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MOTIVATION: Deep learning-based molecule generation becomes a new paradigm of de novo molecule design since it enables fast and directional exploration in the vast chemical space. However, it is still an open issue to generate molecules, which bind to specific proteins with high-binding affinities while owning desired drug-like physicochemical properties. RESULTS: To address these issues, we elaborate a novel framework for controllable protein-oriented molecule generation, named CProMG, which contains a 3D protein embedding module, a dual-view protein encoder, a molecule embedding module, and a novel drug-like molecule decoder. Based on fusing the hierarchical views of proteins, it enhances the representation of protein binding pockets significantly by associating amino acid residues with their comprising atoms. Through jointly embedding molecule sequences, their drug-like properties, and binding affinities w.r.t. proteins, it autoregressively generates novel molecules having specific properties in a controllable manner by measuring the proximity of molecule tokens to protein residues and atoms. The comparison with state-of-the-art deep generative methods demonstrates the superiority of our CProMG. Furthermore, the progressive control of properties demonstrates the effectiveness of CProMG when controlling binding affinity and drug-like properties. After that, the ablation studies reveal how its crucial components contribute to the model respectively, including hierarchical protein views, Laplacian position encoding as well as property control. Last, a case study w.r.t. protein illustrates the novelty of CProMG and the ability to capture crucial interactions between protein pockets and molecules. It's anticipated that this work can boost de novo molecule design. AVAILABILITY AND IMPLEMENTATION: The code and data underlying this article are freely available at https://github.com/lijianing0902/CProMG.
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Aminoácidos , Aprendizado Profundo , Engenharia de ProteínasRESUMO
BACKGROUND AND OBJECTIVES: To systematically investigate the association between the dietary inflammatory index (DII) and gestational diabetes mellitus (GDM), with a focus on the role of BMI in this relationship. METHODS AND STUDY DESIGN: A comprehensive search was conducted in PubMed, Embase, Web of Science, The Cochrane Library, Medline, CINAHL Complete, Chinese Periodical Full-text Database, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and China Wanfang Database for rele-vant observational studies published up to August 2023. The quality of the included studies was assessed using the Newcastle-Ottawa Scale. The pooled effect size was calculated using a random-effects model. Sub-group and meta-regression analyses were performed to explore potential sources of heterogeneity. RESULTS: The study included 54,058 participants from 10 studies. Pregnant women with a higher DII, indicating a pro-inflammatory diet, had a significantly increased risk of GDM compared to those with a lower DII, indicating an anti-inflammatory diet (pooled OR: 1.17, 95% CI: 1.01-1.36; I²=70%, p <0.001). Subgroup analyses revealed a stronger association in normal weight stratification (OR: 1.25, 95%CI: 1.04-1.51), case-control studies (OR: 1.45, 95%CI: 1.03-2.05), Asia (OR: 1.26, 95%CI: 1.10-1.43), Europe (OR: 1.27, 95%CI: 1.09-1.48), 3-day dietary record as a dietary assessment tool (OR: 1.30, 95%CI: 1.16-1.46), physical activity adjustment (OR: 1.28, 95%CI: 1.13-1.46), and energy intake adjustment (OR: 1.33, 95%CI: 1.19-1.48). Meta-regression analysis confirmed that geographical region significantly influenced heterogeneity between studies (p <0.05). CONCLUSIONS: An elevated DII is independently linked to a higher risk of GDM, especially in women of normal weight.
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Diabetes Gestacional , Dieta , Inflamação , Sobrepeso , Humanos , Diabetes Gestacional/epidemiologia , Feminino , Gravidez , Dieta/métodos , Estudos Observacionais como AssuntoRESUMO
AIMS: To examine the mediating effect of resilience between social support and compassion fatigue among intern nursing and midwifery students during COVID-19. BACKGROUND: Compassion fatigue has become exceedingly common among intern nursing and midwifery students, especially during the COVID-19 pandemic. Social support and resilience can help intern nursing and midwifery students control their negative emotions, reduce compassion fatigue, and increase their well-being. However, the mediating effect of resilience between social support and compassion fatigue remains unclear. DESIGN: A multicentre cross-sectional survey. METHODS: A total of 307 intern nursing and midwifery students were recruited from November 2020 to February 2021 in tertiary grade A hospitals in China. Structural equation modelling was applied to analyse the mediating effects of resilience between social support and compassion fatigue. The Social Support Rating Scale, the 10-item Connor-Davidson Resilience Scale, and the Chinese version of the Compassion Fatigue Short Scale were used to collect data. The hypothetical path model was tested by using IBM SPSS version 26.0 and AMOS version 26.0 software. RESULTS: Intern nursing and midwifery students had moderate compassion fatigue. Social support positively affected resilience (ß = 0.514, p < 0.01). Social support negatively affected compassion fatigue (ß = - 0.310, p < 0.01), while resilience negatively affected compassion fatigue (ß = - 0.283, p < 0.01). Resilience played a mediating role between social support and compassion fatigue. CONCLUSION: Social support can directly affect the compassion fatigue of intern nursing and midwifery students during COVID-19 and indirectly through resilience. Stronger resilience can reduce compassion fatigue. Accordingly, resilience-based interventions should be developed to reduce compassion fatigue.
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BACKGROUND: The outcomes of immune checkpoint inhibitors in cancer patients with liver metastases are poor, which may be related to a different tumor microenvironment in liver metastases from primary tumors. This study was aimed to analyze PD-L1 expression and the immune microenvironment status in liver metastases and compare the differences of PD-L1 expression between primary tumors and liver metastases of colorectal cancer. METHODS: 74 cases of pathologically confirmed colorectal cancer with liver metastasis underwent resection from our hospital were included. Tissue microarrays were used for the interpretation of PD-L1 expression, cluster of differentiation 4 (CD4) and CD8 density by immunohistochemistry. We evaluated the disparity between primary tumor and liver metastasis in PD-L1 expression, CD4 and CD8 density and analyzed the factors associated with obvious PD-L1 disparity. RESULTS: The expression of PD-L1 was positively related to the density of CD4 and CD8 in liver metastases. The expression of PD-L1 in liver metastases was higher than in primary tumors in certain subgroups, including patients with concurrent liver metastases (n = 63, p = 0.05), patients receiving concurrent resection of primary and metastatic tumors (n = 56, p = 0.04). The two subgroups generally reflected those without inconsistent external influences, such as treatment and temporal factors, between primary tumors and liver metastases. In these subgroups, the intrinsic differences of microenvironment between primary tumors and liver metastases could be identified. Furthermore, tumor differentiation [moderate vs. poor: OR = 0.23, 95% CI: 0.03-0.99, p = 0.05)] were demonstrated to be associated with obvious discordance of PD-L1 expression between primary tumors and liver metastases. CONCLUSIONS: The expression of PD-L1 in liver metastases was higher than in primary tumors in subgroups, reflecting intrinsic microenvironment differences between primary and metastatic tumors. Obvious discordance of PD-L1 expression between primary tumor and liver metastasis was significantly related to the tumor differentiation.
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Neoplasias Colorretais , Neoplasias Hepáticas , Antígeno B7-H1 , Biomarcadores Tumorais , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral , Microambiente TumoralRESUMO
Objective To investigate the clinicopathological features and prognosis of idiopathic membranous nephropathy(IMN)in adolescents. Methods This was a retrospective study on IMN patients hospitalized between June 2012 and December 2014,and a total of 33 IMN patients aged between 13 and 24 years old were enrolled in the study.Meanwhile,33 IMN patients aged more than 24 years old were selected randomly as control group during the same period.Diagnosis was confirmed by renal biopsy,and the secondary causes of membranous nephropathy were ruled out.Data collected from medical record and biopsy were analyzed. Results In the adolescent IMN group,the mean age at renal biopsy was(20±3)years old,and the male/female ratio was 22/11.Twenty-three cases presented as nephrotic syndrome.Systolic and diastolic pressures were(127±13)mmHg and(77±9)mmHg,respectively.The median 24-hour urine protein was 5.14(3.39,9.31)g/d,and the median serum creatinine was 62(52,73)µmol/L.The positive rate of serum anti-phospholipase A2 receptor in adolescent group was 54%.Compared with control group,the adolescent patients had lower incidence of hypertension and higher baseline estimated glomerular filtration rate level [15.2% vs.39.3%,χ2=4.889,P=0.03;125 ml/(min·1.73m2)vs.100 ml/(min·1.73m2),U=137.5,P<0.001].According to IMN staging criteria in electron microscopy,adolescent patients were classified as one case in stage I,21 in stage â ¡,and 11 in stage â ¢ or higher.The positive rates of IgG1,IgG2,IgG3 and IgG4 subclass staining in glomeruli were 46.9%,3.1%,56.3%,and 87.5%,respectively.Compared with control group,the adolescent patients had lower incidence of renal interstitial fibrosis and arteriolar lesions(6.1% vs.66.7%,χ2=26.19,P<0.001;15.2% vs.66.7%,χ2=18.11,P<0.001).Three patients lost to follow-up while others started steroid combined with cyclosporine A(n=20),cyclophosphamide(n=7),or mycophenolate(n=1)or solely(n=2).After a median follow-up of 18(12,24)months,the median proteinuria decreased to 0.20(0.10,0.42)g/d,whereas serum creatinine level remained stable [69(56.8,81.3)µmol/L].Seventeen patients(56.7%)achieved complete remission(CR),and the remaining 13 patients(43.4%)achieved partial remission(PR).The median time of CR and PR were three and six months,respectively.Only one patient relapsed during the follow-up.Also,21 cases received maintenance therapy including cyclosporine A(n=18),azathioprine(n=2)and mycophenolate(n=1).Conclusions The immunofluorescence IgG subclass in glomeruli and distribution of serum anti-phospholipase A2 receptor in adolescent IMN patients are similar to those in older IMN patients.IMN patients in adolescents responded well to immunosuppressive therapy.Cyclosporine A in low dose as maintenance therapy is effective after achieving remission,and will not increase risk of nephrotoxicity.
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Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/patologia , Adolescente , Adulto , Azatioprina/uso terapêutico , Estudos de Casos e Controles , Creatinina/sangue , Ciclofosfamida/uso terapêutico , Ciclosporina/uso terapêutico , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite Membranosa/diagnóstico , Humanos , Hipertensão/complicações , Imunoglobulina G/análise , Imunossupressores/uso terapêutico , Masculino , Ácido Micofenólico/uso terapêutico , Síndrome Nefrótica/patologia , Proteinúria , Receptores da Fosfolipase A2/metabolismo , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Liver transplantation (LT) is a viable treatment for patients with end-stage chronic liver diseases. The main aim of LT is to prolong life and improve life quality. However, although survival after LT continues to improve, some aspects of recipient's health-related quality of life such as self-management and self-efficacy have been largely ignored. METHODS: A total of 124 LT recipients were included in this study. Questionnaires for general health status information and a "Self-Management Questionnaire for Liver Transplantation Recipients" modified from the Chinese version of "Chronic Disease Self-Management Program Questionnaire Code Book" were used in the survey. Data were collected by self-administered questionnaires. RESULTS: The overall status of self-management in LT recipients was not optimistic. The major variables affecting the self-management of LT recipients were marital status, educational level and employment. The overall status of self-efficacy in LT recipients was around the medium-level. Postoperative time and self-assessment of overall health status were found as the factors impacting on self-efficacy. CONCLUSIONS: The self-management behavior of LT recipients needs to be improved. The health care professionals need to offer targeted health education to individual patients, help them to establish healthy lifestyle, enhance physical activity and improve self-efficacy. The development of the multilevel and multifaceted social support system will greatly facilitate the self-management in LT patients.
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Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Transplante de Fígado/psicologia , Autocuidado , Autoeficácia , Transplantados/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Escolaridade , Emprego , Feminino , Nível de Saúde , Humanos , Transplante de Fígado/efeitos adversos , Masculino , Estado Civil , Pessoa de Meia-Idade , Educação de Pacientes como Assunto , Qualidade de Vida , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
Background: Shift work can disrupt sleep quality and gut health. Nurses and midwives constitute approximately half of the global healthcare shift-working workforce. Our previous study revealed that most midwives were experiencing suboptimal health conditions, characterized by poor sleep quality and a high prevalence of gastrointestinal diseases. The gut-brain axis theory highlights the potential interplay between sleep quality and gut health. However, limited research focuses on this relationship among midwives. Methods: A cross-sectional survey included 2041 midwives from 87 Chinese hospitals between March and October 2023. Participants completed standardized questionnaires assessing sleep quality, gut health, depression, anxiety, and work stress. Binary logistic regression analyzed factors associated with poor sleep, and multiple linear regression examined the influence of sleep quality on gut health. Results: Over 60% of midwives reported poor sleep, with many experiencing gastrointestinal disorders. We observed a bidirectional relationship between sleep quality and gut health among midwives. After multivariable adjustments, midwives with higher gut health scores were more likely to experience poor sleep quality (odds ratio = 1.042, 95% confidence interval = 1.03-1.054). Conversely, midwives with higher sleep quality scores were also more likely to have poor gut health (ß = 0.222, 95% confidence interval = 0.529-0.797). These associations remained robust across sensitivity analyses. Furthermore, depression, anxiety, and work stress significantly affected both sleep quality and gut health among midwives. Conclusion: This study enhances our understanding of the intricate relationship between sleep quality and gut health among midwives. Poor gut health was associated with a higher risk of poor sleep, and vice versa. To improve the overall wellbeing of midwives, the findings emphasize the importance of addressing poor sleep quality and promoting gut health through maintaining a healthy diet, lifestyle, and good mental health. Further studies are needed to confirm our findings and clarify the underlying mechanisms.
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Qualidade do Sono , Humanos , Estudos Transversais , China/epidemiologia , Adulto , Feminino , Prevalência , Inquéritos e Questionários , Pessoa de Meia-Idade , Tocologia/estatística & dados numéricos , Gastroenteropatias/epidemiologia , Transtornos do Sono-Vigília/epidemiologiaRESUMO
The pursuit of multifunctional electrocatalysts holds significant importance due to their comprehension of material chemistry. Amorphous materials are particularly appealing, yet they pose challenges in terms of rational design due to their structural disorder and thermal instability. Herein, we propose a strategy that entails the tandem (low-temperature/250-350 °C) pyrolysis of molecular clusters, enabling preservation of the local short-range structures of the precursor Schiff base nickel (Ni3[2(C21H24N3Ni1.5O6)]). The temperature-dependent residuals demonstrate exceptional activity and stability for at least three distinct electrocatalytic processes, including the oxygen evolution reaction (η10 = 197 mV), urea oxidation reaction (η10 = 1.339 V), and methanol oxidation reaction (1358 mA cm-2 at 0.56 V). Three distinct nickel atom motifs are discovered for three efficient electrocatalytic reactions (Ni1 and Ni1' are preferred for UOR/MOR, while Ni2 is preferred for OER). Our discoveries pave the way for the potential development of multifunctional electrocatalysts through disordered engineering in molecular clusters under tandem pyrolysis.
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The aim of this study was to detect MAC30 expression in human non-small cell lung cancer (NSCLC) and to analyze its association with prognosis of NSCLC patients. Quantitative real-time RT-PCR was performed to examine the expression of MAC30 mRNA in 20 cases of NSCLC and corresponding non-tumor tissue samples. Immunohistochemistry was performed to detect the expression of MAC30 in 95 NSCLC tissues. We found that the expression levels of MAC30 mRNA in NSCLC tissues were significantly higher than those in corresponding non-tumor tissues. High-level MAC30 expression was correlated with poor tumor differentiation, TNM stage, and lymph node metastasis. Patients with high expression levels of MAC30 showed lower overall survival rate than those with low expression levels. Multivariate analysis showed that high MAC30 protein expression was an independent prognostic factor for NSCLC patients. Our study suggests that over-expression of MAC30 may play an important role in the progression of NSCLC and MAC30 expression may offer a valuable marker for predicting the outcome of patients with NSCLC.
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Adenocarcinoma/mortalidade , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/mortalidade , Neoplasias Pulmonares/mortalidade , Proteínas de Membrana/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de SobrevidaRESUMO
BACKGROUND: Medical professionalism is valued globally. However, Western frameworks of medical professionalism may not resonate with the cultural values of non-Western countries. AIMS: This study aims to formulate a professionalism framework for healthcare providers at Peking Union Medical College (PUMC) in China. METHODS: This study was conducted using nominal group technique (NGT) in a convenient sample of 97 participants at PUMC in November and December, 2011. Participants were sorted into 13 occupational groups, each discussing and ranking categories of medical professionalism. The authors compared the results of each group's ranked categories and analyzed meeting transcripts. RESULTS: A pre-existing framework provided eight categories: clinical competence, communication, ethics, humanism, excellence, accountability, altruism, and integrity. Participants created four categories: teamwork, self-management, health promotion, and economic considerations. Clinical competence and communication ranked highly among most groups. Only hospital volunteers and resident physicians included self-management in their top-ranked items. Only public health experts prioritized health promotion. Standardized patients were unique in mentioning "economic considerations." Medical students and attending physicians both referenced Chinese traditional values. CONCLUSIONS: Our study was able to document effects of East Asian cultural influences and conflicts between Western ideologies and Asian traditions that led to divergent interpretations of medical professionalism.
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Atitude do Pessoal de Saúde , Pessoal de Saúde/psicologia , Papel Profissional , Adulto , Altruísmo , China , Competência Clínica , Comunicação , Ética Clínica , Feminino , Promoção da Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Relações Médico-PacienteRESUMO
In order to explore the impact of different anthropogenic disturbances on the ecological environment of natural rivers, the bacterial community in the channel sediments of the Jialing River was taken as the research object, and the high-throughput sequencing technique was used to analyze the community composition and functional changes of bacteria in the channel sediments of rivers with engineering disturbance, tributary disturbance, sand mining disturbance, reclamation disturbance, and undisturbed section. The results showed that there were significant differences in the physical and chemical properties of channel sediments and bacterial community diversity in different disturbance sections of the Jialing River (P<0.05). The undisturbed section had the highest bacterial community diversity, whereas the sand mining disturbance and undisturbed section had the highest bacterial community uniformity, and tributary disturbance and reclamation disturbance both resulted in a decrease in bacterial community diversity and uniformity. The effect of engineering disturbance on bacterial community composition was significantly different from that of the other four disturbance sections. The dominant bacterial phyla were Proteobacteria, Actinobacteriota, Acidobacteriota, and Chloroflexi, and the dominant bacterial classes were γ-Proteobacteria, α-Proteobacteria, and Vicinamibacteria. Sand mining disturbance led to the increase in Actinobacteria, and engineering disturbance promoted the increase in Acidobacteria. Moisture content, total organic carbon, total nitrogen, and total phosphorus were the main environmental factors affecting the changes in sediment microbial communities. The bacterial communities mainly involved four categories of primary metabolic functions, including metabolism, genetic information processing, environmental information processing, and cellular processes, and 18 categories of secondary metabolic functions, such as global and overview maps, carbohydrate metabolism, amino acid metabolism, cofactor and vitamin metabolism, and energy metabolism. Human interference led to significant changes in energy metabolism, cofactor and vitamin metabolism, nucleotide metabolism, replication and repair, and translation (P<0.05). In conclusion, anthropogenic disturbance led to the mutation of bacterial community diversity and function, which destroyed the stability of the microbial community structure in Jialing River sediments.
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Rios , Areia , Humanos , Bactérias/genética , Acidobacteria , VitaminasRESUMO
Background: Female nurses have been considered as a vulnerable population in the context of mental health, due to the nature of their work, which can be stressful and emotionally taxing. Understanding the relationship between depressive symptoms and quality of work life (QWL) can contribute to improving mental health and job performance. However, limited studies have focused on the effect of depressive symptoms on QWL in female nurses. Objectives: The present study aimed to assess the effect of depressive symptoms on female nurses' QWL using propensity score matching (PSM). Methods: A cross-sectional, online study using convenience sampling was conducted among 1,401 female nurses in China. PSM was used to minimize the impact of potential confounders between no depressive symptoms and depressive symptoms. Stepwise multiple linear regression analyses were performed on the PSM samples to explore the effects of depressive symptoms on the QWL. Results: The results revealed there were 33.5% of the female nurses reported depressive symptoms before PSM. And female nurses in this study had a moderate level of QWL before PSM (122.11 ± 18.15), which remained steady after PSM (118.33 ± 18.04). After PSM, the final sample contained 864 female nurses. Stepwise multiple linear regression results indicated that depressive symptoms were the most strongly associated with QWL (ß = -0.454, p < 0.001). Conclusion: This study highlights the importance of developing mental health plans and psychological interventions for female nurses to maintain mental health and QWL, which is critical to the nursing workforce's sustainability.
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The suprachiasmatic nucleus (SCN) drives circadian clock coherence through intercellular coupling, which is resistant to environmental perturbations. We report that primary cilia are required for intercellular coupling among SCN neurons to maintain the robustness of the internal clock in mice. Cilia in neuromedin S-producing (NMS) neurons exhibit pronounced circadian rhythmicity in abundance and length. Genetic ablation of ciliogenesis in NMS neurons enabled a rapid phase shift of the internal clock under jet-lag conditions. The circadian rhythms of individual neurons in cilia-deficient SCN slices lost their coherence after external perturbations. Rhythmic cilia changes drive oscillations of Sonic Hedgehog (Shh) signaling and clock gene expression. Inactivation of Shh signaling in NMS neurons phenocopied the effects of cilia ablation. Thus, cilia-Shh signaling in the SCN aids intercellular coupling.
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Cílios , Relógios Circadianos , Ritmo Circadiano , Proteínas Hedgehog , Neurônios do Núcleo Supraquiasmático , Animais , Camundongos , Cílios/metabolismo , Cílios/fisiologia , Relógios Circadianos/genética , Ritmo Circadiano/fisiologia , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Neurônios do Núcleo Supraquiasmático/fisiologia , Transdução de Sinais , Regulação da Expressão Gênica , Camundongos TransgênicosRESUMO
The rapid development of bioengineering technology has introduced Fc-fusion proteins, representing a novel kind of recombinant protein, as promising biopharmaceutical products in tumor therapy. Numerous related anti-tumor Fc-fusion proteins have been investigated and are in different stages of development. Fc-fusion proteins are constructed by fusing the Fc-region of the antibody with functional proteins or peptides. They retain the bioactivity of the latter and partial properties of the former. This structural and functional advantage makes Fc-fusion proteins an effective tool in tumor immunotherapy, especially for the recruitment and activation of natural killer (NK) cells, which play a critical role in tumor immunotherapy. Even though tumor cells have developed mechanisms to circumvent the cytotoxic effect of NK cells or induce defective NK cells, Fc-fusion proteins have been proven to effectively activate NK cells to kill tumor cells in different ways, such as antibody-dependent cell-mediated cytotoxicity (ADCC), activate NK cells in different ways in order to promote killing of tumor cells. In this review, we focus on NK cell-based immunity for cancers and current research progress of the Fc-fusion proteins for anti-tumor therapy by activating NK cells.
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Fragmentos Fc das Imunoglobulinas , Células Matadoras Naturais , Citotoxicidade Celular Dependente de Anticorpos , Fragmentos Fc das Imunoglobulinas/genética , Imunoterapia , Proteínas Recombinantes de Fusão/genéticaRESUMO
Primary cilia transduce diverse signals in embryonic development and adult tissues. Defective ciliogenesis results in a series of human disorders collectively known as ciliopathies. The CP110-CEP97 complex removal from the mother centriole is an early critical step for ciliogenesis, but the underlying mechanism for this step remains largely obscure. Here, we reveal that the linear ubiquitin chain assembly complex (LUBAC) plays an essential role in ciliogenesis by targeting the CP110-CEP97 complex. LUBAC specifically generates linear ubiquitin chains on CP110, which is required for CP110 removal from the mother centriole in ciliogenesis. We further identify that a pre-mRNA splicing factor, PRPF8, at the distal end of the mother centriole acts as the receptor of the linear ubiquitin chains to facilitate CP110 removal at the initial stage of ciliogenesis. Thus, our study reveals a direct mechanism of regulating CP110 removal in ciliogenesis and implicates the E3 ligase LUBAC as a potential therapy target of cilia-associated diseases, including ciliopathies and cancers.
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Proteínas de Ciclo Celular/metabolismo , Centríolos/metabolismo , Cílios/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Organogênese , Fosfoproteínas/metabolismo , Ubiquitina/metabolismo , Animais , Linhagem Celular , Humanos , Camundongos , Complexos Multiproteicos , Proteínas de Ligação a RNA/metabolismo , Especificidade por Substrato , Ubiquitinação , Peixe-ZebraRESUMO
BACKGROUND: Over the past decade, there has been increasing interest in exploring the relationship between overweight, obesity and vertebral fractures. Nonetheless, available data from studies on the relationship between overweight, obesity and vertebral fractures remains controversial. METHODS: A systematic search was performed in the PubMed and Cochrane Library databases. We selected relevant literature by using these keywords: fracture, vertebral fracture, vertebral compression fracture, overweight, obese, obesity. The retrieval mainly collected publicly published observational studies on the correlation between overweight, obesity and vertebral fractures, excluding the literature that did not meet the inclusion criteria. Meta-analysis for the data extracted from all the included literatures was performed by STATA 12.0 to summarize test performance with forest plots and assess the heterogeneity. RESULTS: Ten studies, including 1,024,181 subjects satisfied the predefined eligibility criteria. The results showed that the overweight (25.0≤ body mass index (BMI) ≤29.9 kg/m2) and obesity (BMI ≥30.0kg/m2) were associated with a decreased risk of vertebral fractures, respectively. The pooled RR is 0.86 [95% CI: 0.79, 0.95] and 0.81[95% CI:0.74-0.90] with no evidence of statistical heterogeneity. However, the relationship between overweight/obesity (BMI ≥25 kg/m2) and vertebral fractures is not statistically significant. CONCLUSIONS: This study showed that overweight and obesity might decrease the risk of vertebral fractures, respectively. However, we did not observe a significant association between overweight/obesity (BMI≥25 kg/m2) and vertebral fractures.
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Background: Dysregulation of lipid metabolism plays important roles in the tumorigenesis and progression of gastric cancer (GC). The present study aimed to establish a prognostic model based on the lipid metabolism-related genes in GC patients. Materials and Methods: Two GC datasets from the Gene Expression Atlas, GSE62254 (n = 300) and GSE26942 (n = 217), were used as training and validation cohorts to establish a risk predictive scoring model. The efficacy of this model was assessed by ROC analysis. The association of the risk predictive scores with patient characteristics and immune cell subtypes was evaluated. A nomogram was constructed based on the risk predictive score model and other prognostic factors. Results: A risk predictive score model was established based on the expression of 19 lipid metabolism-related genes (LPL, IPMK, PLCB3, CDIPT, PIK3CA, DPM2, PIGZ, GPD2, GPX3, LTC4S, CYP1A2, GALC, SGMS1, SMPD2, SMPD3, FUT6, ST3GAL1, B4GALNT1, and ACADS). The time-dependent ROC analysis revealed that the risk predictive score model was stable and robust. Patients with high risk scores had significantly unfavorable overall survival compared with those with low risk scores in both the training and validation cohorts. A higher risk score was associated with more aggressive features, including a higher tumor grade, a more advanced TNM stage, and diffuse type of Lauren classification of GC. Moreover, distinct immune cell subtypes and signaling pathways were found between the high-risk and low-risk score groups. A nomogram containing patients' age, tumor stage, adjuvant chemotherapy, and the risk predictive score could accurately predict the survival probability of patients at 1, 3, and 5 years. Conclusion: A novel 19-gene risk predictive score model was developed based on the lipid metabolism-related genes, which could be a potential prognostic indicator and therapeutic target of GC.
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OBJECTIVE: To explore the consistency of the parameters of the lumbar spine pelvic sagittal plane between the whole spine EOS images (EOS) and traditional X-ray imaging. METHODS: A total of 50 patients (26 males and 24 females) hospitalized in the Spine Surgery Department of Beijing Jishuitan Hospital from May to July 2019 were selected for standard standing EOS full-length spine anterolateral and traditional X-ray lumbar pelvic anterior and lateral X-rays. Two attending physicians used Surgimap software to measure the pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), lumbar lordosis (LL) of the two types of images and repeated these process after two weeks. The consistency test (reliability analysis) was performed on the results measured by two physicians, and the results measured at the two time points were tested for intra-observer consistency (repeatability analysis).The data were combined to perform consistency and difference tests for the parameters between two types of images finally. RESULTS: The mean values of PI measured by EOS imaging and traditional X-ray imaging were(50.5±12.6)° and (51.4±12.2)°, mean difference 0.9, 95% credible interval (0.2-1.6), P=0.020; the mean values of PT were (16.2±8.9)° and (16.9±8.6)°, mean difference 0.7, 95% credible interval (-0.6-2.0), P=0.283; the mean values of SS were (34.3±9.9)° and (34.5±10.4)°, mean difference 0.2, 95% credible interval (-1.2-1.5), P=0.800;the mean values of LL were (42.7±14.9)° and (43.3±15.3)°, mean difference 0.6, 95% confidence interval (-0.8-2.0), P=0.149. The difference in PI between the two imaging methods was statistically significant (P =0.020, P <0.05), but the average difference was small (0.9°), there was no clinical difference. There were no significant differences in PT, SS and LL between the two imaging methods (P>0.05). Inter-group reliability analysis showed excellent agreement between the two physicians in measuring lateral PI, PT, SS and LL using Surgimap software (correlation coefficients within EOS imaging were 0.984, 0.993, 0.980, 0.989;correlation coefficients within X-ray imaging were 0.975, 0.985, 0.976, 0.988). Repeatability analysis showed that PI, PT, SS and LL measured by the two attending physicians at two time points had excellent consistency(ICC within the group was 0.963-0.996). CONCLUSION: In the local lumbar pelvis segment, the PI, PT SS and LL measured by EOS imaging and traditional X-ray imaging had good agreement, and there was no difference in guiding clinical application.
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Lordose , Região Lombossacral , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Masculino , Pelve/diagnóstico por imagem , Reprodutibilidade dos Testes , Estudos Retrospectivos , Raios XRESUMO
The effect of anti-programmed cell death 1 (PD-1) antibody in Epstein-Barr virus-associated gastric cancer (EBVaGC) was debatable, and no predictive biomarkers for efficacy have been reported. Public reports on anti-PD-1 antibody monotherapy-treated EBVaGC with available programmed death ligand-1 (PD-L1) expression status were summarized and analyzed. Relevance with clinicopathologic characteristics of PD-L1 expression by immunohistochemistry was analyzed in 159 patients diagnosed with EBVaGC. Relevance with genomic transcriptome and mutation profile of PD-L1 status in EBVaGC was assessed with three datasets, the cancer genome atlas (TCGA), Gene Expression Omnibus (GEO) GSE51575, and GSE62254. Based on the data from 8 reports, patients with positive PD-L1 expression (n = 30) had significantly superior objective response rate (ORR) than patients with negative PD-L1 expression (n = 9) (63.3% vs. 0%, P = .001) in EBVaGC receiving anti-PD-1 antibody monotherapy. PD-L1 positivity was associated with less aggressive clinicopathological characteristics and was an independent predictor for a longer disease-free survival (hazard ratio [HR] and 95% CI: 0.45 [0.22-0.92], P = .03) and overall survival (HR and 95% CI: 0.17 [0.06-0.43], P < .001). Analysis of public EBVaGC transcriptome and mutation datasets revealed enhanced immune-related signal pathways in PD-L1high EBVaGC and distinct mutation patterns in PD-L1low EBVaGC. PD-L1 positivity indicates a subtype of EBVaGC with 'hot' immune microenvironment, lower aggressiveness, better prognosis, and higher sensitivity to anti-PD-1 immunotherapy.
Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Antígeno B7-H1/genética , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/genética , Humanos , Imunoterapia , Neoplasias Gástricas/genética , Microambiente TumoralRESUMO
BACKGROUND: We previously reported tumor mutation burden (TMB) as a potential prognostic factor for patients with advanced gastric cancer (AGC) receiving immunotherapy. We aimed to comprehensively understand the impact of tumor burden and TMB on efficacy and prognosis in immunotherapy-treated AGC patients. METHODS: A total of 58 patients with refractory AGC receiving PD-1 inhibitor monotherapy from a phase Ib/II clinical trial (ClinicalTrials.gov identifier: NCT02915432) were retrospectively included. Univariate and multivariate logistical regression analyses and the Cox proportional hazards model were performed for prognostic value of baseline factors. Factors reflecting baseline tumor burden, including baseline lesion number (BLN), the maximum tumor size (MTS) and the sum of target lesion size (SLS) were analyzed. The objective response rate (ORR) and disease control rate (DCR) were compared by Chi-square test. RESULTS: In univariate analysis, high BLN was associated with poor median progression-free survival (mPFS) [1.7 months versus 3.4 months; hazard ratio (HR), 2.696, p < 0.05] and median overall survival (mOS) (3.2 months versus 7.6 months; HR, 1.997, p < 0.05), while high TMB was a positive prognostic factor. In multivariable analysis, both BLN and TMB were independent prognostic factors for mOS (BLN: HR, 2.782, p < 0.05; TMB: HR, 0.288, p < 0.05), while MTS or SLS had no association with survival. Better ORR and DCR were observed in the low BLN group (15.4% versus 5.3%, p > 0.05; 86.96% versus 54.29%, p < 0.05). When combining BLN and TMB, the best efficacy and survival were observed in the BLNlowTMBhigh group (ORR: 37.5%, DCR: 62.5%, mPFS and mOS: not reached). The worst efficacy and survival were shown in the BNLhighTMBlow group [ORR: 0% (0/15); DCR: 13.3%; mPFS: 1.7 months; mOS: 2.7 months (all p < 0.05)]. CONCLUSIONS: BLN, rather than factors regarding baseline tumor size, is perhaps a potential predictor for benefit from immunotherapy and its combination with TMB could further risk-stratify patients with AGC receiving immunotherapy.