Exploration of glutaredoxin-1 oxidative modification in carbon nanomaterial-induced hepatotoxicity.

Herein, we present toxicological assessments of carbon nanomaterials in HL-7702 cells, and it was found that reactive oxygen species (ROS) levels were elevated. Mass spectrometry results indicated that cysteine sulfhydryl of glutaredoxin-1 (GLRX1) was oxidized to sulfenic acids and sulfonic acids by excessive ROS, which broke the binding of GLRX1 to apoptosis signal-regulating kinase 1, causing the activation of the JNK/p38 signaling pathway and ultimately hepatocyte apoptosis. However, a lower level of ROS upregulated GLRX1 instead of sulfonation modification of its active sites. Highly expressed GLRX1 in turn enabled the removal of intracellular ROS, thereby exerting inconspicuous toxic effects on cells. Taken together, these findings emphasized that CNM-induced hepatotoxicity is attributable to oxidative modifications of GLRX1 arising from redox imbalance.

The anticancer application of half-sandwich iridium(III) ferrocene-thiosemicarbazide Schiff base complexes.

Ferrocenyl derivatives and organometallic iridium(III) complexes have been prospective substitutes for platinum-based anticancer drugs. Eight half-sandwich iridium(III) ferrocene-thiosemicarbazide (Fc-TSC) Schiff base anticancer complexes were prepared in this study. These complexes displayed a dimeric structure and exhibited a particular fluorescence due to the "enol" orientation of the TSC pro-ligand. An energy-dependent pathway of the uptake mechanism was ascertained, which ended in the lysosome and led to lysosome damage and apoptosis. Flow cytometry confirmed that the complexes could block the cell cycle (G1 phase) and improve the levels of intracellular reactive oxygen species, indicating an anticancer mechanism of oxidation. Then, a lysosomal-mitochondrial anticancer pathway was verified through western blotting. In vivo toxicity assays confirmed that these complexes showed better anti-migration ability and less toxicity in comparison to cisplatin. Thus, these complexes provide a new strategy for the design of non-platinum organometallic anticancer drugs.

Macrophages-derived exo-miR-4449 induced by Cryptococcus affects HUVEC permeability and promotes pyroptosis in BEAS-2B via the HIC1 pathway.

Macrophages have recently been discovered to assume a significant role in the progression of cryptococcosis. However, the potential involvement of macrophage-derived exosomes in the pathogenesis of cryptococcosis remains uncertain. In this study, we investigated the changes of microRNAs in macrophage exosomes (exo-miRNAs) in cryptococcal infections and the role of markedly altered exo-miRNAs in the modulation of Human Umbilical Vein Endothelial Cells (HUVEC) permeability and ROS accumulation and pyroptosis in Human Bronchial Epithelioid Cells (BEAS-2B). Techniques such as microarray analysis and real-time quantitative PCR were used to detect different exo-miRNAs and to screen for the most highly expressed exo-miRNAs. Then its mimics were transfected into HUVEC to study its effect on the monolayer permeability of HUVEC. Finally, the relationship between this exo-miRNAs and the ROS accumulation and pyroptosis was verified by bioinformatics analysis. The results showed that five exo-miRNAs were overexpressed and two exo-miRNAs were reduced, among which, exo-miR-4449 was expressed at the highest level. Exo-miR-4449 could be internalized by HUVEC and enhanced its monolayer permeability. Moreover, exo-miR-4449 was found to promote ROS accumulation and pyroptosis in BEAS-2B through HIC1 pathway. Thus, exo-miR-4449 plays an important role in the pathogenesis of cryptococcosis and holds promise as a significant biomarker for treatment.

Compressive Strain in Platinum-Iridium-Nickel Zigzag-Like Nanowire Boosts Hydrogen Catalysis.

Strain effect in the structurally defective materials can contribute to the catalysis optimization. However, it is challenging to achieve the performance improvement by strain modulation with the help of geometrical structure because strain is spatially dependent. Here, a new class of compressively strained platinum-iridium-metal zigzag-like nanowires (PtIrM ZNWs, M = nickel (Ni), cobalt (Co), iron (Fe), zinc (Zn) and gallium (Ga)) is reported as the efficient alkaline hydrogen evolution reaction (HER) and hydrogen oxidation reaction (HOR) catalysts. Particularly, the optimized PtIrNi ZNWs with 3% compressive strain (cs-PtIrNi ZNWs) can achieve the highest HER/HOR performances among all the catalysts investigate. Their HOR mass and specific activities are 3.2/14.4 and 2.6/32.7 times larger than those of PtIrNi NWs and commercial Pt/C, respectively. Simultaneously, they can exhibit the superior stability and high CO resistance for HOR. Further, experimental and theoretical studies collectively reveal that the compressive strain in cs-PtIrNi ZNWs effectively weakens the adsorption of hydroxyl intermediate and modulates the electronic structure, resulting in the weakened hydrogen binding energy (HBE) and moderate hydroxide binding energy (OHBE), beneficial for the improvement of HOR performance. This work highlights the importance of strain tuning in enhancing Pt-based nanomaterials for hydrogen catalysis and beyond.

BMI-specific inflammatory response to phthalate exposure in early pregnancy: findings from the TMCHESC study.

Studies that have evaluated associations between phthalate metabolites and inflammation have reported inconsistent results among pregnant women, and it is unclear how body mass index (BMI) affects such relationships. Therefore, the present study aimed to examine the association between urinary phthalate metabolite concentrations and the levels of inflammatory biomarkers in the general circulation among 394 pregnant women selected from the Tianjin Maternal and Child Health Education and Service Cohort (TMCHESC) and to determine the role that BMI plays in the relationship. The concentrations of eight inflammatory biomarkers and three phthalate metabolites were measured in serum and urine samples, respectively. Multivariable linear modeling was conducted to examine the association between each phthalate and inflammatory biomarker while controlling for potential confounding factors in BMI-stratified subgroups. Restricted cubic splines were also utilised to explore potential non-linear relationships. In the high-BMI group, positive associations were observed between the levels of mono-n-butyl phthalate (MBP) and interleukin 1 beta (IL-1ß) (ß = 0.192; 95% CI: 0.033, 0.351), monoethyl phthalate (MEP), and C-reaction protein (CRP) (ß = 0.129; 95% CI 0.024, 0.233), and mono-ethylhexyl phthalate (MEHP) and interleukin 6 (IL-6) (ß = 0.146; 95% CI 0.016, 0.277). Restricted cubic spline models also revealed non-linear associations between the levels of MBP and interleukins 10 and 17A (IL-10 and IL-17A) and between MEP and interleukin 8 (IL-8) and tumor necrosis factor alpha (TNF-α) in pregnant women. These results suggest that phthalate exposure plays a potential role in promoting inflammation in the high-BMI group. While the precise mechanisms underlying the proinflammatory effects of phthalates are not fully understood, these findings suggest that BMI may play a role.

Dosimetry and acute radiation enteritis comparison between prone and supine position in IMRT for gynecological cancers.

PURPOSE: To probe the differences of dosimetry and acute radiation enteritis between prone and supine position in gynecological cancer patients treated with intensity-modulate radiotherapy (IMRT). METHODS: Gynecologic tumor patients who received IMRT from January 2020 to July 2021 were analyzed. 60 patients were enrolled and divided into the supine or prone position group according to different radiotherapy positions, including 34 patients in prone position and 26 patients in supine position. The dose-volume histogram of organs at risk (OARs) and the incidence of acute radiation enteritis were compared between the two groups. Multivariate logistic regression analysis was conducted to show the clinical characteristics and dose volume metrics to the association of acute radiation enteritis. RESULTS: The percentage of volume receiving 5 Gy, 10 Gy, 15 Gy, 20 Gy, 30 Gy, 40 Gy, and 45 Gy doses for the small intestine were 79.0%, 67.4%, 59.6%, 44.3%, 17.0%, 8.9%, and 6.0%, respectively in the prone group, which were lower than those in the supine group (P < 0.05). The mean radiation dose (Dmean ) of the small intestine exposure in prone group was decreased (P < 0.001). Compared with the supine group, the prone group who suffered from acute radiation enteritis were much less. The probability of indigestion, nausea, vomiting, diarrhea, and abdominal pain in the prone position were 35.29%, 29.41%, 17.65%, 38.24%, and 5.88%, respectively. The differences in indigestion, nausea, and diarrhea between the two groups were statistically significant (P = 0.012, P = 0.029, and P = 0.041). Multivariate logistic regression analysis was shown that prone position was found to be protective against indigestion (P = 0.002), nausea (P = 0.013), vomiting (P = 0.035), and abdominal pain (P = 0.021). CONCLUSION: Prone position in IMRT for gynecological cancers could significantly reduce radiation dose to the small bowel and colon, which would decrease the occurrence and severity of acute intestinal side effects possibly.

LncRNA FEZF1-AS1 accelerates multiple myeloma progression by regulating IGF2BP1/BZW2 signaling.

Multiple myeloma (MM) is the second largest hematological tumor with clonal proliferation of malignant plasma cells. Growing reports have revealed that the dysregulation of long non-coding RNA (lncRNA) is involved in the MM progression. Nevertheless, lncRNA FEZF1 antisense RNA 1 (FEZF1-AS1) remain not deeply explored. The RNA transcripts and protein level of MM-associated molecule were measured by quantitative real-time polymerase chain reaction or western blot assays, respectively. The clinical correlation was analyzed by Pearson analysis. Molecular interactions among lncRNA FEZF1-AS1, basic leucine zipper and W2 domain 2 (BZW2) and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) were verified by RNA immunoprecipitation and RNA pull-down assays. The survival of MM cells was detected by cell counting kit-8 and flow cytometry assays. Xenograft tumor in vivo was performed to assess tumor growth. The RNA transcripts of lncRNA FEZF1-AS1, BZW2 and IGF2BP1 were upregulated in MM samples compared to those in healthy donors. Knockdown of lncRNA FEZF1-AS1 could inhibit the proliferation and induce cell apoptosis in vitro and in vivo. Besides, lncRNA FEZF1-AS1 could maintain the stability of BZW2 mRNA by interacting IGF2BP1. Moreover, BZW2 silence also downregulated the proliferation but enhanced apoptosis of MM cells, while BZW2 overexpression had an opposite role, which dramatically reversed the regulatory roles of lncRNA FEZF1-AS1. Altogether, lncRNA FEZF1-AS1 facilitated MM development by regulating IGF2BP1/BZW2 signaling, suggesting that lncRNA FEZF1-AS1 might be a candidate for MM treatment.

m6A methyltransferase METTL3 facilitates multiple myeloma cell growth through the m6A modification of BZW2.

N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) has been confirmed to be involved in multiple myeloma (MM) progression, and basic leucine zipper and W2 domains 2 (BZW2) is considered to be a regulator for MM development. However, whether METTL3 mediates MM progression by regulating BZW2 remains unclear. The messenger RNA (mRNA) and protein levels of METTL3 and BZW2 in MM specimens and cells were determined using quantitative real-time PCR and western blot analysis. Cell proliferation and apoptosis were assessed by cell counting kit 8 assay, 5-ethynyl-2'-deoxyuridine assay, colony formation assay, and flow cytometry. Methylated RNA immunoprecipitation-qPCR was used to detect the m6A modification level of BZW2. Xenograft tumor models were constructed to confirm the effect of METTL3 knockdown on MM tumor growth in vivo. Our results showed that BZW2 was upregulated in MM bone marrow specimens and cells. BZW2 downregulation reduced MM cell proliferation and promoted apoptosis, while its overexpression enhanced MM cell proliferation and inhibited apoptosis. METTL3 was highly expressed in MM bone marrow specimens, and its expression was positively correlated with BZW2 expression. BZW2 expression was positively regulated by METTL3. Mechanistically, METTL3 could upregulate BZW2 expression by modulating its m6A modification. Additionally, METTL3 accelerated MM cell proliferation and restrained apoptosis via increasing BZW2 expression. In vivo experiments showed that METTL3 knockdown reduced MM tumor growth by decreasing BZW2 expression. In conclusion, these data indicated that METTL3-mediated the m6A methylation of BZW2 to promote MM progression, suggesting a novel therapeutic target for MM.

Novel AIE Probe for In Situ Imaging of Protein Sulfonation to Assess Cigarette Smoke-Induced Inflammatory Damage.

Cysteine sulfonic acid, a product of protein oxidative damage, is an important sign by which the body and cells sense oxidative stress. Cigarette smoke (CS) can trigger inflammatory reactions in humans that lead to higher levels of oxidative stress and reactive oxygen species (ROS) in the body. Available evidence indicates a possible relationship between protein oxidative damage and cigarette smoke, which is poorly understood due to the limitations of analytical techniques. Herein, we developed a donor-acceptor structured aggregation-induced emission (AIE) fluorescence probe H-1, which exhibited excellent optical properties for the highly sensitive and specific detection of sulfonic acid biomacromolecules. The probe could be easily synthesized by click chemistry conjugating triazole heterocycles onto a triphenylamine fluorophore, followed by a cationization reaction. Due to low cytotoxity, the probe was successfully applied for in situ imaging of intracellular protein sulfonation, achieving visualization of protein sulfonation in cigarette smoke stimulation-induced inflammatory RAW264.7 cell models. Moreover, an immunofluorescence study of the aorta and lung revealed that significant blue fluorescence signals could be observed only in CS-stimulated vascular. It indicated that CS-stimulated vascular sulfonation injury can be monitored using H-1. This study will provide an efficient method for revealing CS-induced oxidative damage-relevant diseases.

A novel senescence-related lncRNA signature that predicts prognosis and the tumor microenvironment in patients with lung adenocarcinoma.

Background: Cellular senescence has recently been considered a new cancer hallmark. However, the factors regulating cellular senescence have not been well characterized. The aim of this study is to identify long non-coding RNAs (lncRNAs) associated with senescence and prognosis in patients with lung adenocarcinoma (LUAD). Methods: Using RNA sequence data from the Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) and senescence genes from the CellAge database, a subset of senescence-related lncRNAs was first identified. Then, using univariate and multivariate Cox regression analyses, a senescence lncRNA signature (LUADSenLncSig) associated with LUAD prognosis was developed. Based on the median LUADSenLncSig risk score, LUAD patients were divided into high-risk and low-risk groups. Kaplan-Meier analysis was used to compare the overall survival (OS) in the high- and low-risk score subgroups. Differences in Gene Set Enrichment Analysis (GSEA), immune infiltration, tumor mutation burden (TMB), tumor immune dysfunction and exclusion (TIDE) module score, chemotherapy, and targeted therapy selection were also compared between the high-risk and low-risk groups. Results: A prognostic risk model was obtained consisting of the following nine senescence-related lncRNAs: LINC01116, AC005838.2, SH3PXD2A-AS1, VIMS-AS1, SH3BP5-AS1, AC092279.1, AC026355.1, AC027020.2, and LINC00996. The LUADSenLncSig high-risk group was associated with poor OS (hazard ratio = 1.17, 95% confidence interval = 1.102-1.242; p < 0.001). The accuracy of the model was further supported based on receiver operating characteristic (ROC), principal component analysis (PCA), and internal validation cohorts. In addition, a nomogram was developed consisting of LUADSenLncSig for LUAD prognosis, which is consistent with the actual probability of OS. Furthermore, immune infiltration analysis showed the low-risk group had a stronger anti-tumor immune response in the tumor microenvironment. Notably, the levels of immune checkpoint genes such as CTLA-4, PDCD-1, and CD274, and the TIDE scores were significantly higher in the low-risk subgroups than in high-risk subgroups (p < 0.001). This finding indicates the LUADSenLncSig can potentially predict immunotherapy efficacy. Conclusion: In this study, a lncRNA signature, LUADSenLncSig, that has dual functions of senescence phenotype identification and prognostic prediction as well as the potential to predict the LUAD response to immunotherapy was developed.

Effects of fast track surgery on perioperative recovery, stress indicators and swallowing function in patients with thyroid cancer.

OBJECTIVE: To explore the effects of fast track surgery (FTS) on perioperative recovery, stress indicators and swallowing function in patients with thyroid cancer. METHODS: One hundred and thirty patients with thyroid cancer admitted to Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Affiliated Hospital of Huzhou Normal University from January 2019 to December 2020 were retrospectively included as study subjects, and were divided into a control group (n = 63, conventional nursing) and a study group (n = 67, FTS). The perioperative recovery indicators, complications, stress response, and swallowing function were compared between the two groups. Logistic regression analysis was used to analyze the risk factors for accelerating postoperative recovery. RESULTS: No statistically significant differences were observed in the scores of Kubota drinking test and Ichiro Fujishima rating scale (IFRS) between the two groups before intervention (P > 0.05). After nursing, the study group had lower scores of Kubota drinking test and higher scores of IFRS than the control group (P < 0.05). The time to drainage tube removal, time to first anal exhaust, time to first getting out of bed activity, length of hospitalization, and medical costs in the study group were lower than those in the control group (P < 0.05). The study group showed lower incidence of postoperative complications than the control group (8.96% vs. 28.57%, P < 0.05). The postoperative C-reactive protein, glucose, epinephrine, cortisol levels and numerical rating scale scores in the study group were lower than those in the control group (P < 0.05). Logistic regression analysis showed that age was an important negative factor for accelerating postoperative recovery of patients with thyroid cancer, and the length of postoperative hospital stay increased significantly with age (P < 0.05). CONCLUSION: The intervention of FTS in the perioperative period for thyroid cancer patients can improve the swallowing function, shorten the recovery time and reduce the incidence of complications, which may be related to the improvement of the perioperative stress response of patients with FTS.

Vertical distribution and temporal evolution of formaldehyde and glyoxal derived from MAX-DOAS observations: The indicative role of VOC sources.

Formaldehyde (HCHO) and glyoxal (CHOCHO) are important oxidization intermediates of most volatile organic compounds (VOCs), but their vertical evolution in urban areas is not well understood. Vertical profiles of HCHO, CHOCHO, and nitrogen dioxide (NO2) were retrieved from ground-based Multi-Axis Differential Optical Absorption Spectroscopy (MAX-DOAS) observations in Hefei, China. HCHO and CHOCHO vertical profiles prefer to occur at higher altitudes compared to NO2, which might be caused by the photochemistry-oxidation of longer-lived VOCs at higher altitudes. Monthly means of HCHO concentrations were higher in summer, while enhanced amounts of NO2 were mainly observed in winter. CHOCHO exhibited a hump-like seasonal variation, with higher monthly-averaged values not only occurred in warm months (July-August) but also in cold months (November-December). Peak values mainly occurred during noon for HCHO but emerged in the morning for CHOCHO and NO2, suggesting that HCHO is stronger link to photochemistry than CHOCHO. We further use the glyoxal to formaldehyde ratio (GFR) to investigate the VOC sources at different altitudes. The lowest GFR value is almost found in the altitude from 0.2 to 0.4 km, and then rises rapidly as the altitude increases. The GFR results indicate that the largest contributor of the precursor VOC is biogenic VOCs at lower altitudes, while at higher altitudes is anthropogenic VOCs. Our findings provide a lot more insight into VOC sources at vertical direction, but more verification is recommended to be done in the future.

YTHDF1 promotes breast cancer progression by facilitating FOXM1 translation in an m6A-dependent manner.

BACKGROUND: N6-methyladenosine (m6A) is the most common post-transcriptional modification at the RNA level. However, the exact molecular mechanisms of m6A epigenetic regulation in breast cancer remain largely unknown and need to be fully elucidated. METHODS:  The integrating bioinformatics analyses were used to screen clinical relevance and dysregulated m6A "reader" protein YTHDF1 in breast cancer from TCGA databases, which was further validated in a cohort of clinical specimens. Furthermore, functional experiments such as the CCK-8 assay, EdU assay, wound healing assay, transwell invasion assay and cell cycle assay were used to determine the biological role of YTHDF1 in breast cancer. RIP, m6A-IP, and CLIP assays were used to find the target of YTHDF1 and further verification by RT-qPCR, western blot, polysome profiling assay. The protein-protein interaction between YTHDF1 and FOXM1 was detected via co-immunoprecipitation. RESULTS: Our study showed that YTHDF1 was overexpressed in breast cancer cells and clinical tissues specimens. At the same time, the high expression level of YTHDF1 was positively correlated with tumor size, lymph node invasion, and distant metastasis in breast cancer patients. YTHDF1 depletion repressed the proliferation, invasion and epithelial-mesenchymal transformation (EMT) and induced G0/G1 phase cell cycle arrest of breast cancer cells in vitro and in vivo. We also demonstrated that FOXM1 is a target of YTHDF1. Through recognizing and binding to the m6A-modified mRNA of FOXM1, YTHDF1 accelerated the translation process of FOXM1 and promoted breast cancer metastasis. Whereas overexpression of FOXM1 in breast cancer cells partially counteracted the tumor suppressed effects caused by YTHDF1 silence, which further verified the regulatory relationship between YTHDF1 and FOXM1. CONCLUSION: Our study reveals a novel YTHDF1/FOXM1 regulatory pathway that contributes to metastasis and progression of breast cancer, suggesting that YTHDF1 might be applied as a potential biomarker and therapeutic target. That also advances our understanding of the tumorigenesis for breast cancer from m6A epigenetic regulation.

Diagnostic Evidence GAuge of Single cells (DEGAS): a flexible deep transfer learning framework for prioritizing cells in relation to disease.

We propose DEGAS (Diagnostic Evidence GAuge of Single cells), a novel deep transfer learning framework, to transfer disease information from patients to cells. We call such transferrable information "impressions," which allow individual cells to be associated with disease attributes like diagnosis, prognosis, and response to therapy. Using simulated data and ten diverse single-cell and patient bulk tissue transcriptomic datasets from glioblastoma multiforme (GBM), Alzheimer's disease (AD), and multiple myeloma (MM), we demonstrate the feasibility, flexibility, and broad applications of the DEGAS framework. DEGAS analysis on myeloma single-cell transcriptomics identified PHF19high myeloma cells associated with progression. Availability: https://github.com/tsteelejohnson91/DEGAS .

Hepatotoxicity-Related Oxidative Modifications of Thioredoxin 1/Peroxiredoxin 1 Induced by Different Cadmium-Based Quantum Dots.

The hepatotoxicity of cadmium-based quantum dots (Cd-QDs) has become the focus with their extensive applications in biomedicine. Previous reports have demonstrated that high oxidative stress and consequent redox imbalance play critical roles in their toxicity mechanisms. Intracellular antioxidant proteins, such as thioredoxin 1 (Trx1) and peroxiredoxin 1 (Prx1), could regulate redox homeostasis through thiol-disulfide exchange. Herein, we hypothesized that the excessive reactive oxygen species (ROS) induced by Cd-QD exposure affects the functions of Trx1 or Prx1, which further causes abnormal apoptosis of liver cells and hepatotoxicity. Thereby, three types of Cd-QDs, CdS, CdSe, and CdTe QDs, were selected for conducting an intensive study. Under the same conditions, the H2O2 level in the CdTe QD group was much higher than that of CdS or CdSe QDs, and it also corresponded to the higher hepatotoxicity. Mass spectrometry (MS) results show that excessive H2O2 leads to sulfonation modification (-SO3H) at the active sites of Trx1 (Cys32 and Cys35) and Prx1 (Cys52 and Cys173). The irreversible oxidative modifications broke their cross-linking with the apoptosis signal-regulating kinase 1 (ASK1), resulting in the release and activation of ASK1, and activation of the downstream JNK/p38 signaling finally promoted liver cell apoptosis. These results highlight the key effect of the high oxidative stress, which caused irreversible oxidative modifications of Trx1 and Prx1 in the mechanisms involved in Cd-QD-induced hepatotoxicity. This work provides a new perspective on the hepatotoxicity mechanisms of Cd-QDs and helps design safe and reliable Cd-containing nanoplatforms.

Circ_0072995 Promotes Ovarian Cancer Progression Through Regulating miR-122-5p/SLC1A5 Axis.

Ovarian cancer is a common cancer affecting women with high morbidity and mortality globally. Circular RNAs (circRNAs) have been found play vital roles in multifarious cancers, including OC. This study aims to explore the biological role and underlying mechanism of circ_0072995 in OC progression. Circ_0072995 was upregulated in OC tissues and cells in a stable structure. Functional experiments indicated that circ_0072995 knockdown suppressed cell proliferation, migration, invasion and accelerated cell apoptosis of OC cells. Mechanistically, miR-122-5p was a direct target of circ_0072995, and its knockdown reversed the effects of circ_0072995 silence on inhibition of OC cell progression. Meanwhile, SLC1A5 was a downstream target gene of miR-122-5p, and miR-122-5p overexpression inhibited the progression of OC cells by targeting SLC1A5. Moreover, circ_0072995 positively regulated SLC1A5 expression via sponging miR-122-5p. Circ_0072995 could play oncogenic role in tumorigenesis and malignant development of OC by regulating miR-122-5p/SLC1A5 axis, providing a novel approach for OC treatment.

Dysregulation of Circadian Clock Genes as Significant Clinic Factor in the Tumorigenesis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality worldwide due to its asymptomatic onset and poor survival rate. This highlights the urgent need for developing novel diagnostic markers for early HCC detection. The circadian clock is important for maintaining cellular homeostasis and is tightly associated with key tumorigenesis-associated molecular events, suggesting the so-called chronotherapy. An analysis of these core circadian genes may lead to the discovery of biological markers signaling the onset of the disease. In this study, the possible functions of 13 core circadian clock genes (CCGs) in HCC were systematically analyzed with the aim of identifying ideal biomarkers and therapeutic targets. Profiles of HCC patients with clinical and gene expression data were downloaded from The Cancer Genome Atlas and International Cancer Genome Consortium. Various bioinformatics methods were used to investigate the roles of circadian clock genes in HCC tumorigenesis. We found that patients with high TIMELESS expression or low CRY2, PER1, and RORA expressions have poor survival. Besides, a prediction model consisting of these four CCGs, the tumor-node-metastasis (TNM) stage, and sex was constructed, demonstrating higher predictive accuracy than the traditional TNM-based model. In addition, pathway analysis showed that these four CCGs are involved in the cell cycle, PI3K/AKT pathway, and fatty acid metabolism. Furthermore, the network of these four CCGs-related coexpressed genes and immune infiltration was analyzed, which revealed the close association with B cells and nTreg cells. Notably, TIMELESS exhibited contrasting effects against CRY2, PER1, and RORA in most situations. In sum, our works revealed that these circadian clock genes TIMELESS, CRY2, PER1, and RORA can serve as potential diagnostic and prognostic biomarkers, as well as therapeutic targets, for HCC patients, which may promote HCC chronotherapy by rhythmically regulating drug sensitivity and key cellular signaling pathways.

ParsVNN: parsimony visible neural networks for uncovering cancer-specific and drug-sensitive genes and pathways.

Prediction of cancer-specific drug responses as well as identification of the corresponding drug-sensitive genes and pathways remains a major biological and clinical challenge. Deep learning models hold immense promise for better drug response predictions, but most of them cannot provide biological and clinical interpretability. Visible neural network (VNN) models have emerged to solve the problem by giving neurons biological meanings and directly casting biological networks into the models. However, the biological networks used in VNNs are often redundant and contain components that are irrelevant to the downstream predictions. Therefore, the VNNs using these redundant biological networks are overparameterized, which significantly limits VNNs' predictive and explanatory power. To overcome the problem, we treat the edges and nodes in biological networks used in VNNs as features and develop a sparse learning framework ParsVNN to learn parsimony VNNs with only edges and nodes that contribute the most to the prediction task. We applied ParsVNN to build cancer-specific VNN models to predict drug response for five different cancer types. We demonstrated that the parsimony VNNs built by ParsVNN are superior to other state-of-the-art methods in terms of prediction performance and identification of cancer driver genes. Furthermore, we found that the pathways selected by ParsVNN have great potential to predict clinical outcomes as well as recommend synergistic drug combinations.

A potentially valuable nano graphene oxide/USPIO tumor diagnosis and treatment system.

Due to increased requirements for precision cancer treatment, cancer chemotherapy and combination therapies have gradually developed in the direction of diagnosis and treatment integration. In this study, a non-toxic nano carrier that demonstrates integrated MRI signal enhancing performance, as well as better chemotherapy and photothermal conversion performance, was prepared and characterized. Furthermore, the carrier was used to construct an integrated system of tumor diagnosis and treatment. Our in vitro studies showed that this system has a considerable inhibition effect on tumor cells during the treatment of chemotherapy when combined with PTT, and in vivo studies showed that the system could improve the MRI signal of the tumor site with application of a safe dosage. Thus, this system based on NGO/USPIO has the potential to be a multi-functional nano drug delivery system integrating diagnosis and treatment benefits and applications that are worthy of further research.

[Effect of TRIM31 Gene Silencing on the Proliferation and Apoptosis of U266 Cells and Its Mechanism].

OBJECTIVE: To investigate the effect of the tripartite motif containing 31 (TRIM31) gene silencing on the proliferation and apoptosis of multiple myeloma cells and its possible mechanism. METHODS: The normal bone marrow plasma cells (nPCs) were selected as control, and the mRNA and protein expression levels of TRIM31 in human multiple myeloma cell lines (U266, RPMI-8226, NCI-H929 and KMS-11) were detected by RT-qPCR and Western blot. Recombinant lentivirol vector containing shRNA-TRIM31 and its negative control were used to infect U266 cells respectively, and the mRNA expression level of TRIM31 in infected cells was detected by RT-qPCR. Then cell proliferation, colony forming and apoptosis were analyzed by CCK-8, soft agar assay, and flow cytometry, respectively. The protein expression levels of TRIM31, cleaved-caspase-3, BCL-2, Bax, p-Akt (Ser473), Akt and PI3K (p110α) were evaluated by Western blot. In addition, the PI3K/Akt signaling pathway-specific inhibitor LY294002 and TRIM31-shRNA lentivirus were used to interfere with U266 cells, and the cell proliferation, apoptosis, and protein expression of p-Akt (Ser473) and Akt were detected by CCK-8, flow cytometry and Western blot, respectively. RESULTS: Compared with nPCs, the expression levels of TRIM31 mRNA and protein in U266, RPMI-8226, NCI-H929 and KMS-11 cells were significantly increased (P<0.001), especially in U266 cells. After lentivirus infection, the levels of TRIM31 mRNA and protein in U266 cells were significantly decreased (P<0.001). TRIM31 silencing significantly inhibited the proliferation of U266 cells (P<0.05), attenuated the ability of cell cloning, improved cell apoptosis, up-regulated the protein expressions of cleaved-caspase-3 and Bas as well as down-regulated expressions of BCL-2, p-Akt (Ser473) and PI3K (p110α). There was no significant effect on Akt protein. Intervention of LY294002 significantly enhanced the inhibition on cell proliferation and the promotion on apoptosis mediated by TRIM31 gene silencing in U266 cells. CONCLUSION: TRIM31 gene silencing can inhibit U266 cell proliferation and promote its apoptosis, which may be closely related to inhibition of PI3K/Akt signaling pathway.