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The combination of the phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor zandelisib with the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib was hypothesized to be synergistic and prevent resistance to single-agent therapy. This phase 1 study (NCT02914938) included a dose-finding stage in patients with relapsed/refractory (R/R) B-cell malignancies (n = 20) and disease-specific expansion cohorts in follicular lymphoma (FL; n = 31) or mantle cell lymphoma (MCL; n = 19). The recommended phase 2 dose was zandelisib 60 mg on Days 1-7 plus zanubrutinib 80 mg twice daily continuously in 28-day cycle. In the total population, the most common adverse events (AEs; all grades/grade 3-4) were neutropenia (35%/24%), diarrhoea (33%/2%), thrombocytopenia (32%/8%), anaemia (27%/8%), increased creatinine (25%/0%), contusion (21%/0%), fatigue (21%/2%), nausea (21%/2%) and increased aspartate aminotransferase (24%/6%). Three patients discontinued due to AEs. The overall response rate was 87% (complete response [CR] = 33%) for FL and 74% (CR = 47%) for MCL. The median duration of response and progression-free survival (PFS) were not reached in either group. The estimated 1-year PFS was 72.3% (95% confidence interval [CI], 51.9-85.1) for FL and 56.3% (95% CI, 28.9-76.7) for MCL (median follow-up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone.
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Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Folicular , Linfoma de Célula do Manto , Pirazóis , Pirimidinas , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/mortalidade , Pirimidinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Adulto , Tiazóis/efeitos adversos , Tiazóis/administração & dosagem , Tiazóis/uso terapêutico , Idoso de 80 Anos ou mais , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Resultado do Tratamento , PiperidinasRESUMO
In this study, super-resolution structured illumination microscope (SIM) was used to analyze molecular mechanism of endocytic acidification inhibitors in the SARS-CoV-2 pandemic, such as Chloroquine (CQ), Hydroxychloroquine (HCQ) and Bafilomycin A1 (BafA1). We fluorescently labeled the SARS-CoV-2 RBD and its receptor ACE2 protein with small molecule dyes. Utilizing SIM imaging, the real-time impact of inhibitors (BafA1, CQ, HCQ, Dynasore) on the RBD-ACE2 endocytotic process was dynamically tracked in living cells. Initially, the protein activity of RBD and ACE2 was ensured after being labeled. And then our findings revealed that these inhibitors could inhibit the internalization and degradation of RBD-ACE2 to varying degrees. Among them, 100â nM BafA1 exhibited the most satisfactory endocytotic inhibition (~63.9 %) and protein degradation inhibition (~97.7 %). And it could inhibit the fusion between endocytic vesicles in the living cells. Additionally, Dynasore, a widely recognized dynein inhibitor, also demonstrated cell acidification inhibition effects. Together, these inhibitors collectively hinder SARS-CoV-2 infection by inhibiting both the viral internalization and RNA release. The comprehensive evaluation of pharmacological mechanisms through super-resolution fluorescence imaging has laid a crucial theoretical foundation for the development of potential drugs to treat COVID-19.
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Enzima de Conversão de Angiotensina 2 , Tratamento Farmacológico da COVID-19 , Cloroquina , Endossomos , Hidrazonas , Hidroxicloroquina , Macrolídeos , SARS-CoV-2 , SARS-CoV-2/efeitos dos fármacos , Endossomos/metabolismo , Endossomos/efeitos dos fármacos , Humanos , Cloroquina/farmacologia , Cloroquina/química , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Macrolídeos/farmacologia , Macrolídeos/química , Hidroxicloroquina/farmacologia , Hidroxicloroquina/química , Hidrazonas/farmacologia , Hidrazonas/química , Endocitose/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , COVID-19/virologia , COVID-19/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Concentração de Íons de Hidrogênio , Internalização do Vírus/efeitos dos fármacos , Chlorocebus aethiopsRESUMO
BACKGROUND AND PURPOSE: The aim was to investigate the causal relationships of inflammatory cytokines and serum metabolites in cerebral small vessel disease (CSVD). METHODS: Bidirectional Mendelian randomization was first conducted to screen inflammatory cytokines and serum metabolites that were associated with imaging features of CSVD, including white matter hyperintensities, recent small subcortical infarcts, cortical cerebral microinfarcts, cerebral microbleeds, lacunes and enlarged perivascular spaces. Sensitivity analyses were performed to evaluate the robustness and pleiotropy of these results. Subsequently, inflammatory cytokines and serum metabolites that were associated with CSVD were subjected to functional enrichment. Finally, mediation analysis was employed to investigate whether inflammatory cytokines or serum metabolites acted as an intermediary for the other in their causal relationship with CSVD. RESULTS: Of the inflammatory cytokines, five were risk factors (e.g., tumour-necrosis-factor-related apoptosis-inducing ligand) and five (e.g., fibroblast growth factor 19) were protective factors for CSVD. Eleven serum metabolites that increased CSVD risk and 13 metabolites that decreased CSVD risk were also identified. The majority of these markers of CSVD susceptibility were lipid metabolites. Natural killer cell receptor sub-type 2B4 was determined to act as a mediating factor of an unidentified metabolite for the enlargement of perivascular spaces. CONCLUSION: Several inflammatory cytokines and serum metabolites had causal relationships with imaging features of CSVD. A natural killer cell receptor mediated in part the promotional effect of a metabolite on perivascular space enlargement.
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Oxidative stress has been considered to be closely related to spaceflight-induced bone loss; however, mechanism is elusive and there are no effective countermeasures. Using cultured rat calvarial osteoblasts exposed to microgravity simulated by a random positioning machine, this study addressed the hypotheses that microgravity-induced shortening of primary cilia leads to oxidative stress and that primary cilium protection prevents oxidative stress and osteogenesis loss. Microgravity was found to induce oxidative stress (as represented by increased levels of reactive oxygen species (ROS) and malondialdehyde production, and decreased activities of antioxidant enzymes), which was perfectly replicated in osteoblasts growing in NG with abrogated primary cilia (created by transfection of an interfering RNA), suggesting the possibility that shortening of primary cilia leads to oxidative stress. Oxidative stress was accompanied by mitochondrial dysfunction (represented by increased mitochondrial ROS and decreased mitochondrial membrane potential) and intracellular Ca2+ overload, and the latter was found to be caused by increased activity of Ca2+ channel transient receptor potential vanilloid 4 (TRPV4), as also evidenced by TRPV4 agonist GSK1016790A-elicited Ca2+ influx. Supplementation of HC-067047, a specific antagonist of TRPV4, attenuated microgravity-induced mitochondrial dysfunction, oxidative stress, and osteogenesis loss. Although TRPV4 was found localized in primary cilia and expressed at low levels in NG, microgravity-induced shortening of primary cilia led to increased TRPV4 levels and Ca2+ influx. When primary cilia were protected by miR-129-3p overexpression or supplementation with a natural flavonoid moslosooflavone, microgravity-induced increased TRPV4 expression, mitochondrial dysfunction, oxidative stress, and osteogenesis loss were all prevented. Our data revealed a new mechanism that primary cilia function as a controller for TRPV4 expression. Microgravity-induced injury on primary cilia leads to increased expression and overactive channel of TRPV4, causing intracellular Ca2+ overload and oxidative stress, and primary cilium protection could be an effective countermeasure against microgravity-induced oxidative stress and loss of osteogenic potential of osteoblasts.
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Cílios , Osteoblastos , Osteogênese , Estresse Oxidativo , Canais de Cátion TRPV , Ausência de Peso , Animais , Ratos , Cílios/metabolismo , Osteoblastos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Células Cultivadas , Morfolinas/farmacologia , Pirróis/farmacologia , GravitaçãoRESUMO
BACKGROUND: Intestinal obstruction caused by endometriosis maybe easily misdiagnosed as a tumor or other occupying disease in emergency condition. How to deal with it depending on the clarity of the preoperative diagnosis and the experience of the surgeon. CASE PRESENTATION: A 47-year-old woman, admitted to our emergency service with abdominal pain and distension for 5 days, anal stop exhausting and defecating for 3 days. Based on imaging and laboratory examination, we made a preoperative diagnosis of rectal endometriosis probably. After 7 days of colon decompression with a intestinal obstruction catheter, an operation of laparoscopic partial rectal and sigmoid resection without protective stoma and total hysterectomy was performed successfully. The patient obtained a smooth postoperative course and doing well after 12-weeks follow up. CONCLUSIONS: Obstruction caused by rectal endometriosis is very rare and easily overlooked by surgeon and gynecologist. Appropriate preoperative diagnosis and preoperative management can reduce the trauma and incidence of complications.
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Endometriose , Obstrução Intestinal , Laparoscopia , Doenças Retais , Colo Sigmoide/cirurgia , Endometriose/complicações , Endometriose/diagnóstico , Endometriose/cirurgia , Feminino , Humanos , Obstrução Intestinal/diagnóstico , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Laparoscopia/métodos , Pessoa de Meia-Idade , Doenças Retais/complicações , Doenças Retais/diagnóstico , Doenças Retais/cirurgiaRESUMO
Macroporous resin chromatography, silica gel column chromatography, preparative thin layer chromatography, and semi-preparative high performance liquid chromatography were performed to isolate two compounds from the acid extract of the lateral roots of Aconitum carmichaelii: a new 9-phenylisoquinoline alkaloid(1) and a known pavine alkaloid(2). Their structures were elucidated by spectroscopy. The absolute configuration of compound 1 was identified by electronic circular dichroism(ECD) and it was determined to be(aS)-7,8-dimethoxy-9-(2-carboxy-4,5-dimethoxyphenyl)-3,4-dihydroisoquinoline-1(2H)-one(1). The cardioprotective effects of 1 and 2 against doxorubicin-induced toxicity in H9 c2 cells were evaluated. Both of the isoquinoline alkaloids showed cardioprotective activity.
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Aconitum , Alcaloides , Medicamentos de Ervas Chinesas , Aconitum/química , Alcaloides/análise , Alcaloides/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Raízes de Plantas/químicaRESUMO
The visualization of self-assembled structure and dynamics at the molecular level has become a powerful method to understand structure-function relationships of self-assembly. Herein, we in situ real-time imaged the dynamic process of benzyl-naphthalimide dyes at the nanoscale and inspected their internal structure with minimum 2.8â nm localization accuracy through single-molecule localization microscopy (SMLM) imaging. We monitored the growth process of three different assemblies in situ, which possessed highly heterogeneous dynamics with different shapes and growth rates. Furthermore, diverse growth rates were also found at different sites in the same assembly. These results highlight the application of super-resolution microscopy techniques for real-time visualization of internal assembled structure and dynamics in situ.
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Corantes Fluorescentes , Imagem Individual de Molécula , Corantes Fluorescentes/química , Microscopia , Imagem Individual de Molécula/métodosRESUMO
KEY MESSAGE: The physical locations of citrus centromere are revealed by combining genetic and immunological assays for the first time and nine citrus centromere-specific markers for cytogenetics are mined. Centromere localization is challenging, because highly redundant repetitive sequences in centromeric regions make sequence assembly difficult. Although several citrus genomes have been released, the centromeric regions and their characteristics remain to be elucidated. Here, we mapped citrus centromeres through half-tetrad analysis (HTA) that included the genotyping of 54 tetraploid hybrids derived from 2n megagametophytes of Nadorcott tangor with 212 single nucleotide polymorphism (SNP) markers. The sizes of centromeric regions, which estimated based on the heterozygosity restitution rate pattern along the chromosomes, ranged from 1.12 to 18.19 Mb. We also profiled the binding sequences with the centromere-specific histone variant CenH3 by chromatin immunoprecipitation sequencing (ChIP-seq). Based on the positions of the top ten CenH3-enriched contigs, the sizes of centromeric regions were estimated to range from 0.01 to 7.60 Mb and were either adjacent to or included in the centromeric regions identified by HTA. We used DNA probes from two repeats selected from the centromeric regions and seven CenH3-binding centromeric repeats to verify centromeric locations by fluorescence in situ hybridization (FISH). Centromere localization in citrus will contribute to the mining of centromeric/pericentromeric markers, thus to facilitate the rapid identification of mechanisms underlying 2n gamete formation and serve the polyploidy breeding.
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Centrômero/genética , Citrus/genética , Citogenética/métodos , Especificidade de Anticorpos , Sequenciamento de Cromatina por Imunoprecipitação , Genes de Plantas/imunologia , Técnicas de Genotipagem/métodos , Hibridização in Situ Fluorescente , Polimorfismo de Nucleotídeo Único , TetraploidiaRESUMO
This study investigated the therapeutic effects of a water-soluble biphenyl compound, WLP-S-14, in acute-on-chronic liver failure (ACLF). Wistar rats were injected intraperitoneally with porcine serum twice a week for 8 weeks prior to administration of 600 mg/kg D-galactosamine and 50 µg/kg lipopolysaccharide to induce ACLF. Study groups were treated intravenously with saline or with 100 or 200 mg/kg WLP-S-14. WLP-S-14 ameliorated ACLF with significant reductions in the mortality rate and transaminase levels, indicating improved liver function. The mechanism underlying these effects may involve decreased levels of tumor necrosis factor-α and interleukin-6, with associated inhibition of apoptotic pathways.
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Compostos de Bifenilo/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Animais , Compostos de Bifenilo/química , Galactosamina/toxicidade , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Estrutura Molecular , Distribuição Aleatória , Ratos , Ratos Wistar , SoroRESUMO
Fuzi is a well-known traditional Chinese medicine developed from the lateral roots of Aconitum carmichaelii Debx. It is rich in alkaloids that display a wide variety of bioactivities, and it has a strong cardiotoxicity and neurotoxicity. In order to discriminate the geographical origin and evaluate the quality of this medicine, a method based on high-performance liquid chromatography (HPLC) was developed for multicomponent quantification and chemical fingerprint analysis. The measured results of 32 batches of Fuzi from three different regions were evaluated by chemometric analysis, including similarity analysis (SA), hierarchical cluster analysis (HCA), principal component analysis (PCA), and linear discriminant analysis (LDA). The content of six representative alkaloids of Fuzi (benzoylmesaconine, benzoylhypaconine, benzoylaconine, mesaconitine, hypaconitine, and aconitine) were varied by geographical origin, and the content ratios of the benzoylmesaconine/mesaconitine and diester-type/monoester-type diterpenoid alkaloids may be potential traits for classifying the geographical origin of the medicine. In the HPLC fingerprint similarity analysis, the Fuzi from Jiangyou, Sichuan, was distinguished from the Fuzi from Butuo, Sichuan, and the Fuzi from Yunnan. Based on the HCA and PCA analyses of the content of the six representative alkaloids, all of the batches were classified into two categories, which were closely related to the plants' geographical origins. The Fuzi samples from Jiangyou were placed into one category, while the Fuzi samples from Butuo and Yunnan were put into another category. The LDA analysis provided an efficient and satisfactory prediction model for differentiating the Fuzi samples from the above-mentioned three geographical origins. Thus, the content of the six representative alkaloids and the fingerprint similarity values were useful markers for differentiating the geographical origin of the Fuzi samples.
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Aconitum/química , Alcaloides/química , Raízes de Plantas/química , Cromatografia Líquida de Alta Pressão , Análise por Conglomerados , Análise Discriminante , Análise de Componente PrincipalRESUMO
Androgen receptor (AR) variants (AR-Vs) expressed in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR-Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo. Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chromatin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa.
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Cromatina/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Próstata/genética , Receptores Androgênicos/metabolismo , Ativação Transcricional/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Azepinas/farmacologia , Benzamidas , Linhagem Celular , Linhagem Celular Tumoral , Dimerização , Masculino , Camundongos Nus , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/genética , Elementos de Resposta , Triazóis/farmacologiaRESUMO
Our immune system uses toxicity of hydrogen peroxide to kill off bacterial invaders. In this contribution, we intended to integrate ROS producing capability of immune system with oxidant-sensitive nature of antibacterial silver nanoparticles (Ag NPs) to develop an oxidant drug delivery system. Prior to execute this strategy, we have developed an efficient one-pot synthetic protocol to produce ultrasmall (5 nm), water-stable, and oxidant-prone Ag NPs. Notably, the yield of as-synthesized Ag NPs is 10-fold higher than standard citrate reduction route. The resulting therapeutically active and well-dispersed Ag NPs are used as nanolids to cap the drug loaded nanochannels of porous silica. Upon exposing to H2O2, dissolution-accompanied aggregation of Ag nanolids unleashes the encapsulated therapeutic entities from channels of nanocarrier. Combination of antibacterial and anti-inflammatory drugs in single nanocarriers can potentially augment the effectiveness of various therapies.
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Portadores de Fármacos/química , Peróxido de Hidrogênio/química , Nanopartículas Metálicas/química , Oxidantes/química , Prata/química , Modelos Moleculares , Conformação Molecular , Óxido Nítrico/química , Porosidade , Dióxido de Silício/químicaRESUMO
Stable Protein One (SP1) is a boiling-stable oligomeric protein. The unique characteristics of SP1 offer a scaffold to design artificial enzymes against extreme temperature. Here, an efficient antioxidase is successfully constructed on the ring-shaped SP1 homododecamer. By means of computational design and genetic engineering, the active center of glutathione peroxidase (GPx), selenocysteine (Sec), is introduced to the SP1 monomer surface, and the self-assembly properties of the protein monomer lead to a ring-shaped SP1 with homododecamer catalytic selenium centers. This artificial selenoenzyme exhibits high GPx catalytic activity and shows a typical ping-pong kinetic mechanism. Moreover, it has a significantly broader temperature range and high thermostability. Owing to having multi-GPx active centers on a SP1 oligomer, this selenium-containing biomacromolecule exerts an excellent capability to protect cells from oxidative damage at the mitochondrial level. This strategy represents a new way to develop thermostable artificial nanoenzymes for some specific applications.
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Glutationa Peroxidase/metabolismo , Nanoestruturas/química , Biocatálise , Engenharia Genética , Glutationa Peroxidase/química , Glutationa Peroxidase/genética , Cinética , Modelos Moleculares , Mutagênese Sítio-Dirigida , Estabilidade Proteica , Teoria Quântica , Selenocisteína/química , Selenocisteína/genética , Selenocisteína/metabolismo , TemperaturaRESUMO
A Ca(2+) -responsive artificial selenoenzyme was constructed by computational design and engineering of recoverin with the active center of glutathione peroxidase (GPx). By combining the recognition capacity for the glutathione (GSH) substrate and the steric orientation of the catalytic selenium moiety, the engineered selenium-containing recoverin exhibits high GPx activity for the catalyzed reduction of H2 O2 by glutathione (GSH). Moreover, the engineered selenoenzyme can be switched on/off by Ca(2+) -induced allosterism of the protein recoverin. This artificial selenoenzyme also displays excellent antioxidant ability when it was evaluated using a mitochondrial oxidative damage model, showing great potential for controlled catalysis in biomedical applications.
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Antioxidantes/química , Cálcio/química , Glutationa Peroxidase/química , Recoverina/química , Selenocisteína/química , Antioxidantes/farmacologia , Sítios de Ligação , Catálise , Peróxido de Hidrogênio/química , Selênio/químicaRESUMO
BACKGROUND: Aberrant expression of tumor protein D52 (TPD52) is associated with some tumors. The role of TPD52 in uterine corpus endometrial carcinoma (UCEC) remains uncertain. OBJECTIVE: We aimed to investigate the involvement of TPD52 in the pathogenesis of UCEC. METHODS: We employed bioinformatics analysis and experimental validation in our study. RESULTS: Our findings indicated that elevated TPD52 expression in UCEC was significantly associated with various clinical factors, including clinical stage, race, weight, body mass index (BMI), histological type, histological grade, surgical approach, and age (p < 0.01). Furthermore, high TPD52 expression was a predictor of poorer overall survival (OS), progress-free survival (PFS), and disease-specific survival (DSS) (p = 0.011, p = 0.006, and p = 0.003, respectively). TPD52 exhibited a significant correlation with DSS (HR: 2.500; 95% CI: 1.153-5.419; p = 0.02). TPD52 was involved in GPCR ligand binding and formation of the cornified envelope in UCEC. Moreover, TPD52 expression was found to be associated with immune infiltration, immune checkpoints, tumor mutation burden (TMB)/ microsatellite instability (MSI), and mRNA stemness indices (mRNAsi). The somatic mutation rate of TPD52 in UCEC was 1.9%. A ceRNA network of AC011447.7/miR-1-3p/TPD52 was constructed. There was excessive TPD52 protein expression. The upregulation of TPD52 expression in UCEC cell lines was found to be statistically significant. CONCLUSION: TPD52 is upregulated in UCEC and may be a useful patent for prognostic biomarkers of UCEC, which may have important value for clinical treatment and supervision of UCEC patients.
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Patients with thymoma (THYM)-associated myasthenia gravis (MG) typically have a poor prognosis and recurring illness. This study aimed to discover important biomarkers associated with immune cell infiltration and THYM-associated MG (THYM-MG) development. Gene expression microarray data were downloaded from The Cancer Genome Atlas website (TCGA) and Gene Expression Omnibus (GEO). A total of 102 differentially expressed genes were investigated. According to the immune infiltration data, the distribution of Tfh cells, B cells, and CD4 T cells differed significantly between the THYM-MG and THYM-NMG groups. WGCNA derived 25 coexpression modules; one hub module (the blue module) strongly correlated with Tfh cells. Combining differential genes revealed 21 intersecting genes. LASSO analysis subsequently revealed 16 hub genes as potential THYM-MG biomarkers. ROC curve analysis of the predictive model revealed moderate diagnostic value. The association between the 16 hub genes and infiltrating immune cells was further evaluated in TIMER2.0 and the validation dataset. Draggability analysis identified the therapeutic target genes PTGS2 and ALB, along with significant drugs including Firocoxib, Alclofenac, Pyridostigmine, and Stavudine. This was validated through MD simulation, PCA, and MM-GBSA analyses. The interaction between numerous activated B cells and follicular helper T cells is closely associated with THYM-MG pathogenesis from a bioinformatics perspective. Hub genes (including SP6, SCUBE3, B3GNT7, and MAGEL2) may be downregulated in immune cells in THYM-MG and associated with progression.
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Male animals often display higher levels of aggression than females. However, the neural circuitry mechanisms underlying this sexually dimorphic aggression remain elusive. Here, we identify a hypothalamic-amygdala circuit that mediates male-biased aggression in mice. Specifically, the ventrolateral part of the ventromedial hypothalamus (VMHvl), a sexually dimorphic region associated with eliciting male-biased aggression, projects densely to the posterior substantia innominata (pSI), an area that promotes similar levels of attack in both sexes of mice. Although the VMHvl innervates the pSI unidirectionally through both excitatory and inhibitory connections, it is the excitatory VMHvl-pSI projections that are strengthened in males to promote aggression, whereas the inhibitory connections that reduce aggressive behavior are strengthened in females. Consequently, the convergent hypothalamic input onto the pSI leads to heightened pSI activity in males, resulting in male-biased aggression. Our findings reveal a sexually distinct excitation-inhibition balance of a hypothalamic-amygdala circuit that underlies sexually dimorphic aggression.
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In this global phase 2 study in patients with relapsed/refractory follicular lymphoma (FL), zandelisib was administered on intermittent dosing to mitigate immune-related adverse events and infections that have been reported with oral PI3Kδ inhibitors administered daily continuously. Eligible patients with measurable disease and progression after at least two prior therapies were administered zandelisib until disease progression or intolerability. The primary efficacy endpoint was objective response rate (ORR) and the key secondary efficacy endpoint was duration of response (DOR). We report on 121 patients with FL administered zandelisib on intermittent dosing after 8 weeks of daily dosing for tumor debulking. The median number of prior therapies was 3 (range, 2-8) and 45% of patients had refractory disease. The ORR was 73% (95% confidence interval [CI], 63.9-80.4), the complete response (CR) rate was 38% (95% CI, 29.3-47.3), and the median DOR was 16.4 months (95% CI, 9.5-not reached). With a median follow-up of 14.3 months (range, 1-30.5), the median progression-free survival was 11.6 months (95% CI, 8.3-not reached). Twenty-one patients (17%) discontinued therapy due to an adverse event. Grade 3-4 class-related toxicities included 6% diarrhea, 5% lung infections, 3% colitis (confirmed by biopsy or imaging), 3% rash, 2% AST elevation, and 1% non-infectious pneumonitis. Zandelisib achieved a high rate of durable responses in heavily pretreated patients with relapsed/refractory FL. The intermittent dosing resulted in a relatively low incidence of severe class-related toxicities, which supports the evaluation of zandelisib as a single agent and in combination with indolent B-cell malignancies.
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Protein self-assembly into exquisite, complex, yet highly ordered architectures represents the supreme wisdom of nature. However, precise manipulation of protein self-assembly behavior in vitro is a great challenge. Here we report that by taking advantage of the cooperation of metal-ion-chelating interactions and nonspecific protein-protein interactions, we achieved accurate control of the orientation of proteins and their self-assembly into protein nanorings. As a building block, we utilized the C2-symmetric protein sjGST-2His, a variant of glutathione S-transferase from Schistosoma japonicum having two properly oriented His metal-chelating sites on the surface. Through synergic metal-coordination and non-covalent interactions, sjGST-2His self-assembled in a fixed bending manner to form highly ordered protein nanorings. The diameters of the nanorings can be regulated by tuning the strength of the non-covalent interaction network between sjGST-2His interfaces through variation of the ionic strength of the solution. This work provides a de novo design strategy that can be applied in the construction of novel protein superstructures.
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Desenho de Fármacos , Glutationa Transferase/química , Nanoestruturas/química , Multimerização Proteica , Animais , Quelantes/química , Estrutura Quaternária de Proteína , Schistosoma japonicum/enzimologiaRESUMO
By combining computational design and site-directed mutagenesis, we have engineered a new catalytic ability into the antibody scFv2F3 by installing a catalytic triad (Trp(29)-Sec(52)-Gln(72)). The resulting abzyme, Se-scFv2F3, exhibits a high glutathione peroxidase (GPx) activity, approaching the native enzyme activity. Activity assays and a systematic computational study were performed to investigate the effect of successive replacement of residues at positions 29, 52, and 72. The results revealed that an active site Ser(52)/Sec substitution is critical for the GPx activity of Se-scFv2F3. In addition, Phe(29)/Trp-Val(72)/Gln mutations enhance the reaction rate via functional cooperation with Sec(52). Molecular dynamics simulations showed that the designed catalytic triad is very stable and the conformational flexibility caused by Tyr(101) occurs mainly in the loop of complementarity determining region 3. The docking studies illustrated the importance of this loop that favors the conformational shift of Tyr(54), Asn(55), and Gly(56) to stabilize substrate binding. Molecular dynamics free energy and molecular mechanics-Poisson Boltzmann surface area calculations estimated the pK(a) shifts of the catalytic residue and the binding free energies of docked complexes, suggesting that dipole-dipole interactions among Trp(29)-Sec(52)-Gln(72) lead to the change of free energy that promotes the residual catalytic activity and the substrate-binding capacity. The calculated results agree well with the experimental data, which should help to clarify why Se-scFv2F3 exhibits high catalytic efficiency.