Fast charging of energy-dense lithium-ion batteries.

Lithium-ion batteries with nickel-rich layered oxide cathodes and graphite anodes have reached specific energies of 250-300 Wh kg-1 (refs. 1,2), and it is now possible to build a 90 kWh electric vehicle (EV) pack with a 300-mile cruise range. Unfortunately, using such massive batteries to alleviate range anxiety is ineffective for mainstream EV adoption owing to the limited raw resource supply and prohibitively high cost. Ten-minute fast charging enables downsizing of EV batteries for both affordability and sustainability, without causing range anxiety. However, fast charging of energy-dense batteries (more than 250 Wh kg-1 or higher than 4 mAh cm-2) remains a great challenge3,4. Here we combine a material-agnostic approach based on asymmetric temperature modulation with a thermally stable dual-salt electrolyte to achieve charging of a 265 Wh kg-1 battery to 75% (or 70%) state of charge in 12 (or 11) minutes for more than 900 (or 2,000) cycles. This is equivalent to a half million mile range in which every charge is a fast charge. Further, we build a digital twin of such a battery pack to assess its cooling and safety and demonstrate that thermally modulated 4C charging only requires air convection. This offers a compact and intrinsically safe route to cell-to-pack development. The rapid thermal modulation method to yield highly active electrochemical interfaces only during fast charging has important potential to realize both stability and fast charging of next-generation materials, including anodes like silicon and lithium metal.

Molecular Catalysis of Energy Relevance in Metal-Organic Frameworks: From Higher Coordination Sphere to System Effects.

The modularity and synthetic flexibility of metal-organic frameworks (MOFs) have provoked analogies with enzymes, and even the term MOFzymes has been coined. In this review, we focus on molecular catalysis of energy relevance in MOFs, more specifically water oxidation, oxygen and carbon dioxide reduction, as well as hydrogen evolution in context of the MOF-enzyme analogy. Similar to enzymes, catalyst encapsulation in MOFs leads to structural stabilization under turnover conditions, while catalyst motifs that are synthetically out of reach in a homogeneous solution phase may be attainable as secondary building units in MOFs. Exploring the unique synthetic possibilities in MOFs, specific groups in the second and third coordination sphere around the catalytic active site have been incorporated to facilitate catalysis. A key difference between enzymes and MOFs is the fact that active site concentrations in the latter are often considerably higher, leading to charge and mass transport limitations in MOFs that are more severe than those in enzymes. High catalyst concentrations also put a limit on the distance between catalysts, and thus the available space for higher coordination sphere engineering. As transport is important for MOF-borne catalysis, a system perspective is chosen to highlight concepts that address the issue. A detailed section on transport and light-driven reactivity sets the stage for a concise review of the currently available literature on utilizing principles from Nature and system design for the preparation of catalytic MOF-based materials.

Circulating tumor and invasive cell expression profiling predicts effective therapy in pancreatic cancer.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) remains a refractory disease; however, modern cytotoxic chemotherapeutics can induce tumor regression and extend life. A blood-based, pharmacogenomic, chemosensitivity assay using gene expression profiling of circulating tumor and invasive cells (CTICs) to predict treatment response was previously developed. The combination regimen of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel (G/nab-P) are established frontline approaches for treating advanced PDAC; however, there are no validated biomarkers for treatment selection. A similar unmet need exists for choosing second-line therapy. METHODS: The chemosensitivity assay was evaluated in metastatic PDAC patients presenting for frontline treatment. A prospective study enrolled patients (n = 70) before receiving either FOLFIRINOX or G/nab-P at a 1:1 ratio. Six milliliters of peripheral blood was collected at baseline and at time of disease progression. CTICs were isolated, gene-expression profiling was performed, and the assay was used to predict effective and ineffective chemotherapeutic agents. Treating physicians were blinded to the assay prediction results. RESULTS: Patients receiving an effective regimen as predicted by the chemosensitivity assay experienced significantly longer median progression-free survival (mPFS; 7.8 months vs. 4.2 months; hazard ratio [HR], 0.35; p = .0002) and median overall survival (mOS; 21.0 months vs. 9.7 months; HR, 0.40; p = .005), compared with an ineffective regimen. Assay prediction for effective second-line therapy was explored. The entire study cohort experienced favorable outcomes compared with historical controls, 7.1-month mPFS and 12.3-month mOS. CONCLUSIONS: Chemosensitivity assay profiling is a promising tool for guiding therapy in advanced PDAC. Further prospective validation is under way (clinicaltrials.gov NCT03033927).

Elemental Depth Profiling of Intact Metal-Organic Framework Single Crystals by Scanning Nuclear Microprobe.

The growing field of MOF-catalyst composites often relies on postsynthetic modifications for the installation of active sites. In the resulting MOFs, the spatial distribution of the inserted catalysts has far-reaching ramifications for the performance of the system and thus needs to be precisely determined. Herein, we report the application of a scanning nuclear microprobe for accurate and nondestructive depth profiling of individual UiO-66 and UiO-67 (UiO = Universitetet i Oslo) single crystals. Initial optimization work using native UiO-66 crystals yielded a microbeam method which avoided beam damage, while subsequent analysis of Zr/Hf mixed-metal UiO-66 crystals demonstrated the potential of the method to obtain high-resolution depth profiles. The microbeam method was further used to analyze the depth distribution of postsynthetically introduced organic moieties, revealing either core-shell or uniform incorporation can be obtained depending on the size of the introduced molecule, as well as the number of carboxylate binding groups. Finally, the spatial distribution of platinum centers that were postsynthetically installed in the bpy binding pockets of UiO-67-bpy (bpy = 5,5'-dicarboxyy-2,2'-bipyridine) was analyzed by microbeam and contextualized. We expect that the method presented herein will be applicable for characterizing a wide variety of MOFs subjected to postsynthetic modifications and provide information crucial for their optimization as functional materials.

Transport Phenomena: Challenges and Opportunities for Molecular Catalysis in Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) are appealing heterogeneous support matrices that can stabilize molecular catalysts for the electrochemical conversion of small molecules. However, moving from a homogeneous environment to a porous film necessitates the transport of both charge and substrate to the catalytic sites in an efficient manner. This presents a significant challenge in the application of such materials at scale, since these two transport phenomena (charge and mass transport) would need to operate faster than the intrinsic catalytic rate in order for the system to function efficiently. Thus, understanding the fundamental kinetics of MOF-based molecular catalysis of electrochemical reactions is of crucial importance. In this Perspective, we quantitatively dissect the interplay between the two transport phenomena and the catalytic reaction rate by applying models from closely related fields to MOF-based catalysis. The identification of the limiting process provides opportunities for optimization that are uniquely suited to MOFs due to their tunable molecular structure. This will help guide the rational design of efficient and high-performing catalytic MOF films with incorporated molecular catalyst for electrochemical energy conversion.

Analysis of Electrocatalytic Metal-Organic Frameworks.

The electrochemical analysis of molecular catalysts for the conversion of bulk feedstocks into energy-rich clean fuels has seen dramatic advances in the last decade. More recently, increased attention has focused on the characterization of metal-organic frameworks (MOFs) containing well-defined redox and catalytically active sites, with the overall goal to develop structurally stable materials that are industrially relevant for large-scale solar fuel syntheses. Successful electrochemical analysis of such materials draws heavily on well-established homogeneous techniques, yet the nature of solid materials presents additional challenges. In this tutorial-style review, we cover the basics of electrochemical analysis of electroactive MOFs, including considerations of bulk stability, methods of attaching MOFs to electrodes, interpreting fundamental electrochemical data, and finally electrocatalytic kinetic characterization. We conclude with a perspective of some of the prospects and challenges in the field of electrocatalytic MOFs.

Macrophage-derived LTB4 promotes abscess formation and clearance of Staphylococcus aureus skin infection in mice.

The early events that shape the innate immune response to restrain pathogens during skin infections remain elusive. Methicillin-resistant Staphylococcus aureus (MRSA) infection engages phagocyte chemotaxis, abscess formation, and microbial clearance. Upon infection, neutrophils and monocytes find a gradient of chemoattractants that influence both phagocyte direction and microbial clearance. The bioactive lipid leukotriene B4 (LTB4) is quickly (seconds to minutes) produced by 5-lipoxygenase (5-LO) and signals through the G protein-coupled receptors LTB4R1 (BLT1) or BLT2 in phagocytes and structural cells. Although it is known that LTB4 enhances antimicrobial effector functions in vitro, whether prompt LTB4 production is required for bacterial clearance and development of an inflammatory milieu necessary for abscess formation to restrain pathogen dissemination is unknown. We found that LTB4 is produced in areas near the abscess and BLT1 deficient mice are unable to form an abscess, elicit neutrophil chemotaxis, generation of neutrophil and monocyte chemokines, as well as reactive oxygen species-dependent bacterial clearance. We also found that an ointment containing LTB4 synergizes with antibiotics to eliminate MRSA potently. Here, we uncovered a heretofore unknown role of macrophage-derived LTB4 in orchestrating the chemoattractant gradient required for abscess formation, while amplifying antimicrobial effector functions.

Computational fluid dynamic analysis of bioprinted self-supporting perfused tissue models.

Natural tissues are incorporated with vasculature, which is further integrated with a cardiovascular system responsible for driving perfusion of nutrient-rich oxygenated blood through the vasculature to support cell metabolism within most cell-dense tissues. Since scaffold-free biofabricated tissues being developed into clinical implants, research models, and pharmaceutical testing platforms should similarly exhibit perfused tissue-like structures, we generated a generalizable biofabrication method resulting in self-supporting perfused (SSuPer) tissue constructs incorporated with perfusible microchannels and integrated with the modular FABRICA perfusion bioreactor. As proof of concept, we perfused an MLO-A5 osteoblast-based SSuPer tissue in the FABRICA. Although our resulting SSuPer tissue replicated vascularization and perfusion observed in situ, supported its own weight, and stained positively for mineral using Von Kossa staining, our in vitro results indicated that computational fluid dynamics (CFD) should be used to drive future construct design and flow application before further tissue biofabrication and perfusion. We built a CFD model of the SSuPer tissue integrated in the FABRICA and analyzed flow characteristics (net force, pressure distribution, shear stress, and oxygen distribution) through five SSuPer tissue microchannel patterns in two flow directions and at increasing flow rates. Important flow parameters include flow direction, fully developed flow, and tissue microchannel diameters matched and aligned with bioreactor flow channels. We observed that the SSuPer tissue platform is capable of providing direct perfusion to tissue constructs and proper culture conditions (oxygenation, with controllable shear and flow rates), indicating that our approach can be used to biofabricate tissue representing primary tissues and that we can model the system in silico.

On decomposition, degradation, and voltammetric deviation: the electrochemist's field guide to identifying precatalyst transformation.

What is the identity of the true electrocatalytic species? This fundamental question has plagued the molecular electrocatalysis community during its decades-long search for selective and efficient transition-metal based electrocatalysts for fuel forming reactions. Identifying when the added species is a precatalyst that transforms into the active catalyst in situ is an extraordinarily complex endeavor. Thankfully, the last decade has witnessed a resurgence of interest in understanding and controlling these transformations, leading to an expansion of the experimental toolkit available to probe catalyst identity. In this Tutorial Review, researchers will learn how the nature of the active catalyst can be uncovered using state-of-the-art electrochemical and spectroscopic methods. Analysis of catalytic voltammograms can quickly furnish qualitative evidence of precatalyst transformation and a library of these tell-tale signs is discussed, along with the chemical phenomena underpinning each feature. Complementary electrochemical and spectroscopic methods for identifying in situ generation of heterogeneous catalysts are also presented, outlining the conditions required for correct application with special emphasis on potential pitfalls when studying weakly-adsorbed material. Case studies are presented to showcase how these different probes can be integrated to develop a comprehensive picture of precatalyst transformation.

Decoding Proton-Coupled Electron Transfer with Potential-p Ka Diagrams: Applications to Catalysis.

The applied potential at which [NiII(P2PhN2Bn)2]2+ (P2PhN2Bn = 1,5-dibenzyl-3,7-diphenyl-1,5-diaza-3,7-diphosphacyclooctane) catalyzes hydrogen production is reported to vary as a function of proton source p Ka in acetonitrile. By contrast, most molecular catalysts exhibit catalytic onsets at p Ka-independent potentials. Using experimentally determined thermochemical parameters associated with reduction and protonation, a coupled Pourbaix diagram is constructed for [NiII(P2PhN2Bn)2]2+. One layer describes proton-coupled electron transfer reactivity involving ligand-based protonation, and the second describes metal-based protonation. An overlay of this diagram with experimentally determined E cat/2 values spanning 15 p Ka units, along with complementary stopped-flow rapid mixing experiments to detect reaction intermediates, supports a mechanism in which the proton-coupled electron transfer processes underpinning the p Ka-dependent catalytic processes involve protonation of the ligand, not the metal center. For proton sources with p Ka values in the range 6-10.6, the initial species formed is the doubly reduced, doubly protonated species [Ni0(P2PhN2BnH)2]2+, despite a higher overpotential for this proton-coupled electron transfer reaction in comparison to forming the metal-protonated isomer. In this complex, each ligand is protonated in the exo position with the two amine moieties on each ligand binding a single proton and positioning it away from the metal center. This species undergoes very slow isomerization to form an endo-protonated hydride species [HNiII(P2PhN2Bn)(P2PhN2BnH)]2+ that can release hydrogen to close the catalytic cycle. Importantly, this slow isomerization does not perturb the initially established proton-coupled electron transfer equilibrium, placing catalysis under thermodynamic control. New details revealed about the reaction mechanism from the coupled Pourbaix diagram and the complementary stopped-flow studies lead to predictions as to how this p Ka-dependent activity might be engendered in other molecular catalysts for multi-electron, multi-proton transformations.

Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition.

Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor-dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments.

Decoding Proton-Coupled Electron Transfer with Potential-pKa Diagrams.

Aqueous potential-pH diagrams, commonly called Pourbaix diagrams, were originally developed to study metal corrosion in the 1930s and 1940s. Pourbaix diagrams have since been widely adopted for use across chemistry disciplines, particularly for the study of aqueous proton-coupled electron transfer reactions. Despite this enormous versatility, a clear extension of analogous diagrams to nonaqueous solvents is lacking. The problem hinges on the difficulty of defining the nonaqueous solution pH. Here, we address this issue by reporting the development of diagrams based on nonaqueous pKa scales. We experimentally construct diagrams for two transition-metal complexes that undergo proton-coupled electron transfer reactivity by recording their reduction potentials in the presence of acids with varying pKa values. These experimental diagrams validate the potential-pKa theory and provide valuable thermochemical information for proton-coupled electron transfer reactions, including for fleetingly stable species.

Identification of an Electrode-Adsorbed Intermediate in the Catalytic Hydrogen Evolution Mechanism of a Cobalt Dithiolene Complex.

Analysis of a cobalt bis(dithiolate) complex reported to mediate hydrogen evolution under electrocatalytic conditions in acetonitrile revealed that the cobalt complex transforms into an electrode-adsorbed film upon addition of acid prior to application of a potential. Subsequent application of a reducing potential to the film results in desorption of the film and regeneration of the molecular cobalt complex in solution, suggesting that the adsorbed species is an intermediate in catalytic H2 evolution. The electroanalytical techniques used to examine the pathway by which H2 is generated, as well as the methods used to probe the electrode-adsorbed species, are discussed. Tentative mechanisms for catalytic H2 evolution via an electrode-adsorbed intermediate are proposed.

Novel application of complementary imaging techniques to examine in vivo glucose metabolism in the kidney.

The metabolic status of the kidney is a determinant of injury susceptibility and a measure of progression for many disease processes; however, noninvasive modalities to assess kidney metabolism are lacking. In this study, we employed positron emission tomography (PET) and intravital multiphoton microscopy (MPM) to assess cortical and proximal tubule glucose tracer uptake, respectively, following experimental perturbations of kidney metabolism. Applying dynamic image acquisition PET with 2-18fluoro-2-deoxyglucose (18F-FDG) and tracer kinetic modeling, we found that an intracellular compartment in the cortex of the kidney could be distinguished from the blood and urine compartments in animals. Given emerging literature that the tumor suppressor protein p53 is an important regulator of cellular metabolism, we demonstrated that PET imaging was able to discern a threefold increase in cortical 18F-FDG uptake following the pharmacological inhibition of p53 in animals. Intravital MPM with the fluorescent glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) provided increased resolution and corroborated these findings at the level of the proximal tubule. Extending our observation of p53 inhibition on proximal tubule glucose tracer uptake, we demonstrated by intravital MPM that pharmacological inhibition of p53 diminishes mitochondrial potential difference. We provide additional evidence that inhibition of p53 alters key metabolic enzymes regulating glycolysis and increases intermediates of glycolysis. In summary, we provide evidence that PET is a valuable tool for examining kidney metabolism in preclinical and clinical studies, intravital MPM is a powerful adjunct to PET in preclinical studies of metabolism, and p53 inhibition alters basal kidney metabolism.

Evaluation of 11C-acetate and 18F-FDG PET/CT in mouse multidrug resistance gene-2 deficient mouse model of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. Previous work from our lab has established the murine multidrug resistance-2 mouse (MDR2) model of HCC as a reasonable preclinical model that parallels the changes seen in human inflammatory associated HCC. The purpose of this study is to evaluate modalities of PET/CT in MDR2(-/-) mice in order to facilitate therapeutic translational studies from bench to bedside. METHODS: 18F-FDG and 11C-acetate PET/CT was performed on 12 m MDR2(-/-) mice (n = 3/tracer) with HCC and 12 m MDR2(-/+) control mice (n = 3/tracer) without HCC. To compare PET/CT to biological markers of HCC and cellular function, serum alpha-fetoprotein (AFP), lysophosphatidic acid (LPA), cAMP and hepatic tumor necrosis factor α (TNFα) were quantified in 3-12 m MDR2(-/-) (n = 10) mice using commercially available ELISA analysis. To translate results in mice to patients 11C-acetate PET/CT was also performed in 8 patents suspected of HCC recurrence following treatment and currently on the liver transplant wait list. RESULTS: Hepatic18F-FDG metabolism was not significantly increased in MDR2(-/-) mice. In contrast, hepatic 11C-acetate metabolism was significantly elevated in MDR2(-/-) mice when compared to MDR2(-/+) controls. Serum AFP and LPA levels increased in MDR2(-/-) mice contemporaneous with the emergence of HCC. This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα. In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false 11C-acetate negative. CONCLUSIONS: Hepatic 11C-acetate PET/CT tracks well with HCC in MDR2(-/-) mice and patients with underlying liver disease. Consequently 11C-acetate PET/CT is well suited to study (1) HCC emergence/progression in patients and (2) reduce animal numbers required to study new chemotherapeutics in murine models of HCC.

Evaluation of homogeneous electrocatalysts by cyclic voltammetry.

The pursuit of solar fuels has motivated extensive research on molecular electrocatalysts capable of evolving hydrogen from protic solutions, reducing CO2, and oxidizing water. Determining accurate figures of merit for these catalysts requires the careful and appropriate application of electroanalytical techniques. This Viewpoint first briefly presents the fundamentals of cyclic voltammetry and highlights practical experimental considerations before focusing on the application of cyclic voltammetry for the characterization of electrocatalysts. Key metrics for comparing catalysts, including the overpotential (η), potential for catalysis (E(cat)), observed rate constant (k(obs)), and potential-dependent turnover frequency, are discussed. The cyclic voltammetric responses for a general electrocatalytic one-electron reduction of a substrate are presented along with methods to extract figures of merit from these data. The extension of this analysis to more complex electrocatalytic schemes, such as those responsible for H2 evolution and CO2 reduction, is then discussed.

Electrochemical reduction of Brønsted acids by glassy carbon in acetonitrile-implications for electrocatalytic hydrogen evolution.

Molecular catalysts for electrochemically driven hydrogen evolution are often studied in acetonitrile with glassy carbon working electrodes and Brønsted acids. Surprisingly, little information is available regarding the potentials at which acids are directly reduced on glassy carbon. This work examines acid electroreduction in acetonitrile on glassy carbon electrodes by cyclic voltammetry. Reduction potentials, spanning a range exceeding 2 V, were found for 20 acids. The addition of 100 mM water was not found to shift the reduction potential of any acid studied, although current enhancement was observed for some acids. The data reported provides a guide for selecting acids to use in electrocatalysis experiments such that direct electrode reduction is avoided.

Thymic selection pathway regulates the effector function of CD4 T cells.

Recently, a new developmental pathway for CD4 T cells that is mediated by major histocompatibility complex class II-positive thymocytes was identified (Choi, E.Y., K.C. Jung, H.J. Park, D.H. Chung, J.S. Song, S.D. Yang, E. Simpson, and S.H. Park. 2005. Immunity. 23:387-396; Li, W., M.G. Kim, T.S. Gourley, B.P. McCarthy, D.B. Sant'angelo, and C.H. Chang. 2005. Immunity. 23:375-386). We demonstrate that thymocyte-selected CD4 (T-CD4) T cells can rapidly produce interferon gamma and interleukin (IL) 4 upon in vivo and in vitro T cell receptor stimulation. These T-CD4 T cells appear to be effector cells producing both T helper type 1 (Th1) and Th2 cytokines, and they maintain a potential to produce Th2 cytokines under Th1-skewing conditions in a signal transducer and activator of transcription 6-independent manner. The IL-4 mRNA level is high in CD4 single-positive thymocytes if they are selected on thymocytes, which is at least partly caused by enhanced histone acetylation of the IL-4 locus. However, mice that can generate T-CD4 T cells showed attenuated immune responses in an allergen-induced airway inflammation model, suggesting a protective role for T-CD4 T cells during an airway challenge. Our results imply that this thymic selection pathway plays an important role in determining the effector function of the resulting CD4 cells and in regulating immune response.

Dextromethorphan-bupropion (Auvelity) for the Treatment of Major Depressive Disorder.

Depression is a significant cause of morbidity and mortality globally. Although various pharmacologic options exist for depression, treatments are limited by delayed or incomplete therapeutic response, low rates of remission, and adverse effects necessitating effective, fast-acting, and better tolerated alternatives. The purpose of this review is to describe the safety and efficacy of dextromethorphan-bupropion (Auvelity), a Food and Drug Administration approved treatment for major depressive disorder in adults. Dextromethorphan modulates glutamate signaling through uncompetitive antagonism of N-methyl-D-aspartate receptors and sigma-1 agonism, while bupropion increases the bioavailability of dextromethorphan by CYP2D6 inhibition. In a phase 3 trial with dextromethorphan-bupropion 45-105 mg for patients with major depressive disorder saw significant reductions in their Montgomery-Åsberg Depression Rating Scale total scores compared to placebo. A phase 2 trial comparing dextromethorphan-bupropion 45-105 mg to bupropion monotherapy led to significant reduction in Montgomery-Åsberg Depression Rating Scale score. Changes in Montgomery-Åsberg Depression Rating Scale with dextromethorphan-bupropion were seen within two weeks in both clinical trials. Remission and response rates were significantly higher with dextromethorphan-bupropion in both studies. The medication was well-tolerated in both trials, with the most common adverse events being rated as mild-to-moderate. Two long-term, open-label studies with dextromethorphan-bupropion saw large reductions in Montgomery-Åsberg Depression Rating Scale scores that were maintained through 12 and 15 months of treatment. In both long-term studies, remission rates approached 70%, while response rates were greater than 80%. These data suggest that dextromethorphan-bupropion is an effective, fast-acting, and well tolerated option for depression treatment and produced remission in a large percentage of patients.

NF-κB2 mutation targets survival, proliferation and differentiation pathways in the pathogenesis of plasma cell tumors.

BACKGROUND: Abnormal NF-κB2 activation has been implicated in the pathogenesis of multiple myeloma, a cancer of plasma cells. However, a causal role for aberrant NF-κB2 signaling in the development of plasma cell tumors has not been established. Also unclear is the molecular mechanism that drives the tumorigenic process. We investigated these questions by using a transgenic mouse model with lymphocyte-targeted expression of p80HT, a lymphoma-associated NF-κB2 mutant, and human multiple myeloma cell lines. METHODS: We conducted a detailed histopathological characterization of lymphomas developed in p80HT transgenic mice and microarray gene expression profiling of p80HT B cells with the goal of identifying genes that drive plasma cell tumor development. We further verified the significance of our findings in human multiple myeloma cell lines. RESULTS: Approximately 40% of p80HT mice showed elevated levels of monoclonal immunoglobulin (M-protein) in the serum and developed plasma cell tumors. Some of these mice displayed key features of human multiple myeloma with accumulation of plasma cells in the bone marrow, osteolytic bone lesions and/or diffuse osteoporosis. Gene expression profiling of B cells from M-protein-positive p80HT mice revealed aberrant expression of genes known to be important in the pathogenesis of multiple myeloma, including cyclin D1, cyclin D2, Blimp1, survivin, IL-10 and IL-15. In vitro assays demonstrated a critical role of Stat3, a key downstream component of IL-10 signaling, in the survival of human multiple myeloma cells. CONCLUSIONS: These findings provide a mouse model for human multiple myeloma with aberrant NF-κB2 activation and suggest a molecular mechanism for NF-κB2 signaling in the pathogenesis of plasma cell tumors by coordinated regulation of plasma cell generation, proliferation and survival.