Sorafenib is the only drug approved for the treatment of hepatocellular carcinoma (HCC). The bioenergetic propensity of cancer cells has been correlated to anticancer drug resistance, but such ...correlation is unclear in sorafenib resistance of HCC.
Six sorafenib-naive HCC cell lines and one sorafenib-resistant HCC cell line (Huh-7R; derived from sorafenib-sensitive Huh-7) were used. The bioenergetic propensity was calculated by measurement of lactate in the presence or absence of oligomycin. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, and siRNA of hexokinase 2 (HK2) were used to target relevant pathways of cancer metabolism. Cell viability, mitochondrial membrane potential, and sub-G1 fraction were measured for in vitro efficacy. Reactive oxygen species (ROS), adenosine triphosphate (ATP) and glucose uptake were also measured. A subcutaneous xenograft mouse model was used for in vivo efficacy.
The bioenergetic propensity for using glycolysis correlated with decreased sorafenib sensitivity (R(2)=0.9067, among sorafenib-naive cell lines; P=0.003, compared between Huh-7 and Huh-7 R). DCA reduced lactate production and increased ROS and ATP, indicating activation of oxidative phosphorylation (OXPHOS). DCA markedly sensitised sorafenib-resistant HCC cells to sorafenib-induced apoptosis (sub-G1 (combination vs sorafenib): Hep3B, 65.4±8.4% vs 13±2.9%; Huh-7 R, 25.3± 5.7% vs 4.3±1.5%; each P<0.0001), whereas siRNA of HK2 did not. Sorafenib (10 mg kg(-1) per day) plus DCA (100 mg kg(-1) per day) also resulted in superior tumour regression than sorafenib alone in mice (tumour size: -87% vs -36%, P<0.001).
The bioenergetic propensity is a potentially useful predictive biomarker of sorafenib sensitivity, and activation of OXPHOS by PDK inhibitors may overcome sorafenib resistance of HCC.
Background and purpose:
Rheumatoid arthritis (RA) is a chronic inflammatory disease. Histone deacetylase inhibitors (HDACi), a new class of anti‐cancer agents, have recently been reported to exhibit ...potent anti‐inflammatory activities. A proof of concept study was carried out with suberoylanilide hydroxamic acid (SAHA) and MS‐275, two HDACi currently undergoing clinical investigations for various oncological indications.
Experimental approach:
The anti‐rheumatic effects of SAHA and MS‐275 were assessed in both mouse and rat collagen induced arthritis (CIA) models.
Key results:
SAHA exhibited moderate prophylactic efficacy. It attenuated paw swelling due to inflammation, decreased bone erosion in both mice and rats and reduced slightly the RA‐induced bone resorption in rats. However, SAHA could not inhibit the onset of arthritis. In contrast, MS‐275 displayed dramatic anti‐rheumatic activities. In prophylactic intervention, high doses of MS‐275 prevented bone erosion and markedly delayed the onset of arthritis; at low doses, MS‐275 strongly attenuated paw swelling, bone erosion, and bone resorption associated with RA. Furthermore, the therapeutic efficacy of MS‐275 was also documented. After the onset of arthritis, it could stop the disease progression and joint destruction. An anti inflammatory effect of MS‐275 was also confirmed through its capacity to decrease serum IL‐6 and IL‐1β levels in the CIA induced mouse model. The anti‐rheumatic activity of MS‐275 was also confirmed through histological observation. No synovial hyperplasia, pannus formation, cartilage or bone destruction were observed in the high dose prophylactic intervention in mice.
Conclusion and implication:
This study strongly supported HDACi as an innovative therapeutic strategy for RA.
British Journal of Pharmacology (2007) 150, 862–872. doi:10.1038/sj.bjp.0707165
A dynamic Verilog-A resistive random access memory (RRAM) compact model, including cycle-to-cycle variation, is developed for circuit/system explorations. The model not only captures dc and ac ...behavior, but also includes intrinsic random fluctuations and variations. A methodology to systematically calibrate the model parameters with experiments is presented and illustrated with a broad set of experimental data, including multilayer RRAM. The physical meanings of the various model parameters are discussed. An example of applying the RRAM cell model to a ternary content-addressable-memory (TCAM) macro is provided. Tradeoffs on the design of RRAM devices for the TCAM macro are discussed in the context of the energy consumption and worst case latency of the memory array.
The bilayer-based Antiferroelectric Tunneling Junction (AFTJ) with ferroelectric (FE) HfZrO 2 (HZO) and dielectric (DE) Al 2 O 3 demonstrates a current ratio of <inline-formula> <tex-math ...notation="LaTeX">> 100\times </tex-math></inline-formula>, a TER (tunneling electroresistance) of <inline-formula> <tex-math notation="LaTeX">> 50\times </tex-math></inline-formula>, multilevel states, <inline-formula> <tex-math notation="LaTeX">> 10^{4} </tex-math></inline-formula> sec retention, and a cycling endurance as high as 10 8 . The concept of tunneling current through DE in an antiferroelectric (AFE) system enhances the capacity to modulate the current/TER ratio and makes the AFTJ feasible for low-power crossbar eNVM (embedded nonvolatile memory) applications.
Aims/hypothesis
Recent reports indicate that B lymphocyte-induced maturation protein 1 (BLIMP-1), encoded by the
Prdm1
gene, expands its control over T cells and is associated with susceptibility to ...colitis in mice with T cell-specific BLIMP-1 deficiency. In this study, we aimed to investigate the potential role of BLIMP-1 in regulating autoimmune diabetes and T helper type 17 (Th17) cells.
Methods
We generated T cell-specific
Blimp1
(also known as
Prdm1
) transgenic (Tg) or conditional knockout (CKO) NOD mice, in which
Blimp1
is overexpressed or deleted in T cells, respectively. By side-by-side analysing these Tg or CKO mice, we further dissected the potential mechanisms of BLIMP-1-mediated modulation on autoimmune diabetes.
Results
Overproduction of BLIMP-1 in T cells significantly attenuated insulitis and the incidence of diabetes in NOD mice. Consistent with these results, the diabetogenic effect of splenocytes was remarkably impaired in
Blimp1
Tg mice. Moreover, overproduction of BLIMP-1 repressed the proliferation and activation of lymphocytes and enhanced the function of regulatory T cells (Tregs) in NOD mice. In contrast, mice lacking BLIMP-1 in T cells markedly increased Th1 and Th17 cells, and developed highly proliferative and activated lymphocytes. Strikingly, overexpansion of Th1 and Th17 cells in CKO mice was significantly reduced by introducing a
Blimp1
transgene, reinforcing the emerging role of BLIMP-1 in autoimmunity.
Conclusions/interpretation
We conclude that BLIMP-1 orchestrates a T cell-specific modulation of autoimmunity by affecting lymphocyte proliferation and activation, Th1 and Th17 cell differentiation, and Treg function. Our results provide a theoretical basis for developing BLIMP-1-manipulated therapies for autoimmune diabetes.
The optical design and performance of the recently opened 13A biological small‐angle X‐ray scattering (SAXS) beamline at the 3.0 GeV Taiwan Photon Source of the National Synchrotron Radiation ...Research Center are reported. The beamline is designed for studies of biological structures and kinetics in a wide range of length and time scales, from angstrom to micrometre and from microsecond to minutes. A 4 m IU24 undulator of the beamline provides high‐flux X‐rays in the energy range 4.0–23.0 keV. MoB4C double‐multilayer and Si(111) double‐crystal monochromators (DMM/DCM) are combined on the same rotating platform for a smooth rotation transition from a high‐flux beam of ∼4 × 1014 photons s−1 to a high‐energy‐resolution beam of ΔE/E ≃ 1.5 × 10−4; both modes share a constant beam exit. With a set of Kirkpatrick–Baez (KB) mirrors, the X‐ray beam is focused to the farthest SAXS detector position, 52 m from the source. A downstream four‐bounce crystal collimator, comprising two sets of Si(311) double crystals arranged in a dispersive configuration, optionally collimate the DCM (vertically diffracted) beam in the horizontal direction for ultra‐SAXS with a minimum scattering vector q down to 0.0004 Å−1, which allows resolving ordered d‐spacing up to 1 µm. A microbeam, of 10–50 µm beam size, is tailored by a combined set of high‐heat‐load slits followed by micrometre‐precision slits situated at the front‐end 15.5 m position. The second set of KB mirrors then focus the beam to the 40 m sample position, with a demagnification ratio of ∼1.5. A detecting system comprising two in‐vacuum X‐ray pixel detectors is installed to perform synchronized small‐ and wide‐angle X‐ray scattering data collections. The observed beamline performance proves the feasibility of having compound features of high flux, microbeam and ultra‐SAXS in one beamline.
The optical design and performance of the BioSAXS beamline at the Taiwan Photon Source are reported
Proton pump inhibitors (PPIs) are used for the long-term treatment of gastroesophageal disorders and the non-prescription medicines for acid reflux. However, there is growing concerns about PPI ...misuse, overuse and abuse. This study aimed to develop an animal model to examine the effects of long-term use of PPI in vivo. Twenty one Wistar rats were given omeprazole orally or intravenously for 30 days, and caerulein as a positive control. After euthanization, the serum and stool were collected to perform MS-based quantitative analysis of metabolites. We carried out 16S-based profiling of fecal microbiota, assessed the expression of bile acid metabolism regulators and examined the immunopathological characteristics of bile ducts. After long-term PPI exposure, the fecal microbial profile was altered and showed similarity to those observed in high-fat diet studies. The concentrations of several metabolites were also changed in various specimens. Surprisingly, morphological changes were observed in the bile duct, including ductal epithelial proliferation, micropapillary growth of biliary epithelium, focal bile duct stricture formation and bile duct obstruction. These are characteristics of precancerous lesions of bile duct. FXR and RXRα expressions were significantly reduced, which were similar to that observed in cholangiocarcinoma in TCGA and Oncomine databases. We established a novel animal model to examine the effects of long-term use of omeprazole. The gut microbes and metabolic change are consequences of long-term PPI exposure. And the results showed the environment in vivo tends to a high-fat diet. More importantly, we observed biliary epithelial hyperplasia, which is an indicator of a high-fat diet.
•To reflect the environmental sensitivity of Vehicle Routing Problem (VRP).•To review the studies on VRP in energy consumption, emissions, reverse logistics.•To identify Green Vehicle Routing Problem ...(GVRP) and its classification.•To suggest the future research directions in GVRP.
Green Logistics has emerged as the new agenda item in supply chain management. The traditional objective of distribution management has been upgraded to minimizing system-wide costs related to economic and environmental issues. Reflecting the environmental sensitivity of vehicle routing problems (VRP), an extensive literature review of Green Vehicle Routing Problems (GVRP) is presented. We provide a classification of GVRP that categorizes GVRP into Green-VRP, Pollution Routing Problem, VRP in Reverse Logistics, and suggest research gaps between its state and richer models describing the complexity in real-world cases. The purpose is to review the most up-to-date state-of-the-art of GVRP, discuss how the traditional VRP variants can interact with GVRP and offer an insight into the next wave of research into GVRP. It is hoped that OR/MS researchers together with logistics practitioners can be inspired and cooperate to contribute to a sustainable industry.
Light absorption spectra and carbon mass of fine particle water‐soluble components were measured during the summer of 2010 in the Los Angeles (LA) basin, California, and Atlanta, Georgia. Fresh LA ...secondary organic carbon had a consistent brown color and a bulk absorption per soluble carbon mass at 365 nm that was 4 to 6 times higher than freshly‐formed Atlanta soluble organic carbon. Radiocarbon measurements of filter samples show that LA secondary organic aerosol (SOA) was mainly from fossil carbon and chemical analysis of aqueous filter extracts identified nitro‐aromatics as one component of LA brown SOA. Interpreting soluble brown carbon as a property of freshly‐formed anthropogenic SOA, the difference in absorption per carbon mass between these two cities suggests most fresh secondary water‐soluble organic carbon formed within Atlanta is not from an anthropogenic process similar to LA. Contrasting emissions of biogenic volatile organic compounds may account for these differences.
Key Points
LA fresh SOA is 4–6 times more brown than Atlanta fresh SOA
Nitro‐aromatics are identified as a component of LA anthropogenic brown SOA
Atlanta SOA forms differently to LA due to biogenic/anthropogenic VOC mix
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