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Chronic graft-versus-host disease (cGVHD) is an autoimmune-like syndrome. CXCR5-PD-1hi peripheral T-helper (Tph) cells have an important pathogenic role in autoimmune diseases, but the role of Tph cells in cGVHD remains unknown. We show that in patients with cGVHD, expansion of Tph cells among blood CD4+ T cells was associated with cGVHD severity. These cells augmented memory B-cell differentiation and production of immunoglobulin G via interleukin 21 (IL-21). Tph cell expansion was also observed in a murine model of cGVHD. This Tph cell expansion in the blood is associated with the expansion of pathogenic tissue-resident T-helper (Trh) cells that form lymphoid aggregates surrounded by collagen in graft-versus-host disease (GVHD) target tissues. Adoptive transfer experiments showed that Trh cells from GVHD target tissues give rise to Tph cells in the blood, and conversely, Tph cells from the blood give rise to Trh cells in GVHD target tissues. Tph cells in the blood and Trh cells in GVHD target tissues had highly overlapping T-cell receptor α and ß repertoires. Deficiency of IL-21R, B-cell lymphoma 6 (BCL6), or T-bet in donor T cells markedly reduced the proportions of Tph cells in the blood and Trh cells in GVHD target tissues and reduced T-B interaction in the lymphoid aggregates. These results indicate that clonally related pathogenic Tph cells and Trh cells traffic between the blood and cGVHD target tissues, and that IL-21R-BCL6 signaling and T-bet are required for the development and expansion of Tph and Trh cells in the pathogenesis of cGVHD.
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Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Humanos , Ratones , Animales , Linfocitos T Colaboradores-Inductores , Linfocitos T CD4-Positivos , Linfocitos B/patología , Enfermedad CrónicaRESUMEN
BACKGROUND/OBJECTIVES: Disease improvement for difficult-to-control pediatric atopic dermatitis may be more challenging to achieve when directed by single specialties due to disjointed and conflicting dialogue with patients. METHODS: The Multidisciplinary Atopic Dermatitis Program (MADP) was developed through collaborations with the Rady Children's Hospital and UC San Diego Health Divisions of Dermatology, Allergy & Immunology and Clinical Pharmacy, to create team-based evaluation and management of children and adolescents with atopic dermatitis (AD). The MADP allows concurrent, comprehensive evaluations by multiple specialists to develop treatment plans. The program includes extensive patient education to support shared decision making, incorporating patient and family's perspectives along with those of clinical experts into their care. Objective severity measures and patient reported outcome data were collected, along with assessment of patient and family satisfaction with the MADP. RESULTS: Data showed significant improvement in AD severity as assessed by providers, patients and families by the first follow-up visit. BSA mean percentage decreased by up to 56% by the 7th visit, and pruritus (NRS), CLDQI and POEM mean scores decreased by more than 4 points, 12 points, and over 11 points, respectively. After management was initiated in the MADP, 72.73% of patients achieved an EASI 50 and 47.73% achieved an EASI 75 from a baseline mean of 21.7. Patients who continued in clinic beyond the second visit showed further clinically significant decreases in disease measures. CONCLUSIONS: The multidisciplinary approach shows success in the treatment of difficult-to-control AD patients with improvements in clinician and patient reported outcome measures.
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Dermatitis Atópica , Adolescente , Humanos , Niño , Dermatitis Atópica/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Prurito , Medición de Resultados Informados por el Paciente , Hospitales Pediátricos , Resultado del Tratamiento , Calidad de VidaRESUMEN
Pancreatic cancer remains one of the most lethal cancers largely due to the inefficient delivery of therapeutics. Nanomaterials have been extensively investigated as drug delivery platforms, showing improved drug pharmacodynamics and pharmacokinetics. However, their applications in pancreatic cancer have not yet been successful due to limited tumor delivery caused by dense tumor stroma and distorted tumor vasculatures. Meanwhile, smaller-sized nanomaterials have shown improved tumor delivery and retention in various tumors, including pancreatic tumors, suggesting their potential in enhancing drug delivery. An ultrafine iron oxide nanoparticle (uIONP) was used to encapsulate 7-ethyl-10-hydroxyl camptothecin (SN38), the water-insoluble active metabolite of pancreatic cancer chemotherapy drug irinotecan. Insulin-like growth factor 1 (IGF-1) was conjugated to uIONP as a ligand for targeting pancreatic cancer cells overexpressing IGF-1 receptor (IGF1R). The SN38 loading and release profile were characterized. The pancreatic cancer cell targeting using IGF1-uIONP/SN38 and subsequently induced cell apoptosis were also investigated. IGF1-uIONP/SN38 demonstrated a stable drug loading in physiological pH with the loading efficiency of 68.2 ± 3.5% (SN38/Fe, wt%) and < 7% release for 24 h. In tumor-interstitial- and lysosomal-mimicking pH (6.5 and 5.5), 52.2 and 91.3% of encapsulated SN38 were released over 24 h. The IGF1-uIONP/SN38 exhibited specific receptor-mediated cell targeting and cytotoxicity Ato MiaPaCa-2 and Panc02 pancreatic cancer cells with IC50 of 11.8 ± 2.3 and 20.8 ± 3.5 nM, respectively, but not to HEK293 human embryonic kidney cells. IGF1-uIONP significantly improved the targeted SN38 delivery to pancreatic cancer cells, holding the potential for in vivo theranostic applications.
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Antineoplásicos Fitogénicos , Nanopartículas , Neoplasias Pancreáticas , Antineoplásicos Fitogénicos/farmacología , Camptotecina , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Células HEK293 , Humanos , Nanopartículas Magnéticas de Óxido de Hierro , Nanopartículas/química , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias PancreáticasRESUMEN
BACKGROUND: Effective learning strategies are crucial to the development of academic skills and information retention, especially in post secondary education where increasingly complex subjects are explored. Active recall-based strategies have been identified as particularly effective for long-term learning. This systematic review investigates the effectiveness of various active recall-based learning strategies for improving academic performance and self-efficacy in higher education students. METHODS: A systematic review of peer-reviewed articles was conducted with a priori criteria by searching PubMed, ScienceDirect, JSTOR, PsycInfo, and Web of Science databases. Search results were screened/extracted and reconciled by two independent authors with the use of a piloted screening tool. Included studies were assessed for quality and risk of bias using the GRADE Quality Assessment Tool for Quantitative Studies. Three overarching study strategies were extracted for further investigation including flashcards, practice testing or retrieval practice, and concept mapping. Within each category, three additional unique search strings were searched, screened, and extracted. A qualitative analysis of the studies was provided. RESULTS: Among the appraised articles, flashcards were found to be popular and correlated with higher GPA and test scores. Self-testing, retrieval practice, and concept mapping were also effective but under-utilized. Concept mapping was found to boost student confidence. CONCLUSION: Active recall strategies exhibit promise for effective learning and additional research in these developing field can support academic pursuits.
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Éxito Académico , Recuerdo Mental , Humanos , Adulto Joven , Estudiantes/psicología , Autoeficacia , AprendizajeRESUMEN
Chemoresistance is a major obstacle in the clinical management of metastatic, castration-resistant prostate cancer (PCa). It is imperative to develop novel strategies to overcome chemoresistance and improve clinical outcomes in patients who have failed chemotherapy. Using a two-tier phenotypic screening platform, we identified bromocriptine mesylate as a potent and selective inhibitor of chemoresistant PCa cells. Bromocriptine effectively induced cell cycle arrest and activated apoptosis in chemoresistant PCa cells but not in chemoresponsive PCa cells. RNA-seq analyses revealed that bromocriptine affected a subset of genes implicated in the regulation of the cell cycle, DNA repair, and cell death. Interestingly, approximately one-third (50/157) of the differentially expressed genes affected by bromocriptine overlapped with known p53-p21- retinoblastoma protein (RB) target genes. At the protein level, bromocriptine increased the expression of dopamine D2 receptor (DRD2) and affected several classical and non-classical dopamine receptor signal pathways in chemoresistant PCa cells, including adenosine monophosphate-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa B (NF-κB), enhancer of zeste homolog 2 (EZH2), and survivin. As a monotherapy, bromocriptine treatment at 15 mg/kg, three times per week, via the intraperitoneal route significantly inhibited the skeletal growth of chemoresistant C4-2B-TaxR xenografts in athymic nude mice. In summary, these results provided the first preclinical evidence that bromocriptine is a selective and effective inhibitor of chemoresistant PCa. Due to its favorable clinical safety profiles, bromocriptine could be rapidly tested in PCa patients and repurposed as a novel subtype-specific treatment to overcome chemoresistance.
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Urokinase-type plasminogen activator (uPA) is expressed at elevated levels in atherosclerotic human arteries, primarily in macrophages. Plasminogen (Plg), the primary physiologic substrate of uPA, is present at significant levels in blood and interstitial fluid. Both uPA and Plg have activities that could affect atherosclerosis progression. Moreover, correlations between increased Plg activation and accelerated atherosclerosis are reported in several human studies. However, a coherent picture of the role of the uPA/Plg system in atherogenesis has not yet emerged, with at least one animal study suggesting that Plg is atheroprotective. We used a transgenic mouse model of macrophage-targeted uPA overexpression in apolipoprotein E-deficient mice to investigate the roles of uPA and Plg in atherosclerosis. We found that macrophage-expressed uPA accelerated atherosclerotic plaque growth and promoted aortic root dilation through Plg-dependent pathways. These pathways appeared to affect lesion progression rather than initiation and to include actions that disproportionately increase lipid accumulation in the artery wall. In addition, loss of Plg was protective against atherosclerosis both in the presence and absence of uPA overexpression. Transgenic mice with macrophage-targeted uPA overexpression reveal atherogenic roles for both uPA and Plg and are a useful experimental setting for investigating the molecular mechanisms that underlie clinically established relationships between uPA expression, Plg activation, and atherosclerosis progression.
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Apolipoproteínas E/genética , Aterosclerosis/metabolismo , Macrófagos/metabolismo , Plasminógeno/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/genética , Animales , Apolipoproteínas E/metabolismo , Aterosclerosis/genética , Aterosclerosis/patología , Estenosis Coronaria/patología , Ratones , Transgenes , Activador de Plasminógeno de Tipo Uroquinasa/metabolismoRESUMEN
Vaccination efforts against COVID-19 must include the pediatric population, not only to protect children and their families from the virus, but also to support a safe return to in-person schooling. Given the novel methodologies and targets used in the COVID-19 vaccines and the potential for multisystem inflammatory syndrome-children, it is insufficient to extrapolate safety and efficacy data between different vaccine candidates or from adult studies. Adequate enrollment in pediatric studies for COVID-19 vaccines is crucial. The Pediatric Pharmacy Association supports continued research, surveillance, and transparency for COVID-19 vaccines in the pediatric population, including those younger than 12 years of age.
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Bone metastasis is a major cause of prostate cancer (PCa) mortality. Although docetaxel chemotherapy initially extends patients' survival, in most cases PCa becomes chemoresistant and eventually progresses without a cure. In this study, we developed a novel small-molecule compound BKM1972, which exhibited potent in vitro cytotoxicity in PCa and other cancer cells regardless of their differences in chemo-responsiveness. Mechanistic studies demonstrated that BKM1972 effectively inhibited the expression of anti-apoptotic protein survivin and membrane-bound efflux pump ATP binding cassette B 1 (ABCB1, p-glycoprotein), presumably via signal transducer and activator of transcription 3 (Stat3). BKM1972 was well tolerated in mice and as a monotherapy, significantly inhibited the intraosseous growth of chemosensitive and chemoresistant PCa cells. These results indicate that BKM1972 is a promising small-molecule lead to treat PCa bone metastasis and overcome docetaxel resistance.