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Journal of Cancer 2024An increasing number of studies have demonstrated that differentially expressed circular RNAs (circRNAs) play critical roles in carcinogenesis. However, the biological...
An increasing number of studies have demonstrated that differentially expressed circular RNAs (circRNAs) play critical roles in carcinogenesis. However, the biological function and clinical significance of hsa_circ_0005927 during gastric carcinogenesis remain unclear. The aim of this study was to investigate the acting mechanism and clinical significance of hsa_circ_0005927 in the invasion and metastasis of gastric cancer (GC). Hsa_circ_0005927 was detected in GC tissues, plasma and gastric juice from patients with GC, and its correlations with clinicopathological parameters were investigated. Receiver operating characteristic curves, Kaplan-Meier survival curves and a prognostic nomogram model were generated to analyze the diagnostic and prognostic value. Real-time cell analyzer, plate colony formation, and Transwell migration and invasion assays were utilized to assess GC cell proliferation, migration and invasion, respectively. Nucleoplasmic separation was applied to determine the distribution of hsa_circ_0005927 in cells. TargetScan and miRanda software were used for target microRNA (miRNA) prediction. Transcriptome sequencing and bioinformatics analysis were performed to annotate the functions of hsa_circ_0005927 in gastric carcinogenesis and metastasis from an RNomic perspective. Key target genes and immune cell infiltrations were analysed. Hsa_circ_0005927 was found downregulated in high-grade intraepithelial neoplasia (HGIEN) tissues and GC tissues. Hsa_circ_0005927 levels in GC tissues were negatively correlated not only with lymphatic metastasis and distal metastasis but also with overall survival and disease-free survival. As a screening biomarker for GC, plasma hsa_circ_0005927 levels significantly increased in the early stages of GC, with a sensitivity and specificity of 52.38% and 76.19%, respectively. Hsa_circ_0005927 was mainly distributed in the cytoplasm, and structurally, it possesses multiple miRNA response elements (MREs) that interact with five miRNAs. A total of 421 downstream target genes of hsa_circ_0005927 were identified by transcriptome sequencing; and bioinformatics analysis suggested that these genes were involved mainly in the negative regulation of the T-cell apoptotic process, the interleukin-27-mediated signaling pathway, growth factor activity, guanylate cyclase activity, transcriptional misregulation in cancer, the cGMP-PKG signaling pathway, and the GnRH signaling pathway during gastric carcinogenesis and metastasis. GUCY1A2 and STK32A are key target genes significantly associated with immune infiltration. Our study revealed that hsa_circ_0005927 is a new player related to the invasion and metastasis of GC and is a potential indicator for early GC screening.
PubMed: 38947400
DOI: 10.7150/jca.96749 -
Journal of Cancer 2024Pancreatic cancer continues to pose a significant threat due to its high mortality rate. While MYB family genes have been identified as oncogenes in certain cancer...
Pancreatic cancer continues to pose a significant threat due to its high mortality rate. While MYB family genes have been identified as oncogenes in certain cancer types, their role in pancreatic cancer remains largely unexplored. The mRNA and protein expression of MYB family genes in pancreatic cancer samples was analyzed using TNMplot, HPA, and TISBID online bioinformatics tools, sourced from the TCGA and GETx databases. The relationship between MYB family gene expression and survival time was assessed through Kaplan-Meier analysis, while the prognostic impact of MYB family gene expression was evaluated using the Cox proportional hazards model. Additionally, Spearman's correlation analysis was employed to investigate the correlation between MYB family genes and TMB/MSI. The integration of data from various databases demonstrated that all MYB family genes exhibited dysregulated expression in pancreatic cancer. However, only the expression of the MYBL2 gene displayed a notable association with the grade and stage of pancreatic cancer. Furthermore, the MYBL2 gene exhibited significant variations in both univariate and multivariate factor analyses.Subsequent functional analyses revealed a significant correlation between MYBL2 expression in pancreatic cancers and various biological processes, such as DNA replication, tumor proliferation, G2M checkpoint regulation, pyrimidine metabolism, and the P53 pathway. Additionally, a notable positive association was observed between MYBL2 expression and tumor mutational burden (TMB), a predictive indicator for response to PD1 antibody treatment. MYBL2 may be a double marker for independent diagnosis and PD1 antibody response prediction of pancreatic cancer patients.
PubMed: 38947375
DOI: 10.7150/jca.96320 -
Frontiers in Immunology 2024The Suppressor of Cytokine Signaling (SOCS) family proteins are important negative regulators of cytokine signaling. SOCS1 is the prototypical member of the SOCS family... (Review)
Review
The Suppressor of Cytokine Signaling (SOCS) family proteins are important negative regulators of cytokine signaling. SOCS1 is the prototypical member of the SOCS family and functions in a classic negative-feedback loop to inhibit signaling in response to interferon, interleukin-12 and interleukin-2 family cytokines. These cytokines have a critical role in orchestrating our immune defence against viral pathogens and cancer. The ability of SOCS1 to limit cytokine signaling positions it as an important immune checkpoint, as evidenced by the detection of detrimental variants in patients with cytokine-driven inflammatory and autoimmune disease. SOCS1 has also emerged as a key checkpoint that restricts anti-tumor immunity, playing both a tumor intrinsic role and impacting the ability of various immune cells to mount an effective anti-tumor response. In this review, we describe the mechanism of SOCS1 action, focusing on the role of SOCS1 in autoimmunity and cancer, and discuss the potential for new SOCS1-directed cancer therapies that could be used to enhance adoptive immunotherapy and immune checkpoint blockade.
Topics: Humans; Suppressor of Cytokine Signaling 1 Protein; Neoplasms; Homeostasis; Inflammation; Animals; Signal Transduction; Autoimmunity; Cytokines
PubMed: 38947335
DOI: 10.3389/fimmu.2024.1419951 -
Frontiers in Immunology 2024C-reactive protein (CRP) is a plasma protein that is evolutionarily conserved, found in both vertebrates and many invertebrates. It is a member of the pentraxin... (Review)
Review
C-reactive protein (CRP) is a plasma protein that is evolutionarily conserved, found in both vertebrates and many invertebrates. It is a member of the pentraxin superfamily, characterized by its pentameric structure and calcium-dependent binding to ligands like phosphocholine (PC). In humans and various other species, the plasma concentration of this protein is markedly elevated during inflammatory conditions, establishing it as a prototypical acute phase protein that plays a role in innate immune responses. This feature can also be used clinically to evaluate the severity of inflammation in the organism. Human CRP (huCRP) can exhibit contrasting biological functions due to conformational transitions, while CRP in various species retains conserved protective functions . The focus of this review will be on the structural traits of CRP, the regulation of its expression, activate complement, and its function in related diseases .
Topics: Humans; C-Reactive Protein; Animals; Inflammation; Immunity, Innate; Protein Conformation; Structure-Activity Relationship; Complement Activation
PubMed: 38947332
DOI: 10.3389/fimmu.2024.1425168 -
Frontiers in Immunology 2024Red blood cells (RBCs), also known as erythrocytes, are underestimated in their role in the immune system. In mammals, erythrocytes undergo maturation that involves the...
Erythrocytes of the common carp are immune sentinels that sense pathogen molecular patterns, engulf particles and secrete pro-inflammatory cytokines against bacterial infection.
INTRODUCTION
Red blood cells (RBCs), also known as erythrocytes, are underestimated in their role in the immune system. In mammals, erythrocytes undergo maturation that involves the loss of nuclei, resulting in limited transcription and protein synthesis capabilities. However, the nucleated nature of non-mammalian RBCs is challenging this conventional understanding of RBCs. Notably, in bony fishes, research indicates that RBCs are not only susceptible to pathogen attacks but express immune receptors and effector molecules. However, given the abundance of RBCs and their interaction with every physiological system, we postulate that they act in surveillance as sentinels, rapid responders, and messengers.
METHODS
We performed a series of experiments with RBCs exposed to , as well as laboratory infections using different concentrations of bacteria.
RESULTS
qPCR revealed that RBCs express genes of several inflammatory cytokines. Using cyprinid-specific antibodies, we confirmed that RBCs secreted tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ). In contrast to these indirect immune mechanisms, we observed that RBCs produce reactive oxygen species and, through transmission electron and confocal microscopy, that RBCs can engulf particles. Finally, RBCs expressed and upregulated several putative toll-like receptors, including and , in response to infection .
DISCUSSION
Overall, the RBC repertoire of pattern recognition receptors, their secretion of effector molecules, and their swift response make them immune sentinels capable of rapidly detecting and signaling the presence of foreign pathogens. By studying the interaction between a bacterium and erythrocytes, we provide novel insights into how the latter may contribute to overall innate and adaptive immune responses of teleost fishes.
Topics: Animals; Carps; Erythrocytes; Cytokines; Aeromonas hydrophila; Gram-Negative Bacterial Infections; Fish Diseases; Phagocytosis; Pathogen-Associated Molecular Pattern Molecules; Immunity, Innate
PubMed: 38947329
DOI: 10.3389/fimmu.2024.1407237 -
Frontiers in Immunology 2024Epithelioid hemangioendothelioma is a rare vascular malignancy, and currently, there is no standard treatment regimen for this disease and existing treatment options...
Epithelioid hemangioendothelioma is a rare vascular malignancy, and currently, there is no standard treatment regimen for this disease and existing treatment options have limited efficacy. In this case report, we present a patient with lung and lymph node metastases from prostate epithelioid hemangioendothelioma who achieved a significant partial response. This was accomplished through alternating nivolumab therapy with ipilimumab and liposomal doxorubicin, resulting in a progression-free-survival more than 6 months to date. The treatment was well-tolerated throughout. Our report suggests that dual immunotherapy alternating with anti-PD-1antibody plus doxorubicin may be a potential treatment modality for epithelioid hemangioendothelioma. However, larger sample studies are necessary to ascertain the effectiveness of this treatment strategy and it is essential to continue monitoring this patient to sustain progression-free survival and overall survival.
Topics: Humans; Male; Doxorubicin; Hemangioendothelioma, Epithelioid; Nivolumab; Prostatic Neoplasms; Programmed Cell Death 1 Receptor; Antineoplastic Combined Chemotherapy Protocols; Immunotherapy; Immune Checkpoint Inhibitors; Ipilimumab; Treatment Outcome; Polyethylene Glycols; Middle Aged
PubMed: 38947327
DOI: 10.3389/fimmu.2024.1384111 -
Frontiers in Immunology 2024Despite advances in surgical and therapeutic approaches, high-grade serous ovarian carcinoma (HGSOC) prognosis remains poor. Surgery is an indispensable component of...
Despite advances in surgical and therapeutic approaches, high-grade serous ovarian carcinoma (HGSOC) prognosis remains poor. Surgery is an indispensable component of therapeutic protocols, as removal of all visible tumor lesions (cytoreduction) profoundly improves the overall survival. Enhanced predictive tools for assessing cytoreduction are essential to optimize therapeutic precision. Patients' immune status broadly reflects the tumor cell biological behavior and the patient responses to disease and treatment. Serum cytokine profiling is a sensitive measure of immune adaption and deviation, yet its integration into treatment paradigms is underexplored. This study is part of the IMPACT trial (NCT03378297) and aimed to characterize immune responses before and during primary treatment for HGSOC to identify biomarkers for treatment selection and prognosis. Longitudinal serum samples from 22 patients were collected from diagnosis until response evaluation. Patients underwent primary cytoreductive surgery or neoadjuvant chemotherapy (NACT) based on laparoscopy scoring. Twenty-seven serum cytokines analyzed by Bio-Plex 200, revealed two immune phenotypes at diagnosis: Immune High with marked higher serum cytokine levels than Immune Low. The immune phenotypes reflected the laparoscopy scoring and allocation to surgical treatment. The five Immune High patients undergoing primary cytoreductive surgery exhibited immune mobilization and extended progression-free survival, compared to the Immune Low patients undergoing the same treatment. Both laparoscopy and cytoreductive surgery induced substantial and transient changes in serum cytokines, with upregulation of the inflammatory cytokine IL-6 and downregulation of the multifunctional cytokines IP-10, Eotaxin, IL-4, and IL-7. Over the study period, cytokine levels uniformly decreased in all patients, leading to the elimination of the initial immune phenotypes regardless of treatment choice. This study reveals distinct pre-treatment immune phenotypes in HGSOC patients that might be informative for treatment stratification and prognosis. This potential novel biomarker holds promise as a foundation for improved assessment of treatment responses in patients with HGSOC. ClinicalTrials.gov Identifier: NCT03378297.
Topics: Humans; Female; Ovarian Neoplasms; Cystadenocarcinoma, Serous; Cytokines; Middle Aged; Aged; Neoadjuvant Therapy; Phenotype; Cytoreduction Surgical Procedures; Biomarkers, Tumor; Neoplasm Grading; Prognosis; Treatment Outcome; Adult
PubMed: 38947323
DOI: 10.3389/fimmu.2024.1394497 -
Frontiers in Immunology 2024Interleukin-17 (IL-17) family cytokines promote protective inflammation for pathogen resistance, but also facilitate autoimmunity and tumor development. A direct signal...
BACKGROUND
Interleukin-17 (IL-17) family cytokines promote protective inflammation for pathogen resistance, but also facilitate autoimmunity and tumor development. A direct signal of IL-17 to regulatory T cells (Tregs) has not been reported and may help explain these dichotomous responses.
METHODS
We generated a conditional knockout of in Tregs by crossing mice to mice ( mice). Subsequently, we adoptively transferred bone marrow cells from mice to a mouse model of sporadic colorectal cancer ( / ), to selectively ablate IL-17 direct signaling on Tregs in colorectal cancer. Single cell RNA sequencing and bulk RNA sequencing were performed on purified Tregs from mouse colorectal tumors, and compared to those of human tumor infiltrating Treg cells.
RESULTS
IL-17 Receptor A (IL-17RA) is expressed in Tregs that reside in mouse mesenteric lymph nodes and colon tumors. Ablation of IL-17RA, specifically in Tregs, resulted in increased Th17 cells, and exacerbated tumor development. Mechanistically, tumor-infiltrating Tregs exhibit a unique gene signature that is linked to their activation, maturation, and suppression function, and this signature is in part supported by the direct signaling of IL-17 to Tregs. To study pathways of Treg programming, we found that loss of IL-17RA in tumor Tregs resulted in reduced RNA splicing, and downregulation of several RNA binding proteins that are known to regulate alternative splicing and promote Treg function.
CONCLUSION
IL-17 directly signals to Tregs and promotes their maturation and function. This signaling pathway constitutes a negative feedback loop that controls cancer-promoting inflammation in CRC.
Topics: Animals; T-Lymphocytes, Regulatory; Interleukin-17; Mice; Mice, Knockout; Humans; Receptors, Interleukin-17; Colorectal Neoplasms; Lymphocytes, Tumor-Infiltrating; Th17 Cells; Mice, Inbred C57BL; Signal Transduction; Disease Models, Animal
PubMed: 38947320
DOI: 10.3389/fimmu.2024.1408710 -
World Journal of Gastroenterology Jun 2024Remarkable progress over the last decade has equipped clinicians with many options in the treatment of inflammatory bowel disease. Clinicians now have the unique... (Review)
Review
BACKGROUND
Remarkable progress over the last decade has equipped clinicians with many options in the treatment of inflammatory bowel disease. Clinicians now have the unique opportunity to provide individualized treatment that can achieve and sustain remission in many patients. However, issues of primary non-response (PNR) and secondary loss of response (SLOR) to non-tumour necrosis factor inhibitor (TNFi) therapies remains a common problem. Specific issues include the choice of optimization of therapy, identifying when dose optimization will recapture response, establishing optimal dose for escalation and when to switch therapy.
AIM
To explores the issues of PNR and SLOR to non-TNFi therapies.
METHODS
This review explores the current evidence and literature to elucidate management options in cases of PNR/SLOR. It will also explore potential predictors for response following SLOR/PNR to therapies including the role of therapeutic drug monitoring (TDM).
RESULTS
In the setting of PNR and loss of response to alpha-beta7-integrin inhibitors and interleukin (IL)-12 and IL-23 inhibitors dose optimization is a reasonable option to capture response. For Janus kinase inhibitors dose optimization can be utilized to recapture response with loss of response.
CONCLUSION
The role of TDM in the setting of advanced non-TNFi therapies to identify patients who require dose optimization and as a predictor for clinical remission is not yet established and this remains an area that should be addressed in the future.
Topics: Humans; Inflammatory Bowel Diseases; Drug Monitoring; Gastrointestinal Agents; Janus Kinase Inhibitors; Treatment Failure; Remission Induction; Treatment Outcome; Drug Substitution
PubMed: 38947290
DOI: 10.3748/wjg.v30.i22.2902 -
MedRxiv : the Preprint Server For... Jun 2024Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors but can also often lead to immune-related adverse...
INTRODUCTION
Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors but can also often lead to immune-related adverse events (irAEs). Predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Using data from 1,327 patients with lung cancer treated with ICIs between 2009 and 2022 at four academic medical centers, we evaluated the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs.
METHODS
Using Cox proportional hazards model, we assessed the association between a polygenic risk score for autoimmune disease (PRS ) and cessation of ICI therapy due to irAEs. All models were adjusted for age at diagnosis, sex, lung cancer histology, type of therapy, recruiting center, and the first 5 principal components. To further understand the differential effects of type of therapy and disease stage on the association between PRS and cessation of ICI due to irAEs, we conducted stratified logistic regression analysis by type of ICI therapy and disease stage.
RESULTS
We found an association between PRS and ICI cessation due to irAEs (HR per SD = 1.18, 95% CI = 1.02 - 1.37, P = 0.03). This association was particularly strong in patients who had ICI cessation due to irAEs within three months of therapy initiation (HR per SD = 1.38, 95% CI = 1.08 - 1.78, P = 0.01). Individuals in the top 20th percentile of PRS had 7.2% ICI discontinuation for irAEs by three months, compared to 3.9% discontinuation by three months among patients in the bottom 80th percentile (log-rank P = 0.02). In addition, among patients who received combination PD-1/PD-L1 and CTLA-4 inhibitor therapy, PRS had an OR per SD of 1.86 (95% CI = 1.08 - 3.51, P = 0.04).
CONCLUSIONS
We demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs, particularly among patients treated with combination ICI therapy. Our results suggest that germline genetics may be used as an adjunctive tool for risk stratification around ICI clinical decision-making in solid tumor oncology.
PubMed: 38947092
DOI: 10.1101/2024.06.10.24308518