tbuckley/cabot-search huggingface dataset:
Abstract 3051: A potent pyrimidinone Axl inhibitor DW17401
Authors: Hefeng Zhang, Xia Peng, Yinchun Ji, Yang Dai, Yanyan Shen, Jing Ai, Wenhu Duan
Journal: Cancer Research (2020)

Abstract Aberrant signaling of Axl frequently occurs in many cancer types. Axl activation has been identified as a key trigger in epithelial to mesenchymal transition (EMT), which accounts for acquired drug resistance to many tyrosine kinase inhibitor therapies. It also has been revealed that Axl signaling is associated with immunosuppression. Therefore, Axl inhibitors may present a promising strategy for cancer therapeutics. We have designed and synthesized a series of pyrimidinone Axl inhibitors, and DW17401 was identified as a highly potent, orally available inhibitor against Axl, with IC50 values of 0.9 nM. DW17401 exhibited significant inhibitory effect against Axl driven cell proliferation, with an IC50 value of less than 0.02 nM for BaF3/TEL-AXL cell line. Oral dosing of DW17401 25 mg/kg (QD) resulted in complete tumor regressions in subcutaneous transplanted model of BaF3/TEL-AXL in nude mice. In addition, DW17401 could also inhibited c-Met kinase and c-Met-mediated tumor cell proliferation and growth with high potency, indicated it therapeutic potential in MET aberrant cancer. Of note, DW17401 presented favorable pharmacokinetic parameters on SD rat with a half-life time of 13.8 h and a plasma exposure value of 32647 ng.h/mL (p.o. at 3 mg/kg). All these data indicated that DW17401 was an effective promising Axl inhibitor for cancer treatment. Citation Format: Hefeng Zhang, Xia Peng, Yinchun Ji, Yang Dai, Yanyan Shen, Jing Ai, Wenhu Duan. A potent pyrimidinone Axl inhibitor DW17401 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3051.
Abstract 5434: Insulinoma-associated protein 1 (INSM1) expression in small cell neuroendocrine carcinoma of the urinary tract
Authors: Isaac E. Kim, Ali Amin, Li Juan Wang, Liang Cheng, Carmen M. Perrino
Journal: Cancer Research (2020)

Abstract Introduction Clinical guidelines including the American Urological Association (AUA) state that neoadjuvant chemotherapy should be administered prior to surgery in cases of muscle invasive urinary bladder small cell neuroendocrine carcinoma. Although the recently described marker insulinoma-associated protein 1 (INSM1) has been reported to be sensitive and specific for neuroendocrine differentiation in neuroendocrine tumors at several sites, its efficacy as a marker in urinary bladder small cell carcinoma has not been well established. This study aims to examine the immunohistochemical expression pattern of INSM1 on whole tissue sections of urinary bladder small cell neuroendocrine carcinoma and compare INSM1 expression to those of established markers of neuroendocrine differentiation. Methods Archived tissue from 32 cases of urinary bladder small cell neuroendocrine carcinoma were obtained from Rhode Island Hospital and The Miriam Hospital. Immunohistochemical stains for CD56, INSM1, synaptophysin, and chromogranin were performed. Staining was scored for intensity (0: no staining; 1: weak; 2: moderate; 3: strong) and proportion of cells stained (0: 0%; 1: &amp;gt;0 to 25%; 2: &amp;gt;25 to 50%; 3: &amp;gt;50 to 75%; 4: &amp;gt;75 to 100%). Results INSM1 was positive (intensity 1-3 or proportion 1-4) in 87% (28/32) of small cell neuroendocrine carcinoma cases (20 with intensity 2-3, 17 with proportion 3-4). CD56, synaptophysin, and chromogranin were positive in 75% (24/32), 60% (19/32), and 44% (14/32) of cases, respectively. While the rate of positivity was high, INSM1 was negative (n=4) or only showed weak intensity staining (n=7) in 34% (11/32) of cases. Conclusion INSM1 is a sensitive marker of small cell neuroendocrine differentiation of the urinary bladder. However, the findings in this study suggest that optimal utilization of INSM1 would be in a limited panel of stains rather than as a stand-alone screening marker given that it is negative or only shows weak intensity staining in a significant proportion of cases. StainNegative [n (%)]Positive [n (%)]INSM14 (13)28 (87)CD568 (25)24 (75)Synaptophysin13 (40)19 (60)Chromogranin18 (56)14 (44) Citation Format: Isaac E. Kim, Ali Amin, Li Juan Wang, Liang Cheng, Carmen M. Perrino. Insulinoma-associated protein 1 (INSM1) expression in small cell neuroendocrine carcinoma of the urinary tract [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5434.
Histamine down‐regulates the FCERI α‐chain expression in human IL‐4‐activated M2 macrophages
Authors: Susanne Mommert, Judith Tabea Schaper, Katrin Schaper‐Gerhardt, Ralf Gutzmer, Thomas Werfel
Journal: Allergy (2020)

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Abstract 748: The small leucine-rich proteoglycan fibromodulin is a potential, novel serum and urinary biomarker for the detection of prostate cancer
Authors: Niradiz Reyes, Alfonso Bettin, Jan Geliebter
Journal: Cancer Research (2020)

Abstract Background: Prostate cancer (PCa) is the most common malignant tumor diagnosed in males and the fifth leading cause of cancer deaths worldwide. The impact of this cancer in the population is due, in part, to the lack of satisfactory methods for early diagnosis and accurate prognosis, which results in delayed clinical treatment of patients. Effective therapy exists for early stages, but it is practically incurable in advanced stages. Therefore, new and better molecular biomarkers are urgently needed for the opportune diagnosis and adequate prediction of the clinical course of the disease. We have previously identified the small leucine-rich proteoglycan, fibromodulin, as a novel, potential tissue biomarker for prostate cancer. Fibromodulin is a secreted proteoglycan which can be detected in different body fluids, such as blood, urine, or prostatic secretions. The aim of the present study was to determine whether fibromodulin concentration in serum and/or urine is able to differentiate PCa patients from patients with benign disease. Methods: Serum and urine samples were collected from a cohort of patients newly diagnosed with PCa (n=44) or with other prostatic disorders (n=46). Samples were also obtained from a group of control healthy individuals within the same age range. The concentration of fibromodulin in the blood and urine samples was measured with a commercial ELISA kit. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance of fibromodulin in serum and urine. This work was approved by the Institutional Review Board of the University of Cartagena. Results: Both serum and urinary levels of fibromodulin were significantly higher in PCa patients compared to patients with benign disorders and healthy controls (p&amp;lt;0.05). Overall, urinary levels were higher than serum levels for each of the three groups. Conclusion: Our results support the potential of fibromodulin as a novel serum and urinary biomarker for PCa. Validation of these results requires prospective studies using a larger cohort of patients, as well as multicenter clinical trials, to define the real value of this protein as a biomarker for PCa. Keywords: Prostate cancer, fibromodulin, biomarkers, proteoglycan. Citation Format: Niradiz Reyes, Alfonso Bettin, Jan Geliebter. The small leucine-rich proteoglycan fibromodulin is a potential, novel serum and urinary biomarker for the detection of prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 748.
Abstract 5045: Predictive factors for successful growth of patient derived xenograft (PDX)
Authors: Tatiana Hernandez, Natalia Baños, Victoria Bonilla, Laura del Puerto, Bernard Doger, Jesus Garcia-Foncillas, Michael Wick, Victor Moreno
Journal: Cancer Research (2020)

Abstract Background: PDXs have become a core component of translational cancer research. Developing these models can become challenging since little is known about which factors influence engraftment rates. We sought to determine which clinical, pathological or molecular factors may predict a higher chance of success for PDX development. Methods: Between March 2017 and August 2019, biopsies obtained from patients with primary or metastatic cancer were implanted into athymic nude mice. Statistical analyses were performed to identify factors that could correlate with final engraftment defined as tumor volume of 150 mm3 in at least three consecutive measurements. We focus on clinical (patient factors) pathological (tumor sample) and molecular characteristics (tumor sample). Information regarding sampling process was also analyzed. Results: 440 tumor samples were collected and implanted. 15 failed due lack of tumor cells. Of 425 tumor-positive samples, 143 PDXs achieved successful growth at time of analysis. The following clinical characteristics were correlated with engraftment success: systemic steroid administration within 2 weeks of sampling (45.5% (30/66) within the steroids-receiving group achieved growth vs 31% (113/359) no-steroids) (p: 0.027). High neutrophils/lymphocytes (NLR) ratio (&amp;gt;5) (42.3% (47/111) of tumors with NLR&amp;gt;5 achieved growth vs 30% (96/313) in the NLR&amp;lt;5 group; P:0,018). Regarding pathological tumor characteristics, higher ki67 levels were correlated with better engraftment rates (Low (Ki67&amp;lt;15%): 10% (5/46) vs. Medium (Ki67:15-30%): 25% (7/28) and high (Ki67&amp;gt;30%): 34% (16/47) (p:0.029). The presence of mucinous cells (signet ring cells) was also correlated with higher chance of tumor engraftment (50% (19) vs. 32% (124/387) (p: 0.022). Negativity for estrogen receptors could also be a positive predictive marker (14% (8/57) of ER+ achieved growth vs 46.7% (7/15) ER negative (p: 0.011). Lastly, sampling source (either primary of metastatic tumors) was not correlated with successful growth. Conclusions: tumors with higher Ki67, mucinous features and ER expression negative have higher chance of PDX development. Some clinical characteristics can also interfere with PDXs development such as use of steroids or NLR. Citation Format: Tatiana Hernandez, Natalia Baños, Victoria Bonilla, Laura del Puerto, Bernard Doger, Jesus Garcia-Foncillas, Michael Wick, Victor Moreno. Predictive factors for successful growth of patient derived xenograft (PDX) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5045.
Abstract 2093: DeepRePath: Finding prognostic features of tumor cell on the histopathologic image of lung cancer using explainable deep convolutional neural network
Authors: Yoon Ho Ko, Soon Auck Hong, Tae-Jung Kim, Ji Hyung Hong, Sang Hoon Chun, Seoree Kim, Ho Jung An, Sungsoo Park, Won Sang Shim
Journal: Cancer Research (2020)

Abstract Introduction Histopathological images in high-powered contain quantitative information for tumor cell morphology, but humans could not sufficiently extract prognostic features of tumor cell morphology associated with tumor recurrence of patient. In this study, we developed and trained the DeepRePath model, a deep convolutional neural network (CNN), on histopathological images to predict the recurrence of resected lung adenocarcinoma (LUAD). Methods A total of 244 haematoxylin and eosin stained histopathology slides of resected LUAD patients were used to train and validate the DeepRePath model. We manually segmented a cancer region in a LUAD tissue slide and captured to an image. All images were captured at x400 magnification and split into 13,329 image patches. We trained the DeepRePath model by transfer learning using 13,329 image patches from 244 LUAD patients. Results 95 out of 244 patients developed recurrence after surgical resection. The DeepRePath model showed an average area under the curve (AUC) of 0.78 in 5-fold cross validation on the training cohort. We plan to employ external validation to evaluate the proposed model. In addition, using gradient-weighted class activation mapping (Grad-CAM), we confirmed that DeepRePath identified and used individual tumor cells with atypia to predict the recurrence of the patient. Conclusions DeepRePath model using transfer learning and CNN can accurately predict recurrence after curative resection of LUAD based on atypia of tumor cell. Citation Format: Yoon Ho Ko, Soon Auck Hong, Tae-Jung Kim, Ji Hyung Hong, Sang Hoon Chun, Seoree Kim, Ho Jung An, Sungsoo Park, Won Sang Shim. DeepRePath: Finding prognostic features of tumor cell on the histopathologic image of lung cancer using explainable deep convolutional neural network [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2093.
Abstract 1272: Enhancer RNA cell line database reveals new associations between TF activity and cancer subtype
Authors: Joseph Azofeifa, Joel Basken, Maria Lai, Ryan Langendorf, Laura Norris, Tim Read, Adam Robbins-Pianka
Journal: Cancer Research (2020)

Abstract Cell type and lineage is driven, in large part, by changes in transcription factor activity. Particularly in cancer, misregulation of transcription factor binding can lead to de-differentiated states and overproliferation. Recent work suggests that enhancer RNAs are a highly predictive readout of transcription factor activity, however, measuring them is an arduous process. We developed an automated strategy to measure nascent RNAs for over 50 different cancer cell line models. By a modified PRO-seq assay, we annotated enhancer RNAs and transcription factors unique to specific cancer backgrounds. Examples include: ESR1 activity in ER+ breast cancer models, AR activity in castration-sensitive prostate models and GATA3 in AML. This database is the first standardized collection of enhancer RNAs and and can be used in conjunction with the BROAD's CCLE and DepMap consortiums to help expedite treatment options. Citation Format: Joseph Azofeifa, Joel Basken, Maria Lai, Ryan Langendorf, Laura Norris, Tim Read, Adam Robbins-Pianka. Enhancer RNA cell line database reveals new associations between TF activity and cancer subtype [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1272.
Assessment of Probable Opioid Use Disorder Using Electronic Health Record Documentation
Authors: Sarah A. Palumbo, Kayleigh M. Adamson, Sarathbabu Krishnamurthy, Shivani Manoharan, Donielle Beiler, Anthony Seiwell, Colt Young, Raghu Metpally, Richard C. Crist, Glenn A. Doyle, Thomas N. Ferraro, Mingyao Li, Wade H. Berrettini, Janet D. Robishaw, Vanessa Troiani
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Electronic health records are a potentially valuable source of information for identifying patients with opioid use disorder (OUD). <h3>Objective</h3> To evaluate whether proxy measures from electronic health record data can be used reliably to identify patients with probable OUD based on<i>Diagnostic and Statistical Manual of Mental Disorders</i>(Fifth Edition) (<i>DSM-5)</i>criteria. <h3>Design, Setting, and Participants</h3> This retrospective cross-sectional study analyzed individuals within the Geisinger health system who were prescribed opioids between December 31, 2000, and May 31, 2017, using a mixed-methods approach. The cohort was identified from 16 253 patients enrolled in a contract-based, Geisinger-specific medication monitoring program (GMMP) for opioid use, including patients who maintained or violated contract terms, as well as a demographically matched control group of 16 253 patients who were prescribed opioids but not enrolled in the GMMP. Substance use diagnoses and psychiatric comorbidities were assessed using automated electronic health record summaries. A manual medical record review procedure using<i>DSM-5</i>criteria for OUD was completed for a subset of patients. The analysis was conducted beginning from June 5, 2017, until May 29, 2020. <h3>Main Outcomes and Measures</h3> The primary outcome was the prevalence of OUD as defined by proxy measures for<i>DSM-5</i>criteria for OUD as well as the prevalence of comorbidities among patients prescribed opioids within an integrated health system. <h3>Results</h3> Among the 16 253 patients enrolled in the GMMP (9309 women [57%]; mean [SD] age, 52 [14] years), OUD diagnoses as defined by diagnostic codes were present at a much lower rate than expected (291 [2%]), indicating the necessity for alternative diagnostic strategies. The<i>DSM-5</i>criteria for OUD can be assessed using manual medical record review; a manual review of 200 patients in the GMMP and 200 control patients identifed a larger percentage of patients with probable moderate to severe OUD (GMMP, 145 of 200 [73%]; and control, 27 of 200 [14%]) compared with the prevalence of OUD assessed using diagnostic codes. <h3>Conclusions and Relevance</h3> These results suggest that patients with OUD may be identified using information available in the electronic health record, even when diagnostic codes do not reflect this diagnosis. Furthermore, the study demonstrates the utility of coding for<i>DSM-5</i>criteria from medical records to generate a quantitative<i>DSM-5</i>score that is associated with OUD severity.
ECMO support for viral induced cardiogenic shock: a bridge too far?
Authors: Trevor J. Williams, Vincent Pellegrino
Journal: European Respiratory Journal (2020)

<b>Decision making in a COVID-19 pandemic may need to be undertaken in the absence of evidence from randomised controlled trials. A recent case study suggests VA-ECMO in severe COVID-19 sepsis and shock is highly unlikely to result in patient survival.</b>https://bit.ly/2YjQPP3
miR-204-3p/Nox4 Mediates Memory Deficits in a Mouse Model of Alzheimer’s Disease
Authors: Wenyuan Tao, Linjie Yu, Shu Shu, Ying Liu, Zi Zhuang, Siyi Xu, Xinyu Bao, Yue Gu, Fang Cai, Weihong Song, Yun Xu, Xiaolei Zhu
Journal: Molecular Therapy (2020)

Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia in the elderly, and the mechanisms of AD are not fully defined. MicroRNAs (miRNAs) have been shown to contribute to memory deficits in AD. In this study, we identified that miR-204-3p was downregulated in the hippocampus and plasma of 6-month-old APPswe/PS1dE9 (APP/PS1) mice. miR-204-3p overexpression attenuated memory and synaptic deficits in APP/PS1 mice. The amyloid levels and oxidative stress were decreased in the hippocampus of APP/PS1 mice after miR-204-3p overexpression. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4) was a target of miR-204-3p, and Nox4 inhibition by GLX351322 protected neuronal cells against Aβ1-42-induced neurotoxicity. Furthermore, GLX351322 treatment rescued synaptic and memory deficits, and decreased oxidative stress and amyloid levels in the hippocampus of APP/PS1 mice. These results revealed that miR-204-3p attenuated memory deficits and oxidative stress in APP/PS1 mice by targeting Nox4, and miR-204-3p overexpression and/or Nox4 inhibition might be a potential therapeutic strategy for AD treatment.
Abstract 2902: Antibody-drug conjugate targeting c-kit/CD117 suppresses imatinib resistant cancer cells
Authors: Jin-Ock Kim, Kwang-Hyeok Kim, Sang Gyu Park
Journal: Cancer Research (2020)

Abstract c-Kit(CD117) is a type III receptor tyrosine kinase that mediates cell proliferation, survival, and differentiation. Gene amplification of c-kit is found in various cancers, including, glioblastoma (GBM) low grade glioma(LGG), gastrointestinal stromal tumor (GIST), sarcoma, melanoma, and small cell lung carcinoma (SCLC), leading to poor prognosis. In addition, the activation of c-kit as a cancer stem cell marker induces resistance of anti-cancer drug by increasing the expression of ABCG2. Imatinib is a first generation RTK inhibitor targeting BCR-ABL, c-kit, and PDGFR and currently using for the treatment of various cancers. Of note, the activating mutation of c-kit is found in various cancers, leading to resistance of imatinib. In this study, we have generated a human antibody targeting c-kit and developed antibody-drug conjugate using SMCC-DM1 to assess the therapeutic efficacy in vitro and in vivo. Citation Format: Jin-Ock Kim, Kwang-Hyeok Kim, Sang Gyu Park. Antibody-drug conjugate targeting c-kit/CD117 suppresses imatinib resistant cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2902.
Abstract 397: Myeloma derived mitochondrial DNA activates TLR9 driven pro-tumoral expansion
Authors: Aisha Jibril, Jayna J. Mistry, Prakrit Kumar, Jamie A. Moore, Charlotte Hellmich, Cesar Gomez, Kristian Bowles, Stuart A. Rushworth
Journal: Cancer Research (2020)

Abstract Multiple myeloma (MM) is reported to cause 85,000 global deaths per year which is estimated to double by 2040. MM is an incurable malignancy of antibody (Ig) secreting differentiated B cells (plasma cells) characterized by the accumulation and localisation of tumor cells in the bone marrow microenvironment (BMM). Mitochondrial genome (mtDNA) contains CpG DNA repeats and CpG DNA has been shown to activate and induce proliferation of memory B cells to secrete Ig. Here we determine if malignant plasma cells maintain their proliferative advantage by releasing mtDNA into the tumour microenvironment which acts as feedback mechanism to induce further proliferation and Ig production by the malignant plasma cell. Human MM cell lines U266 and MM1S were engrafted into NSG immunocompromised mice. Blood sample from control and engrafted mice were collected at various times and plasma was isolated and spun at 15,000g to remove cell debris and large extracellular vesicles. Human and mouse mtDNA was determine by real-time PCR. Results show that human mtDNA can be detected in the plasma from mice engrafted with U266 and MM1S at 2 weeks and 3 weeks post injection of cells. Next, CpG oligonucleotides were used to determine if MM cells can be activated by mtDNA CpG repeats. Primary MM, U226 and MM1S cells were all treated with CpG and CpG control for 4 and 24 hours. Real-time PCR was then used to detect the pro-survival signature showing that IL-1beta, IL-6 and IL-8 were all upregulated by CpG. We then analysed primary MM and MM cell lines for TLR9 expression by flow cytometry and showed that all samples tested had high levels of cytosolic TLR9 expression. Using TLR9 antagonist (ODN TTAGGG (A151)) we show that primary MM cells and MM cell lines have reduced IL-6 and IL-8 expression and decreased cell proliferation. Finally, U266 and MM1S transduced with TLR9 knockdown lentivirus had reduced engraftment, as measured by bioluminescence, in NSG mice. Here we show that MM release mtDNA in vivo and this can induce a tumour directed proliferative response through the engagement of TLR9. This process is necessary for optimum tumor growth and forms part of the malignant phenotype of MM. Citation Format: Aisha Jibril, Jayna J. Mistry, Prakrit Kumar, Jamie A. Moore, Charlotte Hellmich, Cesar Gomez, Kristian Bowles, Stuart A. Rushworth. Myeloma derived mitochondrial DNA activates TLR9 driven pro-tumoral expansion [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 397.