tbuckley/cabot-search huggingface dataset:
A Controlled Trial Comparing Vidarabine with Acyclovir in Neonatal Herpes Simplex Virus Infection
Authors: Richard Whitley, Ann Arvin, Charles Prober, Sandra Burchett, Lawrence Corey, Dwight Powell, Stanley Plotkin, Stuart Starr, Charles Alford, James Connor, Richard Jacobs, Andre Nahmias, Seng-Jaw Soong
Journal: New England Journal of Medicine (1991)

Despite the use of vidarabine, herpes simplex virus (HSV) infection in neonates continues to be a disease of high morbidity and mortality. We undertook a controlled trial comparing vidarabine with acyclovir for the treatment of neonatal HSV infection.
[Reply to letters to the editor] H63D is an haemochromatosis associated allele
Authors: M. Worwood, D.J. Bowen, A.K. Burnett, H.A. Jackson, S. Lawless, R. Raha-Chowdhury, J.D. Shearman, D.F. Wallace, J.S. Dooley, J. Partridge, A.P. Walker, A. Bomford, W.M.C. Rosenberg, A.T. Merryweather-Clarke, K.J.H. Robson, J.J. Pointon
Journal: Gut (1998)

Free to read on publisher website We thank Fairbanks et al for their comments and agree with their conclusion that the H63D mutation may be associated with iron accumulation. This is supported by the recent finding that the HFE protein with the H63D mutation does not reduce the affinity of transferrin for its receptor in the same way as the wild type protein. 1 However, we have reservations about combining data from various groups of patients and controls where the frequency of the mutations in the general population varies greatly...
Abstract 252: Tumor treating fields (TTFields) affect blood brain barrier (BBB) integrity <i>in vitro</i> and <i>in vivo</i>
Authors: Almuth F. Kessler, Clara M. Schaeffer, Malgorzata Burek, Ursula Ruschig, Catherine Tempel-Brami, Tali Voloshin, Moshe Giladi, Ellaine Salvador, Ralf-Ingo Ernestus, Mario Löhr, Carola Förster, Carsten Hagemann
Journal: Cancer Research (2019)

Abstract Background: The blood-brain barrier (BBB) may impede application of drugs to the brain for treatment of malignant brain tumors, in particular glioblastoma multiforme (GBM). Alternating electric fields with intermediate frequency and low intensity, called Tumor Treating Fields (TTFields), are an established novel adjuvant treatment modality for GBM. Here, the effect of TTFields on BBB permeability is analyzed. Material and Methods: After TTFields treatment with a frequency of 100-300 kHz for up to 72 h, immortalized murine brain capillary endothelial cells (cerebEND) grown on cover slips and transwell inserts were stained for immunofluorescent assessment of the tight junction proteins Claudin-5 and ZO-1. Transendothelial electrical resistance (TEER) was applied to investigate BBB integrity. Moreover, BBB permeability was determined by fluorescein isothiocyanate (FITC) staining followed by flow cytometry. For in vivo analysis, the increase in vessel permeability was quantified by utilizing i.v. injected Evans Blue (EB) in rats during TTFields application to the brain (100 kHz, 72 h). Results: The BBB was disturbed by treatment with TTFields as tight junction proteins were delocalized from the cell boundaries to the cytoplasm with maximal effects at 100 kHz. TTFields application significantly reduced the BBB integrity by 65% and significantly increased the BBB permeability for 4 kDa large molecules. Initial recovery of the cell morphology was observed 48 h post-treatment and a complete recovery could be detected after 96 h, indicating a reversibility of the TTFields effect on the BBB. Average accumulation of EB in the rat brain was significantly increased by TTFields application to the rats head. Conclusion: In the future, TTFields could be utilized to deliver drugs generally unable to cross the BBB to the central nervous system as TTFields at a frequency of 100 kHz are potentially able to disrupt the BBB. The data presented on in vitro and in vivo application of TTFields to permeabilize the BBB may be a rationale for a phase I clinical trial and clinical application in the future. Citation Format: Almuth F. Kessler, Clara M. Schaeffer, Malgorzata Burek, Ursula Ruschig, Catherine Tempel-Brami, Tali Voloshin, Moshe Giladi, Ellaine Salvador, Ralf-Ingo Ernestus, Mario Löhr, Carola Förster, Carsten Hagemann. Tumor treating fields (TTFields) affect blood brain barrier (BBB) integrity in vitro and in vivo [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 252.
Abstract 2010: SKI-G-801, an AXL kinase inhibitor, blocks metastasis and induces anti-tumor immune responses in various syngeneic cancer models
Authors: Chun-Feng Xin, Sung Eun Kim, Kyoung-Ho Pyo, Ha Ni Jo, Jae Seok Cho, Jae Hwan Kim, Wongeun Lee, Hee Kyu Lee, Jung-Ho Kim, Ho-Juhn Song, Jong Sung Koh, Byoung Chul Cho
Journal: Cancer Research (2019)

Abstract Introduction: Aberrant AXL expression plays a critical role in cancer cell migration, metastasis and drug resistance. Researchers have revealed that AXL signaling is also over expressed on cells associated with tumor microenvironment. These findings highlight AXL as an attractive drug candidate for targeting tumor evasion and metastasis. Here we present SKI-G-801, a small molecule inhibitor that targets phosphorylation of AXL (IC50 = 20 nM) and its downstream signals. Methods: Inhibitory effects of SKI-G-801 on cancer viability (MTT and colony formation assay), invasion and migration (trans-well invasion assay) were examined in AXL high-expressing lung cancer cells in vitro. LLC2 lung and 4T1 breast cancer bearing mouse models were established. in addition, C57BL/6 mice were injected intravenously with B16F10 melanoma cells to establish lung metastasis model. Mice were administrated with 30 mg/kg of SKI-G-801 orally before (metastasis model) or after (syngeneic model) tumor injection. To elucidate the involvement of AXL inhibitor on tumor microenvironment, the population of T cells and myeloid cells was analyzed by flow cytometry from the LLC2 tumor. Results: Treatment of SKI-G-801 showed strong inhibition of cancer migration and invasion, when its direct killing effect on cancer cells was modest. These results were reproduced in vivo test that pretreatment of SKI-G-801 significantly reduced metastatic burden in B16F10 model (p &amp;lt; 0.05). LLC2 and 4T1 tumors were decreased in SKI-G-801 treatment group (p &amp;lt; 0.05), but not in anthemic nude mice. CD3+CD8+ T cell population and memory Tc cells were increased in SKI- G-801 treatment group (p &amp;lt; 0.05). Especially, granzyme B+ Tc and gp70+ tumor specific Tc were increased (p &amp;lt; 0.05). SKI-G-801 increase the helper T cell population; CD3+CD4+ (p &amp;lt; 0.05), and CD44+ memory Th cells (p &amp;lt; 0.01). Conclusion: SKI-G-801 demonstrates great potential in anti-cancer activity though immune responses. The anti-cancer effects lead to a reversal of the metastatic phenotype in animal model. Our results suggest that SKI-G-801 is a promising drug for prevention against metastatic cancer. Citation Format: Chun-Feng Xin, Sung Eun Kim, Kyoung-Ho Pyo, Ha Ni Jo, Jae Seok Cho, Jae Hwan Kim, Wongeun Lee, Hee Kyu Lee, Jung-Ho Kim, Ho-Juhn Song, Jong Sung Koh, Byoung Chul Cho. SKI-G-801, an AXL kinase inhibitor, blocks metastasis and induces anti-tumor immune responses in various syngeneic cancer models [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 2010.
Abstract 671: Evaluation of machine learning tools for cancer drug response prediction with genomic profile data and drug response data from PDX model studies
Authors: Henry Gu, Jingjing Jiang
Journal: Cancer Research (2019)

Abstract Cancer are diseases caused by genomic aberrations which lead to abnormal cell proliferation and metastasis. Cancer treatment based on cancer mutation profiles are the focus of research and development of cancer precision medicine. Currently only a small percentage of cancer patients’ genomic information are associated with known drug responses, while others lack known cancer drivers or have cancer drivers that are not druggable. Machine learning (ML) tools have been developed recently for cancer biomarker discovery and cancer drug response prediction. However, due to a lack of sufficient amount of high quality drug response data, especially data for new drugs, the application of ML tools in this area is still in its early stage. In this study, we compared the performance of about a dozen ML methods, such as random forest classifiers, logistic regression classifiers, and support vector machines (SVM), trained on data of about 2300 treatment responses to average 12 different cancer drugs in 98 NSCLC, 55 gastric and 38 HCC PDX models with WES, CNV and RNA-seq information. Data preparation including genomic profile data selection, dimensionality feature reduction and processing was performed with considerations of known cancer gene functions, signal pathways, and pharmacodynamics information. Each dataset was randomly divided into training dataset and test dataset for ML algorithm training and evaluation. Performance of ML algorithms in testing was measured by their drug response prediction accuracy. Different regularization methods, such as LASSO and Elastic Net, were also evaluated in order to improve classification accuracy and identify relevant biomarker features. From comparing results from different algorithms or from the same algorithms but with differently prepared datasets, it seems that selection of functionally unknown gene aberrations for data preparation plays a significant role in prediction accuracy. Increasing dataset number or different data selection in different cancer types can improve prediction accuracy. Citation Format: Henry Gu, Jingjing Jiang. Evaluation of machine learning tools for cancer drug response prediction with genomic profile data and drug response data from PDX model studies [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 671.
Abstract 2296: Validation of a novel one-step digital PCR platform with precision circulating cell-free DNA standards
Authors: Megan E. Dueck, Robert Lin, Andrew Anfora, Andrew Zayac, Steve Gallagher, Omo Clement, Dana Ruminsky-Lowe, Paul Hung
Journal: Cancer Research (2019)

Abstract In this study we demonstrate precision quantification of Seraseq ctDNA EGFR T790M mutation mix at AF0.1% (mutant/wild-type ratio) using a novel one-step digital PCR (dPCR) platform. This novel yet simple workflow has the potential to make cancer liquid biopsy a clinical application. EGFR is an important drug target for the treatment of non-small cell lung carcinoma (NSCLC). During the treatment of NSCLC with tyrosine kinase inhibitors (TKIs), there is typically a significant response initially, followed by a secondary mutation as the carcinoma develops resistance. Early detection of cancer can better inform patient treatment and guide drug selection. One key EGFR mutation that leads to TKI resistance is the T790M mutation. Only a few clinical assays have been approved as companion diagnostics in patient biopsies (FFPE or plasma), while a larger number of laboratory developed assays (LDTs) under CLIA/CAP guidance are finding routine use in cancer disease diagnosis or treatment monitoring. Herein we describe the validation of a novel, fully integrated dPCR platform for the detection and absolute quantification of EGFR T790M. The integrated dPCR platform consists of a patented micro-molded plastic consumable and a fully-integrated instrument combining consumable sample loading, thermal cycling and 5-color fluorescence detection. The platform was designed to have a simplified, single-step workflow and provide results in less than one hour. In addition, developments in the micro-molded plastic consumable allow for near-zero dead volume. The novel integrated instrument is 100% dry and contamination-free, making it attractive for the transition to clinical applications. Seraseq ctDNA EGFR T790M mutation mix AF1% and AF0.1% reference standards in combination with a commercially available EGFR T790M dPCR assay were used to validate the novel integrated platform. In conclusion, we highlight the capability to precisely quantify samples as low as 0.1% T790M EGFR in a background of wild-type EGFR with high reproducibility and high accuracy. Citation Format: Megan E. Dueck, Robert Lin, Andrew Anfora, Andrew Zayac, Steve Gallagher, Omo Clement, Dana Ruminsky-Lowe, Paul Hung. Validation of a novel one-step digital PCR platform with precision circulating cell-free DNA standards [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 2296.
Abstract 5225: Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer
Authors: Ritika Tiwari, Nishat Manzar, Vipul Bhatia, Anjali Yadav, Shannon Carskadon, Nilesh Gupta, Amina Zoubeidi, Nallasivam Palanisamy, Bushra Ateeq
Journal: Cancer Research (2019)

Abstract The Serine Peptidase Inhibitor, Kazal type 1 (SPINK1) overexpression represents the second-largest prostate cancer (PCa) subtype associated with increased risk of recurrence and poor prognosis. Regardless of molecular subtype, androgen-deprivation therapy (ADT) remains the mainstay treatment for locally advanced and metastatic PCa patients. However, majority of the treated individuals eventually progress to castration-resistant stage and a subset of these patients develop ADT-induced neuroendocrine prostate cancer. Despite evidences of detrimental effects of ADT on PCa, possible role of androgen signaling in SPINK1-mediated prostate oncogenesis remains unexplored. Here, we show that androgen receptor (AR) functions as a direct transcriptional repressor of SPINK1, and blocking AR signaling relieves its repression, leading to upregulation of SPINK1. In agreement, we observe an inverse association between SPINK1 levels and AR expression across multiple patient cohorts, and in neuroendocrine differentiated LNCaP cells. We show that AR and its corepressor, the RE1-silencing transcription factor (REST), occupy SPINK1 promoter and inhibits its transcription. On the other hand, in the absence of AR, lineage reprogramming factor SOX2 in turn binds to SPINK1 promoter leading to its positive transcriptional regulation in androgen-deprived conditions with concomitant increase in neuroendocrine markers. Additionally, stable knockdown of SPINK1 results in reduced epithelial-mesenchymal transition, decreased stemness and drug resistance. Collectively, our findings provide a plausible explanation to the paradoxical clinical outcomes of ADT, arising due to increase in SPINK1 levels. Finally, we emphasize the need to take a well-informed decision prior to ADT and develop alternative therapeutic strategies for castrate-resistant PCa patients. Citation Format: Ritika Tiwari, Nishat Manzar, Vipul Bhatia, Anjali Yadav, Shannon Carskadon, Nilesh Gupta, Amina Zoubeidi, Nallasivam Palanisamy, Bushra Ateeq. Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity 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 5225.
Abstract 5228: Acute depletion of CTCF disrupts enhancer-promoter regulation of<i>MYC</i>in B-cell acute lymphoblastic leukemia
Authors: Chunliang Li, Yang Zhang
Journal: Cancer Research (2019)

Abstract Acute lymphoblastic leukemia (ALL), including B-ALL and T-ALL, is the most common childhood cancer and the leading cause of cancer death in children and young adults. Comprehensively genomic sequencing strategies have successfully sub-classified ALL based on genetic alterations including chromosomal rearrangement and aberrant gene mutations, of which frequent coding mutations of CTCF were discovered. However, the function of CTCF in ALL was not clearly defined yet. In a cohort of 264 human pediatric B-ALL patients, particularly in those carrying CTCF loss-of-function mutations, we identified a positive correlation of mRNA expression between CTCF and MYC. Then we integrated the miniAID-mClover3 cassette to the both alleles of endogenous human CTCF locus, which allows acute auxin-mediated degradation of the CTCF protein in a human pediatric B-ALL cell line. By employing combination strategies including whole transcriptome analysis and Capture-C, we discovered that only small number of genes were differentially expressed in CTCF depleted cells, among which MYC and it's downstream genes, not other B-ALL associated oncogenes, were specifically enriched. Mechanically, chromatin interaction capture assay reveals that acute depletion of CTCF primarily disrupted direct interaction between MYC promoter and its distal enhancer residing ~1.8 Mb downstream, subsequently down-regulating target genes in human B-ALL cancer cells. Thus, CTCF/MYC regulation axis is essential in B-ALL development. Citation Format: Chunliang Li, Yang Zhang. Acute depletion of CTCF disrupts enhancer-promoter regulation ofMYCin B-cell acute lymphoblastic leukemia [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 5228.
Symbiosis, Selection, and Novelty: Freshwater Adaptation in the Unique Sponges of Lake Baikal
Authors: Nathan J Kenny, Bruna Plese, Ana Riesgo, Valeria B Itskovich
Journal: Molecular Biology and Evolution (2019)

Freshwater sponges (Spongillida) are a unique lineage of demosponges that secondarily colonized lakes and rivers and are now found ubiquitously in these ecosystems. They developed specific adaptations to freshwater systems, including the ability to survive extreme thermal ranges, long-lasting dessication, anoxia, and resistance to a variety of pollutants. Although spongillids have colonized all freshwater systems, the family Lubomirskiidae is endemic to Lake Baikal and plays a range of key roles in this ecosystem. Our work compares the genomic content and microbiome of individuals of three species of the Lubomirskiidae, providing hypotheses for how molecular evolution has allowed them to adapt to their unique environments. We have sequenced deep (>92% of the metazoan "Benchmarking Universal Single-Copy Orthologs" [BUSCO] set) transcriptomes from three species of Lubomirskiidae and a draft genome resource for Lubomirskia baikalensis. We note Baikal sponges contain unicellular algal and bacterial symbionts, as well as the dinoflagellate Gyrodinium. We investigated molecular evolution, gene duplication, and novelty in freshwater sponges compared with marine lineages. Sixty one orthogroups have consilient evidence of positive selection. Transporters (e.g., zinc transporter-2), transcription factors (aristaless-related homeobox), and structural proteins (e.g. actin-3), alongside other genes, are under strong evolutionary pressure in freshwater, with duplication driving novelty across the Spongillida, but especially in the Lubomirskiidae. This addition to knowledge of freshwater sponge genetics provides a range of tools for understanding the molecular biology and, in the future, the ecology (e.g., colonization and migration patterns) of these key species.
Abstract 3963: Deep serial analysis of the TCR/BCR CDR3 adaptome repertoire in peripheral blood of pancreatic cancer patients in a randomized study of neoadjuvant chemotherapy with or without autophagy inhibition
Authors: Yue Wang, Michael T. Lotze
Journal: Cancer Research (2019)

Abstract Pancreatic cancer has a paucity of dendritic cells and almost no T lymphocytes. Here, we used Next Generation Sequencing following dimer avoidance multiplexed PCR (DAM-PCR) immune repertoire to study the characteristics and diversity of the TCR repertoire among PDAC (Pancreatic Ductal Adenocarcinoma) patients who underwent chemotherapy with or without Hydroxycholoroquine followed by surgical extirpation. We sequenced the TCR α,β,γ, and δ chains and the B-cell receptor (BCR) heavy chain (IgH) complementary-determining region 3 (CDR3) repertoire in peripheral blood mononuclear cells (PBMCs) from 10 PDAC patients before (Pre-chemo) and after chemotherapy (Post-chemo) and following operation (Postop). The distribution of CDR3, VD indel, and DJ indel lengths were similar among the Prechemo, Postchemo and Postop groups. The TCR repertoire diversity of PDAC patients was much lower compared to healthy donors (HD). The diversity index (D50) of TCR α and β’s in PDAC patients who received HCQ during chemotherapy was less than in patients without HCQ (p&amp;lt;.05). TRBV expression increased and some public sequences diminished at individual time points following chemotherapy and postop. Full analysis of an ongoing study will be presented. Citation Format: Yue Wang, Michael T. Lotze. Deep serial analysis of the TCR/BCR CDR3 adaptome repertoire in peripheral blood of pancreatic cancer patients in a randomized study of neoadjuvant chemotherapy with or without autophagy inhibition [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 3963.