tbuckley/cabot-search huggingface dataset:
Abstract 1161: Utility of evidence based mesenchymal gene signatures gene expression panel in predicting outcome in stage matched colorectal cancer patients
Authors: Benjamin Johnson, Pankaj Ahluwalia, Chetan Pundkar, Saleh Heneidi, Kimya Jones, Ashis Mondal, Ravindra Kolhe
Journal: Cancer Research (2019)

Abstract Colorectal cancer (CRC) is third deadliest cancer in United States, only behind lung and prostate cancer. Although several therapies are available to treat colorectal cancer but there is need for new prognostic biomarkers to tailor appropriate personalized therapy. Mesenchymal Stem cells (MSCs) are multipotent stem cells which are attracted toward inflammatory sites. In colon cancer, they have been shown to assist in tumor progression. To assess the MSC gene signatures in colon cancer patients, we picked 5 genes from nCounter plexset Mesenchymal Stem cell panel. These genes named: SMAD4, PTK2, GTF3A, CASP3 and HDAC1 were quantified on Nanostring platform. The aim of the study is to quantify these Mesenchymal gene signatures in colorectal cancer patients. Under the IRB approved protocol, a total of 750 colon cancer patients at Medical College of Georgia with 5 years follow-up were initially selected. The patients were stratified on the basis of overall survival in two groups, with higher (&amp;gt; 5 years) and lower survival (&amp;lt;1 year) along with AJCC staging (I to IV), grade, gender and age. A total of 88 patients fitted in our inclusion criteria on the basis of survival duration after diagnosis. The FFPE blocks were acquired from Medical College of Georgia, Augusta. Total RNA was isolated and quantified through Nanodrop method. The statistical analysis of data was performed using student t-test and Pearson correlation. We found PTK2 levels to be high in stage I patients (p = 0.02*). Also, patients with higher survival in stage I had high expression of PTK2 (p=0.04*). Additionally, PTK2 was expressed in higher amounts in lower surviving patient group (0.00*). GTF3 levels were higher in (p = 0.01) stage I. CASP3 showed higher expression in stage III and IV combined. HDAC1 expression was higher in Grade II patients compared to Grade I. HDAC1 expression was also higher in African American population. Citation Format: Benjamin Johnson, Pankaj Ahluwalia, Chetan Pundkar, Saleh Heneidi, Kimya Jones, Ashis Mondal, Ravindra Kolhe. Utility of evidence based mesenchymal gene signatures gene expression panel in predicting outcome in stage matched colorectal cancer patients [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 1161.
50 Portomesenteric venous thrombosis as an indication for intestinal or multivisceral transplantation
Authors: C McKenna, C Dunne, S Yeap, A Butler, N Russell, D Massey, S Middleton, J Woodward, L Sharkey
Journal: Gut (2017)

Introduction  The established indications for Intestinal and Multivisceral (MVT) transplant include IFALD, loss of vascular access and recurrent line sepsis.  Aim  Over the last four years there have been an increasing number of patients with portomesenteric venous thrombosis (PMVT) referred some of whom are not cirrhotic.  Method  Data was collected on all patients who underwent Intestinal or MVT between 2006 and 2013 in Addenbrooke’s hospital, Cambridge and was then divided into pre 2013 and post 2013.  Results  Over the last 8 years there were 73 transplants in 67 patients. Between 2006 and 2013 there were 30 transplants compared to 43 transplants since 2013. Short gut syndrome remains the largest indication for transplant with 16 (53%) transplants between 2006 and 2013 and 22 (51%) transplants from 2013. Prior to 2013 only 3 patients had undergone multivisceral transplant for cirrhosis complicated by PMVT. Since 2013 there have been 8 transplants for cirrhosis complicated by PMVT. Five of these were multivisceral transplants while three underwent a liver-small bowel transplant. In 2016 two patients with PMVT not complicated by cirrhosis underwent isolated Intestinal transplants. One patient required a Whipple procedure but was unable to have this due to PMVT. The other patient had recurrent bleeding with PMVT not amenable to conventional therapy.  Conclusions  While the established indications for Intestinal or MVT remain, there has been an increase in the number of transplants performed for cirrhotic patients with PMVT in which an isolated liver transplant is precluded.
Unintentional injuries and violence among adolescents aged 12–15 years in 68 low-income and middle-income countries: a secondary analysis of data from the Global School-Based Student Health Survey
Authors: Liyuan Han, Dingyun You, Xuping Gao, Shiwei Duan, Guoqing Hu, Haidong Wang, Shiwei Liu, Fangfang Zeng
Journal: The Lancet Child & Adolescent Health (2019)
Abstract 3063: Over expression of protein kinase Nek1 and its modulation by Thioridazine in prostate cancer
Authors: Vibha Singh, Praveen K. Jaiswal, Hari K. Koul, Xiuping Yu, Arrigo Benedetti
Journal: Cancer Research (2019)

Abstract Introduction: Prostate Cancer (PCa) is one of the most common urological malignancies in men in the United States. We have identified NIMA kinase NEK1 through a proteomic approach, that interacts and co-localizes with Tousled Like kinases (TLKs) and has a role in the DDR, upstream of ATR and Chk1. In the present study we have checked the NEK1 activity in PCa patient samples and tested Thioridazine (THD), an anti-psychotic drug and inhibitor of TLKs in inhibiting the activity of NEK1 in human and mice derived prostate cancer cell lines and xenografts derived from LNCaP cells. Material &amp; Methods: We have used tissue microarray (TMA) derived from patient samples and respective benign control. We have used a human prostate cancer cell lines: LNCaP, C4-2, C4-2b, 22Rv1, DU145 and PC3 and normal prostate cell line RWPE-1 as well as TRAMP-C2 cell lines derived from TRAMP mice. Clonogenic activity was measured by colony formation assay. Immunoblotting and immunohistochemistry was done for TLKs, NEK1, p-ATR, p-Chk1, cell cycle and apoptosis related protein in PCa cell lines and tumor tissues from xenografts. Xenografts derived from LNCaP and LNCaP-NEK1 mutant were used in present study. We have used THD (alone) or in combination with the anti-androgen drug bicalutamide in PCa cell lines as well as in xenografts mice model. Results: We found a significant over expression of NEK1 activity as measured by p-NEK1 with PCa samples as compare to benign control (p&amp;lt;0.001) and also correlated with high Gleason score patients. Treatment with THD significantly impaired the colony formation efficiency in human PCa cells in vitro (even of androgen independent lines) as well in TRAMP-C2 cells. THD treatment halts the PCa cells in subG0 phase and affects the cyclin D1, p27, p21 levels and leads to apoptosis with induction of cleaved PARP and Caspase-3 activity. Further p-ATR and p-Chk1 axis was inhibited by treatment with THD and in combination with bicalutamide. Combination therapy of THD and Bicalutamide remarkably inhibited the tumor growth in LNCaP xenografts model while tumor growth in LNCaP xenografts with NEK1 mutant were inhibited by Bicalutamide treatment alone. Following DNA damage, addition of the THD impaired ATR and Chk1 activation, that leads to TLK1&amp;gt;NEK1&amp;gt;ATR&amp;gt;Chk1 pathway activation in PCa. Conclusions: Our data indicated that NEK1 is over-expressed in PCa patients and its activity can be suppressed by treatment with THD (that inhibits its activating kinase, TLK1) in vitro and in vivo. Citation Format: Vibha Singh, Praveen K. Jaiswal, Hari K. Koul, Xiuping Yu, Arrigo Benedetti. Over expression of protein kinase Nek1 and its modulation by Thioridazine in prostate 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 3063.
Timed sequential therapy with high-dose cytarabine and mitoxantrone as an induction regimen for acute myeloid leukemia: An update on adverse events.
Authors: Kristin J. Richardson, Revathi Kollipara, Deborah Ann Katz, Maura Hoyt, Kirstin Gallas, Parameswaran Venugopal, Melissa L. Larson
Journal: Journal of Clinical Oncology (2019)

e18524 Background: Traditionally, patients eligible for induction chemotherapy for AML are treated with the “7+3” regimen, standard doses of infusional cytarabine and an anthracycline, with historical CR rates of 50-60%. We present a retrospective analysis of an alternate induction regimen. Based on timed sequential therapy, it consists of a 2-day treatment with high dose cytarabine, which improves remission rates when used in induction, and dose intensified anthracycline therapy, which improves outcomes while maintaining an acceptable safety profile. Methods: 200 patients were treated from 2010-2015. Patients received 2 doses of cytarabine 2 gm/m 2 (1.5 gm/m 2 age &gt; 70 years) IVPB over 3 hours, 12 hours apart followed by 1 dose of mitoxantrone 30 mg/m 2 IVPB over 1 hour on days 1 and 5. Cytogenetics and adverse events data were collected. IWG remission criteria were used to determine remission status. Results: Median age 57.6 years (range 23-79); 105 (53%) age &gt; 60. 119 male; 81 female. Risk stratification: 12 favorable; 108 intermediate; 80 unfavorable . Overall CR rate (CRR: CR+CRi+CRp) for all patients was 68.5%. CR rates based on risk karyotypes: favorable 100%, intermediate 76.8%, unfavorable 52.5%. Most common G3-4 adverse events: anemia (60% G3, 40% G4), neutropenia (1% G3, 99% G4), thrombocytopenia (0.5% G1, 99.5% G4). 196 patients (98%) had neutropenic fever; 134 (67%) documented infections (100 with G3/4), 62 (31%) neutropenic fever with no source. 52 (26%) experienced bleeding (15 G1, 31 G2, 4 G3, 1 G4, 1 G5). G3/4 renal or hepatic toxicity was rare. No cerebellar toxicity occurred during induction. 30 day mortality 0.5%; 60 day mortality 3%. 62 (31%) patients are still alive; 122 died, 16 lost to follow-up. Conclusions: This two-day induction regimen is an effective treatment for AML with an acceptable safety profile including patients age &gt;60. There is a high response rate, particularly for favorable and intermediate risk karyotypes, with a low rate of early mortality. The high response rates and tolerability with this regimen provides a platform for further clinical trials to enhance outcome by combining with novel targeted therapies for AML.
Abstract 4413: CDK6 overexpression promotes resistance to CDK4/6 inhibitors in breast cancer
Authors: Qing Li, Pedram Razavi, Zhiqiang Li, Arnaud F. Da Cruz Paula, Edi Brogi, Maurizio Scaltriti, Jorge S. Reis-Filho, Sarat Chandarlapaty
Journal: Cancer Research (2019)

Abstract CDK4/6 inhibitors (CDK4/6i) are highly active therapies in estrogen receptor-positive (ER+) breast cancer. Unfortunately, tumor relapse on these agents is frequently encountered in clinical practice with limited data on the biologic mechanisms that can mediate resistance. We utilized cell line models, patient derived xenografts and patient samples to interrogate mechanisms of resistance to CDK4/6 inhibitors. A survey of genomic alterations associated with limited benefit of CDK4/6iidentified several alterations involving the Hippo pathway which could potentially impact CDK6 kinase expression. Immunohistochemistry from these patients revealed increased YAP nuclear translocation and high levels of CDK6 protein specifically in the group of patients with short progression-free survival (PFS) on CDK4/6i. A PDX model of acquired resistance to CDK4/6i also showed that prolonged treatment with CDK4/6i led to a subset of tumors that developed resistance, all of which showed Hippo pathway suppression and CDK6 upregulation. Finally, cell lines models exposed to CDK4/6i showed multiple clones that featured upregulation of CDK6 through suppression of the Hippo pathway or amplification of the CDK6 gene. Identifying CDK6 overexpression as a recurrent feature of CDK4/6i resistant tumors, we next investigated the function(s) of CDK6 in our models. We performed knockdown of CDK6 by shRNA and found its overexpression to be necessary for drug resistance in these models while reinforced CDK6 could restore resistance or confer resistance when overexpressed in naïve cells. Given the close homology of CDK4 and CDK6, we asked whether any differences might exist between CDK4 and CDK6 complexes, performing immunoprecipitation and mass spectrometry (IP-MS) and found CDK6 to bind a distinct partition of proteins from CDK4 including INK4 proteins. In vitro kinase assays revealed that INK4 proteins impaired the ability of CDK4/6i to block CDK6 activity. INK4 proteins were found to cooperate with CDK6 in mediating drug resistance as their knockdown restored drug sensitivity to resistant cells, while INK4 overexpression promoted resistance in CDK6-high cells. Taken together, the data revealed that high levels of a CDK6-INK4 complex to be a recurrent mechanism of resistance to CDK4/6i and suggest novel CDK6 inhibitors as a strategy to overcome resistance. Citation Format: Qing Li, Pedram Razavi, Zhiqiang Li, Arnaud F. Da Cruz Paula, Edi Brogi, Maurizio Scaltriti, Jorge S. Reis-Filho, Sarat Chandarlapaty. CDK6 overexpression promotes resistance to CDK4/6 inhibitors in 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 4413.
A Practical Approach to Low-Dose Aspirin for Primary Prevention
Authors: Kim F. Chiang, Shreya J. Shah, Randall S. Stafford
Journal: JAMA (2019)

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Evaluation of long-term course in children with eosinophilic esophagitis reveals distinct histologic patterns and clinical characteristics
Authors: Cathleen A. Collins, Jacob Palmquist, James A. Proudfoot, Alex Qian, Hannah Wangberg, Emad Khosh-Hemmat, Ranjan Dohil, Seema S. Aceves
Journal: Journal of Allergy and Clinical Immunology (2019)
Prognostic value of serum level of HER-2 extracellular domain (ECD) at diagnosis of HER-2 overexpressed primary breast cancer (BC)
Authors: S. Thureau, F. Clatot, J. Pillé, S. Laberge-Le-Couteulx, O. Rigal, C. Veyret, J. Basuyau, E. Blot
Journal: Journal of Clinical Oncology (2009)

e11508 Background: Serum level of HER2 ECD is an adverse prognostic factor in HER2 over-expressed metastatic BC. We analyzed the prognostic value of serum level of HER2 ECD at the diagnostic of HER2 over-expressed primary BC. Methods: Patients with HER2 over-expressed primary BC treated with adjuvant trastuzumab in 2005 and 2006 were retrospectively analyzed. Serum level of HER2 ECD was assessed on frozen sera collected for CA15–3 measurement before initial treatment. Serum level of HER2 ECD was measured with an Elisa commercial kit (Oncogene Science, Cambridge, MA). The cut-off was 15μg/l as recommended. Results: Pre-treatment serum was available for 65 patients treated for non metastatic HER2 over-expressed BC. Seven patients (11%) had initially an elevated serum level of HER2 ECD (mean 25μg/l, range 15.1–38.9). After an average follow-up of 30 months, 4 patients (57%) out of the 7 with initially elevated serum level of HER2 ECD had a metastatic relapse of BC. In contrast, only 3 patients (5%) out of 58 with initially low serum level of HER2 ECD experienced relapse (p=0.004). Median of serum level of HER2 ECD was 17μg/l in patients who experienced relapse during follow-up whereas it was 8.4μg/l in patients who remained relapse-free (p=0.03). Univariate analysis showed that only elevated serum level of HER2 ECD and absence of hormone receptors expression were linked with metastatic relapse (p=0.0004 and p=0.02, respectively). Multivariate analysis showed that elevated serum level of HER2 ECD and absence of hormone receptors expression were linked with metastatic relapse (p=0.02 and p=0.04, respectively). Survival curves showed also that elevated serum level of HER2 ECD was related with a worse disease-free survival (p=0.0004). Conclusions: In this small series, elevated serum level of HER2 ECD was an adverse prognostic factor for HER2 over- expressed non metastatic primary BC. It was also a predictive factor for early failure of adjuvant treatment with trastuzumab. No significant financial relationships to disclose.
Abstract 3428: The landscape of germline mutations in Chinese patients with solid tumor
Authors: Juming Li, Yongzhong Wei, Xiaoqian Chen, Angen Liu, Junping Shi, Jinwei Hu, Ming Yao
Journal: Cancer Research (2019)

Abstract Background: Germline mutations harbored by cancer patients can be passed from parents on to offspring, which increases the tumor risk in offspring as well. Therefore, investigating the germline mutations in cancer patients has important clinical implications for treatment selection and familial cancer risk assessment. Methods: FFPE tumor and matched blood samples were collected from 3645 Chinese patients with solid tumors for next generation sequencing analysis. The NGS panel targeted 450 cancer genes, 47 of these genes were tumor inheritance susceptibility genes that were mentioned by NCCN guidelines. Genomic alterations including single nucleotide variations (SNV), short and long insertions/deletions (Indel), copy number variations (CNV) and gene rearrangements and fusions were assessed. Results:Germline mutations were identified in 241 of 3645 Chinese patients with solid tumor (6.6%). The patients with germline mutations included 137 males and 104 females with a median age of 54. Tumor types with higher frequency of germline mutations were: ovarian cancer (22.0%), breast cancer (13.4%), pancreatic cancer (9.9%), cholangiocarcinoma (8.6%), small intestinal cancer (8.6%), colorectal cancer (8.6%), soft tissue sarcoma (6.3%), uterine Cancer (5.9%), gastric cancer (5.8%) and bone cancer (5.1%). The distribution of germline mutations were 14.1% in BRCA1, 13.7% in BRCA2, 10.8% in SPINK1, 9.1% in ATM, 5.8% in RAD50, 4.6% in PALB2, 3.7% in BARD1 and FANCA, 3.3% in MSH6 and 2.9% in MLH1, respectively. The types of germline mutations were SNVs and short Indels, but no long Indels, CNV, gene rearrangements or fusions were observed. The percentage of patients with a family history was 27.4%, without family history was 52.7%, unknown was 19.9%. Conclusions:Our data revealed that germline mutations occurred in 6.6% of Chinese solid tumor patients. Gynecological tumor, gastrointestinal tumor, bone and soft tissue tumor are the most common types of tumors that harbored germline mutations. The most common mutant genes were HRD (64.5%) and MMR (10.5%) related genes. More than 50% patients with germline mutations had no family history, which suggests the importance of germline mutations detection for all solid tumor patients to verify if there is a risk of genetic transmission to offspring. NGS based panel sequencing showed the advantage of identifying solid tumor patients with germline mutations, and provided the information of familial cancer risk assessment and guided the precise cancer treatment options. Citation Format: Juming Li, Yongzhong Wei, Xiaoqian Chen, Angen Liu, Junping Shi, Jinwei Hu, Ming Yao. The landscape of germline mutations in Chinese patients with solid tumor [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 3428.
Abstract 669: Dynamic modeling of responses to PDL-1 inhibitors in non-small cell lung cancer: implications for precision combination therapy
Authors: Iman Tavassoly
Journal: Cancer Research (2019)

Abstract Immunotherapy by immune checkpoint blockade has had a promising impact on the treatment of Non-Small Cell Lung Cancer (NSCLC). Although single and combination therapy with checkpoint inhibitors such as PDL-1 inhibitors have been proved to be effective in making the survival of patients with NSCLC longer, but there is always a population of patients which shows resistance to these therapeutic modalities. The source of resistance emerges from signaling pathways and regulatory systems in tumors and the immune system, but the dynamics among tumor components, T cells, and tumor microenvironment contribute in this process as well. To understand the complex system of these interactions, a mathematical model of these pathways and interactions are presented using Ordinary Differential Equations (ODEs). The specific characteristics of NSCLC tumors including metabolic reprogramming have been considered in this model. The model is capable of decoding patient-to-patient variabilities regarding responses to PDL-1 inhibitors, and parameter-sensitivity analysis shows the vulnerable biomarkers to be targeted by combination therapy to give better results in killing the tumor cells. The model can be integrated with PK/PD models to provide an in-silico platform for investigating the therapeutic responses in NSCLC for precision oncology. Note: This abstract was not presented at the meeting. Citation Format: Iman Tavassoly. Dynamic modeling of responses to PDL-1 inhibitors in non-small cell lung cancer: implications for precision combination 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 669.