CXC chemokines and their cognate receptors have been implicated widely in cancer pathogenesis. In this study, we report a critical causal relationship between CXCR6 expression and tumorigenesis in ...the setting of human hepatocellular carcinoma (HCC). Among the CXC chemokine receptors, only CXCR6 was detected in all the hepatoma cell lines studied. Moreover, in HCC tissue, CXCR6 expression was significantly higher than in noncancerous liver tissues. Reduction of CXCR6 or its ligand CXCL16 in cancer cells reduced cell invasion in vitro and tumor growth, angiogenesis, and metastases in vivo. Importantly, loss of CXCR6 led to reduced Gr-1+ neutrophil infiltration and decreased neoangiogenesis in hepatoma xenografts via inhibition of proinflammatory cytokine production. Clinically, high expression of CXCR6 was an independent predictor of increased recurrence and poor survival in HCCs. Human HCC samples expressing high levels of CXCR6 also contained an increased number of CD66b+ neutrophils and microvessels, and the combination of CXCR6 and neutrophils was a superior predictor of recurrence and survival than either marker used alone. Together, our findings suggest that elevated expression of CXCR6 promotes HCC invasiveness and a protumor inflammatory environment and is associated with poor patient outcome. These results support the concept that inhibition of the CXCR6-CXCL16 pathway may improve prognosis after HCC treatment.
Tumor-associated fibroblasts (TAF) is an important part of TME, which inhibits the function of immune cells. CD8+ T cells play a significant role in tumor immunity. T-cell membrane possesses a ...distinct type of molecule with a negative regulatory function. Upon interaction with its corresponding ligand programmed death factor ligand 1 (PD-L1), programmed death factor 1 (PD-1) is activated and thus inhibits the kinase activity of T cells. This study aims to explore the possible effects of TAF on PD-L1 expression in lung cancer cells.
Lung cancer cell lines H1975 and H520 were co-cultured with (experiment) or without TAF (control) via Transwell assay for through 48 hours under the same culture condition. H1975 and H520 cells were counted using a microscope. The protein and mRNA expression levels of PD-L1 were detected by FCM assay and PCR analysis, respectively.
The numbers of lung cancer cells in 100 μm2 for H1975 and H520 cells are (46±21) and (38±10) in the experiment group, respectively, and (16±5) and (12
Cultivation of locust associated rare actinobacteria, Amycolatopsis sp. HCa4, has provided five unusual macrolactams rifamorpholines A-E. Their structures were determined by interpretation of ...spectroscopic and crystallographic data. Rifamorpholines A-E possess an unprecedented 5/6/6/6 ring chromophore, representing a new subclass of rifamycin antibiotics. The biosynthetic pathway for compounds 1-5 involves a key 1,6-cyclization for the formation of the morpholine ring. Compounds 2 and 4 showed potent activities against methicillin-resistant Staphylococcus aureus (MRSA) with MICs of 4.0 and 8.0 μM, respectively.
A rare case of atlantoaxial lateral mass joint interlocking secondary to traumatic posterolateral C1,2 complete dislocation associated with type II odontoid fracture is herein reported and the impact ...of atlantoaxial joint interlocking on fracture reduction discussed. A 72‐year‐old man presented with traumatic atlantoaxial lateral mass joint interlocking without spinal cord signal change, the diagnosis being confirmed by radiography and 3‐D reconstruction digital anatomy. Posterior internal fixation was performed after failure to achieve closed reduction by skull traction. After many surgical attempts at setting had failed because of interlocking of the lateral mass joints, reduction was achieved by compressing the posterior parts of the atlantal and axial screws. Odontoid bone union and C1,2 posterior bone graft fusion were eventually obtained by the 12‐month follow‐up. The patient had a complete neurological recovery with no residual neck pain or radiculopathy.
B7-H3, a novel B7 family member, positively or negatively regulates T-cell responses. We investigated the clinical relevance and prognostic significance of B7-H3 in hepatocellular carcinoma (HCC). ...Western blotting showed B7-H3 upregulation in 17 of 24 (70.8 %) HCC tissues compared with nontumor liver tissues (
p
= 0.028). B7-H3 immunostaining on tissue microarrays containing 240 HCC patient samples indicated that 225 (93.8 %) tumors had aberrant B7-H3 expression, with strong intensity in 79 (32.9 %) cases, whereas B7-H3 expression in peritumor liver cells was weak in most cases (226; 94.2 %). Notably, patients with high/moderate tumor cell B7-H3 expression showed significantly poorer survival (
p
= 0.009) and increased recurrence (
p
= 0.002). After multivariable adjustment, high/moderate B7-H3 expression remained significant for an increased risk of recurrence (hazard ratio = 1.79; 95 % confidence interval = 1.19–2.70;
p
= 0.005). B7-H3 expression correlated with invasive phenotypes like vascular invasion and advanced tumor stage, and the metastatic potential of HCC cell lines. Flow cytometry showed that B7-H3 expression is inversely correlated with proliferation and interferon-γ production by infiltrating T cells. Interferon-γ stimulation significantly upregulated B7-H3 expression in HCC cells in vitro
,
implicating B7-H3 expression as a feedback mechanism to evade anti-tumor immunity. Importantly, the prognostic value of B7-H3 expression was validated in an independent cohort of 206 HCC patients. Collectively, our data suggest that B7-H3 was abundantly expressed in HCC and was associated with adverse clinicopathologic features and poor outcome. Thus, B7-H3 represents an attractive target for diagnostic and therapeutic manipulation in human HCC.
Uridine diphosphate glucuronosyltransferase 1A (UGT1A) is a major phase II drug-metabolism enzyme superfamily involved in the glucuronidation of endobiotics and xenobiotics in humans. Many ...polymorphisms in UGT1A genes are reported to inhibit or decrease UGT1A activity. In this study, two UGT1A1 allozymes, UGT1A1 wild-type and a splice mutant, as well as UGT1A9 wild-type and its three UGT1A9 allozymes, UGT1A9*2(C3Y), UGT1A9*3(M33T), and UGT1A9*5(D256N) were single- or double-expressed in a Bac-to-Bac expression system. Dimerization of UGT1A1 or UGT1A9 allozymes was observed via fluorescence resonance energy transfer (FRET) and co-immunoprecipitation analysis. SNPs of UGT1A altered the ability of protein-protein interaction, resulting in differential FRET efficiencies and donor-acceptor r distances. Dimerization changed the chemical regioselectivity, substrate-binding affinity, and enzymatic activity of UGT1A1 and UGT1A9 in glucuronidation of quercetin. These findings provide molecular insights into the consequences of homozygous and heterozygous UGT1A1 and UGT1A9 allozymes expression on quercetin glucuronidation.
Background
The density of tumor-infiltrating immunocytes (TICs) has been proposed as an independent predictor of intrahepatic recurrence in patients with hepatocellular carcinoma (HCC). However, the ...relative roles of TIC density in predicting tumor extrahepatic metastasis remain to be elucidated.
Methods
The densities of CD3
+
, CD8
+
, granzyme B
+
, FoxP3
+
, CD45RO
+
, CD20
+
, CD1a
+
, CD83
+
, CD57
+
, and CD68
+
TICs were assessed by immunohistochemistry in tissue microarrays containing paired intratumoral (IT) and peritumoral (PT) tissues from 206 consecutive HCC patients who underwent liver transplantation. Occurrence of extrahepatic metastasis, recurrence-free survival (RFS), and cancer-specific survival (CSS) were assessed retrospectively in relation to TIC densities.
Results
CD45RO
+
memory T cell density was lower in tumor tissue compared with peritumor, whereas CD57
+
senescent T cell density was higher. Univariate analysis revealed that increased CD45RO
IT
+
and decreased CD57
PT
+
densities were statistically significantly associated with favorable RFS and CSS, while other types of TICs, intratumorally or peritumorally, showed no prognostic values. Further, the CD45RO
IT
+
/CD57
PT
+
ratio could stratify patients more accurately in terms of RFS and CSS than either marker used alone. Finally, multivariate analysis indicated that a high CD45RO
IT
+
/CD57
PT
+
ratio was independently associated with better RFS (hazard ratio HR = 0.64; 95% confidence interval CI, 0.42 to 0.98;
P
= 0.040) and CSS (HR = 0.51; 95% CI, 0.31 to 0.83;
P
= 0.007), but not CD45RO
IT
+
or CD57
PT
+
individually.
Conclusions
These results suggest that the CD45RO
IT
+
/CD57
PT
+
(memory/senescent T cell) ratio is of vital importance in preventing HCC extrahepatic metastasis and in particular demonstrates its independent prognostic value in liver transplant recipients.
Chaetospirolactone (1), a novel spiro-lactone bearing a rare 1-oxaspiro 4.4 non-7-ene-2,6-dione skeleton, and orsellide F (2), together with six known compounds (3-8), were isolated from an ...endophytic fungus Chaetomium sp. NF00754. Their structures were determined by interpretation of spectroscopic data. The absolute configurations of 1 and 2 were established by analysis of single X-ray crystallographic data and CD spectra. Compounds 3, 4, and 6 showed moderate acetylcholinesterase inhibitory activity with IC
50
values of 7.34, 5.19, and 7.67 μM, respectively.
Purpose
An immune function assay has been proposed as a new strategy to monitor immunosuppression after organ transplantation. However, there are limited data regarding its role in liver transplant ...recipients with hepatocellular carcinoma (HCC). In this study, we sought to determine the utility of this functional assay in assessing the risk of infection, rejection, and tumor recurrence in liver transplant recipients.
Methods
Immune function was determined by ImmuKnow assay that measures the amount of adenosine triphosphate (ATP) produced by CD4 (+) T cells to monitor the global immune status in 342 whole blood samples from 105 liver transplant recipients. The association between ATP value and post-transplant tumor recurrence was evaluated in 60 HCC patients. The ATP value in predicting tumor recurrence in other independent cohort of 92 recipients with HCC was analyzed prospectively.
Results
The mean ATP values of liver transplant recipients with infection (145.2 ± 87.0 ng/ml) or acute rejection (418.9 ± 169.5 ng/ml) were different from those with stable state (286.6 ± 143.9 ng/ml,
P
< 0.05). In recipients with HCC who developed recurrent tumors, the values were significantly lower than those without recurrence (137.8 ± 66.4 vs. 289 ± 133.9 ng/ml,
P
< 0.01); the optimal threshold value to predict post-transplant tumor recurrence was 175 ng/ml. Comparing with the patients in lower immune group (ATP ≤ 175 ng/ml), patients in the higher immune group (ATP > 175 ng/ml) experienced significantly better disease-free survival (
P
< 0.01). Multivariate Cox regression analysis showed the ATP value was an independent predictor of HCC recurrence.
Conclusions
The immune function assay has the potential to assess the risk of infection and rejection in liver transplantation and to predict post-transplant tumor recurrence in recipients with HCC.
To examine how the thymidine phosphorylase (TP) gene expression is upregulated by interferon-alpha (IFN-alpha) in human hepatocellular carcinoma SMMC-7721 cells.
TP mRNA levels were determined by ...RT-PCR. Whether the JAK-STAT cascade mediates IFN-alpha-induced TP mRNA expression was studied by pretreatment with Janus Kinase (JAK) inhibitor, AG-490. Effects of IFN-alpha on TP mRNA stability were detected with additional actinomycin D.
The expression of TP mRNA was induced by IFN-alpha in a dose- and time-dependent manner in SMMC-7721 (human hepatocellular carcinoma) cells. TP mRNA levels rose at 8 h, reached the peak value at 12 h, and remained at a high level up to 72 h in SMMC-7721 cells treated with IFN-alpha 10000 U/ml. IFN-alpha at a dose of 5000 or 10000 U/ml up-regulated TP expression about 3 fold compared with that of non-treated cells (P < 0.05). Induction of TP mRNA expression by IFN-alpha was significantly inhibited in SMMC-7721 cells by pretreatment with AG-490, in comparison with that treated with
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