tbuckley/cabot-search huggingface dataset:
Abstract 987: Organoid-based characterization of patient tumors and microenvironments at single cell resolution
Authors: Ameen A. Salahudeen, Junjie Zhu, Jihang Ju, Arpit Batish, Ken Sutha, James T. Neal, Valeria Giangarra, Luz Montesclaros, Jerald Sapida, Osman Sharifi, Josephine Lee, Grace X. Zheng, Dhananjay A. Wagh, John A. Coller, Joel W. Neal, Sukhmani K. Padda, Chiara Sabatti, Calvin J. Kuo
Journal: Cancer Research (2018)

Abstract The advent of microenvironment directed cancer treatments such as antiangiogenic agents and recent immunotherapies have produced a pressing need for robust and systematic characterization of patient tumors and corresponding stromal populations. However, in vitro cultures of tumor biopsies do not typically preserve both the tumor epithelium and tumor microenvironment as an intact syngeneic unit. To address these limitations, we developed organoid cultures of surgically resected patient cancer biopsies that intrinsically retain diverse tumor microenvironmental cellular components without requiring reconstitution. We compared transcriptome profiles of fresh tumor cell populations to organoid cultures by droplet based single cell 5' RNA sequencing (scRNA-seq). Analysis of &amp;gt;50k single cell transcriptome profiles revealed tumor and stromal cell populations including tumor epithelia, fibroblasts and immune cells in fresh tumors. scRNA-seq of organoid cultures revealed a similar composition of native cancer cells and stromal components in both immune and non immune populations. In particular, 5' scRNA-seq enabled simultaneous characterization of paired T cell receptor alpha and beta chains as well as generalized gene expression in individual cells. We observed clonotype expansion of cytotoxic T cells in both fresh tumors and organoid cultures. The faithful recapitulation of tumor microenvironmental diversity within human organoid cultures should facilitate the in vitro exploration of immunotherapeutic agents and modeling of associated patient-specific responses. Citation Format: Ameen A. Salahudeen, Junjie Zhu, Jihang Ju, Arpit Batish, Ken Sutha, James T. Neal, Valeria Giangarra, Luz Montesclaros, Jerald Sapida, Osman Sharifi, Josephine Lee, Grace X. Zheng, Dhananjay A. Wagh, John A. Coller, Joel W. Neal, Sukhmani K. Padda, Chiara Sabatti, Calvin J. Kuo. Organoid-based characterization of patient tumors and microenvironments at single cell resolution [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 987.
Abstract 14015: Right Ventricular Remodeling is Additive to Global Longitudinal Strain in Predicting Long Term Survival in Patients with Pulmonary Hypertension
Authors: Akiko Goda, Keiko Ryo, Antonia M Delgado, Bhupendar Tayal, Marc Simon, Michael A Mathier, John Gorcsan
Journal: Circulation (2014)

Introduction: Right ventricular (RV) global longitudinal strain has been recently shown to be a marker of prognosis in patients with pulmonary hypertension (PH) but the additive role of RV remodeling on long term outcome is unclear. Hypothesis: Our aim was to test the hypothesis that RV remodeling measured by the RV area to left ventricular (LV) area ratio is additive to RV longitudinal strain in predicting prognosis in PH. Methods: We studied 120 PH patients, excluding patients with LVEF&lt;50%, congenital heart disease, or coronary disease and 15 normal subjects. We measured the RV to LV area ratio in the 4 chamber view at end-diastole as an RV remodeling index and calculated the peak RV global longitudinal strain using 2D speckle tracking. Outcome events were predefined as death or lung transplantation over 8 years. Results: The RV-LV area ratio was larger in PH patients than in normal control subjects as expected (0.64±0.09 vs. 1.18±0.59, p&lt;0.001). Using the RV global longitudinal strain cut off of -15% previously reported, it was significantly associated with death or lung transplant (AUC 0.629, p=0.0138). When the RV remodeling index RV-LV area ratio &gt; 0.73 was combined with RV global longitudinal strain &gt; -15%, patients had a significantly worse prognosis compared to RV strain value or RV remodeling index alone (p=0.0017; Hazard Ratio 2.29, 95% confidence interval of 1.34 to 3.9). Conclusion: RV remodeling by the echocardiographic RV-LV area ratio was additive to RV global longitudinal strain at predicting long term outcomes in PH patients and has promise for clinical applications.
Abstract 14669: Neurological Injury in Intermediate Risk Transcatheter Aortic Valve Implantation
Authors: Jonathon P Fanning, Allan J Wesley, Darren L Walters, Eamonn M Eeles, Adrian G Barnett, Andrew J Clarke, David G Platts, Andrew A Wong, Wendy Strugnell, Cliona O’Sullivan, Oystein Tronstad, John F Fraser
Journal: Circulation (2016)

Background: The application of TAVI to intermediate-risk cohorts is a controversial issue. In particular, significant concern surrounds the poorly defined incidence of neurological injury. While th...
Pericytes in Development and Pathology of Skeletal Muscle
Authors: OrnellaCappellari, GiulioCossu
Journal: Circulation Research (2013)

Increasing attention is currently devoted to the multiple roles that pericytes (also defined as mural, Rouget, or perivascular cells) may play during angiogenesis, vascular homeostasis, and pathology. Many recent excellent reviews thoroughly address these topics (see below); hence, we will not discuss them in detail here. However, not much is known about origin, heterogeneity, gene expression, and developmental potential of pericytes during fetal and postnatal development. This is likely because of the paucity of markers expressed by pericytes and the absence of truly unique ones. Thus, in vivo identification and ex perspective isolation are challenging and explain the relative little data available in comparison with neighbor but far more characterized cells such as the endothelium. Despite this preliminary knowledge, we will propose that contribution to growing mesoderm tissues may be an important role for pericytes. Thus, their ability to contribute to tissue regeneration may be a consequence of their ...
Abstract 14984: Cervical Branch Re-entry in Patients With Type A Acute Aortic Dissection is Related to a Patent False Lumen in the Aortic Arch and Enlargement After Ascending Aortic Replacement
Authors: Shota Yasuda, Kiyotaka Imoto, Keiji Uchida, Susumu Isoda, Norihisa Karube, Keiichiro Kasama, Tomoyuki Minami, Takuma Miyamoto, Yasuko Uranaka, Motohiko Goda, Shinichi Suzuki, Munetaka Masuda
Journal: Circulation (2015)

Background: In some patients with Stanford type A acute aortic dissection (A-AAD) who undergo resection of the entry site by ascending aortic replacement, the aortic arch false lumen is not thrombosed postoperatively, leading to late enlargement. This is attributed to blood leaking into the false lumen at the distal anastomosis. In addition, we hypothesized that a re-entry tear occurring in the distal part of cervical branches can act as an entry after operation. Patients and Methods: We retrospectively studied 85 patients (49 men; mean age 62 ± 12 years). Computed tomographic (CT) scans were evaluated before and after ascending aortic replacement, performed from 2006 through 2014. Patients with intramural hematoma were excluded. The presence of a patent false lumen in one or more cervical branches on preoperative CT was defined as cervical branch re-entry. Results: On preoperative CT, 41 patients (48%) had cervical branch re-entry. The prevalence of hypertension (61% vs. 84%, P = 0.027) and sex (proportion of men, 71% vs. 45%, P = 0.02) differed significantly between patients who had cervical branch re-entry and those who did not. A total of 47 patients (55%) had a patent false lumen in the aortic arch, caused by reverse blood flow from the cervical branch re-entry site in 20 patients, leakage at the distal anastomosis in 13 patients, and both factors in 14 patients. The false lumen remained patent after operation in 34 (83%) of the 41 patients with cervical branch re-entry, as compared with 13 (30%) of the 44 patients without re-entry. The proportion of patients with a patent false lumen after operation was significantly higher in the presence of cervical branch re-entry before operation (P&lt;0.01). The late follow-up rate was 85.9% (73 of 85 patients), with a mean follow-up of 46 ± 26 months. Significant risk factors for a late increase in aortic arch diameter to ≥10 mm were younger age (P = 0.02) and cervical branch re-entry (P = 0.02). Conclusions: The preoperative presence of a cervical branch re-entry in patients with A-AAD is related to a patent false lumen in the aortic arch early after ascending aortic replacement and is a risk factor for late aortic arch enlargement. Total aortic arch replacement should be considered in patients who have A-AAD with cervical branch re-entry.
The effect of public health-oriented drug law reform on HIV incidence in people who inject drugs in Tijuana, Mexico: an epidemic modelling study
Authors: Annick Borquez, Leo Beletsky, Bohdan Nosyk, Steffanie A Strathdee, Alejandro Madrazo, Daniela Abramovitz, Claudia Rafful, Mario Morales, Javier Cepeda, Dimitra Panagiotoglou, Emanuel Krebs, Peter Vickerman, Marie Claude Boily, Nicholas Thomson, Natasha K Martin
Journal: The Lancet Public Health (2018)

As countries embark on public health-oriented drug law reform, health impact evaluations are needed. In 2012, Mexico mandated the narcomenudeo reform, which depenalised the possession of small amounts of drugs and instituted drug treatment instead of incarceration. We investigated the past and future effect of this drug law reform on HIV incidence in people who inject drugs in Tijuana, Mexico.
Leukemia Inhibitory Factor, a Potent Cardiac Hypertrophic Cytokine, Activates the JAK/STAT Pathway in Rat Cardiomyocytes
Authors: HiroakiKodama, KeiichiFukuda, JingPan, ShinjiMakino, AkiyasuBaba, ShingoHori, SatoshiOgawa
Journal: Circulation Research (1997)

Abstract Leukemia inhibitory factor (LIF) is a member of the interleukin-6 family of cytokines, which induces a wide range of responses in a variety of cells. The aim of this study was to investigate whether LIF induces cardiomyocyte hypertrophy and transmits signals through the JAK/STAT (indicating just another kinase/signal transducer and activator of transcription) pathway in primary cultured neonatal rat cardiomyocytes. LIF increased protein content and [3H]phenylalanine uptake in cardiomyocytes in a dose-dependent manner. LIF (103 U/mL) induced rapid tyrosine phosphorylation of gp130, JAK1, JAK2, STAT1, and STAT3 but not Tyk2 or STAT2. LIF also induced autokinase activity of JAK1 in a time-dependent manner. Gel shift assays for interferon gamma activation site/interferon-stimulated responsive element and sis-inducible element (SIE) revealed that LIF induced dimerization of STAT1 and STAT3 and formation of sis-inducing factor complexes, which subsequently interacted with SIE in the promoter. Preincuba...
Multiple-gene targeting and mismatch tolerance can confound analysis of genome-wide pooled CRISPR screens
Authors: Jean-Philippe Fortin, Jenille Tan, Karen E. Gascoigne, Peter M. Haverty, William F. Forrest, Michael R. Costa, Scott E. Martin
Journal: Genome biology (2019)

Genome-wide loss-of-function screens using the CRISPR/Cas9 system allow the efficient discovery of cancer cell vulnerabilities. While several studies have focused on correcting for DNA cleavage toxicity biases associated with copy number alterations, the effects of sgRNAs co-targeting multiple genomic loci in CRISPR screens have not been discussed. In this work, we analyze CRISPR essentiality screen data from 391 cancer cell lines to characterize biases induced by multi-target sgRNAs. We investigate two types of multi-targets: on-targets predicted through perfect sequence complementarity and off-targets predicted through sequence complementarity with up to two nucleotide mismatches. We find that the number of on-targets and off-targets both increase sgRNA activity in a cell line-specific manner and that existing additive models of gene knockout effects fail at capturing genetic interactions that may occur between co-targeted genes. We use synthetic lethality between paralog genes to show that genetic interactions can introduce biases in essentiality scores estimated from multi-target sgRNAs. We further show that single-mismatch tolerant sgRNAs can confound the analysis of gene essentiality and lead to incorrect co-essentiality functional networks. Lastly, we also find that single nucleotide polymorphisms located in protospacer regions can impair on-target activity as a result of mismatch tolerance. We show the impact of multi-target effects on estimating cancer cell dependencies and the impact of off-target effects caused by mismatch tolerance in sgRNA-DNA binding.
Abstract 2353: Analysis of noncoding mutations in cancer revealed novel potentially pathogenic recurrent mutations
Authors: Takahiko Koyama, Laxmi Parida
Journal: Cancer Research (2018)

Abstract Introduction: 98% of mutations are non-coding mutations. Thus far, most non-coding mutations are ignored or merely classified as variant of unknown significance with a few exceptions, despite the fact that non-coding region plays significant role in regulations and other important biological processes. Although they would not be directly druggable, these non-coding mutations might be important for cancer etiology, response to treatments and prognosis assessments. Method: Mutations in non-coding genes, intron, upstream and downstream, and intergenic regions are collected from COSMIC and TCGA as defined in Ensemble GRCh37.75 gene definition and hg19 RefSeq. Over 15 million non-coding mutations are analyzed for recurrence over 10 samples. Mutations in neighborhood of IG genes and dbSNP150 polymorphisms are removed from further investigation. We analyzed remaining mutations for possible super enhancer and transcription factor binding. Result: 911 distinct recurrent mutations are identified. Promoter mutations in protein coding genes like MPRS31, NUDFB9, SZT2, WASF3 in addition to TERT are discovered. Intronic mutations of well-known cancer genes such as HIF1A, NF1, KMT2C, and ATR are discovered with their associated cancer type specificity. As for non-coding RNA's, lincRNA CROCCP2, LINC00969 and miRNA MIR4477 appear frequently. Only 182 mutations are reluctantly classified as intergenic; intergenic loci RP11-96F8.1-KSR1P1, MLLT10P1-DEFB115, and bP-21201H5.1-IGHV1OR21-1 contain unusually high recurrent mutations. Conclusion: Many non-coding mutations worth further investigation are found. Still, it is quite possible that many of these mutations might be artifacts resulting from paralogous alignments, gene definition compatibility and other technical issues. Importantly, we discovered novel intronic mutations in genes already associated with treatments. Mutations in intergenic regions might be involved in regulatory mechanisms and chromosomal structures. Understanding these non-coding mutations will further refine our understanding of biology as well as cancer. Citation Format: Takahiko Koyama, Laxmi Parida. Analysis of noncoding mutations in cancer revealed novel potentially pathogenic recurrent mutations [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 2353.
Rapid and Body Weight–Independent Improvement of Endothelial and High-Density Lipoprotein Function After Roux-en-Y Gastric Bypass
Authors: Elena Osto, Petia Doytcheva, Caroline Corteville, Marco Bueter, Claudia Dörig, Simona Stivala, Helena Buhmann, Sophie Colin, Lucia Rohrer, Reda Hasballa, Anne Tailleux, Christian Wolfrum, Francesco Tona, Jasmin Manz, Diana Vetter, Kerstin Spliethoff, Paul M. Vanhoutte, Ulf Landmesser, Francois Pattou, Bart Staels, Christian M. Matter, Thomas A. Lutz, Thomas F. Lüscher
Journal: Circulation (2015)

Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight loss-independent manner. The present study investigated in rats and patients whether obesity-induced endothelial and high-density lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1-dependent mechanism.Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin9-39 (10 μg·kg(-1)·h(-1)). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDL-mediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB.RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1-mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity.
Abstract 4475: Adenomatous polyposis coli like protein (APCLP) functions as a novel negative regulator of NF-kB signaling in colon cancer cells
Authors: Matthew Martin, Rasika Mundade, Tao Lu
Journal: Cancer Research (2018)

Abstract Colon cancer (CRC) is the second leading cause of cancer related deaths in the United States. CRC is marked by aberrantly activated signaling of the nuclear factor of kappaB (NF-kB), a family of transcription factors which regulate wide varieties of cellular processes. Despite recent advances in comprehension of players of NF-kB signaling, deeper understanding of its regulation is imperative for the development of novel cancer therapeutics. Using the powerful validation-based insertional mutagenesis (VBIM) technique, we recently discovered APCLP as a novel negative regulator of NF-kB. The objective of this study is to elucidate the role APCLP in regulating NF-kB signaling in CRC at the molecular and biological levels and to understand the mechanism by which this regulation occurs. To determine the biological effect of APCLP on NF-kB signaling, we used lentiviral vectors to either overexpress or knockdown (shRNA) APCLP in human CRC cell lines (HT-29, HCT116, DLD-1). We show that overexpression of APCLP decreased the NF-kB activity, reduced cellular proliferation, migratory ability, as well as anchorage-independent growth of cells while knockdown of APCLP had an inverse effect. Furthermore, in vivo experiments in a xenograft mouse model confirmed that APCLP overexpression impeded whereas shRNA knockdown promoted tumor growth. To study the mechanism by which APCLP regulated NF-kB signaling, we conducted co-Immunoprecipitation experiments and confirmed that APCLP and the major subunit of NF-kB, p65, may complex or bind directly to each other. Studies are ongoing regarding the mechanism of interaction between APCLP and p65. In summary, discovery of APCLP and understanding of its molecular mechanism and biological function are significant because the knowledge acquired from this study could lead to utilization of APCLP as a potential biomarker and therapeutic target in CRC as well as other cancers that are driven by hyperactivated NF-kB. Citation Format: Matthew Martin, Rasika Mundade, Tao Lu. Adenomatous polyposis coli like protein (APCLP) functions as a novel negative regulator of NF-kB signaling in colon 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 4475.
Abstract 5782: Selumetinib-based therapy in uveal melanoma patient-derived xenografts
Authors: Didier Decaudin, Rania EL Botty, Béré Diallo, Gerald Massonnet, Justine Fleury, Adnan Naguez, Marine Dubois, Emma J. Davies, Aaron Smith, Joanne Wilson, Colin Howes, Paul Smith, Nathalie Cassoux, Pascale Mariani, Sophie Piperno-Neumann, Sergio Roman Roman, Fariba Nemati
Journal: Cancer Research (2018)

Abstract Purpose: The prognosis of metastatic uveal melanoma (UM) patients remains one of the worst observed in human cancers. The identification of frequently mutated GNAQ/GNA11 and the activation of MAPK signaling in UM raise the possibility of using efficient targeted therapies such as MEK inhibition. The aim of our study was to evaluate drug combinations that might enhance the efficacy of the MEK inhibitor, selumetinib (AZD6244, ARRY-142886), using patient-derived xenografts. Materials: Five UM PDXs were used in this study, i.e., MP34, MP46, MP55, MP77, and MM26, all mutated for GNAQ or GNA11. Selumetinib was administered alone or combined with chemotherapies (dacarbazine and docetaxel) or targeted therapies: the ERK inhibitor, AZ6197 and the mTORC1/2 inhibitor, vistusertib (AZD2014). All targeted therapies were administered orally five days/week at the following doses: selumetinib at 25 mg/kg/day BID, AZ6197 at 50 mg/kg QD, AZD2014 at 15mg/kg QD. Dacarbazine was administered at 40 mg/kg for 5 consecutive days every 28 days and docetaxel at 15 mg/kg weekly. Both were administered intraperitoneally. Results: The combination of selumetinib and dacarbazine did not show improvement of antitumor efficacy in MP34, MM26 and MP55.The results showed a slight increase of overall response rate when selumetinib was combined with docetaxel, in comparison to the treatment with selumetinib or docetaxel alone. Importantly, we observed a significant antitumor effect when selumetinib was used in combination with AZ6197 or AZD2014 with respect to the monotherapies. Preliminary pharmacodynamics studies showed variation of the expression of p-ERK and also p-AKT and/or p-S6 when UM PDX were treated with AZ6197 or AZD2014 alone or in combination with selumetinib. Conclusion: Our data suggest that ERK and mTORC1/2 targeting could represent promising therapeutic approaches for the treatment of metastatic UM patients. Citation Format: Didier Decaudin, Rania EL Botty, Béré Diallo, Gerald Massonnet, Justine Fleury, Adnan Naguez, Marine Dubois, Emma J. Davies, Aaron Smith, Joanne Wilson, Colin Howes, Paul Smith, Nathalie Cassoux, Pascale Mariani, Sophie Piperno-Neumann, Sergio Roman Roman, Fariba Nemati. Selumetinib-based therapy in uveal melanoma patient-derived xenografts [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 5782.