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Multiple myeloma (MM) is an incurable disease, and patients usually receive multiple lines of therapy. Due to the abundance of novel treatments for MM, we conducted a network meta-analysis to identify combinations that could fare better than others in relapsed/refractory MM, in the setting of novel drugs. We searched PubMed and Cochrane databases for phase III trials in previously treated MM that had lenalidomide or bortezomib in the control arm. The primary endpoint was progression-free survival (PFS), extracted as hazard-ratio. We used the P score to rank treatments. Thirteen studies were included. All but two studies compared one novel agent against two, with or without dexamethasone. Based on the P score, daratumumab and pegylated liposomal doxorubicin had a higher probability of achieving better PFS, followed by isatuximab, carfilzomib, pomalidomide, and panobinostat. Although most overall survival data were not mature enough, the addition of a second or third novel agent to either immunomodulatory (IMID) or proteasome inhibitor (PI) backbone seemed to improve survival (HR = 0.84, 95CI 0.77–0.92). Severe adverse events were more frequent with isatuximab, panobinostat, and pomalidomide. In summary, in the absence of trials directly comparing two novel agents-based therapies, we provide a tool that indirectly compares these newer therapies and that can help physicians to prioritize some regimens over others. [ABSTRACT FROM AUTHOR]

Background Information The adenylate cyclase (CyaA) toxin is a major virulent factor of Bordetella pertussis, the causative agent of whooping cough. CyaA toxin is able to invade eukaryotic cells where it produces high levels of cyclic adenosine monophosphate (cAMP) affecting cellular physiology. Whether CyaA toxin can modulate cell matrix adhesion and mechanics of infected cells remains largely unknown. Results In this study, we use a recently proposed multiple bond force spectroscopy (MFS) with an atomic force microscope to assess the early phase of cell adhesion (maximal detachment and local rupture forces) and cell rigidity (Young's modulus) in alveolar epithelial cells (A549) for toxin exposure <1 h. At 30 min of exposure, CyaA toxin has a minimal effect on cell viability (>95%) at CyaA concentration of 0.5 nM, but a significant effect (≈81%) at 10 nM. MFS performed on A549 for three different concentrations (0.5, 5 and 10 nM) demonstrates that CyaA toxin significantly affects both cell adhesion (detachment forces are decreased) and cell mechanics (Young's modulus is increased). CyaA toxin (at 0.5 nM) assessed at three indentation/retraction speeds (2, 5 and 10 μm/s) significantly affects global detachment forces, local rupture events and Young modulus compared with control conditions, while an enzymatically inactive variant CyaAE5 has no effect. These results reveal the loading rate dependence of the multiple bonds newly formed between the cell and integrin-specific coated probe as well as the individual bond kinetics which are only slightly affected by the patho-physiological dose of CyaA toxin. Finally, theory of multiple bond force rupture enables us to deduce the bond number N which is reduced by a factor of 2 upon CyaA exposure ( N ≈ 6 versus N ≈ 12 in control conditions). Conclusions MFS measurements demonstrate that adhesion and mechanical properties of A549 are deeply affected by exposure to the CyaA toxin but not to an enzymatically inactive variant. This indicates that the alteration of cell mechanics triggered by CyaA is a consequence of the increase in intracellular cAMP in these target cells. Significance These results suggest that mechanical and adhesion properties of the cells appear as pertinent markers of cytotoxicity of CyaA toxin. [ABSTRACT FROM AUTHOR]

Background Information Integrin-mediated adhesion is a key process by which cells physically connect with their environment, and express sensitivity and adaptation through mechanotransduction. A critical step of cell adhesion is the formation of the first bonds which individually generate weak contacts (∼tens pN) but can sustain thousand times higher forces (∼tens nN) when associated. Results We propose an experimental validation by multiple bond force spectroscopy (MFS) of a stochastic model predicting adhesion reinforcement permitted by non-cooperative, multiple bonds on which force is homogeneously distributed (called parallel bond configuration). To do so, spherical probes (diameter: 6.6 μm), specifically coated by RGD-peptide to bind integrins, are used to statically indent and homogenously stretch the multiple bonds created for short contact times (2 s) between the bead and the surface of epithelial cells (A549). Using different separation speeds (v = 2, 5, 10 μm/s) and measuring cellular Young's modulus as well as the local stiffness preceding local rupture events, we obtain cell-by-cell the effective loading rates both at the global cell level and at the local level of individual constitutive bonds. Local rupture forces are in the range: [ABSTRACT FROM AUTHOR]