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BACKGROUND: Venous thromboembolism (VTE) causes morbidity and mortality in cancer patients. The association of VTE with known risk factors in chronic lymphocytic leukemia (CLL) is not known. OBJECTIVE: To examine risk factors and mortality associated with VTE in White, Black, and Asian CLL patients. METHODS: The United States SEER-Medicare database (2000-2015) was used for CLL patients ≥ 65 years. Logistic regression was used to examine VTE risk factors and Cox proportional regression was used to evaluate the effect of VTE on mortality in White, Black, and Asian CLL patients. RESULTS: Among 34,075 CLL patients, VTE was diagnosed in 11.6â¯% of 31,395 White, 14.6â¯% of 2062 Black and 6.3â¯% of 618 Asian patients. Risk of having VTE was, ORa = 1.2 (95â¯% CI, 1.0-1.4) for Black patients and ORa = 0.5 (95â¯% CI, 0.4-0.7) for Asian patients compared to White patients. Anemia and heart failure were associated with VTE in all three racial cohorts and were the only risk factors in Asian patients. Other risk factors in White patients were the same as in the overall population, including hypertension, obesity, COPD, kidney disease, diabetes, hyperlipidemia, myocardial infarction, and chemotherapy. In Black patients, other risk factors were hypertension, and chemotherapy. Mortality was slightly higher with VTE in the overall population and in White patients. CONCLUSION: There was difference in VTE risk factors in White, Black, and Asian patients. VTE was marginally associated with mortality in CLL patients. Our findings may help to identify patients at higher risk of VTE in racially diverse CLL populations.
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Impaired clearance of amyloid ß (Aß) in late-onset Alzheimer's disease (AD) affects disease progression. The role of peripheral monocytes in Aß clearance from the central nervous system (CNS) is unclear. We use a flow cytometry assay to identify Aß-binding monocytes in blood, validated by confocal microscopy, Western blotting, and mass spectrometry. Flow cytometry immunophenotyping and correlation with AD biomarkers are studied in 150 participants from the AIBL study. We also examine monocytes in human cerebrospinal fluid (CSF) and their migration in an APP/PS1 mouse model. The assay reveals macrophage-like Aß-binding monocytes with high phagocytic potential in both the periphery and CNS. We find lower surface Aß levels in mild cognitive impairment (MCI) and AD-dementia patients compared to cognitively unimpaired individuals. Monocyte infiltration from blood to CSF and migration from CNS to peripheral lymph nodes and blood are observed. Here we show that Aß-binding monocytes may play a role in CNS Aß clearance, suggesting their potential as a biomarker for AD diagnosis and monitoring.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Disfunção Cognitiva , Progressão da Doença , Camundongos Transgênicos , Monócitos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Doença de Alzheimer/sangue , Humanos , Monócitos/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Feminino , Idoso , Masculino , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/líquido cefalorraquidiano , Camundongos , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/metabolismo , Citometria de Fluxo , Modelos Animais de Doenças , Fagocitose , Pessoa de Meia-IdadeRESUMO
This research aimed to investigate the impacts of a combination of rice husk biochar and organic fertilizer on the physical and chemical properties of soil, the population of soil bacteria, the relative chlorophyll content of leaves, the development of soybean root nodules, and yield components under strongly acid soil conditions. A greenhouse and pot experiment was designed using a randomize complete block design with factorial 2 × 3 treatments and three replications. The experimental treatments comprised two rates of biochar (35 and 70 g/pot) and three rates of organic fertilizer (70, 105, and 140 g/pot). After 100 days of amendment of strongly acidic soils, the results showed that application of treatments B35F70 and B70F140 increased soil pH by 16.80% compared to the control group (CK). On the other hand, treatments B35F140 and B70F105 resulted in an increase of soil electrical conductivity by 66.67% compared to CK. In addition, after 100 days of amendment with treatments B35F105, B35F105, B35F140, B70F105, B70F70, B70F70, and B35F140, organic matter, available phosphorous (P), potassium (K), calcium (Ca), magnesium (Mg), copper (Cu), and zinc (Zn), organic matter, available phosphorous (P), potassium (K), calcium (Ca), magnesium (Mg), copper (Cu), and zinc (Zn), significantly increased when compared to the control group (CK). Treatment B35F140 increased relative leaf chlorophyll content and soybean seed weight per plant by 60.76% and 100.56%, respectively when compared to the CK. Furthermore, treatment B35F70 produced 125% more root nodules than CK. Moreover, each amended strongly acid soil resulted with a significant upsurge in total soil bacteria compared to the CK. Overall, statistics proved that a combination of biochar and organic fertilizer improved soil properties and soybean agronomic attributes.
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Carvão Vegetal , Fertilizantes , Glycine max , Solo , Fertilizantes/análise , Glycine max/crescimento & desenvolvimento , Solo/química , Clorofila/metabolismo , Clorofila/análise , Folhas de Planta/química , Microbiologia do Solo , Concentração de Íons de Hidrogênio , Fósforo/análise , Fósforo/metabolismo , Agricultura/métodos , Raízes de Plantas/crescimento & desenvolvimentoRESUMO
Activating enhancer-binding protein 2 (AP-2) is a family of transcription factors (TFs) that play crucial roles in regulating embryonic and oncogenic development. In addition to splice isoforms, five major family members encoded by the TFAP2A/B/C/D/E genes have been identified in humans, i.e., AP-2α/ß/γ/δ/ε. In general, the first three TFs have been studied more thoroughly than AP-2δ or AP-2ε. Currently, there is a relatively limited body of literature focusing on the AP-2 family in the context of gastroenterological research, and a comprehensive overview of the existing knowledge and recommendations for further research directions is lacking. Herein, we have collected available gastroenterological data on AP-2 TFs, discussed the latest medical applications of each family member, and proposed potential future directions. Research on AP-2 in gastrointestinal tumors has predominantly been focused on the two best-described family members, AP-2α and AP-2γ. Surprisingly, research in the past decade has highlighted the importance of AP-2ε in the drug resistance of gastric cancer (GC) and colorectal cancer (CRC). While numerous questions about gastroenterological disorders await elucidation, the available data undoubtedly open avenues for anti-cancer targeted therapy and overcoming chemotherapy resistance. In addition to gastrointestinal cancers, AP-2 family members (primarily AP-2ß and marginally AP-2γ) have been associated with other health issues such as obesity, type 2 diabetes, liver dysfunction, and pseudo-obstruction. On the other hand, AP-2δ has been poorly investigated in gastroenterological disorders, necessitating further research to delineate its role. In conclusion, despite the limited attention given to AP-2 in gastroenterology research, pivotal functions of these transcription factors have started to emerge and warrant further exploration in the future.
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Fator de Transcrição AP-2 , Humanos , Fator de Transcrição AP-2/metabolismo , Fator de Transcrição AP-2/genética , Gastroenteropatias/genética , Gastroenteropatias/metabolismo , AnimaisRESUMO
Background: Spinal cord injury (SCI) is a catastrophic condition associated with spinal nerve damage, which can lead to complete or partial loss of sensory and motor functions. Chinese herbal compound prescriptions (CHCP) have shown varying degrees of therapeutic effects on spinal cord injuries. However, there is a significant lack of clinical evidence-based research to substantiate these effects. Purpose: This study aims to thoroughly assess the viability of CHCPs in postoperative SCI through network meta-analysis. Methods: Computer searches were conducted across multiple databases, including PubMed, Cochrane Library, Embase, Web of Science, CNKI, Wanfang, VIP, and CBM, from their inception until May 2024. The meta-analysis adhered to the PRISMA guidelines and was registered in the PROSPERO database (CRD42023462686). A network meta-analysis was performed using the BUGSnet software package via R. Study design: A network meta-analysis of randomized clinical trials (RCTs). Results: A total of 26 RCTs involving 1848 patients were ultimately included. The network meta-analysis revealed the effectiveness in improving ASIA motor score as follows: "HQGZD" > "Other Decoctions" > "BYHWD" > "TDHXD" > "THCQD" > "Surgery". For ASIA sensory score, the effectiveness ranking was: "HQGZD" > "Other Decoctions" > "BYHWD" > "TDHXD" > "THCQD" > "Surgery". Additionally, the experimental group had a higher ADL score compared to the control group, with a statistically difference [SMD = 1.08, 95 % CI = (0.88, 1.27), p < 0.05]. The experimental group had fewer adverse events compared to the control group, with a statistically difference [RR = 0.41, 95 % CI (0.22, 0.78), p < 0.05]. Conclusion: The findings suggest that CHCP can mprove postoperative ASIA motor and sensory scores, enhance ADL scores, and reduce adverse events following SCI surgery. Specifically, combining surgery with Huangqi Guizhi Wuwu Decoction or Buyang Huanwu Decoction may provide superior therapeutic effects in SCI treatment. Integrating CHCP into postoperative care for SCI patients may offer potential benefits.
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Procypris mera (Lin, 1933), also known as the Chinese ink carp, currently has a second-class protection status in China. Understanding the structure and characteristics of mitochondrial genes provides essential information for resource conservation and phylogenetic studies of P. mera. Here, we sequenced the mitochondrial genomes of three P. mera (WYL1-3) from three sites and performed phylogenetic analysis. The generated three genomes were 16,587 bp in length, comprising 13 protein-coding genes (PCGs), 22 tRNAs, two rRNAs, and two non-coding regions (control region (CR), D-loop, and light-stranded replication start OL), with a preference for codons ending in A or C. The mitochondrial genomes of WYL2 and WYL3 were identical, differing from that of WYL1 by only five single-nucleotide polymorphisms (SNPs). All mitochondrial PCGs had Ka/Ks ratios of less than one, suggesting purifying selection. Phylogenetic tree analysis based on amino acid sequences suggested that the genus Puntioplites is sister to all other genera of the subfamily Cyprinidae of China; the genus Procypris forms a monophyletic group; and the genera Carassioides, Carassius, and Cyprinus form a monophyletic group. This study contributes to our understanding of the phylogenetic relationships in subfamily Cyprininae in China and lays the foundation for resource conservation and management of P. mera.
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Liver failure (LF) is prevalent in China and is characterized by complex pathogenesis, challenging clinical management, poor prognosis, and rising incidence and mortality rates. The immune status is an important factor affecting LF prognosis. Interleukins (Ils) are a type of cytokine that act and interact with multiple cells, including immune cells. These signaling molecules play important roles in intercellular information transmission, including the regulation of immune cells; mediation of the activation, proliferation, and differentiation of T and B cells; and orchestration of the inflammatory response. To date, many studies have explored the correlation between IL expression and liver disease prognosis, but few studies have evaluated Ils as the prognostic biomarkers of LF. This article reviews the potential use of Ils as the prognostic biomarkers of LF. Particularly, it evaluates the predictive values of IL-21, IL-22, and IL-31, the three often overlooked yet promising prognostic biomarkers, in predicting susceptibility to LF. Harnessing biomarkers for early prognostic insights can facilitate tailored treatment strategies and enhance patient survival. Thus, this article focuses on the identification of IL-21, IL-22, and IL-33 as biomarkers in preclinical and clinical studies on LF and reviews their role as biomarkers in the pathogenesis and diagnosis of LF.
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BACKGROUND: Scant data are available on heterogenous staining of mismatch repair protein in colorectal cancer. OBJECTIVE: This study aimed to improve insights into clinicopathologic features and prognosis of colorectal cancer harboring heterogenous mismatch repair protein staining. DESIGN: A single-center retrospective observational study. SETTING: This study was conducted in a tertiary referral center in China between 2014 and 2018. PATIENTS: Colorectal cancers with heterogenous staining of mismatch repair protein were included. MAIN OUTCOMES MEASURES: Clinicopathologic and molecular features, and survival outcomes were analyzed. RESULTS: A total of 151 out of 6721 colorectal cancers (2.2%) exhibited heterogenous staining for at least one mismatch repair protein, with intraglandular heterogeneity being the most common pattern (89.4%). Heterogenous MLH1 staining was significantly associated with distant metastasis (p = 0.03), while heterogenous MSH2 staining was associated with left-sided (p = 0.03) and earlier pT stage tumors (p = 0.02). The rates of microsatellite instability-high, KRAS and BRAF mutation were 12.6%, 47.3% and 3.4%, respectively. Microsatellite instability-high was significantly associated with higher intraglandular MSH6 heterogeneity frequency (p < 0.001) and decreased MSH6 expression level (< 27.5%, p = 0.01). BRAF mutation was associated with the coexistence of intraglandular and clonal heterogeneity (p = 0.003) and decreased PMS2 expression level (p = 0.01). Multivariable analysis revealed that progression-free survival was significantly associated with tumor stage (p = 0.003), stroma fraction (p = 0.004), and heterogenous PMS2 staining (p = 0.02). Overall survival was linked to tumor stage (p = 0.006) and BRAF mutation (p = 0.01). LIMITATIONS: The limitations of this study include the absence of testing for MLH1 promoter methylation and mismatch repair gene mutations, its retrospective design, and insufficient data related to direct comparison with deficient mismatch repair and proficient mismatch repair colorectal cancer. CONCLUSIONS: Heterogenous mismatch repair protein staining in colorectal cancer exhibits distinct associations with tumor location, stage, microsatellite instability, BRAF mutation and prognosis. It is recommended to report MSH6 heterogeneity as it may indicate microsatellite instability-high. See Video Abstract.
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The glomus tumor is a rare neoplasm that is typically found subungually in the extremities and functions as a specialized neurovascular organ. An extremely rare site for glomus tumors is the breast, with only a few reported cases. Breast glomus tumors present with three typical clinical signs: dull pain, focal tenderness, and cold sensitivity. Less than 10% of all glomus tumors are malignant. We herein present a case of a malignant glomus tumor originating in the breast. Distant metastasis was ruled out, and the tumor was completely resected. However, the patient unexpectedly developed rapid systemic metastasis, detected 5 weeks after tumor removal. Despite the administration of analgesics and targeted therapy, the patient died 1 month later. When treating patients with undiagnosed breast tumors, clinicians should pay attention to unexplained and repeatedly reported symptoms and consider the possibility of a rare disease. Our literature search revealed no cases of malignant glomus tumors originating in the breast, making this case the first of its kind.
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Neoplasias da Mama , Tumor Glômico , Humanos , Tumor Glômico/patologia , Tumor Glômico/diagnóstico , Tumor Glômico/cirurgia , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Neoplasias da Mama/diagnóstico , Pessoa de Meia-Idade , Evolução Fatal , Progressão da DoençaRESUMO
The "innate-like" T cell compartment, known as Tinn, represents a diverse group of T cells that straddle the boundary between innate and adaptive immunity. We explore the transcriptional landscape of Tinn compared to conventional T cells (Tconv) in the human thymus and blood using single-cell RNA sequencing (scRNA-seq) and flow cytometry. In human blood, the majority of Tinn cells share an effector program driven by specific transcription factors, distinct from those governing Tconv cells. Conversely, only a fraction of thymic Tinn cells displays an effector phenotype, while others share transcriptional features with developing Tconv cells, indicating potential divergent developmental pathways. Unlike the mouse, human Tinn cells do not differentiate into multiple effector subsets but develop a mixed type 1/type 17 effector potential. Cross-species analysis uncovers species-specific distinctions, including the absence of type 2 Tinn cells in humans, which implies distinct immune regulatory mechanisms across species.
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Imunidade Inata , Fenótipo , Humanos , Animais , Camundongos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Timo/imunologia , Timo/citologia , Análise de Célula Única , Diferenciação Celular , Camundongos Endogâmicos C57BLRESUMO
Terpene synthases (TPSs) are key enzymes in terpenoids synthesis of plants and play crucial roles in regulating plant defence against pests and diseases. Here, we report the functional characterization of OsTPS19 and OsTPS20, which were upregulated by the attack of brown planthopper (BPH). BPH female adults performed concentration-dependent behavioural responses to (S)-limonene showing preference behaviour at low concentrations and avoidance behaviour at high concentrations. Overexpression lines of OsTPS19 and OsTPS20, which emitted higher amounts of the monoterpene (S)-limonene, decreased the hatching rate of BPH eggs, reduced the lesion length of sheath blight caused by Rhizoctonia solani and bacterial blight caused by Xanthomonas oryzae. While knockout lines of OsTPS19 and OsTPS20, which emitted lower amounts of (S)-limonene, were more susceptible to these pathogens. Overexpression of OsTPS19 and OsTPS20 in rice plants had adverse effects on the incidence of BPH, rice blast, and sheath blight in the field and had no significant impacts on rice yield traits. OsTPS19 and OsTPS20 were found to be involved in fine-tuning the emission of (S)-limonene in rice plants and play an important role in defence against both BPH and rice pathogens.
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To enhance the interfacial property, carbon fiber (CF) was modified with graphene oxide (GO) using a layer-by-layer self-assembly method and subsequently incorporated into phosphate bonded coatings as a reinforcement. CF modified with GO (CF-GO) was characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, X-ray diffractometer, Raman spectroscopy, and thermogravimetric analysis. Additionally, the tribological behavior of phosphate bonded coatings with CF-GO was investigated. The results show that GO is grafted onto the CF surface through electrostatic interactions. Besides, the CF surface becomes rougher due to the modification of GO, leading to a stronger interfacial bond between CF and the coating. Notably, as the content of CF-GO increases, both the friction coefficient and the wear rate of the coating decrease. CF-GO can form a lubricant film on the worn surface, which leads to a decrease in the friction coefficient and wear rate. Moreover, in CF-GO, CF assumes the role of a tree trunk, while GO functions as branches, collaboratively bridging cracks, as well as altering and impeding crack propagation pathways, which can consume the fracture energy and improve the cohesive strength of the coating, further contributing to a lower wear rate. Specifically, the coating with 15 wt % CF-GO exhibits a 34% reduction in the friction coefficient and a 58% decrease in the wear rate compared to those of the coating without CF-GO. These findings highlight the significant potential of CF-GO in enhancing the tribological properties of phosphate bonded coatings, making them more durable for antiwear applications.
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The spoilage of irradiated ready-to-eat chicken feet (RTECF) seriously affects the food's quality, resulting in package swelling and off-flavors, both of which are highly undesirable to stakeholders and consumers. To investigate the spoilage characteristics of irradiated RTECF and the microorganisms responsible for the spoilage and swelling, the changes in physicochemical properties, microbial community, and volatile organic compounds (VOCs) between normal and spoiled RTECF were evaluated. Compared with normal samples, the spoiled RTECF showed a higher pH value and total volatile basic nitrogen (TVB-N) value, lower color value, and texture features (P < 0.05). Acinetobacter, Pseudomonas, Lactobacillus, and Candida were the dominant genera responsible for RTECF spoilage as confirmed through both culture-dependent methods and high-throughput sequencing (HTS). The results of the verification for gas-producing strains showed that Lactobacillus brevis could cause RTECF packaging to swell. A total of 20 key VOCs were identified using headspace solid-phase microextraction combined with gas chromatography-mass spectrometry (HS-SPME-GC-MS). The results of Pearson correlation analysis (|r|>0.8, P < 0.05) showed that 12 dominant core microbial genera had a significant effect on the flavor of RTECF before and after spoilage. This study provides a theoretical reference for solving the problem of RTECF spoilage and improving the overall quality of RTECF products.
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Bactérias , Galinhas , Irradiação de Alimentos , Microbiologia de Alimentos , Compostos Orgânicos Voláteis , Galinhas/microbiologia , Animais , Compostos Orgânicos Voláteis/análise , Compostos Orgânicos Voláteis/química , Compostos Orgânicos Voláteis/metabolismo , Bactérias/classificação , Bactérias/efeitos da radiação , Bactérias/isolamento & purificação , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bactérias/metabolismo , Irradiação de Alimentos/métodos , Microbiota/efeitos da radiação , Embalagem de Alimentos/métodos , Cromatografia Gasosa-Espectrometria de Massas , Concentração de Íons de Hidrogênio , Fast Foods/microbiologia , Fast Foods/análiseRESUMO
Rhizosphere is a vital area for substance exchange and energy transfer between roots and soil microorganisms. Therefore, diazotrophs in the rhizosphere play a pivotal role in facilitating plant nitrogen acquisition. We investigated the variability in the abundance and community structure of soil diazotrophs and the influencing factors across rhizosphere soils of Cunninghamia lanceolata in three locations: Baisha State-owned Forest Farm in Longyan City (BS), Sanming Forest Ecosystem and Global Change Research Station (SM), and Wuyishan National Forest Park in Nanping City (WYS), located in the western region of Fujian Province, quantified the diazotrophic abundance by using real-time quantitative PCR, and assessed the community structure by high-throughput sequencing. The results showed that soil pH, C:N ratio, and C:(N:P) stoichiometry in SM were notably lower compared to those in BS and WYS. In SM, the abundance of the nifH gene was 6.38×108 copies·g-1, significantly lower than 1.35×109 copies·g-1 in BS and 1.10×109 copies·g-1 in WYS. Additionally, α diversity index of diazotrophs was lower in SM compared to BS and WYS, while the community structure of diazotrophs in rhizosphere soils of BS and WYS was similar, which differed significantly from that in SM. The diazotrophic sequences in the three forest farms could be divided into 5 phylum, 8 classes, 15 orders, 23 families and 33 genera, with Proteobacteria, α-proteobacteria, and Bradyrhizobium as the dominant phylotypes. Soil pH, available phosphorus, NO3--N and C:(N:P) ratio were identified as significant factors influencing both the abundance and community structure of nifH genes, with soil pH performing the greatest. Taken together, there were spatial variations in the distribution of diazotrophic abundance and community structure in C. lanceolata rhizosphere soils, with soil pH as the primary driving factor.
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Cunninghamia , Rizosfera , Microbiologia do Solo , Cunninghamia/crescimento & desenvolvimento , China , Solo/química , Nitrogênio/análise , Nitrogênio/metabolismo , Fixação de Nitrogênio , Bactérias Fixadoras de Nitrogênio/metabolismo , Bactérias Fixadoras de Nitrogênio/classificação , Bactérias Fixadoras de Nitrogênio/isolamento & purificação , Bactérias Fixadoras de Nitrogênio/genética , Clima TropicalRESUMO
BACKGROUND: Neoadjuvant immunotherapy with chemotherapy improves outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Given its immunomodulating effect, we investigated whether stereotactic body radiotherapy (SBRT) enhances the effect of immunochemotherapy. METHODS: The SACTION01 study was a single-arm, open-label, phase 2 trial that recruited patients who were 18 years or older and had resectable stage IIA-IIIB NSCLC from the Sun Yat-sen University Cancer Center, Guangzhou, China. Eligible patients received SBRT (24 Gy in three fractions) to the primary tumour followed by two cycles of 200 mg intravenous PD-1 inhibitor, tislelizumab, plus platinum-based chemotherapy. Surgical resection was performed 4-6 weeks after neoadjuvant treatment. The primary endpoint was major pathological response (MPR), defined as no more than 10% residual viable tumour in the resected tumour. All analyses were conducted on an intention-to-treat basis, including all patients who were scheduled for neoadjuvant treatment. The trial was registered with ClinicalTrials.gov (NCT05319574) and is ongoing but closed to recruitment. FINDINGS: Between May 18, 2022, and June 20, 2023, 46 patients (42 men and four women) were enrolled and scheduled for neoadjuvant treatment. MPR was observed in 35 (76%, 95% CI 61-87) of 46 patients. The second cycle of immunochemotherapy was withheld in four (9%) patients due to pneumonia (n=2), colitis (n=1), and increased creatinine (n=1). Grade 3 or worse adverse events related to neoadjuvant treatment occurred in 12 (26%, 95% CI 14-41) patients. The most frequent treatment-related adverse event (TRAE) was alopecia (16 [35%] patients), and the most frequent grade 3 or worse TRAE was neutropenia (six [13%]). There was one treatment-related death, caused by neutropenia. No deaths within 90 days of surgery were reported. INTERPRETATION: Preoperative SBRT followed by immunochemotherapy is well tolerated, feasible, and leads to a clinically significant MPR rate. Future randomised trials are warranted to support these findings. FUNDING: BeiGene.
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The invasion and metastasis of tumors pose significant challenges in the treatment of ovarian cancer (OC), making it difficult to cure. One potential treatment approach that has gained attention is the use of matrix metalloproteinase reactive controlled release micelle preparations. In this study, we developed a novel PEG5000-PVGLIG-hyaluronic acid docetaxel/bakuchiol (PP-HA-DTX/BAK) micelles formulation with desirable characteristics such as particle size, narrow polydispersity index, and a ZETA potential of approximately -5 mV. The surface modification with HA facilitates tumor penetration into the tumor interior, while the incorporation of DSPE-PEG2000-PVGLIG-PEG5000helps conceal DSPE-PEG2000-HA, reducing off-target effects and prolonging drug circulation timein vivo. Bothin vitroandin vivoexperiments demonstrated that these micelles effectively inhibit proliferation, invasion, and metastasis of OC cells while promoting apoptosis. Therefore, our findings suggest that PP-HA-DTX/BAK micelles represent a safe and effective therapeutic strategy for treating OC.
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Docetaxel , Micelas , Invasividade Neoplásica , Neoplasias Ovarianas , Fenóis , Polietilenoglicóis , Docetaxel/química , Docetaxel/farmacologia , Docetaxel/administração & dosagem , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Humanos , Animais , Linhagem Celular Tumoral , Polietilenoglicóis/química , Fenóis/química , Fenóis/farmacologia , Camundongos , Apoptose/efeitos dos fármacos , Ácido Hialurônico/química , Taxoides/química , Taxoides/farmacologia , Taxoides/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Camundongos Nus , Tamanho da Partícula , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Portadores de Fármacos/químicaRESUMO
Continuous dynamic recrystallization (CDRX) is widely acknowledged to occur during hot forming and plays a significant role in microstructure development in alloys with moderate to high stacking fault energy. In this work, the flow stress and CDRX behaviors of the TC18 alloy subjected to hot deformation across a wide range of processing conditions are studied. It is observed that deformation leads to the formation of new low-angle grain boundaries (LAGBs). Subgrains rotate by absorbing dislocations, resulting in an increase in LAGB misorientation and the transition of some LAGBs into high-angle grain boundaries (HAGBs). The HAGBs migrate within the material, assimilating the (sub)grain boundaries. Subsequently, an internal state variable (ISV)-based CDRX model is developed, incorporating parameters such as the dislocation density, adiabatic temperature rise, subgrain rotation, LAGB area, HAGB area, and LAGB misorientation angle distribution. The values of the correlation coefficient (R), relative average absolute error (RAAE), and root-mean-square error (RMSE) between the anticipated true stress and measured stress are 0.989, 6.69%, and 4.78 MPa, respectively. The predicted outcomes demonstrate good agreement with experimental findings. The evolving trends of the subgrain boundary area under various conditions are quantitatively analyzed by assessing the changes in dynamic recovery (DRV)-eliminated dislocations and misorientation angles. Moreover, the ISV-based model accurately predicts the decreases in grain and crystallite sizes with higher strain rates and lower temperatures. The projected outcomes also indicate a transition from a stable and coarse-grained microstructure to a continuously recrystallized substructure.
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Recently, research has confirmed that jasmine tea may help improve the depressive symptoms that are associated with psychiatric disorders. Our team previously found that jasmine tea improved the depressive-like behavior that is induced by chronic unpredictable mild stress (CUMS) in Sprague Dawley (SD) rats. We hypothesized that the metabolic disorder component of depression may be related to the gut microbiota, which may be reflected in the metabolome in plasma. The influence of jasmine tea on gut microbiota composition and the association with depressive-related indexes were explored. Furthermore, the metabolites in plasma that are related to the gut microbiota were identified. SD rats were treated with control or CUMS and administrated jasmine tea for 8 weeks. The 16S rRNA gene amplicon sequencing was used to analyze the gut microbiota in feces samples, and untargeted metabolomics was used to analyze the metabolites in plasma. The results found that jasmine tea significantly ameliorated the depressive behavior induced by CUMS, significantly improved the neurotransmitter concentration (BDNF and 5-HT), and decreased the pro-inflammation levels (TNF-α and NF-κB). The intervention of jasmine tea also alleviated the dysbiosis caused by CUMS; increased the relative abundance of Bacteroides, Blautia, Clostridium, and Lactobacillus; and decreased Ruminococcus and Butyrivibrio in the CUMS-treated rats. Furthermore, the serum metabolites of the CUMS-treated rats were reversed after the jasmine tea intervention, i.e., 22 were up-regulated and 18 were down-regulated, which may have a close relationship with glycerophospholipid metabolism pathways, glycine serine and threonine metabolism pathways, and nicotinate and nicotinamide metabolism pathways. Finally, there were 30 genera of gut microbiota related to the depressive-related indexes, and 30 metabolites in the plasma had a strong predictive ability for depressive behavior. Potentially, our research implies that the intervention of jasmine tea can ameliorate the depression induced by CUMS via controlling the gut flora and the host's metabolism, which is an innovative approach for the prevention and management of depression.
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Toll-like receptor (TLR)7 is a pattern recognition receptor that critically contributes to the pathogenesis of systemic lupus erythematosus (SLE). DS-7011a is an anti-TLR7 monoclonal antibody that prevents TLR7 from signaling. The aim of this first-in-human, double-blind, randomized, and placebo-controlled study was to evaluate the safety, pharmacokinetics, immunogenicity, and pharmacodynamics of single ascending intravenous (IV) and subcutaneous (SC) doses of DS-7011a in healthy subjects (HS) (NCT05203692). On day 1, 80 HS received DS-7011a or placebo 6:2 in 10 cohorts (7 treated IV and 3 SC) of 8 each and were followed for 8 weeks until day 57. Safety was evaluated by recording treatment-emergent adverse events (TEAEs), pharmacokinetics by measuring plasma DS-7011a, immunogenicity by measuring plasma anti-drug antibodies (ADAs), and pharmacodynamics by evaluating the suppression of interleukin-6 production ex vivo in whole blood. DS-7011a was safe and well tolerated across all cohorts. TEAEs were mostly mild in severity and not drug-related. DS-7011a exposure increased with the dose but was not dose proportional, as the elimination of lower doses was accelerated by target-mediated drug disposition. Terminal half-life was about 15-17 days and Tmax upon SC administration was about 5 days. DS-7011a induced ADAs in about half of HS but with no impact on clinical findings and pharmacokinetics. Pharmacodynamic (PD) response also increased with the dose and at the higher doses was of large extent (>90%), early onset, and lasting duration. DS-7011a showed favorable safety, pharmacokinetics, immunogenicity, and PD properties that support its development for the treatment of SLE.
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Introduction: Anti-programmed cell death 1 (PD-1) immunotherapy is the standard of care for metastatic NSCLC but many tumors develop resistance. We hypothesized that combining a T-cell agonist such as varlilumab (anti-CD27 antibody) with checkpoint inhibition may be synergistic and this synergy may be potentiated further by using targeted radiation (RT). Methods: We conducted an open-label, single-center, phase I trial (NCT04081688) to determine the safety and clinical benefit of the atezolizumab and varlilumab in combination with palliative RT in patients with advanced or metastatic NSCLC with progression on prior programmed cell death ligand 1therapy. On day 1 of each 21-day cycle, patients received varlilumab followed by atezolizumab on day 2. RT to a lung lesion was administered between cycle 1 and cycle 2. Results: A total of 15 patients were enrolled (one patient did not start treatment). The median age was 64 years; 10 patients were female. Eight patients (57%) had at least one treatment-related adverse event (AE) and 7 (50%) had at least one grade III or worse treatment-related AE. There was only one grade III immune-related AE requiring steroids (1 diarrhea and colitis); there were no treatment-related deaths. Of the 12 patients evaluable for efficacy, three patients had stable disease (2 with stable disease > 4 mo) and the clinical benefit rate was 25%. The median progression-free survival was two months and the median overall survival was 6.4 months. Conclusions: Varlilumab in combination with atezolizumab and RT was safe and well tolerated; no additional signal was identified for toxicity. Clinical activity for the combination was modest with 25% of patients with stable disease as the best response.