tbuckley/cabot-search huggingface dataset:
Physical Activity Prevents Age-Related Impairment in Nitric Oxide Availability in Elderly Athletes
Authors: StefanoTaddei, FabioGaletta, AgostinoVirdis, LorenzoGhiadoni, GuidoSalvetti, FerdinandoFranzoni, CostantinoGiusti, AntonioSalvetti
Journal: Circulation (2000)

Background—Aging is associated with increased cardiovascular risk and endothelial dysfunction. Since exercise can improve endothelium-dependent vasodilation, in the present study we tested whether long-term physical activity could prevent aging-related endothelial dysfunction. Methods and Results—In 12 young and elderly (age 26.9±2.3 and 62.9±5.8 years, respectively) healthy sedentary subjects and 11 young and 14 elderly matched athletes (age 27.5±1.9 and 66.4±6.1 years, respectively), we studied (with strain-gauge plethysmography) forearm blood flow modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg/100 mL per minute), an endothelium-dependent vasodilator, at baseline, during infusion of NG-monomethyl-l-arginine (L-NMMA) (100 μg/100 mL forearm tissue per minute), a nitric oxide–synthase inhibitor, vitamin C (8 mg/100 mL forearm tissue per minute), an antioxidant, and finally under simultaneous infusion of L-NMMA and vitamin C. The response to sodium nitroprusside (1, 2,...
Circadian Variation of Cardiac K+ Channel Gene Expression
Authors: TakeshiYamashita, AkikoSekiguchi, Yu-kiIwasaki, KouichiSagara, HiroyukiIinuma, SeijiHatano, Long-TaiFu, HiroshiWatanabe
Journal: Circulation (2003)

Background— Many cardiac arrhythmias have their own characteristic circadian variations. Because the expression of many genes, including clock genes, is regulated variably during a day, circadian variations of ion channel gene expression, if any, could contribute to the fluctuating alterations of cardiac electrophysiological characteristics and subsequent arrhythmogenesis. Methods and Results— To examine whether cardiac K+ channel gene expression shows a circadian rhythm, we analyzed the mRNA levels of 8 Kv and 6 Kir channels in rat hearts every 3 hours throughout 1 day. Among these channels, Kv1.5 and Kv4.2 genes showed significant circadian variations in their transcripts: ≈2-fold increase of Kv1.5 mRNA from trough at Zeitgeber time (ZT) 6 to peak at ZT18 and a completely reverse pattern in Kv4.2 mRNA (≈2-fold increase from trough at ZT18 to peak at ZT6). Actually, along with the variations in the immunoreactive proteins, the density of the transient outward and steady-state currents in isolated myocyte...
Increase in Prostaglandin E2 Production by Interleukin-1β in Arterial Smooth Muscle Cells Derived From Patients With Moyamoya Disease
Authors: MariYamamoto, MasaruAoyagi, NaomiFukai, YoshiharuMatsushima, KiyotakaYamamoto
Journal: Circulation Research (1999)

Abstract—Moyamoya disease is a progressive cerebrovascular occlusive disease that primarily affects children. The cause is unknown. We examined the production of prostanoids and the expression of cyclooxygenase-2 (COX-2) in cultured arterial smooth muscle cells (SMCs) derived from patients with moyamoya disease. Twelve moyamoya and 8 control cell strains were examined. The steady-state levels of prostanoids in the culture medium did not differ between moyamoya and control SMCs. When the cells were stimulated with interleukin-1β (IL-1β), prostaglandin E2 (PGE2) release into the medium was significantly greater from moyamoya SMCs than from control SMCs, whereas the amounts of prostacyclin and thromboxane B2 did not differ. IL-1β–induced PGE2 production by moyamoya SMCs was completely blocked by the addition of indomethacin or NS-398. IL-1β significantly stimulated cell migration and DNA synthesis in control SMCs but had an inhibitory effect on moyamoya SMCs. The inhibitory effects on the growth and migratio...
Abstract 5101: Characterization of a mouse model using the Sleeping Beauty transposon method to study diffuse intrinsic pontine glioma (DIPG)
Authors: Ramya Ravindran, Flor M. Mendez, Felipe J. Nunez, Carl Koschmann, Marta Dzaman, Sheeba Pawar, Pedro R. Lowenstein, Maria G. Castro
Journal: Cancer Research (2018)

Abstract Tumors in the brain-stem are difficult to diagnose and treat primarily owing to the location. Diffuse intrinsic pontine glioma (DIPG) is a fatal paediatric brain-stem tumor located in the ventral pons with 100% fatality. These tumors are often treated on the assumption that DIPGs are molecularly similar to adult high grade gliomas; however, they are molecularly distinct. The ACVR1G328V and the H3.1K27M mutations have been seen to recur in DIPGs and we hypothesis that these mutations play an important role in the disease progression. A mutation in the ACVR1 leads to kinase activation and induces downstream signal transduction by phosphorylation of Smads (1/5). H3.1K27M mutations cause genome wide H3K27me3 hypomethylation. We genetically engineered mouse DIPG models using the Sleeping Beauty Transposon (SBT) method to introduce plasmids containing NRASV12/p53-shRNA/ACVR1G328V or NRASV12/p53-shRNA/H3.1K27M into the 4th ventricle of 1-day old pups adjacent to the brain-stem. This generates DIPGs with specific genetic lesions. NRASV12 is a constitutively active oncogene belonging to the RAS family and p53-shRNA is a short hairpin for TP53 tumor suppressor gene. A control tumor model was engineered using plasmids encoding NRASV12 and p53-shRNA. Tumor growth is monitored periodically over time until animals become symptomatic due to tumor burden. At this time point, animals are euthanized and the tumors extracted. We characterized the model for upregulation of phospho-smad 1/5 and markers of neural precursor cells (nestin, Sox2, olig2, GFAP, PDGFRα). In conclusion, we generated a genetically engineered mouse model of DIPG which represents a novel platform to study the molecular pathways underlying disease pathogenesis. An understanding of the functions of mutations that lead up to the disease can help to develop novel therapies for DIPG. Citation Format: Ramya Ravindran, Flor M. Mendez, Felipe J. Nunez, Carl Koschmann, Marta Dzaman, Sheeba Pawar, Pedro R. Lowenstein, Maria G. Castro. Characterization of a mouse model using the Sleeping Beauty transposon method to study diffuse intrinsic pontine glioma (DIPG) [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 5101.
Abstract 425: Linked Target Capture: Rapid and high-performance NGS target enrichment for clinical sequencing applications
Authors: Joel Pel, Wendy Choi, Milenko Despotovic, Laura Gelinas, Amy Leung, Lloyd Ung, Andre Marziali
Journal: Cancer Research (2018)

Abstract With the continued decrease of DNA sequencing costs, targeted next-generation sequencing (NGS) is seeing broad adoption in many research, commercial and clinical settings. However, current target capture methods typically have long, multiday workflows that can limit their clinical utility. In addition, small panels for applications such as liquid biopsy typically have high off-target rates or low uniformity, resulting in an increased cost of sequencing required to reach the desired coverage for variant detection. We have developed a novel library preparation and enrichment method named “Linked Target Capture” that replaces typical multiday "PCR-capture-PCR" workflows with a single, linked "PCR/capture" step. This approach, which uses physically linked capture probes and universal PCR primers, enables users to work from extracted DNA to loaded sequencer in less than a single day with minimal hands-on time. The linked PCR and capture step is cycled multiple times to reduce off-target DNA and increase uniformity, ultimately reducing the cost of sequencing. Additionally, the universal primers and captures probes can be combined to enable detection of DNA fusions with unknown partners. Using this method, we evaluated the ability to detect multiple mutation types from both tissue and cell free DNA, as a function of sequencing usage. Unique Molecular Identifiers (UMIs) were integrated and enabled the detection of variants below 0.1%, represented on both senses of the starting DNA (duplex sequencing). Fusion detection was also demonstrated without a priori knowledge of the fusion partner. Using a 30-gene pan-cancer panel, on-target fraction was measured to be above 95%, and the fraction of the panel covered at greater than 25% of the mean depth was greater than 99%. In summary, we have developed a method that enables rapid and cost-effective detection of clinically relevant cancer variants, such as SNVs and gene fusions. This method holds promise for many NGS areas, including clinical applications requiring rapid and simple workflows, or groups new to NGS where simple workflows and repeatable performance help remove barriers to technology adoption. Citation Format: Joel Pel, Wendy Choi, Milenko Despotovic, Laura Gelinas, Amy Leung, Lloyd Ung, Andre Marziali. Linked Target Capture: Rapid and high-performance NGS target enrichment for clinical sequencing applications [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 425.
PEGylated human IL-10 (AM0010) monotherapy in refractory metastatic colorectal cancer.
Authors: Jeffrey R. Infante, Kyriakos P. Papadopoulos, Aung Naing, Karen A. Autio, Patrick Alexander Ott, Deborah Jean Lee Wong, Johanna C. Bendell, Todd Michael Bauer, Shubham Pant, Peter Van Vlasselaer, Gail Linda Brown, Martin Oft
Journal: Journal of Clinical Oncology (2017)

3571 Background: Colorectal Cancer (CRC) has been refractory to immune therapies. The clinical benefit of immunotherapy is thought to depend on the expansion of activated, intratumoral, tumor specific cytotoxic CD8+ T cells which are low in most CRCs. AM0010 stimulates the survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Patients with CRC who have progressed on SOC first and second line of therapy have a reported 7.1 months OS with TAS-102 (Meyer et al. NEJM372;20, 2015). In this Phase 1 study the efficacy of AM0010 was studied in refractory metastatic CRC patients. Methods: CRC pts progressing on a median of 4 prior therapies (range 2-7) were treated daily with AM0010 in doses of 1 ug/kg SQ daily to 40 ug/kg in a dose escalation design. Tumor responses were assessed using irRC. Serum cytokines, activation of blood derived T cells and peripheral T cell clonality were analyzed. Pretreatment archival tissue samples were evaluated by IHC for tumor infiltration by CD8+T cells. Results: AM0010 was tolerated with reversible TrAEs. 10 pts (of 27) had a G3/4 TrAE. There were no objective responses. 11 patients were treated in dose escalation cohorts (1-10 ug/kg) and 16 pts were treated at or above RP2D (20 ug/kg or 40 ug/kg). Seven of 25 pts with at least one radiographic response evaluation had stable disease at 8 weeks. One patient had SD for 19.4 months. The mPFS (ITT n = 27 pts) was 1.6 months, mOS was 11.7 (range 2.4 – 32+) months. The median follow-up is 25.2 months (range 13-35). AM0010 increased Th1 cytokines IL-18 and IFNg in the serum of patients, while decreasing mediators of chronic, tumor promoting inflammation (Th17 cytokines) and TGFb. Tumor infiltrating granzyme B+ CD8+ T cells increased during the treatment. AM0010 induced de-novo oligoclonal expansion of T cell clones in patients. Conclusions: AM0010 is well tolerated in patients with refractory CRC. Although objective tumor responses were not seen in this very advanced CRC population, the observed immune activation including clonal T cell expansion, prolonged stable disease, and the mOS of 11.7 months is encouraging in this advanced CRC population. Future study of AM0010 in combination with FOLFOX in a second – line of therapy colorectal cancer patients is being planned. Clinical trial information: NCT02009449.
Abstract IA16: Natural history of peripheral nerve sheath tumors in NF1: Identification and characterization of malignant precursor lesions
Authors: Brigitte C. Widemann
Journal: Clinical Cancer Research (2018)

Abstract Neurofibromatosis type 1 (NF1) is a common (incidence 1:2,700) inherited disorder characterized by the development of peripheral nerve sheath tumors, including plexiform neurofibromas (PN) and malignant peripheral nerve sheath tumors (MPNST). While PN are histologically benign they can result in substantial morbidity including pain, disfigurement, and neurologic or functional deficits. Importantly, PN are at risk for transformation to MPNST with a lifetime incidence in NF1 of 15.8%. We are evaluating the natural history of NF1 PN in children enrolled on an NCI natural history study. Patients undergo detailed clinical evaluations and longitudinal evaluation with whole body MRI to assess total body tumor burden. Our studies confirm that PN grow most rapidly in young children and that substantial PN growth in patients ≥15 years old is infrequent and should raise concern for malignant transformation. We also identified the development of distinct nodular lesions (DNL) on MRI. These lesions appear after early childhood, frequently grow more rapidly than the surrounding PN, show a growth rate independent of age, and are avid for fluorodexyglucose on positron emission tomography. On biopsy, some of these lesions were identified as atypical neurofibromas (ANF), which were recently identified as precursor lesions to MPNST, and are characterized by CDKN2A/B loss. We have confirmed that patients with ANF are at greater risk for MPNST and are developing strategies for the evaluation and management of patients with ANF. Surgical resection of ANF, when safely feasible, may reduce the risk for MPNST development. We recently identified that MEK inhibition results in shrinkage of most PN and are expanding our efforts to evaluate the effect of MEK inhibition on DNL and ANF. Citation Format: Brigitte C. Widemann. Natural history of peripheral nerve sheath tumors in NF1: Identification and characterization of malignant precursor lesions [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA16.
Abstract 2523: Cooperativity of HOXA5 and STAT3 is critical for HDAC8 inhibition-mediated transcriptional activation of PD-L1 in human melanoma cells
Authors: Chen Chen Jiang, Yu Fang Wang, Simonne Sherwin, Margaret Farrelly, Fen Liu, Xu Guang Yan, Amanda Croft, Tao Liu, Lei Jin, Xu Dong Zhang
Journal: Cancer Research (2018)

Abstract While the expression of programmed death-ligand 1 (PD-L1) is an important mechanism by which cancer cells evade the immune system, PD-L1 expression in cancer cells are commonly associated with patients' responses to treatment with anti-PD-1/PD-L1 antibodies. However, how PD-L1 expression is regulated in melanoma cells remains to be fully elucidated. Here we report that the class I histone deacetylase (HDAC) HDAC8 controls transcriptional activation of PD-L1 by a transcription complex consisting of transcription factors homeobox A5 (HOXA5) and signal transducer and activator of transcription 3 (STAT3). Inhibition of HDAC8 upregulated PD-L1 in melanoma cells. This was due to an increase in the activity of a fragment of the PD-L1 gene promoter that is enriched with binding sites for both HOXA5 and STAT3. Indeed, knockdown of HOXA5 or STAT3 abolished upregulation of PD-L1 by HDAC8 inhibition. Moreover, HOXA5 and STAT3 were physically associated and appeared interdependent in activating PD-L1 transcription. Functional studies showed that HDAC8-mediated regulation of PD-L1 expression participated in modulating anti-melanoma T cell responses. Collectively, these results identify HDAC8 as an important epigenetic regulator of PD-L1 expression, with implications for better understanding of the interaction between melanoma cells and the immune system. Citation Format: Chen Chen Jiang, Yu Fang Wang, Simonne Sherwin, Margaret Farrelly, Fen Liu, Xu Guang Yan, Amanda Croft, Tao Liu, Lei Jin, Xu Dong Zhang. Cooperativity of HOXA5 and STAT3 is critical for HDAC8 inhibition-mediated transcriptional activation of PD-L1 in human melanoma 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 2523.
Abstract 3989: Dual targeting of ErbB2/ErbB3 for treatment of SCL3A2-NRG1-mediated lung cancer
Authors: Jeong Yeon Jo, Dong Hoon Shin, Ji-Youn Han
Journal: Cancer Research (2018)

Abstract We previously identified an oncogenic fusion gene involving the 5′ region of SLC3A2 and the 3′ region of NRG1 in a patient with invasive mucinous adenocarcinoma (IMA) of the lung. Here, we characterized the SLC3A2-NRG1 fusion gene in non-small cell lung cancer (NSCLC) and established an effective therapy for patients with SLC3A2-NRG1 fusion-positive cancer. The SLC3A2-NRG1 fusion product was composed of the SLC3A2 transmembrane domain and the epidermal growth factor (EGF)-like domain of the neuregulin 1 (NRG1) protein. The NRG1 family is classified as a ligand of the ERBB family. We identified ERBB3 and ERBB4 in the ERBB family as binding partners of the SLC3A2-NRG1 fusion protein via ligand and receptor binding assays. We confirmed that SLC3A2-NRG1 increased formation of a heterocomplex of ERBB3, which lacks tyrosine kinase activity, with ERBB2 using immunofluorescence staining, FACS analysis, and immunoprecipitation. Activation of the ERBB2-ERBB3 heterocomplex by SLC3A2-NRG1 increased colony formation and tumor growth in vivo in a xenograft model through the downstream signaling pathways of PI3K-AKT and MAP kinase. siRNA specific for ERBB2 and ERBB3, pertuzumab (a monoclonal antibody for ERBB2), lumretuzumab (a monoclonal antibody for ERBB3), and afatinib (an ERBB2 kinase inhibitor) all decreased ERBB2-ERBB3 heterocomplex formation, phosphorylation of each protein, and their downstream signaling. In addition, single treatment with pertuzumab, lumretuzumab, or apatinib decreased tumor volume and weight, whereas combination treatment with these drugs and paclitaxel enhanced generation of cleaved-caspase 3, PARP, and TUNEL-positive cells compared with each single treatment. Thus, the SLC3A2-NRG1 fusion gene plays an important role in lung cancer cell proliferation and tumor growth by promoting generation of the ERBB2-ERBB3 heterocomplex, its phosphorylation, and activation of the PI3K/ERK/mTOR signaling pathway. Inhibition of either ERBB2 or ERBB3 alone did not completely shut down downstream signaling of ERBB2 and ERBB3; however, inhibition of both ERBB2 and ERBB3 blocked downstream signaling activated by SLC3A2-NRG1 fusion. ERBB2 and ERBB3 might be promising targets for treatment of SLC3A2-NRG1-positive tumors. Citation Format: Jeong Yeon Jo, Dong Hoon Shin, Ji-Youn Han. Dual targeting of ErbB2/ErbB3 for treatment of SCL3A2-NRG1-mediated lung 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 3989.
Abstract LB-037: 3D organoids from milligrams of genitourinary cancer patients tissue retain key features of original tumors
Authors: Yue Wang, Glauco Souza, Robert J. Amato
Journal: Cancer Research (2018)

Abstract 3D organoid culture, especially that generated from patient samples, is becoming prevalent as 2D cell culture models fail to provide clinical relevance. However, a relatively large amount of starting tissue is still required for this process, and the turnover rate and overall success rate vary greatly if relying solely on spontaneous aggregation. Here, we report the successful use of magnetic 3D bioprinting to drive organoid formation derived from fresh tumor samples of patients with prostate cancer, renal cell cancer, and urothelial cancer. Only milligrams to tens of milligrams of starting tissues (from fine-needle biopsies, core biopsies, or surgical excision) were used. Most organoids formed overnight, with a very high overall success rate (&amp;gt95%, n = 25). We have demonstrated that these cultures can be maintained, passed, and cryopreserved like conventional 2D cultures. More importantly, we characterized the organoids derived from prostatic adenocarcinomas and neuroendocrine tumors by the means of immunostaining and showed that the organoids expressed the same signature proteins as the originating tumors. This clinical concordance is crucial for downstream translational and biological research. We also showed that these adenocarcinoma cells responded to enzalutamide, an androgen receptor inhibitor that is used clinically to treat prostatic adenocarcinoma. In summary, we have established an efficient and robust system to create patient-derived 3D organoids; molecular characterization shows clinical concordance with original patient tumors; and our system shows great potential in drug screening with patient-derived 3D cultures. Citation Format: Yue Wang, Glauco Souza, Robert J. Amato. 3D organoids from milligrams of genitourinary cancer patients tissue retain key features of original tumors [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-037.
Fundamental Mechanisms of Immune Checkpoint Blockade Therapy
Authors: Spencer C. Wei, Colm R. Duffy, James P. Allison
Journal: Cancer Discovery (2018)

Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic approaches. However, the remarkable responses to immunotherapies are currently limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Indeed, an extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Insights into the underlying biological mechanisms and functions of these molecules have, however, lagged significantly behind. Such understanding will be essential for the rational design of next-generation immunotherapies. Here, we review the current state of our understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, and highlight conceptual gaps in knowledge.Significance: This review provides an overview of immune checkpoint blockade therapy from a basic biology and immunologic perspective for the cancer research community. Cancer Discov; 8(9); 1069-86. ©2018 AACR.
Abstract 19293: Removal of Dietary Trimethylamine N-Oxide (TMAO) Attenuates Cardiac Dysfunction in Pressure Overload Induced Heart Failure
Authors: Chelsea L Organ, Zhen Li, Craig Zibilich, W.H. Wilson Tang, Stanley L Hazen, David J Lefer
Journal: Circulation (2016)

Rationale: Patients at increased risk for heart attack and adverse prognosis during heart failure have increased levels of circulating trimethylamine N-oxide (TMAO), a metabolite formed in the metabolism of dietary phosphatidylcholine. Objective: We investigated the effects of withdrawing dietary TMAO from diet on the progression of heart failure following transverse aortic constriction (TAC). Methods and Results: Male C57BLK/6J mice were fed either control diet or a diet containing TMAO (0.12%) starting at 3 weeks prior to surgical TAC and were studied for 17 weeks. At 6 weeks post TAC a subset of animals of the 0.12% TMAO diet were switch to control diet for the remainder of the study. Left ventricular (LV) structure and function were monitored at 3 week intervals and myocardial tissue and blood samples were collected at 17 weeks. Circulating BNP levels were significantly (p < 0.01) higher in the 0.12% TMAO group compared to control. Left ventricular ejection fraction (LVEF) was significantly (p < 0.05)...