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1دورية أكاديمية
المؤلفون: Christopher Collazo, Ian Vargas, Brendon Cara, Carla J. Weinheimer, Ryan P. Grabau, Dmitry Goldgof, Lawrence Hall, Samuel A. Wickline, Hua Pan
المصدر: Bioengineering, Vol 11, Iss 5, p 434 (2024)
مصطلحات موضوعية: machine learning, active deep learning, ground truth, convolutional neural network, deep learning-based preprocessing, Technology, Biology (General), QH301-705.5
الوصف: The progress of incorporating deep learning in the field of medical image interpretation has been greatly hindered due to the tremendous cost and time associated with generating ground truth for supervised machine learning, alongside concerns about the inconsistent quality of images acquired. Active learning offers a potential solution to these problems of expanding dataset ground truth by algorithmically choosing the most informative samples for ground truth labeling. Still, this effort incurs the costs of human labeling, which needs minimization. Furthermore, automatic labeling approaches employing active learning often exhibit overfitting tendencies while selecting samples closely aligned with the training set distribution and excluding out-of-distribution samples, which could potentially improve the model’s effectiveness. We propose that the majority of out-of-distribution instances can be attributed to inconsistent cross images. Since the FDA approved the first whole-slide image system for medical diagnosis in 2017, whole-slide images have provided enriched critical information to advance the field of automated histopathology. Here, we exemplify the benefits of a novel deep learning strategy that utilizes high-resolution whole-slide microscopic images. We quantitatively assess and visually highlight the inconsistencies within the whole-slide image dataset employed in this study. Accordingly, we introduce a deep learning-based preprocessing algorithm designed to normalize unknown samples to the training set distribution, effectively mitigating the overfitting issue. Consequently, our approach significantly increases the amount of automatic region-of-interest ground truth labeling on high-resolution whole-slide images using active deep learning. We accept 92% of the automatic labels generated for our unlabeled data cohort, expanding the labeled dataset by 845%. Additionally, we demonstrate expert time savings of 96% relative to manual expert ground-truth labeling.
وصف الملف: electronic resource
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2دورية أكاديمية
المؤلفون: Samuel A. Wickline, Kirk K. Hou, Hua Pan
المصدر: International Journal of Molecular Sciences, Vol 24, Iss 11, p 9455 (2023)
مصطلحات موضوعية: nanoparticles, peptide polyplexes, RNA, siRNA, mRNA, nucleic acids, Biology (General), QH301-705.5, Chemistry, QD1-999
الوصف: Peptide-based nanoparticles (PBN) for nucleotide complexation and targeting of extrahepatic diseases are gaining recognition as potent pharmaceutical vehicles for fine-tuned control of protein production (up- and/or down-regulation) and for gene delivery. Herein, we review the principles and mechanisms underpinning self-assembled formation of PBN, cellular uptake, endosomal release, and delivery to extrahepatic disease sites after systemic administration. Selected examples of PBN that have demonstrated recent proof of concept in disease models in vivo are summarized to offer the reader a comparative view of the field and the possibilities for clinical application.
وصف الملف: electronic resource
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3دورية أكاديمية
المؤلفون: Ian Vargas, Ryan P. Grabau, Junjie Chen, Carla Weinheimer, Attila Kovacs, William Dominguez-Viqueira, Adam Mitchell, Samuel A. Wickline, Hua Pan
المصدر: International Journal of Molecular Sciences, Vol 24, Iss 8, p 7333 (2023)
مصطلحات موضوعية: acute myocardial infarction, thrombosis, inflammation, inflammasome, PPACK, perfluorocarbon nanoparticles, Biology (General), QH301-705.5, Chemistry, QD1-999
الوصف: Myocardial ischemia reperfusion injury (IRI) in acute coronary syndromes is a condition in which ischemic/hypoxic injury to cells subtended by the occluded vessel continues despite successful resolution of the thrombotic obstruction. For decades, most efforts to attenuate IRI have focused on interdicting singular molecular targets or pathways, but none have successfully transitioned to clinical use. In this work, we investigate a nanoparticle-based therapeutic strategy for profound but local thrombin inhibition that may simultaneously mitigate both thrombosis and inflammatory signaling pathways to limit myocardial IRI. Perfluorocarbon nanoparticles (PFC NP) were covalently coupled with an irreversible thrombin inhibitor, PPACK (Phe[D]-Pro-Arg-Chloromethylketone), and delivered intravenously to animals in a single dose prior to ischemia reperfusion injury. Fluorescent microscopy of tissue sections and 19F magnetic resonance images of whole hearts ex vivo demonstrated abundant delivery of PFC NP to the area at risk. Echocardiography at 24 h after reperfusion demonstrated preserved ventricular structure and improved function. Treatment reduced thrombin deposition, suppressed endothelial activation, inhibited inflammasome signaling pathways, and limited microvascular injury and vascular pruning in infarct border zones. Accordingly, thrombin inhibition with an extraordinarily potent but locally acting agent suggested a critical role for thrombin and a promising therapeutic strategy in cardiac IRI.
وصف الملف: electronic resource
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4دورية أكاديمية
المؤلفون: Qingyu Zhou, James D. Quirk, Ying Hu, Huimin Yan, Joseph P. Gaut, Christine T. N. Pham, Samuel A. Wickline, Hua Pan
المصدر: International Journal of Molecular Sciences, Vol 24, Iss 7, p 6086 (2023)
مصطلحات موضوعية: cisplatin, acute kidney injury, rapamycin, perfluorocarbon nanoparticles, fluorine magnetic resonance imaging, magnetic resonance spectroscopy, Biology (General), QH301-705.5, Chemistry, QD1-999
الوصف: For nearly five decades, cisplatin has played an important role as a standard chemotherapeutic agent and been prescribed to 10–20% of all cancer patients. Although nephrotoxicity associated with platinum-based agents is well recognized, treatment of cisplatin-induced acute kidney injury is mainly supportive and no specific mechanism-based prophylactic approach is available to date. Here, we postulated that systemically delivered rapamycin perfluorocarbon nanoparticles (PFC NP) could reach the injured kidneys at sufficient and sustained concentrations to mitigate cisplatin-induced acute kidney injury and preserve renal function. Using fluorescence microscopic imaging and fluorine magnetic resonance imaging/spectroscopy, we illustrated that rapamycin-loaded PFC NP permeated and were retained in injured kidneys. Histologic evaluation and blood urea nitrogen (BUN) confirmed that renal structure and function were preserved 48 h after cisplatin injury. Similarly, weight loss was slowed down. Using western blotting and immunofluorescence staining, mechanistic studies revealed that rapamycin PFC NP significantly enhanced autophagy in the kidney, reduced the expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), as well as decreased the expression of the apoptotic protein Bax, all of which contributed to the suppression of apoptosis that was confirmed with TUNEL staining. In summary, the delivery of an approved agent such as rapamycin in a PFC NP format enhances local delivery and offers a novel mechanism-based prophylactic therapy for cisplatin-induced acute kidney injury.
وصف الملف: electronic resource
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5دورية أكاديمية
المؤلفون: Krishnan MohanKumar, Kopperuncholan Namachivayam, Tanjing Song, Byeong Jake Cha, Andrea Slate, Jeanne E. Hendrickson, Hua Pan, Samuel A. Wickline, Joo-Yeun Oh, Rakesh P. Patel, Ling He, Benjamin A. Torres, Akhil Maheshwari
المصدر: Nature Communications, Vol 10, Iss 1, Pp 1-17 (2019)
مصطلحات موضوعية: Science
الوصف: The development of neonatal necrotising enterocolitis has been temporally associated with red blood cell transfusions in retrospective human studies. Here, the authors develop a neonatal mouse model of necrotising enterocolitis in anaemic mice receiving red blood cell transfusion that recapitulates features of the human condition.
وصف الملف: electronic resource
Relation: https://doaj.org/toc/2041-1723
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6دورية أكاديمية
المؤلفون: Janet B. McGill, Mariko Johnson, Stacy Hurst, William T. Cade, Kevin E. Yarasheski, Richard E. Ostlund, Kenneth B. Schechtman, Babak Razani, Michael B. Kastan, Donald A. McClain, Lisa de las Fuentes, Victor G. Davila-Roman, Daniel S. Ory, Samuel A. Wickline, Clay F. Semenkovich
المصدر: Diabetology & Metabolic Syndrome, Vol 11, Iss 1, Pp 1-16 (2019)
مصطلحات موضوعية: Chloroquine, Metabolic syndrome, Carotid intima-media thickness, Insulin sensitivity, Glucose disposal, Atheroma, Nutritional diseases. Deficiency diseases, RC620-627
الوصف: Abstract Background Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome. Methods Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment. Results For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups. Conclusions These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting. Trial registration ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007
وصف الملف: electronic resource
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7دورية أكاديمية
المؤلفون: Qingyu Zhou, Justin Doherty, Antonina Akk, Luke E. Springer, Ping Fan, Ivan Spasojevic, Ganesh V. Halade, Huanghe Yang, Christine T. N. Pham, Samuel A. Wickline, Hua Pan
المصدر: Nanomaterials, Vol 12, Iss 3, p 336 (2022)
مصطلحات موضوعية: rapamycin, perfluorocarbon nanoparticle, autophagy, inflammation, pharmacokinetics, biodistribution, Chemistry, QD1-999
الوصف: Cancer treatment-induced toxicities may restrict maximal effective dosing for treatment and cancer survivors’ quality of life. It is critical to develop novel strategies that mitigate treatment-induced toxicity without affecting the efficacy of anti-cancer therapies. Rapamycin is a macrolide with anti-cancer properties, but its clinical application has been hindered, partly by unfavorable bioavailability, pharmacokinetics, and side effects. As a result, significant efforts have been undertaken to develop a variety of nano-delivery systems for the effective and safe administration of rapamycin. While the efficacy of nanostructures carrying rapamycin has been studied intensively, the pharmacokinetics, biodistribution, and safety remain to be investigated. In this study, we demonstrate the potential for rapamycin perfluorocarbon (PFC) nanoparticles to mitigate cisplatin-induced acute kidney injury with a single preventative dose. Evaluations of pharmacokinetics and biodistribution suggest that the PFC nanoparticle delivery system improves rapamycin pharmacokinetics. The safety of rapamycin PFC nanoparticles was shown both in vitro and in vivo. After a single dose, no disturbance was observed in blood tests or cardiac functional evaluations. Repeated dosing of rapamycin PFC nanoparticles did not affect overall spleen T cell proliferation and responses to stimulation, although it significantly decreased the number of Foxp3+CD4+ T cells and NK1.1+ cells were observed.
وصف الملف: electronic resource
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8دورية أكاديمية
المؤلفون: Daniel A. Rauch, John C. Harding, Lee Ratner, Samuel A. Wickline, Hua Pan
المصدر: Nanomaterials, Vol 11, Iss 6, p 1582 (2021)
مصطلحات موضوعية: adult T-cell leukemia/lymphoma, human T-cell leukemia virus type 1, NF-kB activation, p5RHH, siRNA delivery, Chemistry, QD1-999
الوصف: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive, clonal malignancy of mature T cells caused by human T-cell leukemia virus type 1. Although it is a rare tumor type, it serves as an excellent model of a virus driven process that transforms cells and engenders a highly malignant tumor that is extraordinarily difficult to treat. The viral transcriptional transactivator (Tax) in the HTLV-1 genome directly promotes tumorigenesis, and Tax-induced oncogenesis depends on its ability to constitutively activate NF-κB signaling. Accordingly, we developed and evaluated a nano-delivery system that simultaneously inhibits both canonical (p65) and noncanonical (p100) NF-κB signaling pathways locally in tumors after systemic administration. Our results demonstrate that siRNA is delivered rapidly to ATLL tumors after either i.p. or i.v. injection. The siRNA treatment significantly reduced both p65 and p100 mRNA and protein expression. Anti-NF-κB nanotherapy significantly inhibited tumor growth in two distinct tumor models in mice: a spontaneous Tax-driven tumor model, and a Tax tumor cell transplant model. Moreover, siRNA nanotherapy sensitized late-stage ATLL tumors to the conventional chemotherapeutic agent etoposide, indicating a pleiotropic benefit for localized siRNA nanotherapeutics.
وصف الملف: electronic resource
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9دورية أكاديمية
المؤلفون: Huimin Yan, Xin Duan, Kelsey H. Collins, Luke E. Springer, Farshid Guilak, Samuel A. Wickline, M. Farooq Rai, Hua Pan, Christine Pham
المصدر: Precision Nanomedicine, Vol 2, Iss 1 (2019)
مصطلحات موضوعية: Medicine, Medical technology, R855-855.5
الوصف: Inflammation after joint injury leads to joint responses that result in eventual osteoarthritis development. Blockade of inflammation, by suppressing NF-κB expression, has been shown to reduce joint injury-induced chondrocyte apoptosis and reactive synovitis in vivo. Herein, we demonstrate that the suppression of NF-κB p65 expression also significantly mitigates the acute pain sensitivity induced by mechanical injury to the joint. These results suggest that early intervention with anti-NF-κB nanotherapy mitigates both structural and pain-related outcomes, which in turn may impact the progression of post-traumatic osteoarthritis. [READ ARTICLE](https://precisionnanomedicine.com/article/6949)
وصف الملف: electronic resource
Relation: https://doaj.org/toc/2639-9431
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10دورية أكاديمية
المؤلفون: Chandu Vemuri, MD, Gundumi A. Upadhya, MD, Batool Arif, MD, Jianluo Jia, MD, Yiing Lin, MD, PhD, Joseph P. Gaut, MD, PhD, Jawad Fazal, MD, Hua Pan, MD, Samuel A. Wickline, MD, William C. Chapman, MD
المصدر: Transplantation Direct, Vol 4, Iss 9, p e384 (2018)
الوصف: Background. Over 100 000 patients await renal transplantation and 4000 die per year. Compounding this mismatch between supply and demand is delayed graft function which contributes to short-term and long-term graft failures. Previously, we reported that thrombin-targeted perfluorocarbon nanoparticles (PFC-NP) protect kidneys from ischemic renal injury after transient arterial occlusion. Here we hypothesize that perfusion of renal allografts with PFC-NP similarly can protect graft function after an ischemic interval. Methods. After 60 minutes of warm ischemia, male Lewis rats underwent left renal explantation followed by renal perfusion with 5 mL of standard perfusate alone (N = 3) or with 0.3 mL of untargeted PFC-NP (N = 5) or 0.3 mL thrombin-targeted of PFC NP functionalized with phenylalanine-proline-arginine-chloromethylketone (PPACK) (PFC-PPACK), an irreversible thrombin inhibitor (N = 5). Kidneys underwent 6 hours of cold storage, followed by transplantation into recipients and native nephrectomy. Animals were euthanized at 24 hours for tissue collection or at 48 hours for blood and renal tissue collection. A survival experiment was performed using the same protocol with saline control (N = 3), PFC-NP (N = 3) or PFC-PPACK (N = 6). Results. Serum creatinine was improved for the PFC-PPACK groups as compared with control groups (P < 0.04). Kaplan-Meier survival curves also indicated increased longevity (P < 0.05). Blinded histologic scoring revealed markedly attenuated renal damage in the PFC-PPACK group compared to untreated animals (2.75 ± 1.60 versus 0.83 ± 3.89; P = 0.0001) and greater preservation of renal vasculature. Conclusions. These results validate an NP-based approach to improve renal graft function as antithrombin NPs improved allograft function, decreased renal damage, protected vasculature, and improved longevity.
وصف الملف: electronic resource
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