The age-dependent changes in risk weights of the prognostic factors for multiple myeloma

ABSTRACTObjective Multiple myeloma is a highly heterogenous plasma cell malignancy, commonly seen in older patients. Age is one of the important prognostic factors. However, nearly all the prognostic staging systems are based on clinical trials, where patients were relatively fit and young. It is unknown how the presence of biochemical or cytogenetic prognostic factors and their risk weights changes with older age. To further investigate this question, we retrospectively analyzed the data from a consecutive cohort of patients treated with either bortezomib or thalidomide-based therapy.Methods This retrospective study was carried out on a cohort of 1125 newly diagnosed multiple myeloma patients, from January 2008 to December 2019. Patients received bortezomib or thalidomide-based induction and maintenance therapy. Patients accepted hematopoietic stem cell transplantation if eligible. Statistical analysis was conducted by Stata/MP 16.0 and SPSS 26.0.Results With age increasing, the proportion of patients with ISS 3, performance status score ≥2, and the incidence rate of gain(1q) significantly increased. We also found that ISS became less important in older patients. However, cytogenetic abnormalities exerted a consistently adverse impact on survival, both in young and old patients. Older patients had an inferior outcome than their young counterparts. All patients in our cohort benefitted more from bortezomib than thalidomide-based induction therapy, except for patients ≥71 years old.Conclusions ISS may lose prognostic value in patients ≥71 years old. Older patients had an inferior outcome and needed more effective and less toxic treatment.Plain Language SummaryMultiple myeloma is a type of blood cancer commonly seen in older people. To treat this disease, genetic abnormality, the poor physical status of patients and the abundance of tumor cells are the main difficulties. We often draw these conclusions from clinical trials. However, clinical trials always enrolled relatively younger patients, so the presence and significance of these factors may vary from clinical trials to the real world. We conducted the study to find out the real risk in both young and old patients. We found that older patients were more likely to have anemia, poor nutritional status and renal function. We also found older patients had more risk of relapse, progression or death than young patients. Frail physical status is the key obstacle to treating older patients, and tumor burden no longer impacts the outcome of these people. Bortezomib is a powerful drug to treat this disease, but patients ≥71 years old had less benefit than younger ones. More studies should focus on older or frail patients as these patients need more effective and less toxic treatment

Multifunctional photosensitizer-conjugated core-shell Fe3O4@NaYF4:Yb/Er nanocomplexes and their applications in T2-weighted magnetic resonance/upconversion luminescence imaging and photodynamic therapy of cancer cells

Due to non-invasive deep imaging and therapy, multifunctional agents of magnetic resonance (MR)/ upconversion luminescence (UCL) imaging and photodynamic therapy (PDT) play an important role in clinical diagnosis and treatment of cancers, and also in the assessment of therapy effect. In this paper, tetra-sulfonic phthalocyanine aluminium (AlPcS4) photosensitizers-conjugated Fe3O4@NaYF4:Yb/Er (NPs- AlPcS4) nanocomplexes were synthesized for the T2-weighted MR/UCL imaging and PDT of cancer cells. The PEG-coated Fe3O4@NaYF4:Yb/Er nanoparticles (NPs) with a core–shell structure showed strong T2- weighted MR relaxivity (r2 = 42.131 mM21 s21) and UCL emission in the visible region (the bands at about 654–674 nm, 545 nm and 524 nm), and were conjugated successfully with AlPcS4 photosensitizer by electrostatic interaction. By direct observation of XFM and staining with Prussian blue, the element distribution and location of NPs in MCF-7 cells were characterized, respectively. Under irradiation from a 980 nm laser, the death ratio of MCF-7 cells incubated with NPs-AlPcS4 nanocomplexes could be up to about 70%. The results indicated that the as-prepared NPs-AlPcS4 nanocomplexes would be a potential candidate as multifunctional nanoprobes for the dual-modal T2-weighted MR/UCL imaging and PDT of cancers in the future

Enhanced Doxorubicin Transport to Multidrug Resistant Breast Cancer Cells via TiO2 Nanocarriers

In order to overcome the multidrug resistance of breast cancer cells, doxorubicin was loaded onto TiO2 nanoparticles in which the electrostatic interactions hold the drug and the nanoparticles together. The anticancer activity of this nanocomposite was evaluated in multidrug resistant breast cancer cells. In nanocomposite treated MCF-7/ADM cells, drug accumulation increased with enhanced anticancer activity about 2.4 times compared to that of doxorubicin alone. The potential mechanism of enhanced drug accumulation is ascribed to the fact that the nanocomposite directly transports the drugs into cells via internalization, bypassing the P-glycoprotein mediated doxorubicin pumping system. Our results reinforce that the nanocomposite, as a pH controlled drug release system, could be used to overcome multidrug resistance of human breast cancer cells

Virus-triggered Ubiquitination of TRAF3/6 by cIAP1/2 Is Essential for Induction of Interferon-β (IFN-β) and Cellular Antiviral Response*

Viral infection causes activation of transcription factors NF-κB and IRF3, which collaborate to induce type I interferons (IFNs) and cellular antiviral response. Here we show that knockdown of the E3 ubiquitin ligases cIAP1 and cIAP2 markedly inhibited virus-triggered activation of IRF3 and NF-κB as well as IFN-β induction. Knockdown of cIAP1 and cIAP2 also inhibited cytoplasmic dsRNA-triggered cellular antiviral response. Endogenous coimmunoprecipitation experiments indicated that viral infection caused recruitment of cIAP1 and cIAP2 to TRAF3, TRAF6, and VISA. Furthermore, we demonstrated that cIAP1- and cIAP2-mediated virus-triggered ubiquitination of TRAF3 and TRAF6. These findings suggest that virus-triggered ubiquitination of TRAF3 and TRAF6 by cIAP1 and cIAP2 is essential for type I IFN induction and cellular antiviral response

Emulsifiers’ Composition Modulates Venous Irritation of the Nanoemulsions as a Lipophilic and Venous Irritant Drug Delivery System

In this study, a nanoemulsion (NE) system was investigated for intravenous delivery of lipophilic and venous irritant drugs. NEs were prepared to deliver diallyl trisulfide (DT) for systemic therapy of bacterial and fungal infection, egg phospholipid was chosen as the main emulsifier, and two co-emulsifiers were also incorporated, including Poloxamer 188 (P188) and Solutol HS 15 (S15). Soybean oil was used as the dispersed phases, forming stable DT NEs with small particle sizes. The venous irritation of DT NEs was evaluated by in vitro human umbilical cord endothelial cells (CRL 1730) compatibility model with the intracellular adenosine triphosphate (ATP) and guanosine triphosphate (GTP) concentrations as the indices. The intracellular ATP and GTP reduction changed with the incorporation of a variety of co-emulsifiers, which varied in a free DT concentration-dependent manner. It was deduced that the free DT concentrations of NEs containing co-emulsifiers were determined by the partition coefficient of DT between oil and surfactant buffer solution. In conclusion, NE was an appropriate delivery system for lipophilic and venous irritant drug, and optimization of the composition of emulsifiers was an effective method to alleviate the venous irritation of DT NEs