tbuckley/cabot-search huggingface dataset:
Surveillance to Track Progress Toward Polio Eradication — Worldwide, 2017–2018
Authors: Jaymin C. Patel, Ousmane M. Diop, Tracie Gardner, Smita Chavan, Jaume Jorba, Steven G. F. Wassilak, Jamal Ahmed, Cynthia J. Snider
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

When the Global Polio Eradication Initiative (GPEI) began in 1988, cases of poliomyelitis were reported from 125 countries. Since then, only Afghanistan, Nigeria, and Pakistan have experienced uninterrupted transmission of wild poliovirus (WPV). The primary means of detecting poliovirus is through surveillance for acute flaccid paralysis (AFP) among children aged <15 years with testing of stool specimens for WPV and vaccine-derived polioviruses (VDPVs) in World Health Organization (WHO)-accredited laboratories of the Global Polio Laboratory Network (GPLN) (1,2). AFP surveillance is supplemented by environmental surveillance for polioviruses in sewage at selected locations. Analysis of genomic sequences of isolated polioviruses enables assessment of transmission by time and place, potential gaps in surveillance, and emergence of VDPVs (3). This report presents 2017-2018 poliovirus surveillance data, focusing on 31 countries* identified as high-priority countries because of a "high risk of poliovirus transmission and limited capacity to adequately address those risks" (4). Some of these countries are located within WHO regions with endemic polio, and others are in regions that are polio-free. In 2018, 26 (84%) of the 31 countries met AFP surveillance indicators nationally; however, subnational variation in surveillance performance was substantial. Surveillance systems need continued strengthening through monitoring, supervision, and improvements in specimen collection and transport to provide sufficient evidence for interruption of poliovirus circulation.
Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease
Authors: Hisayuki Amano, Arindam Chaudhury, Cristian Rodriguez-Aguayo, Lan Lu, Viktor Akhanov, Andre Catic, Yury V. Popov, Eric Verdin, Hannah Johnson, Fabio Stossi, David A. Sinclair, Eiko Nakamaru-Ogiso, Gabriel Lopez-Berestein, Jeffrey T. Chang, Joel R. Neilson, Alan Meeker, Milton Finegold, Joseph A. Baur, Ergun Sahin
Journal: Cell Metabolism (2019)
Adenovirus Infection and Outbreaks: What You Need to Know
Authors: Charles S. Dela Cruz, Susan Pasnick, Jane E. Gross, Jon Keller, W. Graham Carlos, Bin Cao, Shazia Jamil
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

"Adenovirus Infection and Outbreaks: What You Need to Know." American Journal of Respiratory and Critical Care Medicine, 199(7), pp. P13–P14
Activation of mTOR by inhibitors of translation is dependent on PKC-delta.
Authors: Jun Zhan, Peter Houghton
Journal: Cancer Research (2007)

4155  TOR, a S/T kinase links environmental conditions to translation initiation in eukaryotic cells. Growth factors activate TOR signaling through the PI3K/Akt pathway, whereas nutritional signals and energy charge regulate mTOR via the AMPK/TSC/Rheb pathway. An important function of mTor is to regulate the protein synthesis via phosphorylating its substrates p70S6K1 and 4EBP1. Here we show that inhibition of global translation rapidly activates mTOR signaling leading of phosphorylation of downstream substrates pathway, suggesting a novel mechanism of mTOR regulation in response to decreased translation. Translational inhibitors, such as anisomycin (AN), cyclohexamade (CHX), and emetine (EME) were used to repress the protein synthesis at different stages (peptide formation, or peptide elongation). Each inhibitor induced a rapid concentration-dependent activation of mTOR as indicated by S6K1 phosphorylation (Thr389) and S6(Ser235/6), suggesting indicating a negative feedback from translational machinery to mTOR. To determine whether activation of mTOR was direct, or through activation upstream we used pharmacologic inhibitors and siRNA to determine where in the PI3K-mTOR pathway translation inhibitors activated signaling to mTOR. API-2, an inhibitor of Akt, did not block AN-induced S6K1/S6 phosphorylation, suggesting that the activation of mTR is independent of Akt. AN still induced S6K1 phosphorylation under conditions that suppressed the TSC/Rheb pathway to mTOR (amino acid deprivation or 2’-deoxyglucose). Further, using Rheb siRNAs, we found that AN still stimulated S6K1/S6 phosphorylation, whereas depletion of Rheb blocked serum or amino acid stimulation of S6K1(pT389) phosphorylation. Therefore, this intracellular signal activated mTOR/S6K1 is independent of AKT/TSC/Rheb. However, the phosphorylation of S6K1 is blocked when cells were treated by PKCδ -specific inhibitor rotterlin, suggesting that PKCδ kinase activity is essential for the activation of mTOR induced by translation inhibition. To test this genetically, siRNA was used to decrease the level of PKCδ (~80%), and blocked AN-induced mTOR activation. Furthermore, we found that PKCδ can phosphorylate mTOR in vitro. Taken together, we identified a novel intracellular signaling cascade emanating from the translational machinery that regulates mTOR activity via PKC δ.
Abstract 16905: Association of Triglycerides With Mortality across CKD Stages in Over 1.3 Million US Veterans
Authors: Elani Streja, Melissa Soohoo, Hamid Moradi, Moti L Kashyap, Daniel Gillen, Csaba P Kovesdy, Kamyar Kalantar-Zadeh
Journal: Circulation (2017)

Introduction: Prior studies have shown that high serum triglycerides (TG) levels are associated with worse survival in the general population. However, it is unknown if this TG and mortality associ...
The Impact of Upfront Autologous Transplant on the Survival of Adult Patients with ALCL and PTCL-NOS According to Their <i>ALK</i>, <i>DUSP22</i> and <i>TP63</i> Gene Rearrangement Status - a Joined Nordic Lymphoma Group and Mayo Clinic Analysis
Authors: Martin Bjerregård Pedersen, Thomas Relander, Grete Fossum Lauritzsen, Fredrik Ellin, Sirpa Leppä, Susanna Mannisto, Esa Jantunen, Rhett P. Ketterling, Patrick Bedroske, Ivy Luoma, Christopher Sattler, Jan M.A. Delabie, Christer Sundstrom, Birgitta Sander, Marja-Liisa Karjalainen-Lindsberg, Stephen Hamilton-Dutoit, Mats Ehinger, M Vornanen, Elisabeth Ralfkiaer, Rebecca Boddicker, Nabila Nora Bennani, Naoki Oishi, Michael Boe Moeller, Peter Noergaard, James R. Cerhan, Matthew J Maurer, Knut Liestol, Helle Toldbod, Andrew L Feldman, Francesco d'Amore
Journal: Blood (2017)
The effect of frequency of activity interruptions in prolonged sitting on postprandial glucose metabolism: A randomized crossover trial
Authors: Ida K. Thorsen, Mette Y. Johansen, Nanna S. Pilmark, Naja Z. Jespersen, Cecilie F. Brinkløv, Fabiana B. Benatti, David W. Dunstan, Kristian Karstoft, Bente K. Pedersen, Mathias Ried-Larsen
Journal: Metabolism (2019)
A review of the molecular design and biological activities of RXR agonists
Authors: Nathalia Rodrigues de Almeida, Martin Conda‐Sheridan
Journal: Medicinal Research Reviews (2019)

Abstract An attractive approach to combat disease is to target theregulation of cell function. At the heart of this task are nuclear receptors (NRs); which control functions such as gene transcription. Arguably, the key player in this regulatory machinery is the retinoid X receptor (RXR). This NR associates with a third of the NRs found in humans. Scientists have hypothesized that controlling the activity of RXR is an attractive approach to control cellular functions that modulate diseases such as cancer, diabetes, Alzheimer's disease and Parkinson's disease. In this review, we will describe the key features of the RXR, present a historic perspective of the first RXR agonists, and discuss various templates that have been reported to activate RXR with a focus on their molecular structure, biological activity, and limitations. Finally, we will present an outlook of the field and future directions and considerations to synthesize or modulate RXR agonists to make these compounds a clinical reality.
Reduced Scan Time in 123I-FP-CIT SPECT Imaging Using a Large-Field Cadmium-Zinc-Telluride Camera
Authors: Alexandre Bani Sadr, Nathalie Testart, Perrine Tylski, Christian Scheiber
Journal: Clinical Nuclear Medicine (2019)

Abstract We evaluated the reproducibility of 123 I-ioflupane ( 123 I-FP-CIT) SPECT with shorter scan times using a CZT camera. One hundred ninety-nine 123 I-FP-CIT SPECT scans obtained with standard scan time (30 minutes) were truncated to provide 24-, 18-, and 15-minute study simulations. Striatal binding ratios were automatically calculated and remained stable for all series. At 15 minutes, only 10 of 398 striata (2.5%) showed statistically significant different striatal binding ratios compared with reference series. These series were reviewed by 2 operators, and a perfect agreement was found for each patient. Therefore, CZT camera allows a 2-fold scan time reduction in 123 I-FP-CIT SPECT.
NHS prescribed record number of antidepressants last year
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The number of prescriptions for antidepressants in England has almost doubled in the past decade, new figures have shown.

Data from NHS Digital1 show that 70.9 million prescriptions for antidepressants were given out in 2018, compared with 36 million in 2008.

The number has been steadily increasing year-on-year, with 64.7 million given out in 2016 and 67.5 million prescribed in 2017.

The figure includes all prescription …
B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Authors: Øystein Fluge, Ingrid G. Rekeland, Katarina Lien, Hanne Thürmer, Petter C. Borchgrevink, Christoph Schäfer, Kari Sørland, Jörg Aßmus, Irini Ktoridou-Valen, Ingrid Herder, Merethe E. Gotaas, Øivind Kvammen, Katarzyna A. Baranowska, Louis M.L.J. Bohnen, Sissel S. Martinsen, Ann E. Lonar, Ann-Elise H. Solvang, Arne E.S. Gya, Ove Bruland, Kristin Risa, Kine Alme, Olav Dahl, Olav Mella
Journal: Annals of Internal Medicine (2019)

Previous phase 2 trials indicated benefit from B-lymphocyte depletion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).To evaluate the effect of the monoclonal anti-CD20 antibody rituximab versus placebo in patients with ME/CFS.Randomized, placebo-controlled, double-blind, multicenter trial. (ClinicalTrials.gov: NCT02229942).4 university hospitals and 1 general hospital in Norway.151 patients aged 18 to 65 years who had ME/CFS according to Canadian consensus criteria and had had the disease for 2 to 15 years.Treatment induction with 2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months (n = 77), or placebo (n = 74).Primary outcomes were overall response rate (fatigue score ≥4.5 for ≥8 consecutive weeks) and repeated measurements of fatigue score over 24 months. Secondary outcomes included repeated measurements of self-reported function over 24 months, components of the Short Form-36 Health Survey and Fatigue Severity Scale over 24 months, and changes from baseline to 18 months in these measures and physical activity level. Between-group differences in outcome measures over time were assessed by general linear models for repeated measures.Overall response rates were 35.1% in the placebo group and 26.0% in the rituximab group (difference, 9.2 percentage points [95% CI, -5.5 to 23.3 percentage points]; P = 0.22). The treatment groups did not differ in fatigue score over 24 months (difference in average score, 0.02 [CI, -0.27 to 0.31]; P = 0.80) or any of the secondary end points. Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events.Self-reported primary outcome measures and possible recall bias.B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS.The Norwegian Research Council, Norwegian Regional Health Trusts, Kavli Trust, MEandYou Foundation, and Norwegian ME Association.
Chromatin landscapes reveal developmentally encoded transcriptional states that define human glioblastoma
Authors: Stephen C. Mack, Irtisha Singh, Xiuxing Wang, Rachel Hirsch, Quilian Wu, Rosie Villagomez, Jean A. Bernatchez, Zhe Zhu, Ryan C. Gimple, Leo J.Y. Kim, Andrew Morton, Sisi Lai, Zhixin Qiu, Briana C. Prager, Kelsey C. Bertrand, Clarence Mah, Wenchao Zhou, Christine Lee, Gene H. Barnett, Michael A. Vogelbaum, Andrew E. Sloan, Lukas Chavez, Shideng Bao, Peter C. Scacheri, Jair L. Siqueira-Neto, Charles Y. Lin, Jeremy N. Rich
Journal: The Journal of Experimental Medicine (2019)

Glioblastoma is an incurable brain cancer characterized by high genetic and pathological heterogeneity. Here, we mapped active chromatin landscapes with gene expression, whole exomes, copy number profiles, and DNA methylomes across 44 patient-derived glioblastoma stem cells (GSCs), 50 primary tumors, and 10 neural stem cells (NSCs) to identify essential super-enhancer (SE)–associated genes and the core transcription factors that establish SEs and maintain GSC identity. GSCs segregate into two groups dominated by distinct enhancer profiles and unique developmental core transcription factor regulatory programs. Group-specific transcription factors enforce GSC identity; they exhibit higher activity in glioblastomas versus NSCs, are associated with poor clinical outcomes, and are required for glioblastoma growth in vivo. Although transcription factors are commonly considered undruggable, group-specific enhancer regulation of the MAPK/ERK pathway predicts sensitivity to MEK inhibition. These data demonstrate that transcriptional identity can be leveraged to identify novel dependencies and therapeutic approaches.
First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, and Antitumor Activity
Authors: Hui K. Gan, Michael Millward, Ye Hua, Chuan Qi, Yang Sai, Weiguo Su, Jian Wang, Lilin Zhang, Melanie M. Frigault, Shethah Morgan, Liu Yang, Jason D. Lickliter
Journal: Clinical Cancer Research (2019)

Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib).This open-label, multicenter dose-escalation and -expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity.Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N = 1, 800 mg N = 1, and 1,000 mg N = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, Cmax was 2,414.8 ng/mL, AUC was 17053.9 h·ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks.The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.
Identification of genetic alterations associated with primary resistance to EGFR‐TKIs in advanced non‐small‐cell lung cancer patients with EGFR sensitive mutations
Authors: Fang Wang, Xia‐Yao Diao, Xiao Zhang, Qiong Shao, Yan‐Fen Feng, Xin An, Hai‐Yun Wang
Journal: Cancer Communications (2019)

Abstract Background Identification of activated epidermal growth factor receptor ( EGFR ) mutations and application of EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs) have greatly changed the therapeutic strategies of non‐small‐cell lung cancer (NSCLC). However, the long‐term efficacy of EGFR‐TKI therapy is limited due to the development of drug resistance. The aim of this study was to investigate the correlation between the aberrant alterations of 8 driver genes and the primary resistance to EGFR‐TKIs in advanced NSCLC patients with activated EGFR mutations. Methods We retrospectively reviewed the clinical data from 416 patients with stage III/IV or recurrent NSCLC who received an initial EGFR‐TKI treatment, from April 2004 and March 2011, at the Sun Yat‐sen University Cancer Center. Several genetic alterations associated with the efficacy of EGFR‐TKIs, including the alterations in BIM , ALK , KRAS , PIK3CA , PTEN , MET , IGF1R , and ROS1 , were detected by the routine clinical technologies. The progression‐free survival (PFS) and overall survival (OS) were compared between different groups using Kaplan–Meier survival analysis with the log‐rank test. A Cox regression model was used to estimate multivariable‐adjusted hazard ratios (HRs) and their 95% confidence intervals (95% CIs) associated with the PFS and OS. Results Among the investigated patients, 169 NSCLC patients harbored EGFR‐sensitive mutations. EGFR‐mutant patients having PTEN deletion had a shorter PFS and OS than those with intact PTEN ( P = 0.003 for PFS, and P = 0.034 for OS). In the combined molecular analysis of EGFR signaling pathway and resistance genes, we found that EGFR‐mutant patients coexisted with aberrant alterations in EGFR signaling pathway and those having resistant genes had a statistically poorer PFS than those without such alterations ( P &lt; 0.001). A Cox proportional regression model determined that PTEN deletion (HR = 4.29,95% CI = 1.72–10.70) and low PTEN expression (HR = 1.96, 95% CI = 1.22–3.13), MET FISH + (HR = 2.83,95% CI = 1.37–5.86) were independent predictors for PFS in patients with EGFR‐TKI treatment after adjustment for multiple factor. Conclusions We determined that the coexistence of genetic alterations in cancer genes may explain primary resistance to EGFR‐TKIs.
Association of In Vitro Fertilization With Childhood Cancer in the United States
Authors: Logan G. Spector, Morton B. Brown, Ethan Wantman, Gerard S. Letterie, James P. Toner, Kevin Doody, Elizabeth Ginsburg, Melanie Williams, Lori Koch, Maria J. Schymura, Barbara Luke
Journal: JAMA Pediatrics (2019)

In vitro fertilization (IVF) is associated with birth defects and imprinting disorders. Because these conditions are associated with an increased risk of childhood cancer, many of which originate in utero, descriptions of cancers among children conceived via IVF are imperative.To compare the incidence of childhood cancers among children conceived in vitro with those conceived naturally.A retrospective, population-based cohort study linking cycles reported to the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System from January 1, 2004, to December 31, 2012, that resulted in live births from September 1, 2004, to December 31, 2013, to the birth and cancer registries of 14 states, comprising 66% of United States births and 75% of IVF-conceived births, with follow-up from September 1, 2004, to December 31, 2014. The study included 275 686 children conceived via IVF and a cohort of 2 266 847 children, in which 10 births were randomly selected for each IVF birth. Statistical analysis was performed from April 1, 2017, to October 1, 2018.In vitro fertilization.Cancer diagnosed in the first decade of life.A total of 321 cancers were detected among the children conceived via IVF (49.1% girls and 50.9% boys; mean [SD] age, 4.6 [2.5] years for singleton births and 5.9 [2.4] years for multiple births), and a total of 2042 cancers were detected among the children not conceived via IVF (49.2% girls and 50.8% boys; mean [SD] age, 6.1 [2.6] years for singleton births and 4.7 [2.6] years for multiple births). The overall cancer rate (per 1 000 000 person-years) was 251.9 for the IVF group and 192.7 for the non-IVF group (hazard ratio, 1.17; 95% CI, 1.00-1.36). The rate of hepatic tumors was higher among the IVF group than the non-IVF group (hepatic tumor rate: 18.1 vs 5.7; hazard ratio, 2.46; 95% CI, 1.29-4.70); the rates of other cancers did not differ between the 2 groups. There were no associations with specific IVF treatment modalities or indication for IVF.This study found a small association of IVF with overall cancers of early childhood, but it did observe an increased rate of embryonal cancers, particularly hepatic tumors, that could not be attributed to IVF rather than to underlying infertility. Continued follow-up for cancer occurrence among children conceived via IVF is warranted.
Anti-CD24 Antibody–Nitric Oxide Conjugate Selectively and Potently Suppresses Hepatic Carcinoma
Authors: Fumou Sun, Yang Wang, Xiaojun Luo, Zhaoxiong Ma, Yao Xu, Xinrong Zhang, Tian Lv, Yihua Zhang, Min Wang, Zhangjian Huang, Juan Zhang
Journal: Cancer Research (2019)

Abstract Nitric oxide (NO) has a wide range of potential applications in tumor therapy. However, a targeted delivery system for NO donors has remained elusive, creating a bottleneck that limits its druggability. The antibody–drug conjugate (ADC) is a targeted drug delivery system composed of an antibody linked to an active cytotoxic drug. This design may compensate for the weak targeting ability and various biological functions of the NO donor. In this study, we designed the NO donor HL-2, which had a targeted, cleaved disulfide bond and an attachable maleimide terminal. We conjugated HL-2 with an antibody that targeted CD24 through a thioether bond to generate an ADC-like immunoconjugate, antibody-nitric oxide conjugate (ANC), which we named HN-01. HN-01 showed efficient internalization and significantly increased the release of NO in hepatic carcinoma cells in vitro. HN-01 induced apoptosis of tumor cells and suppressed tumor growth in hepatic carcinoma-bearing nude mice through antibody-dependent co-toxicity; HN-01 also increased NO levels in tumor cells. Collectively, this study expands the concept of ADC and provides an innovative NO donor and ANC to address current challenges in targeted delivery of NO. This new inspiration for an ANC design can also be used in future studies for other molecules with intracellular targets. Significance: This study is the first to expand the concept of ADC with an antibody-nitric oxide conjugate that suppresses hepatic carcinoma in vitro and in vivo.
Intraclonal Plasticity in Mammary Tumors Revealed through Large-Scale Single-Cell Resolution 3D Imaging
Authors: Anne C. Rios, Bianca D. Capaldo, François Vaillant, Bhupinder Pal, Ravian van Ineveld, Caleb A. Dawson, Yunshun Chen, Emma Nolan, Nai Yang Fu, Felicity C. Jackling, Sapna Devi, David Clouston, Lachlan Whitehead, Gordon K. Smyth, Scott N. Mueller, Geoffrey J. Lindeman, Jane E. Visvader
Journal: Cancer Cell (2019)