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Watershed ecosystems play a pivotal role in maintaining the global carbon cycle and reducing global warming by serving as vital carbon reservoirs for sustainable ecosystem management. In this study, we based on the "quantity-mechanism-scenario" frameworks, integrate the MCE-CA-Markov and InVEST models to evaluate the spatiotemporal variations of carbon stocks in mid- to high-latitude alpine watersheds in China under historical and future climate scenarios. Additionally, the study employs the Geographic Detector model to explore the driving mechanisms influencing the carbon storage capacity of watershed ecosystems. The results showed that the carbon stock of the watershed increased by about 15.9 Tg from 1980 to 2020. Fractional Vegetation Cover (FVC), Digital Elevation Model (DEM), and Mean Annual Temperature (MAT) had the strongest explanatory power for carbon stocks. Under different climate scenarios, it was found that the SSP2-4.5 scenario had a significant rise in carbon stock from 2020 to 2050, roughly 24.1 Tg. This increase was primarily observed in the southeastern region of the watersheds, with forest and grassland effectively protected. Conversely, according to the SSP5-8.5 scenario, the carbon stock would decrease by about 50.53 Tg with the expansion of cultivated and construction land in the watershed's southwest part. Therefore, given the vulnerability of mid- to high-latitude mountain watersheds, global warming trends continue to pose a greater threat to carbon sequestration in watersheds. Our findings carry important implications for tackling potential ecological threats in mid- to high-latitude watersheds in the Northern Hemisphere and assisting policymakers in creating carbon sequestration plans, as well as for reducing climate change.
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Carbono , Mudança Climática , Ecossistema , Monitoramento Ambiental , China , Carbono/análise , Sequestro de Carbono , Ciclo do Carbono , Conservação dos Recursos Naturais , Modelos TeóricosRESUMO
BACKGROUND: The beneficial effects of first-line programmed death-1 (PD-1) inhibitors plus chemotherapy in patients with low programmed death-ligand 1 (PD-L1)-expressing advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma are controversial. METHODS: We conducted a retrospective analysis of patients with G/GEJ adenocarcinoma who had undergone first-line treatment with PD-1 inhibitors plus chemotherapy between October 2017 and May 2022. The primary outcomes were objective response rate (ORR) and progression-free survival (PFS). SPSS software V27.0 was used for data analysis. RESULTS: Of 345 enrolled patients, 290 had measurable lesions. The overall ORR was 59.3%. PD-L1 status was available in 171 patients, and 67.8% of them were considered as low PD-L1 expression level (combined positive score (CPS) < 5). Patients with PD-L1 CPS < 5 showed a lower response rate (51.1% vs 70.8%, P = 0.024) and a worse PFS (P = 0.009) compared to those with PD-L1 CPS ≥ 5. In the PD-L1 low-expression cohort, patients with non-diffuse type, GEJ cancer, synchronous metastasis, distant lymph node metastasis, liver metastasis, non-peritoneal metastasis, and HER2 positive were significantly associated with higher response rates to PD-1 inhibitors plus chemotherapy (P < 0.05). The presence of peritoneal metastasis (P = 0.028) and diffuse type (P = 0.046) were identified as independent predictors of poor PFS in multivariate analysis of the PD-L1 CPS < 5 subgroup. When evaluated for correlation with overall survival (OS) in the PD-L1 low-expression subgroup, peritoneal metastasis was found to be the only independent prognostic factor of an increased risk of death (hazard ratio: 2.31, 95% CI 1.09-4.90; P = 0.029). CONCLUSIONS: PD-L1 CPS ≥ 5 is significantly associated with improved response and extended PFS in G/GEJ cancer patients treated with a combination of PD-1 inhibitors and chemotherapy. Specific subgroups within the low PD-L1-expressing population, such as those with non-diffuse-type tumors and without peritoneal metastases, may also benefit from immunotherapy combined with chemotherapy.
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Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Biomarcadores Tumorais , Neoplasias Esofágicas , Junção Esofagogástrica , Inibidores de Checkpoint Imunológico , Neoplasias Gástricas , Humanos , Masculino , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Feminino , Pessoa de Meia-Idade , Junção Esofagogástrica/patologia , Junção Esofagogástrica/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Idoso , Estudos Retrospectivos , Biomarcadores Tumorais/metabolismo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Idoso de 80 Anos ou mais , PrognósticoRESUMO
BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.
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Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina , Cetuximab , Neoplasias Colorretais , Fluoruracila , Leucovorina , Neoplasias Hepáticas , Compostos Organoplatínicos , Proteínas Proto-Oncogênicas B-raf , Humanos , Cetuximab/administração & dosagem , Cetuximab/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Feminino , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Leucovorina/uso terapêutico , Leucovorina/administração & dosagem , Fluoruracila/uso terapêutico , Fluoruracila/administração & dosagem , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Idoso , Adulto , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Camptotecina/administração & dosagem , Resultado do Tratamento , Proteínas ras/genéticaRESUMO
Anaplastic lymphoma kinase (ALK) fusion-positive colorectal cancer (CRC) is a rare and chemotherapy-refractory subtype that lacks established and effective treatment strategies. Additionally, the efficacy and safety of ALK inhibitors (ALKi) in CRC remain undetermined. Herein, we examined a series of ALK-positive CRC patients who underwent various lines of ALKi treatment. Notably, we detected an ALK 1196M resistance mutation in a CRC patient who received multiple lines of chemotherapy and ALKi treatment. Importantly, we found that Brigatinib and Lorlatinib demonstrated some efficacy in managing this patient, although the observed effectiveness was not as pronounced as in non-small cell lung cancer cases. Furthermore, based on our preliminary analyses, we surmise that ALK-positive CRC patients are likely to exhibit inner resistance to Cetuximab. Taken together, our findings have important implications for the treatment of ALK-positive CRC patients.
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Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P = 0.003), higher overall response rate (44.0% versus 13.0%, P = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+ T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239 .
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Aminopiridinas , Benzamidas , Neoplasias Colorretais , Inibidores de Histona Desacetilases , Humanos , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/efeitos adversos , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral , Fator A de Crescimento do Endotélio VascularRESUMO
Background: Patients with initially unresectable colorectal cancer liver metastases (IU-CRLM) might benefit from using an effective systemic treatment followed by resection of liver metastases but the curative success rate is quite low. Indeed, nearly one-third of patients exhibit early recurrence within the first 6 months after surgery, and these individuals often have poor overall survival. Objectives: This study aims to clarify the application value of serial circulating tumor DNA (ctDNA) analysis in predicting the clinical outcome of IU-CRLM patients following liver metastasectomy. Design: A retrospective study was conducted on a cohort of patients with IU-CRLM between February 2018 and April 2021. Methods: Plasma samples at different time points during CRLM treatment [baseline (BL), preoperation (PRE), postoperation (POST), end-of-treatment (EOT), and progressive disease (PD)] were retrospectively collected from patients with initially unresectable CRLM enrolled at the Sun Yat-sen University Cancer Center. Dynamic changes of SEPTIN 9 (SEPT9) and Neuropeptide Y (NPY) methylated circulating tumor DNA (MetctDNA) levels in serial plasma samples were detected using droplet-digital PCR (ddPCR). Results: SEPT9 and NPY genes were hypermethylated in colon cancer cell lines and tissues while no difference was observed between primary and metastatic tumors. Patients with MetctDNA positive at POST or EOT had significantly lower recurrence-free survival (RFS) compared to patients with MetctDNA negative at these time points [POST: Hazard ratio (HR) 9.44, 95% confidence interval (CI) 5.15-17.30, p < 0.001; EOT: HR 11.48, 95% CI 3.27-40.31, p < 0.001]. Multivariate analysis demonstrated that POST (OR 33.96, 95% CI 4.03-286.10, p = 0.001) and EOT (OR 18.36, 95% CI 1.14-295.71, p = 0.04) MetctDNA was an independent risk factor for early recurrence. Time-dependent receiver operating characteristic curve (T-ROC) analysis revealed that area under the curve (AUC) value was greatest at the relapse time point of 6 months post-intervention, with POST-AUC and EOT-AUC values of 0.74 (95% CI 0.66-0.81) and 0.73 (95% CI 0.53-0.94), respectively. Serial MetctDNA analysis showed that RFS was significantly lower in patients with no MetctDNA clearance compared with those with MetctDNA clearance (HR 26.05, 95% CI 4.92-137.81, p < 0.001). Conclusion: Our study confirmed that serial ctDNA analysis of NPY and SEPT9 gene methylation could effectively predict early recurrence in IU-CRLM patients, especially at POST and EOT.
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Hair follicle stem cells (HFSCs) in the bulge are a multipotent adult stem cell population. They can periodically give rise to new HFs and even regenerate the epidermis and sebaceous glands during wound healing. An increasing number of biomarkers have been used to isolate, label, and trace HFSCs in recent years. Considering more detailed data from single-cell transcriptomics technology, we mainly focus on the important HFSC molecular markers and their regulatory roles in this review.
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Background: Transmembrane E3 ubiquitin ligase (RNF43) mutations are present in approximately 6-18% of colorectal cancers (CRC) and could enhance Wnt/ß-catenin signaling, which is emerging as a promising therapeutic target. This study aims to investigate the clinical and molecular characteristics and potential heterogeneity of RNF43-mutant CRC. Methods: A total of 78 patients with RNF43-mutant CRC were enrolled from July 2013 to November 2022. Demographic data, clinical characteristics, treatment regimens used, and survival outcomes were collected and analyzed. Results: Our study uncovered that patients with RNF43 mutations in the N-terminal domain (NTD; n = 50) exhibited shorter overall survival (OS; median months, 50.80 versus not reached; p = 0.043) compared to those in the C-terminal domain (CTD; n = 17). Most RNF43 mutations in NTD had positive primary lymph node status, low tumor mutation burden (TMB-L), and correlated with proficient mismatch repair (pMMR)/microsatellite stable (MSS) status. By contrast, RNF43 mutations in CTD were significantly enriched in deficient MMR (dMMR)/microsatellite instability (MSI-H) tumors with high TMB (TMB-H). N-terminal RNF43-mutated tumors harbored a hotspot variant (RNF43 R117fs), which independently predicted a significantly worse outcome in pMMR/MSS CRC with a median OS of 18.9 months. Patients with RNF43 mutations and the BRAF V600E alterations demonstrated sensitivity to BRAF/EGFR inhibitors. Moreover, we observed that pMMR/MSS patients with RNF43 R117fs mutation had a higher incidence of stage IV, ⩾2 metastatic sites, low TMB, and none of them received PD-1/PD-L1 inhibitor therapy. Conclusion: Our findings provide the first evidence that RNF43 mutations in NTD and the R117fs variant correlate with a poorer prognosis in CRC patients, providing strategies for Wnt-targeted therapy to improve clinical efficacy.
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BACKGROUND: This study updated 3-year analyses to further characterize the impact of docetaxel, cisplatin, and fluorouracil (TPF) chemotherapy followed by surgery. METHODS: This study was a single-center phase 2 clinical trial. Patients with a diagnosis of borderline resectable esophageal squamous cell carcinoma (BR-ESCC) because of the primary tumor or bulky lymph node that potentially invaded adjacent organs were eligible. The treatment started with TPF chemotherapy followed by surgery if the cancer was resectable, or by concurrent chemoradiation if it was unresectable. This updated report presents the 3-year overall survival (OS) and progression-free survival (PFS) rates. RESULTS: Surgery was performed for 27 patients (57.4%), and R0 resection was confirmed in 25 patients (53.2%). Pathologic complete response was confirmed in four patients (8.5%). The median follow-up time for the surviving patients was 44.8 months (range, 3.4-74.6 months). The median OS for all the patients was 41.9 months (95% confidence interval [CI], 18.6-65.3 months), with a median PFS of 38.7 months (95% CI, 23.5-53.9 months). The 3-year survival rate for all the patients was 54.4%. The 3-year survival rate for the R0 patients was 65.4%. CONCLUSION: Long-term follow-up evaluation confirmed that TPF followed by surgery is feasible and promising in terms of survival for BR-ESCC patients. Trial Registration ClinicalTrials.gov identifer: NCT02976909.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Cisplatino , Neoplasias Esofágicas/tratamento farmacológico , Quimioterapia de Indução , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Taxoides , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Paclitaxel , FluoruracilaRESUMO
Background: Focal cortical dysplasia (FCD) IIb and tuberous sclerosis complex (TSC) are common causes of drug-resistant epilepsy in children. However, the etiologies related to the development of FCD IIb and TSC are not fully understood. α-synuclein (α-syn) is a member of synucleins family that plays crucial roles in modulating synaptic transmission in central nervous system. Here, we explored the expression profiles and potential pathogenic functions of α-syn in cortical lesions of epileptic patients with FCD IIb and TSC. Methods: Surgical specimens from epileptic patients with FCD IIb and TSC, as well as FCD rats generated by in utero X-ray-radiation were adopted in this study and studied with immunohistochemistry, immunofluorescence, western blotting, and co-immunoprecipitation etc. molecular biological techniques. Result: Our results showed that α-syn expression was reduced in FCD IIb and TSC lesions. Specifically, α-syn protein was intensely expressed in dysplastic neurons (DNs) and balloon cells (BCs) in FCD IIb lesions, whereas was barely detected in DNs and giant cells (GCs) of TSC lesions. Additionally, p-α-syn, the aggregated form of α-syn, was detected in DNs, BCs, GCs, and glia-like cells of FCD IIb and TSC lesions. We previous showed that the function of N-methyl-D-aspartate receptor (NMDAR) was enhanced in FCD rats generated by X-ray-radiation. Here, we found the interaction between α-syn and NMDAR subunits NMDAR2A, NMDAR2B were augmented in cortical lesions of FCD patients and FCD rats. Conclusion: These results suggested a potential role of α-syn in the pathogenesis of FCD IIb and TSC by interfering with NMDAR.
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Solitary fibrous tumors (SFTs) are rare mesenchymal tumors with unpredictable evolution and with a recurrence or metastasis rate of 10-40%. Current medical treatments for relapsed SFTs remain ineffective. Here, we identify potential therapeutic targets and risk factors, including IDH1 p.R132S, high PD-L1 expression, and predominant macrophage infiltration, suggesting the potential benefits of combinational immune therapy and targeted therapy for SFTs. An integrated risk model incorporating mitotic count, density of Ki-67+ cells and CD163+ cells, MTOR mutation is developed, applying a discovery cohort of 101 primary non-CNS patients with negative tumor margins (NTM) and validated in three independent cohorts of 210 SFTs with the same criteria, and in 36 primary CNS SFTs with NTM. Compared with the existing models, our model shows significantly improved efficacy in identifying high-risk primary non-CNS and CNS SFTs with NTM for tumor progression.Our findings hold promise for advancing therapeutic strategies and refining risk prediction in SFTs.
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Febre Grave com Síndrome de Trombocitopenia , Neoplasias de Tecidos Moles , Tumores Fibrosos Solitários , Humanos , Tumores Fibrosos Solitários/genética , Tumores Fibrosos Solitários/terapia , Tumores Fibrosos Solitários/metabolismo , Fatores de Risco , Neoplasias de Tecidos Moles/patologia , Medição de RiscoRESUMO
BACKGROUND: Pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a life-threatening systemic vasculitis featured by liability to renal involvement. However, there are few studies on the risk factors and predictive models for renal outcomes of AAV in children. METHODS: Data from 179 AAV children in multiple centers between January 2012 and March 2020 were collected retrospectively. The risk factors and predictive model of end-stage renal disease (ESRD) in AAV were explored. RESULTS: Renal involvement was the most typical manifestation (95.5%), and the crescent was the predominant pathological lesion (84.9%). The estimated glomerular filtration rate (eGFR) was evaluated in 114 patients, of whom 59.6% developed ESRD, and the median time to ESRD was 3.20 months. The eGFR [P = 0.006, odds ratio (OR) = 0.955, 95% confidence interval (CI) = 0.924-0.987] and the percentages of global glomerulosclerosis (pGGS; P = 0.018, OR = 1.060, 95% CI = 1.010-1.112) were independent risk factors for ESRD of renal biopsy. Based on the pGGS and eGFR at renal biopsy, we developed three risk grades of ESRD and one predictive model. The KaplanâMeier curve indicated that renal outcomes were significantly different in different risk grades (P < 0.001). Compared with serum creatinine at baseline, the predictive model had higher accuracy (0.86 versus 0.58, P < 0.001) and a lower coefficient of variation (0.07 versus 0.92) in external validation. CONCLUSIONS: Renal involvement is the most common manifestation of pediatric AAV in China, of which more than half deteriorates into ESRD. The predictive model based on eGFR at renal biopsy and the pGGS may be stable and accurate in speculating the risk of ESRD in AAV children. Supplementary file 2 (MP4 18937 KB).
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Myocardial fibrosis is the fundamental remodeling process in myocardial ischemia (MI) and also the major contributor of heart failure and death. Tanshinol (Danshensu in Chinese, DSS), a major ingredient of salvia mitiorrhiza Bunge (Lamiaceae) root, exerted significant cardio protection effects. In this study, we aimed to identify the action target and then uncover the mechanism of DSS alleviating myocardial fibrosis. The pharmacological activities of DSS protecting ischemic cardiac was assessed and the myocardial proteomics was carried out. To identify the target of DSS, a cellular thermal shift assay combined with LC-MS identification was conducted. Surface plasmon resonance assay, molecular dynamics simulation and pharmacological and molecular biology approaches were adopted to explore the action mechanisms of DSS. Our results revealed that DSS effectively alleviated MI-induced left ventricle dysfunctions and the increasements of circulating myocardial markers. Besides, DSS significantly reversed the proteomic profile related to myocardial fibrotic processes and the ERK2 was identified as a crucial cellular target of DSS. DSS abated the temperature-dependent denaturation of ERK2 in a dose-dependent manner and the KD value of DSS and ERK2 was 60.19 µM. After Ang II stimulation, DSS suppressed the phosphorylation of Thr188 rather than the classic residues in TEY motif. DSS interfered the ERK2 homo-dimerization and then blocked the intermolecular autophosphorylation at Thr188 site. Thereout, DSS inhibited the nuclear translocation of ERK2 and the expression of downstream fibrotic biomolecules. Collectively, our results demonstrated that DSS targeted ERK2 and suppressed the intermolecular autophosphorylation at Thr188 residue, thus protecting ischemic myocardia from fibrosis remodeling.
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Cardiomiopatias , Proteômica , Humanos , Fosforilação , Miocárdio/patologia , Cardiomiopatias/patologia , Fibrose , Isquemia/patologiaRESUMO
To explore the clinical effect of "micromovement" in preventing intraoperative acquired pressure injures (IAPIs) among patients experiencing surgery in supine position. A total of 200 patients accepting elective surgery in supine position from 10 May 2023 to 4 July 2023 at Shulan (Hangzhou) Hospital were selected and randomized into two groups (experimental group, n = 100; control group, n = 100). For control group patients, soft silicone foam dressing was applied to the sacrococcygeal region. On the basis of the treatment for control group patients, "micromovement" was implemented among experimental group patients. During this process, the operating table was tilted for 15° leftwards and rightwards alternately every 1 h, and the tilt angle was maintained for 5 min to prevent IAPIs. Finally, comparisons between the two groups were made in terms of the sacrococcygeal IAPI incidence, relative temperature differences (ΔT) on sacrococcygeal skin, and job satisfaction of nurses. Compared with control group patients, patients from the experimental group exhibited lower IAPI incidence (2% vs. 10%), reduced ΔT between the sacrococcygeal skin and surrounding normal skin [0 (-0.1, 0.1) vs. 0.2 (-0.2, 0.4)], and elevated job satisfaction of nurses (80% vs. 66%). All the differences were statistically significant (p < 0.05). "Micromovement" implemented intraoperatively among patients receiving surgery in supine position is able to lower the IAPI incidence by five times and elevate job satisfaction of nurses.
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BACKGROUND: Cysteine dioxygenase 1 (CDO1) is frequently methylated, and its expression is decreased in many human cancers including breast cancer (BC). However, the functional and mechanistic aspects of CDO1 inactivation in BC are poorly understood, and the diagnostic significance of serum CDO1 methylation remains unclear. METHODS: We performed bioinformatics analysis of publicly available databases and employed MassARRAY EpiTYPER methylation sequencing technology to identify differentially methylated sites in the CDO1 promoter of BC tissues compared to normal adjacent tissues (NATs). Subsequently, we developed a MethyLight assay using specific primers and probes for these CpG sites to detect the percentage of methylated reference (PMR) of the CDO1 promoter. Furthermore, both LentiCRISPR/dCas9-Tet1CD-based CDO1-targeted demethylation system and CDO1 overexpression strategy were utilized to detect the function and underlying mechanism of CDO1 in BC. Finally, the early diagnostic value of CDO1 as a methylation biomarker in BC serum was evaluated. RESULTS: CDO1 promoter was hypermethylated in BC tissues, which was related to poor prognosis (p < .05). The CRISPR/dCas9-based targeted demethylation system significantly reduced the PMR of CDO1 promotor and increased CDO1 expression in BC cells. Consequently, this leads to suppression of cell proliferation, migration and invasion. Additionally, we found that CDO1 exerted a tumour suppressor effect by inhibiting the cell cycle, promoting cell apoptosis and ferroptosis. Furthermore, we employed the MethyLight to detect CDO1 PMR in BC serum, and we discovered that serum CDO1 methylation was an effective non-invasive biomarker for early diagnosis of BC. CONCLUSIONS: CDO1 is hypermethylated and acts as a tumour suppressor gene in BC. Epigenetic editing of abnormal CDO1 methylation could have a crucial role in the clinical treatment and prognosis of BC. Additionally, serum CDO1 methylation holds promise as a valuable biomarker for the early diagnosis and management of BC.
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Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Neoplasias , Humanos , Cisteína Dioxigenase/genética , Apoptose , Ciclo Celular , DesmetilaçãoRESUMO
Histopathological images of colorectal liver metastases (CRLM) contain rich morphometric information that may predict patients' outcomes. However, to our knowledge, no study has reported any practical deep learning framework based on the histology images of CRLM, and their direct association with prognosis remains largely unknown. In this study, we developed a deep learning-based framework for fully automated tissue classification and quantification of clinically relevant spatial organization features (SOFs) in H&E-stained images of CRLM. The SOFs based risk-scoring system demonstrated a strong and robust prognostic value that is independent of the current clinical risk score (CRS) system in independent clinical cohorts. Our framework enables fully automated tissue classification of H&E images of CRLM, which could significantly reduce assessment subjectivity and the workload of pathologists. The risk-scoring system provides a time- and cost-efficient tool to assist clinical decision-making for patients with CRLM, which could potentially be implemented in clinical practice.
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The impact of weather variability and air pollutants on tuberculosis (TB) has been a research hotspot. Previous studies have mostly been limited to a certain area or with a small sample size of cases, and multi-scale systematic studies are lacking. In this study, 14,816,329 TB cases were collected from 31 provinces in China between 2004 and 2018 to estimate the association between TB risk and meteorological factors and air pollutants using a two-stage time-series analysis. The impact and lagged time of meteorological factors and air pollutants on TB risk varied greatly in different provinces and regions. Overall cumulative exposure-response summary associations across 31 provinces suggested that high monthly mean relative humidity (RH) (66.8-82.4%, percentile56-100 (P56-100)), rainfall (316.5-331.1 mm, P96-100), PM2.5 exposure concentration (93.3-145.0 µg/m3, P58-100), and low monthly mean wind speed (1.6-2.1 m/s, P0-38) increased the risk of TB incidence, with a relative risk (RR) of 1.10 (95% CI: 1.04-1.16), 1.10 (95% CI: 1.03-1.16), 2.08 (95% CI: 1.18-3.65), and 2.06 (95% CI: 1.27-3.33), and attributable risk percent (AR%) of 9%, 9%, 52%, and 51%, respectively. Conversely, high monthly average wind speed (2.3-2.9 m/s, P54-100) and mean temperature (20.2-25.3 °C, P79-96), and low monthly average rainfall (2.4-25.2 mm, P0-7) and concentration of SO2 (8.1-21.2 µg/m3, P0-16) exposure decreased the risk of TB incidence, with an overall cumulative RR of 0.92 (95% CI: 0.87-0.98), 0.74 (95% CI: 0.59-0.94), 0.87 (95% CI: 0.79-0.95), and 0.72 (95% CI: 0.56-0.93), respectively. Our study provided insights into future planning of public health interventions for TB.
Assuntos
Poluentes Atmosféricos , Poluição do Ar , Tuberculose , Humanos , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Tuberculose/epidemiologia , Tuberculose/etiologia , Conceitos Meteorológicos , China/epidemiologia , Fatores de Risco , Material Particulado/análiseRESUMO
Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive and heterogeneous tumor composed of adenocarcinoma (ACA) and neuroendocrine carcinoma (NEC). The genomic properties and evolutionary clonal origins of MANEC remain unclear. We conduct whole-exome and multiregional sequencing on 101 samples from 33 patients to elucidate their evolutionary paths. We identify four significantly mutated genes, TP53, RB1, APC, and CTNNB1. MANEC resembles chromosomal instability stomach adenocarcinoma in that whole-genome doubling in MANEC is predominant and occurs earlier than most copy-number losses. All tumors are of monoclonal origin, and NEC components show more aggressive genomic properties than their ACA counterparts. The phylogenetic trees show two tumor divergence patterns, including sequential and parallel divergence. Furthermore, ACA-to-NEC rather than NEC-to-ACA transition is confirmed by immunohistochemistry on 6 biomarkers in ACA- and NEC-dominant regions. These results provide insights into the clonal origin and tumor differentiation of MANEC.
Assuntos
Adenocarcinoma , Carcinoma Neuroendócrino , Neoplasias Gástricas , Humanos , Filogenia , Microdissecção , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , GenômicaRESUMO
Aging is characterized by persistent low-grade systematic inflammation, which is largely responsible for the occurrence of various age-associated diseases. We and others have previously reported that long-lived people (such as centenarians) can delay the onset of or even escape certain major age-related diseases. Here, by screening blood transcriptome and inflammatory profiles, we found that long-lived individuals had a relatively lower inflammation level (IL6, TNFα), accompanied by up-regulation of activating transcription factor 7 (ATF7). Interestingly, ATF7 expression was gradually reduced during cellular senescence. Loss of ATF7 induced cellular senescence, while overexpression delayed senescence progress and senescence-associated secretory phenotype (SASP) secretion. We showed that the anti-senescence effects of ATF7 were achieved by inhibiting nuclear factor kappa B (NF-κB) signaling and increasing histone H3K9 dimethylation (H3K9me2). In Caenorhabditis elegans, ATF7 overexpression significantly suppressed aging biomarkers and extended lifespan. Our findings suggest that ATF7 is a longevity-promoting factor that lowers cellular senescence and inflammation in long-lived individuals.