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1.
BMJ Open ; 14(3): e080816, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38443083

RESUMO

OBJECTIVES: This study aims to explore the incidence of, and risk factors for medical adhesive-related skin injury (MARSI) at peripherally inserted central venous catheter (PICC) sites in patients with cancer. DESIGN: A prospective observational cohort study was conducted at a tertiary hospital in Shenzhen, China. SETTING: This was a single-centre study conducted in a tertiary hospital in Shenzhen, China. PARTICIPANTS: A total of 340 patients with cancer and PICC placement from January 2022 to June 2023 were selected using a convenience sampling method. METHODS: Factors potentially associated with PICC-related MARSI (PICC-MARSI) were recorded, including patient demographics, and catheter placement and maintenance. Patients were divided into MARSI and non-MARSI groups. Univariate analysis was performed to screen for associated variables, and logistic regression analysis was used to identify independent risk factors for PICC-MARSI. RESULTS: Of all 340 patients enrolled, 33 (9.7%) developed PICC-MARSI, including skin tear (8, 24.2%), tension injury (5, 15.2%), irritant contact dermatitis (10, 30.3%), allergic dermatitis (7, 21.2%) and maceration (3, 9.1%). Multivariable analysis showed that age (OR=1.058, p=0.001, 95% CI 1.023-1.094), wet skin (OR=4.873, p=0.003, 95% CI 1.728-13.742), dry skin (OR=6.247, p<0.0001, 95% CI 2.239-17.431), oedema (OR=3.302, p=0.008, 95% CI 1.365-7.985), allergy history (OR=6.044, p=0.001, 95% CI 2.040-17.906), dressing type (OR=3.827, p=0.003, 95% CI 1.595-9.185), body mass index (BMI) <18.5 (OR=4.271, p=0.015, 95% CI 1.327-13.742) and BMI 25-30 (OR=2.946, p=0.027, 95% CI 1.131-7.678) were independent risk factors for PICC-MARSI. CONCLUSIONS: Proper catheter maintenance and appropriate dressing selection are crucial for the prevention of this condition.


Assuntos
Cateteres Venosos Centrais , Surdez , Lacerações , Neoplasias , Humanos , Estudos Prospectivos , Cateteres Venosos Centrais/efeitos adversos , China/epidemiologia
2.
J Oral Microbiol ; 16(1): 2334588, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38550659

RESUMO

Background: Epidemiological evidence has confirmed that periodontitis is an essential and independent risk factor of chronic obstructive pulmonary disease (COPD). Porphyromonas gingivalis, a major pathogen implicated in periodontitis, may make a vital contribution to COPD progression. However, the specific effects and molecular mechanism of the link between P. gingivalis and COPD are not clear. Methods and Results: A COPD rat model was constructed by smoke exposure combined intratracheal instillation of E. coli-LPS, then P. gingivalis was introduced into the oral cavity of COPD rats. This research observed that lower lung function, more severe alveolar damage and inflammation occurred in COPD rats with P. gingivalis group. Meanwhile, P. gingivalis/gingipains could colonize the lung tissues and be enriched in bronchoalveolar lavage fluid (BALF) of COPD rats with P. gingivalis group, along with alterations in lung microbiota. Proteomic analysis suggested that Hsp90α/MLKL-meditated necroptosis pathway was up-regulated in P. gingivalis-induced COPD aggravation, the detection of Hsp90α and MLKL in serum and lung tissue verified that Hsp90α/MLKL was up-regulated. Conclusion: These results indicate that P. gingivalis could emigrate into the lungs, alter lung microbiota and lead to aggravation of COPD, which Hsp90α/MLKL might participate in.

3.
Aging (Albany NY) ; 16(3): 2273-2298, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38319706

RESUMO

BACKGROUND: Methods for predicting the outcome of lung adenocarcinoma (LUAD) in the clinic are limited. Anoikis is an important route to programmed cell death in LUAD, and the prognostic value of a model constructed with anoikis-related lncRNAs (ARlncRNAs) in LUAD is unclear. METHODS: Transcriptome and basic information for LUAD patients was obtained from the Cancer Genome Atlas. Coexpression and Cox regression analyses were utilized to identify prognostically significant ARlncRNAs and construct a prognostic signature. Furthermore, the signature was combined with clinical characteristics to create a nomogram. Finally, we performed principal component, enrichment, tumor mutation burden (TMB), tumor microenvironment (TME) and drug sensitivity analyses to evaluate the basic research and clinical merit of the signature. RESULTS: The prognostic signature developed with eleven ARlncRNAs can accurately predict that high-risk group patients have a worse prognosis, as proven by the receiver operating characteristic (ROC) curve (AUC: 0.718). Independent prognostic analyses indicated that the risk score is a significant independent prognostic element for LUAD (P<0.001). In the high-risk group, enrichment analysis demonstrated that glucose metabolism and DNA replication were the main enrichment pathways. TMB analysis indicated that the high-risk group had a high TMB (P<0.05). Drug sensitivity analyses can recognize drugs that are sensitive to different risk groups. Finally, 11 ARlncRNAs of this signature were verified by RT-qPCR analysis. CONCLUSIONS: A novel prognostic signature developed with 11 ARlncRNAs can accurately predict the OS of LUAD patients and offer clinical guidance value for immunotherapy and chemotherapy treatment.


Assuntos
Adenocarcinoma , Neoplasias Pulmonares , RNA Longo não Codificante , Humanos , Anoikis/genética , Prognóstico , RNA Longo não Codificante/genética , Pulmão , Neoplasias Pulmonares/genética , Microambiente Tumoral/genética
4.
Acta Pharm Sin B ; 14(2): 653-666, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38322337

RESUMO

Stress and illness connection is complex and involves multiple physiological systems. Panax ginsengs, reputed for their broad-spectrum "cure-all" effect, are widely prescribed to treat stress and related illnesses. However, the identity of ginseng's "cure-all" medicinal compounds that relieve stress remains unresolved. Here, we identify ginsentides as the principal bioactives that coordinate multiple systems to restore homeostasis in response to stress. Ginsentides are disulfide-rich, cell-penetrating and proteolytic-stable microproteins. Using affinity-enrichment mass spectrometry target identification together with in vitro, ex vivo and in vivo validations, we show that highly purified or synthetic ginsentides promote vasorelaxation by producing nitric oxide through endothelial cells via intracellular PI3K/Akt signaling pathway, alleviate α1-adrenergic receptor overactivity by reversing phenylephrine-induced constriction of aorta, decrease monocyte adhesion to endothelial cells via CD166/ESAM/CD40 and inhibit P2Y12 receptors to reduce platelet aggregation. Orally administered ginsentides were effective in animal models to reduce ADP-induced platelet aggregation, to prevent collagen and adrenaline-induced pulmonary thrombosis as well as anti-stress behavior of tail suspension and forced swimming tests in mice. Together, these results strongly suggest that ginsentides are the principal panacea compounds of ginsengs because of their ability to target multiple extra- and intra-cellular proteins to reverse stress-induced damages.

5.
Medicine (Baltimore) ; 102(40): e35341, 2023 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-37800757

RESUMO

A growing number of studies have found that the lymph node ratio (LNR) is an important indicator of prognosis in non-small-cell lung cancer (NSCLC). Impact analysis for LNR was performed for survival in patients undergoing surgery for stage III NSCLC compared to the surveillance, epidemiology and end results databank. Clinicopathological variables, such as cancer-specific survival (CSS), were taken from the surveillance epidemiology and end result databank of stage III NSCLC patients who underwent surgery, and the LNR threshold stratification of NSCLC patients was computed by X-tile. CSS was assessed by the Kaplan-Meier method with CSS-independent risk factors calculated by multivariate Cox regression analysis. In total, 7011 lung cancer patients were included. Multifactorial analysis showed that LNR and positive node category had predictive value for stage III NSCLC. In patients with stage IIIA NSCLC, Kaplan-Meier analysis demonstrated that patients with T1-2N2 stage had clearly superior CSS than those with T3-4N1 stage (P < .001), which conflicted with the results from the assessment of primary tumor, lymph nodes, and metastasis/N stage. The cutoff values for LNR were 0.31 and 0.59. Kaplan-Meier analysis demonstrated that the CSS was substantially better in patients with LNR-low than in those with LNR-medium or LNR-high (P < .001), which was also proven by multivariate competing risk regression. Subgroup analysis suggested that the survival advantage of a lower LNR was achieved in all subgroups (sex, race, etc). In stage III NSCLC, the LNR is a valuable factor for assessing prognosis, in which a higher LNR indicates a worse prognosis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Prognóstico , Neoplasias Pulmonares/patologia , Razão entre Linfonodos , Estudos Retrospectivos , Estadiamento de Neoplasias , Metástase Linfática/patologia , Linfonodos/patologia
6.
Hum Brain Mapp ; 44(17): 6245-6257, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37837649

RESUMO

Rumination is closely linked to the onset and maintenance of major depressive disorder (MDD). Prior neuroimaging studies have identified the association between self-reported rumination trait and the functional coupling among a network of brain regions using resting-state functional magnetic resonance imaging (MRI). However, little is known about the underlying neural circuitry mechanism during active rumination in MDD. Degree centrality (DC) is a simple metric to denote network integration, which is critical for higher-order psychological processes such as rumination. During an MRI scan, individuals with MDD (N = 45) and healthy controls (HC, N = 46) completed a rumination state task. We examined the interaction effect between the group (MDD vs. HC) and condition (rumination vs. distraction) on vertex-wise DC. We further characterized the identified brain region's functional involvement with Neurosynth and BrainMap. Network-wise seed-based functional connectivity (FC) analysis was also conducted for the identified region of interest. Finally, exploratory correlation analysis was conducted between the identified region of interest's network FCs and self-reported in-scanner affect levels. We found that a left superior frontal gyrus (SFG) region, generally overlapped with the frontal eye field, showed a significant interaction effect. Further analysis revealed its involvement with executive functions. FCs between this region, the frontoparietal, and the dorsal attention network (DAN) also showed significant interaction effects. Furthermore, its FC to DAN during distraction showed a marginally significant negative association with in-scanner affect level at the baseline. Our results implicated an essential role of the left SFG in the rumination's underlying neural circuitry mechanism in MDD and provided novel evidence for the conceptualization of rumination in terms of impaired executive control.


Assuntos
Transtorno Depressivo Maior , Humanos , Encéfalo/diagnóstico por imagem , Córtex Pré-Frontal , Função Executiva , Lobo Frontal , Imageamento por Ressonância Magnética , Mapeamento Encefálico
7.
Medicine (Baltimore) ; 102(43): e35619, 2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37904443

RESUMO

In lobectomy of patients with lung cancer, the principle of operation is to cut off the pulmonary vein first, but it is often not taken seriously in clinical practice. We conducted this research to compare the impact of different sequences of pulmonary vessel ligation on the long-term survival of patients. This cohort study included 1239 patients treated surgically with video-assisted thoracoscopic lobectomy from January 2015 to December 2019 at The Second Affiliated Hospital of Nanchang University. Survival and perioperative indicators were compared between a Vein-first group (VF) and an artery-first group. After matching, 364 patients were included in each group for analysis. VF was associated with better overall survival (hazard ratio: 1.96 [1.4~2.74], P < .0001) and disease-free survival (hazard ratio: 1.65 [1.22~2.24], P = .0011). Meanwhile, the survival advantage of VF was achieved in almost all subgroups, particularly in the pathological tumor node metastasis stage I-II group and squamous cell carcinoma group. We obtained no significant differences in perioperative indications (operation time, hospital stay, etc) between VF and artery-first group. With better overall survival and disease-free survival, especially for pathological stage I-II squamous cell carcinoma, vein-first ligation should be strictly observed in lobectomy for patients with non-small cell lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Estudos de Coortes , Cirurgia Torácica Vídeoassistida/efeitos adversos , Pneumonectomia/efeitos adversos , Carcinoma de Células Escamosas/cirurgia , Estudos Retrospectivos
8.
Aging (Albany NY) ; 15(19): 10473-10500, 2023 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-37812189

RESUMO

BACKGROUND: Precisely forecasting the prognosis of esophageal squamous cell carcinoma (ESCC) patients is a formidable challenge. Cuproptosis has been implicated in ESCC pathogenesis; however, the prognostic value of cuproptosis-associated long noncoding RNAs (CuRLs) in ESCC is unclear. METHODS: Transcriptomic and clinical data related to ESCC were sourced from The Cancer Genome Atlas (TCGA). Using coexpression and Cox regression analysis to identify prognostically significant CuRLs, a prognostic signature was created. Nomogram models were established by incorporating the risk score and clinical characteristics. Tumor Immune Dysfunction and Rejection (TIDE) scores were derived by conducting an immune landscape analysis and evaluating the tumor mutational burden (TMB). Drug sensitivity analysis was performed to explore the underlying molecular mechanisms and guide clinical dosing. RESULTS: Our risk score based on 5 CuRLs accurately predicted poorer prognosis in high-risk ESCC patients across almost all subgroups. The nomogram that included the risk score provided more precise prognostic predictions. Immune pathways, such as the B-cell receptor signaling pathway, were enriched in the datasets from high-risk patients. High TMB in high-risk patients indicated a relatively poor prognosis. High-risk patients with lower TIDE scores were found to benefit more from immunotherapy. High-risk patients exhibited greater responsiveness to Nilotinib, BI-2536, P22077, Zoledronate, and Fulvestrant, as revealed by drug sensitivity analysis. Real-time PCR validation demonstrated significant differential expression of four CuRLs between ESCC and normal cell lines. CONCLUSIONS: The above risk score and nomogram can accurately predict prognosis in ESCC patients and provide guidance for chemotherapy and immunotherapy.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , RNA Longo não Codificante , Humanos , Prognóstico , Carcinoma de Células Escamosas do Esôfago/genética , RNA Longo não Codificante/genética , Neoplasias Esofágicas/genética , Nomogramas , Apoptose
9.
Exp Ther Med ; 26(2): 372, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37415841

RESUMO

The present study aimed to investigate clinical phenotype and genotype characteristics of a male child with SATB2-associated syndrome (SAS) and analyzed the relationship between these characteristics and the possible underlying genetic mechanism. His clinical phenotype was analyzed. Using a high-throughput sequencing platform, his DNA samples were subjected to medical exome sequencing, screened for suspected variant loci and analyzed for chromosomal copy number variations. The suspected pathogenic loci were verified by Sanger sequencing. He presented with phenotypic anomalies of delayed growth, delayed speech and mental development, facial dysmorphism showing the typical manifestation of SAS and motor retardation symptoms. Gene sequencing result analyses revealed a de novo heterozygous repeat insertion shift mutation in the SATB2 gene (NM_015265.3) c.771dupT (p.Met258Tyrfs*46), resulting in a frameshift mutation from methionine to tyrosine at the amino acid site 258 and a truncated protein with 46 amino acids missing. The parents showed no mutation at this locus. This mutation was identified as the nosogenesis of this syndrome in children. To the best of the authors' knowledge, this is the first report on this mutation. The clinical manifestations and gene variation characteristics of 39 previously reported SAS cases were analyzed together with this case. The findings of the present study suggested severely impaired language development, facial dysmorphism and varying degrees of delayed intellectual development as the characteristic clinical manifestations of SAS.

10.
Materials (Basel) ; 16(10)2023 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-37241513

RESUMO

Hot tearing is the most common and serious casting defect that restricts the light weight and integration of magnesium alloy components. In the present study, trace Ca (0-1.0 wt.%) was added to improve the resistance of AZ91 alloy to hot tearing. The hot tearing susceptivity (HTS) of alloys was experimentally measured by a constraint rod casting method. The results indicate that the HTS presents a ν-shaped tendency with the increase in Ca content, and reaches its minimum value in AZ91-0.1Ca alloy. Ca is well dissolved into α-Mg matrix and Mg17Al12 phase at an addition not exceeding 0.1 wt.%. The solid-solution behavior of Ca increases eutectic content and its corresponding liquid film thickness, improves the strength of dendrites at high temperature, and thereby promotes the hot tearing resistance of the alloy. Al2Ca phases appear and aggregate at dendrite boundaries with further increases in Ca above 0.1 wt.%. The coarsened Al2Ca phase hinders the feeding channel and causes stress concentration during the solidification shrinkage, thereby deteriorating the hot tearing resistance of the alloy. These findings were further verified by fracture morphology observations and microscopic strain analysis near the fracture surface based on kernel average misorientation (KAM).

11.
Eur J Ageing ; 20(1): 19, 2023 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-37243805

RESUMO

How do personal networks evolve as individuals age? To what degree do social disadvantage and contextual factors matter for network dynamics in later life? This paper answers these two questions based on egocentric network data of older adults over a ten-year period. Specifically, I use longitudinal and nationally representative data on 1,168 older adults from the National Social Life, Health, and Aging Project. I use between-within models to separate the within- and between-individual effects of sociodemographic characteristics and contextual factors on three aspects of social connectedness in later life: network size, frequency of contact, and proportion of kin. Patterns of network change vary among people of different races and ethnicities as well as educational levels. Black and Hispanic respondents have a significantly smaller network size and a higher average frequency of contact with confidants. Moreover, Hispanic respondents have a higher proportion of kin in the network, compared to White respondents. Similarly, older adults with less education have a smaller network size, higher frequency of contact and higher proportion of kin in their confidant networks compared to those who attended college. Older adults who have better mental health are more likely to have a higher frequency of contact and higher proportion of kin. When an older adult starts to work for pay, their frequency of contact with confidants tends to increase. Older adults living in neighborhoods with stronger social ties are more likely to have a larger network size, higher frequency of contact, and lower proportion of kin in their confidant network. The above results show that disadvantaged backgrounds and contextual factors are associated with certain less favorable network characteristics, which helps to explain the concentration of social disadvantage on certain populations.

12.
Angew Chem Int Ed Engl ; 62(26): e202218148, 2023 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-37103924

RESUMO

The frequent mutation of KRAS oncogene in some of the most lethal human cancers has spurred incredible efforts to develop KRAS inhibitors, yet only one covalent inhibitor for the KRASG12C mutant has been approved to date. New venues to interfere with KRAS signaling are desperately needed. Here, we report a "localized oxidation-coupling" strategy to achieve protein-specific glycan editing on living cells for disrupting KRAS signaling. This glycan remodeling method exhibits excellent protein and sugar specificity and is applicable to different donor sugars and cell types. Attachment of mannotriose to the terminal galactose/N-acetyl-D-galactosamine epitopes of integrin αv ß3 , a membrane receptor upstream of KRAS, blocks its binding to galectin-3, suppresses the activation of KRAS and downstream effectors, and mitigates KRAS-driven malignant phenotypes. Our work represents the first successful attempt to interfere with KRAS activity by manipulating membrane receptor glycosylation.


Assuntos
Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Neoplasias Pulmonares/patologia , Mutação , Polissacarídeos , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais
13.
ACS Appl Mater Interfaces ; 15(12): 15140-15151, 2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-36929922

RESUMO

Multidrug-resistant bacteria caused by the unlimited overuse of antibiotics pose a great challenge to global health. An antibacterial method based on reactive oxygen species (ROS) is one of the effective strategies without inducing bacterial resistance. Owing to the ability of generating ROS, piezocatalytic material-mediated sonodynamic therapy (SDT) has drawn much attention. However, its major challenge is the low ROS generation efficiency in the piezocatalytic process due to the poor charge carrier concentration of piezoelectric materials. Vacancy engineering can regulate the charge density and largely promote ROS generation under ultrasound (US) irradiation. Herein, a US-responsive self-doped barium titanate with controlled oxygen vacancy (Vo) concentrations was successfully synthesized through a facile thermal reduction treatment at different temperatures (i.e., 350, 400, and 450 °C), and the corresponding samples were named as BTO-350, BTO-400, and BTO-450, respectively. Then, the effect of Vo concentrations on ROS generation efficiency during the piezocatalytic process was systematically studied. And BTO-400 was found to possess the highest piezocatalytic activity and excellent sonodynamic antibacterial performance against Escherichia coli and Staphylococcus aureus. Furthermore, its antibacterial mechanism was confirmed that the ROS generated under US could damage bacterial cell membrane and cause considerable leakage of cytoplasmic components and irreversible death of bacteria. Notably, the in vivo results illustrated that the BTO-400 could serve as an effective antibacterial agent and accelerate skin healing via SDT therapy. In all, the Vo defect-modified nano-BaTiO3 has a noticeable potential to induce a rapid and efficient sterilization as well as skin tissue repair by SDT.


Assuntos
Infecções Estafilocócicas , Terapia por Ultrassom , Humanos , Espécies Reativas de Oxigênio/metabolismo , Terapia por Ultrassom/métodos , Esterilização , Antibacterianos/farmacologia , Linhagem Celular Tumoral
14.
J Hematol Oncol ; 16(1): 28, 2023 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-36945046

RESUMO

The tumor microenvironment (TME) has been extensively investigated; however, it is complex and remains unclear, especially in elderly patients. Senescence is a cellular response to a variety of stress signals, which is characterized by stable arrest of the cell cycle and major changes in cell morphology and physiology. To the best of our knowledge, senescence leads to consistent arrest of tumor cells and remodeling of the tumor-immune microenvironment (TIME) by activating a set of pleiotropic cytokines, chemokines, growth factors, and proteinases, which constitute the senescence-associated secretory phenotype (SASP). On the one hand, the SASP promotes antitumor immunity, which enhances treatment efficacy; on the other hand, the SASP increases immunosuppressive cell infiltration, including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), M2 macrophages, and N2 neutrophils, contributing to TIME suppression. Therefore, a deeper understanding of the regulation of the SASP and components contributing to robust antitumor immunity in elderly individuals with different cancer types and the available therapies is necessary to control tumor cell senescence and provide greater clinical benefits to patients. In this review, we summarize the key biological functions mediated by cytokines and intercellular interactions and significant components of the TME landscape, which influence the immunotherapy response in geriatric oncology. Furthermore, we summarize recent advances in clinical practices targeting TME components and discuss potential senescent TME targets.


Assuntos
Imunoterapia , Neoplasias , Fenótipo Secretor Associado à Senescência , Microambiente Tumoral , Humanos , Senescência Celular , Neoplasias/patologia , Citocinas/metabolismo , Envelhecimento
15.
Commun Biol ; 6(1): 155, 2023 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-36750663

RESUMO

The dynamic assembly of the Synaptic-soluble N-ethylmaleimide-sensitive factor Attachment REceptor (SNARE) complex is crucial to understand membrane fusion. Traditional ensemble study meets the challenge to dissect the dynamic assembly of the protein complex. Here, we apply minute force on a tethered protein complex through dual-trap optical tweezers and study the folding dynamics of SNARE complex under mechanical force regulated by complexin-1 (CpxI). We reconstruct the clamp and facilitate functions of CpxI in vitro and identify different interplay mechanism of CpxI fragment binding on the SNARE complex. Specially, while the N-terminal domain (NTD) plays a dominant role of the facilitate function, CTD is mainly related to clamping. And the mixture of 1-83aa and CTD of CpxI can efficiently reconstitute the inhibitory signal identical to that the full-length CpxI functions. Our observation identifies the important chaperone role of the CpxI molecule in the dynamic assembly of SNARE complex under mechanical tension, and elucidates the specific function of each fragment of CpxI molecules in the chaperone process.


Assuntos
Pinças Ópticas , Proteínas SNARE , Proteínas SNARE/química , Proteínas SNARE/metabolismo , Fusão de Membrana
16.
Antib Ther ; 6(1): 13-29, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36683767

RESUMO

Developability refers to the likelihood that an antibody candidate will become a manufacturable, safe and efficacious drug. Although the safety and efficacy of a drug candidate will be well considered by sponsors and regulatory agencies, developability in the narrow sense can be defined as the likelihood that an antibody candidate will go smoothly through the chemistry, manufacturing and control (CMC) process at a reasonable cost and within a reasonable timeline. Developability in this sense is the focus of this review. To lower the risk that an antibody candidate with poor developability will move to the CMC stage, the candidate's developability-related properties should be screened, assessed and optimized as early as possible. Assessment of developability at the early discovery stage should be performed in a rapid and high-throughput manner while consuming small amounts of testing materials. In addition to monoclonal antibodies, bispecific antibodies, multispecific antibodies and antibody-drug conjugates, as the derivatives of monoclonal antibodies, should also be assessed for developability. Moreover, we propose that the criterion of developability is relative: expected clinical indication, and the dosage and administration route of the antibody could affect this criterion. We also recommend a general screening process during the early discovery stage of antibody-derived therapeutics. With the advance of artificial intelligence-aided prediction of protein structures and features, computational tools can be used to predict, screen and optimize the developability of antibody candidates and greatly reduce the risk of moving a suboptimal candidate to the development stage.

17.
Curr Pharm Des ; 29(1): 60-78, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36503445

RESUMO

BACKGROUND: The specific functions of RNA N6-methyladenosine (m6A) modifications in the glioma tumor microenvironment (TME) and glioma patient prognosis and treatment have not been determined to date. OBJECTIVE: The objective of the study was to determine the role of m6A modifications in glioma TME. METHODS: Nonnegative matrix factorization (NMF) methods were used to determine m6A clusters and m6A gene signatures based on 21 genes relating to m6A modifications. TME characteristics for each m6A cluster and m6A gene signature were quantified by established m6A score. The utility of m6A score was validated in immunotherapy and other antiangiogenic treatment cohorts. RESULTS: Three m6A clusters were identified among 3,395 glioma samples, and they were linked to different biological activities and clinical outcomes. The m6A clusters were highly consistent with immune profiles known as immune-inflamed, immune-excluded, and immune-desert phenotypes. Clusters within individual tumors could predict glioma inflammation, molecular subtypes, TME stromal activity, genetic variation, alternative splicing, and prognosis. As for the m6A score and m6A gene signature, patients with low m6A scores exhibited an increased tumor mutation burden, immune activity, neoantigen load, and prolonged survival. A low m6A score indicated the potential for a low level of T-cell dysfunction, a considerably better treatment response, and durable clinical benefits from immunotherapy, bevacizumab and regorafenib. CONCLUSION: Glioma m6A clusters and gene signatures have distinctive TME features. The m6A gene signature may guide prognostic assessments and promote the use of effective strategies.


Assuntos
Glioma , Microambiente Tumoral , Humanos , Metilação , Imunoterapia , Prognóstico , Linfócitos T
18.
Comput Math Methods Med ; 2022: 3545712, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36388160

RESUMO

Tongue diagnosis, a noninvasive examination, is an essential step for syndrome differentiation and treatment in traditional Chinese medicine (TCM). Sublingual vein (SV) is examined to determine the presence of blood stasis and blood stasis syndrome. Many studies have shown that the degree of SV stasis positively correlates with disease severity. However, the diagnoses of SV examination are often subjective because they are influenced by factors such as physicians' experience and color perception, resulting in different interpretations. Therefore, objective and scientific diagnostic approaches are required to determine the severity of sublingual varices. This study aims at developing a computer-assisted system based on machine learning (ML) techniques for diagnosing the severity of sublingual varicose veins. We conducted a comparative study of the performance of several supervised ML models, including the support vendor machine, K-neighbor, decision tree, linear regression, and Ridge classifier and their variants. The main task was to differentiate sublingual varices into mild and severe by using images of patients' SVs. To improve diagnostic accuracy and to accelerate the training process, we proposed using two model reduction techniques, namely, the principal component analysis in conjunction with the slice inverse regression and the convolution neural network (CNN), to extract valuable features during the preprocessing of data. Our results showed that these two extraction methods can reduce the training time for the ML methods, and the Ridge-CNN method can achieve an accuracy rate as high as 87.5%, which is similar to that of experienced TCM physicians. This computer-aided tool can be used for reference clinical diagnosis. Furthermore, it can be employed by junior physicians to learn and to use in clinical settings.


Assuntos
Medicina Tradicional Chinesa , Varizes , Humanos , Medicina Tradicional Chinesa/métodos , Aprendizado de Máquina , Redes Neurais de Computação , Língua , Varizes/diagnóstico por imagem
20.
Discov Oncol ; 13(1): 75, 2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-35982330

RESUMO

BACKGROUND: In non-small-cell lung cancer (NSCLC), there are many factors that affect prognosis, and the lymph node ratio (LNR) may play a significant role. Our study aimed to confirm the value of the LNR in the prognosis of patients with stage II NSCLC. METHODS: Patient data were obtained from the Surveillance, Epidemiology and End Results (SEER) database. The classification for the LNR was best determined using the X-tile method. The correlation between the LNR and overall survival (OS) was validated after the Kaplan-Meier analysis was performed. To determine the correlation between the LNR and survival, stratification and the Cox regression analysis were used. RESULTS: In our study, 14,183 stage II NSCLC patients were included. Among them, 8303 patients had N1 disease. According to the X-tile analysis, the optimal critical points for the LNR in N1 patients with NSCLC was 0.21 and 0.38. We categorized the cohorts as low (LNR-L ≤ 0.21; n = 5158, 62.1%), medium (0.21 < LNR-M ≤ 0.38; n = 1736, 20.9%), and high (LNR-H > 0.38; n = 1409, 17.0%). According to the Kaplan-Meier analysis, the patients with a high LNR were considerably worse than those with a medium or low LNR (P < 0.001), which was also proven by stratified and multivariate analyses. The value of the LNR was reflected in all the subgroup analyses, especially in patients ages < 60 years. The multivariate competing risks regression analysis revealed that younger age, female sex, T1 disease, adenocarcinoma and N0 disease was associated with a better prognosis after controlling for potential confounders (P < 0.001). CONCLUSIONS: For patients with stage II NSCLC, the LNR is valuable for assessing prognosis. A higher LNR indicates a worse prognosis.

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