tbuckley/cabot-search huggingface dataset:
T/NK-Cell Immunophenotype with Coexpression of CD56 Predicts Poor Outcome in Childhood T-ALL. Results of the ALL-BFM 2000 Trial
Authors: Stephan Fuhrmann, Leonid Karawajew, Richard Schabath, Anja Moricke, Martin Zimmermann, Wolf-Dieter Ludwig, Martin Schrappe, Richard Ratei
Journal: Blood (2016)
TET1-mediated epigenetic reprogramming switches metabolism and promotes malignant phenotypes of ovarian cancer
Authors: Rui-Lan Huang, Lin Yu Chen, Pearlly Yan, Tien Shuo Huang, Yu Ping Liao, Jian Liang Chou, Jora M J Lin, Tai Kuang Chao, Michael W Y Chan, Wun Shaing Wayne Chang, Hung-Cheng Lai
Journal: Cancer Research (2015)
Development of antibody fragment auristatin drug conjugates for cancer therapy
Authors: Charlotte F. McDonagh, Lori Westendorf, Melissa Thompson, Kristine Kim, Stephen C. Alley, Ivan Stone, Paul Carter
Journal: Cancer Research (2006)

1189  Conjugation to cytotoxic drugs is one of the most promising ways to enhance the antitumor efficacy of antibodies. For example, monomethyl auristatin E (MMAE) conjugated to the chimeric anti-CD30 antibody, cAC10, is highly efficacious in scid mouse xenograft models of anaplastic large cell lymphoma (ALCL) and Hodgkin’s disease (HD). One parameter that may impact the therapeutic window of such antibody drug conjugates is toxicity due to release of drug at non-tumor sites. Unfortunately, drug liberation following conjugate catabolism appears to be the unavoidable ultimate in vivo fate of IgG drug conjugates. The use of antibody fragments for drug conjugation offers a potential way to circumvent the catabolic fate of IgG drug conjugates. This reflects that small bivalent antibody fragments target tumors efficiently but are eliminated rapidly and primarily by renal filtration which will lessen the exposure of non-tumor sites to free drug and may reduce the observed toxicity. We have created MMAE drug conjugates of various antibody fragments of cAC10, namely, diabodies, minibodies (scFv-CH3) and scFv-Fc fragments and compared their in vitro and in vivo anti-tumor activities to the corresponding IgG drug conjugate. The diabody (53 kDa), minibody (83 kDa) and scFv-Fc (105 kDa) fragments are anticipated to span a broad range of pharmacokinetic parameters allowing investigation of the impact of fragment drug conjugate clearance rate on therapeutic index. The antibody fragments were stably expressed in CHO cells, purified and site-specifically conjugated with 4 equivalents of MMAE using available or engineered cysteine residues. The cAC10 fragment MMAE conjugates and intact IgG bound comparably to CD30+ cells. Additionally, cAC10 fragment MMAE conjugates were cytotoxic against both CD30+ ALCL and HD cell lines in vitro with slight reductions in potency observed compared to the intact IgG (IgG = scFv-Fc > minibody > diabody). Administration of cAC10 fragment MMAE conjugates to scid mouse xenograft models of ALCL resulted in antitumor efficacy for each fragment format. These studies demonstrate that cAC10 antibody fragment MMAE conjugates retain the antigen binding and antitumor activity of the intact IgG conjugate. Further studies to compare the therapeutic windows of antibody fragment drug conjugates to intact IgG drug conjugates are in progress.
High Rates of Minimal Residual Disease-Negative (MRD−) Complete Responses (CR) in Adult and Pediatric and Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL) Treated With KTE-C19 (Anti-CD19 Chimeric Antigen Receptor [CAR] T Cells): Preliminary Results of the ZUMA-3 and ZUMA-4 Trials
Authors: Bijal Shah, Van Huynh, Leonard S. Sender, Daniel W. Lee, Januario E. Castro, William G. Wierda, Andrew C. Dietz, Gary J. Schiller, Marie José Kersten, Rupert Handgretinger, Patrick Brown, Lia Gore, Nicola Gökbuget, Joseph Rosenthal, Marianna Sabatino, Adrian Bot, John M. Rossi, Yizhou Jiang, Lynn Navale, Shanna Stout, Jeff S. Aycock, Jeff Wiezorek, Rajul Jain, Alan S. Wayne
Journal: Blood (2016)
Changes of the Mutational Landscape in Relapsed Acute Myeloid Leukemia
Authors: Franck Rapaport, Marc Robert de Massy, Adil al Hinai, Mathijs A. Sanders, Todd Hricik, Caroline Sheridan, Tak C Lee, Yaseswini Neelamraju, Jay Patel, Stephen S. Chung, Michael W. Becker, Ian D Lewis, Richard D'Andrea, Lars Bullinger, Konstanze Döhner, Hartmut Döhner, Monica L. Guzman, Gail J. Roboz, Martin Carroll, Christopher Y. Park, Christopher E. Mason, Ari Melnick, Ross L. Levine, Peter J.M. Valk, Francine E. Garrett-Bakelman
Journal: Blood (2016)
International Sports Federation’s fight to protect the clean athlete: are we doing enough in the fight against doping?
Authors: Margo Mountjoy, Stuart Miller, Matteo Vallini, Jeremy Foster, James Carr
Journal: British Journal of Sports Medicine (2017)

The antidoping landscape has seen significant changes recently. Doping in sport, and integrity in a wider sense, have been the subject of greater scrutiny than ever before. The WADA and other antidoping organisations (ADOs) have been criticised for being subject to conflicts of interest, whether real or perceived. Conflicts of interest indicate failure of governance. That is, the governance structures within such ADOs are insufficient to give stakeholders comfort that those organisations are free from undue influence. One way in which these criticisms could be addressed is by implementing and enforcing governance principles that would see various components of an antidoping programme, including sample collection, analysis, results management and therapeutic use exemptions (TUEs), independent from that ADO’s political arm—Russia, for example.

Antidoping in Russia is a case in point. The suspensions by WADA of the Russian National Anti-Doping Organisation and the Moscow antidoping laboratory and the allegations related to activities at the (then-WADA-accredited) antidoping laboratory in Sochi 2014, combined with the sanctioning of athletes following retests of samples from the 2008 and 2012 Olympic games, have led to the view that the current antidoping system is not ‘fit for purpose’ today, and certainly not appropriate to face the challenges of the future. Among others, the IOC published a declaration in October 2016, calling for a ‘more robust, more efficient, more transparent and more harmonised WADA anti-doping system… (including) better governance…, increased security… and increased financing’.1 It is incumbent on all stakeholders, including WADA, public authorities (governments) and sport, including the IOC and International (Sporting) Federations (IFs) to share responsibility in facing those challenges.

The Summer Olympic IFs, under the leadership of the Association of Summer Olympic International Federations (ASOIF), commissioned an antidoping study under the guidance of the …
Stereotactic body and conformal radiation therapy in primary and secondary liver malignancies: Local in-field control
Authors: Emily Latacz, Pieter-Jan van Dam, Pieter Meersman, Piet Dirix, Paul Meijnders, Lieselotte Depuydt, Steven Van Laere, Luc Dirix, Reinhilde Weytjens
Journal: Annals of Oncology (2017)
Burden of out-of-pocket spending among high-deductible health plan members with metastatic breast cancer.
Authors: Christine Leopold, Anita K. Wagner, Fang Zhang, Christine Lu, Craig Earle, Larissa Nekhlyudov, Dennis Ross-Degnan, James Frank Wharam
Journal: Journal of Clinical Oncology (2017)

1029 Background: 50% of workers have high-deductible health plans (HDHP) that require major outofpocket (OOP) spending for cancerrelated care. The OOP burden among patients with advanced cancer in HDHPs is unknown. Our objective was to estimate OOP spending for women with metastatic breast cancer (mbc) stratified by health plan type. Methods: Our data source was administrative health insurance claims and enrollment data of members insured though a large national health plan. We included 7142 women age 25-64 with mbc who had at least 6 months enrollment before the diagnosis and at least 12 months followup. We used a time series design and plotted OOP spending stratified by HDHP vs low-deductible plan. Primary outcome measures included: (1) 20042012 calendar trends in total annual OOP spending, (2) monthly total OOP spending in the 6 months before and 24 months after women were diagnosed with mbc, and (3) monthly total OOP spending in the last 6 months of life. Plots were adjusted for age, socioeconomic status, race/ethnicity, and US region of residence, and we then conducted linear regression to assess for statistical significance of trends. Results: In 2004, average annual OOP spending for women with mbc cancer in low-deductible health plans was $1196.2 and increased to $2570 in 2012, a yearly increase of $159.2 (113.2205.2). For women in HDHP average OOP spending in 2004 amounted to $2648 and increased to $3736.4 in 2012, representing an annual increase of $160.4 per year (105.4215.4) Average OOP spending per person month peaked in the month of diagnosis to $1633.8 for women in HDHPs and to $643 among low-deductible plan members. Average OOP spending in the last 6 months of life were $285.7 per person month among low-plan ($1714.2 per 6 months) and $607.3 among HDHP ($3644 per 6 months). Conclusions: To our knowledge, this is the first analysis to estimate OOP spending for women with mbc accounting for enrollment in HDHPs versus low-deductible plans. We found that OOP spending is increasing over time and is high in the last 6 months of life. HDHP members with mbc faced much higher OOP spending than women in traditional plans across all analyses. Findings raise concerns that HDHPs could worsen access to mbc treatments.
Identification and characterization of a FOXA2-regulated transcriptional enhancer at a type 2 diabetes intronic locus that controls GCKR expression in liver cells
Authors: Maykel López Rodríguez, Dorota Kaminska, Kati Lappalainen, Jussi Pihlajamäki, Minna U. Kaikkonen, Markku Laakso
Journal: Genome Medicine (2017)

Genome-wide association studies (GWAS) have identified more than 100 genetic loci associated with type 2 diabetes (T2D). However, the underlying biological mechanisms for many of these associations remain unknown. GWAS signals close to the glucokinase regulatory protein gene (GCKR) have been reported for lipid and glucose metabolism traits and the risk of T2D. We investigated the regulatory function of an intronic locus at GCKR represented by the lead single nucleotide polymorphism (SNP) rs780094. We used ENCODE project histone modification and transcription factor binding data to determine the regulatory features of a GCKR intronic locus formed by the high linkage disequilibrium rs780094(C/T), rs780095(G/A), and rs780096(G/C) SNPs. Characterization of the transcriptional activity of this region was assessed by luciferase reporter assays in HepG2 cells and mouse primary hepatocytes. ChIP-qPCR was used to determine the levels of haplotype specific transcription factor binding and histone marks. A CRISPR-dCas9 transcriptional activator system and qPCR were used to activate the locus and measure GCKR expression, respectively. Differential haplotype expression was measured from human liver biopsies. The ENCODE data suggest the existence of a liver-specific intragenic enhancer at the locus represented by s780094. We observed that FOXA2 increased the transcriptional activity of this region in a haplotype specific way (CGG > TAC; rs780094, rs780095, and rs780096). In addition, the CGG haplotype showed higher binding to FOXA2 and higher levels of the H3K27Ac histone mark. The epigenetic activation of this locus increased the expression of endogenous GCKR in HepG2 cells, confirming that GCKR is the direct target gene of the enhancer. Finally, we confirmed that the CGG haplotype exhibits higher levels of transcription in human liver. Our results demonstrate the existence of a liver-specific FOXA2-regulated transcriptional enhancer at an intronic T2D locus represented by rs780094, rs780095, and rs780096 SNPs that increases GCKR expression. Differential haplotype regulation suggests the existence of cis regulatory effects that may contribute to the associated traits at this locus.
Efficacy of a Type I FLT3 Inhibitor, Crenolanib, with Idarubicin and High-Dose Ara-C in Multiply Relapsed/Refractory FLT3+ AML
Authors: Maro Ohanian, Hagop M. Kantarjian, Gautam Borthakur, Tapan M. Kadia, Marina Konopleva, Guillermo Garcia-Manero, Zeev Estrov, Alessandra Ferrajoli, Koichi Takahashi, Elias J. Jabbour, Naval Daver, Steven M. Kornblau, William G. Wierda, Jan A. Burger, Kiran Naqvi, Christopher B. Benton, Prithviraj Bose, John R. Eckardt, Farhad Ravandi, Jorge E. Cortes
Journal: Blood (2016)
Multifunctional Polymeric Micelles for Combining Chelation and Detection of Iron in Living Cells
Authors: Zhi Liu, Max Purro, Jing Qiao, May P. Xiong
Journal: Advanced Healthcare Materials (2017)

Multifunctional self‐assembled micelles composed of Pluronics F127 polymer chains are developed and investigated for chelation and selective detection of iron(III) in vitro and in iron‐overloaded cells. Tetraphenylethene (TPE) is encapsulated into the micelle core and the iron chelate drug deferoxamine (DFO) is conjugated to micelles to generate a fluorescence quenching detection system termed DFO‐TFM for short, where T stands for TPE, F for F127, and M for micelle. The key to the successful formation of this fluorescence quenching system is due to the near‐ideal overlap between the absorption spectrum of the DFO:iron(III) complex and fluorescence spectrum of TPE. DFO‐TFM can retain the iron‐chelation properties of DFO and exhibits negligible cytotoxicity compared to free DFO. Furthermore, this fluorescence “turn‐off” system can be utilized to detect the presence of iron and to monitor the chelation process in an iron overload cell model. This study serves as an effective proof‐of‐concept model for designing future in vivo systems capable of combining the features of iron chelation with iron detection and efforts toward the development of such detection systems are currently underway.
Abstract P180: Atrogin-1, a Muscle-Specific Ubiquitin Ligase, Drives Atrophic Remodeling of the Heart
Authors: Kedryn K Baskin, Rebecca Salazar, Wenhao Chen, Heinrich Taegtmeyer
Journal: Circulation Research (2011)

The heart adapts to changes in load by remodeling both metabolically and structurally. During this process, cardiomyocytes break down unnecessary or damaged proteins and use the resulting amino acids for the synthesis of new proteins and/or energy provision. Protein degradation via the ubiquitin proteasome system is controlled by ubiquitin ligases, which determine the specific proteins to be degraded. Atrogin-1, a muscle specific ubiquitin ligase, is required for skeletal muscle atrophy, and over-expressing Atrogin-1 inhibits the development of cardiac hypertrophy. We now tested the hypothesis that Atrogin-1 is required for atrophic remodeling of the unloaded heart. Hearts from wild type (WT) and Atrogin-1 -/- mice (8-10 weeks old, n =8-12) were subjected to mechanical unloading by heterotopic transplantation. In WT hearts, seven days of unloading significantly reduced heart weight and myocyte cross-sectional area, while hearts lacking Atrogin-1 significantly hypertrophied (at least a 1.5-fold increase in heart weight, 2-fold increase in myocyte area). Conventional markers of atrophic remodeling, such as the reactivation of the fetal gene program (ANF, MHC isoform switch), were detected in both WT and Atrogin-1 -/- transplanted hearts. Proteasome activity and markers of autophagy were increased after unloading, although not significantly different between WT and Atrogin-1 -/- hearts. Pathways regulating protein synthesis were enhanced in the absence of Atrogin-1; there was an increase in activated Akt and its downstream pathway including mTOR, 4E-BP1, and p70 S6 kinase. Additionally, two known targets of Atrogin-1 involved in hypertrophy and protein synthesis, calcineurin and eukaryotic initiation factor 3f, were upregulated in unloaded Atrogin-1 deficient hearts. Consequently, “unloaded” cardiomyocytes lacking Atrogin-1 in vitro exhibit increased basal rates of protein synthesis. The results suggest that Atrogin-1 not only enhances protein degradation, but also keeps protein synthesis in check. Thus Atrogin-1 has a duel role in regulating cardiac mass.
Liposomal honokiol induced lysosomal degradation of Hsp90 client proteins and protective autophagy in both gefitinib-sensitive and gefitinib-resistant NSCLC cells
Authors: Jianhong Yang, Wenshuang Wu, Jiaolin Wen, Haoyu Ye, Hong Luo, Peng Bai, Minghai Tang, Fang Wang, Li Zheng, Shengyong Yang, Weimin Li, Aihua Peng, Li Yang, Li Wan, Lijuan Chen
Journal: Biomaterials (2017)
Prognostic value of molecular biomarkers in mCRC
Authors: Pilar García Alfonso, Gonzalo García González, Iria Gallego Gallego, Isabel Peligros, Ana Corcuera, Beatriz Puente, de Mena Miriam Lobo, Isabel Echavarria, Ana Belen Ruperez, Gema Aguado, Carmen Sandoval, Andrés Muñoz, Montserrat Blanco-Codesido, Aitana Calvo, Miguel Martin
Journal: Annals of Oncology (2017)
Perspective of Surgical Resident Trainees on Accreditation Council for Graduate Medical Education Changes in Resident Work Environment and Duty Hours
Authors: Nicolas J. Mouawad, Afif Kulaylat, Rebecca L. Hoffman
Journal: JAMA Surgery (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Insights Into The Natural History Of Paroxysmal Nocturnal Hemoglobinuria (PNH): Analysis Of The Presenting Clinical, Haematological and Flow Cytometric Features Of 705 Patients Leads To Improved Classification and Prediction Of Clinical Course
Authors: Stephen John Richards, Richard Kelly, Anita Hill, Anita Dickinson, Fiona Cullen, Jane Shingles, Matthew Cullen, Peter Hillmen
Journal: Blood (2013)
UK government urged to screen for BSE in sheep
Authors: Roger Dobson
Journal: BMJ (2000)

Fast screening tools are urgently needed for detecting any bovine spongiform encephalopathy (BSE) in sheep, the UK Food Standards Agency has warned. The agency said that current research is too slow and warns that if BSE is found in the 40 million strong national flock, existing controls would have to be revised.

Concern has been expressed that some of the 4000 sheep who die of scrapie each year in the United Kingdom have BSE, …
The effects of shoe-worn insoles on gait biomechanics in people with knee osteoarthritis: a systematic review and meta-analysis
Authors: Kathryn E Shaw, Jesse M Charlton, Christina K L Perry, Courtney M de Vries, Matthew J Redekopp, Jordan A White, Michael A Hunt
Journal: British Journal of Sports Medicine (2017)

The effect of shoe-worn insoles on biomechanical variables in people with medial knee osteoarthritis has been studied extensively. The majority of research has focused specifically on the effect of lateral wedge insoles at the knee. The aim of this systematic review and meta-analysis was to summarise the known effects of different shoe-worn insoles on all biomechanical variables during level walking in this patient population to date.Four electronic databases were searched to identify studies containing biomechanical data using shoe-worn insole devices in the knee osteoarthritis population. Methodological quality was assessed and a random effects meta-analysis was performed on biomechanical variables reported in three or more studies for each insole.Twenty-seven studies of moderate-to-high methodological quality were included in this review. The primary findings were consistent reductions in the knee adduction moment with lateral wedge insoles, although increases in ankle eversion with these insoles were also found.Lateral wedge insoles produce small reductions in knee adduction angles and external moments, and moderate increases in ankle eversion. The addition of an arch support to a lateral wedge minimises ankle eversion change, and also minimises adduction moment reductions. The paucity of available data on other insole types and other biomechanical outcomes presents an opportunity for future research.
08.22 The role of transmembrane rather than soluble tnf in spondyloarthritis
Authors: Leonie M van Duivenvoorde, Melissa N van Tok, Iris C Blijdorp, Carmen A Ambarus, George Kollias, Nataliya G Yeremenko, Dominique L Baeten
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> TNF plays a key role in immune-mediated inflammatory diseases including rheumatoid arthritis (RA) and spondyloarthritis (SpA). Here we aimed to investigate how TNF can lead to completely different disease phenotypes such as destructive peripheral polysynovitis in RA versus axial and peripheral remodelling arthritis in SpA. <h3>Materials and methods</h3> We assessed expression of TNF, TNF-R, and TACE (ADAM17) in synovial fluid, synovial tissue, and synovial fibroblasts from SpA and RA. tmTNFtg mice (TgA86)<sup>1</sup> were clinically scored for development of peripheral and axial disease, and sacrificed at the end of the experiments for radiologic and histologic assessment. Mechanistic studies included bone marrow chimaera experiments and crossing with TNF-R1 or TNF-R2 knock-out animals. <h3>Results</h3> Arthritis was characterised by lower levels of sTNF and higher levels of tmTNF in SpA versus RA. This misbalance was related to decreased TACE activity in SpA versus RA FLS, as further confirmed by lower levels of other soluble molecules cleaved by TACE (including sTNF-RI, sTNF-RII, and sCD163) in the inflamed SpA joint. Assessing whether tmTNF has a functional role in SpA pathology, mice selectively over-expressing the transmembrane form of TNF spontaneously developed a deforming arthritis and spondylitis, starting at 4 weeks of age and reaching a 100% incidence. Histology revealed peripheral and axial synovitis, enthesitis, and osteitis, as well as inflammation of the connective tissue located at the junction of the annulus fibrosus with the vertebral bone. tmTNFtg mice did not develop extra-articular inflammation. Structural phenotyping by histology and radiology revealed mild destructive features in combination with foci of hypertrophic chondrocytes and axial and peripheral new bone formation leading to bridging of tail vertebra over time. Mechanistic experiments revealed that this SpA-like phenotype was mediated by tmTNF expression on stromal cells but not on hematopoietic cells and required the expression of TNF-R1. <h3>Conclusions</h3> Collectively, these data suggest that tmTNF expressed by stromal cells is responsible for the key pathological features of SpA. <h3>References</h3> 1.Alexopoulou L, <i>et al</i>. <i>Eur J Immunol</i>1997;27(10):2588–92.