tbuckley/cabot-search huggingface dataset:
Abstract LB-282: Dynamic regulation of CD73 expression in cancer associated fibroblasts enforces immunosuppression via a feedforward adenosinergic pathway
Authors: Miao Yu, Gang Guo, Lei Huang, Libin Deng, Roni Bollag, Andrew Mellor, Huidong Shi, Yan Cui
Journal: Cancer Research (2018)

Abstract CD73 is the major extracellular adenosine-generating ecto-5'-nucleotidase (Nt5e) that metabolizes extracellular (e) AMP and generates immunosuppressive adenosine (eADO). Elevated CD73 expression is often exploited by tumors and other cellular constituents of the tumor microenvironment (TME) as a mechanism of immune evasion. Clinically, a high level of CD73 expression in the tumor microenvironment (TME) is linked to poor prognosis. Experimental evidence also demonstrates that host CD73 activity in both hematopoietic and non-hematopoietic compartments augments the suppressive milieu of the TME. Nevertheless, the identities of CD73-expressing non-hematopoietic cells and factors that regulate CD73 activity of these cells have yet to be clearly defined. Our recent results unravel that cancer associated fibroblasts (CAFs) constitute a crucial non-hematopoietic CD73hi compartment in the TME of human colorectal cancer (CRC) and murine MC38 CRC and EG7 lymphoma ectopic models. Strikingly, the CD73 expression profile among cohorts of published human CRC and breast cancer patient data sets confirmed its significant positive association with that of CAF-related markers, both of which are negatively correlated with poor survival. Cellular and transcriptomic analyses of CAFs in the EG7 TME reveal that CD73 expression in CAFs increases progressively during tumor progression, associated with elevated tissue hypoxia. Mechanistically, we demonstrate that the progressive elevation of CD73 expression in CAFs during tumor progression is caused by elevated eADO in the TME, which is resulted by the hypoxia/necrosis-associated eATP release. Furthermore, this eADO/adenosingeric pathway-induced CD73 upregulation in CAFs is mostly mediated by activation of A2BR and downstream MAPK signaling, which exacerbates eADO accumulation and serves as a feedforward loop of re-enforcing the immunosuppressive TME. Our study demonstrated that clinically and experimentally, high level of CD73 expression in CAFs represents another crucial immune checkpoint in the TME. Targeted inactivation or blockade of A2BR signaling may serve as a new strategy to prevent or alleviate the initiation of the eADO-CD73-associated amplification of immunosuppression in the TME, thereby improving the outcome of immunotherapy. Citation Format: Miao Yu, Gang Guo, Lei Huang, Libin Deng, Roni Bollag, Andrew Mellor, Huidong Shi, Yan Cui. Dynamic regulation of CD73 expression in cancer associated fibroblasts enforces immunosuppression via a feedforward adenosinergic pathway [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-282.
Cardiomyocyte Differentiation of Human Induced Pluripotent Stem Cells
Authors: LimorZwi, OrenCaspi, GilArbel, IritHuber, AmiraGepstein, In-HyunPark, LiorGepstein
Journal: Circulation (2009)

Background— The ability to derive human induced pluripotent stem (hiPS) cell lines by reprogramming of adult fibroblasts with a set of transcription factors offers unique opportunities for basic and translational cardiovascular research. In the present study, we aimed to characterize the cardiomyocyte differentiation potential of hiPS cells and to study the molecular, structural, and functional properties of the generated hiPS-derived cardiomyocytes. Methods and Results— Cardiomyocyte differentiation of the hiPS cells was induced with the embryoid body differentiation system. Gene expression studies demonstrated that the cardiomyocyte differentiation process of the hiPS cells was characterized by an initial increase in mesoderm and cardiomesoderm markers, followed by expression of cardiac-specific transcription factors and finally by cardiac-specific structural genes. Cells in the contracting embryoid bodies were stained positively for cardiac troponin-I, sarcomeric α-actinin, and connexin-43. Reverse-tra...
Abstract 4337: Identification of novel fusion gene, PUM1-TRAF3, as potent biomarker in bile duct cancer
Authors: Dawoon E. Jung, Kahee Kim, Chanyang Kim, Soo Been Park, Jung Hyun Jo, Hee Seung Lee, Si Young Song
Journal: Cancer Research (2018)

Abstract Background: Gene fusion occurs when a part of one gene fuses with a part of another gene by genome rearrangement and may possess oncogenic properties. Bile duct cancer (BDC) are one of the most lethal malignancy, but lack of proper diagnostic or prognostic markers. Our aim was to investigate BDC specific fusion genes found in patient's specimens and its clinical significance. Method : We extracted total RNA from five BDC tissues and normal tissues from the same patients. RNA sequencing was performed and the result data was analyzed using ChimeraScan, Jaffa or FusionCatcher softwares to detect gene fusion. The expression of the detected novel fusion gene was confirmed by ddPCR using tissues from the operated BDC patients and its clinical significance was analyzed with medical information of the patients. Result : We found 52 BDC specific fusion genes by RNA sequencing and we identified novel BDC specific fusion gene, PUM1-TRAF3 by bioinformatics analysis. Total 55 patients with BDC who underwent curative surgery were evaluated to investigate clinical significance of PUM1-TRAF3. There were 28 patients (50.1%) who expressed PUM1-TRAF3 by ddPCR. Patients with PUM1-TRAF3 presented higher rate of female gender (57.1 vs. 25.9, p=0.019), advanced stage (25% vs. 3.7%, p=0.025) and recurrence rate (64.7 vs. 48.1%, p=0.080) compared to patients without PUM1-TRAF3. Disease free survival (DFS) was 12.1 vs. 29.8 (p=0.078) and overall survival was 26.1 vs. 36.6 (p=0.239) between the patients with PUM1-TRAF3 and without PUM1-TRAF3. In multivariated analysis by cox-regression, expression of PUM1-TRAF3 (HR 2.86, p=0.023), advanced stage (HR 2.69, p=0.041), higher CA19-9 (HR 1.00, p=0.011) and positive resection margin (HR 4.57, p=0.002) were significantly associated with short DFS.Conclusion : In this study, we identified novel BDC-specific fusion gene, PUM1-TRAF3. Expression of PUM1-TRAF3 was confirmed in patient's tissues and associated with short DFS in operated BDC patients. PUM1-TRAF3 can be a potent biomarker in BDC. Citation Format: Dawoon E. Jung, Kahee Kim, Chanyang Kim, Soo Been Park, Jung Hyun Jo, Hee Seung Lee, Si Young Song. Identification of novel fusion gene, PUM1-TRAF3, as potent biomarker in bile duct 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 4337.
Abstract 4403: Development of 5-FU modified tumor suppressor miRNAs as a platform for miRNA based cancer therapeutics
Authors: Andrew Fesler, Shixiang Guo, Zachary Ye, Matthew Godwin, Hyaizha Wang, Jingfang Ju
Journal: Cancer Research (2018)

Abstract Despite extensive efforts to develop effective delivery technologies for nucleic acid based therapeutic agents, it remains a challenge to deliver therapeutic miRNAs to cancer cells. We have recently developed a novel approach to modify miRNAs by replacing uracil with 5-Fluorouracil (5-FU) in the guide strand of the miRNA molecule (e.g. miR-129, miR-15a). This modification combines the power of 5-FU with tumor suppressor miRNAs to create a potent, and multi-targeted therapeutic molecule without altering the function of the native miRNA. miRNA with this modification have a number of unique features such as retaining target specificity, vehicle free delivery, enhanced potency, and stability. To demonstrate the general applicability of this approach to other tumor suppressor miRNAs, in this study, we have screened a number of miRNA mimics incorporating this modification (e.g. miR-215, miR-140, miR-200c, miR-194, let-7g, miR-502, miR-506) in several major cancer types including colon cancer, pancreatic cancer, and breast cancer. Our results show that the 5-FU modified miRNAs are more potent (low nM range) at inhibiting cancer cell proliferation than the native miRNAs. More importantly, the miRNA mimics are able to eliminate chemoresistant cancer stem like cells. These modified mimics can be delivered into cancer cells without the aid of a delivery vehicle. The modification also did not alter target specificity of the miRNAs, a critical feature of these miRNA mimics. This work demonstrates the potential of this modification to be applied to a broad spectrum of miRNAs in different cancers, and represents a significant advancement in the development of therapeutic miRNAs for cancer treatment. Citation Format: Andrew Fesler, Shixiang Guo, Zachary Ye, Matthew Godwin, Hyaizha Wang, Jingfang Ju. Development of 5-FU modified tumor suppressor miRNAs as a platform for miRNA based 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 4403.
Abstract 4543: Combined analysis of cell-free DNA methylation in plasma for early detection of NSCLC
Authors: Li Cao, Hao Wang, Xu Dong, Li Zhong
Journal: Cancer Research (2018)

Abstract Introduction: Detection of cell-free DNA (cfDNA) methylations in plasma samples may provide diagnostic information for non-small lung cancer (NSCLC). Here, we evaluated 5 preselected genes for methylation analysis from patient and control plasma samples. Method: Plasma samples were collected from 91 patients who were diagnosed with primary NSCLC with pathological or cytological confirmation. All the cases did not received any surgery or chemotherapy treatments when blood samples were collected. Meanwhile, 58 cases of healthy blood samples were collected as the control group. Methylation specific PCR (methylation specific-PCR, MS-PCR) was used to detect RUNX3, RASSF1A, 3-OST-2, DAPK, PTPRO genes methylation. Data was analyzed individually as well as jointly for the optimal diagnostic accuracy. Results: The DNA methylation rates for the 5 genes RUNX3, RASSF1A, 3-OST-2, DAPK, PTPRO were 47.25% (43/91), 51.65% (47/91), 27.47% (25/91), 36.26% (33/91), and 41.76% (38/91) respectively in patient plasma samples. In the normal control group, only PTPRO gene methylation was detected with the methylation rate of 5.2% (3/58), and the rest of 4 genes were not detected. Methylation of RUNX3 gene was found to have higher frequencies in adenocarcinoma than other cell types of NSCLC (P &amp;lt; 0.05). DAPK gene methylation was found to be associated with the stages of lung cancer, and methylation rate was higher in stage III/IV than in stage I/II (P &amp;lt; 0.05). Combined analysis of the 5 genes methylation rates was achieved the sensitivity 86.81% (79/91) and the specificity 79.31% (46/58). Conclusion: The combined DNA methylation analysis of RUNX3, RASSF1A, 3-OST-2, DAPK, and PTPRO genes with MS-PCR achieved a satisfied sensitivity and specificity in NSCLC diagnosis. Citation Format: Li Cao, Hao Wang, Xu Dong, Li Zhong. Combined analysis of cell-free DNA methylation in plasma for early detection of NSCLC [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 4543.
Predictive Factors of Restenosis After Coronary Implantation of Sirolimus- or Paclitaxel-Eluting Stents
Authors: AdnanKastrati, AlbanDibra, JulindaMehilli, SandraMayer, SusannePinieck, JürgenPache, JosefDirschinger, AlbertSchömig
Journal: Circulation (2006)

Background— The efficacy of drug-eluting stents in reducing restenosis risk has not been uniform across patient subsets. Identifying predictive factors of restenosis may help improve outcomes after percutaneous coronary interventions. Methods and Results— All patients who underwent successful implantation of sirolimus- or paclitaxel-eluting stents in native vessels for de novo lesions between August 2002 and December 2004 were eligible for this study. All data were prospectively collected. Angiographic restenosis was defined as diameter stenosis ≥50% at follow-up in the in-segment area. Target lesion revascularization was defined as any revascularization procedure involving the target lesion. Included in this study were 1845 patients with 2093 target lesions. Multivariable analysis showed that vessel size, final diameter stenosis, and drug-eluting stent type were the strongest predictors of restenosis. A 0.5-mm decrease in vessel size was associated with adjusted odds ratios (ORs) of 1.74 (95% CI, 1.31 to...
Abstract 5053: Mlh1 deficiency increases the risk of hematopoietic malignancies post low- and high-LET radiation exposure
Authors: Rutulkumar Patel, Stanton L. Gerson, Scott M. Welford
Journal: Cancer Research (2018)

Abstract Introduction/Aim: Natural sources of radiation in space include galactic cosmic rays (GCR), solar energetic particles and trapped energetic particles in a planetary magnetic field. These sources are difficult to shield, thus posing significant health risks to astronauts on long-term inter-planetary missions. During space travel, genomic instability is a major concern where astronauts are exposed to potent sources of ionizing radiation, namely GCR consisting of high energy and charged atomic nuclei. In particular, hematopoietic stem cells (HSCs) are susceptible to internal and external stresses that threaten the integrity of the cell, and accumulation of damage can lead to HSCs dysfunction and oncogenesis. Recent data has demonstrated that humans accumulate microsatellite instability with acquired loss of MLH1 protein in HSCs as a function of age. Therefore, we hypothesized that high-LET (linear energy transfer) radiation characteristic of the GCR that will confront astronauts on space missions will damage HSCs and contribute to induction and progression of hematopoietic malignancies. Methods: To study this hypothesis, we employed a DNA mismatch repair deficient mouse model (Mlh1+/-) to study the effects of low-LET γ-ray vs high-LET 56Fe ion radiation on HSCs of potential astronaut population. In vitro colony forming unit assays and in vivo complete blood count (CBC) plus competitive repopulation assays were carried out to understand harmful impact of radiation and Mlh1 deficiency on HSCs functions. In addition, mice were followed up to 18 months post irradiation to observe HSC malignancies in Mlh1+/+ and Mlh1+/- mice. Results: HSC short- and long-term functional assays showed defects in HSCs/HPCs function caused by irradiation, but not depending on Mlh1 status. CBC 5 and 9 months post irradiation demonstrated no impact of irradiation or Mlh1 status on HSC differentiation. However, 56Fe-ion irradiated Mlh1+/- mice showed a significant higher incidence of lymphomagenesis compared to γ-rays irradiated and sham-irradiated Mlh1+/- mice. In addition, immunohistochemistry analysis of lymphomas displayed significant higher incidence of T-cell rich B-cell lymphomas. Conclusion: Thus, the data show that MMR defects in HSCs leads to sensitization to radiation induced hematopoietic malignancy, and that radiation quality effects exacerbate the sensitivity. The findings could have profound effects on astronaut screening and designing better mitigators for space missions. Citation Format: Rutulkumar Patel, Stanton L. Gerson, Scott M. Welford. Mlh1 deficiency increases the risk of hematopoietic malignancies post low- and high-LET radiation exposure [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 5053.
Abstract 1520: Regulation of stemness by perturbation of OCT4-PP1 axis reduces malignancy of embryonal carcinoma
Authors: Bomin Song, Hyonchol Jang
Journal: Cancer Research (2018)

Abstract OCT4 (encoded by pou5f1) is a master regulator of pluripotency and closely related to tumor malignancies. Its associations with cancer drug-resistance, recurrence and poor prognosis of the patients has been widely reported. As OCT4 transcriptional activity is directly and indirectly involved in the maintenance of cancer stemness, inhibition of OCT4 activity could be a strategy to reduced cancer malignancies by eliminating stemness. In this study, we investigated a way to regulate the stemness of embryonal carcinoma (EC) by perturbation of posttranslational modification of OCT4. First, to confirm the role of OCT4 in the maintenance of stemness in ECs, we generated the cells which are downregulated in OCT4 doxycycline-dependently. Down-regulation of OCT4 caused weaker alkaline phosphates staining, reduced tumor sphere formation, and reduced expression of stemness marker proteins. Also, the cells underwent retardation of proliferation, cell-cycle arrest in G1 phase, and eventual apoptosis by OCT4 downregulation. The most altered genes in ECs by OCT4 downregulation were networked to signaling pathways regulating pluripotent stem cells, Hippo signaling pathways and transcriptional misregulation in cancer. Second, to regulate OCT4 transcriptional activity, we used phosphorylation of serine 236th (S236) on OCT4. ECs cells, with which their endogenous OCT4 was substituted with an OCT4 phosphorylation-mimicking mutant (Serine 236 to aspartate; S236D), showed similar phenotype to those cells that were depleted in OCT4. Chemical inhibition or knockdown of PP1 (protein phosphatase 1), which remove the phosphorylation, induced accumulation of S236 phosphorylation, and also caused similar phenotype to those cells that were depleted in OCT4. Finally, to evaluate whether regulation of OCT4 can reduce tumor malignancy, we tested whether drug-tolerant persister cancer cells could be reduced by regulation of OCT4. Co-treatment of inhibits PP1 activity with cisplatin significantly reduced drug-resistant colonies compared with single treatment of cisplatin. These results suggested that stemness of ECs could be regulated by OCT4 posttranslational modifications and regulation of cancer stemness could reduce tumor malignancy. Citation Format: Bomin Song, Hyonchol Jang. Regulation of stemness by perturbation of OCT4-PP1 axis reduces malignancy of embryonal carcinoma [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 1520.
Thixotropy of Blood and Proneness to Thrombus Formation
Authors: LeopoldDintenfass
Journal: Circulation Research (1962)

A study of the viscosity and thixotropy of human blood in the absence of anticoagulants was carried out by means of a rotational cone-in-cone viscometer. The plots of viscosity against the rate of shear on a log-log scale show that the thixotropy of normal blood is pronounced only below 5 sec.-1; abnormally thixotropic blood was characterized by the critical rates of shear of 30 to 60 sec.-1. The significance of thixotropy of blood is due to its intimate relationship with the aggregation of red cells. It is suggested that it may be also related to the proneness of thrombus formation.
Sirolimus (Rapamycin) Monotherapy Prevents Graft Vascular Disease in Nonhuman Primate Recipients of Orthotopic Aortic Allografts
Authors: CamilleDambrin, JochenKlupp, TudorBîrsan, JorgeLuna, TakeshiSuzuki, TuanLam, PeterStähr, BernardHausen, UweChristians, PeterFitzgerald, GeraldBerry, RandallMorris
Journal: Circulation (2003)

Background— Delayed treatment with sirolimus (SRL) halts progression of graft vascular disease (GVD) in nonhuman primate (NHP) aortic allograft recipients. In this study, we investigated whether SRL monotherapy prevents the development of GVD. Methods and Results— Pairs of 3-cm infrarenal aortic segments were exchanged between mixed lymphocyte reaction–mismatched, blood group–compatible NHPs (n=12). Six NHPs were untreated controls, and 6 were treated orally with SRL starting on the day of transplantation. Follow-up was 105 days. SRL doses were adjusted individually by assessing SRL blood concentrations, immune function, and clinical status. The severity of GVD was determined every 3 weeks by intravascular ultrasound, which quantified intimal area (IA) and intimal volume (IV) for the middle 1-cm graft segments. The mean±SEM SRL plasma levels were 14.5±9 ng/mL. In grafts from treated NHPs, IA and IV values on days 63, 84, and 105 were significantly lower than for controls (P<0.05 to P<0.001). On day 105, i...
Differential Protein Kinase C Isoform Regulation and Increased Constitutive Activity of Acetylcholine-Regulated Potassium Channels in Atrial Remodeling
Authors: SamyMakary, NielsVoigt, AngeMaguy, RezaWakili, KunihiroNishida, MasahideHarada, DobromirDobrev, StanleyNattel
Journal: Circulation Research (2011)

Rationale:Atrial fibrillation (AF) causes atrial-tachycardia remodeling (ATR), with enhanced constitutive acetylcholine-regulated K+ current (IKAChC) contributing to action potential duration shortening and AF promotion. The underlying mechanisms are unknown. Objective:To evaluate the role of protein-kinase C (PKC) isoforms in ATR-induced IKAChC activation. Methods and Results:Cells from ATR-dogs (400-bpm atrial pacing for 1 week) were compared to control dog cells. In vitro tachypaced (TP; 3 Hz) canine atrial cardiomyocytes were compared to parallel 1-Hz paced cells. IKAChC single-channel activity was assessed in cell-attached and cell-free (inside-out) patches. Protein expression was assessed by immunoblot. In vitro TP activated IKAChC, mimicking effects of in vivo ATR. Discrepant effects of PKC activation and inhibition between control and ATR cells suggested isoform-selective effects and altered PKC isoform distribution. Conventional PKC isoforms (cPKC; including PKCα) inhibited, whereas novel isoform...
Transfection of Inducible Nitric Oxide Synthase Gene Causes Apoptosis in Vascular Smooth Muscle Cells
Authors: MasatoraIwashina, MasayoshiShichiri, FumiakiMarumo, YukioHirata
Journal: Circulation (1998)

Background—Excess production of nitric oxide (NO) by inducible NO synthase (iNOS) has been implicated in a variety of physiological processes including vascular remodeling. To elucidate whether endogenous NO generated by iNOS is involved in the programmed cell death (apoptosis) of the vasculature, iNOS cDNA– expressing construct was transfected into rat and human vascular smooth muscle cells (VSMCs) by lipofection. Methods and Results—VSMCs transiently transfected with iNOS cDNA functionally expressed 130 kd iNOS protein with full catalytic activity to generate massive NO in proportion to the doses of cDNA used; its enzymatic activity as well as NO production was completely blocked by an NOS inhibitor, NG-monomethyl-l-arginine (LNMMA). Overexpression of iNOS led to a marked inhibition of DNA synthesis as well as induction of apoptosis in VSMCs. Evidence for apoptotic cell death was provided by internucleosomal DNA fragmentation by agarose gel electrophoresis, positive staining for TdT-mediated dUTP biotin...