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Long-term exposure to diethylhexyl phthalate (DEHP), an endocrine-disrupting chemical (EDCs) and plasticizer widely used in consumer products, has been reported to be significantly positively correlated with increased risks of different human diseases, including various cancers, while the potential effect of DEHP on colorectal cancer progression was little studied. In the present study, we showed that DEHP could trigger the metabolic reprogramming of colorectal cancer cells, promote cell growth and decrease fluorouracil (5-FU) sensitivity. Mechanistic studies indicated that DEHP could reduce glycolysis activity and increase oxidative phosphorylation (OXPHOS) in SW620 cells. In addition, in vivo experiments showed that DEHP promoted tumorigenic progression and decreased survival time in mice. Collectively, our findings suggest that DEHP may be a potent risk factor for colorectal cancer development.

Pituitary neuroendocrine tumor (PitNET) is one of the most common intracranial tumors. Due to its extensive tumor heterogeneity and the lack of high-quality tissues for biomarker discovery, the causative molecular mechanisms are far from being fully defined. Therefore, more studies are needed to improve the current clinicopathological classification system, and advanced treatment strategies such as targeted therapy and immunotherapy are yet to be explored. Here, we performed the largest integrative genomics, transcriptomics, proteomics, and phosphoproteomics analysis reported to date for a cohort of 200 PitNET patients. Genomics data indicate that GNAS copy number gain can serve as a reliable diagnostic marker for hyperproliferation of the PIT1 lineage. Proteomics-based classification of PitNETs identified 7 clusters, among which, tumors overexpressing epithelial-mesenchymal transition (EMT) markers clustered into a more invasive subgroup. Further analysis identified potential therapeutic targets, including CDK6, TWIST1, EGFR, and VEGFR2, for different clusters. Immune subtyping to explore the potential for application of immunotherapy in PitNET identified an association between alterations in the JAK1-STAT1-PDL1 axis and immune exhaustion, and between changes in the JAK3-STAT6-FOS/JUN axis and immune infiltration. These identified molecular markers and alternations in various clusters/subtypes were further confirmed in an independent cohort of 750 PitNET patients. This proteogenomic analysis across traditional histological boundaries improves our current understanding of PitNET pathophysiology and suggests novel therapeutic targets and strategies.

Chinese herbal slices (CHSs) are closely associated to microorganisms, whether they are endophytic or epiphytic in plants, or introduced during processing. In this study, the structures and predicted functions of microbial communities in 150 batches of samples from five types of CHSs were investigated by combining pure culture and 16 S rDNA amplicon sequencing. Bile-salt-tolerant gram-negative bacteria were detected in 56.0% of samples, andThe online version contains supplementary material available at 10.1007/s11756-022-01199-0.

Background While some lung adenocarcinoma (LUAD) patients benefit long-term from treatment with immune checkpoint inhibitors, the sad reality is that a considerable proportion of patients do not. The classification of the LUAD tumor microenvironment (TME) can be used to conceptually comprehend primary resistance mechanisms. In addition, the most recent research demonstrates that the release of damage-associated molecular pattern (DAMP) in TME by immunogenic cell death (ICD) may contribute to the adaptive immune response. Currently, however, there is no such comprehensive research on this topic in LUAD patients. Therefore, we set out to investigate how to reverse the poor infiltration characteristics of immune cells and boost antitumor immunity by identifying DAMP model. Methods In this study, ICD-related DAMP genes were selected to investigate their effects on the prognosis of LUAD. To create a risk signature using the TCGA-LUAD cohort, the univariate COX regression and the least absolute shrinkage and selection operator regression were carried out, and the results were verified in a GEO dataset. Subsequently, the multivariate COX regression was applied to establish a prognostic nomogram. And the ESTIMATE and ssGSEA algorithms were utilized to analyze immune activity and the TIDE algorithm was for responsiveness to immunotherapy. Moreover, clinical tissue samples were used to verify the differential expression of 9 DAMP genes in the signature. Results We identified two distinct DAMP molecular subtypes, and there are remarkable differences in survival probability between the two subtypes, and patients with higher levels of DAMP-related genes are “hot tumors” with increased immune activity. In addition, 9 DAMP genes were selected as prognostic signature genes, and clinical outcomes and immunotherapy response were better for participants in the low-risk group. Importantly, according to the area under the curve (AUC) value in evaluating the efficacy of immunotherapy, this signature is superior to existing predictors, such as PD-L1 and TIDE. Conclusions Our study suggests ICD plays an important part in modeling the TME of LUAD patients. And this signature could be utilized as a reliable predictor to estimate clinical outcomes and predict immunotherapy efficacy among LUAD patients.

MotivationRecent advances in DNA sequencing technologies in particular of long reads type greatly improved genomes assembly leading to discrepancies between both published annotations and epigenome tracks which did not keep pace with new assemblies. This comprises the availability of accurate resources which penalizes the progress in research.ResultsHere, we used the latest improved telomere to telomere assembly of the model pennate diatom Phaeodactylum tricornutum to lift over the gene models from Phatr3, a previously annotated reference genome. We used the lifted genome annotation including genes and transposable elements to map the epigenome landscape, namely DNA methylation and post translational modifications of histones providing the community with PhaeoEpiView, a browser that allows the visualization of epigenome data as well as transcripts on an updated reference genome to better understand the biological significance of the mapped data on contiguous genome rather than a fragmented one. We updated previously published histone marks with a more accurate mapping using monoclonal antibodies instead of polyclonal and deeper sequencing. PhaeoEpiView will be continuously updated with the newly published epigenomic data making it the largest and richest epigenome browser of any stramenopile. We expect that PhaeoEpiView will be a standard tool for the coming era of molecular environmental studies where epigenetics holds a place of choice.AvailabilityPhaeoEpiView is available at: https://PhaeoEpiView.univ-nantes.fr

Cancer-testis genes are involved in the occurrence and development of cancer, but the role of cancer-testis-associated lncRNAs (CT-lncRNAs) in hepatocellular carcinoma (HCC) remains to be explored. Here, we discovered a novel CT-lncRNA, LINC01977, based on the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases. LINC01977 was exclusively expressed in testes and highly expressed in HCC. High LINC01977 levels correlated with poorer overall survival (OS) in individuals with HCC. Functional assays showed that LINC01977 promoted HCC growth and metastasis in vitro and in vivo. Mechanistically, LINC01977 directly bound to RBM39 to promote the further entry of Notch2 into the nucleus, thereby preventing the ubiquitination and degradation of Notch2. Furthermore, the RNA binding protein IGF2BP2, one of the m6A modification readers, enhanced the stability of LINC01977, resulting in its high level in HCC. Therefore, the data suggest that LINC01977 interacts with RBM39 and promotes the progression of HCC by inhibiting Notch2 ubiquitination and degradation, indicating that LINC01977 may be a potential biomarker and therapeutic target for HCC patients.

Background Polymorphisms in microRNAs (miRNAs) play an important role in acute coronary syndromes (ACS). The purpose of this study was to assess the association of miR-146a rs2910164 and miR-34b rs4938723 polymorphisms with the development and prognosis of ACS and to explore the underlying mechanisms. Methods A case–control study of 1171 subjects was included to determine the association of miR-146a rs2910164 and miR-34b rs4938723 polymorphisms with ACS risk. An additional 612 patients with different miR-146a rs2910164 genotypes, who underwent percutaneous coronary intervention (PCI) were included in the validation cohort and followed for 14 to 60 months. The endpoint was major adverse cardiovascular events (MACE). A luciferase reporter gene assay was used to validate the interaction of oxi-miR-146a(G) with the IKBA 3'UTR. Potential mechanisms were validated using immunoblotting and immunostaining. Results The miR-146a rs2910164 polymorphism was significantly associated with the risk of ACS (Dominant model: CG + GG vs. CC, OR = 1.270, 95% CI (1.000–1.613), P = 0.049; Recessive model: GG vs. CC + CG, OR = 1.402, 95% CI (1.017–1.934), P = 0.039). Serum inflammatory factor levels were higher in patients with the miR-146a rs2910164 G allele than in those with the C allele. MiR-146a rs2910164 polymorphism in dominant model was associated with the incidence of MACE in post-PCI patients (CG + GG vs. CC, HR = 1.405, 95% CI (1.018–1.939), P = 0.038). However, the miR-34b rs4938723 polymorphism was not associated with the prevalence and prognosis of ACS. The G allele of miR-146a rs2910164 tends to be oxidized in ACS patients. The miRNA fractions purified from monocytes isolated from ACS patients were recognized by the 8OHG antibody. Mispairing of Oxi-miR-146a(G) with the 3'UTR of IKBA results in decreased IκBα protein expression and activation of the NF-κB inflammatory pathway. P65 expression was higher in atherosclerotic plaques from patients carrying the miR-146a rs2910164 G allele. Conclusion The variant of miR-146a rs2910164 is closely associated with the risk of ACS in Chinese Han population. Patients carrying miR-146a rs2910164 G allele may have worse pathological change and poorer post-PCI prognosis, partly due to the oxidatively modified miR-146a mispairing with 3′UTR of IKBA and activating NF-κB inflammatory pathways.

Globally, lung cancer remains the most commonly diagnosed cancer and the leading cause of cancer-related mortality. Lung adenocarcinoma (LUAD) is a common subtype of lung cancer and carries a poor prognosis. Treatment outcomes biomarkers in LUAD are critical, and there is currently a paucity of data; therefore, there is a need for novel biomarkers and newer therapeutic targets.Bayesian analysis was used to obtain the whole-genome t value of LUAD. Gene set enrichment analysis (GSEA) was conducted to obtain the normalized enrichment scores (NES) of the whole genome, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was analyzed using the Gene Set Analysis Toolkit. Herein, we investigated the PPP1R14D expression level at the protein level in LUAD and the impact of PPP1R14D knockdown on the proliferation and apoptosis of LUAD cells in vitro.A total of 483 LUAD samples and 59 normal control samples were included, and 904 differentially expressed genes (DEGs) and 504 LUAD-related genes reported in the literature were obtained. The DEGs showed that PPP1R14D was the most significantly up-regulated gene. Western blot of 30 cases of LUAD tissue and adjacent normal tissue also found that PPP1R14D was significantly highly expressed in cancer tissues. Lentivirus-mediated shRNA strategy effectively inhibited PPP1R14D expression in human LUAD cells DMS53, while PPP1R14D knockdown induced apoptosis and cell proliferation in DMS53 cells.Abnormally up-regulated PPP1R14D promotes the survival and proliferation of tumor cells in human LUAD and may serve as a therapeutic and diagnostic target for LUAD.

A classifier is a software component, often based on Deep Learning, that categorizes each input provided to it into one of a fixed set of classes. An IDK classifier may additionally output “I Don’t Know” (IDK) for certain inputs. Multiple distinct IDK classifiers may be available for the same classification problem, offering different trade-offs between effectiveness, i.e. the probability of successful classification, and efficiency, i.e. execution time. Optimal offline algorithms are proposed for sequentially ordering IDK classifiers such that the expected duration to successfully classify an input is minimized, optionally subject to a hard deadline on the maximum time permitted for classification. Solutions are provided considering independent and dependent relationships between pairs of classifiers, as well as a mix of the two.

A detailed picture of temperature dependent behavior of CsxFA1-xPbI3 perovskite quantum dots across the composition range is constructed by performing in situ optical spectroscopic and structural measurements, supported by theoretical calculations that focus on the relation between A-site chemical composition and surface ligand binding. The thermal degradation mechanism depends not only on the exact chemical composition, but also on the ligand binding energy. The thermal degradation of Cs-rich perovskite quantum dots is induced by a phase transition from black γ-phase to yellow δ-phase, while FA-rich perovskite quantum dots with higher ligand binding energy directly decompose into PbI2. Quantum dot growth to form large bulk size grain is observed for all CsxFA1-xPbI3 perovskite quantum dots at elevated temperatures. In addition, FA-rich quantum dots possess stronger electron−longitudinal optical phonon coupling, suggesting that photogenerated excitons in FA-rich quantum dots have higher probability to be dissociated by phonon scattering compared to Cs-rich quantum dots.

Three-dimensional (3D) tomographic reconstruction in confined-space requires a mapping relationship which considers the refraction distortion caused by optical walls. In this work, a tomography method, namely full-field cross-interface computed tomography (FCICT), is proposed to solve confine-space problems. The FCICT method utilizes Snell’s law and reverse ray-tracing to analytically correct imaging distortion and establishes the mapping relationship from 3D measurement domain to 2D images. Numerical phantom study is first employed to validate the FCICT method. Afterwards, the FCICT is applied on the experimental reconstruction of an illuminated two-phase jet flow which is initially generated inside an optical cylinder and then gradually moves outside. The comparison between accurately reconstructed vapor by FCICT and coarse result by traditional open space tomography algorithm provides a practical validation of FCICT. Based on the 3D vapor reconstructions at different time sequences, the distributions of surface velocity and 3D curvatures are calculated, and their correspondences are systematically analyzed. It is found that the velocity of a surface point is positively correlated with the mean curvature at the same point, which indicates the concavity/convexity of vapor surface is possibly in accordance with the surface velocity. Moreover, the surface velocity presents monotonical increasing trend with larger Gaussian curvature for elliptic surface points only, due to the dominated Brownian motion as the vapor develops.

Background Tissue-resident CD8+T cells (CD103+CD8+T cells) are the essential effector cell population of anti-tumor immune response in tissue regional immunity. And we have reported that IL-33 can promote the proliferation and effector function of tissue-resident CD103+CD8+T cells. As of now, the immunolocalization and the prognostic values of tissue-resident CD8+T cells in human hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) still remain to be illustrated. Methods In our present study, we used the tissue microarrays of HCC and ICC, the multicolor immunohistochemistry (mIHC), and imaging analysis to characterize the tissue-resident CD8+T cells in HCC and ICC tissues. The prognostic values and clinical associations were also analyzed. We also studied the biological functions and the cell–cell communication between tumor-infiltrating CD103+CD8+T cells and other cell types in HCC and ICC based on the published single-cell RNA sequencing (scRNA-seq) data. Results Our work unveiled the expressions of CD8 and CD103 and immunolocalization of tissue-resident CD8+T cells in human HCC and ICC. Elevated CD8+T cells indicated a better overall survival (OS) rate, implying that tumor-infiltrating CD8+T cells in HCC and ICC could serve as an independent prognostic factor. Moreover, the number of CD103+CD8+T cells was increased in HCC and ICC tissues compared with adjacent normal tissues. HCC patients defined as CD8highCD103high had a better OS, and the CD8lowCD103low group tended to have a poorer prognosis in ICC. Evaluation of the CD103+CD8+T-cell ratio in CD8+T cells could also be a prognostic predictor for HCC and ICC patients. A higher ratio of CD103+CD8+T cells over total CD8+T cells in HCC tissues was negatively and significantly associated with the advanced pathological stage. The percentage of higher numbers of CD103+CD8+T cells in ICC tissues was negatively and significantly associated with the advanced pathological stage. In contrast, the higher ratio of CD103+CD8+T cells over total CD8+T cells in ICC tissues was negatively and significantly associated with the advanced pathological stage. In addition, single-cell transcriptomics revealed that CD103+CD8+T cells were enriched in genes associated with T-cell activation, proliferation, cytokine function, and T-cell exhaustion. Conclusion The CD103+ tumor-specific T cells signified an important prognostic marker with improved OS, and the evaluation of the tissue-resident CD103+CD8+T cells might be helpful in assessing the on-treatment response of liver cancer.

Background Vascular hyporeactivity and leakage are key pathophysiologic features that produce multi-organ damage upon sepsis. We hypothesized that pericytes, a group of pluripotent cells that maintain vascular integrity and tension, are protective against sepsis via regulating vascular reactivity and permeability. Methods We conducted a series of in vivo experiments using wild-type (WT), platelet-derived growth factor receptor beta (PDGFR-β)-Cre + mT/mG transgenic mice and Tie2-Cre + Cx43flox/flox mice to examine the relative contribution of pericytes in sepsis, either induced by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) challenge. In a separate set of experiments with Sprague–Dawley (SD) rats, pericytes were depleted using CP-673451, a selective PDGFR-β inhibitor, at a dosage of 40 mg/(kg·d) for 7 consecutive days. Cultured pericytes, vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) were used for mechanistic investigations. The effects of pericytes and pericyte-derived microvesicles (PCMVs) and candidate miRNAs on vascular reactivity and barrier function were also examined. Results CLP and LPS induced severe injury/loss of pericytes, vascular hyporeactivity and leakage (P P P P Conclusions Pericytes are protective against sepsis through regulating vascular reactivity and barrier function. Possible mechanisms include both direct colonization of microvasculature and secretion of PCMVs.

Long non-coding RNAs (LncRNAs) are implicated in malignant progression of human cancers. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a well-known lncRNA, has been reported to play crucial roles in multiple malignancies including head and neck squamous cell carcinoma (HNSCC). However, the underlying mechanisms of MALAT1 in HNSCC progression remain to be further investigated. Here, we elucidated that compared with normal squamous epithelium, MALAT1 was notably upregulated in HNSCC tissues, especially in which was poorly differentiated or with lymph nodes metastasis. Moreover, elevated MALAT1 predicted unfavorable prognosis of HNSCC patients. The results of in vitro and in vivo assays showed that targeting MALAT1 could significantly weaken the capacities of proliferation and metastasis in HNSCC. Mechanistically, MALAT1 inhibited von Hippel–Lindau tumor suppressor (VHL) by activating EZH2/STAT3/Akt axis, then promoted the stabilization and activation of β-catenin and NF-κB which could play crucial roles in HNSCC growth and metastasis. In conclusion, our findings reveal a novel mechanism for malignant progression of HNSCC and suggest that MALAT1 might be a promising therapeutic target for HNSCC treatment.

Glioma stem cells (GSCs) are the important cause of tumorigenesis, recurrence, and chemo(radio)resistance in glioma. Targeting GSCs helps improve the outcomes of glioma treatment. Polo-like kinase 1 (PLK1) is a member of the serine/threonine protein kinase family, which is highly conserved. In recent years, it has been suggested that increased levels of PLK1 and its activity are associated with tumor progression and poor prognosis. We aimed to identify whether PLK1 plays a critical role in stemness maintenance and apoptosis regulation in GSCs. Here we identify that PLK1 inhibition can induce apoptosis and DNA damage of GSCs, we have also delineat the possible underlying molecular mechanisms: PLK1 interacts with YBX1 and directly phosphorylates serine 174 and serine 176 of YBX1. Inhibition of PLK1 reduces the phosphorylation level of YBX1, and decreased phosphorylation of YBX1 prevents its nuclear translocation, thereby inducing apoptosis and DNA damage of GSCs. We confirmed that YBX1 knockdown resulted in the apoptosis and DNA damage of GSCs. These findings uncover that PLK1 inhibition induces cell apoptosis and DNA damage in GSCs through YBX1 phosphorylation, providing new insights into the mechanism by which PLK1 inhibition contributes to the apoptosis of and DNA damage in gliomas.

Glaucoma is the major cause of irreversible blindness in the world characterized by progressive retinal neurodegeneration, in which local inflammation in retina is involved in persistent loss of retinal ganglion cells (RGCs). In order to explore whether aryl hydrocarbon receptor (AhR) and its agonists tryptophan metabolites are involved in the development of glaucoma, we collected serum and retinas from non-glaucoma controls and patients with glaucoma. Results showed altered serum tryptophan metabolism and reduced retinal AhR expression in glaucoma patients. We also showed intraperitoneally injection of tryptophan metabolite 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) down-regulated retinal local inflammation and protected RGC apoptosis from retinal ischemia/reperfusion (IR) injury via AhR activation. We further revealed that ITE could inhibit inflammation in BV2 microglia and alleviate the neurotoxicity of microglial conditioned medium to RGCs under IR. Finally, we illustrated the possible mechanism that ITE limited ERK and NFκB dependent microglial inflammation. In summary, these findings suggest the critical role of tryptophan metabolism and retinal AhR signaling in modulating local inflammation mediated by microglia in glaucoma, and provide a novel avenue to targeting the intrinsically altered AhR signaling resulted from disturbed tryptophan metabolism for glaucoma treatment.

Background Gorham-Stout disease (GSD) is a very rare disorder characterized by massive osteolysis of poorly understood aetiology. The association between GSD involving the skull base and cerebrospinal fluid (CSF) leakage has been reported in the literature. However, few cases of CSF leakage and Chiari-like tonsillar herniation in GSD involving the spine have been reported. Case presentation We present the case of a 20-year-old man with GSD involving the thoracic and lumbar spine, which caused CSF leakage and Chiari-like tonsillar herniation. The patient underwent four spinal surgeries for osteolytic lesions of the spine over a 10-year period. Here, we discuss the possible aetiology of the development of CSF leakage. Epidural blood patch (EBP) was performed at the T11-T12 level to repair the CSF leakage. After EBP treatment, rebound intracranial hypertension (RIH) developed, and tonsillar herniation disappeared 2 months later. Conclusions GSD involving the spine with CSF leakage and Chiari-like tonsillar herniation is relatively rare. For patients who have undergone multiple spinal surgeries, minimally invasive treatment is an alternative treatment for CSF leakage. EBP can repair CSF leakage secondary to GSD and improve chronic brain sagging, with reversibility of Chiari-like malformations.

Most covalent organic frameworks (COFs) are synthesized using solvothermal conditions (>120 °C, >72 h) in harmful organic solvents. We report a strategy for rapidly synthesizing imine-linked COFs (< 60 min) in aqueous acetic acid using sonochemistry, avoiding most of the downsides of solvothermal methods. We first synthesized seven known COFs using this method and obtained crystallinity and porosity comparable to or better than materials from previously reported solvothermal routes. This sonochemical method even works in highly sustainable solvents, such as food-grade vinegar. The generality of the method was demonstrated by preparing two unreported COFs. Finally, we showed that one sonochemical COF is an excellent photocatalyst for sacrificial hydrogen evolution from water with a more sustained catalytic performance than its solvothermal analog. The speed, ease and generality of this sonochemical method with no sacrifice in material quality makes it an enabling methodology for rapid discovery of new functional COF materials.