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Background:: Chemotherapy is the common treatment for cervical cancer, and the occurrence of drug resistance seriously affects the therapeutic effect of cervical cancer. Our previous study found that PRKD2 mutations occurred only in cervical cancer patients with chemotherapy resistance. However, the relationship between PRKD2 and drug resistance of cervical cancer remains unknown. Objective:: We aim to clarify the relationship between PRKD2 and drug resistance of cervical cancer. Methods:: Samples of patient tumor tissue were collected before chemotherapy and sequenced by WES. Chemotherapy clinical response was determined by measuring tumor volume. The expression of PRKD2, cell viability, and apoptosis were assessed by qRT-PCR, Western blot, CCK8, and flow cytometry in SiHa and ME180 cells after transfected with siPRKD2. The chemotherapy sensitivity signaling- related proteins were analyzed by Western blot. The expression levels of PRKD2、TP53, and CDKN1A in tissues were detected by immunohistochemistry staining. Results:: The expression of PRKD2 was higher in chemotherapy-resistant cervical cancer patients. PRKD2 knockdown increased the chemotherapy sensitivity of cervical cancer cells via the TP53/CDKN1A pathway, which led to G1 arrest and cell apoptosis. Furthermore, downregulation of PRKD2 enhances chemotherapeutic sensitivity in cervical cancer patients through the TP53/CDKN1A pathway. Conclusion:: In summary, PRKD2 may be a promising therapeutic target to improve the efficacy of chemotherapy.

Wireless power transfer technique provides a new and promising method for alleviating the limited energy capacity problem, thus receiving much attention. However, previous works usually consider temporal, spatial, or both factors of the current selected node greedily without taking the residual moving distance of the remaining nodes into consideration. Surely, it is not easy to precisely estimate the residual moving distance of the remaining nodes before knowing their exact order in the scheduling path. In this work, the authors are the first to propose the concept of the residual moving distance (cost) and create a mathematical model to roughly estimate the cost of a given node set. Moreover, they design a temporal and spatial priority charging scheduling algorithm with additional considering the global cost (TSPG). Simulation results demonstrate that TSPG outperforms earliest deadline first scheduling algorithm and revised earliest deadline first scheduling algorithm. Moreover, the proposed new model for estimating moving distance in the residual area has all relative error below 9%.

The interlayer spacing of V6O13 was adjusted by polyaniline intercalation for the first time to accelerate Mg2+ transport kinetics.

Currently, a variety of binders are developed to inhibit the rapid capacity fading of Si. The Si anodes are mainly enhanced by the chemical bonding effect on the surface of conventional solid-state binders. However, with a huge volume change of silicon, solid binders are easily deactivated. Herein, a semi-fluid binder termed GPC is designed based on a viscoelastic crosslinking network with abundant active sites and self-healing performance. The backbone of the binder network is

Objective: This study identified the major lactic acid bacteria (LAB) strains from different fermented total mixed rations (FTMRs) via metataxonomic analysis and evaluated the ability of their standard strain as ensiling inoculants for corn stover silage.Methods: The bacterial composition of eight FTMRs were analyzed by 16S rDNA sequencing. Corn stover was ensiled without LAB inoculation (control) or with 1×106 cfu/g LAB standard strain (Lactobacillus vaginalis, Lactobacillus reuteri, Lactobacillus helveticus, or Lactobacillus paralimentarius) selected from the FTMRs or 10 g/t commercial silage inoculant (CSI) around 25°C for 56 days. For each inoculation, a portion of the silage was sampled to analyze ensiling characteristics at time intervals of 0, 1, 3, 7, 14, 28, and 56 days, gas production (GP), microbial crude protein and volatile fatty acids as the measurements of rumen fermentation characteristics were evaluated in vitro with the silages of 56 days after 72 h incubation.Results: Lactobacillus covered >85% relative abundance of all FTMRs, in which L. pontis, L. vaginalis, L. reuteri, L. helveticus, and L. paralimentarius showed >4% in specific FTMRs. CSI, L. helveticus, and L. paralimentarius accelerated the decline of silage pH. Silage inoculated with L. paralimentarius and CSI produced more lactic acid the early 14 days. Silage inoculated with L. paralimentarius produced less acetic acid and butyric acid. For the in vitro rumen fermentation, silage inoculated with CSI produced more potential GP, isobutyric acid, and isovaleric acid; silage inoculated with L. helveticus produced more potential GP and isovaleric acid, silage inoculated with L. paralimentarius or L. reuteri produced more potential GP only.Conclusion: The standard strain L. paralimentarius (DSM 13238) is a promising ensiling inoculant for corn stover silage. The findings provide clues on strategies to select LAB to improve the quality of silage.

Abstract In search for new targets for the diagnosis and treatment of lupus nephritis (LN), we employed TMT-liquid chromatography-triple quadrupole mass spectrometry (TMT-LC–MS/MS) combined with RNA-seq and identified a panel of proteins that was dysregulated both at protein level and mRNA level in active LN patients compared with healthy controls. We chose to study the role of IGFBP2 since it is a relatively understudied protein in the context of LN. We further validated that IGFBP2 significantly increased and correlated with SLE activity index in active LN patients. The receiver operator characteristic (ROC) curve suggested that plasma IGFBP2 had a high diagnostic efficiency for distinguishing between inactive and active LN patients (AUC = 0.992; 95% CI = 0.974–1.000; P < 0.001). We demonstrated neutralizing IGFBP2-downregulated CD4+ T cell activation, upregulated the ratio of Treg, downregulated AKT/mTOR/4E-BP1 pathway, and significantly improved nephritis in MRL/lpr mice. In all, our work demonstrated IGFBP2 as a biomarker specific for active LN and blocking IGFBP2 could be a new target for treating LN. Key messages Plasma IGFBP2 is a promising diagnostic marker for distinguishing stable LN from active LN, and it is also a predictor for the poor prognosis of LN. Blockade of IGFBP2 can significantly improve the pathological damage of LN. IGFBP2 may regulate activation of CD4+ T and Treg ratio. Neutralizing IGFBP2 downregulates AKT/mTOR/4E-BP1 pathway.

To address the limited number of mitochondrial genomes (mitogenomes) in the subfamily Steganinae (Diptera: Drosophilidae), we assembled 12 complete mitogenomes for six representative species in the genus Amiota and six representative species in the genus Phortica. We performed a series of comparative and phylogenetic analyses for these 12 Steganinae mitogenomes, paying special attention to the commonalities and differences in the D-loop sequences. Primarily determined by the lengths of the D-loop regions, the sizes of the Amiota and Phortica mitogenomes ranged from 16,143–16,803 bp and 15,933–16,290 bp, respectively. Our results indicated that the sizes of genes and intergenic nucleotides (IGNs), codon usage and amino acid usage, compositional skewness levels, evolutionary rates of protein-coding genes (PCGs), and D-loop sequence variability all showed unambiguous genus-specific characteristics and provided novel insights into the evolutionary implications between and within Amiota and Phortica. Most of the consensus motifs were found downstream of the D-loop regions, and some of them showed distinct genus-specific patterns. In addition, the D-loop sequences were phylogenetically informative as the data sets of PCGs and/or rRNAs, especially within the genus Phortica.

Xeroderma pigmentosum (XP) is characterized by defective repair of ultraviolet radiation(UVR)-induced DNA damage. Patients have UVR hypersensitivity and increased skin cancer risk. Effective photoprotection has reduced childhood cancer-related deaths, but revealed adolescence-onset neurodegeneration, arising through unknown mechanisms. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We find endoplasmic reticulum stress is upregulated, preceded by oxidative stress, causing substantial 5’,8-cyclopurine and 8-oxopurine DNA damage. Critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity improves phenotypes, albeit inadequately, implying that early detection/prevention strategies are necessary to produce clinically impactful outcomes. Thus, we develop an early detection assay predicting neurodegeneration in at-risk patients.

Background Glioma is the most common malignancy of the central nervous system. Fos-like antigen 1 (FOSL1) is overexpressed and acts as a tumor-promoting factor in glioma. However, the regulation of FOSL1 remains unknown. KLF14, a member of Kruppel-like factors that are involved gene transcription, plays an important role in the regulation of cell proliferation, differentiation and apoptosis. Loss of KLF14 triggers spontaneous tumorigenesis of lung, spleen and lymph node, suggesting its potential as biomarker for cancer. However, its role in glioma still needs to be deciphered. Therefore, we explore the interactions between FOSL1 and KLF14, as well as their role in glioma. Methods We first determined that FOSL1 can be transcriptional inhibited by KLF14 using dual-luciferase reporter gene assays and qPCR assays. Then, through immunohistochemistry (IHC)assay and western blotting (WB) assay in glioma tissues, we demonstrated a negative correlation between FOSL1 and KLF14. Next, KLF14 knockdown cells and double knockdown of KLF14 and FOSL1 cells were generated, and cell growth were detected by different experimental methods (MTT assay, crystal violet staining, cell migration assay). We then used qPCR and WB assay to search for and validate how KLF14 affects tumor cell migration through FOSL1. Finally, we confirmed the inhibition of tumor growth by KLF14 using xenograft tumor model. Results In this study, we showed that KLF14 inhibited the transcription of FOSL1.There is a negative correlation between KLF14 and FOSL1 in glioma tissues. Overexpression of KLF14 reversed the effect of FOSL1 in cell invasion, migration and epithelial-mesenchymal transition in glioma cells, and this was accompanied by the down-regulation of Snail2 and CD44. Moreover, KLF14 overexpression inhibits tumor progression in vivo. Conclusions The present results suggest that KLF14 is a new tumor molecular marker and a potential target for the treatment of glioma, providing a new target for anti-tumor drug research.

In order to solve the practical problems of large water demand and shortage of water resources in traditional wheat/maize intercropping, a planting method of changing stubble retention method is proposed in this paper. This method was used to study the effects of three stubble retention methods of traditional wheat straw incineration, straw return, and straw stubble on grain yield, water use efficiency (WUE), and economic benefits of wheat/maize intercropping. The results showed that, compared with the grain yield of burning and returning, the single cropping of wheat increased by 7.2% and 5.1%, the intercropping of wheat increased by 6.2% and 5.1%, the single cropping of corn increased by 4.7% and 2.5%, and the intercropping of corn increased by 7.2% and 3.3%, respectively; compared with the burned and returned WUE, wheat monoculture increased by 20.4% and 16.2%, respectively, wheat intercropping increased by 17.9% and 14.6%, respectively, corn monoculture increased by 16.7% and 10.9%, respectively, and corn intercropping increased by 11.8% and 17.0%, respectively. In terms of the average value of monoculture wheat, monoculture corn, and wheat/corn, the net benefits of incineration, turning, and stubble treatment are 10946, 11471, and 13454 yuan • hm−2, respectively. Considering the grain yield, water use efficiency, and net income, the standing stubble planting mode is the best planting mode of wheat/maize in this area.

Table S5 shows 16 up-regulated genes and 10 predicted potential transcript factors in the global expression analysis

Table S1 shows clinicopathologic characteristics of 50 CRC patients

Table S2 shows the double-stranded shRNAs targeting selected up-regulated genes and siRNA for PNO1.

This file includes Supplementary Tables S2-S4 and captions for all supplementary tables.

Figure S1. Generation of HLA-A*02-restricted EGFR-specific CD8+ cytotoxic T lymphocytes; Figure S2. SOX2 inhibits IFN-I signaling by promoting autophagy-mediated degradation of STING; Figure S3. Validation of C57BL/6-syngeneic mouse squamous cell carcinoma cells; Figure S4. Characterization of MOC2-E6/E7 tumors; Figure S5: Clinical and immunological correlations of SOX2 expression in human HNSCC; Figure S6. SatVax (Q19D; Q15L) effectively controls tumor growth in larger established tumors and improves survival; Figure S7. Treatment schedule and individual tumor growth curves of Sox2-positive tumors

Figure S2 indicates that higher PNO1 mRNA levels are associated with poorer overall survival, relapse-free survival and shorter time of first progression of patients with breast or lung cancer. PNO1 knockdown decreased cell viability and cell survival of lung and breast cancer cells.

Table S4 summaries the characteristics of antibodies for analyses of Western-bloting, immunofluorescence, immunohistochemistry and co-immunoprecipitation.

Purpose: The response rates of Head and Neck Squamous Cell Carcinoma (HNSCC) to checkpoint blockade are below 20%. We aim to develop a mechanism-based vaccine to prevent HNSCC immune escape.Experimental Design: We performed RNA-Seq of sensitive and resistant HNSCC cells to discover central pathways promoting resistance to immune killing. Using biochemistry, animal models, HNSCC microarray, and immune cell deconvolution, we assessed the role of SOX2 in inhibiting STING-type I interferon (IFN-I) signaling-mediated antitumor immunity. To bypass SOX2-potentiated STING suppression, we engineered a novel tumor antigen–targeted nanosatellite vehicle to enhance the efficacy of STING agonist and sensitize SOX2-expressing HNSCC to checkpoint blockade.Results: The DNA-sensing defense response is the most suppressed pathway in immune-resistant HNSCC cells. We identified SOX2 as a novel inhibitor of STING. SOX2 facilitates autophagy-dependent degradation of STING and inhibits IFN-I signaling. SOX2 potentiates an immunosuppressive microenvironment and promotes HNSCC growth in vivo in an IFN-I-dependent fashion. Our unique nanosatellite vehicle significantly enhances the efficacy of STING agonist. We show that the E6/E7–targeted nanosatellite vaccine expands the tumor-specific CD8+ T cells by over 12-fold in the tumor microenvironment and reduces tumor burden. A combination of nanosatellite vaccine with anti-PD-L1 significantly expands tumor-specific CTLs and limits the populations expressing markers for exhaustion, resulting in more effective tumor control and improved survival.Conclusions: SOX2 dampens the immunogenicity of HNSCC by targeting the STING pathway for degradation. The nanosatellite vaccine offers a novel and effective approach to enhance the adjuvant potential of STING agonist and break cancer tolerance to immunotherapy. Clin Cancer Res; 24(17); 4242–55. ©2018 AACR.

Table S3 summaries primer sequences and probe for quantitative PCR or Northern blotting

Table S6 indicates that PNO1 mRNA expression is significantly up-regulated in various types of malignancies, including CRC, lung cancer, and breast cancer.

The RNA-binding protein PNO1 is critical for ribosome biogenesis, but its potential role in cancer remains unknown. In this study, online data mining, cDNA, and tissue microarrays indicated that PNO1 expression was higher in colorectal cancer tissue than in noncancerous tissue, and its overexpression was associated with worse patient survival. Gain-of-function and loss-of-function studies demonstrated that PNO1 knockdown suppressed growth of colorectal cancer cells in vitro and in vivo, while PNO1 overexpression promoted colorectal cancer cell proliferation in vitro. In colorectal cancer cells expressing wild-type p53, PNO1 knockdown enhanced expression of p53 and its downstream gene p21, and reduced cell viability; these effects were prevented by p53 knockout and attenuated by the p53 inhibitor PFT-α. Moreover, PNO1 knockdown in HCT116 cells decreased levels of 18S rRNA, of 40S and 60S ribosomal subunits, and of the 80S ribosome. It also reduced global protein synthesis, increasing nuclear stress and inhibiting MDM2-mediated ubiquitination and p53 degradation. Overexpressing EBF1 suppressed PNO1 promoter activity and decreased PNO1 mRNA and protein, inhibiting cell proliferation and inducing cell apoptosis through the p53/p21 pathway. In colorectal cancer tissues, the expression of EBF1 correlated inversely with PNO1. Data mining of online breast and lung cancer databases showed increased PNO1 expression and association with poor patient survival; PNO1 knockdown reduced cell viability of cultured breast and lung cancer cells. Taken together, these findings indicate that PNO1 is overexpressed in colorectal cancer and correlates with poor patient survival, and that PNO1 exerts oncogenic effects, at least, in part, by altering ribosome biogenesis.Significance:This study identifies the ribosome assembly factor PNO1 as a potential oncogene involved in tumor growth and progression of colorectal cancer.

Figure S1 shows that the expression levels of endogenous PNO1 in cultured CRC cell lines are relatively higher than that of differentiated Caco2 cells, and PNO1 knockdown reduces cell viability and survival of CRC cells.

List of deferentially expressed genes in HNSCC cancer cells resistant to immune killing

Supplementary Figures 1-3 from EGFRvIII Antibody–Conjugated Iron Oxide Nanoparticles for Magnetic Resonance Imaging–Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma

Supplementary Figure Legends 1-7 from EGFRvIII Antibody–Conjugated Iron Oxide Nanoparticles for Magnetic Resonance Imaging–Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma

The magnetic nanoparticle has emerged as a potential multifunctional clinical tool that can provide cancer cell detection by magnetic resonance imaging (MRI) contrast enhancement as well as targeted cancer cell therapy. A major barrier in the use of nanotechnology for brain tumor applications is the difficulty in delivering nanoparticles to intracranial tumors. Iron oxide nanoparticles (IONP; 10 nm in core size) conjugated to a purified antibody that selectively binds to the epidermal growth factor receptor (EGFR) deletion mutant (EGFRvIII) present on human glioblastoma multiforme (GBM) cells were used for therapeutic targeting and MRI contrast enhancement of experimental glioblastoma, both in vitro and in vivo, after convection-enhanced delivery (CED). A significant decrease in glioblastoma cell survival was observed after nanoparticle treatment and no toxicity was observed with treatment of human astrocytes (P < 0.001). Lower EGFR phosphorylation was found in glioblastoma cells after EGFRvIIIAb-IONP treatment. Apoptosis was determined to be the mode of cell death after treatment of GBM cells and glioblastoma stem cell–containing neurospheres with EGFRvIIIAb-IONPs. MRI-guided CED of EGFRvIIIAb-IONPs allowed for the initial distribution of magnetic nanoparticles within or adjacent to intracranial human xenograft tumors and continued dispersion days later. A significant increase in animal survival was found after CED of magnetic nanoparticles (P < 0.01) in mice implanted with highly tumorigenic glioblastoma xenografts (U87ΔEGFRvIII). IONPs conjugated to an antibody specific to the EGFRvIII deletion mutant constitutively expressed by human glioblastoma tumors can provide selective MRI contrast enhancement of tumor cells and targeted therapy of infiltrative glioblastoma cells after CED. Cancer Res; 70(15); 6303–12. ©2010 AACR.

Supplementary Figure 7 from EGFRvIII Antibody–Conjugated Iron Oxide Nanoparticles for Magnetic Resonance Imaging–Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma

Supplementary Methods from EGFRvIII Antibody–Conjugated Iron Oxide Nanoparticles for Magnetic Resonance Imaging–Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma