tbuckley/cabot-search huggingface dataset:
The MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1/2 and mTORC1 Signaling
Authors: Petros Andrikopoulos, Julius Kieswich, Sabrina Pacheco, Luxme Nadarajah, Steven Michael Harwood, Caroline E. O'Riordan, Christoph Thiemermann, Muhammad M. Yaqoob
Journal: Journal of the American Society of Nephrology (2018)

Background During kidney fibrosis, a hallmark and promoter of CKD (regardless of the underlying renal disorder leading to CKD), the extracellular-regulated kinase 1/2 (ERK1/2) pathway, is activated and has been implicated in the detrimental differentiation and expansion of kidney fibroblasts. An ERK1/2 pathway inhibitor, trametinib, is currently used in the treatment of melanoma, but its efficacy in the setting of CKD and renal fibrosis has not been explored. Methods We investigated whether trametinib has antifibrotic effects in two mouse models of renal fibrosis—mice subjected to unilateral ureteral obstruction (UUO) or fed an adenine-rich diet—as well as in cultured primary human fibroblasts. We also used immunoblot analysis, immunohistochemical staining, and other tools to study underlying molecular mechanisms for antifibrotic effects. Results Trametinib significantly attenuated collagen deposition and myofibroblast differentiation and expansion in UUO and adenine-fed mice. We also discovered that in injured kidneys, inhibition of the ERK1/2 pathway by trametinib ameliorated mammalian target of rapamycin complex 1 (mTORC1) activation, another key profibrotic signaling pathway. Trametinib also inhibited the ERK1/2 pathway in cultured primary human renal fibroblasts stimulated by application of TGF- β 1, the major profibrotic cytokine, thereby suppressing downstream mTORC1 pathway activation. Additionally, trametinib reduced the expression of myofibroblast marker α -smooth muscle actin and the proliferation of renal fibroblasts, corroborating our in vivo data. Crucially, trametinib also significantly ameliorated renal fibrosis progression when administered to animals subsequent to myofibroblast activation. Conclusions Further study of trametinib as a potential candidate for the treatment of chronic renal fibrotic diseases of diverse etiologies is warranted.
Factors associated with suspected nonmelanoma skin cancers, dysplastic nevus, and cutaneous melanoma among first-time SpotMe screening program participants during 2009-2010
Authors: Derek Beaulieu, Hensin Tsao, Dominique S. Michaud, Jean-Phillip Okhovat, Allan C. Halpern, Alan C. Geller
Journal: Journal of the American Academy of Dermatology (2018)
Loss of the FAT1 Tumor Suppressor Promotes Resistance to CDK4/6 Inhibitors via the Hippo Pathway
Authors: Zhiqiang Li, Pedram Razavi, Qing Li, Weiyi Toy, Bo Liu, Christina Ping, Wilson Hsieh, Francisco Sanchez-Vega, David N. Brown, Arnaud F. Da Cruz Paula, Luc Morris, Pier Selenica, Emily Eichenberger, Ronglai Shen, Nikolaus Schultz, Neal Rosen, Maurizio Scaltriti, Edi Brogi, Jose Baselga, Jorge S. Reis-Filho, Sarat Chandarlapaty
Journal: Cancer Cell (2018)
Decreasing mortality and hospitalizations with rising costs related to gastric cancer in the USA: an epidemiological perspective
Authors: Delong Liu, Dhruv Mehta, Supreet Kaur, Arun Kumar, Kaushal Parikh, Lavneet Chawla, Shanti Patel, Amirta Devi, Aparna Saha
Journal: Journal of Hematology & Oncology (2018)

There is no convincing data on the trends of hospitalizations, mortality, cost, and demographic variations associated with inpatient admissions for gastric cancer in the USA. The aim of this study was to use a national database of US hospitals to evaluate the trends associated with gastric cancer. We analyzed the National Inpatient Sample (NIS) database for all patients in whom gastric cancer (ICD-9 code: 151.0, 151.1, 151.2, 151.3, 151.4, 151.5, 151.6, 151.8, 151.9) was the principal discharge diagnosis during the period, 2003–2014. The NIS is the largest publicly available all-payer inpatient care database in the US. It contains data from approximately eight million hospital stays each year. The statistical significance of the difference in the number of hospital discharges, length of stay, and hospital costs over the study period was determined by regression analysis. In 2003, there were 23,921 admissions with a principal discharge diagnosis of gastric cancer as compared to 21,540 in 2014 (P < 0.01). The mean length of stay for gastric cancer decreased by 17% between 2003 and 2014 from 10.9 days to 8.95 days (P < 0.01). However, during this period, the mean hospital charges increased significantly by 21% from $ 75,341 per patient in 2003 to $ 91,385 per patient in 2014 (P < 0.001). There was a more significant reduction in mortality over a period of 11 years from 2428 (10.15%) in 2003 to 1345 (6.24%) in 2014 (P < 0.01). The aggregate charges (i.e., "national bill") for gastric cancer increased significantly from 1.79 bn $ to 1. 96 bn $ (P < 0.001), despite decrease in hospitalization (inflation adjusted). Although the number of inpatient admissions for gastric cancer have decreased over the past decade, the healthcare burden and cost related to it has increased significantly. Inpatient mortality is decreasing which is consistent with overall decrease in gastric cancer-related deaths. Cost increase associated with gastric cancer contributed significantly to the national healthcare bill.
Golf habits among physicians and surgeons: observational cohort study
Authors: Gal Koplewitz, Daniel M Blumenthal, Nate Gross, Tanner Hicks, Anupam B Jena
Journal: BMJ (2018)

To examine patterns of golfing among physicians: the proportion who regularly play golf, differences in golf practices across specialties, the specialties with the best golfers, and differences in golf practices between male and female physicians.Observational study.Comprehensive database of US physicians linked to the US Golfing Association amateur golfer database.41 692 US physicians who actively logged their golf rounds in the US Golfing Association database as of 1 August 2018.Proportion of physicians who play golf, golf performance (measured using golf handicap index), and golf frequency (number of games played in previous six months).Among 1 029 088 physicians, 41 692 (4.1%) actively logged golf scores in the US Golfing Association amateur golfer database. Men accounted for 89.5% of physician golfers, and among male physicians overall, 5.5% (37 309/683 297) played golf compared with 1.3% (4383/345 489) among female physicians. Rates of golfing varied substantially across physician specialties. The highest proportions of physician golfers were in orthopedic surgery (8.8%), urology (8.1%), plastic surgery (7.5%), and otolaryngology (7.1%), whereas the lowest proportions were in internal medicine and infectious disease (<3.0%). Physicians in thoracic surgery, vascular surgery, and orthopedic surgery were the best golfers, with about 15% better golf performance than specialists in endocrinology, dermatology, and oncology.Golfing is common among US male physicians, particularly those in the surgical subspecialties. The association between golfing and patient outcomes, costs of care, and physician wellbeing remain unknown.
Genetic associations and regulation of expression indicate an independent role for 14q32 snoRNAs in human cardiovascular disease
Authors: Kjell E J Håkansson, Eveline A C Goossens, Stella Trompet, Eva van Ingen, Margreet R de Vries, Reginald V C T van der Kwast, Rasmus S Ripa, Jens Kastrup, Philipp J Hohensinner, Christoph Kaun, Johann Wojta, Stefan Böhringer, Saskia Le Cessie, J Wouter Jukema, Paul H A Quax, A Yaël Nossent
Journal: Cardiovascular Research (2018)

We have shown that 14q32 microRNAs are highly involved in vascular remodelling and cardiovascular disease. However, the 14q32 locus also encodes 41 'orphan' small nucleolar RNAs (snoRNAs). We aimed to gather evidence for an independent role for 14q32 snoRNAs in human cardiovascular disease.We performed a lookup of the 14q32 region within the dataset of a genome wide association scan in 5244 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Single nucleotide polymorphisms (SNPs) in the snoRNA-cluster were significantly associated with heart failure. These snoRNA-cluster SNPs were not linked to SNPs in the microRNA-cluster or in MEG3, indicating that snoRNAs modify the risk of cardiovascular disease independently. We looked at expression of 14q32 snoRNAs throughout the human cardio-vasculature. Expression profiles of the 14q32 snoRNAs appeared highly vessel specific. When we compared expression levels of 14q32 snoRNAs in human vena saphena magna (VSM) with those in failed VSM-coronary bypasses, we found that 14q32 snoRNAs were up-regulated. SNORD113.2, which showed a 17-fold up-regulation in failed bypasses, was also up-regulated two-fold in plasma samples drawn from patients with ST-elevation myocardial infarction directly after hospitalization compared with 30 days after start of treatment. However, fitting with the genomic associations, 14q32 snoRNA expression was highest in failing human hearts. In vitro studies show that the 14q32 snoRNAs bind predominantly to methyl-transferase Fibrillarin, indicating that they act through canonical mechanisms, but on non-canonical RNA targets. The canonical C/D-box snoRNA seed sequences were highly conserved between humans and mice.14q32 snoRNAs appear to play an independent role in cardiovascular pathology. 14q32 snoRNAs are specifically regulated throughout the human vasculature and their expression is up-regulated during cardiovascular disease. Our data demonstrate that snoRNAs merit increased effort and attention in future basic and clinical cardiovascular research.
Effects of diet on the childhood gut microbiome and its implications for atopic dermatitis
Authors: Mahboobeh Mahdavinia, Heather E. Rasmussen, Maresa Botha, Thi Dong Binh Tran, Jolice P. Van den Berg, Erica Sodergren, Erika Davis, Krista Engen, Claudia Gray, Nonhlanhla Lunjani, Carol Hlela, Nailliw Z. Preite, Wisdom Basera, Lelani Hobane, Alexandra Watkins, Phillip Engen, Avumile Mankahla, Ben Gaunt, Facey Thomas, Mary C. Tobin, Alan Landay, George M. Weinstock, Ali Keshavarzian, Michael E. Levin
Journal: Journal of Allergy and Clinical Immunology (2018)
A Photoresponsive Hyaluronan Hydrogel Nanocomposite for Dynamic Macrophage Immunomodulation
Authors: Haoyu Wang, Renee‐Tyler Tan Morales, Xin Cui, Jiongxian Huang, Weiyi Qian, Jie Tong, Weiqiang Chen
Journal: Advanced Healthcare Materials (2018)

Abstract Macrophages are a predominant immune cell population that drive inflammatory responses and exhibit transitions in phenotype and function during tissue remodeling in disease and repair. Thus, engineering an immunomodulatory biomaterial has significant implications for resolving inflammation. Here, a biomimetic and photoresponsive hyaluronan (HA) hydrogel nanocomposite with tunable 3D extracellular matrix (ECM) adhesion sites for dynamic macrophage immunomodulation is engineered. Photodegradative alkoxylphenacyl‐based polycarbonate (APP) nanocomposites are exploited to permit user‐controlled Arg–Gly–Asp (RGD) adhesive peptide release and conjugation to a HA‐based ECM for real‐time integrin activation of macrophages encapsulated in 3D HA–APP nanocomposite hydrogels. It is demonstrated that photocontrolled 3D ECM–RGD peptide conjugation can activate αvβ3 integrin of macrophages, and periodic αvβ3 integrin activation can enhance anti‐inflammatory M2 macrophage polarization. Altogether, an emerging use of biomimetic, photoresponsive, and bioactive HA–APP nanocomposite hydrogel is highlighted to command 3D cell–ECM interactions for modulating macrophage polarization, which may shed light on cell–ECM interactions in innate immunity and inspire new biomaterial‐based immunomodulatory therapies.
In high-risk obese or overweight patients, lorcaserin did not increase or decrease CV events at 3.3 years
Authors: James Brophy
Journal: Annals of Internal Medicine (2018)

Source Citation Bohula EA, Wiviott SD, McGuire DK, et al; CAMELLIA-TIMI 61 Steering Committee and Investigators. Cardiovascular safety of lorcaserin in overweight or obese patients. N Engl J Med. 2018;379:1107-17. 30145941
Abstract 18890: An <i>MYH7</i> Mutation Causes Inherited Left Ventricular Noncompaction and Sudden Death in a Large Multigenerational Family
Authors: Gina M Morgan, Rebecca Gutmann, Anthony J Klappa, Xiaodong Zhu, Ferhaan Ahmad, Haider Mehdi, Barry London
Journal: Circulation (2014)

Introduction: Mutations in MYH7 , encoding the cardiac β-myosin heavy chain, cause hypertrophic (HCM) and dilated cardiomyopathy (DCM). Recently, several mutations in MYH7 were reported in patients with left ventricular noncompaction (LVNC), a rare cardiomyopathy characterized by increased trabeculation and sudden death (SCD). No large families with inherited LVNC caused by MYH7 mutations have been reported. Methods: We identified a large family with LVNC and SCD (Pedigree). The proband is a 56 yo woman who presented at age 48 with heart failure, LVNC and a depressed ejection fraction (EF) by echocardiogram (TTE) and cardiac MRI (cMR). Medical records and blood samples were obtained from 20 adult family members, 8 clinically affected (6 LVNC; 2 DCM). DNA was isolated (PureGene), clinical genetic testing for known DCM/LVNC genes was performed on the proband’s affected daughter (GeneDx), and the mutation was identified in family members by direct sequencing. ECGs, TTEs, and cMRs were analyzed to determine PR/QRS/QTc intervals and EF; mutation carriers were compared to non-carriers in the family. Results: A heterozygous missense mutation in a hydrophobic coil in the myosin head was identified in exon 14 of MYH7 (c.1400 T&gt;C; p.Ile467Thr). This mutation was present in all 8 affected members, in 1 clinically unaffected obligate carrier, and in 1 symptomatic subject who had not undergone cardiac testing (penetrance ≥ 0.80). Three obligate carriers suffered SCD. Compared to noncarriers, the EF of mutation carriers was decreased (42 ± 13%, n=9, vs. 58 ±3%, n=4; p=0.03), the PR was borderline long (171 ± 33 vs. 149 ± 12 ms, n=10 each; p=0.06) and the QTc was prolonged (428 ± 32 vs. 405 ± 18 ms, n=10 each; p=0.05). Conclusion: The Ile467Thr mutation in MYH7 causes inherited LVNC with high penetrance and SCD in a large family. Future studies are warranted to differentiate the mechanisms leading from this mutation to LVNC as contrasted with those leading from other MYH7 mutations to HCM and DCM.
At the crossroads of oxygen and iron sensing: hepcidin control of HIF-2α
Authors: Frank S. Lee
Journal: Journal of Clinical Investigation (2018)

Hepcidin is the master regulator of iron metabolism. It plays a key role in the regulation of iron transport across the duodenal epithelium, which in turn is dependent on the oxygen-regulated transcription factor hypoxia-inducible factor 2α (HIF-2α). In this issue of the JCI, Schwartz and colleagues show that duodenal HIF-2α is itself regulated by hepcidin, thereby indicating that this transcription factor is not only regulated by oxygen, but also by iron. This work indicates that the crosstalk between liver hepcidin and intestinal HIF-2α plays an important role during iron overload, systemic iron deficiency, and anemia.
A biodegradable MnSiO3@Fe3O4 nanoplatform for dual-mode magnetic resonance imaging guided combinatorial cancer therapy
Authors: Xiao Sun, Guilong Zhang, Ruohong Du, Rui Xu, Dongwang Zhu, Junchao Qian, Guo Bai, Chi Yang, Zhiyuan Zhang, Xin Zhang, Duohong Zou, Zhengyan Wu
Journal: Biomaterials (2018)
<i>In vivo</i> characterization of a novel norepinephrine transporter PET tracer [<sup>18</sup>F]NS12137 in adult and immature Sprague-Dawley rats
Authors: Francisco R López-Picón, Anna K Kirjavainen, Sarita Forsback, Jatta S Takkinen, Dan Peters, Merja Haaparanta-Solin, Olof Solin
Journal: Theranostics (2018)

Norepinephrine modulates cognitive processes such as working and episodic memory. Pathological changes in norepinephrine and norepinephrine transporter (NET) function and degeneration of the locus coeruleus produce irreversible impairments within the whole norepinephrine system, disrupting cognitive processes. Monitoring these changes could enhance diagnostic accuracy and support development of novel therapeutic components for several neurodegenerative diseases. Thus, we aimed to develop a straightforward nucleophilic fluorination method with high molar activity for the novel NET radiotracer [18F]NS12137 and to demonstrate the ability of [18F]NS12137 to quantify changes in NET expression. Methods: We applied an 18F-radiolabeling method in which a brominated precursor was debrominated by nucleophilic 18F-fluorination in dimethyl sulfoxide. Radiolabeling was followed by a deprotection step, purification, and formulation of the radiotracer. The [18F]NS12137 brain uptake and distribution were studied with in vivo PET/CT and ex vivo autoradiography using both adult and immature Sprague-Dawley rats because postnatal NET expression peaks at 10-20 days post birth. The NET specificity for the tracer was demonstrated by pretreatment of the animals with nisoxetine, which is well-known to have a high affinity for NET. Results: [18F]NS12137 was successfully synthesized with radiochemical yields of 18.6±5.6%, radiochemical purity of >99%, and molar activity of >500 GBq/μmol at the end of synthesis. The in vivo [18F]NS12137 uptake showed peak standard uptake values (SUV) of over 1.5 (adult) and 2.2 (immature) in the different brain regions. Peak SUV/30 min and peak SUV/60 min ratios were calculated for the different brain regions of the adult and immature rats, with a peak SUV/60 min ratio of more than 4.5 in the striatum of adult rats. As expected, in vivo studies demonstrated uptake of the tracer in brain areas rich in NET, particularly thalamus, neocortex, and striatum, and remarkably also in the locus coeruleus, a quite small volume for imaging with PET. The uptake was significantly higher in immature rats compared to the adult animals. Ex vivo studies using autoradiography showed very strong specific binding in NET-rich areas such as the locus coeruleus and the bed nucleus of the stria terminalis, and high binding in larger grey matter areas such as the neocortex and striatum. The uptake of [18F]NS12137 was dramatically reduced both in vivo and ex vivo by pretreatment with nisoxetine, demonstrating the specificity of binding. Conclusions: [18F]NS12137 was synthesized in good yield and high molar activity and demonstrated the characteristics of a good radiotracer, such as good brain penetration, fast washout, and high specific binding to NET.
OA09 Preliminary Clinical Activity of Repotrectinib (TPX-0005) in Advanced ROS1 Fusion-Positive Non-Small Cell Lung Cancer
Authors: S. Ou, B.C. Cho, D. Kim, A. Drilon, J. Lee, J. Lin, V. Zhu, M. Ahn, D.R. Camidge, S. Shanna Stopatschinskaja, J. Liu, J. Cui, D. Hyman, R. Doebele, A. Shaw
Journal: Journal of Thoracic Oncology (2018)
Endoscopic sleeve gastroplasty for severe obesity by full-thickness suturing using the GERDX device
Authors: Andreas Wannhoff, Christopher Hofmann, Benjamin Meier, Dieter Birk, Karel Caca
Journal: Endoscopy (2018)

Obesity is an increasing health problem worldwide. Endoscopic therapies have emerged as treatment option in addition to lifestyle modification and bariatric surgery. One possible endoscopic approach is to reduce the size of the stomach [1] [2]. This approach has been demonstrated to be feasible and efficient using different endoscopic suturing devices [3] [4]. The GERDX device (G-Surg GmbH, Seeon-Seebruck, Germany) allows full-thickness suturing in the upper gastrointestinal tract and was originally used for endoscopic antireflux therapy [5]. The transmural sutures have proven to be durable and to remain in situ even after long follow-up.
Abstract 17507: Simulation of Transcatheter Aortic Valve Replacement and Assessment of Regurgitation in in-vitro Pulsatile Model With Patient-specific Anatomy
Authors: Yutaka Tanaka, Yusuke Aoyama, Kazuto Obama, Saeko Sasuga, Azuma Takahashi, Mitsuo Umezu, Shigeru Saito, Kiyotaka Iwasaki
Journal: Circulation (2016)

Introduction: Aortic regurgitation (AR) following transcatheter aortic valve replacement (TAVR) has been shown to be associated with increased mortality. However, regurgitant volume cannot be direc...
CD34+CD38− leukemic stem cell frequency to predict outcome in acute myeloid leukemia
Authors: Wendelien Zeijlemaker, Tim Grob, Rosa Meijer, Diana Hanekamp, Angèle Kelder, Jannemieke C. Carbaat-Ham, Yvonne J. M. Oussoren-Brockhoff, Alexander N. Snel, Dennis Veldhuizen, Willemijn J. Scholten, Johan Maertens, Dimitri A. Breems, Thomas Pabst, Markus G. Manz, Vincent H. J. van der Velden, Jennichjen Slomp, Frank Preijers, Jacqueline Cloos, Arjan A. van de Loosdrecht, Bob Löwenberg, Peter J. M. Valk, Mojca Jongen-Lavrencic, Gert J. Ossenkoppele, Gerrit J. Schuurhuis
Journal: Leukemia (2018)
Abstract 13560: Insulin Like Growth Factor -1 (IGFBP-1) is Pro-angiogenic and Enhances Hind Limb Perfusion in Insulin Resistant Mice
Authors: Natalie Haywood, Paul Cordell, Nadira Yuldasheva, Nele Warmke, Connor Matthews, Jessica Smith, Jethro Rainford, Harneet Cheema, Richard Cubbon, Mark Kearney, Stephen Wheatcroft
Journal: Circulation (2017)

Low IGFBP-1 levels are permissive for the development of both diabetes and cardiovascular disease. We have previously shown that mice overexpressing IGFBP-1 have increased vascular insulin sensitis...
Characterization of Frontline Treatment Patterns and Attrition Rates According to Subsequent Lines of Therapy in Non-Transplant Patients with Newly Diagnosed Multiple Myeloma
Authors: Rafael Fonseca, Saad Z. Usmani, Maneesha Mehra, Mary Slavcev, Jon Ukropec, Annette Lam, Ravi Potluri
Journal: Blood (2018)
Minimal Residual Disease (MRD) Assessed By Flow Cytometry in Patients with AL Amyloidosis Treated with Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD)
Authors: Victor Jimenez-Zepeda, Peter Duggan, Paola Neri, Jason Tay, Nizar J. Bahlis
Journal: Blood (2017)
Retraction: High-Mobility Group A1 Proteins Regulate p53-Mediated Transcription of <i>Bcl-2</i> Gene
Authors: Francesco Esposito, Mara Tornincasa, Paolo Chieffi, Ivana De Martino, Giovanna Maria Pierantoni, Alfredo Fusco
Journal: Cancer Research (2018)

[This article][1] ([1][2]) has been retracted at the request of the editors. The editors were made aware of concerns regarding potential manipulation of data in the article. An internal review by the editors determined that multiple γ-tubulin Western blot bands appear to be duplicated in Figs. 1A,
Preliminary Safety, Pharmacokinetics (PK) and Pharmacodynamic (PD) Analysis of the Polo-like Kinase-1 (PLK1) Inhibitor PCM-075, in Combination with Low-Dose Cytarabine (LDAC) or Decitabine (D) in Patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML)
Authors: Amer M. Zeidan, Gary J. Schiller, Alexander I Spira, Prapti A. Patel, Michaela L. Tsai, Maya Ridinger, Sandra L Silberman, Mark Erlander, Jorge E. Cortes
Journal: Blood (2018)
FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer
Authors: Thierry Conroy, Pascal Hammel, Mohamed Hebbar, Meher Ben Abdelghani, Alice C. Wei, Jean-Luc Raoul, Laurence Choné, Eric Francois, Pascal Artru, James J. Biagi, Thierry Lecomte, Eric Assenat, Roger Faroux, Marc Ychou, Julien Volet, Alain Sauvanet, Gilles Breysacher, Frédéric Di Fiore, Christine Cripps, Petr Kavan, Patrick Texereau, Karine Bouhier-Leporrier, Faiza Khemissa-Akouz, Jean-Louis Legoux, Béata Juzyna, Sophie Gourgou, Christopher J. O’Callaghan, Claire Jouffroy-Zeller, Patrick Rat, David Malka, Florence Castan, Jean-Baptiste Bachet
Journal: New England Journal of Medicine (2018)

Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer.