tbuckley/cabot-search huggingface dataset:
Rona McLeod MacKie, MD, FRCP, FRCPath—A Trendsetter in the Field of Melanoma
Authors: Neeraj Ramakrishnan, Anshum Sood, Stephanie Steinweg
Journal: JAMA Dermatology (2017)

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Magnitude of benefit for topical crisaborole in the treatment of atopic dermatitis in children and adults does not look promising: a critical appraisal
Authors: A. Ahmed, L. Solman, H.C. Williams
Journal: British Journal of Dermatology (2017)

To assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, for the treatment of mild or moderate atopic dermatitis (AD) in two phase III studies (AD‐301 and AD‐302). Two identically designed multicentre, double‐blind randomized controlled trials were conducted in the U.S.A. Participants were randomized 2 : 1 to receive crisaborole or vehicle treatment. In total 47 and 42 investigational centres were identified for AD‐301 and AD‐302, respectively. Inclusion criteria were identified as age ≥ 2 years, clinical diagnosis of AD (as per the Hanifin and Rajka criteria), ≥ 5% body surface area involvement, and baseline Investigator's Static Global Assessment (ISGA) mild or moderate. Exclusion criteria included previous use of biologics or systemic corticosteroids (within the last 28 days) or a topical calcineurin inhibitor/corticosteroid (within the last 14 days), and active skin infection. Participants were instructed to apply the study drug twice daily to all lesions identified at baseline, and all new lesions identified after day 1 (with weekly review of application instructions). Bland emollients were permitted to be used on skin not treated with the study drug. The primary outcome was defined as ISGA clear or almost clear at day 29, with a 2‐grade or more improvement from baseline. Secondary outcomes included the proportion of patients with an ISGA score of clear or almost clear at day 29, and time to success in ISGA score. Additional outcomes included pruritus severity and signs of AD (erythema, exudation, excoriation, induration/papulation and lichenification), and were measured on a 4‐point scale (none, mild, moderate, severe). Adverse events were also recorded. More participants in the crisaborole‐treated group achieved ISGA scores of clear or almost clear with ≥ 2‐grade improvement than in the vehicle‐treated group (AD‐301, 32·8% vs. 25·4%, P =0·38; AD‐302, 31·4% vs. 18·0%, P <0·001). Greater percentages of clear and almost clear scores were observed in the treatment groups (51·7% vs. 40·6%, P =0·005; 48·5% vs. 29·7%; P <0·001), as well as earlier success in ISGA score and improvement in pruritus (P ≤0·001). No serious treatment‐related adverse events were identified. Based on the study results, the authors suggest that crisaborole is a safe treatment that improves disease severity, pruritus and clinical signs associated with AD.
Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis
Authors: Tien-Phat V. Huynh, Fan Liao, Caroline M. Francis, Grace O. Robinson, Javier Remolina Serrano, Hong Jiang, Joseph Roh, Mary Beth Finn, Patrick M. Sullivan, Thomas J. Esparza, Floy R. Stewart, Thomas E. Mahan, Jason D. Ulrich, Tracy Cole, David M. Holtzman
Journal: Neuron (2017)
First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study
Authors: Ryan J. Sullivan, Jeffrey R. Infante, Filip Janku, Deborah Jean Lee Wong, Jeffrey A. Sosman, Vicki Keedy, Manish R. Patel, Geoffrey I. Shapiro, James W. Mier, Anthony W. Tolcher, Andrea Wang-Gillam, Mario Sznol, Keith Flaherty, Elizabeth Buchbinder, Richard D. Carvajal, Anna M. Varghese, Mario E. Lacouture, Antoni Ribas, Sapna P. Patel, Gary A. DeCrescenzo, Caroline M. Emery, Anna L. Groover, Saurabh Saha, Mary Varterasian, Dean J. Welsch, David M. Hyman, Bob T. Li
Journal: Cancer Discovery (2017)

Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with NRAS-, BRAF V600-, and non-V600 BRAF-mutant solid tumors.Significance: Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS- and BRAF V600- and non-V600-mutant solid-tumor malignancies. Cancer Discov; 8(2); 184-95. ©2017 AACR.See related commentary by Smalley and Smalley, p. 140This article is highlighted in the In This Issue feature, p. 127.
Abstract 15680: Increased Risk of Ischemic Coronary and Cerebrovascular Events in Patients With Chronic Granulomatous Disease
Authors: Grant R Drummond, Courtney P Judkins, Thanh G Phan, Vijaya Sundararajan, Christopher G Sobey, Velandai Srikanth
Journal: Circulation (2013)

Chronic inhibition of NADPH oxidase (NOX) activity confers cardiovascular protection in preclinical models of hypertension, atherosclerosis and stroke, highlighting it as a potential therapeutic target. Here we investigated the risk of cardiovascular events in patients with chronic granulomatous disease (CGD); a rare genetically-determined immunodeficiency disorder caused by a defective NOX complex. A population-level cohort study was performed using linked data, classified according to WHO ICD codes, and capturing all hospitalisations in the Australian state of Victoria from 1993-2010. Logistic regression was used to estimate the risk of ischemic coronary (myocardial infarction/angina) and cerebrovascular (ischemic stroke/transient ischemic attacks) events in CGD versus non-CGD individuals. We identified 77 people with CGD (43.0±26.7 y, mean±SD) and randomly selected 415,800 in-patient non-CGD controls (37.8±25.7 y). A total of 17 (22.1%) CGD patients and 36,598 (8.8%) controls suffered a cardiovascular event during the study period. After adjusting for age and sex, the odds ratio (OR) of a coronary event in CGD versus non-CGD patients was 2.37 [95% confidence interval (CI), 1.20-4.68; P=0.013] while that for a cerebrovascular event was 2.95 (95% CI, 1.13-7.71; P=0.028). Further adjustment for the presence of hypertension markedly attenuated the association of CGD with both coronary (OR, 1.68; 95% CI, 0.80-3.54; P=0.174) and cerebrovascular (OR, 2.19; 95% CI, 0.82-5.88; P=0.118) events. Adjusting for other comorbidities including diabetes, smoking and sleep apnea did not alter the associations. Thus, CGD in humans is associated with increased risk of coronary and cerebrovascular events. These observations, which are at odds with a large body of literature from experimental animal studies, cast doubt over the validity of targeting NOX as a future therapy for cardiovascular disease.
Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment
Authors: Susanne M. Steggerda, Mark K. Bennett, Jason Chen, Ethan Emberley, Tony Huang, Julie R. Janes, Weiqun Li, Andrew L. MacKinnon, Amani Makkouk, Gisele Marguier, Peter J. Murray, Silinda Neou, Alison Pan, Francesco Parlati, Mirna L. M. Rodriguez, Lee-Ann Van de Velde, Tracy Wang, Melissa Works, Jing Zhang, Winter Zhang, Matthew I. Gross
Journal: Journal for ImmunoTherapy of Cancer (2017)

<h3>Background</h3> Myeloid cells are an abundant leukocyte in many types of tumors and contribute to immune evasion. Expression of the enzyme arginase 1 (Arg1) is a defining feature of immunosuppressive myeloid cells and leads to depletion of L-arginine, a nutrient required for T cell and natural killer (NK) cell proliferation. Here we use CB-1158, a potent and orally-bioavailable small-molecule inhibitor of arginase, to investigate the role of Arg1 in regulating anti-tumor immunity. <h3>Methods</h3> CB-1158 was tested for the ability to block myeloid cell-mediated inhibition of T cell proliferation in vitro, and for tumor growth inhibition in syngeneic mouse models of cancer as a single agent and in combination with other therapies. Tumors from animals treated with CB-1158 were profiled for changes in immune cell subsets, expression of immune-related genes, and cytokines. Human tumor tissue microarrays were probed for Arg1 expression by immunohistochemistry and immunofluorescence. Cancer patient plasma samples were assessed for Arg1 protein and L-arginine by ELISA and mass spectrometry, respectively. <h3>Results</h3> CB-1158 blocked myeloid cell-mediated suppression of T cell proliferation in vitro and reduced tumor growth in multiple mouse models of cancer, as a single agent and in combination with checkpoint blockade, adoptive T cell therapy, adoptive NK cell therapy, and the chemotherapy agent gemcitabine. Profiling of the tumor microenvironment revealed that CB-1158 increased tumor-infiltrating CD8<sup>+</sup> T cells and NK cells, inflammatory cytokines, and expression of interferon-inducible genes. Patient tumor samples from multiple histologies expressed an abundance of tumor-infiltrating Arg1<sup>+</sup> myeloid cells. Plasma samples from cancer patients exhibited elevated Arg1 and reduced L-arginine compared to healthy volunteers. <h3>Conclusions</h3> These results demonstrate that Arg1 is a key mediator of immune suppression and that inhibiting Arg1 with CB-1158 shifts the immune landscape toward a pro-inflammatory environment, blunting myeloid cell-mediated immune evasion and reducing tumor growth. Furthermore, our results suggest that arginase blockade by CB-1158 may be an effective therapy in multiple types of cancer and combining CB-1158 with standard-of-care chemotherapy or other immunotherapies may yield improved clinical responses.
Structural Mapping of Adenosine Receptor Mutations: Ligand Binding and Signaling Mechanisms
Authors: Willem Jespers, Anke C. Schiedel, Laura H. Heitman, Robert M. Cooke, Lisa Kleene, Gerard J.P. van Westen, David E. Gloriam, Christa E. Müller, Eddy Sotelo, Hugo Gutiérrez-de-Terán
Journal: Trends in Pharmacological Sciences (2017)
Cerebral blood flow changes after radiation therapy identifies pseudoprogression in diffuse intrinsic pontine gliomas
Authors: Raphael Calmon, Stephanie Puget, Pascale Varlet, Volodia Dangouloff-Ros, Thomas Blauwblomme, Kevin Beccaria, David Grevent, Christian Sainte-Rose, David Castel, Marie-Anne Debily, Christelle Dufour, Stéphanie Bolle, Frederic Dhermain, Ana Saitovitch, Monica Zilbovicius, Francis Brunelle, Jacques Grill, Nathalie Boddaert
Journal: Neuro-Oncology (2017)

The interval between progression and death in diffuse intrinsic pontine glioma (DIPG) is usually <6 months. However, reports of longer patient survival following radiotherapy, in the presence of radiological signs of progression, suggest that these cases may be comparable to pseudoprogression observed in adult glioblastoma. Our aim was to identify such cases and compare their multimodal MRI features with those of patients who did not present the same evolution.Multimodal MRIs of 43 children treated for DIPG were retrospectively selected at 4 timepoints: baseline, after radiotherapy, during true progression, and at the last visit. The patients were divided into 2 groups depending on whether they presented conventional MRI changes that mimicked progression. The apparent diffusion coefficient, arterial spin labeling cerebral blood flow (ASL-CBF), and dynamic susceptibility contrast perfusion relative cerebral blood volume (DSCrCBV) and flow (DSCrCBF) values were recorded for each tumor voxel, avoiding necrotic areas.After radiotherapy, 19 patients (44%) showed radiological signs that mimicked progression: 16 survived >6 months following so-called pseudoprogression, with a median of 8.9 months and a maximum of 35.6 months. All 43 patients exhibited increased blood volume and flow after radiotherapy, but the 90th percentile of those with signs of pseudoprogression had a greater increase of ASL-CBF (P < 0.001). Survival between the 2 groups did not differ significantly. During true progression, DSCrCBF and DSCrCBV values increased only in patients who had not experienced pseudoprogression.Pseudoprogression is a frequent phenomenon in DIPG patients. This condition needs to be recognized before considering treatment discontinuation. In this study, the larger increase of the ASL-CBF ratio after radiotherapy accurately distinguished pseudoprogression from true progression.
Disparities in Hospital-Reported Breast Milk Use in Neonatal Intensive Care Units — United States, 2015
Authors: Ellen O. Boundy, Cria G. Perrine, Jennifer M. Nelson, Heather C. Hamner
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Breast milk is the recommended nutrition for infants. For preterm infants, when mother's milk is not available, pasteurized donor milk is recommended (1). Non-Hispanic black mothers are at increased risk for having a preterm birth and for not breastfeeding (2,3); however, it is not known whether demographic disparities exist in the use of breast milk in neonatal intensive care units (NICUs). Data from CDC's 2015 Maternity Practices in Infant Nutrition and Care (mPINC) survey, which does not collect patient-level demographics, were linked to the 2011-2015 U.S. Census Bureau's American Community Survey (ACS)* to examine use of breast milk in NICUs based on demographic makeup of the hospital's postal code area. Among U.S. hospitals with a NICU, the use of mother's own milk and donor milk were examined by the percentage of non-Hispanic black (black) residents in the hospital postal code area, categorized as being above or below the national average (12.3%). In postal codes with >12.3% black residents, 48.9% of hospitals reported using mothers' own milk in ≥75% of infants in the NICU, and 38.0% reported not using donor milk, compared with 63.8% and 29.6% of hospitals, respectively, in postal codes with ≤12.3% black residents. Further investigation is needed to understand variations in breast milk use in NICUs. Targeted efforts to increase breast milk use in hospitals located in postal codes where the percentage of black mothers is above the national average might help ensure more equitable access to breast milk for preterm and other high-risk infants.
Front-Line Treatment Options for Chronic-Phase Chronic Myeloid Leukemia
Authors: Neil P. Shah
Journal: Journal of Clinical Oncology (2017)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 40-year-old woman with a past medical history of hypertension and occasional premature ventricular contractions was found on routine blood work in June 2011 to have mild thrombocytosis, with a platelet count of 405,000. In November 2011, repeat analysis revealed a platelet count of 433,000, and by February 2012 her platelet count was 509,000. She had no evidence of leukocytosis or anemia and no symptoms of early satiety, night sweats, pruritus, or erythromelalgia. She was referred to a hematologist for evaluation of persistent isolated thrombocytosis in March 2012. Her spleen was not palpable, and a quantitative polymerase chain reaction (PCR) test for JAK2/V617F was negative. A bone marrow biopsy and aspiration revealed a mildly hypercellular marrow (70% to 80% cellularity), with an elevated myeloid:erythroid ratio of 5:1, increased megakaryocytes including micromegakaryocytes in the absence of increased blasts. Cytogenetic analysis revealed the presence of the Philadelphia chromosome translocation in 17 out of 20 metaphases. The remaining three metaphases were normal karyotype. Quantitative PCR for BCR-ABL1 yielded a value of 29.6% on the International Scale.
Abstract 11935: A Novel Wire guided Ablation Catheter For Ablation Of Right Superior Pulmonary Vein In Experimental Pigs
Authors: Xue Zhao, Hui Gong, Jian qiang Hu
Journal: Circulation (2016)

A novel wire guided ablation catheter for ablation of right superior pulmonary vein in pigs Introduction: A novel wire-guided ablation catheter (wire-guided cath) was invented based on principle of compasses for drawing circle. Hypothesis: This study was to investigate if the guiding wire can increase the efficiency and accuracy of catheter manipulation in right superior pulmonary vein (RSPV). Methods: Wire-guided cath was composed of a conventional cold saline-irrigated ablation catheter (conventional cath) &amp; a guide-wire. The guide-wire came out from the distal part of catheter. When pushed into the distal of RSPV, the guide-wire can work as a pivot for the catheter to increase stability of catheter manipulation. EnSite Velocity system was used. Contact/mapping &amp; mapping/ ablation were tried by using the catheters in RSPV separately. Seven pigs were used. Results: In comparison with conventional cath, wire-guided cath took marked less procedure &amp; exposure time to complete the separate contact/mapping at four sites, to do circumferential contact/mapping, &amp; to do radial-linear contact/mapping along RSPV. Furthermore, it can significantly decrease procedure &amp; exposure time by using wire-guided cath to complete the circumferential RSPV ablation &amp; RSPV-antrum radial-linear ablation. During procedures, the ablation catheter had unintentionally fallen into right atrium for 0.7±0.8 times in wire-guided cath group &amp; for 5.1±1.3 times in conventional cath group; it had taken 1.0±0.2 min &amp; 5.0±0.9 min for wire-guided &amp; conventional cath to be pushed back into LA again from atrial septum puncture access. No thrombosis was found on guide-wire &amp; the distal hole of guide-wire lumen, &amp; no scratches, tears &amp; thrombus found in RSPV intima after procedure. Conclusions: The study shows wire-guided cath had significant advantages in manipulation of moving, positioning &amp; contacting, which may help to improve ablation skills of atrial fibrillation for younger EP doctors.
Cilia loss sensitizes cells to transformation by activating the mevalonate pathway
Authors: Yue-Zhen Deng, Zhen Cai, Shuo Shi, Hao Jiang, Yu-Rong Shang, Ning Ma, Jing-Jing Wang, Dong-Xian Guan, Tian-Wei Chen, Ye-Fei Rong, Zhen-Yu Qian, Er-Bin Zhang, Dan Feng, Quan-Li Zhou, Yi-Nan Du, Dong-Ping Liu, Xing-Xu Huang, Lu-Ming Liu, Eugene Chin, Dang-Sheng Li, Xiao-Fan Wang, Xue-Li Zhang, Dong Xie
Journal: The Journal of Experimental Medicine (2017)

Although cilia loss and cell transformation are frequently observed in the early stage of tumorigenesis, the roles of cilia in cell transformation are unknown. In this study, disrupted ciliogenesis was observed in cancer cells and pancreatic cancer tissues, which facilitated oncogene-induced transformation of normal pancreatic cells (HPDE6C7) and NIH3T3 cells through activating the mevalonate (MVA) pathway. Disruption of ciliogenesis up-regulated MVA enzymes through β catenin-T cell factor (TCF) signaling, which synchronized with sterol regulatory element binding transcription factor 2 (SREBP2), and the regulation of MVA by β-catenin-TCF signaling was recapitulated in a mouse model of pancreatic ductal adenocarcinoma (PDAC) and human PDAC samples. Moreover, disruption of ciliogenesis by depleting Tg737 dramatically promoted tumorigenesis in the PDAC mouse model, driven by KrasG12D , which was inhibited by statin, an inhibitor of the MVA pathway. Collectively, this study emphasizes the crucial roles of cilia in governing the early steps of the transformation by activating the MVA pathway, suggesting that statin has therapeutic potential for pancreatic cancer treatment.
Abstract 19622: Trans-apical Off-pump Mitral Valve Repair With Neochords Implantation: One Year Clinical and Echocardiographic Follow-up
Authors: Andrea Colli, Laura Besola, Lorenzo Bagozzi, Erica Manzan, Eleonora Bizzotto, Fabio Zucchetta, Roberto Bellu, Cristiano Sarais, Demetrio Pittarello, Gino Gerosa
Journal: Circulation (2015)

Introduction: TOP-MINI is a new micro invasive surgical procedure to treat degenerative mitral valve regurgitation due to flail/prolapse. Hypothesis: This prospective single centre study sought to assess the safety and effectiveness of the TOP-MINI procedure up to one year follow-up. Methods: Clinical and Echocardiographic outcomes were evaluated at 1, 3, 6 months and 1 year follow-up for all patients underwent TOP-MINI procedure from November 2013 to March 2015. Procedural success was defined as residual MR≤2+ at any time. Results: Sixty-one patients were treated during study period. One year survival was 96.7±2.3%. Freedom from MR&gt;2+ is shown in figure 1 Panel A, Freedom from MR&gt;2+ according to valve anatomy (Type A isolated P2 disease, Type B posterior multisegment disease, Type C anterior or bileaflet and/or calcified disease) is shown in Figure 1 Panel B. Freedom from MR&gt;2+ according to STS risk profile is shown in Figure 2. The trend of Echocardiographic parameters is shown in Figure 3. Conclusions: TOP-MINI is a safe and effective procedure at 1 year FU. Residual MR is influenced by valve anatomy showing good results in Type A and B patients. Future techniques refinements are needed in order to improve outcomes of Type C patients. The lack of annuloplasty procedure does not influence negatively left ventricle reverse remodeling.