tbuckley/cabot-search huggingface dataset:
Abstract 399: Reactive Oxygen Species in Myocardial Ischemic Injury and Protection
Authors: Huang-Tian Yang, Ji-Liang Tan, Jin-Long Liu, Lan Wu, Zhi-Hua Wang
Journal: Circulation Research (2015)

Myocardial injury following ischemia/reperfusion (I/R) is a common clinical scenario in patients suffering from ischemic heart disease. An excessive production of reactive oxygen species (ROS) during the early phase of reperfusion following myocardial ischemia has been proposed to contribute to reperfusion injury. Paradoxically, the ROS has also been recognized as a trigger of pro-survival signaling pathways mediating cardioprotection at a low level. However, the precise mechanisms for the dual role of ROS have not yet been fully clarified. To address this question, using intermittent hypobaric hypoxia (IHH) as a cardioprotective model, combining with H2O2 pre- and post-conditioning, we studied the level and roles of ROS during early reperfusion following ischemia in I/R injury and protection and explored the regulatory mechanisms underlying. Our results reveal that the elevated ROS generated during early reperfusion are injurious but insufficient to reach the threshold to trigger protective signaling pathways. The moderate level of ROS, higher than that elevated by I/R, during early reperfusion is critical for triggering cardioprotection against I/R injury via alleviating intracellular Ca2+ overload and preserving mitochondrial function through the efficient activation of Akt, PKCε[[Unable to Display Character: &amp;#61472;]]and JAK2/STAT3 pathways. We then identified the downstream target of ROS-JAK2/STAT3 signals that interacts with the sarcoendoplasmic reticulum Ca2+-ATPase 2 (SERCA2) to improve the activation of SERCA2 and subsequently regulate intracellular Ca2+ homeostasis. When the heart is exposed to excessive ROS, the activation of protective mechanisms reaches a plateau and fails to counteract the severe nonspecific oxidative stress. These findings provide a new angle to interpret the controversial roles of ROS in myocardial I/R and demonstrate that the differential effects of ROS in myocardial I/R are derived from a quantity-dependent wrestling between its detrimental and signaling roles.
Redox Stress Defines the Small Artery Vasculopathy of Hypertension
Authors: Rhian M. Touyz, Augusto C. Montezano, Francisco Rios, Michael E. Widlansky, Mingyu Liang
Journal: Circulation Research (2017)

Although convincing experimental evidence demonstrates the importance of vascular reactive oxygen and nitrogen species (RONS), oxidative stress, and perturbed redox signaling as causative processes in the vasculopathy of hypertension, this has not translated to the clinic.We discuss this bench-to-bedside disparity and the urgency to progress vascular redox pathobiology from experimental models to patients by studying disease-relevant human tissues.It is only through such approaches that the unambiguous role of vascular redox stress will be defined so that mechanismbased therapies in a personalized and precise manner can be developed to prevent, slow, or reverse progression of small-vessel disorders and consequent hypertension.
18F-FLUORIDE AND 18F-FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY AFTER TRANSIENT ISCHEMIC ATTACK OR MINOR STROKE: A CASE-CONTROL STUDY
Authors: Alex Thomas Vesey, William Jenkins, Rachael Forsythe, James Rudd, Gregom Sng, Alison Fletcher, Nicholas Mills, Marc Dweck, David Newby
Journal: Journal of the American College of Cardiology (2016)
Patient understanding of hepatocellular carcinoma surveillance
Authors: Matthew A. Goldsworthy, Ian A. Rowe
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. To the editor: We read with interest the recent study by Farvardin and colleagues.1 They identify that > 90% of patients were aware that cirrhosis was a risk factor for hepatocellular carcinoma (HCC) and >85% knew that ultrasound scanning was used to screen for its development. Additionally, they report that two thirds of included patients were worried they might develop HCC, and nearly half expressed concern that they were likely to die from HCC. The reported level of patient knowledge is in contrast to our recent study, in which a similar knowledge‐based survey was administered to patients with cirrhosis attending an outpatient clinic.2 Here, only 10% of patients were aware of the role of ultrasound in surveillance for HCC, despite all of them having previously undergone surveillance. While there are differences in the design of these studies, they illustrate that patient knowledge can vary considerably between different populations and practice settings. It is recognized that surveillance for HCC is done either poorly or not at all in many regions.3 Measures to increase the uptake of surveillance are therefore required to maximize the potential, though unproven, benefits that surveillance may offer. Improving patient education is one way in which this might be achieved. However, it is critical to reflect that quality of life is impaired in cirrhosis,4 and any additional anxiety generated by surveillance may exacerbate this. The patient concerns regarding the development of HCC in the study presented are striking. The direct benefit of surveillance to many of those patients is likely to be negligible as the majority will not develop HCC. Indeed, one half of patients included had ascites, and the prognosis for these individuals without liver transplantation is poor. The benefits of early HCC diagnosis in this group are minimal as treatment options are limited, and these patients might reasonably be freed of ongoing worries about the development of HCC. Ultimately, for patients with liver disease, these concerns need to be addressed with education about the risk of HCC, together with balanced information regarding the potential benefits and harms of surveillance, so that they may make an informed decision about participation. Once that step is passed, addressing the barriers to surveillance highlighted by Farvardin and colleagues is an important target for improving the effectiveness of surveillance.
Serum Magnesium Levels and In-Hospital Mortality in Acute Myocardial Infarction
Authors: Ali Shafiq, Abhinav Goyal, Philip G. Jones, Suman Sahil, Mark Hoffman, Mohammed Qintar, Donna M. Buchanan, Mikhail Kosiborod, Suzanne V. Arnold
Journal: Journal of the American College of Cardiology (2017)
A COMPARISON OF THE ISOMETRIC FORCE FATIGUE-RECOVERY PROFILE IN TWO POSTERIOR CHAIN LOWER LIMB TESTS FOLLOWING SIMULATED FOOTBALL
Authors: Pedro E. Alcaraz, Anton Matinlauri, Afy Abedin-Maghanagi, Tomas T. Freitas, Enrique Martínez-Ruiz, Alberto Castillo, Jurdan Mendiguchia, Daniel D. Cohen
Journal: British Journal of Sports Medicine (2017)

Background Lower limb posterior chain isometric peak force (IPF) measured in the supine position was found to be sensitive to match induced fatigue in footballers (McCall et al . 2015). However, hamstrings fatigue following simulated football may be greatest close to full knee extension (Cohen et al . 2014), and the majority of hamstring strains occur in an extended position (Mendiguchia et al . 2012). Objective To evaluate the effects of a simulated match on IPF in a novel test and a supine position test immediately post, and at +48 h, and +72 h post-match. Design A within-subject, repeated-measures design was used to investigate the short-term effects of fatigue following a simulated football match-protocol –the BEAST mod90 4 (Akubat et al . 2014). Participants 17 semi-professional players (age 21.2±2.4 yrs, body mass 73.8±8.9 kg) competing in a Spanish Third-Division team volunteered to participate in the study, which was implemented after the end of their competitive season. Interventions IPF was measured using a portable force platform immediately before (PRE) and after (POST) the BEAST mod90 protocol, and at +48 h and +72 h post match. Two tests were used: (i) Standing with tested leg at 90° hip and 20° knee flexion (90:20); (ii) Supine with tested leg at 90° knee and hip flexion (S90). Main Outcome Measurements Fatigue after a simulated football match-protocol. We hypothesized that the 90:20 would show greater levels of fatigue than the S90. Results IPF significantly declined PRE versus POST match in the 90:20 in both legs (p&lt;0.001), and in the S90 in the non-dominant (p&lt;0.001) and dominant leg (p&lt;0.01). IPF was significantly lower at +48 h compared to PRE in the 90:20 in both legs (p&lt;0.01, p≤0.05), but not in the S90. At +72 h, IPF was not significantly different from PRE in either test. Conclusions These findings suggest potential angle-specific differences in posterior chain fatigue following a simulated match, and that the 90:20 may be more sensitive to post competition residual posterior chain fatigue.
Clinical utility of a functional lumen imaging probe in management of dysphagia following head and neck cancer therapies
Authors: Peter Wu, Michal Szczesniak, Julia Maclean, Lennart Choo, Harry Quon, Peter Graham, Teng Zhang, Ian Cook
Journal: Endoscopy (2017)

Abstract Background and aims Chemoradiotherapy for head and neck cancer (HNC) with/without laryngectomy commonly causes dysphagia. Pharyngoesophageal junction (PEJ) stricturing is an important contributor. We aimed to validate a functional lumen imaging probe (the EndoFLIP system) as a tool for quantitating pretreatment PEJ distensibility and treatment-related changes in HNC survivors with dysphagia and to evaluate the diagnostic accuracy of EndoFLIP-derived distensibility in detecting PEJ strictures. Methods We studied 34 consecutive HNC survivors with long-term (&gt; 12 months) dysphagia who underwent endoscopic dilation for suspected strictures. Twenty non-dysphagic patients undergoing routine endoscopy served as controls. PEJ distensibility was measured at endoscopy with the EndoFLIP system pre- and post-dilation. PEJ stricture was defined as the presence of a mucosal tear post-dilation. Results PEJ stricture was confirmed in 22/34 HNC patients (65 %). During distension up to 60 mmHg, the mean EndoFLIP-derived narrowest cross-sectional area (nCSA) in HNC patients with strictures, without strictures, and in controls were 58 mm2 (95 % confidence interval [CI] 22 to 118), 195 mm2 (95 %CI 129 to 334), and 227 mm2 (95 %CI 168 to 316), respectively. A cutoff of 114 mm2 for the nCSA at the PEJ had perfect diagnostic accuracy in detecting strictures (area under the receiver operating characteristic curve = 1). In patients with strictures, a single session of dilation increased the nCSA by 29 mm2 (95 %CI 20 to 37; P &lt; 0.001). In patients with no strictures, dilation caused no change in the nCSA (mean difference 13 mm2 [95 %CI −4 to 30]; P = 0.13). Conclusions EndoFLIP is a highly accurate technique for the detection of PEJ strictures. EndoFLIP may complement conventional diagnostic tools in the detection of pharyngeal outflow obstruction.
HGG-04. A HIGH-THROUGHPUT IN VITRO DRUG SCREEN OF PATIENT-DERIVED GLIOMATOSIS CEREBRI CELLS FOR PRECISION MEDICINE
Authors: Uday Bhanu Maachani, Prajwal Rajappa, Julia C. Voronina, Mark M. Souweidane, Jeffrey P. Greenfield
Journal: Neuro-Oncology (2017)

Gliomatosis cerebri (GC) represents a rare inoperable astrocytic neoplasm, characterized by extensive diffuse infiltration into three or more lobes of the brain, sometimes forming one or more discreet tumor masses. It is found in children, teenagers, and adults. The origin of the tumor is unknown and an absence of representative cell cultures for GC has made it difficult to study GC biology. Many current therapeutic approaches have failed and novel targeted therapies are urgently needed. In the present study, we describe the establishment of patient-derived GC cells from the biopsy of a temporal lobe portion of a GC tumor in a 9yr old male. Following the biopsy and creation of a GC-derived cell line, identification of drugs of potential interest was performed utilizing high-throughput drug screen and next generation whole exome sequencing (NGS) of the patient’s tumor. We delineated candidate therapeutics unique for this case, including BRAF, VEGFR/PDGFR inhibitors, FGFR inhibitors, and CDK inhibitors. Sensitivity to these inhibitors mirrored the genetic and somatic mutation/alterations within this tumor. Somatic PIK3CA point mutations were detected at adaptor-binding domain (ABD-G106V) of the p110α catalytic subunit, along with PDGFRA (N659K) mutation. Copy number alterations (CNA) included partial focal CDKN2A and CDKN2B deletion. Further, various other genomic alterations in cancer genes of known and unknown significance were also identified. Our findings demonstrate the feasibility of using patient-derived gliomatosis cerebri cell cultures for high-throughput assays and their integration in drug testing, tailoring treatment strategies based on individual tumor genetic profiles.
Abstract 221: MitoROMK Expression Mitigates the Cellular Response to Oxidative Stress
Authors: Alice S Ho, Thomas Derungs, D. Brian Foster, Brian O’Rourke
Journal: Circulation Research (2013)

We have recently reported that mitoROMK overexpression protects against, while knockdown of native ROMK exacerbates, oxidative stress-induced cell death and have proposed mitoROMK as the molecular correlate of the cardioprotective mitoKATP channel (Foster, Ho, et al Circ Res 2012). In order to better understand the mechanisms of protection, here we examined how alterations of ROMK expression affect glutathione redox responses during acute oxidative stress, utilizing cytoplasmic or mitochondrially targeted, genetically-encoded GSSG sensors. The tandem protein construct Grx1-roGFP2, a fusion of human glutaredoxin and redox sensitive GFP (Gutscher et al, Nat Methods 2008) was incorporated into adenoviral gene transfer vectors for expression in cardiac-derived H9C2 cells. Cells were subjected to treatment with the Complex III inhibitor Antimycin A (50µM) to induce endogenous mitochondrial reactive oxygen species (ROS) production, and changes in the glutathione redox potential were determined ratiometrically. MitoROMK overexpressing cells showed a significantly lower rate of mitochondrial matrix GSH oxidation secondary to H2O2 scavenging compared to both control and ROMK knockdown cell lines, indicating enhanced ability to maintain ROS balance. Increases in cytoplasmic GSSG were also blunted by mitoROMK overexpression. To determine if ROMK expression affected ROS-induced mitochondrial calcium overload, we also employed the mitochondrially-targeted ratiometric Ca2+ probe GEM-GECO (Zhao et al Science 2011). The same Antimycin A challenge led to large mitochondrial Ca2+ increase in control and knockdown cell lines, but this response was significantly suppressed in mitoROMK overexpressing cells. This could not be explained by differences in baseline mitochondrial membrane potential (ΔΨm; determined using the potentiometric probe tetramethylrhodamine methyl ester), because both control cells and ROMK overexpressors showed similar ΔΨm, while ROMK knockdown cells were more depolarized. The results suggest that enhanced cell survival in mitoROMK overexpressing cells is mediated by improved mitochondrial ROS balance and calcium handling, providing a key molecular link between mitochondrial K+ channels and cardioprotection.
Letter by Jurado-Román et al Regarding Article, “Thrombus Aspiration in ST-Segment–Elevation Myocardial Infarction: An Individual Patient Meta-Analysis: Thrombectomy Trialists Collaboration”
Authors: Alfonso Jurado-Román, Ignacio Sánchez-Pérez, Fernando Lozano-Ruíz-Poveda
Journal: Circulation (2017)

and some points should be clarified in further studies.However, TA continues to be a helpful
Is Zap-70 Protein Detection by Flow Cytometry a Reliable Tool in CLL Prognostic Evaluation?.
Authors: Magali Le Garff-Tavernier, Michel Ticchioni, Rémi Letestu, Martine Brissard, Frédéric Davi, Monique Sémichon, Françoise Vuillier, Florence Cymbalista, Hélène Merle-Béral
Journal: Blood (2004)
Prognostic significance of protein kinase B\AKT pathway in adult adrenocortical carcinoma.
Authors: Zhenyu Ding, Ming-Feng Zhang, Chun Wang, Qiu Li
Journal: Journal of Clinical Oncology (2015)

e22229 Background: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. Prognostic factors of ACC were lacking in part owing to the paucity of the disease. The expression of Protein Kinase B\AKT pathway has been implicated to be negatively related to long term survival in different cancer types. Previously we reported the clinical features and prognostic influences in an ACC patient cohort. This study was to investigate the expression and prognostic significance of AKT pathway in the same cohort Methods: The adult patients ( ≥ 18 years) with ACC between Jan 1992 and Jan 2013 in West China Hospital were retrospectively analyzed. All patients need to be confirmed pathologically. The tissue samples were retrieved and the expression of AKT pathway was determined by immunohistochemistry (IHC). The Kaplan-Meier and Cox proportional hazards regression models were used for survival analysis. Results: From 1,395 cases with adrenal lesions, 45 adult patients with ACC who had available tissue samples were sorted out and analyzed. The key components of the AKT pathway and their activated form (AKT, p-AKT, mTOR, p-mTOR, and PI3K) were immunostained predominantly in the cytoplasm of tumor cells. The staining intensity varied and the strong signals were detected in 68.9%, 60.0%, 77.8%, 84.4%, and 73.3% for PI3K, AKT, p-AKT, mTOR, and p-mTOR respectively. Those patients with high-level of PI3K were less likely to be symptomatic (16/31) than the low-level counterparts (13/14, p = 0.008). Otherwise, neither of these factors was related to the demographic features. In univariate analysis, none of the factors in the AKT pathway was related to the survival. In multivariate analysis, the expression of AKT (HR = 0.20, 95% CI: 0.05-0.77, p = 0.019), p-AKT (HR = 6.24, 95% CI: 1.43-27.20, p = 0.015), and p-mTOR (HR = 5.86, 95% CI: 1.38-24.79, p = 0.016) were found to be related to the long-term survival, independent of tumor stage, gender, or complete resection. Conclusions: ACC is a rare disease. The AKT pathway was an independent prognostic factor, and future large-scale prospective clinical study is warranted.
DIPG-34. CLINICAL HETEROGENITY OF DIFFUSE BRAIN STEAM TUMORS IN CHILDREN AND ADULTS
Authors: Elena Khukhlaeva
Journal: Neuro-Oncology (2017)

INTRODUCTION: Diffuse brain steam tumors have a poor prognosis despite innovative approach. METHODS AND HUMAN SUBJECTS: More than 4,000 patients with brainstem tumors were examined in Burdenko Neurosurgical Institute in 1986 – 2016. 420 patient with focal lesions have undergone surgery. All other patients (with DIPG) received radiotherapy. Patient population consisted of >16 (70%) and adults. The group of DIPG turned to be heterogeneous. In children the predominant localization was pons (96%) with only 4% in medulla or midbrain. In adults the medullary diffuse tumor were revealed in 36%. The duration of the disease in children with DIPG was 4.2 months, in adults – 9.6 months. It was much longer in diffuse medullary tumors: 27.5 months in children, 14.4 months in adults. Contrast enhancement to the time of diagnosis was revealed only in 50% of patients, all other were non-enhancing, diffusely infiltrative tumors. RESULTS: The more unfavorable results of radiotherapy were observed in children with DIPG. Overall median survival was 7.2 months In adults it was 5.4 years. 14 pediatric patients were treated with nimotuzumab in combination with the standard fractionated radiotherapy of 54Gy at primary diagnosis (International Phase III study). There was no requirement for histological analysis, but central reference neuroradiological diagnostics and follow-ups were required. The median PFS was 5.8 ± 0.3 months (CI: 4.8 - 6.0, range 0.1 - 46.8 months) and the median OS was 9.4 ± 1.0 months (CI: 7.911.6, range 1.5 -- 46.8 months). The results of this study indicated nimotuzumab in combination with standard radiotherapy was not more efficacious than chemotherapy alone. CONCLUSIONS: Diffuse brainstem tumors represent a heterogeneous group of cancers. Nonsurgical methods (liquid biopsy) investigations of brain steam tumor biology are of great importance for better understanding of the molecular and genetic characteristics of these tumors and search of further treatment.
TRTH-02. STIMULATED RAMAN SCATTERING MICROSCOPY PROVIDES RAPID, DIAGNOSTIC HISTOPATHOLOGIC IMAGES DURING PEDIATRIC BRAIN TUMOR SURGERY
Authors: Todd Hollon, Mia Garrard, Jamaal Tarpeh, Balaji Pandian, Yashar Niknafs, Hugh Garton, Cormac Maher, Karin Muraszko, Sandra Camelo-Piragua, Daniel Orringer
Journal: Neuro-Oncology (2017)

INTRODUCTION: Accurate intraoperative histopathologic diagnosis is essential for optimal surgical management of pediatric brain tumors. Standard intraoperative histopathology suffers from intensive tissue preparation and processing artifact. Stimulated Raman histology (SRH) uses the intrinsic biochemical properties of fresh surgical specimens to provide label-free histologic images. We aimed to evaluate the ability of SRH to reveal histopathologic features of pediatric brain tumors for accurate intraoperative diagnosis. METHODS: Pediatric and young adult brain tumor patients (≤26 years) were prospectively enrolled over 20 months. Fresh surgical specimens were imaged intraoperatively using the first clinical fiber-laser-based SRH microscope. Reviewers evaluated SRH images for histopathologic features and diagnostic accuracy was calculated. RESULTS: A total of 23 patients were enrolled and histopathologic diagnoses included pilocytic astrocytoma(8), ganglioglioma(5), medulloblastoma(4), primitive neuroectodermal tumor(2), ependymoma(2), high-grade glioma(1) and germinoma(1). SRH provided rapid histologic images with sub-micron resolution for all specimens without tissue processing artifact. A virtual hematoxylin and eosin color scheme was developed to recreate standard light microscopy conditions. Diagnostic histopathologic features (e.g. pilocytic processes, small round blue cell morphology, etc.) were evaluated in 1,617 400μm x 400μm fields of view for the above listed tumor types. Reviewers identified diagnostic features in 34/35 (97%) fresh surgical specimens using SRH. Additionally, SRH provided unique intraoperative histologic data on immune cell infiltration not detected on standard light microscopy that improved diagnostic accuracy of tumor grade. High stimulated Raman signal at 2845 cm-1 wavenumber, corresponding to CH2 symmetric stretching mode, highlights phagocytosed lipid droplets in tumor-associated macrophages. Lipid-laden macrophage infiltration predicted higher tumor grade with 99% accuracy (AUC: 0.988). CONCLUSION: SRS microscopy provides rapid, high-resolution, intraoperative images for accurate diagnosis and grading of common pediatric brain tumors. Further investigation in a larger pediatric cohort is currently underway.
Catastrophic Epilepsies of Childhood
Authors: MacKenzie A. Howard, Scott C. Baraban
Journal: Annual Review of Neuroscience (2017)

The tragedy of epilepsy emerges from the combination of its high prevalence, impact upon sufferers and their families, and unpredictability. Childhood epilepsies are frequently severe, presenting in infancy with pharmaco-resistant seizures; are often accompanied by debilitating neuropsychiatric and systemic comorbidities; and carry a grave risk of mortality. Here, we review the most current basic science and translational research findings on several of the most catastrophic forms of pediatric epilepsy. We focus largely on genetic epilepsies and the research that is discovering the mechanisms linking disease genes to epilepsy syndromes. We also describe the strides made toward developing novel pharmacological and interventional treatment strategies to treat these disorders. The research reviewed provides hope for a complete understanding of, and eventual cure for, these childhood epilepsy syndromes.