tbuckley/cabot-search huggingface dataset:
The MNK1/2–eIF4E Axis Supports Immune Suppression and Metastasis in Postpartum Breast Cancer
Authors: Qianyu Guo, Margarita Bartish, Christophe Gonçalves, Fan Huang, Julian Smith-Voudouris, Sai Sakktee Krisna, Samuel E.J. Preston, Audrey Emond, Vivian Z. Li, Claudia U. Duerr, Yirui Gui, Aurélie Cleret-Buhot, Pamela Thebault, Hanne Lefrère, Liesbeth Lenaerts, Dany Plourde, Jie Su, Barbara C. Mindt, Shannon A. Hewgill, Tiziana Cotechini, Charles C.T. Hindmarch, William Yang, Elie Khoury, Yao Zhan, Valeria Narykina, Yuhong Wei, Giuseppe Floris, Mark Basik, Frédéric Amant, Daniela F. Quail, Réjean Lapointe, Jörg H. Fritz, Sonia V. del Rincon, Wilson H. Miller
Journal: Cancer Research (2021)

Abstract Breast cancer diagnosed within 10 years following childbirth is defined as postpartum breast cancer (PPBC) and is highly metastatic. Interactions between immune cells and other stromal cells within the involuting mammary gland are fundamental in facilitating an aggressive tumor phenotype. The MNK1/2–eIF4E axis promotes translation of prometastatic mRNAs in tumor cells, but its role in modulating the function of nontumor cells in the PPBC microenvironment has not been explored. Here, we used a combination of in vivo PPBC models and in vitro assays to study the effects of inactivation of the MNK1/2–eIF4E axis on the protumor function of select cells of the tumor microenvironment. PPBC mice deficient for phospho-eIF4E (eIF4ES209A) were protected against lung metastasis and exhibited differences in the tumor and lung immune microenvironment compared with wild-type mice. Moreover, the expression of fibroblast-derived IL33, an alarmin known to induce invasion, was repressed upon MNK1/2–eIF4E axis inhibition. Imaging mass cytometry on PPBC and non-PPBC patient samples indicated that human PPBC contains phospho-eIF4E high–expressing tumor cells and CD8+ T cells displaying markers of an activated dysfunctional phenotype. Finally, inhibition of MNK1/2 combined with anti–PD-1 therapy blocked lung metastasis of PPBC. These findings implicate the involvement of the MNK1/2–eIF4E axis during PPBC metastasis and suggest a promising immunomodulatory route to enhance the efficacy of immunotherapy by blocking phospho-eIF4E. Significance: This study investigates the MNK1/2–eIF4E signaling axis in tumor and stromal cells in metastatic breast cancer and reveals that MNK1/2 inhibition suppresses metastasis and sensitizes tumors to anti–PD-1 immunotherapy.
Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis
Authors: Roser Pinyol, Sara Torrecilla, Huan Wang, Carla Montironi, Marta Piqué-Gili, Miguel Torres-Martin, Leow Wei-Qiang, Catherine E. Willoughby, Pierluigi Ramadori, Carmen Andreu-Oller, Patricia Taik, Youngmin A. Lee, Agrin Moeini, Judit Peix, Suzanne Faure-Dupuy, Tobias Riedl, Svenja Schuehle, Claudia P. Oliveira, Venancio A. Alves, Paolo Boffetta, Anja Lachenmayer, Stephanie Roessler, Beatriz Minguez, Peter Schirmacher, Jean-François Dufour, Swan N. Thung, Helen L. Reeves, Flair J. Carrilho, Charissa Chang, Andrew V. Uzilov, Mathias Heikenwalder, Arun Sanyal, Scott L. Friedman, Daniela Sia, Josep M. Llovet
Journal: Journal of Hepatology (2021)
Abstract 074: Familial Dementia Versus Healthy Lifestyle On The Risk Of Dementia
Authors: Angelique Brellenthin, Duck-chul Lee, Elizabeth Lefferts, Bong kil Song, Youngwon Kim
Journal: Circulation (2021)

Introduction: Familial dementia (FD) is one of the strongest risk factors for dementia. Little is known about the independent and combined associations of having FD and following a healthy lifestyle with the risk of dementia. Hypothesis: We hypothesized that FD and a healthy lifestyle would be independently associated with the risk of dementia and that a healthy lifestyle would attenuate the risk of dementia among those with FD. Methods: Participants were 302,239 men and women aged 60±5 years who completed a baseline examination between 2006-2010 as part of the UK Biobank study. Participants with dementia at baseline were excluded. FD was defined as dementia in a first-degree relative (i.e., mother, father, or siblings). For healthy behaviors, participants were given one point for each of the following: not having obesity (body mass index &lt;30 kg/m 2 ); ≥150 min/wk of moderate-to-vigorous physical activity; sleep duration between 6-9 hr; drinking in moderation (&gt;0 to ≤14 or 7 drinks/wk for men or women, respectively); not smoking; and following a healthy diet (e.g., more fruits and vegetables; less processed meats and refined grains). Participants were categorized on whether they had ≤2 (reference), 3, 4, 5, or 6 healthy behaviors. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) of incident dementia (according to hospital inpatient records and death registry) by FD and number of healthy behaviors. In a joint analysis, participants were categorized based on reporting FD and following ≥3 behaviors. Models were adjusted for age, sex, race, education, socioeconomic status (Townsend deprivation index), hypertension, hypercholesterolemia, diabetes, and depression, with mutual adjustment for healthy behaviors and FD. Results: During an average follow-up of 8 years, 1698 (0.6%) participants developed dementia. Compared to ≤2 healthy behaviors, the HRs (95% CI) were 0.70 (0.57-0.86), 0.58 (0.48-0.70), 0.58 (0.48-0.70) and 0.49 (0.39-0.60) for 3, 4, 5, or 6 behaviors, respectively, after adjusting for the confounders including FD. Compared to no FD, HR (95% CI) of dementia was 1.72 (1.53-1.93) among those with FD after adjusting for the confounders including healthy behaviors. In the joint analysis, compared to those with “FD and ≤2 healthy behaviors”, the HRs (95% CI) for dementia were 0.65 (0.42-0.99), 0.74 (0.47-1.15), and 0.37 (0.25-0.56) for those with “FD and ≥3 behaviors”, “no FD and ≤2 behaviors”, and “no FD and ≥3 behaviors”, respectively. Conclusions: Adopting more healthy behaviors was associated with reduced risk of dementia, independent of FD. In those with FD, adopting at least 3 healthy behaviors may help reduce the risk of developing dementia.
Abstract 15078: Non-selective but Not Selective His Bundle Pacing Uniquely Resolves Acute and Chronic Right Bundle Branch Block
Authors: Rehan Mahmud, Shakeel Jamal, Bdeth Bailey
Journal: Circulation (2020)

Introduction: While acute (Ac) right bundle branch block (RBBB) may be in proximal HB (lead fixation injury) and chronic (Ch) RBBB in distal HB, they both cause terminal QRS delay. Both types of RBBB may be corrected with non-selective (NS) His bundle pacing (HBP), however the mechanism is unknown. Hypothesis: To study the role of high (5V) and low (1V) pacing voltage as well as presence of pre-excitation (in NS-HBP) in resolving Ac and chronic Ch-RBBB. Methods: Of the thirty-nine patients (27 ChRBBB and 12 AcRBBB), 25 ChRBBB and 10 AcRBBB patients showed NS-HBP at 5V and 11/25 ChRBBB and 6/12 AcRBBB patients transitioned to selective (S)-HBP at 1V. Four patients showed S-HBP at 5V and 1V. Results: 1)During NS-HBP at 5V: (In 25 ChRBBB and 10 Ac-RBBB) Complete resolution occurred 12/25ChRBBB and in all 10 AcRBBB. A partial resolution of ChRBBB occurred 13/25 ChRBBB.2. During NS-HBP at 1V: (6/14 ChRBBB and 2/4 AcRBBB showed complete resolution at 1V, remainder showed incomplete RBBB3. During S-HBP at 5V : (2 ChRBBB 2 AcRBBB) only 1 AcRBBB showed resolution of RBBB. 4. During S-HBP at 1V : All 13 ChRBBB and 8 AcRBBB did not show resolution os RBBB including 11 Ch-RBBB and 6 Ac-RBBB RBBB which resolved during 5V NS-HBP, abruptly recurred on transition to S-HBP at a mean of 2.4±0.8V. Conclusions: 1)The lack of RBBB resolution with S-HBP suggests that pacing site was proximal to site of block, however, from the same site NS-HBP either completely or incompletely resolved both Ac- and Ch-RBBB. 2) Partial resolution of RBBB in NS-HBP may be explained by right ventricular free wall pre-excitation when site of Ch-RBBB is distal.3) Complete resolution of both acute and Ch-RBBB in NS-HBP, more so at high pacing voltage, suggest that peri-Hisian tissues may behave more like a specialized conduction tract which uniquely resolves conduction block.
Abstract 12980: Impaired Left Atrial Function is Associated With Increased Rehospitalisation in Patients With Non-valvular Atrial Fibrillation
Authors: Aditya Bhat, Henry H Chen, Shaun Khanna, Gary Gan, Sumreen Nawaz, Fernando Fernandez, Walter P Abhayaratna, C. Raina MacIntyre, Timothy C Tan
Journal: Circulation (2020)

Introduction: Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice with a high clinical and economic burden, largely driven through hospital admissions. Left atrial (LA) size and function have been shown to be powerful predictors of cardiovascular disease. We evaluated the relationship between LA function and AF rehospitalisation. Hypothesis: Impaired LA is a predictor of AF rehospitalisation. Methods: Consecutive patients admitted to a tertiary referral centre (Jan 2013 - Dec 2017) with a diagnosis of non-valvular AF and who underwent transthoracic echocardiogram during their index admission were evaluated for the primary study outcome of AF rehospitalisation. Results: Of the 665 patients (68±14 years, 52% men), 72.2% had paroxysmal AF, 23.4% had persistent AF and 4.4% had permanent AF. The cohort had high cardiovascular comorbidities (33% IHD, 29% HF and 10% previous stroke/TIA). Over a follow-up period of 33 ± 21 months, 253 (38%) patients were rehospitalised for AF. Impaired eGFR (p=0.03), persistent/permanent AF (p=0.05) and indices of LA size and function [see Kaplan Meier curves; LA volume index (LAVI), p&lt;0.01; LA emptying fraction (LAEF), p=0.01; LA expansion index (LAEI), p=0.02; LA function index (LAFI), p&lt;0.01] predicted AF rehospitalisation. Parameters of left ventricular size and function were not predictive of the primary outcome. Multivariable Cox regression models revealed that LAEF (HR 1.58, 95%CI 1.06 to 2.35, p&lt;0.01), LAFI (HR 2.02, 95%CI 1.34 to 3.04, p&lt;0.01) and LAEI (HR 1.58, 95%CI 1.06 to 2.34, p=0.03) were independent predictors of AF rehospitalisation. Conclusions: Impaired LA function is a predictor of AF rehospitalisation.
Re: Paul Abrams, Lynda D. Constable, David Cooper, et al. Outcomes of a Noninferiority Randomised Controlled Trial of Surgery for Men with Urodynamic Stress Incontinence After Prostate Surgery (MASTER). Eur Urol 2021;79:812–23
Authors: Benoit Peyronnet, Jean-Nicolas Cornu
Journal: European Urology (2021)
169P Evaluation of the effectiveness of telephone consultations and the level of satisfaction of patients attending the Unidad Docente Asistencial de Mastología [Mastology Care Teaching Unit] using this method during the COVID health emergency
Authors: N. Camejo, C. Castillo, N. Artagaveytia, D. Amarillo, F. Vitureira, F. Rodriguez, L. Delgado
Journal: Annals of Oncology (2021)
Abstract 11652: Asymptomatic Type 2 Diabetes Mellitus Patients Have Endothelial Function as Poor as Nondiabetics With Severe Coronary Artery Disease
Authors: Woo-young Chung, Hack-Lyoung Kim, Jae-Bin Seo, Jin-Yong Lee, Min-Kyong Moon
Journal: Circulation (2018)

Introduction: Endothelium have key roles in controlling vasomotor function affecting tissue perfusion. Various risk factors or stimuli damage endothelial function. Hypothesis: We intended to invest...
Abstract 15984: <i>Rpl13a</i> Small Nucleolar RNAs Promote Oxidative Stress and Atherosclerosis
Authors: Lisheng Zhang, Jiaohui Wu, Andrew J Vista, Leigh Brian, Yushi Bai, xinhe yin, Hsiang-Ting Ho, Yinzhou Zhu, Christopher L Holley, Neil J FREEDMAN
Journal: Circulation (2020)

Reactive oxygen species (ROS) contribute to atherogenesis. An unusual mechanism that increases cellular ROS levels and oxidative stress involves 4 ubiquitously expressed noncoding small nucleolar RNAs (snoRNAs) from introns of the ribosomal protein L13a ( Rpl13a ) locus: U32a , U33 , U34 , and U35a . We tested the hypothesis that these snoRNAs promote aortic smooth muscle cell (SMC) activation and vascular inflammation, by using “snoKO” mice with targeted deletion of the 4 snoRNAs (but not Rpl13a ). Compared with congenic WT SMCs, snoKO SMCs showed 40±20% lower ROS levels, assessed by DCF fluorescence ( p &lt;0.02). Congruently, ROS levels were 35±5% lower in snoKO than WT aorta and carotid frozen sections ( p &lt;0.01), assessed by CellROX Orange fluorescence. Proliferation and migration evoked by FBS and PDGF-BB, respectively, were each 30±10% less in snoKO than WT SMCs ( p &lt;0.01 for each). To assess SMC migration and proliferation in vivo, we performed carotid artery endothelial denudation. Before injury, snoKO and WT carotid arteries were morphologically equivalent. Four wk after injury, carotid neointimal hyperplasia was 57±9% less and luminal area was 40±20 % more in snoKO than in WT mice ( p &lt;0.01). WT and snoKO mice had equivalent heart rates and systolic blood pressures by tail-cuff plethysmography: 480±20 vs 420±80 beats/min; 133±5, 132±7 mm Hg, respectively (n=5/group). To test whether snoRNAs affect atherosclerosis, we orthotopically transplanted carotid arteries from WT and snoKO mice into congenic Apoe -/- mice. Six wk post-op, atherosclerotic neointima was 70±10% smaller in snoKO than in WT carotids ( p &lt;0.01). To assess SMC-to-foam-cell transdifferentiation, which is ROS-dependent, carotid cross-sections were stained for apoE to identify graft-derived cells and for cholesteryl ester with BODIPY. BODIPY + foam cells comprised 21±3% and 11±7% of neointimal area in WT and snoKO carotids, respectively ( p &lt;0.05). Confocal co-localization of apoE and BODIPY (optical slice thickness 1 μm) showed that graft-derived foam cells were 2.0±0.6-fold more prevalent in WT than in snoKO carotids ( p &lt;0.01). We conclude that Rpl13a snoRNAs promote SMC ROS levels, proliferation and migration in vitro and in vivo, and that these snoRNAs augment atherosclerosis.
Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study
Authors: Ines Pires da Silva, Tasnia Ahmed, Irene L M Reijers, Alison M Weppler, Allison Betof Warner, James Randall Patrinely, Patricio Serra-Bellver, Clara Allayous, Joanna Mangana, Khang Nguyen, Lisa Zimmer, Claudia Trojaniello, Dan Stout, Megan Lyle, Oliver Klein, Camille L Gerard, Olivier Michielin, Andrew Haydon, Paolo A Ascierto, Matteo S Carlino, Celeste Lebbe, Paul Lorigan, Douglas B Johnson, Shahneen Sandhu, Serigne N Lo, Christian U Blank, Alexander M Menzies, Georgina V Long
Journal: The Lancet Oncology (2021)
Abstract 16205: MKP-5 Deficiency Attenuates Pressure Overload-induced Cardiac Hypertrophy
Authors: Kisuk Min, Yan Huang, Frank J Giordano, Sudip Bajpeyi, Anton M Bennett
Journal: Circulation (2020)

Introduction: Cardiac remodeling occurs in response to pathological stimuli including chronic pressure overload, subsequently leading to heart failure. Despite considerable research efforts, the molecular mechanisms responsible for heart failure have yet to be fully elucidated. One of the prominent signaling pathways involved in the development of pathological cardiac hypertrophy is the mitogen-activated protein kinases (MAPKs) pathways. The MAPKs are inactivated by the MAPK phosphatases (MKPs) through direct dephosphorylation. Growing evidence suggests the importance of MKP-5 signaling mechanisms in physiological and pathological processes. However, the role of MKP-5 has not been explored in cardiac muscle. The objective of this study is to investigate how MKP-5-mediated MAPK activity contributes to mechanisms responsible for pressure overload-induced cardiac hypertrophy. Hypothesis: We tested the hypothesis that MKP-5 serves as a central regulator of MAPKs in pressure overload-induced cardiac hypertrophy. Methods: To investigate the role of MKP-5 in cardiac muscle, we caused pressure overload-induced cardiac hypertrophy in wild type (mkp-5 +/+ ) mice and MKP-5 deficient mice (mkp-5 -/- ) through transverse aortic constriction (TAC). Cardiac function was evaluated by echocardiographic analysis at 4 weeks after TAC. Cardiac hypertrophy was measured by heart-to-body weight ratio. Interstitial myocardial fibrosis was evaluated by Sirius red stains and expression of fibrogenic genes was determined by quantitative PCR. Results: Echocardiographic analysis showed that the ejection fraction and fractional shortening of mkp-5 +/+ mice significantly decreased by at 4 weeks after TAC. Heart-to-body weight ratio increased in mkp-5 +/+ mice. However, MKP-5-deficient heart was protected from cardiac dysfunction and cardiac hypertrophy induced by TAC. Importantly, the fibrogenic genes were markedly reduced in mkp-5 -/- mice as compared with mkp-5 +/+ mice at 4 weeks after TAC. Conclusions: Collectively, our study demonstrates that MKP-5 deficiency prevents the heart from pressure overload-induced cardiac hypertrophy and suggests that MKP-5 may serve as a novel therapeutic target for treatment of heart disease.
MEF2C silencing downregulates NF2 and E-cadherin and enhances Erastin-induced ferroptosis in meningioma
Authors: Zhongyuan Bao, Lingyang Hua, Yangfan Ye, Daijun Wang, Chong Li, Qing Xie, Hiroaki Wakimoto, Ye Gong, Jing Ji
Journal: Neuro-Oncology (2021)

Abstract Background Ferroptosis, a programmed cell death characterized by lipid peroxidation, is implicated in various diseases including cancer. Although cell density-dependent E-cadherin and Merlin/Neurofibromin (NF2) loss can modulate ferroptosis, the role of ferroptosis and its potential link to NF2 status and E-cadherin expression in meningioma remain unknown. Methods Relationship between ferroptosis modulators expression and NF2 mutational status was examined in 35 meningiomas (10 NF2 loss and 25 NF2 wild type). The impact of NF2 and E-cadherin on ferroptosis were examined by lactate dehydrogenase (LDH) release, lipid peroxidation, and western blot assays in IOMM-Lee, CH157, and patient-derived meningioma cell models. Luciferase reporter and chromatin immunoprecipitation assays were used to assess the ability of MEF2C (myocyte enhancer factor 2C) to drive expression of NF2 and CDH1 (E-cadherin). Therapeutic efficacy of Erastin-induced ferroptosis was tested in xenograft mouse models. Results Meningioma cells with NF2 inactivation were susceptible to Erastin-induced ferroptosis. Meningioma cells grown at higher density increased expression of E-cadherin, which suppressed Erastin-induced ferroptosis. Maintaining NF2 and E-cadherin inhibited ferroptosis-related lipid peroxidation and meningioma cell death. MEF2C was found to drive the expression of both NF2 and E-cadherin. MEF2C silencing enhanced Erastin-induced ferroptotic meningioma cell death and lipid peroxidation levels in vitro, which was limited by forced expression of MEF2C targets, NF2 and E-cadherin. In vivo, anti-meningioma effect of Erastin was augmented by MEF2C knockdown and was counteracted by NF2 or E-cadherin. Conclusions NF2 loss and low E-cadherin create susceptibility to ferroptosis in meningioma. MEF2C could be a new molecular target in ferroptosis-inducing therapies for meningioma.
78P A dosimetric study of the non-intended irradiation to the internal mammary lymph nodes during locoregional radiotherapy to the breast
Authors: H. Yassen, A.A. Ismail, A.M. Amin Darwish, A. Munir, M.I.L. Abouegylah, A.E.A. Kandil
Journal: Annals of Oncology (2021)
131TiP PRO B: A randomized controlled trial to evaluate the effect of a digital patient-reported outcome monitoring in metastatic breast cancer patients
Authors: M.M. Karsten, T. Pross, F. Kühn, J-U. Blohmer, M. Rose, F. Fischer, C. Breidenbach, U. Grittner, P. Gebert, J. Ferencz, L. Pauler, G. Matthesius, J. Lenz, J. Rocabado, L. Straubing, M. Du Bois, C. Kowalski
Journal: Annals of Oncology (2021)
Abstract 16835: Targeted Disruption of Paraoxonase 3 in a Dahl Salt-Sensitive Rat Model of Chronic Kidney Disease Increases Renal Cortical Pro-Inflammatory Eicosanoids
Authors: Chrysan J Mohammed, Fatimah K Khalaf, Prabhatchandra Dube, Tyler J Reid, Jacob A Connolly, Bella Z Khatibshahidi, Andrew L Kleinhenz, Steven T Haller, David J Kennedy
Journal: Circulation (2020)

Background: Paraoxonase 3 (Pon3), is one of the three isoforms of the paraoxonase gene family. While Pon1 and Pon2 are widely studied, there is a paucity of knowledge regarding Pon3. Pon3 is synthesized in the liver and can circulate bound to high-density lipoproteins. There is significant expression in the kidney also. Pon3 has the ability to metabolize eicosanoids, which can act as signaling molecules and have known roles in the pathophysiology of some renal diseases. Decreased Pon activity is associated with elevated levels of eicosanoid metabolites and adverse clinical outcomes. We tested the hypothesis that targeted disruption of Pon3 results in elevated levels of pro-inflammatory eicosanoids and progression of renal injury. Methods/ Results: Ten week old male Dahl salt-sensitive (SS rats) and Pon3 mutant rats (SS Pon3 KO) were maintained on 8% high salt diet for eight weeks, to initiate salt-sensitive hypertensive renal disease. Previously we observed that SS Pon3 KO rats on eight weeks high salt diet demonstrated significantly increased phenotypic renal injury and mortality. In the current study, we noted that SS Pon3 KO had significantly decreased (p&lt;0.05) glomerular filtration rate compared to SS wild type. Blood pressure (radiotelemetry) as well as plasma angiotensin and aldosterone (LC-MS/MS) were not different between the two groups after high salt diet. We used targeted lipidomic profiling to determine eicosanoid content in renal cortex from SS Pon3 KO and SS wild type rats at the end of eight weeks of high salt diet. We found that hydroxyl fatty acids 5-HEPE and 5-HETE (5-lipoxygenase dependent arachidonic acid metabolites) were significantly (p&lt;0.05) elevated in the renal cortex of SS Pon3 KO compared to SS wild type rats. In addition to being mediators of inflammation, these metabolites are associated with renal cell injury and death. Furthermore, prostaglandin 6-keto-PGF 1α , which has known links to renal inflammation, was significantly (p&lt;0.05) increased in renal cortex of SS- Pon3 KO compared to SS wild type rats. Conclusion: These findings suggest that targeted deletion of Pon3 increases pro-inflammatory eicosanoids (5-HETE and 5-HEPE) and prostaglandins (6-keto-PGF 1α ), as well as increases renal damage independent of blood pressure.