Progress in the treatment of advanced hepatocellular carcinoma with immune combination therapy

Advanced hepatocellular carcinoma(HCC)is a severe malignancy that poses a serious threat to human health.Owing to challenges in early diagnosis,most patients lose the opportunity for radical treatment when diagnosed.Nonetheless,recent advancements in cancer immunotherapy provide new directions for the treatment of HCC.For instance,monoclonal antibodies against immune check-point inhibitors(ICIs)such as programmed cell death protein 1/death ligand-1 inhibitors and cytotoxic t-lymphocyte associated antigen-4 significantly improved the prognosis of patients with HCC.However,tumor cells can evade the immune system through various mechanisms.With the rapid development of genetic engineering and molecular biology,various new immunotherapies have been used to treat HCC,including ICIs,chimeric antigen receptor T cells,engineered cytokines,and certain cancer vaccines.This review summarizes the current status,research progress,and future directions of different immunotherapy strategies in the treatment of HCC.

Influences of immersion bathing in Bacillus velezensis DY-6 on growth performance,non-specific immune enzyme activities and gut microbiota of Apostichopus japonicus

In this study, the influences of immersion bathing in different concentrations of Bacillus velezensis DY-6 on the body weight gain rate and non-specific immune enzyme activities of the coelom fluid of sea cucumber (Apostichopus japonicus) were determined in order to obtain the optimum bacterial concentration. The gut microbiota change in A. japonicus was then analyzed through high-throughput sequencing during the immersion bathing in B. velezensis DY-6 at the optimum concentration for 49 d. The results illustrate that the body weight growth rate of all bathing groups was higher than that of the control. The highest growth rate (25.3%) was achieved when the bacterial concentration was 1×10^3 CFU/mL. The activities of non-specific immune enzymes (ACP, AKP, SOD and LZM) of all bathing groups increased, and the activities of the enzymes of groups bathed with the bacterium at 1×10^3 and 1×10^4 CFU/mL reached the highest on day 21 and day 28. Taking the growth rate and economic cost into consideration, the optimum concentration of B. velezensis DY-6 was 1×10^3 CFU/mL. The influences of immersion bathing in B. velezensis DY-6 at 1×10^3 CFU/mL on the gut microbiota of A. japonicus were then evaluated through 16S rDNA sequencing analysis. Results showed that the gut microbiota changed with the addition of B. velezensis DY-6, and the richness and diversity of the gut microbiota peaked twice on day 14 and day 21, respectively. In association with the non-specific immune enzyme activities and if day 28 was selected as the dividing point, the community structure of the gut microbiota could be obviously divided into two types. The correlation analysis revealed that the non-specific immune enzyme activities were correlated significantly to some gut bacteria (in the phyla Firmicutes, Proteobacteria, and Bacteroidetes) after immersion bathing in B. velezensis DY-6. Our findings will provide the theoretical foundation for probiotic application in sea cucumber farming.

Non-specific immune response of bullfrog Rana catesbeiana to intraperitoneal injection of bacterium Aeromonas hydrophila

Non-specific immune response of bullfrog Rana catesbeiana to pathogenic Aeromonas hydrophila was studied to 60 individuals in two groups.Each bullfrog in bacterium-injected group was injected intraperitoneally(i.p.) with 0.2 ml bacterial suspension at a density of 5.2 × 106 CFU/ml,while each one in control group injected i.p.with 0.2 ml sterile saline solution(0.85%,w/v).Three bullfrogs in both groups were sampled at 0,1,3,7,11,15 and 20 days post-injection(dpi) for the evaluation of non-specific immune parameters.It was observed that intraperitoneal injection of A.hydrophila significantly increased the number of leucocytes and that of NBT-positive cells in peripheral blood.Significant increases in serum bactericidal activity and serum acid phosphatase activity were also observed in the bacterium-injected frogs when compared with those in the control group.However,a significant reduction was detected in vitro in phagocytosis activity of peripheral blood phagocytes.No significant difference in changes in the number of peripheral erythrocytes,serum superoxide dismutase(SOD) activity,and lysozyme activity was detected between the two groups.It is suggested that bullfrogs may produce a series of non-specific immune reactions in response to the A.hydrophila infection.

Effects of Oleanolic Acid on the Immune Complex Allergic Reaction and Inflammation

When oleanolic acid (OA) was administered ig before and after sensitization on d 1 to d 5 and d 11 to d 17,it had no apparent effect on Arthus reaction.When it was administered at 48,24 and 1 h before challenge,however,Arthus reaction was significantly inhibited.OA showed markedly suppressive effects on reversible passive Arthus reaction and leukocyte migratory response.It could significantly stabilize erythrocyte membrane,inhibit the swelling of the rat's hind paw induced by in- jecting mycostatin,reduce the acid phosphatase content in the inflammatory exudate,suppress the syn- thesis or release of PGE,histamine,LTB4 and kinin,and the phlogistic action of PGE_2,histamine,5- HT and kinin.In addition,it could decrease the content of malonyldialdehyde (MDA) in hepatic tissue of alcohol-intoxicated mice,and increase the activity of catalase (CAT) in hepatic tissue of mice.OA had no apparent effect on the activity of super-oxide dismutase (SOD) in rat serum,on the content of immune complex in serum of rat with Arthus reaction,on the phagocytosis of monocytc-macrophage system,on the clearance of enzyme-containing immune complex by macrophage,or on the activity of total complement.

Effect of Dietary Alanyl-glutamine Supplementation on Growth Performance, Development of Intestinal Tract, Antioxidant Status and Plasma Non-specific Immunity of Young Mirror Carp(Cyprinus carpio L.)

Exogenous alanyl-glutamine（Aln-Gln） was evaluated for its effects on growth performance, intestinal structure and function, antioxidant status and non-specific immunity of young carp（Cyprinus carpio L.）. Six diets supplemented with 0, 2.5, 5.0, 7.5, 10.0, or 15.0 g · kg-1 of Aln-Gln were fed to fish for 12 weeks. Supplementation with 7.5, 10.0, or 15.0 g · kg-1 of Aln-Gln significantly increased weight gain rate（WGR）, protein efficiency ratio（PER）, but feed conservation rate（FCR） and survival were not affected（P〉0.05）. The intestinal fold height and number, digestive enzyme, Na＋, K＋-ATPase activities was found to be significantly high（P〈0.05） with increasing dietary Aln-Gln supplementation up to 7.5 g · kg-1, but there were no significant differences for Aln-Gln supplementation from 7.5 to 15.0 g · kg-1. The glutathione peroxidase（GPX） activity, glutathione（GSH）, superoxide dismutase（SOD） activity increased and malondialdehyde（MDA） levels decreased significantly（P〈0.05） in the intestine, hepatopancreas, plasma and muscles. The plasma complement-3（C3） and complement-4（C4） levels were significantly（P〈0.05） improved at 5.0 g · kg-1 level and decreased when over 7.5 g · kg-1. The plasma lysozyme（LSZ） activity increased significantly（P〈0.05） at 7.5, 10.0, or 15.0 g · kg-1 level. In summary, the results showed that Aln-Gln improved growth performance, development and function of the intestine, the activity of the antioxidant defense system and the plasma non-specific immunity of the carps. The optimal Aln-Gln level was 8.24 g · kg-1 diet for WGR based on broken-line regression model analysis.

Effects of Size Grading on Growth and Non-Specific Immunity Factors of the Shrimp Litopenaeus vannamei Boone

The study aims to determine the effects of graded farming on growth performance and non-specific immunity factors of shrimp Litopenaeus vannamei Boone. Three size groups of shrimp, i.e., the small size group [Gs, with an average body length （BL） of （3.04 ± 0.36） cm and body weight （BW） （0.412± 0.35） g], the large group [GL, with a BL of （4.29±0.55） cm and BW of （1.098 ±0.42） g], and the ungraded group [Gm, with a BL of （3.47±0.81） cm and BW of （0.611 ±0.79） g], were reared under the same conditions for 8 wk. Growth performance and non- specific immunity factors were measured. The results showed that BW gain, biomass gain and the specific growth rate of body length （SGRL） were significantly influenced by size grading （one-way ANOVA, P 〈 0.05）. The peroxidase （POD） and antibacterial （Ua） activities of GL were lower than those of G. Superoxide dismutase （SOD） and lysozyme （U1） activities of Gm were lower than those of G. No significant difference （P = 0.121 〉 0.05） was found on phenoloxidase （PO） activity among the three size groups. Synthetically, size grading could enhance growth and rearing efficiency, and did not have a significant influence on the immunity of L. vannamei Boone. Therefore, graded fanning in L. vannamei Boone was feasible in the culture practice.

Effects of the Chinese Medicinal Herb Com plex Additives on Non-specific Immunity of Amursturgeon( Acipenser schrencki Brandt)

This study was to investigate the effects of aqueous decotion from three Chinese medicinal herb additives （ Cyrtomium fortunei, prescription I and prescription II） on non-specific immunity of 1 ＋ age old Amur sturgeon （Acipenser schrencki Brandt） by oral perfusion. Cyrtomiumfortunei, prescription I and prescription II were orally given to 15 fishes for each experimental group once a day, with the concentration of 9,175 and 36 g/S0 kg body weight, respectively. The administration was lasted for 14 days. Meanwhile, distilled water was orally given as the control. After the experiment, some of the experimental fishes were stimulated with high temperature （30 ℃ ） for two hours. Sampling was performed from fishes treated at 22 ℃ and 30 ℃ for measuring the protein content in the serum, phagocytic activity of leucocytes and the activity of the lysozyme in six tissues. The results indicated that Cyrtomiumfortunei and prescription II could help to enhance the content of various proteins and the phagocytic activity of leucocytes. There was no significant change in the effects between these two additives at either the normal temperature or high temperature. Prescription I did not show an obvious effect on the immunity of fishes at the normal temperature, but it did in promo- ting high-efficiency response and improving immunoregulation of fish shocked by some stimuli.

Effect of Ammonia-Nitrogen Stress on Non-specific Immunity of Hybrid Tilapia(Oreochromis niloticus× Oreochromis areus)

The juveniles of hybrid tilapia （ Oreochromis niloticus x Oreochromis areus） were exposed to ananonia-nitrogen （N） （0, 2.5, 5, 10 and 20 mg/L） for 0, 12, 24, 48 and 72 h to evaluate the effect of ammonia-N stress on their non-specific immunity. Results show that the activity of serum lysozyme decreased signifi- candy with extension of stress time （P 〈 0.05）. The total antioxidant capacity （T-AOC） and activity of antioxidase in liver were significantly affected. The activi- ty of T-AOC and total superoxide dismutase （T-SOD） of fish exposed to ammonia-N were initially decreasing then increasing （ P 〈 0.05 ）. Activities of catalase （CAT） and glutathione peroxidase （GSH-Px） were correlated with concentrations of ammonia-N. Fish exposed to lower concentrations （2.5 mg/L or 5 mg/L） showed decreased CAT activity within 24 h （P 〈 0.05 ）, while those exposed to higher concentrations （10 mg/L or 20 mg/L） initially showed increased then decreased activity of CAT. Except for the highest concentration groups, fish exposed to ammonia-N showed inductive activity of GSH-Px （ P 〈 0.05 ）. Under the ex- perimental conditions, non-specific immunity of tilapia was affected by ammonia-N stress, and the impact was increased with increased concentration and extension of time.

A study on the mechanism of acupuncture treatment of acne based on immune inflammation

Acne is a chronic inflammatory skin disease involving hair follicle sebaceous glands,which is characterized by acne,papules,pustules,nodules,cysts and so on.The disorder of immune inflammation is the key link.A variety of factors participate in the immune inflammatory response of acne and interact with each other,leading to the occurrence and development of acne inflammation.Acupuncture can regulate the immune and inflammatory response through many links and improve the skin lesions.This study explains potential mechanisms of acupuncture in the treatment of acne by regulating the body's immune inflammatory response,in order to provide new ideas.

Immunology demystified: A guide for transplant hepatologists

Liver transplantation has become standard practice for treating end-stage liver disease.The success of the procedure relies on effective immunosuppressive medications to control the host's immune response.Despite the liver's inherent capacity to foster tolerance,the early post-transplant period is marked by significant immune reactivity.To ensure favorable outcomes,it is imperative to identify and manage various rejection types,encompassing T-cell-mediated,antibody-mediated,and chronic rejection.However,the approach to prescribing immunosuppressants relies heavily on clinical judgment rather than evidencebased criteria.Given that the majority of patients will require lifelong immunosuppression as the mechanisms underlying operational tolerance are still being investigated,healthcare providers must possess an understanding of immune responses,rejection mechanisms,and the pathways targeted by immunosuppressive drugs.This knowledge enables customization of treatments and improved patient care,even though a consensus on an optimal immunosuppressive regimen remains elusive.

Cryoablation-Induced Anti-Cancer Immune Reaction—Immune Reaction Induced By Cryoablation

Among the ablation procedures used against advanced liver cancer, thermal ablation therapy is widely applied, and the safety and efficacy of this technique have been well characterized. In contrast, the principle of cryosurgery is not only to control local recurrence, but also to stimulate the immune system into initiating an anti-tumor response. In recent years, we have developed a treatment method for patients with advanced liver tumors. From these experiences, repeated treatment was demonstrated to induce anti-cancer immune reaction-related factors. In the present review, mechanisms for anti-tumor immune reaction will be argued with introducing a novel strategy of a cryoablation.

Effect of laparoscopic myomectomy on inflammatory reaction, immune function, stress hormones and ovarian function

Objective: To investigate the effect of laparoscopic myomectomy on inflammatory reaction, immune function, stress hormones and ovarian function. Methods: Selected a total of 82 patients with hysteromyoma accorded with the screening criteria as the objects of study, according to the random data table, the patients were divided into the control group (n=41) and the observation group (n=41);The patients in the control group received traditional laparotomy myomectomy, and the observation group patients received laparoscopic myomectomy. The inflammatory reaction, immune function, stress hormone and ovarian function levels were compared between the two groups before and after treatment (before operation and after 1 d of operation). Results: After comparison, before treatment the difference of TNF-α, CRP, CD3+, CD4+, CD8+, CD4+/CD8+, COR, NE, LH, FSH and E2 levels between the groups was not statistically significant;After treatment, the TNF-α, CRP, CD8+, COR, NE, LH and FSH levels of two groups were significantly increased, and the levels after treatment in the control group were significantly higher than the observation group, the difference was statistically significant;The levels of CD3+, CD4+, CD4+/CD8+ and E2 in the observation group were significantly higher than those in the control group, the difference was statistically significant. Conclusion: Laparoscopic myomectomy can effectively reduce the inflammatory reaction and stress reaction, and have a less influence on the immune function and ovarian function, which is more conducive to postoperative rehabilitation.

Effects of dietary fiber in enteral nutrition on inflammatory reaction, immune response and intestinal mucosal barrier in patients with severe acute pancreatitis

Objective:To study the effects of dietary fiber in enteral nutrition on inflammatory reaction, immune response and intestinal mucosal barrier in patients with severe acute pancreatitis. Methods: The patients with severe acute pancreatitis treated in our hospital between February 2015 and February 2018 were selected and randomly divided into two groups. The observation group received basic treatment combined with enteral nutrition containing dietary fiber, and the control group received basic treatment combined with conventional enteral nutrition. The contents of inflammatory cytokines and intestinal mucosal barrier markers in serum, the number of immune cells in peripheral blood as well as the number of intestinal flora in feces were measured respectively before treatment and 7 d after treatment.Results: Interleukin-8 (IL-8), monocyte chemoattractant protein (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble triggering receptor expressed on myeloid cells-1 (sTREM1), endotoxin, D-lactic acid and diamine oxidase (DAO) contents in serum, the number of CD8+T cells in peripheral blood as well as the number of enterococcus and enterobacterium in feces of both groups were significantly lower while the number of CD3+T cells, CD4+T cells, CD19+B cells and CD16+CD56+NK cells in peripheral blood as well as the number of bifidobacteria and lactobacillus in feces were significantly higher after treatment, and IL-8, MCP-1, sICAM-1, sTREM1, endotoxin, D-lactic acid and DAO contents in serum, the number of CD8+T cells in peripheral blood as well as the number of enterococcus and enterobacterium in feces of observation group after treatment were significantly lower than those of control group while the number of CD3+T cells, CD4+T cells, CD19+B cells and CD16+CD56+NK cells in peripheral blood as well as the number of bifidobacteria and lactobacillus in feces were significantly higher than those of control group.Conclusion: Dietary fiber in enteral nutrition can alleviate inflammatory reaction, improve immune response and correct intestinal mucosal barrier dysfunction in patients with severe acute pancreatitis.

Effects of Tripterygium wilfordii combined with viaminate capsules on psoriasis patients' immune indexes, endothelium, inflammatory reaction, sICAM-1 and NF-kB

Objective: To explore the effects of Tripterygium wilfordii combined with viaminate on psoriasis patients' immune indexes, endothelium, inflammatory reaction, sICAM-1 and NF-kB. Methods: A total of 112 patients with psoriasis admitted in our hospital from September 2015 to November 2017 were randomly divided into control group (n=56) and observation group (n=56). The control group was treated only by Viaminate Capsules, and the observation group was treated with Tripterygium wilfordii tablet on the basis of the control group, the immune function, endothelial, inflammatory response, soluble intercellular adhesion molecules-1 (sICAM-1) and nuclear transcription factor-kB (NF-kB) expression levels were compared before and after treatment in the two groups. Results: Before treatment, CD4+, CD8+, CD4+/CD8+, vascular endothelial growth factor (VEGF), nitric oxide (NO), endothelin-1 (ET-1), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), NF-kB, and sICAM-1 in two groups were no significant difference. After treatment, CD4+and CD4+/CD8+in both groups were significantly increased, while CD8+was significantly lower than before treatment, the CD4+and CD4+/CD8+in the observation group were significantly higher than those in the control group, and CD8+was obviously lower than that of the control group;The VEGF, NO and ET-1 in both groups were dramatically lower than those before treatment, and the VEGF, NO and ET-1 in the observation group were significantly lower than those in the control group;The TNF-α and IFN-γ in two groups were significantly lower than before treatment, and TNF-α and IFN-γ in the observation group were remarkably lower than those in the control group;The NF-kB and sICAM-1 in two groups were obviously decreased than those before treatment, and the NF-kB and sICAM-1 in the observation group were significantly lower than those in the control group. Conclusion: Tripterygium wilfordii combined with viaminate capsules in the treatment of psoriasis patients, can effectively correct their immune dysfunction, improve endothelial function, reduce inflammatory response and inhibit the expression of NF-kB and sICAM-1 expression.

Changes and significance of inflammatory reaction and immune function in children with infectious pneumonia

Objective: To investigate the changes of inflammatory factors and immune function indexes in children with infectious pneumonia, to analyze the relationship between the level of indicators and the severity of the disease. Methods: A total of 160 children with infectious pneumonia were selected as the observation group included bacterial pneumonia group (n=98), mycoplasma pneumonia group (n=32) and viral pneumonia group (n=30), according to the severity of the disease, they were divided into mild group (n=105) and severe group (n=55), at the same time 100 cases of healthy children in the same period were selected as control group, the levels of inflammatory factors and the indexes of immune function were compared between the groups and different courses of disease. Results: Compared with the control group, the levels of hs-CRP and PCT in the observation group were significantly increased, and in the observation group, the bacterial pneumonia group of hs-CRP and PCT levels were significantly higher than those in mycoplasma pneumonia group and viral pneumonia group, compared with the viral pneumonia group hs-CRP level ,the level in the mycoplasma pneumonia group was significantly increased;The comparison of immune function index, the observation group CD3+, CD4+ and CD4+/CD8+ levels [(66.32±8.61)%, (36.51±6.26), (1.21±0.29)] were significantly lower than those of the control group, the level of CD8+ (26.34±5.11)% was significantly higher than the control group (22.75±3.88)%, but the levels of CD3+, CD4+, CD8+and CD4+/CD8+ in each group of the observation group were not statistically significant;The severe group hs-CRP, PCT and CD8+ levels were significantly higher than the mild group, and the levels of CD3+, CD4+ and CD4+/CD8+ were significantly decreased. Conclusion: There is a marked inflammatory response and abnormal cellular immune function in children with infectious pneumonia, and its level detection is of great value in the diagnosis of disease and the assessment of the severity of the disease.

Effects of Methionine on the Immune Function in Animals

Nutrition and immunity are the hot topics in animal’s production, and the effects of methionine on the immunity are already confirmed as the deep research on the nutrition of amino acid and immune function. However, the relationship of the methionine and immunity has not been elucidated clearly, this review aims to clarify the effects of methionine on immune function in the aspects of growth and development immune organs, the histological structure of the immune organs, non-specific immunity, humoral immunity, cellular immunity and cytokines, and to provide foundations for further studies on the relationship between methionine and immune function.

Clinical characteristics of gastrointestinal immune-related adverse events of immune checkpoint inhibitors and their association with survival

BACKGROUND Despite the popularity of immune checkpoint inhibitors(ICIs)in the treatment of advanced cancer,patients often develop gastrointestinal(GI)and non-GI immune-related adverse events(irAEs).The clinical characteristics and survival outcomes of GI-irAEs have not been fully elucidated in previous reports.This necessitates the evaluation of the impact of GI-irAEs on patients receiving ICI treatment.AIM To evaluate the clinical characteristics of GI-irAEs and their impact on survival in patients treated with ICIs.METHODS In this single-center,retrospective,observational study,we reviewed the records of 661 patients who received ICIs for various cancers at Nagoya University Hospital from September 2014 to August 2020.We analyzed the clinical characteristics of patients who received ICI treatment.We also evaluated the correlation between GI-irAE development and prognosis in non-small cell lung cancer(LC)and malignant melanoma(MM).Kaplan-Meier analysis was used to compare the median overall survival(OS).Multivariate Cox proportional hazards models were used to identify prognostic factors.A P value<0.05 was considered statistically significant.RESULTS GI-irAEs occurred in 34 of 605 patients(5.6%)treated with an anti-programmed cell death-1/programmed death-ligand 1(anti-PD-1/PD-L1)antibody alone and in nine of 56 patients(16.1%)treated with an anti-cytotoxic T-lymphocyte antigen 4(CTLA-4)antibody alone or a combination of anti-PD-1 and anti-CTLA-4 antibodies.The cumulative incidence and median daily diarrhea frequency were significantly higher in patients receiving anti-CTLA-4 antibodies(P<0.05).In 130 patients with MM,OS was significantly prolonged in the group that continued ICI treatment despite the development of GI-irAEs compared to the group that did not experience GI-irAEs(P=0.035).In contrast,in 209 patients with non-small cell LC,there was no significant difference in OS between the groups.The multivariate analyses showed that a performance status of 2-3(hazard ratio:2.406;95%confidence interval:1.125–5.147;P=0.024)was an independent predictive factor for OS in patients with MM.CONCLUSION Patients receiving anti-CTLA-4 antibodies develop GI-irAEs more frequently and with higher severity than those receiving anti-PD-1/PD-L1 antibodies.Continuing ICI treatment in patients with MM with GI-irAEs have better OS.

DIFFERENT EFFECT OF MOUSE HEPATOCARCINOMA CELLS WITH DIFFERENT METASTATIC POTENTIAL ON HOST IMMUNE SYSTEM

Objective: To investigate the effect of mouse hepatocarcinoma cell line HCa-F (high metastatic potential) and HCa-P (low metastatic potential) on immune system of the host. Methods: Mice were subcutaneously implanted with HCA-F (F) or HCa-P (P) cells. Cell cycle of lymphocytes from metastatic lymph nodes of tumor-bearing mice was studied by flow cytometry. Fas-L expression of F and P cells was detected immunohistochemically. Apoptosis of macrophages in metastatic lymph nodes was examined by TUNEL methods. Results: For the Hca-F cell bearing mice, the proliferating peak of lymphocytes appeared on 14th day post-inoculation and then decreased rapidly, while for the Hca-P cell bearing mice, the peak appeared on the 7th day post-inoculation and then kept at high level. The expression of Fas-L in F cells was stronger than that in P cells (P<0.01). Apoptosis occurred in macrophages near metastatic F cells in lymph nodes of tumor-bearing mice. Conclusion: Carcinoma cells with high metastatic potential may suppress immune reaction of host through inducing apoptosis of macrophages (one of the important antigen present cells) by Fas-L-Fas interreaction. And the expression of Fas-L in tumor cells may be associated with high metastatic ability to lymph nodes.