M6A-modified lncRNA FAM83H-AS1 promotes colorectal cancer progression through PTBP1.

LncRNA plays a crucial role in cancer progression and targeting, but it has been difficult to identify the critical lncRNAs involved in colorectal cancer (CRC) progression. We identified FAM83H-AS1 as a tumor-promoting associated lncRNA using 21 pairs of stage IV CRC tissues and adjacent normal tissues. In vitro and in vivo experiments revealed that knockdown of FAM83H-AS1 in CRC cells inhibited tumor proliferation and metastasis, and vice versa. M6A modification is critical for FAM83H-AS1 RNA stability through the writer METTL3 and the readers IGF2BP2/IGFBP3. PTBP1-an RNA binding protein-is responsible for the FAM83H-AS1 function in CRC. T4 (1770-2440 nt) and T5 (2440-2743 nt) on exon 4 of FAM83H-AS1 provide a platform for PTBP1 RRM2 interactions. Our results demonstrated that m6A modification dysregulated the FAM83H-AS1 oncogenic role by phosphorylated PTBP1 on its RNA splicing effect. In patient-derived xenograft models, ASO-FAM83H-AS1 significantly suppressed the growth of gastrointestinal (GI) tumors, not only CRC but also GC and ESCC. The combination of ASO-FAM83H-AS1 and oxaliplatin/cisplatin significantly suppressed tumor growth compared with treatment with either agent alone. Notably, there was pathological complete response in all these three GI cancers. Our findings suggest that FAM83H-AS1 targeted therapy would benefit patients primarily receiving platinum-based therapy in GI cancers.

In situ synergistic reduced graphene oxide-boron carbon nitride nanosheet heterostructures for high-performance fabric-based supercapacitors.

We develop a new type of heterostructure nanocomposite made of reduced graphene oxide-boron carbon nitride nanosheets (rGO-BCN) by B-C covalent bonds. The rGO-BCN nanocomposite delivers a large specific surface and excellent electrochemical properties, and is then constructed into flexible fabric-based high-performance supercapacitor electrodes based on the microfluidic electrospinning technology.

Construction of S-scheme CuInS2/ZnIn2S4 heterostructures for enhanced photocatalytic activity towards Cr(VI) removal and antibiotics degradation.

The efficient and ecofriendly removal of pharmaceutical antibiotics and heavy metal Cr(VI) from water sources is a crucial challenge in current environmental management. Photocatalysis presents a viable environmentally friendly solution for eliminating organic contaminants and heavy-metal ions. In this study, a novel S-scheme CuInS2/ZnIn2S4 (CIS/ZIS) heterojunction was developed using a one-pot solvothermal method. The optimized CIS/ZIS heterojunction exhibited considerably improved photocatalytic activity for the removal of antibiotics and Cr(VI), achieving over 90% removal for both tetracycline hydrochloride (TC) (20 mg/L) and Cr(VI) (20 mg/L) under visible light irradiation. The study also delved into the effect of coexisting inorganic anions and assessed the cyclic stability of the composite photocatalysts. This enhancement mechanism can be delineated into three key elements. First, the incorporation of the narrow-gap semiconductor CuInS2 effectively augmented the photoabsorption capacity. Second, the inclusion of ZnIn2S4 caused an increase in surface active sites. Most importantly, the internal electric field at the interface between CuInS2 and ZnIn2S4 expedited the separation of photogenerated carriers. Furthermore, the results revealed that superoxide radical and photogenerated holes are the primary active substance responsible for TC removal, while photogenerated electrons play a central role in the photoreduction of Cr(VI). To gain insights into the transport pathways of photogenerated carriers, we conducted experiments with nitrotetrazolium blue chloride (NBT) and photodeposited gold. This study offers an innovative approach to enhancing the photocatalytic performance of ternary In-based materials by constructing S-scheme heterojunctions.

Adult epithelioid glioblastoma exhibits an extremely poor prognosis and high frequency of SWI/SNF complex mutation: Insights from a retrospective study.

Epithelioid glioblastoma (eGBM) is a rare subtype of GBM. Given the update of the definition of GBM, the understanding of the molecular characteristics and prognosis of "true" adult eGBM remains limited. Herein, we retrospectively analyzed the clinicopathological data of 39 adult eGBM cases. Adult eGBM primarily affected females, with a male-to-female ratio of 1:2.3. The average age of diagnosis was 53 years, and the tumor affected the temporal lobe in 41% of cases (16/39, 41%). Microscopically, the tumors consisted mainly or entirely of epithelioid cells. Perivascular infiltration (10/39, 25.6%) and leptomeningeal dissemination (7/39, 17.9%) were not uncommon. BRAF V600E mutation was detected in 40.9% of cases (n = 9/22). Next-generation sequencing revealed that CDKN2A/B homogeneous deletion was the most frequently mutated gene (8/10, 80%), followed by TERT promoter mutation (7/10, 70%), Cyclin-dependent kinases 4 or 6 (CDK4/6) amplification (5/10, 50%) and BRAF V600E mutation (50%, 5/10). Notably, the incidence of ARID1B mutation in eGBM was 50% (5/10), representing the first report of such a mutation in this subtype of GBM. ARID1B was known to be a subunit of the SWI/SNF chromatin remodeler. Chromosome analysis showed a 7+/10- signature in 90% (9/10) cases. Adult eGBM carried a dismal prognosis compared to GBM with IDH and H3 wild-type (typical GBM) (OS: 13.89 vs 24.30 months; P = .003) and even typical GBM without MGMT promoter methylation (OS: 13.89 vs 22.08 months; P = .036). Based on these findings, it can be concluded that adult eGBM harbors a high frequency of the 7+/10- signature and alterations in the MAPK pathway, SWI/SNF complex and cyclin-related genes and portends an extremely poor prognosis.

A novel grading system combining histological grade and CDKN2A homozygous and hemizygous deletion to predict prognosis in IDH-mutant astrocytoma.

Isocitrate dehydrogenase (IDH)-mutant astrocytoma with microvascular proliferation, necrosis, CDKN2A/B homozygous deletion, or any combination of these features corresponds to World Health Organization grade 4 according to current criteria. However, the prognostic significance of CDKN2A hemizygous deletion in IDH-mutant astrocytoma is not well established. We undertook a comprehensive study that included assessments of histological and genetic approaches to prognosis for these tumors. Samples from a cohort of 114 patients with extended observation were subjected to histological review and molecular analysis. CDKN2A (9p21) deletion was detected by fluorescence in situ hybridization. Overall survival (OS) was calculated via Kaplan-Meier estimation using the log-rank test. Histological grade, Ki-67 index, and the extent of surgical resection correlated with the OS of IDH-mutant astrocytoma patients. Both CDKN2A homozygous deletion and hemizygous deletion were detectable. Patients with CDKN2A homozygous-deletion tumors had the poorest OS; those with CDKN2A hemizygous-deletion tumors had an intermediate OS (p < .001). We then established a novel grading system that combined CDKN2A homozygous and hemizygous deletions with histological grade; the combined grading system was an independent prognostic factor for IDH-mutant astrocytomas. We conclude that CDKN2A homozygous and hemizygous deletion should be combined in a grading system for IDH-mutant astrocytomas.

Epstein-Barr virus-based prognostic model in nodular sclerosis classic Hodgkin lymphoma.

The role of Epstein-Barr virus (EBV) in lymphoma cells of nodular sclerosis classic Hodgkin lymphoma (NScHL) is controversial. Our aim was to explore this and establish a clinically feasible model for risk stratification. We interrogated data from 542 consecutive subjects with NScHL receiving ABVD therapy and demonstrated EBV-infection in their lymphoma cells with EBV-encoded small RNAs (EBERs) in situ hybridization. Subjects were divided into training and validation datasets. As data from the training dataset suggested EBERs-positivity was the only independent prognostic factor for both progression-free survival (PFS) and overall survival (OS), we developed corresponding prognostic models based on it. Our models showed excellent performance in both training and validation cohort. These data indicate the close association of EBV infection and the outcomes of persons with NScHL receiving ABVD. Additionally, our newly developed models should help physicians estimate prognosis and select individualized therapy.

miR-4739 promotes epithelial-mesenchymal transition and angiogenesis in "driver gene-negative" non-small cell lung cancer via activating the Wnt/ß-catenin signaling.

PURPOSE: "Driver gene-negative" non-small cell lung cancer (NSCLC) currently has no approved targeted drug, due to the lack of common actionable driver molecules. Even though miRNAs play crucial roles in various malignancies, their roles in "driver gene-negative" NSCLC keep unclear. METHODS: miRNA expression microarrays were utilized to screen miRNAs associated with "driver gene-negative" NSCLC malignant progression. Quantitative real-time PCR (RT-qPCR) and in situ hybridization (ISH) were employed to validate the expression of miR-4739, and its correlation with clinicopathological characteristics was analyzed in tumor specimens using univariate and multivariate analyses. The biological functions and underlying mechanisms of miR-4739 were investigated both in vitro and in vivo. RESULTS: our research demonstrated, for the first time, that miR-4739 was substantially increased in "driver gene-negative" NSCLC tumor tissues and cell lines, and overexpression of miR-4739 was related to clinical staging, metastasis, and unfavorable outcomes. Functional experiments discovered that miR-4739 dramatically enhanced tumor cell proliferation, migration, and metastasis by promoting the epithelial-to-mesenchymal transition (EMT). Meanwhile, miR-4739 can be transported from cancer cells to the site of vascular epithelial cells through exosomes, consequently facilitating the proliferation and migration of vascular epithelial cells and inducing angiogenesis. Mechanistically, miR-4739 can activate Wnt/ß-catenin signaling both in tumor cells and vascular epithelial cells by targeting Wnt/ß-catenin signaling antagonists APC2 and DKK3, respectively. CONCLUSION: Our work identifies a valuable oncogene, miR-4739, that accelerates malignant progression in "driver gene-negative" NSCLC and serves as a potential therapeutic target for this group of tumors.

Alterations in the Gut Microbiome and Metabolisms in Pregnancies with Fetal Growth Restriction.

Fetuses diagnosed with fetal growth restriction (FGR) are at an elevated risk of stillbirth and adulthood morbidity. Gut dysbiosis has emerged as one of the impacts of placental insufficiency, which is the main cause of FGR. This study aimed to characterize the relationships among the intestinal microbiome, metabolites, and FGR. Characterization was conducted on the gut microbiome, fecal metabolome, and human phenotypes in a cohort of 35 patients with FGR and 35 normal pregnancies (NP). The serum metabolome was analyzed in 19 patients with FGR and 31 normal pregnant women. Multidimensional data was integrated to reveal the links between data sets. A fecal microbiota transplantation mouse model was used to determine the effects of the intestinal microbiome on fetal growth and placental phenotypes. The diversity and composition of the gut microbiota were altered in patients with FGR. A group of microbial species altered in FGR closely correlated with fetal measurements and maternal clinical variables. Fecal and serum metabolism profiles were distinct in FGR patients compared to those in the NP group. Altered metabolites were identified and associated with clinical phenotypes. Integrated multi-omics analysis revealed the interactions among gut microbiota, metabolites, and clinical measurements. Microbiota from FGR gravida transplanted to mice progestationally induced FGR and placental dysfunction, including impaired spiral artery remodeling and insufficient trophoblast cell invasion. Taken together, the integration of microbiome and metabolite profiles from the human cohort indicates that patients with FGR endure gut dysbiosis and metabolic disorders, which contribute to disease pathogenesis. IMPORTANCE Downstream of the primary cause of fetal growth restriction are placental insufficiency and fetal malnutrition. Gut microbiota and metabolites appear to play an important role in the progression of gestation, while dysbiosis induces maternal and fetal complications. Our study elaborates the significant differences in microbiota profiles and metabolome characteristics between women with FGR and normal pregnancies. This is the first attempt so far that reveals the mechanistic links in multi-omics in FGR, providing a novel insight into host-microbe interaction in placenta-derived diseases.

Implications of serum uric acid for female infertility: results from the national health and nutrition examination survey, 2013-2020.

BACKGROUND: There is limited concrete evidence connecting serum uric acid levels to female infertility. Therefore, this study aimed to find out if serum uric acid levels are independently related to female infertility. METHODS: From the National Health and Nutrition Examination Survey (NHANES) 2013-2020, a total sample of 5872 chosen female participants between the ages of 18 and 49 were identified for this cross-sectional study. The serum uric acid levels (mg/dL) of each participant were tested, and the reproductive health questionnaire was used to evaluate each subject's reproductive status. Both in the analyses of the full sample and each subgroup, logistic regression models were used to evaluate the relationship between the two variables. A stratified multivariate logistic regression model was used to perform the subgroup analysis based on serum uric acid levels. RESULTS: Infertility was found in 649 (11.1%) of the 5,872 female adults in this study, with greater mean serum uric acid levels (4.7 mg/dL vs. 4.5 mg/dL). Serum uric acid levels were associated with infertility in both the initial and adjusted models. According to multivariate logistic regression, the odds of female infertility were found to be significantly higher with rising serum uric acid levels (Q4 [≥ 5.2 mg/dL] vs. Q1 [≤ 3.6 mg/dL]), adjusted odds ratio [aOR] = 1.59, p = 0.002]. The data suggests that there is a dose-response relationship between the two. CONCLUSIONS: The results from this nationally representative sample from the United States confirmed the idea that there is a link between increased serum uric acid levels and female infertility. Future research is necessary to evaluate the relationship between serum uric acid levels and female infertility and explicate the underlying mechanisms of this relationship.

Metastasis of breast cancer to bones alters the tumor immune microenvironment.

BACKGROUND: Bone is one of the most frequent sites for breast cancer metastasis. Breast cancer bone metastasis (BCBM) leads to skeletal morbidities including pain, fractures, and spinal compression, all of which severely impact quality of life. Immunotherapy is a promising therapy for patients with advanced cancer, but whether it may provide benefit to metastatic bone cancer is currently unknown. Thus, a better understanding of the immune landscape of bone-disseminated breast cancers may reveal new therapeutic strategies. In this study, we use histopathological analysis to investigate changes within the immune microenvironment of primary breast cancer and paired BCBM. METHODS: Sixty-three patients with BCBM, including 31 with paired primary and bone metastatic lesions, were included in our study. The percentage of stroma and stromal tumor-infiltrating lymphocytes (TILs) was evaluated by histopathological analysis. The quantification of stromal TILs (CD4 + and CD8 +), macrophages (CD68 + and HLA-DR +), programmed cell death protein 1 (PD-1), and programmed cell death protein ligand 1 (PD-L1) was evaluated through immunohistochemical (IHC) staining. Statistical analysis was performed with paired t test, Wilcoxon test, spearman correlation test, and univariate and multivariate cox regression. RESULTS: Median survival after BCBM pathological diagnosis was 20.5 months (range: 3-95 months). Of the immune parameters measured, none correlated with survival after bone metastasis was diagnosed. Compared to the primary site, bone metastases exhibited more tumor stroma (mean: 58.5% vs 28.87%, p < 0.001) and less TILs (mean: 8.45% vs 14.03%, p = 0.042), as determined by H&E analysis. The quantification of primary vs metastatic tissue area with CD4 + (23.95/mm2 vs 51.69/mm2, p = 0.027 and with CD8 + (18.15/mm2 vs 58.95/mm2, p = 0.004) TILs similarly followed this trend and was reduced in number for bone metastases. The number of CD68 + and HLA-DR + macrophages showed no significant difference between primary sites and bone metastases. PD-1 expression was present in 68.25% of the bone metastasis, while PD-L1 expression was only present in 7.94% of the bone metastasis. CONCLUSIONS: Our findings suggest that compared to the primary breast cancer site, bone metastases harbor a less active immune microenvironment. Despite this relatively dampened immune landscape, expression of PD-1 and PD-L1 in the bone metastasis indicates a potential benefit from immune checkpoint inhibitors for some BCBM cases.

Identification of circular RNAs as regulators and noninvasive biomarkers for placenta accreta spectrum.

In brief: Placenta accreta spectrum (PAS) has an urgent need for reliable prenatal biomarkers. This study profiled the circular RNAs (circRNAs) in PAS placenta and maternal blood and identified two circRNAs can regulate trophoblast cells invasion and serve as noninvasive prenatal biomarkers for PAS prediction. Abstract: PAS is one of the most alarming obstetric diseases with high mortality rates. The regulating mechanism underlying PAS remains to be investigated, and reliable blood biomarkers for PAS have not emerged. Circular RNAs (circRNAs) have become important regulators and biomarkers for disparate human diseases. However, the circRNA profiles of PAS were not reported, and the regulatory role and predictive value of circRNAs in PAS were unknown. Here, we comprehensively profiled the circRNAs in the placenta of PAS by transcriptome sequencing and analysis and uncovered 217 abnormally expressed circRNAs. Through competing endogenous RNA network analysis, we found that the target genes of upregulated circRNAs in PAS were enriched in placenta development-related pathways and further uncovered two circRNAs, circPHACTR4 and circZMYM4, that could regulate trophoblast cells invasion and migration in vitro. Finally, we verified that circPHACTR4 and circZMYM4 were also upregulated in the maternal peripheral blood of PAS women before delivery using transcriptome sequencing and RT-qPCR and evaluated their predictive value by ROC curves. We found that circPHACTR4 and circZMYM4 could serve as effective predicting biomarkers for PAS (area under the curve (AUC): 0.86 and 0.85) and propose an improved model for PAS prenatal prediction by combining the conventional ultrasound diagnosis with the new circRNA predictive factors (AUC: 0.91, specificity: 0.89, sensitivity: 0.82).Altogether, this work provides new resources for deciphering the biological roles of circRNAs in PAS, identified two circRNAs that could regulate trophoblast cells invasion during placentation, and revealed two noninvasive diagnostic markers for PAS.

Kinematic Analysis of Bionic Elephant Trunk Robot Based on Flexible Series-Parallel Structure.

Researchers borrow ideas from biological characteristics and behavior in design to make bionic robots that can meet unstructured and complex operating environments. The elephant trunk has been widely imitated by bionic robots because of its strong dexterity and stiffness adjustability. Due to the complex structure of the current elephant trunk robot, a series-parallel elephant trunk robot based on flexible rod actuation and a 6-degree-of-freedom (6-dof) parallel module is proposed in this paper. The bionic robot has a simple structure and redundant kinematics, which can realize the control of stiffness. This work focuses on the modeling of the flexible driving rod, the kinematics of a single parallel module, and the whole biomimetic robot. The kinematics are verified by simulation, which lays a foundation for future research on stiffness regulation.

The Design and Testing of a PEA Powered Ankle Prosthesis Driven by EHA.

Several studies have shown that actuation concepts such as Serial elastic actuator (SEA) can reduce peak power and energy consumption in ankle prostheses. Proper selection and design of the actuation concepts is important to unlock the power source potential. In this work, the optimization design, mechanical design, control scheme, and bench experiments of a new powered ankle-foot prosthesis is proposed. The actuation concept of this prosthesis is parallel elastic actuator (PEA) composed of electro-hydrostatic actuator (EHA) as the power kernel and a unidirectional parallel spring as the auxiliary energy storage element. After the appropriate motor and transmission ratio was selected, a dynamic model of the PEA prosthesis was built to obtain the appropriate spring parameters driven by biological data. The design of the hydraulic and mechanical system and the controller were provided for the implementation of the designed system. Bench experiments were performed to verify the performance. The results showed that the designed prosthesis meets the biomechanical dynamics requirements. This result emphasizes the feasibility of the EHA as a power source and actuator and provides new ideas for the design of ankle-foot prostheses.

Twin-Structured Graphene Metamaterials with Anomalous Mechanical Properties.

Typically, solid materials exhibit transverse contraction in response to stretching in the orthogonal direction and transverse expansion under compression conditions. However, when flexible graphene nanosheets are assembled into a 3D porous architecture, the orientation-arrangement-delivered directional deformation of micro-nanosheets may induce anomalous mechanical properties. In this study, a 3D hierarchical graphene metamaterial (GTM) with twin-structured morphologies is assembled by manipulating the temperature gradient for ice growth during in situ freeze-casting procedures. GTM demonstrates anomalous anisotropic compression performance with programable Poisson's ratios (PRs) and improved mechanical properties (e.g., elasticity, strength, modulus, and fatigue resistance) along different directions. Owing to the designed three-phase deformation of 2D graphene sheets as basic microelements, the twin-structure GTM delivers distinctive characteristics of compressive curves with an apparent stress plateau, and follows a strengthening tendency. This multiscale deformation behavior facilitates the enhancement of energy loss coefficient. In addition, a finite element theory based numerical model is established to optimize the structural design, and validate the multiscale tunable PR mechanism and oriented structural evolution. The mechanical and thermal applications of GTM indicate that the rational manipulation-driven design of meta-structures paves the way for exploring graphene-based multifunctional materials with anomalous properties.

Cancer cell immune mimicry delineates onco-immunologic modulation.

Immune transcripts are essential for depicting onco-immunologic interactions. However, whether cancer cells mimic immune transcripts to reprogram onco-immunologic interaction remains unclear. Here, single-cell transcriptomic analyses of 7,737 normal and 37,476 cancer cells reveal increased immune transcripts in cancer cells. Cells gradually acquire immune transcripts in malignant transformation. Notably, cancer cell-derived immune transcripts contribute to distinct prognoses of immune gene signatures. Optimized immune response signature (oIRS), obtained by excluding cancer-related immune genes from immune gene signatures, and offers a more reliable prognostic value. oIRS reveals that antigen presentation, NK cell killing and T cell signaling are associated with favorable prognosis. Patients with higher oIRS expression are associated with favorable responses to immunotherapy. Indeed, CD83+ cell infiltration, which indicates antigen presentation activity, predicts favorable prognosis in breast cancer. These findings unveil that immune mimicry is a distinct cancer hallmark, providing an example of cancer cell plasticity and a refined view of tumor microenvironment.

In situ Synthesized Monosodium Urate Crystal Enhances Endometrium Decidualization via Sterile Inflammation During Pregnancy.

High level of uric acid (UA) is the major origin of gout, and is highly associated with various pregnant complications, such as preeclampsia and gestational diabetes. However, UA's level and role in the very early stage of pregnancy has not been uncovered. This study aims to investigate the relevance of serum UA and decidualization, an essential process for the establishment and maintenance of pregnancy in women and mice during the early stage of pregnancy. In this study, we first proved that expression level of UA synthase xanthine dehydrogenase (XDH) is highly increased along with decidualization of endometrial stromal cells in both in vitro and in vivo models. Furthermore, serum and endometrial levels of UA are higher in mice with decidualized uterin horn and in vitro decidualized stromal cells. The existence of monosodium urate (MSU) crystal was also confirmed by immunostaining. Next, the roles of MSU on decidualization were explored by both in vitro and in vivo models. Our data shows MSU crystal but not UA enhances the decidualization response of endometrial stromal cells, via the upregulation of inflammatory genes such Ptgs2 and Il11. inhibiting of Cox-2 activity abolishes MSU crystal induced higher expression of decidualization marker Prl8a2. At last, in women, we observed enriched expression of XDH in decidua compare to non-decidualized endometrium, the serum level of UA is significantly increased in women in very early stage of pregnancy, and drop down after elective abortion. In summary, we observed an increased serum UA level in the early stage of women's pregnancy, and proved that the increased level of UA results from the expressed XDH in decidualizing endometrium of both human and mouse, leading to the formation of MSU crystal. MSU crystal can enhance the decidualization response via inflammatory pathways. Our study has uncovered the association between UA, MSU, and decidualization during the early stage of pregnancy.

A Computational Tumor-Infiltrating Lymphocyte Assessment Method Comparable with Visual Reporting Guidelines for Triple-Negative Breast Cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are clinically significant in triple-negative breast cancer (TNBC). Although a standardized methodology for visual TILs assessment (VTA) exists, it has several inherent limitations. We established a deep learning-based computational TIL assessment (CTA) method broadly following VTA guideline and compared it with VTA for TNBC to determine the prognostic value of the CTA and a reasonable CTA workflow for clinical practice. METHODS: We trained three deep neural networks for nuclei segmentation, nuclei classification and necrosis classification to establish a CTA workflow. The automatic TIL (aTIL) score generated was compared with manual TIL (mTIL) scores provided by three pathologists in an Asian (n = 184) and a Caucasian (n = 117) TNBC cohort to evaluate scoring concordance and prognostic value. FINDINGS: The intraclass correlations (ICCs) between aTILs and mTILs varied from 0.40 to 0.70 in two cohorts. Multivariate Cox proportional hazards analysis revealed that the aTIL score was associated with disease free survival (DFS) in both cohorts, as either a continuous [hazard ratio (HR)=0.96, 95% CI 0.94-0.99] or dichotomous variable (HR=0.29, 95% CI 0.12-0.72). A higher C-index was observed in a composite mTIL/aTIL three-tier stratification model than in the dichotomous model, using either mTILs or aTILs alone. INTERPRETATION: The current study provides a useful tool for stromal TIL assessment and prognosis evaluation for patients with TNBC. A workflow integrating both VTA and CTA may aid pathologists in performing risk management and decision-making tasks. FUNDING: National Natural Science Foundation of China, Guangdong Medical Research Foundation, Guangdong Natural Science Foundation.

AOPPs induce HTR-8/SVneo cell apoptosis by downregulating the Nrf-2/ARE/HO-1 anti-oxidative pathway: Potential implications for preeclampsia.

INTRODUCTION: Advanced oxidation protein products (AOPPs), which are novel markers of oxidant-mediated protein damage, are prevalent in numerous diseases. We previously demonstrated that AOPPs act as a new class of pathogenic mediators in preeclampsia by causing trophoblast damage and dysfunction. Herein, we explored whether AOPPs could regulate the Nrf-2/ARE/HO-1 anti-oxidative pathway to facilitate the progression of preeclampsia. METHODS: To investigate the pathophysiology of preeclampsia, we evaluated the effects of AOPPs on trophoblast damage, apoptotic proteins, and Nrf-2/ARE/HO-1 anti-oxidative pathway expression, as well as their underlying mechanisms. RESULTS: AOPPs directly increased the expression of apoptotic proteins and significantly inhibited the expression of Nrf-2/ARE/HO-1 pathway in trophoblasts. Nrf-2 silencing aggravated the AOPPs-induced cell apoptosis in vitro by activating p53 and caspase cascade, whereas Nrf-2 overexpression had the opposite effect. Moreover, Nrf-2 exerted cytoprotective effects by increasing HO-1. DISCUSSION: These findings suggest that AOPPs induce trophoblast apoptosis by triggering p53 and caspase activation via inhibition of the Nrf-2/ARE/HO-1 anti-oxidative pathway. Hence, Nrf-2/ARE/HO-1 pathway activation plays a protective role in AOPPs-induced cell apoptosis; thus, holding potential as a therapeutic target against preeclampsia.

Prevalence of and Risk Factors for Poor Sleep During Different Trimesters of Pregnancy Among Women in China: A Cross-Sectional Study.

BACKGROUND: The management of poor sleep during pregnancy is important for maternal and foetal health. The aim of the present study was to investigate the prevalence of poor sleep quality and risk factors for poor sleep during different trimesters of pregnancy for better management of sleep during pregnancy. METHODS: A cross-sectional study was conducted among pregnant women in Foshan Women's and Children's Hospital. In total, 2281 pregnant women were analysed, and the Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. Cluster logistic regression was used to analyse the risk factors for poor sleep among all participants, and logistic regression models were built to identify potential risk factors for poor sleep quality in different trimesters of pregnancy. RESULTS: Over half of the participants reported poor sleep quality (51.8%). The rate of poor sleep was lowest in the second trimester. Women who were unmarried had >12 years of education, exercised <3 days/week, were in the third trimester, had a high level of nausea and vomiting during pregnancy (NVP) and had a history of infertility had a higher risk of poor sleep. Pregnancy-related factors contributed most to poor sleep. In the first trimester, the main risk factors for poor sleep were a history of infertility and a high level of NVP. In the second trimester, only a high level of NVP was a risk factor for poor sleep. In the last trimester, the risk factors for poor sleep were more education years, exercise <3 days/week and high levels of NVP. CONCLUSION: The prevalence and risk factors for poor sleep were different in different trimesters. Clinicians should screen and address poor sleep prior to the first and, especially, the third trimester of pregnancy. Management of poor sleep should be consistent throughout pregnancy and be adjusted in different trimesters.

The pseudogene PRELID1P6 promotes glioma progression via the hnHNPH1-Akt/mTOR axis.

Research over the past decade has suggested important roles for pseudogenes in glioma. This study aimed to show that pseudogene PRELI domain-containing 1 pseudogene 6 (PRELID1P6) promotes glioma progression. Aberrant expression of genes was screened using The Cancer Genome Atlas database. We found that mRNA level of PRELID1P6 was highly upregulated in glioma and was associated with a shorter survival time. Functional studies showed that the knockdown of PRELID1P6 decreased cell proliferation, sphere formation, and clone formation ability and blocked the cell cycle transition at G0/G1, while overexpression of PRELID1P6 had the opposite effects. Mechanistically, knockdown of PRELID1P6 changed the cellular localization of heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) from nucleus to cytoplasm, which promoted ubiquitin-mediated degradation of hnRNPH1. RNA-sequence and gene set enrichment analysis suggested that knockdown of PRELID1P6 regulates the apoptosis signaling pathway. Western blotting showed that PRELID1P6 increased TRF2 expression by hnRNPH1-mediated alternative splicing effect and activated the Akt/mTOR pathway. Furthermore, Akt inhibitor MK2206 treatment reversed the oncogenic function of PRELID1P6. PRELID1P6 was also found to be negatively regulated by miR-1825. Our result showed that PRELID1P6 promotes glioma progression through the hnHNPH1-Akt/mTOR pathway. These findings shed new light on the important role of PRELID1P6 as a novel oncogene for glioma.