tbuckley/cabot-search huggingface dataset:
Abstract 4391: CD95L mRNA is toxic to cancer cells
Authors: William Putzbach, Ashley Haluck-Kangas, Quan Gao, Aishe A. Sarshad, Elizabeth Bartom, Austin Stults, Abdul S. Qadir, Denise M. Scholtens, Markus Hafner, Marcus Peter
Journal: Cancer Research (2018)

Abstract CD95/Fas ligand (CD95L) is best characterized for its role in activating extrinsic apoptosis through binding to its receptor, CD95. However, we recently reported that the CD95L mRNA is enriched in sequences that when converted to si- or shRNAs kill cancer cells through an RNAi-dependent mechanism. When loaded into the RNA Induced Silencing Complex (RISC), CD95L-derived small RNAs downregulate genes critical for cancer cell survival, eliciting a unique form of cell death we call Death Induced by Survival Gene Elimination (DISE). We now report that expression of full-length CD95L mRNA itself is toxic to cells. Acute expression of either wild-type CD95L mRNA in CD95-deficient cells or a CD95L mRNA with a premature stop codon in CD95 wild-type cells induces cell death. RNA-Seq analysis of small RNA reveals that CD95L mRNA is specifically processed into discrete clusters ~19-25 nucleotides long that map along the CD95L ORF. These clusters of CD95L sequences were bound by AGO proteins in cells about to die, suggesting that the mRNA may be killing cells through an RNAi-dependent mechanism. Generation of AGO-bound CD95L mRNA sequences does not appear to be dependent on the canonical miRNA biogenesis pathway, as clusters of CD95L mRNA were detectable in both Drosha and Dicer deficient HCT116 cells. We propose that CD95L mRNA is toxic to cells through processing and loading of small CD95L-derived RNA sequences into the RISC. Citation Format: William Putzbach, Ashley Haluck-Kangas, Quan Gao, Aishe A. Sarshad, Elizabeth Bartom, Austin Stults, Abdul S. Qadir, Denise M. Scholtens, Markus Hafner, Marcus Peter. CD95L mRNA is toxic to cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4391.
Genomic exploration of sequential clinical isolates reveals a distinctive molecular signature of persistent Staphylococcus aureus bacteraemia
Authors: Stefano G. Giulieri, Sarah L. Baines, Romain Guerillot, Torsten Seemann, Anders Gonçalves da Silva, Mark Schultz, Ruth C. Massey, Natasha E. Holmes, Timothy P. Stinear, Benjamin P. Howden
Journal: Genome Medicine (2018)

Large-scale genomic studies of within-host diversity in Staphylococcus aureus bacteraemia (SAB) are needed to understanding bacterial adaptation underlying persistence and thus refining the role of genomics in management of SAB. However, available comparative genomic studies of sequential SAB isolates have tended to focus on selected cases of unusually prolonged bacteraemia, where secondary antimicrobial resistance has developed. To understand bacterial genetic diversity during SAB more broadly, we applied whole genome sequencing to a large collection of sequential isolates obtained from patients with persistent or relapsing bacteraemia. After excluding genetically unrelated isolates, we performed an in-depth genomic analysis of point mutations and chromosome structural variants arising within individual SAB episodes. We show that, while adaptation pathways are heterogenous and episode-specific, isolates from persistent bacteraemia have a distinctive molecular signature, characterised by a low mutation frequency and high proportion of non-silent mutations. Analysis of structural genomic variants revealed that these often overlooked genetic events are commonly acquired during SAB. We discovered that IS256 insertion may represent the most effective driver of within-host microevolution in selected lineages, with up to three new insertion events per isolate even in the absence of other mutations. Genetic mechanisms resulting in significant phenotypic changes, such as increases in vancomycin resistance, development of small colony phenotypes, and decreases in cytotoxicity, included mutations in key genes (rpoB, stp, agrA) and an IS256 insertion upstream of the walKR operon. This study provides for the first time a large-scale analysis of within-host genomic changes during invasive S. aureus infection and describes specific patterns of adaptation that will be informative for both understanding S. aureus pathoadaptation and utilising genomics for management of complicated S. aureus infections.
Abstract 4155: USP11 regulates UV-induced DNA damage repair and cell survival associated with skin cancer
Authors: Palak Shah, Lei Qiang, Seungwon Yang, Keyoumars Soltani, Yu-Ying He
Journal: Cancer Research (2018)

Abstract UV radiation is a major risk factor for skin cancer, the most common cancer in the United States. UV exposure leads to DNA damage by formation of dimers between adjacent pyrimidine bases. The nucleotide excision repair (NER) process is responsible for removal of UV-induced DNA damage. When the damage is left unrepaired due to inefficient NER in disorders like xeroderma pigmentosum, it leads to skin tumorigenesis. Although the main players of the NER pathway have been characterized, the molecular regulation of the pathway is less understood. Understanding the regulation, particularly post-translational regulation, of the NER pathway has the potential to yield modulators of NER efficiency to prevent skin cancer. We found that chronic UV irradiation led to down-regulation of ubiquitin specific peptidase 11 (USP11) in mouse skin tissue. We also found that USP11 is decreased in skin tumors in mice and humans. Moreover, high-throughput proteomics analysis had predicted that USP11 may interact with NER factor XPC. Hence, we undertook this study to determine the role of USP11 in NER and cellular response to UV. We found that USP11 promoted the NER pathway by regulating XPC activity. USP11 promoted XPC deubiquitination and retention at the DNA damage sites. We also found that USP11 interaction with ubiquitinated XPC was enhanced post-UV irradiation, and that USP11 was recruited to the chromatin post-UV damage. Further, squamous cell carcinoma cells showed reduced survival with inhibition of USP11 after UV exposure. Our findings indicate that USP11 plays an important role in maintaining NER capacity, and suggest that USP11 acts as a tumor suppressor via its role in DNA repair. Citation Format: Palak Shah, Lei Qiang, Seungwon Yang, Keyoumars Soltani, Yu-Ying He. USP11 regulates UV-induced DNA damage repair and cell survival associated with skin cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4155.
Abstract LB-104: Targeting solid malignancies with TEGs: αβT cells engineered to express a defined γδTCR in xenograft mice model
Authors: Inez Johanna, Trudy Straetemans, Sabine Heijhuurs, Koen Jansen, Jacco van Rheenen, Jarno Drost, Zsolt Sebestyen, Jurgen Kuball
Journal: Cancer Research (2018)

Abstract γδT cells mediate cancer immune surveillance by sensing metabolic changes of malignant cells via their γδT cell receptor (TCR). Activation of γδTCR is independent of MHC molecules, making them a valuable addition to current treatment strategies. Moreover, γδTCR are able to differentiate between healthy and leukemic stem cells. This concept led to the development of next generation CAR T cells, so-called TEGs: αβT cells Engineered to express a defined γδTCR. A particular γ9δ2TCR, isolated from “clone 5”, has been selected as the candidate for clinical testing (TEG001). A purification strategy was introduced that combined maximal interference of γδTCR chains with endogenous TCR chains with a GMP-grade anti-αβTCR-bead-based depletion strategy to obtain a pure population of engineered immune cells (Straetemans et al. 2015). TEG001 cells showed a strong and broad recognition of hematological malignancies against both cell lines and primary AML (Marcu-Malina et al. 2011, Gründer et al. 2012). To further broaden the clinical implementation of this novel strategy we here investigated the in vivo efficacy profile against solid malignancies. In this study, we evaluated clinical potency of TEG001 against human organoids engineered with most frequent mutations for colorectal cancer, including APC knockout (APCKO), constitutively active KRAS (KRASG12D), P53 knockout (P53KO), and SMAD4 knockout (SMAD4KO), also known as quadruple mutant organoids. These organoids are tumorigenic and can be successfully engrafted as solid tumor mass in immunodeficient mice (Fumagalli et al., 2017; Drost et al., 2015). Irradiated NSG mice received luciferase-positive quadruple mutant organoids subcutaneously and were subsequently infused with TEGs. Tumor growth was measured by bioluminescence imaging. TEG001 showed reduced tumor growth of quadruple mutant organoids compared to untreated and mock controls. Moreover, TEG001-treated mice showed increased overall survival relative to the control mice, followed up to 130 days after treatment. Our current data shows that TEG001 mediates antitumor reactivity against quadruple mutant organoids as solid tumor model in vivo. This xenograft model allows further preclinical testing of next generation TEGs targeted to solid malignancies. Importantly, TEGs are a promising addition to the currently available immune therapeutic strategies as they target cancer as a metabolic disorder. Citation Format: Inez Johanna, Trudy Straetemans, Sabine Heijhuurs, Koen Jansen, Jacco van Rheenen, Jarno Drost, Zsolt Sebestyen, Jurgen Kuball. Targeting solid malignancies with TEGs: αβT cells engineered to express a defined γδTCR in xenograft mice model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-104.
Abstract 15934: Disparities in the Quality of Cardiovascular Care Between Human Immunodeficiency Virus-Infected versus Human Immunodeficiency Virus-Uninfected Adults
Authors: Joseph A Ladapo, Adam K Richards, Cassandra M DeWitt, Nina T Harawa, Steven Shoptaw, William E Cunningham, John N Mafi
Journal: Circulation (2017)

Introduction: Cardiovascular disease is a major cause of morbidity and mortality among patients with HIV. Objective: Compare use of national guideline-recommended cardiovascular care during office ...
Cost sharing and hereditary cancer risk: Predictors of willingness-to-pay for genetic testing.
Authors: Jennifer Madeline Matro, Karen Ruth, Yu-Ning Wong, Katen C. McCully, Christina Rybak, Michael J. Hall
Journal: Journal of Clinical Oncology (2012)

1544 Background: The increasing availability of genetic testing (GT) in cancer (CA) care has been paralleled by increasing cost-sharing practices by payors that are intended to reduce overuse of health care services. Patients referred for hereditary CA risk assessment may be subject to financial deterrents such as high out-of-pocket (OOP) costs. Little is known about what factors may influence high-risk patients' willingness-to-pay (WTP) for GT. Methods: The Gastrointestinal (GI) Tumor Risk Assessment Registry includes individuals referred for evaluation of genetic CA risk based on personal and/or family hx. At enrollment, participants complete a survey collecting detailed demographic, CA hx, and psychosocial items related to CA risk. Baseline data on 406 participants were available; 21 who did not respond to WTP items were excluded. WTP items included intention for: GT only if paid by insurance; GT even if paid by self; and amount WTP (7 levels, $25 to $2000). Multivariable models examined predictors of WTP (self vs only if paid by insurance) (model 1, logistic), and predictors of amount WTP (model 2, ordinal logistic, 5 levels). All statistical tests are two-sided (α=0.05). Results: Most participants were women (73%), white (92%) and aged 45-64 (58%). 51% had ≥ 4 yr college degree; 22% had household income &gt;$75,000; 42% had hx of GI CA; 56% had &gt; 1 1 st degree relative (FDR) with colorectal CA (CRC). Overall, 82 (21.3%) were willing to have GT only if paid by insurance, and 303 (78.7%) were WTP OOP. Of those WTP, 271 (89%) stated an amount. Independent predictors of WTP (model 1) were: 1) expectation of positive result, 2) confidence to control CA risk, 3) fewer perceived barriers to CRC screening and 4) benefit of guiding screening (all p&lt;0.05). Subjects WTP a higher amount (model 2) were male, more educated, and had greater CA worry, fewer FDR with CRC (all p&lt;0.05), and more positive attitudes toward GT (p&lt;0.01). Conclusions: Patients who are WTP some OOP costs for GT anticipate benefits to control of CA risk afforded by GT. Women and less educated patients may face greater barriers from high co-pays. Identifying patient-level factors associated with WTP for genetic services is increasingly important as GT is integrated into routine CA care.
Abstract 3073: Low copy number of mtDNA is associated with cancer stemness in ESCC
Authors: Takeo Hara, Yasunori Masuike, Koji Tanaka, Tomoki Makino, Makoto Yamasaki, Yasuhiro Miyazaki, Tsuyoshi Takahashi, Yukinori Kurokawa, Hidetoshi Eguchi, Kiyokazu Nakajima, Masaki Mori, Yuichiro Doki
Journal: Cancer Research (2018)

Abstract Alterations of mitochondrial DNA (mtDNA) copy numbers in various human cancers have been studied. However, those of esophageal squamous cell carcinoma (ESCC) is still unclear. In the present study, we investigated the correlation of mtDNA copy number with clinicopathologic features, prognosis and malignant potential of ESCC. MtDNA copy numbers of resected specimen from 80 patients treated with radical esophagectomy were measured by quantitative real-time PCR analyses. Human ESCC cells, TE8 and TE11, were cultured and depletion of mtDNA content was induced by knockdown of mitochondrial transcription factor A expression or treatment with ethidium bromide. The mRNA expression, proliferation, invasion and cell cycle were investigated. The results showed that mtDNA copy number of cancerous parts was 56.0 (37.4-234.5) % of non-cancerous parts and significantly lower (p&amp;lt;0.05). Low mtDNA copy number in resected cancerous tissues was significantly correlated with pathological depth of tumor invasion and pathological stage (p&amp;lt;0.05). The patients with lower mtDNA copy number had significantly poorer 5-year overall and recurrence-free survival than higher group (p&amp;lt;0.01). MtDNA depleted TE8 and TE11 cells proliferated more slowly than control cells under normoxia, but proliferated at almost the same rate even under hypoxic condition. In mtDNA depleted cells, the mRNA expression of cd44 were increased, and the sphere formation abilities were enhanced and the cell cycle arrest at G0/G1 phase was induced. In conclusion, low copy number of mtDNA is associated with cancer stemness in ESCC. MtDNA copy number may be a novel therapeutic target for esophageal squamous cell carcinoma. Citation Format: Takeo Hara, Yasunori Masuike, Koji Tanaka, Tomoki Makino, Makoto Yamasaki, Yasuhiro Miyazaki, Tsuyoshi Takahashi, Yukinori Kurokawa, Hidetoshi Eguchi, Kiyokazu Nakajima, Masaki Mori, Yuichiro Doki. Low copy number of mtDNA is associated with cancer stemness in ESCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3073.
Cooperative Enhancer Activation by TLX1 and STAT5 Drives Development of NUP214-ABL1/TLX1-Positive T Cell Acute Lymphoblastic Leukemia
Authors: Marlies Vanden Bempt, Sofie Demeyer, Michaël Broux, Jolien De Bie, Simon Bornschein, Nicole Mentens, Roel Vandepoel, Ellen Geerdens, Enrico Radaelli, Beat C. Bornhauser, Andreas E. Kulozik, Jules P. Meijerink, Jean-Pierre Bourquin, Charles E. de Bock, Jan Cools
Journal: Cancer Cell (2018)
Prevalence and Estimated Economic Burden of Substandard and Falsified Medicines in Low- and Middle-Income Countries
Authors: Sachiko Ozawa, Daniel R. Evans, Sophia Bessias, Deson G. Haynie, Tatenda T. Yemeke, Sarah K. Laing, James E. Herrington
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Substandard and falsified medicines burden health systems by diverting resources to ineffective or harmful therapies, causing medical complications and prolonging illnesses. However, the prevalence and economic impact of poor-quality medicines is unclear. <h3>Objective</h3> To conduct a systematic review and meta-analysis to assess the prevalence and estimated economic burden of substandard and falsified essential medicines in low- and middle-income countries. <h3>Data Sources</h3> Five databases (PubMed, EconLit, Global Health, Embase, and Scopus) were searched from inception until November 3, 2017. <h3>Study Selection</h3> Publications were assessed to determine whether they examined medicine quality and the prevalence and/or economic burden of substandard and falsified medicines in low- and middle-income countries. Studies with a sample size of 50 or more were included in the meta-analysis. <h3>Data Extraction and Synthesis</h3> The study is registered in PROSPERO and reported via the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Study quality was assessed using an adapted Medicine Quality Assessment Reporting Guidelines scoring metric. Multiple reviewers conducted the data extraction and quality assessment independently. <h3>Main Outcomes and Measures</h3> Prevalence and/or estimated economic impact of substandard and falsified medicines. <h3>Results</h3> Two hundred sixty-five studies that estimated the prevalence of poor-quality essential medicines in low- and middle-income countries were identified. Among 96 studies that tested 50 samples or more (67 839 total drug samples), overall prevalence of poor-quality medicines was 13.6% (95% CI, 11.0%-16.3%), with regional prevalence of 18.7% in Africa (95% CI, 12.9%-24.5%) and 13.7% in Asia (95% CI, 8.2%-19.1%). Of studies included in the meta-analysis, 19.1% (95% CI, 15.0%-23.3%) of antimalarials and 12.4% (95% CI, 7.1%-17.7%) of antibiotics were substandard or falsified. Eight approximations of the economic impact, focused primarily on market size, with poor or undisclosed methods in estimation were identified, ranging from $10 billion to $200 billion. <h3>Conclusions and Relevance</h3> Poor-quality essential medicines are a substantial and understudied problem. Methodological standards for prevalence and rigorous economic studies estimating the burden beyond market size are needed to accurately assess the scope of the issue and inform efforts to address it. Global collaborative efforts are needed to improve supply-chain management, surveillance, and regulatory capacity in low- and middle-income countries to reduce the threat of poor-quality medicines. <h3>Trial Registration</h3> PROSPERO Identifier:CRD42017080266
Abstract P262: Resequencing Study Identifies Epithelial Sodium Channel Genes and Novel Low Frequency Variants Associated with Blood Pressure Salt-sensitivity: The GenSalt Study
Authors: Christopher E Anderson, Changwei Li, Jiang He, Dongfeng Gu, Dabeeru C Rao, James E Hixson, Lawrence C Shimmin, Jianfeng Huang, Charles C Gu, Jichun Chen, Jianxin Li, Tanika N Kelly
Journal: Circulation (2016)

Christopher E. Anderson, Changwei Li, Jiang He, Dongfeng Gu, Dabeeru C. Rao, James E. Hixson, Lawrence C. Shimmin, Jianfeng Huang, Charles C. Gu, Jichun Chen, Jianxin Li, Tanika N. Kelly Genetic association studies have identified significant associations between common variants from the epithelial sodium channel (ENaC) genes and blood pressure responses to dietary sodium interventions. The roles of low-frequency and rare ENaC variants in blood pressure salt-sensitivity remain largely unexplored. To test this hypothesis, we conducted an ENaC candidate gene resequencing study among participants in the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt). The GenSalt study was conducted among 1,906 participants from 633 families who underwent a 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium (307.8 mmol sodium/day) feeding-study. We chose the 300 GenSalt subjects with the highest and 300 GenSalt subjects with the lowest mean arterial pressure responses to the high sodium intervention to participate in the current resequencing study. Functional regions of three ENaC subunit genes ( SCNN1A , SCNN1B and SCNN1G ) were resequenced using the VariantSEQr TM system (Applied Biosystems; Foster City, CA). For gene-based analyses, variants with MAF less than 5% were first collapsed within each ENaC gene. The collapsed indicator variable was then tested for association with blood pressure salt-sensitivity using generalized estimating equations (GEE) to accommodate correlation of genotypes due to family structure and adjust for the fixed effects of age, gender and field center. Single variant analyses were performed for all low-frequency variants with a minor allele frequency (MAF) greater than 1% and less than 5%, again using GEE to accommodate family structure and adjust for covariables. We did not identify any associations between ENaC genes and blood pressure salt-sensitivity in the gene-based analyses. However, single variant analysis identified a novel association between a low-frequency variant in SCNN1G , rs148083677, and blood pressure salt-sensitivity (P=0.02). Each minor allele was associated with 71% lower odds of blood pressure salt-sensitivity. Although replication studies are needed, these findings provide promising evidence of a role for low-frequency ENaC variants in blood pressure salt-sensitivity.
Abstract 19069: Autoregulation of Connexin43 Gap Junction Formation by Internally Translated Isoforms
Authors: James W Smyth, Robin M Shaw
Journal: Circulation (2013)

During each heartbeat, cell-cell electrical coupling via connexin 43 (Cx43) gap junctions allows billions of individual cardiomyocytes to synchronously contract. The Cx43 protein turns over rapidly, rendering regulation of Cx43 trafficking a critical and continuous cellular need. Altered Cx43 trafficking during heart disease disrupts intercellular coupling and can contribute to the arrhythmias of sudden cardiac death. Better understanding of how Cx43 channels are transported to the cell surface will lead to therapies that can preserve normal electrical coupling of diseased heart muscle. We have identified a novel regulatory mechanism whereby internal translation of the coding sequence of Cx43 ( GJA1 ) mRNA generates N-terminally truncated isoforms that regulate trafficking of full length Cx43 channels. Biochemical analysis of human heart and cell lines reveals at least four additional Cx43 isoforms, with a 20 kDa isoform predominating. We find that in frame AUG codons within GJA1 mRNA represent isoform translation initiation sites and that their ablation arrests trafficking of full-length Cx43. The predominant 20 kDa isoform is sufficient to rescue this trafficking defect when expressed in trans , implicating an essential role as a trafficking chaperone for Cx43. Consistent with these data, expression of Cx43 truncated isoforms is enhanced through inhibition of the PI3K/AKT/mTOR pathway in cardiomyocytes, and concomitantly increases Cx43 gap junction plaque size. Such cap-independent internal translation initiation events may represent a common mechanism for auto-regulation of membrane protein trafficking which is likely altered during stress and, based on these studies, represents a potent target for therapeutic preservation of intercellular coupling in heart disease.
Abstract 15950: Predictors of Statin Intolerance in Patients With a New Diagnosis of Atherosclerotic Cardiovascular Disease (ASCVD) Within a Large Integrated Healthcare Institution: The IMPRES Study
Authors: Tami L Bair, Heidi T May, Kirk U Knowlton, Jeffrey L Anderson, Donald L Lappé, Joseph B Muhlestein
Journal: Circulation (2017)

Introduction: Statins are among the most prescribed medications due to the well-documented cardiovascular benefits of safely lowering LDL. However, many patients are unable or unwilling to continue...