Meningeal contrast enhancement in multiple sclerosis: Assessment of field strength, acquisition delay, and clinical relevance.

BACKGROUND/PURPOSE: Leptomeningeal enhancement (LME) on post-contrast FLAIR is described as a potential biomarker of meningeal inflammation in multiple sclerosis (MS). Here we report an assessment of the impact of MRI field strength and acquisition timing on meningeal contrast enhancement (MCE). METHODS: This was a cross-sectional, observational study of 95 participants with MS and 17 healthy controls (HC) subjects. Each participant underwent an MRI of the brain on both a 7 Tesla (7T) and 3 Tesla (3T) MRI scanner. 7T protocols included a FLAIR image before, soon after (Gd+ Early 7T FLAIR), and 23 minutes after gadolinium (Gd+ Delayed 7T FLAIR). 3T protocol included FLAIR before and 21 minutes after gadolinium (Gd+ Delayed 3T FLAIR). RESULTS: LME was seen in 23.3% of participants with MS on Gd+ Delayed 3T FLAIR, 47.4% on Gd+ Early 7T FLAIR (p = 0.002) and 57.9% on Gd+ Delayed 7T FLAIR (p < 0.001 and p = 0.008, respectively). The count and volume of LME, leptomeningeal and paravascular enhancement (LMPE), and paravascular and dural enhancement (PDE) were all highest for Gd+ Delayed 7T FLAIR and lowest for Gd+ Delayed 3T FLAIR. Non-significant trends were seen for higher proportion, counts, and volumes for LME and PDE in MS compared to HCs. The rate of LMPE was different between MS and HCs on Gd+ Delayed 7T FLAIR (98.9% vs 82.4%, p = 0.003). MS participants with LME on Gd+ Delayed 7T FLAIR were older (47.6 (10.6) years) than those without (42.0 (9.7), p = 0.008). CONCLUSION: 7T MRI and a delay after contrast injection increased sensitivity for all forms of MCE. However, the lack of difference between groups for LME and its association with age calls into question its relevance as a biomarker of meningeal inflammation in MS.

Effect of TiC Nanoparticles on a Zn-Al-Cu System for Biodegradable Cardiovascular Stent Applications.

Despite being a weaker metal, zinc has become an increasingly popular candidate for biodegradable implant applications due to its suitable corrosion rate and biocompatibility. Previous studies have experimented with various alloy elements to improve the overall mechanical performance of pure Zn without compromising the corrosion performance and biocompatibility; however, the thermal stability of biodegradable Zn alloys has not been widely studied. In this study, TiC nanoparticles were introduced for the first time to a Zn-Al-Cu system. After hot rolling, TiC nanoparticles were uniformly distributed in the Zn matrix and effectively enabled phase control during solidification. The Zn-Cu phase, which was elongated and sharp in the reference alloy, became globular in the nanocomposite. The strength of the alloy, after introducing TiC nanoparticles, increased by 31% from 259.7 to 340.3 MPa, while its ductility remained high at 49.2% elongation to failure. Fatigue performance also improved greatly by adding TiC nanoparticles, increasing the fatigue limit by 47.6% from 44.7 to 66 MPa. Furthermore, TiC nanoparticles displayed excellent phase control capability during body-temperature aging. Without TiC restriction, Zn-Cu phases evolved into dendritic morphologies, and the Al-rich eutectic grew thicker at grain boundaries. However, both Zn-Cu and Al-rich eutectic phases remained relatively unchanged in shape and size in the nanocomposite. A combination of exceptional tensile properties, improved fatigue performance, better long-term stability with a suitable corrosion rate, and excellent biocompatibility makes this new Zn-Al-Cu-TiC material a promising candidate for biodegradable stents and other biodegradable applications.

The involvement of decomposition and composition processes in restructuring during problem solving.

Decomposition of chunks has been widely accepted as a critical proxy of restructuring, but the role of composition in forming new representations has been largely neglected. This study aims to investigate the roles of both decomposition and composition processes in chunk restructuring, as well as their relationships with "aha" experiences during problem-solving. Participants were asked to move a part of a character to another character to create two new characters. Across three experiments, the characters to be decomposed or composed were varied in terms of tight or loose chunks. The results showed that decomposition or composition of tight chunks led to lower success rates, longer response times, and significantly stronger "Aha!" emotional experiences (mainly in terms of surprise and suddenness). This study provides evidence for the contribution of both decomposition and composition processes to restructuring in creative insight.

Meningeal contrast enhancement in multiple sclerosis: assessment of field strength, acquisition delay, and clinical relevance.

Background/Purpose: Leptomeningeal enhancement (LME) on post-contrast FLAIR is described as a potential biomarker of meningeal inflammation in multiple sclerosis (MS). Here we report a comprehensive assessment of the impact of MRI field strength and acquisition timing on meningeal contrast enhancement (MCE). Methods: This was a cross-sectional, observational study of 95 participants with MS and 17 healthy controls (HC) subjects. Each participant underwent an MRI of the brain on both a 7 Tesla (7T) and 3 Tesla (3T) MRI scanner. 7T protocols included a FLAIR image before, soon after (Gd+ Early 7T FLAIR), and 23 minutes after gadolinium (Gd+ Delayed 7T FLAIR). 3T protocol included FLAIR before and 21 minutes after gadolinium (Gd+ Delayed 3T FLAIR). Results: LME was seen in 23.3% of participants with MS on Gd+ Delayed 3T FLAIR, 47.4% on Gd+ Early 7T FLAIR (p = 0.002) and 57.9% on Gd+ Delayed 7T FLAIR (p < 0.001 and p = 0.008, respectively). The count and volume of LME, leptomeningeal and paravascular enhancement (LMPE), and paravascular and dural enhancement (PDE) were all highest for Gd+ Delayed 7T FLAIR and lowest for Gd+ Delayed 3T FLAIR. Non-significant trends were seen for higher proportion, counts, and volumes for LME and PDE in MS compared to HCs. The rate of LMPE was different between MS and HCs on Gd+ Delayed 7T FLAIR (98.9% vs 82.4%, p = 0.003). MS participants with LME on Gd+ Delayed 7T FLAIR were older (47.6 (10.6) years) than those without (42.0 (9.7), p = 0.008). Conclusion: 7T MRI and a delay after contrast injection increased sensitivity for all forms of MCE. However, the lack of difference between groups for LME and its association with age calls into question its relevance as a biomarker of meningeal inflammation in MS.

Denitrification driven by additional ferrous (Fe2+) and manganous (Mn2+) and removal mechanism of tetracycline and cadmium (Cd2+) by biogenic Fe-Mn oxides.

Zoogloea sp. MFQ7 achieved excellent denitrification of 91.71% at ferrous to manganous ratio (Fe/Mn) of 3:7, pH of 6.5, nitrate concentration of 25 mg L-1 and carbon to nitrogen ratio of 1.5. As the Fe/Mn ratio increasd, the efficiency of nitrate removal gradually decreased, indicating that strain MFQ7 had a higher affinity for Mn2+ than Fe2+. In situ generated biogenic Fe-Mn oxides (BFMO) contained many iron-manganese oxides (MnO2, Mn3O4, FeO(OH), Fe2O3, and Fe3O4) as well as reactive functional groups, which play an significant part in tetracycline (TC) and cadmium (Cd2+) adsorption. The adsorption of TC and Cd2+ by BFMO can better fit the pseudo-second-order and Langmuir models. In addition, multiple characterization results of before and after adsorption indicated that the removal mechanism of BFMO on TC and Cd2+ was probably surface complexation adsorption and redox reactions.

Simultaneous removal of nitrate, oxytetracycline and copper by ferrous-manganese co-driven immobilized bioreactor.

The treatment of polluted water contaminated by nitrate, antibiotics, and heavy metals is a difficult problem in the current water treatment process. In this study, MnFe2O4 modified illite was mixed with sodium alginate (SA) to prepare a biological carrier illite@MnFe2O4@SA (IMFSA), which was used to immobilize strain Zoogloea sp. MFQ7 and construct a bioreactor. The bioreactor can use sodium acetate as a carbon source as well as ferrous and manganese ions as additional electron donors to achieve efficient nitrate removal. The denitrification capability of bioreactor was considerably enhanced by the addition of illite@MnFe2O4 (IMF) in comparison to SA biological carrier. The bioreactor was able to achieve a nitrate removal efficiency of 97.2% when hydraulic retention time is 5.0 h, C/N ratio is 2.0, and the concentration of Fe2+ and Mn2+ were 5.0 mg L-1. Furthermore, the bioreactor can achieve efficient removal of oxytetracycline (91.8%) and copper (85.6%) through the adsorption by IMF and biological iron-manganese precipitates. High-throughput sequencing results indicated that Zoogloea was successfully immobilized into the biocarrier. According to the KEGG database, it is suggested that the addition of modified IMF enhances denitrification and stimulates the expression of genes associated with the iron-manganese redox cycle.

The Dynamic Accumulation Rules of Chemical Components during the Medicine Formation Period of Angelica sinensis and Chemometric Classifying Analysis for Different Bolting Times Using ATR-FTIR.

The dried roots of the perennial herb Angelica sinensis (Oliv.) Diels (AS) are commonly used as medicinal and edible resources. In commercial planting, early bolting and flowering (EB) of ca. 60% in the medicine formation period reduces root yield and quality, becoming a significant bottleneck in agricultural production. In the cultivation process, summer bolting (SB) occurs from June to July, and autumn bolting (AB) occurs in September. The AB root is often mistaken for the AS root due to its similar morphological characteristics. Few studies have involved whether the root of AB could be used as herbal medicine. This study explored and compared the accumulation dynamics of primary and secondary metabolites in AS and EB roots during the vegetative growth stage (from May to September) by light microscopy, ultraviolet spectrometry, and HPLC methods. Under a microscope, the amount of free starch granules and oil chamber in the AS root increased. On the contrary, they decreased further from EB-Jul to EB-Sep. By comparison, the wall of the xylem vessel was slightly thickened and stacked, and the cell walls of parenchyma and root cortex tissue were thickened in the EB root. Early underground bolting reduces soluble sugar, soluble protein, free amino acids, total C element, total N element, ferulic acid, and ligustilide accumulation, accompanied by the lignification of the root during the vegetative growth stage. Furthermore, a total of 55 root samples from different bolting types of AS root (29 samples), SB root (14 samples), and AB root (12 samples) were collected from Gansu Province during the harvesting period (October). The later the bolting occurred, the less difference there was between unbolted and bolted roots in terms of morphological appearance and efficacy components. Fourier transform infrared spectroscopy with the attenuated total reflection mode (ATR-FTIR) provides a "holistic" spectroscopic fingerprinting of all compositions in the tested sample. The ATR-FTIR spectrum of the AB root was similar to that of the AS root. However, the number and location of absorption peaks in the spectra of SB were different, and only one strong absorption peak at 1021 cm-1 was regarded as the characteristic peak of C-O stretching vibration in lignin. The ATR-FTIR spectra can be effectively differentiated based on their various characteristics using orthogonal partial least squares discrimination analysis (OPLS-DA). Results were assessed using multiple statistical techniques, including Spearman's correlation, principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and OPLS-DA. Among these methods, the ATR-FTIR data demonstrated the most effective outcomes in differentiating between viable and non-viable roots for their application in herbal medicine. Essential substances are ferulic acid and flavonoid, which are much more abundant in the AB root. It provides a material basis for the pharmacological action of the AB roots and a theoretical basis for improving their availability.

Nickel induces blood-testis barrier damage through ROS-mediated p38 MAPK pathways in mice.

Nickel (Ni) is an essential common environmental contaminant, it is hazardous to male reproduction, but the precise mechanisms are still unknown. Blood-testis barrier (BTB), an important testicular structure consisting of connections between sertoli cells, is the target of reproductive toxicity caused by many environmental toxins. In this study, ultrastructure observation and BTB integrity assay results indicated that NiCl2 induced BTB damage. Meanwhile, BTB-related proteins including the tight junction (TJ), adhesion junction (AJ) and the gap junction (GJ) protein expression in mouse testes as well as in sertoli cells (TM4) were significantly decreased after NiCl2 treatment. Next, the antioxidant N-acetylcysteine (NAC) was co-treated with NiCl2 to study the function of oxidative stress in NiCl2-mediated BTB deterioration. The results showed that NAC attenuated testicular histopathological damage, and the expression of BTB-related proteins were markedly reversed by NAC co-treatment in vitro and vivo. Otherwise, NiCl2 activated the p38 MAPK signaling pathway. And, NAC co-treatment could significantly inhibit p38 activation induced by NiCl2 in TM4 cells. Furthermore, in order to confirm the role of the p38 MAPK signaling pathway in NiCl2-induced BTB impairment, a p38 inhibitor (SB203580) was co-treated with NiCl2 in TM4 cells, and p38 MAPK signaling inhibition significantly restored BTB damage induced by NiCl2 in TM4 cells. These results suggest that NiCl2 treatment destroys the BTB, in which the oxidative stress-mediated p38 MAPK signaling pathway plays a vital role.

Computed torque control and force analysis for mechanical leg with variable rotation axis powered by servo pneumatic muscle.

It is difficult for a humanoid leg driven by two groups of antagonistic pneumatic muscles (PMs) to achieve a flexible humanoid gait, and its inherent strong coupling nonlinear characteristics make it hard to achieve good tracking performance in a large range of motion. Therefore, a four-bar linkage bionic knee joint structure with a variable axis and a double closed-loop servo position control strategy based on computed torque control are designed to improve anthropomorphic characteristics and the dynamic performance of the bionic mechanical leg powered by servo pneumatic muscle (SPM). Firstly, the relationship between the joint torque, the initial jump angle and the bounce height of the mechanical leg is established, and then we design a double-joint PM bionic mechanical leg containing a four-bar linkage mechanism of the knee joint. Secondly, a cascade position control strategy is developed, which consists of the outer position loop and the inner contraction force loop, and the mapping relationship is designed between joint torque and antagonistic PM contraction force. Finally, we further project bounce action timing of mechanical leg to realize the periodic jumping movement of the mechanical leg, and simulation and physical experiments of the real-style machine platform have been provided to demonstrate the effectiveness of the designed SPM controller.

Autophagy-mediated ferroptosis involved in nickel-induced nephrotoxicity in the mice.

Nickel, as a widely polluted metal, has been shown nephrotoxicity. Ferroptosis is a new type of cell death driven by iron-dependent lipid peroxidation. Our study found that nickel chloride (NiCl2) induced ferroptosis in mouse kidney and TCMK-1 cells. The iron content was significantly increased in the kidney and TCMK-1 cells after NiCl2 treatment. Lipid peroxidation and MDA content were significantly increased, and GSH content and T-SOD activity were significantly decreased after exposure to NiCl2. Moreover, NiCl2 increased COX-2 protein levels, decreased SLC7A11 and GPX4 protein levels, and elevated Ptgs2 mRNA levels. Next, the mechanism of Ni-induced ferroptosis was investigated. The results showed that NiCl2 induced autophagy in TCMK-1 cells, which promoted ferroptosis induced by NiCl2. Furthermore, the data of autophagy activation or inhibition experiment showed that autophagy facilitated ferroptosis through the degradation of the iron regulation protein NCOA4 and FTH1. Otherwise, iron chelator DFOM treatment inhibited ferroptosis induced by NiCl2. Finally, ferroptosis inhibitor Fer-1 treatment significantly alleviated cytotoxicity induced by NiCl2. To sum up, our above results showed that ferroptosis is involved in NiCl2-induced nephrotoxicity, and NiCl2 induces autophagy-dependent ferritin degradation, releases iron ions, leads to iron overload, and induces ferroptosis. This study supplies a new theoretical foundation for the study of nickel and renal toxicity.

Ataxia telangiectasia mutated kinase inhibition promotes irradiation-induced PD-L1 expression in tumour-associated macrophages through IFN-I/JAK signalling pathway.

Tumour-associated macrophages (TAMs) are one of the primary sources of PD-L1 expression in the tumour microenvironment (TME). Ionizing radiation (IR) promotes PD-L1 expression in tumour cells. However, the effect of IR on macrophage PD-L1 expression and the underlying mechanisms remain unclear. ATM kinase, as the key kinase for initiating DNA damage repair (DDR) process, is associated with innate immune STING axis activation. Here, we explored the molecular mechanism implicated in macrophage PD-L1 expression regulated by IR as well as the role of ATM kinase in this process. IR-regulated PD-L1 expression in macrophages and associated signalling pathways were explored by in vitro studies using murine and human macrophage cell lines. A colorectal xenograft murine model was employed to demonstrate the impact of targeting ATM and PD-L1 expression in TAMs following IR on growth of tumour in vivo. IR up-regulated PD-L1 expression in macrophages, which was further augmented by ATM kinase inhibition. ATM inhibition increased IR-induced DNA damage, which activated STING/interferon regulatory factor 3 (IRF3) signalling pathway and up-regulated type I interferon (IFN-I) expression in macrophages. IFN-I bound to the IFN α receptor 1 on macrophages, activated the downstream JAK1 and STAT1/3 signalling and eventually led to PD-L1 up-expression. ATM inhibition augmented IR-induced PD-L1 expression in macrophages and CD8+ T cell infiltration, and promoted anti-tumour efficacy in vivo. These results suggested that ATM inhibition promoted IR-induced PD-L1 expression through the activation of innate immunity in TAMs, which provided a novel approach to enhance the anti-tumour efficacy of RT.

Prediction of radiosensitivity and radiocurability using a novel supervised artificial neural network.

BACKGROUND: Radiotherapy has been widely used to treat various cancers, but its efficacy depends on the individual involved. Traditional gene-based machine-learning models have been widely used to predict radiosensitivity. However, there is still a lack of emerging powerful models, artificial neural networks (ANN), in the practice of gene-based radiosensitivity prediction. In addition, ANN may overfit and learn biologically irrelevant features. METHODS: We developed a novel ANN with Selective Connection based on Gene Patterns (namely ANN-SCGP) to predict radiosensitivity and radiocurability. We creatively used gene patterns (gene similarity or gene interaction information) to control the "on-off" of the first layer of weights, enabling the low-dimensional features to learn the gene pattern information. ANN-SCGP was trained and tested in 82 cell lines and 1,101 patients from the 11 pan-cancer cohorts. RESULTS: For survival fraction at 2 Gy, the root mean squared errors (RMSE) of prediction in ANN-SCGP was the smallest among all algorithms (mean RMSE: 0.1587-0.1654). For radiocurability, ANN-SCGP achieved the first and second largest C-index in the 12/20 and 4/20 tests, respectively. The low dimensional output of ANN-SCGP reproduced the patterns of gene similarity. Moreover, the pan-cancer analysis indicated that immune signals and DNA damage responses were associated with radiocurability. CONCLUSIONS: As a model including gene pattern information, ANN-SCGP had superior prediction abilities than traditional models. Our work provided novel insights into radiosensitivity and radiocurability.

Experimental study on novel biodegradable Zn-Fe-Si alloys.

Bioabsorbable metals are increasingly attracting attention for their potential use as materials for degradable implant devices. Zinc (Zn) alloys have shown great promises due to their good biocompatibility and favorable degradation rate. However, it has been difficult to maintain an appropriate balance among strength, ductility, biocompatibility, and corrosion rate for Zn alloys historically. In this study, the microstructure, chemical composition, mechanical properties, biocompatibility, and corrosion rate of a new ternary zinc-iron-silicon (Zn-Fe-Si) alloy system was studied as a novel material for potential biodegradable implant applications. The results demonstrated that the in situ formed Fe-Si intermetallic phases enhanced the mechanical strength of the material while maintaining a favorable ductility. With Fe-Si reinforcements, the microhardness of the Zn alloys was enhanced by up to 43%. The tensile strength was increased by up to 76% while elongation to failure remained above 30%. Indirect cytotoxicity testing showed the Zn-Fe-Si system had good biocompatibility. Immersion testing revealed the corrosion rate of Zn-Fe-Si system was not statistically different from pure Zn. To understand the underlying phase formation mechanism, the reaction process in this ternary system during the processing was also studied via phase evolution and Gibbs free energy analysis. The results suggest the Zn-Fe-Si ternary system is a promising new material for bioabsorbable metallic medical devices.

Solidification/stabilization of landfill leachate concentrate contaminants using solid alkali-activated geopolymers with a high liquid solid ratio and fixing rate.

Landfill leachate concentrate (LLC) is a highly toxic wastewater that contains many refractory contaminants. One of the technical and economic treatment methods is solidification/stabilization (S/S), where the contaminants of LLC can be sealed in one step to achieve zero wastewater discharge. This study presents the S/S of LLC contaminants using solid alkali-activated geopolymers prepared from blast furnace slag (BFS) and powdery sodium silicate. The stability of the formed geopolymer was studied through unconfined compressive strength (UCS) and leaching tests. The strongest UCS was obtained when the modulus of the activator was 1.16 with a high liquid/solid ratio of 0.64. BFS-based geopolymers presented excellent LLC S/S efficiency. The S/S rates of TOC, CODCr, NH3-N, Cl-, and SO42- were 81%, 89%, 97%, 97%, and 78%, respectively. The S/S rates of heavy metals, i.e., Cd and Pb, were all more than 99%. The results of microstructure characterization showed that the S/S mechanism of LLC pollutants was the dual effect of physical closure and chemical stability. Cl- and SO42- were respectively stabilized in the crystal lattice by Friedel's salt and calcium sulfate, respectively, while organic matter and NH3-N were physically encapsulated in the dense structure of the geopolymer. Overall, BFS based geopolymers demonstrated high treatment capacity and excellent S/S efficiency, and have a potential application prospects in LLC treatment.

Triglyceride metabolism and angiopoietin-like proteins in lipoprotein lipase regulation.

Hypertriglyceridemia is a risk factor for a series of diseases, such as cardiovascular disease (CVD), diabetes and nonalcoholic fatty liver disease (NAFLD). Angiopoietin-like proteins (ANGPTLs) family, especially ANGPTL3, ANGPTL4 and ANGPTL8, which regulate lipoprotein lipase (LPL) activity, play pivotal roles in triglyceride (TG) metabolism and related diseases/complications. There are many transcriptional and post-transcriptional factors that participate in physiological and pathological regulation of ANGPTLs to affect triglyceride metabolism. This review is intended to focus on the similarity and difference in the expression, structural features, regulation profile of the three ANGPTLs and inhibitory models for LPL. Description of the regulatory factors of ANGPTLs and the properties in regulating the lipid metabolism involved in the underlying mechanisms in pathological effects on diseases will provide potential therapeutic approaches for the treatment of dyslipidemia related diseases.

Fabrication and Characterization of In Situ Zn-TiB2 Nanocomposite.

Zinc (Zn) matrix composite has been newly discovered categories of biodegradable materials. With a combination of chemical stability, thermal stability and biocompatibility, ceramic nanoparticles outperformed intermetallics of zinc alloys with inherent advantages of retaining a proper corrosion rate and an exceptional ductility. Compared with Zn alloys, Zn matrix nanocomposites showed an unprecedented strengthening without sacrifices of corrosion rate, which were introduced by intermetallics. In this work, in situ titanium diboride (TiB2) reinforced Zn nanocomposite was prepared via a few cost-effective and economical methods: flux-assisted synthesis (FAS), ultrasound-assisted nanoparticle homogenization and hot rolling. 3 vol.% of TiB2 nanoparticles were synthesized with an average size of 454nm, followed by molten salt assisted ultrasound homogenization and hot rolling. Hot-rolled (HR) Zn-TiB2 performed high strength and high ductility, mostly due to precipitation strengthening (Orowan strengthening). Yield stress (YS) and ultimate tensile stress (UTS) increased by 90% and 45%, respectively, while the elongation to failure retained 23%. The mechanical performance of Zn-TiB2 made it promise to serve as an innovative biodegradable material for load-bearing applications.

Ribosomal protein metallopanstimulin-1 impairs multiple myeloma CAG cells growth and inhibits fibroblast growth factor receptor 3.

INTRODUCTION: It was demonstrated that metallopanstimulin-1 (MPS-1, RPS27) inhibited the growth of tumors formed by head and neck squamous cell carcinoma cells and reduced paxillin gene expression. METHODS: The present study examined whether and how MPS-1 affects another type of cancer, multiple myeloma (CAG). Enhanced expression of MPS-1 dramatically inhibited CAG in vitro and in vivo. RESULTS: Overexpression of MPS-1 resulted in decreased fibroblast growth factor (FGF2) receptor 3 and impaired endogenous MAPK/ErK signaling. MAPK/ErK signaling was not stimulated by adding recombinant FGF2 to myeloma cells overexpressing MPS-1. CONCLUSIONS: These data suggest that MPS-1 suppresses CAG growth and that weakened FGF2 signaling may contribute to this effect.

IRF4 addiction in multiple myeloma.

The transcription factor IRF4 (interferon regulatory factor 4) is required during an immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells. Multiple myeloma, a malignancy of plasma cells, has a complex molecular aetiology with several subgroups defined by gene expression profiling and recurrent chromosomal translocations. Moreover, the malignant clone can sustain multiple oncogenic lesions, accumulating genetic damage as the disease progresses. Current therapies for myeloma can extend survival but are not curative. Hence, new therapeutic strategies are needed that target molecular pathways shared by all subtypes of myeloma. Here we show, using a loss-of-function, RNA-interference-based genetic screen, that IRF4 inhibition is toxic to myeloma cell lines, regardless of transforming oncogenic mechanism. Gene expression profiling and genome-wide chromatin immunoprecipitation analysis uncovered an extensive network of IRF4 target genes and identified MYC as a direct target of IRF4 in activated B cells and myeloma. Unexpectedly, IRF4 was itself a direct target of MYC transactivation, generating an autoregulatory circuit in myeloma cells. Although IRF4 is not genetically altered in most myelomas, they are nonetheless addicted to an aberrant IRF4 regulatory network that fuses the gene expression programmes of normal plasma cells and activated B cells.