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Abstract The chemo‐regulation abilities of chemotherapeutic medications are appealing to address the low immunogenicity, immunosuppressive lactate microenvironment, and adaptive immune resistance of colorectal cancer. In this work, the proteolysis targeting chimera (PROTAC) of BRD4 (dBET57) is found to downregulate colorectal cancer glycolysis through the transcription inhibition of c‐Myc, which also inhibits the expression of programmed death ligand 1 (PD‐L1) to reverse immune evasion and avoid adaptive immune resistance. Based on this, self‐delivery nano‐PROTACs (designated as DdLD NPs) are further fabricated by the self‐assembly of doxorubicin (DOX) and dBET57 with the assistance of DSPE‐PEG2000. DdLD NPs can improve the stability, intracellular delivery, and tumor targeting accumulation of DOX and dBET57. Meanwhile, the chemotherapeutic effect of DdLD NPs can efficiently destroy colorectal cancer cells to trigger a robust immunogenic cell death (ICD). More importantly, the chemo‐regulation effects of DdLD NPs can inhibit colorectal cancer glycolysis to reduce the lactate production, and downregulate the PD‐L1 expression through BRD4 degradation. Taking advantages of the chemotherapy and chemo‐regulation ability, DdLD NPs systemically activated the antitumor immunity to suppress the primary and metastatic colorectal cancer progression without inducing any systemic side effects. Such self‐delivery nano‐PROTACs may provide a new insight for chemotherapy‐enabled tumor immunotherapy.

Background and aim: Xianglian Wan (XLW) as a classic prescription of traditional Chinese medicine protects digestive function; however, few studies have investigated its anti-colorectal cancer effects. This study verified that the effective monomer berberine of XLW plays an antitumo r role by regulating the acetyl-CoA carboxylase (ACC)/fatty acid synthase (FASN) lipid metabolism-related signaling pathway. Experimental procedure: The connection between XLW and FASN was identified through literature mining, bioinformatics and structural biology. In vivo experiments verified the rationality of the antitumor effect of berberine by regulating the ACC/FASN pathway, and in vitro experiments verified the regulatory relationship between berberine and FASN. Results and conclusion: The most frequent Chinese medicine component in XLW was Coptis chinensis. Berberine, the active ingredient of XLW, has a FASN binding site. FASN expression is higher in tumor tissues than in normal tissues. FASN is related to colorectal adenocarcinoma occurrence and patient survival time. Experiments showed that XLW, berberine and orlistat (FASN inhibitor) can cooperate with palmitic acid (PA) to inhibit tumors in mice. Berberine can downregulate FASN and ACC expression in tumor tissues and inhibit the increase in acetyl-CoA, the intermediate product of exogenous PA intake. The mechanism by which berberine inhibits colon cancer cell proliferation by lowering lipids is related to its downregulation of FASN protein expression. The ACC/FASN signaling pathway is a critical pathway through which berberine, the effective monomer of XLW, plays an antitumor role in colon cancer.

Neurotrophic factors, particularly nerve growth factor, enhance neuronal regeneration. However, the in vivo applications of nerve growth factor are largely limited by its intrinsic disadvantages, such as its short biological half-life, its contribution to pain response, and its inability to cross the blood-brain barrier. Considering that let-7 (human miRNA) targets and regulates nerve growth factor, and that let-7 is a core regulator in peripheral nerve regeneration, we evaluated the possibilities of let-7 application in nerve repair. In this study, anti-let-7a was identified as the most suitable let-7 family molecule by analyses of endogenous expression and regulatory relationship, and functional screening. Let-7a antagomir demonstrated biosafety based on the results of in vivo safety assessments and it entered into the main cell types of the sciatic nerve, including Schwann cells, fibroblasts and macrophages. Use of hydrogel effectively achieved controlled, localized, and sustained delivery of let-7a antagomir. Finally, let-7a antagomir was integrated into chitosan conduit to construct a chitosan-hydrogel scaffold tissue-engineered nerve graft, which promoted nerve regeneration and functional recovery in a rat model of sciatic nerve transection. Our study provides an experimental basis for potential in vivo application of let-7a.

Cellular senescence and proliferation are essential for wound healing and tissue remodeling. However, senescence-proliferation cell fate after peripheral nerve injury has not been clearly revealed. Here, post-injury gene expression patterns in rat sciatic nerve stumps (SRP113121) and L4–5 dorsal root ganglia (SRP200823) obtained from the National Center for Biotechnology Information were analyzed to decipher cellular senescence and proliferation-associated genetic changes. We first constructed a rat sciatic nerve crush model. Then, β-galactosidase activities were determined to indicate the existence of cellular senescence in the injured sciatic nerve. Ki67 and EdU immunostaining was performed to indicate cellular proliferation in the injured sciatic nerve. Both cellular senescence and proliferation were less vigorous in the dorsal root ganglia than in sciatic nerve stumps. These results reveal the dynamic changes of injury-induced cellular senescence and proliferation from both genetic and morphological aspects, and thus extend our understanding of the biological processes following peripheral nerve injury. The study was approved by the Animal Ethics Committee of Nantong University, China (approval No. 20190226-001) on February 26, 2019.

The regenerative capacity of peripheral nerves is limited after nerve injury. A number of growth factors modulate many cellular behaviors, such as proliferation and migration, and may contribute to nerve repair and regeneration. Our previous study observed the dynamic changes of genes in L4–6 dorsal root ganglion after rat sciatic nerve crush using transcriptome sequencing. Our current study focused on upstream growth factors and found that a total of 19 upstream growth factors were dysregulated in dorsal root ganglions at 3, 9 hours, 1, 4, or 7 days after nerve crush, compared with the 0 hour control. Thirty-six rat models of sciatic nerve crush injury were prepared as described previously. Then, they were divided into six groups to measure the expression changes of representative genes at 0, 3, 9 hours, 1, 4 or 7 days post crush. Our current study measured the expression levels of representative upstream growth factors, including nerve growth factor, brain-derived neurotrophic factor, fibroblast growth factor 2 and amphiregulin genes, and explored critical signaling pathways and biological process through bioinformatic analysis. Our data revealed that many of these dysregulated upstream growth factors, including nerve growth factor, brain-derived neurotrophic factor, fibroblast growth factor 2 and amphiregulin, participated in tissue remodeling and axon growth-related biological processes Therefore, the experiment described the expression pattern of upstream growth factors in the dorsal root ganglia after peripheral nerve injury. Bioinformatic analysis revealed growth factors that may promote repair and regeneration of damaged peripheral nerves. All animal surgery procedures were performed in accordance with Institutional Animal Care Guidelines of Nantong University and ethically approved by the Administration Committee of Experimental Animals, China (approval No. 20170302-017) on March 2, 2017.

Objective Quantitative analysis and comparison of the expression of ribonucleic acid （RNA） from frozen organs and formaldehyde-fixed and paraffin-embedded （FFPE） tissues. Methods Frozen specimens of human brain, myocardium and liver tissues as well as FFPE samples at different postmortem intervals were collected and mass concentration of RNA was extracted and detected. Reverse transcription-quantitative polymerase chain reaction （RT-qPCR） technology was used to analyze the amplification efficiency and relative expression of each RNA marker. Results The mass concentration and integrity of RNA extracted from FFPE samples were relatively low compared with frozen specimens. The amplification efficiency of RNA markers was related with RNA species and the length of amplification products. Among them, glyceraldehyde-3-phosphate dehydrogenase （GAPDH） and β-actin （ACTB） with relatively long amplification products failed to achieve optimal amplification efficiency, whereas 5S ribosomal RNA （5S rRNA） achieved ideal amplification efficiency and showed quite stable expression across various tissues, therefore it was chosen as internal reference marker. The expression quantity of GAPDH and ACTB in frozen specimens with longer postmortem intervals and in FFPE samples with relatively long amplification products was decreased. The expressions of tissue-specific microRNAs （miRNAs）, GAPDH and ACTB with relatively short amplification products had consistency in the same tissues and FFPE samples. Conclusion Through standardizing the RT-qPCR experiment, selecting the appropriate RNA marker and designing primers of appropriate product length, RNA expression levels of FFPE samples can be accurately quantified

Carotenoids and vitamin A are nutrients crucial to infants’ development. To date, there is limited data on their availability in breastmilk and the associated dietary factors, especially in Hong Kong, where people follow a westernized Chinese diet. This study determined the selected breastmilk’s carotenoid and vitamin A (retinol) contents by ultraperformance liquid chromatography with photodiode detection (UPLC-PDA) and the dietary intakes by three-day food records in 87 Hong Kong lactating mothers, who were grouped into tertiles based on their daily carotenoid intake. Low vitamin A intake (530.2 ± 34.2 µg RAE/day) and breastmilk retinol level (1013.4 ± 36.8 nmol/L) were reported in our participants, suggesting a poor vitamin A status of the lactating participants having relatively higher socioeconomic status in Hong Kong. Mothers in the highest tertile (T3) had higher breastmilk carotenoid levels than those in the lowest (T1) (p < 0.05). There were significant associations between maternal carotenoid intakes and breastmilk lutein levels in the linear regression models (p < 0.05) regardless of dietary supplement intake. Furthermore, maternal dark green vegetable intakes were associated with breastmilk retinol, lutein, and β-carotene levels. These findings can serve as dietary references for lactating mothers to enhance breastmilk carotenoid and vitamin A contents for the benefits of child growth and development.

Macular hemorrhage can occur spontaneously and repeatedly without choroidal neovascularization or other known lesions associated with myopia. We report a case of repeated myopic macular hemorrhage following fish oil supplementation. A 32-year-old male was referred with newly acquired paracentral scotoma in the left eye. Serial retinal imaging, including fundus photography, fluorescein angiography, and spectral-domain optical coherence tomography were performed. Fundus photography and fluorescein angiography showed a subtle red-colored lesion nasal to the fovea. Optical coherence tomography showed a dome shaped elevation in the ellipsoid zone and interdigitation zone in the left eye. No known ocular risk factors for macular hemorrhage, such as choroidal neovascularization, lacquer cracks, Fuch’s spot or choroid thinning or keratoconus were observed. After 2 months without any treatment, the left eye lesion disappeared. However 2 weeks later, another newly developed red-colored lesion close to the left fovea was observed. At that moment, the detailed medical history revealed that the patient had been regularly taking a high dose of commercially available fish oil supplement beginning one month before the first macular hemorrhage. After discontinuation of the fish oil, the second left hemorrhage resolved gradually over the following 8 weeks. No recurrent hemorrhages have been detected at the 12 months follow-up visits. Our observations suggest that the relative value of nutritional supplementation with high doses of fish oil should be cautioned in patients with repetitive retinal hemorrhage.

Hypoxia is a common feature for most malignant tumors, which was also closely related to the oxygen-dependent photodynamic therapy. Based on Förster resonance energy transfer (FRET), a smart nanoprobe (designated as H-Probe) was designed in this paper for hypoxia imaging and photodynamic tumor therapy. Due to the FRET process, H-Probe could respond to hypoxia with a significant fluorescence recovery. Moreover, abundant in vitro investigations demonstrated that the photosensitizer of PpIX in H-Probe could generate large amounts of singlet oxygen to kill cancer cells in the presence of oxygen and light with appropriate wavelength. Also, intravenously injected H-Probe with light irradiation achieved an effective tumor inhibition in vivo with a reduced side effect. This original strategy of integrating hypoxia imaging and tumor therapy in one nanoplatform would promote the development of theranostic nanoplatform for tumor precision therapy.

Elastic wave metamaterials, such as phononic crystals (PnCs) always composed of several materials in terms of periodical structures, possess unique acoustic characteristic which can exhibit outstanding performance in forbidding wave propagation with some specific frequencies. In this paper, due to the thermal sensitivity of the thermally induced shape memory polymers (SMP) and period thermal fields, a tunable planar acoustic metamaterial which is constituent homogeneous is proposed and designed to realize the function of waveguides. A thin plate model composed of homogenous thermally induced SMP and adhered with a series of metallic films at the top boundary which plays the role of local heating sources is established. The homogenous plate can be transferred into acoustic metamaterial once the non-uniform period thermal fields are imported. Based on the Fourier law of heat conduction and finite element method (FEM), a two-dimensional numerical model via COMSOL Multiphysics is carried out to perform the in-plane mode band structures and transmission spectra. The results show that the bandgap will be effectively opened and change obviously as the injected heat flux increases. Furthermore, band structures of 7 × 1 supercell with thermal defect are performed to reveal the design guideline of waveguides which is supposed to be the basis of line-type and L-type waveguides. The tunable characteristics of waveguides based on thermal fields with thermal defects are also discussed. These results may pave a new avenue for the design of tunable acoustic metamaterial composed of thermal sensitive material which own a prospect to be applied in area of acoustic waveguides. [ABSTRACT FROM AUTHOR]

Abstract Background Retinitis pigmentosa is a common genetic disease that causes retinal degeneration and blindness for which there is currently no curable treatment available. Vision preservation was observed in retinitis pigmentosa animal models after retinal stem cell transplantation. However, long-term safety studies and visual assessment have not been thoroughly tested in retinitis pigmentosa patients. Methods In our pre-clinical study, purified human fetal-derived retinal progenitor cells (RPCs) were transplanted into the diseased retina of Royal College of Surgeons (RCS) rats, a model of retinal degeneration. Based on these results, we conducted a phase I clinical trial to establish the safety and tolerability of transplantation of RPCs in eight patients with advanced retinitis pigmentosa. Patients were studied for 24 months. Results After RPC transplantation in RCS rats, we observed moderate recovery of vision and maintenance of the outer nuclear layer thickness. Most importantly, we did not find tumor formation or immune rejection. In the retinis pigmentosa patients given RPC injections, we also did not observe immunological rejection or tumorigenesis when immunosuppressive agents were not administered. We observed a significant improvement in visual acuity (P

Objectives. Chronic total occlusion (CTO) is prevalent in patients with prior coronary artery bypass grafting (CABG). However, data available concerning the prevalence of new-onset CTO of native vessels in patients with prior CABG is limited. Therefore, the objective of the study is to determine predictors for new native-vessel occlusion in patients with prior coronary bypass surgery. Methods. 354 patients with prior CABG receiving follow-up angiography are selected and analyzed in the present study, with clinical and angiographic variables being analyzed by logistic regression to determine the predictors of new native-vessel occlusion. Results. The overall new occlusion rate was 35.59%, with multiple CTOs (42.06%) being the most prevalent (LAD 24.60% and RCA 18.25%, respectively). Additionally, current smoking (OR: 2.67; 95% CI: 2.60 to 2.74; p=0.01), reduced ejection fraction (OR: 1.76; 95% CI: 1.04 to 2.97; p=0.04), severe stenosis (OR: 3.65; 95% CI: 2.55 to 5.24; p=0.01), and diabetes mellitus (OR: 1.86; 95% CI: 1.34 to 2.97; p=0.04) serve as the independent predictors for new native-vessel occlusion. Conclusion. As to high incidence of postoperative CTO, appropriate revascularization strategies and postoperative management should be taken into careful consideration.

AIM:To assess the disinfection methods of diagnostic contact lens and their efficacy in ophthalmology in China.METHODS: Ten Chinese hospitals were surveyed and indicated three commonly used disinfectants 0.05% sodium dichloroisocyanurate(NaDCC), 75% EtOH, or chloramphenicol eye drops(Minims^{®: 0.5%). Lenses were infected with staphylococcus aureus, staphylococcus epidermidis, or pseudomonas aeruginosa, and then disinfected by; 1)wiping; 2)immersing in disinfectant for 5min; 3)immersing in disinfectant for 10min; n=9. Swab wipes from the lenses were cultured for 24h and colony-forming units were counted to assess bacterial load. Lens clarity was subjectively scored for each method.RESULTS: The bacterial load was 1×108/mL ×50μL/lense equals 5×106/lense. Of the three methods the use of 75% EtOH and NaDCC are significantly more effective when used for wiping compared to eye drops(P≤0.01). Wiping with NaDCC or EtOH significantly reduced bacterial load but results were variable and the threat of cross-infection is still present. They were effective if used for 10min, but EtOH adversely affected lens clarity in contrast to NaDCC which had no adverse affects on the lens. Chloramphenicol eye drops were ineffective.CONCLUSION: NaDCC immersion for 10min or longer appears to be a simple and effective way to disinfect diagnostic contact lenses during ophthalmic examination.}

Gradiently denitrated gun propellant (GDGP) prepared by a "gradient denitration" strategy is obviously superior in progressive burning performance to the traditional deterred gun propellant. Currently, the preparation of GDGP employed a tedious two-step method involving organic solvents, which hinders the large-scale preparation of GDGP. In this paper, GDGP was successfully prepared via a novelty and environmentally friendly one-step method. The obtained samples were characterized by FT-IR, Raman, SEM and XPS. The results showed that the content of nitrate groups gradiently increased from the surface to the core in the surface layer of GDGP and the surface layer of GDGP exhibited a higher compaction than that of raw gun propellant, with a well-preserved nitrocellulose structure. The denitration process enabled the propellant surface with regressive energy density and good progressive burning performance, as confirmed by oxygen bomb and closed bomb test. At the same time, the effects of different solvents on the component loss of propellant were compared. The result showed that water caused the least component loss. Finally, the stability of GDGP was confirmed by methyl-violet test. This work not only provided environmentally friendly, simple and economic preparation of GDGP, but also confirmed the stability of GDGP prepared by this method. [ABSTRACT FROM AUTHOR]