tbuckley/cabot-search huggingface dataset:
Arginine Therapy and Cardiopulmonary Hemodynamics in Hospitalized Children with Sickle Cell Anemia: A Prospective, Double-blinded, Randomized Placebo-controlled Clinical Trial
Authors: Richard Onalo, Antoinette Cilliers, Peter Cooper, Claudia R. Morris
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Acute changes in cardiopulmonary hemodynamics that include tricuspid regurgitant jet velocity (TRV) elevation measured by Doppler echocardiography are often encountered during sickle cell vasoocclusive pain and acute chest syndrome (ACS). Arginine and nitric oxide depletion develop in patients with these complications. Arginine administration may therefore improve nitric oxide bioavailability and potentiate pulmonary vasodilatation. Objectives: To evaluate effects of l-arginine supplementation on Doppler indices of cardiopulmonary hemodynamics in children with sickle cell anemia experiencing pain. Methods: This was a prospective, double-blinded, randomized placebo-controlled trial of oral arginine in children with sickle cell anemia age 5-17 years hospitalized with severe pain and/or ACS. Measurements and Main Results: Blood biomarkers and Doppler echocardiographic indices of cardiopulmonary hemodynamics were measured before and after supplementation. The mean change in TRV, pulmonary artery systolic pressure, mean pulmonary artery pressure, and other indices of cardiopulmonary hemodynamics were tested with paired Student's t test and correlated with markers of arginine bioavailability using Pearson correlation. Sixty-six children were randomized into arginine versus placebo groups. An elevated TRV ⩾ 2.5 m/s was seen in 40 (61%) patients. A Day 5 Doppler echocardiogram was performed in 47 patients who remained hospitalized. A greater reduction in median TRV occurred in the arginine group than placebo (22.2%, n = 22 vs. 3.8%, n = 25; p < 0.01). A larger percentage increase in global arginine bioavailability was associated with a lower TRV after 5 days of supplementation (r = -0.533; P = 0.001). Significant differences in multiple indices of cardiopulmonary hemodynamics and mean N-terminal pro B-type brain natriuretic peptide were also noted after arginine therapy. Conclusions: Oral arginine supplementation improves cardiopulmonary hemodynamics during sickle cell disease vasoocclusive pain and ACS.Clinical trial registered with Pan African Clinical Trial Registry https://pactr.samrc.ac.za/Search.aspx (PACTR201611001864290).
Therapy for Muscle-Invasive Urothelial Carcinoma: Controversies and Dilemmas
Authors: Guru P. Sonpavde, Kent W. Mouw, Matthew Mossanen
Journal: Journal of Clinical Oncology (2022)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
Recent Advances in Designing Electroconductive Biomaterials for Cardiac Tissue Engineering
Authors: Mahsa Ghovvati, Mahshid Kharaziha, Reza Ardehali, Nasim Annabi
Journal: Advanced Healthcare Materials (2022)

Implantable cardiac patches and injectable hydrogels are among the most promising therapies for cardiac tissue regeneration following myocardial infarction. Incorporating electrical conductivity into these patches and hydrogels is found to be an efficient method to improve cardiac tissue function. Conductive nanomaterials such as carbon nanotube, graphene oxide, gold nanorod, as well as conductive polymers such as polyaniline, polypyrrole, and poly(3,4-ethylenedioxythiophene):polystyrene sulfonate are appealing because they possess the electroconductive properties of semiconductors with ease of processing and have potential to restore electrical signaling propagation through the infarct area. Numerous studies have utilized these materials for regeneration of biological tissues that possess electrical activities, such as cardiac tissue. In this review, recent studies on the use of electroconductive materials for cardiac tissue engineering and their fabrication methods are summarized. Moreover, recent advances in developing electroconductive materials for delivering therapeutic agents as one of emerging approaches for treating heart diseases and regenerating damaged cardiac tissues are highlighted.
High-risk Pathologic Features Based on Presenting Findings in Advanced Intraocular Retinoblastoma
Authors: Ankit Singh Tomar, Paul T. Finger, Brenda Gallie, Tero T. Kivelä, Ashwin Mallipatna, Chengyue Zhang, Junyang Zhao, Matthew W. Wilson, Rachel C. Brennan, Michala Burges, Jonathan Kim, Jesse L. Berry, Rima Jubran, Vikas Khetan, Suganeswari Ganesan, Andrey Yarovoy, Vera Yarovaya, Elena Kotova, Denis Volodin, Yacoub A. Yousef, Kalle Nummi, Tatiana L. Ushakova, Olga V. Yugay, Vladimir G. Polyakov, Marco A. Ramirez-Ortiz, Elizabeth Esparza-Aguiar, Guillermo Chantada, Paula Schaiquevich, Adriana Fandino, Jason C. Yam, Winnie W. Lau, Carol P. Lam, Phillipa Sharwood, Sonia Moorthy, Quah Boon Long, Vera Adobea Essuman, Lorna A. Renner, Ekaterina Semenova, Jaume Català-Mora, Genoveva Correa-Llano, Elisa Carreras
Journal: Ophthalmology (2022)

To determine the value of clinical features for advanced intraocular retinoblastoma as defined by the eighth edition of the American Joint Committee on Cancer (AJCC) cT3 category and AJCC Ophthalmic Oncology Task Force (OOTF) Size Groups to predict the high-risk pathologic features.International, multicenter, registry-based retrospective case series.Eighteen ophthalmic oncology centers from 13 countries over 6 continents shared evaluations of 942 eyes enucleated as primary treatment for AJCC cT3 and, for comparison, cT2 retinoblastoma.International, multicenter, registry-based data were pooled from patients enrolled between 2001 and 2013. High-risk pathologic features were defined as AJCC categories pT3 and pT4. In addition, AJCC OOTF Size Groups were defined as follows: (1) less than half, (2) more than half but less than two thirds, (3) more than two thirds of globe volume involved, and (4) diffuse infiltrating retinoblastoma.Statistical risk of high-risk pathologic features corresponding to AJCC cT3 subcategories and AJCC OOTF Size Groups.Of 942 retinoblastoma eyes treated by primary enucleation, 282 (30%) showed high-risk pathologic features. Both cT subcategories and AJCC OOTF Size Groups (P < 0.001 for both) were associated with high-risk pathologic features. On logistic regression analysis, cT3c (iris neovascularization with glaucoma), cT3d (intraocular hemorrhage), and cT3e (aseptic orbital cellulitis) were predictive factors for high-risk pathologic features when compared with cT2a with an odds ratio of 2.3 (P = 0.002), 2.5 (P = 0.002), and 3.3 (P = 0.019), respectively. Size Group 3 (more than two-thirds globe volume) and 4 (diffuse infiltrative retinoblastoma) were the best predictive factors with an odds ratio of 3.3 and 4.1 (P < 0.001 for both), respectively, for high-risk pathologic features when compared with Size Groups 1 (i.e., < 50% of globe volume).The AJCC retinoblastoma staging clinical cT3c-e subcategories (glaucoma, intraocular hemorrhage, and aseptic orbital cellulitis, respectively) as well as the AJCC OOTF Size Groups 3 (tumor more than two thirds of globe volume) and 4 (diffuse infiltrative retinoblastoma) both allowed stratification of clinical risk factors that can be used to predict the presence of high-risk pathologic features and thus facilitate treatment decisions.
Natural, synthetic and commercially-available biopolymers used to regenerate tendons and ligaments
Authors: Behzad Shiroud Heidari, Rui Ruan, Ebrahim Vahabli, Peilin Chen, Elena M. De-Juan-Pardo, Minghao Zheng, Barry Doyle
Journal: Bioactive Materials (2022)

Tendon and ligament (TL) injuries affect millions of people annually. Biopolymers play a significant role in TL tissue repair, whether the treatment relies on tissue engineering strategies or using artificial tendon grafts. The biopolymer governs the mechanical properties, biocompatibility, degradation, and fabrication method of the TL scaffold. Many natural, synthetic and hybrid biopolymers have been studied in TL regeneration, often combined with therapeutic agents and minerals to engineer novel scaffold systems. However, most of the advanced biopolymers have not advanced to clinical use yet. Here, we aim to review recent biopolymers and discuss their features for TL tissue engineering. After introducing the properties of the native tissue, we discuss different types of natural, synthetic and hybrid biopolymers used in TL tissue engineering. Then, we review biopolymers used in commercial absorbable and non-absorbable TL grafts. Finally, we explain the challenges and future directions for the development of novel biopolymers in TL regenerative treatment.
Identification and evaluation of a lipid-lowering small compound in preclinical models and in a Phase I trial
Authors: Jiang Wang, Jing Zhao, Cong Yan, Cong Xi, Chenglin Wu, Jingxiang Zhao, Fengwei Li, Yanhua Ding, Rui Zhang, Shankang Qi, Xingjun Li, Chao Liu, Wanting Hou, Hong Chen, Yiping Wang, Dalei Wu, Kaixian Chen, Hualiang Jiang, He Huang, Hong Liu
Journal: Cell Metabolism (2022)
Revolutionizing non-conventional wound healing using honey by simultaneously targeting multiple molecular mechanisms
Authors: Carlos C.F. Pleeging, Frank A.D.T.G. Wagener, Hilde de Rooster, Niels A.J. Cremers
Journal: Drug Resistance Updates (2022)

Hospital-acquired infections and treatment-related wound complications constitute a tremendous burden for the health care system, particularly given the serious increase in multidrug resistant pathogens. Imagine that a large part of nosocomial infections can be prevented using a simple treatment. In this respect, honey is used mainly in topical cutaneous wound care because of its potent broad-spectrum antibacterial and wound healing activities. However, therapeutic use outside this scope has been limited. The current review provides an in-depth view of studies using honey outside the conventional wound care indications. Non-conventional routes of honey application include subcutaneous, intra-socket, abdominal, and oral administration in novel indications, such as post colon surgery, mucositis, and tooth extraction. Honey consistently demonstrates beneficial therapeutic activities in these novel applications, orchestrating antimicrobial and prophylactic activity, reducing inflammation and wound dehiscence, and inducing healing, epithelialization, and analgesic activity. Several molecular mechanisms are responsible for these beneficial clinical effects of honey during the course of wound healing. Pro-inflammatory effects of honey, such as induction of iNOS, IL-1β, and COX-2, are mediated by TLR4 signaling. In contrast, honey's anti-inflammatory actions and flavonoids induce anti-inflammatory and antioxidant pathways by inducing NRF2 target genes, including HO-1 and PRDX1. The molecular and biochemical pathways activated by honey during the different phases of wound healing are also discussed in more detail in this review. Variation between different honey origins exists, and therefore standardized medical-grade honey may offer an optimized and safe treatment. Honey is a valuable alternative to conventional antimicrobial and anti-inflammatory therapies that can strongly reduce nosocomial infections.
Subtyping of microsatellite stability colorectal cancer reveals guanylate binding protein 2 (GBP2) as a potential immunotherapeutic target
Authors: Haizhou Wang, Yabo Zhou, Yangyang Zhang, Shilin Fang, Meng Zhang, Haiou Li, Fei Xu, Lan Liu, Jing Liu, Qiu Zhao, Fan Wang
Journal: Journal for ImmunoTherapy of Cancer (2022)

Proficient-mismatch-repair or microsatellite stability (pMMR/MSS) colorectal cancer (CRC) has limited efficacy for immune checkpoint blockade (ICB) therapy and its underlying mechanism remains unclear. Guanylate binding protein 2 (GBP2) is a member of the GTPase family and is crucial to host immunity against pathogens. However, the correlations between GBP2 and immunosurveillance and immunotherapy for pMMR/MSS CRC have not been reported.Unsupervised clustering was employed to classify immune class and non-immune class in 1424 pMMR/MSS patients from six independent public datasets. This binary classification was validated using immune cells or response related signatures. The correlation between GBP2 and immune microenvironment was explored using well-established biological algorithms, multiplex immunohistochemistry (mIHC), in vitro and in vivo experiments.We classified 1424 pMMR/MSS CRC patients into two classes, 'immune' and 'non-immune', and GBP2 was identified as a gene of interest. We found that lower GBP2 expression was correlated with poor prognosis and metastasis. GBP2 expression was also upregulated in the immune class and highly associated with interferon-γ (IFN-γ) signaling pathway and CD8 +T cell infiltration using gene set enrichment analysis, gene ontology analysis, single-cell sequencing and mIHC. Moreover, reduced GBP2 expression inhibited the antigen processing and presentation machinery and CXCL10/11 expression in MSS CRC cells on IFN-γ stimulation. A Transwell assay revealed that deletion of GBP2 in murine MSS CRC cells reduced CD8 +T cell migration. Mechanistically, GBP2 promoted signal transducer and transcription activator 1 (STAT1) phosphorylation by competing with SHP1 for binding to STAT1 in MSS CRC cells. Finally, an unsupervised subclass mapping (SubMap) algorithm showed that pMMR/MSS patients with high GBP2 expression may correlate with a favorable response to anti-PD-1 therapy. We further confirmed that GBP2 knockout reduced CD8 +T cell infiltration and blunted the efficacy of PD-1 blockade in tumor-bearing mice.Our study reveals that pMMR/MSS CRC is immunogenically heterogeneous and that GBP2 is a promising target for combinatorial therapy with ICB.
Ethics Consultation Services as a Resource and its Implications for Evaluation Activities
Authors: Narcyz Ghinea, Linda Sheahan, Ian Kerridge
Journal: The American Journal of Bioethics (2022)

"Ethics Consultation Services as a Resource and its Implications for Evaluation Activities." The American Journal of Bioethics, 22(4), pp. 59–60This article refers to:Ethics Consultation in U.S. Hospitals: Determinants of Consultation Volume DISCLOSURE STATEMENTNarcyz Ghinea is a former employee of the South Eastern Sydney Local Health District (SESLHD) Clinical Ethics Service. Linda Sheahan is the Head of the SESLHD Clinical Ethics Service. Ian Kerridge is the Chair of the SESLHD Clinical Ethics Committee.Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.
Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer
Authors: Andrew J. Armstrong, Arun A. Azad, Taro Iguchi, Russell Z. Szmulewitz, Daniel P. Petrylak, Jeffrey Holzbeierlein, Arnauld Villers, Antonio Alcaraz, Boris Alekseev, Neal D. Shore, Francisco Gomez-Veiga, Brad Rosbrook, Fabian Zohren, Shunsuke Yamada, Gabriel P. Haas, Arnulf Stenzl
Journal: Journal of Clinical Oncology (2022)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In primary analysis, enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC); however, overall survival data were immature. In the phase III, double-blind, global ARCHES trial (ClinicalTrials.gov identifier: NCT02677896 ), 1,150 patients with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg once daily) plus ADT or placebo plus ADT, stratified by disease volume and prior docetaxel use. Here, we report the final prespecified analysis of overall survival (key secondary end point) and an update on rPFS, other secondary end points, and safety. After unblinding, 180 (31.3%) progression-free patients randomly assigned to placebo plus ADT crossed over to open-label enzalutamide plus ADT. As of May 28, 2021 (median follow-up, 44.6 months), 154 of 574 patients randomly assigned to enzalutamide plus ADT and 202 of 576 patients randomly assigned to placebo plus ADT had died. Enzalutamide plus ADT reduced risk of death by 34% versus placebo plus ADT (median not reached in either group; hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P &lt; .001). Enzalutamide plus ADT continued to improve rPFS and other secondary end points. Adverse events were generally consistent with previous reports of long-term enzalutamide use. In conclusion, enzalutamide plus ADT significantly prolongs survival versus placebo plus ADT in patients with mHSPC.
WITHDRAWN: A neurovascular dual-targeting platelet-like bioinspired nanoplatform for ischemic stroke treatment
Authors: Lu Tang, Yuxiang Fei, Yangnan Su, Aining Zhang, Qiaqia Xiao, Yijun Mei, Yujie Su, Yunman Li, Wei Li, Tingting Wang, Yan Shen, Wei Wang
Journal: Acta Pharmaceutica Sinica B (2022)

This article has been withdrawn at the request of the author(s) and editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal
Table of Contents
Authors: S Cedres, E Felip, A Bayle, P Martin-Romano, Y Loriot, P Casali, L Licitra, A Frezza, A Trama, A Passaro, N Leighl, F Blackhall, S Popat, K Kerr, M Ahn, M Arcila, O Arrieta, D Planchard, F De Marinis, A Dingemans, R Dziadziuszko, C Faivre-Finn, J Feldman, G Curigliano, R Herbst, P Jänne, T John, T Mitsudomi, T Mok, N Normanno, L Paz-Ares, S Ramalingam, L Sequist, J Vansteenkiste, I Wistuba, J Wolf, Y Wu, S Yang, J Yang, Y Yatabe, G Pentheroudakis, S Peters, A Scherpereel, R Cornelissen, Y Oulkhouir, L Greillier, M Kaplan, T Talbot, I Monnet, S Hiret, P Baas, A Nowak, N Fujimoto, A Tsao, A Mansfield, X Zhang, N Hu, D Balli, T Spires, G Zalcman
Journal: Annals of Oncology (2022)
Early Insights into Cancer Epigenetics: Gene Promoter Hypermethylation Emerges as a Potential Biomarker for Cancer Detection
Authors: Susan J. Clark, Peter L. Molloy
Journal: Cancer Research (2022)

Abstract DNA methylation is one of the most intensely studied epigenetic modifications in mammals. In normal cells, it plays an essential role in core biologic processes by assuring the proper regulation of gene expression and stable gene silencing. In cancer cells, genome-wide DNA methylation patterns are altered and often represent an early and fundamental step in neoplastic transformation. The landmark study from Esteller and colleagues, published in Cancer Research in 2001, was the first to reveal high frequency promoter methylation across multiple cancer types. They highlighted that widespread alterations in DNA methylation may be a key characteristic of oncogenesis and proposed aberrant DNA methylation of gene promoters could provide markers for sensitive detection of nearly all cancer types. The authors used a candidate gene approach to show promoter hypermethylation occurred across 12 cancer-associated genes in DNA from over 600 primary tumor samples, representing 15 major tumor types. The profile of promoter hypermethylation differed in every tumor type, suggesting that alterations in DNA methylation are pervasive, but the genes affected may be tumor-specific and impact multiple signaling pathways. Over the past 20 years since this publication, the cancer epigenetics field has exploded to generate thousands of normal and cancer methylome maps and developed sophisticated informatic tools for genome-wide methylome analyses. These methylomes are providing roadmaps for the study of cancer biology and discovery of DNA methylation biomarkers for early detection and monitoring of cancer. See related article by Esteller and colleagues, Cancer Res 2001;61:3225–29.
Cryo-EM structure of the prothrombin-prothrombinase complex
Authors: Eliza A. Ruben, Brock Summers, Michael J. Rau, James A. J. Fitzpatrick, Enrico Di Cera
Journal: Blood (2022)

Abstract The intrinsic and extrinsic pathways of the coagulation cascade converge to a common step where the prothrombinase complex, comprising the enzyme factor Xa (fXa), the cofactor fVa, Ca2+ and phospholipids, activates the zymogen prothrombin to the protease thrombin. The reaction entails cleavage at 2 sites, R271 and R320, generating the intermediates prethrombin 2 and meizothrombin, respectively. The molecular basis of these interactions that are central to hemostasis remains elusive. We solved 2 cryogenic electron microscopy (cryo-EM) structures of the fVa-fXa complex, 1 free on nanodiscs at 5.3-Å resolution and the other bound to prothrombin at near atomic 4.1-Å resolution. In the prothrombin-fVa–fXa complex, the Gla domains of fXa and prothrombin align on a plane with the C1 and C2 domains of fVa for interaction with membranes. Prothrombin and fXa emerge from this plane in curved conformations that bring their protease domains in contact with each other against the A2 domain of fVa. The 672ESTVMATRKMHDRLEPEDEE691 segment of the A2 domain closes on the protease domain of fXa like a lid to fix orientation of the active site. The 696YDYQNRL702 segment binds to prothrombin and establishes the pathway of activation by sequestering R271 against D697 and directing R320 toward the active site of fXa. The cryo-EM structure provides a molecular view of prothrombin activation along the meizothrombin pathway and suggests a mechanism for cleavage at the alternative R271 site. The findings advance our basic knowledge of a key step of coagulation and bear broad relevance to other interactions in the blood.
Regulating Macrophage Polarization in High Glucose Microenvironment Using Lithium‐Modified Bioglass‐Hydrogel for Diabetic Bone Regeneration
Authors: Zerui Wu, Jiaxiang Bai, Gaoran Ge, Tao Wang, Shuo Feng, Qiaoqiao Ma, Xiaolong Liang, Wenming Li, Wei Zhang, Yaozeng Xu, Kaijin Guo, Wenguo Cui, Guochun Zha, Dechun Geng
Journal: Advanced Healthcare Materials (2022)

Diabetes mellitus is a chronic metabolic disease with a proinflammatory microenvironment, causing poor vascularization and bone regeneration. Due to the lack of effective therapy and one-sided focus on the direct angiogenic properties of biomaterials and osteogenesis stimulation, the treatment of diabetic bone defect remains challenging and complex. In this study, using gelatin methacryloyl (GelMA) as a template, a lithium (Li) -modified bioglass-hydrogel for diabetic bone regeneration is developed. It exhibits a sustained ion release for better bone regeneration under diabetic microenvironment. The hydrogel is shown to be mechanically adaptable to the complex shape of the defect. In vitro, Li-modified bioglass-hydrogel promoted cell proliferation, direct osteogenesis, and regulated macrophages in high glucose (HG) microenvironment, with the secretion of bone morphogenetic protein-2 and vascular endothelial growth factor to stimulate osteogenesis and neovascularization indirectly. In vivo, composite hydrogels containing GelMA and Li-MBG (GM/M-Li) release Li ions to relieve inflammation, providing an anti-inflammatory microenvironment for osteogenesis and angiogenesis. Applying Li-modified bioglass-hydrogel, significantly enhances bone regeneration in a diabetic rat bone defect. Together, both remarkable in vitro and in vivo outcomes in this study present an opportunity for diabetic bone regeneration on the basis of HG microenvironment.