tbuckley/cabot-search huggingface dataset:
Biphasic Activation of the JAK/STAT Pathway by Angiotensin II in Rat Cardiomyocytes
Authors: HiroakiKodama, KeiichiFukuda, JingPan, ShinjiMakino, MotoakiSano, ToshiyukiTakahashi, ShingoHori, SatoshiOgawa
Journal: Circulation Research (1998)

Abstract—This study was designed to demonstrate the characteristic pattern of angiotensin II–induced JAK/STAT (indicating just another kinase/signal transducer and activator of transcription) activation in cultured rat cardiomyocytes by comparing it with leukemia inhibitory factor (LIF)-induced activation. Angiotensin II (10−7 mol/l) induced rapid phosphorylation of JAK2 and Tyk2, but not JAK1, and phosphorylated STAT1 and STAT2, but not STAT3, in the early stage up to 30 minutes. The time course of JAK/STAT activation by angiotensin II was apparently slower than that by LIF. Interestingly, angiotensin II phosphorylated STAT3 and rephosphorylated STAT1 in the late stage at 120 minutes. We also found that angiotensin II induced the formation of interferon-stimulating gene factor (ISGF) complexes biphasically, in the early stage at 15 to 30 minutes and in the late stage at 120 minutes, and that angiotensin II induced delayed activation of the sis-inducing factor (SIF) complex at 120 minutes. Formation of IS...
Abstract LB-032: Magnetic 3D bioprinting for the identification of tumor-specific therapies from PDX-derived 3D cultures
Authors: Glauco Souza, Geoffrey Bartholomeusz
Journal: Cancer Research (2018)

Abstract Great efforts have been undertaken in the field of cancer to develop clinically relevant pre-clinical models to permit the translation of research advances into agents that can improve patient outcomes. The use of 2D monolayer and 3D multicellular tumor spheroid cell culture systems has made this process remarkably costly and inefficient. This outcome is a result of discrepancies between simplified in-vitro 2D cell culture models used in drug screening platforms and the complex 3D tumor microenvironment targeted by these same drugs. Patient-derived xenograft (PDX), in which patient tumor tissue implanted into immune-deficient mice, provide improved models of human tumor biology relative to immortalized cancer cell lines. Such models offer possibilities for better preclinical testing of new therapies for the treatment of cancer. A drawback associated with the use of PDX systems is its requirement for immense resources and animals. Also, animal models have limited relevance as a platform for high throughput drug screening. To overcome such limitations, we applied magnetic 3D bioprinting to develop a PDX-derived ex-vivo tumor tissue platform for high-throughput drug screening. The PDX-derived tissue generated using magnetic 3D bioprinting mirrors the original PDX tumor in both tissue architecture and genetic signature. We confirm the predictive value of our screening template by demonstrating a similar response outcome between our model and a PDX mouse system generated from the same original tumor tissue and treated with the same panel of drugs. Utilizing an Inflammatory Breast Cancer (IBC) PDX system as our model system, we screened our ex-vivo tumor tissue template with the anti-cancer drug library and identified 7 lead candidates that had a stronger anti-tumor activity compared to the standard of care agents used to treat IBC patients in the clinics. Incorporating our ex-vivo tumor tissue high throughput screening platform as an early step in a PDX system will permit the identification of new and effective tumor-specific therapies at a time, cost, and resource efficient manner. Citation Format: Glauco Souza, Geoffrey Bartholomeusz. Magnetic 3D bioprinting for the identification of tumor-specific therapies from PDX-derived 3D cultures [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-032.
Abstract 702: IMLEC: A population of innate myelolymphoblastoid effector cell expanded by inactivation of mTOR complex 1
Authors: Fei Tang, Peng Zhang, Peiying Ye, Christopher A. Lazarski, Qi Wu, Ingrid L. Bergin, Timothy P. Bender, Michael N. Hall, Ya Cui, Liguo Zhang, Taijiao Jiang, Yang Liu, Pan Zheng
Journal: Cancer Research (2018)

Abstract Adaptive autoimmunity is restrained by controlling population sizes and pathogenicity of harmful clones, while innate destruction is controlled at effector phase. We report here that deletion of Rptor in hematopoietic stem/progenitor cells causes self-destructive innate immunity by massively increasing the population of previously uncharacterized innate myelolymphoblastoid effector cells (IMLECs). IMLECs are CD3-B220-NK1.1-Ter119- CD11clow/-CD115-F4/80low/-Gr-1- CD11b+, but surprisingly express high levels of PD-L1. Although they morphologically resemble lymphocytes and actively produce transcripts from Immunoglobulin loci, IMLECs have non-rearranged Ig loci, are phenotypically distinguishable from all known lymphocytes, and have a gene signature that bridges lymphoid and myeloid leukocytes. Rptor deletion unleashes differentiation of IMLECs from common myeloid progenitor cells by reducing expression of Myb. Importantly, IMLECs broadly overexpress pattern-recognition receptors and their expansion causes systemic inflammation in response to Toll-like receptor ligands. Our data unveil a novel leukocyte population and an unrecognized role of Raptor/mTORC1 in innate immune tolerance. Moreover, since IMLECs constitutively express high levels of PD-L1, it is interesting to investigate their functions in cancer immunotherapy. Citation Format: Fei Tang, Peng Zhang, Peiying Ye, Christopher A. Lazarski, Qi Wu, Ingrid L. Bergin, Timothy P. Bender, Michael N. Hall, Ya Cui, Liguo Zhang, Taijiao Jiang, Yang Liu, Pan Zheng. IMLEC: A population of innate myelolymphoblastoid effector cell expanded by inactivation of mTOR complex 1 [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 702.
Induction of Cardiomyocyte-Like Cells in Infarct Hearts by Gene Transfer of Gata4, Mef2c, and Tbx5
Authors: KoheiInagawa, KazutakaMiyamoto, HiroyukiYamakawa, NaotoMuraoka, TaketaroSadahiro, TomohikoUmei, RieWada, YoshinoriKatsumata, RuriKaneda, KojiNakade, ChitoseKurihara, YuichiObata, KoichiMiyake, KeiichiFukuda, MasakiIeda
Journal: Circulation Research (2012)

Rationale:After myocardial infarction (MI), massive cell death in the myocardium initiates fibrosis and scar formation, leading to heart failure. We recently found that a combination of 3 cardiac transcription factors, Gata4, Mef2c, and Tbx5 (GMT), reprograms fibroblasts directly into functional cardiomyocytes in vitro. Objective:To investigate whether viral gene transfer of GMT into infarcted hearts induces cardiomyocyte generation. Methods and Results:Coronary artery ligation was used to generate MI in the mouse. In vitro transduction of GMT retrovirus converted cardiac fibroblasts from the infarct region into cardiomyocyte-like cells with cardiac-specific gene expression and sarcomeric structures. Injection of the green fluorescent protein (GFP) retrovirus into mouse hearts, immediately after MI, infected only proliferating noncardiomyocytes, mainly fibroblasts, in the infarct region. The GFP expression diminished after 2 weeks in immunocompetent mice but remained stable for 3 months in immunosuppresse...
Abstract 16587: Edoxaban Associated With Fewer Serious Adverse Events and Lower Mortality Than Warfarin, Regardless of Burden of Comorbidities: Insights From the ENGAGE AF-TIMI 48 Trial
Authors: Ramon Corbalan, Christian Ruff, Tibor Duris, Steen Juul-Möller, Juri Voitk, Marco Trevisan, Elliott Antman, Eugene Braunwald, Robert Giugliano
Journal: Circulation (2016)

Background: Atrial fibrillation (AF) is more frequent in elderly pts and those with underlying cardiac and other comorbidities. The multicenter ENGAGE AF-TIMI 48 trial compared efficacy and safety of edoxaban vs warfarin in 21105 pts with AF over a mean follow up of 2.8 yrs. We hypothesized that despite more adverse events in pts with mod-high comorbidity, the benefits of edoxaban over warfarin would be similar to that seen in pts with less comorbidity. Methods: Pts were classified using the Charlson Comorbidity Index (CCI) as low comorbidity (CCI <4, n=15860 pts) or mod-high comorbidity (CCI ≥4, n=5245 pts). Outcomes included study drug discontinuation, serious (non-bleeding) adverse events (SAEs), hepatic events, new neoplasms, and all cause death. Results: Pts with CCI <4 were more likely male, with higher BMI, enrolled in NA, and received fewer cardiac co-medications. They had higher CHA2DS2VASc (mean 5.2 vs 4.0) and HASBLED (2.7 vs 2.4) scores, and higher median TTR with warfarin (69 vs 67%), P≤0.001...
Abstract 2268: Differential splicing analysis of doxorubicin treatment response in cancer cells
Authors: Edward Simpson, Yunlong Liu
Journal: Cancer Research (2018)

Abstract Background:Splicing of transcripts is an important epigenetic control mechanism that significantly influences expression of protein isoforms in a cell. Alternative splicing is known to contribute to development and progression of cancer, however the impact of cellular splicing profiles on cancer drug response has been largely unexplored. In this study, we integrated two large public data sets and report findings on the basal splicing profiles between doxorubicin treated sensitive and resistant cancer cell lines. We introduced a new method to analyze of splicing data using the quasi-binomial distribution that is incredibly simple, powerful and well suited for comparison of large groups of samples. We also identified exons whose inclusion or exclusion level is likely to be damaging to intended gene products. Finally, we performed RNA-binding protein motif enrichment at these identified exons to characterize proteins that may play a role in their regulation. Methods:Drug response data from the Cancer Therapeutic Response Portal (CTRP) was integrated with RNAseq data from the Cancer Cell Line Encyclopedia (CCLE). AUC values from drug-response time curves in CTRP were used to classify cells as either doxorubicin sensitive, intermediate or resistant. The upper and lower tertiles provided a total of 253 sensitive and 258 resistant cell lines respectively. Splice junction read counts for skipped-exon events were calculated using the matched cell line data from CCLE. Response groups were then used to train a generalized linear model with quasi-binomial family. Results were filtered by group weight significance at an FDR of &amp;lt;=0.01. The remaining events were again filtered for &amp;gt;=10% difference in mean exon inclusion ratio. Results:In total we identified 277 differentially spliced events between doxorubicin sensitive and resistant groups. When performing GO term over-representation our results demonstrated significantly enriched biological processes supporting the role of alternative splicing in EMT and cellular differentiation. This further confirms previous studies linking alternative splicing to these cancer hallmarks, suggesting that splicing may facilitate acquired drug resistance through survival mechanisms similar to those seen in cancer stem cells. Citation Format: Edward Simpson, Yunlong Liu. Differential splicing analysis of doxorubicin treatment response in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2268.
Abstract P396: Presence of Hypertension and the Effect on Clinical Outcome Scores of IV rt-PA Receiving Patients at a Community Primary Stroke Center (PSC) in Urban Los Angeles
Authors: JenniferGarland, AnnaAntonio, AntonioLiu
Journal: Circulation (2014)

Background: Intravenous recombinant tissue plasminogen activator (IV rt-PA) is the only FDA approved thrombolytic treatment for acute ischemic stroke offering at least a 30% chance of improvement over placebo. Purpose: The purpose of the study was to examine the effect of hypertension (HTN) and other various covariates of patients receiving IV rt-PA thrombolysis treatment for ischemic stroke on clinical outcome scores over time: mRS (modified Ranking Scale) & NIHSS (National Institute of Health Stroke Scale). Methods: A retrospective analysis utilized repeated measures design (SAS Windows version 9.3) on patients receiving IV rt-PA thrombolysis treatment for ischemic stroke from Jan 1, 2012 to Dec 31, 2012. The total cohort used for analysis, N=60. Two cases were not included due to death. Baseline measures were taken at admission and one follow-up time point at discharge. All covariates were included first in univariate models. Those which were found to be significant were then included in multivariate a...
Abstract 2762: Identification of novel immunotherapeutic targets in anaplastic thyroid cancer
Authors: Sanjukta Chakraborty, Rachana R. Maniyar, Neha Y. Tuli, Ghada Ben Rahoma, Sarnath Singh, Ameet Kamat, Craig Berzofsky, Cameron Budenz, Augustine Moscatello, Jan Geliebter, Raj K. Tiwari
Journal: Cancer Research (2018)

Abstract Thyroid cancer is the most rapidly increasing cancer in the US with anaplastic thyroid cancer (ATC) being the rarest and most aggressive form. ATC patients display a higher mutational burden and are refractory to current mainstream treatments including second generation kinase inhibitors like vemurafenib (PLX4032). BRAFV600E is one of the most common mutations associated with this phenotype. Presence of BRAFV600E has been associated with an immunosuppressive microenvironment in thyroid cancer that presumably facilitates immune evasion. With recent advancements in immunotherapy, well defined targeted treatment plans can address the unmet medical need of ATC. In an effort to define potential immunotherapeutic targets that can be combined with small molecule inhibitors in this subtype, we evaluated the expression of immune checkpoint molecules in four thyroid cancer cell lines TPC-1 (papillary), BCPAP (BRAFV600E positive papillary), 8505C (BRAFV600E positive anaplastic) and CGTH-W-1 (follicular) by qRT PCR at the basal level and after treatment with vemurafenib and mTORC1 inhibitor rapamycin. Prominent co-stimulatory molecules like CD27, CD30, 4-1BB and DR3 were significantly downregulated at the transcript level in ATC (8505C) as compared to the other thyroid cancer subtypes. We observed a higher baseline expression of co-inhibitory molecules like full length CTLA4 (mCTLA4), soluble CTLA4 (sCTLA4), LAG3, 2B4, PD-1 and PD-L1 in ATC (8505C) compared to the other subtypes of thyroid cancer. Although vemurafenib treatment decreased the expression of PD-L1 as expected, interestingly, it enhanced the expression of co-inhibitory molecules LAIR1, 2B4, mCTLA4 and PD-1 by approximately 1.5 folds. These results suggest an inherent redundancy in inhibitory immune checkpoint molecules that presumably compensate for each other, functionally, making them novel targets in ATC. With our study we identified a distinct group of co-inhibitory molecules in ATC that can be targeted by antagonistic antibodies in a combinatorial treatment regimen with small molecule inhibitors like vemurafenib. Citation Format: Sanjukta Chakraborty, Rachana R. Maniyar, Neha Y. Tuli, Ghada Ben Rahoma, Sarnath Singh, Ameet Kamat, Craig Berzofsky, Cameron Budenz, Augustine Moscatello, Jan Geliebter, Raj K. Tiwari. Identification of novel immunotherapeutic targets in anaplastic thyroid 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 2762.
Abstract 4562: Tumor B7-H3 (CD276) expression and survival of patients with pancreatic cancer
Authors: Kentaro Inamura, Yusuke Yokouchi, Maki Kobayashi, Yosuke Inoue, Akio Saiura, Yutaka Takazawa, Yuichi Ishikawa
Journal: Cancer Research (2018)

Abstract Background: B7-H3 (CD276) belongs to a family of immune modulators that includes PD-L1 (B7-H1 or CD274), and has been associated with tumor immunosuppression. Although several studies have reported the association of B7-H3 expression with prognosis in pancreatic cancer, the results are conflicting and inconclusive. We therefore examined the association of tumor B7-H3 expression with prognosis of pancreatic cancer. Methods: Using tissue microarrays of 150 consecutive cases of pancreatic cancer, we evaluated tumor B7-H3 expression by immunohistochemistry. We examined the prognostic association of B7-H3 expression, using the log-rank test. We also used Cox proportional hazards regression models to compute the mortality hazard ratio (HR), adjusted for covariates including pathological-stage, tumor differentiation, preoperative levels of CEA and CA19-9, and adjuvant chemotherapy. Results: Tumor B7-H3 positivity (10% of tumor cells) was observed in 99 (66%) of 150 cases of pancreatic cancer. In a log-rank test, B7-H3 positivity was associated with higher pancreatic cancer-specific mortality (P = 0.0005). In a multivariable analysis, B7-H3 positivity was independently associated with higher pancreatic cancer-specific mortality (multivariable HR = 1.82; 95% confidence interval [CI] = 1.25-2.71; P = 0.0016). When we divided immunoreactivity of B7-H3 into four scores; i.e., score 0, negative; score 1, weak; score 2, moderate; score 3, strong, the immunoreactivity scores of B7-H3 were 51 (34%), 67 (45%), 20 (13%), 12 (8%) for score 0, 1, 2, 3, respectively. In a log-rank test, higher score of B7-H3 immunoreactivity was associated with higher pancreatic cancer-specific mortality (P = 0.0014). In a multivariable analysis, higher B7-H3 immunoreactivity was independently associated with higher pancreatic cancer-specific mortality (comparing score 3 versus score 0: multivariable HR = 2.78; 95% CI = 1.38-5.25; P for trend = 0.0011). Conclusion: Tumor B7-H3 positivity and higher B7-H3 immunoreactivity are both independently associated with higher mortality of pancreatic cancer. Citation Format: Kentaro Inamura, Yusuke Yokouchi, Maki Kobayashi, Yosuke Inoue, Akio Saiura, Yutaka Takazawa, Yuichi Ishikawa. Tumor B7-H3 (CD276) expression and survival of patients with pancreatic 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 4562.
Abstract 4039: PAX8 increases migration and metastasis of high grade serous ovarian cancer through upregulation of Rho GTPases
Authors: Laura Hardy, Melissa Pergande, Angel Hernandez, Stephanie Cologna, Joanna Burdette
Journal: Cancer Research (2018)

Abstract High grade serous ovarian cancer, the most lethal subtype of ovarian cancer, can originate in either the fallopian tube epithelium (FTE) or ovarian surface epithelium (OSE). PAX8 is a lineage specific transcription factor that is ubiquitously expressed in HGSOC. We have shown that knockdown of PAX8 using shRNA in multiple ovarian tumor cells lines leads to apoptosis, suggesting that PAX8 plays an essential role in cancer survival. In this study, we used CRISPR technology to delete PAX8 from the OVCAR8 cell line. PAX8 deletion led to a decrease in migration and invasion in vitro and an increase in survival and a reduction in tumor volume in vivo. Previous work using RNA-sequencing and ChIP-sequencing identified cell adhesion as a top differentially expressed gene between malignant ovarian cancer and benign fallopian tube cell lines. We performed quantitative proteomic analysis of the OVCAR8-PAX8-/- cell line to define PAX8 altered proteins. We also performed quantitative proteomics and transcriptomic analyses on a previously generated murine OSE cell line with forced PAX8 expression (MOSE-PAX8). These analyses identified several genes that contribute to an increase in migration and EMT. Specifically, our data indicates PAX8 upregulates key drivers involved in altering cell morphology including the GTPases: RhoA, Cdc42, and Ras. Inhibition of RhoA led to a greater decrease in migration for both OVCAR8-PAX8-/- and MOSE-PAX8 when compared to control. Inhibition of Ras had a greater effect in OVCAR8-PAX8-/- while inhibition of Cdc42 had a greater effect in MOSE-PAX8. These data provide a mechanistic explanation for the role of PAX8 on increasing migration and metastasis in ovarian cancer. Citation Format: Laura Hardy, Melissa Pergande, Angel Hernandez, Stephanie Cologna, Joanna Burdette. PAX8 increases migration and metastasis of high grade serous ovarian cancer through upregulation of Rho GTPases [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 4039.
Abstract 1130: The role of TET2 in mammary stem cell fate decision
Authors: Meng-Ju Wu, Chun-Ju Chang
Journal: Cancer Research (2018)

Abstract Epigenetic mechanisms, including DNA methylation, has an essential role in governing the stem cell fate decision. The Ten-Eleven-Translocation (TET) protein family serves as a primary epigenetic regulator responsible for catalyzing the conversion of the modified genomic base 5-methylcytosine into 5-hydroxymethylcytosine to mediate DNA demethylation. It has been shown that loss of TET2 promotes aberrant stem cell self-renewal in hematopoietic malignancy. Interestingly, our recent study has revealed that expression of TET2 directs the breast cancer stem cell-like population to the differentiation cell fate in vitro. Since aberrant stem cell fate is often associated with tumorigenesis, delineating the role that a critical epigenetic regulator (e.g., TET2) plays to govern the mammary stem cell (MaSC) fate will likely provide new strategies used for breast cancer treatment. Thus, to determine the physiological and pathological roles of TET2 in the regulation of MaSC fate and mammary gland development using a mouse model with mammary specific deletion of the Tet2 gene (MMTV-Cre; Tet2fl/fl). Our data show that deletion of Tet2 in mouse mammary gland leads to disrupted mammary epithelial morphology, defective lobular-alveolar development, along with aberrant mammary stem cell fate decision, contributing to an expansion of the MaSC population and development of mammary lesions. Together, the data demonstrate that TET2 plays an important role in controlling MaSC fate decision to maintain epithelial homeostasis, and loss of TET2 may contribute to the development of mammary malignancies. Citation Format: Meng-Ju Wu, Chun-Ju Chang. The role of TET2 in mammary stem cell fate decision [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 1130.
Letter by Shanmugam et al Regarding Article, “Primary Results From the SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) Trial: A Randomized Trial Comparing Empirical, Echocardiography-Guided, and Algorithmic Atrioventricular Delay Programming in Cardiac Resynchronization Therapy”
Authors: NesanShanmugam, GaborBorgulya, LisaAnderson
Journal: Circulation (2011)