tbuckley/cabot-search huggingface dataset:
Cyclooxygenase-2, Asymmetric Dimethylarginine, and the Cardiovascular Hazard From Nonsteroidal Anti-Inflammatory Drugs
Authors: Emanuela Ricciotti, Cecilia Castro, Soon Yew Tang, William T.E. Briggs, James A. West, Dania Malik, Seth D. Rhoades, Hu Meng, Xuanwen Li, Nicholas F. Lahens, Jeffrey A. Sparks, Elizabeth W. Karlson, Aalim M. Weljie, Julian L. Griffin, Garret A. FitzGerald
Journal: Circulation (2018)

Background: Large-scale, placebo-controlled trials established that nonsteroidal anti-inflammatory drugs confer a cardiovascular hazard: this has been attributed to depression of cardioprotective products of cyclooxygenase (COX)–2, especially prostacyclin. An alternative mechanism by which nonsteroidal anti-inflammatory drugs might constrain cardioprotection is by enhancing the formation of methylarginines in the kidney that would limit the action of nitric oxide throughout the vasculature. Methods: Targeted and untargeted metabolomics were used to investigate the effect of COX-2 deletion or inhibition in mice and in osteoarthritis patients exposed to nonsteroidal anti-inflammatory drugs on the l -arginine/nitric oxide pathway. Results: Analysis of the plasma and renal metabolome was performed in postnatal tamoxifen-inducible Cox-2 knockout mice, which exhibit normal renal function and blood pressure. This revealed no changes in arginine and methylarginines compared with their wild-type controls. Moreover, the expression of genes in the l -arginine/nitric oxide pathway was not altered in the renal medulla or cortex of tamoxifen inducible Cox-2 knockout mice. Therapeutic concentrations of the selective COX-2 inhibitors, rofecoxib, celecoxib, and parecoxib, none of which altered basal blood pressure or renal function as reflected by plasma creatinine, failed to elevate plasma arginine and methylarginines in mice. Finally, plasma arginine or methylarginines were not altered in osteoarthritis patients with confirmed exposure to nonsteroidal anti-inflammatory drugs that inhibit COX-1 and COX-2. By contrast, plasma asymmetrical dimethylarginine was increased in mice infused with angiotensin II sufficient to elevate blood pressure and impair renal function. Four weeks later, blood pressure, plasma creatinine, and asymmetrical dimethylarginine were restored to normal levels. The increase in asymmetrical dimethylarginine in response to infusion with angiotensin II in celecoxib-treated mice was also related to transient impairment of renal function. Conclusions: Plasma methylarginines are not altered by COX-2 deletion or inhibition but rather are elevated coincident with renal compromise.
A structured algorithm for judicious use of antibody test in diagnosis of heparin-induced thrombocytopenia (HIT).
Authors: Sriman Swarup, Somedeb Ball, Anita Sultan, Nimesh Adhikari, Kyaw Zin Thein, Khatrina Swarup, Sanjay Awasthi, Lukman Aderoju Tijani
Journal: Journal of Clinical Oncology (2019)

314 Background: HIT diagnosis combines 4T scoring &amp; HIT antibodies (HIT-Ab) testing, with confirmatory serotonin release assay (SRA). Latex immunoturbidometric assay (LIA) shows promise in quick &amp; accurate HIT diagnosis, compared to particle immunofiltration assay (PIFA). We designed a HIT workflow &amp; replaced PIFA with LIA at our hospital, to improve 4T usage rates &amp; HIT diagnosis accuracy in a cost-efficient manner. Methods: In phase I, patients (pts) charts with HIT-Ab (PIFA) ordered between Mar2017-Mar2018 were retrospectively reviewed. Three investigators independently calculated 4T &amp; reviewed PIFA/SRA results, with any alternative anticoagulation (AC) used. In phase II, a new workflow on electronic health record incorporating 4T algorithm with HIT-Ab test order was implemented. Our lab replaced PIFA with LIA. In phase II, charts for pts with LIA results from Jan-Mar 2019 were reviewed. Results: In phase I, 170 pts had PIFA results &amp; 5 such pts (0.02%) had 4T score documented in chart. Per investigators, 113 (66.4%) pts had 4T scores. PIFA showed 60% sensitivity &amp; 50% specificity compared to SRA. 19 pts received AC (4 pts had low 4T with negative PIFA). In phase II, 40 pts with LIA tested, 4T scoring by ordering physicians improved to 100%. Per investigators, 42.5% pts had low 4T scores. Clinicians documented high 4T in 11 pts; investigators confirmed high 4T in 2 pts. AC was used in 5 pts (4 with intermediate-high 4T per investigators) Conclusions: Our study showed that incorporation of 4T scoring in HIT algorithm significantly reduced unnecessary ordering of HIT-Ab, with 100% compliance in 4T reporting. Use of AC was consistent with the level of probability by 4T. Further clinician education can help in reduction of up scoring of 4T noted in our results. [Table: see text]
MRI radiomic features are associated with survival in melanoma brain metastases treated with immune checkpoint inhibitors
Authors: Ankush Bhatia, Maxwell Birger, Harini Veeraraghavan, Hyemin Um, Florent Tixier, Anna Sophia McKenney, Marina Cugliari, Annalise Caviasco, Angelica Bialczak, Rachna Malani, Jessica Flynn, Zhigang Zhang, T Jonathan Yang, Bianca D Santomasso, Alexander N Shoushtari, Robert J Young
Journal: Neuro-Oncology (2019)

Abstract Background Melanoma brain metastases historically portend a dismal prognosis, but recent advances in immune checkpoint inhibitors (ICIs) have been associated with durable responses in some patients. There are no validated imaging biomarkers associated with outcomes in patients with melanoma brain metastases receiving ICIs. We hypothesized that radiomic analysis of magnetic resonance images (MRIs) could identify higher-order features associated with survival. Methods Between 2010 and 2019, we retrospectively reviewed patients with melanoma brain metastases who received ICI. After volumes of interest were drawn, several texture and edge descriptors, including first-order, Haralick, Gabor, Sobel, and Laplacian of Gaussian (LoG) features were extracted. Progression was determined using Response Assessment in Neuro-Oncology Brain Metastases. Univariate Cox regression was performed for each radiomic feature with adjustment for multiple comparisons followed by Lasso regression and multivariate analysis. Results Eighty-eight patients with 196 total brain metastases were identified. Median age was 63.5 years (range, 19–91 y). Ninety percent of patients had Eastern Cooperative Oncology Group performance status of 0 or 1 and 35% had elevated lactate dehydrogenase. Sixty-three patients (72%) received ipilimumab, 11 patients (13%) received programmed cell death protein 1 blockade, and 14 patients (16%) received nivolumab plus ipilimumab. Multiple features were associated with increased overall survival (OS), and LoG edge features best explained the variation in outcome (hazard ratio: 0.68, P = 0.001). In multivariate analysis, a similar trend with LoG was seen, but no longer significant with OS. Findings were confirmed in an independent cohort. Conclusion Higher-order MRI radiomic features in patients with melanoma brain metastases receiving ICI were associated with a trend toward improved OS.
Abstract 873: Acetate Protects the Heart Against Ischemic Injury by Alternating TCA Cycle-related Metabolites and AMP-activated Protein Kinase
Authors: Genki Ichihara, Yoshinori Katsumata, Shinichi Goto, Seien Ko, Takahiro Hiraide, Hiroki Kitakata, Hidenori Moriyama, Kohsuke Shirakawa, Atsushi Anzai, Jin Endo, Masaharu Kataoka, Fukuda Keiichi, Motoaki Sano
Journal: Circulation Research (2019)

Introduction: Acetate is preferentially taken up in the heart, and converted into acetyl-CoA by acetyl-CoA synthetase2 (AceCS2), which is abundant in the mitochondria of cardiomyocytes, resulting in activation of AMPK through an elevation of AMP/ATP ratio. In this context, we investigated the effects of acetate on myocardial ischemic injury in isolated cardiomyocytes and in vivo mouse hearts. Methods and Results: In isolated cardiomyocytes, 13 C-labelled metabolites were analyzed using capillary electrophoresis-electrospray ionization mass spectroscopy (CE-ESI-MS) in order to determine the fate of exogenously administered 13 C-acetate. The oxygen consumption rate (OCR) was evaluated using a flux analyzer. A variety of 13 C-labelled intermediates in the TCA cycle increased 10 minutes after administration of 13 C-acetate followed by a subsequent increase in OCR. The OCR elevation was sustained more than 2 hours after acetate injection. The acetate-induced OCR elevation was partially blocked by the glycolysis inhibitor 2-Deoxyglucose (2-DG), carnitine palmitoyl transferase1A (CPT-1A) inhibitor (etomoxir), and mitochondrial pyruvate carrier (MPC) inhibitor (UK5099). The acetate-induced OCR elevation was also blocked by AMP-activated protein kinase (AMPK) inhibitor (compound C). These findings indicated that acetate caused an elevation in mitochondrial function through activation of various metabolic pathways, which may be related to activation of the AMPK pathway. Next, left anterior descending artery-ligated hearts were processed with focused microwave and analyzed by CE-MS and matrix-assisted laser desorption/ionization imaging mass spectrometry in order to examine the region-specific metabolite changes at the early phase of ischemia. Nicotinamide adenine dinucleotide (NADH) elevation in the ischemic core region was suppressed by acetate administration. Furthermore, acetate inhibited cardiac remodeling in a protective manner several weeks after myocardial ischemia when viewed by cardiac ultrasound. Conclusion: Acetate caused an increase in OCR via both a significant elevation in TCA cycle metabolites and activation of AMPK pathway, and may have a protective effect on myocardial ischemic injury.
Ibrutinib Monotherapy in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Mantle Cell Lymphoma: A Retrospective Single Center Experience from India
Authors: Rayaz Ahmed, Dinesh Bhurani, Narendra Agarwal, Jyotsna Kapoor, Neha Gurha, Manan Shah, Prashant Narang
Journal: Blood (2018)
An indirect comparison of long‐term efficacy of every‐2‐week dosing vs. recommended dosing of ixekizumab in patients who had static Physician's Global Assessment &gt; 1 at week 12
Authors: K. Papp, C. Maari, A. Cauthen, M. Gooderham, L. Spelman, K. Yamanaka, P. Polzer, L. Zhang, O. Osuntokun, M. Augustin
Journal: British Journal of Dermatology (2019)

Long-term efficacy and safety of ixekizumab [160 mg at week 0, then 80 mg every 2 weeks (Q2W) for 12 weeks, followed by every 4 weeks (Q4W) thereafter (i.e. Q2W/Q4W), which is the labelled psoriasis dosing where approved, except in Japan] have been established for the treatment of adults with moderate-to-severe plaque psoriasis. However, some patients may benefit from remaining on Q2W dosing beyond 12 weeks.Among patients who had static Physician's Global Assessment (sPGA) > 1 at week 12, efficacy through week 52 of continuous Q2W dosing in the IXORA-P study was compared indirectly with Q2W/Q4W in the integrated data from the UNCOVER-1, UNCOVER-2 and UNCOVER-3 studies. The continuous Q4W dose group, which had comparable results across studies, was used as the common comparator.In the IXORA-P study, among patients with sPGA > 1 at week 12, 64% of patients in the continuous Q2W group achieved sPGA ≤ 1 at week 52, which was statistically significantly higher than the 36% of patients with sPGA > 1 in the Q2W/Q4W group based on the integrated data from the UNCOVER studies (P = 0·0007). There were no clinically meaningful differences in frequencies of safety events between patients with sPGA ≤ 1 and patients with sPGA > 1 at week 12 in the IXORA-P study.Among patients who did not have clear or almost clear skin at week 12, nearly 30% more patients who were treated continuously with ixekizumab Q2W in IXORA-P had clear or almost clear skin at week 52 when compared indirectly with those who were treated using the labelled psoriasis dosing in integrated UNCOVER studies. What's already known about this topic? Most patients with moderate-to-severe psoriasis who were given the labelled psoriasis dosing of ixekizumab [160-mg loading dose at week 0, 80 mg every 2 weeks (Q2W) through week 12, and 80 mg every 4 weeks (QW4) thereafter] respond quickly with a high percentage of skin clearance. Additionally, patients who achieve static Physician's Global Assessment (sPGA) ≤ 1 by week 12 tend to maintain this response, even after switching to Q4W. What does this study add? Here, we assessed whether patients with sPGA > 1 at week 12 benefited from receiving more frequent dosing beyond the first 12 weeks. The results showed that Q2W dosing beyond 12 weeks resulted in more patients achieving sPGA ≤ 1 by week 52 than the labelled psoriasis dosing among patients with sPGA > 1 at week 12.
ARRB1-Induced NOTCH1 Degradation Is Inhibited By Mir-223 in T-ALL
Authors: Lin Zou, Yi Shu, Yi Wang, Wenqiong Lv, Danyi Peng, Hang Zhang, Guangjie Jiang, Shan Liu, Yanhua Chen, Shi Tang, Guo Fu, Xinkun Qi, Zhidai Liu, Haiyan Liu, Chao Yang, Fangjie Liu, Jie Yu, Penghui Zhang, Bin Qu, Hui Zhao, Tongchuan He
Journal: Blood (2018)
Abstract 711: Therapeutic Effects of Engineered Human Pluripotent Stem Cell-derived Lymphatic Endothelial Cells on Experimental Lymphedema
Authors: Shin-Jeong Lee, Young-Doug Sohn, Eun-Ah Sung, JungWoo Kim, Young-sup Yoon
Journal: Circulation Research (2019)

Current systems generating lymphatic endothelial cell (LEC) from human pluripotent stem cells (hPSCs) have limited value due to low purity, the use of undefined components for differentiation, and poor cell survival in vivo . Here, we developed a fully defined system to differentiate hPSCs into LECs and evaluated their therapeutic and engraftment potential when encapsulated in a nanomatrix gel. hPSCs were cultured with GSK3-β inhibitor for 3 days to induce differentiation into the mesodermal lineage. The mesodermal cells were cultured for another 6 days and double-sorted by PDPN and FLT4. These hPSC-PDPN + FLT4 + cells showed highly purified and fully functional LEC characteristics in vitro. These hPSC-LECs express LEC markers such as PDPN, LYVE1, PROX1, and FLT4 at the mRNA level and the protein level, and formed tube-like structures in Matrigel. We next determined the lymphatic vascular reparative effects of engineered hPSC-LECs. After inducing lymphedema in the tail of mouse, hPSC-LECs, hPSC-LECs/PA-RGDS, human dermal lymphatic endothelial cells (hdLEC), PA-RGDS, or PBS were injected into the tail of mouse. Tail thickness significantly decreased in the groups injected with hPSC-LECs with or without PA-RGDS compared to the other groups at day 28. At day 45, mice injected with PA-RGDS encapsulated hPSC-LECs showed significant decrease in the tail diameter compared to all other groups including those injected with hPSC-LECs. This study demonstrated for the first time that PA-RGDS encapsulation can substantially improve lymphedema repair in mouse tail through enhancement of cell survival and lymphatic neovascularizationThis engineered hPSC-LEC therapy represents a novel option for treating lymphedema.
CircPLEKHM3 acts as a tumor suppressor through regulation of the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis in ovarian cancer
Authors: Lei Zhang, Qing Zhou, Qiongzi Qiu, Ling Hou, Mengting Wu, Jia Li, Xufan Li, Bingjian Lu, Xiaodong Cheng, Pengyuan Liu, Weiguo Lu, Yan Lu
Journal: Molecular Cancer (2019)

Abstract Background Emerging evidence has shown that circular RNAs (circRNAs) play essential roles in cancer biology and are potential biomarkers and targets for cancer therapy. However, the expression and function of circRNAs in ovarian carcinogenesis and its progression remain elusive. Methods RNA sequencing was performed to reveal circRNA expression profiles in ovarian cancerous and normal tissues. Single-molecule RNA in-situ hybridization was used to quantify circPLEKHM3 expression in tumor tissues. Cell-based in-vitro and in-vivo assays were subsequently conducted to support the clinical findings. Results CircPLEKHM3 was identified as one of the most significantly down-regulated circRNAs in ovarian cancer tissues compared with normal tissues. Its expression was further decreased in peritoneal metastatic ovarian carcinomas compared to primary ovarian carcinomas. Patients with lower circPLEKHM3 tend to have a worse prognosis. Functionally, circPLEKHM3 overexpression inhibited cell growth, migration and epithelial–mesenchymal transition, whereas its knockdown exerted an opposite role. Further analyses showed that circPLEKHM3 sponged miR-9 to regulate the endogenous expression of BRCA1, DNAJB6 and KLF4, and consequently inactivate AKT1 signaling. In addition, AKT inhibitor MK-2206 could block the tumor-promoting effect of circPLEKHM3 depletion, and potentiate Taxol-induced growth inhibition of ovarian cancer cells. Conclusions Our findings demonstrated that circPLEKHM3 functions as a tumor suppressor in ovarian cancer cells by targeting the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis and may be used as a prognostic indicator and therapeutic target in ovarian cancer patients. The new strategy for treating ovarian cancer by a combination therapy of Taxol with MK-2206 is worth further investigation, especially in ovarian cancer patients with loss of circPLEKHM3 expression.
Assessment of compliance with USPSTF lung cancer screening guidelines among resident primary care physicians in a university residency program.
Authors: Nerea Lopetegui-Lia, Syed Imran Jafri, Manish Kumar, Shashank Sama, James J. Vredenburgh
Journal: Journal of Clinical Oncology (2019)

43 Background: Lung cancer remains the leading cause of morbidity and mortality, with a predicted 1.8 million deaths worldwide yearly. The United States Preventive Services Task Force (USPSTF) recommends screening for lung cancer with Low Dose Computed Tomography (LDCT) for all genres of age 55 to 80 with a 30 pack-year smoking history, current smokers or have quit within the past 15 years. Early detection has shown to reduce mortality. Only 4% of eligible patients in the US actually undergo lung cancer screening. Methods: A retrospective review of data was performed amongst the University of Connecticut Internal Medicine Residents acting as PCPs at a Clinic in Hartford, CT, USA. Results: 369 medical charts were reviewed. 115 patients (31.1%) met the USPSTF criteria for screening. 5.7% had an appropriately ordered LDCT scan. 2.71% had a LDCT completed and 2.98% had LDCT scheduled but pending or cancelled. 4 patients with smoking history who did not meet USPSTF criteria but had a LDCT due to clinical suspicion for lung cancer. Approximately 11% of patients had chronic obstructive pulmonary disease (COPD) or emphysema and asthma. 5 patients had a first degree relative with history of lung cancer. 6 patients had lung cancer, 3 of which had metastatic lung cancer at the time of diagnosis and are deceased. Conclusions: Lung cancer screening amongst resident PCP is insufficient. The results obtained were lower than the national average. This is likely due to newer trainees focusing less in prevention/screening and more on managing chronic medical conditions. Patients that attend resident PCP clinics in the US are typically of lower socio-economic status, less insurance coverage or uninsured and with a lower level of education. LDCT orders that were cancelled were likely because insurers declined it. Patients not realizing the importance of screening could also be contributing. It is unclear if lung disease or family history attributes a higher risk of developing lung cancer. In conclusion, educating resident PCPs and patients on lung cancer screening, as well as evaluating the reasons for cancelling LDCT could help ensure high quality care.
Multidimensional imaging provides evidence for down-regulation of T cell effector function by MDSC in human cancer tissue
Authors: Yu Si, Simon F. Merz, Philipp Jansen, Baoxiao Wang, Kirsten Bruderek, Petra Altenhoff, Stefan Mattheis, Stephan Lang, Matthias Gunzer, Joachim Klode, Anthony Squire, Sven Brandau
Journal: Science Immunology (2019)

A high intratumoral frequency of neutrophils is associated with poor clinical outcome in most cancer entities. It is hypothesized that immunosuppressive MDSC (myeloid-derived suppressor cell) activity of neutrophils against tumor-reactive T cells contributes to this effect. However, direct evidence for such activity in situ is lacking. Here, we used whole-mount labeling and clearing, three-dimensional (3D) light sheet microscopy and digital image reconstruction supplemented by 2D multiparameter immunofluorescence, for in situ analyses of potential MDSC-T cell interactions in primary human head and neck cancer tissue. We could identify intratumoral hotspots of high polymorphonuclear (PMN)-MDSC and T cell colocalization. In these areas, the expression of effector molecules Granzyme B and Ki67 in T cells was strongly reduced, in particular for T cells that were in close proximity or physically engaged with PMN-MDSC, which expressed LOX-1 and arginase I. Patients with cancer with evidence for strong down-regulation of T cell function by PMN-MDSC had significantly impaired survival. In summary, our approach identifies areas of clinically relevant functional interaction between MDSC and T cells in human cancer tissue and may help to inform patient selection in future combination immunotherapies.
Regulation Of Hematopoietic Stem Cell Trafficking By The Coagulation Pathway
Authors: Shiri Gur Cohen, Tomer Itkin, Orit Kollet, Sagarika Chakrabarty, Aya Ludin, Karin Golan, Alexander Kalinkovich, Xin-Jiang Lu, Jeff R. Crosby, Brett P. Monia, Charles T Esmon, Wolfram Ruf, Tsvee Lapidot
Journal: Blood (2013)
A Phase II Study Of The Combination Of Azacitidine and Lenalidomide In Patients (pts) With Higher Risk Myelodysplastic Syndromes (MDS)
Authors: Guillermo Garcia-Manero, Tapan M. Kadia, Naval Daver, Elias Jabbour, Nitin Jain, Jorge E. Cortes, Zeev Estrov, Gautam Borthakur, Xiao Q Dong, Veeral J Kumar, Hagop M Kantarjian
Journal: Blood (2013)
Abstract 198: Single-cell Reconstruction of Differentiation Trajectory Reveals a Critical Role of Ets1 in Human Cardiac Lineage Commitment
Authors: Hang Ruan, Yingnan Liao, Li Wang, Leng Han
Journal: Circulation Research (2019)

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) is an essential model system, but the dynamic process of this in vitro differentiation, especially the pivotal stages of cardiac cell lineage specification is not fully understood. Here, we generated a rich resource of Single-Cell RNA-sequencing of more than 7,500 single cells to capture the differentiation process of in vitro hESC to CMs across six key time points. We characterized the inter-subpopulation relationship demonstrating that co-existing side populations could play an essential role in early cardiac development by bestowing a supporting cellular microenvironment. Through analyzing the dynamic regulatory networks, loss-of-function screen, and systematically validation of binding signals through ChIP-sequencing, we pinpointed the essential regulatory role of ETS1 in mediating early cardiomyocyte development.