Search

Background Sialic acid-binding immunoglobulin-like lectins (SIGLECs) are widely expressed on immune cell surfaces, play an important role in maintaining immune homeostasis and regulating inflammatory responses, and are increasingly emerging as potential targets for tumor immunotherapy. However, the expression profile and crucial role of SIGLEC11 in gastric cancer (GC) remain unclear. This study aimed to elucidate the prognostic relevance of SIGLEC11 expression and its role in the immune microenvironment in patients with GC.Methods SIGLEC11 expression profile was analyzed using bioinformatics, immunohistochemistry, and immunofluorescence staining. Flow cytometry, mouse tumor models, patient-derived tumor organoid models, and RNA sequencing were used to explore the potential functions with the underlying mechanisms of SIGLEC11 in a coculture system of macrophages and GC cells.Results We demonstrated that SIGLEC11 was predominantly expressed in normal tissues. However, tumor-infiltrating SIGLEC11+ cells in the high SIGLEC11 expression subgroups showed poor overall survival, which was associated with the expression of an immunosuppressive regulator. Our results showed that SIGLEC11 was predominantly expressed in monocytes and macrophages and selectively upregulated in tumor-associated macrophages. Furthermore, SIGLEC11 promoted macrophage M2 polarization via AKT–mTOR signaling. In addition, SIGLEC11+ macrophages accelerate GC progression.Conclusions The abundance of SIGLEC11+ M2-like macrophage-infiltrating tumors may serve as a biomarker for identifying immunosuppressive subtypes of GC. Thus, the potential role of SIGLEC11+ M2 macrophages as therapeutic targets warrants further investigation.

Abstract Background Decision-to-delivery time (DDT), a crucial factor during the emergency caesarean section, may potentially impact neonatal outcomes. This study aims to assess the association between DDT and various neonatal outcomes. Methods A comprehensive search of PubMed, Scopus, Cochrane Library, and Google Scholar databases was conducted. A total of 32 eligible studies that reported on various neonatal outcomes, such as Apgar score, acidosis, neonatal intensive unit (NICU) admissions and mortality were included in the review. Studies were selected based on predefined eligibility criteria, and a random-effects inverse-variance model with DerSimonian-Laird estimate of tau² was used for meta-analysis. Heterogeneity and publication bias were assessed using I² statistics and Egger’s test, respectively. Results The meta-analysis revealed a significant association between DDT

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors worldwide, with extremely aggressive and complicated biology. Krüppel-like factors (KLFs) encode a series of transcriptional regulatory proteins and play crucial roles in a variety of processes, including tumor cell differentiation and proliferation. However, the potential biological functions and possible pathways of KLFs in the progression of PDAC remain elusive. Methods We systematically evaluated the transcriptional variations and expression patterns of KLFs in pancreatic cancer from the UCSC Xena. Based on difference analysis, the non-negative matrix factorization (NMF) algorithm was utilized to identify the immune characteristics and clinical significance of two different subtypes. The multivariate Cox regression was used to construct the risk model and then explore the differences in tumor immune microenvironment (TIME) and drug sensitivity between high and low groups. Through single-cell RNA sequencing (scRNA-seq) analysis, we screened KLF6 and further investigated its biological functions in pancreatic cancer and pan-cancer. Results The KLFs exhibited differential expression and mutations in the transcriptomic profile of PDAC. According to the expression of KLFs, patients were classified into two distinct subtypes, each exhibiting significant differences in prognosis and TIME. Moreover, the KLF signature was developed using univariate Cox and Lasso regression, which proved to be a reliable and effective prognostic model. Furthermore, the KLF_Score was closely associated with immune infiltration, response to immunotherapy, and drug sensitivity and we screened small molecule compounds targeting prognostic genes separately. Through scRNA-seq analysis, KLF6 was selected to further demonstrate its role in the malignance of PC in vitro. Finally, pan-cancer analysis emphasized the biological significance of KLF6 in multiple types of tumors and its clinical utility in assessing cancer prognosis. Conclusion This study elucidated the pivotal role of KLF family genes in the malignant development of PC through comprehensive analysis and revealed that KLF6 would be a novel diagnostic biomolecule marker and potential therapeutic target for PDAC.

Abstract Background Anti‐PD1/PD‐L1 antibody plus human epidermal growth factor receptor 2 (HER2) antibody and chemotherapy have become the new first‐line therapy for HER2 overexpression‐positive advanced gastric cancers (GC), suggesting that HER2 and PD‐L1 play a vital role in guiding systemic treatment for patients with GC. This study aimed to depict the genomic and immune landscapes of Chinese patients with GC and investigate their correlations with HER2 amplification and PD‐L1 expression. Patients and Methods Next‐generation targeted sequencing and PD‐L1 immunohistochemistry were performed on tumor samples from 735 patients with pathologically diagnosed GC. The genomic and immune landscapes and their correlations with HER2 amplification and PD‐L1 expression were analyzed. Results The most commonly mutated genes in Chinese GC were TP53 (64%), CDH1 (20%), ARID1A (18%), HMCN1 (15%), KMT2D (11%), and PIK3CA (11%). Seventy‐six (10%) patients were HER2 amplification, and 291 (40%) had positive PD‐L1 expression. Classifying the total population based on HER2 amplification and PD‐L1 expression level, 735 patients were divided into four subgroups: HER2+/PD‐L1+ (4.5%), HER2+/PD‐L1− (5.9%), HER2−/PD‐L1+ (35.1%), and HER2−/PD‐L1− (54.5%). The HER2+/PD‐L1− and HER2+/PD‐L1+ subgroups exhibited dramatically higher rate of TP53 mutations, CCNE1 and VEGF amplifications. The HER2+/PD‐L1− subgroup also had a markedly higher rate of MYC amplification and KRAS mutations. The HER2−/PD‐L1+ subgroup had significantly higher rate of PIK3CA mutations. HER2+/PD‐L1− subgroup had the highest TMB level and HER2−/PD‐L1+ subgroup had the highest proportion of patients with microsatellite instability‐high than other subgroups. Furthermore, we observed that different HER2 amplification levels had distinct impacts on the correlations between PD‐L1 expression and therapeutic genomic alterations, but no impact on the prognosis. Conclusion The combination of HER2 amplification and PD‐L1 expression in Chinese patients with GC could stratify the total populations into several subgroups with distinctive genomic and immune landscapes, which should be considered when making personalized treatment decisions.

Abstract Background LIPH, a membrane-associated phosphatidic acid-selective phospholipase A1a, can produce LPA (Lysophosphatidic acid) from PA (Phosphatidic acid) on the outer leaflet of the plasma membrane. It is well known that LIPH dysfunction contributes to lipid metabolism disorder. Previous study shows that LIPH was found to be a potential gene related to poor prognosis with pancreatic ductal adenocarcinoma (PDAC). However, the biological functions of LIPH in PDAC remain unclear. Methods Cell viability assays were used to evaluate whether LIPH affected cell proliferation. RNA sequencing and immunoprecipitation showed that LIPH participates in tumor glycolysis by stimulating LPA/LPAR axis and maintaining aldolase A (ALDOA) stability in the cytosol. Subcutaneous, orthotopic xenograft models and patient-derived xenograft PDAC model were used to evaluate a newly developed Gemcitabine-based therapy. Results LIPH was significantly upregulated in PDAC and was related to later pathological stage and poor prognosis. LIPH downregulation in PDAC cells inhibited colony formation and proliferation. Mechanistically, LIPH triggered PI3K/AKT/HIF1A signaling via LPA/LPAR axis. LIPH also promoted glycolysis and de novo synthesis of glycerolipids by maintaining ALDOA stability in the cytosol. Xenograft models show that PDAC with high LIPH expression levels was sensitive to gemcitabine/ki16425/aldometanib therapy without causing discernible side effects. Conclusion LIPH directly bridges PDAC cells and tumor microenvironment to facilitate aberrant aerobic glycolysis via activating LPA/LPAR axis and maintaining ALDOA stability, which provides an actionable gemcitabine-based combination therapy with limited side effects. Graphical Abstract

Abstract Pancreatic cancer, as one of the neoplasms with the highest degree of malignancy, has become a main disease of concerns in recent years. BHLHE40, a critical transcription factor for remodeling of the tumor immune microenvironment, has been described to be substantially increased in a variety of tumor-associated immune cells. Nevertheless, the pro-cancer biological functions and underlying molecular mechanisms of BHLHE40 for pancreatic cancer and its unique microenvironment are unclear. Hereby, we investigated the pro-oncogenic role of BHLHE40 in the pancreatic cancer microenvironment by bioinformatics analysis and cell biology experiments and determined that the expression of BHLHE40 was obviously elevated in pancreatic cancer tissues than in adjacent normal tissues. In parallel, Kaplan–Meier survival analysis unveiled that lower expression of BHLHE40 was strongly associated with better prognosis of patients. Receiver operating characteristic (ROC) curve analysis confirmed the accuracy of the BHLHE40-related prediction model. Subsequent, spearman correlation analysis observed that higher expression of BHLHE40 might be involved in immunosuppression of pancreatic cancer. Silencing of BHLHE40 could inhibit proliferation, invasion, and apoptosis of pancreatic cancer in vitro and in vivo, implying that BHLHE40 is expected to be a potential therapeutic target for pancreatic cancer. In addition, we explored and validated the FGD5-AS1/miR-15a-5p axis as a potential upstream regulatory mode for high expression of BHLHE40 in pancreatic cancer. In summary, our data showed that ceRNA involved in the regulation of BHLHE40 contributes to the promotion of immunosuppressive response in pancreatic and is expected to be a diagnostic marker and potential immunotherapeutic target for pancreatic cancer.

Abstract Objective Systemic chemotherapy is the first-line therapeutic option for head and neck squamous cell carcinoma (HNSCC), but it often fails. This study aimed to develop an effective prognostic model for evaluating the therapeutic effects of systemic chemotherapy. Methods This study utilized CRISPR/cas9 whole gene loss-of-function library screening and data from The Cancer Genome Atlas (TCGA) HNSCC patients who have undergone systemic therapy to examine differentially expressed genes (DEGs). A lipid metabolism-related clustered polygenic model called the lipid metabolism related score (LMRS) model was established based on the identified functionally enriched DEGs. The prediction efficiency of the model for survival outcome, chemotherapy, and immunotherapy response was evaluated using HNSCC datasets, the GEO database and clinical samples. Results Screening results from the study demonstrated that genes those were differentially expressed were highly associated with lipid metabolism-related pathways, and patients receiving systemic therapy had significantly different prognoses based on lipid metabolism gene characteristics. The LMRS model, consisting of eight lipid metabolism-related genes, outperformed each lipid metabolism gene-based model in predicting outcome and drug response. Further validation of the LMRS model in HNSCCs confirmed its prognostic value. Conclusion In conclusion, the LMRS polygenic prognostic model is helpful to assess outcome and drug response for HNSCCs and could assist in the timely selection of the appropriate treatment for HNSCC patients. This study provides important insights for improving systemic chemotherapy and enhancing patient outcomes.

Abstract Neuropathy is a feature more frequently observed in pancreatic ductal adenocarcinoma (PDAC) than other tumors. Schwann cells, the most prevalent cell type in peripheral nerves, migrate toward tumor cells and associate with poor prognosis in PDAC. To unveil the effects of Schwann cells on the neuro-stroma niche, here we perform single-cell RNA-sequencing and microarray-based spatial transcriptome analysis of PDAC tissues. Results suggest that Schwann cells may drive tumor cells and cancer-associated fibroblasts (CAFs) to more malignant subtypes: basal-like and inflammatory CAFs (iCAFs), respectively. Moreover, in vitro and in vivo assays demonstrate that Schwann cells enhance the proliferation and migration of PDAC cells via Midkine signaling and promote the switch of CAFs to iCAFs via interleukin-1α. Culture of tumor cells and CAFs with Schwann cells conditioned medium accelerates PDAC progression. Thus, we reveal that Schwann cells induce malignant subtypes of tumor cells and CAFs in the PDAC milieu.

Abstract Pancreatic cancer (PCa) is one of the most fatal human malignancies. The enhanced infiltration of stromal tissue into the PCa tumor microenvironment limits the identification of key tumor‐specific transcription factors and epigenomic abnormalities in malignant epithelial cells. Integrated transcriptome and epigenetic multiomics analyses of the paired PCa organoids indicate that the basic helix‐loop‐helix transcription factor 40 (BHLHE40) is significantly upregulated in tumor samples. Increased chromatin accessibility at the promoter region and enhanced mTOR pathway activity contribute to the elevated expression of BHLHE40. Integrated analysis of chromatin immunoprecipitation‐seq, RNA‐seq, and high‐throughput chromosome conformation capture data, together with chromosome conformation capture assays, indicate that BHLHE40 not only regulates sterol regulatory element‐binding factor 1 (SREBF1) transcription as a classic transcription factor but also links the enhancer and promoter regions of SREBF1. It is found that the BHLHE40‐SREBF1‐stearoyl‐CoA desaturase axis protects PCa cells from ferroptosis, resulting in the reduced accumulation of lipid peroxidation. Moreover, fatostatin, an SREBF1 inhibitor, significantly suppresses the growth of PCa tumors with high expressions of BHLHE40. This study highlights the important roles of BHLHE40‐mediated lipid peroxidation in inducing ferroptosis in PCa cells and provides a novel mechanism underlying SREBF1 overexpression in PCa.

The most common reason for cancer-related death globally is predicted to be pancreatic cancer (PC), one of the deadliest cancers. The CCCTC-binding factor (CTCF) regulates the three-dimensional structure of chromatin, was reported to be highly regulated in various malignancies. However, the underlying biological functions and possible pathways via which CTCF promotes PC progression remain unclear. Herein, we examined the CTCF function in PC and discovered that CTCF expression in PC tissues was significantly raised compared to neighboring healthy tissues. Additionally, Kaplan-Meier survival analysis demonstrated a strong connection between elevated CTCF expression and poor patient prognosis. A study of the ROC curve (receiver operating characteristic) revealed an AUC value for CTCF of 0.968. Subsequent correlation analysis exhibited a strong relationship between immunosuppression and CTCF expression in PC. CTCF knockdown significantly inhibited the malignant biological process of PC in vitro and in vivo, suggesting that CTCF may be a potential PC treatment target. We also identified the FGD5 antisense RNA 1 (FGD5-AS1)/miR-19a-3p axis as a possible upstream mechanism for CTCF overexpression. In conclusion, our data suggest that ceRNA-mediated CTCF overexpression contributes to the suppression of anti-tumor immune responses in PC and could be a predictive biomarker and potential PC treatment target.

Abstract Background circRNA has been established to play a pivotal role in tumorigenesis development in a variety of cancers; nevertheless, the biological functions and molecular mechanisms of hypoxia-induced exosomal circRNAs in pancreatic cancer remain largely unknown. Methods Differentially expressed circRNAs in exosomes between hypoxic exosomes and normoxic exosomes in PC cells were verified by RNA sequencing. The expression of circPDK1 in PC tumors and PC patients was evaluated by qRT-PCR and ISH, and the biological functions of circPDK1 in PC were verified through a series of in vitro and in vivo experiments. Using Western blotting, Co-IP, RNA pull-down, ChIP, RIP, dual-luciferase assays, and rescue experiments, the underlying mechanism of circPDK1 was verified. Results CircPDK1 was highly abundant in PC tumor tissues and serum exosomes and was associated with poor survival. Exosomal circPDK1 significantly promoted PC cell proliferation, migration, and glycolysis both in vitro and in vivo. Mechanistically, circPDK1 could be activated by HIF1A at the transcriptional level and sponges miR-628-3p to activate the BPTF/c-myc axis. In addition, circPDK1 serves as a scaffold that enhances the interaction between UBE2O and BIN1, inducing the UBE2O-mediated degradation of BIN1. Conclusions We found that circPDK1 was activated by HIF1A at the transcriptional level by modulating the miR-628-3p/BPTF axis and degrading BIN1. Exosomal circPDK1 is a promising biomarker for PC diagnosis and prognosis and represents a potential therapeutic target for PC.

Abstract Background Although a substantial increase in the survival of patients with other cancers has been observed in recent decades, pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest diseases. No effective screening approach exists. Methods Differential exosomal long noncoding RNAs (lncRNAs) isolated from the serum of patients with PDAC and healthy individuals were profiled to screen for potential markers in liquid biopsies. The functions of LINC00623 in PDAC cell proliferation, migration and invasion were confirmed through in vivo and in vitro assays. RNA pulldown, RNA immunoprecipitation (RIP) and coimmunoprecipitation (Co-IP) assays and rescue experiments were performed to explore the molecular mechanisms of the LINC00623/NAT10 signaling axis in PDAC progression. Results A novel lncRNA, LINC00623, was identified, and its diagnostic value was confirmed, as it could discriminate patients with PDAC from patients with benign pancreatic neoplasms and healthy individuals. Moreover, LINC00623 was shown to promote the tumorigenicity and migratory capacity of PDAC cells in vitro and in vivo. Mechanistically, LINC00623 bound to N-acetyltransferase 10 (NAT10) and blocked its ubiquitination-dependent degradation by recruiting the deubiquitinase USP39. As a key regulator of N4-acetylcytidine (ac4C) modification of mRNA, NAT10 was demonstrated to maintain the stability of oncogenic mRNAs and promote their translation efficiency through ac4C modification. Conclusions Our data revealed the role of LINC00623/NAT10 signaling axis in PDAC progression, showing that it is a potential biomarker and therapeutic target for PDAC.

Abstract Background Tumor cells exhibited phenotypic and molecular characteristics similar to their lineage progenitor cells. Liver developmental signaling pathways are showed to be associated with HCC development and oncogenesis. The similarities of expression profiling between liver progenitors (LPs) and HCC suggest that understanding the molecular mechanism during liver development could provide insights into HCC. Methods To profile the dynamic gene expression during liver development, cells from an in vitro liver differentiation model and two paired hepatocellular carcinoma (HCC) samples were analyzed using deep RNA sequencing. The expression levels of selected genes were analyzed by qRT-PCR. Moreover, the role of a key transcription factor, pituitary homeobox 2 (PITX2), was characterized via in vitro and vivo functional assays. Furthermore, molecular mechanism studies were performed to unveil how PITX2C regulate the key developmental factors in LPs, thereby increasing the stemness of HCC. Results PITX2 was found to exhibit a similar expression pattern to specific markers of LPs. PITX2 consists of three isoforms (PITX2A/B/C). The expression of PITX2 is associated with tumor size and overall survival rate, whereas only PITX2C expression is associated with AFP and differentiation in clinical patients. PITX2A/B/C has distinct functions in HCC tumorigenicity. PITX2C promotes HCC metastasis, self-renewal and chemoresistance. Molecular mechanism studies showed that PITX2C could up-regulate RALYL which could enhance HCC stemness via the TGF-β pathway. Furthermore, ChIP assays confirmed the role of PITX2C in regulating key developmental factors in LP. Conclusion PITX2C is a newly discovered transcription factor involved in hepatic differentiation and could increase HCC stemness by upregulating key transcriptional factors related to liver development.

Abstract Background LncRNA-PACERR plays critical role in the polarization of tissue-associated macrophages (TAMs). In this study, we found the function and molecular mechanism of PACERR in TAMs to regulate pancreatic ductal adenocarcinoma (PDAC) progression. Methods We used qPCR to analyse the expression of PACERR in TAMs and M1-tissue-resident macrophages (M1-NTRMs) which were isolated from 46 PDAC tissues. The function of PACERR on macrophages polarization and PDAC proliferation, migration and invasion were confirmed through in vivo and in vitro assays. The molecular mechanism of PACERR was discussed via fluorescence in situ hybridization (FISH), RNA pull-down, ChIP-qPCR, RIP-qPCR and luciferase assays. Results LncRNA-PACERR was high expression in TAMs and associated with poor prognosis in PDAC patients. Our finding validated that LncRNA-PACERR increased the number of M2-polarized cells and facilized cell proliferation, invasion and migration in vitro and in vivo. Mechanistically, LncRNA-PACERR activate KLF12/p-AKT/c-myc pathway by binding to miR-671-3p. And LncRNA-PACERR which bound to IGF2BP2 acts as an m6A-dependent manner to enhance the stability of KLF12 and c-myc in cytoplasm. In addition, the promoter of LncRNA-PACERR was a target of KLF12 and LncRNA-PACERR recruited EP300 to increase the acetylation of histone by interacting with KLF12 in nucleus. Conclusions This study found that LncRNA-PACERR functions as key regulator of TAMs in PDAC microenvironment and revealed the novel mechanisms in cytoplasm and in nucleus.

BackgroundSarcoptes scabiei is a permanent obligate ectoparasite that lives and reproduces in the epidermis of humans and other mammals worldwide. There is a lack of information on the molting process of Sarcoptes scabiei. Ivermectin is widely used to treat Sarcoptes infection in humans and animals, while the survival of molting Sarcoptes mites in the presence of ivermectin is unknown. The aim of the present study is to investigate the molting process of Sarcoptes mites and assess the activity of ivermectin during the molting process of Sarcoptes mites.Methodology/principal findingsmolting Sarcoptes mites were incubated at 35°C and 80% relative humidity and observed hourly until complete molt. Of the 192 molting mites recorded, the longest molt periods for larvae and nymphs were 23 and 30 h, respectively. The activity of ivermectin on molting Sarcoptes mites was also assessed using two concentrations of the drug (0.1 and 0.05 mg/ml). The exposure time for molting mites was determined by 100% mortality of female mites exposed to the solution of ivermectin. While all female mites were killed after exposure to 0.1 mg/ml ivermectin for 2 h and and 0.05 mg/ml for 7 h, 32% and 36% of molting mites survived and successfully molted, respectively.Conclusions/significanceThe present study demonstrated that molting Sarcoptes mites are less susceptible to ivermectin than active mites. As a consequence, mites may survive after two doses of ivermectin given 7 days apart due not only to hatching eggs but also to the resistance of mites during their molting process. Our results provide insight into the optimal therapeutic regimens for scabies and highlight the need for further research on the molting process of Sarcoptes mites.

Abstract Background Both autophagy and glycolysis are essential for pancreatic ductal adenocarcinoma (PDAC) survival due to desmoplasia. We investigated whether targeting a hub gene which participates in both processes could be an efficient strategy for PDAC treatment. Methods The expression pattern of glycolysis signatures (GS) and autophagy signatures (AS) and their correlation with cystatin B (CSTB) in PDAC were analysed. It was discovered how CSTB affected the growth, glycolysis, and autophagy of PDAC cells. We assessed competitive binding to cathepsin B (CTSB) between CSTB and cystatin C (CSTC) via immunoprecipitation (IP) and immunofluorescence (IF). Chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP‐qPCR) and luciferase reporter gene assays were used to unveil the mechanism underlying CSTB upregulation. The expression pattern of CSTB was examined in clinical samples and KrasG12D/+, Trp53R172H/+, Pdx1‐Cre (KPC) mice. Results GS and AS were enriched and closely associated in PDAC tissues. CSTB increased autophagic flux and provided substrates for glycolysis. CSTB knockdown attenuated the proliferation of PDAC cells and patient‐derived xenografts. The liquid chromatography‐tandem mass spectrometry assay indicated CSTB interacted with CTSB and contributed to the proteolytic activity of CTSB in lysosomes. IF and IP assays demonstrated that CSTB competed with CSTC to bind to CTSB. Mutation of the key sites of CSTB abolished the interaction between CSTB and CTSB. CSTB was highly expressed in PDAC due to H3K27acetylation and SP1 expression. High expression of CSTB in PDAC was observed in tissue microarray and patients’ serum samples. Conclusions Our work demonstrated the tumorigenic roles of autophagy and glycolysis in PDAC. CSTB is a key role in orchestrating these processes to ensure energy supply of PDAC cells.