Background & Aims Overexpression of CD151 is associated with poor prognosis for hepatocellular carcinoma (HCC), yet its role in pathogenesis is not known. Methods We analyzed the expression of the ...integrin subunit α6 by quantitative, real-time polymerase chain reaction and immunoblot analyses of 120 HCC tissue samples; its clinical significance was investigated using tissue microarray (TMAs) analysis of samples from 335 patients with HCC. Immunoprecipitation was used to assess the relationship between α6 and CD151. The molecular effects of high expression levels of α6 and CD151 in HCC cells were determined using RNA interference and pharmacologic approaches. Results Overexpression of α6 correlated with poor prognosis of patients with HCC; α6 formed a complex with endogenous CD151 in HCC cells. In cells that expressed high levels of α6 and CD151, laminin-5 promoted cell spreading by inducing the epithelial–mesenchymal transition (EMT); this effect was not observed in cells that expressed high levels of only α6 or CD151. Cells that expressed high levels of α6 and CD151 underwent the EMT in response to laminin-5, through hyperactivation of phosphatidylinositol-3-kinase (PI3K), primarily induced via the PI3K–protein kinase B (Akt)–Snail–phosphatase and tensin homolog feedback pathway. The EMT was reversed by PI3K inhibitors and antibodies against CD151 or α6 in vitro, and was delayed by specific interference with CD151 and α6 in vivo. Conclusions High expression levels of CD151 and α6 promote invasiveness of HCC cells. Either of these proteins, or PI3K signaling, might be targets for therapeutics for subgroups of patients with HCC.
•Addition of recycled glass in cement mortar impaired its mechanical properties.•CO2 curing enhanced compressive and flexural strength of recycled glass mortar.•CO2 curing contributed to decreased ...water absorption and porosity.•CO2 curing improved the microstructures (especially ITZ) of recycled glass mortar.•Porous structure facilitated deeper CO2 penetration and higher CO2 curing degree.
Previous studies have well demonstrated that recycled glass (RG) can be incorporated into cementitious materials to replace 100% river sand as fine aggregates. However, this replacement was found to incur adverse effects on the mechanical properties of the cement mortar. In this study, CO2 curing was employed to ameliorate these drawbacks. The effect of CO2 curing on both of the mechanical properties and microstructure of the RG incorporated cement mortar was studied by a series of laboratory tests. The results showed that replacement of river sand by 100% RG led to a 37% decrease in compressive strength and a 32% reduction in flexural strength of the mortar samples under conventional curing. Whereas, CO2 curing of these samples significantly enhanced both the compressive and flexural strength, with a more pronounced improvement on the former. Such improvements were further reflected by a decrease in both the water absorption and porosity, and by an enhancement of the microstructure. This is attributed to the fact that compared with the mortar samples prepared with 100% river sand, those prepared with 100% RG had a more porous structure due to the smooth surface of RG and thus a poor bonding between the RG and the cement paste. However, such a porous structure encouraged CO2 gas to penetrate and diffuse more easily into the cementitious matrix, resulting in a higher degree of CO2 curing.
Objective
This study evaluated the antitumor activity and safety of pemigatinib in previously treated Chinese patients with advanced cholangiocarcinoma and fibroblast growth factor receptor 2 (FGFR2) ...fusions or rearrangements.
Background
Pemigatinib provided clinical benefits for previously treated patients with cholangiocarcinoma carrying FGFR2 fusions or rearrangements and was approved for this indication in multiple countries.
Methods
In this ongoing, multicenter, single‐arm, phase II study, adult patients with locally advanced or metastatic cholangiocarcinoma carrying centrally confirmed FGFR2 fusions or rearrangements who had progressed on ≥1 systemic therapy received 13.5 mg oral pemigatinib once daily (3‐week cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was objective response rate (ORR) assessed by an independent radiology review committee.
Results
As of January 29, 2021, 31 patients were enrolled. The median follow‐up was 5.1 months (range, 1.5–9.3). Among 30 patients with FGFR2 fusions or rearrangements evaluated for efficacy, 15 patients achieved partial response (ORR, 50.0%; 95% confidence interval CI, 31.3–68.7); 15 achieved stable disease, contributing to a disease control rate of 100% (95% CI, 88.4–100). The median time to response was 1.4 months (95% CI, 1.3–1.4), the median duration of response was not reached, and the median progression‐free survival was 6.3 months (95% CI, 4.9–not estimable NE). Eight (25.8%) of 31 patients had ≥grade 3 treatment‐emergent adverse events. Hyperphosphatemia, hypophosphatasemia, nail toxicities, and ocular disorders were mostly <grade 3, except for 2 events ≥grade 3.
Conclusions
The encouraging antitumor activity and favorable safety profile support the use of pemigatinib as a treatment in previously treated Chinese patients with cholangiocarcinoma and FGFR2 rearrangements.
Densification, microstructure, and mechanical properties of spark plasma sintered HfB2 and HfB2‐SiC ceramics using HfB2 powders from borothermal reduction and boro/carbothermal reduction were ...investigated and compared. It was found that HfB2ceramics obtained by boro/carbothermal reduction exhibited a significantly higher sinterability compared to that by borothermal reduction. Inversely, HfB2‐SiC ceramics obtained by borothermal reduction exhibited a refined microstructure and better mechanical properties (Vickers hardness: 23.60 ± 2.43 GPa; fracture toughness: 5.89 ± 0.30 MPa.m1/2) than that by boro/carbothermal reduction. These results indicated that optimal fabrication of HfB2‐based ceramics could be achieved by the selection of synthetic route of HfB2 powders.
Purpose: To investigate the role of CD24 in tumor invasion and prognostic significance in hepatocellular carcinoma (HCC).
Experimental Design: CD24 expression was measured in stepwise metastatic HCC ...cell lines, tumor, peritumoral tissues, and normal liver tissues
by quantitative real-time PCR and Western blot. The role of CD24 in HCC was investigated by CD24 depletion using small interfering
RNA. Tumor tissue microarrays of 314 HCC patients who underwent resection between 1997 and 2000 were used to detect expression
of CD24, β-catenin, and proliferating cell nuclear antigen. Prognostic significance was assessed using Kaplan-Meier survival
estimates and log-rank tests.
Results: CD24 was overexpressed in the highly metastatic HCC cell line and in tumor tissues of patients with recurrent HCC. Depletion
of CD24 caused a notable decrease in cell proliferation, migration, and invasiveness in vitro . Univariate and multivariate analyses revealed that CD24 was a significant predictor for overall survival and relapse-free
survival. CD24 expression was correlated with poor prognosis independent of α-fetoprotein, tumor-node-metastasis stage, and
Edmondson stage. High CD24 expression was significantly associated with cytoplasmic and nuclear accumulation of β-catenin
( P = 0.023), high tumor proliferative status ( P = 0.018), and diffused intrahepatic recurrence and distant metastasis ( P = 0.026). Adjuvant transcatheter arterial chemoembolization after surgery reduced the rate of early recurrence (â¤1 year)
in CD24 + HCC patients ( P = 0.024) but had no significant effect in CD24 â patients ( P = 0.284).
Conclusions: Overexpression of CD24 in HCC was associated with high invasiveness and metastatic potential, high tumor proliferation status,
and activation of the Wnt/β-catenin pathway. CD24 may be a novel predictor for poor prognosis of HCC patients after surgery.
(Clin Cancer Res 2009;15(17):5518â27)
Multidrug resistance is a major challenge in treating advanced hepatocellular carcinoma (HCC). Although recent studies have reported that the multidrug resistance phenotype is associated with ...abnormal DNA methylation in cancer cells, the epigenetic mechanism underlying multidrug resistance remains unknown. Here, we reported that the level of 5-hydroxymethylcytosine (5-hmC) in human HCC tissues was significantly lower than that in adjacent liver tissues, and reduced 5-hmC significantly correlated with malignant phenotypes, including poor differentiation and microvascular invasion; additionally, loss of 5-hmC was related to chemotherapy resistance in post-transplantation HCC patients. Further, the 5-hmC level was regulated by ten-eleven translocation 2 (TET2), and the reduction of TET2 in HCC contributes to chemotherapy resistance through histone acetyltransferase P300/CBP-associated factor (PCAF) inhibition and AKT signaling hyperactivation. In conclusion, loss of 5-hmC induces chemotherapy resistance through PCAF/AKT axis and is a promising chemosensitivity prediction biomarker and therapeutic target for HCC patients.
Intrahepatic cholangiocarcinoma (ICC) is highly invasive and carries high mortality due to limited therapeutic strategies. In other solid tumors, immune checkpoint inhibitors (ICIs) target cytotoxic ...T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD1), and the PD1 ligand PD-L1 has revolutionized treatment and improved outcomes. However, the relationship and clinical significance of CTLA-4 and PD-L1 expression in ICC remains to be addressed. Deciphering CTLA-4 and PD-L1 interactions in ICC enable targeted therapy for this disease. In this study, immunohistochemistry (IHC) was used to detect and quantify CTLA-4, forkhead box protein P3 (FOXP3), and PD-L1 in samples from 290 patients with ICC. The prognostic capabilities of CTLA-4, FOXP3, and PD-L1 expression in ICC were investigated with the Kaplan-Meier method. Independent risk factors related to ICC survival and recurrence were assessed by the Cox proportional hazards models. Here, we identified that CTLA-4
lymphocyte density was elevated in ICC tumors compared with peritumoral hepatic tissues (
<.001), and patients with a high density of CTLA-4
tumor-infiltrating lymphocytes (TILs
) showed a reduced overall survival (OS) rate and increased cumulative recurrence rate compared with patients with TILs
(
<.001 and
= .024, respectively). Similarly, patients with high FOXP3
TILs (TILs
) had poorer prognoses than patients with low FOXP3
TILs (
= .021,
= .034, respectively), and the density of CTLA-4
TILs was positively correlated with FOXP3
TILs (Pearson
= .31,
<.001). Furthermore, patients with high PD-L1 expression in tumors (Tumor
) and/or TILs
presented worse OS and a higher recurrence rate than patients with TILs
Tumor
. Moreover, multiple tumors, lymph node metastasis, and high Tumor
/TILs
were independent risk factors of cumulative recurrence and OS for patients after ICC tumor resection. Furthermore, among ICC patients, those with hepatolithiasis had a higher expression of CTLA-4 and worse OS compared with patients with HBV infection or undefined risk factors
= .018). In conclusion, CTLA-4 is increased in TILs in ICC and has an expression profile distinct from PD1/PD-L1. Tumor
/TILs
is a predictive factor of OS and ICC recurrence, suggesting that combined therapy targeting PD1/PD-L1 and CTLA-4 may be useful in treating patients with ICC.
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