to sustain therapy. Qualitative studies suggest women take HT to prevent breast cancer recurrence. We sought to assess whether beliefs about HT and screening were associated with ongoing HT adherence. Methods: Patients with a new early-stage breast cancer enrolled in an IRB-approved RCT to reduce disparities in care in New York City were telephone surveyed 6 months after their surgical treatment for breast cancer to assess knowledge, attitudes and beliefs about breast cancer, its treatment and prevention. Adherence was defined as a positive response to “are you now taking hormonal therapy (e.g., tamoxifen, arimidex)?” Beliefs about HT and mammogram screening were assessed. Bivariate analyses were conducted with t tests, chi square or Wilcoxon rank sum tests; multivariate analysis used a stepwise logistic regression. Results: Of 333 enrolled women, 233 were recommended to take HT. Of these, 187 (80%) women were prescribed HT and 172 (92%) were still adherent 6 months after surgery. Fifty-three percent of women were bothered by side effects but all were adherent; however, of the 15 women who stopped HT, 6 (40%) stopped due to side effects. Sixteen percent of women expressed difficulty paying for HT but all were adherent. Patients adherent to HT had stronger beliefs in both HT as treatment and prevention and in the importance of regular mammograms to stay healthy. A multivariate model including race, insurance, HT knowledge and beliefs found that only beliefs about HT and mammogram screening were associated with adherence (belief about HT: OR=1.1; 95%CI: 1.03-1.11; belief about mammogram: OR=1.55; 95% CI: 1.06-2.27) [model c=.84; p&lt;0.0001]. Conclusions: Ongoing HT adherence is related to beliefs about both treatment and screening.Adherence is not related to HT knowledge, side effects, cost, insurance or patient race. Understanding patients’ beliefs about screening and treatment may help physicians enable women to adhere to long-term therapy.
Abstract 18444: Catheter Ablation Decreases the Risk of Readmission in Patients With Atrial Fibrillation and Obstructive Sleep Apnea. A Nationwide Analysis in the United States
Authors: Seyed Hamed Hosseini Dehkordi, Syed A Ahsan, Alejandro Lemor, Shawn Lee, Farid Gholitabar, Navid Gholitabar, Davendra Mehta
Journal: Circulation (2017)

Introduction: Recent studies point to a significant association between obstructive sleep apnea (OSA) and atrial fibrillation (AF). This association has important implications in ablation strategie...
Abstract 2077: A novel assay for PARP-DNA trapping provides insights into the mechanism of action (MoA) of clinical PARP inhibitors (PARPi)
Authors: Giuditta Illuzzi, Mark J O'Connor, Elisabetta Leo
Journal: Cancer Research (2019)

Abstract Treatments with PARPi in cancers with impaired DNA repair mechanisms (i.e. with Homologous Recombination Repair Deficiency, HRD) causes unsupportable genomic instability resulting in tumor cell death. PARPi act via a dual mechanism: 1) they block PARylation activity that normally occurs in response to DNA damage; 2) they trap PARP onto DNA lesions creating potentially cytotoxic PARP-DNA complexes. The longer PARP is inhibited and trapped onto the DNA, the greater the cytotoxic effect of PARPi in preclinical models. However, differences in preclinical PARP trapping potency have not translated into increased clinical efficacy with standard clinical doses used. Therefore, the ability to assess PARP-chromatin trapping in cancer models is critical for understanding the MoA of existing clinical PARPi. To date, this has been achieved by low throughput assays in non-HRD models using high PARPi concentrations and the addition of exogenous DNA damage. Here, we describe the development of a novel assay, a high throughput in situ cell extraction platform, where PARP-chromatin trapping is monitored by immunofluorescence and can be multiplexed with the analysis of other relevant biomarkers. Our novel assay has several advantages compared to conventional methods: the overall experimental process is simpler and less time consuming with results being quantitative and less error prone. Most importantly, the higher throughput allows a thorough evaluation of PARP1-chromatin trapping kinetics and their effects with dose-response in a time-dependent manner for clinical PARPi following both continuous treatment or after a wash out of drug. Using this new assay, we tested the kinetics in isogenic cell line pairs (BRCA2-/- and WT) and followed in parallel the appearance of biomarkers of DNA damage (e.g. γ-H2AX). The data have revealed important elements of differentiation between the MoA of clinical PARPi including the important insight that the strongest PARP trapper (talazoparib) has clearly reduced cytotoxic specificity for HRD cells, which likely explains the significantly reduced dose used in the clinic compared to other PARPi. These along with other data presented highlight how this next generation PARP trapping assays can provide important insights into PARPi MoA. Citation Format: Giuditta Illuzzi, Mark J O'Connor, Elisabetta Leo. A novel assay for PARP-DNA trapping provides insights into the mechanism of action (MoA) of clinical PARP inhibitors (PARPi) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2077.
Abstract 5288: Evaluating the potential to repurpose statins for ovarian cancer therapy
Authors: Paul T. Kroeger, Ronny Drapkin
Journal: Cancer Research (2019)

Abstract The recent exciting results using primary PARP inhibitor maintenance after upfront treatment for advanced ovarian cancer in BRCA1/2 mutation carriers highlight the importance of identifying druggable vulnerabilities in this disease. The fact that not all ovarian cancer patients will benefit from PARP inhibitors or experience durable responses, places great emphasis on the need to identify additional therapies. Re-purposing existing FDA-approved drugs offers an opportunity to accelerate progress in this area. Statins are drugs primarily prescribed for hypercholesterolemia and have been intensely researched for decades. Some of this work has demonstrated, through epidemiologic approaches and limited experimental studies, that statins have anticancer properties. We hypothesized that statins can be repositioned as part of a therapeutic regimen for HGSOC. Here, we demonstrate that certain ovarian cancer cell lines are exquisitely sensitive to treatment with statins. Our ongoing studies reveal that HGSOC cells that are sensitive to stain treatment manifest an amplification of chromosome 1q21. Within this genomic region are the S100 proteins, previously identified as potential biomarkers in several cancer types, as well as the anti-apoptotic protein MCL1. We performed a Reverse Phase Protein Array (RPPA) analysis on higher dose/short exposure, and low dose/longer exposure statin-treated cells. In both conditions, MCL1 levels were altered in statin-sensitive cell lines, while there was no such change in non-sensitive lines. After identifying MCL1 as a potential marker of response, Western blot analysis demonstrated a dose-dependent decrease in protein level of MCL1 with increasing statin concentration. Additionally, a short pro-apoptotic splice variant of MCL1 was produced upon statin treatment, but only in the sensitive lines. Mechanistically, we find that phospho-YAP (inactive) is upregulated after statin treatment. This data corroborated previous research that suggested that multiple different statins decrease nuclear YAP. Given its role as an oncogene, the apparent ability of statins to deactivate YAP and downregulate MCL1 steers statins in a promising direction for their repositioning for future therapeutic use. Citation Format: Paul T. Kroeger, Ronny Drapkin. Evaluating the potential to repurpose statins for ovarian cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5288.
Epidemiology of congenital Chagas disease 6 years after implementation of a public health surveillance system, Catalonia, 2010 to 2015
Authors: Luca Basile, Pilar Ciruela, Ana Requena-Méndez, Mª José Vidal, Eva Dopico, Andrea Martín-Nalda, Elena Sulleiro, Joaquim Gascon, Mireia Jané
Journal: Eurosurveillance (2019)

BackgroundChagas disease is endemic in Latin America and affects 8 million people worldwide. In 2010, Catalonia introduced systematic public health surveillance to detect and treat congenital Chagas disease.AimThe objective was to evaluate the health outcomes of the congenital Chagas disease screening programme during the first 6 years (2010-2015) after its introduction in Catalonia.MethodsIn a surveillance system, we screened pregnant women and newborns and other children of positive mothers, and treated Chagas-positive newborns and children. Diagnosis was confirmed for pregnant women and children with two positive serological tests and for newborns with microhaematocrit and/or PCR at birth or serology at age 9 months.ResultsFrom 2010 to 2015, the estimated screening coverage rate increased from 68.4% to 88.6%. In this period, 33,469 pregnant women were tested for Trypanosoma cruzi and 937 positive cases were diagnosed. The overall prevalence was 2.8 cases per 100 pregnancies per year (15.8 in Bolivian women). We followed 82.8% of newborns until serological testing at age 9-12 months and 28 were diagnosed with Chagas disease (congenital transmission rate: 4.17%). Of 518 siblings, 178 (34.3%) were tested and 14 (7.8%) were positive for T. cruzi. Having other children with Chagas disease and the heart clinical form of Chagas disease were maternal risk factors associated with congenital T. cruzi infection (p < 0.05).ConclusionThe increased screening coverage rate indicates consolidation of the programme in Catalonia. The rate of Chagas disease congenital transmission in Catalonia is in accordance with the range in non-endemic countries.
Abstract 5122: Comprehensive detection of germline and somatic structural mutation in cancer genomes by Bionano Genomics optical mapping
Authors: Andy Pang
Journal: Cancer Research (2019)

Abstract In cancer genetics, the ability to identify constitutive and low-allelic fraction structural variants (SVs) is crucial. Conventional karyotype and cytogenetics approaches are manually intensive. Microarrays and short-read sequencing cannot detect calls in segmental duplications and repeats, often miss balanced variants, and have trouble finding low-frequency mutations. We describe the use of Bionano Genomics’s Saphyr platform to comprehensively identify SVs for studying cancer genomes. DNA &amp;gt;100 kbp is extracted, labelled at specific motifs, and linearized through NanoChannel arrays for visualization. Molecule images are digitized and de novo assembled, creating chromosomal arm scale genome maps. Somatic mutations can be identified by running the variant annotation pipeline that compares the cancer sample’s assembly SVs against &amp;gt;600,000 SVs in Bionano’s control sample SV database, and against a matched control sample’s SVs, if avaliable. Also, two new Bionano pipelines leverage these long molecules to identify additional somatic SVs: the copy number variation (CNV) and the molecule mapping pipelines. By examining the coverage-depth of molecules alignment to the public reference, the pipeline can identify megabases long CNVs. Similarly, clusters of split-molecule alignments can reliably find translocations and other rearrangements. We applied this suite of discovery tools to identify SVs in a well-studied melanoma cell line COLO829. We collected data from the tumor and the matched blood cell line, constructed contiguous assemblies (N50 &amp;gt;50 Mbp), and called &amp;gt;6,000 SVs in each genome. Then, we classified 51 as somatic by comparing the tumor and the blood control. The two new pipelines further increased sensitivity to rearrangements, for example they captured a BRAF duplication, and other chromosome-arm CNVs. We apply these thorough approaches to multiple well-studied cancer lines to identify novel SVs missed by previous studies. In conclusion, with one comprehensive platform, Saphyr can discover a broad range of traditionally refractory but relevant SVs, and further improves our understanding of cancer. Citation Format: Andy Pang. Comprehensive detection of germline and somatic structural mutation in cancer genomes by Bionano Genomics optical mapping [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5122.
A phase I study of AMV564 in patients with intermediate or high-risk myelodysplastic syndromes.
Authors: Guillermo Garcia-Manero, Meagan Jacoby, David Andrew Sallman, Tae Han, Jeanmarie Guenot, Eric Feldman
Journal: Journal of Clinical Oncology (2019)

TPS7071 Background: The CD33 antigen is expressed on myeloblasts in approximately 75% of patients with myelodysplastic syndromes (MDS) and is also expressed on immunosuppressive myeloid-derived suppressor cells (MDSCs) that are prevalent in MDS. AMV564 is a novel bivalent, bispecific (2:2) T-cell engager that binds both CD33 and the invariant CD3ε on T-cells with strong avidity. AMV564 has significant cytotoxic activity against CD33-postive cells, including MDSCs, in animal models, in vitro studies, and in patients (Reusch et al. Clin Can Res 2016 and List et al. ASH 2017). Preliminary results from the phase 1 acute myeloid leukemia (AML) trial have demonstrated safety and activity in patients with AML arising from prior MDS (Westervelt et al. ASH 2018). Methods: AMV564-201 is an open label, phase 1, multicenter, dose-escalation with expansion trial of AMV564 in patients with intermediate-2 or high-risk MDS who are refractory to or relapsed from hypomethylating agents (HMAs) or intensive chemotherapy. The key objectives of the dose-escalation stage of the study are to characterize the safety and tolerability of AMV564, identify a maximum tolerated dose and/or a dose-schedule to evaluate in the dose expansion portion of the study. In the dose expansion stage of the study, the safety and tolerability of AMV564 will be further characterized in addition to a preliminary assessment of efficacy. Other objectives include characterization of AMV564 pharmacokinetics, pharmacodynamics, and immunogenic potential. Approximately 80 patients with intermediate-2 or high-risk MDS will be enrolled. The Dose Escalation Stage will include up to approximately 30 patients, depending on the dose at which the MTD is determined for each schedule, and approximately 50 additional patients will be enrolled in the Expansion Stage. AMV564 will be administered daily as a continuous intravenous (CIV) infusion over a period of 24 hours for 14 days in each cycle. Each cycle will be approximately 4 weeks. A lead-in dose regimen will be utilized for all patients treated at dose levels at or above 50 mcg/day. Patients will receive up to 4 cycles of AMV564 treatment at the assigned dose level. Clinical trial information: NCT03516591.
Skeletal Mineralization in Association with Type X Collagen Expression Is an Ancestral Feature for Jawed Vertebrates
Authors: Mélanie Debiais-Thibaud, Paul Simion, Stéphanie Ventéo, David Muñoz, Sylvain Marcellini, Sylvie Mazan, Tatjana Haitina
Journal: Molecular Biology and Evolution (2019)

Abstract In order to characterize the molecular bases of mineralizing cell evolution, we targeted type X collagen, a nonfibrillar network forming collagen encoded by the Col10a1 gene. It is involved in the process of endochondral ossification in ray-finned fishes and tetrapods (Osteichthyes), but until now unknown in cartilaginous fishes (Chondrichthyes). We show that holocephalans and elasmobranchs have respectively five and six tandemly duplicated Col10a1 gene copies that display conserved genomic synteny with osteichthyan Col10a1 genes. All Col10a1 genes in the catshark Scyliorhinus canicula are expressed in ameloblasts and/or odontoblasts of teeth and scales, during the stages of extracellular matrix protein secretion and mineralization. Only one duplicate is expressed in the endoskeletal (vertebral) mineralizing tissues. We also show that the expression of type X collagen is present in teeth of two osteichthyans, the zebrafish Danio rerio and the western clawed frog Xenopus tropicalis, indicating an ancestral jawed vertebrate involvement of type X collagen in odontode formation. Our findings push the origin of Col10a1 gene prior to the divergence of osteichthyans and chondrichthyans, and demonstrate its ancestral association with mineralization of both the odontode skeleton and the endoskeleton.
Abstract 1149: Systems pathology by Optra 30 color multiplex immunofluorescence automated whole slide imaging system integrated with image analysis
Authors: Abhi Gholap, Anagha P. Jadhav, Suraj Somwanshi, Gurunath Kamble, Isha Doshi, Jiaoti Huang
Journal: Cancer Research (2019)

Abstract Background A paradigm shift from single marker immunohistochemistry (IHC) to multiplexing in molecular histopathology has helped better understand the cellular composition and heterogeneity of sub population of cells in tissues. Presently, one needs to manually exchange filters after each multiplex scan for capturing all fluorophores per staining round. This is very cumbersome and inefficient, as this process requires rescanning the same slide multiple times. Moreover, visual assessment and quantification of biomarkers is limited by inter and intra-observer variability. We hereby present an automated multispectral whole-slide imaging system integrated with image analysis for detection of upto 30-color multiplex assay with spectral unmixing and cell segmentation functionality. Material and Methods Multiplex IHC whole slide imaging Formalin Fixed Paraffin Embedded rat brain; indirect IHC stained sections with 10 antibodies using photostable fluorophores were obtained. The staining was based on antigenic integrity and antibody binding affinity. Optra's multispectral fluorescent whole slide scanning process was optimized to image sensitive antigens in early cycles and robust antigens in latter cycles. The fully automated fluorescence scanning system imaged weakly expressing biomarkers in the visible range (480-620 nm), highly expressing targets in the violet/blue (405-440 nm), far-red (650-680 nm) and NIR (700-800 nm) range across the entire usable light spectrum (350-800 nm). ResultsWe could simultaneously detect up to 30 biomarkers within a single tissue section, using 12 staining-imaging-stripping cycles, with 10 antibodies screened per cycle. Software measures enabled separation of spectrally overlapping markers in the multiplex assay. A computer-controlled X-Y-Z stage used autofocusing at 20X/40X magnification. Integrated image analysis solution performed comprehensive evaluation of antigens of interest with accurate quantification of the target proteins based on parameters including but not limited to hue value/width, intensity threshold scoring, morphological characterization, pixel-count thresholding and color saturation. Conclusion This proposed solution is efficient compared to the current imaging methods to tackle the aforementioned image acquisition and image analysis challenges associated with multiplexing assays. Note: This abstract was not presented at the meeting. Citation Format: Abhi Gholap, Anagha P. Jadhav, Suraj Somwanshi, Gurunath Kamble, Isha Doshi, Jiaoti Huang. Systems pathology by Optra 30 color multiplex immunofluorescence automated whole slide imaging system integrated with image analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1149.
Abstract 13459: Enhancement of Foxo Proteins Suppressing NaV1.5 Expression by Reactive Oxygen Species in Chronic Ischemic Heart Disease
Authors: Weike Mao, Yan Lu, Tao You, Faqian Li, Haodong Xu
Journal: Circulation (2011)

Background: Our previous in vitro studies showed that Foxo1 negatively regulates SCN5a gene transcription. Reactive oxygen species, such as hydrogen peroxide (H2O2), were reported to be increased i...
Abstract 101: Pentraxin-3 exacerbates glioblastoma invasion and angiogenesis through IL8-VEGF signaling in tumor microenvironment: PTX3 is a potential target for GBM suppression
Authors: Umadevi V. Wesley, Paul Clark, Ian Sutton, John Kuo, Robert Dempsey
Journal: Cancer Research (2019)

Abstract Background: Glioblastoma (GBM) is highly invasive and resistant to multimodal treatment due to distorted vasculature and aggravated inflammation in a tumor microenvironment rich in dysregulated cytokines and growth factors. This phenomenon is partly attributed to GBM stem cells (GSC) that release angiogenic and inflammatory cytokines. The glycoprotein pentraxin-3 (PTX3), a modulator of inflammation, is correlated with disease severity in some cancers. However, its role in GBM and the molecular mechanisms of PTX3-mediated oncogenesis remain unclear. In this study, we examined the role of PTX3 in GBM growth and invasion, using in vitro and in vivo models. Methods: Patient derived GSC lines were isolated and validated. Tumor tissue micro arrays (TMA) were used to determine the association of PTX3 expression with patient GBM specimens representing various degree of disease. Intracranial tumor xenograft/orthotopic mouse models, cell culture models, proteomic profiling, immunohistochemistry, molecular and biochemical approaches were used. Results: Proteomic profiling identified increased PTX3 expression in GSCs as compared to GBM lines, and correlated with the degree of GSC invasiveness in an orthotopic tumor xenograft model. Increased PTX3 correlated with cell cycle progression and survival under hypoxic micro-environment. Conditioned media obtained from PTX3-over-expressing U87 cell line enhanced pro-angiogenic tube formation from endothelial cells. TMA screening showed that PTX3 expression is substantially increased in more than 70% of GBM specimans. Furthermore, PTX3 over-expression significantly increased survival of U87 cells under hypoxic conditions and resulted in increased tumor growth and invasion in an intracranial tumor xenograft mouse model. Upregulation of PTX3 in these tumors was associated with increased levels of inflammatory and angiogenic markers including interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), but decreased levels of thrombospondin1, a major anti-angiogenic factor. Downstream activation of PI3K/Akt - NFkB signaling pathways was also observed. Conclusion: PTX3 is dysregulated in GBM, and may augment inflammation and angiogenesis in tumor microenvironment. Thus, PTX3 may serve as an inflammatory marker for GBM microenvironment and also may represent a potential therapeutic target for GBM suppresion. Citation Format: Umadevi V. Wesley, Paul Clark, Ian Sutton, John Kuo, Robert Dempsey. Pentraxin-3 exacerbates glioblastoma invasion and angiogenesis through IL8-VEGF signaling in tumor microenvironment: PTX3 is a potential target for GBM suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 101.