tbuckley/cabot-search huggingface dataset:
Abstract 2869: Blockade of oxidative phosphorylation by metformin promotes anoikis
Authors: Funmilayo Oladunni Adeshakin, Guizhong Zhang, Adeleye O. Adeshakin, Xiaochun Wan
Journal: Cancer Research (2021)

Abstract Metastasis remains the foremost cause of death in cancer patients. Cells with metastasizing potentials are equipped to evade anoikis, a form of cell death resulting from cell detachment from extracellular matrix. Evasion of anoikis signals avails cells the ability to detach, migrate, and invade secondary sites, colonizing these sites thereby promote cancer metastasis. Cellular reprogramming has been identified as a crucial factor for tumor metastasis and yet to be fully explored. Our data showed upregulation in oxidative phosphorylation (OXPHOS) related genes in detached cells compared to adherent cells, suggesting that OXPHOS activity may enhance resistance to anoikis. Accordingly, treatment with metformin, a mitochondrial complex 1 inhibitor promoted anoikis in different cancer cells (cervical cancer - Hela, breast - MCF7, melanoma -B16F10 and Lewis Lungs carcinoma - LLC). Furthermore, metformin decreased spheroid formation, repressed ATP production, accumulated misfolded protein, and sensitized cells to anoikis via activation of caspase 3 and ROS production. More importantly, targeting OXPHOS with metformin inhibited pulmonary tumor metastasis, impaired lung nodules formation, and reduced lung weight in the B16F10 tumor model of balb/c nude mice. Collectively, our findings suggest therapeutic targeting of energy metabolism using metformin as a promising approach to enhance anoikis and attenuate tumor metastasis. Citation Format: Funmilayo Oladunni Adeshakin, Guizhong Zhang, Adeleye O. Adeshakin, Xiaochun Wan. Blockade of oxidative phosphorylation by metformin promotes anoikis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2869.
PDGF-D activation by macrophage-derived uPA promotes AngII-induced cardiac remodeling in obese mice
Authors: Yu-Wen Cheng, Ze-Bei Zhang, Bei-Di Lan, Jing-Rong Lin, Xiao-Hui Chen, Ling-Ran Kong, Lian Xu, Cheng-Chao Ruan, Ping-Jin Gao
Journal: The Journal of Experimental Medicine (2021)

Obesity-induced secretory disorder of adipose tissue–derived factors is important for cardiac damage. However, whether platelet-derived growth factor-D (PDGF-D), a newly identified adipokine, regulates cardiac remodeling in angiotensin II (AngII)–infused obese mice is unclear. Here, we found obesity induced PDGF-D expression in adipose tissue as well as more severe cardiac remodeling compared with control lean mice after AngII infusion. Adipocyte-specific PDGF-D knockout attenuated hypertensive cardiac remodeling in obese mice. Consistently, adipocyte-specific PDGF-D overexpression transgenic mice (PA-Tg) showed exacerbated cardiac remodeling after AngII infusion without high-fat diet treatment. Mechanistic studies indicated that AngII-stimulated macrophages produce urokinase plasminogen activator (uPA) that activates PDGF-D by splicing full-length PDGF-D into the active PDGF-DD. Moreover, bone marrow–specific uPA knockdown decreased active PDGF-DD levels in the heart and improved cardiac remodeling in HFD hypertensive mice. Together, our data provide for the first time a new interaction pattern between macrophage and adipocyte: that macrophage-derived uPA activates adipocyte-secreted PDGF-D, which finally accelerates AngII-induced cardiac remodeling in obese mice.
Correspondence on ‘Role of joint damage, malalignment and inflammation in articular tenderness in rheumatoid arthritis, psoriatic arthritis and osteoarthritis’
Authors: Quirine A Dumoulin, Xanthe M E Matthijssen, Fenne Wouters, Doortje I Krijbolder, Ellis Niemantsverdriet, Annette H M van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2021)

Figure 1 (A) Association of subclinical inflammation with tender MCP joints (N=226 with tenderness vs N=376 without
Physician-Delivered Messaging as a Tool to Increase COVID-19 Knowledge and Preventive Behaviors—Implications Beyond a Pandemic
Authors: Aisha T. Langford
Journal: JAMA Network Open (2021)

Carlos Torres, MD; Lucy Ogbu-Nwobodo, MD, MS, MAS; Marcella Alsan, MD, MPH, PhD; Fatima Cody Stanford, MD, MPH, MPA; Abhijit Banerjee, PhD; Emily Breza, PhD; Arun G. Chandrasekhar, PhD; Sarah Eichmeyer, PhD; Mohit Karnani, MSc; Tristan Loisel, MSc; Paul Goldsmith-Pinkham, PhD; Benjamin A. Olken, PhD; Pierre-Luc Vautrey, MSc; Erica Warner, ScD, MPH; Esther Duflo, PhD; COVID-19 Working Group; Ingabire Grace Balinda; Richard Bido-Medina; Allison Brandt; Kemar Brown; Sherri-Ann Burnett-Bowie; Lindsay Pindyck Carter; Jonathan Chou; Adriana Cohen-Hauseman; Kristen Cotter; Carine Davila; Paola Daza; Ariel Frey-Vogel; Linda Galligani; Wanda Gonzalez; Marita Gove; Daniel Hall; Kayla Theresa Hartjes; Jonathan Hauseman; Linda Herrera Santos; Kelly John Holland; Katie Hsih; Aisha James; Hannah Janoowalla; Gracia Kwete; Desta Lissanu; Merranda Logan; Lizbeeth Lopez; Wanda Lopez-Rodriguez; Njambi Mathenge; Juan Matute; George Molina; Leah Morelli; Maeve O'Neill; Tawakalitu Oseni; Asishana Osho; Vashti Otuya; Numa Perez; Meryl Perlman; Rozanne Puleo; Daniela Romero Crousillat; Ana Maria Rosales; Shiva Saboori; Gloria Salazar; Shannon Scott-Vernaglia; Ashley Yih Shaw; Sahael Stapleton; Clark Van Den Berghe; Christopher Velez
Possibilities of MR-mammography in Diagnosis of Breast Reconstruction following Complex Cancer Treatment (Literature Review with Own Clinical Observations)
Authors: S. V. Serebryakova, T. A. Shumakova, E. A. Yukhno, A. O. Kuckaya
Journal: Radiology - Practice (2021)

Magnetic resonance imaging (MRI) is the most effective method of diagnosing breast pathology due to its high resolution in the study of soft tissues and high sensitivity based on the contrast effect. There is still no consensus on the choice of the optimal method of examination of patients after mastectomy and breast reconstruction. Changes in breast tissue that are associated with surgery and radiation therapy cause difficulties in interpreting mammographic and ultrasound images. MRI using a high-field tomograph (&gt; 1 T), a specialized coil and a paramagnetic contrast agent is highly informative in the detection and differential diagnosis of recurrent formations against the background of infiltrative and scarring changes.
A biofeedback guided program or pelvic floor muscle electric stimulation for early recovery of urinary continence after radical prostatectomy: A single-center study and a meta-analysis of the literature
Authors: M. Maggi, P. Viscuso, A. Arditi, G. Mariotti, F. Del Giudice, G. Di Pierro, A. Gentilucci, G.M. Busetto, E. De Berardinis, S. Salciccia, A. Sciarra
Journal: European Urology (2021)
The COPD assessment test and the modified Medical Research Council scale are not equivalent when related to the maximal exercise capacity in COPD patients
Authors: R. Pisi, M. Aiello, L. Calzetta, A. Frizzelli, P. Tzani, G. Bertorelli, A. Chetta
Journal: Pulmonology (2021)

The management and treatment of Chronic Obstructive Pulmonary Disease (COPD) are based on a cutoff point either of ≥ 10 on the COPD Assessment Test (CAT) or of ≥ 2 of the Medical Research Council (mMRC). Up to now, no study has assessed the equivalence between CAT and mMRC, as related to exercise tolerance in COPD. The aim of this study was to investigate as primary outcome the relationship between CAT and mMRC and maximal exercise capacity in COPD patients. We also evaluated as secondary outcome the agreement between CAT (≥ 10) and mMRC (≥ 2) to categorize patients according to their exercise tolerance.118 consecutive COPD patients (39 females), aged between 47 and 85 years with a wide range of airflow obstruction and lung hyperinflation were studied. Maximal exercise capacity was assessed by cardiopulmonary exercise test.CAT and mMRC scores were significantly related to VO2 peak (p<0.01). CAT (≥ 10) and mMRC (≥ 2) have a high likelihood to be associated to a value of VO2 peak less than 15.7 and 15.6 mL/kg/min, respectively. The interrater agreement between CAT (≥ 10) and mMRC (≥ 2) was found to be fair (κ = 0.20) in all patients but slight when they were subdivided in those with VO2 peak < 15 mL/kg/min and in those with VO2 peak ≥ 15 mL/kg/min (κ = 0.10 and κ = 0.20 respectively).This study shows that CAT and mMRC are useful tools to predict exercise tolerance in COPD, but they cannot be considered as supplementary measures.
Asymptomatic rapid testing for SARS-CoV-2
Authors: Sian Taylor-Phillips, Jacqueline Dinnes
Journal: BMJ (2021)

Primary cutaneous lymphomas (PCLs) are exceedingly rare in children and adolescents, with mycosis fungoides (MF) being the most frequent PCL diagnosed in childhood. There are numerous unusual clinical variants of MF, including the hypopigmented type form (HMF). HMF is exceptional overall, but comparatively common among children. We present an 8-year-old boy with a 3-year history of progressive, generalised, scaly, hypopigmented round patches and few erythematous papules. He was first diagnosed with pityriasis alba (PA), and moisturisers were prescribed with no improvement. Skin biopsy showed typical features of MF, and the patient was successfully treated with narrowband ultraviolet B. HMF may simulate atopic dermatitis, PA, pityriasis lichenoides, tinea versicolour, vitiligo, postinflammatory hypopigmentation or leprosy. Therefore, persistent and unusual hypopigmented lesions should be biopsied to rule out this rare variant of MF.
Effects of Gabapentin on Dorsal Anterior Cingulate Cortex GABA and Glutamate Levels and Their Associations With Abstinence in Alcohol Use Disorder: A Randomized Clinical Trial
Authors: James J. Prisciandaro, Michaela Hoffman, Truman R. Brown, Konstantin Voronin, Sarah Book, Emily Bristol, Raymond F. Anton
Journal: American Journal of Psychiatry (2021)

Although gabapentin has demonstrated efficacy in mitigating alcohol withdrawal symptoms and preventing relapse drinking in individuals with alcohol use disorder (AUD), the neurobiological mechanisms of action underlying these therapeutic effects remain unknown. The present study evaluated changes in GABA and glutamate levels in the dorsal anterior cingulate cortex (dACC) as candidate mechanisms of action.In a 16-week randomized clinical trial, 68 adults with AUD, including a history of alcohol withdrawal syndrome, received 1,200 mg/day of gabapentin (N=37) or placebo (N=31) and nine medical management visits after ≥72 hours of abstinence. Proton MR spectroscopy (1H-MRS) estimates of dACC levels of GABA (N=67) and glutamate (N=64) were acquired before start of treatment and again approximately 14 days after randomization. Percent days abstinent was reported via timeline followback interview.The effects of gabapentin on GABA and glutamate levels were significantly associated with participants' percent days abstinent during early treatment. Specifically, gabapentin was associated with greater increases in glutamate and greater decreases in GABA levels in participants who remained mostly or entirely abstinent, and yet the opposite in participants who drank on more than half of the days preceding the second scan. Furthermore, gabapentin-treated participants with greater increases in glutamate levels during early treatment had significantly more percent days abstinent across the remainder of the study, relative to placebo-treated participants.In addition to providing insight into the mechanisms through which gabapentin may promote abstinence in individuals with AUD, this study also provides evidence for a biomarker of efficacious treatment that may be used to evaluate other glutamatergic or GABAergic medications for AUD and related conditions.
Abstract 3773: Selective Inhibition of iNOS Alone Offers Protection Against Left Ventricular Remodeling Similar to the Combination of ACE-Inhibition and Beta-Blockade in a Murine Model of Reperfused Myocardial Infarction: A Cardiac MR Study
Authors: Ronald J Beyers, Yaqin Xu, R. Jack Roy, Frederick H Epstein, Brent A French
Journal: Circulation (2006)

Introduction: Post-MI LV remodeling is greatly reduced in iNOS knock-out mice. This study tests the hypothesis that selective inhibition of iNOS protects against post-MI LV remodeling similar to conventional therapy. Methods: A total of 19 male C57BL/6 mice (8–10 wks) received 1h coronary occlusion and 28d of reperfusion. Seven of these were left untreated, 5 were treated with 1400W (a highly selective iNOS inhibitor) and 7 with ACE inhibition + β-blockade. Mice were studied by CMR at 4.7T before and at 1, 7 & 28 days post-MI. Alzet minipumps (Durect Corp) were used to deliver 1400W (30 mg/kg-d) from 1h post-reperfusion until Day 14. Captopril & metoprolol were mixed and 50 mg/kg-d of each were similarly applied to 7 mice (AI+BB) from 1h post-reperfusion until Day 28. CMR studies included short-axis black-blood cines covering the entire heart. On Day 1, Gd-DTPA was infused for Gd-enhanced inversion recovery imaging. Myocardial volumes and EF were measured from cine images. Day 1 infarct size was measured ...
Abstract 2376: Diagnostic and predictive biomarkers of radiation pneumonitis
Authors: Marshleen Yadav, Joseph Liu, Zahida Qamri, Naduparambil K. Jacob
Journal: Cancer Research (2021)

Abstract Increased rates of treatment failure in lung cancer patients necessitate treatment with high doses of radiation, which often cause toxicities. However, normal tissue injury in lung may manifest as acute toxicities or as delayed radiation pneumonitis. Identification of early indicators of delayed toxicities will allow timely management and mitigation. In present study, using mouse model, we identified a set of circulating microRNAs as biomarkers that potentially allow early detection of radiation induced lung injury such as inflammation and pneumonitis. Longitudinal analysis of serum samples collected from mice exposed to whole thorax lung irradiation (WTLI) allowed discovery of a panel of evolutionary conserved miRNAs that are potential predictors of radiation pneumonitis. Among these, miR21 and miR29a, miR130a, and miR19a were found peaked between 2-4 weeks after radiation, while miR146a exhibited a peculiar biphasic expression. Some of these changes were found to be associated with concomitant changes in anti- and pro-inflammatory serum cytokines. Several of the biomarkers identified in WTLI model, showed overlapping response in a bleomycin mouse model of acute lung injury. We further tested the translational utility of these biomarkers in single drop blood collected from mice using a validated internal normalizer, miR23a (Yadav et al., Science Translational Medicine, 2020, PMID: 32669422). The response noted for several of the candidate biomarkers identified in mouse model are conserved in specimens collected from human patients who received radiation therapy. In conclusion, our study has identified a panel of microRNA biomarkers with potential to develop as early predictor of pulmonary toxicities in patients receiving therapeutic radiation, and in victims of radiation accidents for timely mitigation. Citation Format: Marshleen Yadav, Joseph Liu, Zahida Qamri, Naduparambil K. Jacob. Diagnostic and predictive biomarkers of radiation pneumonitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2376.
Prospective PhaseII Study of Reduced Toxicity Conditioning Consisted of High Dose-Cytarabine, Fludarabine, Cyclophosphamide +/- Total Body Irradiation Followed By Allogeneic Stem Cell Transplantation
Authors: Senji Kasahara, Hiroshi Nakamura, Yuto Kaneda, Yoshikazu Ikoma, Eri Takada, Kimihiro Yamaguchi, Yuhei Shibata, Takuro Matsumoto, Nobuhiko Nakamura, Soranobu Ninomiya, Junichi Kitagawa, Hideko Goto, Takeshi Hara, Michio Sawada, Takeshi Takahashi, Masahito Shimizu, Hisashi Tsurumi
Journal: Blood (2017)
Abstract 2049: Cell-cycle dependent regulation of Sp1 at DSBs promotes repair via NHEJ and sensitizes cells to PARP inhibition
Authors: Michelle Swift, Jane Azizkhan-Clifford
Journal: Cancer Research (2021)

Abstract DNA double-strand breaks (DSBs) are life-threatening lesions that must be repaired to preserve chromosomal integrity. These lesions are repaired by two primary pathways: homologous recombination (HR) and non-homologous end-joining (NHEJ). The factors that mediate pathway choice are critical to maintain genomic integrity. While many of these factors, epigenetic changes and cell cycle stages are known, with HR predominating in S and G2, the underlying mechanisms that determine pathway choice are not well understood. Previously, we found that the transcription factor Sp1 is rapidly recruited to DSBs and is necessary for repair. Here, we demonstrate that Sp1 integrates repair pathway choice with cell cycle by promoting NHEJ in G1. Sp1 localizes to DSBs in G1 to recruit the NHEJ repair factors 53BP1 and Ku70. Sp1 is phosphorylated by Cyclin A/cdk2 upon entry into S phase, evicting both Sp1 and 53BP1 from the break site, thereby permitting BRCA1 binding and HR. Mutation of this phosphorylation site (Sp1-S59A) results in persistence of Sp1 and 53BP1 at DSBs in S phase cells, precluding BRCA1 binding and HR. We also demonstrate that Sp1 is sumoylated in S phase in response to damage. This sumoylation in recognized by the E3-ubiquitin ligase, RNF4, and therefore polyubiquitylates Sp1 and targets it for proteasomal degradation. Expression of a sumoylation deficient Sp1 (Sp1-K16R) results in Sp1 and 53BP1 occupancy at DSBs in S phase, inhibiting BRCA1 binding to DSBs and HR. HR proteins are commonly mutated in cancers, resulting in cellular “addiction” to alternative repair pathways. Exploiting this addiction is the basis of synthetic lethality and is applicable to the treatment of many types of malignancies. Similar to BRCA1 deficiency, expression of Sp1-S59A or Sp1-K16R also increases cell sensitivity to PARP inhibition in BRCA1+/+ cells because of the inability to recruit BRCA1. Alternatively, synthetic lethality in BRCA1-/- cells requires 53BP1, whereas loss of 53BP1 confers PARPi resistance in a BRCA1 deficient cell. Consistent with this, depletion of Sp1 also results in PARPi resistance in BRCA1-/- cells. Interestingly, Sp1 is overexpressed in many tumors and is associated with poor prognosis. These data corroborate our finding that Sp1 is required for NHEJ and provide preliminary evidence that Sp1 may be a biomarker for PARPi sensitivity. Citation Format: Michelle Swift, Jane Azizkhan-Clifford. Cell-cycle dependent regulation of Sp1 at DSBs promotes repair via NHEJ and sensitizes cells to PARP inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2049.
Abstract 2437: Potency and selectivity evaluation of TEAD covalent inhibitors in living cells by two complementary mass spectrometry methods
Authors: Armelle Buzy, Pascal Paul, Stephanie Hamon, Olivier Venier, Jean-Claude Guillemot, Vincent Mikol, Jurgen Moll, Laurent Debussche, Iris Valtingojer
Journal: Cancer Research (2021)

Abstract The HIPPO pathway plays an important role in cancer progression and among its essential components are the transcription factor proteins from the TEAD family. The TEAD family consists of 4 different members (TEAD1-TEAD4) who modulate gene expression through the interaction with co-activator proteins such as YAP1 and TAZ. Recent studies have shown that the central pocket of TEAD could be an alternative druggable approach for inhibiting YAP1. However, until recently, the irreversible binding mechanism of such a compound in living cells was not clearly established. Here, we report a mass spectrometry-based approach to demonstrate and quantitatively assess the target occupancy of TEADs covalent inhibitors both in vitro cellular and ex vivo tumor models. Applying our method to compounds from different chemical series confirmed that these inhibitors modulate the TEAD central pocket protein in cell cultures and led us to quantify their target occupancy for all TEADs expressed in our cellular models. We extended and strengthened the characterization of our inhibitors by implementing a proteomic LC-MS/MS cysteine profiling strategy - assessing the selectivity of inhibitors across free cysteine residues in the cellular proteome. As a result, we showed a high selectivity of the first inhibitors towards TEADs cysteine binding. To our knowledge, this is the first study proving by direct means and not by indirect biomarker and cell proliferation phenotypes that the central pocket of TEAD is actually available to ligand binding in cells, allowing direct measurement of target engagement for different TEAD proteins and finally demonstrating selectivity of inhibitors. These two-mass spectrometry-based methods developed here are very robust, powerful and can be currently used to help for the development of TEADs inhibitors Citation Format: Armelle Buzy, Pascal Paul, Stephanie Hamon, Olivier Venier, Jean-Claude Guillemot, Vincent Mikol, Jurgen Moll, Laurent Debussche, Iris Valtingojer. Potency and selectivity evaluation of TEAD covalent inhibitors in living cells by two complementary mass spectrometry methods [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2437.