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BACKGROUND: Facing the significant challenge of overcoming drug resistance in cancer treatment, particularly resistance caused by mutations in epidermal growth factor receptor (EGFR), the aim of our study was to identify potent EGFR inhibitors effective against the T790M/C797S/L858R mutant, a key player in resistance mechanisms. METHODS: Our integrated in silico approach harnessed machine learning, virtual screening, and activity evaluation techniques to screen 5105 compounds from three libraries, aiming to find candidates capable of overcoming the resistance conferred by the T790M and C797S mutations within EGFR. This methodical process narrowed the search down to six promising compounds for further examination. RESULTS: Kinase assays identified three compounds to which the T790M/C797S/L858R mutant exhibited increased sensitivity compared to the T790M/L858R mutant, highlighting the potential efficacy of these compounds against resistance mechanisms. Among them, T001-10027877 exhibited dual inhibitory effects, with IC50 values of 4.34 µM against EGFRT790M/C797S/L858R and 1.27 µM against EGFRT790M/L858R. Further investigations into the antiproliferative effects in H1975, A549, H460 and Ba/F3-EGFRL858/T790M/C797S cancer cells revealed that T001-10027877 was the most potent anticancer agent among the tested compounds. Additionally, the induction of H1975 cell apoptosis and cell cycle arrest by T001-10027877 were confirmed, elucidating its mechanism of action. CONCLUSIONS: This study highlights the efficacy of combining computational techniques with bioactivity assessments in the quest for novel antiproliferative agents targeting complex EGFR mutations. In particular, T001-10027877 has great potential for overcoming EGFR-mediated resistance and merits further in vivo exploration. Our findings contribute valuable insights into the development of next-generation anticancer therapies, demonstrating the power of an integrated drug discovery approach.
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Human herpesvirus 8 (HHV-8) infection shows obvious regional and ethnic differences. Although studies have shown that these differences may be associated with lipid metabolism, to date, no large-scale studies have explored this. This study explored the seropositivity rate of HHV-8 among 2516 residents from 10 regions of northwest China and then the correlates of HHV-8 infection with lipid profile. The HHV-8 serological positivity rate was 15.6% among all residents. The HHV-8 seroprevalence ranged 11.2-27.6% among different ethnicities. Across different BMI levels, the positive rates of HHV-8 were 27.6%, 16.9%, and 13.6% for a BMI < 18.5, 18.5-24.9, and ≥25, respectively. HHV-8 seropositivity rate was lower for hypertensive people (12.6%) than for non-hypertensive people (16.7%). Univariate logistic regression analyses revealed that age, hypertension, systolic blood pressure, BMI, total cholesterol, and high-density lipoprotein cholesterol (HDL-C) significantly correlated with HHV-8 seropositivity (p < 0.05). Multivariate logistic regression analysis after adjusting for confounding factors showed that HDL-C (odds ratio [OR]: 0.132, 95% confidence interval [CI], 0.082-0.212; p < 0.001) and BMI (OR: 0.959, 95% CI 0.933-0.986; p = 0.003) were associated with HHV-8 seropositivity. Subgroup analyses concerning ethnicity, sex, or age demonstrated a consistent relationship with HDL-C. The results of HHV-8 seropositivity and BMI were inconsistent in the subgroups. However, Spearman's correlation analysis between HHV-8 serum antibody titer and HDL-C levels showed no linear relationship among HHV-8 seropositive individuals (ρ = -0.080, p = 0.058). HHV-8 serum antibody titers were also not significantly correlated with BMI (ρ = -0.015, p = 0.381). Low HDL-C levels may be an independent risk factor for HHV-8 infection, but there is no significant correlation between HDL-C levels and HHV-8 antibody titers.
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Infecções por Herpesviridae , Herpesvirus Humano 8 , Lipídeos , Humanos , Herpesvirus Humano 8/imunologia , China/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Transversais , Infecções por Herpesviridae/epidemiologia , Infecções por Herpesviridae/sangue , Infecções por Herpesviridae/virologia , Adulto , Estudos Soroepidemiológicos , Idoso , Lipídeos/sangue , Adulto Jovem , Adolescente , Anticorpos Antivirais/sangue , Fatores de Risco , Idoso de 80 Anos ou mais , Índice de Massa CorporalRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ischemic stroke is an acute central nervous system disease that poses a threat to human health. It induces a series of severe pathological mechanisms, ultimately leading to neuronal cell death in the brain due to local ischemia and hypoxia. Buyang Huanwu decoction (BYHWD), as a representative formula for treating ischemic stroke, has shown good therapeutic effects in stroke patients. AIM OF THE STUDY: This study aimed to explore the mechanism of BYHWD in promoting neural remodeling after ischemic stroke from the perspective of neuronal synaptic plasticity, based on the cAMP/PKA/CREB signaling pathway. MATERIALS AND METHODS: A modified suture technique was employed to establish a rat model of MCAO. The rats were divided into sham, model, and BYHWD (20 g/kg) groups. After the corresponding intervention, rat brains from each group were collected. TMT quantitative proteomics technology was employed for the research. Following proteomics studies, we investigated the mechanism of BYHWD in the intervention of ischemic stroke through animal experiments and cell experiments. The experimental animals were divided into sham, model, and BYHWD (5 g/kg, 10 g/kg, and 20 g/kg) groups. Infarct volume and severity of brain injury were measured by TTC staining. HE staining was utilized to evaluate alterations in tissue morphology. The Golgi staining was used to observe changes in cell body, dendrites, and dendritic spines. Transmission electron microscopy was used to observe the ultrastructure of synapses in the cortex and hippocampus. TUNEL staining was conducted to identify apoptotic neurons. Meanwhile, a stable and reliable (OGD/R) SH-SY5Y cell model was established. The effect of BYHWD-containing serum on SH-SY5Y cell viability was measured by CCK-8 kit. The apoptosis situation of SH-SY5Y cells was determined by Annexin V-FITC/PI. Immunofluorescence was employed to measure the fluorescence intensity of synaptic-related factors Syt1, Psd95, and Syn1. Synaptic plasticity pathways were assessed by using RT-qPCR and Western blot to determine the expression levels of cAMP, Psd95, Prkacb, Creb1/p-Creb1, BDNF, Shank2, Syn1, Syt1, Bcl-2, Bcl-2/Bax mRNA and proteins. RESULTS: After treatment with BYHWD, notable alterations were detected in the signaling pathways linked to synaptic plasticity and the cAMP signaling pathway-related targets among the intervention targets. This trend of change was also reflected in other bioinformatics analyses, indicating the important role of synaptic plasticity changes before and after modeling and drug intervention. The results of vivo and vitro experiments showed that BYHWD improved local pathological changes, and reduced cerebral infarct volume, and neurological function scores in MCAO rats. It increased dendritic spine density, improved synaptic structural plasticity, and had a certain neuroprotective effect. BYHWD increased the postsynaptic membrane thickness, synaptic interface curvature, and synaptic quantity. 10% BYHWD-containing serum was determined as the optimal concentration for treatment. 10% BYHWD-containing serum significantly reduced the overall apoptotic rate of (OGD/R) SH-SY5Y cells. Immunofluorescence experiments demonstrated that 10% BYHWD-containing serum could improve synaptic plasticity and increase the relative expression levels of synaptic-related proteins Syt1, Psd95, and Syn1. BYHWD and decoction-containing serum upregulated the mRNA and protein expression levels in (OGD/R) SH-SY5Y cells and MCAO rats, suggesting its ability to improve damaged neuronal synaptic plasticity and enhance transmission efficiency, which might be achieved through the regulation of the cAMP/PKA/CREB pathway. CONCLUSIONS: This study may provide a basis for clinical medication by elucidating the underlying experimental evidence for the promotion of neural plasticity after ischemic stroke by BYHWD.
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Introduction: Members of the plant-specific B3 transcription factor superfamily play crucial roles in various plant growth and developmental processes. Despite numerous valuable studies on B3 genes in other species, little is known about the B3 superfamily in pearl millet. Methods and results: Here, through comparative genomic analysis, we identified 70 B3 proteins in pearl millet and categorized them into four subfamilies based on phylogenetic affiliations: ARF, RAV, LAV, and REM. We also mapped the chromosomal locations of these proteins and analyzed their gene structures, conserved motifs, and gene duplication events, providing new insights into their potential functional interactions. Using transcriptomic sequencing and real-time quantitative PCR, we determined that most PgB3 genes exhibit upregulated expression under drought and high-temperature stresses, indicating their involvement in stress response regulation. To delve deeper into the abiotic stress roles of the B3 family, we focused on a specific gene within the RAV subfamily, PgRAV-04, cloning it and overexpressing it in tobacco. PgRAV-04 overexpression led to increased drought sensitivity in the transgenic plants due to decreased proline levels and peroxidase activity. Discussion: This study not only adds to the existing body of knowledge on the B3 family's characteristics but also advances our functional understanding of the PgB3 genes in pearl millet, reinforcing the significance of these factors in stress adaptation mechanisms.
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INTRODUCTION: Cyclin-dependent protein kinase 4/6 (CDK4/6) is a class of serine/threonine protein kinases that plays a key role in the regulation of the cell cycle. CDK4/6 is highly expressed in cancers such as breast cancer, melanoma, and non-small cell lung cancer (NSCLC). Currently, a variety of CDK4/6 inhibitors have been developed, aiming to develop effective inhibitors to solve CDK4/6 resistance and toxicity. AREAS COVERED: This article searches patents through Espacenet and reviews the development of widely studied CDK inhibitors and FDA-approved CDK4/6 inhibitors, as well as the latest progress of patented inhibitors with good inhibitory activity against CDK4/6 from 2020 to now. EXPERT OPINION: CDK4/6 is highly expressed in many tumors and has become an important anti-tumor target. Among the patents from 2020 to the present, many inhibitors have good kinase inhibitory effects on CDK4/6 and also show great development potential in anti-tumor. However, there is still an urgent need to develop novel CDK4/6 inhibitors that address challenges such as drug resistance, toxicity, and selectivity.
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Antineoplásicos , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Desenvolvimento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Neoplasias , Patentes como Assunto , Inibidores de Proteínas Quinases , Humanos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/farmacologia , AnimaisRESUMO
Prosthetic eye is indispensable as filler after enucleation in patients with anophthalmia, whereas there are still many complications including postoperative infection and eye socket depression or extrusion during the conventional artificial eye material applications. Some Ca-silicate biomaterials showed superior bioactivity but their biological stability in vivo limit the biomedical application as long-term or permanent implants. Herein we aimed to understand the physicochemical and potential biological responses of zinc doping in wollastonite bioceramic used for orbital implants. The wollastonite powders with different zinc dopant contents (CSi-Znx) could be fabricated as porous implants with strut or curve surface pore geometries (cubic, IWP) via ceramic stereolithography. The experimental results indicated that, by increasing zinc-substituting-Ca ratio (up to 9%), the sintering and mechanical properties could be significantly enhanced, and meanwhile the bio-dissolution in vitro and biodegradability in vivo were thoroughly inhibited. In particular, an appreciable angiogenic activity and expected antibacterial efficacy (over 90 %) were synergistically achieved at 9 mol% Zn dopant. In the back-embedding and enucleation and implantation model experiments in rabbits, the superior continuous angiogenesis was corroborated from the 2D/3D fibrovascular reconstruction in the IWP-pore CSi-Zn9 and CSi-Zn13.5 groups within very short time stages. Totally, the present silicate-based bioceramic via selective Zn doping could produce outstanding structural stability and bifunctional biological responses which is especially valuable for developing the next-generation implants with vascular insertion and fixation in orbital reconstruction prothesis.
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Fungal azaphilones have attracted widespread attention due to their significant potential as sources of food pigments and pharmaceuticals. Genome mining and gene cluster activation represent powerful tools and strategies for discovering novel natural products and bioactive molecules. Here, a putative azaphilone biosynthetic gene cluster lut from the endophytic fungus Talaromyces sp. was identified through genome mining. By overexpressing the pathway-specific transcription factor LutB, five new sclerotiorin-type azaphilones (1, 6, 8, and 10-11) together with seven known analogues (2-5, 7, 9, 12) were successfully produced. Compounds 8 and 9 exhibited antibacterial activity against Bacillus subtilis with MIC values of 64 and 16 µg/mL, respectively. Compound 11 showed cytotoxic activity against HCT116 and GES-1 with IC50 values of 10.9 and 4.9 µM, respectively, while 1, 4, 5, and 7-10 showed no obvious cytotoxic activity. Gene inactivation experiments confirmed the role of the lut cluster in the production of compounds 1-12. Subsequent feeding experiments unveiled the novel functional diversity of the dual megasynthase system. Furthermore, a LutC-LutD binary oxidoreductase system was discovered, and in combination with DFT calculations, the basic biosynthetic pathway of the sclerotiorin-type azaphilones was characterized. This study provided a good example for the discovery of new azaphilones and further uncovered the biosynthesis of these compounds.
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Benzopiranos , Proteínas Fúngicas , Família Multigênica , Pigmentos Biológicos , Talaromyces , Talaromyces/genética , Talaromyces/metabolismo , Talaromyces/química , Pigmentos Biológicos/química , Pigmentos Biológicos/metabolismo , Humanos , Benzopiranos/farmacologia , Benzopiranos/química , Benzopiranos/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/química , Endófitos/genética , Endófitos/metabolismo , Endófitos/química , Bacillus subtilis/genética , Bacillus subtilis/metabolismo , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/metabolismo , Linhagem Celular TumoralRESUMO
Polygonatum cyrtonema Hua (P. cyrtonema) rhizomes are rich in flavonoids and other secondary metabolites, exhibiting remarkable antioxidant, anti-tumor, and immunomodulatory effects. Polygonatum flavonoid-biosynthesis-related genes have been characterized already. However, a comprehensive overview of Polygonatum flavonoid biosynthesis pathways is still absent. To articulate the accumulation of the flavonoid biosynthesis pathways, we examined transcriptome changes using Illumina HiSeq from five different tissues and the RNA-seq of 15 samples had over 105 Gb of a clean base, generating a total of 277,955 unigenes. The cDNA libraries of the fruits (F), leaves (L), roots (R), stems (S), and rhizomes (T) of three-year-old P. cyrtonema plants generated 57,591, 53,578, 60,321, 51,530, and 54,935 unigenes. Comparative transcriptome analysis revealed that 379 differentially expressed genes (DEGs) were in the group of F _vs_ T, L _vs_ T, R _vs_ T, and S _vs_ T, and the transcripts of flavonoid-biosynthesis-related DEGs were principally enriched in rhizomes. In addition, combined with WGCNA and the FPKM of five tissues' transcription, nine differentially expressed transcription factor families (MYB, WRKY, AP2/ERF, etc.) were characterized in the red module, the red module positively correlated with rhizome flavonoid accumulation. Quantitative real-time PCR (qRT-PCR) further indicated that BZIP1, C3H31, ERF114, and DREB21 are differentially expressed in rhizomes, accompanied in rhizome development in P. cyrtonema. Therefore, this study provides a foundation for further research into uncovering the accumulation of flavonoid biosynthesis in the rhizomes of P. cyrtonema.
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Resatorvid (TAK-242), a specific inhibitor of Toll-like receptor-4 (TLR4), has attracted attention for its anti-inflammatory properties. Despite this, few studies have evaluated its effects on ulcerative colitis (UC). This study aimed to investigate the effects of TAK-242 on macrophage polarization and T helper cell balance and the mechanism by which it alleviates UC. Our findings indicated that TLR4 expression was elevated in patients with UC, a mouse model of UC, and HT29 cells undergoing an inflammatory response. TAK242 treatment reduced apoptosis in TNF-α and LPS-stimulated HT29 cells and alleviated symptoms of dextran sulfate sodium (DSS)induced colitis in vivo. TAK242 downregulated TLR4 expression and decreased the secretion of pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß while enhancing IL-10 production. TAK-242 also reduced M1 macrophage polarization and diminished Th1 and Th17 cell infiltration while increasing Th2 cell infiltration and M2 macrophage polarization both in vitro and in vivo. Mechanistically, TAK-242 inhibited the JAK2/STAT3 signaling pathway, an important regulator of macrophage polarization and T helper cell balance. Furthermore, the in vivo and in vitro effects of TAK-242 were partially negated by the administration of the JAK2/STAT3 antagonist AG490, suggesting that TAK-242 inhibits the JAK2/STAT3 pathway to exert its biological activities. Taken together, this study underscores TAK-242 as a promising anti-UC agent, functioning by modulating macrophage polarization and T helper cell balance via the TLR4/JAK2/STAT3 signaling pathway.
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BACKGROUND: This study aims to evaluate the ability of laboratories to perform spinal muscular atrophy (SMA) genetic testing in newborns based on dried blood spot (DBS) samples, and to provide reference data and advance preparation for establishing the pilot external quality assessment (EQA) scheme for SMA genetic testing of newborns in China. METHODS: The pilot EQA scheme contents and evaluation principles of this project were designed by National Center for Clinical Laboratories (NCCL), National Health Commission. Two surveys were carried out in 2022, and 5 batches of blood spots were submitted to the participating laboratory each time. All participating laboratories conducted testing upon receiving samples, and test results were submitted to NCCL within the specified date. RESULTS: The return rates were 75.0% (21/28) and 95.2% (20/21) in the first and second surveys, respectively. The total return rate of the two examinations was 83.7% (41/49). Nineteen laboratories (19/21, 90.5%) had a full score passing on the first survey, while in the second survey twenty laboratories (20/20, 100%) scored full. CONCLUSIONS: This pilot EQA survey provides a preliminary understanding of the capability of SMA genetic testing for newborns across laboratories in China. A few laboratories had technical or operational problems in testing. It is, therefore, of importance to strengthen laboratory management and to improve testing capacity for the establishment of a national EQA scheme for newborn SMA genetic testing.
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Testes Genéticos , Atrofia Muscular Espinal , Triagem Neonatal , Humanos , Recém-Nascido , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Projetos Piloto , Testes Genéticos/normas , Testes Genéticos/métodos , Triagem Neonatal/normas , Triagem Neonatal/métodos , China , Teste em Amostras de Sangue Seco/normas , Teste em Amostras de Sangue Seco/métodos , Garantia da Qualidade dos Cuidados de Saúde , Laboratórios Clínicos/normas , Proteína 1 de Sobrevivência do Neurônio Motor/genéticaRESUMO
BACKGROUND: Tinnitus is a complex and heterogeneous disease that has been identified as a common manifestation of COVID-19. To gain a comprehensive understanding of tinnitus symptoms in individuals following COVID-19 infection, we conducted an online survey called the China Ear Nose and Throat Symptom Survey in the COVID-19 Pandemic (CENTSS) among the Chinese population. OBJECTIVE: Our objective was to investigate tinnitus and ear-related symptoms after COVID-19 infection in the Chinese population, with the aim of providing a solid empirical foundation for improved health care. The findings from CENTSS can contribute to the development of enhanced management strategies for tinnitus in the context of long COVID. By gaining a better understanding of the factors contributing to tinnitus in individuals with COVID-19, health care providers can tailor interventions to address the specific needs of affected patients. Furthermore, this study serves as a basis for research on the long-term consequences of COVID-19 infection and its associated tinnitus symptoms. METHODS: A quantitative, online, cross-sectional survey study design was used to explore the impact of the COVID-19 pandemic on experiences with tinnitus in China. Data were collected through an online questionnaire designed to identify the presence of tinnitus and its impacts. Descriptive statistics were used to analyze individuals' demographic characteristics, COVID-19 infection-related ear symptoms, and the cognitive and emotional implications of tinnitus. Univariable and multivariable logistic regression analyses were used to model the cross-sectional baseline associations between demographic characteristics, noise exposure, educational level, health and lifestyle factors, and the occurrence of tinnitus. RESULTS: Between December 19, 2022, and February 1, 2023, we obtained responses from 1262 Chinese participants representing 24 regions, with an average age of 37 years. Among them, 540 patients (42.8%) reported experiencing ear-related symptoms after COVID-19 infection. Only 114 (9%) of these patients sought medical attention specifically for their ear symptoms, while 426 (33.8%) did not seek hospital care. Tinnitus emerged as the most prevalent and impactful symptom among all ear-related symptoms experienced after COVID-19 infection. Of the respondents, female participants (688/888, 77.78%), younger individuals (<30 years), individuals with lower education levels, participants residing in western China, and those with a history of otolaryngology diseases were more likely to develop tinnitus following COVID-19 infection. CONCLUSIONS: In summary, tinnitus was identified as the most common ear-related symptom during COVID-19 infection. Individuals experiencing tinnitus after COVID-19 infection were found to have poorer cognitive and emotional well-being. Different ear-related symptoms in patients post-COVID-19 infection may suggest viral invasion of various parts of the ear. It is therefore crucial to monitor and manage hearing-related changes resulting from COVID-19 as clinical services resume.
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Eukaryotic initiation translation factor 3 subunit h (EIF3H) plays critical roles in regulating translational initiation and predicts poor cancer prognosis, but the mechanism underlying EIF3H tumorigenesis remains to be further elucidated. Here, we report that EIF3H is overexpressed in colorectal cancer (CRC) and correlates with poor prognosis. Conditional Eif3h deletion suppresses colorectal tumorigenesis in AOM/DSS model. Mechanistically, EIF3H functions as a deubiquitinase for HAX1 and stabilizes HAX1 via antagonizing ßTrCP-mediated ubiquitination, which enhances the interaction between RAF1, MEK1 and ERK1, thereby potentiating phosphorylation of ERK1/2. In addition, activation of Wnt/ß-catenin signaling induces EIF3H expression. EIF3H/HAX1 axis promotes CRC tumorigenesis and metastasis in mouse orthotopic cancer model. Significantly, combined targeting Wnt and RAF1-ERK1/2 signaling synergistically inhibits tumor growth in EIF3H-high patient-derived xenografts. These results uncover the important roles of EIF3H in mediating CRC progression through regulating HAX1 and RAF1-ERK1/2 signaling. EIF3H represents a promising therapeutic target and prognostic marker in CRC.
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Neoplasias Colorretais , Sistema de Sinalização das MAP Quinases , Humanos , Animais , Camundongos , Fosforilação , Transformação Celular Neoplásica/genética , Carcinogênese , Via de Sinalização Wnt , Fator de Iniciação 3 em Eucariotos/genética , Fator de Iniciação 3 em Eucariotos/metabolismo , Neoplasias Colorretais/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
Sageretia thea (Osbeck) M.C. Johnst (1968) is an important fruit and medicinal species of Rhamnaceae family. The complete chloroplast genome (cp) of Sageretia genus was sequenced and reported for the first time in this study. The cp genome had a total length of 161,352 bp, consisting of a largesingle-copy (LSC) region of 89,802 bp, a small single-copy (SSC) region of 18,914 bp, and a pair of inverted repeat (IR) regions totaling 26,318 bp. The plastid genome contained 129 genes, including 84 protein-coding genes, 37 tRNA genes, 8 rRNA genes. The overall GC content of the genome was found to be 37.10%. Phylogenetic analysis based on comparison with 27 chloroplast genomes revealed that S. thea is closely related to genera Rhamnus and Berchemia. The findings of this study can provide fundamental insights for the conservation, exploitation, and systematic genomic investigation of Rhamnus plants.
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BACKGROUND: Postoperative fatigue syndrome (POFS) is an important factor in postoperative recovery. However, the effect of anesthetic drugs on postoperative fatigue in female patients has been rarely studied. This study compared the effects of maintaining general anesthesia with propofol or sevoflurane on the incidence of POFS in patients undergoing laparoscopic hysterectomy. METHODS: This prospective, single-blind, randomized controlled trial enrolled patients scheduled for laparoscopic hysterectomy. Eligible patients were randomized into the propofol and sevoflurane groups. The primary outcome was the incidence of POFS within 30 Days, defined by a simplified identity consequence fatigue scale (ICFS-10) scores≥24 or Visual Analogue Scale (VAS) scores of fatigues>6. Secondary outcomes were perioperative grip strength, early ambulation and anal exhaust after surgery, and inpatient days. RESULTS: 32 participants were assigned to the propofol group (P) and 33 to the sevoflurane group (S). Incidence of POFS on postoperative D1 was P (8/32) vs. S (10/33) (p = 0.66, 95% confidence interval [CI]: 16.4-27.00); D3 P (2/32) vs. S (5/33) (p = 0.45,95% CI:5.96-23.76). POFS were not found on postoperative D5 and D30. There were no differences in perioperative grip strength, early ambulation and anal exhaust after surgery, and inpatient days between the two groups. CONCLUSIONS: POFS after scheduled laparoscopic hysterectomy was unaffected by anesthesia with propofol vs. sevoflurane. The incidence of POFS was highest on the first postoperative day, at 27.7%, and declined progressively over the postoperative 30 days. Trial registration Chinese Clinical Trial Registry (No. ChiCTR 2,000,033,861), registered on 14/06/2020).
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Laparoscopia , Éteres Metílicos , Propofol , Humanos , Feminino , Propofol/efeitos adversos , Sevoflurano/efeitos adversos , Estudos Prospectivos , Método Simples-Cego , Histerectomia/efeitos adversos , Laparoscopia/efeitos adversosRESUMO
N6-methyladenosine (m6A) is a crucial RNA modification involved in various biological activities. Computational methods have been developed for the detection of m6A sites in Saccharomyces cerevisiae at base-resolution due to their cost-effectiveness and efficiency. However, the generalization of these methods has been hindered by limited base-resolution datasets. Additionally, RMBase contains a vast number of low-resolution m6A sites for Saccharomyces cerevisiae, and base-resolution sites are often inferred from these low-resolution results through post-calibration. We propose MTTLm6A, a multi-task transfer learning approach for base-resolution mRNA m6A site prediction based on an improved transformer. First, the RNA sequences are encoded by using one-hot encoding. Then, we construct a multi-task model that combines a convolutional neural network with a multi-head-attention deep framework. This model not only detects low-resolution m6A sites, it also assigns reasonable probabilities to the predicted sites. Finally, we employ transfer learning to predict base-resolution m6A sites based on the low-resolution m6A sites. Experimental results on Saccharomyces cerevisiae m6A and Homo sapiens m1A data demonstrate that MTTLm6A respectively achieved area under the receiver operating characteristic (AUROC) values of 77.13% and 92.9%, outperforming the state-of-the-art models. At the same time, it shows that the model has strong generalization ability. To enhance user convenience, we have made a user-friendly web server for MTTLm6A publicly available at http://47.242.23.141/MTTLm6A/index.php.
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Adenosina , Saccharomyces cerevisiae , Humanos , RNA Mensageiro/genética , Saccharomyces cerevisiae/genética , Redes Neurais de Computação , Aprendizado de MáquinaRESUMO
Many patients with non-small cell lung cancer (NSCLC) initially benefit from epidermal growth factor receptor (EGFR) targeted therapy. Unfortunately, varying degrees of resistance or side effects eventually develop. Overcoming and preventing the resistance and side effects of EGFR inhibitors has become a hot topic of research today. Based on the previous studies on AZD-9291, we designed and synthesized two series of 2,4-dichloro-6-methylpyrimidine derivatives, 19 compounds in total, as potential inhibitors of the EGFR kinase. The most promising compound, L-18, showed better inhibitory activity (81.9%) and selectivity against EGFRT790M/L858R kinase. In addition, L-18 showed strong antiproliferative activity against H1975 cells with an IC50 value of 0.65 ± 0.06 µM and no toxicity to normal cells (LO-2). L-18 was able to dose-dependently induce the apoptosis of H1975 cells and produced a cell-cycle-blocking effect, and it can also dose-dependently inhibit the migration and invasion of H1975 cells. L-18 also showed in vivo anticancer efficacy in H1975 cells xenograft mice. We also performed a series of in vivo and in vitro toxicological evaluations of compound L-18, which did not cause obvious injury in mice during administration. These results suggest that L-18 may be a promising drug candidate that warrants further investigation.
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Antineoplásicos , Apoptose , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Receptores ErbB , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Pirimidinas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pirimidinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Apoptose/efeitos dos fármacos , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Estrutura Molecular , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB CRESUMO
BACKGROUND: Cervical LSIL is a precancerous disease which requires regular follow-up. High risk patients need active interventions. Interferon and topical PDT have been used in the treatment of cervical LSIL. The aim of this study was to evaluate the combination use of topical PDT and interferon in the treatment of cervical LSIL. MATERIALS AND METHODS: A prospective study was carried out involving 159 women with cervical LSIL and high risk human papillomaviruses (hr-HPV) infection. Patients were divided into three groups. Group 1-receiving interferon suppository only, Group 2-receiving 19 mg/cm2 ALA plus post PDT interferon, and Group 3-receiving 38 mg/cm2 ALA plus post PDT interferon. The primary endpoint was pathological regression. The secondary endpoints were the HPV negative conversion rate and the adverse effects of treatment. RESULTS: At 6-12 months after PDT, for Group 1, the effective rate, CR rate and HPV negative conversion rate was 48.3 %, 43.3 % and 24.0 %, respectively. For Group 2, the effective rate, CR rate and HPV negative conversion rate were 89.3 %, 71.4 %, and 72.4 %, respectively. For Group 3, the effective rate, CR rate and HPV negative conversion rate were 91.5 %, 66.1 %, and 64.4 %, respectively, significantly higher than those of interferon only group. Two ALA dose group study showed similar efficacy. No patient experienced serious adverse effects. CONCLUSIONS: ALA-PDT combined with interferon therapy was feasible and tolerable. Two ALA dose groups showed similar outcomes in treating cervical LSIL.
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Infecções por Papillomavirus , Fotoquimioterapia , Lesões Intraepiteliais Escamosas , Humanos , Feminino , Interferons/uso terapêutico , Infecções por Papillomavirus/tratamento farmacológico , Estudos Prospectivos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
Acquired resistance to EGFR is a major impediment in lung cancer treatment, highlighting the urgent need to discover novel compounds to overcome EGFR drug resistance. In this study, we utilized in silico methods and bioactivity evaluation for drug discovery to identify novel active anticancer agents targeting EGFRT790M/L858R and EGFRT790M/C797S/L858R. Firstly, we employed ROC-guided machine learning to retrieve nearly 7,765 compounds from a collection of three libraries (comprising over 220,000 compounds). Next, virtual screening, cluster analysis, and binding model analysis were employed to identify six potential compounds. Additionally, the kinase assay revealed that these six compounds demonstrated higher sensitivity to EGFR than c-Met. Among these compounds, T6496 inhibited both EGFRT790M/L858R and EGFRT790M/C797S/L858R kinases, with an IC50 of 3.30 and 8.72 µM. Furthermore, we evaluated the antitumor effects of the six selected compounds, and compound T6496 exhibited the strongest anticancer activity against H1975 cell lines, with an IC50 value of 2.7 µM. These results suggest that T6496 may mitigate EGFR resistance caused by T790M or C797S mutations. Moreover, the AO staining assay, JC-1 staining, ROS experiment and hemolytic toxicity evaluation revealed that T6496 could induce apoptosis in H1975 cell lines in a time-dependent and concentration-dependent manner, and is a potential compound for further structural optimization.Communicated by Ramaswamy H. Sarma.
ROC guided machine learning, virtual screening and bioevaluation was applied to discover six hit compounds for overcoming EGFR resistance mediated by T790M or C797S.The promising compound T6496 could both inhibit EGFRT790M/L858R and EGFRT790M/C797S/L858R, with an IC50 of 3.30 and 8.72 µM.In addition, T6496 and AO-365/43489452 show excellent anticancer activity even better than AZD9291.AO staining assay, JC-1 staining, and ROS experiment revealed that compounds T6496 could induce apoptosis in H1975 cell lines in a time-dependent and concentration-dependent manner.
RESUMO
BACKGROUND: Apolipoprotein A1 (ApoA1) is a member of the apolipoprotein family with diverse functions. It is associated with the pathogenesis and prognosis of several types of tumors. However, the role of serum apolipoprotein A1 (ApoA1) in the prognosis of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. This study aimed to elucidate its influence on clinical outcomes in patients with DLBCL. METHODS: We retrospectively analyzed a cohort of 1583 consecutive DLBCL patients admitted to the Fujian Medical University Union Hospital between January 2011 and December 2021. 949 newly diagnosed DLBCL patients who met the inclusion criteria were enrolled for statistical analysis. Receiver operating characteristic curve analysis was performed to determine the optimal cut-off value for serum ApoA1 levels for prognostic prediction among patients with DLBCL. The correlations between serum ApoA1 levels and clinical and laboratory parameters were analyzed. Prognostic significance was analyzed using univariate and multivariate Cox proportional hazards models. RESULTS: Newly diagnosed patients with DLBCL demonstrated low serum ApoA1 levels (< 0.925 g/L), had more B symptoms, higher levels of serum lactate dehydrogenase (LDH) (>upper limit of normal), poorer performance status (Eastern Cooperative Oncology Group score of 2-4), higher percentage of advanced stage and non-germinal center B-cell (non-GCB) subtype, more cases of > 1 extranodal site, higher International Prognostic Index (IPI) score (3-5), and higher incidence of relapse or refractory diseases compared with those with high serum ApoA1 levels (≥ 0.925 g/L). Low serum ApoA1 levels were an independent adverse prognostic factor for overall survival (OS) but not progression-free survival (PFS). CONCLUSIONS: Low serum ApoA1 levels were associated with poor treatment response and inferior survival in newly diagnosed patients with DLBCL.
Assuntos
Apolipoproteína A-I , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/patologia , Recidiva Local de Neoplasia , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Epiretinal membrane (ERM) is a common age-related retinal disease detected by optical coherence tomography (OCT), with a prevalence of 34.1% among people over 60 years old. This study aims to develop artificial intelligence (AI) systems to assist in the diagnosis of ERM grade using OCT images and to clinically evaluate the potential benefits and risks of our AI systems with a comparative experiment. METHODS: A segmentation deep learning (DL) model that segments retinal features associated with ERM severity and a classification DL model that grades the severity of ERM were developed based on an OCT dataset obtained from three hospitals. A comparative experiment was conducted to compare the performance of four general ophthalmologists with and without assistance from the AI in diagnosing ERM severity. RESULTS: The segmentation network had a pixel accuracy (PA) of 0.980 and a mean intersection over union (MIoU) of 0.873, while the six-classification network had a total accuracy of 81.3%. The diagnostic accuracy scores of the four ophthalmologists increased with AI assistance from 81.7%, 80.7%, 78.0%, and 80.7% to 87.7%, 86.7%, 89.0%, and 91.3%, respectively, while the corresponding time expenditures were reduced. The specific results of the study as well as the misinterpretations of the AI systems were analysed. CONCLUSION: Through our comparative experiment, the AI systems proved to be valuable references for medical diagnosis and demonstrated the potential to accelerate clinical workflows. Systematic efforts are needed to ensure the safe and rapid integration of AI systems into ophthalmic practice.