tbuckley/cabot-search huggingface dataset:
Abstract 16935: Increased Adherence to Guideline-Recommended Therapy is Associated With Decreased Major Adverse Cardiovascular Events and Major Adverse Limb Events Among Patients With Claudication or Critical Limb Ischemia
Authors: Debbie C Chen, Ehrin J Armstrong, Gregory G Westin, Satinder Singh, Khung-Keong Yeo, David Anderson, Ezra A Amsterdam, John R Laird
Journal: Circulation (2013)

Introduction: Treatment guidelines recommend that patients with peripheral arterial disease (PAD) cease smoking and be treated with aspirin, statins, and angiotensin-converting enzyme inhibitors (ACEI). The additive effects of multiple guideline-recommended therapies in symptomatic PAD patients have not been well characterized. Hypothesis: We hypothesized that increased adherence to guideline-recommended therapies for patients with claudication or critical limb ischemia (CLI) undergoing angiography is associated with reduced subsequent major adverse cardiovascular and cerebrovascular events (MACCE: myocardial infarction, stroke, death) and major adverse limb events (MALE: major amputation or surgical bypass). Methods: We analyzed a comprehensive database of all patients with claudication or CLI who underwent diagnostic or interventional lower extremity angiography between 2006 and 2013 at a single vascular center. Baseline demographics, clinical data, and long-term outcomes were obtained. Kaplan-Meier ana...
Abstract A36: Establishment of patient-derived xenograft models of lung adenocarcinoma with two different EGFR mutations, L858R and exon19 deletion
Authors: Kenji Kita, Koji Fukuda, Akihiro Nishiyama, Sachiko Arai, Shinji Takeuchi, Koushiro Ohtsubo, Kaname Yamashita, Masaya Tamura, Isao Matsumoto, Seiji Yano
Journal: Clinical Cancer Research (2018)

Abstract Preclinical tumor models that resemble the characteristics of patients’ tumors are essential for development of novel therapy. Patient-derived tumor xenograft (PDX) models are considered to be interesting candidates. However, success rate of PDX models of lung cancer, especially adenocarcinoma, is much lower than that of other types of tumors, including colon cancer. This study was conducted to establish clinically relevant PDX models of lung cancer. We obtained fresh surgically resected specimens from 20 NSCLC patients (10 squamous cell carcinomas, 9 adenocarcinomas, and 1 large cell carcinoma) who had submitted the written informed consent for this study, which was performed in accordance with protocols approved by the IRB of Kanazawa University. We inoculated the tumor fragments subcutaneously into immunodeficient mice, NOG mice or SCID hairless outbred (SHO) mice. The tumor take rate was 40% (8/20), with higher rates for squamous cell carcinoma (60%, 6/10) than for adenocarcinoma (22%, 2/9). Interestingly, both of two adenocarcinomas that successfully developed PDX tumors had EGFR mutations, L858R and exon 19 deletion, respectively. These PDX tumors maintained histology of adenocarcinoma and EGFR mutation even after repeated in vivo passages. Furthermore, the third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) osimertinib dramatically regressed tumors in these EGFR mutated PDX models. Osimertinib treatment is ongoing in these EGFR-mutated PDX models to obtain tumors that acquired resistance to osimertinib. Our PDX models of lung adenocarcinoma with different EGFR mutations may be useful for investigating the mechanisms of resistance to EGFR-TKIs, including third-generation inhibitor osimertinib. Citation Format: Kenji Kita, Koji Fukuda, Akihiro Nishiyama, Sachiko Arai, Shinji Takeuchi, Koushiro Ohtsubo, Kaname Yamashita, Masaya Tamura, Isao Matsumoto, Seiji Yano. Establishment of patient-derived xenograft models of lung adenocarcinoma with two different EGFR mutations, L858R and exon19 deletion [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A36.
HER2-positive breast cancer resistance to trastuzumab is associated with metabolic switch
Authors: R. Dubianski, E. Sarnowska, M. Leszczynski, S. Kubala, W. Olszewski, N. Rusetska, A.I. Jagiello-Gruszfeld, R. Konopinski, T.J. Sarnowski, J.A. Siedlecki, Z.I. Nowecki
Journal: Annals of Oncology (2018)
Combined Structural and Functional Imaging of the Kidney Reveals Major Axial Differences in Proximal Tubule Endocytosis
Authors: Claus D. Schuh, Marcello Polesel, Evgenia Platonova, Dominik Haenni, Alkaly Gassama, Natsuko Tokonami, Susan Ghazi, Milica Bugarski, Olivier Devuyst, Urs Ziegler, Andrew M. Hall
Journal: Journal of the American Society of Nephrology (2018)

Background The kidney proximal convoluted tubule (PCT) reabsorbs filtered macromolecules via receptor-mediated endocytosis (RME) or nonspecific fluid phase endocytosis (FPE); endocytosis is also an entry route for disease-causing toxins. PCT cells express the protein ligand receptor megalin and have a highly developed endolysosomal system (ELS). Two PCT segments (S1 and S2) display subtle differences in cellular ultrastructure; whether these translate into differences in endocytotic function has been unknown. Methods To investigate potential differences in endocytic function in S1 and S2, we quantified ELS protein expression in mouse kidney PCTs using real-time quantitative polymerase chain reaction and immunostaining. We also used multiphoton microscopy to visualize uptake of fluorescently labeled ligands in both living animals and tissue cleared using a modified CLARITY approach. Results Uptake of proteins by RME occurs almost exclusively in S1. In contrast, dextran uptake by FPE takes place in both S1 and S2, suggesting that RME and FPE are discrete processes. Expression of key ELS proteins, but not megalin, showed a bimodal distribution; levels were far higher in S1, where intracellular distribution was also more polarized. Tissue clearing permitted imaging of ligand uptake at single-organelle resolution in large sections of kidney cortex. Analysis of segmented tubules confirmed that, compared with protein uptake, dextran uptake occurred over a much greater length of the PCT, although individual PCTs show marked heterogeneity in solute uptake length and three-dimensional morphology. Conclusions Striking axial differences in ligand uptake and ELS function exist along the PCT, independent of megalin expression. These differences have important implications for understanding topographic patterns of kidney diseases and the origins of proteinuria.
Adult rhabdomyosarcoma with bleeding tendency as an initial clinical manifestation
Authors: Hideko Goto, Yuto Kaneda, Kimihiro Yamaguchi, Yuhei Shibata, Naoki Watanabe, Naoe Goto, Senji Kasahara, Naoki Katsumura, Takuji Tanaka, Takeshi Takahashi, Hisashi Tsurumi
Journal: Annals of Oncology (2018)
Phase II trial of tepotinib vs sorafenib in Asian patients (pts) with advanced hepatocellular carcinoma (HCC)
Authors: B.-Y. Ryoo, Z. Ren, T.-Y. Kim, H. Pan, K.-M. Rau, H.J. Choi, J.-W. Park, J.H. Kim, C.-J. Yen, B.-H. Kim, D. Zhou, J. Straub, C. Zhao, S. Qin
Journal: Annals of Oncology (2018)
Effect of Cricoid Pressure Compared With a Sham Procedure in the Rapid Sequence Induction of Anesthesia
Authors: Aurélie Birenbaum, David Hajage, Sabine Roche, Alexandre Ntouba, Mathilde Eurin, Philippe Cuvillon, Aurélien Rohn, Vincent Compere, Dan Benhamou, Matthieu Biais, Remi Menut, Sabiha Benachi, François Lenfant, Bruno Riou
Journal: JAMA Surgery (2018)

The use of cricoid pressure (Sellick maneuver) during rapid sequence induction (RSI) of anesthesia remains controversial in the absence of a large randomized trial.To test the hypothesis that the incidence of pulmonary aspiration is not increased when cricoid pressure is not performed.Randomized, double-blind, noninferiority trial conducted in 10 academic centers. Patients undergoing anesthesia with RSI were enrolled from February 2014 until February 2017 and followed up for 28 days or until hospital discharge (last follow-up, February 8, 2017).Patients were assigned to a cricoid pressure (Sellick group) or a sham procedure group.Primary end point was the incidence of pulmonary aspiration (at the glottis level during laryngoscopy or by tracheal aspiration after intubation). It was hypothesized that the sham procedure would not be inferior to the cricoid pressure. The secondary end points were related to pulmonary aspiration, difficult tracheal intubation, and traumatic complications owing to the tracheal intubation or cricoid pressure.Of 3472 patients randomized, mean (SD) age was 51 (19) years and 1777 (51%) were men. The primary end point, pulmonary aspiration, occurred in 10 patients (0.6%) in the Sellick group and in 9 patients (0.5%) in the sham group. The upper limit of the 1-sided 95% CI of relative risk was 2.00, exceeding 1.50, failing to demonstrate noninferiority (P = .14). The risk difference was -0.06% (2-sided 95% CI, -0.57 to 0.42) in the intent-to-treat population and -0.06% (2-sided 95% CI, -0.56 to 0.43) in the per protocol population. Secondary end points were not significantly different among the 2 groups (pneumonia, length of stay, and mortality), although the comparison of the Cormack and Lehane grade (Grades 3 and 4, 10% vs 5%; P <.001) and the longer intubation time (Intubation time >30 seconds, 47% vs 40%; P <.001) suggest an increased difficulty of tracheal intubation in the Sellick group.This large randomized clinical trial performed in patients undergoing anesthesia with RSI failed to demonstrate the noninferiority of the sham procedure in preventing pulmonary aspiration. Further studies are required in pregnant women and outside the operating room.ClinicalTrials.gov Identifier: NCT02080754.
Annotating Transcriptional Effects of Genetic Variants in Disease‐Relevant Tissue: Transcriptome‐Wide Allelic Imbalance in Osteoarthritic Cartilage
Authors: Wouter den Hollander, Irina Pulyakhina, Cindy Boer, Nils Bomer, Ruud van der Breggen, Wibowo Arindrarto, Rodrigo Couthino de Almeida, Nico Lakenberg, Thom Sentner, Jeroen F. J. Laros, Peter A. C. ‘t Hoen, Eline P. E. Slagboom, Rob G. H. H. Nelissen, Joyce van Meurs, Yolande F. M. Ramos, Ingrid Meulenbelt
Journal: Arthritis & Rheumatology (2018)

Objective Multiple single‐nucleotide polymorphisms ( SNP s) conferring susceptibility to osteoarthritis ( OA ) mark imbalanced expression of positional genes in articular cartilage, reflected by unequally expressed alleles among heterozygotes (allelic imbalance [ AI ]). We undertook this study to explore the articular cartilage transcriptome from OA patients for AI events to identify putative disease‐driving genetic variation. Methods AI was assessed in 42 preserved and 5 lesioned OA cartilage samples (from the Research Arthritis and Articular Cartilage study) for which RNA sequencing data were available. The count fraction of the alternative alleles among the alternative and reference alleles together ( φ ) was determined for heterozygous individuals. A meta‐analysis was performed to generate a meta‐ φ and P value for each SNP with a false discovery rate ( FDR ) correction for multiple comparisons. To further validate AI events, we explored them as a function of multiple additional OA features. Results We observed a total of 2,070 SNP s that consistently marked AI of 1,031 unique genes in articular cartilage. Of these genes, 49 were found to be significantly differentially expressed (fold change &lt;0.5 or &gt;2, FDR &lt;0.05) between preserved and paired lesioned cartilage, and 18 had previously been reported to confer susceptibility to OA and/or related phenotypes. Moreover, we identified notable highly significant AI SNP s in the CRLF 1 , WWP 2 , and RPS 3 genes that were related to multiple OA features. Conclusion We present a framework and resulting data set for researchers in the OA research field to probe for disease‐relevant genetic variation that affects gene expression in pivotal disease‐affected tissue. This likely includes putative novel compelling OA risk genes such as CRLF 1 , WWP 2 , and RPS 3 .
Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial
Authors: M. Gross-Goupil, T.G. Kwon, M. Eto, D. Ye, H. Miyake, S.I. Seo, S.-S. Byun, J.L. Lee, V. Master, J. Jin, R. DeBenedetto, R. Linke, M. Casey, B. Rosbrook, M. Lechuga, O. Valota, E. Grande, D.I. Quinn
Journal: Annals of Oncology (2018)

The ATLAS trial compared axitinib versus placebo in patients with locoregional renal cell carcinoma (RCC) at risk of recurrence after nephrectomy.In a phase III, randomized, double-blind trial, patients had >50% clear-cell RCC, had undergone nephrectomy, and had no evidence of macroscopic residual or metastatic disease [independent review committee (IRC) confirmed]. The intent-to-treat population included all randomized patients [≥pT2 and/or N+, any Fuhrman grade (FG), Eastern Cooperative Oncology Group status 0/1]. Patients (stratified by risk group/country) received (1 : 1) oral twice-daily axitinib 5 mg or placebo for ≤3 years, with a 1-year minimum unless recurrence, occurrence of second primary malignancy, significant toxicity, or consent withdrawal. The primary end point was disease-free survival (DFS) per IRC. A prespecified DFS analysis in the highest-risk subpopulation (pT3, FG ≥ 3 or pT4 and/or N+, any T, any FG) was conducted.A total of 724 patients (363 versus 361, axitinib versus placebo) were randomized from 8 May 2012, to 1 July 2016. The trial was stopped due to futility at a preplanned interim analysis at 203 DFS events. There was no significant difference in DFS per IRC [hazard ratio (HR) = 0.870; 95% confidence interval (CI) : 0.660-1.147; P = 0.3211). In the highest-risk subpopulation, a 36% and 27% reduction in risk of a DFS event (HR; 95% CI) was observed per investigator (0.641; 0.468-0.879; P = 0.0051), and by IRC (0.735; 0.525-1.028; P = 0.0704), respectively. Overall survival data were not mature. Similar adverse events (AEs; 99% versus 92%) and serious AEs (19% versus 14%), but more grade 3/4 AEs (61% versus 30%) were reported for axitinib versus placebo.ATLAS did not meet its primary end point; however, improvement in DFS per investigator was seen in the highest-risk subpopulation. No new safety signals were reported.NCT01599754.
Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active psoriatic arthritis (EQUATOR): results from a randomised, placebo-controlled, phase 2 trial
Authors: Philip Mease, Laura C Coates, Philip S Helliwell, Mykola Stanislavchuk, Anna Rychlewska-Hanczewska, Anna Dudek, Walid Abi-Saab, Chantal Tasset, Luc Meuleners, Pille Harrison, Robin Besuyen, Annegret Van der Aa, Neelufar Mozaffarian, Joy M Greer, Rebecca Kunder, Filip Van den Bosch, Dafna D Gladman
Journal: The Lancet (2018)
mTOR inhibitors in uterine and extra-uterine malignant PEComas: A multicenter international case series retrospective analysis
Authors: R. Sanfilippo, R.L. Jones, S. Provenzano, G. Antoniou, J.-Y. Blay, E. Fumagalli, S. Stacchiotti, R.M. Bertulli, O. Mir, N. Hindi, M. Brahmi, A. Dufresne, A.P. Dei Tos, P.G. Casali
Journal: Annals of Oncology (2018)
Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions
Authors: Roger Bouillon, Claudio Marcocci, Geert Carmeliet, Daniel Bikle, John H White, Bess Dawson-Hughes, Paul Lips, Craig F Munns, Marise Lazaretti-Castro, Andrea Giustina, John Bilezikian
Journal: Endocrine Reviews (2018)

Abstract The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D &lt;50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D–deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.
Inflammatory signals directly instruct PU.1 in HSCs via TNF
Authors: Martin Etzrodt, Nouraiz Ahmed, Philipp S. Hoppe, Dirk Loeffler, Stavroula Skylaki, Oliver Hilsenbeck, Konstantinos D. Kokkaliaris, Hans-Michael Kaltenbach, Jörg Stelling, Claus Nerlov, Timm Schroeder
Journal: Blood (2018)
Renal COP9 Signalosome Deficiency Alters CUL3-KLHL3-WNK Signaling Pathway
Authors: Ryan J. Cornelius, Jinge Si, Catherina A. Cuevas, Jonathan W. Nelson, Brittany D.K. Gratreak, Ruggero Pardi, Chao-Ling Yang, David H. Ellison
Journal: Journal of the American Society of Nephrology (2018)

Background The familial hyperkalemic hypertension (FHHt) cullin 3 (CUL3) mutant does not degrade WNK kinases normally, thereby leading to thiazide-sensitive Na-Cl cotransporter (NCC) activation. CUL3 mutant (CUL3 Δ 9) does not bind normally to the COP9 signalosome (CSN), a deneddylase involved in regulating cullin-RING ligases. CUL3 Δ 9 also caused increased degradation of the CUL3-WNK substrate adaptor kelch-like 3 (KLHL3). Here, we sought to determine how defective CSN action contributes to the CUL3 Δ 9 phenotype. Methods The Pax8/LC1 mouse system was used to generate mice in which the catalytically active CSN subunit, Jab1 , was deleted only along the nephron, after full development (KS- Jab1 −/− ). Results Western blot analysis demonstrated that Jab1 deletion increased the abundance of neddylated CUL3. Moreover, total CUL3 expression was reduced, suggesting decreased CUL3 stability. KLHL3 was almost completely absent in KS- Jab1 −/− mice. Conversely, the protein abundances of WNK1, WNK4, and SPAK kinases were substantially higher. Activation of WNK4, SPAK, and OSR1 was indicated by higher phosphorylated protein levels and translocation of the proteins into puncta, as observed by immunofluorescence. The ratio of phosphorylated NCC to total NCC was also higher. Surprisingly, NCC protein abundance was low, likely contributing to hypokalemia and Na + and K + wasting. Additionally, long-term Jab1 deletion resulted in kidney damage. Conclusions Together, the results indicate that deficient CSN binding contributes importantly to the FHHt phenotype. Although defective CUL3 Δ 9-faciliated WNK4 degradation likely contributes, dominant effects on KLHL3 may be a second factor that is necessary for the phenotype.
Risk of Thromboembolism Associated With Atrial Fibrillation Following Noncardiac Surgery
Authors: Jawad H. Butt, Jonas B. Olesen, Eva Havers-Borgersen, Anna Gundlund, Charlotte Andersson, Gunnar H. Gislason, Christian Torp-Pedersen, Lars Køber, Emil L. Fosbøl
Journal: Journal of the American College of Cardiology (2018)
Economic Costs Attributable to Diabetes in Each U.S. State
Authors: Sundar S. Shrestha, Amanda A. Honeycutt, Wenya Yang, Ping Zhang, Olga A. Khavjou, Diana C. Poehler, Simon J. Neuwahl, Thomas J. Hoerger
Journal: Diabetes Care (2018)

OBJECTIVE To estimate direct medical and indirect costs attributable to diabetes in each U.S. state in total and per person with diabetes. RESEARCH DESIGN AND METHODS We used an attributable fraction approach to estimate direct medical costs using data from the 2013 State Health Expenditure Accounts, 2013 Behavioral Risk Factor Surveillance System, and the Centers for Medicare &amp; Medicaid Services’ 2013–2014 Minimum Data Set. We used a human capital approach to estimate indirect costs measured by lost productivity from morbidity (absenteeism, presenteeism, lost household productivity, and inability to work) and premature mortality, using the 2008–2013 National Health Interview Survey, 2013 daily housework value data, 2013 mortality data from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research, and mean wages from the 2014 Bureau of Labor Statistics. Costs were adjusted to 2017 U.S. dollars. RESULTS The estimated median state economic cost was $5.9 billion, ranging from $694 million to $55.5 billion, in total and $18,248, ranging from $15,418 to $30,915, per person with diabetes. The corresponding estimates for direct medical costs were $2.8 billion (range $0.3–22.9) and $8,544 (range $6,591–12,953) and for indirect costs were $3.0 billion (range $0.4–32.6) and $9,672 (range $7,133–17,962). In general, the estimated state median indirect costs resulting from morbidity were larger than costs from mortality both in total and per person with diabetes. CONCLUSIONS Economic costs attributable to diabetes were large and varied widely across states. Our comprehensive state-specific estimates provide essential information needed by state policymakers to monitor the economic burden of the disease and to better plan and evaluate interventions for preventing type 2 diabetes and managing diabetes in their states.
An unusual hemoglobinopathy: compound heterozygosity for hemoglobins C and E
Authors: Michael Spencer Chapman, Kripesh Kiritkumar, Kirstin Lund, Barbara J. Bain
Journal: American Journal of Hematology (2018)

Her blood film (images) showed frequent target cells, moderate numbers of irregularly contracted cells (reflected in the increased MCHC), and moderate numbers of knizocytes (“pinched” or “scraped” cells—cells with two indentations). High performance liquid chromatography (HPLC) revealed peaks in the hemoglobin C (59.7%), hemoglobin F (2.5%), and hemoglobins A2/E (32.9%) windows, together with minor peaks indicating glycated and other post-translationally modified components. Acid and alkaline electrophoresis confirmed that the peak in the A2 window was primarily hemoglobin E. The patient was diagnosed with compound heterozygosity for hemoglobins C and E. The low percentage of hemoglobin E reflects the fact that the βE globin chain is synthesized at a reduced rate, hemoglobin E being a thalassemic hemoglobinopathy. Hemoglobin E and hemoglobin C are found in geographically distinct regions: hemoglobin E occurs among people of Southeast Asian, Northeast Indian, Sri Lankan and Bangladeshi descent, whereas hemoglobin C is found in people of West African descent. For this reason the compound heterozygous state for these two hemoglobins is uncommon. The patient indeed had unusual mixed heritage: her mother was of Thai origin, and her father was of Jamaican and Puerto Rican heritage. She was treated for iron deficiency and started on folic acid supplementation. At follow-up she remained asymptomatic, and a repeat blood count revealed correction of Hb to 107 g/L with some improvement of other blood indices (MCV 65 fL, MCH 23.1 pg) and iron status (serum iron 15 μmol/L and a transferrin saturation of 15%). This compound heterozygous state can be associated with a normal Hb or mild anemia and is generally asymptomatic. Later in life it is of genetic significance in relation to pregnancy, both of these variant hemoglobins being of genetic relevance. The authors have no conflict of interest to declare.