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1.
Artigo em Inglês | MEDLINE | ID: mdl-36728011

RESUMO

STUDY DESIGN: Retrospective observational study. OBJECTIVE: The purpose of this study was to establish a CT classification system of anterolateral spinal ossification and analyze the effects of sagittal spinal parameters on ossification. SUMMARY OF BACKGROUND DATA: Patients with Diffuse idiopathic skeletal hyperostosis (DISH) often present with anterolateral ossification of the spine. Few reports consider anterolateral spinal ossification at each spinal level or explore the influence of sagittal alignment. METHOD: 120 patients (79 males and 41 females) over 60 years old who underwent whole spinal CT scans from October 2018 to November 2021 were analyzed. Volume rendering technique images were used to assess the degree of anterolateral spinal ossification in each intervertebral space, and a classification system was established. Sagittal parameters such as thoracic kyphosis (TK), lumbar lordosis (LL), cervical lordosis (CL), sacral slope (SS), and thoracolumbar junction angle (TLJ) of the patients were measured. Multi-factor stepwise linear regression analysis and ordered logistic regression analysis were used to study the effects of the sagittal parameters on ossification grades. RESULTS: The median age of the study population was 67 years (63-72 IQR). The new classification system classifies the severity of anterolateral spinal ossification in each intervertebral space into grades 0 to 3 with an intra-observer ICC value of 0.909 and inter-observer ICC value of 0.900. Multivariate stepwise linear regression analysis showed that age (OR=1.30, P<0.001), weight (OR=1.23, P=0.013), and CL (OR=1.19, P<0.001) were significantly correlated with total ossification grade. Multi-factor ordered logistic regression analysis showed that there was a statistically significant correlation between CL and the ossification grades of each intervertebral space of T1~T4 (P≤0.005), between TK and each intervertebral space in T4~T12 (P≤0.019), and between TLJ and each intervertebral space in T10~L3 (P≤0.025). LL was significantly and positively correlated with the ossification grades of each intervertebral space in T7~T11 (P≤0.041). LL and SS was significantly negatively correlated with the ossification grades of each intervertebral space in L3~S1 (P≤0.047). CONCLUSION: Our new classification scheme demonstrated good accuracy and reliability for the evaluation of the severity of anterolateral spinal ossification. The effect of sagittal parameters on anterolateral spinal ossification was position-specific. The greater the kyphosis or the smaller the lordosis of a spinal region, the more severe the degree of ossification in the corresponding region. LEVEL OF EVIDENCE: 3.

2.
Comput Biol Med ; 153: 106524, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36623439

RESUMO

The prediction of molecules toxicity properties plays an crucial role in the realm of the drug discovery, since it can swiftly screen out the expected drug moleculars. The conventional method for predicting toxicity is to use some in vivo or in vitro biological experiments in the laboratory, which can easily pose a threat significant time and financial waste and even ethical issues. Therefore, using computational approaches to predict molecular toxicity has become a common strategy in modern drug discovery. In this article, we propose a novel model named MTBG, which primarily makes use of both SMILES (Simplified molecular input line entry system) strings and graph structures of molecules to extract drug molecular feature in the field of drug molecular toxicity prediction. To verify the performance of the MTBG model, we opt the Tox21 dataset and several widely used baseline models. Experimental results demonstrate that our model can perform better than these baseline models.


Assuntos
Descoberta de Drogas , Descoberta de Drogas/métodos
3.
medRxiv ; 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36711941

RESUMO

Background: Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been associated with various chronic diseases and mortality, but results are conflicting. Few studies examined the role of a balanced omega-6/omega-3 ratio in mortality. Methods: We investigated plasma omega-3 and omega-6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort, the UK Biobank. Of 117,546 participants who had complete information on circulating PUFAs, 4,733 died during follow-up, including 2,585 from cancer and 1,017 from cardiovascular disease (CVD). Associations were estimated by multivariable Cox proportional hazards regression with adjustment for relevant risk factors. Results: Results: Risk for all three mortality outcomes increased as the ratio of omega-6/omega-3 PUFAs increased (all P trend < 0.001). Comparing the highest to the lowest quintiles, individuals had 42% (95% CI, 28-57%) higher total mortality, 31% (95% CI, 13-50%) higher cancer mortality, and 40% (95% CI, 12-75%) higher CVD mortality. Moreover, omega-3 and omega-6 PUFAs in plasma were all inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects. Conclusions: Using a population-based cohort in UK Biobank, our study revealed a strong association between the ratio of circulating omega-6/omega-3 PUFAs and the risk of all-cause, cancer, and CVD mortality.

4.
Plant Cell Environ ; 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36658747

RESUMO

Hydrogen sulfide (H2 S) is considered to mediate plant growth and development. However, whether H2 S regulates the adaptation of mangrove plant to intertidal flooding habitats is not well understood. In this study, sodium hydrosulfide (NaHS) was used as an H2 S donor to investigate the effect of H2 S on the responses of mangrove plant Avicennia marina to waterlogging. The results showed that 24-h waterlogging increased reactive oxygen species (ROS) and cell death in roots. Excessive mitochondrial ROS accumulation is highly oxidative and leads to mitochondrial structural and functional damage. However, the application of NaHS counteracted the oxidative damage caused by waterlogging. The mitochondrial ROS production was reduced by H2 S through increasing the expressions of the alternative oxidase genes and increasing the proportion of alternative respiratory pathway in the total mitochondrial respiration. Secondly, H2 S enhanced the capacity of the antioxidant system. Meanwhile, H2 S induced Ca2+ influx and activated the expression of intracellular Ca2+ -sensing-related genes. In addition, the alleviating effect of H2 S on waterlogging can be reversed by Ca2+ chelator and Ca2+ channel blockers. In conclusion, this study provides the first evidence to explain the role of H2 S in waterlogging adaptation in mangrove plants from the mitochondrial aspect.

5.
Plant Mol Biol ; 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36645624

RESUMO

NAC (NAM, ATAF1/2, CUC2) transcription factors (TFs) constitute a plant-specific gene family. It is reported that NAC TFs play important roles in plant growth and developmental processes and in response to biotic/abiotic stresses. Nevertheless, little information is known about the functional and evolutionary characteristics of NAC TFs in mangrove plants, a group of species adapting coastal intertidal habitats. Thus, we conducted a comprehensive investigation for NAC TFs in Avicennia marina, one pioneer species of mangrove plants. We totally identified 142 NAC TFs from the genome of A. marina. Combined with NAC proteins having been functionally characterized in other organisms, we built a phylogenetic tree to infer the function of NAC TFs in A. marina. Gene structure and motif sequence analyses suggest the sequence conservation and transcription regulatory regions-mediated functional diversity. Whole-genome duplication serves as the driver force to the evolution of NAC gene family. Moreover, two pairs of NAC genes were identified as positively selected genes of which AmNAC010/040 may be imposed on less constraint toward neofunctionalization. Quite a few stress/hormone-related responsive elements were found in promoter regions indicating potential response to various external factors. Transcriptome data revealed some NAC TFs were involved in pneumatophore and leaf salt gland development and response to salt, flooding and Cd stresses. Gene co-expression analysis found a few NAC TFs participates in the special biological processes concerned with adaptation to intertidal environment. In summary, this study provides detailed functional and evolutionary information about NAC gene family in mangrove plant A. marina and new perspective for adaptation to intertidal habitats.

6.
Biomater Sci ; 11(2): 618-629, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36484291

RESUMO

Ulcerative colitis (UC) is a chronic nonspecific inflammatory bowel disease often characterized by rapid progression and frequent comorbidities that make its treatment challenging. In colonic ulcers of UC patients, myeloperoxidase (MPO) is highly expressed, which results in an abundance of macrophages and reactive oxygen species. This study developed an active MPO-targeting hyaluronic acid/serotonin ceria nanoenzyme (HA-5-HT@CeO2) using the electrostatic interaction between CeO2 nanoparticles, 5-hydroxyserotonin-cerium oxide and hyaluronic acid. Based on the dual targeting effects of MPO and the macrophage CD44+ receptor in locating the inflammatory site in conjunction with the inflammatory area of the colon through electrostatic action, CeO2 nanoparticles along with multiple similar enzymes were used to eliminate O2, H2O2 and ˙OH and other reactive oxygen species, achieving targeted repair of the intestinal epithelial barrier through the elimination of inflammatory factors. In studies involving pharmacodynamics in vitro and DSS-induced animal models of acute colitis in vivo, HA-5-HT@CeO2 has been shown to reduce inflammation further and treat ulcerative colitis compared to traditional drugs. Additionally, active targeting of MPO inflammation can lead to accurate drug delivery to the site and can minimize the side effects associated with the drug. HA-5-HT@CeO2 is a promising novel drug for the treatment of ulcerative colitis. In addition to illustrating the benefits of this novel nanodrug delivery in treating ulcerative colitis compared to traditional medications, this study provides theoretical and experimental support for its application to any targeted therapy for ulcerative colitis.


Assuntos
Colite Ulcerativa , Animais , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Serotonina/efeitos adversos , Ácido Hialurônico/uso terapêutico , Espécies Reativas de Oxigênio , Peróxido de Hidrogênio/efeitos adversos , Nanomedicina , Inflamação , Modelos Animais de Doenças
7.
Clin Transl Sci ; 15(1): 195-203, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34562067

RESUMO

The objectives of this phase I study are to assess the safety, tolerability, and pharmacokinetics (PKs) of RO7049389 in healthy Chinese volunteers (HVs) and evaluate potential ethnic differences in the safety and PKs using data from this study and the first-in-human study (in which most of the HVs were non-Asian). HVs randomly received a single dose of 200-600 mg of RO7049389 or a placebo in a single ascending dose (n = 28) or multiple doses of 200-400 mg of RO7049389 or a placebo in multiple ascending doses (n = 24). Safety and tolerability were monitored throughout the study. Serial blood samples were collected for PK analysis. RO7049389 was safe and well-tolerated in the HVs. The time to maximum concentration ranged from 1.5 to 3.0 h, and terminal half-life ranged from 3.66 to 14.6 h. A single dose of 200-600 mg and multiple doses of 200-400 mg exhibited nonlinear PKs. In general, the safety profiles were comparable between non-Asian and Asian HVs, but the plasma exposure of RO7049389 in Chinese HVs was higher than that in non-Asian HVs. The data generated from this study will provide guidance for future clinical studies on RO7049389 in Chinese/Asian patients with hepatitis B virus.


Assuntos
Antivirais/farmacocinética , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Voluntários Saudáveis , Segurança , Adolescente , Adulto , China , Método Duplo-Cego , Feminino , Hepatite B Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 34(10): 1041-1047, 2022 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-36473561

RESUMO

OBJECTIVE: To evaluate and summarize the best evidence for early rehabilitation of adults with veno-venous extracorporeal membrane oxygenation (VV-ECMO). METHODS: Evidence on early rehabilitation of adult VV-ECMO patients was searched by computer from 7 English literature databases [PubMed database, cumulative index to nursing and allied health literature (CINAHL), Embase database, Cochrane library database, UpToDate clinical consultant, BMJ best clinical practice, JBI database], 5 Chinese literature databases (China biomedical literature database, China Yimai Tong, China national knowledge infrastructure, Wanfang data, VIP database), 5 guideline networks [National Institute for Health and Care Excellence (NICE), Scottish Intercollegiate Guidelines Network (SIGN), National Guideline Clearinghouse (NGC), Guidelines International Network (GIN), China Guide Network] and 2 professional association websites [Extracorporeal Life Support Organization (ELSO), Chinese Association of Rehabilitation Medicine]. The search period is from January 2011 to December 2021. The appraisal of guidelines for research and evaluation II (AGREE ) and JBI 2014 quality assessment tools were used to evaluate the quality of inclusion guidelines, systematic reviews, expert consensus and original studies, respectively, and to extract and summarize the best evidence for early rehabilitation of adults with VV-ECMO. RESULTS: A total of 2 guidelines, 2 expert consensuses, 2 systematic reviews and 8 original studies [including 1 randomized controlled trial (RCT), 1 non-randomized controlled study, 3 cohort studies and 3 case reports] were included. The evidence was summarized from 9 aspects including the necessity of early rehabilitation, rehabilitation initiation time, rehabilitation location, pre-rehabilitation preparation, pre-rehabilitation assessment, rehabilitation method, rehabilitation frequency and duration, rehabilitation process monitoring and effect evaluation,and finally 24 pieces of the best evidence were summarized. CONCLUSIONS: Early rehabilitation of adults with VV-ECMO is safe and feasible. The summary of the best evidence can provide evidence-based guidance for clinical medical staff to reasonably carry out early rehabilitation.

10.
Nurs Crit Care ; 2022 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-36567483

RESUMO

BACKGROUND: Humanistic care involves caring, concern, paying attention to people's individuality, meeting their needs and respecting their rights, which is the core concept and central task of nursing. Effective care can enhance patients' ability to deal with stress and promote patient recovery. Implementing humanistic care in the intensive care unit (ICU) is particularly important for health care providers. AIMS AND OBJECTIVES: This study aims to develop a framework of the humanistic care in the ICU. DESIGN: The qualitative research followed Strauss' procedural grounded theory approach. METHODS: Purposive sampling and theoretical sampling were used to select 12 nurses in the Department of Critical Medicine, 16 patients, and eight family members for semi-structured interviews from October 2020 to April 2021. Results were summarized and analysed through three-level coding based on grounded principles. RESULTS: Sixteen subcategories and six main categories were extracted after three-level coding, and the final ICU humanistic care framework was formed with home, activity, visit, environment, nursing and safety ("HAVENS") as the core. CONCLUSION: This study provides an explanatory theory of humanistic care in the ICU that can guide nurses' practice in ICU clinical work. RELEVANCE TO CLINICAL PRACTICE: This theory provides guidance for nurses to implement humanistic care in critical care practice to improve the ICU stay experience of critically ill patients.

11.
Front Genet ; 13: 938250, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36561319

RESUMO

Background: Necroptosis has been demonstrated to play a crucial role in the prognosis prediction and assessment of treatment outcome in cancers, including cervical cancer. The purpose of this study was to explore the potential prognostic value of necroptosis-related lncRNAs and their relationship with immune microenvironment and response to treatment in cervical cancer. Methods: Data from The Cancer Genome Atlas (TCGA) were collected to obtain synthetic data matrices. Necroptosis-related lncRNAs were identified by Pearson Correlation analysis. Univariate Cox and multivariate Cox regression analysis and Lasso regression were used to construct a necroptosis-related LncRNAs signature. Kaplan-Meier analysis, univariate and multivariate Cox regression analyses, receiver operating characteristic (ROC) curve, nomogram, and calibration curves analysis were performed to validate this signature. Gene set enrichment analyses (GSEA), immunoassays, and the half-maximal inhibitory concentration (IC50) were also analyzed. Results: Initially, 119 necroptosis-related lncRNAs were identified based on necroptosis-related genes and differentially expressed lncRNAs between normal and cervical cancer samples. Then, a prognostic risk signature consisting of five necroptosis-related lncRNAs (DDN-AS1, DLEU1, RGS5, RUSC1-AS1, TMPO-AS1) was established by Cox regression analysis, and LASSO regression techniques. Based on this signature, patients with cervical cancer were classified into a low- or high-risk group. Cox regression confirmed this signature as an independent prognostic predictor with an AUC value of 0.789 for predicting 1-year OS. A nomogram including signature, age, and TNM stage grade was then established, and showed an AUC of 0.82 for predicting 1-year OS. Moreover, GSEA analysis showed that immune-related pathways were enriched in the low-risk group; immunoassays showed that most immune cells, ESTIMAT scores and immune scores were negatively correlated with risk score and that the expression of immune checkpoint-proteins (CD27, CD48, CD200, and TNFRSF14) were higher in the low-risk group. In addition, patients in the low-risk group were more sensitive to Rucaparib, Navitoclax and Crizotinib than those in the high-risk group. Conclusion: We established a novel necroptosis-related lncRNA based signature to predict prognosis, tumor microenvironment and response to treatment in cervical cancer. Our study provides clues to tailor prognosis prediction and individualized immunization/targeted therapy strategies.

12.
Trends Biochem Sci ; 2022 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-36564250

RESUMO

Prenylation is a post-translational modification (PTM) widely found in primary and secondary metabolism. This modification can enhance the lipophilicity of molecules, enabling them to interact with lipid membranes more effectively. The prenylation of peptides is often carried out by cyanobactin prenyltransferases (PTases) from cyanobacteria. These enzymes are of interest due to their ability to add prenyl groups to unmodified peptides, thus making them more effective therapeutics through the subsequent acquisition of increased membrane permeability and bioavailability. Herein we review the current knowledge of cyanobactin PTases, focusing on their discovery, biochemistry, and bioengineering, and highlight the potential application of them as peptide alkylation biocatalysts to generate peptide therapeutics.

14.
Front Bioeng Biotechnol ; 10: 1091360, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36568296

RESUMO

Currently, bone defect repair is still an intractable clinical problem. Numerous treatments have been performed, but their clinical results are unsatisfactory. As a key element of cell-free therapy, exosome is becoming a promising tool of bone regeneration in recent decades, because of its promoting osteogenesis and osteogenic differentiation function in vivo and in vitro. However, low yield, weak activity, inefficient targeting ability, and unpredictable side effects of natural exosomes have limited the clinical application. To overcome the weakness, various approaches have been applied to produce engineering exosomes by regulating their production and function at present. In this review, we will focus on the engineering exosomes for bone defect repair. By summarizing the exosomal cargos affecting osteogenesis, the strategies of engineering exosomes and properties of exosome-integrated biomaterials, this work will provide novel insights into exploring advanced engineering exosome-based cell-free therapy for bone defect repair.

15.
Microsc Res Tech ; 2022 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-36575979

RESUMO

The study evaluated the effect of calcium-based desensitizing toothpastes on the dentinal tubule occlusion and its influence on the dentin bond strength of universal adhesive. Mid-coronal dentin samples were prepared for hypersensitivity model and treated by the following calcium-based desensitizing toothpastes: no treatment (Control), Clinpro (fTCP), Pro-Relief (Pro-Argin), and Repair & Protect (Novamin). Single Bond Universal adhesive was applied in self-etch or etch-and-rinse mode. The dentinal tubule occlusion and adhesion interface were evaluated under scanning electron microscope (SEM). A double-fluorescence technique was used to examine interfacial permeability under confocal laser scanning microscopy (CLSM). The micro-tensile bond strength (µTBS) was employed, followed by the fracture interface observation. SEM showed the toothpastes occluded dentinal tubules, and the occlusion exhibited stability against acid and abrasion. Hindered resin infiltration was observed in the adhesion interface after desensitization. CLSM showed more water permeation within or under the adhesion interface in etch-and-rinse mode than self-etch mode. Desensitization decreased the µTBS in self-etch mode. When using etch-and-rinse mode, the desensitized samples presented similar µTBS to the control group. No difference in µTBS was found between the two bonding modes, except for the control group. Calcium-based desensitizing toothpastes can effectively occlude the exposed dentinal tubules with acid-resistant and abrasion-resistant stability. The desensitization reduced the dentin bond strength of the universal adhesive system in self-etch mode but did not affect the bond strength of etch-and-rinse mode.

16.
Front Neurosci ; 16: 971010, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389216

RESUMO

End-stage kidney disease (ESKD) is associated with cognitive impairment (CI) and affects different aspects of cortical morphometry, but where these changes converge remains unclear. Fractal dimension (FD) is used to represent cortical complexity (CC), which describes the structural complexity of the cerebral cortex by integrating different cortical morphological measures. This study aimed to investigate changes in CC in patients with ESKD prior to initiation of dialysis and to evaluate the relationship between changes in CC, cognitive performance, and uremic toxins. Forty-nine patients with ESKD naive to dialysis and 31 healthy controls (HCs) were assessed using structural magnetic resonance imaging (MRI) and cognitive tests, including evaluations of global cognitive function, memory, and executive function. Clinical laboratory blood tests were performed on all patients with ESKD, including measurement of nine uremic toxin-related indices. CC was measured using MRI data to determine regional FD values. We estimated the association between cognitive performance, uremic toxin levels, and CC changes. Compared to HCs, patients with ESKD showed significantly lower CC in the left precuneus (p = 0.006), left middle temporal cortex (p = 0.010), and left isthmus cingulate cortex (p = 0.018). Furthermore, lower CC in the left precuneus was associated with impaired long-term delayed memory (Pearson r = 0.394, p = 0.042) in patients with ESKD. Our study suggests that regional decreases in CC are an additional characteristic of patients with ESKD naive to dialysis, related to impaired long-term memory performance. These findings may help further understand the underlying neurobiological mechanisms between brain structural changes and CI in patients with ESKD.

17.
Clin Oral Investig ; 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36348096

RESUMO

OBJECTIVES: To evaluate effects of a novel auxiliary irrigation strategy, proanthocyanidin (PA) + carboxymethyl chitosan/amorphous calcium phosphate (CMC/ACP) nanocomplexes, on maintaining the organic-inorganic structural integrity and hence optimizing the adhesion strength of root dentin. MATERIALS AND METHODS: Dentin specimens (n = 150) were prepared and subjected to the classical irrigating strategy with or without PA and CMC/ACP. The ultrastructure and biomechanical behaviour of dentin were characterized by scanning electron microscopy and atomic force microscope, respectively. Forty single root-canal premolars were employed for push-out bond strength testing. Besides, the antibacterial effects against Enterococcus faecalis were evaluated with confocal laser scanning microscopy. Statistical differences were verified with one-way ANOVA and Tukey's post-tests. RESULTS: The organic-inorganic structural integrity of root dentin was repaired with the synergetic use of PA and CMC/ACP. Correspondingly, the bond stability between the root canal wall and the AH-Plus sealer was significantly reinforced (P < 0.05). Meanwhile, the tissue biomechanical properties and antibacterial behaviour were enhanced compared to that of control group (P < 0.05). CONCLUSIONS: The synergistic utilization of PA and CMC/ACP can preserve the structural integrity of root dentin, contributing to optimizing the sealing effects of root canal. Moreover, the novel irrigation strategy demonstrated a favourable antimicrobial activity. CLINICAL RELEVANCE: The combination of PA and CMC/ACP can serve as a promising auxiliary irrigation strategy to optimize the outcomes of chemical preparation, enhance the sealing effects of root canal and hence improve the success rate of treatment.

18.
Cancer Med ; 2022 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-36404592

RESUMO

BACKGROUD: There were limitations existing in programmed cell-death ligand 1 (PD-L1) as predictive biomarkers for breast cancer (BC), hence exploring the correlation between PD-L1 levels and other biomarkers in BC may become a very useful therapeutic clinical tool. METHODS: A total of 301 Chinese patients with different BC subtypes including 47 HR+/HER2+, 185 HR+/HER2-, 38 HR-/HER2+, and 31 triple-negative breast cancer (TNBC) were enrolled in our study. Next-generation sequencing based Yuansu450 gene panel was used for genomic alteration identification and PD-L1 expression was tested using immunohistochemistry. RESULTS: The most prevalent BC-related mutations were TP53 mutations, followed by mutations in PIK3CA, ERBB2, CDK12, and GATA3 in our Chinese cohort. We found that mutations DDR2 and MYCL were only mutated in HR-/HER2+ subtype, whereas H3-3A and NRAS mutations were only occurred in HR-/HER2- subtype. The percentage of patients with PD-L1-positive expression was higher in patients with HR-/HER2- mainly due to the percentage of PD-L1-high level. Mutational frequencies of TP53, MYC, FAT4, PBRM1, PREX2 were observed to have significant differences among patients with different BC subtypes based on PD-L1 levels. Moreover, a positive correlation was observed between TMB and PD-L1 level in HR+/HER2- subtype, and showed that the proportion of patients with high PD-L1 expression was higher than that of patients with low PD-L1 expression in the HR+/HER2- and HR+/HER2+ cohorts with high Ki67 expression. CONCLUSIONS: The genomic alterations based on PD-L1 and other biomarkers of different cohorts may provide more possibilities for the treatment of BC with different subtypes.

19.
Mol Neurobiol ; 2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36401705

RESUMO

Phosphatidylserine (PtdSer) is an important anionic phospholipid found in eukaryotic cells and has been proven to serve as a beneficial factor in the treatment of neurodegenerative diseases. PtdSer resides in the inner leaflet of the plasma membrane, where it is involved in regulating the AKT and PKC signaling pathways; however, it becomes exposed to the extracellular leaflet during neurodevelopmental processes and neurodegenerative diseases, participating in microglia-mediated synaptic and neuronal phagocytosis. In this paper, we review several characteristics of PtdSer, including the synthesis and translocation of PtdSer, the functions of cytoplasmic and exposed PtdSer, and different PtdSer-detection materials used to further understand the role of PtdSer in the nervous system.

20.
J Org Chem ; 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36417567

RESUMO

An axially chiral indolyl-pyrroloindole scaffold, a new member of axially chiral indole-based scaffolds, has been designed, and the catalytic asymmetric construction of this scaffold has been established by the strategy of organocatalytic asymmetric (2 + 3) cycloaddition of 3,3'-bisindoles with isoindolinone-based propargylic alcohols. By this approach, a series of indolyl-pyrroloindole derivatives bearing both axial chirality and central chirality were synthesized in high yields with excellent diastereo- and enantioselectivities (up to 95% yield, 91:9 dr, 99% ee). This reaction not only realizes the first catalytic asymmetric (2 + n) cycloaddition of 3,3'-bisindoles as 1,2-dinucleophiles but also provides a new strategy for atroposelective construction of axially chiral indole-based scaffolds bearing five-five-membered rings, thus solving the challenges in constructing this class of axially chiral indole-based scaffolds.

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