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BACKGROUND: The interplay between regulatory T cells (Tregs) and neighboring cells, which is pivotal for anti-tumor immunity and closely linked to patient prognosis, remains to be fully elucidated. METHODS: Tissue microarrays of 261 operable NSCLC patients were stained by multiplex immunofluorescence (mIF) assay, and the interaction between Tregs and neighboring cells in the tumor microenvironment (TME) was evaluated. Employing various machine learning algorithms, we developed a spatial immune signature to predict the prognosis of NSCLC patients. Additionally, we explored the interplay between programmed death-1/programmed death ligand-1 (PD-1/PD-L1) interactions and their relationship with Tregs. RESULTS: Survival analysis indicated that the interplay between Tregs and neighboring cells in the invasive margin (IM) and tumor center was associated with recurrence in NSCLC patients. We integrated the intersection of the three algorithms to identify four crucial spatial immune features [P(CD8+Treg to CK) in IM, P(CD8+Treg to CD4) in IM, N(CD4+Treg to CK) in IM, N(CD4+Tcon to CK) in IM] and employed these characteristics to establish SIS, an independent prognosticator of recurrence in NSCLC patients [HR = 2.34, 95% CI (1.53, 3.58), P < 0.001]. Furthermore, analysis of cell interactions demonstrated that a higher number of Tregs contributed to higher PD-L1+ cells surrounded by PD-1+ cells (P < 0.001) with shorter distances (P = 0.004). CONCLUSION: We dissected the cell interplay network within the TME, uncovering the spatial architecture and intricate interactions between Tregs and neighboring cells, along with their impact on the prognosis of NSCLC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Recurrencia Local de Neoplasia , Linfocitos T Reguladores , Microambiente Tumoral , Humanos , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Linfocitos T Reguladores/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Microambiente Tumoral/inmunología , Recurrencia Local de Neoplasia/inmunología , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo , Antígeno B7-H1/metabolismo , Anciano , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismoRESUMEN
BACKGROUND: Neoadjuvant chemotherapy (NAC) combined with immunotherapy is increasingly used in non-small cell lung cancer (NSCLC). Tissue-resident memory T (TRM) cells are the primary subset responding to anti-cancer immunity. However, the immunomodulatory effects of NAC on TRM cells remain unknown. METHODS: We established two NSCLC cohorts including patients undergoing upfront surgery (US) and NAC followed by surgery. Beyond the unpaired comparison between the US cohort (n = 122) and NAC cohort (n = 141) with resection samples, 58 matched pre-NAC biopsy samples were available for paired comparisons. Using multiplex immunofluorescence, we characterized TRM cells (CD103+CD8+) and four heterogeneous TRM subsets, including naive TRM1 (PD-1-Tim-3-), pre-exhausted TRM2 (PD-1+Tim-3-), TRM3 (PD-1-Tim-3+), and terminally exhausted TRM4 (PD-1+Tim-3+). Cell density, cytotoxicity, and two spatial features were defined to evaluate the effect of NAC on TRM subsets. RESULTS: The cell densities, infiltration scores, and cancer-cell proximity scores of TRM cells, especially TRM1&2 subsets, were significantly increased after NAC and associated with better prognosis of patients. In Contrast, no significant change was observed in the TRM4 subset, which was associated with poor prognosis. Besides, the cytotoxicity of TRM subsets was unaltered after NAC. Compared with patients without major pathologic response (MPRs), patients with MPR had higher densities of TRM1&2 subsets and higher cancer-cell proximity scores of TRM2&3 subsets. Furthermore, increased density of CD31 + cancer microvessels was positively associated with both TRM and Tnon-RM cells after NAC. CONCLUSIONS: NAC may remodel the cell density and spatial distribution of TRM subsets, which is associated with favorable therapeutic effect and prognosis in patients with NSCLC.
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It is crucial to decipher the modulation of regulatory T cells (Tregs) in tumor microenvironment (TME) induced by chemotherapy, which may contribute to improving the efficacy of neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer (NSCLC). We retrospectively collected specimens from patients with II-III NSCLC, constituting two cohorts: a neoadjuvant chemotherapy (NAC) cohort (N = 141) with biopsy (N = 58) and postoperative specimens (N = 141), and a surgery-only cohort (N = 122) as the control group. Then, the cell density (Dens), infiltration score (InS), and Treg-cell proximity score (TrPS) were conducted using a panel of multiplex fluorescence staining (Foxp3, CD4, CD8, CK, CD31, ÉSMA). Subsequently, the association of Tregs with cancer microvessels (CMVs) and cancer-associated fibroblasts (CAFs) was analyzed. Patients with NAC treatment have a higher density of Tregs in both paired (P < 0.001) and unpaired analysis (P = 0.022). Additionally, patients with NAC treatment showed higher infiltration score (paired, P < 0.001; unpaired, P = 0.014) and more CD8+T cells around Tregs (paired/unpaired, both P < 0.001). Subgroup analysis indicated that tumors with a diameter of ≤ 5 cm exhibited increase in both Dens(Treg) and InS(Treg), and gemcitabine, pemetrexed and taxel enhanced Dens(Treg) and TrPS(CD8) following NAC. Multivariate analysis identified that the Dens(Tregs), InS(Tregs) and TrPS(CD8) were significantly associated with better chemotherapy response [OR = 8.54, 95%CI (1.69, 43.14), P = 0.009; OR = 7.14, 95%CI (1.70, 30.08), P = 0.024; OR = 5.50, 95%CI (1.09, 27.75), P = 0.039, respectively] and positive recurrence-free survival [HR = 3.23, 95%CI (1.47, 7.10), P = 0.004; HR = 2.70; 95%CI (1.27, 5.72); P = 0.010; HR = 2.55, 95%CI (1.21, 5.39), P = 0.014, respectively]. Moreover, TrPS(CD8) and TrPS(CD4) were negatively correlated with the CMVs and CAFs. These discoveries have deepened our comprehension of the immune-modulating impact of chemotherapy and underscored that the modified spatial landscape of Tregs after chemotherapy should be taken into account for personalized immunotherapy, aiming to ultimately improve clinical outcomes in patients with NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Terapia Neoadyuvante , Linfocitos T Reguladores , Microambiente Tumoral , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Terapia Neoadyuvante/métodos , Femenino , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Persona de Mediana Edad , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Anciano , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacosRESUMEN
Occult lymph node metastasis (OLNM) is one of the main causes of regional recurrence in inoperable N0 non-small cell lung cancer (NSCLC) patients following stereotactic ablation body radiotherapy (SABR) treatment. The integration of immunotherapy and SABR (I-SABR) has shown preliminary efficiency in mitigating this recurrence. Therefore, it is necessary to explore the functional dynamics of critical immune effectors, particularly CD8+ T cells in the development of OLNM. In this study, tissue microarrays (TMAs) and multiplex immunofluorescence (mIF) were used to identify CD8+ T cells and functional subsets (cytotoxic CD8+ T cells/predysfunctional CD8+ T cells (CD8+ Tpredys)/dysfunctional CD8+ T cells (CD8+ Tdys)/other CD8+ T cells) among the no lymph node metastasis, OLNM, and clinically evident lymph node metastasis (CLNM) groups. As the degree of lymph node metastasis escalated, the density of total CD8+ T cells and CD8+ Tdys cells, as well as their proximity to tumor cells, increased progressively and remarkably in the invasive margin (IM). In the tumor center (TC), both the density and proximity of CD8+ Tpredys cells to tumor cells notably decreased in the OLNM group compared with the group without metastasis. Furthermore, positive correlations were found between the dysfunction of CD8+ T cells and HIF-1α+CD8 and cancer microvessels (CMVs). In conclusion, the deterioration in CD8+ T cell function and interactive dynamics between CD8+ T cells and tumor cells play a vital role in the development of OLNM in NSCLC. Strategies aimed at improving hypoxia or targeting CMVs could potentially enhance the efficacy of I-SABR.
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Linfocitos T CD8-positivos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Metástasis Linfática , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Metástasis Linfática/patología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Linfocitos T CD8-positivos/inmunología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Ganglios Linfáticos/patología , Ganglios Linfáticos/inmunología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Microambiente Tumoral/inmunologíaRESUMEN
Primary liver cancer has consistently exhibited a high prevalence and fatality rate, necessitating the investigation of associated diagnostic markers and inhibition mechanisms to effectively mitigate its impact. The significance of apolipoprotein M (ApoM) in impeding the progression of neoplastic ailments is progressively gaining recognition. However, a comprehensive understanding of its underlying mechanism in liver cancer advancement remains to be elucidated. Recent evidence indicates a potential association between ApoM and polyunsaturated fatty acids (PUFAs), with the peroxidation of phospholipids (PLs) containing PUFAs being recognized as a crucial element in the occurrence of ferroptosis. This prompts us to investigate the impact of the APOM gene on the progression of liver cancer through the ferroptosis pathway and elucidate its underlying mechanisms. The findings of this study indicate that the liver cancer cell model, which was genetically modified to overexpress the APOM gene, demonstrated a heightened ferroptosis effect. Moreover, the observed inhibition of the GSH (Glutathione) - GPX4 (Glutathione Peroxidase 4) regulatory axis suggests that the role of this axis in inhibiting ferroptosis is weakened. Through intersection screening and validation, we found that Mucin 1,cell surface associated (MUC1) can inhibit ferroptosis and is regulated by the APOM gene. Bioinformatics analysis and screening identified miR-4489 as a mediator between the two. Experimental results using the dual luciferase reporter gene confirmed that has-miR-4489 targets MUC1's 3'-UTR and inhibits its expression. In conclusion, this study provides evidence that the APOM gene induces a down-regulation in the expression of the ferroptosis-inhibiting gene MUC1, mediated by miR-4489, thereby impeding the advancement of liver cancer cells through the facilitation of ferroptosis.
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Apolipoproteínas M , Carcinoma Hepatocelular , Ferroptosis , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , MicroARNs , Ferroptosis/genética , Humanos , Apolipoproteínas M/genética , Apolipoproteínas M/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Línea Celular Tumoral , Células Hep G2RESUMEN
BACKGROUND: Tissue-resident memory T (TRM) cells can reside in the tumor microenvironment and are considered the primary response cells to immunotherapy. Heterogeneity in functional status and spatial distribution may contribute to the controversial role of TRM cells but we know little about it. METHODS: Through multiplex immunofluorescence (mIF) (CD8, CD103, PD-1, Tim-3, GZMB, CK), the quantity and spatial location of TRM cell subsets were recognized in the tissue from 274 patients with NSCLC after radical surgery. By integrating multiple machine learning methods, we constructed a TRM-based spatial immune signature (TRM-SIS) to predict the prognosis. Furthermore, we conducted a CD103-related gene set enrichment analysis (GSEA) and verified its finding by another mIF panel (CD8, CD103, CK, CD31, Hif-1α). RESULTS: The density of TRM cells was significantly correlated with the expression of PD-1, Tim-3 and GZMB. Four types of TRM cell subsets was defined, including TRM1 (PD-1-Tim-3-TRM), TRM2 (PD-1+Tim-3-TRM), TRM3 (PD-1-Tim-3+TRM) and TRM4 (PD-1+Tim-3+TRM). The cytotoxicity of TRM2 was the strongest while that of TRM4 was the weakest. Compare with TRM1 and TRM2, TRM3 and TRM4 had better infiltration and stronger interaction with cancer cells. The TRM-SIS was an independent prognostic factor for disease-free survival [HR = 2.43, 95%CI (1.63-3.60), P < 0.001] and showed a better performance than the TNM staging system for recurrence prediction. Furthermore, by CD103-related GSEA and mIF validation, we found a negative association between tumor angiogenesis and infiltration of TRM cells. CONCLUSIONS: These findings reveal a significant heterogeneity in the functional status and spatial distribution of TRM cells, and support it as a biomarker for the prognosis of NSCLC patients. Regulating TRM cells by targeting tumor angiogenesis may be a potential strategy to improve current immunotherapy.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Receptor 2 Celular del Virus de la Hepatitis A , Células T de Memoria , Receptor de Muerte Celular Programada 1 , Pronóstico , Linfocitos T CD8-positivos , Microambiente TumoralRESUMEN
Developing novel synthesis technologies is crucial to expanding bifunctional electrocatalysts for energy-saving hydrogen production. Herein, we report an ambient and controllable γ-ray radiation reduction to synthesize a series of noble metal nanoparticles anchored on defect-rich manganese oxides (M@MnO2-x , M=Ru, Pt, Pd, Ir) for glycerol-assisted H2 evolution. Benefiting from the strong penetrability of γ-rays, nanoparticles and defect supports are formed simultaneously and bridged by metal-oxygen bonds, guaranteeing structural stability and active site exposure. The special Ru-O-Mn bonds activate the Ru and Mn sites in Ru@MnO2-x through strong interfacial coordination, driving glycerol electrolysis at low overpotential. Furthermore, only a low cell voltage of 1.68â V is required to achieve 0.5â A cm-2 in a continuous-flow electrolyzer system along with excellent stability. In situ spectroscopic analysis reveals that the strong interfacial coordination in Ru@MnO2-x balances the competitive adsorption of glycerol and OH* on the catalyst surface. Theoretical calculations further demonstrate that the defect-rich MnO2 support promotes the dissociation of H2 O, while the defect-regulated Ru sites promote deprotonation and hydrogen desorption, synergistically enhancing glycerol-assisted hydrogen production.
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Autophagy serves as a pro-survival mechanism for a cell or a whole organism to cope with nutrient stress. Our understanding of the molecular regulation of this fusion event remains incomplete. Here, we identified RUNDC1 as a novel ATG14-interacting protein, which is highly conserved across vertebrates, including zebrafish and humans. By gain and loss of function studies, we demonstrate that RUNDC1 negatively modulates autophagy by blocking fusion between autophagosomes and lysosomes via inhibiting the assembly of the STX17-SNAP29-VAMP8 complex both in human cells and the zebrafish model. Moreover, RUNDC1 clasps the ATG14-STX17-SNAP29 complex via stimulating ATG14 homo-oligomerization to inhibit ATG14 dissociation. This also prevents VAMP8 from binding to STX17-SNAP29. We further identified that phosphorylation of RUNDC1 Ser379 is crucial to inhibit the assembly of the STX17-SNAP29-VAMP8 complex via promoting ATG14 homo-oligomerization. In line with our findings, RunDC1 is crucial for zebrafish in their response to nutrient-deficient conditions. Taken together, our findings demonstrate that RUNDC1 is a negative regulator of autophagy that restricts autophagosome fusion with lysosomes by clasping the ATG14-STX17-SNAP29 complex to hinder VAMP8 binding.
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Background: Treatment of radiotherapy (RT) combined with immune checkpoint inhibitor (ICI) may remarkably improve the prognosis in patients with metastatic non-small cell lung cancer (NSCLC). However, the treatment time of RT, irradiated lesion and the optimum combined scheme, have not been fully determined. Methods: Data regarding overall survival (OS), progression-free survival (PFS), treatment response, and adverse events of 357 patients with advanced NSCLC treated with ICI alone or in combination with RT prior to/during ICI treatment were retrospectively collected. Additionally, subgroup analyses for radiation dose, time interval between RT and immunotherapy, and number of irradiated lesions were performed. Results: Median PFS of the ICI alone and ICI + RT groups was 6 and 12 months, respectively (P<0.0001). The objective response rate (ORR) and disease control rate (DCR) were significantly higher in the ICI + RT group than in the ICI alone group (P=0.014; P=0.015, respectively). However, OS, the distant response rate (DRR), and the distant control rate (DCRt) did not differ significantly between the groups. Out-of-field DRR and DCRt were defined in unirradiated lesions only. Compared with RT application prior to ICI, its application concomitant with ICI led to higher DRR (P=0.018) and DCRt (P=0.002). Subgroup analyses revealed that single-site, high biologically effective dose (BED) (≥72 Gy), planning target volume (PTV) size (<213.7 mL) RT groups had better PFS. In multivariate analysis, PTV volume [≥213.7 vs. <213.7 mL: hazard ratio (HR), 1.89; 95% confidence interval (CI): 1.04-3.42; P=0.035] was an independent predictor of immunotherapy PFS. Additionally, radio-immunotherapy increased the incidence rate of grade 1-2 immune-related pneumonitis compared with ICI alone. Conclusions: Combination therapy using ICIs and radiation may improve PFS and tumor response rates in advanced NSCLC patients regardless of programmed cell death 1 ligand 1 (PD-L1) level or previous treatments. However, it may increase the incidence of immune-related pneumonitis.
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BACKGROUND: Anti-PD-(L)1 immunotherapy has been recommended for non-small cell lung cancer (NSCLC) patients with lymph node metastases (LNM). However, the exact functional feature and spatial architecture of tumor-infiltrating CD8 + T cells remain unclear in these patients. METHODS: Tissue microarrays (TMAs) from 279 IA-IIIB NSCLC samples were stained by multiplex immunofluorescence (mIF) for 11 markers (CD8, CD103, PD-1, Tim3, GZMB, CD4, Foxp3, CD31, αSMA, Hif-1α, pan-CK). We evaluated the density of CD8 + T-cell functional subsets, the mean nearest neighbor distance (mNND) between CD8 + T cells and neighboring cells, and the cancer-cell proximity score (CCPS) in invasive margin (IM) as well as tumor center (TC) to investigate their relationships with LNM and prognosis. RESULTS: The densities of CD8 + T-cell functional subsets, including predysfunctional CD8 + T cells (Tpredys) and dysfunctional CD8 + T cells (Tdys), in IM predominated over those in TC (P < 0.001). Multivariate analysis identified that the densities of CD8 + Tpredys cells in TC and CD8 + Tdys cells in IM were significantly associated with LNM [OR = 0.51, 95%CI (0.29-0.88), P = 0.015; OR = 5.80, 95%CI (3.19-10.54), P < 0.001; respectively] and recurrence-free survival (RFS) [HR = 0.55, 95%CI (0.34-0.89), P = 0.014; HR = 2.49, 95%CI (1.60-4.13), P = 0.012; respectively], independent of clinicopathological factors. Additionally, shorter mNND between CD8 + T cells and their neighboring immunoregulatory cells indicated a stronger interplay network in the microenvironment of NSCLC patients with LNM and was associated with worse prognosis. Furthermore, analysis of CCPS suggested that cancer microvessels (CMVs) and cancer-associated fibroblasts (CAFs) selectively hindered CD8 + T cells from contacting with cancer cells, and were associated with the dysfunction of CD8 + T cells. CONCLUSION: Tumor-infiltrating CD8 + T cells were in a more dysfunctional status and in a more immunosuppressive microenvironment in patients with LNM compared with those without LNM.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Metástasis Linfática/patología , Estado Funcional , Linfocitos Infiltrantes de Tumor/patología , Linfocitos T CD8-positivos , Pronóstico , Microambiente TumoralRESUMEN
N-glycosylation is one of the most common types of protein modifications and it plays a vital role in normal physiological processes. However, aberrant N-glycan modifications are closely associated with the pathogenesis of diverse diseases, including processes such as malignant transformation and tumor progression. It is known that the N-glycan conformation of the associated glycoproteins is altered during different stages of hepatocarcinogenesis. Characterizing the heterogeneity and biological functions of glycans in liver cancer patients will facilitate a deeper understanding of the molecular mechanisms of liver injury and hepatocarcinogenesis. In this article, we review the role of N-glycosylation in hepatocarcinogenesis, focusing on epithelial-mesenchymal transition, extracellular matrix changes, and tumor microenvironment formation. We highlight the role of N-glycosylation in the pathogenesis of liver cancer and its potential applications in the treatment or diagnosis of liver cancer.
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Glicoproteínas , Neoplasias Hepáticas , Humanos , Glicosilación , Glicoproteínas/metabolismo , Neoplasias Hepáticas/genética , Procesamiento Proteico-Postraduccional , Polisacáridos/metabolismo , Microambiente TumoralRESUMEN
Abnormal activation of Wnt/ß-catenin-mediated transcription is closely associated with the malignancy of pancreatic cancer. Family with sequence similarity 83 member A (FAM83A) was shown recently to have oncogenic effects in a variety of cancer types, but the biological roles and molecular mechanisms of FAM83A in pancreatic cancer need further investigation. Here, we newly discovered that FAM83A binds directly to ß-catenin and inhibits the assembly of the cytoplasmic destruction complex thus inhibiting the subsequent phosphorylation and degradation. FAM83A is mainly phosphorylated by the SRC non-receptor kinase family member BLK (B-lymphoid tyrosine kinase) at tyrosine 138 residue within the DUF1669 domain that mediates the FAM83A-ß-catenin interaction. Moreover, FAM83A tyrosine 138 phosphorylation enhances oncogenic Wnt/ß-catenin-mediated transcription through promoting ß-catenin-TCF4 interaction and showed an elevated nucleus translocation, which inhibits the recruitment of histone deacetylases by TCF4. We also showed that FAM83A is a direct downstream target of Wnt/ß-catenin signaling and correlates with the levels of Wnt target genes in human clinical pancreatic cancer tissues. Notably, the inhibitory peptides that target the FAM83A-ß-catenin interaction significantly suppressed pancreatic cancer growth and metastasis in vitro and in vivo. Our results revealed that blocking the FAM83A cascade signaling defines a therapeutic target in human pancreatic cancer.
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Proteínas de Neoplasias , Neoplasias Pancreáticas , beta Catenina , Familia-src Quinasas , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Carcinogénesis/genética , Transformación Celular Neoplásica/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/genética , Fosforilación/genética , Tirosina/metabolismo , Vía de Señalización Wnt/genética , Familia-src Quinasas/genética , Familia-src Quinasas/metabolismo , Neoplasias PancreáticasRESUMEN
Objective: The objective of this article is to assess the rate of anastomotic leak and other perioperative outcomes in patients undergoing esophagectomy with either thoracic or cervical anastomosis. Methods: This meta-analysis was conducted by searching relevant literature studies in Web of Science, Cochrane Library, PubMed, and Embase databases. Articles that included patients undergoing esophagectomy and compared perioperative outcomes of McKeown with Ivor Lewis procedures were included. The primary outcome parameter was anastomotic leak, and secondary outcome parameters were grade ≥2 anastomotic leak, chylothorax, recurrent laryngeal nerve injury, hospital length of stay, intensive care unit (ICU) length of stay, postoperative mortality rate, operative time, blood loss, R0 resection rate, and lymph nodes examined. Results: A total of eight studies, with 3,291 patients (1,857 Ivor Lewis procedure and 1,434 McKeown procedure) were eligible for analysis. Meta-analysis showed that Ivor Lewis procedure was associated with lower rate of anastomosis leak of all grades [risk ratio (RR), 0.67; 95% confidence interval (CI), 0.55-0.82; P = 0.0001], lower rate of recurrent laryngeal nerve injury (RR, 0.14; 95% CI, 0.08-0.25), and shorter length of hospital stay (weighted mean difference, 0.13; 95% CI, 0.04-0.22). Grade ≥2 anastomotic leak, chylothorax, ICU length of stay, postoperative mortality rate, operative time, blood loss, R0 resection rate, and lymph nodes examined were similar between the two groups. Conclusions: Although all grades of anastomotic leak and recurrent laryngeal nerve injury are higher in the McKeown procedure, this meta-analysis supports similar short-term outcomes and oncological efficacy between Ivor Lewis and McKeown esophagectomy.
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BACKGROUND: The leaves of the plant Ilex latifolia Thunb. can be made into Kuding tea, which is a drink rich in polyphenols. This study aimed to observe the effect of Ilex latifolia Thunb. polyphenols (ILTPs) on human lung cancer cell line A549 (A549 cells) by regulating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. METHODS: In vitro cultured cells were treated with ILTPs; the proliferation of A549 cells and BEAS-2B human normal lung epithelial cells (Beas-2B cells) was observed using the 3-(4,5-dimethylazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the survival status of A549 cells was observed by fluorescence staining. The expression of A549 cells was observed by quantitative polymerase chain reaction (qPCR) assay and Western blot analysis, while the compound composition of ILTPs was detected using high-performance liquid chromatography (HPLC). RESULTS: The experimental results showed that the proliferation of Beas-2B cells was unaffected by treatment with 0-500 µg/mL of ILTPs, whereas the decreased proliferation of A549 cells was observed with the increasing concentrations of ILTPs. Additionally, ILTPs elevated the levels of lactate dehydrogenase (LDH) and reactive oxygen species (ROS) and promoted apoptosis in A549 cells. The results of qPCR experiments showed that ILTPs upregulated caspase-9 mRNA expression and downregulated phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), B-cell lymphoma-2 (Bcl-2), nuclear factor-κB (NF-κB), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 alpha (HIF-1α), and cyclooxygenase-2 (COX-2) expression in A549 cells. The Western blot analysis results also showed that ILTPs could reduce the protein expression of PI3K and Akt. The HPLC results showed that the main compounds present in the ILTPs were rutin, kaempferol, isochlorogenic acid A, isochlorogenic acid B, and isochlorogenic acid C. CONCLUSIONS: Thus, this study indicated that the polyphenols of I. latifolia act as a class of natural functional food materials that potently suppress cancer by exerting their inhibitory effects on A549 cell proliferation through five key polyphenolic compounds.
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Ilex , Neoplasias Pulmonares , Células A549 , Humanos , Ilex/metabolismo , Neoplasias Pulmonares/genética , Fosfatidilinositol 3-Quinasa/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Polifenoles/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Factor A de Crecimiento Endotelial VascularRESUMEN
Freeze-drying is a commonly used method in commercial preparations of lactic acid bacteria. However, some bacteria are killed during the freeze-drying process. To overcome this, trehalose and lactose are often used as protective agents. Moreover, high-density culture is an efficient way to grow bacterial strains but creates a hypertonic growth environment. We evaluated the effects of trehalose and lactose, as a primary carbon source or as an additive in fermentation, on the freeze-drying survival of Lactobacillus fermentum FXJCJ6-1, Lactobacillus brevis 173-1-2, and Lactobacillus reuteri CCFM1040. Our results showed that L. fermentum FXJCJ6-1 accumulated but did not use intracellular trehalose in a hypertonic environment, which enhanced its freeze-drying resistance. Furthermore, genes that could transport trehalose were identified in this bacterium. In addition, both the lactose addition and lactose culture improved the freeze-drying survival of the bacterium. Further studies revealed that the added lactose might exert its protective effect by attaching to the cell surface, whereas lactose culture acted by reducing extracellular polysaccharide production and promoting the binding of the protectant to the cell membrane. The different mechanisms of lactose and trehalose in enhancing the freeze-drying resistance of bacteria identified in this study will help to elucidate the anti-freeze-drying mechanisms of other sugars in subsequent investigations.
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Heavy atom-free triplet photosensitizers (PSs) are particularly of interest concerning both fundamental photochemistry study and practical applications. However, achieving efficient intersystem crossing (ISC) in planar heavy atom-free aromatic organic compounds is challenging. Herein, we demonstrate that two perylenebisimide (PBI) derivatives with anthryl and carbazole moieties fused at the bay position, showing twisted π-conjugation frameworks and red-shifted UV-vis absorption as compared to the native PBI chromophore (by 75-1610 cm-1), possess efficient ISC (singlet oxygen quantum yield: ΦΔ = 85%) and a long-lived triplet excited state (τT = 382 µs in fluid solution and τT = 4.28 ms in solid polymer film). Femtosecond transient absorption revealed ultrafast intramolecular charge-transfer (ICT) process in the twisted PBI derivatives (0.9 ps), and the ISC takes 3.7 ns. Pulsed laser excited time-resolved electron paramagnetic resonance (TREPR) spectra indicate that the triplet-state wave function of the twisted PBIs is mainly confined on the PBI core, demonstrated by the zero-field-splitting D parameter. Accordingly, the twisted derivatives have higher T1 energy (ET1 = 1.48-1.56 eV) as compared to the native PBI chromophore (1.20 eV), which is an advantage for the application of the derivatives as triplet PSs. Theoretical computation of the Franck-Condon density of states, based on excited-state dynamics methods, shows that the efficient ISC in the twisted PBI derivatives is due to the increased spin-orbit coupling matrix elements for the S1-T1 and S1-T2 states [spin-orbit coupling matrix element (SOCME): 0.11-0.44 cm-1. SOCME is zero for native PBI], as well as the Herzberg-Teller vibronic coupling. For the planar benzoPBI, the moderate ISC is due to S1 â T2 transition (SOCME: 0.03 cm-1. The two states share a similar energy, ca. 2.5 eV).
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The molecular atlas of postnatal mouse ventricular development has been made available and cardiac regeneration is documented to be a downregulated process. The right ventricle (RV) differs from the left ventricle. How volume overload (VO), a common pathologic state in children with congenital heart disease, affects the downregulated processes of the RV is currently unclear. We created a fistula between the abdominal aorta and inferior vena cava on postnatal day 7 (P7) using a mouse model to induce a prepubertal RV VO. RNAseq analysis of RV (from postnatal day 14 to 21) demonstrated that angiogenesis was the most enriched gene ontology (GO) term in both the sham and VO groups. Regulation of the mitotic cell cycle was the second-most enriched GO term in the VO group but it was not in the list of enriched GO terms in the sham group. In addition, the number of Ki67-positive cardiomyocytes increased approximately 20-fold in the VO group compared to the sham group. The intensity of the vascular endothelial cells also changed dramatically over time in both groups. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the downregulated transcriptome revealed that the peroxisome proliferators-activated receptor (PPAR) signaling pathway was replaced by the cell cycle in the top-20 enriched KEGG terms because of the VO. Angiogenesis was one of the primary downregulated processes in postnatal RV development, and the cell cycle was reactivated under the influence of VO. The mechanism underlying the effects we observed may be associated with the replacement of the PPAR-signaling pathway with the cell-cycle pathway.
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Spiro rhodamine (Rho)-perylene (Pery) electron donor-acceptor dyads were prepared to study the spin-orbit charge transfer intersystem crossing (SOCT-ISC) in these rigid and sterically congested molecular systems. The electron-donor Rho (lactam form) moiety is attached via the N-C bond to the electron acceptor at either 1- or 3-position of the Pery moiety (Rho-Pery-1 and Rho-Pery-3). Severe torsion of the Pery moiety in Rho-Pery-1 was observed. The fluorescence of the two dyads is significantly quenched in polar solvents, and the singlet oxygen quantum yields (ΦΔ) are strongly dependent on solvent polarity (4-36%). Femtosecond transient absorption spectra demonstrate that charge separation (CS) takes 0.51 ps in Rho-Pery-1 and 5.75 ps in Rho-Pery-3, and the charge recombination (CR)-induced ISC is slow (>3 ns). Nanosecond transient absorption spectra indicate that the formation of triplet states via SOCT-ISC takes 24-75 ns for Rho-Pery-1 and 6-15 ns for Rho-Pery-3, and the distorted π-framework of the Pery moiety results in a shorter triplet lifetime of 19.9 vs 291 µs for the planar analogue. Time-resolved electron paramagnetic resonance spectroscopy confirms the SOCT-ISC mechanism.
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BACKGROUND: To treat metastatic breast cancer (MBC) more precisely, many efforts have been made to identify prognostic factors of MBC in many studies. This review aims to qualitatively summarize these studies and to provide a reference for the research of MBC. METHODS: Relevant papers were searched on PubMed, with the search terms including MBC, prognostic factors and prognosis, and the studies aimed at exploring prognostic factors for patients with histologically confirmed MBC, including stage IV at initial diagnosis and metastatic recurrence, were included. RESULTS: A total of 30 papers were included at last. An analysis of prognostic factors frome those studies was conducted. Age at primary diagnosis (6 studies), performance status (4 studies), histological grade (4 studies), hormonal receptor (HR) status (9 studies) and site of metastasis (12 studies) were universally acknowledged prognostic factors. There were four studies revealing that short DFS was significantly associated with better OS, while there was one study not revealing this association. There were various results in different studies with a reference to efficacy. Surgery and endocrine therapy were related to a better prognosis (3 studies). Targeted therapies could also conduce to the prognosis. However, there was still a contention on the role of radiotherapy. In particular, a model was brought out to calculate the risk of death in MBC. Meanwhile, it was found that some biomarkers are related to prognosis as well as per the latest findings in some studies. CONCLUSIONS: In summary, intrinsic characteristics of tumors such as HR status and histological grade are the main factors affecting the prognosis of patients with MBC. Besides traditional factors, some new drugs and biomarkers are also associated with the prognosis of patients with MBC. In the future, the focus of studies shall be on the construction of a practical and high-quality model to predict the risk of death in MBC patients.