Hepatocellular carcinoma immune prognosis score predicts the clinical outcomes of hepatocellular carcinoma patients receiving immune checkpoint inhibitors.

OBJECTIVE: The predictive biomarkers of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) still need to be further explored. This study aims to establish a new immune prognosis biomarker to predict the clinical outcomes of hepatocellular carcinoma patients receiving immune checkpoint inhibitors. METHODS: The subjects of this study were 151 HCC patients receiving ICIs at Harbin Medical University Cancer Hospital from January 2018 to December 2021. This study collected a wide range of blood parameters from patients before treatment and used Cox's regression analysis to identify independent prognostic factors in blood parameters, as well as their ß coefficient. The hepatocellular carcinoma immune prognosis score (HCIPS) was established through Lasso regression analysis and COX multivariate analysis. The cut-off value of HCIPS was calculated from the receiver operating characteristic (ROC) curve. Finally, the prognostic value of HCIPS was validated through survival analysis, stratified analyses, and nomograms. RESULTS: HCIPS was composed of albumin (ALB) and thrombin time (TT), with a cut-off value of 0.64. There were 56 patients with HCIPS < 0.64 and 95 patients with HCIPS ≥ 0.64, patients with low HCIPS were significantly related to shorter progression-free survival (PFS) (13.10 months vs. 1.63 months, P < 0.001) and overall survival (OS) (14.83 months vs. 25.43 months, P < 0.001). HCIPS has also been found to be an independent prognostic factor in this study. In addition, the stratified analysis found a significant correlation between low HCIPS and shorter OS in patients with tumor size ≥ 5 cm (P of interaction = 0.032). The C-index and 95% CI of the nomograms for PFS and OS were 0.730 (0.680-0.779) and 0.758 (0.711-0.804), respectively. CONCLUSIONS: As a new score established based on HCC patients receiving ICIs, HCIPS was significantly correlated with clinical outcomes in patients with ICIs and might serve as a new biomarker to predict HCC patients who cloud benefit from ICIs.

Prognostic value of nutritional and inflammatory markers in patients with hepatocellular carcinoma who receive immune checkpoint inhibitors.

The emergence of immune checkpoint inhibitors (ICIs) has provided a new treatment option for patients with hepatocellular carcinoma (HCC). However, further evaluation is needed for determining biomarkers for the use of ICIs. The present study evaluated the prognostic value of certain nutritional and inflammatory markers in patients with HCC who received ICIs. In the present study, the clinical data of 151 patients with HCC who received ICIs at Harbin Medical University Cancer Hospital from January 2019 to December 2021 were collected. The blood parameters of all patients before treatment were collected to evaluate certain nutritional and inflammatory markers, including the prognostic nutrition index (PNI), nutritional risk index (NRI), geriatric NRI (GNRI), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI) and advanced lung cancer inflammation index (ALI). Patients were grouped using the cut-off value calculated using receiver operating characteristic (ROC) curves, and the relationship between these biomarkers and prognosis was evaluated through survival analysis. Furthermore, the prognostic value of these biomarkers was assessed through multivariate Cox regression analysis and construction of nomograms. Finally, time-ROC curves were plotted to compare the differences in predicting prognosis between the biomarkers. In the preliminary survival analysis, all inflammatory and nutritional markers included in the present study were significantly associated with the prognosis of HCC in patients who received ICIs. Similar results were obtained in a subgroup analysis of patients with different Barcelona Clinic Liver Cancer (BCLC) stages. Multivariate Cox regression analysis demonstrated that GNRI, PNI, BCLC stage and Tumor-Node-Metastasis (TNM) stage were significantly associated with progression-free survival (PFS), whereas GNRI, BCLC stage and TNM stage were also significantly associated with overall survival (OS). Furthermore, the time-ROC curves indicated that nutritional indicators had a higher prognostic value in all indexes, especially GNRI. The C-index (95% confidence interval) of the nomograms for predicting the survival probability of patients who received ICIs were 0.801 (0.746-0.877) and 0.823 (0.761-0.898) for PFS and overall OS, respectively, which also showed high accuracy. In conclusion, the present study demonstrated that PNI, GNRI, NRI, SII, SIRI and ALI were all related to the efficacy of ICIs in HCC and could serve as non-invasive biomarkers for ICI treatment effectiveness. Moreover, compared with inflammatory markers, nutritional markers had greater predictive ability, with GNRI being the biomarker with the best prognostic value.

The combination of circulating IgM and geriatric nutritional risk index predicts the prognostic of hepatocellular carcinoma patients who underwent immune checkpoint inhibitors.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) have shown promise in hepatocellular carcinoma (HCC) treatment. With the increasing use of ICIs in cancer treatment, identifying biomarkers that can predict the prognosis of patients receiving ICIs is of great importance. We aimed to investigate the potential of circulating immunoglobulins and the combination of Geriatric Nutritional Risk Index (GNRI) with IgM to predict prognosis in patients with HCC who received ICIs. METHODS: Clinical and pathological data were collected from 101 patients with HCC who were administered ICIs and underwent circulating immunoglobulin testing between January 2018 and December 2021. Survival analysis, Cox regression analysis, and nomogram construction were performed to evaluate the prognostic value of the indicators. RESULTS: In the preliminary survival analysis, we observed a significant correlation between patient prognosis and IgM levels. Patients with low IgM had shorter survival times. Upon combining the GNRI with IgM, patients with low GNRI and IgM levels had shorter progression-free survival (PFS) and overall survival (OS) (P < 0.001). Additionally, GNRI-IgM had the highest area under the curve (AUC) and was identified as an independent prognostic marker in this study. The C-indices of the nomograms for PFS and OS were 0.797 (0.734-0.860) and 0.827 (0.778-0.876), respectively. CONCLUSIONS: IgM was significantly associated with the prognosis of patients with HCC receiving ICIs. The combination of the GNRI with IgM provided superior prognostic value and served as an independent prognostic marker. The GNRI-IgM can be used to effectively identify patients with HCC who are responsive to ICIs.

C-C motif chemokine ligand 14 inhibited colon cancer cell proliferation and invasion through suppressing M2 polarization of tumor-associated macrophages.

BACKGROUND: Colon cancer is one of the most common cancers with a high incidence and high mortality. Chemokines play a crucial role in the development of cancer. METHODS: Here, qRT-PCR was performed to detect gene expression. Western blot and immunohistochemistry were implemented to examine the expression of C-C motif chemokine ligand 14 (CCL14) in colon tumors. Besides, the expression of CD68 and CD206 in tumors was measured by immunohistochemistry. The percentages of M1- and M2-polarized macrophages were detected by flow cytometry. Furthermore, CCK-8 assay was performed to detect cell proliferation, and Transwell assay for cell invasion. RESULTS: CCL14 was decreased in both colon tumors and colon cancer cells, and many tumor-associated macrophages (TAMs) infiltrated into the tumor. An increase CCL14 inhibited colon cancer cell proliferation. Importantly, CCL14 promoted THP-1 to M1 polarization induced by LPS and IFN-γ, and inhibited THP-1 to M2 polarization induced by IL-4 and IL-13. Besides, CCL14 enhanced the inhibition of M1-polarized macrophages to colon cancer cell proliferation and invasion, and reversed the promotion of M2-polarized macrophages to cell proliferation and invasion. CONCLUSION: Our data demonstrated that CCL14 inhibited the proliferation and invasion of colon cancer cells through suppressing the formation of M2-like TAMs.

Dopamine receptor D2 inhibition alleviates diabetic hepatic stellate cells fibrosis by regulating the TGF-ß1/Smads and NFκB pathways.

Diabetic hepatic fibrosis (DHF) is a progressive liver disease and a chronic complication of diabetes mellitus. The main cause of DHF is the activation of quiescent hepatic stellate cells (HSCs) by high glucose stimulation. Dopamine receptor D2 (DRD2)-mediated dopamine signalling can be involved in the regulation of diabetic liver disease, but the exact role of DRD2 in DHF is still poorly understood. This study aimed to investigate the protective effect of DRD2 inhibition on diabetic liver fibrosis and the potential mechanism. We established both streptozotocin (STZ)-induced type 1 diabetes (T1D, fed for 20 weeks) rat model and high glucose (HG, 40 mmol/L)-stimulated HSCs model. The results from both the rats with STZ and the HSCs treated with HG showed increased expression of DRD2, NOX-5, inflammation-related proteins (IL-6 and TNFα) and fibrosis-related proteins (TGF-ß1, CO-Ⅰ/Ⅲ/ IV, MMP-2/9 and fibronectin). In vivo, the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total antioxidant capacity (T-AOC) levels were significantly increased, and hematoxylin-eosin (HE) staining, Masson staining, and electron microscopy revealed liver lesions and hepatocyte injury. In addition, HG-treated HSCs exhibited altered oxidative stress - related indexes, including superoxide dismutase (SOD), malondialdehyde (MDA) and reactive oxygen species (ROS), changed and abnormally proliferated in vitro. TGF-ß1, the phosphorylated Smad2, nuclear NFκB-p65, phosphorylated NFκB-p65 and phosphorylated IκBα were also increased. Interestingly, haloperidol (DRD2 inhibitor) and n-acetyl-L-cysteine (NAC, an active oxygen scavenger) reduced the above-mentioned changes. In conclusion, DRD2 inhibition can reduce diabetic HSCs oxidative damage and fibrotic proliferation partly via the TGF-ß1/Smads and NFκB pathways.

Exogenous spermine attenuates rat diabetic cardiomyopathy via suppressing ROS-p53 mediated downregulation of calcium-sensitive receptor.

Diabetic cardiomyopathy (DCM) is a severe complication of type 1 diabetic (T1D) patients, manifested as combined diastolic and systolic dysfunction. DCM is associated with impaired calcium homeostasis secondary to decreased calcium-sensitive receptor (CaSR) expression. Spermine, a direct agonist of CaSR, was found deficient in cardiomyocytes of T1D rats. However, the role of spermine in DCM was unclear. Here, we examined the cardioprotective effect of exogenous spermine on DCM in streptozotocin (STZ) induced-T1D rats and high-glucose (HG)-incubated neonatal rat cardiomyocytes. Exogenous spermine significantly attenuated cardiac dysfunction in T1D rats, characterized by improved echocardiography, less fibrosis, reduced myocardial endoplasmic reticulum (ER) stress and oxidative stress, and increased expression of myocardial membrane CaSR. In cultured neonatal rat cardiomyocytes, exogenous spermine attenuated myocardial injury induced by HG treatment, demonstrated by restored cellular glucose uptake capacity, reduced expression of apoptotic markers, lowered level of oxidative stress, ER stress and unfolded protein response, and upregulated cell membrane CaSR. Mechanistically, the cardioprotective effect of spermine appeared dependent upon effective elimination of reactive oxygen species (ROS) and up-regulation of CaSR expression by suppressing the Nrf2-ROS-p53-MuRF1 axis. Taken together, these results suggest that exogenous spermine protects against DCM in vivo and in vitro, partially via suppressing ROS and p53-mediated downregulation of cell membrane CaSR.

Clinical Evaluation of Preoperative Radiotherapy Combined with FOLFOX Chemotherapy on Patients with Locally Advanced Colon Cancer.

This study explores the effect of preoperative radiotherapy combined with FOLFOX chemotherapy on patients with locally advanced colon cancer (LACC). Data of 102 patients with LACC were retrospectively analyzed. All received surgical resection plus postoperative FOLFOX chemotherapy; whereas 58 patients underwent preoperative radiotherapy combined with FOLFOX chemotherapy (CRT group, combined with radiotherapy treatment group), 44 patients did not undergo radiotherapy (non-CRT group). Short- and long-term effects as well as operative complications were compared. The optical density values of the caudal-related homeobox transcription factor 2 and inhibitor of growth 4 in lesions, and malignant molecules including vascular endothelial growth factor and cathepsin-D in serum were compared. The CRT group showed higher total pathological complete tumor response rate and resection rate, and lower incidence of incisional infection than the non-CRT group (all P < 0.05). The CRT group was significantly better in the three-year disease-free survival than the non-CRT group (P < 0.05), but slightly better in the three-year overall survival and disease-free survival in the first, second, and third years (P > 0.05). The optical density values of the caudal-related homeobox transcription factor 2 and inhibitor of growth 4 were higher than those in the non-CRT group (both P < 0.05). The levels of serum vascular endothelial growth factor and cathepsin-D in the CRT group were lower than those in the non-CRT group (both P < 0.05). Preoperative radiotherapy combined with FOLFOX chemotherapy can improve the resection rate and the pathological complete response rate in LACC surgery, and improve the survival time and the disease-free survival condition.

The apoptosis of peripheral blood lymphocytes promoted by hyperbaric oxygen treatment contributes to attenuate the severity of early stage acute pancreatitis in rats.

The aim of this study was to investigate the immunoregulatory effects of hyperbaric oxygen (HBO) via promoting the apoptosis of peripheral blood lymphocytes (PBLs) to attenuate the severity of early stage acute pancreatitis (AP) in rats. Additionally, the persistence of the HBO treatment effects was evaluated. One hundred and twenty male Wistar rats were randomized into four groups: sham, AP, AP + normobaric oxygen (NBO), and AP + HBO. Each group consisted of 30 rats. Four hours after the induction of AP, the 30 rats in the AP + NBO group were given normobaric oxygen treatment with 100 % oxygen at 1 atm for 90 min. The 30 rats in the AP + HBO group received 100 % oxygen at 2.5 atm for 90 min, with a compression/decompression time of 15 min. The 30 rats in the AP group remained untreated. At 6, 12, and 24 h after the induction of AP, surviving rats from each group were sacrificed, and the blood and tissue samples were collected for the following measurements: the partial pressure of oxygen (PaO2) and oxygen saturation (SaO2) of the arterial blood, the levels of serum amylase, lipase, interleukin-2 (IL-2), interferon-γ (IFN-γ), interleukin-10 (IL-10), hepatocyte growth factor (HGF), and reactive oxygen species (ROS), and the mitochondrial membrane potential (∆Ψm) of the PBLs. The expression levels of procaspase-3, caspase-3, procaspase-9, and caspase-9 were also evaluated in the PBLs. Additionally, the apoptosis of PBLs was assessed, and the pancreatic tissues were subjected to a histopathological analysis by pathological grading and scoring. The histopathology of the lung, liver, kidney, duodenum, and heart was also analyzed at 12 h after the induction of AP. Significant differences were found at 6 and 12 h after AP induction. The HBO treatment significantly elevated the PaO2 and SaO2 levels, and the ROS levels in the PBLs. Additionally, HBO downregulated the levels of amylase and lipase. The HBO treatment also reduced the ∆Ψm levels, upregulated the expression of caspase-3 and caspase-9, and increased the apoptosis rate of the PBLs. Moreover, the HBO treatment decreased the serum concentrations of IL-2, IFN-γ and HGF, and reduced the pathological scores of the pancreatic tissue. The histopathological changes of the lung, liver, kidney, duodenum, and heart were also improved. A significant elevation of IL-10 occurred only at the 12-h time point. However, no obvious differences were found at the 24-h time point. This study demonstrated that the HBO treatment can promote the apoptosis of PBLs via a mitochondrial-dependent pathway and inhibit the inflammatory response. These immunoregulatory effects may play an important therapeutic role in attenuating the severity of early stage AP. The repeated administration of HBO or the use of HBO in combination with other approaches may further improve outcomes.