Efficacy and safety of venetoclax-based regimens for the treatment of relapsed/refractory multiple myeloma: a systemic review and meta-analysis.

Background: Patients with relapsed/refractory multiple myeloma (RRMM) usually have dismal prognostic outcomes. Venetoclax, a selective inhibitor of antiapoptotic protein B-cell lymphoma-2 (BCL-2), demonstrates antimyeloma activity in plasma cells with t(11;14) or high BCL-2 expression. Objectives: This meta-analysis aimed to investigate the efficacy and safety of venetoclax-based therapy in RRMM. Design: This is a meta-analysis study. Data Sources and Methods: PubMed, Embase, and Cochrane were searched for studies published up to 20 December 2021. Overall response rate (ORR), rate of very good partial response or better (≧VGPR), and complete response (CR) rate were pooled with the random-effects model. Safety was evaluated by the incidences of grade ≧3 adverse events. Subgroup analysis and meta-regression were performed to identify the causes of heterogeneities. All the analyses were conducted by STATA 15.0 software. Results: A total of 14 studies with 713 patients were included for analysis. The pooled ORR, rate of ≧VGPR, and CR for all patients were 59% [95% confidence interval (CI) = 45-71%], 38% (95% CI = 26-51%), and 17% (95% CI = 10-26%), respectively. The median progression-free survival (PFS) ranged from 2.0 months to not reached (NR), and the median overall survival (OS) ranged from 12.0 months to NR. Meta-regression showed that patients treated with more drugs combined or less heavily pretreated had higher response rates. Patients with t(11;14) had superior ORR [relative risk (RR) = 1.47, 95% CI = 1.05-2.07], ≧VGPR (RR = 1.71, 95% CI = 1.12-2.60), CR (RR = 1.86, 95% CI = 1.34-2.57), PFS [hazard ratio (HR) = 0.47, 95% CI = 0.30-0.65], and OS (HR = 0.30, 95% CI = 0.08-0.52) compared with patients without t(11;14). Most grade ≧3 adverse events were hematologic, gastrointestinal, and infectious related and were manageable. Conclusion: Venetoclax-based therapy is an effective and safe option for RRMM patients, especially those with t(11;14).

Integrated Analysis Reveals Critical Ferroptosis Regulators and FTL Contribute to Cancer Progression in Hepatocellular Carcinoma.

Background: The carcinogenesis and prognosis of hepatocellular carcinoma (HCC) involve complex molecular mechanisms, and ferroptosis is related to the development and therapeutic efficacy of HCC, but the specific mechanism and prognostic role of ferroptosis-related genes in HCC have not been elucidated. Methods: Differentially expressed gene analysis, Cox regression, and unsupervised consensus clustering were applied to identify crucial ferroptosis regulators and establish ferroptosis-related subtypes in HCC. Random forest analysis and survival analysis were adopted to confirm FTL as the hub prognostic and diagnostic ferroptosis regulator in HCC. Results: The ferroptosis-related subtypes based on the crucial prognostic ferroptosis regulators showed that patients in fescluster A had a higher survival probability (p < 0.001) and better clinical characteristics than patients in fescluster B in the TCGA-LIHC cohort. Patients with a high tumor mutation burden (TMB) in fescluster B presented a significantly poorer prognosis. FTL was the core ferroptosis regulator, and its low expression revealed a significant survival advantage compared with its high expression (p = 0.03). The expression and predictive value of FTL were both closely related to the clinical features (p < 0.05). Expression of FTL accurately distinguished HCC from normal tissues in the TCGA-LIHC cohort, ICGC cohort, and GSE14520 dataset. In addition, higher infiltrating fractions of immune cells, such as activated CD8+ T cells and Gamma delta T cells, mainly enriched immune-related signaling pathways, including the IL2-STAT3 signaling pathway and interferon-gamma response signaling pathway, and higher expression of immune checkpoints, including PDCD1, CTLA4, TIGIT, and CD83, were presented in patients with high FTL expression (p < 0.05). Patients with high FTL were more sensitive to some targeted drugs, such as cisplatin, dasatinib, and sorafenib, than those with low FTL (p < 0.05). A nomogram based on FTL accurately predicted the prognosis of HCC. Further knockdown of FTL was determined to significantly inhibit cell proliferation and migration in HCC. Conclusion: Our study validated ferroptosis-related subtypes and FTL with effective prognostic value in HCC and was beneficial for identifying candidates suitable for targeted drug therapy and immunotherapy, thereby offering further insight into individual treatment strategies to improve disease outcomes in HCC patients.

[The Risk Factors of Thrombosis in Patients with Philadelphia Chromosome-negative Myeloproliferative Neoplasms].

OBJECTIVE: To investigate the overview of thrombosis in myeloproliferative neoplasms(MPN) patients, and to explore the risk factors of thrombosis at diagnosis and during follow-up. METHODS: The clinical data of 388 MPN patients treated in our hospital were collected. The patients were followed up by outpatient and phone. The risk factors of thrombosis were analyzed by statistical methods. RESULTS: Among 388 MPN patients, 161 patients (41.49%) showed thromboses at diagnosis or during follow-up. Among them, 92.55% were arterial thromboses, 146 cases (96.27%) were complicated with thromboses at diagnosis, and 36 cases (11.46%) showed newly thromboses or progression of previous thromboses among the 314 received full follow-up patients. Age (P＜0.001, HR:1.033, 95%CI:1.016-1.051), JAK2V617F mutation (P=0.037, HR:1.72, 95%CI: 1.033-2.862), hypertension (P＜0.001, HR:2.639, 95%CI:1.659-4.197) and hyperlipidemia (P＜0.001, HR:2.659, 95%CI:1.626-4.347) were the independent risk factors affecting thrombosis at diagnosis of the patients. During the follow-up, age (P=0.016, HR:1.032, 95%CI: 1.006-1.059) and previous thrombosis history (P=0.019, HR:2.194, 95%CI: 1.135-4.242) were the independent risk factors affecting the progression of thrombosis at different sites or on the basis of the previous thrombosis in the patients. CONCLUSION: Patients with advanced age, JAK2V617F mutation or complicated with hypertension and hyperlipidemia shows a higher risk of thrombosis at diagnosis, while the patients with advanced age or previous thrombosis history shows a higher risk of progression of thrombosis during the follow-up.

Downregulation of SUMO2 inhibits hepatocellular carcinoma cell proliferation, migration and invasion.

This study aimed to evaluate the prognostic value and biological function of small ubiquitin-like modifier 2 (SUMO2) in hepatocellular carcinoma (HCC). SUMO2 expression in HCC tissues was markedly higher than that in normal liver tissues, and patients with high SUMO2 expression had significantly shorter median overall survival than those with low SUMO2 expression. Furthermore, SUMO2 expression was closely correlated with lymph node metastasis and vascular invasion and was a predictor of poor prognosis. The knockdown of SUMO2 in two HCC cell lines (SMMC-7721 and Bel-7404) dramatically suppressed their proliferation, migration and invasion. Western blot analysis showed that the downregulation of SUMO2 significantly reduced the expression of Ki-67, matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in SMMC-7721 and Bel-7404 cells. Similarly, quantitative reverse transcription-PCR revealed consistently decreased expression of MMP-9 and VEGF. Our data suggest that SUMO2 promotes proliferation, migration and invasion of HCC cells via mechanisms involving MMP-9 and VEGF. Therefore, SUMO2 may be a prognostic factor and a promising therapeutic target for patients with HCC.

Effect of T-cadherin on the AKT/mTOR signaling pathway, gastric cancer cell cycle, migration and invasion, and its association with patient survival rate.

Gastric cancer (GC) is among the most common types of human cancer and is associated with recurrence and metastasis, despite comprehensive surgical and medical treatment. Previous studies observed downregulation of T-cadherin expression in GC tissues, suggesting that this protein may act as an oncosuppressor. The current study investigated the activity of T-cadherin in GC tissues. In a follow-up study of 81 patients with GC, a Kaplan-Meier analysis of overall survival revealed a strong association of T-cadherin overexpression with increased overall survival (P<0.01). Furthermore, stable T-cadherin-overexpressing cell lines were established from HGC-27 cells via transfection of a pcDNA3.1-T-cadherin plasmid and in vitro growth and cell cycle of these cells were measured using MTT and flow cytometry assays, respectively. MTT assays revealed that proliferation of engineered T-cadherin-overexpressing cells was significantly inhibited and flow cytometry demonstrated that T-cadherin overexpression in HGC-27 cells induced cell cycle arrest in the G0/G1 phase. Transwell assays demonstrated that T-cadherin-overexpressing HGC-27 cells exhibited reduced invasiveness and metastatic potential. Phosphorylated (p)-protein kinase B (AKT) and p-mammalian target of rapamycin (mTOR) protein levels were reduced in T-cadherin overexpressing HGC-27 cells, suggesting that the AKT/mTOR signaling pathway was involved in the gastric tumor inhibitory effect of T-cadherin. Administration of AKT-activator, insulin-like growth factor-1, to T-cadherin-overexpressing HGC-27 cells significantly affected the proliferation phenotype. In conclusion, the current study provided clinical evidence and revealed a potential mechanism supporting that T-cadherin inhibits gastric tumorigenesis through inhibition of the AKT/mTOR signaling pathway.

Upregulation of T-cadherin suppresses cell proliferation, migration and invasion of gastric cancer in vitro.

As a unique member of the cadherin superfamily, T-cadherin (T-cad) has been demonstrated to be associated with gastric cancer (GC) prognosis. To elucidate the function of T-cad in GC in vitro, the present study firstly examined T-cad protein expression in normal and gastric cancer tissues and cell lines, and it was demonstrated to be significantly downregulated in gastric cancer samples compared with normal samples. Control and T-cad expression vectors were then transfected into the MGC8-03 and AGS GC cell lines. Utilizing MTT, clonogenic, flow cytometry, wound healing and Transwell invasion assays in addition to Western blotting, the present study demonstrated that the overexpression of T-cad suppressed GC cell growth and colony formation via cell cycle arrest at the G0/G1 phase via downregulating the expression of cyclin dependent kinase 4 and Cyclin D1. In addition, overexpression of T-cad significantly inhibited GC cell migration and invasion by increasing E-cadherin and decreasing Vimentin expression. These findings suggest T-cad may be important in GC cell proliferation and metastasis and serve as a promising target for the treatment of GC in the future.

Bortezomib modulates regulatory T cell subpopulations in the process of acute graft-versus-host disease.

BACKGROUND: Acute graft-versus-host disease (aGVHD) combines the wide application of allogeneic bone marrow transplantation (allo-BMT). Recent studies indicate that it is possible to reduce the incidence and severity of aGVHD by using bortezomib. In this study, we explored the changes of T cell subsets after allo-BMT with bortezomib, in order to elucidate the mechanism by which bortezomib attenuates aGVHD. METHODS: Following a single dose of lethal irradiation (TBI, 0.7 Gy/minutes, 8.0 Gy), BALB/c mice were injected with 2 x 10(7) C57BL/6 nucleated BM cells plus 1 x 10(7) splenocytes with or without bortezomib at 1.0 mg/kg. The ratio of CD4+CD25+ Foxp3+ regulatory T cells (Treg) was examined by flow cytometry, and the cytokine levels of IL-2 (Th1) and IL-4 (Th2) were detected by ELISA. Bivariate correlation analysis was carried out to evaluate changes of the Th1 and Th2 cytokines related to the changes of Treg. RESULTS: Bortezomib remarkably reduced aGVHD severity and prolonged the survival time. Along with bortezomib injection, the ratio of Treg was significantly increased and IL-2 level was decreased but IL-4 level was increased. Bivariate correlation analysis results evaluated the correlation between the increment of Treg and changes of Th1 and Th2 cytokines. CONCLUSIONS: Bortezomib may exert its effect by triggering the generation of Treg which might regulate the imbalance of Th1/Th2 during aGVHD.

Toll-like receptor 2-mediated NF-κB inflammatory responses in dry eye associated with cGVHD.

PURPOSE: Dry eye syndrome is one of the most common pathological manifestations in patients with chronic graft-versus-host disease (cGVHD). When dry eye occurs in association with cGVHD, the local inflammation is secondary to the systemic onset of inflammation. Toll-like receptor 2 (TLR2) signaling is thought to be essential for the inflammatory response and for immune disorders. The aim of this study was to explore whether the TLR2-mediated nuclear factor-kappa B (NF-κB) signaling pathway contributes to the inflammatory process of dry eye associated with cGVHD. METHODS: Twenty patients with dry eye related to cGVHD and 20 controls were enrolled in this study. The patients with dry eye associated with cGVHD were diagnosed based on the clinical presentation and related ocular surface examinations such as Schirmer's test and fluorescein staining. In addition, dry eye symptom scoring (National Institutes of Health consensus criteria) and Ocular Surface Disease Index (OSDI) scoring were also evaluated in all patients. Peripheral blood was collected from the patients and the controls for subsequent experiments. mRNA levels of TLR2 and its downstream molecules, NF-κB and tumor necrosis factor (TNF)-α, were measured by quantitative Real-Time PCR (qRT-PCR). The protein level of TNF-α was detected by Enzyme-linked Immuno Sorbent Assay (ELISA). RESULTS: TLR2 mRNA in the peripheral blood from patients with dry eye related to cGVHD increased significantly compared with the controls. NF-κB, the downstream target of TLR2, also showed a marked elevation. The mRNA and protein levels of TNF-α were significantly upregulated in these patients. Importantly, the TLR2 level was strongly correlated with the OSDI and the Schirmer's test (r=0.565, p=0.010<0.05; r=0.564, p=0.016<0.05) in dry eye related to cGVHD compared with the controls. CONCLUSIONS: The TLR2-mediated NF-κB signaling pathway is activated in dry eye associated with cGVHD and contributes to the inflammatory state, which may predict the onset and progression of dry eye associated with cGVHD.