tbuckley/cabot-search huggingface dataset:
MerTK as a therapeutic target in glioblastoma
Authors: Jing Wu, Lauren N Frady, Ryan E Bash, Stephanie M Cohen, Allison N Schorzman, Yu-Ting Su, David M Irvin, William C Zamboni, Xiaodong Wang, Stephen V Frye, Matthew G Ewend, Erik P Sulman, Mark R Gilbert, H Shelton Earp, C Ryan Miller
Journal: Neuro-Oncology (2017)

Glioma-associated macrophages and microglia (GAMs) are components of the glioblastoma (GBM) microenvironment that express MerTK, a receptor tyrosine kinase that triggers efferocytosis and can suppress innate immune responses. The aim of the study was to define MerTK as a therapeutic target using an orally bioavailable inhibitor, UNC2025.We examined MerTK expression in tumor cells and macrophages in matched patient GBM samples by double-label immunohistochemistry. UNC2025-induced MerTK inhibition was studied in vitro and in vivo.MerTK/CD68+ macrophages increased in recurrent tumors while MerTK/glial fibrillary acidic protein-positive tumor cells did not. Pharmacokinetic studies showed high tumor exposures of UNC2025 in a syngeneic orthotopic allograft mouse GBM model. The same model mice were randomized to receive vehicle, daily UNC2025, fractionated external beam radiotherapy (XRT), or UNC2025/XRT. Although median survival (21, 22, 35, and 35 days, respectively) was equivalent with or without UNC2025, bioluminescence imaging (BLI) showed significant growth delay with XRT/UNC2025 treatment and complete responses in 19%. The responders remained alive for 60 days and showed regression to 1%-10% of pretreatment BLI tumor burden; 5 of 6 were tumor free by histology. In contrast, only 2% of 98 GBM mice of the same model treated with XRT survived 50 days and none survived 60 days. UNC2025 also reduced CD206+ macrophages in mouse tumor samples.These results suggest that MerTK inhibition combined with XRT has a therapeutic effect in a subset of GBM. Further mechanistic studies are warranted.
Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor.
Authors: Corey Wayne Speers, Benjamin Chandler, Shuang Zhao, Meilan Liu, Kari Wilder-Romans, Eric Olsen, Shyam Nyati, James M. Rae, Daniel F. Hayes, Daniel Eidelberg Spratt, Daniel Richard Wahl, Felix Yi-Chung Feng, Lori J. Pierce
Journal: Journal of Clinical Oncology (2017)

e12102 Background: Increased rates of locoregional recurrence have been observed in TNBC despite chemotherapy and radiation (RT). A novel radiosensitizer screen nominated the AR as a promising target for treatment of radioresistant breast cancer, including TNBC. We assessed in vitro activity of SEVI (VT-464), a selective CYP17 lyase and AR inhibitor, as a potential radiosensitizer in AR+ TNBC model. Methods: Clonogenic survival assays were used to determine the intrinsic RT sensitivity of 21 breast cancer cell (BCC) lines. IC50 values were determined for 130 clinically available compounds and correlation coefficients were calculated using IC50 values and SF-2Gy. Gene expression was measured using RNA Seq or qRT-PCR and protein expression was measured using RPPA arrays. AR function was assessed using functional inhibition with SEVI in MDA-MB-453, ACC-460, SUM-185 (all three AR+ TNBC), MDA-MB-231 (AR- TNBC), and T47D (AR- ER+) BCC lines. Double-stranded DNA (dsDNA) break repair was assessed with γH2AX foci counting. Results: Our novel radiosensitizer screen identified the activity of bicalutamide, an AR antagonist, in RT-resistant BCC lines (R2 = 0.46, p-value &lt; 0.01). Heterogeneity in AR expression was identified in human BCC lines. There was a strong correlation between AR RNA expression and protein expression across all BC intrinsic subtypes. AR inhibition using SEVI induced radiation sensitivity in vitro with an enhancement ratio (ER) of 1.24-1.62 in three different AR+ TNBC lines. No such radiosensitization was seen in AR(-) TNBC or ER+, AR(-) BCC lines. Radiosensitization was at least partially dependent on impaired dsDNA break repair with significant delays in dsDNA break repair at 16 and 24 hours in all AR+ TNBC lines examined (p-value &lt; 0.01). Conclusions: Our results implicate the AR as a mediator of radioresistance in breast cancer and support the rationale for developing seviteronel as a novel radiosensitizing agent in AR+ TNBC.
Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk
Authors: Anita Villani, Mary-Louise C. Greer, Jennifer M. Kalish, Akira Nakagawara, Katherine L. Nathanson, Kristian W. Pajtler, Stefan M. Pfister, Michael F. Walsh, Jonathan D. Wasserman, Kristin Zelley, Christian P. Kratz
Journal: Clinical Cancer Research (2017)

Abstract In October 2016, the American Association for Cancer Research held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. Herein, we summarize clinical and genetic aspects of RASopathies and Sotos, Weaver, Rubinstein-Taybi, Schinzel-Giedion, and NKX2-1 syndromes as well as specific metabolic disorders known to be associated with increased childhood cancer risk. In addition, the expert panel reviewed whether sufficient data exist to make a recommendation that all patients with these disorders be offered cancer surveillance. For all syndromes, the panel recommends increased awareness and prompt assessment of clinical symptoms. Patients with Costello syndrome have the highest cancer risk, and cancer surveillance should be considered. Regular physical examinations and complete blood counts can be performed in infants with Noonan syndrome if specific PTPN11 or KRAS mutations are present, and in patients with CBL syndrome. Also, the high brain tumor risk in patients with L-2 hydroxyglutaric aciduria may warrant regular screening with brain MRIs. For most syndromes, surveillance may be needed for nonmalignant health problems. Clin Cancer Res; 23(12); e83–e90. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.
Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes
Authors: Annika S. Axelsson, Emily Tubbs, Brig Mecham, Shaji Chacko, Hannah A. Nenonen, Yunzhao Tang, Jed W. Fahey, Jonathan M. J. Derry, Claes B. Wollheim, Nils Wierup, Morey W. Haymond, Stephen H. Friend, Hindrik Mulder, Anders H. Rosengren
Journal: Science Translational Medicine (2017)

Sulforaphane, a natural compound identified by drug repurposing, reduces hepatic glucose production and improves glucose control in type 2 diabetes.
Abstract 17034: Deletion of NAD(P)H Oxidase 2 Attenuates Angiotensin II-induced Skeletal Muscle Atrophy
Authors: Tomoyasu Kadoguchi, Shintaro Kinugawa, Shingo Takada, Arata Fukushima, Takaaki Furihata, Wataru Mizushima, Junichi Matsumoto, Masaya Tsuda, Takashi Yokota, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui
Journal: Circulation (2015)

Introduction: Skeletal muscle atrophy is observed in aging and a variety of diseases including chronic obstructive pulmonary disease, chronic renal failure, and heart failure. It has been considered that it is associated with chronic inflammation in the skeletal muscle. We have previously reported that angiotensin II (Ang II) could directly induce skeletal muscle abnormalities including atrophy in mice. Hypothesis: Here, we hypothesized that the activation of NAD(P)H oxidase by Ang II induced the skeletal muscle atrophy. Methods: Either saline (vehicle) or Ang II (1000 ng/kg/min) was infused into male wild-type (WT) and Nox2 knock out (KO) mice via subcutaneously implanted osmotic minipumps for 4 weeks. Experiments were performed in following 4 groups; WT+vehicle (n=8), KO+vehicle (n=6), WT+Ang II (n=8), and KO+Ang II (n=6). Lower skeletal muscle limbs were removed and used for the analysis. Exercise capacity was measured by using treadmill test. Results: Increased activation of NAD(P)H oxidase and production of superoxide in the skeletal muscle by Ang II were completely inhibited in KO mice. Body and skeletal muscle weight, and myocyte cross sectional area were significantly decreased in WT+Ang II compared to WT+vehicle (24±1 vs. 28±1 g, 356±3 vs. 390±4 mg, and 2351±84 vs. 3221±118 μm2, respectively). These changes were significantly attenuated in KO+Ang II (27±1 g, 392±9 mg, 3012±150 μm2, respectively) Phospho-Akt and phospho-p70S6K, key molecule of protein synthesis, were decreased in WT+Ang II compared to WT+vehicle, which was attenuated in KO+Ang II. On the other hand, protein expressions of Muscle RING Finger-1 and MAFbx/Atrogin-1, key molecule of protein degradation, were significantly increased in WT+Ang II compare to WT+vehicle, which was not affected in KO+Ang II. Mitochondrial electron transfer complex and citrate synthase activities were also impaired in WT+Ang II and were not improved in KO+Ang II. In agreements with these results, exercise, Ang II-induced reduction in exercise capacity was not improved in KO mice. Conclusions: The deletion of Nox2 attenuated the skeletal muscle atrophy and decreased protein synthase induced by Ang II, suggesting that Nox2 plays an essential role in the development of skeletal muscle atrophy.
Targeting the PGD2/CRTH2/DP1 Signaling Pathway in Asthma and Allergic Disease: Current Status and Future Perspectives
Authors: Maciej Kupczyk, Piotr Kuna
Journal: Drugs (2017)

Prostaglandin D2 (PGD2) released by degranulating mast cells is believed to play a key role in orchestrating mechanisms of inflammation in allergies and asthma. The biological effects of PGD2 are mediated by D-prostanoid (DP1), CRTH2 (DP2), and thromboxane prostanoid (TP) receptors. The CRTH2 receptor is involved in induction of migration and activation of T helper type 2 (Th2) lymphocytes, eosinophils, and basophils; up-regulation of adhesion molecules; and promotion of pro-inflammatory Th2-type cytokines (interleukin [IL]-4, 5, 13), whereas the DP receptor is associated with relaxation of smooth muscles, vasodilation, inhibition of cell migration, and apoptosis of eosinophils. A number of CRTH2/PGD2 receptor antagonists have been investigated in asthma and allergic diseases. The CRTH2 antagonist (OC000459) or dual CRTH2 and TP receptor antagonist (ramatroban) were effective in reducing eosinophilia, nasal mucosal swelling, and clinical symptoms of allergic rhinitis, with the latter drug registered for clinical use in this indication. OC000459 and setipiprant reduced the late but not early phase of response in an allergen challenge in atopic asthmatics. In persistent asthma, some molecules induced limited improvement in lung function, quality of life, and asthma symptoms (OC000459, BI671800), but in other trials with AMG 853 and AZ1981 these findings were not confirmed. The clear discrepancy between animal studies and clinical efficacy of CRTH2 antagonism in allergic rhinitis, and lack of efficacy in a general cohort of asthmatics, highlight the issue of patient phenotyping. There is no doubt that the PGD2/CATH2/DP1 pathway plays a key role in allergic inflammation and further studies with selective or combined antagonisms in well defined cohorts of patients are needed.
Comparison of clinical outcomes with IMRT and proton therapy for prostate cancer.
Authors: Nancy P. Mendenhall, William Wong, Curtis Bryant, Sujay A. Vora, Randal H. Henderson, Sameer R. Keole, Bradford S. Hoppe, Carlos E. Vargas, R. Charles Nichols, Thomas Backus Daniels, William M. Mendenhall, Christopher G. Morris, Steven E. Schild
Journal: Journal of Clinical Oncology (2017)

e16555 Background: The ProtecT trial underscores the importance of treatment in men with prostate cancer and life expectancies &gt; 10 years and the validity of radiation therapy (RT). RT can be given with photons or protons (PT). To address the controversy of which is better, clinical outcomes of photon-based intensity modulated RT (IMRT) and PT cohorts from 2 institutions were directly compared. Methods: Under respective IRB approvals, data from 2 cohorts were analyzed. The first was 301 men treated with ultrasound image guided IMRT from 2000-05 to 75.6 Gy in 42 fractions. The second was 1214 men treated with fiducial image guided PT from 2006-10 to 78 CGE in 39 fractions. Median age and followup were 74 y and 7.2 y for IMRT and 66 y and 5.6 y for PT. Hormone therapy (ADT) was used with IMRT and PT, respectively, in 3% and 7% of low-risk patients, 25% and 9.9% of intermediate-risk, and 91% and 57.8% of high-risk. Comparative endpoints were age-stratified 5-year (5Y) survival (OS), ≥ grade 3 gastrointestinal (GI) and urologic (GU) toxicity, and 5Y freedom from biochemical progression (FFBP). Results: There was a lower prevalence of GI (1.3% vs 0.1%, p = 0.0065) and GU (4.3% vs 0.1%, p &lt; 0.0001) toxicity at last follow-up in the PT group. In the IMRT and PT cohorts, OS rates were 90.8% and 88.7% in men ≥75 (p = 0.4083). In men &lt; 75, OS rates were 91.6% and 97.5% in the IMRT and PT low-risk patients (p = 0.003), 92.1% and 95.5% in the IMRT and PT intermediate-risk (p = 0.0535), and 92.0% and 90.0% (p = 0.4975) in the IMRT and PT high-risk. In the IMRT and PT cohorts, respectively, FFBP rates were 92.2% and 98.9% for low-risk patients (p &lt; 0.0001), 87.3% and 94.5% for intermediate-risk patients(p = 0.0226), and 80.3% and 74.4% for high-risk patients (p = 0.5154). Conclusions: In this retrospective comparison of outcomes in cohorts of men treated with IMRT and PT for prostate cancer, FFBP rates were better with PT for men with low- and intermediate-risk disease and similar in men with high-risk disease despite longer and more frequent use of ADT in the IMRT cohort. This study underscores the difficulty of comparing retrospective series, with differences noted in age, RT dose, and ADT use between cohorts. However, the magnitude of improvement with PT is intriguing and warrants prospective testing.
Abstract 38: Simultaneous Optical Pacing and Optical Voltage Mapping in Optogenetic Neonatal Rat Ventricular Myocyte Cultures
Authors: Qince Li, KahYong Goh, Wei Kong, Ruby R Ni, Vladimir Fast, Lufang Zhou
Journal: Circulation Research (2015)

Optogenetics is an emerging technology allowing remote and precise control of cell activity in living tissues. Despite its rapid advancements, application of this innovative technology to cardiovascular research is still limited, in part due to shortage of optogenetic cardiac tissue models and compatible imaging methods. The present study aimed to develop an optogenetic culture model using neonatal rat ventricular myocytes (NRVM) expressing light-gated Channelrhodopsin-2 (ChR2) and characterize activation spread during optical stimulation using optical mapping of membrane potential (Vm). Primary NVRM cultures were infected with lentivirus containing ChR2 gene. Cultures were paced electrically or optically with pulses of blue (470 nm) LED light. Activation spread was simultaneously mapped using Vm-sensitive dye (RH-237) and a photodiode mapping system. Results showed that ChR2 could be readily transduced to NRVMs by the lentiviral method; however, high-level ChR2 expression was associated with substantial cell toxicity. Lower ChR2 expression, achieved by administration of bromodeoxyuridine, had minor effects on cell morphology and function while allowing optical pacing at frequencies of 0.5-3 Hz. Simultaneous Vm mapping showed that conduction velocity, APD80, and dV/dtmax were similar in optogenetic and control cultures. Finally, the optogenetic cultures could be optically paced at multiple sites, leading to significantly reduced overall activation time. In summary, we demonstrated that ChR2 expression can cause cell toxicity in NRVM cultures but the toxicity can be mitigated allowing optical pacing and simultaneous optical activation mapping without significant impairment of electrophysiological function. This optogenetic cardiac culture model expands the availability of optogenetic tools for cardiac research.
Abstract 164: Production of De Novo Cardiomyocytes in Adult Asxl2-/- Hearts
Authors: Rachel Brunner, Martin Gerdes, Tian Wang
Journal: Circulation Research (2015)

The chromatin-associated protein ASXL2 is highly expressed in the heart, where it critically regulates the levels of two repressive histone marks, trimethylated H3 lysine 27 and ubiquitinated H2A. We have previously observed that Asxl2-/- hearts displayed abnormal growth during adulthood, resulting in disproportionally larger heart from 4 months on. This abnormal growth is not due to cardiomyocyte hypertrophy, as demonstrated by measurement of comprehensive dimensions of isolated cardiomyocytes. BrdU labeling showed an elevation in proliferation index in Asxl2-/- hearts at 3 months. At the time of labeling, with rare exceptions, labeled cells are interstitial non-cardiomyocytes in both wildtype control and Asxl2-/- hearts. The vast majority of labeled cells stained positive for vimentin, a mesenchymal marker, and negative for Nkx2.5, Gata4 or c-kit. EdU pulse-chase experiments were performed to determine the fate of labeled cells. After a 4-week chase, a significant number of EdU+/cTnT+ cardiomyocytes were present in Asxl2-/- hearts but not in wildtype control hearts. Expression of the gap junction protein Cx43 was detected between EdU+ cardiomyocytes and neighboring EdU- cardiomyocytes, suggesting electrical coupling. Cardiomyocytes were isolated from pulsed-chased Asxl2-/- hearts for additional morphological analysis. Isolated EdU+/cTnT+ cardiomyocytes vary greatly in cell size, shape and nucleation status, ranging from small, spindle-shaped and mononuclear to large, rod-shaped and binuclear. Taken together, our data suggest that new cardiomyocytes are produced in adult Asxl2-/- hearts from a population of proliferative interstitial cells that are distinct from c-kit+ cardiac stem cells. This raises intriguing possibilities for cardiac repair and regeneration.
Acute Severe Gastrointestinal Tract Bleeding Is Associated With an Increased Risk of Thromboembolism and Death
Authors: Naoyoshi Nagata, Toshiyuki Sakurai, Takuro Shimbo, Shiori Moriyasu, Hidetaka Okubo, Kazuhiro Watanabe, Chizu Yokoi, Mikio Yanase, Junichi Akiyama, Naomi Uemura
Journal: Clinical Gastroenterology and Hepatology (2017)
Improvements in Patient Health-Related Quality of Life (HRQoL) with Clinical Efficacy in Patients Treated with Eltrombopag: Final Results from the Long-Term, Open-Label Extend Study
Authors: Mansoor N. Saleh, James B. Bussel, Abderrahim Khelif, Paul Burgess, Ali El-Ali, Anuja Roy, Victoria Barghout, Mei Sheng Duh, Kelly M. Grotzinger, Abdulgabar Salama
Journal: Blood (2016)
Erratum: CBX7 is a tumor suppressor in mice and humans (Journal of Clinical Investigation (2013) 123:2 (934) DOI: 10.1172/JCI68754)
Authors: Floriana Forzati, Antonella Federico, Pierlorenzo Pallante, Adele Abbate, Francesco Esposito, Umberto Malapelle, Romina Sepe, Giuseppe Palma, Giancarlo Troncone, Marzia Scarfò, Claudio Arra, Monica Fedele, Alfredo Fusco
Journal: Journal of Clinical Investigation (2013)
Management of Hepatitis C Infection: A Retrospective Audit of Treatment Outcomes in Clinical Practice
Authors: F MacCarthy, JM Lee
Journal: Endoscopy (2004)

Background: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. Recently a combination therapy (pegylated interferon and ribavirin) has become the treatment of choice. Treatment outcomes in clinical practice are known to differ from those in the clinical trial situation. We sought to audit outcomes of HCV treatments in the setting of a single clinic managing patients with HCV infection.
Abstract 20202: Pharmacodynamic Interactions Between Nebivolol and Valsartan in Healthy Volunteers
Authors: Chun Lin Chen, Daksha Desai-Krieger, Stephan Ortiz, Majid Kerolous, Harold M Wright
Journal: Circulation (2014)

Introduction: Combining different classes of antihypertensive drugs is more effective for achieving blood pressure (BP) control than increasing the dose of monotherapies. An aim of this study was to investigate pharmacodynamic (PD) interactions between nebivolol, a β1 selective, vasodilatory beta blocker and valsartan, an angiotensin II type 1 receptor blocker. Methods: This was a single-center, randomized, open-label, multiple-dose, three-way crossover trial in 30 healthy adults aged 18-45 years. Participants were randomized into one of six treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol 20 mg, valsartan 320 mg, or nebivolol 20 mg plus valsartan 320 mg. Outcomes included changes in BP, heart rate (HR), plasma angiotensin II, plasma renin activity (PRA), and 24-hour urinary aldosterone. Results: The drop in least square mean values of systolic and diastolic BP was significantly greater following the concomitant administration of nebivolol and valsartan than either monotherapy alone. The mean HR after treatment with nebivolol alone, as well as after the combined treatment, was consistently lower than valsartan monotherapy. A sharp increase in mean Day 7 PRA and plasma angiotensin II occurred in subjects receiving valsartan alone and this was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at Day 7 was substantially decreased after combined treatment, as compared to either monotherapy treatment. All treatments were safe and well tolerated. Conclusions: Nebivolol and valsartan co-administration led to greater reductions in BP compared to either monotherapy. Nebivolol attenuated valsartan-induced increases in angiotensin II levels and PRA and reduced urinary aldosterone levels. Hence, these mechanisms for BP lowering are complementary and provide a rationale for further investigation of this combination in patients with essential hypertension.
A robust methodology for the quantitative assessment of the rat jawbone microstructure
Authors: Marissa Chatterjee, Fernanda Faot, Cassia Correa, Joke Duyck, Ignace Naert, Katleen Vandamme
Journal: International Journal of Oral Science (2017)

Micro-computed tomography can be applied for the assessment of the micro-architectural characteristics of the cortical and trabecular bones in either physiological or disease conditions. However, reports often lack a detailed description of the methodological steps used to analyse these images, such as the volumes of interest, the algorithms used for image filtration, the approach used for image segmentation, and the bone parameters quantified, thereby making it difficult to compare or reproduce the studies. This study addresses this critical need and aims to provide standardized assessment and consistent parameter reporting related to quantitative jawbone image analysis. Various regions of the rat jawbones were screened for their potential for standardized micro-computed tomography analysis. Furthermore, the volumes of interest that were anticipated to be most susceptible to bone structural changes in response to experimental interventions were defined. In the mandible, two volumes of interest were selected, namely, the condyle and the trabecular bone surrounding the three molars. In the maxilla, the maxillary tuberosity region and the inter-radicular septum of the second molar were considered as volumes of interest. The presented protocol provides a standardized and reproducible methodology for the analysis of relevant jawbone volumes of interest and is intended to ensure global, accurate, and consistent reporting of its morphometry. Furthermore, the proposed methodology has potential, as a variety of rodent animal models would benefit from its implementation.