Bortezomib (BTZ) is largely used as a chemotherapeutic agent for the treatment of multiple myeloma. However, one of the significant limiting complications of BTZ is painful peripheral neuropathy ...during BTZ therapy. The purpose of this study was to examine the underlying mechanisms leading to neuropathic pain induced by BTZ.
ELISA and western blot analysis were used to examine the levels of tumor necrosis factor alpha (TNF-α) and its receptor, transient receptor potential ankyrin 1 (TRPA1) and intracellular p38-MAPK and JNK signal in the lumbar dorsal root ganglion. Behavioral test was performed to determine mechanical pain and cold sensitivity in a rat model.
Systemic injection of BTZ significantly increased mechanical pain and cold sensitivity as compared with control animals (P< 0.05 vs. control rats). Our data also showed that protein expression of TRPA1 was upregulated in the dorsal root ganglion of BTZ rats and blocking TRPA1 attenuated mechanical pain and cold sensitivity in control rats and BTZ rats (P< 0.05 vs. vehicle control). Notably, the inhibitory effect of blocking TRPA1 on mechanical pain and cold sensitivity was smaller in BTZ rats than that in control rats. In addition, a blockade of TNF-α attenuated intracellular p38-MAPK and JNK signal in the dorsal root ganglion. This also decreased TRPA1 expression and alleviated mechanical hyperalgesia and cold hypersensitivity in BTZ rats.
We revealed specific signaling pathways leading to neuropathic pain induced by chemotherapeutic BTZ. The data also suggest that blocking TRPA1 and tumor necrosis factor alpha is beneficial to alleviate neuropathic pain during BTZ intervention.
B cell maturation antigen (BCMA) targeted immunotherapies have demonstrated remarkable clinical efficacy in multiple myeloma (MM). Here, we evaluated the BCMA expression in MM and other plasma cell ...dyscrasias (PCDs), hoping to provide a potential treatment strategy for the relapsed/refractory PCDs besides MM.
From January 2018 to August 2021, 377 patients with PCDs were enrolled in this study, including 334 MM, 21 systemic light chain amyloidosis (AL), 5 POEMS syndrome, 14 monoclonal gammopathy of undetermined significance (MGUS), and three monoclonal gammopathy of renal significance (MGRS). The membrane-bound BCMA expression measured by multiparameter flow cytometry was defined by BCMA positivity rate and the mean fluorescence intensity (MFI).
The patients with MM had a median BCMA positive rate of 88.55% (range, 0.2% - 99.9%) and median BCMA MFI of 1281 (range, 109 - 48586). While the median BCMA positive rate in other PCDs was 55.8% (6.2% -98.9%), and the median BCMA MFI was 553 (182- 5930). BCMA expression level was negatively associated with hemoglobin concentration in multivariate analysis in terms of BCMA positive rate and MFI.
In conclusion, BCMA has the potential to be a therapeutic target for other PCDs besides MM.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We have shown previously that polymorphism of activating transcription factor 6 (ATF6) is associated with susceptibility to hepatocellular carcinoma (HCC). Therefore, genes down-regulated by ATF6 ...might play a tumor-suppressing role. In the present study, we identified that expression of protein phosphatase magnesium- or manganous-dependent 1H (PPM1H) mRNA and protein can be inhibited by ATF6 in hepatoma cells and mice with liver Atf6 knockdown. Tumor tissues from 134 HCC patients were analyzed by immunohistochemistry, and PPM1H exhibited higher expression levels in adjacent para-cancer tissues than in HCC tissues. Therefore, patients with higher expression of PPM1H had a better prognosis. PPM1H inhibited proliferation, migration, and invasion of hepatoma cells. In addition, PPM1H inhibited induced HCC nodule formation as well as tumor xenograft growth in diethylnitrosamine/CCl4-induced HCC mouse model and nude mouse tumorigenicity assay, respectively. A 3D model of PPM1H was obtained by homology multi-template modeling, and ribosomal protein S6 kinase B1 (RPS6KB1) in the bone morphogenetic protein (BMP)/transforming growth factor β (TGF-β) pathway was screened out as the potential substrate of PPM1H by Rosetta. PPM1H could directly dephosphorylate p-RPS6KB1. To conclude, we discovered RPS6KB1 as a new PPM1H dephosphorylation substrate. PPM1H exhibited a suppressive effect on HCC progression by dephosphorylating p-RPS6KB1.
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This study found that PPM1H inhibits proliferation, migration, and invasion of hepatoma cells in vitro and suppresses HCC progression in vivo and identified PPM1H as the phosphatase of RPS6KB1 to regulate HCC development. PPM1H expression can be inhibited by ATF6. The ATF6-PPM1H-RPS6KB1 pathway might provide a potential HCC therapeutic target.
Postoperative depression is one of the most common mental disorders in patients undergoing cancer surgery and it often delays postoperative recovery. We investigated whether dezocine, an analgesic ...with inhibitory effect on the serotonin and norepinephrine reuptake, could relieve postoperative depressive symptoms in patients undergoing colorectal cancer surgery.
This randomized, controlled, single-center, double-blind trial was performed in the Second Affiliated Hospital of the Army Medical University. A total of 120 patients were randomly assigned to receive either sufentanil (1.3 μg/kg) with dezocine (1 mg/kg) (dezocine group; n = 60) or only sufentanil (2.3 μg/kg) (control group; n = 60) for patient-controlled intravenous analgesia after colorectal cancer surgery. The primary outcome was the Beck Depression Inventory score at 2 days after surgery. The secondary outcomes included the Beck Anxiety Inventory, sleep quality, and quality of recovery scores.
Compared with those in the control group, patients in the dezocine group had lower depression scores (7.3±3.4 vs. 9.9±3.5, mean difference 2.6, 95% CI: 1.4-3.9; P<0.001) at 2 days after surgery and better night sleep quality at the day of surgery (P = 0.010) and at 1 day after the surgery (P<0.001). No significant difference was found in other outcomes between the two groups.
Intravenous analgesia using dezocine can relieve postoperative depression symptoms and improve sleep quality in patients undergoing colorectal cancer surgery.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The prognosis of relapsed/refractory multiple myeloma (RRMM) patients with the extramedullary disease was significantly poor. Extramedullary multiple myeloma (EMM) patients gained limited benefits ...from traditional drugs. Anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy seems to be a promising approach to treat RRMM patients. However, very few clinical studies are designed for EMM. Our study aimed to compare and assess the safety, efficacy, and pharmacokinetics of anti-BCMA CAR-T cell therapy in EMM and non-EMM.
The results from published anti-BCMA CAR-T clinical trials, in which raw data of EMM patients were available, were reviewed and summarized. Two trials conducted in our clinical centers were analyzed and presented with detailed data.
According to published anti-BCMA CAR-T clinical trials, the ORR of EMM ranged from 57% to 100%, with the complete remission (CR) rate of 29% to 60%. Between February 22, 2017, and September 26, 2019, a total of 61 subjects (EMM 25; non-EMM 36) received anti-BCMA CAR-T cell infusion. The data-cutoff date was April 1, 2021. There were no statistical differences between EMM and non-EMM groups in adverse events (AEs), including cytokine release syndrome (CRS). The most common AEs of grade ≥ 3 in both groups were hematologic toxicities. There was no significant difference in the objective response rate (ORR) and ≥ complete remission (CR) rate between both groups. However, the ≥ CR rate of the EMM group was lower than the non-EMM group receiving the fully human anti-BCMA CAR-T cell therapy (
= 0.026). The median progression-free survival (PFS) for EMM and the non-EMM group was 121 days and 361 days, respectively (
= 0.001). The median overall survival (OS) for EMM and the non-EMM group was 248 days and 1024 days, respectively (
= 0.005). The C
and AUC
for EMM group were lower than non-EMM group (C
,
= 0.016; AUC
,
= 0.016). Extramedullary disease was an independent prognostic risk factor for PFS (hazard ratio, 2.576; 95% CI, 1.343 to 4.941;
= 0.004) and OS (hazard ratio, 2.312; 95% CI, 1.165 to 4.592;
= 0.017) in RRMM patients receiving anti-BCMA CAR-T cell therapy.
Based on our results, EMM patients could benefit from the two anti-BCMA CAR products, although they had a shorter PFS and OS compared with non-EMM patients.
http://www.chictr.org.cn, identifier ChiCTR-OPC-16009113 and ChiCTR1800018137.
Abstract
Background
Extramedullary disease usually implies a dismal outcome in relapsed/refractory multiple myeloma patients, and requires novel treatment approaches. We designed a trial using ...Selinexor, a nuclear export protein 1 inhibitor, together with anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell product CT103A to treat these patients, and describe the first two cases in this report.
Methods
Selinexor was administered with a novel two-step schedule in bridging therapy and in maintenance. The clinical responses and adverse events were recorded after CAR-T infusion and Selinexor administration. In vitro analysis of the influence of Selinexor on CAR-T cell function was performed using myeloma cell lines.
Results
After infusion, both patients achieved stringent complete remission (sCR), and were maintained in sCR at data-cutoff, with survival over 13 and 10 months, respectively. Neither immune effector cell-associated neurotoxicity syndrome nor over grade 2 cytokine release syndrome was observed. Meanwhile, the patients showed good tolerance to the combination. In addition, we demonstrated that low dose of Selinexor could upregulate the expression of BCMA on plasma cell lines and subsequently enhance the function of CAR-T cell in vitro.
Conclusions
The combination of Selinexor and CT103A exerts preliminary synergistic effect, and can be developed as a promising strategy for relapsed/refractory extramedullary myeloma.
Chimeric antigen receptor T-cell therapy (CAR-T) has yielded unprecedented efficacy in B-cell malignancies. With the increasing use of CAR-T-cell therapy, infection has become one of the major ...concerns after CAR-T-cell infusion. Some patients even develop refractory or recurrent infections, posing challenges in treatment, prophylactic, and monitoring strategies. However, the mechanisms underlying the development of these infections were not clear.
We report two cases of infection after CAR-T-cell therapy. Patient 1, diagnosed with multiple myeloma, received anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T)-cell therapy. He developed a refractory urinary infection lasting for over 5 weeks, which was caused by Candida albicans. Whole-exome sequencing revealed that he had an IL-17RA gene mutation. Patient 2, diagnosed with acute lymphoblastic B-cell leukaemia, received anti-CD19 and anti-CD22 CAR-T-cell cocktail therapy and remained in complete remission for over 4 years. The patient had pneumonia five times during the 4 years. Whole-exon sequencing revealed that he had a CX3CR1 gene mutation.
For patients who develop persistent or recurrent infections after CAR-T-cell therapy, it is recommended to screen for immunodeficiency-related gene mutations, and the results may contribute to the management of infections post-CAR-T treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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