tbuckley/cabot-search huggingface dataset:
Abstract 204: Detection and Determination of Protein Network Associated With Atrial Fibrillation Subtypes
Authors: Salah A. Mohamed, Thorsten Hanke, Oliver Klein, Herbert Thiele, Hans H. Sievers, Junfeng Yan
Journal: Circulation Research (2015)

Atrial fibrillation (AF) is associated with increased risks of stroke, cardiac failure, and mortality. The underlying mechanisms and pathology of AF remain elusive. The aim of this study is to proteomically analyze the left atrial appendage tissue obtained from patients suffering from subtypes (paroxysmal, persistent, and long-standing persistent) AF. MALDI Imaging mass spectrometry (MALDI-IMS) was applied to differentiate in classification of pathophysiological AF subtypes, through the direct (in situ) analysis of formalin-fixed paraffin embedded (FFPE) left atrial appendage (LAA) tissue. FFPE LAA tissue were collected from patients with predisposed paroxysmal (n = 9, mean age 69.0±3.1 years), persistent (n = 18, mean age 67.0±2.7 years), and long-standing persistent AF (n = 19, mean age 71.0±2.0 years). Sections were dewaxed and thereupon soused by trypsin solutions using an automated spraying device. Spectra were acquired at a mass range of m/z 800-3500Da and lateral resolution of 80 μm. Two hundred laser shots were acquired per pixel and random walk of 50/position. Data analyses were performed using SCiLS Lab software. Component analysis of MALDI Imaging data through probabilistic latent semantic analysis results in a clear discrimination in the first 3 components of atrial fibrillation. Employing receiver operating characteristic analysis (AUC &gt; 0.7), characteristic intensity distribution in given m/z values, which are discriminative for the considered cluster, was determined to distinguish between paroxysmal vs. persistent AF, and persistent vs. long-persistent AF, m/z values were determined between persistent vs long-persistent AF (1.59±0.12 vs 6.85±3.02, p = 0.02). Follow-up of neurological events in case-controlled assessment presented 13±12% in paroxysmal, 56±12% in persistent and 42±12% long-persistent AF. The tissue-based proteomic approach provides clinically relevant beneficial information in improving risk stratification for AF patients. In the future, this obtained information might be considered new biomarker to support the diagnosis of the severity of AF status. They also suggest a new criterion to determine the most appropriate procedure for each AF subtype to improve postoperative outcomes.
Dissecting the human microbiome with single-cell genomics
Authors: Andrew C. Tolonen, Ramnik J. Xavier
Journal: Genome Medicine (2017)

Recent advances in genome sequencing of single microbial cells enable the assignment of functional roles to members of the human microbiome that cannot currently be cultured. This approach can reveal the genomic basis of phenotypic variation between closely related strains and can be applied to the targeted study of immunogenic bacteria in disease.
Concurrent Inhibition of Pim-1 and FLT3 Kinases in FLT3-ITD Acute Myeloid Leukemia Post-Translationally Downregulates the Anti-Apoptotic Protein Mcl-1 through Downregulation of the Mcl-1 Deubiquitinase USP9X
Authors: Patrick R. Baldwin, Shivani Kapoor, Karthika Natarajan, Rossana Trotta, Adriana Tron, Dennis Huszar, Eduardo Davila, Danilo Perrotti, Maria R. Baer
Journal: Blood (2016)
Abstract 179: Targeted Inhibition of Plasminogen Activator Inhibitor-1 Attenuates Weight Gain and Prevents Vascular Dysfunction Following a High Fat Diet
Authors: Sadiya S Khan, Alexander Mackie, Lauren Beussink-Nelson, Christine E Kamide, Anne S Henkel, Aaron T Place, Mesut Eren, Donald Lloyd-Jones, Sanjiv J Shah, Toshio Miyata, Douglas E Vaughan
Journal: Circulation Research (2015)

Introduction: Elevated plasminogen activator inhibitor-1 (PAI-1) is associated with obesity, but there is controversy whether PAI-1 causes or is a consequence of obesity. We sought to determine whether targeted PAI-1 inhibition with a novel small molecule antagonist (TM5441) alters the development of obesity and/or obesity-induced vascular dysfunction in a diet-induced obesity model. Methods and Results: C57BL/6J mice were fed control, high fat diet (HFD), or high fat diet with TM5441 (HFD+TM5441) for 12 weeks. The HFD had marked weight gain (77±5%) as compared with control (32±2%). TM5441 significantly attenuated weight gain (49±8%, p=0.0075, Figure). HFD-induced hepatic triglyceride accumulation was attenuated by TM5441 (116±31 vs. 76±35 mg trig/g liver, p=0.03). Energy expenditure was reduced in the HFD compared to control (11.1±0.4 vs. 12.9±0.4 kcal/h/kg, p=0.005). However, HFD+TM5441 maintained a level of energy expenditure that was similar to control (13.2±0.6 kcal/h/kg, p=NS). The HFD group demonstrated higher systolic and diastolic blood pressure (141±3; 112±3 mm Hg) compared with control (122±7, 94±8; P&lt;0.05 for both), while administration of TM5441 prevented diet-associated increase (120±6; 93±7 mm Hg, p=NS compared to control) at week 12. Pressure myography of mesenteric arteries in the HFD showed a significant rightward shift in the constrictor response to phenylephrine as compared to control (EC50: 14.5uM vs. 25.1uM, p=0.002). The HFD+TM5441 was similar to control (p=NS). Conclusions: Inhibition of PAI-1 with TM5441 attenuates weight gain, enhances energy expenditure, and prevents obesity-related vascular dysfunction in a murine model of obesity.
Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing
Authors: Natascha Sommer, Maik Hüttemann, Oleg Pak, Susan Scheibe, Fenja Knoepp, Christopher Sinkler, Monika Malczyk, Mareike Gierhardt, Azadeh Esfandiary, Simone Kraut, Felix Jonas, Christine Veith, Siddhesh Aras, Akylbek Sydykov, Nasim Alebrahimdehkordi, Klaudia Giehl, Matthias Hecker, Ralf P. Brandes, Werner Seeger, Friedrich Grimminger, Hossein A. Ghofrani, Ralph T. Schermuly, Lawrence I. Grossman, Norbert Weissmann
Journal: Circulation Research (2017)

Acute pulmonary oxygen sensing is essential to avoid life-threatening hypoxemia via hypoxic pulmonary vasoconstriction (HPV) which matches perfusion to ventilation. Hypoxia-induced mitochondrial superoxide release has been suggested as a critical step in the signaling pathway underlying HPV. However, the identity of the primary oxygen sensor and the mechanism of superoxide release in acute hypoxia, as well as its relevance for chronic pulmonary oxygen sensing, remain unresolved.To investigate the role of the pulmonary-specific isoform 2 of subunit 4 of the mitochondrial complex IV (Cox4i2) and the subsequent mediators superoxide and hydrogen peroxide for pulmonary oxygen sensing and signaling.Isolated ventilated and perfused lungs from Cox4i2-/- mice lacked acute HPV. In parallel, pulmonary arterial smooth muscle cells (PASMCs) from Cox4i2-/- mice showed no hypoxia-induced increase of intracellular calcium. Hypoxia-induced superoxide release which was detected by electron spin resonance spectroscopy in wild-type PASMCs was absent in Cox4i2-/- PASMCs and was dependent on cysteine residues of Cox4i2. HPV could be inhibited by mitochondrial superoxide inhibitors proving the functional relevance of superoxide release for HPV. Mitochondrial hyperpolarization, which can promote mitochondrial superoxide release, was detected during acute hypoxia in wild-type but not Cox4i2-/- PASMCs. Downstream signaling determined by patch-clamp measurements showed decreased hypoxia-induced cellular membrane depolarization in Cox4i2-/- PASMCs compared with wild-type PASMCs, which could be normalized by the application of hydrogen peroxide. In contrast, chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling were not or only slightly affected by Cox4i2 deficiency, respectively.Cox4i2 is essential for acute but not chronic pulmonary oxygen sensing by triggering mitochondrial hyperpolarization and release of mitochondrial superoxide which, after conversion to hydrogen peroxide, contributes to cellular membrane depolarization and HPV. These findings provide a new model for oxygen-sensing processes in the lung and possibly also in other organs.
Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair
Authors: Christopher B. Little, Clare T. Meeker, Suzanne B. Golub, Kate E. Lawlor, Pamela J. Farmer, Susan M. Smith, Amanda J. Fosang
Journal: Journal of Clinical Investigation (2008)

The formula used to calculate cartilage repair is described incorrectly on page 1635.The correct description of the formula appears below.The cartilage repair score at day 28 was calculated by subtracting the number from 1. Positive scores indicate percentage of improvement, and negative scores indicate the percentage by which the score worsened, compared with day 7.The authors regret the error.
Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 2 and Related Disorders
Authors: D. Gareth R. Evans, Hector Salvador, Vivian Y. Chang, Ayelet Erez, Stephan D. Voss, Harriet Druker, Hamish S. Scott, Uri Tabori
Journal: Clinical Cancer Research (2017)

The neurofibromatoses consist of at least three autosomal-dominant inherited disorders: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. For over 80 years, these conditions were inextricably tied together under generalized neurofibromatosis. In 1987, the localization of NF1 to chromosome 17q and NF2 (bilateral vestibular schwannoma) to 22q led to a consensus conference at Bethesda, Maryland. The two main neurofibromatoses, NF1 and NF2, were formally separated. More recently, the SMARCB1 and LZTR1 genes on 22q have been confirmed as causing a subset of schwannomatosis. The last 26 years have seen a great improvement in understanding of the clinical and molecular features of these conditions as well as insights into management. Childhood presentation of NF2 (often with meningioma) in particular predicts a severe multitumor disease course. Malignancy is rare in NF2, particularly in childhood; however, there are substantial risks from benign and low-grade central nervous system (CNS) tumors necessitating MRI surveillance to optimize management. At least annual brain MRI, including high-resolution images through the auditory meatus, and a clinical examination and auditory assessment are required from diagnosis or from around 10 to 12 years of age if asymptomatic. Spinal imaging at baseline and every 2 to 3 years is advised with more frequent imaging if warranted on the basis of sites of tumor involvement. The malignancy risk in schwannomatosis is not well defined but may include an increased risk of malignant peripheral nerve sheath tumor in SMARCB1 Imaging protocols are also proposed for SMARCB1 and LZTR1 schwannomatosis and SMARCE1-related meningioma predisposition. Clin Cancer Res; 23(12); e54-e61. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
Taurine up‐regulated gene 1 functions as a master regulator to coordinate glycolysis and metastasis in hepatocellular carcinoma
Authors: Yang‐Hsiang Lin, Meng‐Han Wu, Ya‐Hui Huang, Chau‐Ting Yeh, Mei‐Ling Cheng, Hsiang‐Cheng Chi, Chung‐Ying Tsai, I‐Hsiao Chung, Ching‐Ying Chen, Kwang‐Huei Lin
Journal: Hepatology (2017)

Cancer cells display altered glucose metabolism characterized by a preference for aerobic glycolysis. The aerobic glycolytic phenotype of hepatocellular carcinoma (HCC) is often correlated with tumor progression and poorer clinical outcomes. However, the issue of whether glycolytic metabolism influences metastasis in HCC remains unclear. In the current study, we showed that knockdown of taurine up‐regulated gene 1 ( TUG1 ) induces marked inhibition of cell migration, invasion, and glycolysis through suppression of microRNA (miR)‐455‐3p. MiR‐455‐3p, which is transcriptionally repressed by p21, directly targets the 3′ untranslated region of adenosine monophosphate‐activated protein kinase subunit beta 2 (AMPKβ2). The TUG1/miR‐455‐3p/AMPKβ2 axis regulates cell growth, metastasis, and glycolysis through regulation of hexokinase 2 (HK2). TUG1 is clearly associated with HK2 overexpression and unfavorable prognosis in HCC patients. Conclusion : Our data collectively highlight that novel regulatory associations among TUG1, miR‐455‐3p, AMPKβ2, and HK2 are an important determinant of glycolytic metabolism and metastasis in HCC cells and support the potential utility of targeting TUG1/HK2 as a therapeutic strategy for HCC. (H epatology 2018;67:188‐203)
Abstract 167: Mir-195-3p/-5p Decrease Cardiac Fibroblast Proliferation and the Transdifferentiation into Myofibroblasts
Authors: Shutong Shen, Xiuzhi Wang, Dongjie Xu, Lichan Tao, Xiaoting Wu, Junjie Xiao, Xinli Li
Journal: Circulation Research (2015)

Aims: MicroRNAs (miRNAs, miRs) contribute to many essential physiological and pathological processes including fibrosis. This study aims at investigating the role of miR-195-3p/-5p in cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts. Methods and results: In isolated primary neonatal cardiac fibrobasts (NRCFs), forced expression of miR-195-3p/-5p with agomiRs could attenuate fibrobast proliferation as determined by EdU and Ki67 staining while inhibition of miR-195-3p/-5p with antagomiRs could increase fibrobast proliferation. By quantitative reverse transcription polymerase chain reactions (RT-PCRs) and western blotting (WB), α-SMA (a marker of myofibroblast transdifferentiation) was found to be suppressed in the miR-195-3p/-5p agomiR-treated NRCFs at both mRNA and protein levels, while was increased in the miR-195-3p/-5p antagomiR-treated NRCFs. Moreover, Chek-1 was identified as a target gene of miR-195-3p/-5p responsible for cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts by RT-PCR and WB and immunofluorescent staining. Silencing of Chek-1 attenuates cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts as detected by α-SMA/EDU staining. In addition, Chek-1 mediated the effects of miR-195-3p/-5p in cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts. Conclusion: Therefore, miR-195-3p/-5p might be promising therapeutic targets for cardiac fibrosis.
A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens
Authors: Aaron Y. Chang, Tao Dao, Ron S. Gejman, Casey A. Jarvis, Andrew Scott, Leonid Dubrovsky, Melissa D. Mathias, Tatyana Korontsvit, Victoriya Zakhaleva, Michael Curcio, Ronald C. Hendrickson, Cheng Liu, David A. Scheinberg
Journal: Journal of Clinical Investigation (2017)

Preferentially expressed antigen in melanoma (PRAME) is a cancer-testis antigen that is expressed in many cancers and leukemias. In healthy tissue, PRAME expression is limited to the testes and ovaries, making it a highly attractive cancer target. PRAME is an intracellular protein that cannot currently be drugged. After proteasomal processing, the PRAME300-309 peptide ALYVDSLFFL (ALY) is presented in the context of human leukocyte antigen HLA-A*02:01 molecules for recognition by the T cell receptor (TCR) of cytotoxic T cells. Here, we have described Pr20, a TCR mimic (TCRm) human IgG1 antibody that recognizes the cell-surface ALY peptide/HLA-A2 complex. Pr20 is an immunological tool and potential therapeutic agent. Pr20 bound to PRAME+HLA-A2+ cancers. An afucosylated Fc form (Pr20M) directed antibody-dependent cellular cytotoxicity against PRAME+HLA-A2+ leukemia cells and was therapeutically effective against mouse xenograft models of human leukemia. In some tumors, Pr20 binding markedly increased upon IFN-γ treatment, mediated by induction of the immunoproteasome catalytic subunit β5i. The immunoproteasome reduced internal destructive cleavages within the ALY epitope compared with the constitutive proteasome. The data provide rationale for developing TCRm antibodies as therapeutic agents for cancer, offer mechanistic insight on proteasomal regulation of tumor-associated peptide/HLA antigen complexes, and yield possible therapeutic solutions to target antigens with ultra-low surface presentation.
Determine the relationship between Ki 67 and Oncotype DX.
Authors: Nasser Mulla, Anwar Alnouri, Muneera Majed Al Majed, Olga Aleynikova, Manuela Pelmus, Anca Florea, Lawrence C. Panasci
Journal: Journal of Clinical Oncology (2016)

e12017 Background: Oncotype DX provides prognostic and predictive information for recurrence in early stage breast cancer patients. Recently an association of Ki67 with prognosis and response have been reported. However, evidence supporting the clinical utility of Ki67 is not sufficient to recommend routine use of this marker for prognosis and prediction of responsiveness to chemotherapy in patients with newly diagnosed early stage breast cancer. We examined the relationship of IHC-measured Ki 67 to Oncotype DX recurrence score. Methods: This retrospective study included 339 consecutive cases of hormone receptor-positive, HER2 negative (T1-2 N0 M0) breast cancer. Patients were divided into low risk (Ki67 < 10%), intermediate risk (10 ≥ Ki67 < 25) and high-risk group (Ki67 ≥ 25). Results: There is high concordance rate between Oncotype DX and Ki67: 88% of the patients in the high Oncotype DX RS group had a high Ki67 score while only 4 patients (1%) of patients with Ki67 < 25 (low and intermediate risks) had a high Oncotype DX RS. There was a modest but significant correlation between Oncotype DX RS and Ki 67 (r = 0.488, P value < 0.001). This correlation remains significant even after controlling for the effect of Nottingham grade and PR (r = 0.381, P value < 0.001). In a multiple regression analysis with Ki67, the size of tumour and Nottingham grade, only Ki67 can explain 52% of variations of Oncotype DX RS (standardized β = 0.487; P value < 0.001). Lower expression of PR is associated with higher Oncotype DX RS (r = 0.410). Conclusions: There is a moderate correlation between Ki67 and Oncotype DX RS. Long-term follow-up of these cases will determine if Ki67 can be used as a marker of distant relapse.
Ability of scat3 and childscat3 to discriminate children with concussion from children with upper limb injuries and uninjured children in the emergency department
Authors: Franz E Babl, Diana V Dionisio, Lucy Davenport, Amy Baylis, Stephen Hearps, Silvia Bressan, Vicki Anderson, Ed Oakley, Gavin A Davis
Journal: British Journal of Sports Medicine (2017)

Objective To evaluate the ability of SCAT3 and ChildSCAT3 to discriminate children with concussion from children with upper limb injuries and uninjured children in the emergency department Design Prospective observational study. Setting Tertiary children’s hospital emergency department. Participants 264 children presenting to ED with concussion (CONC, n=90) and two control groups (i) upper limb injury (ULI, n=90) and (ii) well children (WELL, n=84) with equal sized subgroups in three age bands of 5–8, 9–12, and 13–16 years. Assessment and outcome Child-SCAT3 was used in 5-12 years, SCAT3 in 13–16 years, administered by trained research assistants. Differences between study groups were analysed using ANOVA. Effect sizes were also assessed. Results The number and severity of child and parent reported symptom scores for SCAT3 and the child-SCAT3 were significantly higher in CONC than either control group (p&lt;0.001). Mean double and tandem stance errors were also significantly higher (p&lt;0.001), and immediate memory and concentration were significantly lower for the CONC group (p&lt;0.01). No group differences were found for orientation and digit backwards.Among SCAT3 symptoms, headache and pressure in head had the highest effect size (0.51 and 0.44 respectively, p&lt;0.001). Among Child SCAT3 symptoms, I have headaches and I feel dizzy had the highest effect size (0.31 and 0.23 respectively, p&lt;0.001). There were no significant differences between ULI and WELL control groups. Conclusions Overall, SCAT3 and child-SCAT3 can differentiate concussed from non-concussed patients, in particular for number and symptom severity. However, some neuropsychological subtests do not differentiate concussed patients and controls. Competing interests GAD is an honorary member of the Australian Football League Concussion Working Group, and has attended meetings organised by sporting organisations including the National Football League (USA), National Rugby League (Australia) and FIFA (Switzerland); however has not received any payment, research funding, or other monies from these groups other than for travel costs. GAD is a member of the International Concussion in Sport group that developed the SCAT3 and ChildSCAT3
PET imaging in patients with meningioma—report of the RANO/PET Group
Authors: Norbert Galldiks, Nathalie L Albert, Michael Sommerauer, Anca L Grosu, Ute Ganswindt, Ian Law, Matthias Preusser, Emilie Le Rhun, Michael A Vogelbaum, Gelareh Zadeh, Frédéric Dhermain, Michael Weller, Karl-Josef Langen, Jörg C Tonn
Journal: Neuro-Oncology (2017)

Meningiomas are the most frequent nonglial primary brain tumors and represent about 30% of brain tumors. Usually, diagnosis and treatment planning are based on neuroimaging using mainly MRI or, rarely, CT. Most common treatment options are neurosurgical resection and radiotherapy (eg, radiosurgery, external fractionated radiotherapy). For follow-up after treatment, a structural imaging technique such as MRI or CT is used. However, these structural imaging modalities have limitations, particularly in terms of tumor delineation as well as diagnosis of posttherapeutic reactive changes. Molecular imaging techniques such as PET can characterize specific metabolic and cellular features which may provide clinically relevant information beyond that obtained from structural MR or CT imaging alone. Currently, the use of PET in meningioma patients is steadily increasing. In the present article, we provide recommendations for the use of PET imaging in the clinical management of meningiomas based on evidence generated from studies being validated by histology or clinical course.
Abstract 266: Autophagy Reverses Intramuscular Lipid Accumulation in Myocytes
Authors: Truong N Lam, Romain Harmancey, Heinrich Taegtmeyer
Journal: Circulation Research (2012)

Autophagy, or “self-eating” of the cell, is a tightly regulated “housekeeping” process involved in the degradation and recycling of protein aggregates and damaged organelles. In the failing heart, autophagy has been shown to be an adaptive response. We have previously demonstrated that a common feature of non-ischemic heart failure is lipid accumulation, which in excess can mediate cardiac dysfunction via lipotoxicity. Since autophagy mediates the clearance of lipids through a specific process, known as lipophagy, in hepatocytes, we wondered whether the activation of autophagy in the failing heart protects myocyte from lipotoxicity. To test this hypothesis, L6 myocytes were incubated over a period of 6 days with long chain fatty acids, either 0.5mM or 1.0mM fatty acids (equimolar mixture of oleate and palmitate). On the sixth day of treatment, an autophagic inhibitor (bafilomycin A1, 200nM) or autophagic activator (rapamycin, 1uM) was added to the cell culture medium for 24 hours. Intracellular triglyceride (TG) accumulation was measured in the cells using enzyme quantification assay as well as Oil Red O stain. Immunoblotting was also performed on protein markers to confirm autophagic flux (LC3 and P62) and cell death (Caspase3) in the myocytes. The results indicated that increasing concentrations of fatty acids gradually increased intracellular TG accumulation. Inhibition of autophagy using bafilomycin increased this effect whereas activation of autophagy using rapamycin reduced lipid accumulation in the L6 myocytes. Moreover, fatty acid mediated cell death was increased when autophagy is inhibited. We conclude that autophagy promotes the clearance of lipids from cultured myocytes. These findings suggest that lipophagy may be a protective mechanism in the myocyte through the decrease and reversal of intracellular lipid accumulation.