tbuckley/cabot-search huggingface dataset:
White paper on microbial anti-cancer therapy and prevention
Authors: Neil S. Forbes, Robert S. Coffin, Liang Deng, Laura Evgin, Steve Fiering, Matthew Giacalone, Claudia Gravekamp, James L. Gulley, Hal Gunn, Robert M. Hoffman, Balveen Kaur, Ke Liu, Herbert Kim Lyerly, Ariel E. Marciscano, Eddie Moradian, Sheryl Ruppel, Daniel A. Saltzman, Peter J. Tattersall, Steve Thorne, Richard G. Vile, Halle Huihong Zhang, Shibin Zhou, Grant McFadden
Journal: Journal for ImmunoTherapy of Cancer (2018)

In this White Paper, we discuss the current state of microbial cancer therapy. This paper resulted from a meeting ('Microbial Based Cancer Therapy') at the US National Cancer Institute in the summer of 2017. Here, we define 'Microbial Therapy' to include both oncolytic viral therapy and bacterial anticancer therapy. Both of these fields exploit tumor-specific infectious microbes to treat cancer, have similar mechanisms of action, and are facing similar challenges to commercialization. We designed this paper to nucleate this growing field of microbial therapeutics and increase interactions between researchers in it and related fields. The authors of this paper include many primary researchers in this field. In this paper, we discuss the potential, status and opportunities for microbial therapy as well as strategies attempted to date and important questions that need to be addressed. The main areas that we think will have the greatest impact are immune stimulation, control of efficacy, control of delivery, and safety. There is much excitement about the potential of this field to treat currently intractable cancer. Much of the potential exists because these therapies utilize unique mechanisms of action, difficult to achieve with other biological or small molecule drugs. By better understanding and controlling these mechanisms, we will create new therapies that will become integral components of cancer care.
Abstract 2319: The role of CDKN1A and CDKN2B in the reprogramming of AML cells toward cell cycle arrest
Authors: Michael Roberts, Grace Crossland, Jeffrey Forrester
Journal: Cancer Research (2018)

Abstract AML is the most common acute leukemia in adults, showing rapid progression if left untreated. With current treatments, AML patients frequently achieve remission, but often experience relapse leading to the overall poor prognosis and high mortality of this cancer. We have employed human AML cell lines to examine the response of leukemia cells to phorbol esters. Phorbol esters mimic the action of diacyl glycerol (DAG), an activator of protein kinase C, which regulates several signal transduction pathways and cellular metabolic activities. In response to the phorbol ester PMA, AML cells undergo cell cycle arrest, differentiate into “normal” macrophage-like cells, and ultimately undergo programmed cell death. The transcriptome variations that accompany these changes have been explored by DNA microarray analysis and quantitative real-time PCR, revealing ~1250 genes that are differentially expressed as the cells transition from the cancer state to non-dividing, myeloid cells that initiate apoptosis. Two genes of great interest regarding cell cycle arrest are the cyclin-dependent kinase inhibitors CDKN1A and CDKN2B. We have shown that both of these genes are expressed at extremely low levels in AML cells, but are rapidly up-regulated during the PMA response, in keeping with their proposed function as tumor suppressor genes. We present here results from the transfection of expression plasmids containing the CDKN1A or CDKN2B genes into HL-60 cells, showing ~100 and ~1,000-fold overexpression, respectively. In addition, we have engineered a plasmid containing both genes and demonstrate their co-overexpression. RNA samples from cells transfected with CDKN1A, CDKN2B, and CDKN1A-CDKN2B have been subjected to RNA sequencing. RNA-seq analysis reveals changes in CDKN1A and CDKN2B-mediated gene expression, altering the AML transcriptome in ways that facilitate cell cycle arrest. Finally, we present results on the phenotypic and transcriptome changes of a stable HL-60 cell line containing an inducible CDKN2B gene after dox-induced overexpression, implicating CDKN2B as an important regulator of cell cycle progression in AML cells. Citation Format: Michael Roberts, Grace Crossland, Jeffrey Forrester. The role of CDKN1A and CDKN2B in the reprogramming of AML cells toward cell cycle arrest [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 2319.
Overview of PDEs and Their Regulation
Authors: KenjiOmori, JunKotera
Journal: Circulation Research (2007)

Contraction and relaxation of vascular smooth muscle and cardiac myocytes are key physiological events in the cardiovascular system. These events are regulated by second messengers, cAMP and cGMP, in response to extracellular stimulants. The strength of signal transduction is controlled by intracellular cyclic nucleotide concentrations, which are determined by a balance in production and degradation of cAMP and cGMP. Degradation of cyclic nucleotides is catalyzed by 3′,5′-cyclic nucleotide phosphodiesterases (PDEs), and therefore regulation of PDEs hydrolytic activity is important for modulation of cellular functions. Mammalian PDEs are composed of 21 genes and are categorized into 11 families based on sequence homology, enzymatic properties, and sensitivity to inhibitors. PDE families contain many splice variants that mostly are unique in tissue-expression patterns, gene regulation, enzymatic regulation by phosphorylation and regulatory proteins, subcellular localization, and interaction with association...
FrzA, a Secreted Frizzled Related Protein, Induced Angiogenic Response
Authors: PascaleDufourcq, ThierryCouffinhal, JéromeEzan, LaurentBarandon, CatherineMoreau, DanièleDaret, CécileDuplàa
Journal: Circulation (2002)

Background— The secreted frizzled related proteins (sFRP) are soluble proteins thought to interfere with the Wnt signaling. Our group previously demonstrated that one of these members, sFRP-1/FrzA, is strongly expressed during early phases of the vascularization process in embryonic vasculature and in the endothelium of arteries and capillaries in adults and modulated vascular cell proliferation. Methods and Results— Analysis of the expression of sFRP-1 during cyclic ovarian angiogenesis revealed that sFRP-1 is expressed during the formation of neovessels and becomes undetectable when the vasculature is fully maturated. We then studied the role of FrzA in several distinct angiogenic models. FrzA induced angiogenesis in a chick chorioallantoic membrane model. Moreover, gene transfer of AdFrzA in grafted mesenchymal and glioma cells increased vessel density and tumor growth. FrzA induced formation of vessels, which were enlarged, longer, and appeared to be more mature compared with vessels formed under cont...
Abstract 18362: Cardiac-targeted Therapy With Cardiotrophin-1 Rescues Defective Right Ventricular Adaptation in Severe Pulmonary Arterial Hypertension in Fischer Rats
Authors: Colin Suen, Mohammad Abdul-Ghani, Yupu Deng, Lynn Megeney, Duncan J Stewart
Journal: Circulation (2015)

Introduction: In patients with pulmonary arterial hypertension (PAH), right ventricular (RV) dysfunction is one of the strongest predictors of poor prognosis. Therapies targeting RV failure could lead to significant improvement in exercise tolerance and survival in patients with severe PAH. Cardiotrophin-1 (CT-1) is a member of the IL-6 cytokine family that promotes physiological cardiac hypertrophy and cardiomyocyte survival. Hypothesis: We hypothesized that RV-specific therapy using CT-1 therapy will improve RV adaptation to PAH. Methods: PAH was induced by a single subcutaneous injection of SU5416 (SU; 20 mg/kg) followed by exposure to chronic hypoxia (CH; 10% O2) for 3 weeks. On day 22 post SU, human recombinant cardiotrophin-1 (CT-1, Fate Therapeutics) (6 ug/kg/hr) or vehicle (PBS) was administered via subcutaneously implanted mini-osmotic pumps until end-study at 7 weeks. Echocardiography (Vevo 2100, VisualSonics) was performed weekly starting at baseline (day 21). Results: We observed a ~5-fold reduction in expression of endogenous CT-1 mRNA in the RV of rats treated with SU5416+hypoxia compared to healthy controls. Administration of CT-1 to Fischer rats with PAH had no significant effect on pulmonary hemodynamics (pulmonary acceleration time, RVSP), nor RV/LV+S. At 6 weeks post SU, CT-1 significantly reduced RV dilatation (end diastolic RV/LV internal diameter) (p&lt;0.001), improved RV function (cardiac output, RV fractional area change, p&lt;0.05) (Figure 1), which was associated with an increase in RV capillary density (p&lt;0.05) and a 2-fold improvement in survival (31 vs 12%). Conclusions: Targeted cardiac therapy with CT-1 therapy improved RV adaptation in the SU/CH model of severe PAH without altering pulmonary hemodynamics, which in part was mediated by enhancing RV myocardial angiogenesis. These findings support the development of RV-targeted therapeutics for patients with severe PAH and RV failure.
Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations
Authors: Lisa R. Forbes, Tiphanie P. Vogel, Megan A. Cooper, Johana Castro-Wagner, Edith Schussler, Katja G. Weinacht, Ashley S. Plant, Helen C. Su, Eric J. Allenspach, Mary Slatter, Mario Abinun, Desa Lilic, Charlotte Cunningham-Rundles, Olive Eckstein, Peter Olbrich, R. Paul Guillerman, Niraj C. Patel, Yesim Y. Demirdag, Christa Zerbe, Alexandra F. Freeman, Steven M. Holland, Paul Szabolcs, Andrew Gennery, Troy R. Torgerson, Joshua D. Milner, Jennifer W. Leiding
Journal: Journal of Allergy and Clinical Immunology (2018)
Abstract 15130: The Role of Myocardial Contrast Echocardiography in Identifying the Burden of Myocardial Ischemia in Coronary Artery Disease
Authors: Jayanth R Arnold, Theodoros D Karamitsos, Jane M Francis, Majo Joseph, Roxy Senior, Stefan Neubauer, Harald Becher, Joseph B Selvanayagam
Journal: Circulation (2011)

BACKGROUND Myocardial contrast echocardiography (MCE) is an emerging non-invasive technique for the diagnosis of coronary artery disease (CAD). Previous studies confirm the ability of MCE to detect...
Fibroblast Growth Factor 21 Prevents Atherosclerosis by Suppression of Hepatic Sterol Regulatory Element-Binding Protein-2 and Induction of Adiponectin in Mice
Authors: ZhuofengLin, XueboPan, FanWu, DeweiYe, YiZhang, YuWang, LeigangJin, QizhouLian, YuHuang, HongDing, ChrisTriggle, KaiWang, XiaokunLi, AiminXu
Journal: Circulation (2015)

Background—Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. It acts as a key downstream target of both peroxisome proliferator-activated receptor α and γ, the agonists of which have been used for lipid lowering and insulin sensitization, respectively. However, the role of FGF21 in the cardiovascular system remains elusive. Methods and Results—The roles of FGF21 in atherosclerosis were investigated by evaluating the impact of FGF21 deficiency and replenishment with recombinant FGF21 in apolipoprotein E−/− mice. FGF21 deficiency causes a marked exacerbation of atherosclerotic plaque formation and premature death in apolipoprotein E−/− mice, which is accompanied by hypoadiponectinemia and severe hypercholesterolemia. Replenishment of FGF21 protects against atherosclerosis in apolipoprotein E−/−mice via 2 independent mechanisms, inducing the adipocyte production of adiponectin, which in turn acts on the blood vessels t...
Abstract 5: Restoring Nitroso-Redox Balance as a Therapeutic Approach for Cardiovascular Disease
Authors: Vikram Shettigar, Honglan Wang, Bo Zhang, Steve R Roof, Paul M Janssen, Jonathan P Davis, Richard J Gumina, Brandon J Biesiadecki, Frederick A Villamena, Mark T Ziolo
Journal: Circulation Research (2017)

Anti-oxidant therapy has been an immense clinical disappointment for the treatment of cardiomyopathies. Concurrently with the increase in reactive oxygen species (ROS), there is also a decrease in cardiac levels of nitric oxide (NO), resulting in a nitroso-redox imbalance not addressed by anti-oxidant treatment alone. Key modulators of cardiac function are sensitive to the nitroso-redox balance such as kinases and phosphatases. Thus, along with changes in protein oxidation and/or S-nitrosylation levels, the nitroso-redox imbalance also alters protein phosphorylation. We developed a unique and novel compound (EMEPO) that can correct the nitroso-redox imbalance by simultaneously scavenging ROS and producing NO. We hypothesized that EMEPO is a novel agent that will ameliorate cardiac dysfunction by reestablishing the proper protein post-translational modifications. We demonstrated the efficacy of EMEPO in two cardiac models of nitroso-redox imbalance; a genetic model (NOS1 -/- ) and a disease model- murine myocardial infraction (MI). Both models displayed nitroso-redox imbalance with systolic and diastolic dysfunction. EMEPO treatment had a much greater effect than anti-oxidant treatment alone in palliating the cardiac dysfunction. A major contributor to these dysfunctions observed in cardiomyopathies is altered ryanodine receptor (RyR) activity. EMEPO was able to restore RyR activity and each aberrant post-translational modification (oxidation, S-nitrosylation, and phosphorylation). We believe these EMEPO-induced changes in RyR will occur in many proteins that orchestrate signaling networks and function. Our data highly suggest that simultaneously restoring both ROS and NO levels (i.e., correcting the nitroso-redox imbalance) is a promising therapeutic approach for MI and heart failure patients. Our first designed nitroso-redox balancer, EMEPO, shows great potential as a novel strategy for the treatment of heart disease.
Abstract 16142: Grad 3-Ischemia (QRS Complex Distortion) as a Predictor of Myocardial Damage as Assessed by Cardiac Magnetic Resonance Imaging and Clinical Prognosis in Patients With ST-Elevation Myocardial Infarction
Authors: Karl-PhilippRommel, HadilBadarnih, SteffenDesch, MatthiasGutberlet, GerhardSchuler, HolgerThiele, IngoEitel
Journal: Circulation (2014)

Introduction: Predicting the extent of myocardial damage on early electrocardiographic (ECG) findings could be helpful for improved risk stratification in patients with acute reperfused ST-elevation myocardial infarction (STEMI). Distortion in the terminal portion of the QRS complex (so called grade 3 ischemia, G3I) has been associated with adverse outcomes in STEMI patients. The correlation of G3I with infarct size and microvascular injury is not well defined. Objective: To studied the relation of G3I with myocardial damage as assessed by CMR and the association of G3I with adverse clinical outcomes in a STEMI population treated by primary percutaneous coronary intervention (PCI). Methods: We analyzed the ECGs of 572 consecutive STEMI patients regarding the presence or absence of G3I. G3I was defined as: 1) complete loss of S waves in 2 adjacent leads with typical Rs configuration (i.e. V1-V3), or 2) ST-J point to R wave amplitude ratio >0.5 in other leads with qR configuration. CMR was performed within ...
Abstract 10323: Tadalafil Therapy Improves Endothelial Thrombomodulin in Hypoxemic Patients With Pulmonary Arterial Hypertension Associated With the Eisenmenger Syndrome
Authors: Mariana M Clavé, Nair Y Maeda, Ana M Thomaz, Sonia M Mesquita, Sérgio P Bydlowski, Antonio A Lopes
Journal: Circulation (2015)

Introduction: Thrombomodulin (TM) is a plasma membrane chondroitin sulfate proteoglycan acting as a natural endothelial anticoagulant and anti-thrombotic factor. Binding of TM to thrombin leads to protein C activation with subsequent cleavage of activated coagulation factors V and VIII. In pulmonary arterial hypertension (PAH), particularly in hypoxemic patients with Eisenmenger syndrome, endothelial dysfunction is associated with heightened circulating levels of von Willebrand factor antigen (VWF:Ag) and tissue plasminogen activator (t-PA), but decreased TM reflecting diminished endothelial production. Hypothesis: Plasma TM, t-PA, VWF:Ag and functional parameters may be improved in patients with Eisenmenger syndrome subjected to chronic treatment with tadalafil. Methods: Fifteen patients aged 12 to 51 years (median 30 years) were evaluated at baseline, and 90 and 180 days of treatment with oral tadalafil (single daily dose of 40 mg). The functional capacity was accessed using the six-minute walk test and endothelial markers were analyzed by enzyme-linked immunoassays. Results: At baseline, levels of all three endothelial markers were altered in patients compared to controls (respectively, 8.62±3.50 ng/mL vs . 5.13±1.69 ng/mL for t-PA, 121±21 U/dL vs . 94±23 U/dL for VWF:Ag and 1.92±0.49 ng/mL vs . 3.41±0.50 ng/mL for TM. Tadalafil treatment resulted in improvement of exercise capacity (six-minute walked distance, 6MWD) and peripheral oxygen saturation (O 2 Sat), with decreased hematocrit (Htc). Plasma TM increased mildly but significantly, while t-PA level decreased (Table). Conclusion: In the Eisenmenger syndrome, PAH therapy with tadalafil improves not only the physical capacity, O 2 Sat and Htc, but also endothelial markers. The modest increase in circulating TM may reflect improved endothelial TM production and protection against in situ thrombosis, a largely known complication of this syndrome.
Dissecting complicated viral spreading of enterovirus 71 using in situ bioorthogonal fluorescent labeling
Authors: Hong Pan, Xiangjie Yao, Weihua Chen, Fangfang Wang, Huamei He, Lanlan Liu, Yaqing He, Jinquan Chen, Puzi Jiang, Renli Zhang, Yifan Ma, Lintao Cai
Journal: Biomaterials (2018)
Abstract 2359: Adults with heterozygote carrier of immune deficiency variants have increased risk of cancer
Authors: Daeyoon Kim, Murim Choi, Moon-woo Seong, Sung-Soo Yoon, Youngil Koh, Hongseok Yun
Journal: Cancer Research (2018)

Abstract Introduction: Relationship between several mendelian disorders and cancer has been reported. Although correlation between immune-deficiency disorder and cancer development is well known, most studies have been conducted on patients with established immunodeficient diseases. Rate of tumor development in recessive heterozygous carriers of immunodeficiency genes is not clear yet. Methods: Using whole-genome sequence data from International Cancer Genome Consortium (ICGC) Pan-Cancer Analysis of Working Group (PCAWG) and 1000 Genome projects, we analyzed 110 genes which are associated with immunodeficiency disorder and cancer risk. The 110 genes are reported previously as pathogen of immunodeficiency disorder and present in OMIM database. We selected a pathogenic variant of the 110 genes based on the clinical database such as HGMD and Clivar. Results: Total of 461 pathogenic variants were detected in both cohorts. The prevalence of pathogenic variants of Immunodeficiency disorder was 4.7% in the ICGC-PCAWG cohort and 3.3% in 1000 Genome cohort. Pathogenic variants were observed more frequently in ICGC-PCAWG than in 1000 Genome cohort (p=0.00267) (odds ratio 1.55, 95% confidence interval 1.16-2.06), implying that immune deficiency disorder increases cancer risk. Gallbladder cancer patients most frequently had pathogenic variants (25%, 3/12) followed by ovarian cancer patients (8%, 9/110). The gene with the strongest cancer-evoking potential was TYK2 (p= 4.978 × 10-7). In addition, seven genes were uncovered to be significantly associated with cancer development (RORC, ATM, RTEL1, CTSC, RAG1, PMS2 and IRAK4). Conclusion: In conclusion, using large whole-genome sequencing global projects, we statistically prove the previous notion that immunodeficiency provokes cancer development. We identified specific germline variants associated with cancer, which would be considered as cancer-predisposing genes. Citation Format: Daeyoon Kim, Murim Choi, Moon-woo Seong, Sung-Soo Yoon, Youngil Koh, Hongseok Yun. Adults with heterozygote carrier of immune deficiency variants have increased risk of 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 2359.
Abstract 14741: Asian Dust Has an Impact on the Incidence of Acute Myocardial Infarction ~a Time-stratified Case-crossover Study
Authors: SunaoKojima, KunihikoMatsui, KayoUeda, HiroshiNitta, HisaoOgawa
Journal: Circulation (2014)

Introduction: Air pollution, a mixture of gases and particles that come from manmade and natural sources, has been shown to increase hospi¬tal admission and mortality attributable to cardiovascular diseases. Asian dust (AD), a windblown sand dust originating from mineral soil in the desert, and PM2.5, which comes from cars and trucks, power plants, industrial boilers, other industrial sources and wildfires, are the standard for particulate matter representing air pollution. Hypothesis: We assessed the hypothesis that AD and PM2.5 were associated with the incidence of acute myocardial infarction (AMI) in Kumamoto prefecture. Methods: Kumamoto prefecture is located in southwestern Japan and has a stable population of 1.8 million. A total of 3,670 AMI patients in 2009-2012 in Kumamoto prefecture were entirely registered and 199 AMI patients whose onset date was not definite were excluded in the present study. A time-stratified case-crossover study was conducted to assess the association between particulate m...
Short- Versus Long-Term Duration of Dual-Antiplatelet Therapy After Coronary Stenting
Authors: MarcoValgimigli, GianlucaCampo, MoniaMonti, PascalVranckx, GianfrancoPercoco, CarloTumscitz, FaustoCastriota, FedericoColombo, MatteoTebaldi, GiuseppeFucà, Moh'dKubbajeh, ElisaCangiano, MonicaMinarelli, AntonellaScalone, CaterinaCavazza, AliceFrangione, MarcoBorghesi, JleniaMarchesini, GiovanniParrinello, RobertoFerrari
Journal: Circulation (2012)

Background—The optimal duration of dual-antiplatelet therapy and the risk-benefit ratio for long-term dual-antiplatelet therapy after coronary stenting remain poorly defined. We evaluated the impact of up to 6 versus 24 months of dual-antiplatelet therapy in a broad all-comers patient population receiving a balanced proportion of Food and Drug Administration–approved drug-eluting or bare-metal stents. Methods and Results—We randomly assigned 2013 patients to receive bare-metal, zotarolimus-eluting, paclitaxel-eluting, or everolimus-eluting stent implantation. At 30 days, patients in each stent group were randomly allocated to receive up to 6 or 24 months of clopidogrel therapy in addition to aspirin. The primary end point was a composite of death of any cause, myocardial infarction, or cerebrovascular accident. The cumulative risk of the primary outcome at 2 years was 10.1% with 24-month dual-antiplatelet therapy compared with 10.0% with 6-month dual-antiplatelet therapy (hazard ratio, 0.98; 95% confidenc...