NCF4 attenuates colorectal cancer progression by modulating inflammasome activation and immune surveillance.

The spatiotemporal regulation of inflammasome activation remains unclear. To examine the mechanism underlying the assembly and regulation of the inflammasome response, here we perform an immunoprecipitation-mass spectrometry analysis of apoptosis-associated speck-like protein containing a CARD (ASC) and identify NCF4/1/2 as ASC-binding proteins. Reduced NCF4 expression is associated with colorectal cancer development and decreased five-year survival rate in patients with colorectal cancer. NCF4 cooperates with NCF1 and NCF2 to promote NLRP3 and AIM2 inflammasome activation. Mechanistically, NCF4 phosphorylation and puncta distribution switches from the NADPH complex to the perinuclear region, mediating ASC oligomerization, speck formation and inflammasome activation. NCF4 functions as a sensor of ROS levels, to establish a balance between ROS production and inflammasome activation. NCF4 deficiency causes severe colorectal cancer in mice, increases transit-amplifying and precancerous cells, reduces the frequency and activation of CD8+ T and NK cells, and impairs the inflammasome-IL-18-IFN-γ axis during the early phase of colorectal tumorigenesis. Our study implicates NCF4 in determining the spatial positioning of inflammasome assembly and contributing to inflammasome-mediated anti-tumor responses.

Spatial Distribution, Source Identification, and Potential Ecological Risk Assessment of Heavy Metal in Surface Sediments from River-Reservoir System in the Feiyun River Basin, China.

To investigate the pollution characteristics of the surface sediments of the river-reservoir system in the Feiyun River basin, a sediment heavy metal survey was conducted for the first time in the Feiyun River basin. Surface sediments from 21 sampling sites in the Feiyun River basin were collected, and the concentrations and spatial distribution characteristics of 15 heavy metals (Cr, Ni, Cu, Zn, As, Cd, Pb, Mn, V, Co, Mo, Sb, W, Fe, and Se) were analyzed. Three heavy metal ecological risk assessment methods were used to evaluate the potential risks of heavy metals in sediments, and the sources of major heavy metals were traced by correlation analysis and principal component analysis. The results show that (1) the average concentration of heavy metals (As) (212.64 mg/kg) and (Sb) (4.89 mg/kg) in Feiyun River Basin is 33.3 and 6.89 times the background value of Zhejiang Province; the overall spatial distribution of heavy metals is: the mainstream of Feiyun River > Zhaoshandu Reservoir > Shanxi Reservoir, thereby, the pollution is relatively significant; (2) by processing the geo-accumulation index and enrichment index methods, As and Sb are classified as 'severely polluted', 'moderately severely polluted' and 'severely polluted', 'very severe polluted' respectively; (3) the potential ecological index evaluates the surface sediments in the Feiyun River Basin as a very high risk level, the main environmental risk factors are As, Sb, Cd and Mo; (4) the principal component analysis results show that the heavy metals in the sediments of the Feiyun River Basin may be mainly affected by human activities such as sewage from domestic and agricultural activities, mining and smelting, and the others are affected by natural factors.

Niraparib exhibits a synergistic anti-tumor effect with PD-L1 blockade by inducing an immune response in ovarian cancer.

BACKGROUND: Immune checkpoint blockades (ICBs) therapy showed limited efficacy in ovarian cancer management. Increasing evidence indicated that conventional and targeted therapies could affect tumor-associated immune responses and increase the effectiveness of immunotherapy. However, the effects of Niraparib, one of the poly (ADP) ribose polymerase (PARP) inhibitors, on the immune response remains unclear. Delineating the crosstalk between cytotoxic anticancer agents and cancer-associated immunity may lead to more efficient combinatorial strategies. METHODS: Programmed death ligand 1 (PD-L1) expression in human ovarian cancer cells after PARP inhibitors treatment was examined by western blotting (WB) and flow cytometry. The expression of poly ADP-ribose polymerase (PARP1), PD-L1, and CD8 in human ovarian cancer tissues was detected by immunohistochemistry(IHC). The effect of Niraparib and PD-L1 blockade in ovarian cancer progression was investigated in vivo. The changes of immune cells and cytokines in vitro and in vivo were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Changes of cGAS/STING signal pathway after Niraparib treatment were determined by WB, ELISA. RESULTS: Niraparib upregulated membrane PD-L1 and total PD-L1 expression in ovarian cancer cells and had a synergistic effect with PD-L1 blockade in vivo. In clinical patient samples, Niraparib augmented cytotoxic CD8+T cell proportion and function. In vivo and vitro, Niraparib can also increase the proportion of T cells and combined with PD-L1 blockade could further enhance the effect. Besides, Niraparib activated the cGAS-STING pathway, increasing the levels of cytokines such as CCL5 and CXCL10, which played a vital role in augmenting the infiltration and activation of cytotoxic T cells. CONCLUSIONS: Niraparib could modulate the immune response via the activation of the cGAS/STING pathway, and combination with PD-L1 blockade could further enhance the effect. These results provide a sound theoretical basis for clinical treatment.

Hyperemesis gravidarum induced refeeding syndrome causes blood cell destruction: a case report and literature review.

BACKGROUND: Hyperemesis gravidarum (HG) is a common complication during pregnancy, however, HG associated simultaneous onset of blood cell destruction due to electrolyte abnormalities is rare. In this case, a woman with refeeding syndrome (RFS) secondary to electrolyte abnormalities caused by severe HG was diagnosed and managed in our hospital. CASE PRESENTATION: A 29-year old woman was sent to the local hospitals because of severe HG with appetite loss, weight reduction, general fatigue, and she was identified to have severe electrolyte abnormalities. However, the electrolyte abnormalities were not corrected promptly, and then she had the symptoms of stillbirth, altered mental status, visual hallucination, hemolytic anemia and thrombocytopenia. After transferred to our hospital, we continued to correct the electrolyte abnormalities and the labor induction was performed as soon as possible. The symptoms of blood cell destruction were relieved obviously, and the patient discharged four days later. The electrolyte disturbances and physio-metabolic abnormalities caused by HG helped us diagnose this case as RFS. CONCLUSIONS: This case emphasizes that patients with RFS should be diagnosed appropriately and intervened promptly in order to prevent electrolyte imbalance induced blood cell destruction.

Progress in the management of ovarian granulosa cell tumor: A review.

Ovarian granulosa cell tumor (GCT) is a rare, low-grade malignant tumor that accounts for 70% of the sex cord-stromal tumors. It has two histopathologic types with different clinical and biologic features: adult GCT and juvenile GCT. Most women diagnosed with the adult GCT have a favorable prognosis, with a 5-year survival rate of 97%-98%, but adult GCT has a feature of late relapse; the recurrence time could be more than 20 years after diagnosis. Juvenile GCT has a survival rate of 97% in stage I and a 5-year survival rate of 0%-22% in advanced stage with earlier recurrence than adult GCT. Consequently, the scenario emphasizes the need for early diagnosis, standardized treatment protocols, and long-term follow up. However, there is a lack of consensus regarding accurate diagnosis of GCT and adjuvant treatment. Furthermore, GCT tends to occur in young women, which emphasizes the viability of fertility-sparing surgery. The current review performed a systematic literature review of 60 articles to summarize the latest advances in GCT, with an emphasis on the molecular pathogenesis and survival after fertility-sparing surgery. We found that young women with fertility-sparing surgery had a desirable reproductive and survival outcome compared with those undergoing radical surgery.

Exosomal miR­663b exposed to TGF­ß1 promotes cervical cancer metastasis and epithelial­mesenchymal transition by targeting MGAT3.

Transforming growth factor (TGF)­ß1 is a key cytokine affecting the pathogenesis and progression of cervical cancer. Tumor­derived exosomes contain microRNAs (miRNAs/miRs) that interact with cancer and stromal cells, thereby contributing to tissue remodeling in the tumor microenvironment (TME). The present study was designed to clarify how TGF­ß1 affects tumor biological functions through exosomes released by cervical cancer cells. Deep RNA sequencing found that TGF­ß1 stimulated cervical cancer cells to secrete more miR­663b­containing exosomes, which could be transferred into new target cells to promote metastasis. Further studies have shown that miR­663b directly targets the 3'-untranslated regions (3'­UTR) of mannoside acetylglucosaminyltransferase 3 (MGAT3) and is involved in the epithelial­mesenchymal transition (EMT) process. Remarkably, the overexpression of MGAT3 suppressed cervical cancer cell metastasis promoted by exosomal miR­663b, causing increased expression of epithelial differentiation marker E­cadherin and decreased expression of mesenchymal markers N­cadherin and ß­catenin. Throughout our study, online bioinformation tools and dual luciferase reporter assay were applied to identify MGAT3 as a novel direct target of miR­663b. Exosome PKH67­labeling experiment verified that exosomal miR­663b could be endocytosed by cervical cancer cells and subsequently influence its migration and invasion functions which were measured by wound healing and Transwell assays. The expression of miR­663b and MGAT3 and the regulation of the EMT pathway caused by MGAT3 were detected by quantitative real­time transcription­polymerase chain reaction (qPCR) and western blot analysis. These results, thus, provide evidence that cancer cell­derived exosomal miR­663b is endocytosed by cervical cancer cells adjacent or distant after TGF­ß1 exposure and inhibits the expression of MGAT3, thereby accelerating the EMT process and ultimately promoting local and distant metastasis.

Efficient targeted tumor imaging and secreted endostatin gene delivery by anti-CD105 immunoliposomes.

BACKGROUND: Anti-CD105 mAb-conjugated immunoliposomes, loaded with secreted mouse endostatin gene, were developed for targeted tumor imaging and antiangiogenic gene therapy. METHODS: The liposomes were investigated for size, zeta-potential, lipid content, antibody binding ability, and pcDNA loading capacity. The ability of immunoliposomes to target tumor-derived endothelial cells and perform gene transfer in vitro was measured and their basic biocompatibility was evaluated. A nude mouse/breast cancer xenograft model was used to examine the tumor internalization of fluorescent-labeled liposomes and the clinical potential of immnuoliposomes loaded with pcDNA3.1-CSF1-endostatin. RESULTS: Loaded immunoliposomes were homogenously distributed with a well-defined spherical shape and bilayer, diameter of 122 ± 11 nm, and zeta potential + 1.40 mV. No significant differences were observed in body weight, liver index, oxidative stress, or liver and kidney function in mice after liposomes exposure. The addition of CD105 mAb to liposomes conferred the ability to target tumor-derived endothelial cells in vitro and in vivo. Systemic intravenous administration of fluorescent immunoliposomes in the xenograft model resulted in selective and efficient internalization in tumor vasculature. Treatment of mice with pcDNA3.1-CSF1-endostatin-loaded immunoliposomes suppressed tumor growth by 71%. CONCLUSIONS: These data demonstrate the advantages of using anti-CD105 mAb-conjugated immunoliposomes to enhance tumor targeting, imaging, and gene transfer applications.

An ATP Aptasensor Based on the Peroxidase-like Activity of Hemin/Graphene Oxide Nanosheets.

In the present work, a sensitive electrochemical aptasensor was designed for the detection of adenosine triphosphate (ATP) with hemin/graphene oxide nanosheets (HGNs). Firstly, the ATP aptamer was self-assembled on gold electrode surface, and then HGNs were captured to the modified electrode by π-π stacking. The captured HGNs could catalyze the disproportionation reaction of H2O2, and produced a detectable electrochemical signal by chronoamperometry. ATP was competitively bound to aptamer which led to the release of HGNs from the electrode surface after adding ATP. The decrease of the electrochemical signal, which was calculated by the difference of amperometric responses before and after incubation of ATP, provided a quantitative signal for ATP detection. A linear correlation was achieved between the difference of the amperometric responses and the logarithmic concentration of ATP ranging from 0.5 to 100 nM with a detection limit of 0.08 nM. Besides, the aptasensor also exhibited good selectivity toward ATP against other analogs.

Folate-modified Chitosan Nanoparticles Containing the IP-10 Gene Enhance Melanoma-specific Cytotoxic CD8(+)CD28(+) T Lymphocyte Responses.

BACKGROUND: Adoptive immunotherapy with cytotoxic T lymphocytes (CTLs) has great potential for the treatment of some malignant cancers. Therefore, augmenting the responses of tumor-specific CTLs is significant for the adoptive immunotherapy of melanoma. This study aimed to investigate the anti-tumor response of a combination therapy employing folate-modified chitosan nanoparticles containing IP-10 (interferon-γ-inducible protein-10) plus melanoma TRP2-specific CD8(+)CD28(+) T cells. METHODS: We prepared folate-modified chitosan nanoparticles containing the mouse IP-10 gene (FA-CS-mIP-10), and induced melanoma TRP2-specific CD8(+)CD28(+) T cells by co-culturing them with artificial antigen-presenting cells. B16-bearing mice were treated with FA-CS-mIP-10, melanoma TRP2-specific CD8(+)CD28(+) T cells, a combination of both, and the saline control. Tumor volumes and the survival time of mice were recorded. The proportion of myeloid-derived suppressor cells (MDSCs) infiltrating the tumor microenvironment and regulatory T cells (Tregs) in the spleen was analyzed by flow cytometry. We also detected the proliferation and angiogenesis of tumors by immunohistochemistry and apoptosis by TUNEL. RESULTS: The combination therapy inhibited the progression of melanoma in vivo. Compared with other treatments, it more efficiently inhibited tumor growth and increased the survival time of mice. After treatment with combination therapy, the proportion of MDSCs and Tregs decreased, while the percentage of CXCR3(+)CD8(+) T cells increased. Furthermore, combination therapy inhibited proliferation and promoted apoptosis of tumor cells and significantly inhibited tumor angiogenesis in vivo. CONCLUSION: We describe a novel strategy for improving the anti-tumor response of CD8(+)CD28(+) CTLs by combining them with FA-CS-mIP-10 nanoparticles.

A Smart Detection System Based on Specific Magnetic and Rolling Cycle Amplification Signal-Amplified Dual-Aptamers to Accurately Monitor Minimal Residual Diseases in Patients with T-ALL.

It is a major clinical challenge for clinicians how to early find out minimal residual diseases (MRD) of leukemia. Here, we developed a smart detection system for MRD involving magnetic aptamer sgc8 probe (M-sgc8 probe) to capture CEM cells and rolling cycle amplification probe (RCA-sgc8 probe) to initiate RCA, producing a single-stranded tandem repeated copy of the circular template. The DNA products were hybridized with molecular beacon to generate the amplified fluorescence signal. An in vitro model to mimic MRD was established to evaluate the sensitivity of the smart detection system. The smart detection system was used to detect MRD in patients with T-ALL peri-chemotherapy, which could not only specifically captured T-ALL cells, but also significantly amplified fluorescence signals on them. The sensitivity was 1/20,000. These results indicate that the smart detection system with high specificity and sensitivity could more efficiently monitor the progress of T-ALL peri-chemotherapy.

Self-Assembling Monomeric Nucleoside Molecular Nanoparticles Loaded with 5-FU Enhancing Therapeutic Efficacy against Oral Cancer.

Conventional oligonucleotide based drug delivery systems suffer from lengthy synthetic protocols, high cost, and poor chemical or enzymatic stability under certain circumstances. Canonical free individual nucleosides cannot form stable nanostructures in aqueous solution as drug vehicles. Here, we report the development of a monomeric self-assembled nucleoside nanoparticle (SNNP) into an efficient drug delivery system which has currently no parallel in such field. This was achieved using a l-configurational pyrimido[4,5-d]pyrimidine nucleoside building block that can form robust discrete nanoparticles in just one step with water as the sole solvent. Its high biocompatibility and low toxicity was demonstrated in vitro and in vivo. In mouse xenograft model of oral squamous cell carcinoma (OSCC), SNNP loaded with 5-fluoro-uracile (5-FU-SNNP) remarkably retarded the tumor growth compared with free 5-FU, albeit SNNP alone showed no antitumor effect. The stability in blood circulation and the effective concentration of 5-FU in tumor tissue were increased upon the loading with SNNP. TUNEL and immunohistochemistry analyses further indicated that the superior in vivo antitumor efficacy of 5-FU-SNNP compared to free 5-FU was associated with an enhanced degree of inhibition of cell proliferation and stimulation of cell apoptosis. Furthermore, SNNP alleviated the toxic side effects of 5-FU. These findings suggested that when loaded with SNNP, 5-FU has better antitumor efficacy and lower side effects, indicating that SNNP can efficiently act as a readily accessible, robust, biocompatible and low-toxic nanobiomaterial which may find wide therapeutic applications clinically in the future.

Low-dose lung CT processing using weighted intensity averaging over large-scale neighborhoods.

The aim of the proposed work is to improve low-dose lung CT (LDCT) screening using the processing of weighted intensity averaging over large-scale neighborhoods (WIA-LN). Both current and voltage reductions were considered for LDCT imaging. In the WIA-LN method, the processed pixel intensities are calculated by weighted averaging intensities among a large neighboring region. The weights are determined by the inter-similarity of the surrounding textures. A compute unified device architecture based parallelization was applied to accelerate the implementation. To evaluate the effectiveness of the proposed processing, low-dose lung CT images were obtained under both 75 % reduced tube current and 33.3 % reduced tube voltage condition respectively from a 16 detector rows Siemens CT. The standard routine standard-dose CT images were also collected as the reference images. In addition to clinical data from patients, an anthropomorphic lung phantom was also used in the study. Visual comparison and statistical qualitative analysis of image quality scores on the datasets are made in validation. Compared to the original LDCT images, improved visual and qualitative performance can be observed for the processed images. Statistically significant improvement of noise/artifacts suppression and nodule structure enhancement are achieved by using the proposed method (P < 0.05). The proposed method is capable of providing LDCT images under significantly reduced tube current and voltage settings in low-dose condition. Quality of the processed images was assessed by radiology specialists. Parallelization based algorithm optimization was also performed to increase the clinical applicability of the proposed processing.