ATP-responsive near-infrared fluorescent nanoparticles for synergistic chemotherapy and starvation therapy.

Cancer is a major public health problem worldwide, and traditional chemotherapy or a single therapeutic strategy often fails to achieve expected results in cancer treatment. Thus, the development of a method to realize controlled drug delivery and synergistic therapy is required. Herein, MOF-based nanoparticles named RhI-DOX-GOD@ZIF-90 are synthesized using RhI (a near-infrared fluorescent dye), DOX (an anti-cancer drug) and GOD (glucose oxidase). RhI and DOX are encapsulated inside the ZIF-90 framework and GOD is loaded on the surface of ZIF-90. Owing to the fact that the ATP level in cancer cells is abnormally higher than that in normal cells, RhI-DOX-GOD@ZIF-90 nanoparticles are destructed only in cancer cells. RhI is released to give outstanding NIR emission and realize controlled drug delivery. DOX is released and cancer cells are killed by chemotherapy. Also, GOD is released to consume glucose and achieve the purpose of starving the cancer cells. By making full use of the advantages of near-infrared emission, RhI-DOX-GOD@ZIF-90 nanoparticles can be used to image ATP in tumor-bearing mice. At the same time, DOX and GOD can be released accurately at tumor sites of mice and excellent anti-tumor efficiency by synergistic chemotherapy and starvation therapy is achieved.

Inclusion of organic species in exfoliated montmorillonite nanolayers towards hierarchical functional inorganic-organic nanostructures.

Montmorillonite (Mt) can readily undergo spontaneous delamination or exfoliation into nanolayers by various physical and chemical processes, which allow various strategies to engineer hierarchical functional inorganic-organic nanostructures. This review aims to discuss the recent progress in the liquid-phase exfoliation of Mt into individual nanolayers and the inclusion chemistry of functional organic species, ions, or molecules into the exfoliated Mt nanolayers to produce hierarchical functional inorganic-organic nanostructures. The exfoliation methods include mechanical force, ultrasonication, and intercalation-assisted exfoliation. Techniques for quickly assessing the quality of the exfoliated Mt nanolayers are still needed. Layer-by-layer (LbL) deposition, template, and evaporation-induced inclusions are examined to fabricate hierarchical Mt-organic species nanocomposites with unique functionalities and properties. The nanocomposites can be produced as multilayered porous films, brick-and-mortar coatings, hydrogels with a house-of-cards structure, core-shell materials, and hollow and mesoporous spherical nanocomposites, which exhibit significant potential for adsorption, catalysis, targeted delivery and controlled drug release, highly sensitive sensors, flame retardant coatings, and thermal energy storage and release (i.e. phase change materials). Finally, the challenges and prospects for the future development of hierarchical nanocomposites of exfoliated Mt nanolayers and organic species, particularly in hierarchical supramolecular nanostructured composites, are highlighted.

The genomic architecture of EBV and infected gastric tissue from precursor lesions to carcinoma.

BACKGROUND: Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) present unique molecular signatures, but the tumorigenesis of EBVaGCs and the role EBV plays during this process remain poorly understood. METHODS: We applied whole-exome sequencing, EBV genome sequencing, and whole-genome bisulfite sequencing to multiple samples (n = 123) derived from the same patients (n = 25), which covered saliva samples and different histological stages from morphologically normal epithelial tissues to dysplasia and EBVaGCs. We compared the genomic landscape between EBVaGCs and their precursor lesions and traced the clonal evolution for each patient. We also analyzed genome sequences of EBV from samples of different histological types. Finally, the key molecular events promoting the tumor evolution were demonstrated by MTT, IC50, and colony formation assay in vitro experiments and in vivo xenograft experiments. RESULTS: Our analysis revealed increasing mutational burden and EBV load from normal tissues and low-grade dysplasia (LD) to high-grade dysplasia (HD) and EBVaGCs, and oncogenic amplifications occurred late in EBVaGCs. Interestingly, within each patient, EBVaGCs and HDs were monoclonal and harbored single-strain-originated EBV, but saliva or normal tissues/LDs had different EBV strains from that in EBVaGCs. Compared with precursor lesions, tumor cells showed incremental methylation in promotor regions, whereas EBV presented consistent hypermethylation. Dominant alterations targeting the PI3K-Akt and Wnt pathways were found in EBV-infected cells. The combinational inhibition of these two pathways in EBV-positive tumor cells confirmed their synergistic function. CONCLUSIONS: We portrayed the (epi) genomic evolution process of EBVaGCs, revealed the extensive genomic diversity of EBV between tumors and normal tissue sites, and demonstrated the synergistic activation of the PI3K and Wnt pathways in EBVaGCs, offering a new potential treatment strategy for this disease.

ATP-responsive near-infrared fluorescence MOF nanoprobe for the controlled release of anticancer drug.

A near-infrared (NIR) fluorescence nanoprobe named RhI-DOX@ZIF-90 has been synthesized by wrapping the guest molecule (RhI and DOX) into ZIF-90 framework. The nanoprobe itself is non-fluorescent and the drug (DOX) is inactive. Upon the addition of ATP, the structure of RhI-DOX@ZIF-90 is degraded. The fluorescence of RhI is recovered and DOX is released. The nanoprobe can detect ATP with high sensitivity and selectivity. There is good linear relationship between the nanoprobe and ATP concentration from 0.25 to 10 mM and the detection limit is 0.10 mM. The nanoprobe has the ability to monitor the change of ATP level in living cells and DOX is released inducing apoptosis of cancer cells. RhI-DOX@ZIF-90 is capable of targeting mitochondria, which provides a basis for improving the efficiency of drug delivery by mitochondrial administration. In particular, the nanoprobe is preferentially accumulated in the tumor sites and detect ATP in tumor mice by fluorescence imaging using near-infrared fluorescence. At the same time, DOX can be released accurately in tumor sites and have good anti-tumor efficiency. So, this nanoprobe is a reliable tool to realize early diagnosis of cancer and improve effect of anticancer drug.

Are Anti-Inflammatory Cytokines Associated with Cognitive Impairment in Patients with Insomnia Comorbid with Depression? A Pilot Study.

BACKGROUND: To distinguish insomnia comorbid with depression (ICD) from chronic insomnia disorder (CID) by exploring the relationship between serum levels of frequently overlooked anti-inflammatory cytokines and cognitive function. METHODS: A total of 42 ICD patients, 63 CID patients, and 42 healthy control subjects were enrolled in the study. The Pittsburgh Sleep Quality Index and Hamilton Depression Rating Scale were used to assess sleep quality and depression severity, respectively. The Chinese-Beijing version of Montreal Cognitive Assessment scale (MoCA-C) and Nine-Box Maze Test (NBMT) were used to assess cognitive function. Serum levels of anti-inflammatory interleukins (IL-1RA, IL-4, IL-5, IL-10, IL-13, and IL-28A), transforming growth factor (TGF)-ß1, granulocyte-macrophage colony-stimulating factor, interferon-γ, and the chemokine regulated upon activation, normal T cell expressed and secreted (RANTES) were measured by enzyme-linked immunosorbent assay. RESULTS: The ICD group had significantly more errors in the spatial reference task (H=2.55, Ps=0.03) and spatial working memory task (H=5.67, Ps<0.01) of the NBMT, as well as lower levels of IL-1RA (H=-2.85, Ps=0.01), IL-4 (H=-3.28, Ps<0.01), IL-5 (H=-3.35, Ps<0.01), IL-10 (H=-4.46, Ps<0.01), and IL-28A (H=-2.75, Ps=0.02) than control subjects. Compared with the CID group, the ICD group had significantly more errors in the spatial reference memory task (H=-2.84, Ps=0.01) of the NBMT, and lower levels of IL-5 (H=3.41, Ps<0.01), IL-10 (H=5.30, Ps<0.01), IL-13 (H=3.89, Ps<0.01), and GM-CSF (H=2.72, Ps=0.02). A partial correlation analysis showed that the level of one or more of IL-4, IL-5, IL-10, IL-13, and TGF-ß1 was positively correlated with cognitive function (MoCA-C score and/or performance in spatial memory task) in ICD patients. CONCLUSION: ICD is a distinct condition that can be distinguished from CID based on immune dysfunction and specific types of cognitive dysfunction.

Development and Validation of a Prognostic Signature Based on Immune Genes in Cervical Cancer.

BACKGROUND: Cervical cancer is one of the most common types of gynecological malignancies worldwide. This study aims to develop an immune signature to predict survival in cervical cancer. METHOD: The gene expression data of 296 patients with cervical cancer from The Cancer Genome Atlas database (TCGA) and immune-related genes from the Immunology Database and Analysis Portal (ImmPort) database were included in this study. The immune signature was developed based on prognostic genes. The validation dataset was downloaded from the Gene Expression Omnibus (GEO) database. RESULT: The immune signature namely immune-based prognostic score (IPRS) was developed with 229 genes. Multivariate analysis revealed that the IPRS was an independent prognostic factor for overall survival (OS) and progression-free survival (PFS) in patients with cervical cancer. Patients were stratified into high IPRS and low IPRS groups, and those in the high IPRS group were associated with better survival, which was validated in the validation set. A nomogram with IPRS and stage was constructed to predict mortality in cervical cancer. CONCLUSIONS: We developed a robust prognostic signature IPRS that could be used to predict patients' survival outcome.

Near-Infrared Fluorescence MOF Nanoprobe for Adenosine Triphosphate-Guided Imaging in Colitis.

Adenosine triphosphate (ATP) is mainly produced in mitochondria and plays an important role in lots of pathological processes such as colitis. Unfortunately, to date, few suitable fluorescence probes have been developed for monitoring the ATP level in colitis. Herein, a fluorescence nanoprobe named NIR@ZIF-90 is proposed and prepared by encapsulating a rhodamine-based near-infrared (NIR) dye into zeolitic imidazolate frameworks (ZIF-90). The nanoprobe is nonfluorescent because the emission of NIR is suppressed by the encapsulation, while in the presence of ATP, the framework of ZIF-90 is dissembled to release NIR and thus NIR fluorescence at 750 nm is observed. The nanoprobe shows high sensitivity to ATP with a 72-fold increase and excellent selectivity to ATP over other nucleotides. Moreover, with low cytotoxicity and good mitochondria-targeted ability, NIR@ZIF-90 is used to image ATP in colorectal cancer cells (HCT116). In addition, due to the NIR emission, the nanoprobe is further employed to successfully monitor the ATP level in a colitis mouse model. To the best of our knowledge, the nanoprobe is the first example to study colitis in vivo with the guidance of ATP, which will provide an efficient tool for understanding colitis.

Arginine Vasopressin-Aquaporin-2 Pathway-Mediated Dehydration Effects of Electroacupuncture in Guinea Pig Model of AVP-Induced Eendolymphatic Hydrops.

OBJECTIVE: To investigate the effects of electroacupuncture (EA) on endolymphatic hydrops (EH) and the regulation of arginine vasopressin (AVP)-aquaporin-2 (AQP2) pathway in guinea pigs. METHODS: EH was induced in male guinea pigs by an intraperitoneal injection of AVP. For the treatment, EA was delivered to Baihui (GV 20) and Tinggong (SI 19) acupoints, once per day for 10 consecutive days. In histomorphological studies, cochlear hydrops degree was evaluated by hematoxylin-eosin (HE) staining, and then the ratio of scala media (SM) area to SM + scala vestibuli (SV) area (R value) was calculated. In mechanical studies, a comparison of plasma AVP (p-AVP) concentrations, cyclic adenosine monophosphate (cAMP) levels, vasopressin type 2 receptor (V2R) and AQP2 mRNA expressions in the cochlea were compared among groups. RESULTS: EA significantly reduced cochlear hydrops in guinea pigs (P=0.001). EA significantly attenuated the AVPinduced up-regulation of p-AVP concentrations (P=0.006), cochlear cAMP levels (P=0.003) and AQP2 mRNA expression (P=0.016), and up-regulated the expression of V2R mRNA (P=0.004) in the cochlea. CONCLUSIONS: The dehydrating effect of EA might be associated with its inhibition of AVP-AQP2 pathway activation.

The opposite roles of PAS-5 and Galectin-1 in immune response during the early infection of Angiostrongylus cantonensis.

BACKGROUND: Angiostrongylus cantonensis is a human zoonotic nematode parasite. Our previous studies found that PAS-5 and Galectin-1 (Gal-1) proteins of A. cantonensis could be strongly recognized by sera from mice infected with A. cantonensis. In this study, we further evaluated the potential roles of these two proteins in the induction of immune response in mice. METHODS: Mice were immunized with recombinant PAS-5 or Gal-1 and then challenged with 30 infective A. cantonensis larvae following the last immunization. We then examined the infected mice for changes in serum antibodies and cytokines by ELISA, CD4+ T cells and CD4+CD25+FoxP3+ regulatory T cells (Tregs) by flow cytometry, and tissue damage severity by hematoxylin-eosin (H&E) staining. RESULTS: Compared with control mice, the PAS-5-immunized mice exhibited increased levels of serum antibodies and cytokines (except for IL-10) at different time points post-infection. PAS-5 immunization promoted significant proliferation of CD4+ T cells, and caused more damage in the brain tissue. Vaccination with Gal-1 inhibited the production of antibodies (except for IgG1) and IFN-γ, but promoted the expression of IL-4 and IL-10. Gal-1 immunization results in significant increases in the levels of CD4+CD25+FoxP3+ Tregs, and mild inflammatory changes. CONCLUSIONS: Taken together, our findings show that PAS-5 enhances, but Gal-1 inhibits the immune response in the early stage of A. cantonensis infections.

Genomic comparison of esophageal squamous cell carcinoma and its precursor lesions by multi-region whole-exome sequencing.

Esophageal squamous dysplasia is believed to be the precursor lesion of esophageal squamous cell carcinoma (ESCC); however, the genetic evolution from dysplasia to ESCC remains poorly understood. Here, we applied multi-region whole-exome sequencing to samples from two cohorts, 45 ESCC patients with matched dysplasia and carcinoma samples, and 13 tumor-free patients with only dysplasia samples. Our analysis reveals that dysplasia is heavily mutated and harbors most of the driver events reported in ESCC. Moreover, dysplasia is polyclonal, and remarkable heterogeneity is often observed between tumors and their neighboring dysplasia samples. Notably, copy number alterations are prevalent in dysplasia and persist during the ESCC progression, which is distinct from the development of esophageal adenocarcinoma. The sharp contrast in the prevalence of the 'two-hit' event on TP53 between the two cohorts suggests that the complete inactivation of TP53 is essential in promoting the development of ESCC.The pathogenesis of oesophageal squamous cell carcinoma is a multi-step process but the genetic determinants behind this progression are unknown. Here the authors use multi-region exome sequencing to comprehensively investigate the genetic evolution of precursor dysplastic lesions and untransformed oesophagus.

Electro-acupuncture treatment for internet addiction: Evidence of normalization of impulse control disorder in adolescents.

OBJECTIVE: To observe the impacts of electro-acupuncture (EA) and psychological intervention (PI) on impulsive behavior among internet addiction (IA) adolescents. METHODS: Thirty-two IA adolescents were allocated to either EA (16 cases) or PI (16 cases) group by a randomized digital table. Subjects in the EA group received EA treatment and subjects in the PI group received cognition and behavior therapy. All adolescents underwent 45-d intervention. Sixteen healthy volunteers were recruited into a control group. Barratt Impulsiveness Scale (BIS-11) scores, Young's Internet Addiction Test (IAT) as well as the ratio of brain N-acetyl aspartate (NAA) to creatine (NAA/Cr) and choline (Cho) to creatine (Cho/Cr) were recorded by magnetic resonance spectroscopy before and after intervention respectively. RESULTS: The IAT scores and BIS-11 total scores in both EA and PI group were remarkably decreased after treatment (P<0.05), while EA group showed more significant decrease in certain BIS-11 sub-factors (P<0.05). Both NAA/Cr and Cho/Cr were significantly improved in EA group after treatment (P<0.05); however, there were no significant changes of NAA/Cr or Cho/Cr in PI group after treatment (P>0.05). CONCLUSIONS: Both EA and PI had significantly positive effect on IA adolescents, especially in the aspects of psychological experiences and behavioral expressions, EA might have an advantage over PI in terms of impulsivity control and brain neuron protection. The mechanism underlying this advantage might be related to the increased NAA and Cho levels in prefrontal and anterior cingulate cortices.

Single-cell analyses of circulating tumor cells.

Circulating tumor cells (CTCs) are a population of tumor cells mediating metastasis, which results in most of the cancer related deaths. The number of CTCs in the peripheral blood of patients is rare, and many platforms have been launched for detection and enrichment of CTCs. Enumeration of CTCs has already been used as a prognosis marker predicting the survival rate of cancer patients. Yet CTCs should be more potential. Studies on CTCs at single cell level may help revealing the underlying mechanism of tumorigenesis and metastasis. Though far from developed, this area of study holds much promise in providing new clinical application and deep understanding towards metastasis and cancer development.

[Risk factors for suicide attempt among college students at Central South University].

OBJECTIVE: To understand the prevalence and risk factors for suicidal ideation among college students and to provide a scientific basis for promoting psychological health and suicide prevention. METHODS: 623 college students at Central South University were selected using stratified cluster sampling and administered a suicide ideation questionnaire, a Symptom Check List (SCL-90), an Adolescent Self-Rating Life Events Check List (ASLEC), a Social Support Rating Scale (SSRS) and a questionnaire about background information. Multivariate logistic regression analysis was employed to identify risk factors for suicide ideation. RESULTS: One year prior to our investigation, 14.6% of respondents had suicide ideation, 2.5% had made a specific suicide plan, and 1.8% had made a suicide attempt. The main risk factors for suicide ideation were dissatisfaction with the selected major of study, limited social support, recent negative life events and depressive tendency. CONCLUSIONS: The prevalence of suicide ideation among these college students was high. Appropriate measures focusing on the risk factors identified in this study should be urgently developed to prevent suicides in college students.