tbuckley/cabot-search huggingface dataset:
Abstract 3336: ARID5B activates the TAL1-induced core regulatory circuit and the oncogene MYC, thereby promoting T-cell leukemogenesis
Authors: Wei Zhong Leong, Shi Hao Tan, Phuong Cao Thi Ngoc, Stella Amanda, Alice Wei Yee Yam, Wei-Siang Liau, Zhiyuan Gong, Lee N. Lawton, Daniel G. Tenen, Takaomi Sanda
Journal: Cancer Research (2018)

Abstract The oncogenic transcription factor TAL1/SCL is abnormally expressed in 40-60% cases of T-cell acute lymphoblastic leukemia (T-ALL) cells. It induces an aberrant transcriptional program with its regulatory partners (E-proteins, LMO1/2, GATA3, RUNX1 and MYB) in malignant T cells. However, the critical factors that are directly activated by the TAL1 transcriptional complex and contribute to T-ALL pathogenesis are largely unknown. Here, we identified ARID5B, an AT-rich interactive domain (ARID) family DNA binding protein, as a collaborating oncogenic factor involved in the transcriptional program in T-ALL. Our result indicated that ARID5B expression is downregulated at the CD4, CD8 double negative 2-4 stages in normal thymocytes, while it is activated by the TAL1 complex in human T-ALL cells. The enhancer located approximately 135 kb upstream of the ARID5B gene locus is associated with a super-enhancer in multiple T-ALL samples but not in normal thymus. These data suggested that ARID5B is aberrantly activated in T-ALL cells. Interestingly, ARID5B-bound regions are predominantly associated with active transcription, as shown by the active histone marks (H3K27ac, H3K4me1 and H3K4me3) by ChIP-seq analysis. ARID5B and TAL1 frequently co-occupy target genes and coordinately control their expression. Notably, ARID5B positively regulates the expression of TAL1 and its regulatory partners (GATA3, RUNX1 and MYB). In addition, ARID5B activates the expression of the oncogene MYC. Importantly, ARID5B is required for the survival and growth of T-ALL cells in vitro, and forced expression of ARID5B in immature thymocytes results in thymus retention, radio-resistance and tumor formation in zebrafish. Our results indicate that ARID5B reinforces the oncogenic transcriptional program by positively regulating the core regulatory circuit and the oncogene MYC in T-ALL, thereby contributing to T-cell leukemogenesis. Citation Format: Wei Zhong Leong, Shi Hao Tan, Phuong Cao Thi Ngoc, Stella Amanda, Alice Wei Yee Yam, Wei-Siang Liau, Zhiyuan Gong, Lee N. Lawton, Daniel G. Tenen, Takaomi Sanda. ARID5B activates the TAL1-induced core regulatory circuit and the oncogene MYC, thereby promoting T-cell leukemogenesis [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 3336.
Immigrants’ access to health care: Problems identified in a high-risk tuberculosis population
Authors: R. Linhas, O. Oliveira, P. Meireles, P. Oliveira, M.B. de Melo, J. Lourenço, F. Ferreira, R. Gaio, R. Duarte
Journal: Pulmonology (2018)

Immigrants may utilize health care services differently than other residents and may also have a greater risk for tuberculosis (TB). Identify barriers to healthcare access by immigrants, factors associated with these barriers, and discuss strategies that may reduce these barriers. Anonymous questionnaires were given to immigrants at National Immigrant Support Centres between 2015 and 2016. Barriers to healthcare were identified using logistic regression. One-hundred and nineteen questionnaires were administered to immigrants, 9 of whom (8%) presented with TB while in Portugal. Twenty-one percent of immigrants reported barriers to healthcare access, and 69% had general practitioners (GPs). The presence of barriers to healthcare access was negatively associated with having a GP and with being married or in a de facto union. A considerable proportion of immigrants reported having difficulties accessing healthcare services in Portugal where legally these barriers are nonexistent. Certain factors were associated with these difficulties.
Abstract 3849: Identification and optimization of chemical compounds as potent agonists of human STING with anticancer activity in mice
Authors: Jian Hui Wu
Journal: Cancer Research (2018)

Abstract The host STING pathway plays a critical role in innate immune sensing of cancer, that drives type-I interferons (IFNs) production and promotes aggressive antitumor responses. Compound DMXAA is an agonist of mouse STING (mSTING) and demonstrated potent antitumor activities in several tumor models, including melanoma. However, DMXAA cannot activate human STING (hSTING), which provides a possible rationale for its failure in recent clinical trial. In this project, we aim to identify novel chemical compounds as potent STING agonists. By combining structure-based drug design and in vitro assays, we have discovered two initial hits as STING agonists that belong to two different chemical scaffolds. Direct binding of our compounds with hSTING was confirmed by Surface plasmon resonance (SPR) analysis. Chemical optimization of our initial hits has led to compound #150 and #171. We demonstrated that #150 and #171 at 10 uM have substantially activated STING pathway in HEK293 cells that were transiently transfected with plasmid expressing hSTING. Compound #171 at 20 uM potently activated STING signaling in human THP-1 cells that harbor hSTINGHAQ as well as PBMC cells from a panel of human donors. Importantly, with DMXAA as the control, we demonstrated that #171 at 20 mg/kg via i.p. has significant antitumor effect against TRAMP-c1 tumor in C57/BL6 mice. Citation Format: Jian Hui Wu. Identification and optimization of chemical compounds as potent agonists of human STING with anticancer activity in mice [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 3849.
Abstract B36: A biomarker-guided approach to combining PARP inhibitors with radiotherapy in pediatric sarcomas
Authors: Anang A. Shelat, Christopher L. Tinkle, Elizabeth Stewart, Sara Michele Federico, Brandon Bianski, Marcia Mellado-Lagarde
Journal: Clinical Cancer Research (2018)

Abstract Background: Ewing sarcoma (EWS) expresses high levels of Schlafen-11 (SLFN11). SLFN11 disrupts checkpoint maintenance and may serve as a biomarker to assess sensitivity to Poly (ADP-ribose) polymerase 1 and 2 inhibitors (PARPi). The goal of this study is to evaluate SLFN11 protein expression in a panel of pediatric solid tumors and correlate levels of protein with sensitivity to PARP inhibition combined with ionizing radiation (IR), a component of therapy for many pediatric sarcomas and a potent inducer of DNA damage. Methods: SLFN11 mRNA and protein levels were assessed by quantitative RT-PCR, and immunohistochemistry, Western blot, and immunofluorescence microscopy, respectively. PARPi included talazoparib (TAL), niraparib (NIR), veliparib (VEL), and olaparib (OLA). Approximately 30 minutes after addition of systemic therapy, graded doses of radiation were delivered and viability across a panel of pediatric solid tumor cell lines was measured using the ATP-based Cell TiterGlo assay and confirmed with the colony formation assay. Results: We found that SLFN11 mRNA and protein is expressed at high levels in EWS, and SLFN11 is also variably present in a subset of other pediatric sarcomas, including desmoplastic small round cell tumor, osteosarcoma, and rhabdomyosarcoma. In all tumor cells with detectable SLFN11 expression, viability was reduced by greater than 90% when exposed to 2 Gy IR and 1-10 nM TAL, whereas cells with undetectable levels of SLFN11 were 5-10 times less sensitive. Intriguingly, variation in the potentiation between specific PARPi and IR correlated with the ability to form drug-induced PARP-DNA adducts, with the strong PARP trapper TAL showing ~10-fold higher potency compared to the moderate trapper NIR, and ~300-fold more potency relative to the weak trapper VEL. Consistent with our PARPi findings, the toposiomerase 1 inhibitor irinotecan, which also forms DNA adducts, potentiated with IR similarly to TAL at concentrations &amp;lt;10 nM in tumor cells expressing detectable levels of SLFN11. Conclusion: SLFN11 is present in select pediatric sarcomas and may induce a DNA repair defect that is best exploited by combining low doses of TAL and irinotecan with IR. Citation Format: Anang A. Shelat, Christopher L. Tinkle, Elizabeth Stewart, Sara Michele Federico, Brandon Bianski, Marcia Mellado-Lagarde. A biomarker-guided approach to combining PARP inhibitors with radiotherapy in pediatric sarcomas [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 B36.
Abstract LB-332: Evidence for cutaneous squamous tumors derived from carcinogen-exposed bone marrow
Authors: Sonali Lad, Kelly Johnson, Kelsey Boland, Nyssa Readio, Todd Schuster, Yong Li, Derek Gordon, Rebecca J. Morris
Journal: Cancer Research (2018)

Abstract Cytokeratins are frequently found in the blood and bone marrow of patients with epithelial cancers and are attributed to metastasis. We wondered whether we could find keratin expression in blood and bone marrow in untreated adult mice. To address this problem, we have used classical immunoreactivity, Krt1-14;mTmG transgenic mice together with fluorescence activated cell sorting, and quantitative reverse transcriptase polymerase chain reaction. We have made several novel findings. First, we discovered, rare but distinctive, keratin-14 and keratin-15 immunoreactive cells the size of small lymphocytes in blood and bone marrow of untreated mice. Second, using Krt1-14;mTmG transgenic mice, we found low (8.6 GFP positive cells per 10^6 cells analyzed), but significant numbers (p&amp;lt0.0005) of GFP positive cells in bone marrow of normal adult mice when compared with negative controls. Third, qRT-PCR demonstrated very low but reproducibly detectable expression of keratin-14 mRNA in blood and bone marrow when compared with epidermal keratinocytes: with blood expressing one thousand times, and bone marrow, one hundred thousand times, less than epidermal keratinocytes. Moreover, FACS analysis of fresh bone marrow disclosed a subpopulation of keratin-14 immunoreactive cells that was negative for hematopoietic lineage markers. Furthermore, and even more curious, recipients of bone marrow transplants from DMBA-treated UBC/GFP mice (“toxic bone marrow”) developed GFP-immunoreactive skin tumors upon TPA tumor promotion: four of fifteen mice developed GFP-immunoreactive skin tumors. Of these tumors, four were squamous papillomas, and one was a squamous cell carcinoma. None of the ten control mice receiving normal whole bone marrow developed any skin tumors upon tumor promotion. We conclude from these observations that keratin-14 protein and mRNA are expressed at low, but detectable levels in the blood and bone marrow of mice, and that a subset of “toxic bone marrow” derived cells can be recruited to form epithelial benign and malignant squamous tumors. Building upon these observations should open new avenues of understanding for cutaneous biology, non-melanoma skin cancer, and other epithelia and their cancers. Citation Format: Sonali Lad, Kelly Johnson, Kelsey Boland, Nyssa Readio, Todd Schuster, Yong Li, Derek Gordon, Rebecca J. Morris. Evidence for cutaneous squamous tumors derived from carcinogen-exposed bone marrow [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-332.
Letter by Yasue et al Regarding Article, “Clinical Usefulness, Angiographic Characteristics, and Safety Evaluation of Intracoronary Acetylcholine Provocation Testing Among 921 Consecutive White Patients With Unobstructed Coronary Arteries”
Authors: HirofumiYasue, YujiMizuno, EisakuHarada
Journal: Circulation (2015)
Activated Endocannabinoid System in Coronary Artery Disease and Antiinflammatory Effects of Cannabinoid 1 Receptor Blockade on Macrophages
Authors: KoichiSugamura, SeigoSugiyama, ToshimitsuNozaki, YasushiMatsuzawa, YasuhiroIzumiya, KeishiMiyata, MasafumiNakayama, KoichiKaikita, ToruObata, MotohiroTakeya, HisaoOgawa
Journal: Circulation (2009)

Background— Cannabinoid 1 (CB1) receptor blockade with rimonabant represents a clinical therapeutic strategy for obesity. Recently, the role of the endocannabinoid system has been described in peripheral organs. We sought to determine whether the endocannabinoid system could be involved in human atherosclerosis and whether CB1 receptor blockade could modulate proinflammatory activity in macrophages. Methods and Results— mRNA expression levels of CB1 receptor in coronary atherectomy samples were significantly higher in patients with unstable angina than in those with stable angina (3.62±2.96-fold; n=7; P<0.05). Immunoreactive area analysis of the coronary artery showed that CB1 receptor expression was greater in lipid-rich atheromatous plaques than in fibrous plaques, especially in CD68 macrophages (9.5±1.2% versus 0.6±0.6%; n=5; P<0.01). Levels of blood endocannabinoids were significantly higher in patients with coronary artery disease (n=20) than those without coronary artery disease (n=20) (median [inte...
Abstract 63: Microenvironment-derived mitochondria prime glioma chemoresistance by augmenting NAD+metabolism and PARP-dependent DNA repair
Authors: Yang Liu, Mark Gilbert, Chunzhang Yang
Journal: Cancer Research (2018)

Abstract Background: Mitochondria, the major organelles of cellular metabolism, can be released into the microenvironment and affect adjacent cells, supporting recipient cell metabolism and protecting them from unfavorable conditions. While our knowledge of intercellular mitochondria transfer under normal physiological conditions is expanding, a key question remains unanswered: do microenvironment-derived mitochondria influence the survival and malignant transformation of cancer cells? Methods: In this study, we have established in vitro and in vivo models to aid in the understanding of mitochondrial transfer between astrocytes and glioma cells. Results: We demonstrate that mitochondria are released from normal astrocytes through extracellular vesicles, and are adopted by neighboring glioma cells. Mitochondrial transfer not only improves oxidative metabolism in recipient glioma cells, but also supports the detoxification of chemotherapeutic agents by fueling PARP-dependent DNA repair with ATP and NAD+. Targeting astrocyte mitochondria-releasing pathways increased the cytotoxic effects of chemotherapy, reduced xenograft progression, and prolonged overall survival. Our findings suggest that microenvironment-derived mitochondria confer both metabolic capability and chemoresistance to cancer cells. Conclusion: Targeting microenvironment-derived mitochondria may be important in reducing the capacity for cancer cells to recover from cancer treatment, thereby enhancing treatment efficacy. Citation Format: Yang Liu, Mark Gilbert, Chunzhang Yang. Microenvironment-derived mitochondria prime glioma chemoresistance by augmenting NAD+metabolism and PARP-dependent DNA repair [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 63.
Alleviation of Myocardial Ischemia After Kawasaki Disease by Heparin and Exercise Therapy
Authors: ShigeruTateno, MasaruTerai, KoichiroNiwa, ToshiakiJibiki, HiromichiHamada, KumiYasukawa, TakafumiHonda, ShinjiOana, YoichiKohno
Journal: Circulation (2001)

Background—Heparin promotes angiogenesis. We evaluated the effects of combined treatment with heparin and exercise on myocardial ischemia in the chronic stage of Kawasaki disease. Methods and Results—This study was conducted in 7 patients (aged 6 to 19 years) who had a totally occluded coronary artery and stress-induced myocardial ischemia in the collateral-dependent areas. Twice-daily exercise using a bicycle ergometer was performed with increments of 0.5 W/kg every 3 minutes up to maximal exertion for 10 days. Heparin, which immediately increased circulating hepatocyte growth factor, was given intravenously 10 minutes before each exercise period. Newly developed myocardial infarction, ventricular tachyarrhythmia, anginal attack, or hemorrhagic complication was not observed in any patient. Dipyridamole-loading single photon emission computed tomography documented improved myocardial perfusion in the collateral-dependent areas and a significant reduction in total defect scores in all patients after the co...
Abstract 2571: An integral genomic/expression analysis reveals a cooperative role ofAPCandTP53mutations in identifying cetuximab-sensitive colorectal cancer
Authors: Mingli Yang, Michael J. Schell, Andrey Loboda, Michael V. Nebozhyn, Jiannong Li, Jamie K. Teer, W. Jack Pledger, Timothy J. Yeatman
Journal: Cancer Research (2018)

Abstract The epidermal growth factor receptor (EGFR) is a major therapeutic target in metastatic colorectal cancer (CRC). Mutations in KRAS/NRAS have been identified as the resistance mechanisms to anti-EGFR antibody therapy (cetuximab/pantiumab). However, genomic understanding of the sensitivity to the EGFR-targeted therapy is lacking. A pre-specified, 203-gene cetuximab sensitivity (CTX-S) expression signature score was first validated on two previously published datasets: (1) 77 CTX-treated CRC tumors (progression free survival (PFS)&amp;gt;7 days), and (2) 147 in vitro CTX-treated CRC cell lines. The CTX-S signature was found to be consistently correlated with a newly developed 24-gene APC (truncating) mutations-specific Wnt/β-catenin score on four independent CRC datasets that also include Moffitt (n=468) and TCGA (n=624) CRC datasets. This promoted us to carry out a variety of analyses that revealed a cooperative role of mutant APC + mutant TP53 in identifying cetuximab sensitive subpopulations, which was further evidenced by additional validation analysis on two CRC PDX datasets (n=52 and n=98). While debating or inconclusive, other potential predictive markers of EGFRi therapies have been reported, including BRAF(V600E), PIK3CA mutations, loss of PTEN, and overexpression of HER2 as negative indicators, as well as increased EGFR copy number, and overexpression of EGFR ligands epiregulin and amphiregulin as positive indicators. Here, for the first time, we report that the mutant genes may cooperatively act as positive indicators of EGFRi response. Our study suggests that addition of the routine sequencing of APC and TP53 to extended RAS testing may refine the patient selection strategy to improve cetuximab/pantiumab response and potentially expand the therapeutic opportunity to previously-excluded mutant KRAS/NRAS patients who have “APC + TP53” mutations. Citation Format: Mingli Yang, Michael J. Schell, Andrey Loboda, Michael V. Nebozhyn, Jiannong Li, Jamie K. Teer, W. Jack Pledger, Timothy J. Yeatman. An integral genomic/expression analysis reveals a cooperative role of APC and TP53 mutations in identifying cetuximab-sensitive colorectal 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 2571.
Digital Vascular Response to Angiotensin II in Normotensive and Hypertensive Subjects
Authors: Petergaskell
Journal: Circulation Research (1967)

The critical opening pressure (COP) of digital vessels after digital nerve block and the change in COP caused by angiotensin at 4 mµg/kilo per min intravenously after the block were compared in 9 normotensive subjects, 8 patients with essential hypertension and 7 patients with various kinds of renal hypertension. The COP after nerve block was less than 20 mm Hg in the normotensives and in 6 renal hypertensives, but more than 20 mm Hg in 7 essential hypertensives. The angiotensin reduced the COP in 7 of the normotensives, increased it substantially in 7 essential hypertensives, but had little effect in 6 renal hypertensives. A significantly greater increase in systemic blood pressure occurred in the essential hypertensives than in the normotensive subjects. In normotensive subjects doses of intravenous angiotensin from 2 to 16 mµg/kilo per min decreased the COP whether preceded by digital nerve block or not. Angiotensin at 8 mµg/kilo per min increased total digital vascular resistance as estimated by venou...
Abstract 12627: Clinical Anticancer Agent, RRx-001, protects From Doxorubicin-Induced Cardiotoxicity
Authors: Bryan Oronsky, Jan Scicinski, Pedro Cabrales
Journal: Circulation (2016)

Introduction: Anthracycline (ANT) chemotherapy (e.g., doxorubicin or DOX) is associated with dose-dependent cardiac dysfunction, leading to congestive heart failure, and therefore has limited clinical use. The cardiotoxicity may manifest acutely and/or months or years after treatment. Current clinically used therapies include angiotensin-converting enzyme/angiotensin-receptor antagonists (ARB) which are cardioprotective against ANT toxicity. Hypothesis: Pre-treatment with the hypoxic nitric oxide generating anticancer agent, RRx-001, mitigates acute DOX-induced cardiotoxicity. Candesartan (ARB) was used as a positive control. Methods: 24 BALB/c mice were randomized to prophylactic treatment with vehicle, RRx-001, candesartan or no-intervention control. Within each of the three intervention arms, mice received treatment with DOX. Murine pressure-volume (PV) analysis was performed with microconductance catheters to characterize the degree of cardiovascular dysfunction within each group. The following hemodynamic parameters were monitored: left ventricular systolic pressure (LVSP), heart rate, and maximal rate of increase of left ventricular pressure (±dP/dt max). Results: Five days after doxorubicin injection, untreated mice displayed significantly impaired systolic (LVSP, –27%; dP/dtmax, –25%; LVDP, + 33%; P &lt; 0.05) and global (SV, –52%; EF-20%; SW-62.5%; HR, –18%; CO, –57%; MAP-30%; SVR+20% P &lt; 0.05) LV function when compared with the untreated group. In contrast, RRx-001-treated mice showed improved variables of systolic (LVSP, +27%; dP/dtmax, +25%; LVDP, -33%; P &lt; 0.05) and global (SV, +52%; EF+20%; SW+62.5%; HR, +18%; CO, +57%; MAP+30%; SVR-20% P &lt; 0.05) LV function compared to untreated controls. RRx-001 treated mice demonstrated improved parameters of LV function compared to candesartan, though the differences were not significant. Conclusions: Similar to the positive control, candesartan, the cardiotoxic effects of DOX in mice were attenuated by the prophylactic administration of RRx-001. These results suggest that RRx-001, as a multifunctional anticancer agent, which sensitizes cancer cells to the cytotoxic effects of chemotherapy and radiation, with beneficial cardioprotective effects.