Background: Expression of PD-L1 has been estimated to predict the therapeutic potential of PD-L1 inhibition in solid tumors. Recent studies have demonstrated that PD-L1 plays a critical role in regulatory T-cell (Treg) development and functional maintenance. Although increases in FOXP3+Treg infiltration and PD-L1 expression have been revealed in several malignancies, their correlation in human breast tumors is as yet unclear.Methods: Whole-tissue sections from 501 patients with breast cancer were examined for PD-L1 and FOXP3 expression by immunohistochemistry. Correlation between their expressions and the association with clinicopathological features, intrinsic tumor subtypes and patient's prognosis were studied.Results: PD-L1 expression and FOXP3+Treg infiltrates in tumor tissue demonstrated a high correlation (rs=0.334, p<0.001) in this cohort of breast cancer patients. High PD-L1 expression and increased FOXP3+Treg infiltrates were both associated with high histological grade, negative ER and PR status, and aggressive intrinsic tumor subtypes, especially the basal-like subtype. Tumors with concomitant high expressions of the two markers had the worst prognosis. Multivariate analysis proved both markers to be the independent predictors for decreased overall survival of patients, particularly in the basal-like subtype.Conclusions: The results suggest that PD-L1 and FOXP3+Tregs may work synergistically and their up-regulated expressions promote tumor immune evasion in breast cancer. Combinatorial immunotherapeutic approaches aiming on blocking PD-L1 and depleting Tregs might improve therapeutic efficacy in breast cancer patients, especially those with basal-like carcinoma.
Magnetic composites consisting of magnetite (Fe3O4), graphene oxide (GO), and Mg3Al-OH layered double hydroxide (LDH), denoted as MGL composites, with varying GO contents (RGO) were synthesized by a mechano-hydrothermal (MHT) route using Fe3O4, Mg(OH)2, and Al(OH)3 as the inorganic starting materials. The application of the synthesized MGLs for removing the heavy-metal Pb(II) and the hydrophobic organic pesticide 2,4-dichlorophenoxyacetic acid (2,4-D) from aqueous solutions was investigated. Chemical bonding among the GO, Fe3O4, and LDH components was observed in the MGLs. The MGL composites showed good water-dispersity, strong magnetic response, and high sorption capacities and removal efficiencies for both Pb(II) and 2,4-D pollutants. The sorption capacities of the MGL for the pollutants significantly increased with an increase in RGO. Increasing pH could increase the removal efficiency for Pb(II) but decrease that for 2,4-D. The MGLs showed more affinity for Pb(II) than for 2,4-D in the competitive sorption. In addition, the MGLs could remain almost constant removal efficiency for the pollutants after reuse over six cycles, indicating their potential use as sorbents in wastewater treatment. Furthermore, a Cs effect was observed in the sorption equilibriums, which could be described using the Langmuir-SCA and Freundlich-SCA isotherms. The removal mechanisms of the MGL for Pb(II) and 2,4-D were discussed. The MHT method provided a simple and environmentally friendly route for synthesizing GO-LDH composite materials.
Purpose: Polo-like kinase 4(PLK4) is an important evolutionarily regulator involved in centrosome duplication. We here investigated the expression of PLK4 mRNA and PLK4 in breast cancer, and evaluated its predictive value for response to taxane-based neoadjuvant chemotherapy.Method: The PLK4 mRNA expression was measured in breast cancer tissues and corresponding normal breast tissues from 30 breast cancer patients by quantitative real-time polymerase chain reaction (PCR).The association of the expression of PLK4 with clinicopathological parameters and prognostic significance was evaluated in 154 cases of invasive breast cancer. In addition, we immunohistochemically examined the changes of PLK4 expression in biopsy and postoperative tumor specimens of another 64 breast cancer patients who received taxane-based neoadjuvant chemotherapy.Results: The level of PLK4 mRNA expression in cancerous tissues had a significant difference compared to the corresponding normal breast tissues (P=0.021). There is a correlation of PLK4 expression with higher incidence of lymph node metastasis and distant metastasis or surrounding recurrence (P=0.043; P=0.006). High PLK4 expression was found to be a detrimental prognostic factor measured by overall survival (OS) (P=0.003) and progress-free survival (PFS) (P=0.003). Moreover, the results demonstrated that PLK4 expression was a negative predictor of response to taxane-based neoadjuvant chemotherapy (rs= - 0.253, P=0.044).Conclusion: The findings of this current study indicated that PLK4 expression in breast cancer could be a potential prognostic factor and a negative predictor of response to taxane-based neoadjuvant chemotherapy.
Background Mounting evidence has suggested the essential role of long non-coding RNAs (lncRNAs) in a plethora of malignant tumors, including hepatocellular carcinoma. However, the underlyling mechanisms of lncRNAs remain unidentified in HCC. The present work was aimed to explore the regulatory functions and mechanisms of LncRNA LNCAROD in HCC progression and chemotherapeutic response. Methods The expression of LNCAROD in HCC tissues and cell lines were detected by quantitative reverse transcription PCR (qPCR). Cancer cell proliferation, migration, invasion, and chemoresistance were evaluated by cell counting kit 8 (CCK8), colony formation, transwell, and chemosensitivity assays. Methylated RNA immunoprecipitation qRCR (MeRIP-qPCR) was used to determine N6-methyladenosine (m6A) modification level. RNA immunoprecipitation (RIP) and RNA pull down were applied to identify the molecular sponge role of LNCAROD for modulation of miR-145-5p via the competing endogenous RNA (ceRNA) mechanism, as well as the interaction between LNCAROD and serine-and arginine-rich splicing factor 3 (SRSF3). The interaction between insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and LNCAROD was also identified by RIP assay. Gain- or-loss-of-function assays were used to identify the function and underlying mechanisms of LNCAROD in HCC. Results We found that LNCAROD was significantly upregulated and predicted a poorer prognosis in HCC patients. LNCAROD upregulation was maintained by increased m6A methylation-mediated RNA stability. LNCAROD significantly promoted HCC cell proliferation, migration, invasion, and chemoresistance both in vitro and in vivo. Furthermore, mechanistic studies revealed that pyruvate kinase isoform M2 (PKM2)-mediated glycolysis enhancement is critical for the role of LNACROD in HCC. According to bioinformatics prediction and our experimental data, LNCAROD directly binds to SRSF3 to induce PKM switching towards PKM2 and maintains PKM2 levels in HCC by acting as a ceRNA against miR-145-5p. The oncogenic effects of LNCAROD in HCC were more prominent under hypoxia than normoxia due to the upregulation of hypoxia-triggered hypoxia-inducible factor 1α. Conclusions In summary, our present study suggests that LNCAROD induces PKM2 upregulation via simultaneously enhancing SRSF3-mediated PKM switching to PKM2 and sponging miR-145-5p to increase PKM2 level, eventually increasing cancer cell aerobic glycolysis to participate in tumor malignancy and chemoresistance, especially under hypoxic microenvironment. This study provides a promising diagnostic marker and therapeutic target for HCC patients.
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