Multitargeted therapies for multiple myeloma

Multiple myeloma (MM) comprises 1% of all malignancies and 10% of all hematological malignancies. MM is a malignancy of plasma cells in the bone marrow where complex and dynamic interactions with the bone marrow microenvironment lead to tumor progression, skeletal destruction and angiogenesis. Despite the discovery of several novel treatments against MM, including the proteasome inhibitor bortezomib, it is considered to be an incurable disease with an average 4–5 years overall survival.     

Experimental evolution of the grain of metabolic specialization in yeast

Adaptation to any given environment may be accompanied by a cost in terms of reduced growth in the ancestral or some alternative environment. Ecologists explain the cost of adaptation through the concept of a trade‐off, by which gaining a new trait involves losing another trait. Two mechanisms have been invoked to explain the evolution of trade‐offs in ecological systems, mutational degradation, and functional interference. Mutational degradation occurs when a gene coding a specific trait is not under selection in the resident environment; therefore, it may be degraded through the accumulation of mutations that are neutral in the resident environment but deleterious in an alternative environment. Functional interference evolves if the gene or a set of genes have antagonistic effects in two or more ecologically different traits. Both mechanisms pertain to a situation where the selection and the alternative environments are ecologically different. To test this hypothesis, we conducted an experiment in which 12 experimental populations of wild yeast were each grown in a minimal medium supplemented with a single substrate. We chose 12 different carbon substrates that were metabolized through similar and different pathways in order to represent a wide range of ecological conditions. We found no evidence for trade‐offs between substrates on the same pathway. The indirect response of substrates on other pathways, however, was consistently negative, with little correlation between the direct and indirect responses. We conclude that the grain of specialization in this case is the metabolic pathway and that specialization appears to evolve through mutational degradation.     

PDADMAC as a flocculant for lignosulfonate of NSSC pulping process

The spent liquor (SL) of neutral sulfite semi‐chemical (NSSC) pulping process contains about 8 wt% lignocelluloses that can be extracted and used in the production of value‐added materials. In this work, a flocculation process followed by centrifugation was considered for isolating lignosulfonate and hemicelluloses from SL. It was observed that, by adding 20 mg/g of polydiallyldimethylammuniom chloride (PDADMAC) with 100,000–200,000 g/mol molecular weight to SL, 45% of lignosulfonate and 39% of hemicelluloses were removed at 30°C. The lignocellulose removal was more efficient for the dual flocculation system of low and high molecular weights PDADMAC than for individual PDADMAC systems. Overall, 49% of lignosulfonate, 47% of hemicelluloses and 97% of turbidity were removed from SL from the dual system when 10 mg/g low molecular weight PDADMAC and 10 mg/g high molecular weight PDADMAC were added to the SL at 30°C, subsequently. The thermogravimetric analysis (TGA) of generated flocs showed that all samples had similar thermal behaviour and 13–16 wt% of flocs remained as ash after burning at 700°C in nitrogen. As the flocs are made of lignocellulosic materials and they are thermally stable, they could be used as fillers in paper board production. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:686–691, 2016     

Highly Efficient Solar‐Driven Carbon Dioxide Reduction on Molybdenum Disulfide Catalyst Using Choline Chloride‐Based Electrolyte

Conversion of CO₂ to energy‐rich chemicals using renewable energy is of much interest to close the anthropogenic carbon cycle. However, the current photoelectrochemical systems are still far from being practically feasible. Here the successful demonstration of a continuous, energy efficient, and scalable solar‐driven CO₂ reduction process based on earth‐abundant molybdenum disulfide (MoS₂) catalyst, which works in synergy with an inexpensive hybrid electrolyte of choline chloride (a common food additive for livestock) and potassium hydroxide (KOH) is reported. The CO₂ saturated hybrid electrolyte utilized in this study also acts as a buffer solution (pH ≈ 7.6) to adjust pH during the reactions. This study reveals that this system can efficiently convert CO₂ to CO with solar‐to‐fuel and catalytic conversion efficiencies of 23% and 83%, respectively. Using density functional theory calculations, a new reaction mechanism in which the water molecules near the MoS₂ cathode act as proton donors to facilitate the CO₂ reduction process by MoS₂ catalyst is proposed. This demonstration of a continuous, cost‐effective, and energy efficient solar driven CO₂ conversion process is a key step toward the industrialization of this technology.     

BRCA1 inhibits membrane estrogen and growth factor receptor signaling to cell proliferation in breast cancer

BRCA1 mutations and estrogen use are risk factors for the development of breast cancer. Recent work has identified estrogen receptors localized at the plasma membrane that signal to cell biology. We examined the impact of BRCA1 on membrane estrogen and growth factor receptor signaling to breast cancer cell proliferation. MCF-7 and ZR-75-1 cells showed a rapid and sustained activation of extracellular signal-related kinase (ERK) in response to estradiol (E2) that was substantially prevented by wild-type (wt) but not mutant BRCA1. The proliferation of MCF-7 cells induced by E2 was significantly inhibited by PD98059, a specific ERK inhibitor, or by dominant negative ERK2 expression and by expression of wt BRCA1 (but not mutant BRCA1). E2 induced the synthesis of cyclins D1 and B1, the activity of cyclin-dependent kinases Cdk4 and CDK1, and G(1)/S and G(2)/M cell cycle progression. The intact tumor suppressor inhibited all of these. wt BRCA1 also inhibited epidermal growth factor and insulin-like growth factor I-induced ERK and cell proliferation. The inhibition of ERK and cell proliferation by BRCA1 was prevented by phosphatase inhibitors and by interfering RNA knockdown of the ERK phosphatase, mitogen-activated kinase phosphatase 1. Our findings support a novel tumor suppressor function of BRCA1 that is relevant to breast cancer and identify a potential interactive risk factor for women with BRCA1 mutations.     

Plasma membrane estrogen receptors exist and functions as dimers

A small pool of estrogen receptors (ERalpha and -beta) localize at the plasma membrane and rapidly signal to affect cellular physiology. Although nuclear ERs function mainly as homodimers, it is unknown whether membrane-localized ER exists or functions with similar requirements. We report that the endogenous ER isoforms at the plasma membrane of breast cancer or endothelial cells exist predominantly as homodimers in the presence of 17beta-estradiol (E2). Interestingly, in endothelial cells made from ERalpha /ERbeta homozygous double-knockout mice, membrane ERalpha or ERbeta are absent, indicating that the endogenous membrane receptors derive from the same gene(s) as the nuclear receptors. In ER-negative breast cancer cells or Chinese hamster ovary cells, we expressed and compared wild-type and dimer mutant mouse ERalpha. Only wild-type ERalpha supported the ability of E2 to rapidly activate ERK, cAMP, and phosphatidylinositol 3-kinase signaling. This resulted from E2 activating Gsalpha and Gqalpha at the membrane in cells expressing the wild-type, but not the dimer mutant, ERalpha. Intact, but not dimer mutant, ERalpha also supported E2-induced epidermal growth factor receptor transactivation and cell survival. We also confirmed the requirement of dimerization for membrane ER function using a second, less extensively mutated, human ERalpha. In summary, endogenous membrane ERs exist as dimers, a structural requirement that supports rapid signal transduction and affects cell physiology.     

Cytochalasin B modulation of Caco-2 tight junction barrier: role of myosin light chain kinase

The intracellular mechanisms that mediate cytochalasin-induced increase in intestinal epithelial tight junction (TJ) permeability are unclear. In this study, we examined the involvement of myosin light chain kinase (MLCK) in this process, using the filter-grown Caco-2 intestinal epithelial monolayers. Cytochalasin B (Cyto B) (5 microg/ml) produced an increase in Caco-2 MLCK activity, which correlated with the increase in Caco-2 TJ permeability. The inhibition of Cyto B-induced MLCK activation prevented the increase in Caco-2 TJ permeability. Additionally, myosin-Mg(2+)-ATPase inhibitor and metabolic inhibitors (which inhibit MLCK induced actin-myosin contraction) also prevented the Cyto B-induced increase in Caco-2 TJ permeability. Cyto B caused a late-phase (15-30 min) aggregation of actin fragments into large actin clumps, which was also inhibited by MLCK inhibitors. Cyto B produced a morphological disturbance of the ZO-1 TJ proteins, visually correlating with the functional increase in Caco-2 TJ permeability. The MLCK and myosin-Mg(2+)-ATPase inhibitors prevented both the functional increase in TJ permeability and disruption of ZO-1 proteins. These findings suggested that Cyto B-induced increase in Caco-2 TJ permeability is regulated by MLCK activation.     

Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer

Chemotherapy or irradiation treatment induces breast cancer cell apoptosis, but this can be limited by estradiol (E2) through unknown mechanisms. To investigate this, we subjected estrogen receptor-expressing human breast cancer cells (MCF-7 and ZR-75-1) to paclitaxel (taxol) or to UV irradiation. Marked increases in cell apoptosis were induced, but these were significantly reversed by incubation with E2. Taxol or UV stimulated c-Jun N-terminal kinase (JNK) activity, which was inhibited by E2. Expression of a dominant-negative Jnk-1 protein strongly prevented taxol- or UV-induced apoptosis, whereas E2 inhibition of apoptosis was reversed by expression of constituitively active Jnk-1. As targets for participation in apoptosis, Bcl-2 and Bcl-xl were phosphorylated in response to JNK activation by taxol or UV; this was prevented by E2. Taxol or UV activated caspase activity in a JNK-dependent fashion and caused the cleavage of procaspase-9 to caspase-9, each inhibited by E2. Independently, the steroid also activated extracellular signal-regulated protein kinase activity, which contributed to the antiapoptotic effects. We report novel and rapid mechanisms by which E2 prevents chemotherapy or radiation-induced apoptosis of breast cancer, probably mediated through the plasma membrane estrogen receptor.