tbuckley/cabot-search huggingface dataset:
Survival in Patients With Idiopathic, Familial, and Anorexigen-Associated Pulmonary Arterial Hypertension in the Modern Management Era
Authors: MarcHumbert, OlivierSitbon, AriChaouat, MichèleBertocchi, GilbertHabib, VirginieGressin, AzzedineYaïci, EmmanuelWeitzenblum, Jean-FrançoisCordier, FrançoisChabot, ClaireDromer, ChristophePison, MartineReynaud-Gaubert, AlainHaloun, MarcelLaurent, EricHachulla, VincentCottin, BrunoDegano, XavierJaïs, DavidMontani, RogérioSouza, GéraldSimonneau
Journal: Circulation (2010)

Background— Novel therapies have recently become available for pulmonary arterial hypertension. We conducted a study to characterize mortality in a multicenter prospective cohort of patients diagnosed with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension in the modern management era. Methods and Results— Between October 2002 and October 2003, 354 consecutive adult patients with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension (56 incident and 298 prevalent cases) were prospectively enrolled. Patients were followed up for 3 years, and survival rates were analyzed. For incident cases, estimated survival (95% confidence intervals [CIs]) at 1, 2, and 3 years was 85.7% (95% CI, 76.5 to 94.9), 69.6% (95% CI, 57.6 to 81.6), and 54.9% (95% CI, 41.8 to 68.0), respectively. In a combined analysis population (incident patients and prevalent patients diagnosed within 3 years before study entry; n=190), 1-, 2-, and 3-year survival estimates were 82.9% (95% CI...
Abstract 14756: The Aging-Regulated Protein PNUTS Is Essential for Myocardial and Endothelial Cell Survival in vivo
Authors: Noelia Lozano-Vidal, Denise Berghäuser, Marion Muhly-Reinholz, Stefanie Dimmeler, Reinier A Boon
Journal: Circulation (2016)

Introduction: Phosphatase 1 Nuclear Targeting Subunit (PNUTS, PPP1R10) is a nuclear protein described to act as a binding platform for the PP1 phosphatase complex. PNUTS has recently found to be implicated in cell cycle, cell proliferation in cancer cells and protection against DNA damage response and apoptosis in cardiomyocytes. PNUTS expression is markedly repressed in the heart during aging. Hypothesis: Our objective is to elucidate the potential role of PNUTS in the endothelium and myocardium and determine the mechanism by which PNUTS regulates cardiac homeostasis and endothelial cell function. Methods: Therefore, we generated constitutive and conditional PNUTS-deficient mice by crossing PNUTSflox/flox with the cardiac deletor line Myh6-Cre and the endothelial deletor Cdh5-CreERT2 and analyze their phenotypes. Results: The constitutive deletion of PNUTS was found to be embryonically lethal, as no PNUTS-/- mice or embryos were born. Cardiac-specific Myh6-Cre PNUTSflox/flox led to loss of PNUTS since fi...
The Role of Phylogenetically Conserved Elements in Shaping Patterns of Human Genomic Diversity
Authors: August E Woerner, Krishna R Veeramah, Joseph C Watkins, Michael F Hammer
Journal: Molecular Biology and Evolution (2018)

Evolutionary genetic studies have shown a positive correlation between levels of nucleotide diversity and either rates of recombination or genetic distance to genes. Both positive-directional and purifying selection have been offered as the source of these correlations via genetic hitchhiking and background selection, respectively. Phylogenetically conserved elements (CEs) are short (∼100 bp), widely distributed (comprising ∼5% of genome), sequences that are often found far from genes. While the function of many CEs is unknown, CEs also are associated with reduced diversity at linked sites. Using high coverage (>80×) whole genome data from two human populations, the Yoruba and the CEU, we perform fine scale evaluations of diversity, rates of recombination, and linkage to genes. We find that the local rate of recombination has a stronger effect on levels of diversity than linkage to genes, and that these effects of recombination persist even in regions far from genes. Our whole genome modeling demonstrates that, rather than recombination or GC-biased gene conversion, selection on sites within or linked to CEs better explains the observed genomic diversity patterns. A major implication is that very few sites in the human genome are predicted to be free of the effects of selection. These sites, which we refer to as the human "neutralome," comprise only 1.2% of the autosomes and 5.1% of the X chromosome. Demographic analysis of the neutralome reveals larger population sizes and lower rates of growth for ancestral human populations than inferred by previous analyses.
Targeted Sequencing Analysis of Pulmonary Adenocarcinoma with Multiple Synchronous Ground-Glass/Lepidic Nodules
Authors: Eunhyang Park, Soyeon Ahn, Hyojin Kim, Soo Young Park, Jisun Lim, Hyun Jung Kwon, Yeon Bi Han, Choon-Taek Lee, Sukki Cho, Jin-Haeng Chung
Journal: Journal of Thoracic Oncology (2018)
Abstract 5620: Multispecific antibodies targeting CD38 and PD-L1 show potent tumor cytotoxicity
Authors: Wim van Schooten
Journal: Cancer Research (2018)

Abstract Multivalent antibodies targeting either CD38 alone or CD38 in conjunction with PD-L1 may yield therapeutics with superior biologic activities and provide benefit for treating malignancies expressing low levels of CD38 (DLCBL, daratumumab refractory MM, and NSCLC). Multivalent, multispecific antibodies kill CD38low cells through a variety of mechanisms including stronger and more specific engagement of CD38. Potent and directed immune checkpoint inhibition is realized by adding an anti-PD-L1 binding domain. Teneobio's discovery platform utilizes VH domains (UniDabs) of fully human heavy chain antibodies (UniAbs) to develop bi-, tri-, and tetravalent antibodies. Individual UniDabs targeting CD38 and PDL1 were identified using our unique sequence-based discovery platform and high-throughput lead evaluation pipeline (TeneoSeek). This robust screening workflow enables evaluation of a large diversity of natural fully human antibodies, targeting multiple epitopes on a single antigen and uncovering important sequence activity relationships. We have identified UniDabs that bind five different functional epitopes on human, cynomolgus and mouse CD38 including potent inhibitors of hydrolase and cyclase enzymatic functions. In addition, we generated a large panel of PD-L1 inhibitors that bind with high affinities human and cynomolgus PD-L1. Using different combinations and arrangements of UniDabs, a variety of multivalent antibodies were constructed and evaluated in in vitro models. Data from a range of assay types show that multivalent UniAbs targeting CD38 can be engineered to display superior tumor cell cytotoxicity through multiple mechanisms of action. Summary: Teneobio's discovery platform utilizes VH domains (UniDabs) of fully human heavy chain antibodies (UniAbs) to develop bi-, tri-, and tetravalent antibodies. Multivalent UniAbs targeting CD38 and PD-L1 can be engineered to display superior tumor cell cytotoxicity through multiple mechanisms of action. Citation Format: Wim van Schooten. Multispecific antibodies targeting CD38 and PD-L1 show potent tumor cytotoxicity [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 5620.
Abstract LB-361: Tumor-derived microvesicles promote tumor immune escape through PD-1/PD-L1 interaction
Authors: Dong Ha Kim, Yun Jung Choi, Seon Ye Kim, Jung-Eun Lee, Ki Jung Sung, Jae Cheol Lee, Jin Kyung Rho
Journal: Cancer Research (2018)

Abstract PD-1/PD-L1 pathway blockade is a promising new cancer therapy. Although PD-1/PD-L1 therapy has yielded clinical benefits in several types of cancer, further studies are required to clarify predictive biomarkers for drug efficacy and to understand the fundamental mechanism of PD-1/PD-L1 interaction between host and tumor cells. Here, we show that microvesicles (MVs) derived from lung cancer cells express PD-L1 and play a role in immune escape by reducing T cell activity and promoting tumor growth. The abundance of PD-L1 on MVs represented the quantity of PD-L1 expression on cell surfaces. MVs containing PD-L1 inhibited IFN-γ secretion by Jurkat T cells. The IFN-γ secretion was restored by PD-L1 knockout or masking on the MVs. Both the forced expression of PD-L1 on cells without PD-L1 and treatment with MVs containing PD-L1 enhanced tumor growth in vivo. PD-L1 was present on MVs isolated from the plasma of patients with non-small cell lung cancer, and its abundance in the MVs was correlated with the PD-L1 positivity on tumor tissues. MVs could impair immune functions by reducing cytokine production and inducing apoptosis in CD8+ T cells. Our findings indicate that tumor-derived MVs expressing PD-L1 may be an important mediator of tumor immune escape. Citation Format: Dong Ha Kim, Yun Jung Choi, Seon Ye Kim, Jung-Eun Lee, Ki Jung Sung, Jae Cheol Lee, Jin Kyung Rho. Tumor-derived microvesicles promote tumor immune escape through PD-1/PD-L1 interaction [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-361.
Abstract 20509: Progression From Hypertensive Disorders of Pregnancy to Chronic Hypertension: Obesity Appears Especially Detrimental
Authors: Simon Timpka, Jennifer J Stuart, Lauren J Tanz, Eric B Rimm, Paul W Franks, Janet W Rich-Edwards
Journal: Circulation (2016)

Introduction: Hypertensive disorders of pregnancy (HDP), including preeclampsia and gestational hypertension, complicate 5-10 % of all pregnancies. Affected women have a higher risk of chronic hype...
Abstract 2165: Mini-patient-derived xenograft sensitive assay: A rapid systemic detection method for assessment of cancer therapeutics
Authors: Xiaoqing Pan, Feifei Zhang, Yuan Long, Hui Liu, Lin Guo, Jijun Cheng, Danyi Wen
Journal: Cancer Research (2018)

Abstract Patient-derived xenografts (PDX) have a high predictive power for efficacy of anticancer therapeutics. Limitations such as engraftment failure and time consuming for establishment and expansion of PDX models for drug efficacy testing need to be overcome for immediate application in patient decision-making for therapeutics. We developed a rapid in vivo drug sensitivity assay system so-called OncoVee® Mini-PDX, in which patient-derived tumor cells were arrayed within hollow fiber capsules in vivo over 7 days and screened against clinical relevant regimens. For validation study, the Mini-PDX was assessed by comparing the drug response in PDX tumor-bearing mice to response in Mini-PDX (capsule-containing) mice. The correlation between PDX tumorgrafts assay and Mini-PDX assay was evaluated using PDX models generated from 21 cancer patients. In the 21 cases, the overall predictive accuracy of the PDX assay for sensitivity was 69% and resistance was 88%, respectively. We also extended the approach to the patients with advanced malignancies. We report clinical cases in which Mini-PDX guided treatment improved the outcomes of treated cancer patients. In sum, Mini-PDX assay based on the capsule implantation was developed and optimized for quick assessment of the chemosensitivity of patients' cancers and found to be compatible with that of PDX tumorgrafts assay. This method hold promise for application of personalized chemotherapy for cancer patients. Citation Format: Xiaoqing Pan, Feifei Zhang, Yuan Long, Hui Liu, Lin Guo, Jijun Cheng, Danyi Wen. Mini-patient-derived xenograft sensitive assay: A rapid systemic detection method for assessment of cancer therapeutics [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 2165.
Abstract 4422: <i>miR-125b</i> mediates oral cancer suppression by targeting the antioxidative gene <i>peroxiredoxin like 2A</i> (<i>PRXL2A</i>)
Authors: Yi-Fen Chen, Yun-Yen Wei, Cheng-Chieh Yang, Chung-Ji Liu, Kuo-Wei Chang, Shu-Chun Lin
Journal: Cancer Research (2018)

Abstract Oral squamous cell carcinoma (OSCC) is a globally prevalent malignancy. The molecular mechanisms of this cancer remain to be elucidated to acquire further interception. Peroxiredoxin like 2A (PRXL2A) was named FAM213A previously, has been reported an antioxidant protein that protects cells from oxidative stress. Our previous study has identified the association between PRXL2A up-regulation in OSCC and the worse prognosis of patients. MicroRNAs (miRNAs) are small non-coding RNAs involved in the modulation of physical or pathological properties. miR-125 family genes drive pluripotent regulation in a wide variety of cancers. In this study, we specified the oncogenic eligibility of PRXL2A and clarified miR-125b as its upstream regulator. Down-regulation of miR-125b was observed in OSCC tumors. Lower miR-125b expression in OSCC tissues defined the worse patient prognosis. Reporter assays validated that PRXL2A as a direct target of miR-125b. Exogenous miR-125b expression resulted in the decreased oxidative stress, increased drug sensitivity, and suppressor activities, which was consistent with the knockout of PRXL2A gene in OSCC cells. That the suppressor activities of miR-125b being rescued by PRXL2A denoted the existence of miR-125b-PRXL2A regulatory axis in OSCC pathogenesis. Knockout of PRXL2A drastically attenuated the tumorigenic potential of OSCC cells. Overall, this study proposes novel clues demonstrating that the down-regulation of miR-125b suppressor underlies the PRXL2A up-regulation in OSCC, and this protects tumor cells from oxidative stress leading to the worse patient survival. Citation Format: Yi-Fen Chen, Yun-Yen Wei, Cheng-Chieh Yang, Chung-Ji Liu, Kuo-Wei Chang, Shu-Chun Lin. miR-125b mediates oral cancer suppression by targeting the antioxidative gene peroxiredoxin like 2A (PRXL2A) [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 4422.
Abstract 15604: Combinatorial Treatment with HDAC6 and DNA Methylation Modifiers in Attenuating Lung Vascular Hyperpermeability in LPS-induced Inflammatory Lung Injury
Authors: JohnsonRajasingh, JayakumarThangavel, SheejaRajasingh, BaharBarani, BuddhadebDawn
Journal: Circulation (2014)

Introduction: The pathogenesis of acute lung injury (ALI) is characterized by progressive respiratory failure with bilateral alveolar infiltrates and lung edema due to severe disruption of the lung vascular endothelial barrier. No effective therapy is currently available for prevention and treatment of this condition that is often fatal. No study has examined the efficacy of DNA methyl transferase inhibitor (5-Aza 2-deoxycytidine-Aza) and a specific histone deacetylase6 (HDAC6) inhibitor (Tubastatin A, BioVision, CA) combination (referred to as Aza+HDAC6) on inflammation, apoptosis and endothelial barrier function during sepsis. Hypothesis: Combinatorial treatment with Aza+HDAC6 would preserve lung microvascular endothelial barrier function and prevent protein-rich tissue fluid accumulation during sepsis. Methods and Results: The trans-endothelial electrical resistance (TER) and capillary filtration coefficient (Kfc) data show that in LPS-exposed endothelial cells and mice, therapy with Aza+HDAC6 leads to...
Abstract 20227: Impact of Solid Tumors on Venous Thrombosis: A Novel Unified Model to Understand Cancer-Associated Thrombosis
Authors: Guadalupe Lorenzatti Hiles, Angelica L Cates, Olivia R Palmer, Amir Emamdjomeh, Calvin B Chiu, Layla El-Sawy, Mark L Day, Joan M Greve, José A Diaz
Journal: Circulation (2016)

Cancer-associated thrombosis (C-AT) is poorly understood due to the lack of an animal model that combines these two pathologies in one biological system. Studies examining the incidence and predict...
Abstract 2673: Securidaca1 and 2 induced apoptosis: A PI3K-AKT dependent pathway in cervical cancer
Authors: Titus C. Obasi, Cornelia Braicu, Heiko Noack, Ioana Berindan-Neagoe, Bjorn Junker, Radu N. Oprean
Journal: Cancer Research (2018)

Abstract Background: Securidaca1 and 2 are plant-derived substances isolated from African medicinal plant S. longipedunculata, using new bioactivity-guided method partly described in Obasi et al. (2017). Our previous report suggested that certain fractions from this plant root were able to activate apoptosis in cervical cancer cell lines. Generally, over 90% of cervical cancer has been associated with high-risk human papilloma virus (HPV), whose etiologic molecule E6 oncoprotein is involved in the process of carcinogenesis. The purpose of this study, therefore, is to investigate the proapoptotic potentials of these substances and their ability to block cell survival mechanism, via antiapoptotic effectors of PI3K-AKT downstream. Experimental Procedure: Two cervical cancer cell lines (Caski and BU25TK), positive with HPV were used for the investigation. Cells were treated with the plant-derived substances and the IC50 was determined by MTT assay. Fluorescence microscopy (Annexin V-FITC, MPC and PI staining) was used to investigate autophagy/apoptosis, while relevant genes were analyzed by RT-qPCR. Results: Reduced cell proliferation was earlier achieved in dose- and time-dependent manner by fractions retaining Securidaca1 and 2, with IC50 of 7.03 and 16.39 (μg/mL) respectively on Caski cells. Late apoptosis was also activated on cells treated with securidaca1 fraction, while the securidaca2 in contrast indicated early apoptosis. Analysis by RT-qPCR revealed a fold-change expression of antiapoptotic proteins, MCL-1 and BCL2L1, more pronounced in securidaca1. Interestingly, the AKT-3 was significantly inhibited, correlating with low expression of MCL-1, BCL2L1, VEGFA and CDH-1. Data analysis suggests the most likely activation of apoptosis via PTEN regulated PI3K-AKT pathway and respondent downstream (mTOR/ NF-kB). Conclusion: The ability of Securidaca1 and 2 to kill tumor cells and induce apoptosis in manner involving multiple regulatory pathways enhances their potential against possible resistance and makes them attractive as candidates for anticancer development. Citation Format: Titus C. Obasi, Cornelia Braicu, Heiko Noack, Ioana Berindan-Neagoe, Bjorn Junker, Radu N. Oprean. Securidaca1 and 2 induced apoptosis: A PI3K-AKT dependent pathway in cervical 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 2673.
Abstract 2278: Scalability and reliability improvements to the Iso-Seq analysis pipeline enables higher throughput sequencing of full-length cancer transcripts
Authors: Elizabeth Tseng, Tyson Clark, Meredith H. Ashby
Journal: Cancer Research (2018)

Abstract The characterization of gene expression profiles via transcriptome sequencing has proven to be an important tool for characterizing how genomic rearrangements in cancer affect the biological pathways involved in cancer progression and treatment response. More recently, better resolution of transcript isoforms has shown that this additional level of information can be useful in stratifying patients into cancer subtypes with different outcomes and responses to treatment. The Iso-Seq protocol developed at PacBio is uniquely able to deliver full-length, single molecule cDNA sequences, allowing for the unambiguous, direct determination of splice variants. This has led to the identification of novel cancer biomarker candidates and has yielded new insights into gene fusion events that contribute to cancer progression.1,2,3 Recent improvements to the Iso-Seq bioinformatics pipeline increases the speed and scalability of data analysis while boosting the reliability of isoform detection and cross-platform usability. Here we report evaluation of Iso-Seq runs of human UHRR samples with spiked-in synthetic RNA controls on the Sequel System and show that the new pipeline recovers both more human and synthetic isoforms while reducing the number of false positives. We also share the results of sequencing the well-characterized HCC-1954 breast cancer and matched normal cell lines, which will be made publicly available. Combined with the recent simplification of the Iso-Seq sample preparation protocol, the new analysis pipeline completes a streamlined workflow for revealing the most comprehensive picture of transcriptomes at the throughput needed to characterize cancer samples. 1. Kohli M, et. al. (2017) Androgen Receptor Variant AR-V9 Is Coexpressed with AR-V7 in Prostate Cancer Metastases and Predicts Abiraterone Resistance. Clin Cancer Res. ePub ahead of print. doi: 10.1158/1078-0432.CCR-17-0017 2. Komor MA, et. al. (2017) Identification of differentially expressed splice variants by the proteogenomic pipeline Splicify. Mol Cell Prot. ePub ahead of print. doi: 10.1074/mcp.TIR117.000056 3. Weirather JL, et. al. (2015) Characterization of fusion genes and the significantly expressed fusion isoforms in breast cancer by hybrid sequencing. Nucleic Acids Res, 43 (18), e116. Citation Format: Elizabeth Tseng, Tyson Clark, Meredith H. Ashby. Scalability and reliability improvements to the Iso-Seq analysis pipeline enables higher throughput sequencing of full-length cancer transcripts [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 2278.
Local Tenomodulin Absence, Angiogenesis, and Matrix Metalloproteinase Activation Are Associated With the Rupture of the Chordae Tendineae Cordis
Authors: NaritakaKimura, ChisaShukunami, DaihikoHakuno, MasatoyoYoshioka, ShigenoriMiura, DenitsaDocheva, TokuhiroKimura, YasunoriOkada, GokiMatsumura, ToshiharuShin'oka, RyoheiYozu, JunjiroKobayashi, HatsueIshibashi-Ueda, YujiHiraki, KeiichiFukuda
Journal: Circulation (2008)

Background— Rupture of the chordae tendineae cordis (CTC) is a well-known cause of mitral regurgitation. Despite its importance, the mechanisms by which the CTC is protected and the cause of its rupture remain unknown. CTC is an avascular tissue. We investigated the molecular mechanisms underlying the avascularity of CTC and the correlation between avascularity and CTC rupture. Methods and Results— We found that tenomodulin, which is a recently isolated antiangiogenic factor, was expressed abundantly in the elastin-rich subendothelial outer layer of normal rodent, porcine, canine, and human CTC. Conditioned medium from cultured CTC interstitial cells strongly inhibited tube formation and mobilization of endothelial cells; these effects were partially inhibited by small-interfering RNA against tenomodulin. The immunohistochemical analysis was performed on 12 normal and 16 ruptured CTC obtained from the autopsy or surgical specimen. Interestingly, tenomodulin was locally absent in the ruptured areas of CTC,...