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1.
J Biol Chem ; 300(4): 106794, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38403245

RESUMEN

Retinal bipolar and amacrine cells receive visual information from photoreceptors and participate in the first steps of image processing in the retina. Several studies have suggested the operation of aerobic glycolysis and a lactate shuttle system in the retina due to the high production of this metabolite under aerobic conditions. However, whether bipolar cells form part of this metabolic circuit remains unclear. Here, we show that the monocarboxylate transporter 2 is expressed and functional in inner retinal neurons. Additionally, we used genetically encoded FRET nanosensors to demonstrate the ability of inner retinal neurons to consume extracellular lactate as an alternative to glucose. In rod bipolar cells, lactate consumption allowed cells to maintain the homeostasis of ions and electrical responses. We also found that lactate synthesis and transporter inhibition caused functional alterations and an increased rate of cell death. Overall, our data shed light on a notable but still poorly understood aspect of retinal metabolism.


Asunto(s)
Ácido Láctico , Transportadores de Ácidos Monocarboxílicos , Células Bipolares de la Retina , Animales , Ratones , Metabolismo Energético , Glucosa/metabolismo , Ácido Láctico/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Células Bipolares de la Retina/metabolismo
2.
J Hepatol ; 80(5): 714-729, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38336348

RESUMEN

BACKGROUND & AIMS: Mechanisms behind the impaired response of antigen-specific B cells to therapeutic vaccination in chronic hepatitis B virus (HBV) infection remain unclear. The development of vaccines or strategies to overcome this obstacle is vital for advancing the management of chronic hepatitis B. METHODS: A mouse model, denominated as E6F6-B, was engineered to feature a knock-in of a B-cell receptor (BCR) that specifically recognizes HBsAg. This model served as a valuable tool for investigating the temporal and spatial dynamics of humoral responses following therapeutic vaccination under continuous antigen exposure. Using a suite of immunological techniques, we elucidated the differentiation trajectory of HBsAg-specific B cells post-therapeutic vaccination in HBV carrier mice. RESULTS: Utilizing the E6F6-B transfer model, we observed a marked decline in antibody-secreting cells 2 weeks after vaccination. A dysfunctional and atypical pre-plasma cell population (BLIMP-1+ IRF4+ CD40- CD138- BCMA-) emerged, manifested by sustained BCR signaling. By deploying an antibody to purge persistent HBsAg, we effectively prompted the therapeutic vaccine to provoke conventional plasma cell differentiation. This resulted in an enhanced anti-HBs antibody response and facilitated HBsAg clearance. CONCLUSIONS: Sustained high levels of HBsAg limit the ability of therapeutic hepatitis B vaccines to induce the canonical plasma cell differentiation necessary for anti-HBs antibody production. Employing a strategy combining antibodies with vaccines can surmount this altered humoral response associated with atypical pre-plasma cells, leading to improved therapeutic efficacy in HBV carrier mice. IMPACT AND IMPLICATIONS: Therapeutic vaccines aimed at combatting HBV encounter suboptimal humoral responses in clinical settings, and the mechanisms impeding their effectiveness have remained obscure. Our research, utilizing the innovative E6F6-B mouse transfer model, reveals that the persistence of HBsAg can lead to the emergence of an atypical pre-plasma cell population, which proves to be relevant to the potency of therapeutic HBV vaccines. Targeting the aberrant differentiation process of these atypical pre-plasma cells stands out as a critical strategy to amplify the humoral response elicited by HBV therapeutic vaccines in carrier mouse models. This discovery suggests a compelling avenue for further study in the context of human chronic hepatitis B. Encouragingly, our findings indicate that synergistic therapy combining HBV-specific antibodies with vaccines offers a promising approach that could significantly advance the pursuit of a functional cure for HBV.


Asunto(s)
Hepatitis B Crónica , Hepatitis B , Ratones , Humanos , Animales , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B , Vacunas contra Hepatitis B/uso terapéutico , Anticuerpos contra la Hepatitis B , Diferenciación Celular , Hepatitis B/prevención & control , Hepatitis B/tratamiento farmacológico
3.
Antimicrob Agents Chemother ; 68(5): e0115923, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38506549

RESUMEN

Vancomycin heteroresistance is prone to missed detection and poses a risk of clinical treatment failure. We encountered one clinical Enterococcus faecium strain, SRR12, that carried a complete vanM gene cluster but was determined as susceptible to vancomycin using the broth microdilution method. However, distinct subcolonies appeared within the clear zone of inhibition in the E-test assay, one of which, named SRR12-v1, showed high-level resistance to vancomycin. SRR12 was confirmed as heteroresistant to vancomycin using population analysis profiling and displayed "revive" growth curves with a lengthy lag phase of over 13 hours when exposed to 2-32 mg/L vancomycin. The resistant subcolony SRR12-v1 was found to carry an identical vanM gene cluster to that of SRR12 but a significantly increased vanM copy number in the genome. Long-read whole genome sequencing revealed that a one-copy vanM gene cluster was located on a pELF1-like linear plasmid in SRR12. In comparison, tandem amplification of the vanM gene cluster jointed with IS1216E was seated on a linear plasmid in the genome of SRR12-v1. These amplifications of the vanM gene cluster were demonstrated as unstable and would decrease accompanied by fitness reversion after serial passaging for 50 generations under increasing vancomycin pressure or without antibiotic pressure but were relatively stable under constant vancomycin pressure. Further, vanM resistance in resistant variants was verified to be carried by conjugative plasmids with variable sizes using conjugation assays and S1-pulsed field gel electrophoresis blotting, suggesting the instability/flexibility of vanM cluster amplification in the genome and an increased risk of vanM resistance dissemination.


Asunto(s)
Antibacterianos , Enterococcus faecium , Pruebas de Sensibilidad Microbiana , Familia de Multigenes , Plásmidos , Resistencia a la Vancomicina , Vancomicina , Enterococcus faecium/genética , Enterococcus faecium/efectos de los fármacos , Plásmidos/genética , Vancomicina/farmacología , Resistencia a la Vancomicina/genética , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Humanos , Secuenciación Completa del Genoma
4.
Actas Esp Psiquiatr ; 52(3): 334-346, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38863057

RESUMEN

BACKGROUND: The use of antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), has been linked to adverse effects on bone health, but findings are conflicting. This study aimed to quantify the associations between newer antidepressants and bone mineral density (BMD) and fracture risk through a comprehensive meta-analysis. METHODS: Observational studies on the association between the use of novel antidepressants and BMD and hip fracture were systematically searched in PubMed, Embase, CINAHL, Cochrane Library, and Scopus. Random effects meta-analyses were conducted to pool results across the eligible studies. The heterogeneity, publication bias, and influence were assessed extensively. RESULTS: 14 eligible studies with 1,417,134 participants were identified. Antidepressant use was associated with significantly lower BMD compared to non-use at all skeletal sites examined, with pooled standardized mean differences (SMD) ranging from -0.02 (total hip) to -0.04 (femoral neck). Importantly, antidepressant use was associated with a 2.5-fold increased risk of hip fracture (pooled odds ratio (OR) 2.50, 95% CI 2.26-2.76). While heterogeneity was detected, the overall findings were robust in sensitivity analyses. CONCLUSIONS: This meta-analysis provided strong evidence that novel antidepressants, especially widely used SSRIs, have detrimental impacts on bone health. The observed associations with decreased BMD and doubled hip fracture risk have important clinical implications.


Asunto(s)
Antidepresivos , Densidad Ósea , Fracturas de Cadera , Osteoporosis , Humanos , Densidad Ósea/efectos de los fármacos , Antidepresivos/efectos adversos , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológico , Fracturas de Cadera/inducido químicamente , Fracturas de Cadera/epidemiología , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Fracturas Osteoporóticas/inducido químicamente , Fracturas Osteoporóticas/epidemiología , Factores de Riesgo
5.
Sci Rep ; 14(1): 9781, 2024 04 29.
Artículo en Inglés | MEDLINE | ID: mdl-38684733

RESUMEN

There is a certain relationship between alexithymia and depression, but further investigation is needed to explore their underlying mechanisms. The aims of this study was to explore the mediating role of internet addiction between alexithymia and depression and the moderating role of physical activity. A total of 594 valid responses were included in the analysis, with a mean age of 18.72 years (SD = 1.09). The sample comprised 250 males (42.09%) and 344 females (57.91%). These responses were utilized for descriptive analysis, correlation analysis, regression analysis, and the development of mediation and moderation models. Alexithymia showed positive correlations with depression and internet addiction, and physical activity was negatively correlated with internet addiction and depression. Internet addiction partially mediated the relationship between alexithymia and depression, while physical activity weakened the association between internet addiction and depression, acting as a moderator. Our findings suggest that excessive Internet engagement may mediate the relationship between alexithymia and depression as an emotional regulatory coping strategy, and that physical activity attenuates the predictive effect of Internet addiction on depression.


Asunto(s)
Síntomas Afectivos , Depresión , Ejercicio Físico , Trastorno de Adicción a Internet , Humanos , Trastorno de Adicción a Internet/epidemiología , Depresión/epidemiología , Depresión/etiología , Depresión/prevención & control , Síntomas Afectivos/complicaciones , Síntomas Afectivos/epidemiología , Ejercicio Físico/psicología , China/epidemiología , Estudiantes , Correlación de Datos , Masculino , Femenino , Adolescente , Adulto Joven , Análisis de Regresión
6.
Healthcare (Basel) ; 12(5)2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38470642

RESUMEN

It may be possible to enhance adults' cognitive health and promote healthy aging through processing speed training using the Useful Field of View (UFOV) related activities and software. This study investigated the impact of utilizing UFOV on processing speed improvement in older adults in response to the growing global attention on cognitive health and aging issues. In this quasi-experimental study, 22 individuals (mean age ± SD = 71.9 ± 4.8) participated in the experimental group, and 20 community-based participants (mean age ± SD = 67.1 ± 4.8) were in the control group. The intervention involved ten sessions of UFOV training, each lasting 60 min, conducted twice a week for the experimental group while the control group engaged in volunteer service activities. Measurements of Counting Back, Fabrica, Double-Decision, and Hawkeye were administered to all participants before and after the intervention. The results showed significant improvements in the experimental group for the four measurements (p ≤ 0.01, 0.05, 0.001, 0.001) and non-significant gains in the control group (p ≥ 0.05) for all. Furthermore, mixed repeated-measures ANOVA analysis, with time 1 pre-test measures as the covariate, revealed significant interaction effects between time and group for all measurement indicators (p = 0.05, 0.01, 0.05) except for Fabrica (p > 0.05). In conclusion, these findings support the effectiveness of UFOV cognitive training interventions in enhancing specific cognitive abilities.

7.
J Hazard Mater ; 467: 133633, 2024 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-38335617

RESUMEN

Cadmium (Cd) and arsenic (As) co-contamination is widespread and threatens human health, therefore it is important to investigate the bioavailability of Cd and As co-exposure. Currently, the interactions of Cd and As by in vitro assays are unknown. In this work, we studied the concurrent Cd-As release behaviors and interactions with in vitro simulated gastric bio-fluid assays. The studies demonstrated that As bioaccessibility (2.04 to 0.18 ± 0.03%) decreased with Cd addition compared to the As(V) single system, while Cd bioaccessibility (11.02 to 39.08 ± 1.91%) increased with As addition compared to the Cd single system. Release of Cd and As is coupled to proton-promoted and reductive dissolution of ferrihydrite. The As(V) is released and reduced to As(Ⅲ) by pepsin. Pepsin formed soluble complexes with Cd and As. X-ray photoelectron spectroscopy showed that Cd and As formed Fe-As-Cd ternary complexes on ferrihydrite surfaces. The coordination intensity of As-O-Cd is lower than that of As-O-Fe, resulting in more Cd release from Fe-As-Cd ternary complexes. Our study deepens the understanding of health risks from Cd and As interactions during environmental co-exposure of multiple metal(loid)s.


Asunto(s)
Arsénico , Cadmio , Compuestos Férricos , Humanos , Pepsina A , Digestión
8.
ACS Biomater Sci Eng ; 10(1): 525-536, 2024 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-38099722

RESUMEN

Piezoelectric materials have received increasing attention in bone regeneration due to their prominent role in bioelectricity in bone homeostasis. This study aimed to develop bioactive barium titanate-chitosan-graphene oxide piezoelectric nanoparticles (BCG-NPs) to improve biocompatibility and stimulate bone repair. Butterfly loops, hysteresis loops, and in vitro microcurrent studies on BCG-NPs confirmed their good piezoelectric properties. BCG-NPs exhibited enhanced alkaline phosphatase activity, mineralized nodule formation, and expression of osteogenic-associated proteins and genes in human umbilical cord Wharton's jelly-derived mesenchymal stem cells by creating microelectric environments in response to noninvasive ultrasound stimulation. Further, BCG-NPs upregulated intracellular calcium ions via electrical stimulation. They acted synergistically with piezo-type mechanosensitive ion channel component 1 and calcium-permeable cation channel transient receptor potential vanilloid 4 to activate osteogenic differentiation. In conclusion, ultrasound-assisted BCG-NPs created a microelectric environment that putatively promoted bone repair in a noninvasive manner.


Asunto(s)
Calcio , Osteogénesis , Humanos , Osteogénesis/genética , Vacuna BCG , Biomimética , Regeneración Ósea
9.
Elife ; 122024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38739438

RESUMEN

The retina consumes massive amounts of energy, yet its metabolism and substrate exploitation remain poorly understood. Here, we used a murine explant model to manipulate retinal energy metabolism under entirely controlled conditions and utilised 1H-NMR spectroscopy-based metabolomics, in situ enzyme detection, and cell viability readouts to uncover the pathways of retinal energy production. Our experimental manipulations resulted in varying degrees of photoreceptor degeneration, while the inner retina and retinal pigment epithelium were essentially unaffected. This selective vulnerability of photoreceptors suggested very specific adaptations in their energy metabolism. Rod photoreceptors were found to rely strongly on oxidative phosphorylation, but only mildly on glycolysis. Conversely, cone photoreceptors were dependent on glycolysis but insensitive to electron transport chain decoupling. Importantly, photoreceptors appeared to uncouple glycolytic and Krebs-cycle metabolism via three different pathways: (1) the mini-Krebs-cycle, fuelled by glutamine and branched chain amino acids, generating N-acetylaspartate; (2) the alanine-generating Cahill-cycle; (3) the lactate-releasing Cori-cycle. Moreover, the metabolomics data indicated a shuttling of taurine and hypotaurine between the retinal pigment epithelium and photoreceptors, likely resulting in an additional net transfer of reducing power to photoreceptors. These findings expand our understanding of retinal physiology and pathology and shed new light on neuronal energy homeostasis and the pathogenesis of neurodegenerative diseases.


Asunto(s)
Ciclo del Ácido Cítrico , Glucólisis , Fosforilación Oxidativa , Retina , Animales , Ratones , Retina/metabolismo , Metabolismo Energético , Metabolómica , Epitelio Pigmentado de la Retina/metabolismo , Células Fotorreceptoras Retinianas Bastones/metabolismo , Ratones Endogámicos C57BL , Células Fotorreceptoras Retinianas Conos/metabolismo
10.
Int J Antimicrob Agents ; 64(1): 107185, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38692492

RESUMEN

OBJECTIVES: Using a random forest algorithm, we previously found that teicoplanin-associated gene A (tcaA) might play a role in resistance of methicillin-resistant Staphylococcus aureus (MRSA) to ß-lactams, which we have investigated further here. METHODS: Representative MRSA strains of prevalent clones were selected to identify the role of tcaA in the MRSA response to ß-lactams. tcaA genes were deleted by homologous recombination in the selected MRSA strains, and antibiotic susceptibility tests were applied to evaluate the effect of tcaA on the minimum inhibitory concentrations (MICs) of glycopeptides and ß-lactams. Scanning electron microscopy, RNA sequencing, and quantitative reverse transcription-polymerase chain reaction were performed to explore the mechanism of tcaA in MRSA resistance to ß-lactams. RESULTS: The MIC of penicillin plus clavulanate decreased from 3 mg/L to 0.064 mg/L and that of oxacillin decreased from 16 to 0.5 mg/L when tcaA was knocked out in the LAC strain. Compared with wild-type MRSA isolates, when tcaA was deleted, all selected strains were more susceptible to ß-lactams. Susceptibility to ceftobiprole was restored in the ceftobiprole-resistant strain when tcaA was deleted. tcaA knockout caused "log-like" abnormal division of MRSA, and tcaA deficiency mediated low expression of mecA, ponA, and murA2. CONCLUSIONS: Machine learning is a reliable tool for identifying drug resistance-related genes. tcaA may be involved in S. aureus cell division and may affect mecA, ponA, and murA2 expression. Furthermore, tcaA is a potential resistance breaker target for ß-lactams, including ceftobiprole, in MRSA.


Asunto(s)
Antibacterianos , Cefalosporinas , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Resistencia betalactámica , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/genética , Antibacterianos/farmacología , Cefalosporinas/farmacología , Humanos , Resistencia betalactámica/genética , Proteínas Bacterianas/genética , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/tratamiento farmacológico , beta-Lactamas/farmacología , Técnicas de Inactivación de Genes
11.
Int J Antimicrob Agents ; 63(6): 107162, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38561093

RESUMEN

OBJECTIVES: Fosfomycin has regained attention for treating infections caused by methicillin-resistant Staphylococcus aureus and multidrug-resistant coagulase-negative staphylococci. In this research, our objective was to investigate the mechanisms underlying fosfomycin resistance in Staphylococcus capitis. METHODS: The minimum inhibitory concentrations (MICs) of fosfomycin were assessed in 109 clinical S. capitis isolates by the agar dilution method. By cloning the fos-like genes into the shuttle vector, pTSSCm-Pcap, and observing the change in fosfomycin MICs, the gene function was verified. Core genome multilocus sequence typing and comparative genomics analysis were conducted to determine the population characteristics of S. capitis isolates and analyse the genetic environment of the fos-like genes. RESULTS: We identified a novel fosfomycin resistance gene, fosSC, on the chromosome in 58 out of 109 (53.2%) S. capitis isolates. The deduced products of the fosSC genes shared 67.15-67.88% amino acid sequence identity with FosB. The RN-pT-fosSC transformants carrying fosSC showed a 512-fold increase in the fosfomycin MICs. The fosSC gene was embedded in a conserved genetic context, but IS431mec was located to the left of the fosSC gene in cluster L due to the insertion of staphylococcal cassette chromosome mec. CONCLUSIONS: The chromosomal fosSC genes in some lineages of S. capitis explained their high-level fosfomycin resistance. Ongoing surveillance is crucial for monitoring the potential threat of horizontal transfer, which could be facilitated by the presence of mobile genetic elements surrounding the fosSC gene.


Asunto(s)
Antibacterianos , Farmacorresistencia Bacteriana , Fosfomicina , Pruebas de Sensibilidad Microbiana , Infecciones Estafilocócicas , Staphylococcus capitis , Fosfomicina/farmacología , Antibacterianos/farmacología , Humanos , Infecciones Estafilocócicas/microbiología , Staphylococcus capitis/genética , Staphylococcus capitis/efectos de los fármacos , Farmacorresistencia Bacteriana/genética , Tipificación de Secuencias Multilocus , Genes Bacterianos/genética
12.
Adv Sci (Weinh) ; 11(14): e2305204, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38327127

RESUMEN

Hepatocellular carcinoma (HCC) is a highly lethal malignant tumor, and the current non-invasive diagnosis method based on serum markers, such as α-fetoprotein (AFP), and des-γ-carboxy-prothrombin (DCP), has limited efficacy in detecting it. Therefore, there is a critical need to develop novel biomarkers for HCC. Recent studies have highlighted the potential of exosomes as biomarkers. To enhance exosome enrichment, a silicon dioxide (SiO2) microsphere-coated three-dimensional (3D) hierarchical porous chip, named a SiO2-chip is designed. The features of the chip, including its continuous porous 3D scaffold, large surface area, and nanopores between the SiO2 microspheres, synergistically improved the exosome capture efficiency. Exosomes from both non-HCC and HCC subjects are enriched using an SiO2-chip and performed RNA sequencing to identify HCC-related long non-coding RNAs (lncRNAs) in the exosomes. This study analysis reveales that LUCAT-1 and EGFR-AS-1 are two HCC-related lncRNAs. To further detect dual lncRNAs in exosomes, quantitative real time polymerase chain reaction (qRT-PCR) is employed. The integration of dual lncRNAs with AFP and DCP significantly improves the diagnostic accuracy. Furthermore, the integration of dual lncRNAs with DCP effectively monitors the prognosis of patients with HCC and detects disease progression. In this study, a liquid biopsy-based approach for noninvasive and reliable HCC detection is developed.


Asunto(s)
Carcinoma Hepatocelular , Exosomas , Neoplasias Hepáticas , ARN Largo no Codificante , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , alfa-Fetoproteínas/análisis , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Biomarcadores de Tumor/genética , Exosomas/genética , Exosomas/química , Porosidad , Dióxido de Silicio , Perfilación de la Expresión Génica
13.
Int J Surg ; 2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-39093871

RESUMEN

BACKGROUND: Conventional neoadjuvant chemoradiotherapy (nCRT) yields a pathologic complete response (pCR) rate of 15%-30% for locally advanced rectal cancer (LARC). This study ventures to shift this paradigm by incorporating short-course nCRT with immunotherapy, specifically Envafolimab, to achieve improved treatment efficacy and possibly redefine the standard of care for LARC. MATERIALS AND METHODS: The PRECAM study is a prospective, single-arm, phase 2 clinical trial for LARC in patients with microsatellite stable (MSS) tumors. Participants received short-course radiotherapy (25Gy/5f), followed by two cycles of CAPEOX chemotherapy and six weekly doses of Envafolimab, a PD-L1 antibody, before total mesorectal excision surgery. The primary endpoint was the pCR rate. RESULTS: From April to December 2022, 34 patients were enrolled, of whom 32 completed the study, each diagnosed with an MSS rectal adenocarcinoma. All patients underwent preoperative CRT combined with Envafolimab. Remarkably, a pCR rate of 62.5% (20/32) was attained, and a significant pathologic response rate of 75% (24/32) was achieved. Additionally, 21 of 32 participants achieved a neoadjuvant rectal (NAR) score below 8, suggesting an effective treatment response. Common adverse events included tenesmus (78.1%), diarrhea (62.5%), and leukocyte decrease (40.6%). Two Grade 3 adverse events were noted, one related to liver function abnormality and the other to a decrease in platelet count. Surgical procedures were performed in all cases, with minor complications, including ileus, infections, and anastomotic leakage. As of this report, there have been no reported cases of recurrence or death during the follow-up period, ranging from 12 to 20 months. CONCLUSION: In LARC patients exhibiting MSS tumors, combining short-course nCRT with Envafolimab demonstrated favorable efficacy, leading to a significant pCR rate. Minor adverse effects and surgical complications were observed. These preliminary but promising results underscore the potential of this approach and call for further exploration and validation through a randomized controlled trial.

14.
Signal Transduct Target Ther ; 9(1): 118, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38702343

RESUMEN

Antitumor therapies based on adoptively transferred T cells or oncolytic viruses have made significant progress in recent years, but the limited efficiency of their infiltration into solid tumors makes it difficult to achieve desired antitumor effects when used alone. In this study, an oncolytic virus (rVSV-LCMVG) that is not prone to induce virus-neutralizing antibodies was designed and combined with adoptively transferred T cells. By transforming the immunosuppressive tumor microenvironment into an immunosensitive one, in B16 tumor-bearing mice, combination therapy showed superior antitumor effects than monotherapy. This occurred whether the OV was administered intratumorally or intravenously. Combination therapy significantly increased cytokine and chemokine levels within tumors and recruited CD8+ T cells to the TME to trigger antitumor immune responses. Pretreatment with adoptively transferred T cells and subsequent oncolytic virotherapy sensitizes refractory tumors by boosting T-cell recruitment, down-regulating the expression of PD-1, and restoring effector T-cell function. To offer a combination therapy with greater translational value, mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T cells. The combination of OVs and mRNA vaccine also displays a significant reduction in tumor burden and prolonged survival. This study proposed a rational combination therapy of OVs with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens, in terms of synergistic efficacy and mechanism.


Asunto(s)
Viroterapia Oncolítica , Virus Oncolíticos , Animales , Ratones , Virus Oncolíticos/genética , Virus Oncolíticos/inmunología , Viroterapia Oncolítica/métodos , Terapia Combinada , Vacunas de ARNm/inmunología , Melanoma Experimental/terapia , Melanoma Experimental/inmunología , Microambiente Tumoral/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T/inmunología , Humanos , Línea Celular Tumoral , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/genética , Vacunas contra el Cáncer/administración & dosificación
15.
Am J Clin Exp Immunol ; 12(6): 127-139, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38187364

RESUMEN

This study aimed to improve Knee Osteoarthritis (KOA) therapy by evaluating the knowledge framework and investigating research trends in inflammatory mechanisms. Conducting a thorough search on July 31, 2023, using the Science Citation Index Expanded of the Web of Science Core Collection, we identified 1,083 articles authored by 6,159 individuals from 3,610 institutions across 299 countries. China led in productivity with 377 papers, followed by the United States (253) and Japan (60). The University of California System (20 publications), Guangzhou University of Science and Technology (19), Duke University (18), and Shanghai Jiao Tong University (18) were the top institutions. Notably, the USA and Southern Medical University China held significant centrality in countries and institutions, respectively. Among 1,084 co-occurring keywords, "expression", "rheumatoid arthritis", "articular cartilage", "F kappa b", and "Synovial fluid" emerged as highly correlated topics. Analyzing inflammatory mechanisms in KOA through visualization tools offers insights into the knowledge framework, aiding in identifying future trends for better pain control. The study employed CiteSpace, VOS Viewer, and Tableau to analyze research hotspots and frontiers in inflammation mechanisms in KOA. It focused on essential signaling pathways in articular cartilage, synovial membrane, subchondral bone, and synovial fluids of OA patients and animal models, along with potential therapeutic reagents. Future exploration of the interaction between mechanisms can elucidate key factors in different pathways and the efficacy of injection therapy on inflammation.

17.
Int. braz. j. urol ; 45(2): 273-287, Mar.-Apr. 2019. tab, graf
Artículo en Inglés | LILACS | ID: biblio-1002208

RESUMEN

ABSTRACT Introduction: Several recent randomized clinical trials have evaluated hypofractionated regimens against conventionally fractionated EBRT and shown similar effectiveness with conflicting toxicity results. The current view regarding hypofractionation compared to conventional EBRT among North American genitourinary experts for management of prostate cancer has not been investigated. Materials and Methods: A survey was distributed to 88 practicing North American GU physicians serving on decision - making committees of cooperative group research organizations. Questions pertained to opinions regarding the default EBRT dose and fractionation for a hypothetical example of a favorable intermediate - risk prostate cancer (Gleason 3 + 4). Treatment recommendations were correlated with practice patterns using Fisher's exact test. Results: Forty - two respondents (48%) completed the survey. We excluded from analysis two respondents who selected radical hypofractionation with 5 - 12 fractions as a preferred treatment modality. Among the 40 analyzed respondents, 23 (57.5%) recommend conventional fractionation and 17 (42.5%) recommended moderate hypofractionation. No demographic factors were found to be associated with preference for a fractionation regimen. Support for brachytherapy as a first choice treatment modality for low - risk prostate cancer was borderline significantly associated with support for moderate hypofractionated EBRT treatment modality (p = 0.089). Conclusions: There is an almost equal split among North American GU expert radiation oncologists regarding the appropriateness to consider moderately hypofractionated EBRT as a new standard of care in management of patients with prostate cancer. Physicians who embrace brachytherapy may be more inclined to support moderate hypofractionated regimen for EBRT. It is unclear whether reports with longer follow-ups will impact this balance, or whether national care and reimbursement policies will drive the clinical decisions. In the day and age of patient - centered care delivery, patients should receive an objective recommendation based on available clinical evidence. The stark division among GU experts may influence the design of future clinical trials utilizing EBRT for patients with prostate cancer.


Asunto(s)
Humanos , Masculino , Neoplasias de la Próstata/radioterapia , Braquiterapia/métodos , Oncología por Radiación/normas , Hipofraccionamiento de la Dosis de Radiación/normas , Neoplasias de la Próstata/patología , Estados Unidos , Braquiterapia/normas , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Oncología por Radiación/métodos , Clasificación del Tumor
18.
Int. braz. j. urol ; 45(1): 23-31, Jan.-Feb. 2019. tab, graf
Artículo en Inglés | LILACS | ID: biblio-989975

RESUMEN

ABSTRACT Objectives: To ascertain the opinions of North American genitourinary (GU) experts regarding inclusion of technologies such as prostate - specific membrane antigen (PSMA) and C - 11 choline positron emission tomography (PET) into routine practice. Materials and Methods: A survey was distributed to North American GU experts. Questions pertained to the role of PSMA and C - 11 PET in PCa management. Participants were categorized as "supporters" or "opponents" of incorporation of novel imaging techniques. Opinions were correlated with practice patterns. Results: Response rate was 54% and we analyzed 42 radiation oncologist respondents. 17 participants (40%) have been in practice for > 20 years and 38 (90%) practice at an academic center. 24 (57%) were supporters of PSMA and 29 (69%) were supporters of C - 11. Supporters were more likely to treat pelvic nodes (88% vs. 56%, p < 01) and trended to be more likely to treat patients with moderate or extreme hypofractionation (58% vs. 28%, p = 065). Supporters trended to be more likely to offer brachytherapy boost (55% vs. 23%, p = 09), favor initial observation and early salvage over adjuvant radiation (77% vs. 55%, p = 09), and to consider themselves expert brachytherapists (69% vs. 39%, p = 09). Conclusions: There is a polarization among GU radiation oncology experts regarding novel imaging techniques. A correlation emerged between support of novel imaging and adoption of treatment approaches that are clinically superior or less expensive. Pre - existing biases among GU experts on national treatment - decision panels and leaders of cooperative group studies may affect the design of future studies and influence the adoption of these technologies in clinical practice.


Asunto(s)
Humanos , Masculino , Adulto , Neoplasias de la Próstata/diagnóstico por imagen , Colina/metabolismo , Testimonio de Experto , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Antígenos de Superficie/metabolismo , Pautas de la Práctica en Medicina , Entrevistas como Asunto , Radiofármacos , Clasificación del Tumor
19.
Int. braz. j. urol ; 44(3): 452-460, May-June 2018. tab, graf
Artículo en Inglés | LILACS | ID: biblio-954032

RESUMEN

ABSTRACT Purpose: Most men with stage I testicular seminoma are cured with surgery alone, which is a preferred strategy per national guidelines. The current pattern of practice among US radiation oncologists (ROs) is unknown. Materials and Methods: We surveyed practicing US ROs via an online questionnaire. Respondent's characteristics, self-rated knowledge, perceived patient compliance rates with observation were analyzed for association with treatment recommendations. Results: We received 353 responses from ROs, of whom 23% considered themselves experts. A vast majority (84%) recommend observation as a default strategy, however this rate drops to 3% if the patient is believed to be noncompliant. 33% of respondents believe that survival is jeopardized in case of disease recurrence, and among these respondents only 5% support observation. 22% of respondents over-estimate the likelihood of noncompliance with observation to be in the 50-80% range. Responders with a higher perceived noncompliance rate are more likely to recommend adjuvant therapy (Fisher's exact p<0.01). Only 7% of respondents recommend observation for stage IS seminoma and 45% administer adjuvant RT in patients with elevated pre-orchiectomy alpha-fetal protein levels. Conclusions: Many US ROs over-estimate the likelihood that stage I testicular seminoma patients will be noncompliant with surveillance and incorrectly believe that overall survival is jeopardized if disease recurs on surveillance. Observation is quickly dismissed for patients who are not deemed to be compliant with observation, and is generally not accepted for patients with stage IS disease. There is clearly an opportunity for improved physician education on evidence-based management of stage I testicular seminoma.


Asunto(s)
Humanos , Masculino , Neoplasias Testiculares/radioterapia , Pautas de la Práctica en Medicina/estadística & datos numéricos , Seminoma/radioterapia , Espera Vigilante/métodos , Oncólogos de Radiación/estadística & datos numéricos , Neoplasias Testiculares/patología , Neoplasias Testiculares/tratamiento farmacológico , Estados Unidos , Conocimientos, Actitudes y Práctica en Salud , Vigilancia de la Población/métodos , Encuestas y Cuestionarios , Quimioterapia Adyuvante , Seminoma/patología , Seminoma/tratamiento farmacológico , Progresión de la Enfermedad , Estadificación de Neoplasias
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