Anti-CD20 antibody rituximab is now essential for the treatment of CD20-positive B-cell lymphomas. Decreased expression of CD20 is one of the major mechanisms underlying both innate and acquired ...resistance to rituximab. In this study, we show that histone deacetylase (HDAC) inhibitors augment the cytotoxic activity of rituximab by enhancing the surface expression of CD20 antigen on lymphoma cells. HDAC inhibitors, valproic acid (VPA) and romidepsin, increased CD20 expression at protein and mRNA levels in B-cell lymphoma cell lines with relatively low CD20 expression levels. The VPA-mediated increase in CD20 expression occurred at 1 m, which is clinically achievable and safe, but insufficient for inducing cell death. Chromatin immunoprecipitation assays revealed that HDAC inhibitors transactivated the CD20 gene through promoter hyperacetylation and Sp1 recruitment. HDAC inhibitors potentiated the activity of rituximab in complement-dependent cytotoxic assays. In mouse lymphoma models, HDAC inhibitors enhanced CD20 expression along with histone hyperacetylation in transplanted cells, and acted synergistically with rituximab to retard their growth. The combination with HDAC inhibitors may serve as an effective strategy to overcome rituximab resistance in B-cell lymphomas.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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Hypothesis: Horseshoe vortices are known to emerge around large-scale obstacles, such as bridge pillars, due to an inertia-driven adverse pressure gradient forming on the ...upstream-side of the obstacle. We contend that a similar flow structure can arise in thin-film Stokes flow around micro-obstacles, such as used in textured surfaces to improve wettability. This could be exploited to enhance mixing in microfluidic devices, typically limited to creeping-flow regimes.
Experiments: Numerical simulations based on the Navier–Stokes equations are carried out to elucidate the flow structure associated with the wetting dynamics of a liquid film spreading around a 50 μm diameter micro-pillar. The employed multiphase solver, which is based on the volume of fluid method, accurately reproduces the wetting dynamics observed in current and previous (Mu et al., Langmuir, 2019) experiments.
Findings: The flow structure within the liquid meniscus forming at the foot of the micro-pillar evinces a horseshoe vortex wrapping around the obstacle, notwithstanding that the Reynolds number in our system is extremely low. Here, the adverse pressure gradient driving flow reversal near the bounding wall is caused by capillarity instead of inertia. The horseshoe vortex is entangled with other vortical structures, leading to an intricate flow system with high-potential mixing capabilities.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Hemophilia is considered suitable for gene therapy because it is caused by a single gene abnormality, and therapeutic coagulation factor levels may vary across a broad range. Recent success ...of hemophilia B gene therapy with an adeno‐associated virus (AAV) vector in a clinical trial showed the real prospect that, through gene therapy, a cure for hemophilia may become a reality. However, AAV‐mediated gene therapy is not applicable to patients with hemophilia A at present, and neutralizing antibodies against AAV reduce the efficacy of AAV‐mediated strategies. Because patients that benefit from AAV treatment (hemophilia B without neutralizing antibodies) are estimated to represent only 15% of total patients with hemophilia, the development of basic technologies for hemophilia A and those that result in higher therapeutic effects are critical. In this review, we present an outline of gene therapy methods for hemophilia, including the transition of technical developments thus far and our novel techniques.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Numerical simulations on ammonia/hydrogen/air detonation are performed using a detailed reaction model to investigate the cellular instability and detonation dynamics as a function of hydrogen ...content. The UT-LCS model that includes 32 species and 213 elementary reactions is used in the present simulations. The fifth-order target compact nonlinear scheme captured the unstable detonation dynamics and the complicated flow structure including the propagation of a sub-transverse wave. The simulation performed with different hydrogen dilutions shows that the detonation propagates at the Chapman–Jouguet velocity for all cases, and the cell size for the ammonia/hydrogen mixing ratio
α
=
0.3
becomes approximately 10 times larger than that for
α
=
1.0
(hydrogen/air mixture). A transverse detonation produces a finescale cellular structure on the computed maximum pressure history. This complex shock formation is similar to those of a spinning detonation and two-dimensional propane/oxygen detonation. The cellular irregularity increases with decreasing hydrogen content because ammonia destabilizes the detonation cellular structure with a reduced activation energy of more than approximately 8.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Obesity and metabolic syndrome are the major risk factors for cardiovascular disease. Obesity is caused by increased food intake and/or decreased energy expenditure. Leptin potently inhibits food ...intake and promotes energy expenditure. These effects of leptin involve the activation of proopiomelanocortin (POMC) neurons in the hypothalamus arcuate nucleus (ARC). Disruption of leptin signaling in POMC neuron is considered one of the major causes for obesity.
The present study aimed to examine whether overexpression of interleukin-10 (IL-10) could substitute for the leptin action and ameliorate obesity in leptin-deficient Lep(ob/ob) mice.
Adeno-associated virus (AAV) expressing murine IL-10 (AAV-mIL-10) was injected into the skeletal muscle to overexpress IL-10 in mice. These mice were subsequently subjected to analysis of body weight, food intake, glucose metabolism and underlying mechanisms.
In Lep(ob/ob) mice, AAV-IL-10 ameliorated hyperphagia, obesity, glucose intolerance and insulin resistance, as well as attenuated tumor necrosis factor-α expression. The IL-10 treatment also improved glucose-induced insulin release. Furthermore, IL-10 treatment increased POMC mRNA expression in ARC and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in ARC and white adipose tissue (WAT). In neuron-specific STAT3-null mice that exhibited obesity and hyperphagia, AAV-mIL-10 administration failed to affect food intake, body weight and phosphorylation of STAT3 in WAT.
These results demonstrate that peripheral overexpression of IL-10 induces STAT3 phosphorylation in ARC POMC neurons, and thereby ameliorates hyperphagia and obesity caused by leptin deficiency. IL-10 gene transfer may provide an effective approach for preventing progression of metabolic syndrome due to leptin resistance.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Depression is a common debilitating human disease whose etiology has defied decades of research. A critical bottleneck is the difficulty in modeling depressive episodes in animals. Here, we show that ...a transgenic mouse with chronic forebrain expression of a dominant negative mutant of Polg1, a mitochondrial DNA (mtDNA) polymerase, exhibits lethargic behavioral changes, which are associated with emotional, vegetative and psychomotor disturbances, and response to antidepression drug treatment. The results suggested a symptomatic similarity between the lethargic behavioral change that was recurrently and spontaneously experienced by the mutant mice and major depressive episode as defined by DSM-5. A comprehensive screen of mutant brain revealed a hotspot for mtDNA deletions and mitochondrial dysfunction in the paraventricular thalamic nucleus (PVT) with similar defects observed in postmortem brains of patients with mitochondrial disease with mood symptoms. Remarkably, the genetic inhibition of PVT synaptic output by Cre-loxP-dependent expression of tetanus toxin triggered de novo depression-like episodes. These findings identify a novel preclinical mouse model and brain area for major depressive episodes with mitochondrial dysfunction as its cellular mechanism.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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