tbuckley/cabot-search huggingface dataset:
Abstract 12756: Peripheral Organ nd Systemic Metabolism Respond Early to Cardiac Overload in the Absence of Underlying Metabolic Syndrome and Present in Multiaphasic Fashion During the Transition Toward Cardiac Decompensation
Authors: Chong Wee Liew, Shanshan Xu, Xuerong Wang, Hyerim Whang Kong, Amy Hughes, Susan K Fischer, Giamila Fantuzzi, J. Michael O'Donnell, E. Douglas Lewandowski
Journal: Circulation (2015)

Reduced long chain fatty acid (LCFA) oxidation in pressure overloaded, hypertrophied hearts coincides with an isoform shift of carnitine palmitoyl transferase I from muscle (mCPT1) to liver (LCPT1). Normal rodent hearts expressing exogenous gene for LCPT1 were recently found to recapitulate the reduced LCFA oxidation of hypertrophied hearts, with surprising elevations of atrial natriuretic peptide (ANP) message consistent with hypertrophic signaling and potentially, peripheral fat mobilization. We therefore studied peripheral and systemic metabolism in male C57BL/6 mice subjected to transverse aortic constriction (TAC). At 2 wks, echocardiography showed LV hypertrophy in TAC and increased heart mass to tibia length (52%) at 6 wks compared to hearts of sham-operated mice (SHAM). Functional decline occurred by 16 wks TAC, with reduced ejection fraction (45.6%) and fractional shortening (22.6%) vs SHAM, weeks after changes in peripheral and systemic metabolism. Surprisingly, glucose tolerance (GT) and insulin sensitivity (IS) initially improved with TAC (2 wks) vs SHAM, linked to enhanced insulin signaling in liver and visceral adipose tissue (VAT), a 48% increase in plasma adiponectin, upregulation of oxidative/thermogenic gene expression in subcutaneous adipose (SAT), and downregulated gene expression for lipolysis and lipogenesis in VAT. However, by 6 wks TAC both IS and GT were impaired with reduced insulin signaling in liver and VAT, downregulation of PGC1a and oxidative enzymes in brown adipose tissue and complete reversal of oxidative and lipogenic gene expression in SAT. Metabolic mediators post-TAC included: 1) elevated plasma ANP (TAC=140±16 pg/ml; SHAM=74±7),and brain NP (TAC=850±36 vs SHAM=771±12); 2) elevated blood adiponectin at 2 wks TAC but a reduction at 6 wks persisting to wk 17 that is consistent with IS and GT shifts. These findings demonstrate multiphasic changes in extra-cardiac metabolic responses to pathogenic stress on the heart with changes in insulin signaling, circulating natriuretic peptides and adipokines, and varied gene expression in adipose tissue that are associated with altered insulin response/glucose handling and thermogenesis in mice prior to any functional decline due to cardiac decompensation.
Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma
Authors: Meletios A. Dimopoulos, Andrzej J. Jakubowiak, Philip L. McCarthy, Robert Z. Orlowski, Michel Attal, Joan Bladé, Hartmut Goldschmidt, Katja C. Weisel, Karthik Ramasamy, Sonja Zweegman, Andrew Spencer, Jeffrey S. Y. Huang, Jin Lu, Kazutaka Sunami, Shinsuke Iida, Wee-Joo Chng, Sarah A. Holstein, Alberto Rocci, Tomas Skacel, Richard Labotka, Antonio Palumbo, Kenneth C. Anderson
Journal: Blood Cancer Journal (2020)

Abstract The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. “Continuous therapy” commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients’ quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.
Glycine by MR spectroscopy is an imaging biomarker of glioma aggressiveness
Authors: Vivek Tiwari, Elena V Daoud, Kimmo J Hatanpaa, Ang Gao, Song Zhang, Zhongxu An, Sandeep K Ganji, Jack M Raisanen, Cheryl M Lewis, Pegah Askari, Jeannie Baxter, Michael Levy, Ivan Dimitrov, Binu P Thomas, Marco C Pinho, Christopher J Madden, Edward Pan, Toral R Patel, Ralph J DeBerardinis, A Dean Sherry, Bruce E Mickey, Craig R Malloy, Elizabeth A Maher, Changho Choi
Journal: Neuro-Oncology (2020)

High-grade gliomas likely remodel the metabolic machinery to meet the increased demands for amino acids and nucleotides during rapid cell proliferation. Glycine, a non-essential amino acid and intermediate of nucleotide biosynthesis, may increase with proliferation. Non-invasive measurement of glycine by magnetic resonance spectroscopy (MRS) was evaluated as an imaging biomarker for assessment of tumor aggressiveness.
Dangers of Driving While High
Authors: Bridget Kuehn
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Recent advances in genome editing of stem cells for drug discovery and therapeutic application
Authors: Jaesuk Lee, Delger Bayarsaikhan, Govigerel Bayarsaikhan, Jin-Soo Kim, Elizabeth Schwarzbach, Bonghee Lee
Journal: Pharmacology & Therapeutics (2020)

Genome engineering technologies right from viral vector-mediated to protein-based editing— which include zinc finger nucleases, TALENs, and CRISPR/Cas systems—have been improved significantly. These technologies have facilitated drug discovery and have resulted in the development of potential curative therapies for many intractable diseases. They can efficiently correct genetic errors; however, these technologies have limitations, such as off-target effects and possible safety issues, which need to be considered when employing these techniques in humans. Significant efforts have been made to overcome these limitations and to accelerate the clinical implementation of these technologies. In this review, we focus on the recent technological advancements in genome engineering and their applications in stem cells to enable efficient discovery of drugs and treatment of intractable diseases.
α<sub>1</sub> Antitrypsin therapy modulates the neutrophil membrane proteome and secretome
Authors: Mark P. Murphy, Thomas McEnery, Karen McQuillan, Oisín F. McElvaney, Oliver J. McElvaney, Sarah Landers, Orla Coleman, Anchalin Bussayajirapong, Padraig Hawkins, Michael Henry, Paula Meleady, Emer P. Reeves, Noel G. McElvaney
Journal: European Respiratory Journal (2020)

Obstructive pulmonary disease in patients with α 1 antitrypsin (AAT) deficiency (AATD) occurs earlier in life compared with patients without AATD. To understand this further, the aim of this study was to investigate whether AATD presents with altered neutrophil characteristics, due to the specific lack of plasma AAT, compared with non-AATD COPD. This study focussed on the neutrophil plasma membrane and, by use of label-free tandem mass spectrometry, the proteome of the neutrophil membrane was compared in forced expiratory volume in 1 s (FEV 1 )-matched AATD, non-AATD COPD and in AATD patients receiving weekly AAT augmentation therapy (n=6 patients per cohort). Altered protein expression in AATD was confirmed by Western blot, ELISA and fluorescence resonance energy transfer analysis. The neutrophil membrane proteome in AATD differed significantly from that of COPD as demonstrated by increased abundance and activity of primary granule proteins including neutrophil elastase on the cell surface in AATD. The signalling mechanism underlying increased degranulation involved Rac2 activation, subsequently resulting in proteinase-activated receptor 2 activation by serine proteinases and enhanced reactive oxygen species production. In vitro and ex vivo , AAT reduced primary granule release and the described plasma membrane variance was resolved post-AAT augmentation therapy in vivo , the effects of which significantly altered the AATD neutrophil membrane proteome to that of a non-AATD COPD cell. These results provide strong insight into the mechanism of neutrophil driven airways disease associated with AATD. Therapeutic AAT augmentation modified the membrane proteome to that of a typical COPD cell, with implications for clinical practice.
Significance of minimal residual disease in pediatric mixed phenotype acute leukemia: a multicenter cohort study
Authors: Matthew J. Oberley, Sunil S. Raikar, Gerald B. Wertheim, Jemily Malvar, Richard Sposto, Karen R. Rabin, Jyotinder N. Punia, Alix E. Seif, Viviane C. Cahen, Reuven J. Schore, Dragos C. Luca, Terri Guinipero, William G. Woods, Maurice R. G. O’Gorman, Etan Orgel
Journal: Leukemia (2020)
Early Mortality of Brain Cancer Patients and its Connection to Cytomegalovirus Reactivation During Radiochemotherapy
Authors: Nicole L. Goerig, Benjamin Frey, Klaus Korn, Bernhard Fleckenstein, Klaus Überla, Manuel A. Schmidt, Arnd Dörfler, Tobias Engelhorn, Ilker Eyüpoglu, Paul F. Rühle, Florian Putz, Sabine Semrau, Udo S. Gaipl, Rainer Fietkau
Journal: Clinical Cancer Research (2020)

Abstract Purpose: If routine diagnostics are inconclusive, neurologic deterioration and death of patients with brain cancer are attributed to tumor or therapy. Therefore, diagnosing symptoms of encephalopathy caused by human cytomegalovirus (HCMV) reactivation remains uncommon. We investigated the role of HCMV reactivation in neurologic decline and clinical outcome after the start of radiochemotherapy. Experimental Design: HCMV analyses and extended MRI studies including additional independent retrospective neuroradiologic evaluation were performed at predetermined intervals and in case of sudden neurologic decline for 118 adult patients: 63 histologically proven high-grade gliomas, 55 with brain metastases. Immunophenotyping from simultaneously taken whole-blood samples was carried out to detect immune cells serving as prognostic marker for HCMV-associated complications. Symptomatic viremia and overall survival (OS) were the endpoints. Results: Twenty-four percent (28/118) of all patients (12/44 glioblastoma, 3/13 anaplastic astrocytoma; 8/31 non–small cell lung cancer (NSCLC), 13/24 other brain metastases) developed HCMV-viremia during or within 4 weeks after radiotherapy; 21 of 28 patients experienced concurrent major neurologic decline, reversible by antiviral treatment. Identified by immunophenotyping, pretherapeutically low basophil counts predicted a high-risk for HCMV-associated encephalopathy (glioblastoma: P = 0.002, NSCLC: P = 0.02). Median OS was substantially reduced after HCMV-associated encephalopathy without MRI signs of tumor progression [glioblastoma: 99 vs. 570 days (calculated 1-year OS: 22% vs. 69%; P = 0.01) and NSCLC: 47 vs. 219 days (calculated 1-year OS: 0% vs. 32%; P = 0.02)]. Conclusions: For patients with brain cancer, HCMV reactivation after the start of radiochemotherapy is a frequent risk for cognitively detrimental but treatable encephalopathy and premature death. Routinely performed HCMV diagnostics, assessing basophil counts and study-based anti-viral regimens, are necessary to combat this hidden threat. See related commentary by Lawler et al., p. 3077
Using magnetic particle imaging systems to localize and guide magnetic hyperthermia treatment: tracers, hardware, and future medical applications
Authors: Prashant Chandrasekharan, Zhi Wei Tay, Daniel Hensley, Xinyi Y Zhou, Barry KL Fung, Caylin Colson, Yao Lu, Benjamin D Fellows, Quincy Huynh, Chinmoy Saayujya, Elaine Yu, Ryan Orendorff, Bo Zheng, Patrick Goodwill, Carlos Rinaldi, Steven Conolly
Journal: Theranostics (2020)

Magnetic fluid hyperthermia (MFH) treatment makes use of a suspension of superparamagnetic iron oxide nanoparticles, administered systemically or locally, in combination with an externally applied alternating magnetic field, to ablate target tissue by generating heat through a process called induction. The heat generated above the mammalian euthermic temperature of 37°C induces apoptotic cell death and/or enhances the susceptibility of the target tissue to other therapies such as radiation and chemotherapy. While most hyperthermia techniques currently in development are targeted towards cancer treatment, hyperthermia is also used to treat restenosis, to remove plaques, to ablate nerves and to alleviate pain by increasing regional blood flow. While RF hyperthermia can be directed invasively towards the site of treatment, non-invasive localization of heat through induction is challenging. In this review, we discuss recent progress in the field of RF magnetic fluid hyperthermia and introduce a new diagnostic imaging modality called magnetic particle imaging that allows for a focused theranostic approach encompassing treatment planning, treatment monitoring and spatially localized inductive heating.
Management of Male Breast Cancer: ASCO Guideline
Authors: Michael J. Hassett, Mark R. Somerfield, Elisha R. Baker, Fatima Cardoso, Kari J. Kansal, Dylan C. Kwait, Jennifer K. Plichta, Charité Ricker, Anna Roshal, Kathryn J. Ruddy, Joshua D. Safer, Catherine Van Poznak, Rachel L. Yung, Sharon H. Giordano
Journal: Journal of Clinical Oncology (2020)

To develop recommendations concerning the management of male breast cancer.ASCO convened an Expert Panel to develop recommendations based on a systematic review and a formal consensus process.Twenty-six descriptive reports or observational studies met eligibility criteria and formed the evidentiary basis for the recommendations.Many of the management approaches used for men with breast cancer are like those used for women. Men with hormone receptor-positive breast cancer who are candidates for adjuvant endocrine therapy should be offered tamoxifen for an initial duration of five years; those with a contraindication to tamoxifen may be offered a gonadotropin-releasing hormone agonist/antagonist plus aromatase inhibitor. Men who have completed five years of tamoxifen, have tolerated therapy, and still have a high risk of recurrence may be offered an additional five years of therapy. Men with early-stage disease should not be treated with bone-modifying agents to prevent recurrence, but could still receive these agents to prevent or treat osteoporosis. Men with advanced or metastatic disease should be offered endocrine therapy as first-line therapy, except in cases of visceral crisis or rapidly progressive disease. Targeted systemic therapy may be used to treat advanced or metastatic cancer using the same indications and combinations offered to women. Ipsilateral annual mammogram should be offered to men with a history of breast cancer treated with lumpectomy regardless of genetic predisposition; contralateral annual mammogram may be offered to men with a history of breast cancer and a genetic predisposing mutation. Breast magnetic resonance imaging is not recommended routinely. Genetic counseling and germline genetic testing of cancer predisposition genes should be offered to all men with breast cancer.
Abstract P2-05-08: Integrin alpha6beta4 signaling switches double strand break repair from homologous recombination to non-homologous end joining to alter TNBC cells response to cisplatin
Authors: Min Chen, Brock Marrs, Lei Qi, Teresa Knifley, Stuart G Jarrett, Heidi L Weiss, Rachel L Stewart, John A D'Orazio, Kathleen L O'Connor
Journal: Cancer Research (2020)

Abstract Integrin α6β4 is highly expressed in triple negative breast cancer (TNBC) and drives aggressiveness by stimulating proliferation, angiogenesis, cell migration, invasion and metastasis. Signaling from this integrin stimulates DNA repair and apoptosis resistance, suggesting that it could contribute to therapeutic resistance. Upon testing this hypothesis, we found that integrin α6β4 signaling promoted a three-fold greater sensitivity to cisplatin but exhibited no difference in the response to other chemotherapies tested. Mechanistic investigations revealed that integrin α6β4 stimulated quicker and higher amplitude activations of ATM, Chk2, p53, and 53BP1, which required the β4 signaling domain. Genetic manipulation of gene expression demonstrated that mutant p53 cooperated with integrin α6β4 for cisplatin sensitivity and was necessary for downstream phosphorylation of 53BP1 and enhanced ATM activation. Additionally, we discovered that integrin α6β4 preferentially activated DNA-PKc in response to cisplatin, which led to formation of DNA-PKc-p53 complexes and 53BP1 activation. As a result, integrin α6β4 shifted double strand break repair from homologous recombination (HR) to non-homologous end joining (NHEJ), as demonstrated by HR and NHEJ reporter assays, in normal culture which was amplified by cisplatin treatment. Furthermore, DNA-PKc inhibition blocked integrin α6β4 enhanced cisplatin sensitivity. This signaling, against the backdrop of prominent losses and gains of select DNA repair molecules in breast cancer as a whole, may lead to a novel HR-deficiency that characterizes TNBC and their response to select chemotherapies. In summary, we discovered a novel function of integrin α6β4 in switching DSB repair from HR to NHEJ that results in cisplatin sensitivity in TNBC. Citation Format: Min Chen, Brock Marrs, Lei Qi, Teresa Knifley, Stuart G Jarrett, Heidi L Weiss, Rachel L Stewart, John A D'Orazio, Kathleen L O'Connor. Integrin alpha6beta4 signaling switches double strand break repair from homologous recombination to non-homologous end joining to alter TNBC cells response to cisplatin [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-05-08.
Bedaquiline-Resistant Tuberculosis: Dark Clouds on the Horizon
Authors: Sönke Andres, Matthias Merker, Jan Heyckendorf, Barbara Kalsdorf, Rudolf Rumetshofer, Alexander Indra, Sabine Hofmann-Thiel, Harald Hoffmann, Christoph Lange, Stefan Niemann, Florian P. Maurer
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
Cartilage repair mediated by thermosensitive photocrosslinkable TGFβ1-loaded GM-HPCH via immunomodulating macrophages, recruiting MSCs and promoting chondrogenesis
Authors: Xiongfa Ji, Zehua Lei, Meng Yuan, Hao Zhu, Xi Yuan, Wenbin Liu, Hongxu Pu, Jiawei Jiang, Yu Zhang, Xulin Jiang, Jun Xiao
Journal: Theranostics (2020)

Repairing cartilage defects using thermosensitive hydrogels is an attractive treatment strategy, but the poor mechanical properties and limited understanding of the interactions between hydrogels and cells limit their application.
Abstract 14741: Development and Validation of a Novel Scoring System for Predicting Chronic Outcome After Percutaneous Coronary Intervention for Coronary Chronic Total Occlusion
Authors: Soichiro Ebisawa, Shun Kosaka, Masahisa Yamane, Toshiya Muramatsu, Atsunorui Okamura, Yoshifumi Kashima, Shunsuke Matsuno, Masami Sakurada, Mikihiro Kijima, Masaki Tanabe, Maoto Habara, Koichiro Kuwahara
Journal: Circulation (2017)

Introduction: Although strategies and equipment have been improved, percutaneous coronary intervention (PCI) to coronary chronic total occlusion (CTO) is still challenging and their chronic outcome...
Quantitative HBEAG levels and patterns of TLR-2 and TLR-4 expression on CD14 monocytiees during potent antiviral therapy for chronic hepatitis B (CH-B)
Authors: AJ Thompson, S Locarnini, GK Lau, NV Naoumov, P Desmond, H Mommeja-Marin, CK Hui, N Skinner, K Visvanathan
Journal: Hepatology (2005)
<i>In Silico</i> Models Accurately Predict <i>In Vivo</i> Response for IL6 Blockade in Head and Neck Cancer
Authors: Fereshteh Nazari, Alexandra E. Oklejas, Jacques E. Nör, Alexander T. Pearson, Trachette L. Jackson
Journal: Cancer Research (2020)

Malignant features of head and neck squamous cell carcinoma (HNSCC) may be derived from the presence of stem-like cells that are characterized by uniquely high tumorigenic potential. These cancer stem cells (CSC) function as putative drivers of tumor initiation, therapeutic evasion, metastasis, and recurrence. Although they are an appealing conceptual target, CSC-directed cancer therapies remain scarce. One promising CSC target is the IL6 pathway, which is strongly correlated with poor patient survival. In this study we created and validated a multiscale mathematical model to investigate the impact of cross-talk between tumor cell- and endothelial cell (EC)-secreted IL6 on HNSCC growth and the CSC fraction. We then predicted and analyzed the responses of HNSCC to tocilizumab (TCZ) and cisplatin combination therapy. The model was validated with in vivo experiments involving human ECs coimplanted with HNSCC cell line xenografts. Without artificial tuning to the laboratory data, the model showed excellent predictive agreement with the decrease in tumor volumes observed in TCZ-treated mice, as well as a decrease in the CSC fraction. This computational platform provides a framework for preclinical cisplatin and TCZ dose and frequency evaluation to be tested in future clinical studies. SIGNIFICANCE: A mathematical model is used to rapidly evaluate dosing strategies for IL6 pathway modulation. These results may lead to nonintuitive dosing or timing treatment schedules to optimize synergism between drugs.