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  • 1
    Online Resource
    Online Resource
    Frontiers Media SA ; 2022
    In:  Frontiers in Genetics Vol. 13 ( 2022-5-13)
    In: Frontiers in Genetics, Frontiers Media SA, Vol. 13 ( 2022-5-13)
    Abstract: Background: Clear cell renal cell carcinoma (ccRCC) is the most common solid lesion in the kidney. This study aims to establish an aging and senescence-related mRNA model for risk assessment and prognosis prediction in ccRCC patients. Methods: ccRCC data were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. By applying univariate Cox regression, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression, a new prognostic model based on aging and senescence-related genes (ASRGs) was established. Depending on the prognostic model, high- and low-risk groups were identified for further study. The reliability of the prediction was evaluated in the validation cohort. Pan-cancer analysis was conducted to explore the role of GNRH1 in tumors. Results: A novel prognostic model was established based on eight ASRGs. This model was an independent risk factor and significantly correlated with the prognosis and clinicopathological features of ccRCC patients. The high- and low-risk groups exhibited distinct modes in the principal component analysis and different patterns in immune infiltration. Moreover, the nomogram combining risk score and other clinical factors showed excellent predictive ability, with AUC values for predicting 1-, 3-, and 5-year overall survival in the TCGA cohort equal to 0.88, 0.82, and 0.81, respectively. Conclusion: The model and nomogram based on the eight ASRGs had a significant value for survival prediction and risk assessment for ccRCC patients, providing new insights into the roles of aging and senescence in ccRCC.
    Type of Medium: Online Resource
    ISSN: 1664-8021
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606823-0
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  • 2
    In: Annals of Hematology, Springer Science and Business Media LLC
    Abstract: Chimeric antigen receptor (CAR) T-cell-associated coagulopathy can cause bleeding events. To explore risk factors for hemorrhage after CAR T-cell therapy, we retrospectively analyzed routine indicators in 56 patients with non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia who received anti-CD19 CAR T-cell therapy. Disturbance of coagulation occurred mainly within one month post infusion, especially on day 7 and 14. The cumulative incidence of bleeding events within one month was 32.8%, with the median onset of 7 (range, 0–28) days. All bleeding events were grade 1–3. Patients who experienced bleeding events within one month had longer prothrombin time, higher IL-6, higher IL-10, and lower platelets before lymphodepletion. There were also correlations among coagulation-, inflammatory-, and tumor burden-related markers. Multi-variate analysis showed IL-10 ( 〉 7.98 pg/mL; adjusted odds ratio [OR], 13.84; 95% confidence interval [CI] , 2.03–94.36; P = 0.007) and the endothelial activation and stress index (EASIX, defined as dehydrogenase [U/L] × creatinine [mg/dL] / platelets [×10 9 cells/L]; 〉 7.65; adjusted OR, 7.06; 95% CI, 1.03–48.23; P = 0.046) were significant risk factors for bleeding events. IL-10 plus the EASIX defined three risk groups for bleeding events with cumulative incidence of 100% (hazard ratio [HR], 14.47; 95% CI, 2.78–75.29; P 〈 0.0001), 38.5% (HR, 3.68; 95% CI, 0.82–16.67; P = 0.089), and 11.8% (reference), respectively. Future studies are needed to verify the risk assessment models for bleeding events after CAR T-cell treatment in larger cohorts.
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1458429-3
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  • 3
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4832-4832
    Abstract: Background : Chimeric antigen receptor (CAR) T cells targeting CD19 have achieved great clinical responses in patients with relapsed or refractory acute B lymphoblastic leukemia (R/R B-ALL). However, severe adverse events such as cytokine release syndrome (CRS) and neurotoxicity restrict it to further application. Tocilizumab against human interleukin-6 (IL-6) receptor is a common treatment for CAR-T cell therapy associated cytokine release syndrome. Corticosteroids are used when remission is not reached after the application of tocilizumab as well as neurotoxicity occurs, according to the guidance. However, their suitable timing still remains unclear when taking their efficacy and side effects into consideration. Methods: From January 2016 to July 2020, in our phase 1/2 clinical trials (NCT02965092、NCT04008251), 55 patients with R/R B-ALL were enrolled and injected with anti-CD19 CAR-T cells. Clinical laboratory tests on day 0、4、7、10、14、21、28 after infusion as well as endpoints、adverse events and treatment were recorded. CRS and neurotoxicity were graded according to American Society for Transplantation and Cellular Therapy (ASTCT),and infection severity was classified as mild, moderate, severe, life-threatening, or fatal. (Young et al. Biol Blood Marrow Transplant 2016; 22:359-70.) Patients were assigned to four cohorts based on the fold change of IL-6 and the use of Tocilizumab. We defined fold change as the ratio of peak before Tocilizumab given to baseline in Tocilizumab group and the ratio of peak within 28 days to baseline in non- Tocilizumab group. According to the statistics, two groups were separated into high level (fold change over 5) and low level (fold change below 5), respectively. Wilcoxon tests、Log-rank tests and Fisher's exact tests were used to analyze statistics in GraphPad Prism 9. Results: During the observation period of 28-day-postinfusion, the use of Tocilizumab or corticosteroids did not significantly reduce the response rate or increase infectious risk (P & gt;0.99, P=0.052). Doing a median follow-up of 7 months, the use of corticosteroids was significantly associated with shorter overall survival (OS) and progression-free survival (PFS), while it did not appear when Tocilizumab was applied alone. In addition, significantly fold change of IL-6, IL-10 were observed among subjects suffering cytokine release syndrome before the use of Tocilizumab or corticosteroids and higher levels of TNF-α were observed in 3 subjects with mild neurotoxicity (P=0.0002, P & lt;0.0001, P=0.0004). In high level group, patients treated with Tocilizumab had mild CRS limiting to grade 1-2, with shorter duration of CRS (median=5) than non-Tocilizumab (median=6) , though it is without significant difference (P=0.874). In low level group, the use of Tocilizumab is associated with shorter PFS(P=0.0275)as well as severe cytokine release syndrome. Two patients developed grade 4 CRS after infusing Tocilizumab,with apparently increased level of IL-10 (fold change=200) or IFN-γ (fold change=114.24). Neurotoxicity occurred in four patients in Tocilizumab group, and their IL-6 levels increased significantly after treatment, reaching an average peak of 1000pg/ml (157-22001.9). No neurotoxicity were observed in non-Tocilizumab group. Conclusion: Our study demonstrate that severe and persistent CRS could be avoided by applying Tocilizumab when IL-6 has increased over 5-fold from baseline. Tocilizumab is not recommended to use with little change of IL-6 because it fails to suppress the inflammatory response, and may trigger the activation of other cytokines and accelerate the progress of disease recurrence in patients. Although corticosteroids were associated with relapse, we still suggested that corticosteroids should be administrated to antagonize neurotoxicity with symptoms and significantly increased IL-6 levels after the infusion of Tocilizumab. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 4
    Online Resource
    Online Resource
    IOP Publishing ; 2019
    In:  IOP Conference Series: Earth and Environmental Science Vol. 252 ( 2019-07-09), p. 032082-
    In: IOP Conference Series: Earth and Environmental Science, IOP Publishing, Vol. 252 ( 2019-07-09), p. 032082-
    Type of Medium: Online Resource
    ISSN: 1755-1315
    Language: Unknown
    Publisher: IOP Publishing
    Publication Date: 2019
    detail.hit.zdb_id: 2434538-6
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  • 5
    In: Journal of Hematology & Oncology, Springer Science and Business Media LLC, Vol. 16, No. 1 ( 2023-01-21)
    Abstract: T cell receptor (TCR)-T cells possess similar effector function, but milder and more durable signal activation compared with chimeric antigen receptor-T cells. TCR-T cell therapy is another active field of cellular immunotherapy for cancer. Methods We previously developed a human anti-CD19 antibody (ET190L1) and generated novel CD19-specific γ/δ TCR-T cells, ET019003, by fusing the Fab fragment of ET190L1 with γ/δ TCR constant chain plus adding an ET190L1-scFv/CD28 co-stimulatory molecule. ET019003 cells were tested in preclinical studies followed by a phase 1 clinical trial. Results ET019003 cells produced less cytokines but retained comparable antitumor potency than ET190L1-CAR-T cells in vivo and in vitro. In the first-in-human trial, eight patients with relapsed or refractory DLBCL were treated. CRS of grade 1 was observed in three (37.5%) patients; ICANS of grade 3 was noted in one (12.5%) patient. Elevation of serum cytokines after ET019003 infusion was almost modest. With a median follow-up of 34 (range 6–38) months, seven (87.5%) patients attained clinical responses and six (75%) achieved complete responses (CR). OS, PFS and DOR at 3 years were 75.0%, 62.5%, and 71.4%, respectively. Notably, patient 1 with primary CNS lymphoma did not experience CRS or ICANS and got an ongoing CR for over 3 years after infusion, with detectable ET019003 cells in CSF. ET019003 showed striking in vivo expansion and persisted in 50% of patients at 12 months. Three patients received a second infusion, one for consolidation therapy after CR and two for salvage therapy after disease progression, but no response was observed. ET019003 expansion was striking in the first infusion, but poor in the second infusion. Conclusions CD19-specific γ/δ TCR-T cells, ET019003, had a good safety profile and could induce rapid responses and durable CR in patients with relapsed or refractory DLBCL, even primary CNS lymphoma, presenting a novel and potent therapeutic option for these patients. Trial registration : NCT04014894.
    Type of Medium: Online Resource
    ISSN: 1756-8722
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2429631-4
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  • 6
    In: Cytotherapy, Elsevier BV, Vol. 25, No. 7 ( 2023-07), p. 739-749
    Type of Medium: Online Resource
    ISSN: 1465-3249
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2071176-1
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  • 7
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2021
    In:  Carcinogenesis Vol. 42, No. 10 ( 2021-10-26), p. 1270-1280
    In: Carcinogenesis, Oxford University Press (OUP), Vol. 42, No. 10 ( 2021-10-26), p. 1270-1280
    Abstract: Increasing studies have indicated the critical roles of long non-coding RNAs (lncRNAs) in the tumorigenesis of cancers. LncRNA AGAP2 antisense RNA 1 (AGAP2-AS1) can serve as an oncogenic role in some cancers, including prostate cancer (PCa). However, the underling mechanism of such lncRNA in PCa has not been fully studied. Therefore, it is meaningful to investigate the role and underlying mechanism of AGAP2-AS1 in PCa. AGAP2-AS1 was confirmed to be highly expressed in PCa cells. Functionally, AGAP2-AS1 silencing inhibited cell proliferation, migration, invasion and epithelial–mesenchymal transition process and induced apoptosis. According to mechanism assays, AGAP2-AS1 sponged miR-628-5p, which was found to restrain PCa cell growth. Besides, FOXP2 was identified as a target gene of miR-628-5p, and its expression was negatively regulated by miR-628-5p and positively modulated by AGAP2-AS1. Importantly, we found that FOXP2 could function as the upstream gene of AGAP2-AS1. Through rescue experiments, we discovered that FOXP2 up-regulation countered AGAP2-AS1 knockdown-mediated inhibition on PCa cell growth. Finally, it was found that AGAP2-AS1 could activate WNT pathway, and LiCl could reverse the influence of AGAP2-AS1 on PCa biological behaviors. To conclude, AGAP2-AS1/miR-628-5p/FOXP2 feedback loop facilitated PCa cell growth via activating WNT pathway.
    Type of Medium: Online Resource
    ISSN: 0143-3334 , 1460-2180
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474206-8
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  • 8
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 10321-10322
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    Online Resource
    Online Resource
    American Society of Hematology ; 2022
    In:  Blood Vol. 140, No. Supplement 1 ( 2022-11-15), p. 10294-10295
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 10294-10295
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
    Online Resource
    Online Resource
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2831-2831
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2831-2831
    Abstract: Background CAR T-cell therapy has shown remarkable efficacy for the treatment of hematologic malignancy. However, this novel adoptive cell therapy is associated with toxicities such as cytokine release syndrome (CRS), CAR-T related encephalopathy syndrome (CRES/ICANS) and infection. While as one of the most common toxicities after CAR T-cell therapy in the first month, infectious complications have not been systematically studied. we aim to explore the incidence, clinical and microbiological characteristics and identify high risk factors for infection in patients with ALL, NHL, and MM. The trial was registered on the Chinese Clinical Trial Registry (ChiCTR-OIC-17011180; ChiCTR1800018143). Methods 72 patients with ALL, 56 patients with NHL and 42 patients with MM from January 2016 to December 2020 are involved in the cohort and the baseline data and the clinical characteristics of infection are retrospectively analyzed within 28 days. Infections were defined as a microbiologic, histopathologic, corroborating laboratory, radiographic or clinical diagnosis, and classified as bacterial (bacteremia or site infection), viral (respiratory or other), or fungal (proven or probable). Infection severity was classified as mild, moderate, severe, life-threatening, or fatal. (Young et al.Biol Blood Marrow Transplant 2016; 22:359-70.)CRS was graded by ASTCT. We used univariate and stepwise multivariable Poisson regression to identify associations between baseline clinical characteristics and infection density, and Cox proportional hazards regression to assess high-risk factors for infection. Results Among 170 patients, a total of 119 infections occurred in 99 patients within 28 days, with a cumulative infection rate of 58.2%. The incidence of infection in ALL patients is higher than that of MM and NHL patients. Among 72 ALL patients, 46 (63.9%) patients developed infections, and among 42 MM patients, 24 patients (53.1%) developed infections. The difference in infections between these two groups of patients was statistically significant (Chi-Square test, P=0.038 & lt;0.05). There was no significant difference in infection between the ALL and NHL groups, and the MM patients and NHL groups had no significant difference in infection (Chi-square test: ALL vs NHL P=0.168; NHL vs MM P=0.497) . 78 patients had 98 bacterial infections and the cumulative incidence of bacterial infection was 45.9%. The cumulative incidence of viral infection was 8.24%, and fungal infection was 4.12%. Bacterial infections are the main types of infections in patients with different tumors, followed by viral infections, and finally fungal infections. There was no statistic significant difference in the severity of infection among different tumors, whether it was the number of patients or events (Kruskal-Wallis test, P=0.646 ,P=0.605) 75 infection events occurred in patients who were agranulocytosis, and 90% of patients with bloodstream infections had neutropenia at the time of infection. When agranulocytosis lasted for 28 days, the cumulative infection rate was 38.8%. 91 patients had both CRS and infection. The cumulative incidence of CRS and infection was 68.8% and 58.2%, respectively. Among patients with grade 3-4 CRS, 18 of 30 infections (60%) occurred after the peak of CRS. The adjusted baseline characteristic model showed that ALL patients, previous 30 days of infection history, refractory disease, ANC & lt;0.5×10 9/L before infusion and≥4 prior antitumor treatment regimens had a higher infection density within 28 days; Grade 3 or 4 CRS was the only high-risk factor related to infection after infusion in the multivariate analysis. Conclusions Infection is one of the common complications of CAR-T cell therapy in patients with hematological malignancy. Bacterial infections occur in most patients regardless of the type of disease. ALL patients, previous 30 days of infection history,refractory disease, ANC & lt;0.5×10 9/L before infusion and Grade 3 or 4 CRS are risk factors for infection. Keywords:chimeric antigen receptor t cell;hematological malignancy; bacterial infection Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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