tbuckley/cabot-search huggingface dataset:
Abstract 16414: Non-High-Density-Lipoprotein Cholesterol is an Important Residual Risk Factor in the Secondary Prevention for Patients With Established Atherosclerotic Cardiovascular Diseases
Authors: Wei-Tien Chang, Wei-Hsian Yin, Fang-Ju Lin, Wei-Kung Tseng, Yen-Wen Wu, Yi-Heng Li, Hung-I Yeh, Jaw-Wen Chen, Chau-Chung Wu
Journal: Circulation (2016)

Introduction: Secondary prevention of cardiovascular (CV) events is important for patients with established atherosclerotic CV diseases (ASCVD). Non-high-density-lipoprotein cholesterol (N-HDL-C) has been increasingly signified as an important risk factor for ASCVD.

Purpose: To verify the role of N-HDL-C in the secondary prevention for patients with established ASCVD.

Materials and Methods: Taiwanese Secondary Prevention for Patients with AtheRosCLErotic Disease (T-SPARCLE) Registry is a prospective cohort conducted since 2010 enrolling patients with established ASCVD from 18 centers in Taiwan. In this study, N-HDL-C levels at enrollment was divided into four groups (&lt 100, 100-129, 130-159 and ≥ 160 mg/dl) to stratify the risk associated with composite primary end point of cardiovascular death, myocardial infarction, stroke, and cardiac arrest with cardiopulmonary resuscitation. Multivariate Cox proportional hazards model was employed to elucidate the role of N-HDL-C in predicting the primary outcome. Further, analysis was done in patients already under statin treatment to clarify the value of N-HDL-C in this era of statin therapy.

Results: A total of 4,099 patients (male 74.4%, age 65.6 ± 11.9 years old) were enrolled from Jan. 2010 to Aug. 2014. One hundred and nine primary outcomes were recorded during follow-up with a mean of 2 years. In multivariate Cox proportional hazards model, N-HDL-C ≥ 160 (HR 2.01, 95% CI 1.02 - 3.98, P &lt 0.05) and 130-159 mg/dl (HR 1.97, 95% CI 1.04 - 3.72, P &lt 0.05), together with smoking (HR 1.62, 95% CI 1.02 - 2.58, P &lt 0.05), diabetes mellitus (HR 1.63, 95% CI 1.10 - 2.41, P &lt 0.05), congestive heart failure (HR 2.21, 95% CI 1.41 - 3.46, P &lt 0.001) and estimated glomerular filtration rate (eGFR) &lt 30 ml/min (HR 3.25, 95% CI 1.78 - 5.95, P &lt 0.001), serve as independent risk factors for major CV events. For patients already under statin treatment (n=2,933), N-HDL-C ≥ 160 (HR 2.39, 95% CI 1.10 - 5.22, P &lt 0.05) is still associated with greater risk compared to N-HDL-C &lt 100 mg/dl.

Conclusion: N-HDL-C is an important residual risk factor in the secondary prevention for patients with established ASCVD. Aggressive control to lower N-HDL-C is mandated in this group of patients.
Bendamustine, pomalidomide, and dexamethasone for relapsed and/or refractory multiple myeloma
Authors: Dharshan Sivaraj, Michael M Green, Yubin Kang, Gwynn D Long, David A Rizzieri, Zhiguo Li, Anderson H Garrett, Jackie L McIntyre, Nelson J Chao, Cristina Gasparetto
Journal: Blood Cancer Journal (2018)
Myocardial Smad4 Is Essential for Cardiogenesis in Mouse Embryos
Authors: LanyingSong, WenshengYan, XinbinChen, Chu-xiaDeng, QinWang, KaiJiao
Journal: Circulation Research (2007)

Congenital heart diseases are the most commonly observed human birth defects and are the leading cause of infant morbidity and mortality. Accumulating evidence indicates that transforming growth factor-β/bone morphogenetic protein signaling pathways play critical roles during cardiogenesis. Smad4 encodes the only common Smad protein in mammals, which is a critical nuclear mediator of transforming growth factor-β/bone morphogenetic protein signaling. The aim of this work was to investigate the roles of Smad4 during heart development. To overcome the early embryonic lethality of Smad4−/− mice, we specifically disrupted Smad4 in the myocardium using a Cre/loxP system. We show that myocardial-specific inactivation of Smad4 caused heart failure and embryonic lethality at midgestation. Histological analysis revealed that mutant mice displayed a hypocellular myocardial wall defect, which is likely the primary cause for heart failure. Both decreased cell proliferation and increased apoptosis contributed to the my...
Abstract 4070: The relationship between members of the canonical NF-κB pathway, components of the tumor microenvironment and cancer-specific survival in colorectal cancer patients
Authors: Jean A. Quinn, Lindsay Bennett, Meera Patel, Lynette Loi, Mikaela Frixou, Antonia Roseweir, James H. Park, Paul G. Horgan, Donald C. McMillan, Joanne Edwards
Journal: Cancer Research (2018)

Abstract The canonical NF-κB pathway regulates the transcription of many genes which may be involved in processes such as inflammation and proliferation, suggesting a potential link between the tumor, the tumor microenvironment and cancer-specific survival in colorectal cancer patients. Immunohistochemistry was used to assess the expression of the upstream kinase TAK1/pTAK1 and four members of the canonical NF-κB pathway in tissue microarrays. Protein expression was determined using the weighted histoscore method. BRaf status, tumor stroma percentage, local inflammation, systemic inflammation and cancer-specific survival were examined in patients with colorectal cancer. Cytoplasmic IKKβ was significantly associated with the inflammatory cell infiltrate (p=0.0015), systemic inflammation (p=0.03) and cancer-specific survival (p=0.046). In contrast, no significant association was found with the other three members. Cytoplasmic pTAK1 was associated with the tumor microenvironment (p=0.045) and cancer-specific survival (p=0.032). On multivariate analysis only cytoplasmic IKKβ associated with survival (HR1.75, 95%CI 1.05-291, p=0.033) and this was independent of TNM stage and markers of the tumor microenvironment. When cytoplasmic IKKβ was stratified with BRaf status (wild type (n=151) or mutant (n=48)), it was no longer associated with cancer-specific survival. However, when cytoplasmic pTAK1 was stratified with BRaf status its association with cancer-specific survival was strengthened. Cytoplasmic pTAK1 was significantly associated with cancer-specific survival in patients with wild type BRaf (p=0.014). In patients with BRaf mutations there was no significant association with cancer-specific survival (p=0.105), however the numbers were low and this is currently being investigated in a larger cohort. The results of the present study show that high expression of cytoplasmic IKKβ was associated with decreased cancer-specific survival and with markers of the tumor microenvironment in patients with colorectal cancer. Expression of cytoplasmic pTAK1 was associated with cancer-specific survival and this was enhanced in patients with tumors expressing wild type BRaf. Citation Format: Jean A. Quinn, Lindsay Bennett, Meera Patel, Lynette Loi, Mikaela Frixou, Antonia Roseweir, James H. Park, Paul G. Horgan, Donald C. McMillan, Joanne Edwards. The relationship between members of the canonical NF-κB pathway, components of the tumor microenvironment and cancer-specific survival in colorectal cancer patients [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 4070.
Abstract 11005: Activation of Hypothalamic Mineralocorticoid Receptor-Independent Epithelial Sodium Channels Leads to Salt-Sensitive Hypertension in Mouse Model of Metabolic Syndrome
Authors: Mutsumi Kunita-Takanezawa, Koji Ito, Takuya Kishi, Yoshitaka Hirooka
Journal: Circulation (2015)

Introduction and Hypothesis: Metabolic syndrome (MetS) is often associated with salt-sensitive hypertension. In genetic salt-sensitive hypertensive models, activation of the hypothalamic mineralocorticoid receptor (MR)-epithelial sodium channel (ENaC) pathway has been established as a major worsening factor. However, in MetS, contribution of the hypothalamic MR-ENaC pathway to salt-sensitive hypertension remains unknown. Therefore, we determined whether the hypothalamic MR-ENaC pathway activation leads to salt-sensitive hypertension in MetS. Methods and Results: Diet-induced obesity (DIO) was achieved in male C57BL/6 mice by feeding them a high-fat diet from 4 weeks of age. Mice fed a normal diet served as controls (CON). Mice at 12 weeks of age were given tap water with regular salt (RS) or 1% NaCl (high salt; HS) for 8 weeks. HS led to increased systolic blood pressure only in DIO-mice, and not in CON-mice (DIO-HS: 122±3 mmHg vs DIO-RS: 107±2 mmHg, CON-HS: 109±2 mmHg vs CON-RS: 105±1 mmHg, n=6/group, p&lt;0.05). In DIO-mice, 24-h urinary norepinephrine excretion after salt loading was significantly higher than that before salt loading (244±18 ng/day vs 371±29 ng/day, n=6 in each, p&lt;0.05). HS-induced hypertension was significantly prevented by intracerebroventricular infusion of the ENaC blocker benzamil (Ben), but not the MR blocker spironolactone (Spl; DIO-HS-Vehicle 122±1 mmHg, DIO-HS-Ben 108±1 mmHg, DIO-HS-Spl 119±1 mmHg, n=6 in each, p&lt;0.05). Expression of hypothalamic serum and glucocorticoid-regulated kinase (SGK) 1, a marker of MR activity, did not differ between in CON-mice and DIO-mice. However, the SGK1 phosphorylation level was greater in DIO-mice than in CON-mice, suggesting MR-independent SGK1 activation. Water intake and urinary sodium excretion did not differ between in DIO-HS-Vehicle and DIO-HS-Ben. Interestingly, salt loading-induced plasma arginine vasopressin (AVP) secretion was significantly prevented in DIO-HS-Ben. Conclusions: These findings suggest that salt-induced hypertension in DIO-mice results from MR-independent hypothalamic SGK1-ENaC activation with systemic AVP secretion. Hypothalamic ENaC could be a novel therapeutic target in salt-induced hypertension of MetS.
Abstract 3294: Functional annotation for alternative splicing to investigate disrupted splicing in cancer
Authors: Daejin Hyung, Jihyun Kim, Soo Young Cho, Charny Park
Journal: Cancer Research (2018)

Abstract Alternative splicing (AS) plays a key role to confer human genome complexity. The advent of mRNA high-throughput sequencing facilitates to identify precise differential alternative splicing analysis. Massive result estimated from RNA-Seq should be sorted out whether AS has functional impact or not. Previous studies investigated protein domain or nonsense-mediated decay of AS event region. However other functional sites on exon inclusion region also exist. For example, miRNA binding site, and post-translational modification of AS site already are reported to assign functional impact. Therefore we developed ASpedia (http://combio.snu.ac.kr/aspedia/) to annotation functional impact of AS event. AS events of our database were generated from human genome hg19 ENSEMBL and Refseq. ASpedia provides a database, explore system, and AS browser to annotate functional impact evidence encompassing DNA, RNA, and protein. The user could query multiple AS events from differential AS analysis result. Currently our system supports a jar execution file to convert input query file from MISO or rMATS result. The variant of splicing factor (SF) disrupts normal splicing. It could be assumed that target genes of mutated SF could be transcribed to aberrant isoforms by changed splicing machinery. Therefore we investigated the comprehensive SF variant status from TCGA somatic mutation and copy number. SF3B1 (2% in BRCA) and U2AF1 (4% in AML, and 2% in LUAD) were shown to recurrent mutation including hotspot. ELAVL2 known dispensable splicing factor to brain tissue were highly recurrent in deletion (18% in GBM). In order to examine aberrant AS events caused SF variants, we estimated exon-inclusion proportion Percent-Spliced-In (PSI) values for identifiable AS events using TCGA RNA-Seq dataset. Using differentially AS event analysis, we identified AS events that were significantly differentially spliced in the presence of a U2AF S34F/Y mutation (119 in AML). And we purposed to finding In order to investigate functional site, the differentially spliced AS events were additionally annotated using ASpedia. Finally we identified the landscape of that AS events were altered by SF variants, and we proved that a part of the events was involved in cancer-associated functions. Citation Format: Daejin Hyung, Jihyun Kim, Soo Young Cho, Charny Park. Functional annotation for alternative splicing to investigate disrupted splicing in 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 3294.
Transforming Growth Factor-β Function Blocking Prevents Myocardial Fibrosis and Diastolic Dysfunction in Pressure-Overloaded Rats
Authors: FumitakaKuwahara, HisashiKai, KeisukeTokuda, MamikoKai, AkiraTakeshita, KensukeEgashira, TsutomuImaizumi
Journal: Circulation (2002)

Background— Excessive myocardial fibrosis impairs cardiac function in hypertensive hearts. Roles of transforming growth factor (TGF)-β in myocardial remodeling and cardiac dysfunction were examined in pressure-overloaded rats. Methods and Results— Pressure overload was induced by a suprarenal aortic constriction in Wistar rats. Fibroblast activation (proliferation and phenotype transition to myofibroblasts) was observed after day 3 and peaked at days 3 to 7. Thereafter, myocyte hypertrophy and myocardial fibrosis developed by day 28. At day 28, echocardiography showed normal left ventricular fractional shortening, but the decreased ratio of early to late filling velocity of the transmitral Doppler velocity and hemodynamic measurement revealed left ventricular end-diastolic pressure elevation, indicating normal systolic but abnormal diastolic function. Myocardial TGF-β mRNA expression was induced after day 3, peaked at day 7, and remained modestly increased at day 28. An anti–TGF-β neutralizing antibody, w...
Abstract CT017: Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients
Authors: Maria E. Rodriguez-Ruiz, Jose L. Perez-Gracia, Inmaculada Rodriguez, Carlos Alfaro, Ignacio Gil-Bazo, Alfonso Gurpide, Andres Salazar, Ignacio Melero
Journal: Cancer Research (2018)

Abstract BACKGROUND: Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects on distant non-irradiated lesions. PATIENTS AND METHODS: In this pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered one week before each cycle. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating PBMCs and serum concentrations of a cytokine panel were sequentially determined before and during treatment. RESULTS: Combined treatment was feasible, safe and well tolerated, without grade 3-4 adverse events. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR and combined treatment. No objective responses were observed, while nine patients (Disease control rate=71%) presented stable disease (five in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. Dendritic-cell vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting stable disease. CONCLUSIONS: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and provides evidence of immune-associated activity and signs of preliminary clinical efficacy. Citation Format: Maria E. Rodriguez-Ruiz, Jose L. Perez-Gracia, Inmaculada Rodriguez, Carlos Alfaro, Ignacio Gil-Bazo, Alfonso Gurpide, Andres Salazar, Ignacio Melero. Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients [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 CT017.
Abstract 1155: The SRGTM rat: A novel SCID rat for humanization studies
Authors: Fallon K. Noto, Bisoye Towobola, Angela Arey, Goutham Narla, Christopher Chengelis, Tseten Yeshi
Journal: Cancer Research (2018)

Abstract In vivo modeling of human cancer in genetically engineered rodents can provide insights into tumor kinetics, genetics and molecular biology, and allow for the testing of drug efficacy. Over the recent years, studies have demonstrated that immunodeficient mice, such as the NSG, reconstituted with functional human immune cells, such as peripheral blood mononuclear cells (PBMCs), are promising models for immuno-oncology efficacy studies. Immune humanized mice engrafted with human cancer cells show human-specific immune responses when treated with drugs that target immune pathways, such as CTLA-4 and PD-1, leading to the inhibition of tumor growth. These models provide a critical platform to study how the immune system can be engaged to drive anti-cancer efficacy. Although the NSG and similar immunodeficient mouse strains have been beneficial for human immuno-oncology studies, there are many caveats to performing these studies in mice, including inconsistent tumor kinetics, small tumor size for downstream analyses, limited blood for PK/PD studies due to the small size of the mouse, and graft vs. host disease (GvHD) onset around 4-6 weeks post-engraftment. Humanized rat models would allow for the development of larger tumors and the ability to perform serial blood sampling on a routine basis throughout the course of treatment. We have created a Rag2 null, Il2rg null rat on the Sprague Dawley background (SRGTM) that lacks B, T, and NK cells and supports the growth of multiple human cancer cell lines, including lines that do not engraft or grow well in existing mouse models: HCT-116, H358, and VCaP. The SRGTM rat is also permissive to immune humanization with PBMCs. PBMC-engrafted SRGTM rats have a significant amount of human CD45+ lymphocytes in peripheral blood, of which the majority are T cells, comparable to immune-humanized NSG and NOG mice. Some animals also show significant levels of circulating human B cells. Interestingly, the incidence of GvHD is delayed to 12-14 weeks post-engraftment in the immune humanized SRG™ rat. We are currently assessing functionality of the PBMC-immune humanized SRG™ rat in immuno-oncology studies as well as characterizing the ability of the SRG™ rat to support the growth of human patient derived xenografts (PDX). The generation of this novel humanized SRG™ rat model could allow for a more permissive host system to test existing and novel immunomodulatory strategies for the treatment of human disease. Citation Format: Fallon K. Noto, Bisoye Towobola, Angela Arey, Goutham Narla, Christopher Chengelis, Tseten Yeshi. The SRGTM rat: A novel SCID rat for humanization studies [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 1155.
Comparative biodistribution analysis across four different <sup>89</sup>Zr-monoclonal antibody tracers—The first step towards an imaging warehouse
Authors: Frederike Bensch, Michaël M. Smeenk, Suzanne C. van Es, Johan R. de Jong, Carolina P. Schröder, Sjoukje F. Oosting, Marjolijn N. Lub-de Hooge, C. Willemien Menke-van der Houven van Oordt, Adrienne H. Brouwers, Ronald Boellaard, Elisabeth G.E. de Vries
Journal: Theranostics (2018)

Rationale: Knowledge on monoclonal antibody biodistribution in healthy tissues in humans can support clinical drug development.Molecular imaging with positron emission tomography (PET) can yield information in this setting.However, recent imaging studies have analyzed the behavior of single antibodies only, neglecting comparison across different antibodies.Methods: We compared the distribution of four 89 Zr-labeled antibodies in healthy tissue in a retrospective analysis based on the recently published harmonization protocol for 89 Zr-tracers and our delineation protocol.Results: The biodistribution patterns of 89 Zr-lumretuzumab, 89 Zr-MMOT0530A, 89 Zr-bevacizumab and 89 Zr-trastuzumab on day 4 after tracer injection were largely similar.The highest tracer concentration was seen in healthy liver, spleen, kidney and intestines.About one-third of the injected tracer dose was found in the circulation, up to 15% in the liver and only 4% in the spleen and kidney.Lower tracer concentration was seen in bone marrow, lung, compact bone, muscle, fat and the brain.Despite low tracer accumulation per gram of tissue, large-volume tissues, especially fat, can influence overall distribution: On average, 5-7% of the injected tracer dose accumulated in fat, with a peak of 19% in a patient with morbid obesity. Conclusion:The similar biodistribution of the four antibodies is probably based on their similar molecular structure, binding characteristics and similar metabolic pathways.These data provide a basis for a prospectively growing, online accessible warehouse of molecular imaging data, which enables researchers to increase and exchange knowledge on whole body drug distribution and potentially supports drug development decisions.
Temporal Regulation of the Bacterial Metabolite Deoxycholate during Colonic Repair Is Critical for Crypt Regeneration
Authors: Umang Jain, Chin-Wen Lai, Shanshan Xiong, Victoria M. Goodwin, Qiuhe Lu, Brian D. Muegge, George P. Christophi, Kelli L. VanDussen, Bethany P. Cummings, Erick Young, John Hambor, Thaddeus S. Stappenbeck
Journal: Cell Host & Microbe (2018)
Retrospective Analysis of Surgery Versus Endovascular Intervention in Takayasu Arteritis
Authors: DavidSaadoun, MarcLambert, TristanMirault, MathieuResche-Rigon, FabienKoskas, PhilippeCluzel, CécileMignot, YolandSchoindre, LaurentChiche, Pierre-YvesHatron, JosephEmmerich, PatriceCacoub
Journal: Circulation (2012)

Background—With recent advances in endovascular treatment, percutaneous endoluminal angioplasty has become particularly attractive for arterial lesions of Takayasu arteritis. However, data came from case reports or small series, and the long-term outcome has not been reported. The incidence of potential vascular complications after surgery or endovascular treatment is still to be determined. Methods and Results—This retrospective multicenter study analyzed the results and outcomes of 79 consecutive patients with Takayasu arteritis (median age, 39 years; interquartile range [IQR], 25–50 years; 63 women [79.7%]) who underwent 166 vascular procedures (surgery, 104 [62.7%]; endovascular repair, 62 [37.3%]) for the management of arterial complications. After a follow-up of 6.5 years (IQR, 2.2–11.5 years), 70 complications were observed, including restenosis (n=53), thrombosis (n=7), bleeding (n=6), and stroke (n=4). The overall 1-, 3-, 5-, and 10-year arterial complication–free survival rates were 78% (IQR, 69...