tbuckley/cabot-search huggingface dataset:
Analysis of Launch and Postapproval Cancer Drug Pricing, Clinical Benefit, and Policy Implications in the US and Europe
Authors: Kerstin N. Vokinger, Thomas J. Hwang, Paola Daniore, ChangWon C. Lee, Ariadna Tibau, Thomas Grischott, Thomas J. Rosemann, Aaron S. Kesselheim
Journal: JAMA Oncology (2021)

<h3>Importance</h3> The high cost of cancer medicines is a public health challenge. Policy makers in the US and Europe are debating reforms to drug pricing that would cover both the prices of new medicines when entering the market and price increases after they are launched. <h3>Objective</h3> To assess launch prices, postlaunch price changes, and clinical benefit of cancer drugs in the US compared with 3 European countries (England, Germany, and Switzerland). <h3>Design, Setting, and Participants</h3> This economic evaluation identified all new drugs that were approved for use in the US, England, Germany, and Switzerland with initial indications for treatment of adult solid tumor and hematologic cancers. Analysis included drugs approved by the US Food and Drug Administration between January 1, 2009, and December 31, 2019, and by the European Medicines Agency and Swissmedic until December 31, 2019. Prices were adjusted for currency and inflation. Clinical benefit of drugs indicated for solid tumors was assessed using the American Society of Clinical Oncology Value Framework and European Society for Medical Oncology Magnitude of Clinical Benefit Scale. Using Spearman rank correlation coefficients, correlations between clinical benefit and launch prices and postlaunch price changes for each country were evaluated. <h3>Main Outcomes and Measures</h3> Launch prices, postlaunch price changes, and clinical benefit of cancer drugs. <h3>Results</h3> The cohort included 65 drugs: 47 (72%) approved for solid tumors and 18 (28%) for hematologic cancers. In all countries, the lowest median monthly treatment costs at launch were greater in 2018-2019 vs 2009-2010: $14 580 vs $5790 in the US, $5888 vs $4289 in Germany, $6593 vs $5784 in Switzerland, and $6867 vs $3939 in England. Between 2009 and 2019, 48 of 65 (74%) cancer drugs had price increases in the US that were greater than inflation. Only 1 of 62 (2%) drugs in England, 0 of 60 drugs in Germany, and 7 of 56 drugs (13%) in Switzerland had a median price increase greater than inflation. There were no associations between launch prices or postlaunch price changes and clinical benefit in any assessed country. <h3>Conclusions and Relevance</h3> During this economic evaluation study period, launch prices of cancer drugs were substantially higher in the US than in the assessed similar high-income European countries, a gap that increased in the years after approval. Cancer drug prices frequently increased faster than inflation in the US but decreased on inflation-adjusted terms in Europe. Price changes were not associated with clinical benefit in any country.
PSEN1-selective gamma-secretase inhibition in combination with kinase or XPO-1 inhibitors effectively targets T cell acute lymphoblastic leukemia
Authors: Inge Govaerts, Cristina Prieto, Charlien Vandersmissen, Olga Gielen, Kris Jacobs, Sarah Provost, David Nittner, Johan Maertens, Nancy Boeckx, Kim De Keersmaecker, Heidi Segers, Jan Cools
Journal: Journal of Hematology & Oncology (2021)

Abstract Background T cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype that comprises 10–15% of childhood and 20–25% of adult ALL cases. Over 70% of T-ALL patients harbor activating mutations in the NOTCH1 signaling pathway and are predicted to be sensitive to gamma-secretase inhibitors. We have recently demonstrated that selective inhibition of PSEN1-containing gamma-secretase complexes can overcome the dose-limiting toxicity associated with broad gamma-secretase inhibitors. In this study, we developed combination treatment strategies with the PSEN1-selective gamma-secretase inhibitor MRK-560 and other targeted agents (kinase inhibitors ruxolitinib and imatinib; XPO-1 inhibitor KPT-8602/eltanexor) for the treatment of T-ALL. Methods We treated T-ALL cell lines in vitro and T-ALL patient-derived xenograft (PDX) models in vivo with MRK-560 alone or in combination with other targeted inhibitors (ruxolitinib, imatinib or KPT-8602/eltanexor). We determined effects on proliferation of the cell lines and leukemia development and survival in the PDX models. Results All NOTCH1-signaling-dependent T-ALL cell lines were sensitive to MRK-560 and its combination with ruxolitinib or imatinib in JAK1- or ABL1-dependent cell lines synergistically inhibited leukemia proliferation. We also observed strong synergy between MRK-560 and KPT-8602 (eltanexor) in all NOTCH1-dependent T-ALL cell lines. Such synergy was also observed in vivo in a variety of T-ALL PDX models with NOTCH1 or FBXW7 mutations. Combination treatment significantly reduced leukemic infiltration in vivo and resulted in a survival benefit when compared to single treatment groups . We did not observe weight loss or goblet cell hyperplasia in single drug or combination treated mice when compared to control. Conclusions These data demonstrate that the antileukemic effect of PSEN1-selective gamma-secretase inhibition can be synergistically enhanced by the addition of other targeted inhibitors. The combination of MRK-560 with KPT-8602 is a highly effective treatment combination, which circumvents the need for the identification of additional mutations and provides a clear survival benefit in vivo. These promising preclinical data warrant further development of combination treatment strategies for T-ALL based on PSEN1-selective gamma-secretase inhibition.
Local memory CD4 T cell niches in respiratory viral infection
Authors: Kurt B. Pruner, Marion Pepper
Journal: The Journal of Experimental Medicine (2021)

Respiratory viral infections present a major threat to global health and prosperity. Over the past century, several have developed into crippling pandemics, including the SARS-CoV-2 virus. Although the generation of neutralizing serum antibodies in response to natural immunity and vaccination are considered to be hallmarks of viral immune protection, antibodies from long-lived plasma cells are subject to immune escape from heterologous clades of zoonotic, recombined, or mutated viruses. Local immunity in the lung can be generated through resident memory immune subsets that rapidly respond to secondary infection and protect from heterologous infection. Although many immune cells are required to achieve the phenomenon of resident memory, herein we highlight the pleiotropic functions of CD4 tissue resident memory T cells in the lung and discuss the implications of resident memory for vaccine design.
An Analysis of Methylome Evolution in Primates
Authors: Arne Sahm, Philipp Koch, Steve Horvath, Steve Hoffmann
Journal: Molecular Biology and Evolution (2021)

Although the investigation of the epigenome becomes increasingly important, still little is known about the long-term evolution of epigenetic marks and systematic investigation strategies are still lacking. Here, we systematically demonstrate the transfer of classic phylogenetic methods such as maximum likelihood based on substitution models, parsimony, and distance-based to interval-scaled epigenetic data. Using a great apes blood data set, we demonstrate that DNA methylation is evolutionarily conserved at the level of individual CpGs in promotors, enhancers, and genic regions. Our analysis also reveals that this epigenomic conservation is significantly correlated with its transcription factor binding density. Binding sites for transcription factors involved in neuron differentiation and components of AP-1 evolve at a significantly higher rate at methylation than at the nucleotide level. Moreover, our models suggest an accelerated epigenomic evolution at binding sites of BRCA1, chromobox homolog protein 2, and factors of the polycomb repressor 2 complex in humans. For most genomic regions, the methylation-based reconstruction of phylogenetic trees is at par with sequence-based reconstruction. Most strikingly, phylogenetic reconstruction using methylation rates in enhancer regions was ineffective independently of the chosen model. We identify a set of phylogenetically uninformative CpG sites enriched in enhancers controlling immune-related genes.
A Magnetic Resonance Imaging Index to Predict Crohn’s Disease Postoperative Recurrence: The MONITOR Index
Authors: Marion Schaefer, Valérie Laurent, Aurélie Grandmougin, Lucine Vuitton, Arnaud Bourreille, Amandine Luc, Isabelle Clerc-Urmes, Xavier Orry, Eric Frampas, Marjolaine De Billy, Lieven Pouillon, Catherine Le Berre, Claire Gay, Jeremy Meyer, Cédric Baumann, Laurent Peyrin-Biroulet
Journal: Clinical Gastroenterology and Hepatology (2021)
KLF2 Mediates the Suppressive Effect of Laminar Flow on Vascular Calcification by Inhibiting Endothelial BMP/SMAD1/5 Signaling
Authors: Juan Huang, Yujie Pu, Hongsong Zhang, Liping Xie, Lei He, Cheng-Lin Zhang, Chak Kwong Cheng, Yingsong Huo, Song Wan, Shaoliang Chen, Yuhong Huang, Chi Wai Lau, Li Wang, Yin Xia, Yu Huang, Jiang-Yun Luo
Journal: Circulation Research (2021)

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Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells
Authors: Andrew J. Schwartz, Joshua W. Goyert, Sumeet Solanki, Samuel A. Kerk, Brandon Chen, Cristina Castillo, Peggy P. Hsu, Brian T. Do, Rashi Singhal, Michael K. Dame, Ho-Joon Lee, Jason R. Spence, Samira Lakhal-Littleton, Matthew G. Vander Heiden, Costas A. Lyssiotis, Xiang Xue, Yatrik M. Shah
Journal: Nature Metabolism (2021)
Generation of systemic antitumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel
Authors: Kai Han, Jutaek Nam, Jin Xu, Xiaoqi Sun, Xuehui Huang, Olamide Animasahun, Abhinav Achreja, Jin Heon Jeon, Benjamin Pursley, Nobuhiko Kamada, Grace Y. Chen, Deepak Nagrath, James J. Moon
Journal: Nature Biomedical Engineering (2021)
Abstract 419: Admission to Hospital With Ongoing Resuscitation - Are There Survivors?
Authors: Stephan Seewald, Jan Wnent, Jan-Thorsten Gräsner, Andreas Bohn, Matthias Fischer, Barbara Jakisch
Journal: Circulation (2019)

Introduction: The Emergency Medical Service Systems (EMS) in Germany are physician-based and provided by a two-tier system: One unit comprises physician staffing, and the second paramedics. Both units are simultaneously dispatched for a CPR call and are to arrive on scene at the same time. The physicians are allowed to terminate resuscitation efforts on scene or to indicate a transport to hospital under ongoing resuscitation.The aim of this study was to find out which patient survived after hospital admission with ongoing resuscitation. Materials and Methods: Data from the German Resuscitation Registry from the period 2014-2018, which have documented a hospital admission under ongoing resuscitation, will be examined. We excluded all patients without information on hospital outcome. Results: During the period, 7.146 patients were admitted to hospital under ongoing CPR. We included 2,884 patients with complete information on hospital outcome in this study. Of those, 73% were male and, on average, 62.2 years old. In 52% of all cases, mechanical chest compression devices were used. 12% of all patients admitted to hospital with ongoing resuscitation survived 24 hours and 4% can discharged alive, 2% with good neurological outcome (CPC ½). Patients survived to hospital discharge were younger (57.4 vs. 62.4 years), more male (79% vs. 73%) and have a shorter resuscitation free interval (3:49 vs. 4:53 min). If the patients can discharge alive, the initial rhythm were more often VF/pVT (71% vs. 30%) and more often the emergency physician presumed a cardiac cause of the arrest (79% vs. 67%). The rate of bystander resuscitation (39% vs. 36%) and telephone-guided CPR is similar between the two groups (18% vs. 16%). Conclusions: At all, 4% of all patients admitted to hospital under ongoing CPR can be discharged alive. The discharged patients are younger, more often male and have more often a cardiac cause of the arrest. More detailed analyses are necessary to define criteria for transport under ongoing resuscitation.
Artificial Intelligence, Social Media, and Suicide Prevention: Principle of Beneficence Besides Respect for Autonomy
Authors: Hui Zhang, Yuming Wang, Zhenxiang Zhang, Fangxia Guan, Hongmei Zhang, Zhiping Guo
Journal: The American Journal of Bioethics (2021)

The target article by Laacke et al. (2021) focuses on the specific context of identifying people in social media with a high risk of depression by using artificial intelligence (AI) technologies. I...
Diagnostic endoscopic submucosal dissection for invasive cancer with the four cardinal points traction strategy.
Authors: Pierre Lafeuille, Jérôme Rivory, Jérémie Jacques, Florian Rostain, Paul Bonniaud, Thomas Lambin, Mathieu Pioche
Journal: Endoscopy (2021)

Endoscopic submucosal dissection (ESD) is the reference technique to achieve en bloc resection of a superficial neoplasm located in the gastrointestinal tract [1]. Nevertheless, this method is technically challenging, can be time-consuming, and is often reserved for experts. New strategies to facilitate the procedure are requested. Although countertraction strategies by enlarging the submucosal space, like in the clip and rubber band approach, make dissection easier in the front of the lesion, lateral side and distal incisions are sometimes difficult to dissect because of the angle effect [2] [3] [4] [5]. Therefore, to avoid these limitations, we propose the new "four cardinal points strategy" to apply traction to the complete lesion with a wire with four loops attached at four opposite edges after circumferential incision.
Mobocertinib: A Potential Treatment for NSCLC with EGFR Exon 20 Insertions
Authors: Jose M. Pacheco
Journal: Cancer Discovery (2021)

Amivantamab is the only FDA-approved therapy for non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions. Unfortunately, patients eventually develop progression of disease on this therapy, and most do not respond to this treatment. In this issue of Cancer Discovery, Gonzalvez and colleagues and Riely and colleagues highlight preclinical and early clinical data supporting mobocertinib as a potentially efficacious agent for NSCLC with EGFR exon 20 insertions.See related article by Riely et al., p. 1688.See related article by Gonzalvez et al., p. 1672.
Prognostic Impact of Past History of Other Malignancies in Diffuse Large B Cell Lymphoma
Authors: Kazuna Tanba, Yoshiaki Chinen, Hitoji Uchiyama, Nobuhiko Uoshima, Kazuho Shimura, Shin-ichi Fuchida, Miki Kiyota, Mitsushige Nakao, Yuji Shimura, Tsutomu Kobayashi, Shigeo Horiike, Katsuya Wada, Chihiro Shimazaki, Hiroto Kaneko, Yutaka Kobayashi, Masafumi Taniwaki, Junya Kuroda
Journal: Blood (2017)
Secretin activates brown fat and induces satiation
Authors: Sanna Laurila, Lihua Sun, Minna Lahesmaa, Katharina Schnabl, Kirsi Laitinen, Riku Klén, Yongguo Li, Miroslav Balaz, Christian Wolfrum, Katja Steiger, Tarja Niemi, Markku Taittonen, Mueez U-Din, Tommi Välikangas, Laura L. Elo, Olli Eskola, Anna K. Kirjavainen, Lauri Nummenmaa, Kirsi A. Virtanen, Martin Klingenspor, Pirjo Nuutila
Journal: Nature Metabolism (2021)
Gonadal Function Recovery in Patients With Advanced Hodgkin Lymphoma Treated With a PET-Adapted Regimen: Prospective Analysis of a Randomized Phase III Trial (AHL2011)
Authors: Isabelle Demeestere, Judith Racape, Julie Dechene, Jehan Dupuis, Franck Morschhauser, Virginie De Wilde, Julien Lazarovici, Hervé Ghesquieres, Mohamed Touati, David Sibon, Magda Alexis, Anne-Claire Gac, Hannah Moatti, Emmanuelle Virelizier, Hervé Maisonneuve, Delphine Pranger, Roch Houot, Luc-Matthieu Fornecker, Adrian Tempescul, Marc André, René-Olivier Casasnovas
Journal: Journal of Clinical Oncology (2021)

The prospective, randomized AHL2011 trial demonstrated that the use of the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (ABVD) after two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPescalated) in early responders on the basis of a positron emission tomography (PET)-driven strategy was safe and minimized toxicity compared with standard 6 BEACOPPescalated cycles. This substudy investigated the benefit of this strategy in gonadal function and fertility in patients under 45 years old.Ovarian function was assessed by serum measurement of follicle-stimulating hormone (FSH), estradiol, and anti-müllerian hormone in women, and semen analysis, FSH, and testosterone levels were used to evaluate testicular function in men at baseline, end of treatment, and during 5 years of follow-up.A total of 145 women and 424 men, enrolled between May 19, 2011, and April 29, 2014, were included. The risk of premature ovarian insufficiency (FSH > 24 IU/L) and of having a low ovarian reserve (anti-müllerian hormone < 0.5 ng/mL) was reduced after treatment in the PET-driven group (odds ratio [OR], 0.20; 95% CI, 0.08 to 0.50; P = .001 and OR, 0.15; 95% CI, 0.04 to 0.56, P = .005, respectively). Both parameters were correlated with age and dose of alkylating agents. However, no significant differences were observed in terms of pregnancy rates. Men in the PET-driven group had a higher recovery rate of sperm parameters after treatment compared with the standard BEACOPPescalated group, as well as a lower risk of severe testicular damage (OR, 0.26; 95% CI, 0.13 to 0.5; P < .0001) and a higher likelihood of achieving pregnancy (OR, 3.7; 95% CI, 1.4 to 9.3; P = .004).Although both treatments affected ovarian reserve and spermatogenesis, the PET-driven strategy decreased the risk of gonadal dysfunction and infertility in advanced Hodgkin lymphoma.
The efficacy of lapine preconditioned or genetically modified IL4 over-expressing bone marrow-derived mesenchymal stromal cells in corticosteroid-associated osteonecrosis of the femoral head in rabbits
Authors: Masahiro Maruyama, Seyedsina Moeinzadeh, Roberto Alfonso Guzman, Ning Zhang, Hunter W. Storaci, Takeshi Utsunomiya, Elaine Lui, Elijah Ejun Huang, Claire Rhee, Qi Gao, Zhenyu Yao, Michiaki Takagi, Yunzhi Peter Yang, Stuart B. Goodman
Journal: Biomaterials (2021)
VP5-2021: IMpower133: Gene expression (GE) analysis in long-term survivors (LTS) with ES-SCLC treated with first-line carboplatin and etoposide (CE) ± atezolizumab (atezo)
Authors: S.V. Liu, T.S.K. Mok, A.S. Mansfield, R.H. De Boer, G. Losonczy, S. Sugawara, M.J. Krzakowski, A. Smolin, M.J. Hochmair, M.C. Garassino, C.M. Gay, J.V. Heymach, L.A. Byers, M. McCleland, B.Y. Nabet, S. Morris, L. Adler, D. Shames, M. Reck
Journal: Annals of Oncology (2021)
Physiological Traits and Adherence to Sleep Apnea Therapy in Individuals with Coronary Artery Disease
Authors: Andrey V. Zinchuk, Jen-hwa Chu, Jiasheng Liang, Yeliz Celik, Sara Op de Beeck, Nancy S. Redeker, Andrew Wellman, H. Klar Yaggi, Yüksel Peker, Scott A. Sands
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Untreated obstructive sleep apnea (OSA) is associated with adverse outcomes in patients with coronary artery disease (CAD). Continuous positive airway pressure (CPAP) is the most common treatment, but despite interventions addressing established adherence determinants, CPAP use remains poor. Objectives: To determine whether physiological traits that cause OSA are associated with long-term CPAP adherence in patients with CAD. Methods: Participants in the RICCADSA (Randomized Intervention with CPAP in CAD and OSA) trial with objective CPAP adherence (h/night) over 2 years and analyzable raw polysomnography data were included (N = 249). The physiological traits-loop gain, arousal threshold (ArTH), pharyngeal collapsibility (Vpassive), and pharyngeal muscle compensation (Vcomp)-were measured by using polysomnography. Linear mixed models were used to assess the relationship between the traits and adherence. We also compared actual CPAP adherence between those with physiologically predicted "poor" adherence (lowest quartile of predicted adherence) and those with physiologically predicted "good" adherence (all others). Measurements and Main Results: The median (interquartile range) CPAP use declined from 3.2 (1.0-5.8) h/night to 3.0 (0.0-5.6) h/night over 24 months (P < 0.001). In analyses adjusted for demographics, anthropometrics, OSA characteristics, and clinical comorbidities, a lower ArTH was associated with worse CPAP adherence (0.7 h/SD of the ArTH; P = 0.021). Both high and low Vcomp were associated with lower adherence (P = 0.008). Those with predicted poor adherence exhibited markedly lower CPAP use than those with predicted good adherence for up to 2 years of follow-up (group differences of 2.0-3.2 h/night; P < 0.003 for all). Conclusions: A low ArTH, as well as a very low and high Vcomp, are associated with worse long-term CPAP adherence in patients with CAD and OSA. Physiological traits-alongside established determinants-may help predict and improve CPAP adherence. Clinical trial registered with www.clinicaltrials.gov (NCT00519597).
Cardiac, renal, and metabolic effects of sodium–glucose co‐transporter 2 inhibitors: a position paper from the European Society of Cardiology ad‐hoc task force on sodium–glucose co‐transporter 2 inhibitors
Authors: William G. Herrington, Gianluigi Savarese, Richard Haynes, Nikolaus Marx, Linda Mellbin, Lars H. Lund, Paul Dendale, Petar Seferovic, Giuseppe Rosano, Natalie Staplin, Colin Baigent, Francesco Cosentino
Journal: European Journal of Heart Failure (2021)
Systematic profiling of SARS-CoV-2-specific IgG epitopes at amino acid resolution
Authors: Huan Qi, Ming-liang Ma, He-wei Jiang, Jian-ya Ling, Ling-yun Chen, Hai-nan Zhang, Dan-yun Lai, Yang Li, Zi-wen Guo, Chuan-sheng Hu, Shu-juan Guo, Qing-feng Meng, Yan Ren, Xiao Yang, Wei Wang, Jie Zhou, Xiao-dong Zhao, Hua Li, Sheng-ce Tao
Journal: Cellular and Molecular Immunology (2021)
Humoral and Cellular Immune Responses to SARS–CoV‐2 Infection and Vaccination in Autoimmune Disease Patients With B Cell Depletion
Authors: David Simon, Koray Tascilar, Katja Schmidt, Bernhard Manger, Leonie Weckwerth, Maria Sokolova, Laura Bucci, Filippo Fagni, Karin Manger, Florian Schuch, Monika Ronneberger, Axel Hueber, Ulrike Steffen, Dirk Mielenz, Martin Herrmann, Thomas Harrer, Arnd Kleyer, Gerhard Krönke, Georg Schett
Journal: Arthritis & Rheumatology (2021)

Objective B cell depletion is an established therapeutic principle in a wide range of autoimmune diseases. However, B cells are also critical for inducing protective immunity after infection and vaccination. We undertook this study to assess humoral and cellular immune responses after infection with or vaccination against SARS–CoV‐2 in patients with B cell depletion and controls who are B cell–competent. Methods Antibody responses (tested using enzyme‐linked immunosorbent assay) and T cell responses (tested using interferon‐γ enzyme‐linked immunospot assay) against the SARS–CoV‐2 spike S1 and nucleocapsid proteins were assessed in a limited number of previously infected (n = 6) and vaccinated (n = 8) autoimmune disease patients with B cell depletion, as well as previously infected (n = 30) and vaccinated (n = 30) healthy controls. Results As expected, B cell and T cell responses to the nucleocapsid protein were observed only after infection, while respective responses to SARS–CoV‐2 spike S1 were found after both infection and vaccination. A SARS–CoV‐2 antibody response was observed in all vaccinated controls (30 of 30 [100%]) but in none of the vaccinated patients with B cell depletion (0 of 8). In contrast, after SARS–CoV‐2 infection, both the patients with B cell depletion (spike S1, 5 of 6 [83%]; nucleocapsid, 3 of 6 [50%]) and healthy controls (spike S1, 28 of 30 [93%]; nucleocapsid, 28 of 30 [93%]) developed antibodies. T cell responses against the spike S1 and nucleocapsid proteins were found in both infected and vaccinated patients with B cell depletion and in the controls. Conclusion These data show that B cell depletion completely blocks humoral but not T cell SARS–CoV‐2 vaccination response. Furthermore, limited humoral immune responses are found after SARS–CoV‐2 infection in patients with B cell depletion.