tbuckley/cabot-search huggingface dataset:
Allergenic components of the mRNA‐1273 vaccine for COVID‐19: Possible involvement of polyethylene glycol and IgG‐mediated complement activation
Authors: Ludger Klimek, Natalija Novak, Beatriz Cabanillas, Marek Jutel, Jean Bousquet, Cezmi A. Akdis
Journal: Allergy (2021)

Following the emergency use authorization of the mRNA-1273 vaccine on the 18th of December 2020, two mRNA vaccines are in current use for the prevention of coronavirus disease 2019 (COVID-19). For both mRNA vaccines, the phase III pivotal trials excluded individuals with a history of allergy to vaccine components. Immediately after the initiation of vaccination in the United Kingdom, Canada, and the United States, anaphylactic reactions were reported. While the culprit trigger requires investigation, initial reports suggested the excipient polyethylene glycol 2000 (PEG-2000)-contained in both vaccines as the PEG-micellar carrier system-as the potential culprit. Surface PEG chains form a hydrate shell to increase stability and prevent opsonization. Allergic reactions to such PEGylated lipids can be IgE-mediated, but may also result from complement activation-related pseudoallergy (CARPA) that has been described in similar liposomes. In addition, mRNA-1273 also contains tromethamine (trometamol), which has been reported to cause anaphylaxis to substances such as gadolinium-based contrast media. Skin prick, intradermal and epicutaneous tests, in vitro sIgE assessment, evaluation of sIgG/IgM, and basophil activation tests are being used to demonstrate allergic reactions to various components of the vaccines.
Cardiovascular, Renal, and Metabolic Outcomes of Dapagliflozin Versus Placebo in a Primary Cardiovascular Prevention Cohort: Analyses From DECLARE-TIMI 58
Authors: Avivit Cahn, Itamar Raz, Lawrence A. Leiter, Ofri Mosenzon, Sabina A. Murphy, Erica L. Goodrich, Ilan Yanuv, Aliza Rozenberg, Deepak L. Bhatt, Darren K. McGuire, John P.H. Wilding, Ingrid A.M. Gause-Nilsson, Anna Maria Langkilde, Marc S. Sabatine, Stephen D. Wiviott
Journal: Diabetes Care (2021)

OBJECTIVE International guidelines propose prescribing sodium–glucose cotransporter 2 (SGLT2) inhibitors to patients with type 2 diabetes (T2D) as secondary prevention in patients with established atherosclerotic cardiovascular disease (ASCVD) or for primary prevention of cardiovascular events in high-risk patients with multiple risk factors (MRF) for ASCVD. The current analyses expand on the cardiovascular renal and metabolic effects of SGLT2 inhibitors in MRF patients. RESEARCH DESIGN AND METHODS In DECLARE-TIMI 58, 17,160 patients with T2D and MRF (59.4%) or established ASCVD (40.6%) were randomized to dapagliflozin versus placebo; patients were followed for a median of 4.2 years. The cardiovascular and renal outcomes in the MRF cohort were studied across clinically relevant subgroups for treatment effect and subgroup-based treatment interaction. RESULTS Among patients with MRF, the reduction with dapagliflozin in risk of cardiovascular death or hospitalization for heart failure (CVD/HHF) (hazard ratio [HR] 0.84, 95% CI 0.67–1.04) and the renal-specific outcome (HR 0.51, 95% CI 0.37–0.69) did not differ from that for patients with ASCVD (Pinteraction 0.99 and 0.72, respectively). The effect on CVD/HHF was entirely driven by a reduction in HHF (HR 0.64, 95% CI 0.46–0.88). The benefits of dapagliflozin on HHF and on the renal-specific outcome, among the subset with MRF, were directionally consistent across clinically relevant subgroups. At 48 months, HbA1c, weight, systolic blood pressure, and urinary albumin–to–creatinine ratio were lower with dapagliflozin versus placebo and estimated glomerular filtration rate was higher (P &amp;lt; 0.001). CONCLUSIONS In patients with T2D and MRF, dapagliflozin reduced the risk of HHF and adverse renal outcomes regardless of baseline characteristics. These analyses support the benefit of dapagliflozin for important outcomes in a broad primary prevention population.
VEGFR1 signaling in retinal angiogenesis and microinflammation
Authors: Akiyoshi Uemura, Marcus Fruttiger, Patricia A. D'Amore, Sandro De Falco, Antonia M. Joussen, Florian Sennlaub, Lynne R. Brunck, Kristian T. Johnson, George N. Lambrou, Kay D. Rittenhouse, Thomas Langmann
Journal: Progress in Retinal and Eye Research (2021)

Five vascular endothelial growth factor receptor (VEGFR) ligands (VEGF-A, -B, –C, -D, and placental growth factor [PlGF]) constitute the VEGF family. VEGF-A binds VEGF receptors 1 and 2 (VEGFR1/2), whereas VEGF-B and PlGF only bind VEGFR1. Although much research has been conducted on VEGFR2 to elucidate its key role in retinal diseases, recent efforts have shown the importance and involvement of VEGFR1 and its family of ligands in angiogenesis, vascular permeability, and microinflammatory cascades within the retina. Expression of VEGFR1 depends on the microenvironment, is differentially regulated under hypoxic and inflammatory conditions, and it has been detected in retinal and choroidal endothelial cells, pericytes, retinal and choroidal mononuclear phagocytes (including microglia), Müller cells, photoreceptor cells, and the retinal pigment epithelium. Whilst the VEGF-A decoy function of VEGFR1 is well established, consequences of its direct signaling are less clear. VEGFR1 activation can affect vascular permeability and induce macrophage and microglia production of proinflammatory and proangiogenic mediators. However the ability of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B) to compete against each other for receptor binding and to heterodimerize complicates our understanding of the relative contribution of VEGFR1 signaling alone toward the pathologic processes seen in diabetic retinopathy, retinal vascular occlusions, retinopathy of prematurity, and age-related macular degeneration. Clinically, anti-VEGF drugs have proven transformational in these pathologies and their impact on modulation of VEGFR1 signaling is still an opportunity-rich field for further research.
PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment
Authors: Elliot Israel, Loren C. Denlinger, Leonard B. Bacharier, Lisa M. LaVange, Wendy C. Moore, Michael C. Peters, Steve N. Georas, Rosalind J. Wright, David T. Mauger, Patricia Noel, Praveen Akuthota, Julia Bach, Eugene R. Bleecker, Juan Carlos Cardet, Tara F. Carr, Mario Castro, Angeles Cinelli, Suzy A.A. Comhair, Ronina A. Covar, Laura Crotty Alexander, Emily A. DiMango, Serpil C. Erzurum, John V. Fahy, Merritt L. Fajt, Benjamin M. Gaston, Eric A. Hoffman, Fernando Holguin, Daniel J. Jackson, Sonia Jain, Nizar N. Jarjour, Yuan Ji, Nicholas J. Kenyon, Michael R. Kosorok, Monica Kraft, Jerry A. Krishnan, Rajesh Kumar, Andrew H. Liu, Mark C. Liu, Ngoc P. Ly, M. Alison Marquis, Fernando D. Martinez, James N. Moy, Wanda K. O’Neal, Victor E. Ortega, David B. Peden, Wanda Phipatanakul, Kristie Ross, Lewis J. Smith, Stanley J. Szefler, W. Gerald Teague, Abigail F. Tulchinsky, Pandurangan Vijayanand, Michael E. Wechsler, Sally E. Wenzel, Steven R. White, Amir A. Zeki, Anastasia Ivanova
Journal: Journal of Allergy and Clinical Immunology (2021)
In Vivo Printing of Nanoenabled Scaffolds for the Treatment of Skeletal Muscle Injuries
Authors: Jacob P. Quint, Azadeh Mostafavi, Yori Endo, Adriana Panayi, Carina S. Russell, Atousa Nourmahnad, Chris Wiseman, Laleh Abbasi, Mohamadmahdi Samandari, Amir Sheikhi, Kristo Nuutila, Indranil Sinha, Ali Tamayol
Journal: Advanced Healthcare Materials (2021)

Abstract Extremity skeletal muscle injuries result in substantial disability. Current treatments fail to recoup muscle function, but properly designed and implemented tissue engineering and regenerative medicine techniques can overcome this challenge. In this study, a nanoengineered, growth factor‐eluting bioink that utilizes Laponite nanoclay for the controlled release of vascular endothelial growth factor (VEGF) and a GelMA hydrogel for a supportive and adhesive scaffold that can be crosslinked in vivo is presented. The bioink is delivered with a partially automated handheld printer for the in vivo formation of an adhesive and 3D scaffold. The effect of the controlled delivery of VEGF alone or paired with adhesive, supportive, and fibrilar architecture has not been studied in volumetric muscle loss (VML) injuries. Upon direct in vivo printing, the constructs are adherent to skeletal muscle and sustained release of VEGF. The in vivo printing of muscle ink in a murine model of VML injury promotes functional muscle recovery, reduced fibrosis, and increased anabolic response compared to untreated mice. The in vivo construction of a therapeutic‐eluting 3D scaffold paves the way for the immediate treatment of a variety of soft tissue traumas.
A mussel-inspired supramolecular hydrogel with robust tissue anchor for rapid hemostasis of arterial and visceral bleedings
Authors: Ziwen Qiao, Xueli Lv, Shaohua He, Shumeng Bai, Xiaochen Liu, Linxi Hou, Jingjing He, Dongmei Tong, Renjie Ruan, Jin Zhang, Jianxun Ding, Huanghao Yang
Journal: Bioactive Materials (2021)

In recent years, the developed hemostatic technologies are still difficult to be applied to the hemostasis of massive arterial and visceral hemorrhage, owing to their weak hemostatic function, inferior wet tissue adhesion, and low mechanical properties. Herein, a mussel-inspired supramolecular interaction-cross-linked hydrogel with robust mechanical property (308.47 ± 29.20 kPa) and excellent hemostatic efficiency (96.5% ± 2.1%) was constructed as a hemostatic sealant. Typically, we combined chitosan (CS) with silk fibroin (SF) by cross-linking them through tannic acid (TA) to maintain the structural stability of the hydrogel, especially for wet tissue adhesion ability (shear adhesive strength = 29.66 ± 0.36 kPa). Compared with other materials reported previously, the obtained CS/TA/SF hydrogel yielded a lower amount of blood loss and shorter time to hemostasis in various arterial and visceral bleeding models, which could be ascribed to the synergistic effect of wound closure under wet state as well as intrinsic hemostatic activity of CS. As a superior hemostatic sealant, the unique hydrogel proposed in this work can be exploited to offer significant advantages in the acute wound and massive hemorrhage with the restrictive access of therapeutic moieties.
Long-term survival of favorable-risk patients with metastatic renal cell carcinoma treated with second-line axitinib in a multicenter phase II study.
Authors: Ilya Tsimafeyeu, Pavel S. Borisov, Andrey Semenov, Roman Leonenkov, Olga Novikova, Sergey Gamayunov, Nadezhda Mikhailova, Anastasia Bondarenko, Ahmed Abdelgafur
Journal: Journal of Clinical Oncology (2021)

332 Background: Tyrosine kinase inhibitors remain possible treatment options in favorable risk patients newly diagnosed with metastatic renal cell carcinoma (mRCC). In phase II study (FavorAx), axitinib showed the activity in mRCC patients with a favorable risk and history of prior VEGFR-directed therapy. Here we present the outcomes from expansion study cohort with 4 years follow-up. Methods: Patients were required to have clear-cell mRCC, favorable risk according to IMDC criteria, and to have received first-line treatment with sunitinib or pazopanib. Prior treatment with other agents was not permitted. Axitinib was given orally at a starting dose of 5 mg twice daily with possible dose titration. Treatment was continued until disease progression according to RECIST version 1.1, unacceptable toxicity, death, or withdrawal of consent. All patients were assessed for efficacy. Endpoints included progression-free survival (PFS, primary); overall survival (OS), objective response rate (ORR), and safety (secondary). Results: A total of 55 patients were assessed, 58% of whom were male. Median age was 64 years. 29 (53%) patients had 2 and more metastatic sites. 73% and 27% of patients received first-line sunitinib or pazopanib. The median PFS was 19 months (95% CI, 15–23) and the median OS was 29.4 months (95% CI, 21.5–37). The 4-year OS rate was 36%. The objective response rate was 31% and 2 (3.6%) patients achieved a complete response. Disease progression was the single reason for discontinuation of axitinib. After disease progression, 62% of patients received third-line therapy. The toxicity was consistent with previously reported data. The most common adverse events associated with axitinib were hypertension, fatigue, and diarrhea, each occurring in more than 20% of patients. Conclusions: Second-line axitinib continues to show efficacy in favorable risk patients with mRCC. Long-term OS and PFS were observed with axitinib. Clinical trial information: NCT02700568 .
Methodologic and Reporting Issues in Published Meta-analysis—Reply
Authors: David Fraguas, Covadonga M. Díaz-Caneja, Celso Arango
Journal: JAMA Pediatrics (2021)

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 Pediatrics 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 Pediatrics journal
Androgen Receptor Regulates CD44 Expression in Bladder Cancer
Authors: Joseph L. Sottnik, Lauren Vanderlinden, Molishree Joshi, Ana Chauca-Diaz, Charles Owens, Donna E. Hansel, Colin Sempeck, Debashis Ghosh, Dan Theodorescu
Journal: Cancer Research (2021)

The androgen receptor (AR) is important in the development of both experimental and human bladder cancer. However, the role of AR in bladder cancer growth and progression is less clear, with literature indicating that more advanced stage and grade disease are associated with reduced AR expression. To determine the mechanisms underlying these relationships, we profiled AR-expressing human bladder cancer cells by AR chromatin immunoprecipitation sequencing and complementary transcriptomic approaches in response to
Bilateral disease and risk of prostate cancer progression in an active surveillance cohort.
Authors: Nabila Khondakar, Luke P. O'Connor, Cheyenne Williams, Michael Daneshvar, Jillian Egan, Nitin Yerram, Brad Webster, Maria Merino, Peter L. Choyke, Bradford Wood, Baris Turkbey, Peter A. Pinto
Journal: Journal of Clinical Oncology (2021)

207 Background: Active surveillance (AS) is considered the standard of care for managing patients with low-risk prostate cancer. Identifying risk factors for disease progression on AS can improve risk stratification. As previously described, the presence of bilateral disease may affect disease progression. Current systematic biopsy techniques inadequately predict presence of bilateral disease. We hypothesize that combined mpMRI-guided fusion biopsy and systematic biopsy will improve detection of bilateral disease. Methods: Our institutional database of patients referred for AS from 2007-2020 was queried. All AS patients received combined 12-core systematic biopsy and mpMRI-Fusion biopsy (Cbx), and those with Gleason Grade group 1 (GG1) on confirmatory Cbx were included. Cox regression analysis identified baseline characteristics associated with AS progression, defined as progression to GG ≥ 2. The distributions of GG and National Comprehensive Cancer Network (NCCN) risk categories were also compared. Results: 103 patients with prostate cancer and at least one follow-up biopsy at our institution were included in the analysis. 30% (31/103) had bilateral disease and 70% (72/103) had unilateral disease. On univariable and multivariable analysis, both PSAD (univariable HR = 1.6; 95% CI: 1.1-2.2; multivariable HR = 1.7; CI: 1.2-2.5) and presence of bilateral disease (univariable HR = 2.2; 95% CI: 1.3-4.0; multivariable HR = 2.2; 95% CI: 1.2-4.0) at time of confirmatory biopsy were significantly associated with AS progression. On Kaplan-Meier analysis, median time from Cbx to AS progression ≥ GG2 for the whole cohort was 52 months (95% CI: 44 - 68). The median time to progression for patients with unilateral and bilateral disease was 68 months and 52 months, respectively (log-rank test, p = 0.0055). Bilateral disease was marginally associated with receiving an NCCN score of high or very high on upgraded biopsy (RR: 3.16, 95% CI: 1.004-9.932). NCCN score at time of confirmatory biopsy was not associated with progression. However, NCCNs scores and GG at time of progression were higher among patients with bilateral disease (p = 0.015 and p = 0.024). Ultimately, use of combined biopsy resulted in 16.1% more bilateral cancers detected when compared to systematic biopsy. Conclusions: Detection of bilateral disease using combined biopsy was significantly associated with disease progression in patients on AS. Notably, combined biopsy resulted in greater detection of bilateral disease than systematic biopsy alone. Identifying presence of bilateral disease using combined biopsy could ultimately contribute to management decisions in patients on AS.
Transcriptome programming of IL‐3‐dependent bone marrow‐derived cultured mast cells by stem cell factor (SCF)
Authors: Ying Wang, Kazufumi Matsushita, Jennifer Jackson, Takafumi Numata, Yue Zhang, Gao Zhou, Mindy Tsai, Stephen J. Galli
Journal: Allergy (2021)

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Single-cell DNA targeted sequencing (scDNA-seq) to test therapeutic vulnerabilities in urothelial cancer (UC) patient-derived organoids (PDO).
Authors: Kyrillus Shohdy, Weisi Liu, Alicia Alonso, Jenny Xiang, M. Laura Martin, Olivier Elemento, Bishoy Morris Faltas
Journal: Journal of Clinical Oncology (2021)

464 Background: Genomic alterations in FGFR3, PIK3CA, and CDKN2A are common actionable targets in urothelial cancer (UC). We aimed to determine the efficacy of alpelisib, a PIK3CA inhibitor, and abemaciclib, a CDK4/6 inhibitor in bladder cancer patient-derived organoid using single-cell targeted DNA sequencing. Methods: We established a patient-derived UC organoid (PDO) harboring the FGFR3 mutation (p.Y375C), the PIK3CA (p. E452K) mutation, and CDKN2A deletion, which we characterized using whole-genome sequencing. We generated dose-response curves of alpelisib, abemaciclib, and erdafitinib (an FGFR3 inhibitor) in PDO cells to determine the IC 50 concentrations. The scDNA-seq (Tapsteri) platform was used to measure changes in the variant allele frequencies (VAF) and clonal fractions post-treatment. The Chi-square test for trend was used to test for linear trend across ordered categories. Results: scDNA-seq was performed after treating PDO cells with 3uM erdafitinib or DMSO. A total of 7000 single cells were obtained (4179 cells treated with erdafitinib vs. 2821 cells treated with DMSO). After removing variants mutated in &lt;50% of cells, we identified 94 clonal variants. As expected, cells harboring FGFR3 Y375C have significantly decreased post erdafitinib treatment compared to DMSO-treated cells (66.05% vs. 82.36%, p&lt;0.0001). We identified mutations in two genes ( RAB31 and SMAD4) that were associated with clonal expansion following FGFR3 inhibition (12% vs. 53% and 13% vs. 26%, respectively). We treated PDO cells with 3uM abemaciclib. We identified three genes harboring SNVs ( RB1, GNAQ, and SMAD4). The SNVs harboring cells were significantly decreased after abemaciclib compared to DMSO (p&lt;0.0001). Then, we treated the cells with 1uM alpelisib for 72 hours alone or combined with abemaciclib (0.1uM). We identified that 100% of cells harbored the PIK3CA mutation E452K at pre-treatment, which limited our ability to detect significant changes in VAF post-treatment. Instead, we analyzed the effect on the FGFR3 Y375C clone. Using trend analysis, there was a significant reduction of FGFR3-mutant cells observed across the three conditions, abemaciclib + alpelisib vs. alpelisib alone vs. DMSO (74% vs. 85% vs. 92%, trend test p&lt;0.0001), suggesting in vitro efficacy of alpelisib alone and significant synergism with the addition of abemaciclib. Conclusions: This study established the feasibility of using scDNA-seq as a promising tool to study the clonal evolution patterns in patient-derived UC organoids. Combined pharmacologic inhibition of CDK4/6 and PIK3CA showed more in vitro sensitivity than PIK3CA inhibition alone.
Association of dyspnoea, mortality and resource use in hospitalised patients
Authors: Jennifer P. Stevens, Tenzin Dechen, Richard M. Schwartzstein, Carl R. O'Donnell, Kathy Baker, Robert B. Banzett
Journal: European Respiratory Journal (2021)

As many as one in 10 patients experience dyspnoea at hospital admission but the relationship between dyspnoea and patient outcomes is unknown. We sought to determine whether dyspnoea on admission predicts outcomes.We conducted a retrospective cohort study in a single, academic medical centre. We analysed 67 362 consecutive hospital admissions with available data on dyspnoea, pain and outcomes. As part of the Initial Patient Assessment by nurses, patients rated "breathing discomfort" using a 0 to 10 scale (10="unbearable"). Patients reported dyspnoea at the time of admission and recalled dyspnoea experienced in the 24 h prior to admission. Outcomes included in-hospital mortality, 2-year mortality, length of stay, need for rapid response system activation, transfer to the intensive care unit, discharge to extended care, and 7- and 30-day all-cause readmission to the same institution.Patients who reported any dyspnoea were at an increased risk of death during that hospital stay; the greater the dyspnoea, the greater the risk of death (dyspnoea 0: 0.8% in-hospital mortality; dyspnoea 1-3: 2.5% in-hospital mortality; dyspnoea ≥4: 3.7% in-hospital mortality; p<0.001). After adjustment for patient comorbidities, demographics and severity of illness, increasing dyspnoea remained associated with inpatient mortality (dyspnoea 1-3: adjusted OR 2.1, 95% CI 1.7-2.6; dyspnoea ≥4: adjusted OR 3.1, 95% CI 2.4-3.9). Pain did not predict increased mortality. Patients reporting dyspnoea also used more hospital resources, were more likely to be readmitted and were at increased risk of death within 2 years (dyspnoea 1-3: adjusted hazard ratio 1.5, 95% CI 1.3-1.6; dyspnoea ≥4: adjusted hazard ratio 1.7, 95% CI 1.5-1.8).We found that dyspnoea of any rating was associated with an increased risk of death. Dyspnoea ratings can be rapidly collected by nursing staff, which may allow for better monitoring or interventions that could reduce mortality and morbidity.
Abstract 15957: Cancer Survivorship and Incident Cardiovascular Events in the Aric Study
Authors: Roberta Florido, Natalie R Daya, Silvia Koton, Chiadi E Ndumele, Stuart D Russell, Roger S Blumenthal, Kunihiro Matsushita, Ye Jin Mok, Ashley Felix, Morgan Grams, Josef Coresh, Corinne E Joshu, Elizabeth A Platz, Elizabeth Selvin
Journal: Circulation (2019)

Introduction: Limited retrospective data suggests that cancer survivors may have increased risk of cardiovascular disease (CVD), possibly due to shared risk factors between cancer and CVD, as well ...