tbuckley/cabot-search huggingface dataset:
Sp1 and Sp3 mediate transcription of the human receptor tyrosine kinase Axl gene.
Authors: Mudduluru Giridhar, Post Stefan, Allgayer Heike
Journal: Cancer Research (2007)

2100  Axl belongs to the Tyro 3 family of receptor tyrosine kinases (RTKs), and was originally identified as a transforming gene in human leukaemias. It transduces antiapoptotic and/or mitogenic signals into the cytoplasm by binding growth factors like vitamin K-dependent protein growth-arrest-specific gene 6(GAS6) in a variety of cell lines. Furthermore, Axl is expressed at high levels in malignant glioma, metastatic colon, ovarian and breast cancers. So far there is not much known about the promoter and transcriptional regulation of this gene. Therefore, the following study was initiated to characterize the promoter and major cis-acting elements in the 5’-region of Axl. Initially, a 2.4 kb upstream sequence from the translational start site of the Axl gene was cloned into the pGL3 luciferase reporter vector, and further deletion constructs were generated comprising different sizes based on a TRANSFAC cis-acting elements database search. A minimal GC-rich Axl gene promoter -556/+7 upstream region from the translational initiation site was sufficient for basal promoter activity in transient transfections regardless of the cell type. Axl has multiple transcription start sites between -62 to -460, among them -169 is the major and -460 is the second most transcribed start site. A pivotal role for Sp1 in the constitutive expression of the Axl gene was demonstrated through electrophoretic mobility shift assays, transient expression of mutant Axl promoter-reporter gene constructs, chromatin immunoprecipitations, and inhibitionof Sp1 binding using Mithramycin-A in RKO and HCT116 cells. At least four Sp1-binding sites were identified. The two sites (Sp1a: -225 to -219 bp, and Sp1b: -248 to -243 bp) most proximal to the translation start site were found to be indispensable for Axl promoter activity, whereas mutation of other two more upstream (Sp1c: -513 to -506 bp and Sp1d: -531 to -521 bp) Sp-binding sites had a minor influence on basal promoter activity. Gel shift analysis identifies Sp1 and Sp3 transcription factors bound to the Sp1a,b,c and d motifs, and mutations of all Sp1 motifs abolished the binding of either factor, significantly reduced Axl promoter activity. In addition, we identified binding sites of MZF1 (Myeloid zinc finger protein 1) and AP1 (Activator protein 1) transcription factors. Site-directed mutagenesis abolishing the binding of MZF1/AP-1 to either motif diminished promoter activity by 20 and 30 percent respectively. Taken together, we have characterized the Axl promoter and show first evidence that especially Sp1 and Sp3 transcription factors play a critical role in regulating the proximal promoter activities of Axl.
Validation and Potential of Albumin-Bilirubin Grade and Prognostication in a Nationwide Survey of 46,681 Hepatocellular Carcinoma Patients in Japan: The Need for a More Detailed Evaluation of Hepatic Function
Authors: Atsushi Hiraoka, Kojiro Michitaka, Takashi Kumada, Namiki Izumi, Masumi Kadoya, Norihiro Kokudo, Shoji Kubo, Yutaka Matsuyama, Osamu Nakashima, Michiie Sakamoto, Tadatoshi Takayama, Takashi Kokudo, Kosuke Kashiwabara, Masatoshi Kudo
Journal: Liver Cancer (2017)

&lt;b&gt;&lt;i&gt;Background/Aim:&lt;/i&gt;&lt;/b&gt; Recently, albumin-bilirubin (ALBI) scoring/grading, consisting of only albumin and total bilirubin, has been proposed. We examined the efficacy of this grading system for determining hepatic function in patients with hepatocellular carcinoma (HCC). &lt;b&gt;&lt;i&gt;Methods/Materials:&lt;/i&gt;&lt;/b&gt; The prognoses of 46,681 HCC patients based on results obtained from a nationwide survey conducted in Japan from 2001 to 2007 were evaluated using (1) Japan Integrated Staging (JIS), consisting of Child-Pugh classification and TNM staging (TNM), (2) modified JIS (m-JIS), consisting of liver damage grading and TNM, and (3) ALBI-TNM (ALBI-T), consisting of ALBI grading and TNM, and the results were compared. A subanalysis was also performed to define a cutoff value for ALBI scores for a more detailed stratification of hepatic function. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; ALBI-T, JIS, and m-JIS each showed good capacity for the stratification of prognoses. Although the Akaike information criterion for ALBI-T was nearly equal to that for JIS and m-JIS, the Kaplan-Meier curves and median survival times obtained with ALBI-T were always superior to the corresponding scores. When the indocyanine green retention test (&lt;30%) was used as an additional cutoff value for ALBI score (-2.270, area under the curve 0.828) to divide ALBI grade into 4 levels (modified ALBI [mALBI] grade), mALBI grade was able to stratify the prognosis of patients at any TNM stage in order of grade. Modified ALBI-T (mALBI-T), using mALBI grading and TNM, produced a more detailed stratification for prognosis. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; The predictive value for prognosis of ALBI-T was found to be equal to that of JIS and m-JIS. In addition, mALBI grading and mALBI-T, as proposed in the present study, might provide a more detailed assessment of the hepatic function and prognosis of HCC patients.
Shortage or Surplus of Physicians in the United States—Reply
Authors: Ezekiel J. Emanuel, Emily Gudbranson
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Modification of structural lesions on MRI of the sacroiliac joints by etanercept in the EMBARK trial: a 12-week randomised placebo-controlled trial in patients with non-radiographic axial spondyloarthritis
Authors: Walter P Maksymowych, Stephanie Wichuk, Maxime Dougados, Heather E Jones, Ron Pedersen, Annette Szumski, Lisa Marshall, Jack F Bukowski, Robert G Lambert
Journal: Annals of the Rheumatic Diseases (2017)

Objective To evaluate the impact on structural lesions observed on MRI in the sacroiliac joints (SIJ) at 12 weeks in patients with non-radiographic axial spondyloarthritis (nr-axSpA) receiving etanercept or placebo in EMBARK (Effect of Etanercept on Symptoms and Objective Inflammation in nr-axSpA, a 104 week study). Methods Patients were randomised to double-blind etanercept 50 mg/week or placebo for 12 weeks. Structural lesions at baseline and 12 weeks were scored by two independent readers using the Spondyloarthritis Research Consortium of Canada (SPARCC) SIJ structural score (SSS) on T1-weighted MRI. Change in SPARCC SSS and correlation with improvement in clinical outcomes was evaluated. Results MRI scans from 185 patients (etanercept, n=88; placebo, n=97) were reviewed. At baseline, there were no significant differences in mean SPARCC SSS between etanercept and placebo. From baseline to 12 weeks, change in mean SPARCC SSS was significantly greater for etanercept than placebo for erosion (–0.57 vs –0.08, respectively, adjusted p value=0.017) and backfill (0.36 vs 0.06, adjusted p value=0.022). A treatment difference was also present for the subgroup of patients with SIJ inflammation on MRI (SPARCC bone marrow oedema ≥2): erosion: –0.81 versus –0.13 for etanercept versus placebo, respectively, p=0.007; backfill: 0.48 versus 0.08, respectively, p=0.032. Decrease in erosion and increase in backfill correlated with improvement in more clinical outcomes for etanercept than placebo. Conclusion Treatment with etanercept was associated with significantly greater reduction in erosions and increase in backfill at 12 weeks compared with placebo, consistent with a very early reparative response to antitumour necrosis factor therapy. The impact on disease progression in spondyloarthritis should be studied further. Trial registration number NCT01258738; Post-results.
Polysomnographic phenotypes and their cardiovascular implications in obstructive sleep apnoea
Authors: Andrey V Zinchuk, Sangchoon Jeon, Brian B Koo, Xiting Yan, Dawn M Bravata, Li Qin, Bernardo J Selim, Kingman P Strohl, Nancy S Redeker, John Concato, Henry K Yaggi
Journal: Thorax (2017)

Background Obstructive sleep apnoea (OSA) is a heterogeneous disorder, and improved understanding of physiologic phenotypes and their clinical implications is needed. We aimed to determine whether routine polysomnographic data can be used to identify OSA phenotypes (clusters) and to assess the associations between the phenotypes and cardiovascular outcomes. Methods Cross-sectional and longitudinal analyses of a multisite, observational US Veteran (n=1247) cohort were performed. Principal components-based clustering was used to identify polysomnographic features in OSA’s four pathophysiological domains (sleep architecture disturbance, autonomic dysregulation, breathing disturbance and hypoxia). Using these features, OSA phenotypes were identified by cluster analysis (K-means). Cox survival analysis was used to evaluate longitudinal relationships between clusters and the combined outcome of incident transient ischaemic attack, stroke, acute coronary syndrome or death. Results Seven patient clusters were identified based on distinguishing polysomnographic features: ‘mild’, ‘periodic limb movements of sleep (PLMS)’, ‘NREM and arousal’, ‘REM and hypoxia’, ‘hypopnoea and hypoxia’, ‘arousal and poor sleep’ and ‘combined severe’. In adjusted analyses, the risk (compared with ‘mild’) of the combined outcome (HR (95% CI)) was significantly increased for ‘PLMS’, (2.02 (1.32 to 3.08)), ‘hypopnoea and hypoxia’ (1.74 (1.02 to 2.99)) and ‘combined severe’ (1.69 (1.09 to 2.62)). Conventional apnoea–hypopnoea index (AHI) severity categories of moderate (15≤AHI&lt;30) and severe (AHI ≥30), compared with mild/none category (AHI &lt;15), were not associated with increased risk. Conclusions Among patients referred for OSA evaluation, routine polysomnographic data can identify physiological phenotypes that capture risk of adverse cardiovascular outcomes otherwise missed by conventional OSA severity classification.
Abstract 17241: Electrocardiographic Left Atrial Abnormalities and Risk of Stroke in Patients With Atrial Fibrillation
Authors: Yuko Inoue, Esra G Ipek, Luisa Ciuffo, Jonathan Chrispin, Irfan M Khurram, Mohammadali Habibi, Stefan L Zimmerman, Joseph E Marine, Jack Rickard, David D Spragg, Saman Nazarian, Joao A Lima, Ronald D Berger, Hugh Calkins, Hiroshi Ashikaga
Journal: Circulation (2016)

Introduction:  Mounting evidence suggests that left atrial (LA) structural remodeling plays an important role in the mechanism of stroke in patients with a history of atrial fibrillation (AF). We evaluated the association among the severity of LA abnormality on electrocardiogram (ECG), the severity of LA structural remodeling by cardiac magnetic resonance (CMR), and a history of stroke or transient ischemic attack in patients with AF referred for catheter ablation.   Methods:  A total of 229 consecutive patients (age 60±10 years, 72% male) referred for catheter ablation of AF who were in sinus rhythm at the time of pre-ablation ECG recording and CMR were included, with (n=21; the stroke group) and without (n=208; control group) a history of stroke or TIA. The severity of LA abnormality on ECG was quantified from the P wave terminal force in lead V 1  (PTFV 1 ).   Results:  In the stroke group, PTFV 1  was significantly higher compared with the control group (8,107±5,921  vs.  4,865±3,205μV*ms; p 2 ) and decrease in left ventricular ejection fraction (%) were associated with an increase in PTFV 1  (47.7 and 74,1μV*ms; p=0.027 and 0.005, respectively). Multivariable analysis demonstrated that the PTFV 1  and LA emptying fraction were associated with a history of stroke (odds ratio 1.23 and 0.94; p=0.002 and 0.037, respectively) after adjusting for the CHA 2 DS 2 -VASc score and the LA minimum volume.   Conclusions:  PTFV 1  is an independent marker of stroke, and provides an incremental value to the CHA 2 DS 2 -VASc score in patients with AF. Evaluation of LA abnormalities by 12-lead ECG    may improve the current risk stratification of stroke in patients with AF.
Identification of Occupational Settings With Very High Risks of Lung Cancer
Authors: Roy E. Albert, M.D., Bernard S. Pasternack, Ph.D., Roy E. Shore, Ph.D., Norton Nelson, Ph.D.
Journal: JNCI Journal of the National Cancer Institute (1979)

Journal Article Identification of Occupational Settings With Very High Risks of Lung Cancer Get access Roy E. Albert, M.D., Roy E. Albert, M.D. New York University Institute of Environmental Medicine, 550 First Avenue New York, New York 10016 Search for other works by this author on: Oxford Academic PubMed Google Scholar Bernard S. Pasternack, Ph.D., Bernard S. Pasternack, Ph.D. New York University Institute of Environmental Medicine, 550 First Avenue New York, New York 10016 Search for other works by this author on: Oxford Academic PubMed Google Scholar Roy E. Shore, Ph.D., Roy E. Shore, Ph.D. New York University Institute of Environmental Medicine, 550 First Avenue New York, New York 10016 Search for other works by this author on: Oxford Academic PubMed Google Scholar Norton Nelson, Ph.D. Norton Nelson, Ph.D. New York University Institute of Environmental Medicine, 550 First Avenue New York, New York 10016 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 63, Issue 6, December 1979, Pages 1289–1290, https://doi.org/10.1093/jnci/63.6.1289 Published: 01 December 1979
A compound chimeric antigen receptor strategy for targeting multiple myeloma
Authors: K H Chen, M Wada, K G Pinz, H Liu, X Shuai, X Chen, L E Yan, J C Petrov, H Salman, L Senzel, E L H Leung, X Jiang, Y Ma
Journal: Leukemia (2017)

Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.
A forgotten and hidden disease
Authors: Pugazhenthan Thangaraju, MK Showkath Ali
Journal: BMJ (2017)

A 50 year old man presented to a clinic with a two year history of multiple hypopigmented patches spread over the trunk and all four limbs (fig 1⇓). The patches were variable in size with central clearing; some margins were well defined and some poorly. Hair growth over the lesions was sparse, and he had loss of sensation over some of the patches. The peripheral nerves—ulnar, lateral popliteal, and posterior tibial—were thickened, with mild weakness in the muscles they supplied, but there was no loss of sensation in the hands and feet. A slit-skin smear …
Somatic Superenhancer Duplications and Hotspot Mutations Lead to Oncogenic Activation of the KLF5 Transcription Factor
Authors: Xiaoyang Zhang, Peter S. Choi, Joshua M. Francis, Galen F. Gao, Joshua D. Campbell, Aruna Ramachandran, Yoichiro Mitsuishi, Gavin Ha, Juliann Shih, Francisca Vazquez, Aviad Tsherniak, Alison M. Taylor, Jin Zhou, Zhong Wu, Ashton C. Berger, Marios Giannakis, William C. Hahn, Andrew D. Cherniack, Matthew Meyerson
Journal: Cancer Discovery (2017)

Abstract The Krüppel-like family of transcription factors plays critical roles in human development and is associated with cancer pathogenesis. Krüppel-like factor 5 gene (KLF5) has been shown to promote cancer cell proliferation and tumorigenesis and to be genomically amplified in cancer cells. We recently reported that the KLF5 gene is also subject to other types of somatic coding and noncoding genomic alterations in diverse cancer types. Here, we show that these alterations activate KLF5 by three distinct mechanisms: (i) Focal amplification of superenhancers activates KLF5 expression in squamous cell carcinomas; (ii) Missense mutations disrupt KLF5–FBXW7 interactions to increase KLF5 protein stability in colorectal cancer; (iii) Cancer type–specific hotspot mutations within a zinc-finger DNA binding domain of KLF5 change its DNA binding specificity and reshape cellular transcription. Utilizing data from CRISPR/Cas9 gene knockout screening, we reveal that cancer cells with KLF5 overexpression are dependent on KLF5 for their proliferation, suggesting KLF5 as a putative therapeutic target. Significance: Our observations, together with previous studies that identified oncogenic properties of KLF5, establish the importance of KLF5 activation in human cancers, delineate the varied genomic mechanisms underlying this occurrence, and nominate KLF5 as a putative target for therapeutic intervention in cancer. Cancer Discov; 8(1); 108–25. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1
Key issues surrounding the health impacts of electronic nicotine delivery systems (ENDS) and other sources of nicotine
Authors: Jeffrey Drope, Zachary Cahn, Rosemary Kennedy, Alex C. Liber, Michal Stoklosa, Rosemarie Henson, Clifford E. Douglas, Jacqui Drope
Journal: CA A Cancer Journal for Clinicians (2017)

Abstract Answer questions and earn CME/CNE Over the last decade, the use of electronic nicotine delivery systems (ENDS), including the electronic cigarette or e‐cigarette, has grown rapidly. More youth now use ENDS than any tobacco product. This extensive research review shows that there are scientifically sound, sometimes competing arguments about ENDS that are not immediately and/or completely resolvable. However, the preponderance of the scientific evidence to date suggests that current‐generation ENDS products are demonstrably less harmful than combustible tobacco products such as conventional cigarettes in several key ways, including by generating far lower levels of carcinogens and other toxic compounds than combustible products or those that contain tobacco. To place ENDS in context, the authors begin by reviewing the trends in use of major nicotine‐containing products. Because nicotine is the common core—and highly addictive—constituent across all tobacco products, its toxicology is examined. With its long history as the only nicotine product widely accepted as being relatively safe, nicotine‐replacement therapy (NRT) is also examined. A section is also included that examines snus, the most debated potential harm‐reduction product before ENDS. Between discussions of NRT and snus, ENDS are extensively examined: what they are, knowledge about their level of “harm,” their relationship to smoking cessation, the so‐called gateway effect, and dual use/poly‐use. CA Cancer J Clin 2017;67:449‐471. © 2017 American Cancer Society.
Cannabis Use and Risk of Prescription Opioid Use Disorder in the United States
Authors: Mark Olfson, Melanie M. Wall, Shang-Min Liu, Carlos Blanco
Journal: American Journal of Psychiatry (2017)

Objective: The authors sought to determine whether cannabis use is associated with a change in the risk of incident nonmedical prescription opioid use and opioid use disorder at 3-year follow-up. Method: The authors used logistic regression models to assess prospective associations between cannabis use at wave 1 (2001–2002) and nonmedical prescription opioid use and prescription opioid use disorder at wave 2 (2004–2005) of the National Epidemiologic Survey on Alcohol and Related Conditions. Corresponding analyses were performed among adults with moderate or more severe pain and with nonmedical opioid use at wave 1. Cannabis and prescription opioid use were measured with a structured interview (the Alcohol Use Disorder and Associated Disabilities Interview Schedule–DSM-IV version). Other covariates included age, sex, race/ethnicity, anxiety or mood disorders, family history of drug, alcohol, and behavioral problems, and, in opioid use disorder analyses, nonmedical opioid use. Results: In logistic regression models, cannabis use at wave 1 was associated with increased incident nonmedical prescription opioid use (odds ratio=5.78, 95% CI=4.23–7.90) and opioid use disorder (odds ratio=7.76, 95% CI=4.95–12.16) at wave 2. These associations remained significant after adjustment for background characteristics (nonmedical opioid use: adjusted odds ratio=2.62, 95% CI=1.86–3.69; opioid use disorder: adjusted odds ratio=2.18, 95% CI=1.14–4.14). Among adults with pain at wave 1, cannabis use was also associated with increased incident nonmedical opioid use (adjusted odds ratio=2.99, 95% CI=1.63–5.47) at wave 2; it was also associated with increased incident prescription opioid use disorder, although the association fell short of significance (adjusted odds ratio=2.14, 95% CI=0.95–4.83). Among adults with nonmedical opioid use at wave 1, cannabis use was also associated with an increase in nonmedical opioid use (adjusted odds ratio=3.13, 95% CI=1.19–8.23). Conclusions: Cannabis use appears to increase rather than decrease the risk of developing nonmedical prescription opioid use and opioid use disorder.