tbuckley/cabot-search huggingface dataset:
AB0798 EFFECT OF ANTIRHEUMATIC THERAPY ADMINISTERED IN ACCORDANCE WITH “TREAT TO TARGET” PRINCIPLES ON DIASTOLIC DYSFUNCTION OF THE LEFT VENTRICLES IN PATIENTS WITH ACTIVE EARLY PSORIATIC ARTHRITIS
Authors: E. Markelova
Journal: Annals of the Rheumatic Diseases (2020)

Background: Рsoriatic arthritis (PsA) are chronic inflammatory diseases, with massive increase of cardiovascular events (CVE) and cardiovascular death. Diastolic dysfunction of the left ventricles (LVDD) is a risk factor for the development of the heart failure. Objectives: to study the effect of antirheumatic therapy administered in accordance with “Treat to target” principles on LVDD in early PsA (EPsA) patients (pts). Methods: 48 (F.-23) DMARD-naive PsA pts, according to the CASPAR criteria, age 36[27; 45] years (yrs.), PsA duration – 6[4; 8] months. All pts were assessed for transthoracic echocardiography. Diastolic function was determined by early and atrial peak filling rates derived from differential volume-time-curve analysis. Methotrexate therapy was started in all pts with an escalation of the dose up to 25 mg/week subcutaneously. In case of no remission 3 months later, MT was added with biologic therapy: Adalimumab, Certolizumab pegol, Ustekinumab. Antihypertensive therapy received all pts with arterial hypertension (AH). All p less then 0.05 considered to statistical significance. Results: At baseline LVDD was identified in 5(10.4%). The LVDD pts were older, in more cases they had AH, abdominal obesity (p&lt;0.05). Significant negative correlations were found between LVDD and body mass index (BMI) (r=-0.41), age (r=-0.71), total cholesterol (r=-0.44), triglycerides (r=-0.48), low density lipoproteins (r=-0.44), systolic (r=-0.59) and diastolic blood pressure (r=-0.4), for all p&lt;0,01. By 18 months of therapy significantly decreased DAS from 4.06[3.48; 4.91] to 0,97[0,65;1,48]; C-RP from 19.4 [8.8;37.5] to 2.2 [0.9; 4.6]mg/l, for all p&lt;0,001. DAS remission was achieved in 69% of pts. We didn’t find significant differences between baseline and after treatment the frequency of LVDD – 5(10,4%) to 4(8.3%). Conclusion: in pts with EPsA frequently (10.4%) were detected LVDD, which are associated with a АН, age, higher BMI. Low prevalence LVDD in patients with EPsA is possibly caused by short duration of disease and early start of antirheumatic therapy. This has implications for development of preventive strategies for heart failure in EPsA patients. Disclosure of Interests: None declared
Clinical Development of BRAF plus MEK Inhibitor Combinations
Authors: Vivek Subbiah, Christina Baik, John M. Kirkwood
Journal: Trends in cancer (2020)

Genomic profiling shows that many solid tumors are characterized by specific driver aberrations, and this has expanded the therapeutic options for many patients. The mitogen-activated protein kinase (MAPK) pathway is a key cell signaling pathway involved in regulating cellular growth, proliferation, and survival. Driver mutations in the BRAF gene, a key player in the MAPK pathway, are described in multiple tumor types, including subsets of melanoma, non-small cell lung cancer (NSCLC), and anaplastic thyroid cancer (ATC), making BRAF a desirable target for inhibition. BRAF inhibitors have shown efficacy in several cancers; however, most patients eventually develop resistance. To delay or prevent resistance, combination therapy targeting BRAF and MEK, a downstream signaling target of BRAF in the MAPK pathway, was evaluated and demonstrated synergistic benefit. BRAF and MEK inhibitor combinations have been approved for use in various cancers by the US FDA. We review the clinical data for various BRAF plus MEK combination regimens in three cancer types with underlying BRAF driver mutations: melanoma, NSCLC, and ATC. We also discuss practical treatment considerations and management of selected combination therapy toxicities.
Herb-sourced emodin inhibits angiogenesis of breast cancer by targeting VEGFA transcription
Authors: Gengyi Zou, Xiaotong Zhang, Lun Wang, Xiyang Li, Tianyu Xie, Jin Zhao, Jie Yan, Longlong Wang, Haoyu Ye, Shunchang Jiao, Rong Xiang, Yi Shi
Journal: Theranostics (2020)

Anti-angiogenesis is an important and promising strategy in cancer therapy.However, the current methods using anti-vascular endothelial growth factor A (VEGFA) antibodies or inhibitors targeting VEGFA receptors are not as efficient as expected partly due to their low efficiencies in blocking VEGFA signaling in vivo.Until now, there is still no method to effectively block VEGFA production in cancer cells from the very beginning, i.e., from the transcriptional level.Here, we aimed to find bioactive small molecules to block VEGFA transcription.Methods: We screened our natural compound pool containing 330 small molecules derived from Chinese traditional herbs for small molecules activating the expression of seryl-tRNA synthetase (SerRS), which is a newly identified potent transcriptional repressor of VEGFA, by a cell-based screening system in MDA-MB-231 cell line.The activities of the candidate molecules on regulating SerRS and VEGFA expression were first tested in breast cancer cells.We next investigated the antiangiogenic activity in vivo by testing the effects of candidate drugs on the vascular development in zebrafish and by matrigel plug angiogenesis assay in mice.We further examined the antitumor activities of candidate drugs in two triple-negative breast cancer (TNBC)-bearing mouse models.Furthermore, streptavidin-biotin affinity pull-down assay, coimmunoprecipitation assays, docking analysis and chromatin immunoprecipitation were performed to identify the direct targets of candidate drugs.Results: We identified emodin that could greatly increase SerRS expression in TNBC cells, consequently reducing VEGFA transcription.Emodin potently inhibited vascular development of zebrafish and blocked tumor angiogenesis in TNBC-bearing mice, greatly improving the survival.We also identified nuclear receptor corepressor 2 (NCOR2) to be the direct target of emodin.Once bound by emodin, NCOR2 got released from SerRS promoter, resulting in the activation of SerRS expression and eventually the suppression of VEGFA transcription. Conclusion:We discovered a herb-sourced small molecule emodin with the potential for the therapy of TNBC by targeting transcriptional regulators NCOR2 and SerRS to suppress VEGFA transcription and tumor angiogenesis.
AB0308 NO SIGNS OF CONGESTIVE HEART DISEASE PROGRESSION IN PATIENTS WITH RHEUMATOID ARTHRITIS ON IL-6 RECEPTOR ANTAGONIST AFTER 12 MONTHS TREATMENT
Authors: A. Martynova, T. Popkova, H. Gerasimova
Journal: Annals of the Rheumatic Diseases (2020)

Background: N-terminal pro-brain natriuretic peptide (NT-proBNP) is a known marker of heart dysfunction, mainly described in patients with high activity of rheumatoid arthritis (RA). Further knowledge of the influence of the IL-6 receptor antagonist, tocilizumab (TCZ), on NT-proBNP levels and systolic heart function is yet to be obtained. Objectives: Access the effect of 12 months TCZ therapy on NT-proBNP levels, transthoracal ehocardiography results and analyze the association between congestive heart disease progression and RA activity. Methods: 37 RA patients (pts) (31F/6M); median age 56,5 [48; 63,5] years; disease duration 48 [6; 348] months; DAS28 score 6,15 [5,44; 6,45]; rheumatoid factor (RF)+100%; anti–citrullinated protein antibody (ACPA) + 79,6% were treated in an open-label study with TCZ (8 mg/kg every 4 weeks). Identification of NT-pro-BNT in blood serum, transthoracal ultrasound evaluation of left ventriculum ejection fraction (LVEF), E/A ratio performed at baseline and 12 months. Results: 11 (29,7%) pts had congestive heart disease (CHD) (II functional class of NYHA), 7 (18,9%) pts having signs of mild left ventricular dysfunction (LVD) as dyspnea, shortness of breath, cardiotropic treatment remained the same in the course of the study. After 12 month TCZ treatment as RA activity lowered (DAS28 2.32 [1,75; 3,15], р&lt;0,05), NT-proBNP levels decreased (100,95 [57.9; 117.6] pg/ml to 90,46 [33.62; 106.6] pg/ml), along with elevation of LVEF (60,75 [60; 70]% to 67,68 [62.5; 73.5], p = 0,001). Increase of E/A (0,97 [0.8; 1.17] to 1,04 [0.7; 1.42] correlated with decrease of NT-proBNP level (r = -0,63, p=0,036). Raise of LVEF over 12 months correlated with decrease of RA activity according to SDAI scale (r= -0,670, p&lt;0,05). No significant relationship between NT-proBNP levels, LVEF, E/A and other scales measuring RA activity was found. Clinically all patients had improvement in evaluation of their health and no signs of CHD or RVD progression were found. Conclusion: Use of TCZ in patients with active RA showed none to positive influence on heart condition, specifically, lowering NT-proBNP levels, improving LVEF and reducing clinical signs of LVD. References: [1]Pan Y, Li D, Ma J, Shan L, Wei M. NT-proBNP test with improved accuracy for the diagnosis of chronic heart failure. Medicine (Baltimore). 2017 Dec;96(51):e9181. [2]D Novikova, I Kirillova, E Markelova et al. The first report of significantly improvement of NT-proBNP level in rheumatoid arthritis patients treated with tofacitinib during 12-month follow-up, European Heart Journal, Volume 40, Issue Supplement_1, October 2019, ehz745.0836. [3]Pappas DA, Nyberg F, Kremer JM et al. Clin Rheumatol. 2018 Sep;37(9):2331-2340. Disclosure of Interests: None declared
3D Printing Silicone Elastomer for Patient‐Specific Wearable Pulse Oximeter
Authors: Sara Abdollahi, Eric J. Markvicka, Carmel Majidi, Adam W. Feinberg
Journal: Advanced Healthcare Materials (2020)

Abstract Commercial pulse oximeters are used clinically to measure heart rate and blood oxygen saturation and traditionally made from rigid materials. However, these devices are unsuitable for continuous monitoring due to poor fit and mechanical mismatch. Soft materials that match the elastic properties of biological tissue provide improved comfort and signal‐to‐noise but typically require molding to manufacture, limiting the speed and ease of customizing for patient‐specific anatomy. Here, freeform reversible embedding (FRE) 3D printing is used to create polydimethylsiloxane (PDMS) elastomer cuffs for use on the hand and foot. FRE enables printing liquid PDMS prepolymer in 3D geometries within a sacrificial hydrogel bath that provides support during cure. This serves as proof‐of‐concept for fabricating patient‐specific pulse oximeters with pressure sensing, termed P 3 ‐wearable. A sizing analysis establishes dimensional accuracy of FRE‐printed PDMS compared to anatomical computer‐aided design models. The P 3 ‐wearable successfully outputs photoplethysmography (PPG) and pressure amplitude signals wirelessly to a tablet in real time and the PPG is used to calculate heart rate, blood oxygen content, and activity state. The results establish that FRE printing of PDMS can be used to fabricate patient‐specific wearable devices and measure heart rate and blood oxygenation on par with commercial devices.
Abstract A31: Deregulation of NOTCH 1/NR4A2 signaling axis in head and neck cancer pathogenesis
Authors: Sanjib Chaudhary, Ramesh Pothuraju, Zafar Sayed, Dwight T. Jones, Surinder K. Batra, Muzafar A. Macha
Journal: Clinical Cancer Research (2020)

Abstract Background: Notch1 and its intracellular cytoplasmic domain (NICD) are dysregulated in many solid tumors, including head and neck squamous cell carcinoma (HNSCC), and associated with disease initiation and progression. NICD-mediated upregulation of nuclear receptor related 1 (NURR1/NR4A2) is linked to differentiation/development, homeostasis, and cellular metabolism. However, the role and molecular mechanism(s) of Notch1/NICD- NR4A2 axis in HNSCC pathogenesis are still unknown and need to be investigated. Methods: The clinicopathologic importance of Notch1 and NR4A2 was investigated using HNSCC patient samples and publicly available databases. NR4A2 was stably knocked out (KO) and Notch1 signaling was blocked using small-molecule inhibitor (PF3084014) in HNSCC cell lines and analyzed for tumorigenic and metastatic potential. We also examined the whole-genome NR4A2 target genes using ChIP sequencing. Results: Both Notch1 and NR4A2 were highly overexpressed in HNSCC patients. Inhibition of Notch1 signaling or NR4A2 KO significantly decreased the clonogenicity and migratory potential of HNSCC cells. Our ChIP analysis revealed that NR4A2 regulates genes involved in metabolism, hypoxia, cell cycle progression, integrin and Wnt signaling. Interestingly, we observed that NR4A2 regulates stem cell markers including Sox2, Nanog, and CD44 and their expression was drastically reduced upon Notch 1 inhibition. Conclusion: Targeting Notch1-NR4A2 signaling axis may be crucial for inhibition of cancer stem cell-mediated HNSCC pathogenesis. Citation Format: Sanjib Chaudhary, Ramesh Pothuraju, Zafar Sayed, Dwight T. Jones, Surinder K. Batra, Muzafar A. Macha. Deregulation of NOTCH 1/NR4A2 signaling axis in head and neck cancer pathogenesis [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A31.
Annealing-modulated nanoscintillators for nonconventional X-ray activation of comprehensive photodynamic effects in deep cancer theranostics
Authors: Yao-Chen Chuang, Chia-Hui Chu, Shih-Hsun Cheng, Lun-De Liao, Tsung-Sheng Chu, Nai-Tzu Chen, Arthur Paldino, Yu Hsia, Chin-Tu Chen, Leu-Wei Lo
Journal: Theranostics (2020)

Photodynamic therapy (PDT), which involves the generation of reactive oxygen species (ROS) through interactions of a photosensitizer (PS) with light and oxygen, has been applied in oncology.Over the years, PDT techniques have been developed for the treatment of deep-seated cancers.However, (1) the tissue penetration limitation of excitation photon, (2) suppressed efficiency of PS due to multiple energy transfers, and (3) insufficient oxygen source in hypoxic tumor microenvironment still constitute major challenges facing the clinical application of PDT for achieving effective treatment.We present herein a PS-independent, ionizing radiation-induced PDT agent composed of yttrium oxide nanoscintillators core and silica shell (Y2O3:Eu@SiO2) with an annealing process.Our results revealed that annealed Y2O3:Eu@SiO2 could directly induce comprehensive photodynamic effects under X-ray irradiation without the presence of PS molecules.The crystallinity of Y2O3:Eu@SiO2 was demonstrated to enable the generation of electron-hole (e --h + ) pairs in Y2O3 under ionizing irradiation, giving rise to the formation of ROS including superoxide, hydroxyl radical and singlet oxygen.In particular, combining Y2O3:Eu@SiO2 with fractionated radiation therapy increased radio-resistant tumor cell damage.Furthermore, photoacoustic imaging of tumors showed re-distribution of oxygen saturation (SO2) and reoxygenation of the hypoxia region.The results of this study support applicability of the integration of fractionated radiation therapy with Y2O3:Eu@SiO2, achieving synchronously in-depth and oxygen-insensitive X-ray PDT.Furthermore, we demonstrate Y2O3:Eu@SiO2 exhibited radioluminescence (RL) under X-ray irradiation and observed the virtually linear correlation between X-ray-induced radioluminescence (X-RL) and the Y2O3:Eu@SiO2 concentration in vivo.With the pronounced X-RL for in-vivo imaging and dosimetry, it possesses significant potential for utilization as a precision theranostics producing highly efficient X-ray PDT for deep-seated tumors.
Electrostatic Intraperitoneal Aerosol Delivery of Nanoparticles: Proof of Concept and Preclinical Validation
Authors: Leen Van de Sande, Mohammad Rahimi‐Gorji, Silvia Giordano, Enrico Davoli, Cristina Matteo, Sönke Detlefsen, Katharina D'Herde, Helena Braet, Molood Shariati, Katrien Remaut, Feifan Xie, Charlotte Debbaut, Ghader Ghorbaniasl, Sarah Cosyns, Wouter Willaert, Wim Ceelen
Journal: Advanced Healthcare Materials (2020)

Abstract There is an increasing interest in intraperitoneal delivery of chemotherapy as an aerosol in patients with peritoneal metastasis. The currently used technology is hampered by inhomogenous drug delivery throughout the peritoneal cavity because of gravity, drag, and inertial impaction. Addition of an electrical force to aerosol particles, exerted by an electrostatic field, can improve spatial aerosol homogeneity and enhance tissue penetration. A computational fluid dynamics model shows that electrostatic precipitation (EP) results in a significantly improved aerosol distribution. Fluorescent nanoparticles (NPs) remain stable after nebulization in vitro, while EP significantly improves spatial homogeneity of NP distribution. Next, pressurized intraperitoneal chemotherapy with and without EP using NP albumin bound paclitaxel (Nab‐PTX) in a novel rat model is examined. EP does not worsen the effects of CO 2 insufflation and intraperitoneal Nab‐PTX on mesothelial structural integrity or the severity of peritoneal inflammation. Importantly, EP significantly enhances tissue penetration of Nab‐PTX in the anatomical regions not facing the nozzle of the nebulizer. Also, the addition of EP leads to more homogenous peritoneal tissue concentrations of Nab‐PTX, in parallel with higher plasma concentrations. In conclusion, EP enhances spatial homogeneity and tissue uptake after intraperitoneal nebulization of anticancer NPs.
Radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent radiotherapy and gemcitabine after induction with gemcitabine and carboplatin
Authors: R. M. Michel, D. Gallardo-Rincon, C. Villarreal-Garza, A. Astorga-Ramos, J. Zamora, L. Martinez-Barrera, J. de la Garza, O. Arrieta
Journal: Journal of Clinical Oncology (2009)

e18504 Background: The combination of chemotherapy (CT) and thoracic radiation (RT) is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). The most favorable CT regime, timing of full-dose CT and the best way to combine CT with RT to maximize systemic and radiosensitizing effects remain to be determined. The aim of this study was to assess the efficacy, safety and tolerability of gemcitabine concurrent with RT after induction CT (gemcitabine + carboplatin) in locally advanced NSCLC. Methods: Patients with histologically proven NSCLC IIIA and IIIB received carboplatin (AUC of 2.5) and gemcitabine (800 mg/m 2 ) on day 1 and 8, every 21 days (two cycles), followed by conventional fractioned RT (60Gy) with concomitant weekly gemcitabine 200 mg/m 2 and by consolidation CT. Survival was analyzed with Kaplan-Meier. Results: Median follow-up was of 11.9 months, 11 patients (57.9%) had stage IIIB disease. Patient inclusion was discontinued due to high grade 3/4 radiation pneumonitis events (5/19 patients, 26.3%). One treatment-related death from radiation pneumonitis occurred. The most common hematological side effects grade 3/4 were anemia and neutropenia 3/19 (15.8%) each and thrombocytopenia 4/19 (21.1%) during induction CT. Partial response was observed in 11 patients (57.9%) following induction. After concurrent chemo-radiotherapy, overall response was 68.4%. Four patients underwent surgical resection. Median progression-free survival was 12 ± 1 months (95% CI, 9.8 -14.1). Overall survival was of 21 ± 3.5 months (95% CI, 14–27.9). Conclusions: Concurrent RT with gemcitabine after induction CT with gemcitabine and carboplatin showed a high response rate. However, it is associated with excessive pulmonary toxicity. Adjustments in gemcitabine dosage during RT or changes in RT planning could reduce toxicity. No significant financial relationships to disclose.
Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with <i>BRCA1/2</i>- and Non–<i>BRCA1/2</i>-Mutant Cancers
Authors: Timothy A. Yap, Rebecca Kristeleit, Vasiliki Michalarea, Stephen J. Pettitt, Joline S.J. Lim, Suzanne Carreira, Desamparados Roda, Rowan Miller, Ruth Riisnaes, Susana Miranda, Ines Figueiredo, Daniel Nava Rodrigues, Sarah Ward, Ruth Matthews, Mona Parmar, Alison Turner, Nina Tunariu, Neha Chopra, Heidrun Gevensleben, Nicholas C. Turner, Ruth Ruddle, Florence I. Raynaud, Shaun Decordova, Karen E. Swales, Laura Finneran, Emma Hall, Paul Rugman, Justin P.O. Lindemann, Andrew Foxley, Christopher J. Lord, Udai Banerji, Ruth Plummer, Bristi Basu, Juanita S. Lopez, Yvette Drew, Johann S. de Bono
Journal: Cancer Discovery (2020)

Abstract Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)–deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K–AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3β suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K–AKT pathway alterations. Significance: In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic–pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K–AKT pathway alterations. This article is highlighted in the In This Issue feature, p. 1426