tbuckley/cabot-search huggingface dataset:
B-Mode Ultrasonography versus Contrast-Enhanced Ultrasonography for Surveillance of Hepatocellular Carcinoma: A Prospective Multicenter Randomized Controlled Trial
Authors: Masatoshi Kudo, Kazuomi Ueshima, Yukio Osaki, Masashi Hirooka, Yasuharu Imai, Kazunobu Aso, Kazushi Numata, Masayuki Kitano, Takashi Kumada, Namiki Izumi, Yasukiyo Sumino, Chikara Ogawa, Kohei Akazawa
Journal: Liver Cancer (2019)

Current practice guidelines recommend the use of ultrasound (US) as an initial surveillance tool for hepatocellular carcinoma (HCC) in patients with liver cirrhosis. Patients with liver cirrhosis, however, frequently have coarse liver parenchyma, masking the presence of tiny nodules during B-mode US. Contrast-enhanced US (CEUS) with Sonazoid has a long-lasting, stable Kupffer phase, which makes it possible to scan the entire liver to depict small lesions. In addition, defect reperfusion imaging (reinjection imaging) enables to determine whether the detected nodule is HCC or not. This prospective, multicenter, randomized, controlled trial was conducted to demonstrate the usefulness of Kupffer phase surveillance in the detection of small HCC compared to B-mode US.A total of 23 institutions joined this study. In total, 656 patients with hepatitis B- or C-related liver cirrhosis were randomized either to the B-mode US surveillance group (n = 313) or the Kupffer phase CEUS with Sonazoid surveillance group (n = 309). The primary endpoint was the maximum size of HCC at the time of the first detection. Secondary endpoints included time to HCC detection, number of tumors, and Barcelona Clinic Liver Cancer stage at the first detection, and sensitivity, specificity, and accuracy of each method in the diagnosis, and the cumulative detection rate of HCC.The mean HCC size at the first detection was significantly smaller in the CEUS (13.0 ± 4.1 mm; n = 28) than in the B-mode US group (16.7 ± 4.1 mm; n = 26) (p = 0.011). Of the 38 patients with HCV cirrhosis diagnosed with HCC by US alone, mean tumor size at the first detection was significantly smaller in the 20 patients diagnosed by CEUS alone than in the 18 diagnosed by B-mode US alone (12.7 ± 3.1 vs. 17.6 ± 7.0 mm, p = 0.012). In contrast, among the 16 patients with HBV cirrhosis diagnosed by US alone, mean tumor size at the first detection was similar in the 8 patients diagnosed by CEUS alone and the 8 diagnosed by B-mode US (13.6 ± 6.0 vs. 14.5 ± 2.7 mm, p = 0.715).Kupffer phase CEUS surveillance with Sonazoid is extremely useful for the early detection and confirmation of HCC using a reinjection technique. Kupffer phase CEUS with Sonazoid contrast combined with the reinjection technique is, therefore, recommended as first-line screening tool for HCC in patients with liver cirrhosis, especially those with very coarse liver parenchyma.
Identification and Application of Gene Expression Signatures Associated with Lifespan Extension
Authors: Alexander Tyshkovskiy, Perinur Bozaykut, Anastasia A. Borodinova, Maxim V. Gerashchenko, Gene P. Ables, Michael Garratt, Philipp Khaitovich, Clary B. Clish, Richard A. Miller, Vadim N. Gladyshev
Journal: Cell Metabolism (2019)
Nonsteroidal Antiinflammatory Drugs
Authors: Jan Koch-Weser, Lee S. Simon, John A. Mills
Journal: New England Journal of Medicine (1980)

New Nonsteroidal Antiinflammatory DrugsWithin the past 10 years, a number of new NSAID's have become available in the United States. Most are representatives of two groups of compounds, the indoles, of which the prototype is indomethacin, and the phenylpropionates. Other chemical classes that have antiinflammatory properties but have not been widely exploited clinically include the pyrazolones, represented by phenylbutazone and its metabolite oxyphenylbutazone, the quinazolones, imidazoles, and phenothiazines. Several anthranilic acid derivatives, the fenamates, have been available in Europe for almost a decade but have not achieved an important status. The inhibition of prostaglandin biosynthesis appears to be a . . .
The ORMDL3 asthma susceptibility gene regulates systemic ceramide levels without altering key asthma features in mice
Authors: Nincy Debeuf, Assem Zhakupova, Regula Steiner, Sofie Van Gassen, Kim Deswarte, Farzaneh Fayazpour, Justine Van Moorleghem, Karl Vergote, Benjamin Pavie, Kelly Lemeire, Hamida Hammad, Thorsten Hornemann, Sophie Janssens, Bart N. Lambrecht
Journal: Journal of Allergy and Clinical Immunology (2019)
Optimization of CSF biological investigations for CNS lymphoma diagnosis
Authors: Marine Armand, Myrto Costopoulos, Jennifer Osman, Sihem Tarfi, Caroline Houillier, Sylvain Choquet, Hervé Agnelo, Patrick Bonnemye, Emily Ronez, Catherine Settegrana, Carole Soussain, Khê Hoang‐Xuan, Magali Le Garff‐Tavernier, Frédéric Davi
Journal: American Journal of Hematology (2019)

Diagnosis of lymphoma leptomeningeal dissemination is challenging and relies on a wide array of methods. So far, no consensus biological guidelines are available. This increases the chance of intra- and interpractice variations, despite the shared concern to perform the minimum amount of tests while preserving clinically relevant results.We evaluated a training cohort of 371 cerebrospinal fluid (CSF) samples from patients with putative lymphomatous central nervous system (CNS) localization using conventional cytology (CC), flow cytometry (FCM), molecular clonality assesment by PCR and cytokine quantification (CQ). This led us to propose a biological algorithm, which was then verified on a validation cohort of 197 samples. The samples were classified according to the clinical context and the results of each technique were compared. Using all four techniques was not useful for exclusion diagnosis of CNS lymphoma (CNSL), but they proved complementary for cases with suspected CNSL. This was particularly true for CQ in primary CNSL. Overall, diagnosis can be obtained with a two-step approach. The first step comprises CC and FCM, as results are available quickly and FCM is a sensitive method. Both PCR and CQ can be postponed and performed in a second step, depending on the results from the first step and the clinical context.The proposed algorithm missed none of the CNSL samples of the validation cohort. Moreover, applying this algorithm would have spared 30% of PCR tests and 20% of CQ over a one-year period, without compromising clinical management.
Using What We Already Have: Uncovering New Drug Repurposing Strategies in Existing Omics Data
Authors: Jill M. Pulley, Jillian P. Rhoads, Rebecca N. Jerome, Anup P. Challa, Kevin B. Erreger, Meghan M. Joly, Robert R. Lavieri, Kelly E. Perry, Nicole M. Zaleski, Jana K. Shirey-Rice, David M. Aronoff
Journal: The Annual Review of Pharmacology and Toxicology (2019)

The promise of drug repurposing is to accelerate the translation of knowledge to treatment of human disease, bypassing common challenges associated with drug development to be more time- and cost-efficient. Repurposing has an increased chance of success due to the previous validation of drug safety and allows for the incorporation of omics. Hypothesis-generating omics processes inform drug repurposing decision-making methods on drug efficacy and toxicity. This review summarizes drug repurposing strategies and methodologies in the context of the following omics fields: genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiomics, phenomics, pregomics, and personomics. While each omics field has specific strengths and limitations, incorporating omics into the drug repurposing landscape is integral to its success.
Molecular Mass‐Dependent Resorption and Bone Regeneration of 3D Printed PPF Scaffolds in a Critical‐Sized Rat Cranial Defect Model
Authors: Karissa Nettleton, Derek Luong, Alex P. Kleinfehn, Laura Savariau, Christopher Premanandan, Matthew L. Becker
Journal: Advanced Healthcare Materials (2019)

Abstract The emergence of additive manufacturing has afforded the ability to fabricate intricate, high resolution, and patient‐specific polymeric implants. However, the availability of biocompatible resins with tunable resorption profiles remains a significant hurdle to clinical translation. In this study, 3D scaffolds are fabricated via stereolithographic cDLP printing of poly(propylene fumarate) (PPF) and assessed for bone regeneration in a rat critical‐sized cranial defect model. Scaffolds are printed with two different molecular mass resin formulations (1000 and 1900 Da) with narrow molecular mass distributions and implanted to determine if these polymer characteristics influence scaffold resorption and bone regeneration in vivo. X‐ray microcomputed tomography (µ‐CT) data reveal that at 4 weeks the lower molecular mass polymer degrades faster than the higher molecular mass PPF and thus more new bone is able to infiltrate the defect. However, at 12 weeks, the regenerated bone volume of the 1900 Da formulation is nearly equivalent to the lower molecular mass 1000 Da formulation. Significantly, lamellar bone bridges the defect at 12 weeks with both PPF formulations and there is no indication of an acute inflammatory response.
Readability of websites containing information about prostate cancer treatment options.
Authors: Chandy Ellimoottil, Anthony Polcari, Adam Kadlec, Gopal Nand Gupta
Journal: Journal of Clinical Oncology (2012)

e16544 Background: 90 million adults have literacy skills that test below a high school reading level. Websites written above this level can pose a challenge for those seeking more information about prostate cancer treatment options. In this study, we determine the readability of selected websites, using a systematic search process and validated readability formulas. Methods: We identified the three most popular keywords (“prostate cancer,” “prostatectomy,” and “prostate cancer treatment”) from 513 terms related to prostate cancer treatment options. Three physician searchers (CE, AP, AK) systematically collected 270 websites from the top three search engines, representing 95 % of all internet searches (Google, Yahoo, and Bing). We excluded sites that were non-English, not primarily text, irrelevant and/or duplicated, and then categorized the remaining sites by source (government, academic practice, nonacademic practice, commercial, nonprofit, news, health website, other) and treatment type. We used validated readability instruments, the Flesch-Kincaid (FK) grade level and Flesch reading ease, to calculate scores for each site. We also calculated an intraclass correlation coefficient, in order to assess inter-rater agreement among our three searchers. Results: Sixty-two unique websites were available for analysis. The mean FK grade level of all sites was 11.4 (SD +/- 0.95, range 8.0-12.0), indicating that on average, passages were written at an eleventh grade reading level. The mean Flesch reading ease score on all sites was 35.6 (SD +/- 15.7, range 0.0-65.5), indicating that on average, passages were slightly easier to read than passages more suited for university graduates (0-30). Only three sites (4.8%) were written below a high school reading level (&lt; 9.0). The intraclass correlation coefficient between the three searchers was 0.96 for grade level and 0.97 for reading ease. Conclusions: Few websites with discussions on prostate cancer treatment options are written below a high school reading level. This is problematic for patients with a low literacy level who search online for more information. Clinicans should be aware of this finding and guide patients to websites written at their patient's reading level.
Endothelial Foxp1 Suppresses Atherosclerosis via Modulation of Nlrp3 Inflammasome Activation
Authors: Tao Zhuang, Jie Liu, Xiaoli Chen, Lin Zhang, Jingjiang Pi, Huimin Sun, Li Li, Robert Bauer, Haikun Wang, Zuoren Yu, Qi Zhang, Brian Tomlinson, Paul Chan, Xiangjian Zheng, Edward Morrisey, Zhongmin Liu, Muredach Reilly, Yuzhen Zhang
Journal: Circulation Research (2019)

Rationale: Endothelial dysfunction results in sustained and chronic vascular inflammation, which is central to atherosclerotic diseases. However, transcriptional regulation of vascular endothelial inflammation has not been well clarified. Objective: This study aims to explore Foxp (forkhead box P) transcription factor 1 in regulation of endothelial homeostasis, atherogenesis, and its mechanisms. Methods and Results: To assess the importance of Foxp1 in atherosclerosis, Foxp1 expression was analyzed in human coronary artery and mouse artery, and we observed significant downregulation of Foxp1 in atherosclerotic and atherosusceptible endothelium. Endothelial-specific Foxp1 knockout mice ( Foxp1 ECKO ) were bred onto Apoe KO mice to generate endothelial Foxp1-deletion hyperlipidemic model Foxp1 ECKO ;Apoe KO , which displayed significant increases in atherosclerotic lesion formation in aortas and aortic roots with enhanced monocyte adhesion, migration, and infiltration into the vascular wall and formation of inflammatory lipid-laden macrophages. In contrast, endothelial-specific Foxp1 overexpression mice Foxp1 ECTg ;Apoe KO exhibited reduced atherosclerotic lesion formation with less monocyte infiltration. Foxp1 was further identified as a gatekeeper of vessel inflammation by direct regulation of endothelial inflammasome components, including Nlrp3 (NLR [nucleotide-binding and leucine-rich repeat immune receptors] family pyrin domain containing 3), caspase-1, and IL (interleukin)-1β. Moreover, endothelial Foxp1 was found to be regulated by Klf2 (Kruppel-like factor 2). Oscillatory shear stress downregulated Foxp1 expression via repressing Klf2 expression in endothelium, and, therefore, promoted endothelial inflammasome activation, leading to atherosclerotic lesion formation. Simvastatin upregulated the reduced expression of Klf2 and Foxp1 in atherosusceptible vascular endothelium and alleviated vascular inflammation contributing to its inhibitory effect in atherosclerosis. Conclusions: These data are the first in vivo experimental validation of an atheroprotective role of endothelial Klf2 and Foxp1, which reveals a Klf2-Foxp1 transcriptional network in endothelial cells as a novel regulator of endothelial inflammasome activation for atherogenesis, therefore, provides opportunities for therapeutic intervention of atherosclerotic diseases and uncovers a novel atheroprotective mechanism for simvastatin.
IL6 Promotes a STAT3-PRL3 Feedforward Loop via SHP2 Repression in Multiple Myeloma
Authors: Phyllis S.Y. Chong, Jianbiao Zhou, Julia S.L. Lim, Yan Ting Hee, Jing-Yuan Chooi, Tae-Hoon Chung, Zea Tuan Tan, Qi Zeng, Daniel D. Waller, Michael Sebag, Wee-Joo Chng
Journal: Cancer Research (2019)

Overexpression of PRL-3, an oncogenic phosphatase, was identified as a novel cluster in patients with newly diagnosed multiple myeloma. However, the regulation and oncogenic activities of PRL-3 in multiple myeloma warrant further investigation. Here, we report that IL6 activates STAT3, which acts as a direct transcriptional regulator of PRL-3. Upregulation of PRL-3 increased myeloma cell viability and rephosphorylated STAT3 in a biphasic manner through direct interaction and deactivation of SHP2, thus blocking the gp130 (Y759)-mediated repression of STAT3 activity. Abrogation of PRL-3 reduced myeloma cell survival, clonogenicity, and tumorigenesis, and detailed mechanistic studies revealed "deactivation" of effector proteins such as Akt, Erk1/2, Src, STAT1, and STAT3. Furthermore, loss of PRL-3 efficiently abolished nuclear localization of STAT3 and reduced its occupancy on the promoter of target genes c-Myc and Mcl-1, and antiapoptotic genes Bcl2 and Bcl-xL. PRL-3 also played a role in the acquired resistance of myeloma cells to bortezomib, which could be overcome by PRL-3 silencing. Of clinical relevance, STAT3 and PRL-3 expression was positively correlated in five independent cohorts, and the STAT3 activation signature was significantly enriched in patients with high PRL-3 expression. Furthermore, PRL-3 could be used as a biomarker to identify high-risk patients with multiple myeloma that exhibited poor prognosis and inferior outcome even when treated with novel combinational therapeutics (proteasome inhibitors and immunomodulatory imide drugs). Conclusively, our results support a feedforward mechanism between STAT3 and PRL-3 that prolongs prosurvival signaling in multiple myeloma, and suggest targeting PRL-3 as a valid therapeutic opportunity in multiple myeloma. SIGNIFICANCE: IL6 promotes STAT3-dependent transcriptional upregulation of PRL-3, which in turn re-phosphorylates STAT3 and aberrantly activates STAT3 target genes, leading to bortezomib resistance in multiple myeloma.
Association of <i>APOL1</i> Risk Alleles With Cardiovascular Disease in Blacks in the Million Veteran Program
Authors: Alexander G. Bick, Elvis Akwo, Cassianne Robinson-Cohen, Kyung Lee, Julie Lynch, Themistocles L. Assimes, Scott DuVall, Todd Edwards, Huaying Fang, S. Matthew Freiberg, Ayush Giri, Jennifer E. Huffman, Jie Huang, Leland Hull, Rachel L. Kember, Derek Klarin, Jennifer S. Lee, Michael Levin, Donald R. Miller, Pradeep Natarajan, Danish Saleheen, Qing Shao, Yan V. Sun, Hua Tang, Otis Wilson, Kyong-Mi Chang, Kelly Cho, John Concato, J. Michael Gaziano, Sekar Kathiresan, Christopher J. O’Donnell, Daniel J. Rader, Philip S. Tsao, Peter W. Wilson, Adriana M. Hung, Scott M. Damrauer
Journal: Circulation (2019)

Background: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 ( APOL1 ) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. Methods: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. Results: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01–1.21]; P =0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05–1.36; P =0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01–1.29l; P =0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. Conclusions: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.
Staging Cardiac Damage in Patients With Symptomatic Aortic Valve Stenosis
Authors: E. Mara Vollema, Mohammed R. Amanullah, Arnold C.T. Ng, Pieter van der Bijl, Francesca Prevedello, Yoong Kong Sin, Edgard A. Prihadi, Nina Ajmone Marsan, Zee Pin Ding, Philippe Généreux, Philippe Pibarot, Martin B. Leon, Jagat Narula, See Hooi Ewe, Victoria Delgado, Jeroen J. Bax
Journal: Journal of the American College of Cardiology (2019)
The effect of smoking history on survival outcome: An exploratory analysis of a phase III study of gemcitabine and cisplatin in patients with advanced non-small cell lung cancer (NSCLC)
Authors: B. Nguyen, S. Paul, K. Posther, A. Sandler
Journal: Journal of Clinical Oncology (2006)

7141 Background: Exploratory analyses of data from phase II and phase III NSCLC studies of epidermal growth factor receptor (EGFR) inhibitors have shown that smoking history (specifically never smokers) is associated with positive clinical outcomes, indicating increased sensitivity to these agents. A phase III trial in chemonaïve patients (pts) with advanced NSCLC demonstrated that the regimen of gemcitabine-cisplatin is superior to cisplatin alone in terms of response rate, time to disease progression, and overall survival [JCO 2000;18:122–30]. We analyzed data from this trial to examine the effect of smoking history on survival outcome. Methods: All pts entered in the study were combined (524 pts) in a subgroup analysis conducted to evaluate the effect of smoking history (smokers vs non-smokers at baseline; number of never smokers unknown) on survival. In addition, 220 pts with a history of smoking were grouped by the total number of pack-years (pk-yrs) smoked (≤37.5 vs &gt;37.5 pk-yrs), and each group was analyzed with regard to survival relative to the group’s median number of pk-yrs. Results: There was no significant difference in median survival time between smokers (n = 220) and non-smokers (n = 304) (8.5 vs 8.1 months, respectively; hazard ratio [HR]: 0.97 [95% CI: 0.81–1.17]; p-value = 0.739). Although the 112 pts who smoked ≤37.5 pk-yrs had a median of 22.5 pk-yrs and the 108 pts who smoked &gt;37.5 pk-yrs had a median of 55.5 pk-yrs, there was no significant difference in median survival time between the groups (9.2 vs 8.5 months, respectively; HR: 1.00 [95% CI: 0.75–1.34]; p-value = 0.9897). Conclusions: In pts with advanced NSCLC, analyses of survival outcomes for chemotherapy with the combination of gemcitabine-cisplatin or cisplatin indicate that survival is independent of smoking history (smokers vs non-smokers at baseline), unlike targeted therapies, such as EGFR inhibitors for which smoking history (specifically never smokers) is a clinical predictor of the sensitivity of these agents and of survival. [Table: see text]