tbuckley/cabot-search huggingface dataset:
Triplet Therapy with Palbociclib, Taselisib, and Fulvestrant in<i>PIK3CA</i>-Mutant Breast Cancer and Doublet Palbociclib and Taselisib in Pathway-Mutant Solid Cancers
Authors: Javier Pascual, Joline S.J. Lim, Iain R. Macpherson, Anne C. Armstrong, Alistair Ring, Alicia F.C. Okines, Rosalind J. Cutts, Maria Teresa Herrera-Abreu, Isaac Garcia-Murillas, Alex Pearson, Sarah Hrebien, Heidrun Gevensleben, Paula Z. Proszek, Michael Hubank, Margaret Hills, Jenny King, Mona Parmar, Toby Prout, Laura Finneran, Jason Malia, Karen E. Swales, Ruth Ruddle, Florence I. Raynaud, Alison Turner, Emma Hall, Timothy A. Yap, Juanita S. Lopez, Nicholas C. Turner
Journal: Cancer Discovery (2020)

Abstract Cyclin-dependent kinase 4/6 (CDK4/6) and PI3K inhibitors synergize in PIK3CA-mutant ER-positive HER2-negative breast cancer models. We conducted a phase Ib trial investigating the safety and efficacy of doublet CDK4/6 inhibitor palbociclib plus selective PI3K inhibitor taselisib in advanced solid tumors, and triplet palbociclib plus taselisib plus fulvestrant in 25 patients with PIK3CA-mutant, ER-positive HER2-negative advanced breast cancer. The triplet therapy response rate in PIK3CA-mutant, ER-positive HER2-negative cancer was 37.5% [95% confidence interval (CI), 18.8–59.4]. Durable disease control was observed in PIK3CA-mutant ER-negative breast cancer and other solid tumors with doublet therapy. Both combinations were well tolerated at pharmacodynamically active doses. In the triplet group, high baseline cyclin E1 expression associated with shorter progression-free survival (PFS; HR = 4.2; 95% CI, 1.3–13.1; P = 0.02). Early circulating tumor DNA (ctDNA) dynamics demonstrated high on-treatment ctDNA association with shorter PFS (HR = 5.2; 95% CI, 1.4–19.4; P = 0.04). Longitudinal plasma ctDNA sequencing provided genomic evolution evidence during triplet therapy. SIGNIFICANCE: The triplet of palbociclib, taselisib, and fulvestrant has promising efficacy in patients with heavily pretreated PIK3CA-mutant ER-positive HER2-negative advanced breast cancer. A subset of patients with PIK3CA-mutant triple-negative breast cancer derived clinical benefit from palbociclib and taselisib doublet, suggesting a potential nonchemotherapy targeted approach for this population. This article is highlighted in the In This Issue feature, p. 1
Domestic HPV vaccine price and economic returns for cervical cancer prevention in China: a cost-effectiveness analysis
Authors: Zhuoru Zou, Christopher K Fairley, Jason J Ong, Jane Hocking, Karen Canfell, Xiaomeng Ma, Eric P F Chow, Xianglong Xu, Lei Zhang, Guihua Zhuang
Journal: The Lancet Global Health (2020)

Coinciding with the release of the first Chinese domestic human papillomavirus (HPV) vaccine Cecolin in 2019, and the substantial advancements in cervical cancer screening technology, we aimed to evaluate the cost-effectiveness of the combined strategies of cervical cancer screening programmes and universal vaccination of girls (aged 9-14 years) with Cecolin in China.We did a cost-effectiveness analysis in China, in which we developed a Markov model of cervical cancer to evaluate the incremental cost-effectiveness ratios of 61 intervention strategies, including a combination of various screening methods at different frequencies with and without vaccination, and also vaccination alone, from a health-care system perspective. We did univariate and probabilistic sensitivity analyses to assess the robustness of the model's findings.Compared with no intervention, various combined screening and vaccination strategies would incur an additional cost of US$6 157 000-22 146 000 and result in 691-970 quality-adjusted life-years (QALYs) gained in a designated cohort of 100 000 girls aged 9-14 years over a lifetime. With a willingness-to-pay threshold of three times the Chinese per-capita gross domestic product (GDP), careHPV screening (a rapid HPV test) once every 5 years with vaccination would be the most cost-effective strategy with an incremental cost-effectiveness ratio of $21 799 per QALY compared with the lower-cost non-dominated strategy on the cost-effectiveness frontier, and the probability of it being cost-effective (44%) outperformed other strategies. Strategies that combined screening and vaccination would be more cost-effective than screening alone strategies when the vaccination cost was less than $50 for two doses, even with a lower willingness-to-pay of one times the per-capita GDP.careHPV screening once every 5 years with vaccination is the most cost-effective strategy for cervical cancer prevention in China. A reduction in the domestic HPV vaccine price is necessary to ascertain a good economic return for the future vaccination programme. The findings provide important evidence that informs health policies for cervical cancer prevention in China.National Natural Science Foundation of China.
The risk of respiratory tract infections in patients with psoriasis treated with interleukin 23 pathway–inhibiting biologics: A meta-estimate of pivotal trials relevant to decision making during the COVID-19 pandemic
Authors: Maha N. Syed, Daniel B. Shin, Marilyn T. Wan, Kevin L. Winthrop, Joel M. Gelfand
Journal: Journal of the American Academy of Dermatology (2020)
A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma
Authors: Franck Morschhauser, Pierre Feugier, Ian W. Flinn, Robin Gasiorowski, Richard Greil, Árpád Illés, Nathalie A. Johnson, Jean-François Larouche, Pieternella J. Lugtenburg, Caterina Patti, Gilles A. Salles, Marek Trněný, Sven de Vos, Farheen Mir, Divya Samineni, Su Y. Kim, Yanwen Jiang, Elizabeth Punnoose, Arijit Sinha, Emma Clark, Nathalie Spielewoy, Kathryn Humphrey, Alexandra Bazeos, Andrew D. Zelenetz
Journal: Blood (2020)
CD122-Selective IL2 Complexes Reduce Immunosuppression, Promote Treg Fragility, and Sensitize Tumor Response to PD-L1 Blockade
Authors: Justin M. Drerup, Yilun Deng, Sri Lakshmi Pandeswara, Álvaro S. Padrón, Ryan M. Reyes, Xinyue Zhang, Jenny Mendez, Aijie Liu, Curtis A. Clark, Wanjiao Chen, José R. Conejo-Garcia, Vincent Hurez, Harshita Gupta, Tyler J. Curiel
Journal: Cancer Research (2020)

The IL2 receptor (IL2R) is an attractive cancer immunotherapy target that controls immunosuppressive T regulatory cells (Treg) and antitumor T cells. Here we used IL2Rβ-selective IL2/anti-IL2 complexes (IL2c) to stimulate effector T cells preferentially in the orthotopic mouse ID8agg ovarian cancer model. Despite strong tumor rejection, IL2c unexpectedly lowered the tumor microenvironmental CD8+/Treg ratio. IL2c reduced tumor microenvironmental Treg suppression and induced a fragile Treg phenotype, helping explain improved efficacy despite numerically increased Tregs without affecting Treg in draining lymph nodes. IL2c also reduced Treg-mediated, high-affinity IL2R signaling needed for optimal Treg functions, a likely mechanism for reduced Treg suppression. Effector T-cell IL2R signaling was simultaneously improved, suggesting that IL2c inhibits Treg functions without hindering effector T cells, a limitation of most Treg depletion agents. Anti-PD-L1 antibody did not treat ID8agg, but adding IL2c generated complete tumor regressions and protective immune memory not achieved by either monotherapy. Similar anti-PD-L1 augmentation of IL2c and degradation of Treg functions were seen in subcutaneous B16 melanoma. Thus, IL2c is a multifunctional immunotherapy agent that stimulates immunity, reduces immunosuppression in a site-specific manner, and combines with other immunotherapies to treat distinct tumors in distinct anatomic compartments. SIGNIFICANCE: These findings present CD122-targeted IL2 complexes as an advancement in cancer immunotherapy, as they reduce Treg immunosuppression, improve anticancer immunity, and boost PD-L1 immune checkpoint blockade efficacy in distinct tumors and anatomic locations.
Correspondence on ‘Systemic evaluation of the relationship between psoriasis, psoriatic arthritis and osteoporosis: observational and Mendelian randomisation study’
Authors: Young Ho Lee
Journal: Annals of the Rheumatic Diseases (2020)

With great interest, I have read the article by Xia et al ,1 which evaluated the relationship between psoriasis, psoriatic arthritis (PsA) and osteoporosis. This Mendelian randomisation (MR) study suggests that the effect of PsA on osteoporosis is secondary, but not causal. However, it is important to discuss some methodological issues in MR. First, MR is a powerful tool for analysing causal relationships between exposures and outcomes because of minimisation of residual confounding.2 3 However, MR is often vulnerable to bias resulting from pleiotropy.2 Therefore, the use of a variety of robust methods working in diverse ways and relying on different assumptions has been recommended to derive valid …
Building resilient societies after COVID-19: the case for investing in maternal, neonatal, and child health
Authors: Chandni Maria Jacob, Despina D Briana, Gian Carlo Di Renzo, Neena Modi, Flavia Bustreo, Gabriella Conti, Ariadne Malamitsi-Puchner, Mark Hanson
Journal: The Lancet Public Health (2020)

SummaryResilient societies respond rapidly and effectively to health challenges and the associated economic consequences, and adapt to be more responsive to future challenges. Although it is only possible to recognise resilience retrospectively, the COVID-19 pandemic has occurred at a point in human history when, uniquely, sufficient knowledge is available on the early-life determinants of health to indicate clearly that a focus on maternal, neonatal, and child health (MNCH) will promote later resilience. This knowledge offers an unprecedented opportunity to disrupt entrenched strategies and to reinvest in MNCH in the post-COVID-19 so-called new normal. Furthermore, analysis of the short-term, medium-term, and longer-term consequences of previous socioeconomic shocks provides important insights into those domains of MNCH, such as neurocognitive development and nutrition, for which investment will generate the greatest benefit. Such considerations apply to high-income countries (HICs) and low-income and middle-income countries (LMICs). However, implementing appropriate policies in the post-COVID-19 recovery period will be challenging and requires political commitment and public engagement.
A Decade of Disparities in Diabetes Technology Use and HbA1c in Pediatric Type 1 Diabetes: A Transatlantic Comparison
Authors: Ananta Addala, Marie Auzanneau, Kellee Miller, Werner Maier, Nicole Foster, Thomas Kapellen, Ashby Walker, Joachim Rosenbauer, David M. Maahs, Reinhard W. Holl
Journal: Diabetes Care (2020)

As diabetes technology use in youth increases worldwide, inequalities in access may exacerbate disparities in hemoglobin A
Correspondence on ‘Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort’
Authors: Maria Vincenza Mastrolia, Rino Agostiniani, Chiara Azzari, Roberto Bernardini, Ugo Bottone, Giovanni Battista Calabri, Flavio Civitelli, Rita Consolini, Roberto Danieli, Rosalia Di Silvio, Susanna Falorni, Luigi Gagliardi, Salvatore Grosso, Marco Martini, Graziano Memmini, Diego Peroni, Marco Pezzati, Giovanni Suriano, Luca Tafi, Angelina Vaccaro, Pier Luigi Vasarri, Gabriele Simonini
Journal: Annals of the Rheumatic Diseases (2020)

We read with interest the clinical study entitled ‘Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort’ by Pouletty et al .1 In this series, the authors suggest that paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PMIS-TS) may represent a new inflammatory syndrome, different from classical Kawasaki disease (KD) as it occurs at an older age, and with a higher frequency of severe myocarditis.1

Likewise to this study, our Pediatric Tuscany Network (PTN)—16 paediatric units serving a region of 593 606 people aged less than 18 years—worked out the COVASAKI survey to detect the incidence of PMIS-TS cases and the eventual rise of KD in Tuscany during COVID-19 pandemic. Between 1 February 2000 and 30 June 2020, we tracked children with PMIS-TS and KD, aiming to compare the number of KD cases in the same 5 months of the previous 5 years and overall with the total number in the last 5 years.

No PMIS-TS cases were reported in our region. Ten KD children were diagnosed in 5 units (incidence two per month). Demographics, clinical and imaging findings, treatment and outcome of patients are reported in table 1. No specific intensive support was required. No coronary involvement was reported. Nasopharyngeal swabs (performed in 7/10) and serological …
Drug-Induced Arrhythmias: A Scientific Statement From the American Heart Association
Authors: James E. Tisdale, Mina K. Chung, Kristen B. Campbell, Muhammad Hammadah, Jose A. Joglar, Jacinthe Leclerc, Bharath Rajagopalan
Journal: Circulation (2020)

Many widely used medications may cause or exacerbate a variety of arrhythmias. Numerous antiarrhythmic agents, antimicrobial drugs, psychotropic medications, and methadone, as well as a growing list of drugs from other therapeutic classes (neurological drugs, anticancer agents, and many others), can prolong the QT interval and provoke torsades de pointes. Perhaps less familiar to clinicians is the fact that drugs can also trigger other arrhythmias, including bradyarrhythmias, atrial fibrillation/atrial flutter, atrial tachycardia, atrioventricular nodal reentrant tachycardia, monomorphic ventricular tachycardia, and Brugada syndrome. Some drug-induced arrhythmias (bradyarrhythmias, atrial tachycardia, atrioventricular node reentrant tachycardia) are significant predominantly because of their symptoms; others (monomorphic ventricular tachycardia, Brugada syndrome, torsades de pointes) may result in serious consequences, including sudden cardiac death. Mechanisms of arrhythmias are well known for some medications but, in other instances, remain poorly understood. For some drug-induced arrhythmias, particularly torsades de pointes, risk factors are well defined. Modification of risk factors, when possible, is important for prevention and risk reduction. In patients with nonmodifiable risk factors who require a potentially arrhythmia-inducing drug, enhanced electrocardiographic and other monitoring strategies may be beneficial for early detection and treatment. Management of drug-induced arrhythmias includes discontinuation of the offending medication and following treatment guidelines for the specific arrhythmia. In overdose situations, targeted detoxification strategies may be needed. Awareness of drugs that may cause arrhythmias and knowledge of distinct arrhythmias that may be drug-induced are essential for clinicians. Consideration of the possibility that a patient's arrythmia could be drug-induced is important.
A Decision-Making Algorithm for Children With Suspected Coronavirus Disease 2019
Authors: Lauren Ha, David Mizrahi, Kirsten K. Ness
Journal: JAMA Pediatrics (2020)

weight across the life span certainly warrant exploration.However, the focus of our study was specifically to investigate the role of energy-balance behaviors in mediating the association between video game use and BMI in childhood.Inclusion of aggression, or other emotional drivers of weight, was therefore beyond the scope of the study.Additionally, while we agree that previous research suggests there is an association between aggression and BMI, 2 we also note that the evidence for an association between aggression and video game use in childhood is more mixed.For example, a meta-analysis of 101 video game studies in children found minimal associations between video game use and childhood aggression. 3Furthermore, a previous longitudinal study using the same data set as our study (the UK-based Millenium Cohort) found no association between video game use at age 5 years and conduct problems at age 7 years (the only measure of aggression available in this data set). 4This suggests it is unlikely that conduct problems (as an indicator of aggression) would have been considered for inclusion as a mediator within our final model had we explored this association.It is also important to highlight that in the United Kingdom, children are restricted in their ability to buy violent video games by the Pan-European Game Information age rating system. 5This means video game use in our sample of 5-year-old children is unlikely to have included violent games, which are of particular concern in relation to aggressive behaviors. 6 We therefore feel that the inclusion of aggression as a potential mediator was not appropriate for this study.However, this is certainly an interesting area of research and future studies could consider exploring these associations further in cohorts of older teenagers and young adults, using appropriate measures of aggression and stress.
Abstract 13838: Efficacy and Safety of Sacubitril/Valsartan in Acute Decompensated Heart Failure in High-Risk Patients in the PIONEER-HF Trial
Authors: David D Berg, Eric J Velazquez, Carol I Duffy, Yared Gurmu, Eugene Braunwald, David A Morrow
Journal: Circulation (2019)

Introduction: In pts stabilized during hospitalization (hosp) for acute decompensated heart failure (ADHF), initiation of sacubitril/valsartan (sac/val) compared with enalapril (enal) decreases the...
Issues and recommendations from the OHBM COBIDAS MEEG committee for reproducible EEG and MEG research
Authors: Cyril Pernet, Marta I. Garrido, Alexandre Gramfort, Natasha Maurits, Christoph M. Michel, Elizabeth Pang, Riitta Salmelin, Jan Mathijs Schoffelen, Pedro A. Valdes-Sosa, Aina Puce
Journal: Nature Neuroscience (2020)
Wide QRS Complex Tachycardia With a Dominant R-Wave in Lead aVR—Is It Ventricular Tachycardia?
Authors: Xiao-yan Yang, Xin-tian Song, Yi Zhang
Journal: JAMA Internal Medicine (2020)

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Cardiac output improvement by pecavaptan: a novel dual‐acting vasopressin <scp>V1a/V2</scp> receptor antagonist in experimental heart failure
Authors: Thomas Mondritzki, Thuy Anh Mai, Julia Vogel, Elisabeth Pook, Pierre Wasnaire, Carsten Schmeck, Jörg Hüser, Wilfried Dinh, Hubert Truebel, Peter Kolkhof
Journal: European Journal of Heart Failure (2020)

Aims Arginine vasopressin (AVP) mediates deleterious effects via vascular V1a and renal V2 receptors in heart failure (HF). Despite positive short‐term decongestive effects in phase II HF studies, selective V2 receptor antagonism has shown no long‐term mortality benefit, potentially related to unopposed V1a receptor activation. We compared the novel dual V1a/V2 receptor antagonist pecavaptan with the selective V2 receptor antagonist tolvaptan in pre‐clinical HF models. Methods and results In vitro IC50 determination in recombinant cell lines revealed similar receptor selectivity profiles (V2:V1a) of tolvaptan and pecavaptan for human and dog AVP receptors, respectively. Two canine models were used to compare haemodynamic and aquaretic effects: (i) anaesthetised dogs with tachypacing‐induced HF, and (ii) conscious telemetric dogs with a non‐invasive cardiac output (CO) monitor. Tolvaptan and pecavaptan exhibited no differences in urinary output. In HF dogs, pecavaptan counteracted the AVP‐induced increase in afterload and decrease in CO (pecavaptan: 1.83 ± 0.31 L/min; vs. tolvaptan: 1.46 ± 0.07 L/min, P &lt; 0.05). In conscious telemetric animals, pecavaptan led to a significant increase in CO (+0.26 ± 0.17 L/min, P = 0.0086 vs. placebo), in cardiac index (+0.58 ± 0.39 L/min/m 2 , P = 0.009 vs. placebo) and a significant decrease in total peripheral resistance (−5348.6 ± 3601.3 dyn × s/cm 5 , P &lt; 0.0001 vs. placebo), whereas tolvaptan was without any significant effect. Conclusions Simultaneous blockade of vascular V1a and renal V2 receptors efficiently induces aquaresis and counteracts AVP‐mediated haemodynamic aggravation in HF models. Dual V1a/V2 antagonism may lead to improved outcomes in HF.
Apo AI Nanoparticles Delivered Post Myocardial Infarction Moderate Inflammation
Authors: Adele L. Richart, Medini Reddy, Mina Khalaji, Alaina L. Natoli, Sarah E. Heywood, Andrew L. Siebel, Graeme L. Lancaster, Andrew J. Murphy, Andrew L. Carey, Brian G. Drew, Svetlana A. Didichenko, Alexei V. Navdaev, Bronwyn A. Kingwell
Journal: Circulation Research (2020)

Rationale: Decades of research have examined immune-modulatory strategies to protect the heart after an acute myocardial infarction and prevent progression to heart failure but have failed to translate to clinical benefit. Objective: To determine anti-inflammatory actions of n-apo AI (Apo AI nanoparticles) that contribute to cardiac tissue recovery after myocardial infarction. Methods and Results: Using a preclinical mouse model of myocardial infarction, we demonstrate that a single intravenous bolus of n-apo AI (CSL111, 80 mg/kg) delivered immediately after reperfusion reduced the systemic and cardiac inflammatory response. N-apo AI treatment lowered the number of circulating leukocytes by 30±7% and their recruitment into the ischemic heart by 25±10% (all P &lt;5.0×10 −2 ). This was associated with a reduction in plasma levels of the clinical biomarker of cardiac injury, cardiac troponin-I, by 52±17% ( P =1.01×10 −2 ). N-apo AI reduced the cardiac expression of chemokines that attract neutrophils and monocytes by 60% to 80% and lowered surface expression of integrin CD11b on monocytes by 20±5% (all P &lt;5.0×10 −2 ). Fluorescently labeled n-apo AI entered the infarct and peri-infarct regions and colocalized with cardiomyocytes undergoing apoptosis and with leukocytes. We further demonstrate that n-apo AI binds to neutrophils and monocytes, with preferential binding to the proinflammatory monocyte subtype and partially via SR-BI (scavenger receptor BI). In patients with type 2 diabetes, we also observed that intravenous infusion of the same n-apo AI (CSL111, 80 mg/kg) similarly reduced the level of circulating leukocytes by 12±5% (all P &lt;5.0×10 −2 ). Conclusions: A single intravenous bolus of n-apo AI delivered immediately post–myocardial infarction reduced the systemic and cardiac inflammatory response through direct actions on both the ischemic myocardium and leukocytes. These data highlight the anti-inflammatory effects of n-apo AI and provide preclinical support for investigation of its use for management of acute coronary syndromes in the setting of primary percutaneous coronary interventions.