tbuckley/cabot-search huggingface dataset:
Intraoperative Resection Guidance with Photoacoustic and Fluorescence Molecular Imaging Using an Anti–B7-H3 Antibody-Indocyanine Green Dual Contrast Agent
Authors: Katheryne E. Wilson, Sunitha V. Bachawal, Jürgen K. Willmann
Journal: Clinical Cancer Research (2018)

Purpose: Breast cancer often requires surgical treatment including breast-conserving surgical resection. However, with current postsurgical histologic margin analysis, one quarter of breast cancer patients undergo reexcision to achieve negative margins corresponding to decreased local recurrence and better outcomes. Therefore, a method with high resolution and specificity for intraoperative margin assessment is needed.Experimental Design: First, quantitative immunofluorescence staining of B7-H3 expression was assessed in four pathologic stages of breast cancer progression of the MMTV-PyMT transgenic murine model. Next, an antibody-dye contrast agent, B7-H3-ICG, was injected into mice prior to surgical resection of breast cancer. Anatomic ultrasound, spectroscopic photoacoustic (sPA), and fluorescence imaging were used to guide resection of mammary glands suspected of containing cancer. Resected tissues were processed for H&E staining and pathologic assessment and compared with sPA and fluorescence imaging signals.Results: Tissue containing DCIS (46.0 ± 4.8 a.u.) or invasive carcinoma (91.7 ± 21.4 a.u.) showed significantly higher (P < 0.05) B7-H3 expression than normal and hyperplastic tissues (1.3 ± 0.8 a.u.). During image-guided surgical resection, tissue pieces assessed as normal or hyperplastic (n = 17) showed lower average sPA (3.17 ± 0.48 a.u.) and fluorescence signal [6.83E07 ± 2.00E06 (p/s)/(μW/cm²)] than DCIS and invasive carcinoma tissue (n = 63) with an average sPA signal of 23.98 ± 4.88 a.u. and an average fluorescence signal of 7.56E07 ± 1.44E06 (p/s)/(μW/cm²) with AUCs of 0.93 [95% confidence interval (CI), 0.87-0.99] and 0.71 (95% CI, 0.57-0.85), respectively.Conclusions: It was demonstrated that sPA and fluorescence molecular imaging combined with B7-H3-ICG agent can assess the disease status of tissues with high diagnostic accuracy, intraoperatively, with high resolution, sensitivity, and specificity. Clin Cancer Res; 24(15); 3572-82. ©2018 AACR.
Personalized medicine in non-small cell lung cancer: a review from a pharmacogenomics perspective
Authors: Wenxiao Jiang, Guiqing Cai, Peter C. Hu, Yue Wang
Journal: Acta Pharmaceutica Sinica B (2018)

Non-small cell lung cancer is a prevalent and rapidly-expanding challenge to modern medicine. While generalized medicine with traditional chemotherapy yielded comparatively poor response rates and treatment results, the cornerstone of personalized medicine using genetic profiling to direct treatment has exalted the successes seen in the field and raised the standard for patient treatment in lung and other cancers. Here, we discuss the current state and advances in the field of personalized medicine for lung cancer, reviewing several of the mutation-targeting strategies that are approved for clinical use and how they are guided by patient genetic information. These classes include inhibitors of tyrosine kinase (TKI), anaplastic lymphoma kinase (ALK), and monoclonal antibodies. Selecting from these treatment plans and determining the optimal dosage requires in-depth genetic guidance with consideration towards not only the underlying target genes but also other factors such as individual metabolic capability and presence of resistance-conferring mutations both directly on the target gene and along its cascade(s). Finally, we provide our viewpoints on the future of personalized medicine in lung cancer, including target-based drug combination, mutation-guided drug design and the necessity for data of population genetics, to provide rough guidance on treating patients who are unable to get genetic testing.
Pre-clinical in vivo evaluation of cormatrix as right-sided valved conduit
Authors: H. Talacua, Khadija Mulder, Geert van Hout, B. Sanders, P.F. Grundeman, Aryan Vink, C.V.C. Bouten, J. Kluin
Journal: Circulation (2015)

Introduction: Although not FDA approved for heart valve repair, decellularized porcine small intestinal submucosa (Cormatrix) is currently used in quite a lot of institutes to reconstruct heart valves in patients. Recently, surgeons experienced clinical failures using Cormatrix as a patch in heart valve repair and words of caution were raised. The aim of this study was to pre-clinically evaluate CorMatrix as right-sided heart valved conduit in a xenogeneic animal model Methods: CorMatrix was used as valved conduit in the right ventricular outflow tract in sheep (n=10) and lambs (n=10). Valved conduits were home-made and explanted after 1 month, 3 months or 6 months. Valve function was assessed by echocardiography directly after implantation and prior to termination. Explants were analyzed using histology, scanning electron microscopy, mechanical testing, biochemical analysis and immunohistochemistry Results: All valved conduits were successfully implanted. 5 sheep and 2 lambs did not survive until planned follow-up. Diseased animals died due to valve failure after 1 or 2 months. Valve leaflets where thickened with signs of a massive inflammatory response. 5 sheep (1 month n=3, 3 months n=1 and 6 months n=1) and 8 lambs (1 month n=3, 3 months n=3, 6 months n=2) survived until planned follow up. In these animals, on echocardiography a well functioning valve with no signs of stenosis or insufficiency was seen. However all explants showed only limited signs of cellular infiltration or neotissue formation Conclusions: In the chronic sheep and lamb model, 13 out of 20 CorMatrix pulmonary valved conduits were intact and showed good functionality, although only limited signs of tissue remodeling. However, 7 out of 20 valves failed owing to a massive inflammatory response. Further analysis is needed to understand the disturbing dichotomous outcome before clinical application can be advised.
TCTAP C-089 Bidirectional Approach to Chronic Total Occlusion of the Left Circumflex Artery with Single Guiding Catheter Using the Wire Rendezvous Technique and Chasing Wire Technique
Authors: Keisuke Nakabayashi, Nobuhito Kaneko, Hiroshi Ando, Minoru Shimizu
Journal: Journal of the American College of Cardiology (2018)
Lymphangioma on 68Ga-NOTA-Evans Blue PET/MRI
Authors: Guozhu Hou, Xiaoqing Li, Bo Hou, Weixun Zhou, Wuying Cheng
Journal: Clinical Nuclear Medicine (2018)

Abstract A 17-year-old adolescent boy with a history of hypoproteinemia underwent 68 Ga-NEB PET/MRI to evaluate possible lymphatic disorders suggested by FDG PET/CT imaging. The images revealed multiple lesions with increased 68 Ga-NEB uptake and high signal on T2-weighted images, consistent with likely lymphatic disorder. Histopathological examination from biopsied specimen confirmed lymphangioma.
Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
Authors: Pratiksha Gulati, Julia Rühl, Abhilash Kannan, Magdalena Pircher, Petra Schuberth, Katarzyna J. Nytko, Martin Pruschy, Simon Sulser, Mark Haefner, Shawn Jensen, Alex Soltermann, Wolfgang Jungraithmayr, Maya Eisenring, Thomas Winder, Panagiotis Samaras, Annett Tabor, Rene Stenger, Roger Stupp, Walter Weder, Christoph Renner, Christian Münz, Ulf Petrausch
Journal: Clinical Cancer Research (2018)

Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed.Experimental Design: Fibroblast activation protein (FAP)-specific CARs with different costimulatory domains, including CD28, Δ-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the Δ-CD28 CAR was tested clinically in a patient with MPM.Results: All the three CARs demonstrated FAP-specific functionality in vitro Gene expression data indicated a distinct activity profile for the Δ-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the Δ-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the Δ-CD28 CAR could be detected for up to 21 days and showed functionality.Conclusions: Overall, anti-FAP-Δ-CD28/CD3ζ CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981-93. ©2018 AACR.
A viral protein kinase drug target for tumors?
Authors: Richard F. Ambinder
Journal: Journal of Clinical Investigation (2018)

The human gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), are both associated with tumors. Standard antiviral therapies are ineffective at treating these tumors. A serine/threonine kinase important for viral replication is conserved across the herpesviruses. Expression of the KSHV protein kinase in transgenic mice under the control of a ubiquitin promoter was associated with B cell lymphoproliferative disease and lymphoma. If the viral protein kinase is important in the pathogenesis of KSHV lymphoproliferative disease or lymphoma, the kinase may present a very good target for pharmacologic therapies.
Quantitative comparison of PD-L1 immuno-histochemical assays in hepatocellular carcinoma: The Blueprint-HCC study
Authors: D.J. Pinato, F. Mauri, P. Spina, O. Cain, A. Siddique, R.D. Goldin, S. Victor, C. Pizio, A. Akarca, R. Boldorini, L. Mazzucchelli, J.R.M. Black, S. Shetty, T. Marafioti, R. Sharma
Journal: Journal of Hepatology (2018)
Characterization of asthma in the adolescent population
Authors: M. Ödling, N. Andersson, S. Ekström, E. Melén, A. Bergström, I. Kull
Journal: Allergy (2018)

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Narrow terms of reference mean that Jeremy Hunt’s review of gross negligence manslaughter will miss the point
Authors: Toby Reynolds
Journal: BMJ (2018)

In February England’s health secretary announced a review into gross negligence manslaughter in healthcare.1 This followed Hadiza Bawa-Garba’s 2015 conviction on this charge and the subsequent High Court decision to strike her from the medical register.

It may come too late for Bawa-Garba, but many hoped that this review, led by Norman Williams, would tackle the alarming …
Spermidine/spermine N1-acetyltransferase-mediated polyamine catabolism regulates beige adipocyte biogenesis
Authors: Fang Yuan, Lin Zhang, Yang Cao, Wei Gao, Can Zhao, Yuan Fang, Kamyar Zahedi, Manoocher Soleimani, Xiang Lu, Zhuyuan Fang, Qin Yang
Journal: Metabolism (2018)
P256Telomere lengths and the rejuvenating factor GDF11 in coronary artery disease
Authors: T B Opstad, A A Kalstad, AÅ Pettersen, H Arnesen, I Seljeflot
Journal: Cardiovascular Research (2018)

Background/Introduction: Telomeres are dynamic chromosome-end structures that protect DNA in our genome from deterioration.Throughout life, telomere lengths (TLs) become shorter, and the rate of this process has been associated with lifestyle and the onset of age-related diseases.Moreover, the aging-associated factor growth differentiation factor 11 (GDF11) has been suggested as a rejuvenating factor.Together, the interplay of these aspects that possibly modulate the aging process is of interest to explore.Purpose: To investigate the associations between leukocyte TLs (LTLs) and chronological age, comorbidities and clinical outcome in patients with coronary artery disease (CAD).Potential covariations between LTL and GDF11 were further assessed.Methods: 300 patients with stable CAD, 20% female, age range 36-81 yrs, were included.Within 2 years, a composite of new clinical events (unstable angina pectoris, myocardial infarction (MI), stroke and deaths) was recorded.DNA and RNA were isolated from whole blood for the analysis of LTLs and GDF11 gene expression, respectively.LTLs were measured by PCR using telomerespecific primers and determined relatively to a single copy gene (36B4).The amount of GDF11 was measured as relative quantification using PCR and the house-keeping gene b2M.Results: We observed that patients with previously suffered MI presented with 20% shorter LTLs vs. patients without (p ¼ 0.015), however, only in men (p ¼ 0.009, n ¼ 115).To further explore this association, LTLs were divided into quartiles (Qs) and further dichotomized at the distinctive cut-off level between Q3 and Q4.LTLs in the upper Q were associated with 60% lower frequency of having suffered a previous MI (p ¼ 0.008, adjusted for age, treated hypertension, body mass index (BMI), triglycerides, HDL and fasting glucose).LTLs were not differently distributed according to sex or the presence of treated hypertension (52%), diabetes type 2 (25%), metabolic syndrome (35%) and clinical outcome (12%).In the total cohort, LTLs were further inversely correlated to age (r ¼ -0.17, p ¼ 0.007), however, only in women (r ¼ -0.37, p ¼ 0.006).In all subjects, GDF11 gene-expression was weakly and inversely correlated to age (r ¼ -0.16, p ¼ 0.010).Overall, no correlation was observed between LTLs and gene-expression of GDF11.However, when dividing into subgroups, a strong correlation was observed in overweight women (BMI > 25), (r ¼ 0.40, p ¼ 0.028).Conclusions: Although no association between LTLs and clinical outcome was observed, LTLs correlated to the severity of CAD in men, in this case previously suffered MI.In women, LTLs seem to be more associated with age.The results may indicate gender-related differences in regulatory mechanisms of TLs and a possible metabolically influenced association between LTLs and GDF11.
ENDOSCOPIC ULTRASOUND AS A PREDICTOR AND GUIDE TO SUCCESSFUL ENDOTHERAPY IN CHRONIC PANCREATITIS
Authors: P Somani, M Sharma
Journal: Endoscopy (2018)

Pancreatic calculi (PC), are a sequelae of chronic pancreatitis (CP) and may obstruct and produce ductal hypertension leading to pain. Indications for endotherapy include stones < 5 mm size, non-impacted stones in head of pancreas and absence of downstream strictures. The assessment prior to the procedure is done by MRCP or CT. However, problems are encountered during ERCP clearance which are not anticipated despite MRCP/CT. EUS can help by providing concordance or discordance with MRCP images and may help in further clarification.
Abstract 12893: Design and cGMP-Generating Actions of a Novel Selective and Non-Selective Particulate Guanylyl Cyclase B Activator Targeting Cardiorenal Fibrotic Remodeling
Authors: S. J Sangaralingham, Brenda K Huntley, Tomoko Ichiki, John C Burnett
Journal: Circulation (2016)

Introduction: Cardiorenal fibrotic remodeling (CFR), often in the setting of heart failure (HF) and kidney disease (CKD), is a major cause for increased risk in mortality, for which there are no effective drugs. C-type natriuretic peptide (CNP) is a 22 amino acid (AA) ligand for the particulate guanylyl cyclase receptor-B (GC-B) and exerts anti-fibrotic actions, with little effect on blood pressure (BP) or renal function, via its second messenger cGMP. To overcome CNP’s limited efficacy with its short half-life, we designed 2 novel CNP-based peptides (C53 and CU32). C53 consists of CNP plus a 31 AA N-terminus extension, while CU32 is the CNP ring fused with the N- and C-termini of urodilatin (GC-A agonist). Here we investigated the cGMP generating actions of C53 and CU32, with the goal of advancing novel GC-B/cGMP therapeutics for CFR. Hypotheses: We hypothesized that C53 and CU32 would have cGMP activating actions in vivo, however only C53 would generate cGMP production selectively via GC-B in vitro. We also hypothesize that the addition of the C-termini to CU32 would form a non-selective GC-B/cGMP agonist with renal and BP lowering actions. Methods: HEK293 cells expressing human GC-B or -A and human fibroblasts (hFs), where GC-B is abundant, were stimulated with C53 or CU32 (10-8M) for 10 min. Two groups of normal rats (n=8) received a 75 min equimolar IV infusion of C53 or CU32. Change in mean arterial pressure (ΔMAP), sodium (Na) excretion and plasma and urinary cGMP were assessed. *p&lt;0.05. Results: C53 and CU32 activated cGMP in GC-B cells (C53: 75±9, CU32: 24±2 pmol/well*), while only CU32 activated cGMP in GC-A cells (C53: 0±0, CU32: 50±3 pmol/well*). In hFs, both C53 and CU32 generated cGMP. In vivo, plasma cGMP (C53: 91±4, CU32: 94±6 pmol/ml) and urinary cGMP excretion (C53: 177±28, CU32: 227±28 pmol/min) were similar with both peptides. Yet, CU32 induced a greater reduction in ΔMAP (C53: -7±1, CU32: -16±3 mmHg*) and increased Na excretion (C53: 1.4±0.2, CU32: 2.4±0.2 uEq/m*) compared to C53. Conclusions: We report the engineering of a selective (C53) and non-selective (CU32) GC-B agonist that has favorable cGMP generating action in hFs and in vivo. Thus, C53 and CU32 may represent novel GC-B therapeutics that could be tailored to specific phases of HF or CKD to prevent CFR.
P153More on noncoding RNAs: genetic associations, regulation of expression and in vitro studies show an independent role for small nucleolar RNAs in cardiovascular disease
Authors: A Y Nossent, KJE Hakansson, EAC Goossens, S Trompet, RVTC Van Der Kwast, M R De Vries, R Ripa, J Kastrup, J W Jukema, PHA Quax
Journal: Cardiovascular Research (2018)
Primary biliary cholangitis (PBC) in the U.S.: clinical characteristics of patients enrolled in TARGET-PBC
Authors: C. Bowlus, E. Carey, G. Demuth, K. Deane, M.J. Mayo, W. Ray Kim, B. Bacon, D. Bernstein, P.J. Thuluvath, L. Michael Weiss, M.W. Fried
Journal: Journal of Hepatology (2018)
Ascending dose trials of a retroviral replicating vector (Toca 511) in patients with recurrent high-grade glioma.
Authors: Joan M. Robbins, Tiffany T. Huang, Douglas J. Jolly, Noriyuki Kasahara, Manish K. Aghi, Michael A. Vogelbaum, Timothy F. Cloughesy, Susan Marina Chang, Santosh Kesari, Tom Mikkelsen, Steven N. Kalkanis, Joseph C. Landolfi, J. Bradley Elder, E. Antonio Chiocca, Harry E. Gruber, Daniel Pertschuk
Journal: Journal of Clinical Oncology (2014)

3078^ Background: We are conducting ascending dose trials in subjects with High Grade Glioma (HGG, NCT01156584 and NCT01470794), using an investigational retroviral replicating vector (Toca 511, vocimagene amiretrorepvec). Toca 511 encodes an optimized yeast cytosine deaminase that converts 5-fluorocytosine (5-FC) to the anticancer drug 5-FU in infected tumors. Preclinical models provide support for a dual mechanism of action of Toca 511+5-FC that includes both direct killing of tumor by locally produced 5-FU, and induction of a local and systemic immunotherapeutic response resulting in: 1) long term survival after cessation of 5-FC treatment and 2) resistance to tumor re-challenge. Methods: Toca 511 is administered once, followed by repeat courses of oral Toca FC (an extended-release formulation of 5-FC). One trial employs direct intra-tumoral injection of Toca 511 and the other administration into the cavity wall after resection of a recurrent tumor. Results: Over 30 patients have been treated in each of these dose escalation trials with 6 and 5 viral dose levels respectively studied to date. Treatment at all dose levels has been well tolerated. Post-treatment resection in some patients showed viral protein and DNA and RNA sequences including the CD protein and gene, suggesting viral spread and persistence. MRI changes consistent with tumor regression and clinical improvements were observed in some patients post-Toca FC dosing. Pooled survival data in these ongoing studies show 82% (28/34) and 46% (13/28) survival at 6 months and 12 months, respectively. Conclusions: Completion of these studies is planned, including further dose escalation of Toca 511 and of Toca FC. A third ascending dose study, NCT01985256, in patients with HGG, will evaluate the safety and tolerability of Toca 511 injected intravenously followed by injections into the cavity wall after resection and repeated courses of Toca FC. The current studies provide evidence for the same dual mechanism of action noted in preclinical studies and survival data warrant investigation in a larger clinical trial. Clinical trial information: NCT01156584, NCT01470794, NCT01985256.
Hepatitis C patients with HIV co-infection demonstrate unique liver-related complications and health behaviors compared to HCV mono-infected patients
Authors: M. Lu, N.P. Markowitz, Y. Zhou, K.-H. Wu, L.B. Rupp, S. Trudeau, J.A. Boscarino, M.A. Schmidt, Y.G. Daida, S.C. Gordon
Journal: Journal of Hepatology (2018)