Paleo-marine redox environment fluctuation during the early Cambrian: Insight from iron isotope in the Tarim Basin, China.

The Ediacaran to Cambrian period is generally considered to be the vital transition in the history of marine redox environment and life evolution on earth. The ocean oxygenation levels during this transition period are still debated. Since iron is widely involved in biogeochemical cycles and undergoes redox cycling both in the seawater and sediments, it has become a significant proxy to reconstruct paleo-marine environment. In order to constrain the paleo-marine redox state in the early Cambrian, the iron isotope composition of bulk rock (δ56FeT) is interpreted combining with iron-speciation, redox sensitive elements and pyrite sulfur isotope (δ34Spy) of Yuertusi Formation in Tarim Block. The δ56FeT values varies from -0.39 ‰ to 0.48 ‰, with an average of 0.07 ‰, mainly controlled by pyrite mineral facies in this study. Based on the mechanism of pyrite generation in different redox condition, it is proposed that the marine environment of the lower Cambrian in the Tarim basin is dominated by anoxic with intermittent euxinic state. The dynamic evolution of redox environment can be divided into three intervals. The gradual decrease of δ56Fe in Interval I indicates the paleo-marine environment changed from anoxic ferruginous to euxinic, and the paleo-marine sulfate reservoir decreased to a limited level, which might be attributed to abundant burial of organic matter and pyrite. For Interval II, δ56Fe values first increase to evident positive because of partial oxidization then decreased to that of seawater (about 0 ‰) due to complete oxidization. In Interval III, the continuous decrease of δ56Fe values infers a sustaining oxidization. In summary, the paleo-marine environment of the lower Cambrian Yuertusi Formation evolved from anoxic ferruginous to euxinic and then oxidized continuous. Iron isotope statistics from geological historical periods indicate that seawater was relatively oxidized after the NOE event but did not reach the oxidation levels of present-day seawater.

Directed evolution unlocks oxygen reactivity for a nicotine-degrading flavoenzyme.

The flavoenzyme nicotine oxidoreductase (NicA2) is a promising injectable treatment to aid in the cessation of smoking, a behavior responsible for one in ten deaths worldwide. NicA2 acts by degrading nicotine in the bloodstream before it reaches the brain. Clinical use of NicA2 is limited by its poor catalytic activity in the absence of its natural electron acceptor CycN. Without CycN, NicA2 is instead oxidized slowly by dioxygen (O2), necessitating unfeasibly large doses in a therapeutic setting. Here, we report a genetic selection strategy that directly links CycN-independent activity of NicA2 to growth of Pseudomonas putida S16. This selection enabled us to evolve NicA2 variants with substantial improvement in their rate of oxidation by O2. The encoded mutations cluster around a putative O2 tunnel, increasing flexibility and accessibility to O2 in this region. These mutations further confer desirable clinical properties. A variant form of NicA2 is tenfold more effective than the wild type at degrading nicotine in the bloodstream of rats.

Impact of dialysis dependence on survival for multiple myeloma with renal impairment: a multicenter study in China.

Renal impairment (RI) is a very common complication of multiple myeloma (MM) with a negative impact on survival. Herein we retrospectively analyzed 334 MM patients with renal impairment at diagnosis from three hospitals in China. All 334 patients were divided into three groups, including dialysis dependence (n=43), dialysis independence (n=42), and without dialysis (n=249). Compared with dialysis independence and without dialysis groups, dialysis dependence group had the lowest overall hematologic response (48.8% vs. 97.6% vs. 77.1%, P<0.001) and overall renal response (0.0% vs. 97.6% vs. 72.7%, P<0.001), as well as the highest early mortality within 24 months (50.0% vs. 24.4% vs. 26.3%, P=0.006). Dialysis dependence group had similar progression-free survival (24 vs. 26 vs. 27 months, P=0.231) and significantly shorter overall survival (25 vs. 69 vs. 45 months, P=0.001). Dialysis dependence was independently associated with high mortality within 24 months and shorter overall survival. In conclusion, MM patients with dialysis dependence still tend to suffer a dismal disease course, including a high probability to suffer early mortality, worse hematological and renal response, as well as shorter survival. Dialysis independence could be very promising for survival improvement.

Nursing management of treatment-related venous thromboembolism in patients with multiple myeloma.

Objectives: Venous thromboembolism (VTE) is a common complication among patients with newly diagnosed multiple myeloma (NDMM). Therefore, this study aimed to analyze the incidence and risk factors associated with VTE in the current era of thromboprophylaxis and to propose appropriate nursing measures. Methods: A total of 1,539 NDMM patients were retrospectively analyzed. All patients underwent VTE risk assessment and received aspirin or low molecular weight heparin (LMWH) to prevent thrombosis, followed by appropriate care based on their individual thrombosis risk. The incidence of VTE and its related risk factors were then analyzed. Results: All patients received at least four cycles of therapy containing immunomodulators (IMiDs) and/or proteasome inhibitors (PIs). We assigned 371 patients (24.1%) to the moderate-risk thrombosis group, who received daily aspirin (75 mg) for thrombosis prevention and 1,168 patients (75.9%) to the high-risk group, who received daily low molecular weight heparin (3,000 IU) for thrombosis prevention two times a day. Among all the patients, 53 (3.4%) experienced lower extremity venous thromboembolism events, with three of those patients experiencing a concurrent pulmonary embolism. A multivariate analysis indicated that bed rest lasting more than 2 months and plasma cells of ≥60% were independent factors associated with thrombosis. Conclusion: More effective risk assessment models are needed to predict thrombosis accurately. In addition, nurses involved in the treatment and management of thrombosis should continually engage in professional development to enhance their knowledge and skills.

Characteristics and Risk Factors of Ultra-High-Risk Patients with Newly Diagnosed Multiple Myeloma.

OBJECTIVE: To investigate the clinical characteristics and risk factors of ultra-high-risk (UHR) patients with newly diagnosed multiple myeloma (MM). METHODS: We screened UHR patients with a survival of less than 24 months and we selected patients with a concurrent survival of more than 24 months as a control group. We retrospectively analyzed the clinical characteristics of UHR patients with newly diagnosed MM and screened related risk factors. RESULTS: In total we analyzed 477 patients, which included 121 (25.4%) UHR patients and 356 (74.6%) control patients. Median overall survival (OS) and progression-free survival (PFS) of UHR patients was 10.5 months (7.5-13.5 months) and 6.3 months (5.4-7.2 months), respectively. Univariate logistic regression analysis showed that age > 65 years, hemoglobin (HGB) < 100 g/L, lactate dehydrogenase (LDH) > 250 U/L, serum creatinine (SCr) > 2 mg/dL, corrected serum calcium (CsCa) > 2.75 mmol/L, B-type natriuretic peptide (BNP) or N-terminal prohormone BNP (NT-proBNP) > 2 upper limit of normal (ULN), high-risk cytogenetics, Barthel index score, and International Staging System (ISS) stage III were associated with UHR MM. In a multivariate analysis, age > 65 years, LDH > 250 U/L, CsCa > 2.75 mmol/L, BNP or NT-proBNP > 2 ULN, high-risk cytogenetics, and Barthel index score were independent risk factors for UHR MM. Moreover, UHR patients had a worse response rate than control patients. CONCLUSION: Our study highlighted the characteristics of UHR MM patients and suggested that the combination of organ insufficiency and highly malignant myeloma cells resulted in poor outcomes of patients with UHR MM.

Prognostic nomogram for multiple myeloma early relapse after autologous stem cell transplant in the novel agent era.

BACKGROUND: The present study intended to establish a predictive nomogram for early relapse (ER) (<12 months) after autologous stem cell transplantation (ASCT) in the novel drug era for multiple myeloma (MM). PATIENTS AND METHODS: The nomogram was designed and constructed to a retrospective clinical data of newly diagnosed MM patients received novel agent induction therapy and subsequent ASCT at three centers in China from July 2007 to December 2018. The retrospective study was conducted among 294 patients in the training cohort and 126 in the validation cohort. The nomogram's predictive accuracy was evaluated by the concordance index, calibration curve and decision clinical curve. RESULTS: The study cohort included 420 newly diagnosed MM patients, and 100 (23.8%) were identified as having ER, including 74 in the training cohort and 26 in the validation cohort. According to the result of multivariate regression in the training cohort, the prognostic variables included in the nomogram were high-risk cytogenetics, LDH > UNL, and response less than very good partial response (VGPR) after ASCT. The calibration curve showed good fitness between the nomogram predictions and the actual observations and the nomogram was further validated by a clinical decision curve. The nomogram's C-index achieved 0.75 (95% CI, 0.70-0.80), which was higher than that of the Revised International Staging System (R-ISS) (0.62), ISS (0.59), and Durie-Salmon (DS) staging system (0.52). The discrimination ability of the nomogram in the validation cohort was superior to that of the other staging systems (C-index: 0.73 vs. R-ISS (0.54), ISS (0.55), and DS staging system (0.53)). DCA showed the prediction nomogram adds much more clinical utility. Different scores of the nomogram draw a distinction of OS. CONCLUSION: The present nomogram could serve as a feasible and accurate prediction of ER in novel drug induction transplantation-eligible MM patients, which could help modify the post-ASCT strategy for patients at high risk of ER.

Prognostic value of t(4;14) translocation in newly diagnosed multiple myeloma patients in novel agent era.

OBJECTIVE: To evaluate the prognostic value of t(4; 14) translocation for newly diagnosed multiple myeloma (MM) patients in the novel agent era. METHODS: We retrospectively analyzed 606 newly diagnosed MM patients treated with novel agents. The propensity score matching technique was used to reduce the bias between groups. RESULTS: Among 606 patients, t(4; 14) was observed in 108 (17.8%) patients, among which 79 (73.1%) were accompanied by 1q21 gain and/or del 17p. Median overall survival (OS) (56.2 vs. 87.3 months) and progression-free survival (PFS) (25.7 vs. 37.6 months) were significantly shorter in patients with t(4;14) compared with patients without cytogenetic abnormalities. Univariate Cox proportional hazards regression analysis showed that the t(4;14) was not associated with shorter OS (p = 0.666) and PFS (p = 0.164). The multivariable analysis also showed t(4;14) was not a poor prognostic factor for OS and PFS of patients with newly diagnosed MM (p > 0.05). After balancing the distribution of factors between patients with and without t(4;14) by the propensity score matching technique, patients with t(4;14) had similar OS (57.6 vs. 56.5 months, p = 0.964) and PFS (26.5 vs. 28.1 months, p = 0.740) with the patients without t(4;14). CONCLUSIONS: These results demonstrated that t(4; 14) alone may be not a poor prognostic factor patients with newly diagnosed MM in the novel agent era.

Low Barthel index score is a poor prognostic factor for newly diagnosed multiple myeloma patients.

The basic activities of daily life may affect the prognosis of multiple myeloma (MM) patients and the Barthel index (BI) is currently the most widely used tool to evaluate basic activities of daily life, but few studies have evaluated its prognostic value in MM. We retrospectively enrolled patients with newly diagnosed MM and analyzed the association between the BI and the survival of newly diagnosed MM patients. We totally analyzed 538 patients and found that median overall survival (OS) and progression-free survival (PFS) were significantly shorter in the low BI (≤ 85) group compared with the high BI (> 85) group. Univariate Cox proportional hazards regression analysis showed that the low BI was associated with shorter OS and PFS. It was also confirmed that the low BI was poor prognostic factor for OS and PFS in multivariable analyses. In the propensity score matching analysis, patients with low BI also had shorter OS and PFS. Our study suggested that the low BI was a poor prognostic factor for patients with newly diagnosed MM.

CD20 expression: A risk stratification factor for newly diagnosed multiple myeloma with t(11;14).

Objective: Translocation (11;14) is one of the most frequent recurrent cytogenetic abnormalities in multiple myeloma (MM), while its clinical prognostic value remains controversial. CD20 expression is uncommon in MM while strongly associated with t(11;14). This study aimed to investigate whether CD20 could provide further prognostic value in MM patients harboring t(11;14). Methods: CD20 expression detected by flow cytometry was retrospectively analyzed in 211 newly diagnosed MM patients with t(11;14). The clinical characteristics and outcomes were analyzed between CD20 positive and negative patients. Results: CD20 expression was found in 34.6% (73/211) newly diagnosed MM (NDMM) patients with t(11;14), associated with lower serum creatine levels and lower incidence of plasmacytoma. Based on similar treatment regimens, CD20 positive patients had a comparable overall response rate to CD20 negative patients, whereas had a lower CR/sCR (complete response/stringent complete response) rate than the latter (31.4% vs. 46.4%, P =0.045). Nevertheless, CD20 positive patients had a longer tendency of progression-free survival (PFS) (59.0 vs. 29.0 months, P =0.163) and significantly longer overall survival (OS) (99.0 vs. 56.0 months, P=0.003) than CD20 negative patients. Further investigation among CD20 expression proportion showed that strong expression of CD20 (>80% of bone marrow plasma cells) exhibited the longest OS (median not reached, P =0.011). However, the favorable impact of CD20 expression on survival was eliminated with the contaminant presence of cytogenetic abnormalities besides t(11;14). Autologous stem cell transplantation (ASCT) could improve the prognosis of CD20 negative t(11;14) patients. Multivariate analysis confirmed that CD20 expression was an independent favorable indicator for longer OS in t(11;14) MM patients. Conclusion: CD20 expression is a favorable prognostic factor in NDMM with t(11;14) and could provide further risk-stratification value in this heterogeneous disease subgroup.

Newly diagnosed multiple myeloma patients with CD56 expression benefit more from autologous stem cell transplantation.

BACKGROUND: Several studies showed that lack of CD56 expression was a poor prognostic factor for patients with newly diagnosed multiple myeloma (NDMM). However, other studies were not able to confirm the prognostic value of CD56 in NDMM. This study aimed to evaluate the prognostic value of CD56 expression for patients with NDMM who received autologous stem cell transplantation (ASCT). METHODS: We retrospectively analyzed 370 patients with NDMM under 66 years old and the propensity score matching technique was used to reduce the bias between two groups. RESULTS: CD56 expression was observed in 250 (67.6%) patients, and only half of transplant-eligible patients received ASCT for financial and adverse effects concerns after induction therapy. 54.8% (137/250) CD56 positive patients received ASCT; and 47.5% (57/120) CD56 negative patients received ASCT. Univariate and multivariate analyses showed that ASCT was correlated with longer overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p < 0.001) for CD56 positive patients. However, ASCT had no impact on OS and PFS in univariate and multivariate analysis (p > 0.05). In the propensity score matching analysis, 186 CD56 positive patients were identified, 93 patients had received ASCT and 93 patients had no ASCT. Among 120 CD56 negative patients, 80 patients, 40 in each group, were identified. Among 186 matched CD56 positive patients, patients with ASCT had longer OS (87.6 vs.56.1 months, p = 0.049) and PFS (36.7 vs.30.9 months, p = 0.040). However, ASCT had no impact on OS and PFS for matched CD56 negative patients (p > 0.05). CONCLUSIONS: These results demonstrated that ASCT may improve OS and PFS of CD56 positive patients and had no impact on survival of CD56 negative patients.

Binding Interface and Electron Transfer Between Nicotine Oxidoreductase and Its Cytochrome c Electron Acceptor.

The enzyme nicotine oxidoreductase (NicA2) is a member of the flavoprotein amine oxidase family that uses a cytochrome c protein (CycN) as its oxidant instead of dioxygen, which is the oxidant used by most other members of this enzyme family. We recently identified a potential binding site for CycN on the surface of NicA2 through rigid body docking [J. Biol. Chem. 2022, 298 (8), 102251]. However, this potential binding interface has not been experimentally validated. In this paper, we used unnatural amino acid incorporation to probe the binding interface between NicA2 and CycN. Our results are consistent with a structural model of the NicA2-CycN complex predicted by protein-protein docking and AlphaFold, suggesting that this is the binding site for CycN on NicA2's surface. Based on additional mutagenesis of potentially redox active residues in NicA2, we propose that electron transfer from NicA2's flavin to CycN's heme occurs without the assistance of a protein-derived wire.

Mechanisms underlying synergism between circularized tumor necrosis factor-related apoptosis inducing ligand and bortezomib in bortezomib-sensitive or -resistant myeloma cells.

Mechanisms underlying interactions between a novel, clinically relevant circularized tumor necrosis factor-related apoptosis inducing ligand (TRAIL) agonist, circularly permuted TRAIL (CPT) have been examined in multiple myeloma (MM) cells sensitive or resistant to bortezomib (BTZ). Various MM cell lines for example, U266, including those resistant to bortezomib-resistant U266 cells were exposed to low nanomolar concentrations of bortezomib ± CPT and apoptosis monitored. Circularly permuted TRAIL and bortezomib synergistically induced apoptosis in both BTZ-naïve and -resistant cells. The regimen up-regulated DR4 receptor internalization in MM cells, known to modulate both NF-κB and extrinsic apoptotic pathways. CPT/BTZ disrupted the non-canonical NF-κB pathway, reflected by tumor necrosis factor (TNF) receptor associated factors 3 (TRAF3) up-regulation, NF-κB inducing kinase down-regulation, diminished p52 and p50 processing, and B-cell lymphoma-extra large (BCL-XL) down-regulation, but failed to inactivate the canonical NF-κB pathway, reflected by unchanged or increased expression of phospho-p65. The regimen also sharply increased extrinsic apoptotic pathway activation. Cells exhibiting TRAF3 knock-down, dominant-negative Fas-associated protein with death domain, knock-down of caspase-8, BCL-2/BCL-XL, or exposure to a caspase-9 inhibitor displayed markedly reduced CPT/BTZ sensitivity. Concordant results were observed in bortezomib-resistant cells. The regimen was also active in the presence of stromal cells and was relatively sparing toward normal CD34+ hematopoietic cells. Finally, ex vivo results revealed synergism in primary MM primary cells, including those BTZ, and the CPT/BTZ regimen significantly decreased tumor growth in a patient-derived MM xenograft model. These results indicate that the CPT/BTZ regimen acts via the non-canonical NF-κB as well as intrinsic/extrinsic apoptotic pathways to induce cell death in MM cells, and may represent an effective strategy in the setting of bortezomib resistance.

The enzyme pseudooxynicotine amine oxidase from Pseudomonas putida S16 is not an oxidase, but a dehydrogenase.

The soil-dwelling bacterium Pseudomonas putida S16 can survive on nicotine as its sole carbon and nitrogen source. The enzymes nicotine oxidoreductase (NicA2) and pseudooxynicotine amine oxidase (Pnao), both members of the flavin-containing amine oxidase family, catalyze the first two steps in the nicotine catabolism pathway. Our laboratory has previously shown that, contrary to other members of its enzyme family, NicA2 is actually a dehydrogenase that uses a cytochrome c protein (CycN) as its electron acceptor. The natural electron acceptor for Pnao is unknown; however, within the P. putida S16 genome, pnao forms an operon with cycN and nicA2, leading us to hypothesize that Pnao may also be a dehydrogenase that uses CycN as its electron acceptor. Here we characterized the kinetic properties of Pnao and show that Pnao is poorly oxidized by O2, but can be rapidly oxidized by CycN, indicating that Pnao indeed acts as a dehydrogenase that uses CycN as its oxidant. Comparing steady-state kinetics with transient kinetic experiments revealed that product release primarily limits turnover by Pnao. We also resolved the crystal structure of Pnao at 2.60 Å, which shows that Pnao has a similar structural fold as NicA2. Furthermore, rigid-body docking of the structure of CycN with Pnao and NicA2 identified a potential conserved binding site for CycN on these two enzymes. Taken together, our results demonstrate that although Pnao and NicA2 show a high degree of similarity to flavin containing amine oxidases that use dioxygen directly, both enzymes are actually dehydrogenases.

Incidence of multiple myeloma in Kailuan cohort: A prospective community-based study in China.

BACKGROUND: Previous retrospective studies showed that the incidence and mortality rates for MM in China were lower than those in western countries. A large-scale prospective study on incidence and mortality rates of MM is still lacking. METHODS: Based on the prospective Kailuan Cohort study in China, we included all patients with MM in Kailuan Cohort from June 1, 2008 to December 31, 2016. Using the numbers of diagnosed cases and deaths during the study period as the numerators and the corresponding observed person-years as the denominators respectively, we calculated crude incidence and mortality rates. The 95% confidence intervals for crude incidence rate and mortality rate were estimated base on Poisson distribution. Rates were standardized by direct standardization according to the China population in 2000 and Segi' world standard population. RESULTS: A total of 22 members from Kailuan Cohort were first diagnosed with MM between 2008 and 2016. The calculated crude incidence rates were 2.8 (95% CI, 1.7-4.2) per 100,000 person-years for all participants. The standardized incidence rate was 0.9 per 100,000 person-years (95% CI, 0.5-2.1) when standardized by 2000 China population census data, and 1.0 per 100,000 person-years (95% CI, 0.6-1.8) when standardized by Segi's world standard population (WSP). The calculated crude mortality rates were 2.3 (95% CI, 1.4-3.6) per 100,000 person-years. The mortality standardized by 2000 China population census data was 0.7 per 100,000 person-years (95% CI, 0.3-1.9), and 0.9 per 100,000 population (95% CI, 0.5-1.7) when standardized by Segi's WSP. Both incidence and mortality for males were higher than that for females almost in all age groups. Both rates increased steadily with age. CONCLUSION: In this community-based prospective cohort study, we found that the incidence of MM in China was far lower than that in American and Europe.

Echocardiography-defined pulmonary hypertension is an adverse prognostic factor for newly diagnosed multiple myeloma patients.

BACKGROUND: Pulmonary hypertension (PH) is a common but rarely recognized comorbidity of multiple myeloma (MM) patients, while its prognostic significance for MM has been rarely reported. METHODS: We retrospectively analyzed the clinical characteristics and prognostic value of baseline echocardiography-defined PH in 426 newly diagnosed MM (NDMM) patients. RESULTS: Echocardiograph-defined PH was found in 12.7% (54/426) of NDMM patients, associated with older age, anemia, and renal insufficiency, as well as severe diastolic dysfunction and higher BNP and NT-pro-BNP levels. Patients with PH presented with a higher prevalence of atrial fibrillation, while with a similar incidence of thrombosis compared with those without PH. Based on similar treatment regimens and autologous stem cell transplantation (ASCT) rates, patients without PH have deeper and better responses than those with PH (p = 0.002). With the remission of MM, 81.5% of PH was reversible, accompanied by improvement of right ventricular dysfunction and normalization of BNP/NT-pro-BNP levels, while could reoccur at MM relapse. Survival analysis revealed that PH was an adverse prognostic factor, associated with reduced progression-free survival (PFS) (21 vs. 50 months, p < 0.001) and overall survival (OS) (45 vs. 90 months, p = 0.014). Multivariate analysis further verified that baseline PH was an independent predictor for shorter PFS and OS. CONCLUSION: In conclusion, echocardiography-defined PH is an adverse prognostic indicator for MM patients and should be routinely evaluated in MM patients at diagnosis to make a precise prognosis.

Polypropylene Random Copolymer Based Composite Used for Fused Filament Fabrication: Printability and Properties.

Fused filament fabrication (FFF) is one of the most commonly used additive manufacturing technologies. However, the applied material for commercial FFF is limited. Presently, though being one of the most used polymer materials, polypropylene (PP) is rarely used in FFF because of its serious warpage and shrinkage problems. This study investigated the impact of addition of short glass fibers (GF) and ethylene propylene diene monomer (EPDM) on the printability of polypropylene random copolymer (PPR) based FFF and mechanical properties of the printed samples, as well as other properties including rheology, thermal behaviors, and morphology. The results show that the modified PPR has excellent printability, as the printed samples are of good geometrical accuracy. The addition of GF can significantly improve the strength and modulus of the composite, but it also leads to serious decrease in toughness. EPDM addition can effectively improve the toughness of the composite, showing a complementary effect with GF. This work has important meaning in expanding the FFF applicable material and in broadening the application of PP.

The Prognostic Role of Prothrombin Time and Activated Partial Thromboplastin Time in Patients with Newly Diagnosed Multiple Myeloma.

PURPOSE: To evaluate the prognostic role of prothrombin time (PT) and activated partial thromboplastin time (APTT) for newly diagnosed multiple myeloma (MM). METHODS: We retrospectively analyzed 354 patients with newly diagnosed MM who received primary treatment in our center. The propensity score matching technique was used to reduce the bias between groups. RESULTS: Among 354 patients, lengthened PT or APTT was observed in 154 (43.5%) patients and 200 (56.5%) patients had normal PT and APTT. Patients with lengthened PT or APTT had significantly shorter median overall survival (OS) (37.5 vs. 73.8 months, p < 0.001) and progression-free survival (PFS) (23.1 vs. 31.6 months, p = 0.001) than those with normal PT and APTT. Univariate Cox proportional hazards regression analyses showed that lengthened PT or APTT was associated with shorter OS (HR = 2.100, 95% CI: 1.525-2.893, p < 0.001). Lengthened PT or APTT was also a poor prognostic factor for OS (HR = 3.183, 95% CI: 1.803-5.617, p < 0.001) in multivariable analyses. The poor effect of lengthened PT or APTT on PFS was confirmed in univariate analysis (HR = 1.715, 95% CI: 1.244-2.365, p = 0.001), but it had no impact on PFS in multivariate analysis (p = 0.197). In the propensity score matching analysis, 154 patients, 77 in each group, were identified. Among 154 matched patients, the OS of patients with lengthened PT or APTT was shorter (38.4 vs. 51.0 months, p = 0.030), but PFS was similar (29.0 vs. 35.0 months, p = 0.248). CONCLUSION: These results demonstrated that lengthened PT or APTT was an independent poor prognostic factor for patients with newly diagnosed MM.

Cyclopamine sensitizes multiple myeloma cells to circularly permuted TRAIL-induced apoptosis.

Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a promising anti-myeloma drug prototype. The aim of the present study was to investigate the synergistic effects of cyclopamine and circularly permuted TRAIL (CPT) on the proliferation and apoptosis of multiple myeloma cells. The results showed that the inhibitory effects of cyclopamine on the proliferation of human myeloma RPMI-8226 and SKO-007 cells were weak. RPMI-8226 cells were sensitive to CPT; however, the proliferation of SKO-007 cells was not effectively inhibited by CPT. SKO-007 cells were thus considered resistant to cyclopamine and CPT and used for subsequent experiments. Treatment with a combination of cyclopamine and CPT significantly inhibited cell proliferation. Moreover, the Q value showed that cyclopamine combined with CPT could synergistically inhibit the proliferation of SKO-007 cells. Cyclopamine increased CPT-induced apoptosis in the SKO-007 cells and exhibited a synergistic induction of apoptosis when combined with CPT. Moreover, the combination of cyclopamine and CPT decreased the ratio of myeloma stem cells. Quantitative PCR showed that cyclopamine decreased the mRNA expression levels of GLI1/GLI2/GLI3 and increased the expression levels of death receptor 4. In conclusion, the present study showed that a combination of cyclopamine and CPT exhibited synergistic effects on the inhibition of proliferation and induction of apoptosis in myeloma cells.

Deep and partial immunoparesis is a poor prognostic factor for newly diagnosed multiple myeloma patients.

We retrospectively analyzed immunosuppression status in 287 newly diagnosed multiple myeloma (MM) patients and assessed the prognostic value of immunoparesis on survival. Deep immunoparesis was defined that one of uninvolved immunoglobulins was below 50% the lower limit of normal ranges, partial immunoparesis was defined at least two suppressed uninvolved immunoglobulins. We found that patients with deep and partial immunoparesis had a significantly shorter median overall survival (OS) and progression-free survival (PFS). Moreover, deep and partial immunoparesis was a poor prognostic factor for OS and PFS in univariate and multivariable analyses. To reduce the bias between the groups, we performed a 1:1 propensity score matching technique for analysis and found that patients with deep and partial immunoparesis also had shorter OS and PFS. Our study showed that deep and partial immunoparesis can be defined an independent poor prognostic factor for patients with newly diagnosed MM.

What Multiple Myeloma With t(11;14) Should Be Classified Into in Novel Agent Era: Standard or Intermediate Risk?

OBJECTIVE: To investigate the prognostic value of t(11;14) for de novo multiple myeloma (MM) patients in novel agent era. METHODS: A total of 455 patients with fluorescence in situ hybridization (FISH), before treatments from three hospitals in China, were included in the study. All patients received autologous stem cell transplantation (ASCT) after induction therapy as consolidation. High risk (HR) cytogenetics were defined as t(4;14), t(14;16), and/or del 17p. RESULTS: A total of 152 patients were in the HR group. Of patients without HR cytogenetics, 55 were in the t(11;14) group, and 248 were in the standard risk (SR) group without t(11;14). Gain in 1q21 was observed in 38.9% patients with t(11;14). There were no differences in median progression free survival (PFS) and overall survival (OS), respectively, between patients in the t(11;14) group and those in the SR group. Patients in the t(11;14) group had the longer median PFS and OS, respectively, compared with those in the HR group. Regardless of coexisting with 1q21 gain or not, patients in the t(11;14) group still had similar median PFS and OS compared to those in the SR group. Finally, multivariate analysis indicated that including 1q21 gain and bone marrow plasma cell with CD20 expression, no variables were found to predict the outcome of the t(11;14) group in our cohort. CONCLUSIONS: These results confirm that outcomes of t(11;14) MM are similar to standard risk patients when they receive novel agent induction therapy consolidated by ASCT. Gain of 1q21 coexists with t(11;14) frequently. In addition, both bone marrow plasma cell with CD20 expression and 1q21 gain have no impact on median PFS or OS for patients with t(11;14).