The Mediating Roles of Impulsiveness and Maladjustment in the Association of Psychological Resilience with Drug Addiction during Isolated Detoxification.

Background: Studies have shown that psychological resilience is a key factor in drug rehabilitation. To explore the feasibility of developing psychological resilience as an addiction treatment intervention, it is essential to explore the role that it plays in drug addiction. Objectives: This study aimed to investigate the relationship between psychological resilience and drug addiction, as well as to examine the underlying mediational roles of maladjustment and impulsiveness in this association. Methods: We used a cross-sectional design that included a sample of 140 male drug addicts in compulsory isolation centers and used questionnaires and scales to ascertain their level of drug addiction, psychological resilience, maladjustment, impulsiveness, social support, and loneliness. Correlation and mediation effect analyses were performed to determine the roles of impulsiveness and maladjustment in the association of psychological resilience with drug addiction. Results: Psychological resilience was an inverse predictor of drug addiction. The results of the mediation effect analysis showed that maladjustment acted as a mediator between resilience and drug addiction and between impulsiveness and drug addiction. Furthermore, impulsiveness and maladjustment jointly mediated the relationship between psychological resilience and drug addiction. Conclusion: These findings highlight the importance of psychological resilience in maladjustment and impulsiveness for drug addicts and suggest that the role of psychological resilience in drug addiction needs to be further explored.

Exosomal CLIC1 released by CLL promotes HUVECs angiogenesis by regulating ITGß1-MAPK/ERK axis.

Accumulating evidences have suggested that exosomes are closely associated with tumor progression by affecting cell-cell communication. Here, we aimed to investigate the roles and regulatory mechanism of exosomes released from chronic lymphocytic leukemia (CLL). The expression levels of genes and proteins in cells and exosomes were examined by quantitative real-time PCR and Western blotting, respectively. MEC-1 cell-derived exosomes were obtained and co-cultured with human umbilical vein endothelial cells (HUVECs), then the capabilities of cell proliferation, metastasis and angiogenesis of HUVECs were measured by CCK-8, wound healing, transwell and tube formation assay, respectively. Chloride intracellular channel 1 (CLIC1) was significantly increased in CLL patients and markedly enriched in exosomes secreted by CLL cells. Exosomal CLIC1 secreted from MEC-1 cells were successfully transferred into HUVECs and significantly promoted the phenotypes of proliferation, metastasis and angiogenesis of HUVECs. Mechanically, exosomal CLIC1 secreted from MEC-1 cells obviously activated MAPK/ERK signaling through upregulating integrin ß1 (ITGß1) expression in HUVECs. Furthermore, rescue experiments revealed that either silencing ITGß1 or PD98059 treatment obviously reversed the regulatory effects of exosomal CLIC1 secreted from MEC-1 cells in HUVECs. In conclusion, CLL cell-derived exosomes accelerated HUVECs metastasis and angiogenesis through transferring CLIC1 to regulate ITGß1-MAPK/ERK signaling, indicating that CLIC1 may be a therapeutic target of CLL exosomes in the tumor microenvironment.

TIGIT expression is upregulated in T cells and causes T cell dysfunction independent of PD-1 and Tim-3 in adult B lineage acute lymphoblastic leukemia.

T cell immunoglobulin and ITIM domain (TIGIT) is a novel immune checkpoint receptor and plays critical roles in cancer immunity. Adult acute lymphoblastic leukemia (ALL) remains a treatment challenge despite years of research. In this study, we analyzed the status of TIGIT expression in circulating T cells from patients with adult ALL. Compared to the data in healthy controls, the expression of TIGIT in CD4+CD25- T cells and CD8+ T cells in adult ALL patients presented a small but significant upregulation. Stimulation via the CD3/CD28 route increased TIGIT mRNA expression at 24 h, which peaked at 48 h and was maintained at 72 h post-stimulation. The frequency of TIGIT+ cells, on the other hand, consistently increased over time. ALL protein lysate or Wilms' Tumor 1 peptide could significantly increase the expression of TIGIT in ALL, but not healthy control T cells. Compared to TIGIT- cells, the TIGIT+ cells presented significantly higher PD-1 and Tim-3 expression directly ex vivo, and significantly lower IL-2, IFN-γ, and TNF-α after CD3/CD28 stimulation. The high inhibitory molecule and low cytokine expression signature was especially pronounced in ALL TIGIT+ CD4+CD25- T cells and TIGIT+ CD8+ T cells. Blocking TIGIT alone could minimally increase cytokine expression independent of PD-1 and Tim-3 blocking, whereas blocking TIGIT, PD-1, and Tim-3 altogether was significantly more effective. Together, these data demonstrated that TIGIT regulated T cell function in adult ALL patients, and may serve as a treatment target for ALL.

Characterization of CD4+ T cell-mediated cytotoxicity in patients with multiple myeloma.

Multiple myeloma (MM) is an incurable cancer characterized by the development of malignant plasma cells. The CD8 T cell-mediated cytotoxicity is considered a major player in antitumor immunity, but in MM patients, the CD8 T cells displayed senescence markers and were functionally impaired. To investigate whether cytotoxic CD4 T cells could act as a treatment alternative in MM, we examined the frequency and function of naturally occurring cytotoxic CD4 T cells in MM patients. The cytotoxic CD4 T cells were identified as granzyme-A, granzyme B-, and perforin-expressing CD4 T cells, and their frequencies were significantly upregulated in MM patients when compared with healthy controls. The frequencies of cytotoxic CD4 T cells in MM patients were not associated with the frequencies of cytotoxic CD8 T cells, but were negatively associated with disease severity. Interestingly, the expression levels of inhibitory molecules, including PD-1 and CTLA-4, were significantly lower in cytotoxic CD4 T cells than in cytotoxic CD8 T cells. When co-incubated with autologous CD38+CD138+ plasma cells, CD4 T cells were capable of eliminating plasma cells with varying degrees of efficacy. In MM patients, the frequency of circulating plasma cells was negatively correlated with the frequency of cytotoxic CD4 T cells. Therefore, CD4 T cell-mediated cytotoxicity existed naturally in MM patients and could potentially act as an option in antitumor therapies.

Personalized Drug Analysis in B Cell Chronic Lymphocytic Leukemia Patients.

BACKGROUND B cell chronic lymphocytic leukemia (B-CLL) is the most common adult leukemia in the Western world. Although therapeutic advances have notably improved the outcome for many patients, B-CLL remains an incurable disease. The purpose of this study was to search for therapeutic drugs based on altered pathways in individual patients. MATERIAL AND METHODS Genes from microarray data were mapped to 300 Homo sapiens-related pathways. Individual pathway aberrance analysis was used to identify altered pathways. Drug data, obtained from connectivity map (cMAP), were subjected to drug-set enrichment analysis. To analyze the relations between drug-induced pathways and disease-induced altered pathways in individuals, Pearson correlation analysis was applied. RESULTS The disease-induced pathways with P-values <0.05 in individual samples were recorded and presented in a heatmap. Drug-induced pathways were analyzed in the 104 samples. After Pearson correlation analysis between altered pathways and drug, the 20 top-ranked drugs that were most relevant to disease were obtained. There were 9 drugs with positive scores and 11 with negative scores. CONCLUSIONS With this method, we identified the 20 top-ranked drugs that were most relevant to disease. The drugs with negative scores may play therapeutic roles in B-CLL.

CD19(+) CD20(-) CD27(hi) IL-s10-producing B cells are overrepresented in R-CHOP-treated DLBCL patients in complete remission.

Treatment of diffuse large B cell lymphoma (DLBCL) with rituximab, an anti-CD20 monoclonal antibody, has resulted in significantly improved patient responses with longer event-free intervals and higher overall survival rates. However, since rituximab depletes all CD20-expressing cells, including noncancerous B cells, the effects of rituximab on the normal immunity of DLBCL patients under remission need to be examined. Here, we observed that DLBCL patients under remission contained significantly lower frequencies of total B cells, with a significantly overrepresented interleukin (IL)-10-producing B cell (B10) population in the peripheral blood. Further examination confirmed that a large fraction of B10 cells was CD20(-) CD27(hi) plasmablasts, possibly explaining the persistence of B10 cells after R-CHOP treatment. We also observed that the percentage of B10 cells in DLBCL patients in remission gradually reduced during the first year of achieving complete remission, primarily due to the replenishment of non-B10 B cells. Despite this, the percentage of B10 cells in DLBCL patients after 1 year of achieving complete remission was still higher than that in controls. CD4(+) and CD8(+) T cells cocultured with B10-enriched B cells secreted significantly lower levels of proinflammatory cytokines IFN-g and TNF-a, compared to those incubated with B10-depleted B cells. Together, our data observed a long-lasting overrepresentation of B10 cells in DLBCL patients under remission. Whether this change could impact on the overall anti-tumor immunity during remission requires further studies.

Functional interleukin-21 polymorphism is a protective factor of diffuse large B-cell lymphoma.

Interleukin-21 (IL-21) is a recently discovered cytokine and plays critical roles in antitumor immune responses. Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. In this study, we investigated the association between IL-21 genetic polymorphisms and the susceptibility to DLBCL, and the possible functions of these polymorphisms. Two IL-21 polymorphisms, rs907715G/A and rs2221903A/G, were examined in 212 DLBCL patients and 232 healthy controls. Data showed that percentages of rs907715GA and AA genotypes were significantly lower in patients than in controls (odds ratio [OR]=0.60, 95% confidence interval [CI]: 0.40-0.90, p=0.014; OR=0.31, 95% CI: 0.17-0.56, p<0.001, respectively). Frequency of the rs2221903A/G polymorphism did not reveal any significant differences between patients and healthy donors. Further analyses demonstrated a significantly decreased number of rs907715AA genotype in patients with advanced Ann Arbor stages (III+IV). Moreover, we investigated the correlation between IL-21 polymorphisms and serum level of IL-21. Results showed that subjects carrying rs907715AA had significantly increased level of IL-21 than those with GG genotype or GA genotype. These data suggest that rs907715G/A polymorphism may act as a protective factor of DLBCL and might affect the serum level of IL-21.

Tim-3 expression is increased on peripheral T cells from diffuse large B cell lymphoma.

T cell immunoglobulin- and mucin-domain-containing molecule 3 (Tim-3) plays a critical role in immune tolerance by suppressing the activation and proliferation of T cells. The purpose of this study was to investigate the effect of Tim-3 on the development of diffuse large B cell lymphoma (DLBCL). A total of 40 newly diagnosed DLBCL patients and 30 healthy donors were recruited. Tim-3 expression on peripheral CD4+ T and CD8+ T cells was analyzed by flow cytometry. Data showed that expression of Tim-3 was significantly increased on both CD4+ and CD8+ T cells in DLBCL patients than in healthy controls (P < 0.001 and P < 0.001, respectively). Also, level of Tim-3 on CD4+ T cells was positively correlated with CD8+ T cells in patients (P < 0.001). Further analyses revealed that patients with advanced tumor stages had elevated Tim-3 expression on CD4+ and CD8+ T cells compared to those with primary tumor stages. In addition, levels of Tim-3 on CD4+ and CD8+ T cells were significantly elevated in DLBCL patients with bone marrow involvement or B symptoms. Our results suggest that Tim-3 is involved in the development of DLBCL.

Fibroblast growth factor receptor 4 polymorphism is associated with increased risk and poor prognosis of non-Hodgkin's lymphoma.

Fibroblast growth factor receptor 4 (FGFR4) is expressed in various cell types and plays important roles in regulating immune responses. Evidence has shown that FGFR4 rs351855 (Gly388Arg) polymorphism may act as a risk factor for many diseases. In the current study, we investigated the association between FGFR4 polymorphisms and the susceptibility to non-Hodgkin's lymphoma (NHL) in the Chinese population. Two polymorphisms in the FGFR4 gene (rs351855G/A and rs147603016G/A) were detected by polymerase chain reaction-restriction fragment length polymorphism in 421 NHL cases and 486 healthy controls. Results showed that prevalence of rs351855AA genotype was significantly increased in patients than in controls (odds ratio [OR] = 2.02, 95% confidence interval [CI] 1.91-3.23, P < 0.001). Similarly, rs351855A allele presented significantly higher numbers in cases compared to healthy donors (49.8 versus 40.1%, P < 0.001). Further study revealed that the frequency of the rs351855G/A polymorphism was clearly elevated in cases with B cell subtype than those with T cell subtypes. When analyzing the survival time of NHL patients with FGFR4 rs351855G/A polymorphism, cases with AA genotype had significantly shorter survival time compared to the patients with GG genotype (P < 0.001) or GA genotype (P < 0.001). These results suggest that FGFR4 rs351855G/A polymorphism is associated with increased susceptibility to NHL and could be used as a marker for predicting the prognosis of the malignancy.