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Abstract : Multiple myeloma has been attributed to the proliferation, chemoresistance, and angiogenesis of tumor cells in human multiple myeloma. Hence, agents that can inhibit STAT3 transcription activation may have a role as cancer therapeutics. Our findings show that AKBA inhibited constitutive STAT3 expression in human MM cells. STAT3 activation was blocked by IL-6, which was reversed, but it was reversible. Interestingly, treatment of cells with pervanadate reduced the effect of AKBA to reduce STAT3 phosphorylation, implying the presence of a protein phosphatase, despite the absence of a protein tyrosine phosphatase. We discovered that AKBA produced Src homology region 2 domain-containing phosphatase 1, which may have been responsible for its role in STAT3 dephosphorylation. Moreover, deletion of the SHP-1 gene by small interfering RNA reduced the ability of AKBA to inhibit STAT3 transcriptionation by small interfering RNA deletions. Overall, our findings indicate that AKBA is a novel inhibitor of STAT3 transcription and may have promise in cancer treatment.
Source link: https://doi.org/10.1158/1541-7786.mcr-08-0154
We note unexpected finding that constitutive NF-B cellular expression in ten of 14 primary MM samples tested is refractory to inhibition by bortezomib, which was unexpected. Moreover, when MM patient-derived bone marrow stromal cells were cocultured with MM patient-derived bone marrow stromal cells, microenvironment elements crucial for MM growth and survival, increased in NF-B activity were also observed in MM cells that were also refractory to bortezomib. Similarly, MM-BMSCs activated PIR NF-B gene expression in the RPMI8226 MM cell line, resulting in increased NF-B-dependent transcription and resistance to bortezomib-induced apoptosis. Our findings show that primary MM cells routinely have PIR NF-B activity, which is further enhanced by the presence of patient-derived BMSCs. PIR NF-B's mechanism may lead to the development of novel diagnostic biomarkers and/or therapeutic targets for MM therapy.
Source link: https://doi.org/10.1158/1541-7786.mcr-08-0108
With the introduction of several new agents, myeloma therapy has dramatically changed, and there are now options for the management of relapsed or refractory disease, as well as novel drug classes with specific mechanisms of action and cellular therapies. Continuous lenalidomide-based therapy is used extensively at first-line, and resistance to lenalidomide has been a key determining factor in the selection of salvage therapy. Daratumab is increasingly used in first-line, and patients who relapse while on daratumumab will soon be a common problem.
Source link: https://doi.org/10.1182/blood.2020008734
Both tumor biology and suboptimal/absent responses to therapy may differ from HR definition, and a consistent identification of risk factors is essential for proper care of these patients. MRD's primary aim, as well as outside bone marrow, should be achieved and sustaining negativity, and medications should be modified in patients with frailty to reduce toxicity and improve quality of life.
Source link: https://doi.org/10.1182/blood.2020008733
Abstract The standard of care for eligible patients with newly diagnosed multiple myeloma has been high-dose melphalan assisted by autologous transplantation for over 25 years. Immunotherapy is currently changing the face of MM management, and daratumab is the first-in-class human monoclonal antibody against CD38 that has been approved in the setting of newly diagnosed MM. In a frontline setting, this review explores the various options available for the treatment of transplantation-eligible patients with MM.
Source link: https://doi.org/10.1182/blood.2020008735
Abstract The development of a variety of human cancer cells, including multiple myeloma, has been traced to signal transducers and transcription 3 promoters. Multiple myelo cells were found that ursolic acid, a pentacyclic triterpenoid, inhibited both constitutive and interleukin-6-inducible STAT3 transcription in a dose- and time-dependent manner. Indeed, we discovered that ursolic acid induced the production of tyrosine phosphatase SHP-1 protein and mRNA. Eventually, ursolic acid reduced proliferation and caused apoptosis and cell aggregation in cell cycle's G1-G0 phase. In multiple myeloma cells, this triterpenoid subsequently potentiated the apoptotic effects of thalidomide and bortezomib. Overall, these results show that ursolic acid is a novel blocker of STAT3 transcription activation, which may have a role in the prevention and treatment of multiple myeloma and other cancers.
Source link: https://doi.org/10.1158/1541-7786.mcr-06-0348
Methods: We've tested the plasma levels of MVs and cytokines IL-10, IL-17, and TGF- in MM and Waiting Smoldering MM from patients and compared them to thrombotic disease. TGF- and MV were both significantly higher in patients with thrombotic events when using univariate analysis. In the WWSMM and Dexamethasone/Bortezomib subgroup, the TGF- values of immunomodulatory derivatives patients were lower. Conclusion: The increased number of MVs in active regimens have provided further insight into the underlying mechanisms of hypercoagulation in MM.
Source link: https://doi.org/10.3390/jcm11102720
Mesenchymal stem/stromal cells are self-renewing and multipotent progenitors that make up the primary cellular compartment of the bone marrow stroma. Melflufen is a new anticancer peptide-drug conjugate compound for patients with relapsed refractory multiple myeloma. We established co-cultures of BMSCs with MM. 1S myeloma cells to see if BMSCs raise or decrease the cytotoxicity of melflufen, melphalan, bortezomib, or doxorubicin in BMSCs. We investigated how the drugs affected BMSC differentiation into adipocytes and osteoblasts, as well as the BMSC-funded establishment of vascular networks. BMSCs were more sensitive to melflufen than to melphalan, according to our results. As was the case with melphalan, bortezomib, and doxorubicin, the cytotoxicity of melflufen in myeloma cells was not affected by the co-culture with BMSCs, not affected by melflufen in myeloma cells. Melphalan and doxorubicin influenced BMSC differentiation in similar ways. Overall, our findings show that melflufen has a significant effect on BMSCs, which may have a lot to do with therapy success.
Source link: https://doi.org/10.3390/cells11091574
In MM patients, one month after the two-dose primary vaccination the highest non-responder rate was reported with lower CD19 + B-cell counts. 18% of patients with MM, 10% with SOT, and 4% with IBD became seronegative after the second dose, while no one from the control group went negative. However, antibody levels in IBD patients treated with TNF- inhibitors rose more rapidly than in controls. Specifically, booster vaccination increased antibody levels > 8fold in seroresponders and induced anamnestic responses, as well as those with undetectable pre-booster antibodies. However, antibody levels in IBD patients with TNF- inhibitors were lower than those in untreated IBD patients and controls, as well as controls. Conclusion Immunomonitoring vaccine-specific antibody and cellular responses is indicated to detect vaccination failures and eventually establishing personalized vaccination regimens, including shorter booster intervals, in all patients with secondary immunodeficiencies.
Source link: https://doi.org/10.3389/fimmu.2022.889138
Abstract: Histone deacetylase inhibitors have demonstrated promise as candidate radiosensitizers for several forms of cancer. In this research, we find that suberoylanilide hydroxamic acid in low amounts has no cytotoxic effects on cytotoxic cells, but it can dramatically raise radiosensitivity of MM cells. SAHA appears to have a tendency to block RAD51 protein response to ionizing radiation, which is consistent with an inhibiting factor in the initiation of RAD51 protein foci in irradiated MM cells. These effects of SAHA on RAD51 focus are independent of cell-cycle distribution shifts.
Source link: https://doi.org/10.1158/1541-7786.mcr-11-0587
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