The tumor microenvironment generally shows a substantial immunosuppressive activity in hepatocellular carcinoma (HCC), accounting for the suboptimal efficacy of immune-based treatments for this ...difficult-to-treat cancer. The crosstalk between tumor cells and various cell types in the tumor microenvironment is strongly related to HCC progression and treatment resistance. Monocytes are recruited to the HCC tumor microenvironment by various factors and become tumor-associated macrophages (TAMs) with distinct phenotypes. TAMs often contribute to weakened tumor-specific immune responses and a more aggressive phenotype of malignancy. Recent single-cell RNA-sequencing data have demonstrated the central roles of specific TAMs in tumorigenesis and treatment resistance by their interactions with various cell populations in the HCC tumor microenvironment. This review focuses on the roles of TAMs and the crosstalk between TAMs and neighboring cell types in the HCC tumor microenvironment.
Calf diarrhea is associated with enteric infections, and also provokes the overuse of antibiotics. Therefore, proper treatment of diarrhea represents a therapeutic challenge in livestock production ...and public health concerns. Here, we describe the ability of a fecal microbiota transplantation (FMT), to ameliorate diarrhea and restore gut microbial composition in 57 growing calves. We conduct multi-omics analysis of 450 longitudinally collected fecal samples and find that FMT-induced alterations in the gut microbiota (an increase in the family Porphyromonadaceae) and metabolomic profile (a reduction in fecal amino acid concentration) strongly correlate with the remission of diarrhea. During the continuous follow-up study over 24 months, we find that FMT improves the growth performance of the cattle. This first FMT trial in ruminants suggest that FMT is capable of ameliorating diarrhea in pre-weaning calves with alterations in their gut microbiota, and that FMT may have a potential role in the improvement of growth performance.
The effect of prophylactic antiviral therapy (AVT) on survival of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unknown. This study aimed to determine whether ...prophylactic AVT could improve long-term survival in patients undergoing transarterial chemotherapy (TAC).
Between 2002 and 2016, 2860 newly diagnosed HBV-related patients with HCC treated with TAC were screened to analyze 2 groups based on prophylactic use of antivirals. Treatment effects were analyzed using propensity score (PS) matching (1:1) separately for the entire cohort and each subgroup. The primary endpoint was overall survival.
A total of 1547 patients met the inclusion criteria and 1084 were PS matched for the 2 groups. Median follow-up duration was 16.55 months. In the entire unmatched cohort, patients receiving prophylactic AVT survived significantly longer than those who did not. Among AVT-untreated patients, baseline high viremia and HBV reactivation during treatment were significantly associated with shorter survival. Regarding types of antivirals, survival was significantly longer for patients receiving high-potency antivirals than those receiving low-potency antivirals. Survival differed with antiviral response. In the PS-matched cohort, the prophylactic AVT group survived significantly longer than the nonprophylactic group, irrespective of viral status or tumor stage. Prophylactic AVT remained an independent factor for survival. The association of prophylactic AVT with decreased risk of mortality persisted in patient subgroups after adjusting for baseline risk factors. Sensitivity analyses also confirmed estimated treatment effects.
Prophylactic AVT is associated with significantly improved long-term survival among patients undergoing TAC. High-potency antivirals are indicated for this approach.Hepatitis B virus-associated morbidity is a well-known complication during transarterial chemotherapy (TAC). Our large-scale study demonstrated that prophylactic therapy with high-potency antivirals provides a significantly better survival in TAC-treated patients, irrespective of baseline viremia status or tumor stage.
Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line ...immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying human NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer.
The glycosylphosphatidylinositol‐anchored sperm hyaluronidases (Hyals), sperm adhesion molecule 1 (SPAM1) and HYAL5, have long been believed to assist in sperm penetration through the cumulus‐oocyte ...complex (COC), but their role in mammalian fertilization remains unclear. Previously, we have shown that mouse sperm devoid of either Spam1 or Hyal5 are still capable of penetrating the COC and that the loss of either Spam1 or Hyal5 alone does not cause male infertility in mice. In the present study, we found that Spam1/Hyal5 double knockout (dKO) mice produced significantly fewer offspring compared with wild‐type (WT) mice, and this was due to defective COC dispersal. A comparative analysis between WT and Spam1/Hyal5 dKO epididymal sperm revealed that the absence of these 2 sperm Hyals resulted in a marked accumulation of sperm on the outside of the COC. This impaired sperm activity is likely due to the deficiency in the sperm Hyals, even though other somatic Hyals are expressed normally in the dKO mice. The fertilization ability of the Spam1/Hyal5 dKO sperm was restored by adding purified human sperm Hyal to the in vitro fertilization medium. Our results suggest that Hyal deficiency in sperm may be a significant risk factor for male sterility.—Park, S., Kim, Y.‐H., Jeong, P.‐S., Park, C., Lee, J.‐W., Kim, J.‐S., Wee, G., Song, B.‐S., Park, B.‐J., Kim, S.‐H., Sim, B.‐W., Kim, S.‐U., Triggs‐Raine, B., Baba, T., Lee, S.‐R., Kim, E. SPAM1/HYAL5 double deficiency in male mice leads to severe male subfertility caused by a cumulus‐oocyte complex penetration defect. FASEB J. 33, 14440‐14449 (2019). www.fasebj.org
Antifibrotic agent for the treatment of liver fibrosis has not been developed so far. Long term treatment of chronic hepatitis B patients with antiviral drugs tenofovir disoproxil fumarate (TDF) and ...entecavir (ETV) results in the regression of liver fibrosis, but the underlying mechanism has not been clarified. Therefore, we aimed to investigate the direct impact of TDF and ETV on liver fibrosis.
Activated hepatic stellate cell (HSC) cell lines were used to evaluate the effects of TDF and ETV. After treatment with each antiviral agent, cell viability, morphology, apoptotic features, autophagy and antifibrosis signalling pathways were examined. Then, collagen deposition, fibrosis markers and activated HSCs were measured in liver tissues of the liver fibrosis model mice.
After TDF treatment, the viabilities of LX2 and HSC-T6 cells were decreased, and the cells exhibited apoptotic features, but ETV did not induce these effects. Cleavage of PARP and Caspase-3 and the inhibition of the antiapoptotic gene Bcl-xl indicated activated HSC apoptosis following TDF treatment. TDF simultaneously increased autophagy, which also regulated apoptosis through crosstalk. TDF inactivated the PI3K/Akt/mTOR signalling pathway, which was associated with the activation of both apoptosis and autophagy. In the liver fibrosis mouse model, the fibrotic area and activated HSC markers were decreased by TDF but not ETV treatment. Additionally, apoptotic cells were concentrated in the periportal fibrotic area after TDF treatment, which indicated the specific antifibrotic effect of TDF.
TDF directly ameliorates liver fibrosis by downregulating the PI3K/Akt/mTOR signalling pathway, which results in the apoptosis of activated HSCs. The antifibrotic effects of TDF indicate that it may be a therapeutic agent for the treatment of liver fibrosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and ...programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68
macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells (
< 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8
T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4
and CD8
T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8
T cells in HCC.
When interferons (IFNs) bind to their receptors, they upregulate numerous IFN-stimulated genes (ISGs) with antiviral and immune regulatory activities. Hepatitis C virus (HCV) is a single-stranded, ...positive-sense RNA virus that affects over 71 million people in the global population. Hepatocytes infected with HCV produce types I and III IFNs. These endogenous IFNs upregulate a set of ISGs that negatively impact the outcome of pegylated IFN-α and ribavirin treatments, which were previously used to treat HCV. In addition, the
genotype was the primary polymorphism responsible for a suboptimal treatment response to pegylated IFN-α and ribavirin. However, recently developed direct-acting antivirals have demonstrated a high rate of sustained virological response without pegylated IFN-α. Herein, we review recent studies on types I and III IFN responses to in HCV-infected hepatocytes. In particular, we focused on open issues related to IFN responses in the direct-acting antiviral era.
Whole blood viscosity (WBV) is increased in cancer patients and associated with the advanced stage with systemic metastases. However, relevance of WBV in hepatocellular carcinoma (HCC) remains ...unclear. This pilot study included a discovery cohort of 148 treatment-naïve HCC patients with preserved liver function, and a validation cohort of 33 treatment-experienced HCC patients with nivolumab. Systolic and diastolic WBV was measured using an automated scanning capillary tube viscometer at diagnosis or before the nivolumab treatment. Extrahepatic metastases were observed in 15 treatment-naïve patients (11.3%) at diagnosis. Portal vein tumor thrombosis (PVTT), tumor size, number of tumors, and systolic/diastolic WBV were factors associated with extrahepatic metastases. Systolic WBV and diastolic WBV were significantly increased in patients with metastases compared with patients without metastases. Multivariate logistic regression showed that high diastolic WBV > 16 cP was an independent factor associated with metastases. Notably, patients who developed extrahepatic metastases during the observation period among patients without metastases at diagnosis had higher diastolic WBV initially. Patients with high diastolic WBV had poor survival, and multivariate Cox regression analyses showed high diastolic WBV was an independent risk factor for poor survival with the Child-Pugh B7 and PVTT. High diastolic WBV also predicted poor survival in patients with low alpha-fetoprotein (AFP) and proteins induced by vitamin K antagonist-II (PIVKA-II) levels. In 33 nivolumab-treated patients, high diastolic WBV before the treatment was also tended to be associated with overall and progression-free survival. Our study is the first in which high WBV is associated with the distant metastases and survival in patients with HCC, but future prospective, large cohort studies are necessary to validate the results.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
