tbuckley/cabot-search huggingface dataset:
Overcoming Adaptive Resistance to KRAS Inhibitors Through Vertical Pathway Targeting
Authors: Rona Yaeger, David B. Solit
Journal: Clinical Cancer Research (2020)

KRAS G12C inhibitors have shown promise in KRAS G12C-mutant lung cancer but intrinsic and acquired resistance are common. Cotreatment with inhibitors of the protein phosphatase SHP2 can abrogate the adaptive response of cancer cells to KRAS inhibitors resulting in greater suppression of MAPK signaling and enhanced tumor growth inhibition.See related article by Ryan et al., p. 1633.
Lung cancer: CT screening in former or current smokers significantly reduces mortality, study finds
Authors: Susan Mayor
Journal: BMJ (2020)

Regular computed tomographic (CT) screening in current and former smokers reduces lung cancer mortality by around a quarter at 10 years, a large randomised trial suggests.1

“There can no longer be any doubt as to the efficacy of periodic low-dose CT screening in reducing mortality from lung cancer,” said Stephen Duffy, professor of cancer screening at Queen Mary University of London, and John Field, professor of molecular oncology at the University of Liverpool, in an editorial2 published alongside the study results in the New England Journal of Medicine .

“The task for evaluation is …
The pseudoallergen receptor MRGPRX2 on peripheral blood basophils and eosinophils: Expression and function
Authors: Bettina Wedi, Manuela Gehring, Alexander Kapp
Journal: Allergy (2020)

Abstract Background Mas‐related G protein‐coupled receptor X2 (MRGPRX2) is regarded as a mast cell‐specific receptor mediating non–IgE‐dependent activation. We aimed to investigate whether human basophils and eosinophils express functional MRGPRX2. Methods Flow cytometry, immunocytochemistry, immunofluorescence, Western blot, and RT‐PCR were performed in highly purified peripheral blood basophils and eosinophils of atopic and nonatopic donors. To assess functional activity, fluorescent avidin‐based degranulation assay, calcium mobilization, cytokine production in supernatants, assessment of viability/apoptosis, and tricolor granulocyte activation test were used. Results MRGPRX2 was significantly expressed by basophils and eosinophils but not neutrophils. Functional capacity was shown by anti‐MRGPRX2 mAb‐induced calcium influx and concentration‐dependent induction of degranulation. Sequential stimulation in the calcium mobilization assay gave no evidence for desensitization or receptor internalization. Anti‐MRGPRX2 mAb significantly promoted survival. Inhibition of apoptosis could be due to released IL‐3, IL‐5, and GM‐CSF found in supernatants. Short‐term incubation with IL‐3 dose‐dependently upregulated MRGPRX2 expression in both, stimulation for 24 hours with anti‐IgE, C5a, fMLP, and IL‐3 in basophils and by IL‐3, IL‐5, and IL‐33 in eosinophils. Among known mast cell MRGPRX2 agonists ciprofloxacin but not PMX‐53 was functional on basophils and eosinophils. In basophils of allergic subjects, tricolor granulocyte activation test using grass pollen demonstrated MRGPRX2 upregulation associated with degranulation and CD63 expression. Conclusion Unraveling the regulation and signaling mechanisms of MRGPRX2 on basophils and eosinophils might enable the development of new therapeutic strategies to prevent or inhibit allergic and nonallergic hypersensitivity. Moreover, addressing MRGPRX2 might have potential for diagnostic purposes in (drug) hypersensitivity.
Use of argon plasma coagulation to successfully retrieve a snare forceps stuck in a laser-cut covered self-expandable metal biliary stent
Authors: Koichiro Mandai, Koji Uno, Azumi Suzuki, Kiyohito Tanaka, Kenjiro Yasuda
Journal: Endoscopy (2020)

A 77-year-old man who had undergone chemotherapy for distal biliary cancer was admitted to our hospital for obstructive jaundice due to stent occlusion. A laser-cut covered self-expandable metal stent (CSEMS; fully covered X-Suit NIR; Olympus Medical Systems, Tokyo, Japan) had been placed 12 months earlier for malignant biliary stenosis. We decided to replace the laser-cut CSEMS with a new CSEMS. The stent was held with a snare forceps (SD-5U-1; Olympus Medical Systems) and pulled towards the papilla, but it could not be removed from the bile duct ([Fig. 1 a]). We tried to retrieve the snare forceps, but the snare became stuck in the stent ([Fig. 1 b]). The endoscope was removed, leaving the snare forceps in place ([Fig. 1 c]), and was reinserted along the forceps to cut the snare. The snare could not be cut using a Loop Cutter (FS-5Q-1; Olympus Medical Systems) ([Fig. 1 d]). Argon plasma coagulation (APC; VIO300 D with APC2, at 80 W with a flow rate of 2 L/min; ERBE Elektromedizin, Tubingen, Germany) was then used, and the snare was successfully cut ([Video 1]). The snare forceps was retrieved and a new CSEMS was inserted within the laser-cut CSEMS.
Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency
Authors: Scott B. Drutman, Davood Mansouri, Seyed Alireza Mahdaviani, Anna-Lena Neehus, David Hum, Ruslana Bryk, Nicholas Hernandez, Serkan Belkaya, Franck Rapaport, Benedetta Bigio, Robert Fisch, Mahbuba Rahman, Taushif Khan, Fatima Al Ali, Majid Marjani, Nahal Mansouri, Lazaro Lorenzo-Diaz, Jean-François Emile, Nico Marr, Emmanuelle Jouanguy, Jacinta Bustamante, Laurent Abel, Stéphanie Boisson-Dupuis, Vivien Béziat, Carl Nathan, Jean-Laurent Casanova
Journal: New England Journal of Medicine (2020)

Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitric oxide synthase 2 (Nos2) are susceptible to the related murine CMV infection.We studied a previously healthy 51-year-old man from Iran who after acute CMV infection had an onset of progressive CMV disease that led to his death 29 months later. We hypothesized that the patient may have had a novel type of inborn error of immunity. Thus, we performed whole-exome sequencing and tested candidate mutant alleles experimentally.We found a homozygous frameshift mutation in NOS2 encoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, all NOS2 variants that we found in homozygosity in public databases encoded functional proteins, as did all other variants with an allele frequency greater than 0.001.These findings suggest that inherited NOS2 deficiency was clinically silent in this patient until lethal infection with CMV. Moreover, NOS2 appeared to be redundant for control of other pathogens in this patient. (Funded by the National Center for Advancing Translational Sciences and others.).
DNA Methylation Is Predictive of Mortality in Current and Former Smokers
Authors: Jarrett D. Morrow, Barry Make, Elizabeth Regan, MeiLan Han, Craig P. Hersh, Ruth Tal-Singer, John Quackenbush, Augustine M. K. Choi, Edwin K. Silverman, Dawn L. DeMeo
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Smoking results in at least a decade lower life expectancy. Mortality among current smokers is two to three times as high as never smokers. DNA methylation is an epigenetic modification of the human genome that has been associated with both cigarette smoking and mortality.Objectives: We sought to identify DNA methylation marks in blood that are predictive of mortality in a subset of the COPDGene (Genetic Epidemiology of COPD) study, representing 101 deaths among 667 current and former smokers.Methods: We assayed genome-wide DNA methylation in non-Hispanic white smokers with and without chronic obstructive pulmonary disease (COPD) using blood samples from the COPDGene enrollment visit. We tested whether DNA methylation was associated with mortality in models adjusted for COPD status, age, sex, current smoking status, and pack-years of cigarette smoking. Replication was performed in a subset of 231 individuals from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study.Measurements and Main Results: We identified seven CpG sites associated with mortality (false discovery rate < 20%) that replicated in the ECLIPSE cohort (P < 0.05). None of these marks were associated with longitudinal lung function decline in survivors, smoking history, or current smoking status. However, differential methylation of two replicated PIK3CD (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta) sites were associated with lung function at enrollment (P < 0.05). We also observed associations between DNA methylation and gene expression for the PIK3CD sites.Conclusions: This study is the first to identify variable DNA methylation associated with all-cause mortality in smokers with and without COPD. Evaluating predictive epigenomic marks of smokers in peripheral blood may allow for targeted risk stratification and aid in delivery of future tailored therapeutic interventions.
Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome
Authors: Jesper J. Linde, Henning Kelbæk, Thomas F. Hansen, Per E. Sigvardsen, Christian Torp-Pedersen, Jan Bech, Merete Heitmann, Olav W. Nielsen, Dan Høfsten, Jørgen T. Kühl, Ilan E. Raymond, Ole P. Kristiansen, Ida H. Svendsen, Maria H.D. Vall-Lamora, Charlotte Kragelund, Martina de Knegt, Jens D. Hove, Tem Jørgensen, Gitte G. Fornitz, Rolf Steffensen, Birgit Jurlander, Jawdat Abdulla, Stig Lyngbæk, Hanne Elming, Susette K. Therkelsen, Erik Jørgensen, Lene Kløvgaard, Lia Evi Bang, Peter Riis Hansen, Steffen Helqvist, Søren Galatius, Frants Pedersen, Ulrik Abildgaard, Peter Clemmensen, Kari Saunamäki, Lene Holmvang, Thomas Engstrøm, Gunnar Gislason, Lars V. Køber, Klaus F. Kofoed
Journal: Journal of the American College of Cardiology (2020)
Corticosteroid injections: glass half-full, half-empty or full then empty?
Authors: John W Orchard
Journal: British Journal of Sports Medicine (2020)

Cortisone is the most common class of injection in musculoskeletal medicine. Expert guidelines, such as the 2017 edition of Therapeutic Guidelines: Rheumatology (Australia),1 generally recommend corticosteroid injections (CSI) as a treatment for most tendon and joint pain conditions (including those listed in table 1). I quote, ‘local corticosteroid injections should only be given by, or under the supervision of, clinicians with appropriate training and experience’.1 I find it remarkable that the guidelines do not spell out that cortisone injections should only be given where high-quality evidence shows that benefits outweigh the harms; that is, the widespread recommendations to use CSI for multiple joints and multiple tendons are ‘eminence-based’ (who should give them) rather than ‘evidence-based’ (when they should be given).

View this table:

Table 1 
Comparison of short-term (mainly benefit) versus long-term effects (possible harm) of corticosteroid injection for common indications



To be fair, I see that ‘appropriate training’ could cover ‘knowing the indications’ for a treatment but at a time where medical overtreatment is incontrovertible—it exists and no one denies it exists—I argue that the case for ‘indication-based treatment’ should be explicit.

Systematic reviews have examined whether cortisone injections are beneficial or harmful. A typical systematic review concludes as per the text in box 1. This conclusion was from a 2002 systematic review on the use of CSI for tennis …
Long-Term Safety and Efficacy of Durable Polymer Cobalt-Chromium Everolimus-Eluting Stents in Patients at High Bleeding Risk
Authors: Sabato Sorrentino, Bimmer E. Claessen, Rishi Chandiramani, Paul Guedeney, Birgit Vogel, Usman Baber, Vinuta Rau, Jin Wang, Mitchell Krucoff, Ken Kozuma, Junbo Ge, Ashok Seth, Raj Makkar, Yuqi Liu, Sripal Bangalore, Deepak L. Bhatt, Dominick J. Angiolillo, Shigeru Saito, Franz-Josef Neumann, James Hermiller, Marco Valgimigli, Roxana Mehran
Journal: Circulation (2020)

Long-term outcomes in patients at high bleeding risk (HBR) undergoing percutaneous coronary intervention with a drug-eluting stent are unclear. Therefore, we aimed to evaluate long-term adverse events in HBR patients undergoing percutaneous coronary intervention with cobalt-chromium everolimus-eluting stent implantation.We analyzed stratified data from 4 all-comers postapproval registries. Patients with at least 1 of the following criteria were categorized as HBR: age ≥75 years, history of major bleeding (MB), history of stroke, chronic oral anticoagulant use, chronic kidney disease, anemia, or thrombocytopenia. Additionally, in a separate analysis, patients were categorized according to the recently published Academic Research Consortium HBR criteria. The Kaplan-Meier method was used for time-to-event analyses. Coronary thrombotic events (CTE) included myocardial infarction or definite/probable stent thrombosis. MB was defined according to the TIMI (Thrombolysis in Myocardial Infarction) or GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) scales. Impact of CTE and MB on subsequent risk of mortality was assessed using multivariable Cox regression with MB and CTE included as time-updated covariates.Of the total 10 502 patients included, 3507 (33%) were identified as HBR. Compared with non-HBR patients, those at HBR had more comorbidities, higher lesion complexity, and a higher risk of 4-year mortality (Hazard Ratio [HR] 4.38 [95% CI, 3.76-5.11]). Results were qualitatively similar when using Academic Research Consortium criteria to define HBR. Risk of mortality was increased after CTE (HR 5.02 [95% CI, 3.93-6.41]), as well as after MB (HR 4.92 [95% CI, 3.82-6.35]). Of note, this effect was consistent across the spectrum of bleeding risk (P-interaction test 0.97 and 0.06, respectively).Compared with the non-HBR population, HBR patients experienced worse 4-year outcomes after percutaneous coronary intervention with cobalt-chromium everolimus-eluting stent. Both CTE and MB had a significant impact on subsequent risk of mortality irrespective of bleeding risk.
How We Approach Smoldering Multiple Myeloma
Authors: Noopur Raje, Andrew J. Yee
Journal: Journal of Clinical Oncology (2020)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
Practical Guide to Qualitative Analysis
Authors: Margaret L. Schwarze, Amy H. Kaji, Amir A. Ghaferi
Journal: JAMA Surgery (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
The Future of Biosimilars: Maximizing Benefits Across Immune-Mediated Inflammatory Diseases
Authors: HoUng Kim, Rieke Alten, Luisa Avedano, Axel Dignass, Fernando Gomollón, Kay Greveson, Jonas Halfvarson, Peter M. Irving, Jørgen Jahnsen, Péter L. Lakatos, JongHyuk Lee, Souzi Makri, Ben Parker, Laurent Peyrin-Biroulet, Stefan Schreiber, Steven Simoens, Rene Westhovens, Silvio Danese, Ji Hoon Jeong
Journal: Drugs (2020)

Biologics have transformed the treatment of immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Biosimilars—biologic medicines with no clinically meaningful differences in safety or efficacy from licensed originators—can stimulate market competition and have the potential to expand patient access to biologics within the parameters of treatment recommendations. However, maximizing the benefits of biosimilars requires cooperation between multiple stakeholders. Regulators and developers should collaborate to ensure biosimilars reach patients rapidly without compromising stringent quality, safety, or efficacy standards. Pharmacoeconomic evaluations and payer policies should be updated following biosimilar market entry, minimizing the risk of imposing nonmedical barriers to biologic treatment. In RA, disparities between treatment guidelines and national reimbursement criteria could be addressed to ensure more uniform patient access to biologics and enable rheumatologists to effectively implement treat-to-target strategies. In IBD, the cost-effectiveness of biologic treatment earlier in the disease course is likely to improve when biosimilars are incorporated into pharmacoeconomic analyses. Patient understanding of biosimilars is crucial for treatment success and avoiding nocebo effects. Full understanding of biosimilars by physicians and carefully considered communication strategies can help support patients initiating or switching to biosimilars. Developers must operate efficiently to be sustainable, without undermining product quality, the reliability of the supply chain, or pharmacovigilance. Developers should also facilitate information sharing to meet the needs of other stakeholders. Such collaboration will help to ensure a sustainable future for both the biosimilar market and healthcare systems, supporting the availability of effective treatments for patients.
頭頸部の再発性もしくは転移性扁平上皮癌におけるスニチニブの第2相試験: GORTEC 2006-01
Authors: H Machiels Jean-Pascal, Henry Stephanie, Zanetta Sylvie, Kaminsky Marie-Christine, Michoux Nicolas, Rommel Denis, Schmitz Sandra, Bompas Emmanuelle, Dillies Anne-Francoise, Faivre Sandrine, Moxhon Anne, Duprez Thierry, Guigay Joel
Journal: Journal of Clinical Oncology (2010)
Human volatilome analysis using eNose to assess uncontrolled asthma in a clinical setting
Authors: Mariana Farraia, João Cavaleiro Rufo, Inês Paciência, Francisca Castro Mendes, Ana Rodolfo, Tiago Rama, Sílvia M. Rocha, Luís Delgado, Paul Brinkman, André Moreira
Journal: Allergy (2020)

Abstract Background Analyses of exhaled volatile organic compounds (VOCs) have shown promising results when distinguishing individuals with asthma. Currently, there are no biomarkers for uncontrolled asthma. Therefore, we aimed to assess, in a real‐life clinical setting, the ability of the exhaled VOC analysis, using an electronic nose (eNose), to identify individuals with uncontrolled asthma. Methods A cross‐sectional study was conducted, and breath samples from 199 participants (130 females, aged 6‐78, 66% with asthma) were analysed using an eNose. A multivariate unsupervised cluster analysis, using the resistance data from 32 sensors, could distinguish three clusters of VOC patterns in the training and testing groups. Comparisons between the clusters were performed using the one‐way ANOVA, Kruskal‐Wallis and chi‐squared tests. Results In the training set (n = 121), three different clusters covering asthma, lung function, symptoms in the previous 4 weeks and age were identified. The pairwise comparisons showed significant differences with respect to chest tightness during exercise, dyspnoea and gender. These findings were confirmed in the testing set (n = 78) where the training model identified three clusters. The participants who reported fewer respiratory symptoms (dyspnoea and night‐time awakenings) were grouped into one cluster, while the others comprised participants who showed similar poor control over symptoms with the distribution of the individuals with asthma being significantly different between them. Conclusions In a clinical setting, the analysis of the exhaled VOC profiles using an eNose could be used as a fast and noninvasive complementary assessment tool for the detection of uncontrolled asthma symptoms.
A Phase I Study of Safety, Pharmacokinetics, and Pharmacodynamics of Concurrent Everolimus and Buparlisib Treatment in Advanced Solid Tumors
Authors: Taofeek K. Owonikoko, R. Donald Harvey, Bradley Carthon, Zhengjia Chen, Colleen Lewis, Hanna Collins, Chao Zhang, David H. Lawson, Olatunji B. Alese, Mehmet Asim Bilen, Gabriel L. Sica, Conor E. Steuer, Walid L. Shaib, Christina Wu, Wayne B. Harris, Mehmet Akce, Ragini R. Kudchagkar, Bassel F. El-Rayes, Sagar Lonial, Suresh S. Ramalingam, Fadlo Raja Khuri
Journal: Clinical Cancer Research (2020)

Concurrent inhibition of mTOR and PI3K led to improved efficacy in preclinical models and provided the rationale for this phase I study of everolimus and buparlisib (BKM120) in patients with advanced solid tumor.We used the Bayesian Escalation with Overdose Control design to test escalating doses of everolimus (5 or 10 mg) and buparlisib (20, 40, 60, 80, and 100 mg) in eligible patients. Pharmacokinetic assessment was conducted using blood samples collected on cycle 1, days 8 and 15. Pharmacodynamic impact on mTOR/PI3K pathway modulation evaluated in paired skin biopsies collected at baseline and end of cycle 1.We enrolled 43 patients, median age of 63 (range, 39-78) years; 25 (58.1%) females, 35 (81.4%) Caucasians, and 8 (18.6%) Blacks. The most frequent toxicities were hyperglycemia, diarrhea, nausea, fatigue, and aspartate aminotransferase elevation. Dose-limiting toxicities observed in 7 patients were fatigue (3), hyperglycemia (2), mucositis (1), acute kidney injury (1), and urinary tract infection (1). The recommended phase II dose (RP2D) for the combination was established as everolimus (5 mg) and buparlisib (60 mg). The best response in 27 evaluable patients was progressive disease and stable disease in 3 (11%) and 24 (89%), respectively. The median progression-free survival and overall survival were 2.7 (1.8-4.2) and 9 (6.4-13.2) months. Steady-state pharmacokinetic analysis showed dose-normalized maximum concentrations and AUC values for everolimus and buparlisib in combination to be comparable with single-agent pharmacokinetic.The combination of everolimus and buparlisib is safe and well-tolerated at the RP2D of 5 and 60 mg on a continuous daily schedule.
Influenza in U.S. Detention Centers — The Desperate Need for Immunization
Authors: Carlo Foppiano Palacios, John J. Openshaw, Mark A. Travassos
Journal: New England Journal of Medicine (2020)

Interview with Dr. Mark Travassos on preventing the spread of influenza among detained migrants and asylum seekers. (09:44)Download Since September 2018, at least seven children have died in U.S. Customs and Border Protection custody, including three from influenza-related complications. Outbreaks and deaths in detention centers point to the need for influenza immunization in these facilities.
Health-Related Quality of Life in Solid Organ Transplant Recipients With vs Without Keratinocyte Carcinoma
Authors: Melvin Frie, Coby Annema, Emily S. X. Knijff, Stephan J. L. Bakker, Adelita V. Ranchor, Michele F. Eisenga, Emöke Rácz
Journal: JAMA Dermatology (2020)

This cross-sectional study compares health-related quality of life between solid organ transplant recipients with vs without keratinocyte carcinoma using the Basal and Squamous Cell Carcinoma Quality of Life questionnaire and the Short Form 36 Health Survey.