Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 730
Filtrar
1.
bioRxiv ; 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36711668

RESUMO

Our understanding of the lymphatic vascular system lags far behind that of the blood vascular system, limited by available imaging technologies. We present a label-free optical imaging method that visualizes the lymphatic system with high contrast. We developed an orthogonal polarization imaging (OPI) in the shortwave infrared range (SWIR) and imaged both lymph nodes and lymphatic vessels of mice and rats in vivo through intact skin, as well as human mesenteric lymph nodes in colectomy specimens. By integrating SWIR-OPI with U-Net, a deep learning image segmentation algorithm, we automated the lymph node size measurement process. Changes in lymph nodes in response to cancer progression were monitored in two separate mouse cancer models, through which we obtained insights into pre-metastatic niches and correlation between lymph node masses and many important biomarkers. In a human pilot study, we demonstrated the effectiveness of SWIR-OPI to detect human lymph nodes in real time with clinical colectomy specimens. One Sentence Summary: We develop a real-time high contrast optical technique for imaging the lymphatic system, and apply it to anatomical pathology gross examination in a clinical setting, as well as real-time monitoring of tumor microenvironment in animal studies.

2.
Biomaterials ; 294: 122004, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36669302

RESUMO

New antimicrobials are urgently needed to combat Gram-negative bacteria, particularly multi-drug resistant (MDR) and phenotypically resistant biofilm species. At present, only sequence-defined alpha-peptides (e.g. polymyxin B) can selectively target Gram-negative bacterial lipopolysaccharides. We show that a copolymer, without a defined sequence, shows good potency against MDR Gram-negative bacteria including its biofilm form. The tapered blocky co-beta-peptide with controlled N-terminal hydrophobicity (#4) has strong interaction with the Gram-negative bacterial lipopolysaccharides via its backbone through electrostatic and hydrogen bonding interactions but not the Gram-positive bacterial and mammalian cell membranes so that this copolymer is non-toxic to these two latter cell types. The new #4 co-beta-peptide selectively kills Gram-negative bacteria with low cytotoxicity both in vitro and in a mouse biofilm wound infection model. This strategy provides a new concept for the design of Gram-negative selective antimicrobial peptidomimetics against MDR and biofilm species.

3.
Int J Artif Intell Educ ; : 1-38, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36685293

RESUMO

Personalized gamification aims to address shortcomings of the one-size-fits-all (OSFA) approach in improving students' motivations throughout the learning process. However, studies still focus on personalizing to a single user dimension, ignoring multiple individual and contextual factors that affect user motivation. Unlike prior research, we address this issue by exploring multidimensional personalization compared to OSFA based on a multi-institution sample. Thus, we conducted a controlled experiment in three institutions, comparing gamification designs (OSFA and Personalized to the learning task and users' gaming habits/preferences and demographics) in terms of 58 students' motivations to complete assessments for learning. Our results suggest no significant differences among OSFA and Personalized designs, despite suggesting user motivation depended on fewer user characteristics when using personalization. Additionally, exploratory analyses suggest personalization was positive for females and those holding a technical degree, but negative for those who prefer adventure games and those who prefer single-playing. Our contribution benefits designers, suggesting how personalization works; practitioners, demonstrating to whom the personalization strategy was more or less suitable; and researchers, providing future research directions. Supplementary Information: The online version contains supplementary material available at 10.1007/s40593-022-00326-x.

4.
Artigo em Inglês | MEDLINE | ID: mdl-36539078

RESUMO

BACKGROUND: The 3 core domains of delirium (cognitive, higher level thinking, circadian) do not include the less common noncore psychotic symptoms. However, psychosis might inform about perturbations of neural circuitry, outcomes, or suggest tailored clinical management. OBJECTIVE: We assessed for the first time the relationships between psychosis and other characteristics of delirium in patients without confounders for delirium phenotype, such as dementia or antipsychotics treatment. METHODS: Cross-sectional analysis of 366 adults with delirium per the Delirium Rating Scale Revised-98, whose items distinguish hallucinations and delusions from other types of misperceptions and abnormal thought content, assessed during the preceding 24 hours to capture symptom severity fluctuation. The relationship of psychosis with other delirium characteristics was assessed using bivariate comparisons and analysis of variance as appropriate for groups with no psychosis and any psychosis (hallucinations and/or delusions), and subgroups with only hallucinations, only delusions, or both. A discriminant logistic model assessed variables associated with presence of any psychotic features versus none. RESULTS: Delirium with any psychotic features occurred in 44.5% (163 of 366). Of the 366, 119 (32.5%) had only hallucinations (Hall), 14 (3.8%) had only delusions (Del), and 30 (8.2%) had both (Both). In the psychotic group (n = 163), 73.0% were Hall, 8.6% Del, and 18.4% Both. All psychotic patient groupings had significantly greater delirium severity on the Delirium Rating Scale Revised-98. Delusions and hallucinations were discordant for occurring together. The discriminant model found increased odds of having psychosis as 3 symptom severities increased (visuospatial ability, thought process, and sleep-wake cycle) where these each represented a delirium core domain. The noncore symptom of lability of affect had high odds ratio for psychosis, while motor retardation reduced odds of psychosis in this model. CONCLUSIONS: Consistent with prior reports, psychosis occurred in less than half of delirious patients with delusions being infrequent, and an association with affective lability was found. We are the first to report that psychotic features are a marker for more severe delirium affecting all core domains. Given that previous functional magnetic resonance imaging research found a correlation between neural network dysconnectivity with greater severity of delirium, psychotic symptoms might be a clinical marker for greater underlying cerebral cortical neural circuitry dysfunction.

6.
Acta Biomater ; 153: 243-259, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36374749

RESUMO

There are no drugs or treatment methods known to prevent the development of post-traumatic osteoarthritis (PTOA), a type of osteoarthritis (OA) that is triggered by traumatic joint injuries and accounts for ∼12% of the nearly 600 million OA cases worldwide. Lack of effective drug delivery techniques remains a major challenge in developing clinically effective treatments, but cationic delivery carriers can help overcome this challenge. Scaling up treatments that are effective in in vitro models to achieve success in preclinical in vivo models and clinical trials is also a challenging problem in the field. Here we use a cationic green fluorescent protein (GFP) as a carrier to deliver Insulin-Like Growth Factor 1 (IGF-1), a drug considered as a potential therapeutic for PTOA. GFP-IGF-1 conjugates were first synthesized as fusion proteins with different polypeptide linkers, and their transport properties were characterized in human cartilage explants. In vitro experimental data were used to develop a predictive mathematical transport model that was validated using an independent in vitro experimental data set. The model was used to predict the transport of these fusion proteins upon intra-articular injection into human knee joints. The predictions included results for the rate and extent of fusion protein penetration into cartilage, and the maximum levels of fusion proteins that would escape into systemic circulation through the joint capsule. Together, our transport measurements and model set the stage for translation of such explant culture studies to in vivo preclinical studies and potentially clinical application. STATEMENT OF SIGNIFICANCE: The lack of blood supply in cartilage and rapid clearance of drugs injected into human knees presents a major challenge in developing clinically effective treatments for osteoarthritis. Cationic delivery carriers can target negatively charged cartilage and help overcome this problem. Scaling up treatments that are effective in vitro to achieve success in vivo is also challenging. Here, we use a cationic green fluorescent protein (GFP) to deliver Insulin-Like Growth Factor-1 (IGF-1) into cartilage. Experiments measuring transport of GFP-IGF-1 fusion proteins in human cartilage explants were used to develop and validate a mathematical model to predict fusion protein transport upon injection into human knee joints. This work translates such explant culture studies to in vivo preclinical studies and potentially clinical application.


Assuntos
Cartilagem Articular , Fator de Crescimento Insulin-Like I , Osteoartrite , Humanos , Cartilagem Articular/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Articulação do Joelho , Osteoartrite/tratamento farmacológico , Proteínas Recombinantes de Fusão/farmacologia , Sistemas de Liberação de Medicamentos
7.
Bioconjug Chem ; 33(11): 2065-2075, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36282941

RESUMO

Nanoparticle (NP) drug carriers have revolutionized medicine and increased patient quality of life. Clinically approved formulations typically succeed because of reduced off-target toxicity of the cargo. However, increasing carrier accumulation at disease sites through precise targeting remains one of the biggest challenges in the field. Novel multivalent ligand presentations and self-assembled constructs can enhance cell association, but an inability to draw direct comparisons across formulations has hindered progress. Furthermore, how nanoparticle structure influences function often is unclear. In this report, we leverage the well-characterized hyaluronic acid (HA)-CD44 binding pair to investigate how the surface architecture of modified NPs impacts their association with ovarian cancer cells that overexpress CD44. We functionalized anionic liposomes with 5 kDa HA by either covalent conjugation via surface coupling or electrostatic self-assembly using the layer-by-layer (LbL) adsorption method. Comparing these two methods, we observed a consistent enhancement of NP-cell association with the self-assembly LbL technique, particularly with higher molecular weight (≥10 kDa) HA. To further optimize association, we increased the surface-available HA. We synthesized a bottlebrush glycopolymer composed of a polynorbornene backbone and pendant 5 kDa HA and layered this macromolecule onto NPs. Flow cytometry revealed that the LbL HA bottlebrush NP outperformed the LbL linear display of HA. Cellular visualization by deconvolution optical microscopy corroborated results from all three constructs. Using exogenous HA to block NP-CD44 interactions, we found the LbL HA bottlebrush NP had a 4-fold higher binding avidity than the best-performing LbL linear HA NP. We further observed that decreasing the density of HA bottlebrush side chains to 75% had minimal impact on LbL NP stability or cell association, though we did see a reduction in binding avidity with this side-chain-modified NP. Our studies indicate that LbL surfaces are highly effective for multivalent displays, and the mode in which they present a targeting ligand can be optimized for NP cell targeting.


Assuntos
Ácido Hialurônico , Nanopartículas , Humanos , Ácido Hialurônico/química , Ligantes , Qualidade de Vida , Nanopartículas/química , Receptores de Hialuronatos/metabolismo , Portadores de Fármacos/química , Linhagem Celular Tumoral
8.
Eur J Phys Rehabil Med ; 58(5): 715-722, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36052889

RESUMO

BACKGROUND: Combining action observation (AO) and motor imagery (MI) training may induce greater brain activity in areas usually involved in Parkinson's disease (PD) and lead to greater behavioral and neurophysiological effects than when used separately. AIM: To determine the effects of combining AO, MI, and gait training on balance and freezing of gait in individuals with PD. DESIGN: This is a single-blinded, randomized controlled clinical trial. SETTING: Laboratory of Intervention and Analysis of Movement (LIAM) from the Department of Physical Therapy of a Brazilian University. POPULATION: Study sample consisted of individuals diagnosed with idiopathic PD by a neurologist specialized in movement disorders. METHODS: 39 individuals with PD were divided into experimental (EG=21) and control groups (CG=18). EG performed 12 sessions of AO, MI, and gait training, whereas CG watched PD-related educational videos and performed 12 sessions of gait training. Balance (measured using the Mini Balance Evaluation Systems Test [MiniBESTest]) and freezing of gait (measured using the Freezing of Gait Questionnaire) were reassessed one day after the end of the intervention. RESULTS: We did not observe significant intra- and intergroup differences in freezing of gait. For the EG, we observed a significant intragroup difference in the total score of MiniBESTest (F=5.2; P=0.02), and sensory orientation (F=4.5; P=0.04) and dynamic gait (F=3.6; P=0.03) domains. MiniBESTest domains were not different between groups. CONCLUSIONS: Combining AO, MI, and gait training was not more effective than isolated gait training for balance and freezing of gait in individuals with PD. CLINICAL REHABILITATION IMPACT: MI training can moderate AO effects and enhance motor learning when both therapies are combined. Therefore, this approach may still have the potential to be included in the treatment of PD. New studies should investigate whether the factors that influence these results are related to the protocol's sensitivity in changing the evaluated parameters or to the time and intensity of AO and MI training.


Assuntos
Transtornos Neurológicos da Marcha , Doença de Parkinson , Terapia por Exercício/métodos , Marcha/fisiologia , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/reabilitação , Humanos , Imagens, Psicoterapia/métodos , Doença de Parkinson/reabilitação , Equilíbrio Postural/fisiologia
9.
Foods ; 11(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36076845

RESUMO

Sugarcane is primarily harvested to meet up to 80% of global sugar demand. Recently, lipids recovered from their biomass (straw and bagasse) have attracted much attention due to their possible utilisation in biofuel production but also by the presence of health-promoting compounds as phytosterols (i.e., improvement of cardiovascular function) or 1-octacosanol (i.e., anti-obesity). Although this fraction is commonly obtained through solid-liquid isolation, there is scarce information about how different solvents affect the composition of the extracts. This research work aimed to study whether, in sugarcane straw and bagasse samples, Soxtec extraction with widely used dichloromethane (DCM) would be suitable to recover most of the lipid classes when compared to other available solvents such as food grade ethanol (EtOH) or solvents without regulation restrictions for food and drug applications (i.e., acetone and ethyl acetate). The obtained results allow concluding that sugarcane waxes from straw and bagasse are complex lipid mixtures of polar and non-polar compounds. According to the extraction yield, the best results were obtained with ethanol (5.12 ± 0.30% and 1.97 ± 0.31%) for both straw and bagasse, respectively. The extractant greatly influenced the lipid composition of the obtained product. Thus, DCM enriched the isolates in glycerolipids (mono-, di- and triglycerides), free fatty acids, fatty alcohols, fatty aldehydes, phytosterols and hydrocarbons. On the other hand, EtOH resulted in polar isolates rich in glycolipids. Therefore, depending on the application and objectives of future research studies, the solvent to recover such lipids needs to be carefully selected.

10.
Biomaterials ; 288: 121721, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35981926

RESUMO

Current clinical products delivering the osteogenic growth factor bone morphogenetic protein 2 (BMP-2) for bone regeneration have been plagued by safety concerns due to a high incidence of off-target effects resulting from bolus release and supraphysiological doses. Layer-by-layer (LbL) film deposition offers the opportunity to coat bone defect-relevant substrates with thin films containing proteins and other therapeutics; however, control of release kinetics is often hampered by interlayer diffusion of drugs throughout the film during assembly, which causes burst drug release. In this work, we present the design of different laponite clay diffusional barrier layer architectures in self-assembled LbL films to modulate the release kinetics of BMP-2 from the surface of a biodegradable implant. Release kinetics were tuned by incorporating laponite in different film arrangements and with varying deposition techniques to achieve release of BMP-2 over 2 days, 4 days, 14 days, and 30 days. Delivery of a low dose (0.5 µg) of BMP-2 over 2 days and 30 days using these LbL film architectures was then compared in an in vivo rat critical size calvarial defect model to determine the effect of BMP-2 release kinetics on bone regeneration. After 6 weeks, sustained release of BMP-2 over 30 days induced 3.7 times higher bone volume and 7.4 times higher bone mineral density as compared with 2-day release of BMP-2, which did not induce more bone growth than the uncoated scaffold control. These findings represent a crucial step in the understanding of how BMP-2 release kinetics influence treatment efficacy and underscore the necessity to optimize protein delivery methods in clinical formulations for bone regeneration. This work could be applied to the delivery of other therapeutic proteins for which careful tuning of the release rate is a key optimization parameter.


Assuntos
Proteína Morfogenética Óssea 2 , Regeneração Óssea , Animais , Proteína Morfogenética Óssea 2/farmacologia , Preparações de Ação Retardada/farmacologia , Osteogênese , Próteses e Implantes , Ratos
11.
J Clin Immunol ; 42(8): 1708-1720, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35907101

RESUMO

OBJECTIVE: The Bacille Calmette-Guérin (BCG) vaccine is routinely applied in Brazil. Adverse events (AE) may occur in patients with inborn or acquired immunodeficiencies, varying between local (BCGitis) or disseminated (BCGosis) reactions. We evaluated 53 individuals with local or disseminated adverse events to BCG vaccination to assess if they had inborn errors of immunity (IEI). METHODS: Patients diagnosed with an adverse event following BCG vaccination between 2014 and 2017 were included in the study. We collected clinical data, immunophenotyped T and B lymphocytes, and natural killer cells (NK), assessed oxidative function of neutrophils through dihydrorhodamine (DHR) 123 testing, and genotyped 361 genes related to IEI through targeted (panel) sequencing. RESULTS: The median age of the 53 individuals was four months (IQ 1.5-12), and 52.8% were male. Forty-eight (90.6%) individuals presented only locoregional AE and five (9.4%) presented both locoregional and disseminated AE. Nine (16.9%) patients were diagnosed with an IEI. Four of them presented BCGitis and five presented BCGosis after BCG vaccination. Clinically, four presented chronic granulomatous disease (CGD), three Mendelian susceptibility to mycobacterial disease (MSMD), and two severe combined immunodeficiency (SCID). Patients with IEI had a higher frequency of systemic symptomatology (p = 0.002), history of other infections (p < 0.001), parental consanguinity (p = 0.01), familial history of sick siblings (p < 0.001), or early deaths in the family (p < 0.01). CONCLUSION: There is a high frequency of IEI in patients with locoregional and disseminated adverse events to BCG vaccination, revealing the need for the investigation of IEI accompanied by clinical and familial inquiry.


Assuntos
Vacina BCG , Imunodeficiência Combinada Severa , Tuberculose , Pré-Escolar , Feminino , Humanos , Masculino , Vacina BCG/efeitos adversos , Brasil/epidemiologia , Imunodeficiência Combinada Severa/genética , Tuberculose/diagnóstico , Vacinação/efeitos adversos
12.
Artigo em Inglês | MEDLINE | ID: mdl-35907169

RESUMO

Functional foods containing probiotics are generally administered as dairy products. Non-dairy beverages are another possibility, but probiotic functionality must be confirmed in such vehicles. In the present study, a craft wheat beer brewed with the probiotic yeast Saccharomyces cerevisiae UFMG A-905 (905) was evaluated in a murine model of Salmonella Typhimurium infection. Unfiltered or filtered beer brewed with 905, a commercial wheat beer used as a negative control, or saline were administered orally to mice before and during oral S. Typhimurium challenge. High fecal levels of yeast were only counted in mice treated with the unfiltered 905 beer, which also had reduced mortality and body weight loss due to S. Typhimurium infection. Increased levels of intestinal IgA, translocation to liver and spleen, liver and intestinal lesions, pro-inflammatory cytokines in liver and ileum, and hepatic and intestinal myeloperoxidase and eosinophilic peroxidase activities were observed in animals infected with S. Typhimurium. All these parameters were reduced by the treatment with unfiltered 905 beer. In conclusion, the results show that a craft wheat beer brewed with S. cerevisiae UFMG A-905 maintained the probiotic properties of this yeast when administered orally to mice challenged with S. Typhimurium.

13.
Science ; 377(6604): eabm5551, 2022 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-35862544

RESUMO

To accelerate the translation of cancer nanomedicine, we used an integrated genomic approach to improve our understanding of the cellular processes that govern nanoparticle trafficking. We developed a massively parallel screen that leverages barcoded, pooled cancer cell lines annotated with multiomic data to investigate cell association patterns across a nanoparticle library spanning a range of formulations with clinical potential. We identified both materials properties and cell-intrinsic features that mediate nanoparticle-cell association. Using machine learning algorithms, we constructed genomic nanoparticle trafficking networks and identified nanoparticle-specific biomarkers. We validated one such biomarker: gene expression of SLC46A3, which inversely predicts lipid-based nanoparticle uptake in vitro and in vivo. Our work establishes the power of integrated screens for nanoparticle delivery and enables the identification and utilization of biomarkers to rationally design nanoformulations.


Assuntos
Antineoplásicos , Biomarcadores Farmacológicos , Proteínas de Transporte de Cobre , Composição de Medicamentos , Sistemas de Liberação de Fármacos por Nanopartículas , Nanopartículas , Neoplasias , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Proteínas de Transporte de Cobre/genética , Expressão Gênica , Genômica , Humanos , Lipossomos , Camundongos , Nanomedicina , Nanopartículas/administração & dosagem , Nanopartículas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo
14.
Adv Chronic Kidney Dis ; 29(2): 86-102.e1, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35817530

RESUMO

Monoclonal gammopathies occur secondary to a broad range of clonal B lymphocyte or plasma cell disorders, producing either whole or truncated monoclonal immunoglobulins. The kidneys are often affected by these monoclonal proteins, and, although not mutually exclusive, can involve the glomeruli, tubules, interstitium, and vasculature. The nephrotoxic potential of these monoclonal proteins is dependent on a variety of physicochemical characteristics that are responsible for the diverse clinicopathologic manifestations, including glomerular diseases with organized deposits, glomerular diseases with granular deposits, and other lesions, such as C3 glomerulopathy and thrombotic microangiopathy with unique pathophysiologic features. The diseases that involve primarily the tubulointerstitial and vascular compartments are light chain cast nephropathy, light chain proximal tubulopathy, crystal-storing histiocytosis, and crystalglobulin-induced nephropathy with distinct acute and chronic clinicopathologic features. The diagnosis of a monoclonal gammopathy-related kidney disease is established by identification of an underlying active or more commonly, low-grade hematologic malignancy, serologic evidence of a monoclonal gammopathy when detectable, and most importantly, monoclonal protein-induced pathologic lesions seen in a kidney biopsy, confirming the association with the monoclonal protein. Establishing a diagnosis may be challenging at times, particularly in the absence of an overt hematologic malignancy, with or without monoclonal gammopathy, such as proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Overall, the treatment is directed against the underlying hematologic disorder and the potential source of the monoclonal protein.


Assuntos
Glomerulonefrite , Neoplasias Hematológicas , Nefropatias , Paraproteinemias , Glomerulonefrite/diagnóstico , Glomerulonefrite/etiologia , Glomerulonefrite/terapia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/patologia , Humanos , Rim/metabolismo , Nefropatias/diagnóstico , Nefropatias/etiologia , Nefropatias/terapia , Glomérulos Renais/patologia , Paraproteinemias/complicações , Paraproteinemias/diagnóstico , Paraproteinemias/terapia
15.
Mayo Clin Proc ; 97(7): 1294-1304, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35787856

RESUMO

OBJECTIVE: To evaluate the association of baseline and postinfusion patient characteristics with acute kidney injury (AKI) in the month after chimeric antigen receptor T-cell (CAR-T) therapy. METHODS: We retrospectively reviewed records of 83 patients with non-Hodgkin lymphoma undergoing CAR-T therapy (axicabtagene ciloleucel) between June 2016 and November 2020. Patients were followed up to 1 month after treatment. Post-CAR-T AKI was defined as a more than 1.5-fold increase in serum creatinine concentration from baseline (on the day of CAR-T infusion) at any time up to 1 month after CAR-T therapy. RESULTS: Of 83 patients, 14 (17%) developed AKI during follow-up. At 1 month after CAR-T infusion, 10 of 14 (71%) AKI events had resolved. Lower baseline estimated glomerular filtration rate, use of intravenous contrast material, tumor lysis prophylaxis, higher peak uric acid and creatine kinase levels during follow-up, and change in lactate dehydrogenase from baseline to peak level within 1 month after initiation of CAR-T therapy were significantly associated with AKI incidence during follow-up. Incidence of AKI was also higher in patients who received higher doses of corticosteroids and tocilizumab. CONCLUSION: Acute kidney injury occurred in approximately 1 in 6 patients who received axicabtagene ciloleucel for non-Hodgkin lymphoma. Patients with high tumor burden receiving higher total doses of corticosteroids or tocilizumab should be closely monitored for development of AKI. Lower baseline kidney function at CAR-T initiation, exposure to contrast material, and progressive increase in levels of tumor lysis markers (uric acid, lactate dehydrogenase, creatine kinase) after CAR-T infusion may predict risk of AKI during the 1 month after infusion.


Assuntos
Injúria Renal Aguda , Linfoma não Hodgkin , Neoplasias , Receptores de Antígenos Quiméricos , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Antígenos CD19 , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Meios de Contraste , Creatina Quinase , Creatinina , Humanos , Incidência , Lactato Desidrogenases , Linfoma não Hodgkin/induzido quimicamente , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/terapia , Neoplasias/complicações , Receptores de Antígenos Quiméricos/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Ácido Úrico
16.
Proc Natl Acad Sci U S A ; 119(23): e2118697119, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35648828

RESUMO

The blood­brain barrier represents a significant challenge for the treatment of high-grade gliomas, and our understanding of drug transport across this critical biointerface remains limited. To advance preclinical therapeutic development for gliomas, there is an urgent need for predictive in vitro models with realistic blood­brain-barrier vasculature. Here, we report a vascularized human glioblastoma multiforme (GBM) model in a microfluidic device that accurately recapitulates brain tumor vasculature with self-assembled endothelial cells, astrocytes, and pericytes to investigate the transport of targeted nanotherapeutics across the blood­brain barrier and into GBM cells. Using modular layer-by-layer assembly, we functionalized the surface of nanoparticles with GBM-targeting motifs to improve trafficking to tumors. We directly compared nanoparticle transport in our in vitro platform with transport across mouse brain capillaries using intravital imaging, validating the ability of the platform to model in vivo blood­brain-barrier transport. We investigated the therapeutic potential of functionalized nanoparticles by encapsulating cisplatin and showed improved efficacy of these GBM-targeted nanoparticles both in vitro and in an in vivo orthotopic xenograft model. Our vascularized GBM model represents a significant biomaterials advance, enabling in-depth investigation of brain tumor vasculature and accelerating the development of targeted nanotherapeutics.


Assuntos
Barreira Hematoencefálica , Neoplasias Encefálicas , Permeabilidade Capilar , Glioblastoma , Nanopartículas , Animais , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/metabolismo , Células Endoteliais/metabolismo , Glioblastoma/irrigação sanguínea , Glioblastoma/metabolismo , Humanos , Camundongos , Microfluídica , Nanopartículas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Adv Healthc Mater ; 11(15): e2200905, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35670244

RESUMO

With the advent of bioinformatic tools in efficiently predicting neo-antigens, peptide vaccines have gained tremendous attention in cancer immunotherapy. However, the delivery of peptide vaccines remains a major challenge, primarily due to ineffective transport to lymph nodes and low immunogenicity. Here, a strategy for peptide vaccine delivery is reported by first fusing the peptide to the cytosolic domain of the stimulator of interferon genes protein (STINGΔTM), then complexing the peptide-STINGΔTM protein with STING agonist 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). The process results in the formation of self-assembled cGAMP-peptide-STINGΔTM tetramers, which enables efficient lymphatic trafficking of the peptide. Moreover, the cGAMP-STINGΔTM complex acts not only as a protein carrier for the peptide, but also as a potent adjuvant capable of triggering STING signaling independent of endogenous STING protein-an especially important attribute considering that certain cancer cells epigenetically silence their endogenous STING expression. With model antigen SIINFEKL, it is demonstrated that the platform elicits effective STING signaling in vitro, draining lymph node targeting in vivo, effective T cell priming in vivo as well as antitumoral immune response in a mouse colon carcinoma model, providing a versatile solution to the challenges faced in peptide vaccine delivery.


Assuntos
Vacinas Anticâncer , Neoplasias , Animais , Proteínas de Membrana , Camundongos , Neoplasias/terapia , Nucleotídeos Cíclicos , Peptídeos , Vacinas de Subunidades
18.
Gastroenterology ; 162(7): 1858-1875.e2, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35248539

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a chronic condition affecting one quarter of the global population. Although primarily linked to obesity and metabolic syndrome, undernutrition and the altered (dysbiotic) gut microbiome influence NAFLD progression. Both undernutrition and NAFLD prevalence are predicted to considerably increase, but how the undernourished gut microbiome contributes to hepatic pathophysiology remains far less studied. Here, we present undernutrition conditions with fatty liver features, including kwashiorkor and micronutrient deficiency. We then review the gut microbiota-liver axis, highlighting key pathways linked to NAFLD progression within both overnutrition and undernutrition. To conclude, we identify challenges and collaborative possibilities of emerging multiomic research addressing the pathology and treatment of undernourished NAFLD.


Assuntos
Microbioma Gastrointestinal , Desnutrição , Hepatopatia Gordurosa não Alcoólica , Disbiose/metabolismo , Microbioma Gastrointestinal/fisiologia , Humanos , Fígado/patologia , Desnutrição/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia
19.
Biomaterials ; 283: 121432, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35245732

RESUMO

Non-compressible torso hemorrhage (NCTH) is associated with significant mortality in preventable deaths, both in the field and in civilian settings. Current management strategies of these injuries include fluid resuscitation, the use of foaming materials to occlude damaged vessels, and fibrin sealants. Researchers in the field have proposed multiple alternatives to these treatments, such as hemostatic sponges, self-assembling peptide materials, in situ crosslinking hydrogels, and intravenous nanoparticles, which are then challenged in a wide variety of injury models to evaluate their efficacy. This review first discusses the treatment of NCTH in the clinic and field before providing an overview of materials in literature designed for this same purpose, with the intention of summarizing the treatment options and research currently available in this field. The mechanisms of these hemostats, as well as their effectiveness in promoting hemostasis (evaluated through survival, bleeding time, and blood loss volume) are summarized side-by-side for easy comparison across various studies and animal models. Ultimately, a better understanding of existing technologies and the metrics through which they are evaluated may facilitate the development of safer, more effective therapies for non-compressible torso hemorrhage and internal bleeding.


Assuntos
Hemorragia , Hemostáticos , Animais , Hemorragia/terapia , Hemostasia , Hemostáticos/uso terapêutico , Hidrogéis , Tronco/lesões
20.
Epilepsia ; 63(3): 598-628, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34985766

RESUMO

OBJECTIVE: This is a systematic review aimed at summarizing the evidence related to instruments that have been developed to measure stigma or attitudes toward epilepsy and on stigma-reducing interventions. METHODS: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. A broad literature search (1985-2019) was performed in 13 databases. Articles were included if they described the development and testing of psychometric properties of an epilepsy-related stigma or attitude scale or stigma-reducing interventions. Two reviewers independently screened abstracts, reviewed full-text articles, and extracted data. Basic descriptive statistics are reported. RESULTS: We identified 4234 abstracts, of which 893 were reviewed as full-text articles. Of these, 38 met inclusion criteria for an instrument development study and 30 as a stigma-reduction intervention study. Most instruments were initially developed using well-established methods and were tested in relatively large samples. Most intervention studies involved educational programs for adults with pre- and post-evaluations of attitudes toward people with epilepsy. Intervention studies often failed to use standardized instruments to quantify stigmatizing attitudes, were generally underpowered, and often found no evidence of benefit or the benefit was not sustained. Six intervention studies with stigma as the primary outcome had fewer design flaws and showed benefit. Very few or no instruments were validated for regional languages or culture, and there were very few interventions tested in some regions. SIGNIFICANCE: Investigators in regions without instruments should consider translating and further developing existing instruments rather than initiating the development of new instruments. Very few stigma-reduction intervention studies for epilepsy have been conducted, study methodology in general was poor, and standardized instruments were rarely used to measure outcomes. To accelerate the development of effective epilepsy stigma-reduction interventions, a paradigm shift from disease-specific, siloed trials to collaborative, cross-disciplinary platforms based upon unified theories of stigma transcending individual conditions will be needed.


Assuntos
Epilepsia , Estigma Social , Adulto , Comitês Consultivos , Atitude , Epilepsia/diagnóstico , Humanos , Psicometria
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA