tbuckley/cabot-search huggingface dataset:
Global yellow fever vaccination coverage from 1970 to 2016: an adjusted retrospective analysis
Authors: Freya M Shearer, Catherine L Moyes, David M Pigott, Oliver J Brady, Fatima Marinho, Aniruddha Deshpande, Joshua Longbottom, Annie J Browne, Moritz U G Kraemer, Kathleen M O'Reilly, Joachim Hombach, Sergio Yactayo, Valdelaine E M de Araújo, Aglaêr A da Nóbrega, Jonathan F Mosser, Jeffrey D Stanaway, Stephen S Lim, Simon I Hay, Nick Golding, Robert C Reiner
Journal: The Lancet Infectious Diseases (2017)

BackgroundSubstantial outbreaks of yellow fever in Angola and Brazil in the past 2 years, combined with global shortages in vaccine stockpiles, highlight a pressing need to assess present control strategies. The aims of this study were to estimate global yellow fever vaccination coverage from 1970 through to 2016 at high spatial resolution and to calculate the number of individuals still requiring vaccination to reach population coverage thresholds for outbreak prevention.MethodsFor this adjusted retrospective analysis, we compiled data from a range of sources (eg, WHO reports and health-service-provider registeries) reporting on yellow fever vaccination activities between May 1, 1939, and Oct 29, 2016. To account for uncertainty in how vaccine campaigns were targeted, we calculated three population coverage values to encompass alternative scenarios. We combined these data with demographic information and tracked vaccination coverage through time to estimate the proportion of the population who had ever received a yellow fever vaccine for each second level administrative division across countries at risk of yellow fever virus transmission from 1970 to 2016.FindingsOverall, substantial increases in vaccine coverage have occurred since 1970, but notable gaps still exist in contemporary coverage within yellow fever risk zones. We estimate that between 393·7 million and 472·9 million people still require vaccination in areas at risk of yellow fever virus transmission to achieve the 80% population coverage threshold recommended by WHO; this represents between 43% and 52% of the population within yellow fever risk zones, compared with between 66% and 76% of the population who would have required vaccination in 1970.InterpretationOur results highlight important gaps in yellow fever vaccination coverage, can contribute to improved quantification of outbreak risk, and help to guide planning of future vaccination efforts and emergency stockpiling.FundingThe Rhodes Trust, Bill & Melinda Gates Foundation, the Wellcome Trust, the National Library of Medicine of the National Institutes of Health, the European Union's Horizon 2020 research and innovation programme.
Is ultraviolet exposure acquired at work the most important risk factor for cutaneous squamous cell carcinoma? Results of the population-based case-control study FB-181
Authors: J. Schmitt, E. Haufe, F. Trautmann, H.-J. Schulze, P. Elsner, H. Drexler, A. Bauer, S. Letzel, S.M. John, M. Fartasch, T. Brüning, A. Seidler, S. Dugas-Breit, M. Gina, W. Weistenhöfer, K. Bachmann, I. Bruhn, B.M. Lang, S. Bonness, J.P. Allam, W. Grobe, T. Stange, S. Westerhausen, P. Knuschke, M. Wittlich, T.L. Diepgen
Journal: British Journal of Dermatology (2017)

Squamous cell carcinoma (SCC) is one of the most frequent types of cancer constituting a significant public health burden. Prevention strategies focus on limiting ultraviolet (UV) exposure during leisure time. However, the relative impact of occupational and nonoccupational UV exposure for SCC occurrence is unclear. To investigate the association between occupational and nonoccupational UV exposure for SCC in a multicentre population‐based case–control study hypothesizing that high occupational UV exposure increases the risk of SCC. Consecutive patients with incident SCC (n = 632) were recruited from a German national dermatology network. Population‐based controls (n = 996) without history of skin cancer were recruited from corresponding residents' registration offices and propensity score matched to cases. Lifetime UV exposure, sociodemographic and clinical characteristics were assessed by trained physicians. Occupational and nonoccupational UV exposure doses were estimated by masked investigators using established reference values. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were assessed using conditional logistic regression adjusting for relevant confounders. Total solar UV exposure was significantly associated with increased SCC. The OR for high (> 90th percentile) vs. low (< 40th percentile) and high vs, moderate (40–59th percentile) occupational UV exposure was 1·95 (95% CI 1·19–3·18) and 2·44 (95% CI 1·47–4·06) for SCC. Adjusting for occupational UV exposure, nonoccupational UV exposure was not significantly related to SCC incidence. Dose–response relationships were observed for occupational but not for nonoccupational solar UV exposure. Solar occupational UV exposure is a major determinant of incident SCC. Our findings indicate that prevention strategies should be further expanded to the occupational setting.
Adenine Enrichment at the Fourth CDS Residue in Bacterial Genes Is Consistent with Error Proofing for +1 Frameshifts
Authors: Liam Abrahams, Laurence D Hurst
Journal: Molecular Biology and Evolution (2017)

Beyond selection for optimal protein functioning, coding sequences (CDSs) are under selection at the RNA and DNA levels. Here, we identify a possible signature of "dual-coding," namely extensive adenine (A) enrichment at bacterial CDS fourth sites. In 99.07% of studied bacterial genomes, fourth site A use is greater than expected given genomic A-starting codon use. Arguing for nucleotide level selection, A-starting serine and arginine second codons are heavily utilized when compared with their non-A starting synonyms. Several models have the ability to explain some of this trend. In part, A-enrichment likely reduces 5' mRNA stability, promoting translation initiation. However T/U, which may also reduce stability, is avoided. Further, +1 frameshifts on the initiating ATG encode a stop codon (TGA) provided A is the fourth residue, acting either as a frameshift "catch and destroy" or a frameshift stop and adjust mechanism and hence implicated in translation initiation. Consistent with both, genomes lacking TGA stop codons exhibit weaker fourth site A-enrichment. Sequences lacking a Shine-Dalgarno sequence and those without upstream leader genes, that may be more error prone during initiation, have greater utilization of A, again suggesting a role in initiation. The frameshift correction model is consistent with the notion that many genomic features are error-mitigation factors and provides the first evidence for site-specific out of frame stop codon selection. We conjecture that the NTG universal start codon may have evolved as a consequence of TGA being a stop codon and the ability of NTGA to rapidly terminate or adjust a ribosome.
Noninvasive Tests Do Not Accurately Differentiate Nonalcoholic Steatohepatitis From Simple Steatosis: A Systematic Review and Meta-analysis
Authors: Pauline Verhaegh, Roisin Bavalia, Bjorn Winkens, Ad Masclee, Daisy Jonkers, Ger Koek
Journal: Clinical Gastroenterology and Hepatology (2017)
S100A4 Is a Biomarker and Regulator of Glioma Stem Cells That Is Critical for Mesenchymal Transition in Glioblastoma
Authors: Kin-Hoe Chow, Hee Jung Park, Joshy George, Keiko Yamamoto, Andrew D. Gallup, Joel H. Graber, Yuanxin Chen, Wen Jiang, Dennis A. Steindler, Eric G. Neilson, Betty Y.S. Kim, Kyuson Yun
Journal: Cancer Research (2017)

Glioma stem cells (GSC) and epithelial-mesenchymal transition (EMT) are strongly associated with therapy resistance and tumor recurrence, but the underlying mechanisms are incompletely understood. Here, we show that S100A4 is a novel biomarker of GSCs. S100A4+ cells in gliomas are enriched with cancer cells that have tumor-initiating and sphere-forming abilities, with the majority located in perivascular niches where GSCs are found. Selective ablation of S100A4-expressing cells was sufficient to block tumor growth in vitro and in vivo We also identified S100A4 as a critical regulator of GSC self-renewal in mouse and patient-derived glioma tumorspheres. In contrast with previous reports of S100A4 as a reporter of EMT, we discovered that S100A4 is an upstream regulator of the master EMT regulators SNAIL2 and ZEB along with other mesenchymal transition regulators in glioblastoma. Overall, our results establish S100A4 as a central node in a molecular network that controls stemness and EMT in glioblastoma, suggesting S100A4 as a candidate therapeutic target. Cancer Res; 77(19); 5360-73. ©2017 AACR.
Three versus six months adjuvant oxaliplatin-based chemotherapy for patients with stage III colon cancer: The French participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project.
Authors: Thierry Andre, Franck Bonnetain, Laurent Mineur, Jaafar Bennouna, Jérôme Desrame, Roger Faroux, Jérôme Dauba, Dewi Vernerey, Nasredine Aissat, Christophe Louvet, Céline Lepère, Olivier Jean Marie Dupuis, Yves Becouarn, May Mabro, Joëlle Egreteau, Olivier Bouche, Gael Deplanque, Marc Ychou, Aimery De Gramont, Julien Taieb
Journal: Journal of Clinical Oncology (2017)

3500 Background: The IDEA international collaboration was established to combine data from 6 randomized trials to assess whether a 3-month (3M) of oxaliplatin/fluoropyrimidines-based adjuvant chemotherapy (CT) is non-inferior to the 6-month (6M) for 3-year disease free survival (DFS) in stage III colon cancer (CC). Methods: French IDEA randomized patients (pts) between 3M and 6M of CT with mFOLFOX6 or XELOX (physician/pts choice). DFS was estimated using the Kaplan–Meier method and described using 3 years DFS rate. Results: Among 2022 randomized pts between May 2009 and May 2014, 2010 (99.4%) received CT and were enrolled in the mITT population: 49.9 and 50.1% in 3M and 6M, respectively. 99.5% of the mITT pts had stage III (N1: 74.9%; N2: 25.2%); median age 63.9 years; mFOLFOX6: 90% and XELOX 10% of pts. DFS median follow-up is 50.2 months. There were 578 DFS events (314 in 3M and 264 in 6M arm) leading to a 3-year DFS rate of 72.1% in the 3M vs. 75.7% in the 6M (HR=1.24; 95%CI 1.05–1.46, p=0.0112). For pts receiving mFOLFOX6, 3-year DFS rate was 72.0% in the 3M vs. 76.3% in the 6M (HR=1.27; 95%CI 1.07–1.51 p=0.0069). 94.2% and 78.0% of pts completed 3 and 6 months of CT, respectively. Median oxaliplatin doses intensity were 96.9% in 3M and 72.1% in 6M (495.0 and 735.1 mg/m2). By considering the neuropathy grade with 15375 neuropathy longitudinal measurements the overall maximal neuropathy grade 0-1/2/3-4 was 63.6/28.5/7.9% in 3M and 33.4/41.3/25.3% in 6M; p&lt;0.0001. At last follow-up assessment, with a median of 43.1 months, final residual grade 2/3-4 neuropathy was 2.1/0.4% in 3M and 5.4/1.3% in 6M; p&lt;0.0001. Conclusions: The IDEA France study, with 90% of patients treated with mFOLFOX6 regimen has shown that 6 months adjuvant treatment is superior to 3 months treatment. IDEA France study results should be considered in line with the international IDEA project that will also be presented at ASCO 2017. Clinical trial information: 2009-010384-16.
Targeting angiogenesis driven by fibroblast growth factor using RPT835, an FGFR2 inhibitor.
Authors: Evgenia Stepanova, Eliso Solomko, Oxana Ryabaya, Nina Peretolchina, Ilya Tsimafeyeu, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2013)

e22097 Background: The fibroblast growth factor (FGF)/FGF receptors (FGFR) signaling axis plays a key role in driving tumor angiogenesis. There is little data on the targeting of FGF-induced angiogenesis. We describe here the targeting angiogenesis driven by FGF using RPT835, novel inhibitor of the FGFR2 extracellular domain (received from RusPharmTech, LLC). Methods: To assess the efficacy of RPT835 on FGF-mediated endothelial cells proliferation, the human umbilical vein endothelial FGFR-expressing cells (HUVEC) were incubated in a 96-well microculture plate and were treated with serially diluted RPT835 or Brivanib as a control. Basic FGF was added at a concentration of 25 ng/ml. Control wells were left untreated. Cell growth inhibition was determined using Promega’s Cell Titer-Glo assay. In vivo angiogenesis was measured with subcutaneously implanted Matrigel plugs containing bFGF (100 ng/ml) or bFGF (100 ng/ml) + bevacizumab (10 mg/kg) or bFGF (100 ng/ml) + RPT835 (15 mg/kg). Control group was without stimulation and treatment. Each group included 3 mice. Number of endothelial cells/vessels was calculated. Results: Basic FGF significantly increased proliferation of the HUVEC cells (P=0.001) in untreated control group. RPT835 significantly inhibited FGF-triggered endothelial cell proliferation when compared with control (P&lt;0.001) or brivanib (P&lt;0.001, IC50=289 nmol/L) with IC50 of 11 nmol/L. In vivo, bFGF induced proliferation of endotheliocytes and mature vessels formation (P&lt;0.001). There were no vessels in FGFR2 inhibitor group. Bevacizumab did not decrease number of vessels in comparison with FGF-stimulated angiogenesis (P=0.9). Conclusions: Inhibition of bFGF/FGFR2 pathway resulted in effects on endothelial cells proliferation andmature vessels formation. Bevacizumab had no activity in FGF-induced angiogenesis.
Charting the transcriptional regulatory changes in mouse liver during fasting
Authors: Elodie Thierion, Duncan T. Odom
Journal: Hepatology (2017)

1University of CambridgeCancer Research UK Cambridge InstituteCambridgeUnited Kingdom *ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:Duncan T OdomUniversity of Cambridge, Cancer Research UK Cambridge Institute,Robinson WayCambridge, CB2 0RE, United KingdomE‐mail: [email protected]Tel: +44‐1223‐404500
CONKO-005: Adjuvant Chemotherapy With Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial
Authors: Marianne Sinn, Marcus Bahra, Torsten Liersch, Klaus Gellert, Helmut Messmann, Wolf Bechstein, Dirk Waldschmidt, Lutz Jacobasch, Martin Wilhelm, Bettina M. Rau, Robert Grützmann, Arndt Weinmann, Georg Maschmeyer, Uwe Pelzer, Jens M. Stieler, Jana K. Striefler, Michael Ghadimi, Sven Bischoff, Bernd Dörken, Helmut Oettle, Hanno Riess
Journal: Journal of Clinical Oncology (2017)

Purpose Gemcitabine is standard of care in the adjuvant treatment of resectable pancreatic ductal adenocarcinoma (PDAC). The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with gemcitabine has shown efficacy in the treatment of advanced PDAC and was considered to improve survival in patients with primarily resectable PDAC after R0 resection. Patients and Methods In an open-label, multicenter trial, patients were randomly assigned to one of two study arms: gemcitabine 1,000 mg/m2 days 1, 8, 15, every 4 weeks plus erlotinib 100 mg once per day (GemErlo) or gemcitabine (Gem) alone for six cycles. The primary end point of the study was to improve disease-free survival (DFS) from 14 to 18 months by adding erlotinib to gemcitabine. Results In all, 436 patients were randomly assigned at 57 study centers between April 2008 and July 2013. A total of 361 instances (83%) of disease recurrence were observed after a median follow-up of 54 months. Median treatment duration was 22 weeks in both arms. There was no difference in median DFS (GemErlo 11.4 months; Gem 11.4 months) or median overall survival (GemErlo 24.5 months; Gem 26.5 months). There was a trend toward long-term survival in favor of GemErlo (estimated survival after 1, 2, and 5 years for GemErlo was 77%, 53%, and 25% v 79%, 54%, and 20% for Gem, respectively). The occurrence or the grade of rash was not associated with a better survival in the GemErlo arm. Conclusion To the best of our knowledge, CONKO-005 is the first study to investigate the combination of chemotherapy and a targeted therapy in the adjuvant treatment of PDAC. GemErlo for 24 weeks did not improve DFS or overall survival over Gem.
Incremental Innovation of Ex Vivo Hematopoietic Stem Cell Engineering to Expand Clinical Gene Therapy Applications
Authors: Erika Zonari, Giacomo Desantis, Carolina Petrillo, Oriana Meo, Samantha Scaramuzza, Maria Rosa Lidonnici, Anna Kajaste-Rudnitski, Fabio Ciceri, Sarah Marktel, Alessandro Aiuti, Giuliana Ferrari, Luigi Naldini, Bernhard Gentner
Journal: Blood (2016)
Pharmacokinetics of once daily IV busulfan: Implications of fixed-infusion rate dosing
Authors: Shahbal Kangarloo, Farrukh Naveed, Diana Quinlan, Michelle Geddes, M. Chaudhry, Douglas Stewart, Anthony Magliocco, James Russell
Journal: Cancer Research (2007)

931  Busulfan (Bu) given in myeloablative doses is a frequent component of cytotoxic preparative regimens for hematopoietic stem cell transplantation. Previously we have shown that it is feasible to individualize the dose of Bu based on a pharmacokinetically guided test dose strategy prior to administration of high dose Bu. We also found that exposure to Bu as indicated by area under the concentration/time curve (AUC) above 6000 µM.min is associated with poorer clinical outcome. Intravenous (IV) chemotherapy agents typically are infused over a set time and based on the patient’s weight (W) or body surface area (BSA). Due to variability in W and BSA among different patients the rate of infusion can vary over two-fold, and this variability often influences drug kinetics. Objectives: To optimize IV Bu in a manner that would allow predictable kinetics for individualized dose modification in order to avoid Bu exposure above an AUC of 6000 µM.min associated with toxicities. Methods: Pharmacokinetic (PK) analysis was performed on 121 patients given 3.2 mg/kg IV Bu over a 3 hr infusion, and 54 patients dosed at 3.2 mg/kg IV Bu at a fixed infusion rate of 80 mg/hr. Bu concentrations in plasma were determined by UV-HPLC. All PK data were analyzed by non-compartmental and compartmental analysis using WinNonlin Version 5.0.1 software (Pharsight Corporation, Mountain View, CA, USA). Results: The mean (±SD) rate of infusion for the 3 hr dosing was 78.3 ± 13 mg/hr with an observed range of 50 mg/hr to 119 mg/hr. The observed range of AUC for the 3 hr IV dosing was 2184 µM.min to 7794 µM.min whereas this range for the 80 mg/hr dosing was 2557 µM.min to 5296 µM.min. There was less variability observed in the kinetics of IV Bu with the fixed-infusion rate dosing. The mean (% coefficient of variance) AUC for the 80 mg/hr dosing was 3872 (17%) µM.min and the mean (% CV) for the 3 hr dosing was 4707 (24%) µM.min. The distributions for the two populations were compared by the Kolmogorov-Smirnov test (KS-test). The maximum difference between the cumulative distributions (D) was 0.42 with a P-value of   3000 µM.min. Conclusions: IV busulfan given at a fixed infusion rate has predictable and more consistent kinetics as compared to when Bu is given over a fixed time period. This allows for more reliable and accurate dose adjustment of this drug where it was not possible to achieve with fixed-time dosing. These results justify further research and debate about whether other IV chemotherapy agents should be infused with a fixed-infusion rate, and whether fixed-infusion rate dosing protocols should be used during phase I dose escalating pharmacokinetic trials.
Loss of Tumor Suppressor <i>STAG2</i> Promotes Telomere Recombination and Extends the Replicative Lifespan of Normal Human Cells
Authors: Zharko Daniloski, Susan Smith
Journal: Cancer Research (2017)

Sister chromatids are held together by cohesin, a tripartite ring with a peripheral SA1/2 subunit, where SA1 is required for telomere cohesion and SA2 for centromere cohesion. The STAG2 gene encoding SA2 is often inactivated in human cancer, but not in in a manner associated with aneuploidy. Thus, how these tumors maintain chromosomal cohesion and how STAG2 loss contributes to tumorigenesis remain open questions. Here we show that, despite a loss in centromere cohesion, sister chromatids in STAG2 mutant tumor cells maintain cohesion in mitosis at chromosome arms and telomeres. Telomere maintenance in STAG2 mutant tumor cells occurred by either telomere recombination or telomerase activation mechanisms. Notably, these cells were refractory to telomerase inhibitors, indicating recombination can provide an alternative means of telomere maintenance. STAG2 silencing in normal human cells that lack telomerase led to increased recombination at telomeres, delayed telomere shortening, and postponed senescence onset. Insofar as telomere shortening and replicative senescence prevent genomic instability and cancer by limiting the number of cell divisions, our findings suggest that extending the lifespan of normal human cells due to inactivation of STAG2 could promote tumorigenesis by extending the period during which tumor-driving mutations occur. Cancer Res; 77(20); 5530-42. ©2017 AACR.
Brigatinib (BRG) in crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC): Updates from ALTA, a pivotal randomized phase 2 trial.
Authors: Myung-Ju Ahn, D. Ross Camidge, Marcello Tiseo, Karen L. Reckamp, Karin Holmskov Hansen, Sang-We Kim, Rudolf M. Huber, Howard Jack West, Harry J.M. Groen, Maximilian J. Hochmair, Natasha B. Leighl, Scott N. Gettinger, Corey J. Langer, Luis G. Paz-Ares, Egbert F. Smit, Edward S. Kim, William Reichmann, David Kerstein, Dong-Wan Kim
Journal: Journal of Clinical Oncology (2017)

e20503 Background: Most ALK+ NSCLC patients (pts) receiving CRZ eventually experience disease progression. Based on promising activity in a phase 1/2 trial, a randomized phase 2 trial of the ALK inhibitor BRG in pts with CRZ-refractory, advanced ALK+ NSCLC (ALTA; NCT02094573) was initiated. Responses and adverse events (AEs) varied with starting dose; therefore, ALTA was designed to evaluate 2 distinct BRG regimens. Methods: Pts were stratified by presence of baseline (BL) brain metastases and best response to prior CRZ and randomized 1:1 to receive BRG at 90 mg qd (arm A) or 180 mg qd with a 7-d lead-in at 90 mg (arm B). Primary endpoint was investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1. Results: In 222 pts (arm A/B, n=112/n=110), median age was 51/57 y; 71%/67% had brain metastases. As of May 31, 2016, 51%/56% (A/B) continued to receive BRG; median follow-up was 10.2/11.0 mo. Table shows efficacy. In pts with measurable BL brain metastases (A/B, n=26/n=18), confirmed intracranial ORR was 46%/67%. Most common treatment-emergent AEs (A/B) were: nausea 36%/43%, diarrhea 21%/39%, cough 23%/36%, headache 28%/30%, vomiting 28%/26%; grade ≥3 AEs included increased CPK 3%/10%, hypertension 6%/6%, pneumonia 3%/5%, increased lipase 5%/3%. A subset of pulmonary AEs with early onset (median: Day 2) occurred in 14/219 (6%) treated pts (3%, grade ≥3); 7/14 pts were successfully retreated. Dose reductions (8%/23%, A/B) and discontinuations (3%/10%) due to AEs were reported. Conclusions: BRG showed substantial activity, robust PFS, and acceptable safety at both dose levels, with numerically improved efficacy (particularly PFS and intracranial ORR) at 180 mg (with lead-in). Clinical trial information: NCT02094573. [Table: see text]