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There is increasing evidence that circular RNAs (circRNAs) can serve as microRNA (miRNA) sponges to regulate metastasis of multiple tumors, including pancreatic ductal adenocarcinoma (PDAC). However, the role of the circRNA/miRNA regulatory network in metastasis of PDAC has not been elucidated. The purpose of this study is to explore the role of circ_0047744/miR-21/SOCS5 in the metastasis of PDAC. We found that circRNA_0047744 was weakly expressed in PDAC tissues and cell lines. The expression of circ_0047744 was negatively correlated with lymph node metastasis and positively correlated with overall survival in PDAC patients. Functionally, the overexpression of circ_0047744 suppressed cell migration and invasion in vitro and in vivo. Mechanistically, circ_0047744 could regulate SOCS5 expression by acting as a sponge of miR-21 to inhibit migration and invasion of PDAC cells. Our study demonstrates that circ_0047744 acts as an anti-oncogene to inhibit PDAC metastasis by regulating the miR-21/SOCS5 axis, indicating that circ_0047744 may be a potential novel therapeutic target for PDAC patients.

Emerging evidence suggests that cytotoxic therapy may promote drug resistance and metastasis while inhibiting the growth of primary tumors. As yet, however, the underlying mechanisms remain unclear. Here, we aimed to investigate the pro-metastatic effects of adriamycin (ADR) therapy on breast cancer cells and to investigate the mechanisms underlying these effects. Differentially expressed genes between MCF-7 and ADR-resistant MCF-7 breast cancer cells were identified using high-throughput RNA-seq and differential gene expression analyses. In vitro transwell and scratch wound-healing assays, and an in vivo spontaneous metastasis model were used to study the metastatic potential of the breast cancer cells. The relationship between SIRT7 and TEK expression was studied using promoter activity, electrophoretic mobility shift (EMSA), CHIP-qPCR and Co-IP assays. Using transcriptome sequencing, we identified two key genes (SIRT7 and TEK) that might contribute to the pro-metastatic effect of ADR on breast cancer cells. SIRT7 acted as a negative regulator for TEK by inducing deacetylation of H3K18 at the TEK promoter. Through transcription factor prediction and double fluorescence experiments, we found that EST-1 could bind to the TEK promoter. Knockdown of EST-1 removed the transcriptional inhibition of TEK that was mediated by up-regulation of SIRT7. Co-IP showed that SIRT7 interacts directly with EST-1 in breast cancer cells, indicating that SIRT7 may induce H3K18 deacetylation at the TEK promoter region by directly binding to EST-1. In vitro and in vivo results showed that overexpression of SIRT7 or inhibition of TIE2 significantly reduced ADR-dependent breast cancer cell invasion/metastasis. Our findings suggest that ADR therapy may accelerate breast cancer metastasis in a SIRT7/TEK(TIE2) dependent manner.

Background: ATP-Binding Cassette subfamily G member 2 (ABCG2) is a semi-transport protein that plays a key role in human diseases, including bladder cancer and lung cancer, and maybe resistant to chemotherapy drugs. Objective: The present study aimed to determine the role and underlying mechanisms of breast cancer resistance protein (ABCG2) in breast cancer and to study the reversal effect of inhibiting ABCG2 expression on the drug resistance of breast cancer cells and provide new ideas for gene-targeted therapy of breast cancer. Methods: The structure and genomic alterations of ABCG2 were systematically investigated using GeneCards and cBioPortal to reveal the genetic alterations (including amplification and deep deletions) of ABCG2. We performed the correlation between ABCG2 expression and clinicopathological parameters using the data in bc-GenExMiner 4.4. Then, the protein-protein interaction and functional enrichment analysis of ABCG2 were performed based on the STRING, bc-GenExMiner 4.4, and Enrichr databases. Besides, we analyzed the pathway activity of genes that interact with ABCG2 using GSCALite and PharmGKB. Using magnetic nanoparticles polyMAG as the carrier of ABCG2-siRNA, polyMAG-ABCG2-siRNA was transfected into the Doxorubicin (DOX)-resistant breast cancer cell line MCF-7/ADR and directly into the tumors in nude mice. Patent US20150328485 points out that magnetic nanoparticles can be attached to an anti-cancer drug, such as an antibody-based anti-cancer drug. Results: We found a statistically significant correlation between ABCG2 expression and clinicopathological parameters, such as Estrogen Receptor (ER), Progesterone Receptor (PR), and human epidermal growth factor receptor-2 (HER2), and nodal status in breast cancer patients. ABCG2 is closely related to SLC2A9, KIT, ABCG1, and MRPS7, which suggests that these proteins may be functional partners of breast cancer. The expression of ABCG2 is correlated with the activation or inhibition of multiple oncogenic pathways. Moreover, we found that ABCG2 is involved in the DOX signaling pathway. The small interfering RNA (siRNA) carried by magnetic nanoparticles can reduce the expression of ABCG2, thereby significantly improving the therapeutic effect of DOX on tumors. Conclusion: Our findings provide a more in-depth understanding of ABCG2 as a biomarker for predicting DOX-resistance and insights into the development of related therapeutic targets in breast cancer.

Photodynamic therapy (PDT) has been extensively investigated for decades for tumor treatment because of its non-invasiveness, spatiotemporal selectivity, lower side-effects, and immune activation ability. It can be a promising treatment modality in several medical fields, including oncology, immunology, urology, dermatology, ophthalmology, cardiology, pneumology, and dentistry. Nevertheless, the clinical application of PDT is largely restricted by the drawbacks of traditional photosensitizers, limited tissue penetrability of light, inefficient induction of tumor cell death, tumor resistance to the therapy, and the severe pain induced by the therapy. Recently, various photosensitizer formulations and therapy strategies have been developed to overcome these barriers. Significantly, the introduction of nanomaterials in PDT, as carriers or photosensitizers, may overcome the drawbacks of traditional photosensitizers. Based on this, nanocomposites excited by various light sources are applied in the PDT of deep-seated tumors. Modulation of cell death pathways with co-delivered reagents promotes PDT induced tumor cell death. Relief of tumor resistance to PDT with combined therapy strategies further promotes tumor inhibition. Also, the optimization of photosensitizer formulations and therapy procedures reduces pain in PDT. Here, a systematic summary of recent advances in the fabrication of photosensitizers and the design of therapy strategies to overcome barriers in PDT is presented. Several aspects important for the clinical application of PDT in cancer treatment are also discussed.

BackgroundAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a multisystem autoimmune disease with small-vessel involvement. In AAV, microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are major clinicopathologic variants. In addition, myeloperoxidase (MPO) and proteinase 3 (PR3) are major target antigens. The objective of the study was to explore the predictive factors for long-term survival in AAV patients.Materials and MethodsA multicenter retrospective study was carried out on 407 patients between 2005 and 2020. Clinical parameters were obtained from laboratory tests including the ANCA types, antinuclear antibody (ANA), extractable nuclear antigen (ENA), anti-streptolysin O (ASO), glomerular filtration rate (GFR), and the laboratory examinations for the blood routine, liver function, renal function, and immunity, etc. The data for clinical parameters were collected from electronic medical records (EMRs), and the data for patient survival were acquired through regular follow-up. The association of clinical parameters with overall survival (OS) along with 3-year and 5-year survival rates was analyzed, and the nomogram as a predictive model was established according to the analysis results.ResultsIn the present study, 336 (82.6%) patients and 46 (11.3%) patients were diagnosed with MPA and GPA, respectively. The mean and median OS for all the patients were 2,285 and 2,290 days, respectively. The 1-year, 3-year, 5-year, and 10-year cumulative survival rates for all the patients were 84.2%, 76.3%, 57.2%, and 32.4%, respectively. Univariate and multivariate survival analyses indicated that the independent prognostic factors included age, pathological categories (MPA, GPA, and other types), serum ANCA types (negative or positive for MPO and/or PR3), ANA, ASO, GFR, lymphocyte, neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP), and these clinical parameters except for ASO were used to construct a nomogram. The nomogram for 3-year and 5-year survival rates had a C-index of 0.721 (95% CI 0.676–0.766). The calibration curves showed that the predicted values of the nomogram for 3-year and 5-year survival rates were generally consistent with practical observed values, and decision curve analysis (DCA) further demonstrated the practicability and accuracy of the predictive model.ConclusionLaboratory tests at diagnosis have great significance in the prediction of long-term survival in AAV patients.

Chronic myelogenous leukaemia (CML) has a special phenomenon of chromosome translocation, which is called Philadelphia chromosome translocation. However, the detailed connection of this structure is troublesome and expensive to be identified. Low-coverage whole genome sequencing (LCWGS) could not only detect the previously unknown chromosomal translocation, but also provide the breakpoint candidate small region (with an accuracy of ±200 bases). Importantly, the sequencing cost of LCWGS is about US$300. Then, with the Sanger DNA sequencing, the precise breakpoint can be determined at a single base level. In our project, with LCWGS, BCR and ABL1 are successfully identified to be disrupted in three CML patients (at chr22:23,632,356 and chr9:133,590,450; chr22:23,633,748 and chr9:133,635,781; chr22: 23,631,831 and chr9:133,598,513, respectively). Due to the reconnection after chromosome breakage, classical fusion gene (BCR::ABL1) was found in bone marrow and peripheral blood. The precise breakpoints were helpful to investigate the pathogenic mechanism of CML and could better guide the classification of CML subtypes. This LCWGS method is universal and can be used to detect all diseases related to chromosome variation, such as solid tumours, liquid tumours and birth defects.

Background Transfer RNA-derived fragments (tRFs) are a new class of small non-coding RNAs. Recent studies suggest that tRFs participate in some pathological processes. However, the biological functions and mechanisms of tRFs in non-small cell lung cancer (NSCLC) are largely unknown. Methods Differentially expressed tRFs were identified by tRF and tiRNA sequencing using 9 pairs of pre- and post-operation plasma from patients with NSCLC. Quantitative real-time PCR (qRT-PCR) and fluorescence in situ hybridization (FISH) were used to determine the levels of tRF in tissues, plasma, and cells. Gain- and loss-of-function experiments were implemented to investigate the oncogenic effects of tRF on NSCLC cells in vitro and in vivo. Chromatin immunoprecipitation (ChIP), luciferase reporter, RNA pulldown, mass spectrum, RNA immunoprecipitation (RIP), Western blot, co-immunoprecipitation (Co-IP) assays, and rescue experiments were performed to explore the regulatory mechanisms of tRF in NSCLC. Results AS-tDR-007333 was an uncharacterized tRF and significantly up-regulated in NSCLC tissues, plasma, and cells. Clinically, AS-tDR-007333 overexpression could distinguish NSCLC patients from healthy controls and associated with poorer prognosis of NSCLC patients. Functionally, overexpression of AS-tDR-007333 enhanced proliferation and migration of NSCLC cells, whereas knockdown of AS-tDR-007333 resulted in opposite effects. Mechanistically, AS-tDR-007333 promoted the malignancy of NSCLC cells by activating MED29 through two distinct mechanisms. First, AS-tDR-007333 bound to and interacted with HSPB1, which activated MED29 expression by enhancing H3K4me1 and H3K27ac in MED29 promoter. Second, AS-tDR-007333 stimulated the expression of transcription factor ELK4, which bound to MED29 promoter and increased its transcription. Therapeutically, inhibition of AS-tDR-007333 suppressed NSCLC cell growth in vivo. Conclusions Our study identifies a new oncogenic tRF and uncovers a novel mechanism that AS-tDR-007333 promotes NSCLC malignancy through the HSPB1-MED29 and ELK4-MED29 axes. AS-tDR-007333 is a potential diagnostic or prognostic marker and therapeutic target for NSCLC.

Background Abnormal metabolic pathways have been considered as one of the hallmarks of cancer. While numerous metabolic pathways have been studied in various cancers, the direct link between metabolic pathway gene expression and cancer prognosis has not been established. Results Using two recently developed bioinformatics analysis methods, we evaluated the prognosis potential of metabolic pathway expression and tumor-vs-normal dysregulations for up to 29 metabolic pathways in 33 cancer types. Results show that increased metabolic gene expression within tumors corresponds to poor cancer prognosis. Meta differential co-expression analysis identified four metabolic pathways with significant global co-expression network disturbance between tumor and normal samples. Differential expression analysis of metabolic pathways also demonstrated strong gene expression disturbance between paired tumor and normal samples. Conclusion Taken together, these results strongly suggested that metabolic pathway gene expressions are disturbed after tumorigenesis. Within tumors, many metabolic pathways are upregulated for tumor cells to activate corresponding metabolisms to sustain the required energy for cell division.

Background: Some stemness-associated transcription factors consistently play essential roles in the maintenance of pluripotency or induce the differentiation of cancer stem cells (CSCs). However, the regulatory mechanism of CSC stemness mediated by transcription factors has not been extensively explored. Here, we show that two transcription factors (YB-1 and ERα), which are simultaneously highly expressed in estrogen receptor (ER)-positive CSCs, interact with each other to regulate the stemness and differentiation of ER-positive CSCs. Methods: The expression of YB-1 was examined in ER-positive CSCs and patient specimens. Western blot, real-time PCR, cell viability analysis, tumorsphere formation assay and subcutaneous tumorigenesis assays were used to study the stemness functions of YB-1 and ERα in CSCs. The relationship between YB-1 and ERα in cells was studied by promoter activity analysis, the electrophoretic mobility shift assay (EMSA) and the Co-IP assay. The mechanisms and functional significance of YB-1 in the sensitivity of CSCs to tamoxifen were further investigated with both in vitro and in vivo models. Results: YB-1 was aberrantly upregulated in the cancerous tissue of ER-positive breast cancer patients and in CSCs. Knockdown of YB-1 in ER-positive CSCs significantly inhibited cell stemness and induced differentiation, and the expression of YB-1 could be regulated by estrogen signaling and ERα in ER-positive breast CSCs. The Co-IP results showed that YB-1 interacted directly with ERα specifically in ER-positive non-CSCs and that YB-1 induced ERα degradation by ubiquitination via direct interaction in differentiated cells. Cell differentiation induced by FBS could inhibit YB-1 phosphorylation and promote YB-1 protein transfer from the nucleus to the cytoplasm. Moreover, cell differentiation induced by targeting inhibited the expression of YB-1 in ER-positive CSCs, which increased the sensitivity of cells to tamoxifen in vitro and in vivo. Conclusion: The ERα/YB-1 axis has an important role in the regulation of ER-positive breast cancer stemness. The dephosphorylation of YB-1 and the interaction between YB-1 and ERα may be the switch that initiates the differentiation of ER-positive CSCs. Targeting YB-1 to sensitize ER-positive CSCs to antiestrogen therapy might represent a new therapeutic strategy that warrants further exploration.

In recent years, nanomaterials and nanotechnology have emerged as vital factors in the medical field with a unique contribution to cancer medicine. Given the increasing number of cancer patients, it is necessarily required to develop innovative strategies and therapeutic modalities to tackle hypoxia, which forms a hallmark and great barrier in treating solid tumors. The present review details the challenges in nanotechnology-based hypoxia, targeting the strategies and solutions for better therapeutic performances. The interaction between hypoxia and tumor is firstly introduced. Then, we review the recently developed engineered nanomaterials towards multimodal hypoxia tumor therapies, including chemotherapy, radiotherapy, and sonodynamic treatment. In the next part, we summarize the nanotechnology-based strategies for overcoming hypoxia problems. Finally, current challenges and future directions are proposed for successfully overcoming the hypoxia tumor problems.

Chemotherapy resistance is that the most important reason behind of carcinoma treatment failure but the underlying molecular mechanisms are unclear. Members of the tripartite motifcontaining protein (TRIM) family play crucial roles in the carcinogenesis and development of resistance against chemotherapy. Herein, we first confirmed that TRIM58 is highly expressed in triple-negative breast cancer tissues and drug-resistant MCF7/ADR cells. Furthermore, TRIM58 knockdown resulted in increased sensitivity of MCF7/ADR cells toward doxorubicin in vitro and in vivo. In contrast, TRIM58 overexpression in breast cancer cells increased doxorubicin resistance. TRIM58 was found to interact with DDX3, a protein recently reported to modulate resistance against chemotherapy. We found that TRIM58 negatively regulates DDX3 expression downstream of the P53/P21 pathway, and that DDX3 is degraded by TRIM58-mediated ubiquitination. Knockdown of DDX3 reversed doxorubicin chemotherapy sensitivity induced by TRIM58 knockdown via the P53/P21 pathway.Our study reveals that TRIM58 mediates a novel mechanism underlying the development of resistance against chemotherapy in breast cancer and provides potential targets for developing novel therapeutic targets for breast cancer.

Optoelectronic science and 2D nanomaterial technologies are currently at the forefront of multidisciplinary research and have numerous applications in electronics and photonics. The unique energy and optically induced interfacial electron transfer in these nanomaterials, enabled by their relative band alignment characteristics, can provide important therapeutic modalities for healthcare. Given that nano-heterostructures can facilitate photoinduced electron-hole separation and enhance generation of reactive oxygen species (ROS), 2D nano-heterostructure-based photosensitizers can provide a major advancement in photodynamic therapy (PDT), to overcome the current limitations in hypoxic tumor microenvironments. Herein, a bismuthene/bismuth oxide (Bi/BiOx)-based lateral nano-heterostructure synthesized using a regioselective oxidation process is introduced, which, upon irradiation at 660 nm, effectively generates 1 O2 under normoxia but produces cytotoxic •OH and H2 under hypoxia, which synergistically enhances PDT. Furthermore, this Bi/BiOx nano-heterostructure is biocompatible and biodegradable, and, with the surface molecular engineering used here, it improves tumor tissue penetration and increases cellular uptake during in vitro and in vivo experiments, yielding excellent oxygen-independent tumor ablation with 660 nm irradiation, when compared with traditional PDT agents.

OBJECTIVE: To investigate the impact of family history of diabetes (FHD) on blood glucose, lipid levels and perinatal outcomes in pregnant women with gestational diabetes mellitus (GDM). METHODS: A total of 1265 GDM women who gave childbirth in Women’s Hospital, Zhejiang University School of Medicine during January to December 2019 were enrolled in the study, including 253 women with FHD and 1012 women without FHD. The t-test or χ (2) test were used to compare the blood lipid, blood glucose levels and perinatal outcomes including large for gestational age infant, small for gestational age infant, macrosomia, cesarean delivery, preeclampsia, preterm labor, postpartum hemorrhage, fetal distress. The correlation between FHD and perinatal outcomes were estimated by Logistic regression analysis. RESULTS: The high density lipoprotein level at third-trimester was significantly lower in GDM women with FHD ( P

Basal-like breast cancer (BLBC) accounts for approximately 15% of all breast cancer cases, and patients with BLBC have a low survival rate. Our previous study demonstrated that the KLF5 transcription factor promotes BLBC cell proliferation and tumor growth. In this study, we demonstrated that the histone deacetylase inhibitors (HDACi), suberoylanilide hydroxamic acid (SAHA), and trichostatin A (TSA), increased KLF5 acetylation at lysine 369 (K369), downregulated KLF5 protein expression levels, and decreased cell viability in BLBC cell lines. HDACi target KLF5 for proteasomal degradation by promoting KLF5 protein ubiquitination. K369 acetylation of KLF5 decreases the binding between KLF5 and its deubiquitinase, BAP1. These findings revealed a novel mechanism by which HDACi suppress BLBC, and a novel crosstalk between KLF5 protein acetylation and ubiquitination.

Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer. Various endeavor has been made to explore the molecular biology basis of TNBC. Herein, we reported a novel function of factor Kinectin 1 (KTN1) as a carcinogenic promoter in TNBC. KTN1 expression in TNBC was increased compared with adjacent tissues or luminal or Her2 subtypes of breast cancer, and TNBC patients with high KTN1 expression have poor prognosis. In functional studies, knockdown of KTN1 inhibited the proliferation and invasiveness of TNBC both in vitro and in vivo, while overexpression of KTN1 promoted cancer cell proliferation and invasiveness. RNA-seq analysis revealed that the interaction of cytokine-cytokine receptor, particularly CXCL8 gene, was upregulated by KTN1, which was supported by the further experiments. CXCL8 depletion inhibited the tumorigenesis and progression of TNBC. Additionally, rescue experiments validated that KTN1-mediated cell growth acceleration in TNBC was dependent on CXCL8 both in vitro and in vivo. Furthermore, it was found that KTN1 enhanced the phosphorylation of NF-κB/p65 protein at Ser536 site, and specifically bound to NF-κB/p65 protein in the nucleus and cytoplasm of cells. Moreover, the transcription of CXCL8 gene was directly upregulated by the complex of KTN1 and NF-κB/p65 protein. Taken together, our results elucidated a novel mechanism of KTN1 gene in TNBC tumorigenesis and progression. KTN1 may be a potential molecular target for the development of TNBC treatment.

The emergence of novel two-dimensional (2D) monoelemental materials (Xenes) has shown remarkable potential for their applications in different fields of technology, as well as addressing new discoveries in fundamental science. Xenes (e.g., borophene, silicene, germanene, stanene, phosphorene, arsenene, antimonene, bismuthene, and tellurene) are of particular interest because they are the most chemically tractable materials for synthetic exploration. Owing to their excellent physical, chemical, electronic and optical properties, Xenes have been regarded as promising agents for biosensors, bioimaging, therapeutic delivery, and theranostics, as well as in several other new bio-applications. In this tutorial review, we summarize their general properties including the classification of Xenes according to their bulk properties. The synthetic and modification methods of Xenes are also presented. Furthermore, the representative Xene nanoplatforms for various biomedical applications are highlighted. Finally, research progress, challenges, and perspectives for the future development of Xenes in biomedicines are discussed.

Pancreatic cancer is the fourth leading cause of cancer-related death with the characteristics of chemoresistance and early metastasis. Panaxadiol, a triterpenoid saponin extracted from the roots of American ginseng, has been proved to display anti-tumor activity in colon cancer. In this study, we found panaxadiol significantly inhibited proliferation, and induced apoptosis in human pancreatic cancer cell lines PANC-1 and Patu8988 in a dose-dependent manner. Furthermore, the expression of apoptosis-related proteins (Bax, Bcl2, Cleaved-caspase3) was detected via western blot and immunofluorescence staining. In addition, panaxadiol was also found to inhibit the migration of pancreatic cancer cells by wound healing and transwell assays. In vivo, the growth of xenograft pancreatic cancer models was also notably suppressed by panaxadiol compared to the control group. Moreover, the down-regulation of JAK2-STAT3 signaling pathway was responsible for the underlying pro-apoptosis mechanism of panaxadiol, and this result was in good agreement with molecular docking analysis between panaxadiol and STAT3. In conclusion, our work comprehensively explored the anti-tumor ability in PANC-1 and Patu8988 cells of panaxadiol and provided a potential choice for the clinical treatment of pancreatic cancer patients.

Circulating tumor cell (CTC) clusters, which are multicellular groups of CTCs, were recently suggested to had the greater potential of forming distal metastasis than single CTCs. However, our understanding of the forming of CTC clusters is still limited since there are few existing methods to study cancer cells aggregation kinetics, especially for a small number of cells. Herein we report a high-throughput miniaturized microwell-based cell aggregation-chip (AG-chip) to enable better characterize of the tumor cells clustering process. We successfully demonstrated the capability of the AG-chip in determining cell aggregation, and found that: (1) high metastatic breast cancer cells (MDA-MB-231 & MDA-MB-436) have stronger aggregation capacities than those low metastatic breast cancer cells (MCF-7 & SK-BR-3); (2) cells with similar aggregation ability were distinguished through the analysis of aggregation kinetics; (3) the detected aggregation ability can be used to indicate the metastatic potential of the cells; (4) the inhibition of integrins could regulate the cell clustering via blockage of cell adhesion or/and cell migration. This newly developed microdevice may promote further study of CTC clusters and metastasis.

A new schiff base cobalt(III) complex [N,N′-bis(2′-hydroxyphenylacetone)-o-ethanediamine] cobalt(III) (M3) has been synthesized and characterized by single X-ray crystallography. The cytotoxicity of complex M3 was evaluated against HeLa, LoVo, A549, A549/cis cancer cell lines, and the normal cell lines LO2 by MTT assays. The IC50 is in the range of 6.27-22.68 μM, which is somewhat lower than cisplatin on the basis of platinum molar concentration. Furthermore, anticancer mechanistic studies showed that the complex M3 inhibited cell proliferation by blocking DNA synthesis and then acted on nuclear division of HeLa cells over time. Moreover, western blot analysis indicated M3 dramatically decreased the target protein c-Myc and KLF5 expression levels, and activated many signaling pathways including ER stress, apoptosis, cell cycle and DNA damage in HeLa. M3 did not affect proteasomal activity.

Immunomodulation of macrophages against cancer has emerged as an encouraging therapeutic strategy. However, there exist two major challenges in effectively activating macrophages for antitumor immunotherapy. First, ligation of signal regulatory protein alpha (SIRPα) on macrophages to CD47, a "don't eat me" signal on cancer cells, prevents macrophage phagocytosis of cancer cells. Second, colony stimulating factors, secreted by cancer cells, polarize tumor-associated macrophages (TAMs) to a tumorigenic M2 phenotype. Here, it is reported that genetically engineered cell-membrane-coated magnetic nanoparticles (gCM-MNs) can disable both mechanisms. The gCM shell genetically overexpressing SIRPα variants with remarkable affinity efficiently blocks the CD47-SIRPα pathway while the MN core promotes M2 TAM repolarization, synergistically triggering potent macrophage immune responses. Moreover, the gCM shell protects the MNs from immune clearance; and in turn, the MN core delivers the gCMs into tumor tissues under magnetic navigation, effectively promoting their systemic circulation and tumor accumulation. In melanoma and breast cancer models, it is shown that gCM-MNs significantly prolong overall mouse survival by controlling both local tumor growth and distant tumor metastasis. The combination of cell-membrane-coating nanotechnology and genetic editing technique offers a safe and robust strategy in activating the body's immune responses for cancer immunotherapy.

Optical techniques using developed laser and optical devices have made a profound impact on modern medicine, with "biomedical optics" becoming an emerging field. Sophisticated technologies have been developed in cancer nanomedicine, such as photothermal therapy and photodynamic therapy, among others. However, single-mode phototherapy cannot completely treat persistent tumors, with the challenges of relapse or metastasis remaining; therefore, combinatorial strategies are being developed. In this review, the role of light in cancer therapy and the challenges of phototherapy are discussed. The development of combinatorial strategies with other therapeutic methods, including chemotherapy, immunotherapy, gene therapy, and radiotherapy, is presented and future directions are further discussed. This review aims to highlight the significance of light in cancer therapy and discuss the combinatorial strategies that show promise in addressing the challenges of phototherapy.

Ferritin, an iron-storage protein, regulates cellular iron metabolism and oxidative stress. The ferritin structure is characterized as a spherical cage, inside which large amounts of iron are deposited in a safe, compact and bioavailable form. All ferritins readily catalyze Fe(II) oxidation by peroxides at the ferroxidase center to prevent free Fe(II) from participating in oxygen free radical formation via Fenton chemistry. Thus, ferritin is generally recognized as a cytoprotective stratagem against intracellular oxidative damage The expression of cytosolic ferritins is usually regulated by iron status and oxidative stress at both the transcriptional and post-transcriptional levels. The mechanism of ferritin-mediated iron recycling is far from clarified, though nuclear receptor co-activator 4 (NCOA4) was recently identified as a cargo receptor for ferritin-based lysosomal degradation. Cytosolic ferritins are heteropolymers assembled by H- and L-chains in different proportions. The mitochondrial ferritins are homopolymers and distributed in restricted tissues. They play protective roles in mitochondria where heme- and Fe/S-enzymes are synthesized and high levels of ROS are produced. Genetic ferritin disorders are mainly related to the L-chain mutations, which generally cause severe movement diseases. This review is focused on the biochemistry and function of mammalian intracellular ferritin as the major iron-storage and anti-oxidation protein.

Individuals with autism spectrum disorder (ASD) or attention-deficit hyperactivity disorder (ADHD) may have unhealthy bodyweight. This meta-analysis was performed to understand the weight status in individuals with ASD or ADHD. PubMed, Embase, Cochrane and ISI Web of Science databases were searched from inception until June 2020 to identify relevant studies. Prevalence estimates and their 95% confidence intervals (CIs) of obesity, overweight and underweight were separately pooled using random-effects models. A total of 95 studies were included in the meta-analysis. The pooled estimates of the prevalence of obesity, overweight and underweight were 21.8%, 19.8% and 6.4% in individuals with ASD and 14.7%, 20.9% and 4.0% in individuals with ADHD. In subgroup analyses, an increasing trend in the prevalence of unhealthy weight was observed from children aged 2 to 5 years to adults with ASD (obesity: from 16.7% to 31.3%, overweight: from 16.2% to 27.2%, underweight from 5.3% to 8.6%) and from children aged 6 to 12 years to adults with ADHD (obesity: from 13.5% to 19.3%, overweight: from 18.8% to 31.2%). The worrisome epidemic of obesity and overweight in individuals with ASD, ADHD highlighted the need for weight management.

Background. The microliposome maintenance (MCM) complex, MCM2-7, is revealed to be involved in multiple cellular processes and plays a key role in the development and progression of human cancers. However, the MCM complex remains poorly elaborated in hepatic carcinoma (HCC). Methods. In the study, we found the mRNA and protein level by bioinformatics. We also explored the prognostic value, genetic alteration, interaction network, and functional enrichment of MCM2-7. The MCM expression and correlation among these MCMs in HCC cell lines were identified by western blot. Results. MCM2-7 was significantly increased in HCC tissues compared to normal liver tissues. The high level of MCM2-7 had a positive correlation with poor prognosis. However, MCM2-7 alterations were not correlated with poor OS. MCMs were both increased in HCC cell lines compared to the normal hepatocyte cell line. Furthermore, the positive correlation was found among MCMs in HCC cell lines. Conclusions. The MCM complex was increased in HCC tissues and cell lines and negatively correlated with prognosis, which might be important biomarkers for HCC.

Thallium (Tl) is an extremely toxic heavy metal and exists in very low concentrations in the environment, but its sensing is largely underexplored as compared to its neighboring elements in the periodic table (especially mercury and lead). In this work, we developed a ratiometric phosphorescent nanoprobe for thallium detection based on Mn-doped ZnSe quantum dots (QDs) and water-soluble carbon dots (C-dots). Upon excitation with 360 nm, Mn-doped ZnSe QDs and C-dots can emit long-lived and spectrally resolved phosphorescence at 580 and 440 nm, respectively. In the presence of thallium, the phosphorescence emission from Mn-doped ZnSe QDs could be selectively quenched, while that from C-dots retained unchanged. Therefore, a ratiometric phosphorescent probe was thus developed, which can eliminate the potential influence from both background fluorescence and other analyte-independent external environment factors. Several other heavy metal ions caused interferences to thallium detection but could be efficiently masked with EDTA. The proposed method offered a detection limit of 1 μg/L, which is among the most sensitive probes ever reported. Successful application of this method for thallium detection in biological serum as well as in environmental water and soil samples was demonstrated.

Overexpression and crystallization of uric acid have been recognized as the course of hyperuricemia and gout, which is produced via xanthine oxidase (XOD)-catalyzed oxidation of xanthine. Therefore, the medicinal therapy of hyperuricemia and gout is majorly based on the inhibition of the XOD enzymatic pathway. The spectroscopic nature of xanthine and uric acid, namely both absorption (near the ultraviolet region) and emission (non-fluorescent) characteristics, hinders optical assay development for XOD analysis. Therefore, the state-of-the-art analysis of XOD and the screening of XOD inhibitors are majorly based on chromatography. Here, we found the near ultraviolet absorption of uric acid overlapped well with the absorption of a large bandgap semiconductor quantum dots, ZnS. On the other hand, the intrinsic weak fluorescence of ZnS QDs can be substantially improved via transition metal ion doping. Therefore, herein, we developed an inner filter effect-based assay for XOD analysis and inhibitor screening with Mn-doped ZnS QDs. The phosphorescence of Mn-doped ZnS QDs could be quenched by uric acid generated from xanthine catabolism by XOD, leading to the phosphorescence turn-off detection of XOD with a limit of detection (3σ) of 0.02 U L-1. Furthermore, the existence of XOD inhibitors could inhibit the XOD enzymatic reaction, resulting in weakened phosphorescence quenching. Therefore, the proposed assay could also be explored for the facile screening analysis of XOD inhibitors, which is important for the potential medicinal therapy of hyperuricemia and gout.

Objective A key step in managing non-alcoholic fatty liver disease (NAFLD) is to differentiate nonalcoholic steatohepatitis (NASH) from simple steatosis (SS). Method Serum samples were collected from three groups: NASH patients ( N = 21), SS patients ( N = 38) and healthy controls ( N = 31). High performance liquid chromatography-mass spectrometry (HPLC-MS) was used to analyse the metabolic profile of the serum samples. The acquired data were processed by multivariate principal component analysis (PCA) and orthogonal partial least-squares-discriminant analysis (OPLS-DA) to identify novel metabolites. The potential biomarkers were quantitatively determined and their diagnostic power was further validated. Results A total of 56 metabolites were capable of distinguishing NASH from SS samples based on the OPLS-DA model. Pyroglutamate was found to be the most promising factor in distinguishing the NASH from SS groups. With an optimal cut-off value of 4.82 mmol/L, the sensitivity and specificity of the diagnosis of NASH were 72% and 85%, respectively. The area under the receiver operating characteristic (AUROC) of the pyroglutamate levels of NASH versus SS patients was more than those of tumor necrosis factor-α, adiponectin and interleukin-8. Conclusion These data suggest that pyroglutamate may be a new and useful biomarker for the diagnosis of NASH.

Electrode position after deep brain stimulation (DBS) for Parkinson's disease (PD) needs to be confirmed, but there are concerns about the risk of postoperative magnetic resonance imaging (MRI) after DBS. These issues could be avoided by fusion images obtained from preoperative MRI and postoperative computed tomography (CT). This study aimed to investigate image fusion technology for displaying the position of the electrodes compared with postoperative MRI. This was a retrospective study of 32 patients with PD treated with bilateral subthalamic nucleus (STN) DBS between April 2015 and March 2016. The postoperative (same day) CT and preoperative MRI were fused using the Elekta Leksell 10.1 planning workstation (Elekta Instruments, Stockholm, Sweden). The position of the electrodes was compared between the fusion images and postoperative 1-2-week MRI. The position of the electrodes was highly correlated between the fusion and postoperative MRI (all r between 0.865 and 0.996; all P0.001). The differences of the left electrode position in the lateral and vertical planes was significantly different between the two methods (0.30 and 0.24mm, respectively, both P0.05), but there were no significant differences for the other electrode and planes (all P0.05). The position of the electrodes was highly correlated between the fusion and postoperative MRI. The CT-MRI fusion images could be used to avoid the potential risks of MRI after DBS in patients with PD.

Male infertility has become a very serious problem in the human reproduction system, but the molecular mechanism of infertility remains largely unknown. Fertilization is the phenomenon in which a sperm and oocyte find each other, interact, and fuse. Sperm-oocyte fusion-related factors on the sperm side play crucial roles in male infertility. For example, IZUMO1 is well-known as a sperm protein essential for fusion of a sperm and oocyte, but its dysfunction or mutation can result in male infertility. Recent studies showed a novel sperm protein named Bactericidal/permeability-increasing protein (BPI), which takes part in the sperm-oocyte fusion process. The complexity and expected redundancy of the factors involved makes the process intricate, with a still poorly understood mechanism, which is difficult to comprehend in full detail. This review summarizes the known molecules involved in the process of sperm-oocyte fusion, mainly focusing on the relevant factors on the sperm side, whose dysregulation may potentially be associated with male infertility. New insights may come from these molecules in this review, can facilitate the development of new treatments of male infertility, and may have a diagnostic value in infertility.

Supplemental Digital Content is available in the text, Background: Weight status and autism spectrum disorder (ASD) are rising public health concerns. An increasing number of reports indicate that individuals with ASD may have unhealthy weight status, but the evidence is mixed. To understand the weight status in individuals with ASD and provide strategies for prevention and intervention, we describe the protocol for a systematic review and meta-analysis aimed at assessing the prevalence of obesity, overweight, and underweight in ASD. Methods: A broad range of key bibliographic databases including MEDLINE (PubMed), Embase, Cochrane, and ISI Web of Science will be searched to identify studies reporting the prevalence of obesity, overweight, and underweight in patients with ASD. Retrieved records will be independently screened by 2 authors and relevant estimates will be extracted from studies reporting data on obesity, overweight, and underweight prevalence among individuals with ASD. The assessment of study quality will be conducted primarily using the Newcastle–Ottawa scale and checklist proposed by the Joanna Briggs Institute. Prevalence estimates of obesity and overweight will be separately pooled using random-effects model. The pooled estimates will be summarized and presented by regional groupings. Subgroup analysis will be conducted for variables (such as study setting, participants’ age, and geographical region) across studies, depending on data availability. Between-study heterogeneity will be assessed using the I2 statistic and explored through subgroup analyses. This systematic review and meta-analysis will be reported following the preferred reporting items for systematic reviews and meta-analyses checklist and the meta-analysis of observational studies in epidemiology statements guidelines for meta-analysis and systematic reviews of observational studies. Results: In this study, we will outline details of the aims and methods on the meta-analysis of weight status of individuals with ASD. Conclusion: The results of this study will summarize the current data of weight status of individuals with ASD. Registration: PROSPERO-National Institute of Health Research (NIHR) Prospective Register of Systematic Reviews (CRD42019130790).

Rationale: NOTCH4 receptor has been implicated in triple-negative breast cancer (TNBC) development and breast cancer stem cell (BCSC) regulation. However, the potential of NOTCH4 as a BCSC marker and the underlying mechanisms remain unclear. Methods: In this study, we determined the expression and activation of NOTCH4 in breast cancer cell lines and tumor samples by qRT-PCR, western blotting and immunohistochemistry. Subsequently, in vitro and in vivo serial dilution experiments were performed to demonstrate the application of NOTCH4 as an efficient mesenchymal-like (ML)-BCSC marker in TNBC. Stable overexpression of activated NOTCH4 and knockdown cell lines were established using lentivirus. RNA-seq and qRT-PCR were employed to reveal the downstream effectors of NOTCH4, followed by dual-luciferase reporter and chromatin immunoprecipitation assays to identify the genuine binding sites of NOTCH4 on SLUG and GAS1 promoters. Transwell assay, mammosphere formation and chemoresistance experiments were performed to determine the effects of SLUG, GAS1 and NOTCH4 on the mesenchymal-like characteristics of TNBC cells. Survival analysis was used to study the relation of NOTCH4, SLUG and GAS1 with prognosis of breast cancer. Results: NOTCH4 is aberrantly highly expressed and activated in TNBC, which contributes to the maintenance of ML-BCSCs. Furthermore, NOTCH4 shows significantly higher efficiency in labeling ML-BCSCs than the currently commonly used CD24-CD44+ marker. Mechanistically, NOTCH4 transcriptionally upregulates SLUG and GAS1 to promote EMT and quiescence in TNBC, respectively. The effects of NOTCH4 can be mimicked by simultaneous overexpression of SLUG and GAS1. Moreover, SLUG is also involved in harnessing GAS1, a known tumor suppressor gene, via its anti-apoptotic function. Conclusions: Our findings reveal that the NOTCH4-SLUG-GAS1 circuit serves as a potential target for tumor intervention by overcoming stemness of ML-BCSCs and by conquering the lethal chemoresistance and metastasis of TNBC.

The expression and functions of microRNA (miR)-411 have been investigated in several types of cancer. However, until now, miR-411 in human breast cancer has not been examined. The present study investigated the expression, biological functions and molecular mechanisms of miR-411 in human breast cancer, discussing whether it offers potential as a therapeutic biomarker for breast cancer in the future. The expression levels of miR-411 in human breast cancer tissues and cells were measured using reverse transcription-quantitative polymerase chain reaction analysis. Following transfection with miR-411 mimics, an MTT assay, cell migration and invasion assay, western blot analysis and luciferase assay were performed in human breast cancer cell lines. According to the results, it was found that miR-411 was significantly downregulated in breast cancer, and associated with lymph node metastasis and histological grade. Additionally, it was observed that miR-411 suppressed cell growth, migration and invasion in the breast cancer cells. The present study also provided the first evidence, to the best of our knowledge, that miR-411 was likely to directly target specificity protein 1 in breast cancer. These findings indicated that miR-411 may be used a therapeutic biomarker for the treatment of breast cancer in the future.

β-agonists are phenylethanolamines with different substituent groups on the aromatic ring and the terminal amino group which have the effect of nutrition redistribution and can accumulate in body tissues causing acute or chronic poisoning when consumed. Therefore, it is very important to establish a fast screening method for the detection of several kinds of β-agonists in food safety control. In this study, the aptamer-agonists (AP-Ago) has screened out by Isothermal Titration Calorimetric method. AP-Ago was a single-strand DNA with 22 base-pairs. The dissociation constant (Kd) to phenylethanolamine (PHL) was 3.34 × 10(-5)mol L(-1). The AP-Ago based electrode was constructed by self-assembling on gold electrode. A label-free electrochemical aptasensor was then developed with AP-Ago-based gold electrode, which was sensitive to phenylethanolamine(PHL), clenbuterol (CLB), ractopamine (RAC), salbutamol (SAL) and procaterol (PRO). The detection limits were 0.04 ng/mL (RAC), 0.35 pg/mL (CLB), 1.0 pg/mL (PHL), 0.53 pg/mL (SAL) and 1.73 pg/mL(PRO), respectively, The detection time was 15 min. The reproductivity of the mentioned aptasensor is good with RSD of 2.09%. Comparing with ELISA and HPLC on β-agonists detection in actual sample, this aptasensor is advantage of fewer steps and fast screen-detection of these five β-agonists or their mixtures. This study suggests that the aptasensor can be developed to a rapid screening means with multi-β-agonists (may be one or more) in sample.

Photoacoustic imaging (PAI) is an attractive imaging modality, which is promising for clinical cancer diagnosis due to its advantages on deep tissue penetration and fine spatial resolution. However, few tumor catalytic/responsive PAI strategies are developed. Here, we design an exosome-like nanozyme vesicle for in vivo H

Glioma is the commonest malignant tumor in the central nervous system (CNS), characterized by rapid growth. However, the molecular mechanism underlying the growth remains unclear. Immunity-related GTPase family M protein (IRGM) participates in immune response to pathogen and tumorigenesis. Proliferation and autophagy are two crucial functions contributing to aggressive growth. Therefore, our aims were to probe whether IRGM regulates glioma proliferation and autophagy. In this study, we found that 47 glioma specimens had more IRGM expression than 11 non-cancerous brain tissues with immunohistochemistry. IRGM was also up-regulated in human glioma cell lines U87, U251 and A172 and so on compared with immortalized astrocytes. Importantly, overexpression of IRGM significantly increased the cell colonies formation, cell proliferation and Akt activation (Thr308 and Ser473 sites) than matched control. On another hand, all of IRGM, autophagy marker LC3II and autophagy adaptor p62 gradually increased after starvation 2 and 4 h. Furthermore, western blot and immunofluorescence results showed that knockdown of IRGM inhibited the formation of LC3-II and the expression of p62. Our data uncovered that IRGM acted in glioma proliferation and autophagy, providing a new target with dual roles for the future translation research.

Systemic lupus erythematosus (SLE) is a type of autoimmune disease that damages multiple organs, including the heart, joints, liver and kidneys. The main characteristics of SLE are the deposition of circulating autoantibodies; autoantigen complexes in the renal system; and abnormal expression of complements, cytokines and chemokines. Lupus nephritis (LN) is the most serious manifestation of SLE and is characterized by inflammation of the kidney. This review summarizes recent clinical applications of protein biomarkers including autoantibodies, complements, cytokines and chemokines and some new protein biomarkers in SLE and LN. The clinical differential diagnosis of protein biomarkers related to prognosis and diagnosis is discussed and highlighted. Protein biomarkers play crucial roles in the study of SLE and LN. Useful biomarkers will provide insights into effective treatments for these diseases.

Objective To investigate whether γH2AX levels were different in the spermatozoa of healthy men compared with infertility patients, and to assess the possible correlations between γH2AX and conventional semen parameters and double-stranded breaks (DSBs) identified with the use of comet assay. Design Prospective study. Setting Clinical laboratory. Patient(s) Semen from 100 male infertile patients and 100 healthy sperm donors. Intervention(s) Human sperm samples were analyzed in terms of World Health Organization parameters. The γH2AX levels were detected by means of flow cytometry. DSBs of sperm were detected by means of comet assay. Morphology slides were made and the sperm morphology assessed according to strict criteria. Main Outcome Measure(s) Conventional semen analyses, γH2AX levels in sperm, DNA DSBs in sperm, and correlations among γH2AX, conventional semen analyses, and DSBs. Result(s) Concentration, viability, motility, and normal sperm morphology were significantly lower in male infertility patients compared with healthy men. Also, γH2AX levels and the number of DSBs were significantly higher in the sperm of infertile subjects compared with healthy men. γH2AX levels correlated negatively with conventional semen parameters and positively with DSBs. A threshold γH2AX level of 18.55% was identified as a cutoff value to discriminate infertile subjects from fertile control subjects with a specificity of 86.0% and a sensitivity of 83.0%. The positive and negative predictive values of the 18.55% γH2AX threshold were high: 87.7% and 85.5%, respectively. Conclusion(s) γH2AX levels were higher in the sperm of male infertility patients than in healthy men. γH2AX levels in sperm, as evaluated with the use of flow cytometry, might be a useful biomarker for evaluating DSBs in human spermatozoa.

Breast cancer-specific gene 1 (BCSG1), also referred to as γ-synuclein (SNCG), is highly expressed in human infiltrating breast carcinomas, but not in normal or benign breast tissue. The present study aimed to evaluate the effects of BCSG1 siRNA delivered by lentiviral vector on breast cancer cells and investigate the underlying mechanisms. BCSG1 RNAi lentiviral vector was constructed and transfected into MDA-MB-231 cells. BCSG1 mRNA levels were determined by quantitative polymerase chain reaction analysis. Cell proliferation, migration and apoptosis were evaluated by using the cell counting kit‑8, Transwell assay and flow cytometry, respectively, followed by western blotting to determine the relative levels of AKT, extracellular signal‑regulated kinase (ERK), p-AKT and p-ERK expression. BCSG1 mRNA levels were significantly reduced in MDA-MB‑231 cells following transfection of BCSG1 siRNA delivered by lentiviral vector. Cell migration and proliferation were significantly decreased and the cell cycle was arrested. Western blot analysis indicated that the protein levels of p-AKT and p-ERK were significantly lower in the BCSG1 siRNA-treated groups compared with the control and negative control groups. Therefore, BCSG1 siRNA delivered by lentiviral vector was able to significantly reduce BCSG1 expression, suppress cell migration and proliferation, possibly through the reduction of the protein levels of p-AKT and p-ERK.

Human cytomegalovirus (HCMV) infection is a global concern and highly infectious. HCMV-infected individuals are often carriers with damaged immunity. However few diagnostic indicators block HMCV control and prevention. Thus, we measured 21 serum proteins related to HCMV infection using iTRAQ-labeling based quantitative proteomic approaches and SAA1 and APOE were confirmed as candidate serum indicators for identification of HMCV infection according to ROC curve analysis and that co-occurrence of SAA1 and APOE are better markers than individual proteins.

Distant metastasis is the main cause of breast cancer-related death; however, effective therapeutic strategies targeting metastasis are still scarce. This is largely attributable to the spatiotemporal intratumor heterogeneity during metastasis. Here we show that protein deacetylase SIRT7 is significantly downregulated in breast cancer lung metastases in human and mice, and predicts metastasis-free survival. SIRT7 deficiency promotes breast cancer cell metastasis, while temporal expression of Sirt7 inhibits metastasis in polyomavirus middle T antigen breast cancer model. Mechanistically, SIRT7 deacetylates and promotes SMAD4 degradation mediated by β-TrCP1, and SIRT7 deficiency activates transforming growth factor-β signaling and enhances epithelial-to-mesenchymal transition. Significantly, resveratrol activates SIRT7 deacetylase activity, inhibits breast cancer lung metastases, and increases survival. Our data highlight SIRT7 as a modulator of transforming growth factor-β signaling and suppressor of breast cancer metastasis, meanwhile providing an effective anti-metastatic therapeutic strategy., Metastatic disease is the major reason for breast cancer-related deaths; therefore, a better understanding of this process and its players is needed. Here the authors report the role of SIRT7 in inhibiting SMAD4-mediated breast cancer metastasis providing a possible therapeutic avenue.

Objective To construct bispecific antibodies, which can block interleukin 12 (IL-12)/IL-23 p40 subunit and tumor necrosis factor α (TNF-α) simultaneously, and identify their biological function and inhibitory effect on psoriasis formation in mice. Methods Based on the sequences of adalimumab and ustekinumab, three kinds of bispecific antibodies were designed, named BiAU003, BiAU022 and BiAU023. The specificity and binding capacity of bispecific antibodies were determined by ELISA. After co-treated with bispecific antibodies and TNF-α, the level of endothelial leukocyte adhesion molecule-1 (ELMA-1) labeled with fluorescein isothiocyanate (FITC) in human umbilical vein endothelial cells (HUVECs) were examined by flow cytometry. Human peripheral blood mononuclear cells (PBMCs) were purified and cultured in the medium containing IL-2 and IL-12 in the absence or presence of bispecific antibodies. Commercial ELISA kit was used to detect interferon γ (IFN-γ) concentration in the supernatant. BALB/c mice were used for psoriasis model construction through injection of IL-12 and TNF-α subcutaneously. Then they were treated with the bispecific antibodies. Psoriasic skin was measured in thickness and scale under microscopy after HE staining. Results The three kinds of bispecific antibodies could specifically recognize IL-12/23 p40 and TNF-α protein, and inhibit IFN-γ secretion and the expression of ELAM-1 protein. Data also indicated that bispecific antibodies inhibited the formation of psoriasic skin, and showed an equal or superior effect to control antibody drug. Conclusion The novel bispecific antibodies, BiAU003, BiAU022 and BiAU023, can serve as an antagonist of TNF-α and IL-12/23 p40, and have a blocking effect on mouse psoriasis formation.

Yongsheng Su,1 Jian Hu,1 Zhibin Huang,1 Yubin Huang,1 Bingsheng Peng,1 Ni Xie,2 Hui Liu1 1Department of Burn and Plastic Surgery, The People’s Hospital of Baoan Shenzhen Affiliated to Southern Medical University, 2Core Laboratory, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, People’s Republic of China Abstract: Malignant melanoma (MM) is the most dangerous type of skin cancer with annually increasing incidence and death rates. However, chemotherapy for MM is restricted by low topical drug concentration and multidrug resistance. In order to surmount the limitation and to enhance the therapeutic effect on MM, a new nanoformulation of paclitaxel (PTX)-loaded cholic acid (CA)-functionalized star-shaped poly(lactide-co-glycolide) (PLGA)-d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) nanoparticles (NPs) (shortly PTX-loaded CA-PLGA-TPGS NPs) was fabricated by a modified method of nanoprecipitation. The particle size, zeta potential, morphology, drug release profile, drug encapsulation efficiency, and loading content of PTX-loaded NPs were detected. As shown by confocal laser scanning, NPs loaded with coumarin-6 were internalized by human melanoma cell line A875. The cellular uptake efficiency of CA-PLGA-TPGS NPs was higher than those of PLGA NPs and PLGA-TPGS NPs. The antitumor effects of PTX-loaded NPs were evaluated by the MTT assay in vitro and by a xenograft tumor model in vivo, demonstrating that star-shaped PTX-loaded CA-PLGA-TPGS NPs were significantly superior to commercial PTX formulation Taxol®. Such drug delivery nanocarriers are potentially applicable to the improvement of clinical MM therapy. Keywords: malignant melanoma, paclitaxel, nanoparticles, enhanced therapeutic effects, drug delivery

Little is known about the role of progranulin (PGRN) in cervical cancer, which is an autocrine growth factor. We used immunohistochemistry, western blot, and ELISA to determine the expression levels of PGRN in cervical cancer and cervical cancer cell lines. Immortalized normal cervical cell line H8 with lower PGRN expression was treated with recombinant human PGRN (rhPGRN) and forced expression of PGRN by transfection and cell proliferation were determined. PGRN knockdown by siRNA was also performed in HeLa cells with high PGRN expression and cell proliferation was also determined. Furthermore, H8 cell xenograft mouse model was employed to determine if PGRN treatment could increase tumorigenesis of H8 cell xenograft. Our results showed that PGRN expression was significantly increased in cervical cancer tissue and high expression of PGRN is closely correlated with the degree of malignancy in cervical cancer cell lines. Increased PGRN expression or rhPGRN treatment increased the proliferation of H8 cells. Consistently, PGRN knockdown in HeLa cells by siRNA transfection reduced proliferation of HeLa cells. In H8 cell xenograft model, both intraperitoneal and intratumoral rhPGRN treatments increased tumorigenic capacity of H8 cell line. Our results suggested that PGRN could be used as both a diagnostic biomarker and therapeutic target.

There is a great demand for long-term cellular tracers because of their great importance in monitoring biological processes, pathological pathways, therapeutic effects, etc. Herein we report a new type of fluorescence "turn-on" probe for tracing live cells over a long period of time. We synthesized the fluorogenic probe by attaching a large number of tetraphenylethene (TPE) labels to a chitosan (CS) chain. The resultant TPE-CS bioconjugate shows a unique aggregation-induced emission (AIE) behavior. It is nonfluorescent when dissolved but becomes highly emissive when its molecules are aggregated. The AIE aggregates can be readily internalized by HeLa cells. The cellular staining by the TPE-CS aggregates is so indelible that it enables cell tracing for as long as 15 passages. The internalized AIE aggregates are kept inside the cellular compartments and do not contaminate other cell lines in the coculture systems, permitting the differentiation of specific cancerous cells from normal healthy cells.

Open Access Article. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence., Early detection and appropriate management of chronic kidney disease can reduce the progression of kidney failure and cardiovascular disease. The urine albumin to creatinine ratio (UACR) test is a standard urine test for identifying individuals at high risk of developing progressive kidney disease. In this study, IDATPE, a novel fluorescent probe with aggregation-induced emission (AIE) features, is successfully developed for creatinine detection and quantitation. An excellent correlation between fluorescent light intensity and creatinine concentration is achieved. In addition, BSPOTPE, a reported excellent AIE bioprobe for human serum albumin (HSA) quantitation, is used together with IDATPE in artificial urine for UACR testing. The mutual interference of HSA and creatinine when the bioprobes are used for quantitation is characterised, with promising results. Further improvements and potential applications in CKD quantitation are highlighted.

We developed a new strategy to restrict the motions of AIE molecules through host-guest inclusion, affording a catalogue of new molecular luminogens.

Gestational diabetes mellitus (GDM) is considered to be a typical condition of glucose intolerance in which a woman previously undiagnosed with diabetes exhibits high levels of blood glucose during the third trimester of pregnancy. It can hence be defined as any degree of intolerance to glucose with its first recognition only during the pregnancy. Approximately 7 % of all cases of pregnancy are found to be variedly complicated with GDM and this result in more than 200,000 cases annually. In US only, GDM has been found to complicate about 7–14 % cases annually, and the trend seems to have increased by 35–100 % in the recent years. A history of GDM can be considered to be one of the sturdiest risk factors concerning the development of type 2 diabetes. Among women who have a history of GDM, the risk of developing classical type 2 diabetes usually ranges from 20 to 50 %. Evidences collected from various efficacy trials suggest that lifestyle interventions like weight management can modulate and prevent type 2 diabetes in at-risk individuals. The cornerstone of GDM management is glycemic control, and hence, it is attributed to be the main focus of attention for the therapy. In this review, we have tried to highlight the various risk factors associated with GDM along with the available therapeutic options in the treatment and management of the disease.

BACKGROUND Regulated on activation normal T-cell expressed and secreted (RANTES)-chemokine ligand 5 plays a key role in mediating heart transplant rejection. Suppression of RANTES-mediated signals can reduce leukocyte recruitment and mitigate transplant rejection severity. The present study describes the construction of an adenovirus overexpression vector encoding a natural S24F RANTES variant as a means of reducing leukocyte recruitment, resulting in the prevention of allograft rejection. METHODS The in vitro transendothelial chemotaxis assay was used to compare RANTES-induced transmigration of peripheral blood mononuclear cells across human umbilical vein endothelial cells cultured on the upper Transwell chamber. Intracoronary delivery of Ad-S24F, Ad-Null, or phosphate-buffered saline was performed in BALB/c donor hearts that were transplanted into the abdominal cavity of C57BL/6 recipients as a measure of allograft survival. Intragraft inflammatory cell infiltrates and associated proinflammatory cytokine expression profiles were detected by immunohistochemistry and quantitative real-time polymerase chain reaction on day 6 after transplantation, respectively. RESULTS Regulated on activation normal T-cell expressed and secreted-induced peripheral blood mononuclear cell transendothelial chemotaxis is inhibited by S24F (Ad-S24F, 9.2%±0.02%; Ad-Null, 17.7%±0.02%; medium control, 15.1%±0.01%; P