Comparing the clinical efficacy and safety of second-line targeted therapy and immunotherapy in patients with mid- to advanced stages of hepatocellular carcinoma - A systematic review and meta-analysis of randomized clinical trials.

OBJECTIVE: The aim of this study was to examine the efficacy and safety of second-line immunotherapy and targeted treatment in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: From January 2000 to January 2023, ProQuest, PubMed, Web of Science, Scopus, Embase, and the Cochrane Library databases were searched for randomized controlled trials (RCTs) using immunotherapy or targeted therapy as second-line therapy for mid-to-advanced stages of HCC. Overall survival (OS), progression-free survival (PFS), and adverse events (AEs) are all examples of measures of success. RESULTS: This analysis included twenty Randomized Clinical Trials (RCTs) from phases II and III. Collective data revealed better OS with immunotherapy (HR = 0.79; 95% CI: 0.67, 0.93 vs. 0.85; 95% CI: 0.78, 0.92), while the targeted therapy played a more effective role in PFS (0.67; 95% CI: 0.56, 0.81). Also, the second-line immunotherapy had a lower odds ratio of AEs of grades 3-5 than the targeted therapy did (OR = 1.75; 95% CI = 0.89, 3.46). CONCLUSIONS: Overall, it appears that targeted medication and immunotherapy as a second-line treatment strategy have generally improved substantially, as well as progression-free survival for patients with mid-to-advanced HCC. Although it is difficult to judge their efficiency, the occurrences of AEs were greater in targeted therapy compared to immunotherapy.

[Expression of gamma-aminobutyric acid type A receptor beta3 subunit in murine cleft palate induced by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin].

Objective: To investigate the expression of gamma-aminobutyric acid type A receptor beta3 subunit (GABRB3) on cleft palate in C57BL/6J mice induced by 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD). Methods: Sixty C57BL/6J pregnant mice on gestation day (GD) 10.5 were divided into two groups: one group was administered through gastric tubes one dose of 28 µg/kg TCDD (experimental group) and the other group was administered through gastric tubes one dose of 5.6 ml/kg corn oil (control group). Embryos were removed by cesarean section from pregnant mice during the palatal formation stage (GD 13.5-17.5) and the palatal tissue studied in morphological and histological observation. The relative mRNA and protein expression of GABRB3 was measured by real-time quantitative PCR and Western blotting. Localization of GABRB3 protein was measured by immunohistochemistry or immunofluorescence. Results: The incidence of cleft palate at GD17.5 was 100% in experimental group and there was no cleft palate occurred in the control group (0); elevation of palatine processes in experimental group was completed on GD15.5 which was clearly delayed by a day compared with that in control group. On GD14.5-GD17.5, the mRNA expression (0.561±0.073, 0.728±0.104, 0.782±0.137, 0.686±0.145) and protein expression (0.288±0.013, 0.404±0.017, 0.399±0.012, 0.307±0.010) in the experimental group were significantly lower than the control group mRNA expression (0.818±0.088, 0.865±0.086, 1.021±0.054, 1.163±0.179) and protein expression (0.481±0.017, 0.456±0.009, 0.474±0.016, 0.529±0.015)(P<0.05). Immunohistochemistry and immunofluorescence showed that GABRB3 was mainly expressed in the mesenchymal cells and medial edge epithelium. Conclusions: TCDD delayed palatal shelf elevation and eventually led to cleft palate may be associated with a decrease in GABRB3. GABRB3 may play an important role in the elevation and fusion phases of the palate development.

EDACO, a derivative of myricetin, inhibits the differentiation of Gaoyou duck embryonic osteoclasts in vitro.

1. This study determined the effects of (E)-3-(2-(4-(3-(2,4-dimethoxyphenyl)acryloyl)phenoxy)ethoxy)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (EDACO) on the differentiation of Gaoyou duck embryonic osteoclasts cultured in vitro. 2. Bone marrow mononuclear cells (BM-MNC) were collected from 23-d-old Gaoyou duck embryos and induced by macrophage colony-stimulating factor and receptor activator of nuclear factor κB ligand in the presence of EDACO at different concentrations (i.e. 10, 20, 40, 80 and 160 µM). Tartrate-resistant acid phosphatase (TRAP) staining and resorption ability determination were conducted. 3. Results suggested that EDACO suppressed the shaping of positive multinucleated cells and the number of TRAP-positive cells in the 20, 40, 80 and 160 µM EDACO groups was significantly decreased (P < 0.05 or P < 0.01). Besides, the absorption activity of differentiated duck embryonic osteoclasts was significantly inhibited (P < 0.05) in both 80 and 160 µM EDACO groups. 4. Overall, EDACO can inhibit the differentiation of BM-MNC into mature osteoclasts in duck embryos.1.

MicroRNA-214 functions as an oncogene in human osteosarcoma by targeting TRAF3.

OBJECTIVE: Osteosarcoma is a malignant bone tumor with high incidence. The prognosis of osteosarcoma is very poor when it is diagnosed with metastasis. Numerous studies have demonstrated that aberrant expressions of microRNAs are involved in cancer initiation and development. However, the potential role of miR-214 in osteosarcoma remains largely unrevealed. The current study investigated the relationship between the miR-214 and TNF receptor-associated factor 3 (TRAF3) in osteosarcoma tissues and cell lines. We also aimed to evaluate the potential roles of miR-214 on the occurrence and metastasis in osteosarcoma and verify its effect on the regulation of TRAF3. PATIENTS AND METHODS: The miR-214 expression and TRAF3 expression in osteosarcoma tissue samples and cell line were measured using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Followed by transfection assays, transwell assay was conducted to detect the migration and invasion abilities of osteosarcoma cells. Subsequently, Western blotting and luciferase reporter assay were performed in osteosarcoma cells to confirm the target of miR-214. RESULTS: The results showed that miR-214 expression levels were significantly increased not only in osteosarcoma tissues but also in osteosarcoma cell lines as compared with adjacent normal tissues and matched cell lines, respectively. On the contrary, the TRAF3 expression levels in osteosarcoma tissues and cell lines were frequently decreased compared to the control group. Moreover, TRAF3 was identified as a direct target of miR-214 and the inverse relationship between them was also observed in osteosarcoma tissues. Additionally, we found that miR-214 restoration could significantly promote osteosarcoma cell invasion and migration via targeting TRAF3. CONCLUSIONS: MicroRNA-214 functioned as an oncogene in osteosarcoma via targeting TRAF3, which may provide new insights into osteosarcoma prevention and treatment.

[Analysis of drug resistance of Acinetobacter baumannii in wound of children with traffic injury and its relationship with antibiotic use].

Objective: To know the drug resistance of Acinetobacter baumannii (AB) in wound of children with traffic injury and its relationship with antibiotic use. Methods: Wound exudate of 226 children with traffic injury admitted to our unit from January 2010 to December 2015 were collected. API bacteria identification panels and fully automatic microbiological identification system were used to identify pathogens. Kirby-Bauer paper disk diffusion method was used to detect the drug resistance of pathogens to 18 antibiotics including amoxycillin/clavulanic acid, piperacillin/tazobactam, and imipenem. The detection situation of pathogen of children's wounds and drug resistance of detected AB to 18 antibiotics in each year were collected. Forty-six AB positive children (2 children excluded) were divided into imipenem-resistant group (IR, n=19) and non imipenem-resistant group (NIR, n=25) according to whether AB was 100% resistant to imipenem. Drug resistance of AB in wounds of children to 18 antibiotics in two groups was compared. The antibiotic use of AB positive children was collected, and the antibiotic use intensity of children in two groups was compared. Data were processed with Fisher's exact test, independent sample t test, and corrected t test. Results: (1) The detection rates of pathogen in wounds of children in 2010-2015 were 95.6% (43/45), 89.8% (53/59), 81.3% (148/182), 81.1% (107/132), 81.6% (120/147), and 77.5% (62/80), respectively, showing a trend of decreasing year by year. A total of 665 strains and 75 pathogens were detected, and the top 5 pathogens with detection rate from high to low were AB, Pseudomonas aeruginosa, Enterobacter cloacae, Staphylococcus epidermidis, and Escherichia coli, respectively. (2) Drug resistance rates of AB to amoxycillin/clavulanic acid, cefazolin, aztreonam, and piperacillin were all 100%, while AB was 100% sensitive to polymyxin, and the total drug resistance rates of AB to the other 13 antibiotics were all above 50%. The drug resistance rate of AB in wounds of children to piperacillin was higher than that to piperacillin/tazobactam in 2010-2015. (3) Except for imipenem, amoxycillin/clavulanic acid, cefazolin, aztreonam, piperacillin, and polymyxin, the drug resistance rates of AB in wounds of children in group IR to the other 12 antibiotics were higher than those in group NIR (with P values below 0.01). Besides, AB strains in wounds of children in group IR were completely resistant to at least 3 kinds of antibiotics including carbapenems, aminoglycosides, and quinolones, so that they were multidrug-resistant AB. (4) A total of 32 antibiotics were used in 46 AB positive children, and the 10-top-used antibiotics with use intensity from high to low were cefoperazone/sulbactam, piperacillin/tazobactam, cefazolin, imipenem, ceftizoxime, amoxycillin/clavulanate, ceftazidime, cefepime, amoxycillin/sulbactam, and cefmetazole, respectively. (5) Twenty-one antibiotics were not included in the comparison because of their small amount of usage. For the other 11 antibiotics, only the use intensity of metronidazole of children in two groups was statistically different (t=-3.104, P<0.05). There was no statistically significant difference in total antibiotic use of children in two groups (t=0.368, P>0.05). Conclusions: AB is one of the main pathogens in wounds of children with traffic injury, with high drug resistant rate. The high intensity of antibiotic use may lead to its drug resistance. In this study, the top-used antibiotics were in accord with AB resistant drugs, indicating a lack of normative use of antibiotics.

Integrating conventional and antibody-based targeted anticancer treatment into immunotherapy.

In advanced cancer, current conventional therapies or immunotherapies cannot eradicate all tumor cells for most patients. Integration of these two treatments for synergistic effects could eradicate more tumor cells and increase the overall survival rates. However, since how conventional treatments impact on immune system remains unclear, proper integration is still a challenge. Intensive chemo/radiotherapy may impair ongoing immune responses, while lower intensity of therapy might not kill enough tumor cells, both leading to tumor relapse. Current understanding of mechanisms of resistance to conventional and targeted cancer therapies has focused on cell intrinsic pathways that trigger DNA damage/repair or signaling pathways related to cell growth. Recent reports show that host T cells properly primed against tumor-specific antigens after conventional treatment, which can integrate with direct cytotoxic effects induced by radiation or chemotherapy to profoundly control tumors. Following cytotoxic anticancer treatment, tumor-derived DAMPs (damage-associated molecular patterns) can be sensed by innate cells, which drives type I interferon production for cross-priming of CD8+ T cells. Some types and protocols of chemotherapy or radiation can increase tumor-infiltrating lymphocytes that overcome resistance to immunotherapy. As such, a deeper understanding of the immune mechanisms of conventional and targeted cancer therapies will lead toward novel combinatorial anticancer strategies with improved clinical benefit.

[Advances in the research of treating multi-drug resistant bacterial infections].

It is imperative to research the treatment strategy for infections caused by multi-drug resistant (MDR) bacteria, as there are increasing reports showing that more and more patients are decimated by the infections of MDR bacteria and the development of antimicrobial drugs is in downturn. Current researches mainly focus on the following three aspects: developing new antimicrobial agents with the aid of basic scientific achievements in finding new antibacterial targets, achieving antimicrobial purpose by specific lysis of host bacteria with phages of high specificity, and killing bacteria potently by destroying its cytomembrane using broad-spectrum antimicrobial peptides.

Prediction of Complement-Binding Capacity of HLA Antibodies Based on Mean Fluorescence Intensity.

BACKGROUND: Human leukocyte antigen (HLA) antibodies estimated by Luminex single-antigen beads, especially those that fix complement, are associated with antibody-mediated rejection and graft failure. However, the relationship between HLA antibody strength and complement-binding ability is controversial. METHODS: Serum samples of 31 sensitized renal patients waiting for renal transplantation were retrospectively analyzed by IgG-Luminex to identify HLA antibodies and in parallel by C1q-Luminex to determine the complement binding of HLA antibodies. RESULTS: The percentage of HLA class I antibodies binding with C1q was lower than that of HLA class II antibodies (43.2% vs. 51.3%, P = .006). The mean fluorescence intensities (MFI) of IgG-Luminex correlated with the MFI of C1q-Luminex for the same antibodies (Spearman correlation; class I, r = 0.665, P < .01; class II, r = 0.761, P < .01). Receiver operating characteristic (ROC) curve analysis showed that the MFIs of HLA antibodies by IgG-Luminex predicted their C1q-binding abilities (area under the curve [AUC] class I = 0.917; AUC class II = 0.927). Using MFI cutoff values of 8238 and 6754 in IgG-Luminex for HLA class I and class II antibodies, respectively, the sensitivity and specificity for C1q binding were 82.4% and 87.4% for class I antibodies and 90.9% and 82% for class II antibodies. CONCLUSIONS: The MFI of HLA antibodies by IgG-Luminex predicts the complement-binding capability to a certain extent before transplantation.

Sequential therapy with "vacuum sealing drainage-artificial dermis implantation-thin partial thickness skin grafting" for deep and infected wound surfaces in children.

OBJECTIVE: To evaluate the efficacy of a "vacuum sealing drainage (VSD) - artificial dermis implantation (ADI) - thin partial thickness skin grafting (TSG)" sequential therapy for deep and infected wounds in children. MATERIALS AND METHODS: Fifty-three pediatric patients with deep and infected wounds were treated with sequential VSD-ADI-TSG therapy. The efficacy of this treatment was compared with that of the surgical debridement-change dressings-thin partial thickness skin grafting previously performed on 20 patients. Survival of tissue grafts, color and flexibility, subcutaneous fullness and scar formation of the graft site were examined and compared. RESULTS: The sequential therapy combined the advantages of the VSD treatment, in reducing tissue necrosis and infection on the wound surfaces and promoting the growth of granulation tissue, with the enhancement of grafting by artificial dermis. Compared with the 20 controls, skin grafted on the artificial dermis was more smooth and glossy, while the textures of the region were more elastic, and the scars were significantly lighter in Vancouver scale. CONCLUSION: The sequential VSD-ADI-TSG therapy is a simple and effective treatment for children with deep and infected wounds. LEVEL OF EVIDENCE: IV.

Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells.

The immune mechanisms regulating epithelial cell repair after injury remain poorly defined. We demonstrate here that lymphotoxin beta receptor (LTßR) signaling in intestinal epithelial cells promotes self-repair after mucosal damage. Using a conditional gene-targeted approach, we demonstrate that LTßR signaling in intestinal epithelial cells is essential for epithelial interleukin-23 (IL-23) production and protection against epithelial injury. We further show that epithelial-derived IL-23 promotes mucosal wound healing by inducing the IL-22-mediated proliferation and survival of epithelial cells and mucus production. Additionally, we identified CD4(-)CCR6(+)T-bet(-) RAR-related orphan receptor gamma t (RORγt)(+) lymphoid tissue inducer cells as the main producers of protective IL-22 after epithelial damage. Thus, our results reveal a novel role for LTßR signaling in epithelial cells in the regulation of intestinal epithelial cell homeostasis to limit mucosal damage.

Blockade of OX40/OX40 ligand to decrease cytokine messenger RNA expression in acute renal allograft rejection in vitro.

AIM: The aim of this study was to investigate cytokine messenger RNA (mRNA) expression by peripheral blood mononuclear cells (PBMCs) from renal recipients experiencing acute rejection by blocking OX40-OX40L interactions with recombinant human OX40-Fc fusion protein (rhOX40Fc) in vitro. METHODS: PBMCs were isolated from 20 recipients experiencing acute rejection episodes (rejection group) and 20 recipients with stable graft function (stable group). Levels of Th1 (interferon [IFN]-γ) and Th2 (interleukin [IL]-4) mRNA expressions by PBMCs were measured using real-time reverse transcriptase-polymerase chain reactions. RESULTS: IFN-γ mRNA expression levels were significantly higher in the rejection than the stable group (P < .05). Levels of IL-4 mRNA expression were not significantly different. Among the rejection group, rhOX40Fc reduced significantly the expression of IFN-γ and IL-4 mRNA by anti-CD3-monoclonal antibody stimulated PBMCs (P < .05, and P < .01, respectively). CONCLUSIONS: Blocking of the interaction between OX40 and OX40L in vitro inhibited production of Thl and Th2 type cytokines.

Factors of impact on graft function at 2 years after transplantation in living-donor kidney transplantation: a single-center study in china.

OBJECTIVE: The aim was to investigate the factors that affect graft function at 2 years after transplantation in living related-donor kidney transplantation. METHODS: We retrospectively reviewed the clinical data of 144 patients who underwent living related-donor kidney transplantation in our hospital from December 2005 to December 2008. Recipients were divided into 2 groups according to glomerular filtration rate (GFR) at 2 years after transplantation: ≤60 mL/min/1.73 m2 (n=51) and >60 mL/min/1.73 m2 (n=93). Variables which affected graft function were compared between the groups. The significant factors were analyzed using logistic regression. RESULTS: Univariate analysis showed significant differences for donor age, donor GFR, recipient weight, recipient body mass index, donor-to-recipient body weight ratio, and acute rejection episodes (P<.05). Logistic regression analysis revealed the independent factors affecting renal function at 2 years after transplantation to be donor GFR (ß=0.032; odds ratio [OR] 1.032; P=.004) and recipient body weight (ß=-0.069; OR 0.934; P=.001). Receiver operating characteristic (ROC) curve analysis showed cutoff values of donor GFR and recipient body weight to be >111.25 mL/min/1.73 m2, and ≤67 kg, respectively. Areas under the ROC curve of donor GFR and recipient body weight were 0.612 and 0.665, respectively. Sensitivity and specificity of donor GFR were 43.0% and 78.4%, respectively. Sensitivity and specificity of recipient body weight were 82.8% and 45.1%, respectively. CONCLUSIONS: Donor GFR and recipient body weight were the independent factors effecting renal function at 2 years after transplantation.

Genome analyses of three strains of Rhodobacter sphaeroides: evidence of rapid evolution of chromosome II.

Three strains of Rhodobacter sphaeroides of diverse origin have been under investigation in our laboratory for their genome complexities, including the presence of multiple chromosomes and the distribution of essential genes within their genomes. The genome of R. sphaeroides 2.4.1 has been completely sequenced and fully annotated, and now two additional strains (ATCC 17019 and ATCC 17025) of R. sphaeroides have been sequenced. Thus, genome comparisons have become a useful approach in determining the evolutionary relationships among different strains of R. sphaeroides. In this study, the concatenated chromosomal sequences from the three strains of R. sphaeroides were aligned, using Mauve, to examine the extent of shared DNA regions and the degree of relatedness among their chromosome-specific DNA sequences. In addition, the exact intra- and interchromosomal DNA duplications were analyzed using Mummer. Genome analyses employing these two independent approaches revealed that strain ATCC 17025 diverged considerably from the other two strains, 2.4.1 and ATCC 17029, and that the two latter strains are more closely related to one another. Results further demonstrated that chromosome II (CII)-specific DNA sequences of R. sphaeroides have rapidly evolved, while CI-specific DNA sequences have remained highly conserved. Aside from the size variation of CII of R. sphaeroides, variation in sequence lengths of the CII-shared DNA regions and their high sequence divergence among strains of R. sphaeroides suggest the involvement of CII in the evolution of strain-specific genomic rearrangements, perhaps requiring strains to adapt in specialized niches.

The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT.

Costimulatory molecules on antigen-presenting cells (APCs) play an important role in T cell activation and expansion. However, little is known about the surface molecules involved in direct T-T cell interaction required for their activation and expansion. LIGHT, a newly discovered TNF superfamily member (TNFSF14), is expressed on activated T cells and immature dendritic cells. Here we demonstrate that blockade of LIGHT activity can reduce anti-CD3-mediated proliferation of purified T cells, suggesting that T cell-T cell interaction is essential for this proliferation. To test the in vivo activity of T cell-derived LIGHT in immune homeostasis and function, transgenic (Tg) mice expressing LIGHT in the T cell lineage were generated. LIGHT Tg mice have a significantly enlarged T cell compartment and a hyperactivated peripheral T cell population. LIGHT Tg mice spontaneously develop severe autoimmune disease manifested by splenomegaly, lymphadenopathy, glomerulonephritis, elevated autoantibodies, and severe infiltration of various peripheral tissues. Furthermore, the blockade of LIGHT activity ameliorates the severity of T cell-mediated diseases. Collectively, these findings establish a crucial role for this T cell-derived costimulatory ligand in T cell activation and expansion; moreover, the dysregulation of T cell-derived LIGHT leads to altered T cell homeostasis and autoimmune disease.

Motion-induced perceptual extrapolation of blurred visual targets.

In the motion-extrapolation hypothesis, the visual system can extrapolate the instantaneous position of a moving object from its past trajectory. The existence of such a mechanism in human vision has been intensely debated. Here, we show compelling perceptual extrapolation of both first- and second-order moving stimuli, the magnitude of which depends on blurring of the visual target. The spatiotemporal characteristics of the extrapolation can be quantitatively accounted for by a simple model based on temporally biphasic neuronal response, a property widely observed among sensory neurons. Thus, motion-induced perceptual extrapolation exists in human vision, and spatial blurring is an important factor in the interaction between motion and perceptual localization.

Cutting edge: membrane lymphotoxin regulates CD8(+) T cell-mediated intestinal allograft rejection.

Blocking the CD28/B7 and/or CD154/CD40 costimulatory pathways promotes long-term allograft survival in many transplant models where CD4(+) T cells are necessary for rejection. When CD8(+) T cells are sufficient to mediate rejection, these approaches fail, resulting in costimulation blockade-resistant rejection. To address this problem we examined the role of lymphotoxin-related molecules in CD8(+) T cell-mediated rejection of murine intestinal allografts. Targeting membrane lymphotoxin by means of a fusion protein, mAb, or genetic mutation inhibited rejection of intestinal allografts by CD8(+) T cells. This effect was associated with decreased monokine induced by IFN-gamma (Mig) and secondary lymphoid chemokine (SLC) gene expression within allografts and spleens respectively. Blocking membrane lymphotoxin did not inhibit rejection mediated by CD4(+) T cells. Combining disruption of membrane lymphotoxin and treatment with CTLA4-Ig inhibited rejection in wild-type mice. These data demonstrate that membrane lymphotoxin is an important regulatory molecule for CD8(+) T cells mediating rejection and suggest a strategy to avoid costimulation blockade-resistant rejection.

The critical role of LIGHT, a TNF family member, in T cell development.

Negative selection refers to the selective deletion of autoreactive thymocytes but its molecular events have not been well defined. In this study, we demonstrate that a cellular ligand for herpes virus entry mediator and lymphotoxin receptor (LIGHT), a newly identified member of the TNF superfamily, may play a critical role in negative selection. Using TCR transgenic mice, we find that the blockade of LIGHT signaling in vitro and in vivo prevents negative selection induced by peptide and intrathymically expressed Ags, resulting in the rescue of thymocytes from apoptosis. Furthermore, the thymi of LIGHT transgenic mice show severe atrophy with remarkably reduced CD4(+)CD8(+) double-positive cells caused by increased apoptosis, suggesting that LIGHT can delete immature T cells in vivo. Taken together, these results demonstrate a critical role of LIGHT in thymic negative selection of the T cell repertoire.

Progressive depletion of peripheral B lymphocytes in 4-1BB (CD137) ligand/I-Ealpha)-transgenic mice.

Interaction of 4-1BB (CD137) and its ligand (4-1BBL) is thought to positively regulate cell-mediated and humoral immune responses. We have prepared transgenic mouse strains that express 4-1BBL cDNA under the control of MHC class II I-Ealpha promoter. The 4-1BBL-transgenic mice show progressive splenomegaly and selective depletion of B220(+) B cells accompanied with low levels of circulating IgG and defective humoral responses to Ag challenge. In addition, splenocytes from the transgenic mice fail to provide stimulation for allogeneic T cells in both lymphoproliferative and CTL responses in vitro, whereas their T cells remain functionally normal. Our results reveal unexpected functions of 4-1BBL in the regulation of humoral immune responses and Ag presentation.