tbuckley/cabot-search huggingface dataset:
Abstract 2823: Sample storage conditions alter microbiome profiles - its potential relevance for cancer patients undergoing fecal microbial transplants
Authors: Samir V. Jenkins, Kieng B. Vang, Allen Gies, Robert J. Griffin, Se-Ran Jun, Intawat Nookaew, Ruud Petrus Dings
Journal: Cancer Research (2019)

Abstract Background and Objective: Fecal microbiota transplantation helps restore beneficial bacteria in cancer patients after intense antibiotics administration. Here we investigated the influence of different stabilization and storage strategies on the quality and composition of the fecal microbial community. Methods: Same-day isolated murine DNA was compared to samples stored for one month in air at ambient temperature, with or without preservative buffers (i.e. EDTA and lysis buffer), different temperatures (i.e. 4°C, -20°C, and -80°C), and hypoxic conditions. Results: Only storage in lysis buffer significantly reduced DNA content, yet without integrity loss. Storage in EDTA affected alpha diversity the most, which was also reflected in cluster separation. Distinct changes were also seen in the phyla and bacterial species abundance per storage strategy. Metabolic function analysis showed 22 pathways not significantly affected by storage conditions, whereas the tyrosine metabolism pathway was significantly changed in all strategies except by EDTA. Conclusions: Overall, each long-term storage strategy introduced a unique post-collection bias, which is important to take into account when interpreting data. Funded by COBRE P20GM103625. Citation Format: Samir V. Jenkins, Kieng B. Vang, Allen Gies, Robert J. Griffin, Se-Ran Jun, Intawat Nookaew, Ruud Petrus Dings. Sample storage conditions alter microbiome profiles - its potential relevance for cancer patients undergoing fecal microbial transplants [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 2823.
Abstract 4592: CD44v6 promotes aggressive phenotypes mediated through activating EGFR pathway via COL11A1/PTPRG axis
Authors: Joanne Jeou-Yuan Chen, Jing-You Guo
Journal: Cancer Research (2019)

Abstract Cell surface receptor CD44, an important player in stem cells and cancer biology, is expressed in multiple isoforms via alternative splicing. CD44 isoforms containing variant exon 6 (CD44v6)-encoded sequences are frequently overexpressed in human tumors. In many cancers, CD44v6 serves as a marker of cancer stem cells and accounts for the metastatic susceptibility of the tumors. CD44v6 predicts for poor prognosis in several cancers. However, the actions and underlying mechanisms related to CD44v6-mediated malignant phenotypes remain to be established. In this study, we performed cDNA microarray and Gene Set Enrichment Analysis (GSEA) of the genome-wide expression profiles in cells ectopically expressing the standard form CD44 (CD44s) or CD44v6, and showed that pathways related to cell migration, invasion and metastasis are enriched in CD44v6-expressing cells which are in contrast to cell growth regulatory pathways identified in CD44s cells. In support, overexpression of CD44v6 promoted cell migration and invasion. In silico analyses of genes preferentially regulated in CD44v6-expressing cells against a multi-cancer metastasis-associated gene expression signature dataset and the gene set indicative of embryonic stem cell identity, Collagen XIA1 (COL11A1) was identified as the top candidate in CD44v6-upregulated genes. COL11A1, encoding the α1 chain of the minor fibrillar collagen XI, has been found to be highly expressed in a variety of cancers, and is implicated in the processes of metastasis, angiogenesis, and drug resistance. COL11A1 expression is correlated with cancer aggressiveness and progression, and lymph node metastasis. Using gain- and loss-of-function approaches, we further demonstrated that CD44v6 drives tumor cell invasion in part mediated through the induction of metastasis-related gene COL11A1. Upon examining the involvement of receptor tyrosine kinase pathways, we showed that EGFR is constitutively activated in CD44v6-expressing cells, and that COL11A1 supports CD44v6-mediated EGFR activation via suppressing the expression of PTPRG, an EGFR negative regulator. Our data thus suggest that CD44v6 promotes aggressive phenotypes mediated through activating EGFR pathway via COL11A1/PTPRG axis. Citation Format: Joanne Jeou-Yuan Chen, Jing-You Guo. CD44v6 promotes aggressive phenotypes mediated through activating EGFR pathway via COL11A1/PTPRG axis [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 4592.
Abstract 11269: Uridine Triphosphate More Accurately Estimates Fractional Flow Reserve in Humans
Authors: Jaya B Rosenmeier, Jakob Raunsøe, Søren Galatius, Morten Zaar, Jan S Jensen
Journal: Circulation (2011)

Background_ Fractional flow reserve (FFR) is a highly recommended diagnostic method to guide stent treatment. Adenosine (ADO) is the preferred pharmacologic vasodilator agent for the measurement of...
Abstract 1891: Oncogenic <i>MDM2</i>-containing exosomes promote pre-metastatic niche establishment
Authors: Lucia Casadei, Federica Calore, Ameya Deshmukh, Abeba Zewdu, Danielle A. Braggio, Paolo Fadda, Martin Wabitsch, Gonzalo Lopez, Jennifer Leight, Dina Lev, Carlo M. Croce, Raphael E. Pollock
Journal: Cancer Research (2019)

Abstract Extracellular vesicles (EVs) have an important role in the communication between cells for their ability to transfer proteins and other biologically active molecules. EVs have been also described to have unique functions during pre-metastatic niche establishment and maintenance. MDM2 oncoprotein is the best-characterized cellular antagonist of p53 and its amplification is one of the most known mechanisms for tumor development. MDM2 amplification occurs in more than forty different types of malignancies and in 100% of well-differentiated and dedifferentiated liposarcoma (DDLPS). Retroperitoneal DDLPS is especially concerning given its propensity for multifocal local and distant recurrence, accounting for an overall survival rate of 10% at 10 years. Here, we show the presence of MDM2 in tumor EVs and specifically in both DDLPS cell line-derived EVs and patient-serum EVs. We also show the ability of MDM2-cargo to be transferred to recipient preadipocytes. Furthermore, we also demonstrated that this transfer is able to promote a pre-metastatic niche establishment in the DDLPS tumor microenvironment fat bearing areas, inducing: (I) tumor associated phenotype such as enhanced proliferation and migration, in the recipient preadipocytes, by downregulation of MDM2 downstream pathway; (II) pro-inflammatory phenotype through the release of pro-inflammatory cytokines such as IL-8; (III) release of active metalloproteinases such as MMP2 which is crucial for the invasiveness of many disseminating tumors. In conclusion here we report the presence of MDM2, in the patient circulation; importantly showing that MDM2 triggers the release of active MMP-2, we also propose a possible mechanism for pre-metastatic niche establishment and DDLPS multifocal loco-regional recurrence. Citation Format: Lucia Casadei, Federica Calore, Ameya Deshmukh, Abeba Zewdu, Danielle A. Braggio, Paolo Fadda, Martin Wabitsch, Gonzalo Lopez, Jennifer Leight, Dina Lev, Carlo M. Croce, Raphael E. Pollock. Oncogenic MDM2-containing exosomes promote pre-metastatic niche establishment [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 1891.
Abstract 15471: Development and Validation of a Mortality Risk Prediction Model Using Global Longitudinal Strain in Patients With Acute Heart Failure
Authors: In-Chang Hwang, Goo-Yeong Cho, Hong-Mi Choi, Yeonyee E Yoon, Jin Joo Park, Jun-Bean Park, Jae-Hyeong Park
Journal: Circulation (2018)

Introduction: Most of the mortality risk prediction models developed in patients with acute heart failure (AHF) do not include left ventricular ejection fraction (LVEF), the most widely used LV fun...
Doxycycline as a preventive treatment of skin toxicity in patients with metastatic colorectal cancer treated with an anti-EGFR and chemotherapy: interim analysis to evaluate skin toxicities
Authors: P. Ramirez Daffos, B. González-Astorga, E. Jiménez, S. Rubiales, M. Bolaños, E. Ceballos, J. Rodríguez, J. Reina
Journal: Annals of Oncology (2019)
Anti-CD134 (OX-40) monoclonal antibody therapy in combination with irradiation results in a CD8+ T cell-dependent therapeutic immunity to lung cancer
Authors: Hiroshi Yokouchi, Koichi Yamazaki, Eiki Kikuchi, Naofumi Shinagawa, Fumihiro Honmura, Satoshi Oizumi, Hirotoshi Dosaka-Akita, Masaharu Nishimura
Journal: Cancer Research (2006)

646  The role of radiotherapy as a treatment of localized cancer is well established. However, it has been documented that ionizing radiation can render additional negative impact on immune function of cancer hosts. To overcome this problem, combination strategies using irradiation and various immunological modalities have been tried. On the other hand, recent studies have demonstrated that deliberate ligation of CD134 (OX-40), a T-cell co-stimulatory molecule, enhances anticancer immunity in tumor-bearing hosts. Here, we designed the treatment protocol that consisted of intratumoral administration of agonistic anti-CD134 monoclonal antibody (mAb) and local irradiation, and examined its therapeutic effect. Ovalbumin (OVA)-expressing Lewis lung carcinomas (LLC-OVA) were inoculated intradermally into C57BL/6 mice. When the tumors diameter reached 7-9 mm on day 5, the tumor-bearing mice were locally irradiated by Co-60 with a single dose of 20Gy and intratumorally injected with anti-CD134 mAb. Five days after the treatment, the tumor-bearing mice were further treated with anti-CD134 mAb every 2 days for 3 times. The combination therapy provided greater efficacy than either single treatments against well-established lung tumors and prolonged survival of the treated mice. OVA-MHC tetramer+ CD8+ T cells were detected in draining lymph nodes obtained from mice treated with combination therapy, and the strong antigen-specific cytotoxicity was confirmed by 51Cr-release assay. Such augmented induction of CTL was not detected in other single treatments. In vivo depletion studies suggested that the therapeutic immunity was mainly CD8+ T cell-dependent. Moreover, the combination therapy induced durable tumor immunity verified by tumor-rechallenge model. These results demonstrated that combining anti-CD134 mAb therapy with irradiation will become a powerful new approach to the management of lung cancer.
Abstract 1822: A mitochondrial pfeRNA associates with Far Upstream Element Binding Protein 1 (FUBP1) to promote lung adenocarcinoma tumorigenesis
Authors: Nadege T. Fackche, Yuping Mei, Tomoaki Ito, Matthew Garner, Malcolm Brock
Journal: Cancer Research (2019)

Abstract Background: Protein Functional Effector RNAs (pfeRNAs) are novel small non-coding RNA molecules with great prognostic and diagnostic potential for NSCLC. They feature direct binding to, and regulation of phosphorylated proteins involved in lung cancer tumorigenesis pathways. Using next-generation sncRNA deep sequencing, we have identified a mitochondrial pfeRNA (mtpfeRNA) that could play a key role in tumorigenesis and cancer development of lung adenocarcinoma (ADC). Methods: Using next-generation sncRNA deep sequencing, we analysed ADC and human normal bronchial epithelial (HBE) cell lines; and biospecimens including matched biopsy-proven ADC tissue, histologically normal adjacent lung tissue, benign lymph node, and (iv) malignant lymph nodes; Identifying a mitochondrial pfeRNA that could play critical roles in lung cancer tumorigenesis. Next, we examined the impact of this mtpfeRNA on lung ADC cell line viability. Liquid chromatography-tandem mass spectrometry analysis and reverse immunoprecipitation assays were used to identify critical interacting protein partners known to drive tumorigenesis. We further correlated our findings to clinical staging of ADC tumor cores by IHC staining. Results: The expression levels of mtpfeRNA were upregulated in ADC compared to that of squamous cell carcinoma and normal human bronchial epithelial cells. We also noted that blocking the upregulated mtpfeRNA resulted in significant decreases in cell viability in ADC cells. Next, we determined that mtpfeRNA binds to Far Upstream Element Binding Protein 1 (FUBP1). Furthermore, we confirmed that both mtpfeRNA and FUBP1 expression correlated to stages and lymph node metastasis in patients with ADC. Conclusion: We revealed novel functions of a mtpfeRNA in ADC, providing potential molecules for developing diagnostics and targeted therapy to improve the dismal survival rate of patients with ADC. Citation Format: Nadege T. Fackche, Yuping Mei, Tomoaki Ito, Matthew Garner, Malcolm Brock. A mitochondrial pfeRNA associates with Far Upstream Element Binding Protein 1 (FUBP1) to promote lung adenocarcinoma tumorigenesis [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 1822.
Annual vs Biennial Screening: Diagnostic Accuracy Among Concurrent Cohorts Within the Ontario Breast Screening Program
Authors: Anna M Chiarelli, Kristina M Blackmore, Lucia Mirea, Susan J Done, Vicky Majpruz, Ashini Weerasinghe, Linda Rabeneck, Derek Muradali
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Background The Ontario Breast Screening Program recommends annual mammography to women age 50–74 years at increased risk because of family history of breast or ovarian cancer or personal history of ovarian cancer or mammographic density 75% or greater. Few studies have examined the diagnostic accuracy of recommendations based on risk factors and included screen film as well as digital mammography. Methods A retrospective design identified concurrent cohorts of women age 50–74 years screened annually or biennially with digital mammography only between 2011 and 2014 and followed until 2016 or breast cancer diagnosis. Diagnostic accuracy measures were compared between women screened annually because of first-degree relative of breast or ovarian cancer or personal history of ovarian cancer (n = 67 795 women), mammographic density 75% or greater (n = 51 956), or both (n = 3758) and those screened biennially (n = 526 815). The association between recommendation and sensitivity and specificity was assessed using generalized estimating equation models. All P values are two-sided. Results For annual screening because of family or personal history vs biennial, sensitivity was statistically significantly higher (81.7% vs 70.6%; OR = 1.86, 95% CI = 1.48 to 2.34), particularly for invasive cancers and postmenopausal women. Although there was no statistically significant difference in sensitivity for annual screening for mammographic density 75% or greater, specificity was statistically significantly lower (91.3%; OR = 0.87, 95% CI = 0.80 to 0.96) vs biennial (92.3%), particularly for women age 50–59 years. Conclusion Compared with biennial screening, annual screening improved detection for women with a family or personal history of breast and/or ovarian cancer, supporting screening that is more frequent. The benefit for annual screening for women with higher mammographic density must be weighed against possible harms of increased false positives.
TRIB3 Stabilizes High TWIST1 Expression to Promote Rapid APL Progression and ATRA Resistance
Authors: Jian Lin, Wu Zhang, Li-Ting Niu, Yong-Mei Zhu, Xiang-Qin Weng, Yan Sheng, Jiang Zhu, Jie Xu
Journal: Clinical Cancer Research (2019)

The resistance to differentiation therapy and early death caused by fatal bleeding endangers the health of a significant proportion of patients with acute promyelocytic leukemia (APL). This study aims to investigate the molecular mechanisms of all-trans retinoic acid (ATRA) resistance and uncover new potential therapeutic strategies to block the rapid progression of early death.The important role of TWIST1 in APL leukemogenesis was first determined by gain- and loss-of-function assays. We then performed in vivo and in vitro experiments to explore the interaction of TWIST1 and TRIB3 and develop a potential peptide-initiated therapeutic opportunity to protect against early death and induction therapy resistance in patients with APL.We found that the epithelial-mesenchymal transition (EMT)-inducing transcription factor TWIST1 is highly expressed in APL cells and is critical for leukemic cell survival. TWIST1 and TRIB3 were highly coexpressed in APL cells compared with other subtypes of acute myeloid leukemia cells. We subsequently demonstrated that TRIB3 could bind to the WR domain of TWIST1 and contribute to its stabilization by inhibiting its ubiquitination. TRIB3 depletion promoting TWIST1 degradation reverses resistance to induction therapy and improves sensitivity to ATRA. On the basis of a detailed functional screen of synthetic peptides, we discovered a peptide analogous to the TWIST1 WR domain that specifically represses APL cell survival by disrupting the TRIB3/TWIST1 interaction.Our data not only define the essential role of TWIST1 as an EMT-TF in patients with APL but also suggest that disrupting the TRIB3/TWIST1 interaction reverses induction therapy resistance and blocks rapid progression of APL early death.See related commentary by Peeke and Gritsman, p. 6018.
Machine Learning Approach to Inpatient Violence Risk Assessment Using Routinely Collected Clinical Notes in Electronic Health Records
Authors: Vincent Menger, Marco Spruit, Roel van Est, Eline Nap, Floor Scheepers
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Inpatient violence remains a significant problem despite existing risk assessment methods. The lack of robustness and the high degree of effort needed to use current methods might be mitigated by using routinely registered clinical notes. <h3>Objective</h3> To develop and validate a multivariable prediction model for assessing inpatient violence risk based on machine learning techniques applied to clinical notes written in patients' electronic health records. <h3>Design, Setting, and Participants</h3> This prognostic study used retrospective clinical notes registered in electronic health records during admission at 2 independent psychiatric health care institutions in the Netherlands. No exclusion criteria for individual patients were defined. At site 1, all adults admitted between January 2013 and August 2018 were included, and at site 2 all adults admitted to general psychiatric wards between June 2016 and August 2018 were included. Data were analyzed between September 2018 and February 2019. <h3>Main Outcomes and Measures</h3> Predictive validity and generalizability of prognostic models measured using area under the curve (AUC). <h3>Results</h3> Clinical notes recorded during a total of 3189 admissions of 2209 unique individuals at site 1 (mean [SD] age, 34.0 [16.6] years; 1536 [48.2%] male) and 3253 admissions of 1919 unique individuals at site 2 (mean [SD] age, 45.9 [16.6] years; 2097 [64.5%] male) were analyzed. Violent outcome was determined using the Staff Observation Aggression Scale–Revised. Nested cross-validation was used to train and evaluate models that assess violence risk during the first 4 weeks of admission based on clinical notes available after 24 hours. The predictive validity of models was measured at site 1 (AUC = 0.797; 95% CI, 0.771-0.822) and site 2 (AUC = 0.764; 95% CI, 0.732-0.797). The validation of pretrained models in the other site resulted in AUCs of 0.722 (95% CI, 0.690-0.753) at site 1 and 0.643 (95% CI, 0.610-0.675) at site 2; the difference in AUCs between the internally trained model and the model trained on other-site data was significant at site 1 (AUC difference = 0.075; 95% CI, 0.045-0.105;<i>P</i> &lt; .001) and site 2 (AUC difference = 0.121; 95% CI, 0.085-0.156;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Internally validated predictions resulted in AUC values with good predictive validity, suggesting that automatic violence risk assessment using routinely registered clinical notes is possible. The validation of trained models using data from other sites corroborates previous findings that violence risk assessment generalizes modestly to different populations.
Plug-and-Play Protein Modification Using Homology-Independent Universal Genome Engineering
Authors: Yudong Gao, Erin Hisey, Tyler W.A. Bradshaw, Eda Erata, Walter E. Brown, Jamie L. Courtland, Akiyoshi Uezu, Yu Xiang, Yarui Diao, Scott H. Soderling
Journal: Neuron (2019)
Abstract 4611: Identifying drivers of mammary tumorigenesis &amp; elucidating the mechanisms of cancer initiation in DNA replication defective Chaos3 mice
Authors: Marquita Winters, John Schimenti
Journal: Cancer Research (2019)

Abstract Distinguishing commonly deleted genes as drivers or passengers of human cancers are key to delineating mechanisms of tumor initiation. The “Chaos3” mouse model of spontaneous breast cancer carries a missense mutation in a gene called Mcm4 (minichromosome maintenance 4), causing destabilization of the MCM2-7 replicative helicase, which in turn causes elevated genomic instability. Approximately 80% of female mice homozygous for this mutation in the C3HeB/FeJ strain background develop mammary tumors with an average latency of 12 months. Genomic analysis of these tumors revealed a recurrent subset of genes with copy number alterations such as Arid1a and Nf1. This project aims to: 1) test whether the genes Arid1a and Nf1 act as mammary tumor drivers in the Chaos3 breast cancer model; 2) understand the genome-wide effects of Arid1a loss in mammary tumorigenesis; 3) identifying potential therapeutic targets for Arid1a-deficient mammary tumors; and 4) unravel the mechanism by which destabilization of MCM2-7 replicative helicase leads to cancer onset. To achieve these aims, several experiments such as conditional mutagenesis, CUTandRUN, RNA-seq, and replication timing profiling were conducted to address my aims. Preliminary data indicates that heterozygous loss of Arid1ain Chaos3 mammary tumors produces a distinct transcriptional profile compared to mammary tumors without Arid1a deletion. Additionally, Chaos3 primary cells have markedly altered replication timing patterns in certain regions of the genome that might explain increased susceptibility to mutations. My experiments can validate new candidates like Arid1a as a driver of sporadic breast cancer in humans. In addition, these studies will not only lend insight into how key tumor suppressors are deleted in the Chaos3 model, but also potentially reveal features of genomic regions that are particularly susceptible to genetic or environmental perturbations to DNA replication. The Chaos3 sporadic breast cancer mouse model mimics sporadic human luminal breast cancer and can be used as a tool to better understand the biology and genetics of a common disease that plagues women worldwide. Citation Format: Marquita Winters, John Schimenti. Identifying drivers of mammary tumorigenesis &amp; elucidating the mechanisms of cancer initiation in DNA replication defective Chaos3 mice [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 4611.