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Drawing inspiration from the jumping mechanisms of insects (e.g., click beetles), bistable structures can convert slow deformations of soft actuating material into fast jumping motions (i.e., power amplification). However, bistable jumpers often encounter large energy barriers for energy release/re-storage, posing a challenge in achieving multimodal (i.e., height/distance) and continuous jumps at the insect scale (body length under 20 mm). Here, a new offset-buckling bistable design is introduced that features antisymmetric equilibrium states and tunable energy barriers. Leveraging this design, a Boundary Actuation Tunable Energy-barrier (BATE) jumper (body length down to 15 mm) is developed, and transform BATE jumper from height-jump mode (up to 12.7 body lengths) to distance-jump mode (up to 20 body lengths). BATE jumpers can perform agile continuous jumping (within 300 ms for energy release/re-storage times) and real-time status detection is further demonstrated. This insect-level performance of the proposed BATE jumper showcases its potential toward future applications in exploration, search, and rescue.
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Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment but has shown limited efficacy in gynecologic cancers. VISTA (V-domain Ig suppressor of T-cell activation), a member of the B7 family, is emerging as another checkpoint that regulates the anti-tumor immune responses within the tumor microenvironment. This paper reviews the structure, expression, and mechanism of action of VISTA. Furthermore, it highlights recent advances in VISTA-blocking therapies and their potential in improving outcomes for patients with gynecologic cancers. By understanding the role of VISTA in mediating the immune evasion of gynecologic tumors, we can develop more effective combinatory treatment strategies that could overcome resistance to current ICB therapies.
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Antígenos B7 , Neoplasias dos Genitais Femininos , Inibidores de Checkpoint Imunológico , Evasão Tumoral , Microambiente Tumoral , Humanos , Neoplasias dos Genitais Femininos/imunologia , Feminino , Antígenos B7/imunologia , Antígenos B7/metabolismo , Microambiente Tumoral/imunologia , Evasão Tumoral/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Animais , Imunoterapia/métodosRESUMO
GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C-like (3CL) protease inhibitor that was recently approved for treating mild to moderate coronavirus disease 2019 patients in China. Since cytochrome P450 (CYP) enzymes, primarily CYP3A, are the main metabolic enzymes of GST-HG171, hepatic impairment may affect its pharmacokinetic (PK) profile. Aiming to guide clinical dosing for patients with hepatic impairment, this study, using a non-randomized, open-label, single-dose design, assessed the impact of hepatic impairment on the PK, safety, and tolerability of GST-HG171. Patients with mild and moderate hepatic impairment along with healthy subjects were enrolled (n = 8 each), receiving a single oral dose of 150 mg GST-HG171, with concurrent administration of 100 mg ritonavir to sustain CYP3A inhibition before and after GST-HG171 administration (-12, 0, 12, and 24 hours). Compared to subjects with normal hepatic function, the geometric least-squares mean ratios (90% confidence intervals) for GST-HG171's maximum plasma concentration (Cmax), area under the concentration-time curve up to the last quantifiable time (AUC0-t), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) in subjects with mild hepatic impairment were 1.14 (0.99, 1.31), 1.07 (0.88, 1.30), and 1.07 (0.88, 1.29), respectively. For moderate hepatic impairment, the ratios were 0.87 (0.70, 1.07), 0.82 (0.61, 1.10), and 0.82 (0.61, 1.10), respectively. Hepatic impairment did not significantly alter GST-HG171's peak time (Tmax) and elimination half-life (T1/2). GST-HG171 exhibited good safety and tolerability in the study. Taken together, mild to moderate hepatic impairment minimally impacted GST-HG171 exposure, suggesting no need to adjust GST-HG171 dosage for patients with mild to moderate hepatic impairment in the clinic.Clinical TrialsRegistered at ClinicalTrials.gov (NCT06106113).
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Inibidores do Citocromo P-450 CYP3A , Fígado , Inibidores de Proteases , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Área Sob a Curva , China , Tratamento Farmacológico da COVID-19 , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Inibidores do Citocromo P-450 CYP3A/farmacocinética , População do Leste Asiático , Fígado/efeitos dos fármacos , Hepatopatias , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/farmacocinética , Ritonavir/efeitos adversos , Ritonavir/farmacocinéticaRESUMO
For either healthy or diseased organisms, lipids are key components for cellular membranes; they play important roles in numerous cellular processes including cell growth, proliferation, differentiation, energy storage and signaling. Exercise and disease development are examples of cellular environment alterations which produce changes in these networks. There are indications that alterations in lipid metabolism contribute to the development and progression of a variety of cancers. Measuring such alterations and understanding the pathways involved is critical to fully understand cellular metabolism. The demands for this information have led to the emergence of lipidomics, which enables the large-scale study of lipids using mass spectrometry (MS) techniques. Mass spectrometry has been widely used in lipidomics and allows us to analyze detailed lipid profiles of cancers. In this article, we discuss emerging strategies for lipidomics by mass spectrometry; targeted, as opposed to global, lipid analysis provides an exciting new alternative method. Additionally, we provide an introduction to lipidomics, lipid categories and their major biological functions, along with lipidomics studies by mass spectrometry in cancer samples. Further, we summarize the importance of lipid metabolism in oncology and tumor microenvironment, some of the challenges for lipodomics, and the potential for targeted approaches for screening pharmaceutical candidates to improve the therapeutic efficacy of treatment in cancer patients.
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Acute inflammation is the body's first defense in response to pathogens or injury that is partially governed by a novel genus of endogenous lipid mediators that orchestrate the resolution of inflammation, coined specialized pro-resolving mediators (SPMs). SPMs, derived from omega-3-polyunstaturated fatty acids (PUFAs), include the eicosapentaenoic acid-derived and docosahexaenoic acid-derived Resolvins, Protectins, and Maresins. Herein, we review their biosynthesis, structural characteristics, and therapeutic effectiveness in various diseases such as ischemia, viral infections, periodontitis, neuroinflammatory diseases, cystic fibrosis, lung inflammation, herpes virus, and cancer, especially focusing on therapeutic effectiveness in respiratory inflammation and ischemia-related injuries. Resolvins are sub-nanomolar potent agonists that accelerate the resolution of inflammation by reducing excessive neutrophil infiltration, stimulating macrophage functions including phagocytosis, efferocytosis, and tissue repair. In addition to regulating neutrophils and macrophages, Resolvins control dendritic cell migration and T cell responses, and they also reduce the pro-inflammatory cytokines, proliferation, and metastasis of cancer cells. Importantly, several lines of evidence have demonstrated that Resolvins reduce tumor progression in melanoma, oral squamous cell carcinoma, lung cancer, and liver cancer. In addition, Resolvins enhance tumor cell debris clearance by macrophages in the tumor's microenvironment. Resolvins, with their unique stereochemical structure, receptors, and biosynthetic pathways, provide a novel therapeutical approach to activating resolution mechanisms during cancer progression.
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Clear cell renal cell carcinoma (ccRCC), the most common type of renal cell carcinoma (RCC), is not sensitive to traditional radiotherapy and chemotherapy. The polyphenolic compound Gallic acid (GA) can be naturally found in a variety of fruits, vegetables and plants. Autophagy, an intracellular catabolic process, regulates the lysosomal degradation of organelles and portions in cytoplasm. It was reported that autophagy and GA could affect the development of several cancers. Therefore, the aim of the present study was to evaluate the effects of GA on ccRCC development and clarify the role of autophagy in this process. In the present study, the effects of GA on the proliferation, migration and invasion of ccRCC cells were investigated in vitro by Cell Counting Kit8, colony formation, flow cytometry, wound healing and Transwell migration assays, respectively. Additionally, the effects of GA on ccRCC growth and metastasis were evaluated using hematoxylineosin and immunohistochemical staining in vivo. Moreover, it was sought to explore the underlying molecular mechanisms using transmission electron microscopy, western blotting and reverse transcriptionquantitative PCR analyses. In the present study, it was revealed that GA had a more potent viability inhibitory effect on ccRCC cells (786O and ACHN) than the effect on normal renal tubular epithelial cell (HK2), which demonstrated that GA selectively inhibits the viability of cancer cells. Furthermore, it was identified that GA dosedependently inhibited the proliferation, migration and invasion of ccRCC cells in vitro and in vivo. It was demonstrated that GA promoted the release of autophagy markers, which played a role in regulating the PI3K/Akt/Atg16L1 signaling pathway. All the aforementioned data provided evidence for the great potential of GA in the treatment of ccRCC.
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Proteínas Relacionadas à Autofagia , Autofagia , Carcinoma de Células Renais , Movimento Celular , Proliferação de Células , Ácido Gálico , Neoplasias Renais , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Humanos , Ácido Gálico/farmacologia , Autofagia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Movimento Celular/efeitos dos fármacos , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Progressão da Doença , Masculino , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Transporte/metabolismoRESUMO
T cells are often absent from human cancer tissues during both spontaneously induced immunity and therapeutic immunotherapy, even in the presence of a functional T cell-recruiting chemokine system, suggesting the existence of T cell exclusion mechanisms that impair infiltration. Using a genome-wide in vitro screening platform, we identified a role for phospholipase A2 group 10 (PLA2G10) protein in T cell exclusion. PLA2G10 up-regulation is widespread in human cancers and is associated with poor T cell infiltration in tumor tissues. PLA2G10 overexpression in immunogenic mouse tumors excluded T cells from infiltration, resulting in resistance to anti-PD-1 immunotherapy. PLA2G10 can hydrolyze phospholipids into small lipid metabolites, thus inhibiting chemokine-mediated T cell mobility. Ablation of PLA2G10's enzymatic activity enhanced T cell infiltration and sensitized PLA2G10-overexpressing tumors to immunotherapies. Our study implicates a role for PLA2G10 in T cell exclusion from tumors and suggests a potential target for cancer immunotherapy.
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Neoplasias , Linfócitos T , Regulação para Cima , Animais , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Fosfolipases A/imunologia , Fosfolipases A/genética , Fosfolipases A2/imunologia , Linfócitos T/imunologia , Regulação para Cima/imunologiaRESUMO
Background: GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C like protease inhibitor that has demonstrated greater potency and efficacy compared to Nirmatrelvir in pre-clinical studies. We aimed to evaluate the efficacy and safety of orally administered GST-HG171 plus Ritonavir in patients with coronavirus disease 2019 (COVID-19) infected with emerging XBB and non-XBB variants. Methods: This randomised, double-blind, placebo-controlled phase 2/3 trial was conducted in 47 sites in China among adult patients with mild-to-moderate COVID-19 with symptoms onset ≤72 h. Eligible patients were randomised 1:1 to receive GST-HG171 (150 mg) plus Ritonavir (100 mg) or corresponding placebo tablets twice daily for 5 days, with stratification factors including the risk level of disease progression and vaccination status. The primary efficacy endpoint was time to sustained recovery of clinical symptoms within 28 days, defined as a score of 0 for 11 COVID-19-related target symptoms for 2 consecutive days, assessed in the modified intention-to-treat (mITT) population. This trial was registered at ClinicalTrials.gov (NCT05656443) and Chinese Clinical Trial Registry (ChiCTR2200067088). Findings: Between Dec 19, 2022, and May 4, 2023, 1525 patients were screened. Among 1246 patients who underwent randomisation, most completed basic (21.2%) or booster (74.9%) COVID-19 immunization, and most had a low risk of disease progression at baseline. 610 of 617 who received GST-HG171 plus Ritonavir and 603 of 610 who received placebo were included in the mITT population. Patients who received GST-HG171 plus Ritonavir showed shortened median time to sustained recovery of clinical symptoms compared to the placebo group (13.0 days [95.45% confidence interval 12.0-15.0] vs. 15.0 days [14.0-15.0], P = 0.031). Consistent results were observed in both SARS-CoV-2 XBB (45.7%, 481/1053 of mITT population) and non-XBB variants (54.3%, 572/1053 of mITT population) subgroups. Incidence of adverse events was similar in the GST-HG171 plus Ritonavir (320/617, 51.9%) and placebo group (298/610, 48.9%). The most common adverse events in both placebo and treatment groups were hypertriglyceridaemia (10.0% vs. 14.7%). No deaths occurred. Interpretation: Treatment with GST-HG171 plus Ritonavir has demonstrated benefits in symptom recovery and viral clearance among low-risk vaccinated adult patients with COVID-19, without apparent safety concerns. As most patients were treated within 2 days after symptom onset in our study, confirming the potential benefits of symptom recovery for patients with a longer duration between symptom onset and treatment initiation will require real-world studies. Funding: Fujian Akeylink Biotechnology Co., Ltd.
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Purpose: Dysregulated expression of microRNA (miRNAs) in lung cancer has been wildly reported. The clinicopathologic significance of miR-9-5p in non-small-cell lung cancer (NSCLC) patients and its effect on NSCLC progression were explored in this study. Patients and methods: A total of 76 NSCLC patients were included. miR-9-5p expression was evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Then, in vitro experiments including cell growth curve assays, colony formation assays, and transwell migration assays were performed. Further clinicopathological and prognostic values were explored using bioinformatics analysis of the TCGA database. Results: miR-9-5p expression was significantly increased in tumor tissues (both P < 0.0001). miR-9-5p expression was relatively higher in larger tumors (P = 0.0327) and in lung squamous carcinoma (LUSC) (P = 0. 0143). In addition, miR-9-5p was significantly upregulated in the normal lung tissues of cigarette smokers (P = 0.0099). In vitro, miR-9-5p was correlated with cell proliferation and migration. After that, bioinformatics analysis of the TCGA database indicated that miR-9-5p was correlated with tumor size (P = 0.0022), lymphatic metastasis (P = 0.0141), LUSC (P < 0.0001), and smoking history (P < 0.0001). Finally, a prognostic study indicated high miR-9-5p expression was correlated with poor prognosis in LUAD (P = 0.0121). Conclusion: Upregulation of miR-9-5p may have an oncogenic effect in NSCLC and may be related to smoking. The conclusion of this study may help find new prognostic and therapeutic targets for NSCLC and the exploration of the relationship between smoking and lung cancer.
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Recent research has revealed that airway epithelial calcium-activated chloride channel-1 (CLCA1) is implicated in the inflammation of multiple human respiratory diseases, but the specific role in acute respiratory distress syndrome (ARDS) remains unknown. To investigate the role of CLCA1 in ARDS, 80 participants, including 26 ARDS patients, 26 patients with community-acquired pneumonia (CAP) and 28 control subjects, were enrolled in this study. As the result shows, the level of CLCA1 was significantly increased in ARDS patients and positively correlated with neutrophil infiltration and the poor prognosis of ARDS. Then, the level of CLCA1 also elevated in the LPS-induced ARDS mouse model, and the administration of CLCA1 significantly regulated the phenotypes of ARDS in mice, such as lung injury score, BALF protein concentration, neutrophils infiltration and the secretions of inflammatory factors. Furthermore, administration of CLCA1 substantially altered the phosphorylation of p38 in the ARDS mouse model, whereas repressing the expression of CLCA1 or inhibiting the activation of p38 both alleviated the inflammatory response of ARDS. In summary, CLCA1 was notably correlated with ARDS and exacerbated the ARDS phenotypes through the p38 MAPK pathway.
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Pneumonia , Síndrome do Desconforto Respiratório , Animais , Camundongos , Canais de Cloreto/metabolismo , Lipopolissacarídeos , Pulmão/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno , Pneumonia/metabolismo , Síndrome do Desconforto Respiratório/genética , HumanosRESUMO
Alfalfa (Medicago sativa) is a perennial forage legume that is widely distributed all over the world; therefore, it has an extremely complex genetic background. Though population structure and phylogenetic studies have been conducted on a large group of alfalfa nuclear genomes, information about the chloroplast genomes is still lacking. Chloroplast genomes are generally considered to be conservative and play an important role in population diversity analysis and species adaptation in plants. Here, 231 complete alfalfa chloroplast genomes were successfully assembled from 359 alfalfa resequencing data, on the basis of which the alfalfa chloroplast pan-genome was constructed. We investigated the genetic variations of the alfalfa chloroplast genome through comparative genomic, genetic diversity, phylogenetic, population genetic structure, and haplotype analysis. Meanwhile, the expression of alfalfa chloroplast genes under cold stress was explored through transcriptome analysis. As a result, chloroplast genomes of 231 alfalfa lack an IR region, and the size of the chloroplast genome ranges from 125,192 bp to 126,105 bp. Using population structure, haplotypes, and construction of a phylogenetic tree, it was found that alfalfa populations could be divided into four groups, and multiple highly variable regions were found in the alfalfa chloroplast genome. Transcriptome analysis showed that tRNA genes were significantly up-regulated in the cold-sensitive varieties, while rps7, rpl32, and ndhB were down-regulated, and the editing efficiency of ycf1, ycf2, and ndhF was decreased in the cold-tolerant varieties, which may be due to the fact that chloroplasts store nutrients through photosynthesis to resist cold. The huge number of genetic variants in this study provide powerful resources for molecular markers.
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Genoma de Cloroplastos , Medicago sativa , Medicago sativa/genética , Filogenia , Perfilação da Expressão Gênica , Cloroplastos/genéticaRESUMO
BACKGROUND: A substantial number of patients with bladder cancer fail to benefit from immune checkpoint inhibitors (ICIs). We aim to investigate whether the addition of other therapeutic modalities into immunotherapy may augment the immune reactivity, thereby improving the overall response rate. METHODS: We conducted a comprehensive assessment of the immunological changes following immunotherapy and chemotherapy, employing both single-cell RNA sequencing and bulk RNA sequencing analyses. RESULTS: The bladder cancer patient treated with ICIs exhibited a higher abundance of B cells and T follicular helper cells compared to the treatment-naïve patient. Analysis of public datasets and the in-house RJBLC-I2N003 cohort revealed the induction of tertiary lymphoid structure (TLS) neogenesis and maturation by immunotherapy. The IMvigor 210 study suggested that TLS could serve as a predictor of immunotherapy response and patient prognosis. In addition, genome-wide transcriptome data unveiled a shift towards the immune-enriched subtype over the desert subtype in patients receiving neoadjuvant chemotherapy. Notably, the proportions of CD20 + B cells, T follicular helper cells, and TLSs were significantly increased. In patients treated with a combination of neoadjuvant chemotherapy and ICIs, TLS positivity and maturity were improved compared to the baseline. Furthermore, neoadjuvant chemoimmunotherapy resulted in a higher rate of pathological complete response compared to monotherapies. CONCLUSIONS: This work pinpointed the individual effect of immunotherapy and chemotherapy in fostering TLS development, and underscored the superior effectiveness of combined modalities in enhancing TLS maturation and response rates.
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Estruturas Linfoides Terciárias , Neoplasias da Bexiga Urinária , Humanos , Imunoterapia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária , Linfócitos B , Microambiente Tumoral , PrognósticoRESUMO
BACKGROUND: Addison's disease (AD) is a rare but potentially fatal disease in Western countries, which can easily be misdiagnosed at an early stage. Severe adrenal tuberculosis (TB) may lead to depression in patients. CASE SUMMARY: We report a case of primary adrenal insufficiency secondary to adrenal TB with TB in the lungs and skin in a 48-year-old woman. The patient was misdiagnosed with depression because of her depressed mood. She had hyperpigmentation of the skin, nails, mouth, and lips. The final diagnosis was adrenal TB that resulted in the insufficient secretion of adrenocortical hormone. Adrenocortical hormone test, skin biopsy, T cell spot test of TB, and adrenal computed tomography scan were used to confirm the diagnosis. The patient's condition improved after hormone replacement therapy and TB treatment. CONCLUSION: Given the current status of TB in high-burden countries, outpatient doctors should be aware of and pay attention to TB and understand the early symptoms of AD.
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Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics, such as targeted therapy and immunotherapy, including anti-programmed cell death protein (anti-PD) therapy. We demonstrate that programmed death-1 homolog (PD-1H), an immune coinhibitory molecule, is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells express PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell-mediated immune responses. Importantly, ablation of AML cell-surface PD-1H by antibody blockade or genetic knockout significantly inhibited AML progression by promoting T cell activity. In addition, the genetic deletion of PD-1H from host normal myeloid cells inhibited AML progression, and the combination of PD-1H blockade with anti-PD therapy conferred a synergistic antileukemia effect. Our findings provide the basis for PD-1H as a potential therapeutic target for treating human AML.
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Evasão da Resposta Imune , Leucemia Mieloide Aguda , Animais , Humanos , Camundongos , Medula Óssea , Imunidade Celular , Imunoterapia , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
This study is aimed to evaluate the safety, tolerability, and pharmacokinetics (PK), as well as to select an appropriate dosing regimen for the pivotal clinical trial of GST-HG171, an orally bioavailable, potent, and selective 3CL protease inhibitor by a randomized, double-blind, and placebo-controlled phase I trial in healthy subjects. We conducted a Ph1 study involving 78 healthy subjects to assess the safety, tolerability, and PK of single ascending doses (150-900 mg) as well as multiple ascending doses (MADs) (150 and 300 mg) of GST-HG171. Additionally, we examined the food effect and drug-drug interaction of GST-HG171 in combination with ritonavir through a MAD regimen of GST-HG171/ritonavir (BID or TID) for 5 days. Throughout the course of these studies, no serious AEs or deaths occurred, and no AEs necessitated study discontinuation. We observed that food had no significant impact on the exposure of GST-HG171. However, the presence of ritonavir substantially increased the exposure of GST-HG171, which facilitated the selection of the GST-HG171/ritonavir dose and regimen (150/100 mg BID) for subsequent phase II/III trials. The selected dose regimen was achieved through concentrations continuously at 6.2-9.9-fold above the levels required for protein-binding adjusted 50% inhibition (IC50) of viral replication in vitro. The combination of 150 mg GST-HG171/100 mg ritonavir demonstrated favorable safety and tolerability profiles. The PK data obtained from GST-HG171/ritonavir administration guided the selection of appropriate dose for a pivotal phase II/III trial currently in progress. (This study has been registered at ClinicalTrials.gov under identifier NCT05668897).
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COVID-19 , Ritonavir , Humanos , Ritonavir/uso terapêutico , Interações Medicamentosas , Antivirais/uso terapêutico , Administração Oral , Método Duplo-Cego , Relação Dose-Resposta a DrogaRESUMO
BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well as astrocyte-microglia interaction, which both contribute to evolution of NMOSD lesions. MAIN BODY: Through transcriptomic and flow cytometry analyses, we found that Bruton's tyrosine kinase (BTK), a crucial protein of B-cell receptor was upregulated both in the blood and cerebrospinal fluid of NMOSD patients. Blockade of BTK with zanubrutinib, a highly specific BTK inhibitor, mitigated the activation and maturation of B cells and reduced production of causal aquaporin-4 (AQP4) autoantibodies. In a mouse model of NMO, we found that both BTK and pBTK expression were significantly increased in microglia. Transmission electron microscope scan demonstrated that BTK inhibitor ameliorated demyelination, edema, and axonal injury in NMO mice. In the same mice colocalization of GFAP and Iba-1 immunofluorescence indicated a noticeable increase of astrocytes-microglia interaction, which was alleviated by zanubrutinib. The smart-seq analysis demonstrated that treatment with BTK inhibitor instigated microglial transcriptome changes including downregulation of chemokine-related genes and genes involved in the top 5 biological processes related to cell adhesion and migration, which are likely responsible for the reduced crosstalk of microglia and astrocytes. CONCLUSIONS: Our results show that BTK activity is enhanced both in B cells and microglia and BTK inhibition contributes to the amelioration of NMOSD pathology. These data collectively reveal the mechanism of action of BTK inhibition and corroborate BTK as a viable therapeutic target.
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Neuromielite Óptica , Animais , Humanos , Camundongos , Tirosina Quinase da Agamaglobulinemia/metabolismo , Aquaporina 4 , Linfócitos B/metabolismo , Microglia/metabolismo , Neuromielite Óptica/patologia , Receptores de Antígenos de Linfócitos B/metabolismoRESUMO
FcRγ-deficient natural killer (NK) cells, designated as g-NK cells, exhibit enhanced antibody-dependent cellular cytotoxicity (ADCC) capacity and increased IFN-γ and TNF-α production, rendering them promising for antiviral and antitumor responses. g-NK cells from peripheral blood (PB) are often associated with prior human cytomegalovirus (HCMV) infection. However, the prevalence, phenotype, and function of g-NK cells in umbilical cord blood (UCB-g-NK) remain unclear. Here, we demonstrate significant phenotypical differences between UCB-g-NK and PB-g-NK cells. Unlike PB-g-NK cells, UCB-g-NK cells did not show heightened cytokine production upon CD16 engagement, in contrast to the conventional NK (c-NK) cell counterparts. Interestingly, following in vitro activation, UCB-g-NK cells also exhibited elevated levels of IFN-γ production, particularly when co-cultured with HCMV and plasma from g-NK+ adults. Furthermore, g-NK+ plasma from PB even facilitated the in vitro expansion of UCB-g-NK cells. These findings underscore the phenotypic and functional heterogeneity of g-NK cells based on their origin and demonstrate that components within g-NK+ plasma may directly contribute to the acquisition of an adult phenotype by the "immature" UCB-g-NK cells.
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Sangue Fetal , Ativação Linfocitária , Adulto , Humanos , Células Matadoras Naturais , Citotoxicidade Celular Dependente de Anticorpos , CitomegalovirusRESUMO
Extracting muscle synergies from surface electromyographic signals (sEMGs) during exercises has been widely applied to evaluate motor control strategies. This study explores the relationship between upper-limb muscle synergies and the performance of joystick manipulation tasks. Seventy-seven subjects, divided into three classes according to their maneuvering experience, were recruited to perform the left and right reciprocation of the joystick. Based on the motion encoder data, their manipulation performance was evaluated by the mean error, standard deviation, and extreme range of position of the joystick. Meanwhile, sEMG and acceleration signals from the upper limbs corresponding to the entire trial were collected. Muscle synergies were extracted from each subject's sEMG data by non-negative matrix factorization (NMF), based on which the synergy coordination index (SCI), which indicates the size of the synergy space and the variability of the center of activity (CoA), evaluated the temporal activation variability. The synergy pattern space and CoA of all participants were calculated within each class to analyze the correlation between the variability of muscle synergies and the manipulation performance metrics. The correlation level of each class was further compared. The experimental results evidenced a positive correlation between manipulation performance and maneuvering experience. Similar muscle synergy patterns were reflected between the three classes and the structure of the muscle synergies showed stability. In the class of rich maneuvering experience, the correlation between manipulation performance metrics and muscle synergy is more significant than in the classes of trainees and newbies, suggesting that long-term training and practicing can improve manipulation performance, stability of synergy compositions, and temporal activation variability but not alter the structure of muscle synergies determined by a specific task. Our approaches and findings could be applied to 1) reduce manipulation errors, 2) assist maneuvering training and evaluation to enhance transportation safety, and 3) design technical support for sports.
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Influenza vaccines faced significant challenges in achieving sufficient protective efficacy and production efficiency in the past. In recent decades, novel influenza vaccines, characterized by efficient and scalable production, advanced platforms, and new adjuvant technologies, have overcome some of these weaknesses and have been widely licensed. Furthermore, researchers are actively pursuing the development of next-generation and universal influenza vaccines to provide comprehensive protection against potential pandemic subtypes or strains. However, new challenges have emerged as these novel vaccines undergo evaluation and authorization. In this review, we primarily outline the critical challenges and advancements in research and development (R&D) and highlight the improvements in regulatory responses for influenza vaccines.
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Levels of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) are useful biomarkers of disease activity and disability in neuromyelitis optica spectrum disorder (NMOSD). Here we investigated the association of sNfL and sGFAP levels with brain and spinal cord volumes in patients with NMOSD. Fifteen patients with NMOSD were enrolled in this prospective study. The median baseline level of sNfL was 42.2 (IQR, 16.1-72.6) pg/mL and decreased to 8.5 (IQR, 7.4-16.6) pg/mL at the end of the study. The reduction in sNfL was associated with a 7.5% loss of cervical spinal cord volume (CSCV) (p = 0.001). The levels of sGFAP reduced from 239.2 (IQR, 139.0-3393.3) pg/mL at baseline to 108.5 (IQR, 74.2-154.6) pg/mL. However, there was no strong correlation between sGFAP levels and CSCV changes during the follow-up period. Our data suggested that sNfL level is a useful biomarker for predicting spinal cord atrophy in patients with NMOSD.