Asymmetric Cyclodextrin-Dimer-Involved Nanoassemblies by Selective Host-Guest Interactions: Concentration-Dependent Morphology Evolution and Light-Regulated Biomedical Applications.

Supramolecular assembly has attracted significant attention and has been applied to various applications. Herein, a ß-γ-CD dimer was synthesized to complex different guest molecules, including single-strand polyethylene glycol (PEG)-modified C60 (PEG-C60), photothermal conversion reagent (IR780), and dexamethasone (Dexa), according to the complexation constant-dependent specific selectivity. Spherical or cylindrical nanoparticles, monolayer or bilayer vesicles, and bilayer fusion vesicles were discovered in succession if the concentration of PEG-C60 was varied. Moreover, if near-infrared light was employed to irradiate these nanoassemblies, the thermo-induced morphological evolution, subsequent cargo release, photothermal effect, and singlet oxygen (1O2) generation were successfully achieved. The in vitro cell experiments confirmed that these nanoparticles possessed excellent biocompatibility in a normal environment and achieved superior cytotoxicity by light regulation. Such proposed strategies for the construction of multilevel structures with different morphologies can open a new window to obtain various host-guest functional materials and achieve further use for disease treatment.

Synergistic chemo-photo anticancer therapy by using reversible Diels-Alder dynamic covalent bond mediated polyprodrug amphiphiles and immunoactivation investigation.

Highly efficient endocytosis and multi-approach integrated therapeutic tactics are important factors in oncotherapy. With the aid of thermally reversible furan-maleimide dynamic covalent bonds and the "polyprodrug amphiphiles" concept, thermo- and reduction-responsive PEG(-COOH)Fu/MI(-SS-)CPT copolymers were fabricated by the Diels-Alder (D-A) coupling of hydrophilic Fu(-COOH)-PEG and hydrophobic MI(-SS-)-CPT building blocks. The copolymers could self-assemble to form composite nanoparticles with a photothermal conversion reagent (IR780) and maintain excellent stability. In the in vitro simulated environments, the composite nanoparticles could detach Fu(-COOH)-PEG chains by a retro-D-A reaction upon near-infrared light (NIR) irradiation and reduce the size to facilitate endocytosis. Once in the intracellular environment, glutathione (GSH) could trigger a cascade reaction to release active CPT drugs to achieve chemotherapy, which could be further promoted by NIR light induced photothermal therapy. The in vivo mouse tumor model experiments demonstrated that these nanoparticles had an excellent therapeutic effect on solid tumors and inhibited their recurrence. Not only that, the synergistic chemical and optical therapy induced body immune response was also systematically evaluated; the maturation of dendritic cells, the proliferation of T cells, the increase of high mobility group box protein 1, and the decrease of immunosuppressive regulatory T cells confirmed that such synergistic therapy could effectively provide immune protection to the body. We believe such in situ generation of small-sized therapeutic units brought by a dynamically reversible D-A reaction could expand the pathway to design next generation drug delivery systems possessing superior design philosophy and excellent practice effects compared to currently available ones.

A2AR limits IL-15-induced generation of CD39+ NK cells with high cytotoxicity.

CD39-mediated inhibition of natural killer (NK) cell activity has been demonstrated, but the characteristics of CD39+ NK cells in humans are not known. We investigated the characteristics of human circulating CD39+ NK cells. In healthy donors, the proportion of circulating CD39+ NK cells in total NK cells was relatively low compared with that of CD39- NK cells. Nonetheless, a higher proportion of CD39+ NK cells expressed CD107a. Similarly, a higher proportion of CD39+ NK cells expressed CD107a in patients with hepatitis B virus or patients with hepatocellular carcinoma. Stimulation with NK-sensitive K562 cells or interleukin (IL)-12/IL-18 activated CD39+ NK cells to express higher levels of CD107a, IFN-γ and TNF-α, relative to CD39- NK cells. Importantly, IL-15 induced the generation of CD39+ NK cells. In contrast, A2A adenosine receptor (A2AR) ligation suppressed the generation of CD39+ NK cells by inhibiting IL-15 signaling. These data for the first time demonstrated that A2AR counteracts IL-15-induced generation of human CD39+ NK cells, which have a stronger cytotoxicity than CD39- NK cells. IL-15-induced human CD39+ NK cells might be better choice for immunotherapy based on adoptive transfer of NK cells.

Highly flexible hydrogel dressing with efficient antibacterial, antioxidative, and wound healing performances.

Bacterial induced wound infection is very common in real life, but the abuse of antibiotics means that is poses a potential threat to human health. The development of non-antibiotic type antibacterial materials appears to be of importance. Herein, a microenvironment-responsive and biodegradable hydrogel complex, consisting of an acid-degradable antibacterial hydrogel and a hydrogen peroxide (H2O2)-responsive polymer/gold hybrid film with photothermal conversion ability was constructed based on polyethylenimine (PEI), polyethylene glycol (PEG), hexachlorocyclic triphosphonitrile (HCCP), and gold nanoparticles. The resultant hydrogel showed excellent adhesion to various surfaces, whether in air or underwater. However, a simple glycerine and water (v/v = 1/1) mixed solution could rapidly promote the detachment of the hydrogel from skin automatically, without any external force and no residue was left, exhibiting a manmade controllable flexible feature. Moreover, the in vitro antibacterial performance against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus (S. aureus), as well as wound healing investigations conducted in living mice confirmed that these hydrogels possessed excellent antibacterial, antioxidative, and wound healing abilities. We believe this proof of concept could create a novel pathway for the design and construction of highly efficient hydrogel dressings using readily available polymeric materials and that the resulting dressing have potential for clinical applications.

PD-1 blockade improves the anti-tumor potency of exhausted CD3+CD56+ NKT-like cells in patients with primary hepatocellular carcinoma.

CD3+CD56+ NKT-like cells play pivotal roles in the anti-tumor immune defense response. However, little is known regarding circulating NKT-like cells in patients with primary hepatocellular carcinoma (HCC). In the present study, we demonstrate that circulating NKT-like cells in HCC patients are functionally impaired and anti-PD-1 blockade improves their anti-tumor potency. Circulating NKT cells were mainly comprised of CD8+ T cells. The frequencies and absolute counts of circulating NKT-like cells were comparable between HCC patents compared to healthy donors. NKT-like cells in HCC patients were impaired in their production of TNF-α and IFN-γ as well as cytotoxicity. The level of activating receptor NKG2D was significantly decreased on NKT-like cells in HCC patients. In contrast, the expression of inhibitory receptors PD-1, Tim-3, and CTLA-4 were markedly increased on NKT-like cells in HCC patients. Meanwhile, the expression of PD-L1 was also upregulated on NKT-like cells in HCC patients. In detail, PD-1+ NKT-like cells expressed lower levels of NKG2D, higher levels of Tim-3, and CTLA-4, and less IFN-γ when compared with PD-1- NKT-like cells. Importantly, PD-1 blocked with anti-PD-1 antibody effectively improved the effector function of NKT-like cells from HCC patients or healthy donors. Our findings unveil the functional characterization of NKT-like cells in HCC patients and provide the potential targets to improve their function, which might benefit the optimization of HCC immunotherapy.

Siglec-7 is an indicator of natural killer cell function in acute myeloid leukemia.

Immune dysfunction is an established risk factor in acute myeloid leukemia (AML). The cytotoxicity of natural killer (NK) cells is greatly impaired in AML, and the profile of NK cell receptors is markedly altered in AML; however, this is not yet well characterized. In this study, we found the downregulation of Siglec-7 could be utilized as a potential marker of NK cell dysfunction in AML. The absolute numbers and percentages of NK cells were declined in the peripheral blood of patients with AML, and the levels of activating receptors NKG2D, NKp46, and NKp30 were reduced in NK cells from patients with AML compared with healthy controls. In contrast, the levels of inhibitory receptors TIM-3, ILT-4, ILT-5, and PD-1 were increased in NK cells from patients with AML. Of note, the level of Siglec-7 in NK cells from patients with AML was significantly lower than that in NK cells from healthy controls, and Siglec-7+ NK cells displayed higher levels of activating receptors and stronger cytotoxicity when compared with Siglec-7- NK cells. Our data indicate that decreased Siglec-7 level may predict NK cell dysfunction in AML, and NK cells may be promising targets of immunotherapy for AML.

Childhood Clear Cell Sarcoma of Kidney: Incidence and Survival.

This study is to describe current incidence of childhood clear cell sarcoma of kidney (CCSK) and to investigate the present survival of this cancer. Surveillance, Epidemiology, and End Result (SEER) data was used to identify children with CCSK and Wilms tumor (WT) aged 0-19 years in the US. Age-adjusted incidences were estimated over the decades. Age- and sex-specific epidemiology was also presented. Propensity score matching was used to balance features of CCSK and WT cases. Log rank test was used to compare survivals and Cox regression was used to evaluate independent effects of factors. The present age-adjusted incidence of childhood CCSK was 0.205 per million, which remained stable for years and ranked third in all pediatric renal tumors. The incidence rate ratios for boy and age under 4 were 3 and 21, respectively. The current 5-year overall survival (OS) rate for CCSK was 87%, which is not evidently inferior to that for WT (90%); however the outcome of CCSK was significantly poorer if both groups were well-balanced (OS rate was 86 vs. 95%). Early year of diagnosis and distant metastasis were independent survival factors. In conclusion, occurrence of CCSK remains stable over the years, with an age-adjusted incidence of 0.205 per million. Boy and age under 4 are risk factors for tumor development. CCSK currently has a favorable outcome but its nature may be more aggressive than common kidney tumor, which in turn proves efficacy of modern treatment.

Modulation of Interhemispheric Functional Coordination in Breast Cancer Patients Receiving Chemotherapy.

OBJECTIVES: Chemotherapy induces cognitive impairments including memory impairment attention deficit and executive dysfunction in patients with breast cancer (BC) during or after chemotherapy. Previous studies identified brain structural and functional changes in BC patients receiving chemotherapy; however, there are no studies assessing functional connectivity (FC) between homotopic brain regions in BC patients using a voxel-mirrored homotopic connectivity (VMHC) method. In the present study, we explored cognitive function and whole brain homotopic FC in BC patients receiving chemotherapy compared with healthy controls using the VMHC method. METHODS: The present cross-sectional study included 35 premenopausal women with breast cancer who received chemotherapy, as well as 32 age- and sex-matched healthy controls (HC). All subjects underwent resting-state functional magnetic resonance imaging, which measured homotopic brain FC, and cognitive neuropsychological assessments evaluating attention, memory, and executive function domains. RESULTS: The BC group had lower VMHC than the HC group in the cingulated posterior, insular and postcentral regions. No region exhibited higher VMHC in the BC group than in HC group. Correlation analysis in the BC group indicated that VMHC values in the cingulated posterior were significantly correlated with executive function tests, and that the VMHC values in the insular were significantly correlated with memory tests. CONCLUSION: The present study showed that VMHC decreased in different brain regions including cingulated posterior, insular and postcentral regions. A significant correlation was observed between the VMHC values in the brain regions and neuropsychological tests. These results suggested that changes in VMHC values in different brain regions may underlie cognitive changes in BC patients receiving chemotherapy.

A progressive neurological condition with acquired sea-blue histiocytosis further the diagnosis of Niemann-Pick type C1 in a 10-year-old boy.

Sea-blue histiocytes in bone marrow can be associated with a number of conditions and have indeed often been reported in Niemann-Pick diseases, mostly in Niemann-Pick type B, but also Niemann-Pick type C. Rarely, it was reported to be related to a progressive neurological condition. In this work, early bone marrow aspirations in a boy following the discovery of hepatosplenomegaly at 1 month of age and later isolated splenomegaly did not reveal abnormal cells (which is not uncommon). Numerous sea-blue histiocytes were found in a repeated exam when the child was 10-year old, at a time he had developed a progressive neurological condition with frequent falls, clumsiness, slow and slurred speech, intellectual disability, dystonic movements, and dysphagia. Acquired sea-blue histiocytes should be considered initially on the basis of clinical symptoms. Whole-exome sequencing identified two variants in the NPC1 gene, leading to the diagnosis of Niemann-Pick type C1. This case points out the presence of sea-blue histiocytes in the bone marrow and has helped to reach a diagnosis of NPC1 which was very difficult to establish even after years of study. Given the rarity of this pathology and the variety of clinical presentations, it is important to communicate the possible forms of presentation of this syndrome.

Classification of schizophrenia by intersubject correlation in functional connectome.

Functional connectomes have been suggested as fingerprinting for individual identification. Accordingly, we hypothesized that subjects in the same phenotypic group have similar functional connectome features, which could help to discriminate schizophrenia (SCH) patients from healthy controls (HCs) and from depression patients. To this end, we included resting-state functional magnetic resonance imaging data of SCH, depression patients, and HCs from three centers. We first investigated the characteristics of connectome similarity between individuals, and found higher similarity between subjects belonging to the same group (i.e., SCH-SCH) than different groups (i.e., HC-SCH). These findings suggest that the average connectome within group (termed as group-specific functional connectome [GFC]) may help in individual classification. Consistently, significant accuracy (75-77%) and area under curve (81-86%) were found in discriminating SCH from HC or depression patients by GFC-based leave-one-out cross-validation. Cross-center classification further suggests a good generalizability of the GFC classification. We additionally included normal aging data (255 young and 242 old subjects with different scanning sequences) to show factors could be improved for better classification performance, and the findings emphasized the importance of increasing sample size but not temporal resolution during scanning. In conclusion, our findings suggest that the average functional connectome across subjects contained group-specific biological features and may be helpful in clinical diagnosis for schizophrenia.

Neural Correlates of Auditory Verbal Hallucinations in Schizophrenia and the Therapeutic Response to Theta-Burst Transcranial Magnetic Stimulation.

Auditory verbal hallucinations (AVHs) are a core symptom of schizophrenia, and resistant to antipsychotic medication in a substantial proportion of patients. This study aimed to investigate the neural correlates of AVHs in schizophrenia patients and its response to a modified continuous theta-burst stimulation (cTBS) by transcranial magnetic stimulation. In a cross-sectional experiment, resting-state functional magnetic resonance images were collected from 31 AVH schizophrenia patients, 26 non-AVH schizophrenia patients, and 33 sex-/age-matched healthy controls (HCs). Functional connectivity strength (FCS) maps were compared among groups by 1-way analysis of variance (ANOVA). In a longitudinal experiment, 16 and 11 AVH patients received real and sham cTBS treatment for 15 days, respectively. Notably, this was not a randomized control trail. Changes in AVH and FCS were analyzed by 2-way ANOVA and 2-sample t-test, respectively. In the cross-sectional experiment, comparison of FCS maps identified 8 clusters among groups, but only one cluster (in left cerebellum) differed significantly in AVH patients compared to both HCs and non-AVH patients. In the longitudinal experiment, the real cTBS group showed a greater improvement in symptoms and a larger FCS decrease in left cerebellum than the sham group. Pearson's correlation analysis indicated that baseline FCS of the overlapping cerebellum cluster (between the cross-sectional and longitudinal findings) was negatively correlated with symptom improvement in the real treatment group. These findings emphasize the role of the left cerebellum in both the pathophysiology and clinical treatment of AVHs in schizophrenia patients.

The attention network changes in breast cancer patients receiving neoadjuvant chemotherapy: Evidence from an arterial spin labeling perfusion study.

To investigate the neural mechanisms underlying attention deficits that are related to neoadjuvant chemotherapy in combination with cerebral perfusion. Thirty one patients with breast cancer who were scheduled to receive neoadjuvant chemotherapy and 34 healthy control subjects were included. The patients completed two assessments of the attention network tasks (ANT), neuropsychological background tests, and the arterial spin labeling scan, which were performed before neoadjuvant chemotherapy and after completing chemotherapy. After neoadjuvant chemotherapy, the patients exhibited reduced performance in the alerting and executive control attention networks but not the orienting network (p < 0.05) and showed significant increases in cerebral blood flow (CBF) in the left posterior cingulate gyrus, left middle occipital gyrus, bilateral precentral gyrus, inferior parietal gyrus, supramarginal gyrus, angular gyrus, precuneus, cuneus, superior occipital gyrus, calcarine cortex, and temporal gyrus (p < 0.01 corrected) when compared with patients before chemotherapy and healthy controls. A significant correlation was found between the decrease performance of ANT and the increase in CBF changes in some brain regions of the patients with breast cancer. The results demonstrated that neoadjuvant chemotherapy influences hemodynamic activity in different brain areas through increasing cerebral perfusion, which reduces the attention abilities in breast cancer patients.

The Working Memory and Dorsolateral Prefrontal-Hippocampal Functional Connectivity Changes in Long-Term Survival Breast Cancer Patients Treated with Tamoxifen.

Background: Tamoxifen is the most widely used drug for treating patients with estrogen receptor-sensitive breast cancer. There is evidence that breast cancer patients treated with tamoxifen exhibit cognitive dysfunction. However, the underlying neural mechanism remains unclear. The present study aimed to investigate the neural mechanisms underlying working memory deficits in combination with functional connectivity changes in premenopausal women with breast cancer who received long-term tamoxifen treatment. Methods: A total of 31 premenopausal women with breast cancer who received tamoxifen and 32 matched healthy control participants were included. The participants completed n-back tasks and underwent resting-state functional magnetic resonance imaging, which measure working memory performance and brain functional connectivity, respectively. A seed-based functional connectivity analysis within the whole brain was conducted, for which the dorsolateral prefrontal cortex was chosen as the seed region. Results: Our results indicated that the tamoxifen group had significant deficits in working memory and general executive function performance and significantly lower functional connectivity of the right dorsolateral prefrontal cortex with the right hippocampus compared with the healthy controls. There were no significant changes in functional connectivity in the left dorsolateral prefrontal cortex within the whole brain between the tamoxifen group and healthy controls. Moreover, significant correlations were found in the tamoxifen group between the functional connectivity strength of the dorsolateral prefrontal cortex with the right hippocampus and decreased working memory performance. Conclusion: This study demonstrates that the prefrontal cortex and hippocampus may be affected by tamoxifen treatment, supporting an antagonistic role of tamoxifen in the long-term treatment of breast cancer patients.

Executive Function Alternations of Breast Cancer Patients After Chemotherapy: Evidence From Resting-state Functional MRI.

RATIONALE AND OBJECTIVES: Chemotherapy has many side effects on breast cancer patients, including cognition and other brain functions impairment, which can be studied using functional magnetic resonance imaging (fMRI). Our study aimed at investigating the executive function alternations of breast cancer patients after chemotherapy using resting-state fMRI. MATERIALS AND METHODS: This study included 32 breast cancer patients (BC group) and 24 control subjects (HC group). The functional connectivity of the dorsolateral prefrontal cortex (DLPFC) of the two groups was calculated from the resting-state fMRI data, and the correlation between the strength of the right DLPFC's connectivity and the behavior performance was analyzed with two-tailed Pearson correlative analysis. RESULTS: Evaluation of the capability of processing various complex cognition events showed that the executive function of the BC group was impaired after chemotherapy in comparison with the HC group. The functional connectivities of the right DLPFC with the right inferior frontal gyrus, right medial frontal gyrus, and left superior temporal gyrus in the BC group were significantly decreased in comparison with those in the HC group, respectively. The executive deficits were found correlated with the functional connectivity between the right DLPFC and the right inferior frontal gyrus. Meantime, the functional connectivity from the right DLPFC to the right middle temporal gyrus and the precuneus was compensatorily increased in the BC group, respectively. CONCLUSIONS: These findings suggest that breast cancer patients after chemotherapy demonstrate executive control impairment, and provide evidence that the observed defects are correlated with alternations in the executive network of the brain.

[Study on the psychological health condition among junior and senior high school students in Beijing, Shanghai and Guangzhou].

OBJECTIVE: To describe the status and difference of students' mental health in junior high school, ordinary high school and vocational high school in Beijing, Shanghai and Guangzhou. METHODS: 135 schools and 14 473 students were randomly selected and stratified to draw the sample. Mental Health Test (MHT) was used to measure the status of students' mental health. RESULTS: Among 13 286 valid questionnaire, 2.1% students were mentally disabled, more females reported their mental problems (2.1%) than males (1.9%). Students from Shanghai (2.5%) and Beijing (2.3%) were more likely to report their mental problems than students from Guangzhou (1.6%), which were statistically significant. The top three mental problems includes anxiety (42.6%), physical condition (11.1%) and self - blame tendency (9.7%), etc. CONCLUSION: Students from Beijing, Shanghai and Guangzhou got different extend of mental problems.

[Effects of egg and milk supplementation on growth and development among children in poor rural area].

OBJECTIVE: To evaluate the effects of egg and milk supplementation on growth and development and body composition among children in poor rural area in Tianyang County of Guangxi province. METHODS: Total four schools were randomly selected from four towns in Tianyang County of Guangxi province as intervention group in April, 2013. The intervention measures included that these students were given salty egg (net weight: 50 g) and ultra-high-temperature-sterilization school milk (net weight: 200 g) every school day and these schools were equipped with standard kitchens. Another four schools of familiar socio-economic level, teaching quality and size from the same town were randomly chosen as control group and none of the intervention measures were implemented. About 25 students were randomly selected and stratified by grades from grade one to grade five. The height, weight, and body composition of all students were measured in April, 2013 and one year after the intervention. A total of 978 students were measured at baseline from age 6 to 13, 552 students as intervention group and 426 as control group. t-test was used to compare the differences between groups and multivariate unconditional logistic regression was used to analyze the factors of malnutrition. RESULTS: After one year intervention, 892 students were measured randomly, with 515 students in intervention group and 377 in control one. The average weight of boys in intervention group increased (3.6 ± 1.7) kg compared with baseline. It was significantly higher than that of control group ((2.9 ± 1.5) kg) (t = 4.40, P < 0.001). The boy's lean body mass of intervention group increased (2.6 ± 1.4) kg, higher than the control group ((2.0 ± 1.2) kg) (t = 3.95, P < 0.001). The decrease of malnutrition rate of intervention schools (11.8%) was significantly higher than that of the control schools (4.7%, χ² = 16.90, P < 0.001), and the odds ratio was 0.37 (95% CI: 0.23-0.59). The risk difference of overweight and obesity was not statistically significant between the two groups (OR = 1.68, 95% CI: 0.57-4.94). CONCLUSION: After supplementing milk and egg, the nutritional status of the poor rural pupils was improved.