tbuckley/cabot-search huggingface dataset:
Abstract 1885: CRISPR/Cas9 engineered immortalized breast epithelial MCF10A reporter line for EMT studies and anti-cancer drug discovery
Authors: Weiguo Shu, Sangeeta Kumari, Diana Douglas, Luis G. Rodriguez, Robert Newman
Journal: Cancer Research (2019)

Abstract Metastasis is responsible for most cancer-related deaths. One model for the mechanism of metastasis involves epithelial-to-mesenchymal transition (EMT), a process characterized by the decrease in cell adhesion and increase in cell motility. Cells undergoing EMT often display downregulation of epithelial markers (such as, E-cadherin) and upregulation of mesenchymal markers (such as, Vimentin). Besides metastasis, EMT has also been reported to be associated with other pathological conditions, such as acquired therapeutic drug resistance. Given the roles that EMT may play in these various pathological processes, it is of increasing interest as a target for anti-cancer treatment and drug discovery. In vitro reporter models have proven to be a valuable tool for dissecting the signaling pathways that regulate the EMT process and for screening compounds targeting EMT. In previously developed EMT reporter cell lines, the reporter gene was driven by a truncated EMT marker gene promoter. Therefore, the establishment of a more physiologically relevant reporter cell models is critical for advancing our knowledge of EMT. E-cadherin, a hallmark of epithelial cells, has been implicated in the onset of metastatic dissemination. Utilizing CRISPR/Cas9 knock-in technology, we have generated an E-cadherin (ECAD)-emerald green fluorescent protein (EmGFP) reporter model using immortalized breast epithelial MCF10A cells. In the reporter cells, EmGFP gene was tagged at the C-terminus of E-cadherin, allowing for real-time monitoring of EMT progression in live cells. The targeted knock-in of ECAD-EmGFP allele was verified at the genomic DNA, transcript (mRNA), and protein levels. Bio-functional evaluation of the reporter cell line revealed that treatment of ECAD-EmGFP reporter cells with TGFβ led to EMT induction, as demonstrated by a reduction in E-cadherin-GFP expression and increase in vimentin and fibronectin expressions. Additional functional characterization revealed that the reporter cells possessed an enhanced migration capacity upon EMT induction with TGF-β. In summary, this MCF10A-Ecad-EmGFP reporter cell line can serve as a physiologically relevant in vitro cell model for studying EMT cancer biology and anti-EMT drug discovery. Citation Format: Weiguo Shu, Sangeeta Kumari, Diana Douglas, Luis G. Rodriguez, Robert Newman. CRISPR/Cas9 engineered immortalized breast epithelial MCF10A reporter line for EMT studies and anti-cancer drug discovery [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 1885.
Chemoradiation and surgery versus chemoradiation followed by neoadjuvant chemotherapy and surgery in locally advanced rectal cancer: A retrospective analysis of a single center experience
Authors: B. Lima, L. Oliveira, A. Rolo, C. Carvalho, I. Faustino, A. Teixeira, C. Coutinho, P. Carvalho
Journal: Annals of Oncology (2019)
A new molecular diagnostic tool for <i>pneumocystis jirovecii</i>-pneumonia (PjP) detection: Results from European multicenter clinical study CS-2011.
Authors: Matthias Karrasch, Berit Schulte, Ingo Autenrieth, Olivier Denis, Antoni Torres, Cornelius Knabbe, Gerd Luedke, Eberhard Straube, Peter M. Keller, Jan Weile
Journal: Journal of Clinical Oncology (2013)

e20652 Background: Pneumocystis pneumonia (PCP) is a frequent and serious infectious complication in tumor patients. PCP is caused by Pneumocystis jirovecii, a fungal pathogen which is uncultivable in vitro. Highly-sensitive and time-efficient diagnostic tools are needed for early PCP treatment, especially in patients with impaired immune status. Methods: We evaluated a prototype of a new non-invasive molecular diagnostic tool (Unyvero System) using polymerase chain reaction (PCR) for P. jirovecii detection in respiratory samples (bronchoalveolar lavage fluid, tracheal aspirates, sputum) of hospitalized patients suffering from pneumonia. Results were obtained in an open-label, multicentric, non-randomized clinical study (CS-2011) conducted in 5 European hospitals. Unyvero system test results were compared to study site specific PCR results for P. jirovecii detection. Discrepant results were analysed for clinical relevance of molecular diagnostic tool results. Results: P. jirovecii was detected in 11 patients (1.49 %) out of 739 evaluable study patients: Of these, 8 cases (1.08 %) were detected only with the Unyvero System, 2 cases only with site-established techniques and 1 case with both methods. An independent academic cross-check of these 8 Unyvero System -positive cases showed that 5 cases were false positives due to signal reading failure. The remaining 3 cases could be confirmed as true positives by control PCP-PCR, indicating Unyvero P. jiroveciidetection results of 2 false negatives, 4 true positives and 5 false positives. Conclusions: The overall detection rate for P. jirovecii was low (11 out of 739) in this study population. Although more positive cases were found using the Unyvero System, it remains unclear if this was of clinical significance, especially as two clinically confirmed PCP cases could not be detected. The Unyvero System prototypes had a rate of 0.7% false positive results (5 out of 739 samples) which might have led to an overtreatment under real conditions. However, the correct detection of 4 positive cases within 3 hours might render the Unyvero System a valuable diagnostic future tool.
Abstract 4060: Discovery and screening of protein biomarkers with the FirePlex Technology Platform
Authors: Amy Perea, Russell Neuner, Bianca Heinrich, Graeme Doran, Wayne Austin, Conor Rafferty, Matt Camilleri, Michael Tackett, Long To, Elnaz Atabakhsh, James Murray, Daniel Pregibon
Journal: Cancer Research (2019)

Abstract In patients and animal models, molecular biomarkers are used as indicators of normal and pathogenic processes. In drug discovery and screening pipelines, molecular biomarkers are used to assess the mechanism of action, efficacy, and toxicity of lead compounds. To address the need for rapid and sensitive biomarker quantitation, we have developed the FirePlex® Technology Platform. Utilizing patented hydrogel particles and a three-region encoding design, FirePlex assays allow for true, in-well multiplexing, providing flexible and customizable quantification of miRNA and protein analytes. To facilitate biomarker discovery studies, we offer our standard-throughput, flow cytometry-based assays which enable quantitation of up to 75 miRNA or protein analytes per sample, from only 20 µl of input. These assays demonstrate 5 logs of dynamic range and offer highly sensitive quantitation of analytes in serum, plasma, cell culture supernatant, urine, and CSF without the need for sample processing or RNA isolation. For drug discovery and screening studies, we offer our high-throughput FirePlex (FirePlex®-HT) Immunoassays for quantitation of up to 10 protein analytes per sample from only 6.25 µl biofluid input, in 384-well plate format. FirePlex-HT assays provide 3-4 logs dynamic range, demonstrate 1-100 pg/ml sensitivity, and have been validated in serum, plasma, and cell culture supernatant. The two-step workflow, no-wash assay format, and readout on high-content imagers limit hands-on time and are amenable to automation, thus making FirePlex-HT ideally suited for high-throughput screening studies. In addition, here we introduce our high-throughput miRNA assays for screening miRNA biomarkers in 96-well or 38-4well plate format, with readout on high-content imagers. Here we present data from miRNA and protein profiling studies using the FirePlex platform, and introduce the simplified workflow of the FirePlex-HT® immunoassays with data demonstrating the performance for quantifying key cytokines in multiplex, in biological samples. Together, this novel combination of multiplexed, high-sensitivity assays and bioinformatics tools enables rapid quantitation of protein biomarker signatures in biofluid specimens. Citation Format: Amy Perea, Russell Neuner, Bianca Heinrich, Graeme Doran, Wayne Austin, Conor Rafferty, Matt Camilleri, Michael Tackett, Long To, Elnaz Atabakhsh, James Murray, Daniel Pregibon. Discovery and screening of protein biomarkers with the FirePlex Technology Platform [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 4060.
Abstract 1282: Understanding the kinomic contributions to tyrosine kinase inhibitor resistance in triple negative breast cancer
Authors: Cory Lefebvre, David Litchfield, Alison Allan
Journal: Cancer Research (2019)

Abstract There is an increasing need to develop targeted therapies for triple negative breast cancer (TNBC), as conventional chemotherapy, anti-hormone or anti-HER2 therapies are ineffective at combatting systemic disease. TNBC tumors often have increased expression of receptor tyrosine kinases such as EGFR (epidermal growth factor receptor) and the hepatocyte growth factor (HGF) receptor, c-Met; presenting as potential targets for treatment. However, targeted anti-Met and anti-EGFR therapies have faced mixed results in clinical trials due to acquired resistance. We hypothesize that dynamic changes in the kinome contribute to the acquired resistance of TNBC tumors to c-Met and EGFR inhibitors. Using MDA-MB-468 and MDA-MB-231 TNBC cell lines, we investigated the effects of the c-Met inhibitors cabozantinib and tivantinib and the EGFR inhibitor erlotinib on cell proliferation and activation of target receptors and downstream signalling pathways. We observed that cabozantinib and erlotinib significantly inhibited the proliferation (p≤0.05) of one and/or both TNBC cell lines in a cytostatic fashion. Similarly, tivantinib demonstrates growth inhibitory effects but in a mostly cytotoxic manner; consistent with recent reports of its mechanism in inhibiting microtubule polymerization. Exposure to erlotinib (24 hrs) resulted in decreased expression of phosphorylated and total EGFR in both TNBC cell lines and a decrease in activation (phosphorylated:total expression) of ERK1/2 in MDA-MB-468 cells (p≤0.05). Tivantinib and cabozantinib did not appear to have any effects on activation of c-Met or ERK1/2 in MBA-MB-231 or MDA-MB-468 cells following 24-hour exposure. Ongoing studies are aimed at implementing a novel kinomics strategy using SILAC and multiplexed inhibitor beads for kinase enrichment to investigate the dynamic changes in the kinome of susceptible and resistant cell lines in response to erlotinib and cabozantinib. With better understanding of the underlying mechanisms, we can potentially discover targets that could attenuate induced resistance to tyrosine kinase inhibitors. Citation Format: Cory Lefebvre, David Litchfield, Alison Allan. Understanding the kinomic contributions to tyrosine kinase inhibitor resistance in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1282.
Abstract 1592: Genome-wide meta-analysis of keratinocytic cancers identifies 26 novel risk loci
Authors: Upekha E. Liyanage, Matthew H. Law, Xikun Han, Jiyuan An, Jue-Sheng Ong, Puya Gharahkhani, Mark M. Iles, Rachel E. Neale, Catherine Olsen, Stuart Macgregor, David C. Whiteman
Journal: Cancer Research (2019)

Abstract Background: Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) (collectively referred to as keratinocytic skin cancers (KC)) are the most common forms of cancer in fair-skinned people. KCs account for the highest expenditure of any cancer type in the Australian healthcare system. Knowledge about the genetic architecture of skin cancer may help elucidate the biology of the disease. Methods: We conducted a genome-wide meta-analysis of KC, including 28248 cases and 353855 controls from United Kingdom, United States and Australian populations. We performed LD score regression to determine the genetic correlation between KC, BCC, SCC, and melanoma. Results: We identified 41 independent genome-wide significant SNPs associated with KC risk, 16 of which have not been reported previously. A further 10 loci were implicated using gene-based tests. New loci included common variants in BRCA2 (rare variants increase risk of various cancers) and CTLA4 (immune response; antibodies targeting CTLA-4 are used to treat melanoma). We found a strong genetic correlation between BCC and SCC, 0.93 (95% confidence interval [CI] 0.71 - 1.16). The genetic correlation between melanoma and BCC was 0.66 (95% CI: 0.41 - 0.91). Comparatively lower genetic correlations were identified between melanoma and SCC 0.43 (95% CI: 0.12 - 0.74), and melanoma and KC 0.52 (95% CI: 0.27 - 0.76). Conclusions: We have identified novel genetic loci associated with KC risk which will lead to a greater understanding of the biology of KC. Future work will leverage the genetic correlations between BCC, SCC and melanoma to further advance our understanding of these cancers. Citation Format: Upekha E. Liyanage, Matthew H. Law, Xikun Han, Jiyuan An, Jue-Sheng Ong, Puya Gharahkhani, Mark M. Iles, Rachel E. Neale, Catherine Olsen, Stuart Macgregor, David C. Whiteman. Genome-wide meta-analysis of keratinocytic cancers identifies 26 novel risk loci [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 1592.
Ulceration and Alopecia of the Scalp Owing to C2 Radiculoneuropathy Following Posterior Atlanto-Axial Fixation
Authors: Alexandra Prenner, Roland Blum, Sebastian F. Bigdon, Luca Borradori
Journal: JAMA Dermatology (2019)

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The first-in-class anti-CD47 antibody Hu5F9-G4 is active and well tolerated alone or with azacitidine in AML and MDS patients: Initial phase 1b results.
Authors: David Andrew Sallman, William Bruce Donnellan, Adam Steven Asch, Daniel Junseung Lee, Monzr Al Malki, Guido Marcucci, Daniel Aaron Pollyea, Suman Kambhampati, Rami S. Komrokji, Joanna Van Elk, Ming Lin, Balaji Agoram, James Y Chen, Jens-Peter Volkmer, Chris H.M. Takimoto, Mark Chao, Paresh Vyas
Journal: Journal of Clinical Oncology (2019)

7009 Background: Hu5F9-G4 (5F9) is an antibody targeting CD47, a macrophage immune checkpoint and “don’t eat me” signal on cancers. CD47 blockade induces tumor phagocytosis and eliminates leukemia stem cells (LSC) in AML models. Azacitidine (AZA) synergizes with 5F9 by inducing “eat me” signals on AML, enhancing phagocytosis. This trial explored the safety/efficacy of 5F9 alone or with AZA in AML/MDS patients (pts). Methods: This Phase 1b treated: r/r AML/MDS pts with 5F9; and untreated AML (induction chemo ineligible) and higher risk MDS pts with 5F9+AZA. A 5F9 priming/intrapatient dose escalation regimen (1-30 mg/kg weekly) was used to mitigate on target anemia. Results: 10 (6 AML, 4 MDS) r/r pts received 5F9 (median 2 prior therapies (range 1-6). 24 untreated pts (15 AML, 9 MDS) received 5F9+AZA. In total, median age was 73, 62% of AML pts were intermediate or poor cytogenetic risk (38% unknown), all MDS pts were intermediate or high risk by IPSS-R. 5F9 alone or with AZA was well-tolerated with no MTD reached. 5F9 did not potentiate AZA toxicities. Treatment-related AEs ( &gt; 10% of pts) for 5F9+AZA were anemia (25%), thrombocytopenia (20%), and infusion reactions (15%). In 25 efficacy evaluable pts, 8/15 (53%) untreated AML/MDS pts had a CR/CRi to 5F9+AZA (5/10 (50%) in AML, 3/5 (60%) in MDS). 1/10 (10%) r/r AML/MDS pts had a response (MLFS) to 5F9 alone. LSC frequency was reduced/eliminated in most 5F9+aza responders; 50% of responders were MRD negative by flow cytometry. 4/10 (40%) AML pts became RBC transfusion independent and 4/5 (80%) MDS pts had hematologic improvement. Time to response was more rapid (median 1.9 mos) than expected for AZA alone. As of Jan 2019, no responder has relapsed (median follow-up of 3.4 mos (range 1.1 – 6.8 mos). 2 pts had successful allogeneic transplant. Conclusions: 5F9+AZA is a novel immunotherapy blocking a key macrophage checkpoint. It has been well tolerated with robust activity in AML/MDS pts with rapid CRs and MRD negativity. Adding 5F9 to cytotoxic agents may be a promising treatment strategy. An expansion cohort is ongoing. Funded by Forty Seven and the California Institute for Regenerative Medicine. Clinical trial information: NCT03248479.
Abstract 35: Transendocardial Mesenchymal Stem Cell Injection Demonstrates Reverse Remodeling Effects of Global LV Volumes and Enhanced Lateral Papillary Muscle Shortening
Authors: Louis Vincent, Makoto Natsumeda, Angela C Rieger, Victoria Florea, Bryon A Tompkins, Wayne Balkan, Lionel Leroux, Joshua M Hare
Journal: Circulation Research (2017)

Rationale: Secondary mitral regurgitation (MR) carries a poor prognosis despite improvements in surgical and transcatheter interventions. Mesenchymal stem cell (MSC) therapy for heart disease reduces infarct size and left ventricle (LV) dilatation, reverses remodeling, and improves regional contractility and functional capacity. However, it is unknown if the benefits of MSC therapy on LV structure and function apply to lateral papillary muscle shortening, an important predictor of secondary MR severity. Hypothesis: Test the hypothesis that administration of MSCs promotes interpapillary muscle distance (IPMD) shortening. Methods/Results: This retrospective analysis draws on results from autologous or allogeneic MSC injection therapies in a Göttingen swine model of chronic ischemic cardiomyopathy (ICM). MRI was used to measure end-diastolic volume (EDV), end-systolic volume (ESV), diastolic/systolic IPMD, and IPMD shortening. NOGA mapping and angiographic tracings of left ventriculography allowed for assessment of the effect of injection localized to papillary muscles (defined as injection within cardiac segments 4, 6, 10 and 12 in the 16-segment model). Three months after stem cell injection, EDV increased in both placebo- (12.2±3.6 mL; p=0.002) and MSC- (10.2±2.6 mL; p=0.03) treated swine. ESV increased only in placebo- (7.1±2.2 mL; p=0.003) but not MSC- treated swine. Systolic IPMD was maintained with MSC therapy (1.20±0.74 mm; p=0.33) but increased in placebo (1.83±0.60 mm; p=0.01). Systolic IPMD was preserved whether MSC injection was localized to papillary muscle (0.53±0.49 mm; p=0.44) or not (0.22±0.40 mm; p=0.24). Notably, IPMD shortening was significantly greater in MSC- (8.1±5.6%; p=0.02) but not placebo-injected (4.7±5.0%; p=0.69) swine. There were no between group differences in IPMD shortening (p=0.08). Conclusion: This study is the first to show that transendocardial MSC injections significantly enhanced IPMD shortening and lateral interpapillary muscle contraction in a model of chronic ICM. This effect was independent of injection site.
Survival outcomes in the elderly with limited stage diffuse large B-cell lymphoma treated with chemotherapy: SEER propensity-matched analysis.
Authors: Ravi Kaisreddy, Venkata Vosuri, Somasekhar Bandi
Journal: Journal of Clinical Oncology (2019)

e19046 Background: Current data shows a median age of diffuse large b-cell lymphoma (DLBCL) diagnosis of 70 years. More than 50% of elderly DLBCL patients can be expected to be cured by modern immunochemotherapy. Survival outcomes in elderly patients with limited stage DLBCL treated with chemotherapy outside of clinical trials are poorly characterized. Our objective is to determine survival pattern and factors that influence survival in elderly patients with limited stage DLBCL treated with chemotherapy through analysis of data from a large nationwide cancer registry in modern treatment era. Methods: The Surveillance Epidemiology and End Results (SEER 18) treatment database (2001-2013) was used to detect limited stage (Ann Arbor lymphoma stage I and II) DLBCL (ICD-O-3 code: 9680/3) adult cases with ages between 60-80 years treated with chemotherapy. Patients were divided into two cohorts. Cohort 1 included patients aged ≥60 to 70 yrs and Cohort 2 included patients aged &gt; 70 to 80 yrs. The variable "First Malignant Primary Indicator" was used to differentiate between primary DLBCL and secondary DLBCL cases. Overall survival (OS) was calculated using the Kaplan-Meier methods and multivariate cox regression model to determine the impact of race, gender, radiation use and primary malignant indicator on survival using 1:1 propensity score matching. Chi square test was applied to delineate for any significant difference between two cohorts. Results: Overall, 11138 patients were included with 5569 patients in each cohort. The relative incidence of limited stage secondary DLBCL was greater for cohort 2 when compared to cohort 1 (26% vs. 15%, p &lt; 0.01). The odds of receiving radiation was 27% higher in cohort 1 compared to cohort 2 (p &lt; 0.0001). Compared to cohort 1 (median OS-130 months), cohort 2 had worse median OS of 72 months (p &lt; 0.0001). Female gender, not receiving radiation and secondary status have shown strong relationship with increased risk of death on multivariate cox regression analysis in the elderly limited stage DLBCL patients. Conclusions: Overall survival was worse in age group 70-80 yrs when compared to age group 60-70 yrs in limited stage DLBCL patients treated with chemotherapy. This may be due to differences in treatment approaches. Female gender, not receiving radiation and secondary status are poor prognostic factors of survival in above group of patients. Race has no impact on survival.