tbuckley/cabot-search huggingface dataset:
Abstract 11550: Human Mesenchymal Stem Cell-Derived Microvesicles Mitigate Aortic Smooth Muscle Cell Activation via miR-147 and Attenuate Aortic Aneurysm Formation
Authors: Ashish K Sharma, Guanyi Lu, Morgan D Salmon, Ricardo C Gehrau, Valeria R Mas, Mark L Weiss, Gorav Ailawadi, Gilbert R Upchurch
Journal: Circulation (2015)

Objective: Mesenchymal stem cells (MSCs) can release microvesicles (MVs) but their effects on aortic aneurysm (AA) formation are unknown. We hypothesize that MSC-derived MVs can inhibit AA formation via modulation of specific microRNAs (miRs). Methods: An elastase-perfusion abdominal AA model was used with 8- to 12- week old male mice. The abdominal aorta was perfused for 5 minutes with porcine pancreatic elastase and treated with or without human umbilical cord MSC-derived MVs (1x10 6 given intravenously on day 1). On day14 following perfusion, the abdominal aortic diameter was measured by video micrometry and expressed as percentage increase over baseline. miRNA microarray was performed on aortic tissue using Affymetrix GeneChip hybridization. MVs were transfected with either miR-147b mimic or inhibitor (25nM, Invitrogen, CA) using Lipofectamine RNAiMAX and co-cultured with aortic smooth muscle cells (AoSMCs) followed by treatment with transient elastase (5 minutes) or recombinant IL-17 (10 ng/ml). Cytokines were analyzed in cell culture supernatants after 24 hrs. Groups were compared by ANOVA followed by Bonferroni post hoc test. Results: Treatment of elastase-perfused WT mice with MVs caused a significant attenuation of aortic diameter compared to elastase-perfused mice alone (102.4±6 vs. 162.6±17.9% respectively; mean +/- S.E.; n=5, p=0.03). A significant mitigation of pro-inflammatory cytokines (IL-17, HMGB1, MCP-1, TNF-α and KC), inflammatory cell infiltration (CD3+ T cells, macrophages and neutrophils) and decrease in elastic fiber disruption occurred in aortic tissue from elastase-perfused mice treated with MVs compared to elastase-perfused mice alone. miRNA analysis of aortic tissue demonstrated a significant upregulation of miR-147b (10-fold; p&lt;0.001), miR-19a (9-fold; p&lt;0.001) and a downregulation of miR-98 (1.2 fold; p&lt;0.05) in mice with AA compared to controls (n=5 mice/group). Treatment of AoSMCs with elastase or IL-17 induced cytokines (IL-6, RANTES, MCP-1, TNF-α and KC) which were attenuated by co-cultures with MVs transfected with miR-147 inhibitor. Conclusions: MSC-derived MVs attenuate aortic inflammation and inhibit AoSMC activation via miR-147 suggesting a novel protective mechanism in AA pathobiology.
Probing the mechanism of bupivacaine drug release from multivesicular liposomes
Authors: Soumyarwit Manna, Yong Wu, Yan Wang, Bonhye Koo, Lynn Chen, Peter Petrochenko, Yixuan Dong, Stephanie Choi, Darby Kozak, Berk Oktem, Xiaoming Xu, Jiwen Zheng
Journal: Journal of Controlled Release (2018)
Monocyte-to-lymphocye ratio (MLR) and LDH level in metastatic colorectal cancer (mCRC) patients (pts)
Authors: D. Basile, L. Gerratana, C. Corvaja, G. Pelizzari, S.K. Garattini, C. Lisanti, M. Bartoletti, L. Bortot, V. Fanotto, E. Ongaro, F. Cortiula, A. Parnofiello, M.G. Vitale, L. Da Ros, P. Di Nardo, E. Torrisi, M. Guardascione, G. Miolo, A. Buonadonna, F. Puglisi
Journal: Annals of Oncology (2018)

Background: Tumor microenvironment (TME) is a pitch for multiple players, where the crosstalk between tumor and immune cells determines the fate of tumor progression. In fact, immune system may either destroy or paradoxically promote cancer growth, by recruiting immunosuppressive and inflammatory cells. MLR and LDH levels could be dynamic biomarkers that provide indirect information about TME and are associated with poor prognosis in many tumors. Therefore, we evaluated their prognostic impact in mCRC pts. Methods: We conducted a retrospective cohort study evaluating consecutive data of 165 mCRC pts treated in 2004-2017 at the Unit of Medical Oncology and Oncology Prevention, CRO of Aviano. The prognostic impact of MLR and LDH levels on overall survival (OS) was analyzed through uni- and multivariate Cox regression analysis. Results: At median follow-up of 61.87 months, median OS was 30.74 months. Overall, 100 pts (62%) were aged <65, 63 pts (39%) had a left tumor, 9 (6%) had a BRAF mutation and 45 (28%) had a KRAS mutation, underestimated for the missing data. High levels of LDH (>480 U/L) and MLR (>0.44) were discovered in 35 (21%) and 40 pts (24%), respectively. By univariate analysis, resection (HR 0.25, P < 0.001, 95% CI 0.14-0.45), metastasectomy (HR 0.46, P < 0.001, 95%CI 0.30-0.70) and sidness (left tumors: HR 0.58, P = 0.035, 95%CI 0.36-0.96) were associated with better OS. Conversely, older age (HR 1.63, P = 0.014, 95%CI 1.10-2.42), KRAS mutation (HR 1.77, P = 0.017, 95%CI 1.19-2.85), LDH or MLR high (HR 2.92, P < 0.001, 95% CI 1.77-4.79) or both (HR 4.02, P < 0.001, 95%CI 1.93-8.37) were associated with worse OS. By multivariate analysis, metastasectomy (HR 0.53, P = 0.04, 95%CI 0.29-0.97), KRAS mutation (2.10, P = 0.014, 95% CI 1.16-3.79), LDH or MLR high (HR 3.05, P < 0.001, 95%CI 1.68-5.55) or both (HR 2.65, P = 0.039, 95%CI 1.05-6.68) confirmed their impact on OS. Interestingly, high MLR was associated with right and rectum tumors P = 0.007). Conclusions: We showed that high baseline LDH, MLR or both are poor prognostic factors in mCRC pts adding further evidence of the interlink between immune system, inflammation and cancer. However, further prospective and translational studies are needed to better deepen this topic. Legal entity responsible for the study: CRO, IRCCS, National Cancer Institute of Aviano. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Glioblastoma multiforme cells are sensitive to lysis mediated by killer dendritic cells via granule-dependent and death receptor-dependent mechanisms of cytotoxicity
Authors: T. Tyrinova, O. Leplina, S. Mishinov, M. Tikhonova, A. Kalinovskiy, S. Chernov, V. Stupak, A. Ostanin, E. Chernykh
Journal: Annals of Oncology (2018)

Background: Glioblastoma multiforme (GB) is the most common type of primary brain tumors, that virtually always relapses, despite initial treatment with surgical resection, radio- and chemotherapy. Nowadays new promising approaches are developed in treating GB based on dendritic cell (DC) vaccines for the enhancement of the anti-tumor immune response. IFNα-induced monocyte-derived DCs possess properties of myeloid DCs, plasmacytoid DCs and NK cells. The present study focuses on the role of death-inducing mechanisms in DC cytotoxicity against GB cells. Methods: The study was conducted in 26 donors and 21 GB patients. DCs were generated by culturing of plastic-adherent peripheral blood mononuclear cells in the presence of GM-CSF and IFN-α followed by the addition of LPS. The tumor cell lines were obtained from tissues of 14 GB patients. DC cytotoxicity against tumor cells was studied using MTT-assay. Results: Donor DCs induced death of GB cell lines (min-max cytotoxicity 11-80%). The lysis of GB cells was accompanied with the increase of Annexin V+ apoptotic tumor cells. GB cells expressed death receptors TNF-R1, TRAIL-R2 and Fas. To examine death receptor-mediated killer activity, donor DC were pretreated with soluble forms of TNF family receptors. The blocking of TNF-R1-signaling pathway decreased DC cytotoxicity against GB cells by 25% on average. rhTRAIL-R2 or rhFas pretreatment slightly abolished DC cytotoxicity (with an average of 10%). The most blocking effect on DC cytotoxicity against GB cells was observed if DCs were pretreated with concanamicin A, an inhibitor of granule-dependent killing (Δ up to 60%). GB patient DCs were characterized by reduced cytotoxicity against autologous GB cell lines compared to donor values. Low cytotoxicity of patient DCs was associated with decreased level of membrane TNFα (mTNFα), but intact FasL, TRAIL, perforin and granzyme B molecule expression. The addition of IL-2 into patient DCs enhanced cytotoxicity of DCs towards autologous GB cells and increased mTNFα expression on DCs. Conclusions: Thus, DCs with tumoricidal activity and ex vivo regulation of DC cytotoxic function may become a new approach to obtain effective anti-tumor DC-vaccines. Legal entity responsible for the study: Elena Chernykh. Funding: Grant of the Foundation of the President of the Russian Federation. Disclosure: All authors have declared no conflicts of interest.
Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial
Authors: Javier Martin-Broto, Silvia Stacchiotti, Antonio Lopez-Pousa, Andres Redondo, Daniel Bernabeu, Enrique de Alava, Paolo G Casali, Antoine Italiano, Antonio Gutierrez, David S Moura, Maria Peña-Chilet, Juan Diaz-Martin, Michele Biscuola, Miguel Taron, Paola Collini, Dominique Ranchere-Vince, Xavier Garcia del Muro, Giovanni Grignani, Sarah Dumont, Javier Martinez-Trufero, Emanuela Palmerini, Nadia Hindi, Ana Sebio, Joaquin Dopazo, Angelo Paolo Dei Tos, Axel LeCesne, Jean-Yves Blay, Josefina Cruz
Journal: The Lancet Oncology (2018)
BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma
Authors: Raunak Shrestha, Noushin Nabavi, Yen-Yi Lin, Fan Mo, Shawn Anderson, Stanislav Volik, Hans H. Adomat, Dong Lin, Hui Xue, Xin Dong, Robert Shukin, Robert H. Bell, Brian McConeghy, Anne Haegert, Sonal Brahmbhatt, Estelle Li, Htoo Zarni Oo, Antonio Hurtado-Coll, Ladan Fazli, Joshua Zhou, Yarrow McConnell, Andrea McCart, Andrew Lowy, Gregg B. Morin, Tianhui Chen, Mads Daugaard, S. Cenk Sahinalp, Faraz Hach, Stephane Le Bihan, Martin E. Gleave, Yuzhuo Wang, Andrew Churg, Colin C. Collins
Journal: Genome Medicine (2019)

Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis. To search for novel therapeutic targets for PeM, we performed a comprehensive integrative multi-omics analysis of the genome, transcriptome, and proteome of 19 treatment-naïve PeM, and in particular, we examined BAP1 mutation and copy number status and its relationship to immune checkpoint inhibitor activation. We found that PeM could be divided into tumors with an inflammatory tumor microenvironment and those without and that this distinction correlated with haploinsufficiency of BAP1. To further investigate the role of BAP1, we used our recently developed cancer driver gene prioritization algorithm, HIT'nDRIVE, and observed that PeM with BAP1 haploinsufficiency form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies. Our findings reveal BAP1 to be a potential, easily trackable prognostic and predictive biomarker for PeM immunotherapy that refines PeM disease classification. BAP1 stratification may improve drug response rates in ongoing phases I and II clinical trials exploring the use of immune checkpoint blockade therapies in PeM in which BAP1 status is not considered. This integrated molecular characterization provides a comprehensive foundation for improved management of a subset of PeM patients.
Predicting age from the transcriptome of human dermal fibroblasts
Authors: Jason G. Fleischer, Roberta Schulte, Hsiao H. Tsai, Swati Tyagi, Arkaitz Ibarra, Maxim N. Shokhirev, Ling Huang, Martin W. Hetzer, Saket Navlakha
Journal: Genome biology (2018)

Biomarkers of aging can be used to assess the health of individuals and to study aging and age-related diseases. We generate a large dataset of genome-wide RNA-seq profiles of human dermal fibroblasts from 133 people aged 1 to 94 years old to test whether signatures of aging are encoded within the transcriptome. We develop an ensemble machine learning method that predicts age to a median error of 4 years, outperforming previous methods used to predict age. The ensemble was further validated by testing it on ten progeria patients, and our method is the only one that predicts accelerated aging in these patients.
Abstract 19664: Dual versus Single Antiplatelet Therapy After Trans Catheter Aortic Valve Replacement: A Meta-analysis of Randomized Controlled Trials
Authors: Hitesh Raheja, Vivek Kumar, Vinod Namana, Kirti Chopra, Gerald Hollander, Norbert Moskovits, Bilal Malik, Robert Frankel, Jacob Shani
Journal: Circulation (2017)

Background: Dual anti-platelet therapy (DAPT) with aspirin and clopidogrel is a commonly practiced strategy after trans-catheter aortic valve replacement (TAVR). However there is lack of sufficient...
Epithelial-Mesenchymal Transition Directs Stem Cell Polarity via Regulation of Mitofusin
Authors: Meng-Ju Wu, Yu-Syuan Chen, Mi Ran Kim, Chao-Ching Chang, Silpa Gampala, Yingsheng Zhang, Yueyang Wang, Chih-Yu Chang, Jer-Yen Yang, Chun-Ju Chang
Journal: Cell Metabolism (2018)
Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma
Authors: L. Rasche, D. Alapat, M. Kumar, G. Gershner, J. McDonald, C. P. Wardell, R. Samant, R. Van Hemert, J. Epstein, A. F. Williams, S. Thanendrarajan, C. Schinke, M. Bauer, C. Ashby, R. G. Tytarenko, F. van Rhee, B. A. Walker, M. Zangari, B. Barlogie, F. E. Davies, G. J. Morgan, N. Weinhold
Journal: Leukemia (2018)
FRI0237 Pegloticase treatment significantly decreases mean arterial blood pressure in patients with chronic gout
Authors: H. Choi, R. Johnson, A. Yeo, P. Lipsky
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> There are significant correlations between serum uric acid (sUA) and blood pressure (BP) in individuals with and without gout.<sup>1</sup> Limited data suggest that lowering sUA may decrease BP<sup>2</sup>, but no consistent effect has been noted.<sup>3</sup> Recent guidelines suggest the need for more aggressive management of increased BP.<sup>4</sup> <h3>Objectives</h3> To determine the impact of persistent, very low sUA levels on BP in subjects with chronic refractory gout treated with pegloticase, a recombinant uricase conjugated to polyethylene glycol approved for chronic refractory gout that decreases sUA to &lt;1 mg/dL. <h3>Methods</h3> This analysis used results from two, 6 month randomised clinical trials (RCTs) in which subjects were treated with 8 mg pegloticase every 2 or 4 weeks (q2w or q4w) or placebo.<sup>5</sup> sUA responders maintained sUA &lt;6 mg/dL.<sup>5</sup> Sitting BP was measured at each visit and estimated glomerular filtration rate (eGFR) was determined at baseline and after 3 and 6 months. <h3>Results</h3> Serial BP measures were obtained in 173 subjects during the course of the RCTs. Significant reductions in mean arterial pressure (MAP) from baseline to 6 months were noted in q2w responders (p=0.0029) (figure 1), whereas reductions in MAP in other groups were not significant. Notably, 18/29 (62.1%) of q2w sUA responders experienced persistent reductions in MAP (p=0.01 compared to other groups). Changes in both systolic and diastolic BP paralleled the change in MAP. Of the q2w sUA responders exhibiting persistent decreases in MAP, there were no significant differences in baseline age, gender, race, body mass index, history of hypertension, gout duration, MAP, sUA, cholesterol, eGFR, or urinary UA/creatine ratio compared with those who did not lower MAP. There were no significant changes in eGFR in sUA responders to pegloticase treatment over the course of the study and there was no significant correlation between change from baseline MAP and eGFR in these subjects (p=0.43). <h3>Conclusions</h3> Responders to biweekly pegloticase experienced significant reductions in MAP that were independent of changes in renal function. <h3>References</h3> [1] Lee JJ, et al. <i>J Clin Hyperten</i>2013;15:435. [2] Agarwal V, et al. <i>J Clin Hyperten</i>2013;15:435. [3] Franca GPH, et al. Cochrane Database Syst Rev. 2017;4:CD008652. [4] Whelton PK, et al. J Am Coll Cardiol2017Nov 13. [Epub ahead of print]. [5] Sundy JS, et al. JAMA2011;306:711. <h3>Disclosure of Interest</h3> H. Choi Grant/research support from: AstraZeneca, Consultant for: Horizon Pharma, Selecta, R. Johnson: None declared, A. Yeo Consultant for: Horizon Pharma, P. Lipsky Consultant for: Horizon Pharma
Abstract 21161: Use of an Open Access Multi-Sponsor Data Sharing Platform in Cardiology
Authors: Muthiah Vaduganathan, Amulya Nagarur, Arman Qamar, Ravi B Patel, Ann Marie Navar, Eric D Peterson, Deepak L Bhatt, Gregg C Fonarow, Clyde W Yancy, Javed Butler
Journal: Circulation (2017)

Background: Sharing of patient-level clinical trial data has been widely endorsed, yet little is known how extensively these have been utilized in cardiology. Methods: We extracted data from ClinicalStudyDataRequest.com (CSDR), a large, multi-sponsor, open access platform hosting patient-level data from completed studies sponsored by 13 pharmaceutical companies. Results: From January 2013 to May 2017, the platform had data from 3,374 clinical trials of which 537 (16%) were specific to cardiometabolic therapeutics (phase 1 36%; phase 2 17%; phase 2/3 1%; phase 3 42%; phase 4 4%). These covered 74 therapies and 398,925 patients ( Figure 1 ). Diabetes mellitus (60%) and hypertension (15%) were the most common study topics ( Figure 2 ). Median time from study completion to data availability was 79 months. As of March 2017, CSDR had received 305 submitted proposals, of which 154 had signed data sharing agreements. Thirty of these proposals were related to cardiometabolic therapies and requested data from 81 unique studies (90% of which were phase 3/4). Most proposals were from the US (53%) and half did not report a funding source. Most proposals focused on post hoc exploratory analyses, research methodology, or meta-analyses; only 2 re-analyzed the original study primary hypothesis. To date, 3 peer-reviewed papers have been published (median 19 months from the data sharing agreement). Conclusions: Although data from over 500 cardiometabolic trials have been made available on a large, multi-sponsor open access platform, only 15% of these trials have been accessed by investigators thus far and few findings have reached publication.
The significance of retinoblastoma binding protein 6(RbBP6) and apoptotic regulators, Bax, p53 and Bcl2 expression in A549 cell lines
Authors: Lesetja R. Motadi, Zodwa Dlamini, Kanti Bhoola
Journal: Cancer Research (2006)

4060  Background: Tumours of the lung are the main cause of cancer related deaths and the incidence of such tumours shows a continuous rise worldwide. Apoptosis is a genetically controlled form of cell death regulated by specific gene. Defect in the regulation of apoptosis has been associated with tumorigenesis. p53 and the ratio between pro- (Bax) and anti-apoptotic (Bcl2) genes are central regulators of apoptosis, any mutation or malfunction of these genes will results in apoptosis defect. With the role of p53 in apoptosis already established, the question becomes how is RbBP6 gene that has been associated with p53-dependent pathway involved in apoptosis and whether correlation exist between Bax, Bcl2 and RbBP6. Materials and Method: With ethical approval human A549 cell lines were purchased at highveld biotech and maintained in 10% FCS- HamsF12 media at 37°C in a CO2 incubator. Antibodies against p53, Bax and Bcl2 were purchased from Cell Signalling and that of RbBP6 donated by Prof J Rees from University of the Western Cape. Cells on the cover slide were stained using standard DOKA protocol. For PCR analysis, total RNA was extracted from human A549 the RNA was reverse-transcribed in 20μl reaction volume using first-strand cDNA synthesis kit for RT-PCR (Roche Diagnostic Corporation, SA). Results: Immunocytochemistry analyses showed upregulation of RbBP6, Bax and Bcl2 in the cytoplasm of the cells while that of p53 seemed to be downregulated. RbBP6 and Bcl2 expression, evaluated by PCR technique was observed in A549 cell lines as compared to that in MRC5 cell lines. However, p53 and Bax were less expressed in A549 cell as compared to the normal. Since RbBP6 has been linked with domains that facilitate the binding of p53 tumour suppressor gene/protein, it is possible that RbBP6 might be involved in apoptosis. The indirect correlation between p53 and RbBP6 might suggest that perhaps it is involved in p53-independent pathway. These studies suggest the involvement of RbBP6 in tumorigenic apoptosis.
An IgM antibody targeting the receptor binding site of influenza B blocks viral infection with great breadth and potency
Authors: Chenguang Shen, Minwei Zhang, Yuanzhi Chen, Limin Zhang, Guosong Wang, Junyu Chen, Siyuan Chen, Zizhen Li, Feixue Wei, Jing Chen, Kunyu Yang, Shuxin Guo, Yujing Wang, Qingbing Zheng, Hai Yu, Wenxin Luo, Jun Zhang, Honglin Chen, Yixin Chen, Ningshao Xia
Journal: Theranostics (2018)

Broadly neutralizing antibodies (bnAbs) targeting the receptor binding site (RBS) of hemagglutinin (HA) have potential for developing into powerful anti-influenza agents. Several previously reported influenza B bnAbs are nevertheless unable to neutralize a portion of influenza B virus variants. HA-specific bnAbs with hemagglutination inhibition (HI) activity may possess the ability to block virus entry directly. Polymeric IgM antibodies are expected to more effectively inhibit virus attachment and entry into target cells due to their higher avidity and/or steric hindrance. We therefore hypothesized that certain RBS-targeted IgM antibodies with strong cross-lineage HI activity might display broader and more potent antiviral activity against rapidly evolving influenza B viruses. Methods: In this study, we generated IgM and IgG bnAbs targeting the RBS of influenza B virus using the murine hybridoma technique. IgM and IgG versions of the same antibodies were then developed by isotype switching and characterized in subsequent in vitro and in vivo experiments. Results: Two IgM and two IgG bnAbs against influenza B virus HA were identified. Of these, one IgM subtype antibody, C7G6-IgM, showed strong HI and neutralization activities against all 20 representative influenza B strains tested, with higher potency and broader breadth of anti-influenza activity in vitro than the IgG subtype variant of itself, or other previously-reported influenza B bnAbs. Furthermore, C7G6-IgM conferred excellent cross-protection against distinct lineages of influenza B viruses in mice and ferrets, performing better than the anti-influenza drug oseltamivir, and showed an additive antiviral effect when administered in combination with oseltamivir. Mechanistically, C7G6-IgM potently inhibits infection with influenza B virus strains from different lineages by blocking viral entry. Conclusion: In summary, our study highlights the potential of IgM subtype antibodies in combatting pathogenic microbes. Moreover, C7G6-IgM is a promising candidate for the development of prophylactics or therapeutics against influenza B infection.