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1.
Transl Lung Cancer Res ; 11(8): 1578-1590, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36090640

RESUMO

Background: Cell free DNA (cfDNA) is an exciting biomarker with applications across the cancer care continuum. Determinants of cfDNA shedding dynamics remain an active research area. We performed a detailed analysis of tumor volume and factors associated with detection of cfDNA mutations. Methods: Patients with advanced non-small cell lung cancers (NSCLCs) were prospectively enrolled on a plasma biomarker protocol. Next generation sequencing (NGS) was performed using a validated, bias-corrected, hybrid-capture panel assay of lung cancer-associated genes. Volume of tumor in different subsites and total tumor volume were determined through manual volume delineation using PET/CT and brain magnetic resonance imaging (MRI) imaging. The primary endpoint was detection of cfDNA mutation; secondary endpoints were overall survival (OS) and variant allele frequency (VAF). Results: There were 110 patients included, 78 of whom had at least one mutation detected. Median total tumor volume for the entire cohort, patients with mutation detected, and patients with no mutation detected were 66 mL (range, 2-1,383 mL), 76 mL (range, 5-1,383 mL), and 45 mL (range, 2-460 mL), respectively (P=0.002; mutation detected vs. not). The optimal total tumor volume threshold to predict increased probability of mutation detection was 65 mL (P=0.006). Total tumor volume greater than 65 mL was a significant predictor of mutation detection on multivariate analysis (OR: 4.30, P=0.003). Significant predictors of OS were age (HR: 1.04, P=0.002), detection of cfDNA mutation (HR: 2.11, P=0.024), and presence of bone metastases (HR: 1.66, P=0.047). Conclusions: Total tumor volume greater than 65 mL was associated with cfDNA mutation detection in patients with advanced NSCLC.

2.
Chemosphere ; 308(Pt 1): 136311, 2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36067810

RESUMO

Potentially toxic elements (PTEs) pollution causes a great threat to microbial metabolism, which plays a vital role in studying soil nutrient cycling and predicting carbon (C) storage in agroecosystems. However, the responses of microbial metabolism characteristic to heavy metal contamination and the mechanisms through which microbial metabolism mediate nutrient cycling and C dynamics in contaminated soil remain elusive. Here, we performed an incubation experiment over 80 days to investigate the variations in microbial metabolic limitation under various Pb levels (0, 100, 500, 800, 1500, 2000, and 3000 mg Pb kg-1 dry soil) in cropland soil using extracellular enzymatic stoichiometry, and to reveal the impact of Pb stress on soil C storage by associating with microbial metabolic quotients (qCO2) and C use efficiency (CUE). The results showed microbial relative C limitation and phosphorus (P) limitation were observed in Pb-contaminated soils. Pb addition enhanced the microbial relative C limitation by approximately 7.3%, while decreasing the P limitation by approximately 12.3%. Furthermore, Pb addition led to higher qCO2 (from 8.75 to 108 µg C kg-1 MBC-1 d-1) duo to the increase of microbial relative C limitation, suggesting that the more CO2 was released of per unit of microbial biomass C. The increase of microbial relative C limitation reduced CUE (from 0.35 to 0.10) because of the change in microbial metabolism from growth to respiration maintenance under Pb stress. Consequently, the CUE and qCO2 together determined the loss of soil C. Our study reveals that microbial relative C limitation is the dominant driver of soil C loss and provides important knowledge of microbial metabolic limitation regulating soil C turnover in PTEs-contaminated agricultural soils.

3.
BMC Pregnancy Childbirth ; 22(1): 698, 2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36088304

RESUMO

BACKGROUND: Fetal macrosomia is common occurrence in pregnancy, which is associated with several adverse prognosis both of maternal and neonatal. While, the accuracy of prediction of fetal macrosomia is poor. The aim of this study was to develop a reliable noninvasive prediction classifier of fetal macrosomia. METHODS: A total of 3600 samples of routine noninvasive prenatal testing (NIPT) data at 12+ 0-27+ 6 weeks of gestation, which were subjected to low-coverage whole-genome sequencing of maternal plasma cell-free DNA (cfDNA), were collected from three independent hospitals. We identified set of genes with significant differential coverages by comparing the promoter profiling between macrosomia cases and controls. We selected genes to develop classifier for noninvasive predicting, by using support vector machine (SVM) and logistic regression models, respectively. The performance of each classifier was evaluated by area under the curve (AUC) analysis. RESULTS: According to the available follow-up results, 162 fetal macrosomia pregnancies and 648 matched controls were included. A total of 1086 genes with significantly differential promoter profiling were found between pregnancies with macrosomia and controls (p < 0.05). With the AUC as a reference,the classifier based on SVM (CMA-A2) had the best performance, with an AUC of 0.8256 (95% CI: 0.7927-0.8586). CONCLUSIONS: Our study provides that assessing the risk of fetal macrosomia by whole-genome promoter nucleosome profiling of maternal plasma cfDNA based on low-coverage next-generation sequencing is feasible.


Assuntos
Ácidos Nucleicos Livres , Macrossomia Fetal , Estudos de Casos e Controles , China , Feminino , Macrossomia Fetal/diagnóstico , Macrossomia Fetal/genética , Humanos , Recém-Nascido , Nucleossomos , Gravidez , Estudos Retrospectivos
4.
Urology ; 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36115426

RESUMO

OBJECTIVE: To characterize patterns of failure using prostate-specific membrane antigen positron emission tomography (PSMA PET) after radical prostatectomy (RP) and salvage radiotherapy (SRT). METHODS: Patients with rising PSA post-RP+SRT underwent 68Ga-HBED-iPSMA PET/CT on a single-arm, prospective imaging trial (NCTXXXXXXXX). Scans were centrally reviewed with pattern-of-failure analysis by involved site. Positive scans were classified using three failure categories: pelvic nodal, extra-pelvic nodal or distant non-nodal. Associations with failure categories were analyzed using cumulative incidence and generalized logits regression. RESULTS: We included 133 men who received SRT a median of 20 months post-RP; 56% received SRT to the prostatic fossa alone, while 44% received pelvic SRT. PSMA PET/CT was performed a median of 48 months post-SRT. Overall, 31% of PSMA PET/CT scans were negative, 2% equivocal and 67% had at least one positive site. Scan detection was significantly associated with PSA level prior to PSMA PET/CT. Analysis of 89 positive scans demonstrated pelvic nodal (53%) was the most common relapse and fossa relapse was low (9%). Overall, positive scans were pelvic (n=35, 26%), extra-pelvic nodal (n=26, 20%) or distant non-nodal failure (n=28, 21%), and 70% of positive scans were oligorecurrent. We observed similar cumulative incidence for all failure categories and relatively few clinicodemographic associations. Men treated with pelvic SRT had reduced odds of pelvic failure versus exclusive fossa treatment. CONCLUSION: Pelvic, extra-pelvic nodal and distant non-nodal failures occur with similar incidence post-SRT. Regional nodal relapse is relatively common, especially with fossa-only SRT. A high oligorecurrence rate suggests a potentially important role for PSMA-guided focal therapies.

5.
Biochem Biophys Res Commun ; 627: 214-219, 2022 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-36058105

RESUMO

Dengue virus (DENV) has developed rapidly in the past few decades and has been becoming the most widespread arbovirus in the world. The vital role of NS2B-NS3 in virus replication and maturation of relevant proteins makes it the most promising target for anti-DENV drug discovery, although none of NS2B-NS3 inhibitors have been approved for the market so far. In this study, potent NS2B-NS3 covalent inhibitors were discovered via chemical modification of a published covalent inhibitor WSL-01 (IC50 = 129 nM), yielding promising analogs WSL-75 and WSL-84 (IC50 = 24.8 nM and IC50 = 32.89 nM, respectively) with more than 10-fold increased enzymatic activities compared to the lead compound, and no evident cellular toxicity was observed. Further comprehensive structure-activity relationship analysis through covalent docking and molecular dynamics simulation provides informative understanding of the binding modes of covalent inhibitors targeting NS2B-NS3, which would be beneficial for novel NS2B-NS3 inhibitory development.


Assuntos
Vírus da Dengue , Antivirais/química , Antivirais/farmacologia , Vírus da Dengue/metabolismo , Simulação de Acoplamento Molecular , Inibidores de Proteases/farmacologia , Serina Endopeptidases/metabolismo , Proteínas não Estruturais Virais/química
6.
Crit Care ; 26(1): 267, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064613

RESUMO

AIM: To compare the safety and effects of unrestricted visiting policies (UVPs) and restricted visiting policies (RVPs) in intensive care units (ICUs) with respect to outcomes related to delirium, infection, and mortality. METHODS: MEDLINE, Cochrane Library, Embase, Web of Science, CINAHL, CBMdisc, CNKI, Wanfang, and VIP database records generated from their inception to 22 January 2022 were searched. Randomized controlled trials and quasi-experimental studies were included. The main outcomes investigated were delirium, ICU-acquired infection, ICU mortality, and length of ICU stay. Two reviewers independently screened studies, extracted data, and assessed risks of bias. Random­effects and fixed-effects meta­analyses were conducted to obtain pooled estimates, due to heterogeneity. Meta-analyses were performed using RevMan 5.3 software. The results were analyzed using odds ratios (ORs), 95% confidence intervals (CIs), and standardized mean differences (SMDs). RESULTS: Eleven studies including a total of 3741 patients that compared UVPs and RVPs in ICUs were included in the analyses. Random effects modeling indicated that UVPs were associated with a reduced incidence of delirium (OR = 0.4, 95% CI 0.25-0.63, I2 = 71%, p = 0.0005). Fixed-effects modeling indicated that UVPs did not increase the incidences of ICU-acquired infections, including ventilator-associated pneumonia (OR = 0.96, 95% CI 0.71-1.30, I2 = 0%, p = 0.49), catheter-associated urinary tract infection (OR 0.97, 95% CI 0.52-1.80, I2 = 0%, p = 0.55), and catheter-related blood stream infection (OR = 1.15, 95% CI 0.72-1.84, I2 = 0%, p = 0.66), or ICU mortality (OR = 1.03, 95% CI 0.83-1.28, I2 = 49%, p = 0.12). Forest plotting indicated that UVPs could reduce the lengths of ICU stays (SMD = - 0.97, 95% CI - 1.61 to 0.32, p = 0.003). CONCLUSION: The current meta-analysis indicates that adopting a UVP may significantly reduce the incidence of delirium in ICU patients, without increasing the risks of ICU-acquired infection or mortality. Further large-scale, multicenter studies are needed to confirm these indications.


Assuntos
Delírio , Pneumonia Associada à Ventilação Mecânica , Estado Terminal/epidemiologia , Estado Terminal/terapia , Delírio/epidemiologia , Delírio/prevenção & controle , Humanos , Unidades de Terapia Intensiva , Tempo de Internação , Políticas
7.
Biosci Rep ; 2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36094557

RESUMO

Previous document have reported that the DTYMK gene were involved in the progression of cancers. However, its significance in the analysis of pan-cancer and specific molecular mechanism were still poorly understood. In the current study, we conducted a comprehensive study of the DTYMK gene associated with its clinical relevance across a broad spectrum of human tumors. In addition, association among DTYMK gene and tumor immunogenic features was also explored. Considering the results of pan-cancer analysis, the specific tumor lung adenocarcinoma(LUAD) was chosen to further study the DTYMK-induced signaling pathways and intercellular communications in tumor progression. Our findings demonstrated that DTYMK may be a new biomarker for the prognosis and immunotherapy in various cancers. Importantly, DTYMK was expected to be a guiding marker gene for clinical prognosis and tumor personalized therapy in LUAD.

8.
Colloids Surf B Biointerfaces ; 218: 112772, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35985128

RESUMO

This study developed, a novel polypropylene (PP) mesh combined with poly (L-lactic acid) (PLA) electrospun nanofibers loaded sirolimus (SRL). The PP mesh was combined with PLA/SRL (1/0, 1/0.01, 1/0.02; mass ratios) composed electrospun membrane characterized by FTIR spectroscopy, XPS and SEM, and evaluated for cytocompatibility in vitro. In an in vivo study, a total of 84 Sprague-Dawley rats were employed to evaluate the efficacy of the novel composite PP mesh anti-adhesion, mechanical properties and inflammation. As a results, the PLA/SRL membrane could compound with PP mesh stably and load SRL. Although tensile testing showed that the mechanical properties of composite mesh decreased in vivo, the integration strength between the tissue and mesh was still able to counteract intra-abdominal pressure. Compared with the native PP mesh group, the novel PP mesh group showed a lower score for abdominal adhesion and inflammation. More importantly, the novel PP mesh completely integrated with the abdominal wall and had sufficient mechanical strength to repair abdominal wall defects.


Assuntos
Herniorrafia , Polipropilenos , Animais , Herniorrafia/métodos , Inflamação/tratamento farmacológico , Ácido Láctico/química , Poliésteres , Polipropilenos/química , Polipropilenos/farmacologia , Ratos , Ratos Sprague-Dawley , Sirolimo/farmacologia , Telas Cirúrgicas , Aderências Teciduais/tratamento farmacológico
9.
Front Oncol ; 12: 890248, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35978805

RESUMO

Background: Circulating tumor cells (CTCs) have been recognized as a sensitive biomarker for breast cancer (BC). This study aimed to comprehensively compare CTC with imaging modalities, including ultrasonography, mammography, and contrast-enhanced magnetic resonance imaging (MRI) in screening for BC in Chinese women. Methods: Three hundred forty-three participants were enrolled in this study, including 102 treatment-naive BC patients, 177 with breast benign diseases (BBD) and 64 healthy female patients. All participants underwent CTC testing and at least one of the following examinations, ultrasonography, mammography, and MRI at the Second Affiliated Hospital of Zhejiang University between December 2017 and November 2020. CTCs were quantitatively assessed using cell counting (CTC detection rate/counts) and categorically examined using a cutoff value (CTC classification). The diagnostic power of CTC tests and imaging modalities, including accuracy and capability to predict clinicopathological characteristics of BC, were evaluated and compared. Results: CTC classification with a cutoff value of 2 showed a "good" diagnostic accuracy of 0.889 for early- to mid-stage BC comparable to breast imaging modalities using Breast Imaging-Reporting and Data System (BI-RADS). MRI demonstrated the highest sensitivity of 0.872 for BC, and CTC classification had the highest specificity of 0.938. A relatively low sensitivity was found for mammography in this cohort of patients. Successful detection of BC by CTC detection rate/counts, but not CTC classification, correlated with two important clinicopathological features, American Joint Committee on Cancer (AJCC) stage and tumor-node-metastasis (TNM) stage. The detection power of certain imaging modalities was also associated with AJCC stage (ultrasonography, p = 0.0438 and MRI, p = 0.0422) and lymph node metastasis (ultrasonography, 0.0157). There were clear correlations between CTC tests (counts or classification) and imaging BI-RADS scoring system in detecting positive BC cases (p < 0.05). Further correlation analysis suggested that CTC quantity, but not CTC classification, had the capability to predict clinicopathological traits of BC that were identified by ultrasonography. Conclusions: CTC tests have a diagnostic potency comparable to breast imaging modalities, and may be used as an alternative screening tool for BC.

10.
Int J Biol Sci ; 18(13): 5019-5037, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35982891

RESUMO

Hepatocellular carcinoma (HCC) progression is closely related to pathological fibrosis, which involves heterotypic intercellular interactions (HIIs) between liver cancer cells and fibroblasts. Here, we studied them in a direct coculture model, and identified fibronectin from fibroblasts and integrin-α5ß1 from liver cancer cells as the primary responsible molecules utilizing CRISPR/Cas9 gene-editing technology. Coculture led to the formation of 3D multilayer microstructures, and obvious fibronectin remodeling was caused by upregulated integrin-α5ß1, which greatly promoted cell growth in 3D microstructures. Integrin-α5 was more sensitive and specific than integrin-ß1 in this process. Subsequent mechanistic exploration revealed the activation of integrin-Src-FAK, AKT and ERK signaling pathways. Importantly, the growth-promoting effect of HIIs was verified in a xenograft tumor model, in which more blood vessels were observed in bigger tumors derived from the coculture group than that derived from monocultured groups. Hence, we conducted triculture by introducing human umbilical vein endothelial cells, which aligned to and differentiated along multilayer microstructures in an integrin-α5ß1 dependent manner. Furthermore, fibronectin, integrin-α5, and integrin-ß1 were upregulated in 52 HCC tumors, and fibronectin was related to microvascular invasion. Our findings identify fibronectin, integrin-α5, and integrin-ß1 as tumor microenvironment-related targets and provide a basis for combination targeted therapeutic strategies for future HCC treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Células Endoteliais/metabolismo , Fibroblastos/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Integrina alfa5beta1/genética , Integrina alfa5beta1/metabolismo , Integrinas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Microambiente Tumoral
11.
BMC Surg ; 22(1): 319, 2022 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-35987609

RESUMO

PURPOSE: To compare the clinical and radiological outcomes of percutaneous kyphoplasty (PKP) and percutaneous vertebroplasty (PVP) in the treatment of stage III Kummell disease without neurological deficit. METHODS: This retrospective study involved 41 patients with stage III Kummell disease without neurological deficit who underwent PKP or PVP from January 2018 to December 2019. Demographic data and clinical characteristics were comparable between these two groups before surgery. Operation time, volume of injected bone cement, intraoperative blood loss and time of hospital stay were analyzed. Visual analog scale (VAS) scoring and Oswestry disability index (ODI) scoring were assessed for each patient before and after operation. Radiographic follow-up was assessed by the height of anterior (Ha), the height of middle (Hm), Cobb's angle, and Vertebral wedge ratio (VWR). The preoperative and postoperative recovery values of these data were used for comparison. RESULTS: The two groups showed no significant difference in demographic features (p > 0.05). What's more, the operation time, intraoperative blood loss, and time of hospital stay revealed no sharp statistical distinctions either (p > 0.05), except PKP used more bone cement than PVP (7.4 ± 1.7 mL vs 4.7 ± 1.4 mL, p < 0.05). Radiographic data, such as the Ha improvement ratio (35.1 ± 10.2% vs 16.2 ± 9.4%), the Hm improvement ratio (41.8 ± 11.3% vs 22.4 ± 9.0%), the Cobb's angle improvement (10.0 ± 4.3° vs 3.5 ± 2.1°) and the VWR improvement ratio (30.0 ± 10.6% vs 12.7 ± 12.0%), were all better in PKP group than that in PVP group (p < 0.05). There were no statistical differences in the improvement of VAS and ODI 1-day after the surgery between these two groups (p > 0.05). However, at the final follow-up, VAS and ODI in PKP group were better than that in PVP (p < 0.05). Cement leakage, one of the most common complications, was less common in the PKP group than that in the PVP group (14.3% vs 45.0%, p < 0.05). And there was 1 case of adjacent vertebral fractures in both PKP and PVP (4.8% vs 5.0%, p > 0.05), which showed no statistical difference, and there were no severe complications recorded. CONCLUSIONS: For stage III Kummell disease, both PKP and PVP can relieve pain effectively. Moreover, PKP can obtain more satisfactory reduction effects and less cement leakage than PVP. We suggested that PKP was more suitable for stage III Kummell disease without neurological deficit compared to PVP from a vertebral reduction point of view.


Assuntos
Fraturas por Compressão , Cifoplastia , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Espondilose , Vertebroplastia , Perda Sanguínea Cirúrgica , Cimentos Ósseos/uso terapêutico , Fraturas por Compressão/cirurgia , Humanos , Fraturas por Osteoporose/cirurgia , Estudos Retrospectivos , Fraturas da Coluna Vertebral/etiologia , Fraturas da Coluna Vertebral/cirurgia , Espondilose/complicações , Resultado do Tratamento , Vertebroplastia/efeitos adversos
12.
Cell Physiol Biochem ; 56(4): 436-448, 2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36037065

RESUMO

BACKGROUND/AIMS: It is unknown whether cancer stem cells respond differentially to treatment compared with progeny, potentially providing therapeutic vulnerabilities. Our program pioneered use of ultra-high single dose radiotherapy, which cures diverse metastatic diseases at a higher rate (90-95%) than conventional fractionation (~65%). Single dose radiotherapy engages a distinct biology involving microvascular acid sphingomyelinase/ceramide signaling, which, via NADPH oxidase-2-dependent perfusion defects, initiates an adaptive tumor SUMO Stress Response that globally-inactivates homologous recombination repair of double stand breaks, conferring cure. Accumulating data show diverse stem cells display heightened-dependence on homologous recombination repair to repair resolve double stand breaks. METHODS: Here we use colorectal cancer patient-derived xenografts containing logarithmically-increased Lgr5+ stem cells to explore whether optimizing engagement of this acid sphingomyelinase dependent biology enhances stem cell dependent tumor cure. RESULTS: We show radioresistant colorectal cancer patient-derived xenograft CLR27-2 contains radioresistant microvasculature and stem cells, whereas radiosensitive colorectal cancer patient-derived xenograft CLR1-1 contains radiosensitive microvasculature and stem cells. Pharmacologic or gene therapy enhancement of single dose radiotherapy-induced acid sphingomyelinase/ceramide-mediated microvascular dysfunction dramatically sensitizes CLR27-2 homologous recombination repair inactivation, converting Lgr5+ cells from the most resistant to most sensitive patient-derived xenograft population, yielding tumor cure. CONCLUSION: We posit homologous recombination repair represents a vulnerability determining colorectal cancer stem cell fate, approachable therapeutically using single dose radiotherapy.


Assuntos
Neoplasias Colorretais , Lesões do Sistema Vascular , Animais , Ceramidas , Neoplasias Colorretais/genética , Modelos Animais de Doenças , Humanos , Células-Tronco Neoplásicas , Esfingomielina Fosfodiesterase/genética
13.
J Clin Oncol ; : JCO2201148, 2022 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-35802849

RESUMO

PURPOSE: Photon involved-field radiotherapy (IFRT) is the standard-of-care radiotherapy for patients with leptomeningeal metastasis (LM) from solid tumors. We tested whether proton craniospinal irradiation (pCSI) encompassing the entire CNS would result in superior CNS progression-free survival (PFS) compared with IFRT. PATIENTS AND METHODS: We conducted a randomized, phase II trial of pCSI versus IFRT in patients with non-small-cell lung cancer and breast cancers with LM. We enrolled patients with other solid tumors to an exploratory pCSI group. For the randomized groups, patients were assigned (2:1), stratified by histology and systemic disease status, to pCSI or IFRT. The primary end point was CNS PFS. Secondary end points included overall survival (OS) and treatment-related adverse events (TAEs). RESULTS: Between April 16, 2020, and October 11, 2021, 42 and 21 patients were randomly assigned to pCSI and IFRT, respectively. At planned interim analysis, a significant benefit in CNS PFS was observed with pCSI (median 7.5 months; 95% CI, 6.6 months to not reached) compared with IFRT (2.3 months; 95% CI, 1.2 to 5.8 months; P < .001). We also observed OS benefit with pCSI (9.9 months; 95% CI, 7.5 months to not reached) versus IFRT (6.0 months; 95% CI, 3.9 months to not reached; P = .029). There was no difference in the rate of grade 3 and 4 TAEs (P = .19). In the exploratory pCSI group, 35 patients enrolled, the median CNS PFS was 5.8 months (95% CI, 4.4 to 9.1 months) and OS was 6.6 months (95% CI, 5.4 to 11 months). CONCLUSION: Compared with photon IFRT, we found pCSI improved CNS PFS and OS for patients with non-small-cell lung cancer and breast cancer with LM with no increase in serious TAEs.

14.
Clin Transl Med ; 12(7): e986, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35858011

RESUMO

BACKGROUND: Programmed death-ligand 1 (PD-L1) has functional roles in cancer stem-like cell (CSC) phenotypes and chemoresistance besides immune evasion. Chemotherapy is a common treatment choice for colorectal cancer (CRC) patients; however, chemoresistance limits its effectiveness of treatment. METHODS: We examined the role of S100A14 (SA14) in CRC by adopting PD-L1high subpopulations within CRC cell lines and patient tumours, by establishing PD-L1high chemoresistant CRC sublines through prolonged exposure to 5-fluorouracil/oxaliplatin-based chemotherapy in vitro and in vivo, and by analysing a public database. RESULTS: We identified a novel function of SA14 as a regulator of immune surveillance, major CSC phenotypes, and survival capacity under hostile microenvironments, including those harbouring chemotherapeutics, and as a prognostic biomarker in CRC. Mechanistically, SA14 inhibits PD-L1 expression by directly interacting with signal transducer and activator of transcription 3 (STAT3) and inducing its proteasome-mediated degradation. While gain-of-SA14 causes loss of PD-L1 expression and tumourigenic potential and sensitisation to chemotherapy-induced apoptosis in chemoresistant CRC cells, loss-of-SA14 causes increases in PD-L1 expression, tumourigenic potential, and chemoresistance in vitro and in vivo. We further show that a combinatorial treatment with chemotherapy and recombinant SA14 protein effectively induces apoptosis in PD-L1high chemoresistant CRC cells. CONCLUSIONS: Our results suggest that SA14-based therapy is an effective strategy to prevent tumour progression and that SA14 is a predictive biomarker for anti-PD-L1 immunotherapy and chemotherapy in combination.


Assuntos
Neoplasias Colorretais , Fator de Transcrição STAT3 , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Proteínas de Ligação ao Cálcio , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Humanos , Evasão da Resposta Imune , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral
15.
Biomed Rep ; 17(2): 66, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35815188

RESUMO

The diagnostic value of the 9P21 gene determined using fluorescence in situ hybridization (FISH) combined with BRCA1-associated protein 1 (BAP1) and methylthioadenosine phosphorylase (MTAP) expression detection by immunohistochemistry, was investigated in serous effusion samples of malignant mesothelioma. A total of 70 serous disease samples with serous effusion were collected from June 2017 to June 2020. Following biopsy specimen pathological diagnosis, samples were divided into malignant mesothelioma and benign mesothelioma. Differential expression of BAP1 and MTAP genes were identified in mesothelioma and mesenchymal hyperplasia. The 9P21 gene fragment was lost in mesothelioma. The positive rates of FISH, BAP1 and MTAP in biopsy specimens were 98.00, 94.00 and 90.00%. The specificity of the three were 96.00, 85.71 and 77.27%, the sensitivity were 90.00, 95.92 and 93.75%, and the positive rate of the combined detection of the three was 93.33%. The positive rate of serous fluid samples detected by the three methods (9P21 FISH probe combined with BAP1 and MTAP expression detected immunohistochemically) was 96.00, 92.00 and 88.00%, the specificity were 90.00, 77.27 and 71.43%, the sensitivity was 96.00, 93.75 and 89.80%, and the positive rate of the three combined detections was 91.33%. It was demonstrated that there was a high consistency between serous fluid samples and biopsy samples. According to clinicopathological analysis, sex, age, lesion site, Ki67 had little association with the occurrence and development of malignant mesothelioma, while asbestos exposure history was closely associated to the occurrence of mesothelioma. A high level of BAP1 gene was positively associated with the prognosis of mesothelioma, while a high level of MTAP gene was negatively associated with the prognosis of mesothelioma (P<0.05). Therefore, 9P21 FISH probe combined with BAP1 and MTAP can be used as a new method for the detection of malignant mesothelioma, and provide an important basis for the early diagnosis of mesothelioma.

16.
Biomed Res Int ; 2022: 8118909, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35845949

RESUMO

The CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) plays an extremely important role of the programed death receptor ligand-1 (PD-L1) protein. Our study is aimed at investigating the expression of CMTM6 and PD-L1 proteins in triple-negative breast cancer and their correlation with the clinical pathological data of patients. We selected 89 cases of triple-negative breast cancer and 62 cases of normal breast tissue specimens. Immunohistochemical methods were used to detect the expression levels of CMTM6 and PD-L1 and to carefully study differences in their expression. The expression of CMTM6 and PD-L1 in TNBC was higher than that in normal breast tissue, and the expression of the two was positively correlated (p < 0.05). In TNBC, CMTM6 expression is positively correlated with tumor size, lymph node metastasis, Ki67 proliferation index, and TNM stage (p < 0.05). PD-L1 expression is positively correlated with tumor size, lymph node metastasis, Ki67 proliferation index, TNM stage, and vascular infiltration (p < 0.05). Kaplan-Meier analysis showed that the positive expression of CMTM6 and PD-L1 had no correlation with the survival rate of patients (p > 0.05). According to KM-plotter, we found that a higher CMTM6 expression was positively related with relapse-free survival rate of patients (p < 0.05). A higher PD-L1 expression was positively correlated with relapse-free, overall, and distant metastasis survival rate of patients (p < 0.05). In timer database, we found a positive correlation between the expression of CMTM6 and PD-L1 in triple-negative breast cancer. Both CMTM6 and PD-L1 are highly expressed in TNBC, and their expressions are positively related. In the future, the two gene might become targets for the treatment of TNBC, providing a basis of clinical treatment of TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Antígeno B7-H1/metabolismo , Humanos , Antígeno Ki-67 , Metástase Linfática , Recidiva Local de Neoplasia , Prognóstico , Neoplasias de Mama Triplo Negativas/patologia
17.
Int J Biol Sci ; 18(10): 3993-4005, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844788

RESUMO

Lymph nodes (LNs) are a common site of metastasis in many solid cancers. Tumour cells can migrate to LNs for further metastatic colonization of distant organs, indicating poor prognosis and requiring different clinical interventions. The histopathological diagnostic methods currently used to detect clinical lymph node metastasis (LNM) have limitations, such as incomplete visualization. To obtain a complete picture of metastatic LNs on the spatial and temporal scales, we used ultimate 3D imaging of solvent-cleared organs (uDISCO) and 3D rapid immunostaining. MC38 cells labelled with EGFP were injected into the left footpads of C57BL/6 mice. Draining lymph nodes (DLNs) harvested from these mice were cleared using the uDISCO method. Metastatic colorectal cancer (CRC) cells in various regions of DLNs from mice at different time points were quantified using 3D imaging of whole-mount tissue. Several stages of tumour cell growth and distribution in LNs were identified: 1) invasion of lymphatic vessels (LVs) and blood vessels (BVs); 2) dispersion outside LVs and BVs for proliferation and expansion; and 3) re-entry into BVs and efferent lymphatic vessels (ELVs) for further distant metastasis. Moreover, these data demonstrated that mouse fibroblast cells (MFCs) could not only promote LNM of tumour cells but also metastasize to LNs together with tumour cells, thus providing a "soil" for tumour cell colonization. In conclusion, 3D imaging of whole-mount tissue and spatiotemporal analysis of LNM may collectively constitute an auxiliary method to improve the accuracy of clinical LNM detection.


Assuntos
Imageamento Tridimensional , Vasos Linfáticos , Animais , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Metástase Linfática/patologia , Vasos Linfáticos/patologia , Camundongos , Camundongos Endogâmicos C57BL
18.
Front Chem ; 10: 953523, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35903190

RESUMO

Diarylamines are a class of important skeleton widely existing in drugs or natural products. To discover novel diarylamine analogues as potential drugs, two series of diamide and carboxamide derivatives containing diarylamine scaffold were designed, synthesized and evaluated for their potential cytotoxic activities. The bioassay results indicated that some of the obtained compounds (C5, C6, C7, C11) exhibited good cytotoxic effect on cancer cell lines (SGC-7901, A875, HepG2), especially, compound C11 present significantly selective proliferation inhibition activity on cancer and normal cell lines (MARC145). In addition, the possible apoptosis induction for highly potential molecules was investigated, which present compound C11 could be used as novel lead compound for discovery of promising anticancer agents.

19.
J Obstet Gynaecol ; : 1-9, 2022 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-35815559

RESUMO

Beclin1 is a key regulator of a family of autophagy-related proteins. The aim of our study was to elucidate the clinicopathological and prognostic significance of Beclin1 expression which is a positive regulator of autophagy in cervical cancer. The results showed that a total of 2682 patients were enrolled in 21 case-control studies. The results showed that, as for Beclin1 expression, significant differences were found in cervical cancer vs. normal cervical tissues (p<.00001) and cancer tissues with vs. no lymph node metastasis (p<.00001); tumour diameter no less than vs. less than 4 cm (p=.001), myometrial invasion depth no less than vs. less than 1/2 and FIGO I vs. II (p=.02); relationship between Beclin1 expression and prognosis of cervical cancer (p=.03). Kaplan-Meier's plotter showed that Beclin1 expression was negative. It was associated with overall, post-progressive and distant metastatic survival. According to the Oncomine database, Beclin1 mRNA expression in cervical cancer tissues was higher than that in normal tissues. Cox multivariate showed that lymph node metastasis and TNM stage were important factors affecting the survival time of patients. Beclin1 expression can be used as an indicator of prognosis in patients, and provide methods and ideas for prevention and treatment.

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