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Objective To assess the influences of self-and interviewer-administered methods on the scores of anxiety and depression questionnaires among the patients with sports injuries.Methods A total of 532 participants with sports injuries treated in the Sports Medicine Center of West China Hospital,Sichuan University from November 2022 to May 2023 were included.They were randomly assigned to either the interviewer-administered group (n=270) or the self-administered group (n=262) to complete the generalized anxiety disorder (GAD-7) and the patient health questionnaire (PHQ-9) scales.The total scores and prevalence rates of anxiety and depression were compared between the two groups.Results There was no statistically significant difference in gender,occupation,or surgical site between the two groups (all P>0.05).The self-administered group had higher scores of GAD-7 and PHQ-9 scales than the interviewer-administered group (P<0.001,P<0.001).A greater proportion of participants in the self-administered group than in the interview-administered group met the criteria for mild to moderate anxiety and depression (P<0.001,P=0.002).The prevalence rates of moderate to severe anxiety (GAD-7≥10) and depression (PHQ-9≥10) showed no statistically significant difference between the two groups (P=0.761,P=0.086).Conclusion This study demonstrates that the participants in the self-administered group are more likely to report mild to moderate symptoms of anxiety and depression than those in the interviewer-administered group.
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Ansiedade , Depressão , Humanos , Inquéritos e Questionários , Depressão/epidemiologia , Depressão/diagnóstico , Feminino , Ansiedade/epidemiologia , Masculino , Adulto , Traumatismos em Atletas/psicologia , Traumatismos em Atletas/epidemiologia , China/epidemiologia , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVES: To observe the effect of electroacupuncture (EA) on behavior and hippocampal protein phosphorylation in rats with chronic fatigue syndrome (CFS), so as to explore its mechanisms underlying improvement of CFS. METHODS: Male SD rats were randomly divided into control, model and EA groups (n=12 rats in each group). The CFS model was established by chronic multifactor combined with stress stimulation (treadmill training + restraint stress + sleep disturbance + crowded environment). For rats of the EA group, EA (1 mA, frequency of 10 Hz) was applied to "Shenting" (GV24) (with an acupuncture needle penetrated from GV24 to "Baihui" ï¼»GV20ï¼½) and "Dazhui" (GV14) for 15 min, once daily for 28 days. After treatment, the body weight, food intake and water intake of rats in each group were observed. The fatigue degree of rats was evaluated by Semi-quantitative score observation table of the general condition of experimental rats.The open field test (OFT) was used to assess the rats'anxiety severity by detecting the total number of grid-crossing and the times of the central area entered in 5 min, and Morris water maze test was employed to assess the rats' learning-memory ability by detecting the escape latency in 1 min, and the times of the original platform quadrant crossing in 1 min. The hippocampaus was taken for phosphorylated Label-free quantitative proteomics analysis by using Maxquant technology based on full scan mode to calculate the integral of each peptide signal of liquid chromatography-mass spectrometry(LC-MS). The differentially-expressed proteins (>1.5 folds for up-regulation or <0.67 folds for down-regulation) were evaluated by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. RESULTS: Compared with the control group, the body weight, food intake, and the times of original-platform quadrant crossing of spatial exploring of Morris water maze test were significantly decreased (P<0.01, P<0.05) , and the score of general conditions, times of grid-crossing and center area-entering of OFT, and the escape latency of navigation task were apparently increased (P<0.01) in rats of the model group. After EA intervention, the decreased original-platform quadrant crossing, and the increased score of general conditions, times of grid-crossing and the escape latency of navigation task were all reversed (P<0.01, P<0.05). Outcomes of proteomics analysis indicated that compared with the model group, there were 297 differentially expressed peptide (48 up-regulated and 249 down-regulated) segments in the control group, and there were 245 differentially expressed peptide (185 up-regulated and 60 down-regulated) segments in the EA group, in which, 25 overlapping peptide segments were reversed after EA treatment, corresponding to 24 proteins, mainly involving cytoskeletal structure. GO function annotation analysis showed that the top three differentially expressed phosphorylated proteins involved in the effect of EA intervention were the actin filament polymerization, protein depolymerization and cytoskeletal tissue in the biological process, the actin binding, structural molecular activity and cytoskeletal protein binding in the molecular function, and the cytoskeleton, dendrites and dendritic trees in the cellular component, respectively. The KEGG pathway annotation analysis for differentially expressed phosphorylated proteins showed that theinsulin secretion, axon guidance, phosphatidylinositol signaling system and lysine biosynthesis, etc. were involved in the effect of EA intervention. CONCLUSIONS: EA of GV24-GV20 and GV14 can improve the general state, anxiety and learning-memory ability of CFS model rats, which may be related to its functions in regulating the hippocampal protein phosphorylation level, and repairing the structure and function of synapses in hippocampus.
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Eletroacupuntura , Síndrome de Fadiga Crônica , Hipocampo , Ratos Sprague-Dawley , Animais , Masculino , Ratos , Hipocampo/metabolismo , Síndrome de Fadiga Crônica/terapia , Síndrome de Fadiga Crônica/metabolismo , Fosforilação , Humanos , Pontos de Acupuntura , Modelos Animais de DoençasRESUMO
OBJECTIVES: To observe the effect of electroacupuncture (EA) on the changes of behavior and hippocampal inflammatory factors in rats with chronic fatigue syndrome (CFS), so as to explore its possible mechanisms in the treatment of CFS. METHODS: Twenty-seven SD rats were randomly divided into control, model and electroacupuncture (EA) groups (n=9 rats in each group). The CFS model was established by multi-factor compound stress stimulation method. Rats of the EA group received EA (10 Hz) at "Shenting" (GV24) penetrating "Baihui" (GV20), "Dazhui" (GV14) for 15 min, twice a day for 14 days. The general conditions, Morris water maze test, open field test, the exhausted running platform were conducted for determining the rats' locomotor and learning-memory activities. H.E. staining was used to observe the morphological structure of neurons in hippocampal CA1 region. The contents of interleukin (IL)-10, IL-17 and transforming growth factor (TGF) ß1 in hippocampus and serum of rats were detected by ELISA, and the positive expressions of IL-10, IL-17 and TGF-ß1 in hippocampal CA1 region were detected by immunofluorescence staining. RESULTS: Compared with the control group, the score of general condition was increased (P<0.05), the escape latency was prolonged (P<0.05), the number of crossing the original platform was decreased (P<0.05), the numbers of crossing the grid and entering the central area were increased (P<0.05), and the exhaustive treadmill time was shortened (P<0.05) in the model group. The contents of IL-10 in the hippocampus and serum were decreased (P<0.05), while IL-17 and TGF-ß1 contents were increased (P<0.05). The immunofluorescence intensity of IL-10 in the hippocampus was decreased (P<0.05), while the intensity of IL-17 and TGF-ß1 were increased (P<0.05). After treatment, compared with the model group, the score of general condition was decreased (P<0.05), the escape latency was shortened (P<0.05), the number of crossing the original platform was increased (P<0.05), the numbers of crossing the grid and entering the central area were decreased (P<0.05), and the exhaustive treadmill time was prolonged (P<0.05) in the EA group. The contents of IL-10 in the hippocampus and serum were increased (P<0.05), while IL-17 and TGF-ß1 levels were decreased (P<0.05). The immunofluorescence intensity of IL-10 in the hippocampus was increased (P<0.05), while the intensity of IL-17 and TGF-ß1 were decreased (P<0.05). H.E. staining showed that in the model group, the number of neurons in the hippocampus decreased, with disordered arrangement and loose structure, and a small numbers of neuronal nuclei were missing. The degree of tissue damage of the EA group was milder than that of the model group. CONCLUSIONS: EA can alleviate fatigue and spatial learning and memory impairment in CFS rats, which may be related to the regulation of peripheral and central inflammation.
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Eletroacupuntura , Síndrome de Fadiga Crônica , Ratos , Animais , Ratos Sprague-Dawley , Interleucina-10 , Síndrome de Fadiga Crônica/terapia , Interleucina-17/genética , Fator de Crescimento Transformador beta1/genética , HipocampoRESUMO
BACKGROUND: Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that develop postnatally in non-lymphoid tissues and are associated with pathological conditions. TLS typically comprise B-cell follicles containing and are encompassed by T- cell zones and dendritic cells. The prognostic and predictive value of TLS in the tumor microenvironment (TME) as potential mediators of antitumor immunity have gained interest. However, the precise relationship between localization and maturation of TLS and the clinical outcome of their presence in clear cell renal cell carcinoma (ccRCC) is yet to be elucidated. METHODS: Immunohistochemistry and multispectral fluorescence were used to evaluate the TLS heterogeneity along with TME cell-infiltrating characterizations. A thorough investigation of the prognostic implications of the TLS heterogeneity in 395 patients with ccRCC from two independent cohorts was conducted. Associations between TLS heterogeneity and immunologic activity were assessed by quantifying the immune cell infiltration. RESULTS: Infiltrated TLS were identified in 34.2% of the ccRCC samples (N=395). These TLS were found to be tumor-proximal, tumor-distal, or both in 37.8%, 74.1%, and 11.9% of the TLS-positive cases, respectively. A higher proportion of early TLS was found in tumor-distal TLS (p=0.016), while tumor-proximal TLS primarily comprised secondary follicle-like structures (p=0.004). In the main study cohort (Fudan University Shanghai Cancer Center, N=290), Kaplan-Meier analyses revealed a significant correlation between the presence of tumor-proximal TLS and improved progression-free survival (PFS, p<0.001) and overall survival (OS, p=0.002). Conversely, the presence of tumor-distal TLS was associated with poor PFS (p=0.02) and OS (p=0.021). These findings were further validated in an external validation set of 105 patients with ccRCC. Notably, the presence of mature TLS (namely secondary follicle-like TLS, with CD23+ germinal center) was significantly associated with better clinical outcomes in patients with ccRCC. Furthermore, novel nomograms incorporating the presence of tumor-proximal TLS demonstrated remarkable predictability for the 8-year outcomes of resected ccRCC (area under the curve >0.80). Additionally, ccRCC samples with tumor-distal TLS enriched with primary follicle-like TLS exhibited higher programmed death-ligand 1 tumor-associated macrophages levels and regulatory T cells infiltration in the tumor-distal region, indicative of a suppressive TME. CONCLUSION: This study for the first time elucidates the impact of TLS localization and maturation heterogeneities on the divergent clinical outcomes of ccRCC. The findings reveal that most TLS in ccRCC are located in the tumor-distal area and are associated with immature, immunosuppressive characterizations. Furthermore, our findings corroborate previous research demonstrating that tumor-proximal TLS were associated with favorable clinical outcomes.
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Carcinoma de Células Renais , Neoplasias Renais , Estruturas Linfoides Terciárias , Humanos , Carcinoma de Células Renais/patologia , China , Prognóstico , Neoplasias Renais/patologia , Microambiente TumoralRESUMO
[This retracts the article DOI: 10.1016/j.omtn.2020.09.025.].
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Chronic fatigue syndrome is a neurological disorder characterized by extreme fatigue that lasts for a long time and doesn't alleviate with rest. The number of the cases has been increasing during the era of COVID-19 pandemic. Acupuncture may have some effect on chronic fatigue syndrome, but its mechanism remains unclear. This article was to summarize the specific manifestations of abnormal central mechanism in patients with chronic fatigue syndrome through laboratory tests and neuroimaging. It was found from the laboratory evaluation that there were changes in the structure of the frontal cortex, thalamus and other brain tissues; factors, including IFN-α and IL-10 in cerebrospinal fluid were found abnormal; results of oxidative and nitrosative stress and changes in neurobiochemical substances, e.g. hypothalamus hormone levels and neurotransmitter concentrations, were observed. With magnetic resonance imaging and positron emission tomography, it was shown that the partial brain of persons with chronic fatigue syndrome had morphological changes with diminished grey matter and white; changes in cerebral blood flow velocity caused by decreased perfusion and functional activity with abnormal connectivity in brain were detected. In addition, there was significant decrease in glucose metabolism accompanied with neuroinflammatory response; metabolic disorders of serotonergic, cholinergic, glutamatergic and γ-aminobutyric acid energy neurotransmitters were also discovered. The regulatory effect of acupuncture on the above central neurological abnormalities in chronic fatigue syndrome model animals was elaborated, and the direction for further research was analyzed in order to provide ideas for further research on the central mechanism of acupuncture treatment for chronic fatigue syndrome.
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BACKGROUND: Papillary renal cell carcinoma (PRCC) can be divided into type 1 (PRCC1) and type 2 (PRCC2) and PRCC2 share a more invasive phenotype and worse prognosis. This study aims to identify potential prognostic and therapeutic biomarkers in PRCC2. METHODS: A cohort from The Cancer Genome Atlas and two datasets from Gene Expression Omnibus were examined. Common differentially expressed genes (DEGs) were screened and potential biomarkers were explored by using Kaplan-Meier method and cox regression analysis. Functional enrichment analysis was utilized to evaluate the potential biological functions. Tumor infiltrating immune cells were estimated by CIBERSORT algorithm. Ninety-two PRCC2 samples from Fudan University Shanghai Cancer Center were obtained, and immunostaining was performed to validate prognostic and therapeutic significance of the potential biomarker. RESULTS: PRCC2 has worse overall survival and shares distinct molecular characteristics from PRCC1. There was significant higher expression level of Targeting protein for Xklp2 (TPX2) in PRCC2 compared with normal tissues. Higher expression level of TPX2 was significantly associated with worse overall survival in PRCC2 and kinesin family genes expression were found significantly elevated in high risk PRCC2. Abundance of tumor infiltrating M1 macrophage was significantly higher in PRCC2 and it was also associated with worse overall survival. In the FUSCC cohort, higher TPX2 expression was significantly correlated with worse overall and progression-free survival. Retrospective analysis indicated that mTOR inhibitor (everolimus) had greater efficacy in the high-risk group than in the low-risk group (overall response rate: 28.6% vs. 16.7%) and that everolimus had greater efficacy than sunitinib in the high-risk group (overall response rate: 28.6% vs. 20%). CONCLUSIONS: TPX2 was a prognostic and therapeutic biomarker in PRCC2. Higher abundance of tumor infiltrating M1 macrophage was significantly associated with worse overall survival in PRCC2. mTOR inhibitors may have good efficacy in patients with high-risk PRCC2.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Prognóstico , Estudos Retrospectivos , Everolimo/uso terapêutico , China , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
Transporter associated with antigen processing 1(TAP1) serves as a protein to transport antigenic peptides from the surface of the endoplasmic reticulum to the lumen of the endoplasmic reticulum when the antigens are presented by major histocompatibility complex type I (MHC-I), which has been identified to play a critical role in antigen presentation in innate immunity. In tumors, the role of TAP1 seems to remain controversial. On the one hand, given the role of TAP1 in antigen presentation, it is indicated that high TAP1 expression corresponds to the emergence of more neoantigens epitopes that facilitate the recognition for phagocytes, T cells and other cells. On the other hand, the genetic ablation of transporter associated with antigen processing (TAP) results in the presentation of new class I-restricted epitopes encoded in house-keeping products. Opposite result has been revealed by studies in other tumors suggest, which implies a more complex function of TAP1. Therefore, it's significant to clarify the role of TAP1 in clear cell renal cell carcinoma (ccRCC). In this study, we found the elevated expression levels in mRNA and protein of TAP1 in ccRCC tissues, which indicated a relatively worse prognosis. Transwell assay and Scratch assay in vitro demonstrated the promotive role of TAP1 in ccRCC migration as well as a significant role in metastasis. And the increased expression of TAP1 resulted in more immune cells infiltrated in cancer tissues. TAP1 was also demonstrated to be related to immune regulator genes, as gene set enrichment analysis (GSEA) indicated its significant role in immune regulation. The results of CancerSEA indicated the positive association of the high-level TAP1 expression with epithelial-mesenchymal transition (EMT) and the inverse association with Cell Cycle. The effective drugs were also predicted based on TAP1 expression, of which the high level was indeed associated with resistance to multiple drugs, but some effective drugs still identified based on high TAP1 expression. According to the analysis of various databases, the role of TAP1 in ccRCC was explored, especially in relationship of TAP1 with tumor microenvironment. These results indicate that TAP1 can serve as a potential target for treatment of ccRCC.
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PYCARD is a protein engaged in inflammation, pyroptosis, and apoptosis. However, the function of PYCARD in human cancers remains unclear. The objective of our study was to explore PYCARD expression and prognostic value in human cancers. Public databases were used to assess PYCARD expression and prognostic value. The TISIDB database was used to explore the associations between PYCARD expression and different immune subtypes. The correlations between PYCARD expression and ICP genes, MMR genes, MSI, and TMB were also investigated. The immunotherapy response was assessed using the TIDE database. Single-cell RNA databases evaluated the PYCARD expression of immune cells. External datasets and immunohistochemical staining were conducted to validate PYCARD expression and prognostic value. The results showed that PYCARD expression varied in several cancers and was associated with prognosis, immune-related genes, published biomarkers, and immunotherapy response. Of note, PYCARD expression was upregulated in renal cancers with high diagnostic ability. Upregulation of PYCARD was correlated with worse prognosis in KIRC and external validation cohorts. In conclusion, PYCARD demonstrated strong correlations with prognosis, immune response, and disease progression in pan-cancer analysis. In ccRCC, PYCARD might serve as a biomarker for diagnosis and therapeutic target-boosting immunotherapy response.
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BACKGROUND: To identify the malignant potential and prognostic indicators of renal epithelioid angiomyolipoma (eAML), clinicopathological and molecular features as well as the drug efficacy of 67 eAML cases were analyzed. MATERIALS AND METHODS: Sixty-seven renal eAML patients were enrolled and the immunohistochemical features of these patients were examined. FFPE slides of all patients were re-examined. 21 patients with metastasis received Everolimus 10 mg orally once daily. Responses were evaluated with RECIST criteria by three authors. A risk stratification model was constructed using the following factors: pT3 and pT4, presence of necrosis, mitotic count ≥ 2; the presence of atypical mitoses; severe nuclear atypia, SMA negative, Ki-67 ≥ 10%. RESULTS: The average percentage of the epithelioid component was 85.6% (range 80-95%). Immunohistochemically, Ki-67 ≥ 10% and negative SMA staining were significantly correlated with malignant characteristics (Ki-67: p < 0.001; SMA: p = 0.001). Survival analysis suggested that pT3-pT4 stage, presence of necrosis, severe nuclear atypia, presence of atypical mitoses, mitotic count ≥ 2, Ki-67 ≥ 10% and negative SMA expression were significantly associated with poorer PFS and OS (p < 0.05). The risk model sufficiently discriminated recurrence/metastasis (AUC = 0.897) and cancer-specific mortality (AUC = 0.932) of renal eAML patients in different risk groups. 21 patients had received Everolimus targeted therapy after recurrence/metastasis. The best response for Everolimus treatment was 8/21 (38.1%) partial responses (PR), 9/21 (42.9%) stable disease (SD) and 4/21 (19.0%) progressive disease (PD). CONCLUSION: The risk stratification model could well distinguish eAML patients at high risk of recurrence/metastasis. Everolimus targeted treatment showed good efficacy in patients with recurrence/metastasis.
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Angiomiolipoma , Neoplasias Renais , Células Epitelioides/metabolismo , Células Epitelioides/patologia , Everolimo/uso terapêutico , Humanos , Antígeno Ki-67 , Neoplasias Renais/patologia , Necrose , Estudos RetrospectivosRESUMO
Intestinal flora dysbiosis may play an important role in the occurrence and development of chronic fatigue syndrome (CFS), which may induce the inflammatory response and metabolic disturbance of patients with CFS. Acupuncture and moxibustion may achieve anti-fatigue effect by affecting the diversity and quantity of intestinal flora, improving intestinal barrier function, and regulating brain-gut peptides.
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Terapia por Acupuntura , Síndrome de Fadiga Crônica , Microbioma Gastrointestinal , Moxibustão , Síndrome de Fadiga Crônica/terapia , HumanosRESUMO
Tribbles homolog 3 (TRIB3), a pseudokinase that regulates multiple intracellular signaling pathways, has been reported to promote the growth of multiple tumors. However, its role in clear cell renal cell carcinoma (ccRCC) remains unelucidated. We evaluated the role of TRIB3 in ccRCC using publicly available data from The Cancer Genome Atlas and analyzed its relationship with the tumor microenvironment; moreover, we used gene knockout and overexpression techniques to detect the effects of TRIB3 on the biological behavior of ccRCC cells. RT-qPCR and western blotting were used to detect transfection efficiency, and the invasiveness of ccRCC cells was determined by Transwell migration assays. We found that TRIB3 overexpression was significantly associated with increased grade, stage, and distant metastasis, positively correlated with ccRCC invasiveness, and also an independent risk factor for overall survival (OS). In addition, 361 differentially expressed genes (DEGs) related to TRIB3 were identified. Functional enrichment analysis showed that DEGs were mainly enriched in humoral immune responses, collagen-containing extracellular matrix, and serine hydrolase activity. Immune landscape characterization revealed that TRIB3 expression was significantly and negatively associated with CD8+ T and hematopoietic stem cells, whereas it was positively associated with NK T and macrophage M1 cells. Single-cell sequencing showed that localization and binding targets of TRIB3 mainly involved monocytes/macrophages and CD4+ and CD8+ T cells. Overall, our study revealed that elevated TRIB3 expression represents a promising prognostic marker for ccRCC patients and may play a key role in tumor microenvironment modulation.
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Carcinoma de Células Renais , Proteínas de Ciclo Celular/metabolismo , Neoplasias Renais , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Biomarcadores Tumorais/genética , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Renais/metabolismo , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Prognóstico , Proteínas Serina-Treonina Quinases/metabolismo , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Dual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. Camrelizumab is a monoclonal antibody against PD-1, and famitinib is a multitargeted receptor tyrosine kinase inhibitor with antiangiogenesis and antiproliferation activities against tumor cells. We conducted an open-label, multicenter phase 2 basket study of camrelizumab and famitinib in eight cohorts of genitourinary or gynecological cancers. Here, findings in cohort of advanced or metastatic urothelial carcinoma with platinum-progressive disease (cohort 2) are presented. METHODS: Patients who had progressed after platinum-based chemotherapy for advanced or metastatic disease or had progressed within 12 months after completion of platinum-based (neo)adjuvant therapy were given camrelizumab (200 mg intravenously every 3 weeks) plus famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Totally, 36 patients were recruited. With a median duration from enrollment to data cut-off of 11.9 months (range 6.1-28.5), ORR was 30.6% (95% CI 16.3% to 48.1%). Median duration of response (DoR) was 6.3 months (95% CI 2.1 to not reached). Median progression-free survival (PFS) was 4.1 months (95% CI 2.2 to 8.2), and median overall survival (OS) was 12.9 months (95% CI 8.8 to not reached). Patients with bladder cancer (n=18) had numerically better outcomes, with an ORR of 38.9% (95% CI 17.3% to 64.3%) and a median PFS of 8.3 months (95% CI 4.1 to not reached). Median DoR and OS in this subpopulation had not been reached with lower limit of 95% CI of 4.2 months for DoR and 11.3 months for OS, respectively. Of 36 patients, 22 (61.1%) had grade 3 or 4 treatment-related adverse events, mainly decreased platelet count and hypertension. CONCLUSIONS: Camrelizumab plus famitinib showed potent antitumor activity in advanced or metastatic urothelial carcinoma patients after platinum-based chemotherapy. Patients with bladder cancer seemed to have better response to this combination. TRIAL REGISTRATION NUMBER: NCT03827837.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/tratamento farmacológico , Feminino , Humanos , Indóis , Masculino , Platina/farmacologia , Platina/uso terapêutico , Pirróis , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
OBJECTIVE: This study aims to identify potential prognostic and therapeutic biomarkers in papillary renal cell carcinoma (pRCC). METHODS: Two microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified. The protein-protein interaction (PPI) networks and functional annotations of DEGs were established. Survival analysis was utilized to evaluate the prognostic significance of the DEGs and the association between the expression level of candidate biomarkers and various tumour-infiltrating immune cells was explored. The role of PTTG1 in tumour microenvironments (TME) was further explored using Single-cell RNA-seq and its prognostic and therapeutic significance was validated in Fudan University Shanghai Cancer Centre (FUSCC) cohort. RESULTS: Eight genes, including BUB1B, CCNB1, CCNB2, MAD2L1, TTK, CDC20, PTTG1, and MCM were found to be negatively associated with patients' prognosis. The expression level of PTTG1 was found to be significantly associated with lymphocytes, immunomodulators, and chemokine in the TCGA cohort. Single-cell RNA-seq information indicated that PTTG1 was strongly associated with the proliferation of T cells. In the FUSCC cohort, the expression level of PTTG1 was also statistically significant for both progression-free survival (PFS) and overall survival (OS) prediction (HR = 2.683, p < .001; HR = 2.673, p = .001). And higher expression level of PTTG1 was significantly associated with immune checkpoint blockade (ICB) response in the FUSCC cohort (χ2=3.99, p < .05). CONCLUSIONS: Eight genes were identified as a prognostic biomarker and the expression level of PTTG1 was also found to serve as a potential predictor for ICB response in pRCC patients.Key messages:Eight genes, including BUB1B, CCNB1, CCNB2, MAD2L1, TTK, CDC20, PTTG1, and MCM were found to be negatively associated with pRCC patients' prognosis.Expression level of PTTG1 was significantly associated with tumour microenvironment including lymphocytes, immunomodulators, and chemokines.Higher expression level of PTTG1 was significantly associated with immune checkpoint blockade (ICB) response in FUSCC cohort.
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Carcinoma de Células Renais , Neoplasias Renais , Biomarcadores , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/terapia , China , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores Imunológicos , Imunoterapia , Neoplasias Renais/genética , Prognóstico , Microambiente Tumoral/genéticaRESUMO
As prostate cancer (PCa) is one of the most commonly diagnosed cancer worldwide, identifying potential prognostic biomarkers is crucial. In this study, the survival information, gene expression, and protein expression data of 344 PCa cases were collected from the Cancer Proteome Atlas (TCPA) and the Cancer Genome Atlas (TCGA) to investigate the potential prognostic biomarkers. The integrated prognosis-related proteins (IPRPs) model was constructed based on the risk score of each patients using machine-learning algorithm. IPRPs model suggested that Elevated RAD50 expression (p = 0.016) and down-regulated SMAD4 expression (p = 0.017) were significantly correlated with unfavorable outcomes for PCa patients. Immunohistochemical (IHC) staining and western blot (WB) analysis revealed significant differential expression of SMAD4 and RAD50 protein between tumor and normal tissues in validation cohort. According to the overall IHC score, patients with low SMAD4 (p < 0.0001) expression and high RAD50 expression (p = 0.0001) were significantly correlated with poor outcomes. Besides, expression of SMAD4 showed significantly negative correlation with most immune checkpoint molecules, and the low SMAD4 expression group exhibited significantly high levels of LAG3 (p < 0.05), TGFß (p < 0.001), and PD-L1 (p < 0.05) compared with the high SMAD4 expression group in the validation cohort. Patients with low SMAD4 expression had significantly higher infiltration of memory B cells (p = 0.002), CD8 + T cells (p < 0.001), regulatory T cells (p = 0.006), M2-type macrophages (p < 0.001), and significantly lower infiltration of naïve B cells (p = 0.002), plasma cells (p < 0.001), resting memory CD4 + T cells (p < 0.001) and eosinophils (p = 0.045). Candidate proteins were mainly involved in antigen processing and presentation, stem cell differentiation, and type I interferon pathways. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00070-1.
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Increasing evidence indicates that DNA polymerase epsilon (POLE), which mediates DNA damage repair, is significantly associated with tumor prognosis. This study aimed to analyze POLE expression in tumor samples and its prognostic value for patients with clear cell renal cell carcinoma (ccRCC). We found significantly elevated POLE expression in ccRCC tissues compared with normal tissues of multiple independent cohorts. The POLE expression levels of 523 patients with ccRCC (The Cancer Genome Atlas RNA-seq data) and 179 patients with ccRCC with immunohistochemical data (Fudan University Shanghai Cancer Center) were analyzed to investigate the prognostic implications of POLE expression. Cox regression analyses were implemented to explore the effect of POLE expression on the prognosis of pan-cancer. These findings revealed that elevated POLE expression levels significantly correlated with shorter overall survival (p < 0.001, n = 701) of patients with ccRCC. These data indicate that POLE expression may serve as a prognostic biomarker for cancers. Although POLE mutations were not significantly associated with survival benefits conferred upon patients with ccRCC, a CD4+ T cell-regulated immune microenvironment was significantly activated. Moreover, we found that POLE expression in cancers significantly correlated with an immunosuppressive tumor microenvironment, higher intratumoral heterogeneity, and expression of immune checkpoint genes PDCD1, CTLA4, and CD86, possibly mediated via the JAK/STAT and Notch signaling pathways. In conclusion, the present study is the first to our knowledge to indicate that elevated POLE expression is significantly associated with poor survival and an immune-suppressive tumor microenvironment in ccRCC. These findings suggest that POLE can serve as a biomarker for guiding molecular diagnosis and facilitating the development of novel individual therapeutic strategies for patients with advanced ccRCC.
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Elevation in homocysteine (Hcy) level is associated with insulin resistance; however, the causality between them and the underlying mechanism remain elusive. Here, we show that Hcy induces insulin resistance and causes diabetic phenotypes by protein cysteine-homocysteinylation (C-Hcy) of the pro-insulin receptor (pro-IR). Mechanistically, Hcy reacts and modifies cysteine-825 of pro-IR in the endoplasmic reticulum (ER) and abrogates the formation of the original disulfide bond. C-Hcy impairs the interaction between pro-IR and the Furin protease in the Golgi apparatus, thereby hindering the cleavage of pro-IR. In mice, an increase in Hcy level decreases the mature IR level in various tissues, thereby inducing insulin resistance and the type 2 diabetes phenotype. Furthermore, inhibition of C-Hcy in vivo and in vitro by overexpressing protein disulfide isomerase rescues the Hcy-induced phenotypes. In conclusion, C-Hcy in the ER can serve as a potential pharmacological target for developing drugs to prevent insulin resistance and increase insulin sensitivity.
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Antígenos CD/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Homocisteína/metabolismo , Hiper-Homocisteinemia/metabolismo , Resistência à Insulina , Processamento de Proteína Pós-Traducional , Receptor de Insulina/metabolismo , Tecido Adiposo/metabolismo , Animais , Células CHO , Cricetulus , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Modelos Animais de Doenças , Furina/genética , Furina/metabolismo , Células HEK293 , Células Hep G2 , Homocisteína/sangue , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/genética , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , RatosRESUMO
Traditionally, clear cell papillary renal cell carcinoma (ccpRCC) was considered to share similar molecular and histological characteristics with clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC). Here we aimed to identify somatic and germline variants of ccpRCC. For this purpose, we conducted whole-exome sequencing to detect somatic variants in the tissues of 18 patients with pathologically confirmed ccpRCC, who underwent surgical treatment at Fudan University Shanghai Cancer Center. Targeted sequencing was conducted to detect germline variants in paired tumor or normal tissues or blood. Somatic and germline variants of ccRCC and Renal cell carcinoma included in The Cancer Genome Atlas data and other published data were analyzed as well. The molecular profiles of ccpRCC, ccRCC and pRCC were compared. Among the 387 somatic variants identified, TCEB1 (3/18) and VHL (3/18) variants occurred at the highest frequencies. Germline mutation detection showed that nine variants associated with Fanconi anemia (VAFAs) pathway (FANCA, 6/18; FANCI, 3/18) were identified in 18 ccpRCC patients. Among ccpRCC patients with VAFAs, five out of eight patients had second primary malignancy or family history of cancer. Somatic variants characteristics may distinguish ccpRCC from ccRCC or pRCC and germline VAFAs may be a molecular characterization of ccpRCC. Compared with ccRCC or pRCC, ccpRCC patients may be significantly correlated with higher risk of developing second primary malignancy.
Assuntos
Carcinoma Papilar/genética , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Segunda Neoplasia Primária/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma Papilar/patologia , Carcinoma de Células Renais/patologia , China , Diagnóstico Diferencial , Variação Genética/genética , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/patologia , Transdução de Sinais/genéticaRESUMO
OBJECTIVE: To observe the effect of electroacupuncture (EA) on the expression of NF-κB p65 in hippocampus and the morphology of hippocampus in rats with chronic fatigue syndrome (CFS), so as to explore its mechanism in improving cognitive dysfunction of CFS. METHODS: Forty-eight SD rats were randomly divided into control, model, EA and inhibitor groups (n=12 in each group). The CFS model was established by multi-factor compound stress stimulation method. Rats of the EA group received EA (50 Hz, 1 mA) at "Baihui" (GV20), Emotional Area I and bilateral Sensory Area for 30 min, once daily for 15 days. For rats in the inhibitor group, pyrrolidine dithiocarbamate (100 mg·kg-1·d-1) was injected intraperitoneally, once a day for 15 days. Learning and memory ability was evaluated by Morris water maze test. HE staining was used to observe the morphology of hippocampus. Western blot was used to determine the expression level of NF-κB p65 in hippocampus. RESULTS: After mode-ling, the general status score was increased ï¼P<0.01ï¼, the escape latency was prolonged(P<0.01), the times of crossing the platform was decreased(P<0.01), and the expression level of NF-κB p65 in hippocampus tissue was significantly increased (P<0.05) in the model group compared with the control group. Compared with the model group, the general status score was decreased ï¼P<0.01ï¼, the escape latency was shortened(P<0.01), the times of crossing the platform was increased(P<0.01), and the expression level of NF-κB p65 in hippocampus tissue was significantly decreased (P<0.05) in the EA and inhibitor groups. HE staining showed that in the model group, the hippocampal nerve cells were arranged disorderly, the structure was loose, and the number of apoptotic bodies and inflammatory cells was significantly increased. The degree of tissue damage of the EA and inhibitor groups was milder than that of the model group. CONCLUSION: EA can improve the cognitive function in CFS rats, which may be associated with its effect in inhibiting the expression of NF-κB and reducing the inflammation response in hippocampus.
Assuntos
Doença de Alzheimer , Eletroacupuntura , Síndrome de Fadiga Crônica , Animais , Cognição , Síndrome de Fadiga Crônica/genética , Síndrome de Fadiga Crônica/terapia , Hipocampo , NF-kappa B/genética , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE: Blockade of immune checkpoint and angiogenesis is an effective treatment strategy for advanced or metastatic renal cell carcinoma (RCC). We report the results of camrelizumab plus famitinib in the RCC cohort of an open-label, multicenter, phase II basket study. PATIENTS AND METHODS: Eligible patients were enrolled to receive camrelizumab (200 mg i.v. every 3 weeks) and famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per RECIST version 1.1. RESULTS: Totally, 38 patients were recruited, including 13 (34.2%) treatment-naïve and 25 (65.8%) previously treated patients. With a median duration from enrollment to data cutoff of 16.5 months (range, 6.1-20.4), 23 patients achieved a confirmed objective response, and ORR was 60.5% [95% confidence interval (CI), 43.4-76.0]. Responses in 18 (78.3%) responders were still ongoing, and Kaplan-Meier estimated median duration of response had not been reached yet (range, 1.0+-14.8+ months). Median progression-free survival (PFS) was 14.6 months (95% CI, 6.2-not reached). ORR was 84.6% (95% CI, 54.6-98.1) in treatment-naïve patients and 48.0% (95% CI, 27.8-68.7) in pretreated patients; median PFS had not been reached and was 13.4 months (95% CI, 4.1-not reached), respectively. Most common grade 3 or 4 treatment-related adverse events included proteinuria (18.4%), hypertension (18.4%), decreased neutrophil count (13.2%), palmar-plantar erythrodysesthesia syndrome (10.5%), and hypertriglyceridemia (10.5%). No treatment-related deaths occurred, and no new safety signals were observed. CONCLUSIONS: Camrelizumab plus famitinib showed potent and enduring antitumor activity in patients with advanced or metastatic RCC, both in treatment-naïve and previously treated population.