Multiregional transcriptomic profiling provides improved prognostic insight in localized non-small cell lung cancer.

Lung Cancer remains the leading cause of cancer deaths in the USA and worldwide. Non-small cell lung cancer (NSCLC) harbors high transcriptomic intratumor heterogeneity (RNA-ITH) that limits the reproducibility of expression-based prognostic models. In this study, we used multiregional RNA-seq data (880 tumor samples from 350 individuals) from both public (TRACERx) and internal (MDAMPLC) cohorts to investigate the effect of RNA-ITH on prognosis in localized NSCLC at the gene, signature, and tumor microenvironment levels. At the gene level, the maximal expression of hazardous genes (expression negatively associated with survival) but the minimal expression of protective genes (expression positively associated with survival) across different regions within a tumor were more prognostic than the average expression. Following that, we examined whether multiregional expression profiling can improve the performance of prognostic signatures. We investigated 11 gene signatures collected from previous publications and one signature developed in this study. For all of them, the prognostic prediction accuracy can be significantly improved by converting the regional expression of signature genes into sample-specific expression with a simple function-taking the maximal expression of hazardous genes and the minimal expression of protective genes. In the tumor microenvironment, we found a similar rule also seems applicable to immune ITH. We calculated the infiltration levels of major immune cell types in each region of a sample based on expression deconvolution. Prognostic analysis indicated that the region with the lowest infiltration level of protective or highest infiltration level of hazardous immune cells determined the prognosis of NSCLC patients. Our study highlighted the impact of RNA-ITH on the prognostication of NSCLC, which should be taken into consideration to optimize the design and application of expression-based prognostic biomarkers and models. Multiregional assays have the great potential to significantly improve their applications to prognostic stratification.

Reversible Co(II)-Co(III) Transformation in a Family of Metal-Dipyrazolate Frameworks.

Transformation between oxidation states is widespread in transition metal coordination chemistry and biochemistry, typically occurring in solution. However, air-induced oxidation in porous crystalline solids with retention of crystallinity is rare due to the dearth of materials with high structural stability that are inherently redox active. Herein, we report a new family of such materials, four isostructural cobalt-pyrazolate frameworks of face-centered cubic, fcu, topology, fcu-L-Co, that are sustained by Co8 molecular building blocks (MBBs) and dipyrazolate ligands, L. fcu-L-Co were observed to spontaneously transform from Co(II)8 to Co(III)8 MBBs in air with retention of crystallinity, marking the first such instance in metal-organic frameworks (MOFs). This transformation can also be achieved through water vapor sorption cycling, heating, or chemical oxidation. The reverse reactions were conducted by exposure of fcu-L-Co(III) to aqueous hydrazine. fcu-L-Co(II) exhibited high gravimetric water vapor uptakes of 0.55-0.68 g g-1 at 30% relative humidity (RH), while in fcu-L-Co(III) the inflection point shifted to lower RH and framework stability improved. Insight into the transformation between fcu-L-Co(II) and fcu-L-Co(III) was gained from single crystal X-ray diffraction and in situ spectroscopy. Overall, the crystal engineering approach we adopted has afforded a new family of MOFs that exhibit cobalt redox chemistry in a confined space coupled with high porosity.

Characterization of driver mutations identifies gene signatures predictive of prognosis and treatment sensitivity in multiple myeloma.

In multiple myeloma (MM), while frequent mutations in driver genes are crucial for disease progression, they traditionally offer limited insights into patient prognosis. This study aims to enhance prognostic understanding in MM by analyzing pathway dysregulations in key cancer driver genes, thereby identifying actionable gene signatures. We conducted a detailed quantification of mutations and pathway dysregulations in 10 frequently mutated cancer driver genes in MM to characterize their comprehensive mutational impacts on the whole transcriptome. This was followed by a systematic survival analysis to identify significant gene signatures with enhanced prognostic value. Our systematic analysis highlighted 2 significant signatures, TP53 and LRP1B, which notably outperformed mere mutation status in prognostic predictions. These gene signatures remained prognostically valuable even when accounting for clinical factors, including cytogenetic abnormalities, the International Staging System (ISS), and its revised version (R-ISS). The LRP1B signature effectively distinguished high-risk patients within low/intermediate-risk categories and correlated with significant changes in the tumor immune microenvironment. Additionally, the LRP1B signature showed a strong association with proteasome inhibitor pathways, notably predicting patient responses to bortezomib and the progression from monoclonal gammopathy of unknown significance to MM. Through a rigorous analysis, this study underscores the potential of specific gene signatures in revolutionizing the prognostic landscape of MM, providing novel clinical insights that could influence future translational oncology research.

The prognostic effect of infiltrating immune cells is shaped by proximal M2 macrophages in lung adenocarcinoma.

The spatial arrangement of immune cells within the tumor microenvironment (TME) and their interactions play critical roles in the initiation and development of cancer. Several advanced technologies such as imaging mass cytometry (IMC) providing the immunological landscape of the TME with single-cell resolution. In this study, we develop a new method to quantify the spatial proximity between different cell types based on single-cell spatial data. Using this method on IMC data from 416 lung adenocarcinoma patients, we show that the proximity between different cell types is more correlated with patient prognosis compared to the traditional features such immune cell density and fractions. Consistent with previous reports, our results validate that proximity of T helper (Th) and B cells to cancer cells is associated with survival benefits. More importantly, we discover that the proximity of M2 macrophages to multiple immune cells is associated with poor prognosis. When Th/B cells are stratified into M2-distal and M2-proximal, the abundance of the former but not the latter category of Th/B cells is correlated with enhanced patient survival. Additionally, the abundance of M2-distal and M2-proximal cytotoxic T cells (Tc) is respectively associated with good and poor prognosis. Our results indicate that the prognostic effect of Th, Tc, and B cells in the tumor microenvironment is modulated by the nearby M2 macrophages. The proposed new method proposed can be readily applied to all single-cell spatial data for revealing functional impact of immune cell interactions.

Elimination of Trace Tetracycline with Alkyl Modified MIL-101 in Water.

The overuse of antibiotics poses a serious threat to human health and ecosystems. Therefore, the development of high-performance antibiotic removal materials has attracted increasing attention. However, the adsorption and removal of trace amounts of antibiotics in aqueous systems still face significant challenges. Taking tetracycline (TC) as a representative antibiotic and based on its structural characteristics, a series of TC adsorbents are prepared by grafting alkyl groups to the framework of MIL-101(Cr). The adsorptive capacity of the modified materials for tetracycline markedly surpasses that of MIL-101(Cr), with MIL-101-dod achieving the best adsorption performance. MIL-101-dod demonstrated an outstanding ability to adsorb tetracycline at low concentrations, where a 5.0 mg sample of MIL-101-dod can reduce the concentration of a 90 mL 5 ppm tetracycline solution to below 1 ppb, significantly superior to other sorbents. XPS and IR tests indicate that MIL-101-dod has multiple weak interactions with tetracycline molecules, including C─H…O and C─H…π. This work provides theoretical and experimental support for the development of adsorbents for low-concentration antibiotics.

Prognostic stratification in DLBCL patients with aberrant MYC gene.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by a subset of patients who exhibit treatment resistance and poor prognoses. Genomic assays have been widely employed to identify high-risk individuals characterized by rearrangements in the MYC, BCL2 and BCL6 genes. These patients typically undergo more aggressive therapeutic treatments; however, there remains a significant variation in their treatment outcomes. This study introduces an MYC signature score (MYCSS) derived from gene expression profiles, specifically designed to evaluate MYC overactivation in DLBCL patients. MYCSS was validated across several independent cohorts to assess its ability to stratify patients based on MYC-related genetic and molecular aberrations, enhancing the accuracy of prognostic evaluations compared to conventional MYC biomarkers. Our results indicate that MYCSS significantly refines prognostic accuracy beyond that of conventional MYC biomarkers focused on genetic aberrations. More importantly, we found that nearly 50% of patients identified as high risk by traditional MYC metrics actually share similar survival prospects with those having no MYC aberrations. These patients may benefit from standard GCB-based therapies rather than more aggressive treatments. MYCSS provides a robust signature that identifies high-risk patients, aiding in the precision treatment of DLBCL, and minimizing the potential for overtreatment.

Simultaneous capture of trace benzene and SO2 in a robust Ni(II)-pyrazolate framework.

Benzene and SO2, coexisting as hazardous air pollutants in some cases, such as in coke oven emissions, have led to detrimental health and environmental effects. Physisorbents offer promise in capturing benzene and SO2, while their performance compromises at low concentration. Particularly, the simultaneous capture of trace benzene and SO2 under humid conditions is attractive but challenging. Here, we address this issue by constructing a robust pyrazolate metal-organic framework (MOF) sorbent featuring rich accessible Ni(II) sites with low affinity to water and good stability. This material achieves a high benzene uptake of 5.08 mmol g-1 at 10 Pa, surpassing previous benchmarks. More importantly, it exhibits an adsorption capacity of ~0.51 mmol g-1 for 10 ppm benzene and ~1.21 mmol g-1 for 250 ppm SO2 under 30% relative humidity. This work demonstrates that a pioneering MOF enables simultaneous capture of trace benzene and SO2, highlighting the potential of physisorbents for industrial effluent remediation, even in the presence of moisture.

Unlocking the potential: strategic synthesis of a previously predicted pyrazolate-based stable MOF with unique clusters and high catalytic activity.

The metal-organic framework (MOF) constructed from [Co4Pz8] clusters (Pz = pyrazolate) and 1,3,5-tris(pyrazolate-4-yl) benzene (BTP3-) ligands was structurally predicted many years ago, and expected to be a promising candidate for various applications owing to its unique clusters and highly open 3D framework structure. However, this MOF has not been experimentally prepared yet, despite extensive efforts were made. In this work, we present the successful construction of this MOF, hereinafter referred to as BUT-124(Co), by adopting a two-step synthesis strategy, involving the initial construction of a template framework (BUT-124(Cd)) followed by a post-synthetic metal metathesis process. The effects of various cobalt sources and solvents were systematically investigated, and an innovative stepwise metathesis strategy was employed to optimize the exchange rates and the porosity of the material. BUT-124(Co) demonstrates high catalytic activity in the oxygen evolution reaction (OER), achieving a competitive performance with an overpotential of 393 mV at a current density of 10 mA cm-2, and also affords remarkable long-term stability during potentiostatic electrolysis in 1 M KOH solution, surpassing the durability of many benchmark catalysts. This work not only introduces a novel MOF material with promising properties but also exemplifies a strategic synthesis approach for pyrazolate-based MOFs, paving the way for advancements in diverse application fields.

Recovery of High-Purity SF6 from Humid SF6/N2 Mixture within a Co(II)-Pyrazolate Framework.

Sulfur hexafluoride (SF6) is extensively employed in the power industry. However, its emissions significantly contribute to the greenhouse effect. The direct recovery of high purity SF6 from industrial waste gases would benefit its sustainable use, yet this represents a considerable challenge. Herein, we report the enrichment of SF6 from SF6/N2 mixtures via adsorptive separation in a stable Co(II)-pyrazolate MOF BUT-53 (BUT: Beijing University of Technology), which features dynamic molecular traps. BUT-53 exhibits an excellent SF6 adsorption uptake of 2.82 mmol/g at 0.1 bar and 298 K, as well as an unprecedented SF6/N2 (10:90) selectivity of 2485. Besides, the remarkable SF6/N2 selectivity of BUT-53 enables recovery of high purity (>99.9%) SF6 from a low concentration (10%) mixture through a breakthrough experiment. The excellent SF6/N2 separation efficiency was also well maintained under humid conditions (RH = 90%) over multiple cycles. Molecular simulation, single-crystal diffraction, and adsorption kinetics studies elucidate the associated adsorption mechanism and water tolerance.

Achieving Record C2H2 Packing Density for Highly Efficient C2H2/C2H4 Separation with a Metal-Organic Framework Prepared by a Scalable Synthesis in Water.

Adsorptive C2H2/C2H4 separation using metal-organic frameworks (MOFs) has emerged as a promising technology for the removal of C2H2 (acetylene) impurity (1%) from C2H4 (ethylene). The practical application of these materials involves the optimization of separation performance as well as development of scalable and green production protocols.Herein, we report the efficient C2H2/C2H4 separation in a MOF, Cu(OH)INA (INA: isonicotinate) which achieves a record C2H2 packing density of 351 mg cm-3 at 0.01 bar through high affinity towards C2H2. DFT (density functional theory) calculations reveal the synergistic binding mechanism through pore confinement and the oxygen sites in pore wall.The weakly basic nature of binding sites leads to a relatively low heat of adsorption (Qst) of approximately 36 kJ/mol, which is beneficial for material regeneration and thermal management. Furthermore, a scalable and environmentally friendly synthesis protocol with a high space-time yield of 544 kg m-3 day-1 has been developed without using any modulating agents. This material also demonstrates enduring separation performance for multiple cycles, maintaining its efficacy after exposure to water or air for three months.

Deficiency of m 6 A RNA methylation promotes ZBP1-mediated cell death.

m 6 A RNA methylation suppresses the immunostimulatory potential of endogenous RNA. Deficiency of m 6 A provokes inflammatory responses and cell death, but the underlying mechanisms remain elusive. Here we showed that the noncoding RNA 7SK gains immunostimulatory potential upon m 6 A depletion and subsequently activates the RIG-I/MAVS axis to spark interferon (IFN) signaling cascades. Concomitant excess of IFN and m 6 A deficiency synergistically facilitate the formation of RNA G-quadruplexes (rG4) to promote ZBP1-mediated necroptotic cell death. Collectively, our findings delineate a hitherto uncharacterized mechanism that links m 6 A dysregulation with ZBP1 activity in triggering inflammatory cell death.

Identifying high-risk multiple myeloma patients: A novel approach using a clonal gene signature.

Multiple myeloma (MM) is a heterogeneous disease with a small subset of high-risk patients having poor prognoses. Identifying these patients is crucial for treatment management and strategic decisions. In this study, we developed a novel computational framework to define prognostic gene signatures by selecting genes with expression driven by clonal copy number alterations. We applied this framework to MM and developed a clonal gene signature (CGS) consisting of 22 genes and evaluated in five independent datasets. The CGS provided significant prognostic values after adjusting for well-established factors including cytogenetic abnormalities, International Staging System (ISS), and Revised ISS (R-ISS). Importantly, CGS demonstrated higher performance in identifying high-risk patients compared to the GEP70 and SKY92 signatures recommended for prognostic stratification of MM. CGS can further stratify patients into subgroups with significantly differential prognoses when applied to the high- and low-risk groups identified by GEP70 and SKY92. Additionally, CGS scores are significantly associated with patient response to dexamethasone, a commonly used treatment for MM. In summary, we proposed a computational framework that requires only gene expression data to identify CGSs for prognosis prediction. CGS provides a useful biomarker for improving prognostic stratification in MM, especially for identifying the highest-risk patients.

Enhanced Catalytic Activity of Crystalline Phosphorus Nanosheets Fabricated via Solvothermal Phase Transformation.

The newly reported crystalline phosphorus nanosheets (cryst-P NSs) exhibit promising features for industrial applications, including outstanding air-water stability and facile large-scale production. However, their complex crystallization impedes a priori tailoring. Herein, the temporal evolution of cryst-P NSs was investigated with the optimized synthesis parameters. The occurrence of self-assembly and solid-state rearrangement unveiled the existence of an intermediate phase as the bulk crystalline precursor and the predominance of nonclassical crystallization pathway(s). With the upgraded synthesis protocol simultaneously strengthening the merits of cryst-P NSs, their catalytic performances were evaluated in various electro- and/or photocatalytic reactions spanning hydrogen and oxygen evolution, full water splitting, CO2 reduction, and organic pollutant decomposition. Superior catalytic activities and orders of magnitude longer lifetimes were consistently discerned compared with the widely employed black phosphorus nanosheets with similar size and thickness. The exciting discoveries in both fundamental crystallization and catalytic applications drastically thrust the comprehension of elemental phosphorus, shedding light on the encouraging capabilities of solvothermal synthesis strategies in the design and systematic tailoring of phosphorus materials.

Pt-O-Ce interaction enhanced by Al substitution to promote the acetone degradation through accelerating the breaking of CC bond in acetic acid intermediate.

The reaction rate of volatile organic compounds (VOCs) oxidation is controlled by the rate-limiting step in the total reaction process. This study proposes a novel strategy, by which the rate-limiting step of acetone oxidation is accelerated by enhanced chemical bond interaction with more electrons transfer through Al-substituted CeO2 loaded Pt (Pt/Al-CeO2). Results indicate that the rate-limiting step in the process of acetone oxidation is the decomposition of acetic acid. Al substitution enhances the Pt-O-Ce interaction that transfers more electrons from Pt/Al-CeO2 to acetic acid, promoting the breaking of its CC bond with a lower free energy barrier. Attributing to these, the reaction rate of Pt/Al-CeO2 is 13 times as high as that of Pt/CeO2 and its TOFPt value is 11 times as high as that of Pt/CeO2 at 150 °C. Moreover, the CO2 selectivity of Pt/Al-CeO2 also increases by 22 %. This work establishes the relationship between Pt-O-Ce interaction and acetone oxidation that provides novel perspectives on the development of efficient materials for VOCs oxidation.

Three-Dimensional Bimetallic Ammonium K-Eu Nitrate with a Rare (6,6)-Connected Ion Topology Exhibiting Structural Phase Transition and Photoluminescence Properties.

A K-Eu bimetallic ammonium metal-nitrate three-dimensional (3D) framework incorporating R-N-methyl-3-hydroxyquinuclidine, (RM3HQ)2KEu(NO3)6 (RM3HQ = R-N-methyl-3-hydroxyquinuclidine, 1), was characterized and reported. Distinguishing from the former hybrid rare-earth double perovskites, 1 adopts a mixed corner- and face-sharing K+/Eu3+-centered polyhedral connectivity to form a 3D inorganic framework, showing a rare (6, 6)-connected ion topology with a 66 framework. Notably, 1 exhibits clear phase transition, and the switchable thermodynamic behavior is confirmed by variable-temperature dielectric measurements and second-harmonic generation response. Moreover, 1 also shows photoluminescence properties. The activator Eu3+ plays a crucial role in this process, leading to a significant narrow emission at 592 nm with a photoluminescence quantum yield (PLQY) of 20.76%. The fluorescence lifetime (FLT) of 1 is 4.32 ms. This finding enriches the bimetallic hybrid system for potential electronic and/or luminescence applications.

Prevalence of metabolic syndrome among patients with hepatocellular carcinoma of different etiologies: a retrospective study.

AIMS: This study compared the prevalences of metabolic syndrome and of cardiac or kidney comorbidities among patients with hepatocellular carcinoma (HCC) associated with metabolic dysfunction-related fatty liver disease (MAFLD), chronic infection with hepatitis B or C virus (HBV or HCV), or the combination of MAFLD and chronic HBV infection. METHODS: Medical records were retrospectively analyzed for patients with HCC who underwent hepatectomy between March 2013 and March 2023. Patients with HCC of different etiologies were compared in terms of their clinicodemographic characteristics and laboratory data before surgery. RESULTS: Of the 2422 patients, 1,822 (75.2%) were chronically infected with HBV without MAFLD and HCV, 415 (17.2%) had concurrent MAFLD and chronic HBV infection but no HCV infection, 121 (5.0%) had MAFLD without hepatitis virus infection, and 64 (2.6%) were chronically infected with HCV in the presence or absence of MAFLD and HBV infection. Compared to patients chronically infected with HBV without MAFLD and HCV, those with MAFLD but no hepatitis virus infection showed significantly lower prevalence of cirrhosis, ascites, portal hypertension, alpha-fetoprotein concentration ≥ 400 ng/mL, tumor size > 5 cm, multinodular tumors and microvascular invasion. Conversely, they showed significantly higher prevalence of metabolic syndrome, hypertension, type 2 diabetes, abdominal obesity, history of cardiovascular disease, T-wave alterations, hypertriglyceridemia and hyperuricemia, as well as higher risk of arteriosclerotic cardiovascular disease. Compared to patients with MAFLD but no hepatitis virus infection, those with concurrent MAFLD and chronic infection with HBV showed significantly higher prevalence of cirrhosis, ascites and portal hypertension, but significantly lower prevalence of hypertension and history of cardiovascular disease. Compared to patients with other etiologies, those chronically infected with HCV in the presence or absence of MAFLD and HBV infection, showed significantly higher prevalence of cirrhosis, portal hypertension, ascites, and esophagogastric varices. CONCLUSION: Patients with HCC associated with MAFLD tend to have a background of less severe liver disease than those with HCC of other etiologies, but they may be more likely to suffer metabolic syndrome or comorbidities affecting the heart or kidneys.

Gas-Liquid Interface Route to Hybrid Copper Bromine Perovskite Single-Crystal Membrane with Dielectric Transitions and Ferromagnetic Exchanges.

Single-crystal membranes (SCMs) show great promise in the fields of sensors, light-emitting diodes, and photodetection. However, the growth of a large-area single-crystal membranes is challenging. We report a new organic-inorganic SCMs [HCMA]2CuBr4 (HCMA = cyclohexanemethylamine) crystallized at the gas-liquid interface. It also has low-temperature ferromagnetic order, high-temperature dielectric anomalies, and narrow band gap indirect semiconductor properties. Specifically, the reversible phase transition of the compound occurs at 350/341 K on cooling/heating and exhibits dielectric anomalies and stable switching performance near the phase transition temperature. The ferromagnetic exchange interaction in the inorganic octahedra and the organic layer enables ferromagnetic ordering at low-temperature 10 K. Finally, the single crystal exhibits an indirect semiconducting property with a narrow band gap of 0.99 eV. Such rich multichannel physical properties make it a potential application in photodetection, information storage and sensors.

Rare-Earth Metal-Organic Framework with Nonplanar Porphyrin Groups for High-Efficiency Photocatalysis.

Nonplanar porphyrins play crucial roles in many biological processes and chemical reactions as catalysts. However, the preparation of artificial nonplanar porphyrins suffers from complicated organic syntheses. Herein, we present a new rare-earth porphyrinic metal-organic framework (RE-PMOF), BUT-233, which is a three-dimensional (3D) framework structure with the flu topology consisting of 4-connected BBCPPP-Ph ligands H4BBCPPP-Ph = 5',5⁗-(10,20-diphenylporphyrin-5,15-diyl)bis([1,1':3',1″-terphenyl]-4,4'' dicarboxylic acid) and 8-connected Eu6 clusters. Noteworthily, the porphyrin cores of the BBCPPP-Ph ligands in BUT-233 are nonplanar with a ruffle-like conformation. In contrast, the porphyrin core in the free ligand H4BBCPPP-Ph is in a nearly ideally planar conformation, as confirmed by its single-crystal structure. BUT-233 is microporous with 6-8 Špores and a Brunauer-Emmett-Teller (BET) surface area of 649 m2/g, as well as high stability in common solvents. The MOF was used as a photocatalyst for the oxidation degradation of a chemical warfare agent model molecule CEES (CEES = 2-chloroethyl ethyl sulfide) under the light-emitting diode (LED) irradiation and an O2 atmosphere at room temperature. CEES was almost completely converted into its nontoxic light-oxidized product CEESO (CEESO = 2-chloroethyl ethyl sulfoxide) in only 5 min with t1/2 = 2 min (t1/2: half-life). Moreover, the toxic deep-oxidized product 2-chloroethyl ethyl sulfone (CEESO2) was not detected. The catalytic activity of BUT-233 was high in comparison with those of some previously reported MOF catalysts. The results of photo/electrochemical property studies suggested that the high catalytic activity of BUT-233 was benefited from the presence of nonplanar porphyrin rings on its pore surface.

Enhancing prognostic power in multiple myeloma using a plasma cell signature derived from single-cell RNA sequencing.

Multiple myeloma (MM) is a heterogenous plasma cell malignancy, for which the established prognostic models exhibit limitations in capturing the full spectrum of outcome variability. Leveraging single-cell RNA-sequencing data, we developed a novel plasma cell gene signature. We evaluated and validated the associations of the resulting plasma cell malignancy (PBM) score with disease state, progression and clinical outcomes using data from five independent myeloma studies consisting of 2115 samples (1978 MM, 65 monoclonal gammopathy of undetermined significance, 35 smoldering MM, and 37 healthy controls). Overall, a higher PBM score was significantly associated with a more advanced stage within the spectrum of plasma cell dyscrasias (all p < 0.05) and a shorter overall survival in MM (hazard ratio, HR = 1.72; p < 0.001). Notably, the prognostic effect of the PBM score was independent of the International Staging System (ISS) and Revised ISS (R-ISS). The downstream analysis further linked higher PBM scores with the presence of cytogenetic abnormalities, TP53 mutations, and compositional changes in the myeloma tumor immune microenvironment. Our integrated analyses suggest the PBM score may provide an opportunity for refining risk stratification and guide decisions on therapeutic approaches to MM.