Chromosomal copy number amplification-driven Linc01711 contributes to gastric cancer progression through histone modification-mediated reprogramming of cholesterol metabolism.

BACKGROUND: Chromosome gains or localized amplifications are frequently observed in human gastric cancer (GC) and are major causes of aberrant oncogene activation. However, the significance of long non-coding RNAs (LncRNAs) in the above process is largely unknown. METHODS: The copy number aberrations (CNAs) data of GC samples were downloaded and analyzed from the TCGA database. qRT-PCR and fluorescence in situ hybridization were used to evaluate the expression of Linc01711 in GC. The effects of Linc01711 on GC progression were investigated through in vitro and in vivo assays. The mechanism of Linc01711 action was explored through transcriptome sequencing, chromatin immunoprecipitation sequencing, RNA immunoprecipitation, RNA pull-down and chromatin isolation by RNA purification (ChIRP) assays. RESULTS: We report for the first time a novel DNA copy number amplification-driven LncRNA on chromosome 20q13, designated Linc01711 in human GC, which is highly associated with malignant features. Functionally, Linc01711 significantly accelerates the proliferation and metastasis of GC. Mechanistically, Linc01711 acts as a modular scaffold to promote the binding of histone acetyltransferase HBO1 and histone demethylase KDM9. By coordinating the localization of the HBO1/KDM9 complex, Linc01711 specifies the histone modification pattern on the target genes, such as LPCAT1, and consequently facilitates the cholesterol synthesis, thereby contributing to tumor progression. CONCLUSIONS: Our findings suggest that copy number amplification-driven Linc01711 may serve as a promising prognostic predictor for GC patients and targeting Linc01711-related cholesterol metabolism pathway may be meaningful in anticancer strategies.

Effects of smartphone-based hypnotic intervention for undergraduate students' shyness during the COVID-19 pandemic: A randomized controlled trial.

BACKGROUND: Since the outbreak of the COVID-19 pandemic, university students have been exposed to a heightened vulnerability towards developing psychological issues, such as psychological distress and shyness. Internet-based interventions offer a convenient avenue for scalability, thus prompting the development of a smartphone-based hypnotic intervention aimed at addressing shyness among university students. OBJECTIVE: We devised an innovative smartphone-based hypnotic intervention called mHypnosis to examine its impact on shyness among undergraduate students. Furthermore, we aimed to investigate whether the apprehension of negative evaluations before treatment could serve as a predictor for the effectiveness of the intervention on shyness. METHODS: Eighty students with high shyness scores were randomly assigned to the experimental group and the control group. Another 40 participants with low shyness score were selected as the baseline group. The Shyness Scale (SS), Fear of Negative evaluation scale (FNE), Self-Acceptance Questionnaire (SAQ), and Self-Esteem Scale (SES) were used to evaluate the effect of hypnotic intervention. RESULTS: Before the intervention, the scores of the experimental and control groups on the SS, FNE, SAQ, and SES were higher than those in the baseline group (p < 0.05). There was no significant difference in scores between the experimental and control group (p > 0.05). After the intervention, the scores of the SS, FNE, SAQ, and SES were significantly lower in the experimental group than those in the control group (p < 0.05). The pretest score of FNE could predict the shyness score after hypnotic intervention (B = 0.35, p < 0.05). CONCLUSION: Smartphone-based hypnotic intervention had a significant effect on ameliorating shyness during the COVID-19 pandemic; fear of negative evaluation can be a target for treating shyness.

Analyzing 20 years of Resting-State fMRI Research: Trends and collaborative networks revealed.

Resting-state functional magnetic resonance imaging (rs-fMRI), initially proposed by Biswal et al. in 1995, has emerged as a pivotal facet of neuroimaging research. Its ability to examine brain activity during the resting state without the need for explicit tasks or stimuli has made it an integral component of brain imaging studies. In recent years, rs-fMRI has witnessed substantial growth and found widespread application in the investigation of functional connectivity within the brain. To delineate the developmental trajectory of rs-fMRI over the past two decades, we conducted a comprehensive analysis using bibliometric tool Citespace. Our analysis encompassed publication trends, authorship networks, institutional affiliations, international collaborations, as well as emergent themes in references and keywords. Our study reveals a remarkable increase in the volume of rs-fMRI publications over the past two decades, underscoring the burgeoning interest and potential within this field. Harvard University stands out as the institution with the highest number of research papers published in the realm of RS-fMRI, while the United States holds the highest overall influence in this domain. The recent emergence of keywords such as "machine learning" and "default mode," coupled with citation surges in reference to rs-fMRI, have paved new avenues for research within this field. Our study underscores the critical importance of integrating machine learning techniques into rs-fMRI investigations, offering valuable insights into brain function and disease diagnosis. These findings hold profound significance for the field of neuroscience and may furnish insights for future research employing rs-fMRI as a diagnostic tool for a wide array of neurological disorders, thus emphasizing its pivotal role and potential as a tool for investigating brain functionality.

Overexpressed transferrin receptor implied poor prognosis and relapse in gastrointestinal stromal tumors.

Ferroptosis, as a novel-induced programmed cell death, plays critical roles in the pathogenesis of cancers. However, the promising biomarkers of ferroptosis in gastrointestinal stromal tumor (GIST) remain to be elucidated. Herein, the expression of ferroptosis-related genes was analyzed in GIST. Among the 64 ferroptosis-related genes, transferrin receptor (TFRC) expression presented a remarkable upregulation in high-risk patients through Gene Expression Omnibus (GEO) dataset analysis, as well as its significant change after imatinib was treated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of TFRC-relevant genes revealed that TFRC expression was closely associated with cell growth pathways and metabolism-related pathways. Furthermore, patients at high risk of recurrence were more likely to exhibit high TFRC expression by immunohistochemistry. Additionally, high TFRC expression indicated an undesirable state of patient relapse, which could serve as a powerful significant independent predictor of recurrence-free survival (RFS). In summary, we systematically summarize the expression characteristics and clinical relevance of TFRC and show that TFRC can be used as a prognostic factor, which can be considered a potential therapeutic target in GIST.

Genome-wide identification and expression profiling of B3 transcription factor genes in Populus alba × Populus glandulosa.

B3-domain containing transcription factors (TFs) are well known to play important roles in various developmental processes, including embryogenesis, seed germination, etc. Characterizations and functional studies of the B3 TF superfamily in poplar are still limited, especially on their roles in wood formation. In this study, we conducted comprehensive bioinformatics and expression analysis of B3 TF genes in Populus alba × Populus glandulosa. A total of 160 B3 TF genes were identified in the genome of this hybrid poplar, and their chromosomal locations, syntenic relationships, gene structures, and promoter cis-acting elements were analyzed. Through domain structure and phylogenetic relationship analyses, these proteins were classified into four families LAV, RAV, ARF, and REM. Domain and conservation analyses revealed different gene numbers and different DNA-binding domains among families. Syntenic relationship analysis suggested that approximately 87% of the genes resulted from genome duplication (segmental or tandem), contributing to the expansion of the B3 family in P. alba × P. glandulosa. Phylogeny in seven species revealed the evolutionary relationship of B3 TF genes across different species. B3 domains among the eighteen proteins that were highly expressed in differentiating xylem had a high synteny, suggesting a common ancestor for these seven species. We performed co-expression analysis on the representative genes in two different ages of poplar, followed by pathways analysis. Among those genes co-expressed with four B3 genes, 14 were involved in lignin synthases and secondary cell walls biosynthesis, including PagCOMT2, PagCAD1, PagCCR2, PagCAD1, PagCCoAOMT1, PagSND2, and PagNST1. Our results provide valuable information for the B3 TF family in poplar and show the potential of B3 TF genes in engineering to improve wood properties.

Long noncoding RNA SPRY4-IT1 acts as a miR-101-5p sponge to promote gastrointestinal stromal tumor progression by inhibiting ZEB1.

OBJECTIVES: Research on long noncoding RNAs (lncRNAs) has been conducted in different areas of oncology. Currently, the biological significance of lncRNAs and their regulatory features in gastrointestinal stromal tumors (GIST) remain largely unknown. We have previously identified SPRY4-IT1 overexpression in GIST through lncRNA sequencing of GIST tissues. Coincidentally, SPRY4-IT1 is an intron of the SPRY4 gene, and SPRY4 is specifically highly expressed in GIST. Thus the aim of the present study was to investigate the role of lncRNA SPRY4-IT1 in GIST pathogenesis. METHODS: Herein, we screened for SPRY4-IT1 and analyzed its possible phenotypes using Gene set enrichment analysis (GSEA). The phenotypes of GIST were verified using CCK-8, colony formation, and wound-healing assays. The ceRNA mechanism was determined by the location of lncRNA SPRY4-IT1, and its relationship to the Ago2 protein. The SPRY4-IT1/miR-101-5p/ZEB1 axis was predicted using online software and sequencing. Luciferase and pull-down assays were performed for verification. Pathway-associated and phenotype-associated proteins were detected by western blotting. RESULTS: Sequencing analysis revealed 117 differentially expressed lncRNAs in GIST and normal gastric tissue samples. Accordingly, SPRY4-IT1 was screened out and its phenotype was predicted by GSEA. Mechanistically, SPRY4-IT1 was identified as a competing endogenous RNA (ceRNA) that downregulated miR-101-5p and upregulated ZEB1, which activated extracellular signal-regulated kinase (ERK) signaling to stimulate GIST proliferation, invasion, and epithelial-mesenchymal transition. Although this effect was regulated by a negative feedback loop through SPRY4, it was still controlled by SPRY4-IT1. CONCLUSIONS: In GIST, we revealed a ceRNA mechanism by which SPRY4-IT1 modulates ZEB1 by sponging miR-101-5p, eventually driving tumor cell proliferation, migration, and epithelial-mesenchymal transition (EMT).

Efficacy and Safety of Camrelizumab in Combination with Docetaxel + S-1 Sequenced by Camrelizumab + S-1 for Stage III (PD-1+/MSI-H/EBV+/dMMR) Gastric Cancer: Study Protocol for a Single-Center, Prospective, Open-Label, Single-Arm Trial.

Background: Gastric cancer occupies the fourth highest morbidity rate of cancers worldwide. A higher incidence of gastric cancer had been found in East Asia compared to the other regions. Gastrectomy with radical lymph node dissection is the cornerstone of curative treatment for Stage III gastric cancer, and postoperative systemic chemotherapy with docetaxel, S-1 improved patients' disease-free survival rates. However, advances in immunotherapy bring innovations in the management of patients with gastric cancer. The objective of this study was to explore the efficacy and safety of camrelizumab in combination with docetaxel + S-1, sequenced by camrelizumab + S-1 in stage III gastric cancer patients who are EBV positive, with defective mismatch repair and CPS ≥5. Methods and analysis: This prospective, open-label, single-arm trial was performed at Renji Hospital. In this study, a total of 70 adult patients aged 18-80 years with Stage III (PD-1+/MSI-H/EBV+/dMMR) gastric cancer confirmed by post-operative pathology will be enrolled after screening. Participants will receive the specific chemotherapy regimen until 1 year after the operation or until tumor recurrence or metastasis. The primary outcome is the 3-year disease-free survival rate measured by the Clopper-Pearson method and 95% confidence intervals. The secondary outcomes include overall survival, incidence and severity of adverse effects, and laboratory abnormalities. The data will be analyzed by the Kaplan-Meier method and log-rank test. The patients will be followed up every 3 months with imaging investigation until clinical remission. Ethics and dissemination: All participants will provide informed consent. The protocol has been approved by the Shanghai Jiaotong University School of Medicine, Renji Hospital Ethics Committee (KY2019-191). The results will be disseminated through peer-reviewed manuscripts, reports and presentations. Clinical Trial Registration: ClinicalTrials.gov, identifier: ChiCTR1900027123. Registration date November 2019; first enrolment December 2019; expected end date December 2021; trial status: Ongoing. Brief Abstract: A clinical trial for Stage III (PD-1+/MSI-H/EBV+/dMMR) gastric cancer patients who accepted anti-PD-1 therapy combined with docetaxel + S-1 as the first-line treatment and explored improvements in three-year disease-free survival rate.

The nerve-tumour regulatory axis GDNF-GFRA1 promotes tumour dormancy, imatinib resistance and local recurrence of gastrointestinal stromal tumours by achieving autophagic flux.

Complete surgical resection, accessible therapeutic targets and effective tyrosine kinase inhibitors (TKIs) have not completely cured gastrointestinal stromal tumours (GISTs), with most patients suffering from residual tumours and recurrence. The existence of nerve infiltration in GIST provides a way for tumour cells to escape local resection and systemic targeted therapy, which may challenge the previous understanding of its behaviour patterns and inspire the development of more radical excision and more precise targeted therapy. Moreover, tumour dormancy has emerged as a major cause of drug resistance and tumour relapse. Among these pathways, the nerve-tumour regulatory axis GDNF-GFRA1 is activated in GISTs, assists tumour cells in achieving dormancy and protects them from apoptosis under environmental stress by enhancing autophagic flux. The concrete mechanism is that the GDNF-regulating interaction between GFRA1 and the lysosomal calcium channel MCOLN1 activates Ca2+-dependent TFEB signalling. Activated TFEB transcriptionally regulates intracellular lysosome levels, which could achieve feedback upregulation of cellular autophagy flux during TKI treatment. This dormancy-transition axis fills parts of the mechanistic vacancy before the onset of secondary mutations, and strategies for TKIs combined with targeting GFRA1-dependent autophagy have distinct promise as prospective clinical therapies.

Low Distribution of TIM-3+ Cytotoxic Tumor-Infiltrating Lymphocytes Predicts Poor Outcomes in Gastrointestinal Stromal Tumors.

There are multiple tumor-infiltrating lymphocytes (TILs) and relevant immune checkpoints existing in gastrointestinal stromal tumor (GIST), which provides opportunities and rationales for developing effective immunotherapies. Recent studies have suggested that checkpoint TIM-3/Gal-9 plays a pivotal role on immune response in multiple tumors, similar to the PD-1/PD-L1, emerging as a potential therapeutic target. However, their functions in GIST are unrevealed. Hence, the expression of immune checkpoints TIM-3 and Gal-9, as well as the infiltration of CD8+ T cells and NK cells, is described in 299 cases of GIST specimens. The results showed that TIM-3 and Gal-9 are mainly expressed in TILs, rarely in tumor cells. Expression levels of TIM-3 and Gal-9 significantly differ in varying risks of GIST and exert opposite distribution trends. Indicated by prognosis analysis, high TIM-3 expression of TILs was associated with improved outcome, while low expression levels of TIM-3 in combination with low amounts of CD8+ and CD56+ TILs predict extremely poor survival. The integrated analysis of TIM-3+, CD8+, and CD56+ TILs as one biomarker is a reliable independent predictor of prognosis. In conclusion, low densities of TIM-3+ TILs are associated with poor survival, and integrated immune biomarkers lead to superior predictors of GIST prognosis.

Clinicopathologic characteristics, diagnostic clues, and prognoses of patients with multiple sporadic gastrointestinal stromal tumors: a case series and review of the literature.

BACKGROUND: Most sporadic gastrointestinal stromal tumors (GISTs) occur as solitary tumors, while multiple sporadic GISTs are extremely rare and often misdiagnosed as metastatic GISTs, leading to inappropriate treatment. This study aimed to investigate the clinicopathological characteristics, diagnostic clues, and prognoses of multiple sporadic GISTs. METHODS: Twenty-seven patients with multiple sporadic GISTs and 11 patients with metastatic GISTs mimicking sporadic GISTs were analyzed. The clinicopathological characteristics, genetic mutation types, and prognoses were summarized. In addition, 1066 cases of primary GISTs with a single lesion diagnosed at the same hospital were included as controls. RESULTS: Compared with 1066 cases of primary GIST with a single lesion, multiple sporadic GISTs occurred at an older age, were more common in women than in men, and were located mainly in the stomach. They were generally small in size, had a low mitotic index and were more often rated as very low risk/low risk. Mutation analysis of all available lesions revealed different KIT/PDGFRA mutation patterns among tumors from the same patients. No patient relapsed during the follow-up period. Among 11 patients with metastatic GISTs that mimicked multiple sporadic GISTs, multiple lesions from the same patient always had concordant pathological and mutational characteristics; namely, they carried an identical KIT/PDGFRA mutation, and the mitotic index was usually high. CONCLUSIONS: The prognoses of patients with multiple sporadic GISTs were not worse than those of patients with a single lesion of the same risk under the same treatment. When it was difficult to distinguish multiple sporadic GISTs from metastatic GISTs, multiple lesions in the same patient carried different KIT/PDGFRA mutation patterns, which supported tumor multiplicity, while the concordant hypermitotic phase in multiple lesions of GISTs suggested that the tumor was metastatic.

METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer.

BACKGROUND: As one of the most frequent chemical modifications in eukaryotic mRNAs, N6-methyladenosine (m6A) modification exerts important effects on mRNA stability, splicing, and translation. Recently, the regulatory role of m6A in tumorigenesis has been increasingly recognized. However, dysregulation of m6A and its functions in tumor epithelial-mesenchymal transition (EMT) and metastasis remain obscure. METHODS: qRT-PCR and immunohistochemistry were used to evaluate the expression of methyltransferase-like 3 (METTL3) in gastric cancer (GC). The effects of METTL3 on GC metastasis were investigated through in vitro and in vivo assays. The mechanism of METTL3 action was explored through transcriptome-sequencing, m6A-sequencing, m6A methylated RNA immunoprecipitation quantitative reverse transcription polymerase chain reaction (MeRIP qRT-PCR), confocal immunofluorescent assay, luciferase reporter assay, co-immunoprecipitation, RNA immunoprecipitation and chromatin immunoprecipitation assay. RESULTS: Here, we show that METTL3, a major RNA N6-adenosine methyltransferase, was upregulated in GC. Clinically, elevated METTL3 level was predictive of poor prognosis. Functionally, we found that METTL3 was required for the EMT process in vitro and for metastasis in vivo. Mechanistically, we unveiled the METTL3-mediated m6A modification profile in GC cells for the first time and identified zinc finger MYM-type containing 1 (ZMYM1) as a bona fide m6A target of METTL3. The m6A modification of ZMYM1 mRNA by METTL3 enhanced its stability relying on the "reader" protein HuR (also known as ELAVL1) dependent pathway. In addition, ZMYM1 bound to and mediated the repression of E-cadherin promoter by recruiting the CtBP/LSD1/CoREST complex, thus facilitating the EMT program and metastasis. CONCLUSIONS: Collectively, our findings indicate the critical role of m6A modification in GC and uncover METTL3/ZMYM1/E-cadherin signaling as a potential therapeutic target in anti-metastatic strategy against GC.

PTPRU, As A Tumor Suppressor, Inhibits Cancer Stemness By Attenuating Hippo/YAP Signaling Pathway.

BACKGROUND: PTPRU is an important signaling molecule that regulates a variety of cellular processes; however, the role of PTPRU in cancer development has remained elusive. Here, we report that PTPRU serves as a tumor suppressor that inhibits cancer stemness by attenuating Hippo/YAP signaling pathway. METHODS: Primary cancer cells and cell line cells were used in the study. The gene expression data were downloaded from R2 analysis and visualization platform and Kaplan-Meier analysis was performed to study the relationship between survival and PTPRU expression. qRT-PCR and Western blot were employed to study the expression of target genes in tissues and cells. Sphere and colony formation, proliferation, migration activities and the expression of stem cell and EMT markers were employed for characterizing the stemness. Gene manipulation was achieved by lentivirus-mediated gene delivery system. Luciferase reporter gene assay was used to study the transcriptional activity of the promoter, and ChIP-qPCR was employed to study the target binding sequence of the protein. Spearman correlation analysis was performed to study the correlation between two genes. Student's t-test was used for determination of the significance between two experimental groups. RESULTS: PTPRU is downregulated in colorectal and gastric cancer tissues and cancer stem cells. High expression of PTPRU predicts poor prognosis. Overexpression of PTPRU attenuates the stemness of gastric cancer stem cells and knockdown of PTRPU improves the maintenance of the stemness of cancer stem cells. Mechanistic analysis showed that PTPRU inhibits Hippo/YAP signaling by suppressing the expression of YAP in a transcriptional level. Overexpression of YAP restored PTPRU-induced inhibited stemness of gastric cancer stem cells. CONCLUSION: PTPRU serves as a tumor suppressor that inhibits the stemness of cancer stem cell by inhibiting Hippo/YAP signaling pathway.

Aberrant accumulation of Dickkopf 4 promotes tumor progression via forming the immune suppressive microenvironment in gastrointestinal stromal tumor.

BACKGROUND: Drug resistance and tumor recurrence are the major concerns in clinical practices of gastrointestinal stromal tumor (GIST), with the urgent requirement for exploring undiscovered pathways driving malignancy. To deal with these, recent studies have made many efforts to explore prognosis indicators and establish potential therapeutic targets. METHODS: Expression profiles of different risks of GISTs were described and abundant clinical evidences supported our findings in this study. Following exploration in vitro by cell experiments and verification in vivo using tumor microarray were taken to elucidate the underlying mechanism, which drove the malignancy in GIST. RESULTS: Dickkopf 4 (DKK4), as the canonical Wnt pathway antagonist, was unexpectedly and universally upregulated in high-risk GISTs, and aberrant accumulation of DKK4 was closely correlated with poor prognosis. In addition, tumor-derived DKK4 could decrease immune cells infiltration and activation in the tumor microenvironment, which decreased the antitumor effects in return. And this phenomenon was recurrent in human tumor specimens. CONCLUSIONS: Our findings identified DKK4 as a proper tumor biomarker for prognosis predicting and recurrence monitoring, and suggested a novel immune-escape mechanism driving malignancy in GIST, which might be a potential therapeutic target to improve the effects of canonical RTK therapy and combined immunotherapy.

Co-liquefaction of spent coffee grounds and lignocellulosic feedstocks.

Co-liquefaction of spent coffee grounds (SCG) with paper filter (PF), corn stalk (CS) and white pine bark (WPB) respectively, was examined in subcritical water for bio-crude oil production. The optimum reaction temperature was 250°C, and the mixing biomass ratio was 1:1. SCG and CS was identified to be the best feedstock combination with a significant positive synergetic effect in the co-liquefaction process with 5% NaOH as a catalyst. The yield of bio-crude oil was increased by 20.9% compared to the mass averaged yield from two feedstocks, and the oil quality was also improved in terms of viscosity and relative molecular mass. A negative effect presented in the co-liquefaction of SCG/WPB. The resulting bio-crude oils were characterized by elemental analyzer, GC-MS, GPC and viscometer, indicating that mixing feedstock in the co-liquefaction process also influenced the higher heating value (HHV), viscosity, molecular mass and chemical composition of bio-crude oil.

The prospects of Jerusalem artichoke in functional food ingredients and bioenergy production.

Jerusalem artichoke, a native plant to North America has recently been recognized as a promising biomass for bioeconomy development, with a number of advantages over conventional crops such as low input cultivation, high crop yield, wide adaptation to climatic and soil conditions and strong resistance to pests and plant diseases. A variety of bioproducts can be derived from Jerusalem artichoke, including inulin, fructose, natural fungicides, antioxidant and bioethanol. This paper provides an overview of the cultivation of Jerusalem artichoke, derivation of bioproducts and applicable production technologies, with an expectation to draw more attention on this valuable crop for its applications as biofuel, functional food and bioactive ingredient sources.