tbuckley/cabot-search huggingface dataset:
Quantitative Tissue Pharmacokinetics and EPR Effect of AGuIX Nanoparticles: A Multimodal Imaging Study in an Orthotopic Glioblastoma Rat Model and Healthy Macaque
Authors: Vu‐Long Tran, François Lux, Nicolas Tournier, Benoit Jego, Xavier Maître, Maria Anisorac, Claude Comtat, Sébastien Jan, Katalin Selmeczi, Michael J. Evans, Olivier Tillement, Bertrand Kuhnast, Charles Truillet
Journal: Advanced Healthcare Materials (2021)

Abstract AGuIX are emerging radiosensitizing nanoparticles (NPs) for precision radiotherapy (RT) under clinical evaluation (Phase 2). Despite being accompanied by MRI thanks to the presence of gadolinium (Gd) at its surface, more sensitive and quantifiable imaging technique should further leverage the full potential of this technology. In this study, it is shown that 89 Zr can be labeled on such NPs directly for positron emission tomography (PET) imaging with a simple and scalable method. The stability of such complexes is remarkable in vitro and in vivo. Using a glioblastoma orthotopic rat model, it is shown that injected 89 Zr‐AGuIX is detectable inside the tumor for at least 1 week. Interestingly, the particles seem to efficiently infiltrate the tumor even in necrotic areas, which places great hope for the treatment of radioresistant tumor. Lastly, the first PET/MR whole‐body imaging is performed in non‐human primate (NHP), which further demonstrates the translational potential of these bimodal NP.
Abstract 310: National Institutes of Health Research Investment for the Leading Causes of Disability-Adjusted Life Years in the United States
Authors: Ryan A Coute, Brian Nathanson, Michael C Kurz, Nathan L Haas, Bryan McNally, Timothy J Mader
Journal: Circulation (2019)

Background: Cardiac arrest (CA) is a leading cause of disability-adjusted life years (DALY) in the United States (U.S.). The National Institutes of Health (NIH) does not report annual research funding for CA. Our objective was to calculate and compare the NIH research investment for CA to other leading causes of DALY in the U.S. Methods: A search within NIH RePORTER for the year 2016 was performed using the following terms: cardiac arrest, cardiopulmonary resuscitation, heart arrest, circulatory arrest, pulseless electrical activity, ventricular fibrillation, or resuscitation. Grants were individually reviewed and categorized as CA research (yes/no) using predefined criteria and the sum of funding for grants meeting inclusion criteria were tabulated. DALY were calculated as the sum of years of life lost (YLL) and years lived with disability (YLD) using all adult non-traumatic EMS-treated out-of-hospital CA (OHCA) from the CARES database for 2016. Total DALY for the study population were extrapolated to a national level. The leading causes of DALY were obtained from the Global Burden of Disease study. Funding data were extracted from the 2016 NIH Categorical Spending Report. Research funding were compared using U.S. dollars invested per DALY as the outcome measure. Results: The search yielded 285 NIH-funded grants, of which 65 (22.8%) were classified as CA research. Total NIH funding for CA research in 2016 was $28.5M. A total of 59,752 cases from CARES met study inclusion criteria for the DALY analysis. The total DALY following adult OHCA in the U.S. were 4,354,192 (YLL 4,350,825; YLD 3,365). Per annual DALY, the NIH invested $284 for diabetes, $89 for stroke, $53 for ischemic heart disease, and $7 for CA research in 2016 (FIGURE). Conclusion: The NIH investment into CA research is less than other leading causes of death and disability in the U.S. These results should help inform the debate regarding how to best utilize limited resources to improve public health.
Palliative Psychiatry for Severe and Enduring Anorexia Nervosa Includes but Goes beyond Harm Reduction
Authors: Anna L. Westermair, Daniel Z. Buchman, Sarah Levitt, Manuel Trachsel
Journal: The American Journal of Bioethics (2021)

Bianchi et al. (2021) argue that for some patients with severe and enduring anorexia nervosa (SEAN) approaches that do not aim for complete clinical recovery are ethically warranted. We believe tha...
Retraction—Family planning in COVID-19 times: access for all
Authors: Marleen Temmerman
Journal: The Lancet Global Health (2021)

In this invited Comment,1Temmerman M Family planning in COVID-19 times: access for all.Lancet Glob Health. 2021; 9: e728-e729Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar significant portions of text were used verbatim from several other pieces of published work without proper attribution. Although the sources were cited, the verbatim text should have been indicated by quotation marks. I therefore wish to retract this Comment. I sincerely regret the lapse. I declare no competing interests RETRACTED: Family planning in COVID-19 times: access for allThe COVID-19 pandemic has substantially strained health systems and transformed the sexual and reproductive health environment worldwide. A WHO survey showed that across 105 countries, 90% have had health service disruptions as a result of the COVID-19 pandemic.1 One of the most commonly disrupted areas is family planning services, with 68% of countries reporting service disruptions. The Guttmacher Institute estimated that a 10% decline in use of short-term and long-acting reversible contraceptives across 132 low-income and middle-income countries would increase the unmet need for contraception over the course of 1 year to 48·6 million women, resulting in 15 million additional unintended pregnancies, 1·7 million additional women with major obstetric complications without care, and more than 3 million additional women resorting to unsafe abortions. Full-Text PDF Open Access
Surgical Culture Shifts and Randomized Clinical Trials
Authors: Pablo E. Serrano, Mohit Bhandari, Marko Simunovic
Journal: JAMA Network Open (2021)

N. Bryce Robinson, MD; Stephen Fremes, MD; Irbaz Hameed, MD; Mohamed Rahouma, MD; Viola Weidenmann, BS; Michelle Demetres, MLIS; Mahmoud Morsi, MD; Giovanni Soletti, MD; Antonino Di Franco, MD; Marco A. Zenati, MD; Shahzad G. Raja, MBBS; David Moher, PhD; Faisal Bakaeen, MD; Joanna Chikwe, MD; Deepak L. Bhatt, MD; Paul Kurlansky, MD; Leonard N. Girardi, MD; Mario Gaudino, MD
New Aspects of Diabetes Research and Therapeutic Development
Authors: Leslie S. Satin, Scott A. Soleimanpour, Emily M. Walker
Journal: Pharmacological Reviews (2021)

Both type 1 and type 2 diabetes mellitus are advancing at exponential rates, placing significant burdens on health care networks worldwide. Although traditional pharmacologic therapies such as insulin and oral antidiabetic stalwarts like metformin and the sulfonylureas continue to be used, newer drugs are now on the market targeting novel blood glucose–lowering pathways. Furthermore, exciting new developments in the understanding of beta cell and islet biology are driving the potential for treatments targeting incretin action, islet transplantation with new methods for immunologic protection, and the generation of functional beta cells from stem cells. Here we discuss the mechanistic details underlying past, present, and future diabetes therapies and evaluate their potential to treat and possibly reverse type 1 and 2 diabetes in humans. <h3>Significance Statement</h3> Diabetes mellitus has reached epidemic proportions in the developed and developing world alike. As the last several years have seen many new developments in the field, a new and up to date review of these advances and their careful evaluation will help both clinical and research diabetologists to better understand where the field is currently heading.
Targeting the Extracellular HSP90 Co-Chaperone Morgana Inhibits Cancer Cell Migration and Promotes Anticancer Immunity
Authors: Laura Seclì, Lidia Avalle, Pietro Poggio, Giuseppe Fragale, Cristiana Cannata, Laura Conti, Andrea Iannucci, Giovanna Carrà, Cristina Rubinetto, Barbara Miniscalco, Emilio Hirsch, Valeria Poli, Alessandro Morotti, Marco De Andrea, Emilia Turco, Federica Cavallo, Federica Fusella, Mara Brancaccio
Journal: Cancer Research (2021)

HSP90 is secreted by cancer cells into the extracellular milieu, where it exerts protumoral activities by activating extracellular substrate proteins and triggering autocrine signals through cancer cell surface receptors. Emerging evidence indicates that HSP90 co-chaperones are also secreted and may direct HSP90 extracellular activities. In this study, we found that the HSP90 co-chaperone Morgana is released by cancer cells and, in association with HSP90, induces cancer cell migration through TLR2, TLR4, and LRP1. In syngeneic cancer mouse models, a mAb targeting Morgana extracellular activity reduced primary tumor growth via macrophage-dependent recruitment of CD8+ T lymphocytes, blocked cancer cell migration, and inhibited metastatic spreading. Overall, these data define Morgana as a new player in the HSP90 extracellular interactome and suggest that Morgana may regulate HSP90 activity to promote cancer cell migration and suppress antitumor immunity. SIGNIFICANCE: This work suggests the potential therapeutic value of targeting the extracellular HSP90 co-chaperone Morgana to inhibit metastasis formation and enhance the CD8+ T-cell-mediated antitumor immune response.
Abstract 406: Oxidative Stress Mediated Myocardial Lipid Dysfunction
Authors: Manikandan Panchatcharam, Mini Chandra, Jonathan Fox, Shenuarin Bhuiyan, Wayne Orr, Christopher Kevil, Jonathan Steven Alexander, Joseph C Wu, Diana Escalante-Alcalde, Sumitra Miriyala
Journal: Circulation Research (2016)

Lipid phosphate phosphatases-3 control the conversion of bioactive lipid phosphates to their dephosphorylated counterparts. Oxidative stress transactivates microRNA-92a, which is a negative regulator of LPP3. We found that LPP3 expression was markedly downregulated in ischemic regions after ischemia/reperfusion (I/R) injury. We observed a similar trend in the myocardium from patients samples with acute MI at 24h. Our in vitro studies indicate that overexpression of LPP3 protects the cardiomyocyte against reactive oxygen species (ROS)-induced cardiac injury and knockout of LPP3 gene in the myocardium increases cardiac dysfunction and mortality. Using XF24 Seahorse analyzer we determined the effect of ROS on respiration in pluripotent stem cell-derived cardiomyocytes (iPSC-CM). Adding Phorbol 12-myristate 13-acetate (PMA) to these cells immediately increased oxygen consumption as compared to LPP3 overexpressed cells. This apparent increase in respiration was reversible by oligomycin, which blocks ATP synthase. The rate of oxygen consumption per cell was significantly lower in stimulated compared to LPP3 overexpressed iPSC-CM. The most noticeable difference in the O 2 consumption was found in the presence of carbonilcyanide p-trifluromethoxyphenylhydrazone (FCCP). FCCP is an inner membrane pore opener which resets the proton gradient between mitochondrial matrix and interspace, resulting in continuous transport of protons and consuming O 2 at the maximum potential. Remarkably, while the FCCP treatment increased O 2 consumption in LPP3 overexpressed cells (P&lt;0.05), the treatment showed no effect on the O 2 consumption in the PMA stimulated alone. The result indicated that the low basal oxidative phosphorylation activity in stimulated cells was due to unusually low oxidative phosphorylation potential. To explore the free radical regulation of LPP3 overexpressed cells, superoxide anion was measured using dihydroethidium, a fluorescent cholesterol analog. The levels of superoxide radicals in PMA treated cells were consistently and significantly higher than the levels in LPP3 overexpressed cells (P&lt;0.05). In turn, the radicals can be removed by adding MitoTEMPO (a specific scavenger of mitochondrial superoxide).
Application of Interactive Video Games as Rehabilitation Tools to Improve Postural Control and Risk of Falls in Prefrail Older Adults
Authors: Hammad S. Alhasan, Patrick C. Wheeler, Daniel T. P. Fong
Journal: Cyborg and Bionic Systems (2021)

The purpose of this study was to examine whether interactive video game (IVG) training is an effective way to improve postural control outcomes and decrease the risk of falls. A convenience sample of 12 prefrail older adults were recruited and divided into two groups: intervention group performed IVG training for 40 minutes, twice per week, for a total of 16 sessions. The control group received no intervention and continued their usual activity. Outcome measures were centre of pressure (COP), mean velocity, sway area, and sway path. Secondary outcomes were Berg Balance Scale, Timed Up and Go (TUG), Falls Efficacy Scale International (FES-I), and Activities-Specific Balance Confidence (ABC). Assessment was conducted with preintervention (week zero) and postintervention (week eight). The intervention group showed significant improvement in mean velocity, sway area, Berg Balance Scale, and TUG ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"><mml:mi>p</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.01</mml:mn></mml:math> ) compared to the control group. However, no significant improvement was observed for sway path ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.35</mml:mn></mml:math> ), FES-I ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.383</mml:mn></mml:math> ), and ABC ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.283</mml:mn></mml:math> ). This study showed that IVG training led to significant improvements in postural control but not for risk of falls.
Immunogenicity of SARS-CoV-2 messenger RNA vaccines in patients with cancer
Authors: Alfredo Addeo, Pankil K. Shah, Natacha Bordry, Robert D. Hudson, Brenna Albracht, Mariagrazia Di Marco, Virginia Kaklamani, Pierre-Yves Dietrich, Barbara S. Taylor, Pierre-Francois Simand, Darpan Patel, Jing Wang, Intidhar Labidi-Galy, Sara Fertani, Robin J. Leach, Jose Sandoval, Ruben Mesa, Kate Lathrop, Nicolas Mach, Dimpy P. Shah
Journal: Cancer Cell (2021)
Rare Type 1-like and Type 2-like Calrecticulin Mutants Induce Similar Myeloproliferative Neoplasms Than Type 1 and Type 2 Mutants in Mice
Authors: Katte Rao Toppaldoddi, Maira da Costa Cacemiro, Olivier Bluteau, Amélie Pioch, Barbara Panneau-Schmaltz, Delphine Muller, Nicole Casadevall, Hana Raslova, Stefan N. Constantinescu, Isabelle Plo, William Vainchenker, Caroline Marty
Journal: Blood (2017)
Abstract 285: Endoplasmic Reticulum Stress Induces Mitochondrial ROS Overproduction and Contributes to Electrical Remodeling in Heart Failure
Authors: Man Liu, Guangbin Shi, Dmitry Terentyev, Anyu Zhou, Samuel C Dudley
Journal: Circulation Research (2016)

Introduction: Heart failure (HF) is associated with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR), which has three branches (PERK, IRE1 and ATF6α). UPR inhibits protein translation, and we hypothesized UPR contributes to electrical remodeling in HF. Methods: HF was induced in C57BL/6 mice 6-7 weeks after unilateral nephrectomy, deoxycorticosterone acetate pellet implantation, and salt water substitution. Sham operated mice were used as controls. Isolated ventricular myocytes were utilized for whole-cell patch clamp recording and ROS measurement by DCFDA with confocal imaging. Heart tissue was used for mRNA and protein measurements. GSK2606414, a specific inhibitor of PERK, was applied to myocytes at 4-30 nM for 6-20 h. Results: The action potential duration was prolonged in HF myocytes (204±26 vs. 100±16 ms of sham, P&lt;0.05). The mRNA and protein levels of the UPR effectors indicated that the PERK and IRE1 branches were activated in HF heart tissue. The peak I Na , I to , I K1 , and I Kslow were decreased significantly in HF group, while I CaL and other K + currents were not affected. A PERK inhibitor, GSK2606414, restored I Na and I K,slow . Current changes were similar to those observed in myocytes under tunicamycin-induced ER stress. Significant reduction of channel protein levels were observed for K v 4.3, Kir2.1, K v 1.5, and Ca v 1.2, but not Na v 1.5, suggesting that I Na reduction was mediated by PERK but not by translational downregulation. Significant ROS production was observed in mouse cardiomyocytes under ER stress, which was suppressed by GSK2606414. Confocal imaging of ROS indicates the source to be mitochondria. Conclusions: TM-treated cardiomyocyte changes indicated that reductions of I Na , I to , I K1 and I K,slow were mediated by ER stress. Proportionally decreased protein and current levels of K v 4.3, Kir2.1, and K v 1.5 suggested direct effects of ER stress. The downregulation of Na v 1.5 and K v 1.5 could be prevented by PERK inhibition. Nevertheless, the effect of PERK inhibition on I Na was indirect and mediated by a PERK-dependent elevation in mitochondrial ROS. In conclusion, the UPR contributes to electrical remodeling in HF by direct and indirect means. Targeting the UPR may be a novel antiarrhythmic strategy.
Second-line FOLFOX chemotherapy for advanced biliary tract cancer – Authors' reply
Authors: Angela Lamarca, Daniel H Palmer, Harpreet Singh Wasan, Paul J Ross, Yuk Ting Ma, Arvind Arora, Stephen Falk, Roopinder Gillmore, Jonathan Wadsley, Kinnari Patel, Alan Anthoney, Anthony Maraveyas, Tim Iveson, Justin S Waters, Claire Hobbs, Safia Barber, W David Ryder, John Ramage, Linda M Davies, John A Bridgewater, Juan W Valle
Journal: The Lancet Oncology (2021)
Underperformance of Contemporary Phase III Oncology Trials and Strategies for Improvement
Authors: Changyu Shen, Enrico G. Ferro, Huiping Xu, Daniel B. Kramer, Rushad Patell, Dhruv S. Kazi
Journal: Journal of the National Comprehensive Cancer Network (2021)

Statistical testing in phase III clinical trials is subject to chance errors, which can lead to false conclusions with substantial clinical and economic consequences for patients and society.We collected summary data for the primary endpoints of overall survival (OS) and progression-related survival (PRS) (eg, time to other type of event) for industry-sponsored, randomized, phase III superiority oncology trials from 2008 through 2017. Using an empirical Bayes methodology, we estimated the number of false-positive and false-negative errors in these trials and the errors under alternative P value thresholds and/or sample sizes.We analyzed 187 OS and 216 PRS endpoints from 362 trials. Among 56 OS endpoints that achieved statistical significance, the true efficacy of experimental therapies failed to reach the projected effect size in 33 cases (58.4% false-positives). Among 131 OS endpoints that did not achieve statistical significance, the true efficacy of experimental therapies reached the projected effect size in 1 case (0.9% false-negatives). For PRS endpoints, there were 34 (24.5%) false-positives and 3 (4.2%) false-negatives. Applying an alternative P value threshold and/or sample size could reduce false-positive errors and slightly increase false-negative errors.Current statistical approaches detect almost all truly effective oncologic therapies studied in phase III trials, but they generate many false-positives. Adjusting testing procedures in phase III trials is numerically favorable but practically infeasible. The root of the problem is the large number of ineffective therapies being studied in phase III trials. Innovative strategies are needed to efficiently identify which new therapies merit phase III testing.
Neutralising capacity against Delta (B.1.617.2) and other variants of concern following Comirnaty (BNT162b2, BioNTech/Pfizer) vaccination in health care workers, Israel
Authors: Yaniv Lustig, Neta Zuckerman, Ital Nemet, Nofar Atari, Limor Kliker, Gili Regev-Yochay, Einav Sapir, Orna Mor, Sharon Alroy-Preis, Ella Mendelson, Michal Mandelboim
Journal: Eurosurveillance (2021)

SARS-CoV-2 Delta (B.1.617.2) variant of concern (VOC) and other VOCs are spreading in Europe. Micro-neutralisation assays with sera obtained after Comirnaty (BNT162b2, BioNTech/Pfizer) vaccination in 36 healthcare workers (31 female) demonstrated significant fold change reduction in neutralising titres compared with the original virus: Gamma (P.1) 2.3, Beta (B.1.351) 10.4, Delta 2.1 and 2.6. The reduction of the Alpha (B.1.1.7) variant was not significant. Despite being lower, remaining neutralisation capacity conferred by Comirnaty against Delta and other VOCs is probably protective.
PGC1α-Mediated Metabolic Reprogramming Drives the Stemness of Pancreatic Precursor Lesions
Authors: Rama Krishna Nimmakayala, Sanchita Rauth, Ramakanth Chirravuri Venkata, Saravanakumar Marimuthu, Palanisamy Nallasamy, Raghupathy Vengoji, Subodh M. Lele, Satyanarayana Rachagani, Kavita Mallya, Mokenge P. Malafa, Moorthy P. Ponnusamy, Surinder K. Batra
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Metabolic reprogramming and cancer stem cells drive the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). However, the metabolic and stemness programs of pancreatic precursor lesions (PPL), considered early PDAC development events, have not been thoroughly explored. Experimental Design: Meta-analyses using gene expression profile data from NCBI Gene Expression Omnibus and IHC on tissue microarrays (TMA) were performed. The following animal and cellular models were used: cerulean-induced KrasG12D; Pdx1 Cre (KC) acinar-to-ductal metaplasia (ADM) mice, KrasG12D; Smad4Loss; Pdx-1 Cre (KCSmad4−) intraductal papillary mucinous neoplasm (IPMN) mice, LGKC1 cell line derived from the doxycycline-inducible Gnas IPMN model, and human IPMN organoids. Flow cytometry, Seahorse extracellular flux analyzer, qRT-PCR, and sphere assay were used to analyze metabolic and stemness features. SR18292 was used to inhibit PGC1α, and short hairpin RNA was used to knockdown (KD) PGC1α. Results: The meta-analysis revealed a significant upregulation of specific stemness genes in ADM-mediated pancreatic intraepithelial neoplasms (PanIN) and IPMN. Meta- and TMA analyses followed by in vitro and in vivo validation revealed that ADM/PanIN exhibit increased PGC1α and oxidative phosphorylation (OXPhos) but reduced CPT1A. IPMN showed elevated PGC1α, fatty acid β-oxidation (FAO) gene expression, and FAO-OXPhos. PGC1α was co-overexpressed with its coactivator NRF1 in ADM/PanINs and with PPARγ in IPMN. PGC1α KD or SR18292 inhibited the specific metabolic and stemness features of PPLs and repressed IPMN organoid growth. Conclusions: ADM/PanINs and IPMNs show specific stemness signatures with unique metabolisms. Inhibition of PGC1α using SR18292 diminishes the specific stemness by targeting FAO-independent and FAO-dependent OXPhos of ADM/PanINs and IPMNs, respectively.
Gene therapy knockdown of Hippo signaling induces cardiomyocyte renewal in pigs after myocardial infarction
Authors: Shijie Liu, Ke Li, Leonardo Wagner Florencio, Li Tang, Todd R. Heallen, John P. Leach, Yidan Wang, Francisco Grisanti, James T. Willerson, Emerson C. Perin, Sui Zhang, James F. Martin
Journal: Science Translational Medicine (2021)

Gene therapy–mediated disruption of Hippo signaling results in tissue renewal and improved function in pigs after myocardial infarction.