tbuckley/cabot-search huggingface dataset:
Light‐Controlled Precise Delivery of NIR‐Responsive Semiconducting Polymer Nanoparticles with Promoted Vascular Permeability
Authors: Weizhi Qi, Tingting Li, Chen Zhang, Fei Liu, Jun Wang, Dandan Chen, Xiaofeng Fang, Changfeng Wu, Kai Li, Lei Xi
Journal: Advanced Healthcare Materials (2021)

The endothelial barrier plays an essential role in health and disease by protecting organs from toxins while allowing nutrients to access the circulation. However, it is the major obstacle that limits the delivery of therapeutic drugs to the diseased tissue. Here, it is reported for the first time that near-infrared (NIR) laser pulses can transiently promote the delivery of semiconducting polymer nanoparticles passing the vascular barrier via photoacoustic-effect-induced accumulation, only by the aid of pulse laser irradiation. This strategy enables selective and substantial accumulation of the NIR-absorbing nanoparticles inside specific tissues, implying the discovery of an unprecedented approach for light-controlled nanoparticle delivery. Especially, the nanoparticle delivery in solid tumors by 10-min laser scanning is approximately six times higher than that of the enhanced permeability and retention (EPR) effect in 24 h under current experimental conditions. Further results confirm that this strategy facilitates substantial accumulation of nanoparticles in the mouse brain with intact skull. This approach thus opens a new door for tissue-specific delivery of nanomaterials with an unprecedented level of efficiency and precision.
Impact on clinical outcomes of right ventricular response to percutaneous correction of secondary mitral regurgitation
Authors: Thomas Caiffa, Antonio De Luca, Elena Biagini, Laura Lupi, Francesco Bedogni, Matteo Castrichini, Miriam Compagnone, Maurizio Tusa, Alessandra Berardini, Marco Merlo, Enrico Fabris, Antonio Popolo Rubbio, Daniela Tomasoni, Mattia Di Pasquale, Roberto Arosio, Andrea Perkan, Giulia Barbati, Francesco Saia, Marianna Adamo, Davide Stolfo, Gianfranco Sinagra
Journal: European Journal of Heart Failure (2021)
Pilot-scale production of expansile nanoparticles: Practical methods for clinical scale-up
Authors: Aaron H Colby, Rong Liu, Robert P Doyle, Alyssa Merting, Heng Zhang, Natasha Savage, Ngoc-Quynh Chu, Beth A Hollister, William McCulloch, Joanna E Burdette, Cedric J Pearce, Kebin Liu, Nicholas H Oberlies, Yolonda L Colson, Mark W Grinstaff
Journal: Journal of Controlled Release (2021)

One of the foremost challenges in translating nanoparticle technologies to the clinic is the requirement to produce materials on a large-scale. Scaling nanoparticle production methods is often non-trivial, and the success of these endeavors is frequently governed by whether or not an intermediate level of production, i.e., "pilot-scale" production, can be achieved. Pilot-scale production at the one-liter scale serves as a proof-of-concept that large-scale production will be possible. Here, we describe the pilot-scale production of the expansile nanoparticle (eNP) technology including verification of activity and efficacy following scaleup. We describe the challenges of sonication-based emulsification procedures and how these were overcome by use of a Microfluidizer technology. We also describe the problem-solving process that led to pre-polymerization of the nanoparticle polymer-a fundamental change from the lab-scale and previously published methods. Furthermore, we demonstrate good control over particle diameter, polydispersity and drug loading and the ability to sterilize the particles via filtration using this method. To facilitate long-term storage of these larger quantities of particles, we investigated six lyoprotectants and determined that sucrose is the most compatible with the current system. Lastly, we demonstrate that these changes to the manufacturing method do not adversely affect the swelling functionality of the particles, their highly specific localization to tumors, their non-toxicity in vivo or their efficacy in treating established intraperitoneal mesothelioma xenografts.
Abstract 15124: Myocardial Effects of Intermedin and Its Underlying Mechanisms
Authors: Ana L Pires, Marta Pinho, Adelino Leite-Moreira
Journal: Circulation (2011)

Intermedin (IMD) a novel peptide related to adrenomedullin (AM) is a potential mediator in the pathogenesis of cardiovascular disease, whose action in the myocardium remains to be elucidated. This ...
MO10-6 Phase 1 study of retifanlimab (anti-PD-1) and INCB001158 (arginase inhibitor), alone or in combination, in solid tumors
Authors: Takafumi Koyama, Toshio Shimizu, Nobuaki Matsubara, Satoru Iwasa, Yoichi Naito, Shunsuke Kondo, Kenichi Harano, Kan Yonemori, Daisuke Kotani, Kiyotaka Yoh, Yubing Yao, Tetsuya Mita, Eiji Ueda, Toshihiko Doi, Noboru Yamamoto, Yasutoshi Kuboki
Journal: Annals of Oncology (2021)
Resequencing 250 Soybean Accessions: New Insights into Genes Associated with Agronomic Traits and Genetic Networks
Authors: Chunming Yang, Jun Yan, Shuqin Jiang, Xia Li, Haowei Min, Xiangfeng Wang, Dongyun Hao
Journal: Genomics Proteomics & Bioinformatics (2021)

The limited knowledge of genomic diversity and functional genes associated with the traits of soybean varieties has resulted in slow progress in breeding. In this study, we sequenced the genomes of 250 soybean landraces and cultivars from China, America, and Europe, and investigated their population structure, genetic diversity and architecture, and the selective sweep regions of these accessions. Five novel agronomically important genes were identified, and the effects of functional mutations in respective genes were examined. The candidate genes GSTT1, GL3, and GSTL3 associated with the isoflavone content, CKX3 associated with yield traits, and CYP85A2 associated with both architecture and yield traits were found. The phenotype-gene network analysis revealed that hub nodes play a crucial role in complex phenotypic associations. This study describes novel agronomic trait-associated genes and a complex genetic network, providing a valuable resource for future soybean molecular breeding.
Diversity of the National Medical Student Body
Authors: Devin B Morris, Philip A Gruppuso, Eli Y Adashi
Journal: New England Journal of Medicine (2021)

As Morris et al. state in their Special Report (April 29 issue), 1 the continuing inequities and lack of representation of racial minorities in medical schools pose a threat to the health of our country.Their report calls for more to be done "to enhance the diversity of applicants in the pipeline [such as] investment in undergraduate bridge programs."To that end, we hope to draw attention to a pilot program recently created by Congress for students from underrepresented groups to have structured and longitudinal experiences at Veterans Affairs (VA) hospitals. 2 The program, which we helped to design, specifically prioritizes first-generation college students and those from areas that have been federally designated as having a shortage of health care professionals.Early exposure and experience will help these students successfully enter medical school, thereby increasing representation.A diverse and innovative medical student body is critical to tackling the challenges from the current pandemic and beyond.We hope to see robust utilization and expansion of the VA program, as well as the creation of more targeted programs promoting medical careers among students with diverse backgrounds.
P18-2 Clinical usefulness of universal screening for Lynch syndrome in gynecological cancer of a single-center investigation
Authors: Yukiko Ando, Tatsuro Horiuchi, Miho Masuda, Makiko Ikeda, Miki Yasuda, Hajime Morishita, Kenji Oida, Hiroshi Sato, Nao Taguchi, Masaya Hirose, Tetsuro Yamamoto
Journal: Annals of Oncology (2021)
Systemic Sclerosis–Associated Interstitial Lung Disease: How to Incorporate Two Food and Drug Administration–Approved Therapies in Clinical Practice
Authors: Dinesh Khanna, Alain Lescoat, David Roofeh, Elana J. Bernstein, Ella A. Kazerooni, Michael D. Roth, Fernando Martinez, Kevin R. Flaherty, Christopher P. Denton
Journal: Arthritis & Rheumatology (2021)

Systemic sclerosis (SSc; scleroderma) has the highest individual mortality of all rheumatic diseases, and interstitial lung disease (ILD) is among the leading causes of SSc-related death. Two drugs are now approved by the US Food and Drug Administration (FDA) and indicated for slowing the rate of decline in pulmonary function in patients with SSc-associated ILD (SSc-ILD): nintedanib (a tyrosine kinase inhibitor) and tocilizumab (the first biologic agent targeting the interleukin-6 pathway in SSc). In addition, 2 generic drugs with cytotoxic and immunoregulatory activity, mycophenolate mofetil and cyclophosphamide, have shown comparable efficacy in a phase II trial but are not FDA-approved for SSc-ILD. In light of the heterogeneity of the disease, the optimal therapeutic strategy for the management of SSc-ILD is still to be determined. The objectives of this review are 2-fold: 1) review the body of research focused on the diagnosis and treatment of SSc-ILD; and 2) propose a practical approach for diagnosis, stratification, management, and therapeutic decision-making in this clinical context. This review presents a practical classification of SSc patients in terms of disease severity (subclinical versus clinical ILD) and associated risk of progression (low versus high risk). The pharmacologic and nonpharmacologic options for first- and second-line therapy, as well as potential combination approaches, are discussed in light of the recent approval of tocilizumab for SSc-ILD.
Pembrolizumab-induced cytokine release syndrome in a patient with metastatic lung adenocarcinoma: a case report
Authors: Paul Sackstein, Jacob Zaemes, Chul Kim
Journal: Journal for ImmunoTherapy of Cancer (2021)

Cytokine release syndrome (CRS) is a well-described immune-related adverse event following chimeric antigen receptor T-cell therapy, but has rarely been reported following anti-programmed death ligand-1 therapy. We report the case of a 55-year-old man with metastatic lung adenocarcinoma who presented with fever, chills and hypotension. Initial labs were notable for highly elevated serum ferritin levels and mildly elevated triglyceride levels. He was ultimately diagnosed with pembrolizumab-induced CRS complicated by multiorgan failure. The patient was treated with steroids and tocilizumab with normalization of inflammatory markers and resolution of renal failure. This case not only highlights the importance of considering CRS in patients who have developed multiorgan failure after immune checkpoint inhibitor therapy, but also demonstrates clinical similarities between CRS and other hyperinflammatory states such as hemophagocytic lymphohistiocytosis.
Engineered extracellular vesicles for concurrent Anti-PDL1 immunotherapy and chemotherapy
Authors: Yundi Chen, Lixue Wang, Mingfeng Zheng, Chuandong Zhu, Guosheng Wang, Yiqiu Xia, Ethan J. Blumenthal, Wenjun Mao, Yuan Wan
Journal: Bioactive Materials (2021)

Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 have been approved for the treatment of a variety of cancers. However, the efficacy of antibody-based ICIs could be further improved by mitigating anti-drug antibodies, proteolytic cleavage, and on-target off-tumor toxicity. One strategy for accomplishing this is through the use of extracellular vesicles (EVs), cell derived submicron vesicles with many unique properties. We constructed an engineered MDA-MB-231 cell line for harvesting EVs. This was accomplished by overexpressing a high-affinity variant human PD-1 protein (havPD-1), while simultaneously knocking out intrinsic PD-L1 and beta-2 microglobulin. The engineered havPD-1 EVs reduced PD-L1 overexpressing cancer cell proliferation and induced cellular apoptosis. Moreover, the EVs were shown to efficiently block PD-L1 mediated T cell suppression. Meanwhile antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not observed. The havPD-1 EVs treatment resulted in robust anti-tumor activity in both preventative co-implantation and therapeutic xenograft tumor models reconstituted with human T cells. The efficacy of the havPD-1 EVs was shown to be comparable to clinical anti-PD1 monoclonal antibodies. Additionally, loading the havPD-1 EVs with a potent PARP inhibitor was shown to further augment treatment efficacy. In brief, the engineered universal EVs harboring havPD-1 proteins can be used for cancer concurrent immunotherapy and chemotherapy.
Soft Tissue Implants: Additive Manufacturing of Multi‐Scale Porous Soft Tissue Implants That Encourage Vascularization and Tissue Ingrowth (Adv. Healthcare Mater. 14/2021)
Authors: Fergal B. Coulter, Ruth E. Levey, Scott T. Robinson, Eimear B. Dolan, Stefano Deotti, Michael Monaghan, Peter Dockery, Brian S. Coulter, Liam P. Burke, Aoife J. Lowery, Rachel Beatty, Ryan Paetzold, James J. Prendergast, Gabriella Bellavia, Stefania Straino, Francesca Cianfarani, Monica Salamone, Carmelo M. Bruno, Kevin M. Moerman, Giulio Ghersi, Garry P. Duffy, Eoin D. O'Cearbhaill
Journal: Advanced Healthcare Materials (2021)

In article number 2100229 by Eoin O'Cearbhaill, Garry Duffy and co-workers, the “liquid rope coil effect” is harnessed to produce porous silicone coatings that are additively manufactured onto the surface of soft-tissue implants, aiming to address notorious challenges of long-term tissue integration and fibrosis associated with these implants. In vivo studies show that this coating encourages highly vascularised tissue ingrowth
Reversal of emphysema by restoration of pulmonary endothelial cells
Authors: Shu Hisata, Alexandra C. Racanelli, Pouneh Kermani, Ryan Schreiner, Sean Houghton, Brisa Palikuqi, Balvir Kunar, Aiyuan Zhou, Keith McConn, Allyson Capili, David Redmond, Daniel J. Nolan, Michael Ginsberg, Bi-Sen Ding, Fernando J. Martinez, Joseph M. Scandura, Suzanne M. Cloonan, Shahin Rafii, Augustine M.K. Choi
Journal: The Journal of Experimental Medicine (2021)

Chronic obstructive pulmonary disease (COPD) is marked by airway inflammation and airspace enlargement (emphysema) leading to airflow obstruction and eventual respiratory failure. Microvasculature dysfunction is associated with COPD/emphysema. However, it is not known if abnormal endothelium drives COPD/emphysema pathology and/or if correcting endothelial dysfunction has therapeutic potential. Here, we show the centrality of endothelial cells to the pathogenesis of COPD/emphysema in human tissue and using an elastase-induced murine model of emphysema. Airspace disease showed significant endothelial cell loss, and transcriptional profiling suggested an apoptotic, angiogenic, and inflammatory state. This alveolar destruction was rescued by intravenous delivery of healthy lung endothelial cells. Leucine-rich α-2-glycoprotein-1 (LRG1) was a driver of emphysema, and deletion of Lrg1 from endothelial cells rescued vascular rarefaction and alveolar regression. Hence, targeting endothelial cell biology through regenerative methods and/or inhibition of the LRG1 pathway may represent strategies of immense potential for the treatment of COPD/emphysema.
肝臓学における細胞外小胞:生理学的役割,病因への関与および治療機会【JST・京大機械翻訳】
Authors: Azparren-Angulo Maria, Royo Felix, Gonzalez Esperanza, Liebana Marc, Brotons Bruno, Berganza Jesus, Goni-de-Cerio Felipe, Manicardi Nicolo, Abad-Jorda Laia, Gracia-Sancho Jordi, M Falcon-Perez Juan
Journal: Pharmacology & Therapeutics (2021)
Cancer Clinical Trial Participation at the 1-Year Anniversary of the Outbreak of the COVID-19 Pandemic
Authors: Joseph M. Unger, Hong Xiao, Michael LeBlanc, Dawn L. Hershman, Charles D. Blanke
Journal: JAMA Network Open (2021)

<h3>Importance</h3> During the initial outbreak of the COVID-19 pandemic, cancer clinical trial participation decreased precipitously. Given the continued pandemic—especially the severe wave of new cases and deaths in winter 2020 to 2021—a vital question is whether trial enrollments have remained low or even worsened. <h3>Objective</h3> To examine the experience of cancer clinical trial enrollment 1 year after the COVID-19 outbreak. <h3>Design, Setting, and Participants</h3> This cohort study examines initial enrollments to treatment trials and cancer control and prevention (CCP) trials conducted by the SWOG Cancer Research Network between January 1, 2016, and February 28, 2021. Participants include patients enrolled in the trials. <h3>Exposures</h3> Landmark time points reflecting the onset and the apex, respectively, of the initial COVID-19 wave (March 1 to April 25, 2020) and the winter 2020 to 2021 wave (October 4, 2020, to January 23, 2021). <h3>Main Outcomes and Measures</h3> This study used interrupted time-series analysis to examine enrollments over time related to the COVID-19–derived exposure variables using negative-binomial regression. Relative risk (RR) estimates representing weekly enrollment changes compared with expected rates (had the pandemic not occurred) were derived. The numbers of enrollments lost during the pandemic were estimated. <h3>Results</h3> Overall, 29 398 patients (mean [SD] age, 60.3 [13.2] years) were enrolled (24 034 before the pandemic and 5364 during the pandemic), with 9198 patients (31.3%) aged 65 years or older, 17 199 female patients (58.6%), 3039 Black patients (10.8%), and 2260 Hispanic patients (7.9%). Most enrollments (19 451 [66.2%]) were to treatment trials. During the initial COVID-19 wave, there was a 9.0% model-estimated weekly reduction in enrollments (RR, 0.91; 95% CI, 0.89-0.93;<i>P</i> &lt; .001), with effects compounding each week. Enrollment recovered thereafter, but decreased again during the winter 2020 to 2021 wave, although by only 2.0% each week (RR, 0.98; 95% CI, 0.97-0.99;<i>P</i> &lt; .001). Overall, during the pandemic, actual enrollments were 77.3% of expected enrollments (5364 of 6913 enrollments; 95% CI, 70.5%-85.0%;<i>P</i> &lt; .001). Actual enrollments were 54.0% of expected enrollments for CCP trials (1421 of 2641 enrollments; 95% CI, 43.0%-67.0%;<i>P</i> &lt; .001) and 91.0% of expected enrollments for treatment trials (3922 of 4304 enrollments; 95% CI, 81.0%-102.0%;<i>P</i> = .12). <h3>Conclusions and Relevance</h3> In this cohort study, clinical trial enrollments decreased during the full year of the COVID-19 pandemic. Enrollment reductions were primarily to CCP trials, whereas, remarkably, there was not strong evidence of enrollment reductions to treatment trials. This finding suggests that clinical research rapidly adapted to the circumstances of enrolling and treating patients on protocols during the COVID-19 pandemic.
Antibody Response After a Third Dose of the mRNA-1273 SARS-CoV-2 Vaccine in Kidney Transplant Recipients With Minimal Serologic Response to 2 Doses
Authors: Ilies Benotmane, Gabriela Gautier, Peggy Perrin, Jérôme Olagne, Noëlle Cognard, Samira Fafi-Kremer, Sophie Caillard
Journal: JAMA (2021)

Brian J. Boyarsky, MD; William A. Werbel, MD; Robin K. Avery, MD; Aaron A. R. Tobian, MD, PhD; Allan B. Massie, PhD; Dorry L. Segev, MD, PhD; Jacqueline M. Garonzik-Wang, MD, PhD
Modeling High-Grade Serous Ovarian Carcinoma Using a Combination of<i>In Vivo</i>Fallopian Tube Electroporation and CRISPR-Cas9–Mediated Genome Editing
Authors: Katie Teng, Matthew J. Ford, Keerthana Harwalkar, YuQi Li, Alain S. Pacis, David Farnell, Nobuko Yamanaka, Yu-Chang Wang, Dunarel Badescu, Tuyet Nhung Ton Nu, Jiannis Ragoussis, David G. Huntsman, Jocelyne Arseneau, Yojiro Yamanaka
Journal: Cancer Research (2021)

Abstract Ovarian cancer is the most lethal gynecologic cancer to date. High-grade serous ovarian carcinoma (HGSOC) accounts for most ovarian cancer cases, and it is most frequently diagnosed at advanced stages. Here, we developed a novel strategy to generate somatic ovarian cancer mouse models using a combination of in vivo electroporation and CRISPR-Cas9–mediated genome editing. Mutation of tumor suppressor genes associated with HGSOC in two different combinations (Brca1, Tp53, Pten with and without Lkb1) resulted in successfully generation of HGSOC, albeit with different latencies and pathophysiology. Implementing Cre lineage tracing in this system enabled visualization of peritoneal micrometastases in an immune-competent environment. In addition, these models displayed copy number alterations and phenotypes similar to human HGSOC. Because this strategy is flexible in selecting mutation combinations and targeting areas, it could prove highly useful for generating mouse models to advance the understanding and treatment of ovarian cancer. Significance: This study unveils a new strategy to generate genetic mouse models of ovarian cancer with high flexibility in selecting mutation combinations and targeting areas.
2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes: Executive Summary
Authors: Ezra A. Amsterdam, Nanette K. Wenger, Ralph G. Brindis, Donald E. Casey, Theodore G. Ganiats, David R. Holmes, Allan S. Jaffe, Hani Jneid, Rosemary F. Kelly, Michael C. Kontos, Glenn N. Levine, Philip R. Liebson, Debabrata Mukherjee, Eric D. Peterson, Marc S. Sabatine, Richard W. Smalling, Susan J. Zieman
Journal: Circulation (2014)

The writing
Systemic inhibition of PTPN22 augments anticancer immunity
Authors: Won Jin Ho, Sarah Croessmann, Jianping Lin, Zaw H. Phyo, Soren Charmsaz, Ludmila Danilova, Aditya A. Mohan, Nicole E. Gross, Fangluo Chen, Jiajun Dong, Devesh Aggarwal, Yunpeng Bai, Janey Wang, Jing He, James M. Leatherman, Mark Yarchoan, Todd D. Armstrong, Neeha Zaidi, Elana J. Fertig, Joshua C. Denny, Ben H. Park, Zhong-Yin Zhang, Elizabeth M. Jaffee
Journal: Journal of Clinical Investigation (2021)

Both epidemiologic and cellular studies in the context of autoimmune diseases have established that protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a key regulator of T cell receptor (TCR) signaling. However, its mechanism of action in tumors and its translatability as a target for cancer immunotherapy have not been established. Here, we show that a germline variant of PTPN22, rs2476601, portended a lower likelihood of cancer in patients. PTPN22 expression was also associated with markers of immune regulation in multiple cancer types. In mice, lack of PTPN22 augmented antitumor activity with greater infiltration and activation of macrophages, natural killer (NK) cells, and T cells. Notably, we generated a small molecule inhibitor of PTPN22, named L-1, that phenocopied the antitumor effects seen in genotypic PTPN22 knockout. PTPN22 inhibition promoted activation of CD8+ T cells and macrophage subpopulations toward MHC-II–expressing M1-like phenotypes, both of which were necessary for successful antitumor efficacy. Increased PD-1/PD-L1 axis expression in the setting of PTPN22 inhibition could be further leveraged with PD-1 inhibition to augment antitumor effects. Similarly, cancer patients with the rs2476601 variant responded significantly better to checkpoint inhibitor immunotherapy. Our findings suggest that PTPN22 is a druggable systemic target for cancer immunotherapy.
Effect of a deep learning-based system on the miss rate of gastric neoplasms during upper gastrointestinal endoscopy: a single-centre, tandem, randomised controlled trial
Authors: Lianlian Wu, Renduo Shang, Prateek Sharma, Wei Zhou, Jun Liu, Liwen Yao, Zehua Dong, Jingping Yuan, Zhi Zeng, Yuanjie Yu, Chunping He, Qiutang Xiong, Yanxia Li, Yunchao Deng, Zhuo Cao, Chao Huang, Rui Zhou, Hongyan Li, Guiying Hu, Yiyun Chen, Yonggui Wang, Xinqi He, Yijie Zhu, Honggang Yu
Journal: The Lancet. Gastroenterology & hepatology (2021)
Central venous access devices for the delivery of systemic anticancer therapy (CAVA): a randomised controlled trial
Authors: Jonathan G Moss, Olivia Wu, Andrew R Bodenham, Roshan Agarwal, Tobias F Menne, Brian L Jones, Robert Heggie, Steve Hill, Judith Dixon-Hughes, Eileen Soulis, Evi Germeni, Susan Dillon, Elaine McCartney
Journal: The Lancet (2021)