Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.033
Filtrar
1.
Biochim Biophys Acta Mol Basis Dis ; 1869(1): 166569, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36243293

RESUMO

BACKGROUND: Hippocampus plays critical roles in drug addiction. Cocaine-induced modifications in dopamine receptor function and the downstream signaling are important regulation mechanisms in cocaine addiction. Rac regulates actin filament accumulation while Cdc42 stimulates the formation of filopodia and neurite outgrowth. Based on the region specific roles of small GTPases in brain, we focused on the hippocampal subregions to detect the regulation of Cdc42 signaling in long-term morphological and behavioral adaptations to cocaine. METHODS: Genetically modified mouse models of Cdc42, dopamine receptor D1 (D1R) and D2 (D2R) and expressed Cdc42 point mutants that are defective in binding to and activation of its downstream effector molecules PAK and N-WASP were generated, respectively, in CA1 or dentate gyrus (DG) subregion. RESULTS: Cocaine induced upregulation of Cdc42 signaling activity. Cdc42 knockout or mutants blocked cocaine-induced increase in spine plasticity in hippocampal CA1 pyramidal neurons, leading to a decreased conditional place preference (CPP)-associated memories and spatial learning and memory in water maze. Cdc42 knockout or mutants promoted cocaine-induced loss of neurogenesis in DG, leading to a decreased CPP-associated memories and spatial learning and memory in water maze. Furthermore, by using D1R knockout, D2R knockout, and D2R/Cdc42 double knockout mice, we found that D2R, but not D1R, regulated Cdc42 signaling in cocaine-induced neural plasticity and behavioral changes. CONCLUSIONS: Cdc42 acts downstream of D2R in the hippocampus and plays an important role in cocaine-induced neural plasticity through N-WASP and PAK-LIMK-Cofilin, and Cdc42 signaling pathway correlatively links specific brain regions (CA1, dentate gyrus) to cocaine-induced CPP behavior.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína , Camundongos , Animais , Transtornos Relacionados ao Uso de Cocaína/genética , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Hipocampo/metabolismo , Cocaína/farmacologia , Cocaína/metabolismo , Dopamina/metabolismo , Camundongos Knockout
2.
Talanta ; 252: 123862, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36084571

RESUMO

Facile, efficient, and inexpensive biosensing systems are in high demand for biomedical test. In recent years, numerous smartphone-based biosensing systems have been developed to match demand for biomedical test in source-limited environment. However, application of these smartphone-based biosensing systems was limited because of performance gap between the smartphone-based systems and commercial plate readers. In this study, we have developed a smart tablet-phone-based colorimetric plate reader (STPCPR) with intelligent and dynamic light modulation for broad-range colorimetric assays. The STPCPR allows controllable modulation of exciting light in three different color channels that is lack in conventional smartphone-based system. Using optimized exciting modulation, the STPCPR shows higher sensitivities, lower detection limits, and broader detection ranges in test of pigments, proteins, and cells when compared to conventional plate readers and smartphone-based system. Therefore, the developed STPCPR can serve as an ideal next-generation smartphone-based biosensing system for point-of-care colorimetric test in diverse biomedical applications in source-limited environment.


Assuntos
Técnicas Biossensoriais , Colorimetria , Smartphone , Desenho de Equipamento , Testes Imediatos , Bioensaio
3.
Food Chem ; 401: 134129, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36099821

RESUMO

In this study, quantitative monitoring of low-frequency (20 kHz) and high-frequency (355 kHz) ultrasound-induced inactivation of Kunitz (KTI) and Bowman-Birk inhibitor (BBI) using RP-HPLC was achieved, and its consistency with a traditional TI activity assay was verified. The effect of TI concentration, ultrasonic frequency, power density and pH on inactivation kinetics of KTI and BBI was explored. Results showed that the pseudo-first-order kinetic rate constants of KTI and BBI were decreased by over 60% when the initial TI concentration was increased from 100 mg/L to 1000 mg/L. Also, the amounts of inactivated KTI and BBI were increased by around 4-fold at the higher TI concentration of 1000 mg/L (20 kHz, 1.71 W/mL and pH 4). The colloidal environment and ultrasonic conditions influenced the secondary and tertiary structure and particle size of TIs in LF-induced inactivation. In comparison, the abovementioned conditions affected the oxidation of methionine and the conformational change of TIs in HF-induced inactivation.


Assuntos
Inibidor da Tripsina de Soja de Bowman-Birk , Inibidor da Tripsina de Soja de Bowman-Birk/química , Inibidor da Tripsina de Soja de Kunitz/química , Inibidores da Tripsina/química , Cinética , Ultrassom , Metionina
4.
J Hazard Mater ; 441: 129875, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36067554

RESUMO

Although iron-based metal-organic frameworks (Fe-MOFs) have displayed the photocatalytic activity, there is still abundant room for improving their photocatalytic performance through tuning the structures. In this work, four novel iron-based metal-organic frameworks (Fe-MOFs) were successfully synthesized via ligand modulation for better photocatalytic Cr(VI) reduction, in which MTBDC-TPT-Fe had the highest catalytic activity (MTBDC = 2,5-bis(methylthio)terephthalic acid, TPT = 2,4,6-tri(4-pyridyl)- 1,3,5-triazine). The boosted photocatalytic reduction may be mainly ascribed to the enhanced electron push-pull effect between iron-oxygen clusters and organic ligands. The introduction of -SCH3 groups can enhance the light absorption and donate electrons to iron center under visible-light irradiation, meanwhile the separation and transfer of photogenerated charge carriers can be enhanced resulting from the electron-pulling effect when introducing TPT. Moreover, enhanced specific surface areas and positive skeleton charge due to the introduction of TPT may improve active sites exposure and Cr(VI) adsorption, thereby enhancing photocatalytic Cr(VI) reduction activity without the presence of any assisted scavengers. In addition, the photocatalytic mechanism (i.e. active species) were also studied and presented. This work confirmed an effective structure-performance regulation strategy on Fe-MOFs for photocatalytic Cr(VI) reduction.

5.
HERD ; : 19375867221136234, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36411958

RESUMO

PURPOSE: To explore the impact of different acoustic stimuli of varying sound pressure levels on physical responses and the perception of senior adults. BACKGROUND: Noise-related health problems have been gaining increased attention as studies have shown an association with negative impacts on physiological parameters resulting in cardiovascular morbidity and mortality. However, a gap in knowledge exists in exploring the impact of exposure to sound recordings in the actual environment on physiological measurements. METHODS: Five acoustic stimuli were recorded in real life and 120 senior adults listened to them in a sound treated room to analyze the impacts of low-, middle-, and high-decibel sounds on their heart rate, blood pressure, and perception. The physical responses, heart rate, and blood pressure were measured during the sound exposure, and questionnaires were administered afterward. RESULTS: Exposure to different sounds resulted in fluctuations and an inconsistent trend in heart rate, systolic pressure, and diastolic pressure. According to the physical measures and subjective evaluations, sport sounds and traffic noise were given the lowest rating for preference, while music was perceived as the most comfortable. CONCLUSIONS: A sound pressure level below 55-65 dB(A) correlates with increased comfort and less increase in heart rate and blood pressure. Senior adults with normal hearing preferred and were most comfortable with music, while those with severe hearing impairment preferred entertainment sounds the most.

6.
J Gastrointest Oncol ; 13(5): 2366-2374, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36388693

RESUMO

Background: Neoadjuvant chemoradiotherapy is recommended for locally advanced rectal cancer, allowing preoperative down-staging of the primary tumor to facilitate complete surgical removal. However, further investigation is warranted for identifying whether radiotherapy is necessary for rectal mucinous adenocarcinoma (RMAC). Thus, this study was designed to explore the relationship between mFOLFOX6 with or without preoperative radiotherapy and therapeutic efficacy in locally advanced RMAC. Methods: A total of 81 patients were retrospectively enrolled, with MRI-defined clinical stage II/III RMAC received neoadjuvant treatment with mFOLFOX6 alone (group A) or mFOLFOX6 plus radiation (group B), followed by total mesorectal excision. Tumor down-staging and tumor response were assessed based on post-treatment MRI-defined radiographical and pathological findings. Follow-up data were retrieved, and the Kaplan-Meier curve was used to determine the relationship between the 3-year disease-free survival (DFS) and overall survival (OS) in the two groups. Results: There were no significant differences in the clinical baseline characteristics of patients between group A and group B. The sphincter preservation rate in group B was 60.9%, higher than in group A (20.0%) (P=0.031). The rate of pathological complete response (pCR) was 14.0% in group B, while no patients had pCR in group A (P=0.029), and the tumor response rate in group B was higher than in group A (52.0% vs. 16.1%, P=0.001). The 3-year probability of OS in group A and B was 77.4% and 72.0% (P=0.509), and 3-year DFS was 58.1% and 56.0% (P=0.592), respectively. Conclusions: Neoadjuvant mFOLFOX6-based chemoradiotherapy could be a promising therapeutic option for patients with RMAC, which was associated with a high rate of pCR and sphincter preservation in comparison to treated with mFOLFOX6 alone.

7.
J Comput Assist Tomogr ; 46(6): 961-967, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36399536

RESUMO

OBJECTIVE: Inferior intercavernous sinus (iICS) is a venous channel below the pituitary gland. Inferior intercavernous sinus injury is predisposed to cause venous bleeding during dura incision in transsphenoidal surgery for pituitary adenomas. Therefore, this study aimed to perform a radiological assessment of iICS before transsphenoidal surgery for pituitary microadenoma. METHODS: A retrospective evaluation was performed on 156 patients who underwent magnetic resonance imaging examinations in our hospital before endoscopic transsphenoidal surgery for pituitary microadenoma. Both sagittal reformatted and coronal contrast-enhanced (CE) sampling perfection with application optimized contrast using different flip angle evolutions (SPACE) images were interpreted for the presence, shape, and size of the iICS. RESULTS: In CE SPACE, the iICS was identified in 72 patients (46.15%) with pituitary microadenoma. The iICS was appeared as a filiform-shaped hyperintense structure below the pituitary gland on coronal CE SPACE planes and a crescent-shaped hyperintense structure on sagittal CE SPACE planes. The mean ± SD width, depth, and height of iICS were 11.15 ± 3.47 mm, 5.29 ± 1.24 mm, and 1.41 ± 0.19 mm, respectively. CONCLUSIONS: Contrast-enhanced SPACE may serve as a promising technique in evaluating iICS and individualized preoperative planning before transsphenoidal surgery for pituitary microadenoma.


Assuntos
Adenoma , Neoplasias Hipofisárias , Humanos , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/patologia , Estudos Retrospectivos , Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Adenoma/patologia , Imageamento por Ressonância Magnética/métodos
8.
Front Surg ; 9: 992490, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36386543

RESUMO

Background: Endometriosis is now considered to be a systemic disease rather than a disease that primarily affects the pelvis. Dienogest (DNG) has unique advantages in the treatment of endometriosis, but it also has side effects. Alternatively, Traditional Chinese Medicine (TCM) has been used for over 2000 years in the treatment and prevention of disease and growing numbers of Chinese scholars are experimenting with the combined use of Dienogest and TCM for endometriosis treatment. Objectives: This review evaluated the efficacy and safety of TCM in combination with Dienogest in the treatment of endometriosis through meta-analysis. Methods: MEDLINE, Embase, the Cochrane Library, PubMed, Web of Science, China National Knowledge Infrastructure, Journal Integration Platform, and Wanfang were used in literature searches, with a deadline of May 31, 2022. Literature quality was assessed using the Cochrane Collaboration "risk of bias" (ROB2) tool, and the "meta" package of R software v.4.1 was used for meta-analysis. Dichotomous variables and continuous variables were assessed using the relative risk (RR) and 95% confidence intervals (95% CI); standard mean differences (MD) and 95% CI, respectively. Results: Twelve human randomized controlled trials (RCTs) and one retrospective study, all 13 written in the Chinese language, were included in the meta-analysis (720 experiments and 719 controls). The result indicated that TCM plus Dienogest was superior to Dienogest/TCM alone in increasing the cure rates (RR = 1.3780; 95% CI, 1.1058, 1.7172; P = 0.0043), remarkable effect rate (RR = 1.3389; 95% CI, 1.1829, 1.5154; P < 0.0001), invalid rate (RR = 0.2299; 95% CI, 0.1591, 0.3322; P < 0.0001), and rate of adverse effects (RR = 0.6177; 95% CI, 0.4288, 0.8899; P = 0.0097). The same conclusion was drawn from the subgroup analysis. Conclusion: Results suggest that TCM combined with Dienogest is superior to Dienogest or TCM alone and can be used as a complementary treatment for endometriosis. TCMs have potential to improve clinical efficacy and reduce the side effects of Dienogest. This study was financially supported by Annual Science and Technology Steering Plan Project of Zhuzhou. PROSPERO has registered our meta-analysis as CRD42022339518 (https://www.crd.york.ac.uk/prospero/record_email.php).

9.
ACS Chem Neurosci ; 2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36401579

RESUMO

BACKGROUND: Our previous study has illuminated that PGC-1α downregulation promoted chronification of pain after burn injury. RNA-seq analysis predicted association between Sp1 and chronic constriction injury (CCI)-provoked neuropathic pain. Further ChIP-Atlas data investigation suggested the binding to Sp1 to PGC-1α. Thereby, we performed this study to illustrate the functional relevance of the Sp1/PGC-1α axis in neuropathic pain. METHODS: Neuropathic pain was induced by CCI in vivo in rats, followed by assessment of neuropathic pain-like behaviors. The expression of Sp1 and correlated genes was determined in CCI rat spinal cord tissues. Furthermore, microglia were exposed to lipopolysaccharide (LPS) to mimic inflammation and then cocultured with neurons. Knockdown and ectopic expression methods were used in vivo and in vitro to define the role the Sp1/HDAC2/PGC-1α axis. RESULTS: Sp1 expression was upregulated in spinal cord tissues of CCI rats. Silencing Sp1 ameliorated CCI-induced neuropathic pain, as reflected by elevated paw withdrawal threshold and paw withdrawal latency, as well as alleviated microglia activation, neuronal dysfunction, inflammatory responses, mitochondrial dysfunction, and oxidative stress in spinal cord tissues. Sp1 knockdown also reversed LPS-induced microglial inflammation and neuronal dysfunction. Sp1 promoted histone deacetylation in the PGC-1α promoter and inhibited PGC-1α expression via recruiting HDAC2. PGC-1α overexpression diminished CCI-induced neuropathic pain and LPS-induced inflammation and mitochondrial dysfunction, based on which Sp1 aggravated microglial inflammation and neuronal dysfunction in neuropathic pain. CONCLUSION: This study elucidated the promoting effects of Sp1 on CCI-induced neuropathic pain via the HDAC2/PGC-1α axis.

10.
Trends Neurosci ; 45(12): 884-898, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36404455

RESUMO

Diverse inhibitory neurons in the mammalian brain shape circuit connectivity and dynamics through mechanisms of synaptic plasticity. Inhibitory plasticity can establish excitation/inhibition (E/I) balance, control neuronal firing, and affect local calcium concentration, hence regulating neuronal activity at the network, single neuron, and dendritic level. Computational models can synthesize multiple experimental results and provide insight into how inhibitory plasticity controls circuit dynamics and sculpts connectivity by identifying phenomenological learning rules amenable to mathematical analysis. We highlight recent studies on the role of inhibitory plasticity in modulating excitatory plasticity, forming structured networks underlying memory formation and recall, and implementing adaptive phenomena and novelty detection. We conclude with experimental and modeling progress on the role of interneuron-specific plasticity in circuit computation and context-dependent learning.


Assuntos
Plasticidade Neuronal , Neurônios , Humanos , Animais , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Aprendizagem/fisiologia , Mamíferos
11.
Front Cell Infect Microbiol ; 12: 979641, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405962

RESUMO

We evaluated the immunogenicity and protective ability of a chimpanzee replication-deficient adenovirus vectored COVID-19 vaccine (BV-AdCoV-1) expressing a stabilized pre-fusion SARS-CoV-2 spike glycoprotein in golden Syrian hamsters. Intranasal administration of BV-AdCoV-1 elicited strong humoral and cellular immunity in the animals. Furthermore, vaccination prevented weight loss, reduced SARS-CoV-2 infectious virus titers in the lungs as well as lung pathology and provided protection against SARS-CoV-2 live challenge. In addition, there was no vaccine-induced enhanced disease nor immunopathological exacerbation in BV-AdCoV-1-vaccinated animals. Furthermore, the vaccine induced cross-neutralizing antibody responses against the ancestral strain and the B.1.617.2, Omicron(BA.1), Omicron(BA.2.75) and Omicron(BA.4/5) variants of concern. These results demonstrate that BV-AdCoV-1 is potentially a promising candidate vaccine to prevent SARS-CoV-2 infection, and to curtail pandemic spread in humans.


Assuntos
COVID-19 , Vacinas Virais , Cricetinae , Animais , Humanos , Mesocricetus , Administração Intranasal , Pan troglodytes , COVID-19/prevenção & controle , Anticorpos Antivirais , Vacinas contra COVID-19 , SARS-CoV-2/genética , Adenoviridae/genética
12.
Humanit Soc Sci Commun ; 9(1): 406, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36406149

RESUMO

Urbanization has exposed people to extreme sound levels. Although researchers have investigated the ability of people to listen, analyze, and distinguish sound, the concept of noise has not been clearly articulated from a human perspective. The lack of knowledge on how people perceive noise limits our capacity to control it in a targeted manner. This study aimed to interpret the definition of noise from the public perspective based on a grounded theory approach. Seventy-eight participants were interviewed about noise, and four categories of perceived understanding of noise were identified: challenges, definitions of noise, opportunities, and action. As one of the challenges, urbanization is associated with increased noise levels around the human environment. In terms of definition, perceiving sound as noise is considered to be a result of the complex and dynamic process that includes sound, the environment, and humans. Sound and humans interact with the environment. In terms of opportunities, noise may have positive roles on certain occasions, dispelling the misconception that noise is exclusively negative. In addition, we found that noise perception has gradually shifted from noise control to noise utilization. In terms of action, noise can be controlled at the sound sources, susceptible target groups, susceptible behaviors and states, locations, and times where noise is perceived with high frequency. In this study, we investigated several aspects of noise, ranging from noise control, soundscape definition, and 'soundscape indices' (SSID) integration and application. Our findings provide an additional basis for developing better definitions, control, and utilization strategies of noise in the future, thereby improving the quality of the sound environment.

13.
Biochem Biophys Rep ; 32: 101386, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36407484

RESUMO

Background: Glioblastoma (GBM) is a very frequent primary tumour in the cerebrospinal nervous system. Temozolomide (TMZ) is the first-line treatment for patients with GBM. However, some of GBM patients do not respond to TMZ. O6-methylguanine-DNA-methytransferase (MGMT) remains a major cause. In a previous study, we detected antibodies against MGMT peptides in patients with glioma, and five highly responsive autoantibodies anti-MGMT-02, anti-MGMT-04, anti-MGMT-07, anti-MGMT-10, and anti-MGMT-18 were identified that could be used to dynamically assess chemotherapy-resistant TMZ. Therefore, targeting MGMT peptides may be a potential therapeutic approach for GBM to fight TMZ resistance. Methods: First, MGMT-02 and MGMT-04 polypeptides with cell-penetrating peptides were designed and connected to FITC tracer for immunofluorescence localisation. CCK-8 and colony formation assay were performed to evaluate cell proliferation ability. Western blot and immunofluorescence analysis were used to detected the expression of apoptosis-related protein. Flow cytometry was used to detect the proportion of apoptosis in cells. TMZ-resistant effect of MGMT-02/04 peptides was assessed in intracranial xenograft nude mouse model. Results: We also found reduced apoptosis of cells treated with MGMT-02 and MGMT-04 peptides and TMZ compared with those treated separately with TMZ in vivo and in vitro experiences. Conclusion: The results of this study indicate that MGMT-02 and MGMT-04 peptides have a role in glioma resistance and that MGMT peptides may serve as a precise target for TMZ-resistant GBM.

14.
Clin Obes ; : e12566, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36416295

RESUMO

Epigenetic modifications such as DNA methylation may influence gene expression and phenotypes, including obesity in childhood. The directionality of this relationship is nevertheless unclear, and some evidence suggests that adiposity modifies the epigenome, rather than the other way around. In this pilot study, we utilize data from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) study to examine whether measures of adiposity in childhood and early adolescence are associated with repeated measures of blood leukocyte DNA methylation at LINE-1 repetitive elements and two genes implicated in growth and adiposity: H19 and HSD11B2. Longitudinal epigenetic data were generated from cord blood and blood from follow-up visits in early and late adolescence. We assessed interactions between age and measures of body mass index (BMI) at 5 years of age and weight, BMI and waist circumference in early adolescence to infer whether adiposity deflects age-related DNA methylation changes throughout childhood. Applying linear mixed-effects models, we found an inverse association between measures of childhood BMI (kg/m2 ) and early-teen weight (kg) with repeat measures of H19 DNA methylation. We did not observe any statistically significant associations (p-value <.05) between any anthropometric measures and DNA methylation at LINE-1 or HSD11B2. We did not demonstrate statistically significant evidence in support of deflection of age-related DNA methylation trajectories by adiposity-related measures (age by adiposity interaction term). Given the pilot nature of this study, the relationships between repeat measures of DNA methylation and adiposity-measures across childhood merit further exploration in larger study populations.

15.
ACS Appl Mater Interfaces ; 14(46): 52182-52192, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36347823

RESUMO

Microwave-absorbing materials with wide bandwidth and high absorptivity are increasingly playing an important role in over-the-air (OTA) testing. In this work, a kind of pyramid absorbing material was prepared using flame-retardant absorbers as the filler. In addition, a coating was used to further improve the flame-retardant properties of the microwave-absorbing material. To obtain excellent microwave absorption performance (MWAP), a high-frequency structure simulator (HFSS) was adopted to design structural materials. Here, the total height, the base height, the decapitation height of the pyramid tip, the distance between the pyramids, and other parameters were analyzed; then, the actual processing and molding were realized. The MWAP of -30 dB was achieved at 2.7-18 GHz, and the MWAP of -10 dB was also met at 2-18 GHz. In particular, the study also investigated the MWAP of large angle, which can meet the MWAP of -10 dB at 2-18 GHz and MWAP of -30 dB at 4-18 GHz. Most importantly, the absorption mechanism of the pyramid structure was explored. The influence of the tip was proved by the distribution of the electromagnetic field in the pyramid. It can be regarded as a multilayer microwave-absorbing material due to the impedance gradient of the pyramid, which can provide an effective research idea and method for future engineering applications.

16.
BMJ Open ; 12(11): e065299, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36379662

RESUMO

OBJECTIVE: Neratinib plus capecitabine (Ner+Cap) were proved to be clinically beneficial as a third-line treatment for women with human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer (MBC). The objective of this study was to evaluate the cost-effectiveness of Ner+Cap from the Chinese healthcare perspective. DESIGN: A three-state Markov simulation model was performed based on the results of NALA trial. The utilities of health state and disutilities of adverse events were derived from the published literature. Direct costs of anticancer agents, drug administration, routine follow-up and serious adverse events management were calculated in the model. Uncertainty was evaluated through univariate and probability sensitivity analysis. PARTICIPANTS: Patients with confirmed HER2-positive MBC who previously received at least two HER2-targeted treatments and were aged ≥18 years with an Eastern Cooperative Oncology Group performance status 0 or 1. A total of 621 patients were enrolled in the NALA trial. INTERVENTIONS: Third-line treatment with Ner+Cap or lapatinib plus capecitabine (Lap+Cap). MAIN OUTCOME MEASURES: The primary health outcomes of the model were costs, expected life-years (LYs), quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). RESULTS: When compared with Lap+Cap, Ner+Cap provided an additional 0.431 LYs and 0.339 QALYs, and increased the cost by $4299.2. The corresponding ICERs were 9970.1/LY and $12 670.2/QALY. Univariate sensitivity analyses suggested that the results were generally robust. Besides, Ner+Cap had a 100% probability of being cost-effective according to probabilistic sensitivity analysis. CONCLUSIONS: Ner+Cap was likely to be a cost-effective regimen as the third-line therapy for women with HER2-positive MBC at the willingness-to-pay threshold of $37 653.0/QALY in China.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Adolescente , Adulto , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Capecitabina/uso terapêutico , China , Análise Custo-Benefício , Lapatinib/uso terapêutico , Anos de Vida Ajustados por Qualidade de Vida , Receptor ErbB-2/metabolismo , Ensaios Clínicos como Assunto
17.
BMC Pulm Med ; 22(1): 427, 2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36402959

RESUMO

BACKGROUND: Currently, the microbial etiology of community-acquired pneumonia in children remains challenging. While Gram stain and sputum culture are commonly used to detect bacterial pathogens, it is unclear whether these approaches can predict single pathogen from bronchoalveolar lavage fluid (BALF) culture. METHODS: A retrospective study involving 287 children hospitalized for pneumonia was conducted. Sputum specimens were collected on admission; and BALF specimens were collected within 24 h after admission. Taking BALF culture as the reference standard, the sensitivity and specificity of Sputum Gram stain (SGS), sputum culture, and BALF Gram stain (BGS) were calculated. The agreement between these approaches and BALF culture was compared using kappa statistics. RESULTS: For SGS, the specificity was 23%. The overall sensitivity was 70%, including 87% for Gram-positive (G+) cocci, 56% for Gram-negative (G-) cocci, and 50% for G-bacilli. For sputum culture, the specificity was 70%. The overall sensitivity was 64%, including 71% for Streptococcus pneumoniae, 71% for Moraxella catarrhalis, and 64% for Haemophilus influenzae. For BGS, the specificity was 71%. The overall sensitivity was 60%, including 77% for G+cocci, 38% for G-cocci, and 44% for G-bacilli. While SGS had poor agreement with BALF culture, both sputum culture and BGS had moderate agreement with BALF culture. CONCLUSIONS: Both sputum culture and BGS are helpful in predicting single bacterial pathogen from BALF culture among children with community-acquired pneumonia. Sputum cultures and BGS can provide early clues for BALF pathogen when BALF culture results are pending or bronchoscopy is not performed.


Assuntos
Infecções Comunitárias Adquiridas , Pneumonia , Humanos , Criança , Líquido da Lavagem Broncoalveolar/microbiologia , Escarro/microbiologia , Estudos Retrospectivos , Infecções Comunitárias Adquiridas/diagnóstico , Infecções Comunitárias Adquiridas/microbiologia , Pneumonia/diagnóstico , Bactérias
18.
Respir Res ; 23(1): 316, 2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36403040

RESUMO

BACKGROUND: Eosinophilic asthma is a common subtype of severe asthma with high morbidity and mortality. The cytokine IL-5 has been shown to be a key driver of the development and progression of disease. Although approved monoclonal antibodies (mAbs) targeting IL-5/IL-5R have shown good safety and efficacy, some patients have inadequate responses and frequent dosing results in medication nonadherence. RESULTS: We constructed a novel trivalent bispecific nanobody (Nb) consisting of 3 VHHs that bind to 2 different epitopes of IL-5 and 1 epitope of albumin derived from immunized phage display libraries. This trivalent IL-5-HSA Nb exhibited similar IL-5/IL-5R blocking activities to mepolizumab (Nucala), an approved targeting IL-5 mAb. Surprisingly, this trivalent Nb was 58 times more active than mepolizumab in inhibiting TF-1-cell proliferation. In primate studies, the trivalent IL-5-HSA Nb showed excellent pharmacokinetic properties, and peripheral blood eosinophil levels remained significantly suppressed for two months after a single dose. In addition, the trivalent IL-5-HSA Nb could be produced on a large scale in a P. pastoris X-33 yeast system with high purity and good thermal stability. CONCLUSIONS: These findings suggest that the trivalent bispecific IL-5-HSA Nb has the potential to be a next-generation therapeutic agent targeting IL-5 for the treatment of severe eosinophilic asthma.


Assuntos
Asma , Eosinofilia Pulmonar , Animais , Interleucina-5/metabolismo , Interleucina-5/uso terapêutico , Eosinofilia Pulmonar/tratamento farmacológico , Eosinofilia Pulmonar/metabolismo , Asma/metabolismo , Eosinófilos/metabolismo , Anticorpos Monoclonais/uso terapêutico
19.
BMC Neurol ; 22(1): 421, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36368955

RESUMO

BACKGROUND: Meningoencephalocele is a rare malformation caused by congenital and acquired lesions. The association between recurrent bacterial meningitis and meningoencephaloceles with cerebrospinal fluid (CSF) leak is reported in the literature. We report a rare case of meningoencephalocele secondary to chronic idiopathic intracranial hypertension as a result of hospitalization repeatedly for meningitis due to the lack of CSF leak. CASE PRESENTATION: This study presents a case of a patient with a decade of recurrent meningitis. With clinical symptoms and imaging examination with chronic idiopathic intracranial hypertension, this patient was diagnosed with meningoencephalocele. With the treatment of acetazolamide to decrease CSF product, the patient had no recurrence of meningitis over the 6-months follow-up period. CONCLUSION: In patients with recurrent intracranial infections but no history of immunodeficiency, cranial trauma, or neurosurgery, the possibility of meningitis should be considered appropriately, even in the absence of CSF otorrhea or rhinorrhea.


Assuntos
Infecções do Sistema Nervoso Central , Rinorreia de Líquido Cefalorraquidiano , Hipertensão Intracraniana , Meningites Bacterianas , Meningocele , Pseudotumor Cerebral , Humanos , Pseudotumor Cerebral/complicações , Rinorreia de Líquido Cefalorraquidiano/diagnóstico , Rinorreia de Líquido Cefalorraquidiano/etiologia , Rinorreia de Líquido Cefalorraquidiano/cirurgia , Meningocele/complicações , Meningocele/diagnóstico por imagem , Encefalocele/complicações , Encefalocele/diagnóstico por imagem , Vazamento de Líquido Cefalorraquidiano/complicações , Meningites Bacterianas/complicações , Meningites Bacterianas/diagnóstico , Meningites Bacterianas/tratamento farmacológico
20.
Nat Commun ; 13(1): 6881, 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371464

RESUMO

Severe infection commonly results in immunosuppression, which leads to impaired pathogen clearance or increased secondary infection in both humans and animals. However, the exact mechanisms remain poorly understood. Here, we demonstrate that IL-33 results in immunosuppression by inducing thymic involution-associated naive T cell dysfunction with aberrant expression of aging-associated genes and impairs host control of infection in mouse disease models of schistosomiasis or sepsis. Furthermore, we illustrate that IL-33 triggers the excessive generation of medullary thymic epithelial cell (mTEC) IV (thymic tuft cells) in a Pou2f3-dependent manner, as a consequence, disturbs mTEC/cortical TEC (cTEC) compartment and causes thymic involution during severe infection. More importantly, IL-33 deficiency, the anti-IL-33 neutralizing antibody treatment, or IL-33 receptor ST2 deficient thymus transplantation rescues T cell immunity to better control infection in mice. Our findings not only uncover a link between severe infection-induced IL-33 and thymic involution-mediated naive T cell aging, but also suggest that targeting IL-33 or ST2 is a promising strategy to rejuvenate T cell immunity to better control severe infection.


Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1 , Linfócitos T , Humanos , Camundongos , Animais , Linfócitos T/fisiologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Timo , Células Epiteliais/metabolismo , Envelhecimento/fisiologia , Senescência Celular
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...