Notes

New Zealand Population Rules for the EQ-5D-5L Constructed From the non-public Value Groups of Individuals in the Country wide Survey.
Therapeutic ex vivo T cell expansion is limited by low rates and poor functionality, especially for T cells from aged cancer patients. Here, we describe a novel method for T cell stimulation and expansion using a system named SunTag-based clustering of anti-CD3/CD28 scFv (SBCS). In this method, SunTag was used to recruit up to 13 copies of anti-CD3/CD28 scFv for T cell activation. Compared with the traditional method using immobilized CD3/CD28 antibodies, the SBCS system produced approximately 1.5-fold greater expansion of T cells from healthy donors, and more than 2-fold greater expansion of T cells from aged cancer patients after stimulation. The efficiency of expansion depended mainly on the concentration of the clustered polymers of anti-CD3 scFv rather than anti-CD28 scFv. We also demonstrated that the SBCS-expanded T cells could be used to prepare functional chimeric antigen receptor modified T cells for antitumor therapy.Pancreatic cancer is a highly invasive malignant tumor of the digestive system with an unfavorable prognosis worldwide. Resatorvid This trait is thought to be largely attributed to chemoresistance. Chemotherapy is the only hope for patients with advanced pancreatic cancer. Therefore, seeking new effective chemotherapy drugs has become an urgent need. The purpose of our study was to explore whether deoxyelephantopin (DET), a sesquiterpene lactone, has a potential antitumor effect in pancreatic cancer. Additionally, the antitumor effects of DET alone or in combination with gemcitabine (GEM) and the potential mechanism of this combination were revealed. In vitro experiments showed that DET suppressed the proliferation, invasion and metastasis of pancreatic cancer cells, induced cell apoptosis via oxidative stress, and enhanced GEM sensitivity by inhibiting the NF-κB signaling pathway. Beyond that, in vivo experiments showed that DET not only inhibited pancreatic tumor growth and metastasis but also amplified the antitumor capacity of GEM, which was related to the downregulation of NF-κB and its downstream gene products. In summary, it is possible that DET could be developed as a single agent or combined with conventional chemotherapy drugs to improve the treatment of pancreatic cancer.Dehydrodolichyl diphosphate synthase (DHDDS) catalyzes the committed step in dolichol synthesis. Recessive mutations in DHDDS cause retinitis pigmentosa (RP59), resulting in blindness. We hypothesized that rod photoreceptor-specific ablation of Dhdds would cause retinal degeneration due to diminished dolichol-dependent protein N-glycosylation. Dhddsflx/flx mice were crossed with rod-specific Cre recombinase-expressing (Rho-iCre75) mice to generate rod-specific Dhdds knockout mice (Dhddsflx/flx iCre+). In vivo morphological and electrophysiological evaluation of Dhddsflx/flx iCre+ retinas revealed mild retinal dysfunction at postnatal (PN) 4 weeks, compared with age-matched controls; however, rapid photoreceptor degeneration ensued, resulting in almost complete loss of rods and cones by PN 6 weeks. Retina dolichol levels were markedly decreased by PN 4 weeks in Dhddsflx/flx iCre+ mice, relative to controls; despite this, N-glycosylation of retinal proteins, including opsin (the dominant rod-specific glycoprotein), persisted in Dhddsflx/flx iCre+ mice. These findings challenge the conventional mechanistic view of RP59 as a congenital disorder of glycosylation.Glioblastoma (GBM) is the most common and most aggressive brain tumor, associated with high levels of reactive oxidative species (ROS) due to metabolic and signaling aberrations. High ROS levels are detrimental to cells, but it remains incompletely understood how cancer cells cope with the adverse effects. Here we show that C/EBPβ, a ROS responsive transcription factor, regulates the transcription of NQO1 and GSTP1, two antioxidative reductases, which neutralize ROS in the GBM and mediates their proliferation. C/EBPβ is upregulated in EGFR overexpressed GBM cells, inversely correlated with the survival rates of brain tumor patients. Interestingly, C/EBPβ binds the promoters of NQO1 and GSTP1 and escalates their expression. Overexpression of C/EBPβ selectively decreases the ROS in EGFR-overexpressed U87MG cells and promotes cell proliferation via upregulating NQO1 and GSTP1; whereas knocking down C/EBPβ elevates the ROS and reduces proliferation by repressing the reductases. Accordingly, C/EBPβ mediates the brain tumor growth in vivo, coupling with NQO1 and GSTP1 expression and ROS levels. Hence, C/EBPβ regulates the expression of antioxidative reductases and balances the ROS, promoting brain tumor proliferation.Detecting reactive oxygen species (ROS) that play a critical role as redox modulators and signalling molecules in biological systems currently requires invasive methods such as ROS -specific indicators for imaging and quantification. We developed a non-invasive, real-time, label-free imaging technique for assessing the level of ROS in live cells and thawed cryopreserved tissues that is compatible with in-vivo imaging. The technique is based on autofluorescence multispectral imaging (AFMI) carried out in an adapted fluorescence microscope with an expanded number of spectral channels spanning specific excitation (365 nm-495 nm) and emission (420 nm-700 nm) wavelength ranges. We established a strong quantitative correlation between the spectral information obtained from AFMI and the level of ROS obtained from CellROX staining. The results were obtained in several cell types (HeLa, PANC1 and mesenchymal stem cells) and in live kidney tissue. Additioanly,two spectral regimes were considered with and without UV excitation (wavelengths > 400 nm); the latter being suitable for UV-sensitive systems such as the eye. Data were analyzed by linear regression combined with an optimization method of swarm intelligence. This allowed the calibration of AFMI signals to the level of ROS with excellent correlation (R = 0.84, p = 0.00) in the entire spectral range and very good correlation (R = 0.78, p = 0.00) in the limited, UV-free spectral range. We also developed a strong classifier which allowed us to distinguish moderate and high levels of ROS in these two regimes (AUC = 0.91 in the entire spectral range and AUC = 0.78 for UV-free imaging). These results indicate that ROS in cells and tissues can be imaged non-invasively, which opens the way to future clinical applications in conditions where reactive oxygen species are known to contribute to progressive disease such as in ophthalmology, diabetes, kidney disease, cancer and neurodegenerative diseases.
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