tbuckley/cabot-search huggingface dataset:
US will display drug prices on TV advertisements, says health secretary
Authors: Owen Dyer
Journal: BMJ (2018)

A legal and political battle is brewing as the US government plans to require drug advertisements on television to display the list price of a 30 day supply of their product.

The US health secretary, Alex Azar, had sharp words for the industry trade group, PhRMA, which sought to pre-empt his announcement of the draft rule by proposing a compromise measure just hours before Azar was due to give a speech on the subject before the National Academy of Medicine.

PhRMA’s president, Steve Ubl, said that the industry would voluntarily change its advertisements from next April to add messages directing consumers to company websites with pricing information.

Calling the timing of the proposal “no coincidence,” Azar said in his speech that “placing information on a website is not the same …
CD8+ T-cells contribute to lesion stabilization in advanced atherosclerosis by limiting macrophage content and CD4+ T-cell responses
Authors: Janine van Duijn, Eva Kritikou, Naomi Benne, Thomas van der Heijden, Gijs H van Puijvelde, Mara J Kröner, Frank H Schaftenaar, Amanda C Foks, Anouk Wezel, Harm Smeets, Hideo Yagita, Ilze Bot, Wim Jiskoot, Johan Kuiper, Bram Slütter
Journal: Cardiovascular Research (2018)

T lymphocytes play an important role in atherosclerosis development, but the role of the CD8+ T-cell remains debated, especially in the clinically relevant advanced stages of atherosclerosis development. Here, we set out to determine the role of CD8+ T-cells in advanced atherosclerosis.Human endarterectomy samples analysed by flow cytometry showed a negative correlation between the percentage of CD8+ T-cells and macrophages, suggesting a possible protective role for these cells in lesion development. To further test this hypothesis, LDLr-/- mice were fed a western-type diet (WTD) for 10 weeks to induce atherosclerosis, after which they received CD8α-depleting or isotype control antibody for 6 weeks. Depletion of CD8+ T-cells in advanced atherosclerosis resulted in less stable lesions, with significantly reduced collagen content in the trivalve area, increased macrophage content and increased necrotic core area compared with controls. Mechanistically, we observed that CD8 depletion specifically increased the fraction of Th1 CD4+ T-cells in the lesions. Treatment of WTD-fed LDLr-/- mice with a FasL-neutralizing antibody resulted in similar changes in macrophages and CD4+ T-cell skewing as CD8+ T-cell depletion.These findings demonstrate for the first time a local, protective role for CD8+ T-cells in advanced atherosclerosis, through limiting accumulation of Th1 cells and macrophages, identifying a novel regulatory mechanism for these cells in atherosclerosis.
How much is the pharmaceutical industry's cost of capital for clinical research of novel drugs?
Authors: Henry Jacob Conter
Journal: Journal of Clinical Oncology (2014)

6558 Background: Attracting private research investment to fund clinical trials in rare tumor types can be difficult. This is compounded by the inability of investors to directly invest in higher-risk trials, lack of interest in by large pharmaceutical companies, and a lack of understanding of what return on investment would be acceptable. Methods: A project finance model was created. The owner of the desired compound would license it to a special investment vehicle (SIV). The SIV would purchase the license from the holder by raising cash through a repurchase agreement with a financial institution in exchange for zero-coupon (Z-) bonds issued by the SIV. The financial institution could short sell the bonds to investors. Bond holders could hold the debt or purchase credit default swaps (CDS) to hedge risk. The Merton Model was employed to value the debt and calculate the yield per dollar of future revenue. Published clinical trial phase transition probabilities were used to estimate success. The hazard for failure was calculated from the time from phase I initiation (extracted from clinicaltrials.gov) to FDA approval, assuming an 80% failure rate, for all novel drugs approved since 2000. Results: Phase transition probabilities were 76.8%, 59.4%, and 57.1% for phase I-II, phase II-III, and phase III-FDA approval, respectively. After completion of pre-clinical work, the value of the compound would be $0.24. The value of the license could either be $0 or $0.31, $0.31 or $0.49, $0.49 or $0.74 at the end of phase I, II, or III trials, when adjusted for inflation. If the face value of debt was equal to the initial value of the compound, the z-bond would yield 20.7%, 8.2% and 13.6% annually with continuous compounding for phase I, II, and III, trials. A minimum equity of 29.3%, 19.7%, and 37% would need to be raised in addition to the debt financing to purchase the license for phase I, II, and III trials, respectively. For the 28 drugs approved, the mean approval time was 6.5 years (range 3.2-10.9). A perfectly hedged CDS would cost $0.84. Conclusions: Project financing techniques allow for a quantitative determination of the cost of capital for different stages of drug development. This financial structure could be employed to finance trials for rare tumors.
Interpretation of time-to-event outcomes in randomized trials: an online randomized experiment
Authors: I.R. Weir, G.D. Marshall, J.I. Schneider, J.A. Sherer, E.M. Lord, B. Gyawali, M.K. Paasche-Orlow, E.J. Benjamin, L. Trinquart
Journal: Annals of Oncology (2018)

BackgroundMultiple features in the presentation of randomized controlled trial (RCT) results are known to influence comprehension and interpretation. We aimed to compare interpretation of cancer RCTs with time-to-event outcomes when the reported treatment effect measure is the hazard ratio (HR), difference in restricted mean survival times (RMSTD), or both (HR+RMSTD). We also assessed the prevalence of misinterpretation of the HR.MethodsWe carried out a randomized experiment. We selected 15 cancer RCTs with statistically significant treatment effects for the primary outcome. We masked each abstract and created three versions reporting either the HR, RMSTD, or HR+RMSTD. We randomized corresponding authors of RCTs and medical residents and fellows to one of 15 abstracts and one of 3 versions. We asked how beneficial the experimental treatment was (0–10 Likert scale). All participants answered a multiple-choice question about interpretation of the HR. Participants were unaware of the study purpose.ResultsWe randomly allocated 160 participants to evaluate an abstract reporting the HR, 154 to the RMSTD, and 155 to both HR+RMSTD. The mean Likert score was statistically significantly lower in the RMSTD group when compared with the HR group (mean difference −0.8, 95% confidence interval, −1.3 to −0.4, P < 0.01) and when compared with the HR+RMSTD group (difference −0.6, −1.1 to −0.1, P = 0.05). In all, 47.2% (42.7%−51.8%) of participants misinterpreted the HR, with 40% equating it with a reduction in absolute risk.ConclusionMisinterpretation of the HR is common. Participants judged experimental treatments to be less beneficial when presented with RMSTD when compared with HR. We recommend that authors present RMST-based measures alongside the HR in reports of RCT results.
Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study
Authors: Andrea Necchi, Andrea Anichini, Daniele Raggi, Alberto Briganti, Simona Massa, Roberta Lucianò, Maurizio Colecchia, Patrizia Giannatempo, Roberta Mortarini, Marco Bianchi, Elena Farè, Francesco Monopoli, Renzo Colombo, Andrea Gallina, Andrea Salonia, Antonella Messina, Siraj M. Ali, Russell Madison, Jeffrey S. Ross, Jon H. Chung, Roberto Salvioni, Luigi Mariani, Francesco Montorsi
Journal: Journal of Clinical Oncology (2018)

Purpose To determine the activity of pembrolizumab as neoadjuvant immunotherapy before radical cystectomy (RC) for muscle-invasive bladder carcinoma (MIBC) for which standard cisplatin-based chemotherapy is poorly used. Patients and Methods In the PURE-01 study, patients had a predominant urothelial carcinoma histology and clinical (c)T≤3bN0 stage tumor. They received three cycles of pembrolizumab 200 mg every 3 weeks before RC. The primary end point in the intention-to-treat population was pathologic complete response (pT0). Biomarker analyses included programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 pharmDx assay), genomic sequencing (FoundationONE assay), and an immune gene expression assay. Results Fifty patients were enrolled from February 2017 to March 2018. Twenty-seven patients (54%) had cT3 tumor, 21 (42%) cT2 tumor, and two (4%) cT2-3N1 tumor. One patient (2%) experienced a grade 3 transaminase increase and discontinued pembrolizumab. All patients underwent RC; there were 21 patients with pT0 (42%; 95% CI, 28.2% to 56.8%). As a secondary end point, downstaging to pT&lt;2 was achieved in 27 patients (54%; 95% CI, 39.3% to 68.2%). In 54.3% of patients with PD-L1 CPS ≥ 10% (n = 35), RC indicated pT0, whereas RC indicated pT0 in only 13.3% of those with CPS &lt; 10% (n = 15). A significant nonlinear association between tumor mutation burden (TMB) and pT0 was observed, with a cutoff at 15 mutations/Mb. Expression of several genes in pretherapy lesions was significantly different between pT0 and non-pT0 cohorts. Significant post-therapy changes in the TMB and evidence of adaptive mechanisms of immune resistance were observed in residual tumors. Conclusion Neoadjuvant pembrolizumab resulted in 42% of patients with pT0 and was safely administered in patients with MIBC. This study indicates that pembrolizumab could be a worthwhile neoadjuvant therapy for the treatment of MIBC when limited to patients with PD-L1–positive or high-TMB tumors.
Impact of prognostic factors and risk groups on overall survival (OS) in patients treated with pembrolizumab vs investigator’s choice chemotherapy for advanced urothelial cancer (UC): Post hoc analysis of KEYNOTE-045
Authors: J. Bellmunt, R. de Wit, D.J. Vaughn, Y. Fradet, J.L. Lee, L. Fong, N.J. Vogelzang, M.A. Climent, D. Petrylak, T.K. Choueiri, A. Necchi, W.R. Gerritsen, H. Gurney, D.I. Quinn, S. Culine, C.N. Sternberg, E. Jensen, T. Frenkl, R.F. Perini, D. Bajorin
Journal: Annals of Oncology (2018)
The analysis of treatment sequencing and clinical outcomes in BRAF-positive and BRAF-negative unresectable/metastatic melanoma patients treated with systemic therapies in routine practice
Authors: A.M. Czarnecka, P. Teterycz, I. Lugowska, P. Rogala, T. Switaj, P.L. Rutkowski
Journal: Annals of Oncology (2018)
TLR8-Mediated Metabolic Control of Human Treg Function: A Mechanistic Target for Cancer Immunotherapy
Authors: Lingyun Li, Xia Liu, Katherine L. Sanders, James L. Edwards, Jian Ye, Fusheng Si, Aiqin Gao, Lan Huang, Eddy C. Hsueh, David A. Ford, Daniel F. Hoft, Guangyong Peng
Journal: Cell Metabolism (2018)
GW29-e1758 Successful Closure of Left Atrial Appendages with Anatomies Unsuitable for Watchman Device by a Novel LAmbre Occluder
Authors: Shuang Li, Mengyun Zhu, Kai Tang, Dongdong Zhao, Qi Chen, Yatyin Lam, Jie Cheng, Wei Chen, Jun Zhang, Jingying Zhang, Weiya Xu
Journal: Journal of the American College of Cardiology (2018)
Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis
Authors: Babita Madan, Nathan Harmston, Gahyathiri Nallan, Alex Montoya, Peter Faull, Enrico Petretto, David M. Virshup
Journal: Journal of Clinical Investigation (2018)

Activating mutations in the Wnt pathway drive a variety of cancers, but the specific targets and pathways activated by Wnt ligands are not fully understood. To bridge this knowledge gap, we performed a comprehensive time-course analysis of Wnt-dependent signaling pathways in an orthotopic model of Wnt-addicted pancreatic cancer, using a porcupine (PORCN) inhibitor currently in clinical trials, and validated key results in additional Wnt-addicted models. The temporal analysis of the drug-perturbed transcriptome demonstrated direct and indirect regulation of more than 3,500 Wnt-activated genes (23% of the transcriptome). Regulation was both via Wnt/β-catenin and through the modulation of protein abundance of important transcription factors, including MYC, via Wnt-dependent stabilization of proteins (Wnt/STOP). Our study identifies a central role of Wnt/β-catenin and Wnt/STOP signaling in controlling ribosome biogenesis, a key driver of cancer proliferation.
Policies That Limit Emergency Department Visits and Reimbursements Undermine the Emergency Care System
Authors: Maria C. Raven
Journal: JAMA Network Open (2018)

Shih-Chuan Chou, MD, MPH; Suhas Gondi, BA; Olesya Baker, PhD; Arjun K. Venkatesh, MD, MBA, MHS; Jeremiah D. Schuur, MD, MHS
Ventricular Response to Dobutamine Stress CMR Is a Predictor for Outcome in Fontan Patients
Authors: Eva van den Bosch, Sjoerd S.M. Bossers, Daniëlle Robbers-Visser, Eric Boersma, Jolien W. Roos-Hesselink, Hans M.P.J. Breur, Nico A. Blom, Lucia J.M. Kroft, Miranda M. Snoeren, Livia Kapusta, Willem A. Helbing
Journal: JACC. Cardiovascular imaging (2018)
Abstract B43: Validation of a network-based strategy for the optimization of combinatorial target selection in breast cancer therapy
Authors: Tatiana Martins Tilli, Nicolas Carels, Jack Adam Tuszynski, Manijeh Pasdar
Journal: Clinical Cancer Research (2018)

Abstract Network-based strategies provided by systems biology are attractive tools for cancer therapy. Modulation of cancer networks by anticancer drugs may alter the response of malignant cells and/or drive network reorganization into the inhibition of cancer progression. Previously, using systems biology approach and cancer signaling networks, we identified the top 5 highly expressed and connected proteins (HSP90AB1, CSNK2B, TK1, YWHAB, and VIM) in the invasive MDA-MB-231 breast cancer cell line. Here, we have knocked down the expression of these proteins, individually or together using siRNAs. The transfected cell lines were assessed for in vitro cell growth, colony formation, migration, and invasion relative to control transfected MDA-MB-231, the noninvasive MCF-7 breast carcinoma cell line, and the nontumoral mammary epithelial cell line MCF-10A. The knockdown of the top-5 upregulated connectivity hubs successfully inhibited the in vitro proliferation, colony formation, anchorage independence, migration, and invasion in MDA-MB-231 cells, with minimal effects in the control transfected MDA-MB-231 cells or MCF-7 and MCF-10A cells. The in vitro validation of bioinformatics predictions regarding optimized multitarget selection for therapy suggests that protein expression levels together with protein-protein interaction network analysis may provide an optimized combinatorial target selection for a highly effective antimetastatic precision therapy in triple-negative breast cancer. This approach increases the ability to identify not only druggable hubs as essential targets for cancer survival, but also interactions most susceptible to synergistic drug action. The data provided in this report constitute a preliminary step toward the personalized clinical application of our strategy to optimize the therapeutic use of anticancer drugs. Citation Format: Tatiana Martins Tilli, Nicolas Carels, Jack Adam Tuszynski, Manijeh Pasdar. Validation of a network-based strategy for the optimization of combinatorial target selection in breast cancer therapy [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B43.
Cesarean section in China, Taiwan, and Hong Kong—A safe choice for women and clinicians?
Authors: Mairead Black, Sohinee Bhattacharya
Journal: PLoS Medicine (2018)

Mairead Black and Sohinee Bhattacharya discuss research findings on preferences for cesarean delivery in Asian settings and share their Perspective on facilitating woman-centered birth choices in China following the end of the one-child policy.
The sphingosine kinase-1/sphingosine-1-phosphate axis in cancer: Potential target for anticancer therapy
Authors: Xiangjin Zheng, Wan Li, Liwen Ren, Jinyi Liu, Xiaocong Pang, Xiuping Chen, De Kang, Jinhua Wang, Guanhua Du
Journal: Pharmacology & Therapeutics (2018)
Association Between Third-Trimester Tdap Immunization and Neonatal Pertussis Antibody Concentration
Authors: C. Mary Healy, Marcia A. Rench, Laurie S. Swaim, E. O’Brian Smith, Haleh Sangi-Haghpeykar, Marsenia H. Mathis, Monte D. Martin, Carol J. Baker
Journal: JAMA (2018)

<h3>Importance</h3> Immunization with tetanus, diphtheria, and acellular pertussis (Tdap) vaccine is recommended in the United States during weeks 27 through 36 of pregnancy to prevent life-threatening infant pertussis. The optimal gestation for immunization to maximize concentrations of neonatal pertussis toxin antibodies is unknown. <h3>Objective</h3> To determine pertussis toxin antibody concentrations in cord blood from neonates born to women immunized and unimmunized with Tdap vaccine in pregnancy and optimal gestational age for immunization to maximize concentrations of neonatal antibodies. <h3>Design, Setting, and Participants</h3> Prospective, observational, cohort study of term neonates in Houston, Texas (December 2013-March 2014). <h3>Exposures</h3> Tdap immunization during weeks 27 through 36 of pregnancy or no Tdap immunization. <h3>Main Outcomes and Measures</h3> Primary outcome was geometric mean concentrations (GMCs) of pertussis toxin antibodies in cord blood of Tdap-exposed and Tdap-unexposed neonates and proportions of Tdap-exposed and Tdap-unexposed neonates with pertussis toxin antibody concentrations of 15 IU/mL or higher, 30 IU/mL or higher, and 40 IU/mL or higher, cutoffs representing quantifiable antibodies or levels that may be protective until the infant immunization series begins. Secondary outcome was the optimal gestation for immunization to achieve maximum pertussis toxin antibodies. <h3>Results</h3> Six hundred twenty-six pregnancies (mean maternal age, 29.7 years; 41% white, 27% Hispanic, 26% black, 5% Asian, 1% other; mean gestation, 39.4 weeks) were included. Three hundred twelve women received Tdap vaccine at a mean gestation of 31.2 weeks (range, 27.3-36.4); 314 were unimmunized. GMC of neonatal cord pertussis toxin antibodies from the Tdap-exposed group was 47.3 IU/mL (95% CI, 42.1-53.2) compared with 12.9 IU/mL (95% CI, 11.7-14.3) in the Tdap-unexposed group, for a GMC ratio of 3.6 (95% CI, 3.1-4.2;<i>P</i> &lt; .001). More Tdap-exposed than Tdap-unexposed neonates had pertussis toxin antibody concentrations of 15 IU/mL or higher (86% vs 37%; difference, 49% [95% CI, 42%-55%]), 30 IU/mL or higher (72% vs 17%; difference, 55% [95% CI, 49%-61%]), and 40 IU/mL or higher (59% vs 12%; difference, 47% [95% CI, 41%-54%]);<i>P</i> &lt; .001 for each analysis. GMCs of pertussis toxin antibodies were highest when Tdap vaccine was administered during weeks 27 through 30 and declined thereafter, reaching a peak at week 30 (57.3 IU/mL [95% CI, 44.0-74.6]). <h3>Conclusions and Relevance</h3> Immunization with Tdap vaccine during the third trimester of pregnancy, compared with no immunization, was associated with higher neonatal concentrations of pertussis toxin antibodies. Immunization early in the third trimester was associated with the highest concentrations.
A p53-Responsive miRNA Network Promotes Cancer Cell Quiescence
Authors: Ting La, Guang Zhi Liu, Margaret Farrelly, Nicole Cole, Yu Chen Feng, Yuan Yuan Zhang, Simonne K. Sherwin, Hamed Yari, Hessam Tabatabaee, Xu Guang Yan, Su Tang Guo, Tao Liu, Rick F. Thorne, Lei Jin, Xu Dong Zhang
Journal: Cancer Research (2018)

: Cancer cells in quiescence (G0 phase) are resistant to death, and re-entry of quiescent cancer cells into the cell-cycle plays an important role in cancer recurrence. Here we show that two p53-responsive miRNAs utilize distinct but complementary mechanisms to promote cancer cell quiescence by facilitating stabilization of p27. Purified quiescent B16 mouse melanoma cells expressed higher levels of miRNA-27b-3p and miRNA-455-3p relative to their proliferating counterparts. Induction of quiescence resulted in increased levels of these miRNAs in diverse types of human cancer cell lines. Inhibition of miRNA-27b-3p or miRNA-455-3p reduced, whereas its overexpression increased, the proportion of quiescent cells in the population, indicating that these miRNAs promote cancer cell quiescence. Accordingly, cancer xenografts bearing miRNA-27b-3p or miRNA-455-3p mimics were retarded in growth. miRNA-27b-3p targeted cyclin-dependent kinase regulatory subunit 1 (CKS1B), leading to reduction in p27 polyubiquitination mediated by S-phase kinase-associated protein 2 (Skp2). miRNA-455-3p targeted CDK2-associated cullin domain 1 (CAC1), which enhanced CDK2-mediated phosphorylation of p27 necessary for its polyubiquitination. Of note, the gene encoding miRNA-27b-3p was embedded in the intron of the chromosome 9 open reading frame 3 gene that was transcriptionally activated by p53. Similarly, the host gene of miRNA-455-3p, collagen alpha-1 (XXVII) chain, was also a p53 transcriptional target. Collectively, our results identify miRNA-27b-3p and miRNA-455-3p as important regulators of cancer cell quiescence in response to p53 and suggest that manipulating miRNA-27b-3p and miRNA-455-3p may constitute novel therapeutic avenues for improving outcomes of cancer treatment. SIGNIFICANCE: Two novel p53-responsive microRNAs whose distinct mechanisms of action both stabilize p27 to promote cell quiescence and may serve as therapeutic avenues for improving outcomes of cancer treatment.
Drug companies are incentivised to profit not to improve health, says report
Authors: Melanie Newman
Journal: BMJ (2018)

Government funding for health innovation is subsidising drug industry profits while providing little public health benefit, a report from leading health economists says.1

Most new drugs are not meeting public needs while economic and regulatory incentives have created a “highly inefficient pharmaceutical sector” which spends more on marketing than research and development, and focuses the research it does do on profits, the report explains.

This leads to prohibitively high prices, but also to the sidelining of treatments aimed at prevention or cure in favour of drugs with long term, high volume sales potential.

In …
Alma-Ata at 40 years: reflections from the Lancet Commission on Investing in Health
Authors: David A Watkins, Gavin Yamey, Marco Schäferhoff, Olusoji Adeyi, George Alleyne, Ala Alwan, Seth Berkley, Richard Feachem, Julio Frenk, Gargee Ghosh, Sue J Goldie, Yan Guo, Sanjeev Gupta, Felicia Knaul, Margaret Kruk, Rachel Nugent, Osondu Ogbuoji, Jinyuan Qi, Srinath Reddy, Helen Saxenian, Agnés Soucat, Dean T Jamison, Lawrence H Summers
Journal: The Lancet (2018)