tbuckley/cabot-search huggingface dataset:
Abstract LB-301: Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia
Authors: CHUJING ZHANG, Stella Amanda, Cheng Wang, Tze King Tan, Zulfaqar Ali Muhammad, Wei Zhong Leong, Ley Moy Ng, Shojiro Kitajima, Zhenhua Li, Allen Eng Juh Yeoh, Shi Hao Tan, Takaomi Sanda
Journal: Cancer Research (2020)

Abstract Aldehyde dehydrogenases (ALDHs) have been implicated as a stem cell marker both in normal and malignant cells. Elevated ALDH activity is associated with the stemness capability as well as the drug resistance in various cancers. As a notable example, ALDH1A2, one of ALDH family genes, is ectopically overexpressed in T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological disease that results from malignant transformation of T-cell progenitors. However, its roles and molecular functions in T-ALL pathogenesis are poorly understood. In our study, we demonstrated that the oncogenic transcription factor TAL1 directly induces an expression of ALDH1A2 in T-ALL cells, while normal T-cells do not express this gene. The TAL1 transcriptional complex binds to an intragenic regulatory element of ALDH1A2 and aberrantly activates the alternative promoter of the short isoform, which is specific to T-ALL cells. Using in vitro enzymatic assay, we found that the short isoform still retain enzymatic activity in catalyzing the oxidation of aldehydes. Importantly, ALDH1A2 promotes the viability and survival of T-ALL cells. Unbiased gene expression and metabolome profiling demonstrated that ALDH1A2 promotes glycolysis and mitochondria respiration, thereby supporting energy production. Additionally, expression of the short ALDH1A2 attenuated the amount of reactive oxygen species (ROS) both in vitro and in vivo. Furthermore, forced expression of short ALDH1A2 in T-cells increased overall penetrance of T-cell malignancy induced by the AKT2 oncogene in a zebrafish model. Taken together, our data suggests that ALDH1A2 is crucial and advantageous for T-ALL cell viability and survival by mediating energy production and by protecting cancer cells from oxidative stresses, thus serving as a requisite to maintain the hyperproliferative state of T-ALL cells (“onco-requisite”). Citation Format: CHUJING ZHANG, Stella Amanda, Cheng Wang, Tze King Tan, Zulfaqar Ali Muhammad, Wei Zhong Leong, Ley Moy Ng, Shojiro Kitajima, Zhenhua Li, Allen Eng Juh Yeoh, Shi Hao Tan, Takaomi Sanda. Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia [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 LB-301.
Abstract 6327: Artesunate reduces tumor growth and induces different kinds of cell death in docetaxel-resistant prostate carcinoma cells
Authors: Vitus Braeunig, Patricia Schupp, Sascha Markowitsch, Olesya Vakhrusheva, Holger Erb, Thomas Efferth, Axel Haferkamp, Eva Juengel
Journal: Cancer Research (2020)

Abstract Introduction: Prostate carcinoma (PCa) is the most common cancer in men. The therapeutic effect of approved compounds, such as docetaxel, is limited due to the development of therapy resistance, making new treatment options essential. Artesunate (ART), used in Traditional Chinese Medicine, has shown anti-tumor activity in several tumor types. However, little is known about the efficacy of ART on therapy-resistant PCa. Therefore, the impact of ART on docetaxel-resistant PCa cells was investigated. Material and Methods: Parental (=sensitive) and docetaxel-resistant PCa cell lines, PC3, DU145, and LNCaP, were exposed to ART [1-100 µM] for 24, 48, or 72 hours. Cells not exposed to ART served as controls. Tumor cell growth, proliferation, cell cycling, and the expression of cell cycle regulating proteins were assessed. Apoptotic, ferroptotic, and necrotic effects were also evaluated. Results: Exposure to ART significantly reduced tumor cell growth and proliferation of parental and docetaxel-resistant PCa cells in a time- and dose-dependent manner. Cell cycle arrest in the G0/G1 phase after 48h exposure to 37.5 µM ART was observed in parental LNCaP and in all three resistant cell lines. The observed changes in cell growth and cell cycle phases were accompanied by marked modulation of cell cycle regulating proteins. Significant apoptotic effects were observed in parental PC3 and both parental and resistant LNCaP, whereas ferroptosis was apparent in parental and resistant DU145 after exposure to ART. Necrotic events were not detectable in the PCa cells after ART exposure. Conclusion: ART induced anti-tumor effects, though differing according to the cell line, were apparent in not only parental but also in docetaxel-resistant PCa cells. Thus, adding ART to standard therapies might be a promising treatment strategy for patients with advanced prostate cancer. Further investigations are necessary to verify our findings. Citation Format: Vitus Braeunig, Patricia Schupp, Sascha Markowitsch, Olesya Vakhrusheva, Holger Erb, Thomas Efferth, Axel Haferkamp, Eva Juengel. Artesunate reduces tumor growth and induces different kinds of cell death in docetaxel-resistant prostate carcinoma 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 6327.
<i>C9orf72</i> poly(GR) aggregation induces TDP-43 proteinopathy
Authors: Casey N. Cook, Yanwei Wu, Hana M. Odeh, Tania F. Gendron, Karen Jansen-West, Giulia del Rosso, Mei Yue, Peizhou Jiang, Edward Gomes, Jimei Tong, Lillian M. Daughrity, Nicole M. Avendano, Monica Castanedes-Casey, Wei Shao, Björn Oskarsson, Giulio S. Tomassy, Alexander McCampbell, Frank Rigo, Dennis W. Dickson, James Shorter, Yong-Jie Zhang, Leonard Petrucelli
Journal: Science Translational Medicine (2020)

G 4 C 2 repeat–derived poly(GR) plays a key role in mediating TDP-43 mislocalization and aggregation in vitro and in vivo.
Abstract 921: TLR5 agonists enhance anti-tumor immunity and overcome resistance to immune checkpoint therapy
Authors: Caleb Gonzalez, Sarah Williamson, Seth Gammon, David Piwnica-Worms
Journal: Cancer Research (2020)

Abstract Despite the success of immune checkpoint therapies (ICT) in achieving durable responses in subsets of cancer patients, not all patients respond to these types of therapies. Primary and adaptive resistance to immunotherapies present a considerable obstacle in achieving enhanced survival in a broader population of patients. Innate immune activators have been actively pursued for their antitumor potential. Herein, we report that a syngeneic 4T1 mammary carcinoma murine model for established highly refractory triple negative breast cancer showed enhanced survival when treated intra-tumorally with the TLR5 agonist flagellin, in combination with intra-peritoneal antibodies targeting CTLA-4 and PD-1. Long-term survivor mice showed immunologic memory upon tumor re-challenge and a distinctive immune activating cytokine profile that engaged both innate and adaptive components of the immune system. Of note, low serum levels of G-CSF at weeks 6 and 7 correlated highly with enhanced survival at week 18 (Hazzard Ratio 11, p &amp;lt; 0.01, n=11). Furthermore, we also observed enhanced survival with combination TLR5 agonist plus ICT in the poorly immunogenic B16-F10 melanoma tumor model. Combination immune checkpoint therapy plus innate immune activation with TLR5 agonists may offer a new therapeutic strategy to treat ICT-refractory solid tumors. Citation Format: Caleb Gonzalez, Sarah Williamson, Seth Gammon, David Piwnica-Worms. TLR5 agonists enhance anti-tumor immunity and overcome resistance to immune checkpoint therapy [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 921.
Abstract 1378: Targeting the metabolic-epigenetic axis to sensitize HR-proficient ovarian cancer to PARP inhibitors
Authors: Erika S. Dahl, Kelly E. Leon, Chi-Wei Chen, Qingyuan Jia, Raquel Buj, Nathaniel W. Snyder, Katherine M. Aird
Journal: Cancer Research (2020)

Abstract Overexpression of the oncogene cyclin E1 is considered one of the initiating factors in fallopian tube transformation and ovarian tumorigenesis. Patients with high cyclin E1 expression have worse overall survival than patients with low expression. Cyclin E1 overexpression increases expression of DNA damage response (DDR) genes in order to tolerate DNA damage and bypass senescence, a state of cell cycle arrest. However, the mechanism by which cyclin E1-high cells transcriptionally increase DDR gene expression to bypass senescence remains unclear. We found that cyclin E1 overexpression alters the metabolic-epigenetic axis through wildtype isocitrate dehydrogenase I (wtIDH1), a TCA cycle enzyme. Upregulation of wtIDH1 in cyclin E1-high cells increased the transcription of multiple DDR genes related to homologous recombination (HR), including BRCA1, BRCA2, and RAD51. Published data from our lab demonstrates that wtIDH1 primarily converts isocitrate to alpha-ketoglutarate (αKG) in cyclin E1-high ovarian cancer cells, and suppression of wtIDH1 and αKG pools induces senescence through increased repressive histone marks. Our current data suggest that wtIDH1 is both necessary and sufficient for HR gene expression in cyclin E1-high cells in part through modulation of histone methylation. Functionally, inhibition of wtIDH1 in cyclin E1-high fallopian tube cells induced senescence via decreased HR and marked accumulation of DNA damage. Cyclin E1-high ovarian cancer tumors are HR-proficient and resistant to emerging poly(ADP-ribose) polymerase (PARP) inhibitors. Interestingly, inhibition of both wtIDH1 and PARP in combination increased apoptosis of cyclin E1-high ovarian cancer cells in vitro, suggesting this may be a novel therapy for HR-proficient ovarian cancers. Together, our data suggest that wtIDH1-mediated metabolism affects the epigenome in cyclin E1-high cells, which contributes to both fallopian tube transformation and HR-proficiency. Targeting wtIDH1 with current FDA-approved inhibitors may therefore be a rational therapeutic strategy for cyclin E1-high ovarian cancer patients. Citation Format: Erika S. Dahl, Kelly E. Leon, Chi-Wei Chen, Qingyuan Jia, Raquel Buj, Nathaniel W. Snyder, Katherine M. Aird. Targeting the metabolic-epigenetic axis to sensitize HR-proficient ovarian cancer to PARP inhibitors [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 1378.
Abstract 3543: Facile genome-wide detection of genomic fusions and other somatic chromosomal abnormalities through Bionano Whole Genome Imaging
Authors: Alex Hastie, Andy W. Pang, Joyce Lee, Ernest T. Lam, Thomas Anantharaman, Henry Sadowski, Mark Oldakowski
Journal: Cancer Research (2020)

Abstract Genome instability is a key hallmark of cancer. Instability is important because it allows the genome to acquire growth advantage by amplifying or creating oncogenes by fusing otherwise non-pathogenic genes and by deleting/inactivating tumor suppressor genes. Several gene fusions have been discovered and some have been exploited for therapies as they produce fusion proteins that can be targeted by chemotherapeutics such as tyrosine-kinase inhibitors targeting BCR-ABL used to treat CML. In addition, other genomic fusions serve as diagnostic or prognostic indicators important for cancer management. Clinically, fusions are generally detected through targeted assays like NGS panels, PCR and FISH, or through karyotyping. High resolution, whole genome approaches to detect fusions are needed as current approaches have innate limitations, such as karyotyping (low resolution) and whole genome sequencing (blind in the ~66% of the genome containing repeats). Bionano whole genome imaging is able fill in the gaps, providing high resolution (~2kbp breakpoint precision) and ability to span complicated genomic repeats. Here we demonstrate an easy, fluid, largely automated workflow for whole genome detection of fusions and other somatic variants. The Bionano workflow involves a novel rapid isolation protocol for extremely high molecular weight DNA, labeling the DNA to create a barcode across the genome and automated data collection using the Bionano Saphyr system. The assay is inexpensive and the whole workflow can be accomplished from cells/tissue to variant calls within 4 days turnaround time. Because this approach is whole genome and not masked/hidden by repeat elements, we are able to detect novel fusions that have not previously been detected. In a standard assay, whole genome imaging can detect variants at 5% allele fraction and with increased coverage fusions down to 1% allele fraction can be efficiently detected. Whole genome imaging for novel fusion detection and genome instability studies will likely play an increasing role as a complementary genomics tool in cancer research going forward. Citation Format: Alex Hastie, Andy W. Pang, Joyce Lee, Ernest T. Lam, Thomas Anantharaman, Henry Sadowski, Mark Oldakowski. Facile genome-wide detection of genomic fusions and other somatic chromosomal abnormalities through Bionano Whole Genome Imaging [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 3543.
<i>Vital Signs:</i> Characteristics of Drug Overdose Deaths Involving Opioids and Stimulants — 24 States and the District of Columbia, January–June 2019
Authors: Julie O’Donnell, R. Matt Gladden, Christine L. Mattson, Calli T. Hunter, Nicole L. Davis
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Provisional estimates indicate that drug overdose deaths increased in 2019 after a slight decrease in 2018. In 2018, overdose deaths primarily involved opioids, with continued increases in deaths involving illicitly manufactured fentanyls (IMFs). Deaths involving stimulants such as cocaine and methamphetamine are also increasing, mainly in combination with opioids.CDC analyzed data on drug overdose deaths during January-June 2019 from 24 states and the District of Columbia (DC) in the State Unintentional Drug Overdose Reporting System to describe characteristics and circumstances of opioid- and stimulant-involved overdose deaths.Among 16,236 drug overdose deaths in 24 states and DC, 7,936 (48.9%) involved opioids without stimulants, 5,301 (32.6%) involved opioids and stimulants, 2,056 (12.7%) involved stimulants without opioids, and 943 (5.8%) involved neither opioids nor stimulants. Approximately 80% of overdose deaths involved one or more opioid, and IMFs were involved in three of four opioid-involved overdose deaths. IMFs, heroin, cocaine, or methamphetamine (alone or in combination) were involved in 83.8% of overdose deaths. More than three in five (62.7%) overdose deaths had documentation of at least one potential opportunity for overdose prevention intervention.Identifying opportunities to intervene before an overdose death and implementing evidence-based prevention policies, programs, and practices could save lives. Strategies should address characteristics of overdoses involving IMFs, such as rapid overdose progression, as well as opioid and stimulant co-involvement. These efforts should be complemented by efforts to prevent initiation of prescription opioid and stimulant misuse and illicit drug use.
Diagnostic accuracy of capsule endoscopy compared with colonoscopy for polyp detection: systematic review and meta-analyses
Authors: Tue Kjølhede, Anne Mette Ølholm, Lasse Kaalby, Kristian Kidholm, Niels Qvist, Gunnar Baatrup
Journal: Endoscopy (2020)

Abstract Background Colon capsule endoscopy (CCE) is a technology that might contribute to colorectal cancer (CRC) screening programs as a filter test between fecal immunochemical testing and standard colonoscopy. The aim was to systematically review the literature for studies investigating the diagnostic yield of second-generation CCE compared with standard colonoscopy. Methods A systematic literature search was performed in PubMed, Embase, and Web of Science. Study characteristics including quality of bowel preparation and completeness of CCE transits were extracted. Per-patient sensitivity and specificity were extracted for polyps (any size, ≥ 10 mm, ≥ 6 mm) and lesion characteristics. Meta-analyses of diagnostic yield were performed. Results The literature search revealed 1077 unique papers and 12 studies were included. Studies involved a total of 2199 patients, of whom 1898 were included in analyses. The rate of patients with adequate bowel preparation varied from 40 % to 100 %. The rates of complete CCE transit varied from 57 % to 100 %. Our meta-analyses demonstrated that mean (95 % confidence interval) sensitivity, specificity, and diagnostic odds ratio were: 0.85 (0.73–0.92), 0.85 (0.70–0.93), and 30.5 (16.2–57.2), respectively, for polyps of any size; 0.87 (0.82–0.90), 0.95 (0.92–0.97), and 136.0 (70.6–262.1), respectively, for polyps ≥ 10 mm; and 0.87 (0.83–0.90), 0.88 (0.75–0.95), and 51.1 (19.8–131.8), respectively, for polyps ≥ 6 mm. No serious adverse events were reported for CCE. Conclusion CCE had high sensitivity and specificity for per-patient polyps compared with standard colonoscopy However, the relatively high rate of incomplete investigations limits the application of CCE in a CRC screening setting.
xCT: A Critical Molecule That Links Cancer Metabolism to Redox Signaling
Authors: Jinyun Liu, Xiaojun Xia, Peng Huang
Journal: Molecular Therapy (2020)

System xc- cystine/glutamate antiporter, composed of a light-chain subunit (xCT, SLC7A11) and a heavy-chain subunit (CD98hc, SLC3A2), is mainly responsible for the cellular uptake of cystine in exchange for intracellular glutamate. In recent years, the xCT molecule has been found to play an important role in tumor growth, progression, metastasis, and multidrug resistance in various types of cancer. Interestingly, xCT also exhibits an essential function in regulating tumor-associated ferroptosis. Despite significant progress in targeting the system xc- transporter in cancer treatment, the underlying mechanisms still remain elusive. It is also unclear why solid tumors are more sensitive to xCT inhibitors such as sulfasalazine, as compared to hematological malignancies. This review mainly focuses on the role of xCT cystine/glutamate transporter in regard to tumor growth, chemoresistance, tumor-selective ferroptosis, and the mechanisms regulating xCT gene expression. The potential therapeutic implications of targeting the system xc- and its combination with chemotherapeutic agents or immunotherapy to suppress tumor growth and overcome drug resistance are also discussed.
Abstract 5910: Single-cell multiomic analysis of SNV, CNV, and protein expression
Authors: Aik Ooi, Pedro Mendez, Dalia Dhingra, Nigel Beard, David Ruff
Journal: Cancer Research (2020)

Abstract Recent advancements in precision medicine, while highly promising, presents a major technical challenge to researchers due to disease heterogeneity. The emergence of single-cell technologies has greatly refined the resolution in which sample diversity can be investigated, enhancing the efficiency of selecting appropriate molecular targets. Additionally, applying multiomic analysis on single cells would further improve the understanding of cell-to-cell heterogeneity by providing unique insights on cellular and genetic composition. Using a two-step droplet microfluidic technology, the Mission Bio Tapestri Platform enables multiplex-PCR based high-throughput targeted DNA sequencing in single cells to obtain single-nucleotide variation (SNV) and copy number variation (CNV) information. By leveraging this technology, a new workflow is developed to detect protein expression in addition to DNA genotype in the same single cells. In this approach, cells are labeled with a pool of oligonucleotide-conjugated antibodies prior to loading the cells into the Tapestri Instrument for targeted DNA analysis. Sequencing libraries are then prepared from both antibody oligonucleotides and the amplified DNA sequences, followed by identification of single-cell DNA genotypes and protein signatures from the sequencing readout. In a mixed population of four cell lines, single-cell SNV and CNV information from 127 targeted amplicons and the protein data from 10 antibodies independently classified the cells into appropriate clusters. This method has been successfully performed on clinical samples with myeloid malignancies. In an acute myeloid leukemia (AML) sample, combined single-cell SNV, CNV, and protein expression data illustrated the heterogeneity within the sample. The data clearly identified CD3+ T cells and CD19+ B cells without pathogenic SNVs and CNVs. CD34hiCD11blo and CD34loCD11bhi subpopulations were also identified within the cells carrying the same pathogenic SNVs and CNVs. We believe that this novel multiomic technology will enable new discoveries in the complex relationship between genotype and phenotype, leading to a better understanding of disease biology, and subsequently better design of diagnostics and therapies. Citation Format: Aik Ooi, Pedro Mendez, Dalia Dhingra, Nigel Beard, David Ruff. Single-cell multiomic analysis of SNV, CNV, and protein expression [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 5910.