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1.
Heliyon ; 10(7): e28469, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38560267

RESUMO

There is mounting evidence that coronavirus disease 2019 (COVID-19) can cause immune dysregulation. The consequence of this immune dysregulation may contribute to susceptibility to tuberculosis (TB). Thyroid gland involvement by TB is extremely uncommon and typically the result of disseminated infection. It can be hard to diagnose because there are no identifiable symptoms. We present the case of a Chinese patient who had a fever again after COVID-19 infection that was finally diagnosed as thyroid tuberculosis with a cold abscess. Clinicians should maintain a high index of suspicion for high-risk patients from endemic regions with medical comorbidities, such as immunocompromised disease and malnutrition.

2.
Adv Sci (Weinh) ; : e2305715, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38417117

RESUMO

Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non-canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP-DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP-DILI. Mice with hepatocyte-specific rescue of GSDME reproduced APAP-induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP-induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte-derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte-specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon-stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase-1 (CPS1), promoted its degradation via K48-linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl-fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP-DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP-DILI.

3.
Viruses ; 16(2)2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38399984

RESUMO

The interaction between migratory birds and domestic waterfowl facilitates viral co-infections, leading to viral reassortment and the emergence of novel viruses. In 2022, samples were collected from duck farms around Poyang Lake in Jiangxi Province, China, which is located within the East Asia-Australasia flyway. Three strains of H4N6 avian influenza virus (AIV) were isolated. Genetic and phylogenetic analyses showed that the isolated H4N6 avian influenza viruses (AIVs) belonged to new genotypes, G23 and G24. All isolated strains demonstrated dual receptor binding properties. Additionally, the isolated strains were able to replicate efficiently not only in avian cells but also in mammalian cells. Furthermore, the H4N6 AIV isolates could infect chickens, with viral replication detected in the lungs and extrapulmonary organs, and could transmit within chicken flocks through contact, with viral shedding detected only in oropharyngeal swabs from chickens in the contact group. Notably, the H4N6 AIV could infect mice without prior adaptation and replicate in the lungs with high viral titers, suggesting that it is a potential threat to humans. In conclusion, this study provides valuable insight into the characteristics of H4N6 strains currently circulating in China.


Assuntos
Vírus da Influenza A , Influenza Aviária , Animais , Camundongos , Galinhas , China , Patos , Mamíferos , Filogenia
4.
ACS Appl Mater Interfaces ; 16(8): 9702-9712, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38363797

RESUMO

Magnetic resonance angiography (MRA) contrast agents are extensively utilized in clinical practice due to their capability of improving the image resolution and sensitivity. However, the clinically approved MRA contrast agents have the disadvantages of a limited acquisition time window and high dose administration for effective imaging. Herein, albumin-coated gadolinium-based nanoparticles (BSA-Gd) were meticulously developed for in vivo ultrahigh-resolution MRA. Compared to Gd-DTPA, BSA-Gd exhibits a significantly higher longitudinal relaxivity (r1 = 76.7 mM-1 s-1), nearly 16-fold greater than that of Gd-DTPA, and an extended blood circulation time (t1/2 = 40 min), enabling a dramatically enhanced high-resolution imaging of microvessels (sub-200 µm) and low dose imaging (about 1/16 that of Gd-DTPA). Furthermore, the clinically significant fine vessels were successfully mapped in large mammals, including a circle of Willis, kidney and liver vascular branches, tumor vessels, and differentiated arteries from veins using dynamic contrast-enhanced MRA BSA-Gd, and have superior imaging capability and biocompatibility, and their clinical applications hold substantial promise.


Assuntos
Angiografia por Ressonância Magnética , Nanopartículas , Animais , Angiografia por Ressonância Magnética/métodos , Gadolínio DTPA , Meios de Contraste , Gadolínio , Imageamento por Ressonância Magnética/métodos , Mamíferos
5.
J Transl Med ; 22(1): 212, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38419050

RESUMO

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is known for abnormal lipid metabolism and widespread activation of HIF-2α. Recently, the importance of autophagy in ccRCC has been focused, and it has potential connections with HIF-2α and lipid metabolism. However, the specific regulatory mechanism between HIF-2α, autophagy, and lipid metabolism in ccRCC is still unclear. METHODS: In this study, Bioinformatics Analysis and Sequencing of the whole transcriptome were used to screen our target. The expression of TBC1D5 in renal clear cell carcinoma was confirmed by database analysis, immunohistochemistry, PCR and Western blot. The effects of TBC1D5 on tumor cell growth, migration, invasion and lipid metabolism were examined by CCK8, Transwell and oil red staining, and the mechanism of TBC1D5 on autophagy was investigated by Western blot, fluorescence microscopy and electron microscopy. Chloroquine and rapamycin were used to verified the key role of autophagy in effects of TBC1D5 on tumor cell. The regulatory mechanism of TBC1D5 in renal clear cell carcinoma (RCC) was investigated by shhif-2α, shTBC1D5, mimic, inhibitor, ChIP and Luciferase experiments. The animal model of ccRCC was used to evaluate the biological function of TBC1D5 in vivo. RESULTS: In this study, TBC1D5 was found to be an important bridge between autophagy and HIF-2α. Specifically, TBC1D5 is significantly underexpressed in ccRCC, serving as a tumor suppressor which inhibits tumor progression and lipid accumulation, and is negatively regulated by HIF-2α. Further research has found that TBC1D5 regulates the autophagy pathway to reverse the biological function of HIF-2α in ccRCC. Mechanism studies have shown that HIF-2α regulates TBC1D5 through hsa-miR-7-5p in ccRCC, thereby affecting tumor progression and lipid metabolism through autophagy. CONCLUSIONS: Our research reveals a completely new pathway, HIF-2α/hsa-miR-7-5p/TBC1D5 pathway affects ccRCC progression and lipid metabolism by regulating autophagy.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Animais , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Metabolismo dos Lipídeos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica
6.
Neural Netw ; 172: 106125, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38320348

RESUMO

Graph Contrastive Learning (GCL) is increasingly employed in graph representation learning with the primary aim of learning node/graph representations from a predefined pretext task that can generalize to various downstream tasks. Meanwhile, the transition from a specific pretext task to diverse and unpredictable downstream tasks poses a significant challenge for GCL's generalization ability. Most existing GCL approaches maximize mutual information between two views derived from the original graph, either randomly or heuristically. However, the generalization ability of GCL and its theoretical principles are still less studied. In this paper, we introduce a novel metric GCL-GE, to quantify the generalization gap between predefined pretext and agnostic downstream tasks. Given the inherent intractability of GCL-GE, we leverage concepts from information theory to derive a mutual information upper bound that is independent of the downstream tasks, thus enabling the metric's optimization despite the variability in downstream tasks. Based on the theoretical insight, we propose InfoAdv, a GCL framework to directly enhance generalization by jointly optimizing GCL-GE and InfoMax. Extensive experiments validate the capability of InfoAdv to enhance performance across a wide variety of downstream tasks, demonstrating its effectiveness in improving the generalizability of GCL.


Assuntos
Teoria da Informação , Aprendizagem , Generalização Psicológica
7.
Environ Sci Pollut Res Int ; 31(10): 15746-15758, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38305974

RESUMO

The transition from paraquat (PQ) to diquat (DQ), both organic dication herbicides, in China has led to significant increases in the number of acute DQ poisoning cases. Case studies have shown that acute DQ poisoning resulted in injury to the central nervous system (CNS), but the mechanism underlying the injury remains to be explored. The present study aimed to investigate how DQ influenced purinergic signaling between astrocytes and microglia and whether extracellular ATP (eATP) was involved in promoting neuroinflammation induced by acute DQ toxicity through the activation of the P2X4/NLRP3 signaling pathway. We constructed a rat model of acute DQ toxicity to observe the pathological changes in hippocampal tissues after DQ exposure and measure the expression levels of IL-1ß and TNF-α in the hippocampal tissue. We also established an in vitro co-culture model of C6 astrocytes and BV-2 microglia using transwell chambers, measured the amount of eATP secreted into C6 astrocytes after DQ treatment, and assessed the inflammatory response and changes in the P2X4/NLRP3 signaling pathway in BV-2 microglia. The results showed that the neurons in the hippocampal tissue of rats exhibited loose arrangement, nuclear consolidation, and necrosis after DQ exposure, and IL-1ß and TNF-α levels were signification higher in the hippocampal tissue after DQ exposure. DQ exposure to the co-cultured cells induced an increase in ATP secretion from C6 astrocytes as well as a significant increase of P2X4, NLRP3, IL-1ß, and IL-18 expression in BV-2 microglia. In contrast, pretreatment of C6 astrocytes with apyrase (an ATP hydrolase) resulted in a significant decrease of P2X4, NLRP3, IL-1ß, and IL-18 expression in BV-2 microglia. Furthermore, inhibition of P2X4 expression in BV-2 microglia by transfection with si-P2X4 effectively reversed the increase of NLRP3, IL-1ß, and IL-18 in BV-2 microglia induced by DQ when co-cultured with C6 astrocytes. These results indicate that astrocytes can activate the P2X4/NLRP3 signaling pathway in microglia through the DQ-induced extracellular release of ATP to promote neuroinflammation in rat hippocampal tissue.


Assuntos
Astrócitos , Microglia , Ratos , Animais , Microglia/metabolismo , Astrócitos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-18/farmacologia , Diquat , Doenças Neuroinflamatórias , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-1beta/metabolismo , Trifosfato de Adenosina/metabolismo , Hipocampo/metabolismo
8.
Spectrochim Acta A Mol Biomol Spectrosc ; 311: 124038, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38364516

RESUMO

Paper-based analytical devices (PADs) integrated with smartphones have shown great potential in various fields, but they also face challenges such as single signal reading, complex data processing and significant environmental impacting. In this study, a colorimetric PAD platform has been proposed using bimetallic nickel-cobalt selenides as highly active peroxidase mimic, smartphone with 3D-printing dark-cavity as a portable detector and an artificial neural network (ANN) model as multi-signal processing tool. Notably, the optimized nickel-cobalt selenides (Ni0.75Co0.25Se with Ni to Co ratio of 3/1) exhibit excellent peoxidase-mimetic activities and are capable of catalyzing the oxidation of four chromogenic reagents in the presence of H2O2. Using a smartphone with image capture function as a friendly signal readout tool, the Ni0.75Co0.25Se based four channel colorimetric sensing paper is used for multi-signal quantitative analysis of H2O2 by determining the Grey, red (R), green (G) and blue (B) channel values of the captured pictures. An intelligent on-site detection method for H2O2 has been constructed by combining an ANN model and a self-programmed easy-to-use smartphone APP with a dynamic range of 5 µM to 2 M. Noteworthy, machine learning-assisted smartphone sensing devices based on nanozyme and 3D printing technology provide new insights and universal strategies for visual ultrasensitive detection in a variety of fields, including environments monitoring, biomedical diagnosis and safety screening.


Assuntos
Níquel , Smartphone , Peróxido de Hidrogênio/análise , Colorimetria/métodos , Cobalto
9.
Artigo em Chinês | MEDLINE | ID: mdl-38297849

RESUMO

Objective:This study aims to analyze the threshold changes in distortion product otoacoustic emissions(DPOAE) and auditory brainstem response(ABR) in adult Otof-/- mice before and after gene therapy, evaluating its effectiveness and exploring methods for assessing hearing recovery post-treatment. Methods:At the age of 4 weeks, adult Otof-/- mice received an inner ear injection of a therapeutic agent containing intein-mediated recombination of the OTOF gene, delivered via dual AAV vectors through the round window membrane(RWM). Immunofluorescence staining assessed the proportion of inner ear hair cells with restored otoferlin expression and the number of synapses.Statistical analysis was performed to compare the DPOAE and ABR thresholds before and after the treatment. Results:AAV-PHP. eB demonstrates high transduction efficiency in inner ear hair cells. The therapeutic regimen corrected hearing loss in adult Otof-/- mice without impacting auditory function in wild-type mice. The changes in DPOAE and ABR thresholds after gene therapy are significantly correlated at 16 kHz. Post-treatment,a slight increase in DPOAE was observeds,followed by a recovery trend at 2 months post-treatment. Conclusion:Gene therapy significantly restored hearing in adult Otof-/- mice, though the surgical delivery may cause transient hearing damage. Precise and gentle surgical techniques are essential to maximize gene therapy's efficacy.


Assuntos
Orelha Interna , Perda Auditiva , Camundongos , Animais , Emissões Otoacústicas Espontâneas/fisiologia , Audição/fisiologia , Perda Auditiva/genética , Perda Auditiva/terapia , Terapia Genética , Limiar Auditivo/fisiologia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Proteínas de Membrana
10.
Hortic Res ; 11(1): uhad258, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38298899

RESUMO

Scutellaria baicalensis Georgi, also known as huang-qin in traditional Chinese medicine, is a widely used herbal remedy due to its anticancer, antivirus, and hepatoprotective properties. The S. baicalensis genome was sequenced many years ago; by contrast, the proteome as the executer of most biological processes of S. baicalensis in the aerial parts, as well as the secondary structure of the roots (xylem, phloem, and periderm), is far less comprehensively characterized. Here we attempt to depict the molecular landscape of the non-model plant S. baicalensis through a multi-omics approach, with the goal of constructing a highly informative and valuable reference dataset. Furthermore, we provide an in-depth characterization dissection to explain the two distinct flavonoid biosynthesis pathways that exist in the aerial parts and root, at the protein and phosphorylated protein levels. Our study provides detailed spatial proteomic and phosphoproteomic information in the context of secondary structures, with implications for the molecular profiling of secondary metabolite biosynthesis in non-model medicinal plants.

11.
Carbohydr Polym ; 331: 121910, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38388046

RESUMO

Herein, we introduced a liquid-metal/polymerisable deep eutectic solvent (LM/PDES) system to the carboxymethyl cellulose (CMC) and acrylic acid solution to prepare a double-cross-linked CMC-polyacrylic acid (PAA)-LM/PDES superabsorbent hydrogel via graft crosslinking polymerisation for 5 min. FTIR and XRD provided evidence for the coordinate crosslinking between Ga3+ and carboxy groups in the CMC-PAA-LM/PDES gel structure and chemical crosslinking between CMC and PAA components. The pore size of the obtained hydrogels gradually decreases with the increase of LM-AA/PDES content. The rigid CMC polysaccharide chains increased the distance between the ionic groups on the flexible PAA molecular chains, resulting in high osmotic pressure. In addition, the synergistic effects of hydrophilic groups, electrostatic repulsion, macroporous structures and double crosslinking on the CMC and PAA structures provided a driving force and space for the gel to absorb electrolyte containing liquid. The absorption capacity of the CMC-PAA-LM/PDES gel for physiological saline reached 97 g/g, which exceeded that of a single cross-linked CMC-PAA gel and a reported superabsorbent material (71 g/g). This work solved the problem of long heating times and insufficient mechanical properties for the preparation of superabsorbent gels, providing a theoretical reference for improving the absorption capacity of superabsorbent materials for electrolyte-containing aqueous solutions.

12.
Cell Signal ; 117: 111104, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38373667

RESUMO

BACKGROUND: Anoikis is a distinctive type of apoptosis. It is involved in tumor progression and metastasis. But its function in castration-resistant prostate cancer (CRPC) remains veiled. We aimed to develop a prognostic indicator based on anoikis-related long non-coding RNAs (arlncRNAs) and to investigate their biological function in CRPC. MATERIAL AND METHOD: Differentially expressed anoikis-related genes were extracted from two CRPC datasets, GSE51873, and GSE78201. Four lncRNAs associated with the anoikis-related genes were selected. A risk model based on these lncRNAs was developed and validated in The Cancer Genome Atlas (TCGA) and the Memorial Sloan-Kettering Cancer Center (MSKCC) prostate cancer cohorts. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, immune infiltration, immune checkpoints expression, and drug susceptibility were performed based on the model. To identify the biofunction of anoikis-related lncRNA, CCK-8 assays, colony formation assays, and flow cytometry were used. RESULT: Twenty-nine anoikis-related genes were differentially expressed in the CRPC datasets. And 36 prognostic arlncRNAs were selected for the LASSO Cox analysis. Patients were subsequently classified into two subtypes by constructing an anoikis-related lncRNA based prognostic index (ARPI). The accuracy of this index was validated. KEGG enrichment analysis revealed that the high-ARPI group was enriched in cancer-related and immune-related pathways. Immune infiltration analysis has indicated a positive association between high-ARPI groups and increased immune infiltration. Fulvestrant, OSI-027, Lapatinib, Dabrafenib, and Palbociclib were identified as potential sensitive drugs for high-ARPI patients. In vitro experiments exhibited that silencing LINC01138 dampened the proliferation, migration and enzalutamide resistance in CRPC. Furthermore, it stimulated apoptosis and inhibited the eithelial-mesenchymal transition process. CONCLUSION: Four arlncRNAs were identified and a risk model was established to predict the prognosis of patients with prostate cancer. Immune infiltration and drug susceptibility analysis revealed a potential therapeutic strategy for patients with castration-resistant prostate cancer.


Assuntos
Neoplasias de Próstata Resistentes à Castração , RNA Longo não Codificante , Masculino , Humanos , Anoikis/genética , RNA Longo não Codificante/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Citometria de Fluxo , Expressão Gênica
13.
Psychoneuroendocrinology ; 163: 106984, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38340540

RESUMO

PURPOSE: This prospective cohort study aimed to investigate the effect of maternal polycystic ovary syndrome (PCOS) on the offspring early development. METHODS: A total of 91 mother-child pairs, consisting of 33 PCOS and 58 non-PCOS, were recruited. Peripheral blood tests were performed during 12-16, 24-28, and 32-36 weeks of gestation. Ages & Stages Questionnaires (ASQ) were utilized to assess the motor development of offspring at 27 months of age. Logistic regression models were employed to compare groups and control confounding variables. RESULTS: Women with PCOS had a higher level of testosterone and free androgen index than the non-PCOS group in all three detection windows. There were no intergroup differences in any of the five domains of specific ASQ domain scores or the body measurements of the offspring at 27 months old. Stratification by sex of offspring suggested that no significant differences were detected in the male offspring. However, in the female offspring, the PCOS group exhibited lower gross motor scores in female offspring than the non-PCOS group (48.1 ± 11.8 vs. 55.2 ± 8.1, P = 0.027), as well as lower fine motor scores (48.5 ± 8.5 vs. 53.6 ± 11.0, P = 0.028). The gross motor score of female offspring in the PCOS group remained lower even after adjustments. Each 1 ng/mL increase in testosterone at 12-16 weeks of gestation was associated with a decrease in gross motor score of female offspring by 12.2 (95% CI = -23.3 to -1.0, P = 0.038). The highest tertile of testosterone at 12-16 weeks of gestation was associated with a 7.75-point decrease in gross motor score of female offspring compared to the lowest tertile of testosterone (95% CI = -14.9 to -0.6, P = 0.040), with a significant linear trend observed (P for trend = 0.031). CONCLUSIONS: The findings of this study suggest that maternal PCOS could exert a negative influence on the gross motor development of female offspring, potentially associated with intrauterine androgen exposure during the early stages of pregnancy.


Assuntos
Síndrome do Ovário Policístico , Gravidez , Humanos , Masculino , Feminino , Pré-Escolar , Estudos de Coortes , Androgênios , Estudos Prospectivos , Testosterona
14.
Pharmacol Ther ; 256: 108610, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38367868

RESUMO

Accumulating evidence indicates that epigenetic events undergo deregulation in various cancer types, playing crucial roles in tumor development. Among the epigenetic factors involved in the epigenetic remodeling of chromatin, the chromodomain helicase DNA-binding protein (CHD) family frequently exhibits gain- or loss-of-function mutations in distinct cancer types. Therefore, targeting CHD remodelers holds the potential for antitumor treatment. In this review, we discuss epigenetic regulations of cancer development. We emphasize proteins in the CHD family, delving deeply into the intricate mechanisms governing their functions. Additionally, we provide an overview of current therapeutic strategies targeting CHD family members in preclinical trials. We further discuss the promising approaches that have demonstrated early signs of success in cancer treatment.


Assuntos
Cromatina , Neoplasias , Humanos , DNA Helicases/genética , DNA Helicases/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Mutação , Proteínas de Ligação a DNA/metabolismo , Montagem e Desmontagem da Cromatina , Epigênese Genética
15.
Biomedicines ; 12(1)2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38255301

RESUMO

NKG2D is an activating receptor expressed by all human NK cells and CD8 T cells. Harnessing the NKG2D/NKG2D ligand axis has emerged as a viable avenue for cancer immunotherapy. However, there is a long-standing controversy over whether soluble NKG2D ligands are immunosuppressive or immunostimulatory, originating from conflicting data generated from different scopes of pre-clinical investigations. Using multiple pre-clinical tumor models, we demonstrated that the impact of the most characterized human solid tumor-associated soluble NKG2D ligand, the soluble MHC I chain-related molecule (sMIC), on tumorigenesis depended on the tumor model being studied and whether the tumor cells possessed stemness-like properties. We demonstrated that the potential of tumor formation or establishment depended upon tumor cell stem-like properties irrespective of tumor cells secreting the soluble NKG2D ligand sMIC. Specifically, tumor formation was delayed or failed if sMIC-expressing tumor cells expressed low stem-cell markers; tumor formation was rapid if sMIC-expressing tumor cells expressed high stem-like cell markers. However, once tumors were formed, overexpression of sMIC unequivocally suppressed tumoral NK and CD8 T cell immunity and facilitated tumor growth. Our study distinguished the differential impacts of soluble NKG2D ligands in tumor formation and tumor progression, cleared the outstanding controversy over soluble NKG2D ligands in modulating tumor immunity, and re-enforced the viability of targeting soluble NKG2D ligands for cancer immunotherapy for established tumors.

16.
Cell Signal ; 116: 111060, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38242269

RESUMO

The mammalian target of rapamycin complex1 (mTORC1) can response to amino acid to regulate metabolism and cell growth. GATOR2 act as important role in amino acid mediated mTORC1 signaling pathway by repressing GTPase activity (GAP) of GATOR1. However, it is still unclear how GATOR2 regulates mTORC1 signaling pathway. Here, we found that K63-ubiquitination of Sce13, one component of GATOR2, suppresses the mTORC1 activity by lessening the inter-interaction of GATOR2. Mechanistically, the ubiquitination of Sec13 was mediated by SPOP. Subsequently, the ubiquitination of Sec13 attenuated its interaction with the other component of GATOR2, thus suppressing the activity of mTORC1. Importantly, the deficiency of SPOP promoted the faster proliferation and migration of breast cancer cells, which was attenuated by knocking down of Sec13. Therefore, SPOP can act as a tumor suppressor gene by negatively regulating mTORC1 signaling pathway.


Assuntos
Aminoácidos , Serina-Treonina Quinases TOR , Ciclo Celular , Proliferação de Células , Alvo Mecanístico do Complexo 1 de Rapamicina
17.
Lancet ; 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38280389

RESUMO

BACKGROUND: Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9. METHODS: This single-arm, single-centre trial enrolled children (aged 1-18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing. FINDINGS: Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 1011 vector genomes [vg] and five received 1·5 × 1012 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1-2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40-57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5-4·0 kHz. In the participant who received the 9 × 1011 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 1012 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery. INTERPRETATION: AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality, and Shanghai Refreshgene Therapeutics.

18.
J Hepatocell Carcinoma ; 11: 95-111, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38250306

RESUMO

Purpose: Transarterial chemoembolization (TACE) represents a significant therapeutic modality for hepatocellular carcinoma (HCC). We aimed to develop a gene signature to accurately predict patient TACE response and explore the underlying mechanisms. Methods: Three independent datasets were utilized, including GSE104580, GSE14520 and external validation from the Cancer Hospital Chinese Academy of Medical Sciences. GSE104580 was randomly partitioned into a training set and a validation set, whereas GSE14520 was categorized into a resection group and a TACE group. Logistic regression was used to develop a TACE effectiveness model. Immunohistochemistry is utilized to confirm the protein expression trends of the signature genes. Immune infiltration and functional enrichment analyses were conducted to investigate the potential underlying mechanisms. Results: A 2-gene signature consisting of glycine N-methyltransferase (GNMT) and matrix metalloproteinase-12 (MMP12) was constructed, and based on this, all the patients were assigned TACE effectiveness scores and categorized into high effectiveness (HE) and low effectiveness (LE) groups. The HE group exhibited a better prognosis than the LE group in the various cohorts (p < 0.05). In the external validation set, immunohistochemistry confirmed the expression of the signature genes exhibiting an upregulated trend of GNMT in the HE group and MMP12 in the LE group, the LE group also exhibited a poorer prognosis [for overall survival (OS), HE group: 881 days vs LE group: 273 days (p < 0.05), and for progression-free survival (PFS), HE group: 458 days vs LE group: 136 days (p < 0.05)]. Multivariate analysis in all the datasets identified LE status as an independent risk factor for OS, disease-free survival (DFS) and PFS. The infiltration level of M0 macrophages and activated mast cells in the LE group was significantly higher than in the HE group. The hypoxia signaling pathway and glycolysis pathway were significantly enriched in the LE group. Conclusion: The loss of GNMT and the overexpression of MMP12 may be critical factors influencing TACE efficacy.

19.
Adv Mater ; : e2311970, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38198824

RESUMO

[4-(3,6-dimethyl-9H-carbazol-9yl)butyl]phosphonic acid (Me-4PACz) self-assembled molecules (SAM) are an effective method to solve the problem of the buried interface of NiOx in inverted perovskite solar cells (PSCs). However, the Me-4PACz end group (carbazole core) cannot forcefully passivate defects at the bottom of the perovskite film. Here, a Co-SAM strategy is employed to modify the buried interface of PSCs. Me-4PACz is doped with phosphorylcholine chloride (PC) to form a Co-SAM to improve the monolayer coverage and reduce leakage current. The phosphate group and chloride ions (Cl- ) in PC can inhibit NiOx surface defects. Meantime, the quaternary ammonium ions and Cl- in PC can fill organic cations and halogen vacancies in the perovskite film to enable defects passivation. Moreover, Co-SAM can promote the growth of perovskite crystals, collaboratively solve the problem of buried defects, suppress nonradiative recombination, accelerate carrier transmission, and relieve the residual stress of the perovskite film. Consequently, the Co-SAM modified devices show power conversion efficiencies as high as 25.09% as well as excellent device stability with 93% initial efficiency after 1000 h of operation under one-sun illumination. This work demonstrates the novel approach for enhancing the performance and stability of PSCs by modifying Co-SAM on NiOx .

20.
Int J Surg Pathol ; 32(1): 104-108, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37016968

RESUMO

Melanosis of the urinary bladder, so-called melanosis vesicae, is a rare condition characterized by dark, velvety bladder mucosa observed by cystoscopy examination. Up to 20 examples have been reported in the English literature, and the etiology of this disease still needs to be discovered. We present an 82-year-old woman with a history of pelvic organ prolapse-associated urinary symptoms. The patient was found to have pigmented urinary bladder mucosa on cystoscopy and underwent a total hysterectomy and bladder mucosal biopsy. Histologically, pigmented granules were evident in the bladder stroma and epithelium, highlighted by Periodic Acid-Schiff (PAS) stain, suggestive of lipofuscin in nature. We outline the diagnostic features of bladder melanosis, discuss the diagnostic mimickers, and thoroughly review the literature on the subject.


Assuntos
Melanose , Doenças da Bexiga Urinária , Neoplasias da Bexiga Urinária , Feminino , Humanos , Idoso de 80 Anos ou mais , Bexiga Urinária/cirurgia , Bexiga Urinária/patologia , Doenças da Bexiga Urinária/diagnóstico , Doenças da Bexiga Urinária/cirurgia , Doenças da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/patologia , Melanose/diagnóstico , Melanose/patologia , Cistoscopia
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