lncRNA Profiling of Exosomes and Its Communication Role in Regulating Silica-Stimulated Macrophage Apoptosis and Fibroblast Activation.

Long-term silica particle exposure leads to interstitial pulmonary inflammation and fibrosis, called silicosis. Silica-activated macrophages secrete a wide range of cytokines resulting in persistent inflammation. In addition, silica-stimulated activation of fibroblast is another checkpoint in the progression of silicosis. The pathogenesis after silica exposure is complex, involving intercellular communication and intracellular signaling pathway transduction, which was ignored previously. Exosomes are noteworthy because of their crucial role in intercellular communication by delivering bioactive substances, such as lncRNA. However, the expression profile of exosomal lncRNA in silicosis has not been reported yet. In this study, exosomes were isolated from the peripheral serum of silicosis patients or healthy donors. The exosomal lncRNAs were profiled using high-throughput sequencing technology. Target genes were predicted, and functional annotation was performed using differentially expressed lncRNAs. Eight aberrant expressed exosomal lncRNAs were considered to play a key role in the process of silicosis according to the OPLS-DA. Furthermore, the increased expression of lncRNA MSTRG.43085.16 was testified in vitro. Its target gene PARP1 was critical in regulating apoptosis based on bioinformatics analysis. In addition, the effects of exosomes on macrophage apoptosis and fibroblast activation were checked based on a co-cultured system. Our findings suggested that upregulation of lncRNA MSTRG.43085.16 could regulate silica-induced macrophage apoptosis through elevating PARP1 expression, and promote fibroblast activation, implying that the exosomal lncRNA MSTRG.43085.16 might have potential as a biomarker for the early diagnosis of silicosis.

The usefulness of contrast echocardiography in the evaluation of cardiac masses: a multicenter study.

BACKGROUND: Cardiac masses can encompass a variety of conditions, such as tumors, thrombi, vegetations, calcific lesions, and other rare diseases. Treatment and management of these types of cardiac masses differ considerably. Thus, accurately distinguishing among thrombi, benign tumors, and malignant tumors in the heart is of great importance. Contrast echocardiography (CE) has emerged as a promising technology. Although published guidelines suggest that CE can enhance image quality and assist in differentiating between benign and malignant lesions, most studies on CE diagnosis of cardiac masses are limited to case reports or retrospective/small-sample-sized prospective cohorts. This study aims to evaluate the diagnostic accuracy of CE in patients with suspected cardiac masses and address the insufficient evidence for differential diagnosis using CE. METHODS: Between April 2018 and July 2022, a prospective multicenter study was conducted, which included 145 consecutive patients suspected to have cardiac masses based on transthoracic echocardiography. All patients underwent CE examinations. The echocardiographic diagnosis relied on qualitative factors such as echogenicity, boundary, morphology of the base, mass perfusion, pericardial effusion, and motility as well as quantitative factors such as the area of the masses and the peak intensity ratio of the masses to adjacent myocardium (A1/A2). RESULTS: The final confirmed diagnoses were as follows: 2 patients had no cardiac mass, 4 patients had pseudomass, 43 patients had thrombus, 66 patients had benign tumors, and 30 patients had malignant tumors. The receiver operating characteristic (ROC) analysis indicated that an optimal A1/A2 cutoff value of 0.499 distinguished a cardiac tumor from a thrombus, with AUC, sensitivity, specificity, PPV, and NPV of 0.977, 97.9%, 90.7%, 95.9%, and 95.1%, respectively. The optimal A1/A2 cutoff value of 1.583 distinguished a cardiac tumor from a thrombus, with AUC, sensitivity, specificity, PPV, and NPV of 0.950, 93.3%, 93.9%, 87.5%, and 96.9%, respectively. CONCLUSIONS: Combined with qualitative and quantitative analyses, CE has the potential to accurately differentiate among different types of cardiac masses.

Polypeptides inhibit HIV-1 replication by interfering viral Vpu-mediated tetherin degradation.

Background: HIV-1 Vpu acts by counteracting the tethering function of tetherin and resulting in the release of HIV-1 virion. Disrupting Vpu-tetherin interactions may provide a promising new target for antiretroviral therapy. Methods: Polypeptides that covered the amino acid sequence on the interface of Vpu-tetherin complex were designed. Phenotypic susceptibilities and cellular toxicities to the polypeptides were measured. The mechanisms of the anti-HIV-1 polypeptides were determined by the Western blot analysis and laser confocal scanning. Seven 20-mer polypeptides from wild-type Vpu amino acid sequence were designed. Results: We report the design and identification of 3 novel anti-HIV-1 polypeptides that derived from Vpu sequence which can efficiently inhibit HIV-1 infection. A pilot mechanism study showed that the active polypeptide could counteract Vpu-mediated tetherin downregulation. Laser confocal image scanning study showed that the polypeptides bound on the cell surface with a receptor specific binding manner, which may target tetherin that expressed on cell surface. Conclusion: Our work provided first evidence that counteracting Vpu-mediated tetherin downregulation could be a target for novel anti-HIV-1 drug design. Future works to provide direct evidence of inhibitors interact with tetherin at atomic resolution and the development of small molecules inhibitors targeting Vpu-tetherin interactions may open a new avenue for novel antiretroviral therapy.

Antiviral, antioxidant, and anti-inflammatory activities of rhein against white spot syndrome virus infection in red swamp crayfish (Procambarus clarkii).

IMPORTANCE: Aquaculture is essential for ensuring global food security by providing a significant source of animal protein. However, the spread of the white spot syndrome virus (WSSV) has resulted in considerable economic losses in crustacean industries. In this study, we evaluated the antiviral activity of rhein, the primary bioactive component of Rheum palmatum L., against WSSV infection, and many pathological aspects of WSSV were also described for the first time. Our mechanistic studies indicated that rhein effectively arrested the replication of WSSV in crayfish by modulating innate immunity to inhibit viral gene transcription. Furthermore, we observed that rhein attenuated WSSV-induced oxidative and inflammatory stresses by regulating the expression of antioxidant and anti-inflammatory-related genes while enhancing innate immunity by reducing total protein levels and increasing phosphatase activity. Our findings suggest that rhein holds great promise as a potent antiviral agent for the prevention and treatment of WSSV in aquaculture.

[Source Analysis and Health Risk Assessment of Heavy Metals in the Groundwater of Shijiazhuang, a Typical City in North China Plain].

Increasing attention has been paid to the heavy metal pollution in groundwater. The source analysis and risk assessment of heavy metals will provide data and method support for the targeted control of heavy metal pollution in groundwater. In this study, 20 sampling sites were selected in Shijiazhuang City. The APCS-MLR model and health risk model were applied to analyze and evaluate the pollution sources and health risks of 10 types of heavy metals in the groundwater of Shijiazhuang. The results showed that ① the mean concentration of heavy metals in groundwater followed the order of Fe>Zn>Mn>Cu>Al>Pb>Cr>As>Cd>Hg, and the mean ρ(Fe) and ρ(Pb) were 260.3 µg·L-1 and 10.01 µg·L-1, respectively. According to the results of the single factor and Nemerow index, Pb, Fe, and Cd primarily contributed to the heavy metal pollution in the groundwater. ② The concentration of heavy metals ranged from 47.30 to 2560 µg·L-1. In terms of spatial distribution, the highest concentration appeared at S3 (2560 µg·L-1), whereas the lowest concentration was at S9 (47.30 µg·L-1). ③ Source analysis results showed that industrial and agricultural activities, transportation emission, and geological background were the major heavy metal sources, among which the contribution of industrial and agricultural activities was the highest (47.83%). ④ The industrial-agricultural activities posed a potential threat to adults (HI>1); however, the non-cancer and the cancer risks of other sources for both adults and children were at an acceptable level (HI<1) and potential threat level, respectively; industrial-agricultural activities were the major source of non-cancer (adults:52.46%, children:52.45%) and cancer risks (adults:65.22%, children:65.69%), among which Cd and As showed high cancer risk. Therefore, to ensure the safety of the groundwater environment, strictly controlling the pollution sources and further strengthening the risk control of heavy metal pollution in groundwater are necessary.

Smart Nanoplatform for Visualizing Hydrogen Sulfide and Amplifying Oxidative Stress to Tumor Apoptosis.

Oxidative stress is involved in various signaling pathways and serves a key role in inducing cell apoptosis. Therefore, it is significant to monitor oxidative stress upon drug release for the assessment of therapeutic effects in cancer cells. Herein, a glutathione (GSH)-responsive surface-enhanced Raman scattering (SERS) nanoplatform is proposed for ultra-sensitively monitoring the substance related with oxidative stress (hydrogen sulfide, H2S), depleting reactive sulfur species and releasing anticancer drugs to amplify oxidative stress for tumor apoptosis. The Au@Raman reporter@Ag (Au@M@Ag) nanoparticles, where a 4-mercaptobenzonitrile molecule as a Raman reporter was embedded between layers of gold and silver to obtain sensitive SERS response, were coated with a covalent organic framework (COF) shell to form a core-shell structure (Au@M@Ag@COFs) as the SERS nanoplatform. The COF shell loading doxorubicin (DOX) of Au@M@Ag@COFs exhibited the GSH-responsive degradation capacity to release DOX, and its Ag layer as the sensing agent was oxidized to Ag2S by H2S to result in its prominent changes in SERS signals with a low detection limit of 0.33 nM. Moreover, the releasing DOX can inhibit the generation of H2S to promote the production of reactive oxygen species, and the depletion of reactive sulfur species (GSH and H2S) in cancer cells can further enhance the oxidative stress to induce tumor apoptosis. Overall, the SERS strategy could provide a powerful tool to monitor the dynamic changes of oxidative stress during therapeutic processes in a tumor microenvironment.

Amperometric Identification of Single Exosomes and Their Dopamine Contents Secreted by Living Cells.

Dopamine (DA) is an important neurotransmitter, which not only participates in the regulation of neural processes but also plays critical roles in tumor progression and immunity. However, direct identification of DA-containing exosomes, as well as quantification of DA in single vesicles, is still challenging. Here, we report a nanopipette-assisted method to detect single exosomes and their dopamine contents via amperometric measurement. The resistive-pulse current measured can simultaneously provide accurate information of vesicle translocation and DA contents in single exosomes. Accordingly, DA-containing exosomes secreted from HeLa and PC12 cells under different treatment modes successfully detected the DA encapsulation efficiency and the amount of exosome secretion that distinguish between cell types. Furthermore, a custom machine learning model was constructed to classify the exosome signals from different sources, with an accuracy of more than 99%. Our strategy offers a useful tool for investigating single exosomes and their DA contents, which facilitates the analysis of DA-containing exosomes derived from other untreated or stimulated cells and may open up a new insight to the research of DA biology.

Distinct immune microenvironment of lung adenocarcinoma in never-smokers from smokers.

Lung cancer in never-smokers (LCINS) presents clinicopathological and molecular features distinct from that in smokers. Tumor microenvironment (TME) plays important roles in cancer progression and therapeutic response. To decipher the difference in TME between never-smoker and smoker lung cancers, we conduct single-cell RNA sequencing on 165,753 cells from 22 treatment-naive lung adenocarcinoma (LUAD) patients. We find that the dysfunction of alveolar cells induced by cigarette smoking contributes more to the aggressiveness of smoker LUADs, while the immunosuppressive microenvironment exerts more effects on never-smoker LUADs' aggressiveness. Moreover, the SPP1hi pro macrophage is identified to be another independent source of monocyte-derived macrophage. Importantly, higher expression of immune checkpoint CD47 and lower expression of major histocompatibility complex (MHC)-I in cancer cells of never-smoker LUADs imply that CD47 may be a better immunotherapy target for LCINS. Therefore, this study reveals the difference of tumorigenesis between never-smoker and smoker LUADs and provides a potential immunotherapy strategy for LCINS.

A multi-channel responsive AuNP@COF core-shell nanoprobe for simultaneous subcellular profiling of multiple cancer biomarkers.

The abnormal change in the expression profile of multiple cancer biomarkers is closely related to tumor progression and therapeutic effect. Due to their low abundance in living cells and the limitations of existing imaging techniques, simultaneous imaging of multiple cancer biomarkers has remained a significant challenge. Here, we proposed a multi-modal imaging strategy to detect the correlated expression of multiple cancer biomarkers, MUC1, microRNA-21 (miRNA-21) and reactive oxygen (ROS) in living cells, based on a porous covalent organic framework (COF) wrapped gold nanoparticles (AuNPs) core-shell nanoprobe. The nanoprobe is functionalized with Cy5-labeled MUC1 aptamer, a ROS-responsive molecule (2-MHQ), and a miRNA-21-response hairpin DNA tagged by FITC as the reporters for different biomarkers. The target-specific recognition can induce the orthogonal molecular change of these reporters, producing fluorescence and Raman signals for imaging the expression profiles of membrane MUC1 (red fluorescence channel), intracellular miRNA-21 (green fluorescence channel), and intracellular ROS (SERS channel). We further demonstrate the capability of the cooperative expression of these biomarkers, along with the activation of NF-κB pathway. Our research provides a robust platform for imaging multiple cancer biomarkers, with broad potential applications in cancer clinical diagnosis and drug discovery.

Safety and Efficacy of CT-Guided Iodine-125 Brachytherapy for Portal Vein Tumor Thrombus in Hepatocellular Carcinoma.

RATIONALE AND OBJECTIVES: Portal vein tumor thrombus (PVTT) seriously reduces the survival of patients with hepatocellular carcinoma (HCC). CT-guided iodine-125 (125I) brachytherapy has the advantage of a high local control rate and is minimally invasive. This study aims to evaluate the safety and efficacy of 125I brachytherapy for treating PVTT in HCC patients. MATERIALS AND METHODS: Thirty-eight patients diagnosed with HCC complicated with PVTT and treated with 125I brachytherapy for PVTT were included in this retrospective study. The local tumor control rate, local tumor progression-free survival, and overall survival (OS) were analyzed. Cox proportional hazards regression analysis was performed to identify predictors affecting survival. RESULTS: The local tumor control rate was 78.9% (30/38). The median local tumor progression-free survival was 11.6 (95% confidence interval [CI]: 6.7, 16.5) months, and the median overall survival was 14.5 (95% CI: 9.2, 19.7) months. Multivariate Cox analysis showed that age <60 years (hazard ratio [HR] = 0.362; 95% CI: 0.136, 0.965; p = 0.042), type I+II PVTT (HR = 0.065; 95% CI: 0.019, 0.228; p < 0.001), and tumor diameter <5 cm (HR = 0.250; 95% CI: 0.084, 0.748; p = 0.013) were significant predictors of OS. There were no serious adverse events related to 125I seed implantation during the follow-up period. CONCLUSION: CT-guided 125I brachytherapy is effective and safe for treating PVTT of HCC, with a high local control rate and no severe adverse events. Patients younger than 60 years old with type I+II PVTT and a tumor diameter less than 5 cm have a more favorable OS.

Comparing the efficacy and complications of unilateral biportal endoscopic fusion versus minimally invasive fusion for lumbar degenerative diseases: a systematic review and mate-analysis.

BACKGROUND: Unilateral biportal endoscopic (UBE) has been gradually applied in clinical practice. UBE has two channels, with good visual field and operating space, and has achieved good results in the treatment of lumbar spine diseases. Some scholars combine UBE with vertebral body fusion to replace traditional open fusion surgery and minimally invasive fusion surgery. The efficacy of biportal endoscopic transforaminal lumbar interbody fusion (BE-TLIF) is still controversial. In this systematic review and meta-analysis, BE-TLIF and minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) are compared in the efficacy and complications of lumbar degenerative diseases. METHODS: PubMed, Cochrane Library, Web of Science and China National Knowledge Infrastructure (CNKI) were used to search literatures related to BE-TLIF before January 2023, to identify relevant studies, and systematically review all literatures. Evaluation indicators mainly include operation time, hospital stay, estimated blood loss, visual analog scale (VAS), Oswestry Disability Index (ODI), and Macnab. RESULTS: A total of 9 studies were included in this study; a total of 637 patients were collected, and 710 vertebral bodies were treated. Nine studies showed that there was no significant difference in VAS score, ODI, fusion rate, and complication rate between BE-TLIF and MI-TLIF at the final follow-up after surgery. CONCLUSION: This study suggests that BE-TLIF is a safe and effective surgical approach. BE-TLIF surgery has similar good efficacy to MI-TLIF in the treatment of lumbar degenerative diseases. And compared with MI-TLIF, it has the advantages of early postoperative relief of low-back pain, shorter hospital stay, and faster functional recovery. However, high-quality prospective studies are needed to validate this conclusion.

Systematic elucidation of the bioactive alkaloids and potential mechanism from Sophora flavescens for the treatment of eczema via network pharmacology.

ETHNOPHARMACOLOGY RELEVANCE: Sophora flavescens is a frequently used traditional Chinese medicine (TCM) for the treatment of skin disorders, diarrhea, vaginal itching and inflammatory diseases. In particular, the root of S. flavescens combination with other herbs mainly treat eczema ailment in the clinical applications. However, a holistic network pharmacology approach to understanding the mechanism by which alkaloids in S. flavescens treat eczema has not been pursued. AIM OF THE STUDY: To examine the network pharmacological potential effect of S. flavescens on eczema, we studied the alkaloids, performed protein targets prediction and investigated interacting signal pathways. Furthermore, animal experiment was carried out to evaluate its efficacy and real-time quantitative polymerase chain reactions (RT-qPCR) analysis was explored the mechanism of action. MATERIALS AND METHODS: The detail information on alkaloids from S. flavescens were obtained from a handful of public databases on the basis of oral bioavailability (OB ≥ 30%) and drug-likeness (DL ≥ 0.18). Then, correlations between compounds and protein targets were linked using the STRING database, and targets associated with eczema were gathered by the GeneCards database. Human genes were identified and subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) functional enrichment analysis. Particularly, matrine, the crucial alkaloid from S. flavescens, was estimated using a 2,4-dinitrochlorobenzene (DNCB)-induced eczema Kunming (KM) mice model, administered (50 mg/kg and 10 mg/kg) to mice for 22 days. On the last day, the activities of serum tumor necrosis factor α (TNF-α), interleukin-4 (IL-4) and histopathologic examinations were determined. For further to elucidate the mechanisms, the mRNA levels of TNF-α, STAT3, TP53, AKT1, IL-6, JUN and EGFR in dorsal skin tissues were also tested. RESULTS: Network analysis collected and identified 35 alkaloids from S. flavescens. Among them, in total 10 dominating alkaloids, including matrine, oxymatrine, sophoridine, sophocarpine, oxysophocarpine, allomatrine, sophoramine, anagyrine, cytisine and N-methylcytisine. And 71 related targets were provided of alkaloids for the treatment of eczema from S. flavescens. Furthermore, matrine dose-dependently (50 or 10 mg/kg, 22 days, apply to dorsal skin) remarkable decreased the serum levels of TNF-α and IL-4, and significantly alleviated the skin lesions. The effects of 50 mg/kg of matrine were almost identical to those of 200 mg/kg of the positive drug dexamethasone (DXM). The further RT-qPCR analyses could reveal that matrine down-regulate TNF-α, STAT3 and TP53 at transcriptional level in dorsal skin tissues. CONCLUSION: Pharmacological network analysis can utilize to illuminate the pharmacodynamic substances and the potential molecular mechanism of S. flavescens for treating eczema. Matrine, as the crucial alkaloid from S. flavescens, could be a promising drug candidate for the treatment of eczema ailment.

Macrophage-derived exosomal lncRNA MSTRG.91634.7 inhibits fibroblasts activation by targeting PINK1 in silica-induced lung fibrosis.

Silicosis is a fibrotic lung disease caused by the inhalation of free crystalline silica. Its pathogenesis is extremely complex and involves a variety of cells. Exosomes emerge as a favorable candidate for communication between cells. LncRNA is a major component transported by exosomes in many inflammatory diseases. However, the role of exosomal lncRNA in the pathogenesis of silicosis is still unclear. In this study, the decreased expression of a novel exosomal lncRNA MSTRG.91634.7 in silicosis patients was identified according to high-throughput sequencing. Then, this macrophage-derived exosomal lncRNA MSTRG.91634.7 could regulate the fibroblast's activation by targeting PINK1 in a co-culture system of THP-1 and MRC-5. Finally, the mouse was exposed to 3 mg/50 µL silica to set up the silicosis model. AAV-ov-Pink1 was intratracheally injected to overexpress PINK1 in mice lungs. Our results suggested that PINK1, the target protein of lncRNA MSTRG.91634.7, participated in restricting the silica-induced lung inflammation and fibrosis in mice.

The aggravate role of exosomal circRNA11:120406118|12040782 on macrophage pyroptosis through miR-30b-5p/NLRP3 axis in silica-induced lung fibrosis.

Silica dust inhalation could lead to silicosis, and there is no specific biomarker for its early diagnosis and no effective treatment due to the lack of research on its pathogenesis. The homeostasis of macrophages was considered to be crucial during the development of silicosis from persistent chronic inflammation to irreversible fibrosis. However, its regulatory mechanism and the communication between macrophages and others are still not clear. Exosomal circRNAs emerge as favorable candidates for cellular communication. Therefore, our study aimed to illustrate the regulatory mechanism of silicosis from the view of exosomal circRNAs. Our study identified a novel exosomal circRNA, circRNA11:120406118|12040782, in the peripheral serum of silicosis patients. Furthermore, the detailed role of circRNA11:120406118|12040782 was investigated both in silicosis mouse model and in silica-stimulated macrophages and fibroblasts. On the one hand, circRNA11:120406118|12040782 was shown to regulate silica-stimulated macrophage pyroptosis through circRNA11:120406118|12040782/miR-30b-5p/NLRP3 network. And this macrophage-derived cirRNA could promote the activation of fibroblasts. On the other hand, overexpressing miR-30b-5p, the crucial component of circRNA11:120406118|12040782/miR-30b-5p/NLRP3 regulatory network, could inhibit pyroptosis and attenuate silica-induced lung inflammation and fibrosis in mice. Our findings suggested that exosomal circRNA11:120406118|12040782 could aggravate NLRP3-mediated macrophages pyroptosis through sponging miR-30b-5p in silicosis development, which provide an experimental basis and shed light on the early diagnosis and treatment of silicosis.

Hepatitis B virus (HBV) codon adapts well to the gene expression profile of liver cancer: an evolutionary explanation for HBV's oncogenic role.

Due to the evolutionary arms race between hosts and viruses, viruses must adapt to host translation systems to rapidly synthesize viral proteins. Highly expressed genes in hosts have a codon bias related to tRNA abundance, the primary RNA translation rate determinant. We calculated the relative synonymous codon usage (RSCU) of three hepatitis viruses (HAV, HBV, and HCV), SARS-CoV-2, 30 human tissues, and hepatocellular carcinoma (HCC). After comparing RSCU between viruses and human tissues, we calculated the codon adaptation index (CAI) of viral and human genes. HBV and HCV showed the highest correlations with HCC and the normal liver, while SARS-CoV-2 had the strongest association with lungs. In addition, based on HCC RSCU, the CAI of HBV and HCV genes was the highest. HBV and HCV preferentially adapt to the tRNA pool in HCC, facilitating viral RNA translation. After an initial trigger, rapid HBV/HCV translation and replication may change normal liver cells into HCC cells. Our findings reveal a novel perspective on virus-mediated oncogenesis.

Cumulative Evidence for Relationships Between Multiple Variants in the TERT and CLPTM1L Region and Risk of Cancer and Non-Cancer Disease.

Background: Genetic studies previously reported that variants in TERT-CLPTM1L genes were related to susceptibility of cancer and non-cancer diseases. However, conclusions were not always concordant. Methods: We performed meta-analyses to assess correlations between 23 variants within TERT-CLPTM1L region and susceptibility to 12 cancers and 1 non-cancer disease based on data in 109 papers (involving 139,510 cases and 208,530 controls). Two approaches (false-positive report probability test and Venice criteria) were adopted for assessing the cumulative evidence of significant associations. Current study evaluated the potential role of these variants based on data in Encyclopedia of DNA Elements (ENCODE) Project. Results: Thirteen variants were statistically associated with susceptibility to 11 cancers and 1 non-cancer disease (p < 0.05). Besides, 12 variants with eight cancers and one non-cancer disease were rated as strong evidence (rs2736098, rs401681, and rs402710 in bladder cancer; rs2736100, rs2853691, and rs401681 in esophageal cancer; rs10069690 in gastric cancer; rs2736100 and rs2853676 in glioma; rs2242652, rs2736098, rs2736100, rs2853677, rs31489, rs401681, rs402710, rs465498, and rs4975616 in lung cancer; rs2736100 in idiopathic pulmonary fibrosis and myeloproliferative neoplasms; and rs401681 in pancreatic and skin cancer). According to data from ENCODE and other public databases, 12 variants with strong evidence might fall within putative functional regions. Conclusions: This paper demonstrated that common variants of TERT-CLPTM1L genes were related to susceptibility to bladder, esophageal, gastric, lung, pancreatic, and skin cancer, as well as to glioma, myeloproliferative neoplasms, and idiopathic pulmonary fibrosis, and, besides, the crucial function of the TERT-CLPTM1L region in the genetic predisposition to human diseases is elucidated.

The genomic and transcriptome characteristics of lung adenocarcinoma patients with previous breast cancer.

BACKGROUND: Breast cancer and lung cancer are the top two malignancies in the female population and the number of patients with breast cancer and subsequent primary lung cancer has increased significantly in recent years. However, the unique molecular characteristics of this group of patients remains unclear. PURPOSE: To identify the genomic and transcriptome characteristics of primary lung adenocarcinoma patients with previous breast cancer by comparison with single primary lung adenocarcinoma (SPLA) patients. METHODS: The tumor and normal pulmonary tissue specimens of ten primary pulmonary adenocarcinoma patients with previous breast cancer (multiple primary cancer, MPC) and ten SPLA patients were prospectively collected. The whole exome sequencing (WES) and RNA sequencing (RNA-seq) were performed to analyze the gene mutation and expression differences between MPC and SPC patients. RESULTS: The results of WES indicated that the mutations of TRIM73, DLX6 and CNGB1 only existed in MPC patients. The results of RNA-seq manifested the occurrence of second primary lung adenocarcinoma in breast cancer patients was closely associated with cytokine-cytokine receptor action, autophagy, PI3L-Akt, cAMP and calcium ion signaling pathways. Besides, the expression levels of FGF10 and VEGFA genes were significantly increased in MPC patients. CONCLUSION: The occurrence of second primary lung adenocarcinoma may be related to the cytokine-cytokine receptor action, autophagy, PI3L-Akt, cAMP and calcium ion signaling pathways. Furthermore, the mutations of TRIM73, DLX6 and CNGB1 and high expression of FGF10 and VEGFA might play an important role in the development of lung adenocarcinoma in breast cancer patients. However, more in-depth investigations are needed to verify above findings.

A comparative investigation on the mechanical properties and cytotoxicity of Cubic, Octet, and TPMS gyroid structures fabricated by selective laser melting of stainless steel 316L.

Metallic lattice structures can be fabricated by selective laser melting (SLM) with purposefully designed pores and controlled pore sizes that can bio mimic the natural bone, providing adequate mechanical and biological support for the patients. Strut-based structures, like Cubic, Octet; and sheet-based structures, like triply periodic minimal surface (TPMS) gyroid, have been studied extensively in the past. However, it lacks enough comparative study on the mechanical properties and cytotoxicity among these structures. Therefore, Cubic, Octet, and TPMS gyroid of Stainless steel 316 L (SS316L) are designed, manufactured, and characterized at 40/50/60% relative densities in this study. Moreover, the flowability, density characteristics, and cytotoxicity of SS316L powder are validated to ascertain its suitability for 3D printing and implant application. Based on refining the Gibson-Ashby model, it is possible to predict or design the mechanical properties via adjusting the relative densities. The results indicate these structures demonstrated appropriate Young's modulus and outstanding biocompatibility.

Epidemiological evidence for associations between variants in microRNA and cancer risk.

Numerous papers have reported variants in microRNAs (miRNAs) associated with cancer risk; these results, however, are controversial. We seek to offer an updated, comprehensive synopsis of genetic associations between single nucleotide polymorphisms (SNPs) in miRNAs and cancer risk. We did a systematic field synopsis and meta-analysis to investigate 29 SNPs in 24 miRNAs associated with risk of 18 different kinds of cancer based on data from 247 eligible articles. We graded levels of cumulative epidemiological evidence of significant association using Venice criteria and a false-positive report probability (FPRP) test. We constructed functional annotations for these variants using data from the Encyclopedia of DNA Elements Project. We used FPRP to find additional noteworthy associations between 278 SNPs in 117 miRNAs and risk of 26 cancers based on each SNP with one data source. Sixteen SNPs were statistically associated with risk of 17 cancers. We graded the cumulative epidemiological evidence as strong for statistical associations between 10 SNPs in 8 miRNAs and risk of 11 cancers, moderate for 9 SNPs with 12 cancers and weak for 11 SNPs with 11 cancers. Bioinformatics analysis suggested that the SNPs with strong evidence might fall in putative functional regions. In addition, 38 significant associations were observed in 38 SNPs and risk of 13 cancers. This study offered a comprehensive research on miRNA gene variants and cancer risk and provided referenced information for the genetic predisposition to cancer risk in future research.

Large-scale omics data reveal the cooperation of mutation-circRNA-miRNA-target gene network in liver cancer oncogenesis.

Aims: Clarifying the initial trigger of the differentially expressed genes in cancers helps researchers understand the cellular system as a whole network. Materials & methods: We retrieve the transcriptome and translatome of tumor and normal tissues from ten liver cancer patients and define differentially expressed genes and tumor-specific mutations. We associate the oncogenesis with the mutations by target prediction and experimental verification. Results: Upregulated genes have tumor-specific mutations in 3'UTRs that abolish the binding of miRNAs. For downregulated genes, their corresponding miRNAs are mutually targeted by two circRNAs, with mutations in base-pairing regions. Transfection experiments support the oncogenic role of these mutations. Conclusions: The tumor-specific mutations serve as the initial trigger of liver cancer. The mutation-circRNA-miRNA-target gene chain is completed.