Myeloid leukemia-derived galectin-1 downregulates CAR expression to hinder cytotoxicity of CAR T cells.

BACKGROUND: Chimeric antigen receptor (CAR) T cells have shown significant activity in B-lineage malignancies. However, their efficacy in myeloid leukemia has not been successful due to unclear molecular mechanisms. METHODS: We conducted in vitro and in vivo experiments to investigate whether myeloid leukemia cells directly induce CAR down-regulation. Furthermore, we designed a CD33 CARKR in which all lysines in the cytoplasmic domain of CAR were mutated to arginine and verified through in vitro experiments that it could reduce the down-regulation of surface CARs and enhance the killing ability. Transcriptome sequencing was performed on various AML and ALL cell lines and primary samples, and the galectin-1-specific inhibitory peptide (anginex) successfully rescued the killing defect and T-cell activation in in vitro assays. RESULTS: CAR down-regulation induced by myeloid leukemia cells under conditions of low effector-to-tumor ratio, which in turn impairs the cytotoxicity of CAR T cells. In contrast, lysosomal degradation or actin polymerization inhibitors can effectively alleviate CAR down-regulation and restore CAR T cell-mediated anti-tumor functions. In addition, this study identified galectin-1 as a critical factor used by myeloid leukemia cells to induce CAR down-regulation, resulting in impaired T-cell activation. CONCLUSION: The discovery of the role of galectin-1 in cell surface CAR down-regulation provides important insights for developing strategies to restore anti-tumor functions.

Sirt3 regulates NLRP3 and participates in the effects of plantainoside D on acute lung injury sepsis.

Sepsis, a common critical disease, has high morbidity and mortality. Acute lung injury (ALI) is one of the important complications of sepsis, its effective treatment measures remain scarce. The purpose of the present study was to search for the biomarker and effective treatment measures. Lipopolysaccharide (LPS) was used to establish sepsis induced ALI model in vivo and in vitro. Proteomics, immunoprecipitation, molecular docking techniques, and Sirt3 knockout (KO) mice and silence MLE-12 cells were used to search for biomarker and treatment measures for sepsis ALI. 38 differentially expressed proteins were found in the lung tissues of sepsis ALI mice, among which Sirt3 changed most. Further study found that Sirt3 could inhibit NLRP3 activation. Sirt3 KO or silence significantly aggravated sepsis induced ALI and MLE-12 cell injury. Plantainoside D (PD), an effective component of Plantago asiatica L., significantly improved sepsis induced ALI by regulation of Sirt3/NLRP3 pathway. In conclusion, Sirt3 may be the important molecular targets for sepsis ALI. PD could protect sepsis ALI via Sirt3/NLRP3 signal pathway. The findings provide a new treatment target for sepsis ALI and a potential treatment measure.

Aryl sulfonyl fluoride synthesis via palladium-catalyzed fluorosulfonylation of aryl thianthrenium salts.

We developed an efficient palladium-catalyzed fluorosulfonylation reaction of aryl thianthrenium salts to smoothly prepare various aryl sulfonyl fluorides using cheap Na2S2O4 as a convenient sulfonyl source in combination with N-fluorobenzenesulfonimide (NFSI) as an ideal fluorine source under mild reduction conditions. A one-pot synthesis of aryl sulfonyl fluorides starting from various arenes was established as well without the need for separating aryl thianthrenium salts. The practicality of this protocol was demonstrated by gram-scale synthesis, derivatization reactions, and excellent yields.

Long-term follow-up of donor-derived CD7 CAR T-cell therapy in patients with T-cell acute lymphoblastic leukemia.

BACKGROUND: Donor-derived CD7-directed chimeric antigen receptor (CAR) T cells showed feasibility and early efficacy in patients with refractory or relapsed T-cell acute lymphoblastic leukemia (r/r T-ALL), in a previous phase I trial report, at a median follow-up of 6.3 months. Here we report long-term safety and activity of the therapy after a 2-year follow-up. METHODS: Participants received CD7-directed CAR T cells derived from prior stem cell transplantation (SCT) donors or from HLA-matched new donors after lymphodepletion. The target dose was 1 × 106 (± 30%) CAR T cells per kg of patient weight. The primary endpoint was safety with efficacy secondary. This report focuses on the long-term follow-up and discusses them in the context of previously reported early outcomes. RESULTS: Twenty participants were enrolled and received infusion with CD7 CAR T cells. After a median follow-up time of 27.0 (range, 24.0-29.3) months, the overall response rate and complete response rate were 95% (19/20 patients) and 85% (17/20 patients), respectively, and 35% (7/20) of patients proceeded to SCT. Six patients experienced disease relapse with a median time-to-relapse of 6 (range, 4.0-10.9) months, and 4 of these 6 patients were found to have lost CD7 expression on tumor cells. Progression-free survival (PFS) and overall survival (OS) rates 24 months after treatment were respectively 36.8% (95% CI, 13.8-59.8%) and 42.3% (95% CI, 18.8-65.8%), with median PFS and OS of respectively 11.0 (95% CI, 6.7-12.5) months and 18.3 (95% CI, 12.5-20.8) months. Previously reported short-term adverse events (< 30 days after treatment) included grade 3-4 cytokine release syndrome (CRS; 10%) and grade 1-2 graft-versus-host disease (GVHD; 60%). Serious adverse events reported > 30 days after treatment included five infections and one grade 4 intestinal GVHD. Despite good CD7 CAR T-cell persistence, non-CAR T and natural killer cells were predominantly CD7-negative and eventually returned to normal levels in about half of the participants. CONCLUSIONS: In this 2-year follow-up analysis, donor-derived CD7 CAR T-cell treatment demonstrated durable efficacy in a subset of patients with r/r T-ALL. Disease relapse was the main cause of treatment failure, and severe infection was a noteworthy late-onset adverse event. TRIAL REGISTRATION: ChiCTR2000034762.

Dietary iron affects lipid deposition, nutritional element, and muscle quality in coho salmon (Oncorhynchus kisutch).

We investigated effect of dietary iron (Fe) on the lipid deposition, nutritional element, and muscle quality in coho salmon. Four level Fe diets at 23.7, 46.4, 77.3, and 127.7 mg/kg were fed to the post-larval coho salmon for 12 weeks. Our results showed that dietary Fe decreased the content of triglyceride and the activity of fatty acid synthetase, ATP-citrate lyase, and acetyl-CoA carboxylase. The content of Fe in muscle was increased with increasing dietary Fe levels, and dietary Fe affected the content of nutritional elements. In addition, dietary Fe levels affected the composition of fatty acids and the content of free amino acids, and increased muscle fiber size. The lower dietary Fe levels also affected the hardness, chewiness, resilience, springiness, cohesiveness, and gumminess of salmon muscle. In all, dietary Fe inhibited the lipid deposition and affected the content of nutritional element and muscle quality in coho salmon.

Effect of Dietary Linoleic Acid (18:2n-6) Supplementation on the Growth Performance, Fatty Acid Profile, and Lipid Metabolism Enzyme Activities of Coho Salmon (Oncorhynchus kisutch) Alevins.

A 12-week feeding trial aimed to evaluate the effects of dietary linoleic acid (LA, 18:2n-6) on the growth performance, fatty acid profile, and lipid metabolism enzyme activities of coho salmon (Oncorhynchus kisutch) alevins. Six experimental diets (47% crude protein and 15% crude lipid) were formulated to contain graded LA levels of 0.11%, 0.74%, 1.37%, 2.00%, 2.63%, and 3.26%. Each diet was fed to triplicate groups of 50 alevins with an initial body weight of 0.364 ± 0.002 g, which were randomly assigned to 18 white plastic tanks (0.8 × 0.6 × 0.6 m, 240 L/tank). Fish were reared in a freshwater flow-through rearing system and fed to apparent satiation four times daily. The survival rate was not significantly different among the treatments (p > 0.05). However, the 1.37% LA group significantly improved the final body weight and specific growth rate (SGR) (p < 0.05) of alevins. The feed conversion ratio (FCR) in the 1.37% LA group was significantly lower than those in other groups (p < 0.05). The whole-body lipid content significantly decreased (p < 0.05) with dietary LA levels increasing from 0.74% to 2.00%. The fatty acid composition of the total lipid in muscle was closely correlated with those in the diets. The dietary LA level of 1.37% led to significantly higher activities of liver lipoprotein lipase (LPL) and hepatic lipase (HL) than those of other groups (p < 0.05). Hepatic malate dehydrogenase (MDH) and fatty acid synthase (FAS) decreased with the increase in the dietary LA levels from 0.11% to 1.37%. The lowest MDH and FAS activities were obtained in the 1.37% LA group (p < 0.05). This study indicated that an appropriate amount of dietary LA was beneficial for the growth and lipid metabolism of coho salmon alevins, and the results of the quadratic regression analysis of the SGR and FCR indicated that the optimal dietary LA requirements were 1.25% and 1.23% for coho salmon alevins, respectively.

Amentoflavone-loaded nanoparticles enhanced chemotherapy efficacy by inhibition of AKR1B10.

Therapeutic nanoparticles can be combined with different anticancer drugs to achieve a synergistic therapy and avoid the limitations of traditional medicine and thus have clinical prospects for cancer. Herein, an effective nanoplatform was developed for self-assembling AMF@DOX-Fe3+-PEG nanoparticles (ADPF NPs) via the coordination of ferric ions (Fe3+), amentoflavone (AMF), doxorubicin (DOX), and PEG-polyphenol. The ADPF NPs possessed high drug loading efficiency, good stability and dispersion in water, prolonged blood circulation, and pH-dependent release, which leading to targeted drug transport and enhanced drug accumulation in the tumor. The AMF from the ADPF NPs could inhibit the expression of the Aldo-keto reductase family 1B10 (AKR1B10) and nuclear factor-kappa B p65 (NF-κB p65), which reduced the cardiotoxicity induced by DOX and enhanced the chemotherapy efficacy. This study established a new strategy of combining drug therapy with a nanoplatform. This new strategy has a wide application prospect in clinical tumor therapy.

Effects of Dietary Vitamin C on the Growth Performance, Biochemical Parameters, and Antioxidant Activity of Coho Salmon Oncorhynchus kisutch (Walbaum, 1792) Postsmolts.

Vitamin C (VC) plays an essential role in fish physiological function and normal growth. However, its effects and requirement of coho salmon Oncorhynchus kisutch (Walbaum, 1792) are still unknown. Based on the influences on growth, serum biochemical parameters, and antioxidative ability, an assessment of dietary VC requirement for coho salmon postsmolts (183.19 ± 1.91 g) was conducted with a ten-week feeding trial. Seven isonitrogenous (45.66% protein) and isolipidic (10.76% lipid) diets were formulated to include graded VC concentrations of 1.8, 10.9, 50.8, 100.5, 197.3, 293.8, and 586.7 mg/kg, respectively. Results showed that VC markedly improved the growth performance indexes and liver VC concentration, enhanced the hepatic and serum antioxidant activities, and increased the contents of serum alkaline phosphatase (AKP) activity, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and total cholesterol (TC) whereas decreased the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) activities, and triglyceride (TG) level. Polynomial analysis showed that the optimal VC levels in the diet of coho salmon postsmolts were 188.10, 190.68, 224.68, 132.83, 156.57, 170.12, 171.00, 185.50, 142.77, and 93.08 mg/kg on the basis of specific growth rate (SGR), feed conversion ratio (FCR), liver VC concentration, catalase (CAT), hepatic superoxide dismutase (SOD) activities, malondialdehyde (MDA) content, and serum total antioxidative capacity (T-AOC), AKP, AST, and ALT activities, respectively. The dietary VC requirement was in the range of 93.08-224.68 mg/kg for optimum growth performance, serum enzyme activities, and antioxidant capacity of coho salmon postsmolts.

Neglect among preschool non-only-child in urban area of Nantong City / 中国学校卫生

Objective@#To understand the neglect status among preschool non-only-child in Nantong, and to provide theoretical basis for the prevention and intervention of non-only child neglect.@*Methods@#Using the method of random cluster sampling, a total of 1 141 parents of children from 9 kindergartens in the main urban area of Nantong were investigated with National Neglect Norm Scale for Children aged 3 to 6 years.@*Results@#The neglect rate of preschool children in Nantong City was 28.6%, with neglect score being (40.21±6.67). The neglect rate of non-only-child was 32.6%, with neglect score being (41.14±6.73). The total and physical neglect rate of non-only-child were higher than that of only child, and the total neglect score and physical, emotional, educational, safety, medical neglect dimensional scores were higher than that of only-child, the difference were all statistically significant ( χ 2/ t = 6.21, 17.57; 3.95, 4.98, 3.45, 2.70, 2.01, 3.11, P <0.05). In non-only-child, univariate analysis showed that there were no significant differences in neglect rate and scores among children by gender and family types ( P >0.05); There was no significant difference in the child neglect rate between different age groups and children in different families ( χ 2 =3.59, 2.99, P >0.05), but there was a statistically significant difference in the degree of neglect ( t=2.79, 3.04, P <0.05). The neglect rate and score of non-only-child with high level of family income, parental education and parental relationship was relatively low, while the neglect rate and score in non-only-child whose grandparents serving as primary caregiver were higher ( P <0.05). Multivariate Logistic regression analysis showed that family monthly income less than 5 000 yuan was associated with 2.73 times higher risk of neglect compared to children with family monthly income more than 12 000 yuan. The risk of neglect among children whose grandparents serving as caregivers was associated with 2.17 times higher than children with parental care. The risk of neglect of children with poor parental relationship was 2.29 times higher than that of children with good parental relationship ( P <0.05).@*Conclusion@#The neglect among preschool non-only-child in Nantong City is common. Improvement in family economic status, parental care and parent relationship might help reduce neglect among preschool non-only-child.

Neglect among preschool non-only-child in urban area of Nantong City / 中国学校卫生

Objective@#To understand the neglect status among preschool non-only-child in Nantong, and to provide theoretical basis for the prevention and intervention of non-only child neglect.@*Methods@#Using the method of random cluster sampling, a total of 1 141 parents of children from 9 kindergartens in the main urban area of Nantong were investigated with National Neglect Norm Scale for Children aged 3 to 6 years.@*Results@#The neglect rate of preschool children in Nantong City was 28.6%, with neglect score being (40.21±6.67). The neglect rate of non-only-child was 32.6%, with neglect score being (41.14±6.73). The total and physical neglect rate of non-only-child were higher than that of only child, and the total neglect score and physical, emotional, educational, safety, medical neglect dimensional scores were higher than that of only-child, the difference were all statistically significant ( χ 2/ t = 6.21, 17.57; 3.95, 4.98, 3.45, 2.70, 2.01, 3.11, P <0.05). In non-only-child, univariate analysis showed that there were no significant differences in neglect rate and scores among children by gender and family types ( P >0.05); There was no significant difference in the child neglect rate between different age groups and children in different families ( χ 2 =3.59, 2.99, P >0.05), but there was a statistically significant difference in the degree of neglect ( t=2.79, 3.04, P <0.05). The neglect rate and score of non-only-child with high level of family income, parental education and parental relationship was relatively low, while the neglect rate and score in non-only-child whose grandparents serving as primary caregiver were higher ( P <0.05). Multivariate Logistic regression analysis showed that family monthly income less than 5 000 yuan was associated with 2.73 times higher risk of neglect compared to children with family monthly income more than 12 000 yuan. The risk of neglect among children whose grandparents serving as caregivers was associated with 2.17 times higher than children with parental care. The risk of neglect of children with poor parental relationship was 2.29 times higher than that of children with good parental relationship ( P <0.05).@*Conclusion@#The neglect among preschool non-only-child in Nantong City is common. Improvement in family economic status, parental care and parent relationship might help reduce neglect among preschool non-only-child.

Polyphenol-Based Paclitaxel Prodrug Self-Assembled Nanoplatform for Tumor Synergistic Therapy.

With the development of nanomedicine, studies focus on self-assembled nanoplatforms to reduce the toxicity of paclitaxel (PTX), promote the immune function at low-toxicity PTX, and achieve tumor synergistic therapy. Herein, a new nanoplatform was prepared with self-assembled 5-hydroxydopamine (DA)-PTX@tannic acid (TA)-Fe3+ nanoparticles (TDPP NPs) by consolidation of targeted DA-PTX and TA with the assistance of coordination between polyphenols and Fe3+. The polyphenol-based TDPP NPs can reduce the toxicity of PTX and thereby realize the in vitro and in vivo synergistic effect against tumors. The low-toxicity TDPP NPs can enhance the expression of CD40 immune protein. Moreover, the TDPP NPs possessed a small size (52.2±4 nm), high drug loading efficiency (95%), and stable pharmacokinetics, ensuring high tumor accumulation of TDPP NPs by enhanced permeability and retention effect. Our work sheds new light on the nanoformulation of PTX with low toxicity and synergistic therapy effect, which may find clinical applications in the future.

Myricetin-Based Self-Assembled Nanoparticles for Tumor Synergistic Therapy by Antioxidation Pathway.

Nanoplatforms are nano-scale systems that can transport different small molecular anticancer drugs or chemosensitization motif to accumulate in tumor cells without obvious side-effect in normal cells and achieve a synergistic therapy. In this paper the new self-assembled nanoparticles (NPs) merging doxorubicin (DOX) and myricetin (MYR) with ferric ions (Fe3+) and polyphenol was employed for forming the DOX@MYR-Fe3+ NP (FDMP NP). The FDMP NPs could reduce the DOX-induced toxicity in blood; and they could not cause damage to the heart and kidney tissues by the reasons that the MYR could enhance the anti-oxidation capability in normal cells, which resulted in preventing ROS-induced damage. Additionally, the FDMP NPs were characteristic of small size (37.70 ± 6.30 nm), high DOX loading efficiency (46.67 ± 1.58%), pH-controlled release and excellent stable pharmacokinetics, that inducing drug release and enhancing drug accumulation in the tumor. Moreover, the FDMP NPs could inhibit the expression of the hypoxia-inducible factor-1 α(HIF-1α) and the key angiogenesis mediator vascular endothelial growth factor (VEGF) both in vitro and in vivo, which succeed in preventing the generation of new blood vessel networks; that is the mechanism of the synergistic effect against tumors induced by FDMP NPs.

Cordyceps acid alleviates lung cancer in nude mice.

The aim of this study is to examine the effect of cordyceps acid (CA) on lung cancer in mice. A lung cancer animal model was established by inoculating lung cancer cells under the armpit of nude mice. The mental state, body weight, and tumor growth of nude mice were recorded in detail. The levels of Nrf-2/HO-1/NLRP3/NF-κB pathway and apoptosis in tumor tissues of nude mice were detected by the Western blot analysis and immunohistochemical methods. Our results show that CA inhibited lung cancer by regulating the Nrf-2/HO-1/NLRP3/NF-κB signal. In summary, CA has an obvious tumor inhibiting effect on lung cancer via regulation of the Nrf-2/HO-1/NLRP3/NF-κB signal.

The Epigenetic Regulator EZH2 Instructs CD4 T Cell Response to Acute Viral Infection via Coupling of Cell Expansion and Metabolic Fitness.

The protection of a majority of viral vaccines is mediated by CD4 T cell-dependent humoral immunity. The methyltransferase enhancer of zeste homolog 2 (EZH2) dictates the differentiation of naive CD4 T cells into distinct effector T helper subsets at the onset of acute viral infection. However, whether and how EZH2 manipulates differentiated virus-specific CD4 T cell expansion remain to be elucidated. Here, we found that EZH2 is integral for virus-specific CD4 T cell expansion in a mouse model of acute viral infection. By a mechanism that involves fine-tuning the mechanistic target of rapamycin (mTOR) signaling, EZH2 participates in integrating metabolic pathways to support cell expansion. The genetic ablation of EZH2 leads to impaired cellular metabolism and, consequently, poor CD4 T cell response to acute viral infection. Thus, we identified EZH2 as a novel regulator in virus-specific CD4 T cell expansion during acute viral infection.IMPORTANCE The CD4 T cell response is critical in curtailing viral infection or eliciting efficacious viral vaccination. Highly efficient expansion of virus-specific CD4 T cells culminates in a qualified CD4 T cell response. Here, we found that the epigenetic regulator EZH2 is a prerequisite for the virus-specific CD4 T cell response, with a mechanism coupling cell expansion and metabolism. Thus, our study provides valuable insights for strategies targeting EZH2 to improve the efficacy of CD4 T cell-based viral vaccines and to help treat diseases associated with aberrant CD4 T cell responses.

The Coronavirus PEDV Evades Type III Interferon Response Through the miR-30c-5p/SOCS1 Axis.

Porcine epidemic diarrhea virus (PEDV) is an economically important pathogen that has evolved several mechanisms to evade type I IFN responses. Type III interferon (IFN-λ), an innate cytokine that primarily targets the mucosal epithelia, is critical in fighting mucosal infection in the host and has been reported to potently inhibit PEDV infection in vitro. However, how PEDV escapes IFN-λ antiviral response remains unclear. In this study, we found that PEDV infection induced significant IFN-λ expression in type I IFN-defective Vero E6 cells, but virus-induced endogenous IFN-λ did not reduce PEDV titers. Moreover, we demonstrated that PEDV escaped IFN-λ responses by substantially upregulating the suppressor of cytokine signaling protein 1 (SOCS1) expression, which impaired the induction of IFN-stimulated genes (ISGs) and dampened the IFN-λ antiviral response and facilitated PEDV replication in Vero E6 cells. We further showed that PEDV infection increased SOCS1 expression by decreasing host miR-30c-5p expression. MiR-30c-5p suppressed SOCS1 expression through targeting the 3' untranslated region (UTR) of SOCS1. The inhibition of IFN-λ elicited ISGs expression by SOCS1 was specifically rescued by overexpression of miR-30c-5p. Collectively, our findings identify a new strategy by PEDV to escape IFN-λ-mediated antiviral immune responses by engaging the SOCS1/miR-30c axis, thus improving our understanding of its pathogenesis.

Targeted Prodrug-Based Self-Assembled Nanoparticles for Cancer Therapy.

BACKGROUND: Targeted prodrug has various applications as drug formulation for tumor therapy. Therefore, amphoteric small-molecule prodrug combined with nanoscale characteristics for the self-assembly of the nano-drug delivery system (DDS) is a highly interesting research topic. METHODS AND RESULTS: In this study, we developed a prodrug self-assembled nanoplatform, 2-glucosamine-fluorescein-5(6)-isothiocyanate-glutamic acid-paclitaxel (2DA-FITC-PTX NPs) by integration of targeted small molecule and nano-DDS with regular structure and perfect targeting ability. 2-glucosamine (DA) and paclitaxel were conjugated as the targeted ligand and anti-tumor chemotherapy drug by amino acid group. 2-DA molecular structure can enhance the targeting ability of prodrug-based 2DA-FITC-PTX NPs and prolong retention time, thereby reducing the toxicity of normal cell/tissue. The fluorescent dye FITC or near-infrared fluorescent dye ICG in prodrug-based DDS was attractive for in vivo optical imaging to study the behavior of 2DA-FITC-PTX NPs. In vitro and in vivo results proved that 2DA-FITC-PTX NPs exhibited excellent targeting ability, anticancer activity, and weak side effects. CONCLUSION: This work demonstrates a new combination of nanomaterials for chemotherapy and may promote prodrug-based DDS clinical applications in the future.

Association between childhood neglect and the autonomic nerves disorder in students of sixth graders / 中国学校卫生

Objective@#To explore prevalence of childhood neglect and autonomic nervous function, and its association in sixth graders students in Harbin, and to provide clues to improve physical and mental health of children and adolescents.@*Methods@#Cluster sampling method was used to select 1 259 students from grade 6 in 5 schools in two districts of Harbin, and Childhood Trauma Questionnaire-Short Form (CTQ-SF) and TOHO University Medical Index (TMI) were filled in.@*Results@#The total rate of childhood neglect was 45.7%, of which the rate of emotional neglect and physical neglect were 18.8%, 40.8%. The rate of autonomic nerves disorder was 47.2%. The rate of autonomic nerves disorder in students suffered from neglect, emotional neglect, physical neglect are higher than those without any of neglect(χ2=50.52, 32.02, 43.61, P<0.01), and with the increase of the degree of neglect, the rate of autonomic nervous disorder were gradually increasing(χ2=47.99, 47.07, 49.24, P<0.01). After controlled for gender, neglect, emotional neglect, physical neglect were positively associated with autonomic nerves disorder(OR=1.53-2.34, P<0.05), and the odd ratio for autonomic nerves disorder among those with mild-to-moderate,moderate-to-severe and extremely servere neglect was 1.37, 1.83, 5.10 compared to those with none or mild neglect.@*Conclusion@#Childhood neglect is closely related to adolescent the autonomic nerves disorder in sixth graders students in Harbin. Moreover, the more serious the childhood neglect is, the higher the detection rate of autonomic nerves disorder is. In order to improve the physical and mental health of children and adolescents, it is necessary to pay attention to childhood neglect and early assessment of their autonomic function.

Tumour microenvironment-responsive semiconducting polymer-based self-assembly nanotheranostics.

A Pt prodrug polyphenol and gadolinium ion loaded cancer theranostics nanoplatform based on mild acidic pH and thermal sensitive polymer was designed for photoacoustic (PA)/ magnetic resonance(MR)/ positron emission tomography (PET) multimodal imaging-guided chemo-photothermal combination therapy. The Pt drug release can be controlled by tumour-specific acidic pH and heat generated by external NIR irradiation. The nanoparticles were stable under normal physiological environment and released the drug under tumour acidic pH and NIR laser irradiation, which can reduce the side effect of drug to normal organs. Moreover, the MR signal can be significantly enhanced (~3-fold increase in T1 relaxivity) under the acidic tumour microenvironment, which is favorable for cancer diagnosis. The nanoparticles exhibited excellent tumour accumulation and led to complete tumour eradication with low power NIR laser irradiation. This promising approach provides a new avenue for imaging-guided combination therapy.

Interferon gamma inhibits transmissible gastroenteritis virus infection mediated by an IRF1 signaling pathway.

Interferon gamma (IFN-γ) is best known for its ability to regulate host immune responses; however, its direct antiviral activity is less well studied. Transmissible gastroenteritis virus (TGEV) is an economically important swine enteric coronavirus and causes acute diarrhea in piglets. At present, little is known about the function of IFN-γ in the control of TGEV infection. In this study, we demonstrated that IFN-γ inhibited TGEV infection directly in ST cells and intestine epithelial IPEC-J2 cells and that the anti-TGEV activity of IFN-γ was independent of IFN-α/ß. Moreover, IFN-γ suppressed TGEV infection in ST cells more efficiently than did IFN-α, and the combination of IFN-γ and IFN-α displayed a synergistic effect against TGEV. Mechanistically, using overexpression and functional knockdown experiments, we demonstrated that porcine interferon regulatory factor 1 (poIRF1) elicited by IFN-γ primarily mediated IFN-γ signaling cascades and the inhibition of TGEV infection by IFN-γ. Importantly, we found that TGEV elevated the expression of poIRF1 and IFN-γ in infected small intestines and peripheral blood mononuclear cells. Thus, IFN-γ plays a crucial role in curtailing enteric coronavirus infection and may serve as an effective prophylactic and/or therapeutic agent against TGEV infection.

Organosilica-Based Hollow Mesoporous Bilirubin Nanoparticles for Antioxidation-Activated Self-Protection and Tumor-Specific Deoxygenation-Driven Synergistic Therapy.

A major concern about glucose oxidase (GOx)-mediated cancer starvation therapy is its ability to induce serious oxidative damage to normal tissues through the massive production of H2O2 byproducts in the oxygen-involved glucose decomposition reaction, which may be addressed by using a H2O2 scavenger, known as an antioxidation agent. Surprisingly, H2O2 removal accelerates the aerobic glycometabolism of tumors by activating the H2O2-dependent "redox signaling" pathway of cancer cells. Simultaneous oxygen depletion further aggravates tumor hypoxia to increase the toxicity of a bioreductive prodrug, such as tirapazamine (TPZ), thereby improving the effectiveness of cancer starvation therapy and bioreductive chemotherapy. Herein, a "nitrogen-protected silica template" method is proposed to design a nanoantioxidant called an organosilica-based hollow mesoporous bilirubin nanoparticle (HMBRN), which can act as an excellent nanocarrier to codeliver GOx and TPZ. In addition to efficient removal of H2O2 for self-protection of normal tissues via antioxidation, GOx/TPZ-coloaded HMBRN can also rapidly deplete intratumoral glucose/oxygen to promote a synergistic starvation-enhanced bioreductive chemotherapeutic effect for the substantial suppression of solid tumor growth. Distinct from the simple combination of two treatments, this study introduces antioxidation-activated self-protection nanotechnology for the significant improvement of tumor-specific deoxygenation-driven synergistic treatment efficacy without additional external energy input, thus realizing the renaissance of precise endogenous cancer therapy with negligible side effects.