Mapping the intellectual structure and landscape of colorectal cancer immunotherapy: A bibliometric analysis.

Immunotherapy, particularly immune checkpoint inhibitor (ICIs) therapy, stands as an innovative therapeutic approach currently garnering substantial attention in cancer treatment. It has become a focal point of numerous studies, showcasing significant potential in treating malignancies, including lung cancer and melanoma. The objective of this research is to analyze publications regarding immunotherapy for colorectal cancer (CRC), investigating their attributes and identifying the current areas of interest and cutting-edge advancements. We took into account the publications from 2002 to 2022 included in the Web of Science Core Collection. Bibliometric analysis and visualization were conducted using CiteSpace, VOSviewer, R-bibliometrix, and Microsoft Excel. The quantity of publications associated with this domain has been steadily rising over the years, encompassing 3753 articles and 1498 reviews originating from 573 countries and regions, involving 19,166 institutions, 1011 journals, and 32,301 authors. In this field, China, the United States, and Italy are the main countries that come forward for publishing. The journal with the greatest impact factor is CA-A Cancer Journal for Clinicians. Romain Cohen leads in the number of publications, while Le Dt stands out as the most influential author. The immune microenvironment and immune infiltration are emerging as key hotspots and future research directions in this domain. This research carries out an extensive bibliometric examination of immunotherapy for colorectal cancer, aiding researchers in understanding current focal points, investigating possible avenues for research, and recognizing forthcoming development trends.

JPT2 Affects Trophoblast Functions and Macrophage Polarization and Metabolism, and Acts as a Potential Therapeutic Target for Recurrent Spontaneous Abortion.

Recurrent spontaneous abortion (RSA) is a pregnancy-related condition with complex etiology. Trophoblast dysfunction and abnormal macrophage polarization and metabolism are associated with RSA; however, the underlying mechanisms remain unknown. Jupiter microtubule-associated homolog 2 (JPT2) is essential for calcium mobilization; however, its role in RSA remains unclear. In this study, it is found that the expression levels of JPT2, a nicotinic acid adenine dinucleotide phosphate-binding protein, are decreased in the villous tissues of patients with RSA and placental tissues of miscarried mice. Mechanistically, it is unexpectedly found that abnormal JPT2 expression regulates trophoblast function and thus involvement in RSA via c-Jun N-terminal kinase (JNK) signaling, but not via calcium mobilization. Specifically, on the one hand, JPT2 deficiency inhibits trophoblast adhesion, migration, and invasion by inhibiting the JNK/atypical chemokine receptor 3 axis. On the other hand, trophoblast JPT2 deficiency contributes to M1 macrophage polarization by promoting the accumulation of citrate and reactive oxygen species via inhibition of the JNK/interleukin-6 axis. Self-complementary adeno-associated virus 9-JPT2 treatment alleviates embryonic resorption in abortion-prone mice. In summary, this study reveals that JPT2 mediates the remodeling of the immune microenvironment at the maternal-fetal interface, suggesting its potential as a therapeutic target for RSA.

FKBP5 regulates trophoblast-macrophage crosstalk in recurrent spontaneous abortion through PI3K/AKT and NF-κB signaling pathways.

FK506-binding protein 5 (FKBP5) contributes to many diseases; However, it remains unclear whether FKBP5 is relevant to recurrent spontaneous abortion (RSA) and the mechanisms by which it is involved in maternal-fetal immunological tolerance. Placental tissue was collected in women with normal pregnancy and RSA and examined for FKBP5 expression. Human trophoblast cell lines and THP-1-derived M0 macrophages were used to explore the role of FKBP5 in RSA and its mechanism. The role of FKBP5 on pregnancy outcomes was assessed using a mouse model of miscarriage. This study found that upregulation of FKBP5 at the placental interface is involved in the pathogenesis of RSA by depressing trophoblast function and promoting M1-type macrophage polarization. First, FKBP5 expression was upregulated in the villi of RSA, and FKBP5 regulated trophoblast function by inhibiting HAPLN1 expression through suppression of PI3K/AKT signaling. In addition, FKBP5 inhibited trophoblast IL-6 secretion by suppressing PI3K/AKT signaling, thereby promoting macrophage polarization toward the M1 phenotype. Meanwhile, FKBP5 was significantly elevated in decidual macrophages from patients with RSA and promoted M1 macrophage polarization via ROS/NF-κB signaling and further inhibited trophoblast function. Finally, FKBP5 inhibitors improved embryo resorption rate in miscarried mice. In conclusion, FKBP5 is essential in maintaining pregnancy and trophoblast-macrophage crosstalk in the maternal-fetal interface, which may be a potential target for diagnosing and treating RSA.

Profilin1 Regulates Trophoblast Invasion and Macrophage Differentiation.

Unexplained recurrent spontaneous abortion (URSA) has been associated with the dysfunction of trophoblasts and decidual macrophages. Current evidence suggests that profilin1 (PFN1) plays an important role in many biological processes. However, little is known about whether PFN1 is related to URSA. Herein, the location of PFN1 was detected by immunohistochemistry, and the level of PFN1 was detected by quantitative real-time PCR, Western blot analysis, and immunohistochemistry. The proliferation of trophoblasts was detected by CCK8 and 5-ethynyl-2'-deoxyuridine assays, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays were used to detect apoptosis of trophoblasts. The migration and invasion ability of trophoblasts was assessed by using the wound-healing test and transwell test. Polarization of macrophages was detected in macrophages cultured in trophoblast conditioned medium. PFN1 expression was observed in cytotrophoblasts, syncytiotrophoblasts, and extravillous trophoblasts and was decreased in the villous tissue of patients with URSA. The migration and invasion ability and cell viability of trophoblastic cell lines that underwent PFN1 knockdown significantly decreased, and apoptosis increased. Opposite findings were observed after the overexpression of PFN1 in trophoblastic cells. In addition, PFN1 could regulate trophoblast function through phosphatidylinositol 3-kinase/AKT signal transduction rather than mitogen-activated protein kinase signaling pathways. Finally, knockdown of PFN1 in trophoblasts promoted tumor necrosis factor-α secretion to induce macrophage polarization to M1 phenotype, mediated by the NF-κB signaling pathway. These findings indicate that PFN1 has a broad therapeutic potential for patients with URSA.

Human genes with relative synonymous codon usage analogous to that of polyomaviruses are involved in the mechanism of polyomavirus nephropathy.

Human polyomaviruses (HPyVs) can cause serious and deleterious infections in human. Yet, the molecular mechanism underlying these infections, particularly in polyomavirus nephropathy (PVAN), is not well-defined. In the present study, we aimed to identify human genes with codon usage bias (CUB) similar to that of HPyV genes and explore their potential involvement in the pathogenesis of PVAN. The relative synonymous codon usage (RSCU) values of genes of HPyVs and those of human genes were computed and used for Pearson correlation analysis. The involvement of the identified correlation genes in PVAN was analyzed by validating their differential expression in publicly available transcriptomics data. Functional enrichment was performed to uncover the role of sets of genes. The RSCU analysis indicated that the A- and T-ending codons are preferentially used in HPyV genes. In total, 5400 human genes were correlated to the HPyV genes. The protein-protein interaction (PPI) network indicated strong interactions between these proteins. Gene expression analysis indicated that 229 of these genes were consistently and differentially expressed between normal kidney tissues and kidney tissues from PVAN patients. Functional enrichment analysis indicated that these genes were involved in biological processes related to transcription and in pathways related to protein ubiquitination pathway, apoptosis, cellular response to stress, inflammation and immune system. The identified genes may serve as diagnostic biomarkers and potential therapeutic targets for HPyV associated diseases, especially PVAN.

Hypoxia-induced polarization of M2 macrophages and C-C motif chemokine ligand 5 secretion promotes the migration and invasion of trophoblasts†.

In the early stage of pregnancy, hypoxia in the placenta is of great significance to the migration and invasion of trophoblasts. In addition, changes to the polarity and activity of macrophages can affect embryo implantation, trophoblast migration and invasion, and vascular remodeling by affecting cytokine secretion. However, the mechanism of the effects of hypoxic conditions in the placenta on trophoblasts remains unknown. We used gene knockdown on macrophages, and drug treatment on trophoblasts, and cultured them under hypoxic and normoxic conditions. The cells were then subjected to wound-healing assays, Transwell cell invasion experiments, quantitative real-time reverse transcription Polymerase Chain Reaction (PCR), western blotting, and immunofluorescence. The polarization of macrophages in each group, the migration and invasion ability of trophoblasts, and changes to the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway were detected. Hypoxic conditions induce M2 polarization of macrophages. The conditioned medium from macrophages under hypoxic conditions increased the migration and invasion of trophoblasts and enhanced the levels of phosphorylated (p)-PI3K and p-AKT in trophoblasts. After C-C motif chemokine ligand 5 knockdown in macrophages, the ability of conditioned medium from macrophages cultured under hypoxic conditions to promote the migration and invasion of trophoblasts was weakened significantly. The use of PI3K/AKT signaling pathway agonists could reverse the attenuation effect caused by C-C motif chemokine ligand 5 knockdown.

Deletion of ACLY Disrupts Histone Acetylation and IL-10 Secretion in Trophoblasts, Which Inhibits M2 Polarization of Macrophages: A Possible Role in Recurrent Spontaneous Abortion.

Changes to macrophage polarization affect the local microenvironment of the placenta, resulting in pathological pregnancy diseases such as recurrent spontaneous abortion (RSA). Macrophages are in close contact with trophoblasts during placental development, and trophoblast-derived cytokines are important regulators of macrophage polarization and function. Histone acetylation can affect the expression and secretion of cytokines, and ATP citrate lyase (ACLY) is an important factor that regulates histone acetylation. The aim of this study was to investigate the effect of ACLY expression differences in trophoblast on macrophage polarization and its mechanism. Our data demonstrate that ACLY level in placental villi of patients with RSA is decreased, which may lead to the inhibition of histone acetylation in trophoblasts, thereby reducing the secretion of IL-10. Reduced IL-10 secretion activates endoplasmic reticulum stress in macrophages, thus inhibiting their M2 polarization.

A regulatory miRNA-mRNA network is associated with transplantation response in acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a life-threatening complication characterized by rapid decline in renal function, which frequently occurs after transplantation surgery. However, the molecular mechanism underlying the development of post-transplant (post-Tx) AKI still remains unknown. An increasing number of studies have demonstrated that certain microRNAs (miRNAs) exert crucial functions in AKI. The present study sought to elucidate the molecular mechanisms in post-Tx AKI by constructing a regulatory miRNA-mRNA network. RESULTS: Based on two datasets (GSE53771 and GSE53769), three key modules, which contained 55 mRNAs, 76 mRNAs, and 151 miRNAs, were identified by performing weighted gene co-expression network analysis (WGCNA). The miRDIP v4.1 was applied to predict the interactions of key module mRNAs and miRNAs, and the miRNA-mRNA pairs with confidence of more than 0.2 were selected to construct a regulatory miRNA-mRNA network by Cytoscape. The miRNA-mRNA network consisted of 82 nodes (48 mRNAs and 34 miRNAs) and 125 edges. Two miRNAs (miR-203a-3p and miR-205-5p) and ERBB4 with higher node degrees compared with other nodes might play a central role in post-Tx AKI. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that this network was mainly involved in kidney-/renal-related functions and PI3K-Akt/HIF-1/Ras/MAPK signaling pathways. CONCLUSION: We constructed a regulatory miRNA-mRNA network to provide novel insights into post-Tx AKI development, which might help discover new biomarkers or therapeutic drugs for enhancing the ability for early prediction and intervention and decreasing mortality rate of AKI after transplantation.

Risk Factors for Delirium in the Palliative Care Population: A Systematic Review and Meta-Analysis.

Objective: Delirium is common and highly distressing for the palliative care population. Until now, no study has systematically reviewed the risk factors of delirium in the palliative care population. Therefore, we performed a systematic review and meta-analysis to evaluate delirium risk factors among individuals receiving palliative care. Methods: We systematically searched PubMed, Medline, Embase, and Cochrane database to identify relevant observational studies from database inception to June 2021. The methodological quality of the eligible studies was assessed by the Newcastle Ottawa Scale. We estimated the pooled adjusted odds ratio (aOR) for individual risk factors using the inverse variance method. Results: Nine studies were included in the review (five prospective cohort studies, three retrospective case-control studies and one retrospective cross-section study). In pooled analyses, older age (aOR: 1.02, 95% CI: 1.01-1.04, I 2 = 37%), male sex (aOR:1.80, 95% CI: 1.37-2.36, I 2 = 7%), hypoxia (aOR: 0.87, 95% CI: 0.77-0.99, I 2 = 0%), dehydration (aOR: 3.22, 95%CI: 1.75-5.94, I 2 = 18%), cachexia (aOR:3.40, 95% CI: 1.69-6.85, I 2 = 0%), opioid use (aOR: 2.49, 95%CI: 1.39-4.44, I 2 = 0%), anticholinergic burden (aOR: 1.18, 95% CI: 1.07-1.30, I 2 = 9%) and Eastern Cooperative Oncology Group Performance Status (aOR: 2.54, 95% CI: 1.56-4.14, I 2 = 21%) were statistically significantly associated with delirium. Conclusion: The risk factors identified in our review can help to highlight the palliative care population at high risk of delirium. Appropriate strategies should be implemented to prevent delirium and improve the quality of palliative care services.

Toll-like receptor 10 (TLR10) exhibits suppressive effects on inflammation of prostate epithelial cells.

Prostate inflammation (PI) is closely related to the development and progression of chronic prostatic diseases: benign prostatic hyperplasia and prostate cancer. Toll-like receptor (TLR) 2 has been reported to be associated with inflammatory diseases, such as infections, autoimmune diseases, and cancers. Meanwhile, TLR10, which can form heterodimers with TLR2, has been considered an orphan receptor without an exact function. The present study therefore aims to examine the effects of TLR2 and TLR10 on PI. Prostate samples and clinical data were obtained from the patients diagnosed with benign prostatic hyperplasia. The inflammatory cell model was established by adding lipopolysaccharide to RWPE-1 cells. Prostate tissues/cells were examined by histological, molecular, and biochemical approaches. Both TLR2 and TLR10 were found to be expressed in prostate tissues and RWPE-1 cells. mRNA/protein expression levels of TLR2 and TLR10 were both positively correlated with prostate tissue inflammatory grades. Lipopolysaccharide-stimulated RWPE-1 cells expressed higher levels of TLR2, TLR10, high mobility group box 1 (HMGB1), phospho-nuclear factor kappa-light-chain-enhancer of activated B-cells P65 (phospho-NF-κB P65), interleukin (IL)-6, and IL-8 than control cells. Moreover, HMGB1, phospho-NF-κB P65, IL-6, and IL-8 were downregulated after TLR2 knockdown and upregulated after TLR10 knockdown in RWPE-1 cells. TLR2 stimulation can activate the inflammatory signaling cascade in prostate epithelial cells. Conversely, TLR10 exhibited suppressive effects on inflammation. With antagonistic functions, both TLR2 and TLR10 were involved in PI. TLR10 could be a novel target in modulating inflammatory signal transduction of prostate epithelial cells.