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Translational Cancer Research May 2024The nectin adhesion molecule CD112, an important component of tumor progression, belongs to the nectin family. However, a comprehensive evaluation of its clinical...
BACKGROUND
The nectin adhesion molecule CD112, an important component of tumor progression, belongs to the nectin family. However, a comprehensive evaluation of its clinical relevance and mechanism in various cancers is yet to be conducted.
METHODS
This investigation fully examined the relationship between prognosis and CD112 expression. We clarified the function of CD112 in tumor immunity by employing The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. This involved examining its connections to tumor mutation burden (TMB), DNA methylation, tumor immune invasion, mismatch repair (MMR), microsatellite instability (MSI), and common immune checkpoint inhibitors (ICIs). Additionally, the impact of CD112 knockdown on cell function was examined in colorectal cancer (CRC) cell lines.
RESULTS
In the current study, we found malignant tissues express high levels of CD112, which was related to TMB, MMR, MSI, and DNA methylation. Survival analysis indicated that patients with high CD112 expression had an unfavorable prognosis more frequently. In addition, CD112 expression was negatively associated with infiltration levels of CD4 positive (CD4) T cells, CD8 positive (CD8) T cells, and T cells. Western blotting and pathway enrichment analysis showed that CD112 is significantly linked to epithelial-to-mesenchymal transition (EMT). Additionally, CRC cells migrate and proliferate less when CD112 was knocked down. CD112 expression was found to be negatively associated with anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) treatment outcomes in patients.
CONCLUSIONS
CD112 may act as a possible prognostic marker in immune therapy and may stimulate tumor growth by upregulating the EMT pathway.
PubMed: 38881943
DOI: 10.21037/tcr-23-2258 -
Scientific Reports Jun 2024The Repeat Expansion Diseases (REDs) arise from the expansion of a disease-specific short tandem repeat (STR). Different REDs differ with respect to the repeat involved,...
The Repeat Expansion Diseases (REDs) arise from the expansion of a disease-specific short tandem repeat (STR). Different REDs differ with respect to the repeat involved, the cells that are most expansion prone and the extent of expansion. Furthermore, whether these diseases share a common expansion mechanism is unclear. To date, expansion has only been studied in a limited number of REDs. Here we report the first studies of the expansion mechanism in induced pluripotent stem cells derived from a patient with a form of the glutaminase deficiency disorder known as Global Developmental Delay, Progressive Ataxia, And Elevated Glutamine (GDPAG; OMIM# 618412) caused by the expansion of a CAG-STR in the 5' UTR of the glutaminase (GLS) gene. We show that alleles with as few as ~ 120 repeats show detectable expansions in culture despite relatively low levels of R-loops formed at this locus. Additionally, using a CRISPR-Cas9 knockout approach we show that PMS2 and MLH3, the constituents of MutLα and MutLγ, the 2 mammalian MutL complexes known to be involved in mismatch repair (MMR), are essential for expansion. Furthermore, PMS1, a component of a less well understood MutL complex, MutLβ, is also important, if not essential, for repeat expansion in these cells. Our results provide insights into the factors important for expansion and lend weight to the idea that, despite some differences, the same mechanism is responsible for expansion in many, if not all, REDs.
Topics: Humans; Glutaminase; Trinucleotide Repeat Expansion; Induced Pluripotent Stem Cells; MutL Proteins; CRISPR-Cas Systems
PubMed: 38877099
DOI: 10.1038/s41598-024-64480-z -
Biomedicine & Pharmacotherapy =... Jul 2024The unresectable or postoperative recurrence of advanced metastatic colorectal cancer (CRC) is the difficulty of its clinical management, and pharmacological therapy is...
The unresectable or postoperative recurrence of advanced metastatic colorectal cancer (CRC) is the difficulty of its clinical management, and pharmacological therapy is the main source of benefit. Immune checkpoint inhibitors are therapeutic options but are effective in approximately 5 % of patients with deficient mismatch repair (MMR)/microsatellite instability CRC and are ineffective in patients with MMR-proficient (pMMR)/microsatellite stable (MSS) CRCs, which may be associated with the tumor microenvironment (TME). Here, we propose a new combination strategy and evaluate the efficacy of rapamycin (Rapa) combined with anti-PD-1 (αPD-1) in CT26 tumor-bearing mice, azoxymethane (AOM)/dextran sodium sulfate (DSS) inflammation-associated CRC mice, CT26-Luc tumor-bearing mice with postoperative recurrence, and CT26 liver metastasis mice. The results revealed that Rapa improved the therapeutic effect of αPD-1 and effectively inhibited colorectal carcinogenesis, postoperative recurrence, and liver metastasis. Mechanistically, Rapa improved the anticancer effect of αPD-1, associated with Rapa reprograming of the immunosuppressive TME. Rapa effectively depleted α-SMA cancer-associated fibroblasts and degraded collagen in the tumor tissue, increasing T lymphocyte infiltration into the tumor tissue. Rapa induced the downregulation of programed cell death 1 ligand 1 (PD-L1) protein and transcript levels in CT26 cells, which may be associated with the inhibition of the mTOR/P70S6K signaling axis. Furthermore, co-culture of tumor cells and CD8 T lymphocytes demonstrated that Rapa-induced PD-L1 downregulation in tumor cells increased spleen-derived CD8 T lymphocyte activation. Therefore, Rapa improves the anti-tumor effect of αPD-1 in CRCs, providing new ideas for its use to improve combinatorial strategies for anti-PD-1 immunotherapy.
Topics: Animals; Tumor Microenvironment; Colorectal Neoplasms; Sirolimus; B7-H1 Antigen; Mice; Cell Line, Tumor; Immune Checkpoint Inhibitors; Mice, Inbred BALB C; Drug Resistance, Neoplasm; Programmed Cell Death 1 Receptor; Male; Humans; Liver Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38876047
DOI: 10.1016/j.biopha.2024.116883 -
Oncology Letters Aug 2024Metadherin (MTDH), initially discovered in primary astrocytes of the human fetus through rapid subtraction hybridization and labeled as astrocyte elevated gene-1,...
Metadherin (MTDH), initially discovered in primary astrocytes of the human fetus through rapid subtraction hybridization and labeled as astrocyte elevated gene-1, represents a widely recognized oncogene present in multiple types of cancers. However, the role of MTDH in different types of cancer remains unclear. To address this, a comprehensive analysis of MTDH across various types of cancers was conducted by utilizing multiple databases such as The Cancer Genome Atlas. The present analysis discovered that MTDH exhibits differential expression in different types of cancer and is associated with important factors including tumor mutational burden and microsatellite instability. These findings highlighted the significance of MTDH in the tumor microenvironment and its involvement in the development of immune cells in specific cancers. Furthermore, the results of the present study indicated that the expression of MTDH is strongly correlated with clinical prognosis, mutations and immune cell infiltration. MTDH could serve as a potential indicator of patient prognosis and potentially play a role in modulating the immune system. Given its potential as a novel immunological checkpoint, MTDH may be a viable target for tumor immunotherapy.
PubMed: 38872862
DOI: 10.3892/ol.2024.14482 -
Archives of Pathology & Laboratory... Jun 2024The College of American Pathologists (CAP) accreditation requirements for clinical laboratory testing help ensure laboratories implement and maintain systems and...
General Applicability of Existing College of American Pathologists Accreditation Requirements to Clinical Implementation of Machine Learning-Based Methods in Molecular Oncology Testing.
CONTEXT.—
The College of American Pathologists (CAP) accreditation requirements for clinical laboratory testing help ensure laboratories implement and maintain systems and processes that are associated with quality. Machine learning (ML)-based models share some features of conventional laboratory testing methods. Accreditation requirements that specifically address clinical laboratories' use of ML remain in the early stages of development.
OBJECTIVE.—
To identify relevant CAP accreditation requirements that may be applied to the clinical adoption of ML-based molecular oncology assays, and to provide examples of current and emerging ML applications in molecular oncology testing.
DESIGN.—
CAP accreditation checklists related to molecular pathology and general laboratory practices (Molecular Pathology, All Common and Laboratory General) were reviewed. Examples of checklist requirements that are generally applicable to validation, revalidation, quality management, infrastructure, and analytical procedures of ML-based molecular oncology assays were summarized. Instances of ML use in molecular oncology testing were assessed from literature review.
RESULTS.—
Components of the general CAP accreditation framework that exist for traditional molecular oncology assay validation and maintenance are also relevant for implementing ML-based tests in a clinical laboratory. Current and emerging applications of ML in molecular oncology testing include DNA methylation profiling for central nervous system tumor classification, variant calling, microsatellite instability testing, mutational signature analysis, and variant prediction from histopathology images.
CONCLUSIONS.—
Currently, much of the ML activity in molecular oncology is within early clinical implementation. Despite specific considerations that apply to the adoption of ML-based methods, existing CAP requirements can serve as general guidelines for the clinical implementation of ML-based assays in molecular oncology testing.
PubMed: 38871357
DOI: 10.5858/arpa.2024-0037-CP -
Hormone and Metabolic Research =... Jun 2024This study attempted to build a prostate cancer (PC) prognostic risk model with mitochondrial feature genes. PC-related MTGs were screened for Cox regression analyses,...
This study attempted to build a prostate cancer (PC) prognostic risk model with mitochondrial feature genes. PC-related MTGs were screened for Cox regression analyses, followed by establishing a prognostic model. Model validity was analyzed via survival analysis and receiver operating characteristic (ROC) curves, and model accuracy was validated in the GEO dataset. Combining risk score with clinical factors, the independence of the risk score was verified by using Cox analysis, followed by generating a nomogram. The Gleason score, microsatellite instability (MSI), immune microenvironment, and tumor mutation burden were analyzed in two risk groups. Finally, the prognostic feature genes were verified through a q-PCR test. Ten PC-associated MTGs were screened, and a prognostic model was built. Survival analysis and ROC curves illustrated that the model was a good predictor for the risk of PC. Cox regression analysis revealed that risk score acted as an independent prognostic factor. The Gleason score and MSI in the high-risk group were substantially higher than in the low-risk group. Levels of ESTIMATE Score, Immune Score, Stromal Score, immune cells, immune function, immune checkpoint, and immunopheno score of partial immune checkpoints in the high-risk group were significantly lower than in the low-risk group. Genes with the highest mutation frequencies in the two groups were SPOP, TTN, and TP53. The q-PCR results of the feature genes were consistent with the gene expression results in the database. The 10-gene model based on MTGs could accurately predict the prognosis of PC patients and their responses to immunotherapy.
PubMed: 38870985
DOI: 10.1055/a-2330-3696 -
Journal of Health, Population, and... Jun 2024This study aimed to conduct a bibliometric analysis of research articles on the relationship between inflammatory bowel disease (IBD) and colorectal cancer (CRC) using...
OBJECTIVE
This study aimed to conduct a bibliometric analysis of research articles on the relationship between inflammatory bowel disease (IBD) and colorectal cancer (CRC) using CiteSpace to summarize the current research status, hotspots, and trends in this field and present the results visually.
METHOD
Research articles on the relationship between IBD and CRC published from 2000 to 2023 and in English were selected from the Web of Science Core Collection (Woscc) database. The articles were downloaded as "full record and references". CiteSpace was used to conduct cooperative, cluster, co-citation, and burst analyses.
RESULTS
The literature search revealed 4244 articles; of which, 5 duplicates were removed, resulting in the inclusion of 4239 articles in this study. The United States of America had the highest number of publications, with Mayo Clinic and Harvard University being the most active institutions, and Bas Oldenburg being the most active author. Collaboration among core authors was inadequate. JA Eaden was the most cited author, and CRC was the most common keyword. Burst analysis indicated that Sun Yat-sen University might be one of the institutions with a large contribution to this research field in the future. Cluster analysis showed that earlier research focused more on microsatellite instability, whereas "gut microbiota" and "oxidative stress" are considered current research hotspots and trends.
CONCLUSION
At present, the primary focus areas of research are "gut microbiota" and "oxidative stress". With the improvement of healthcare policies and standards, regular endoscopic monitoring of patients with IBD has become an indispensable diagnostic and therapeutic practice. More drugs will be developed to reduce the risk of progression from IBD to CRC. The findings of this study provide valuable insights into the relationship between IBD and CRC for researchers in the same field.
Topics: Bibliometrics; Humans; Inflammatory Bowel Diseases; Colorectal Neoplasms; Biomedical Research; Global Health
PubMed: 38867343
DOI: 10.1186/s41043-024-00577-5 -
Annals of Oncology : Official Journal... Jun 2024Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary...
BACKGROUND
Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer. At the first interim analysis, the trial met one of its dual-primary endpoints with statistically significant progression-free survival benefits in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis.
PATIENTS AND METHODS
RUBY is a phase 3, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer who were randomly assigned (1:1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual-primary endpoint.
RESULTS
A total of 494 patients were randomized (245 in dostarlimab arm; 249 in placebo arm). In the overall population, with 51% maturity, RUBY met the dual-primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death (HR = 0.69; 95% CI, 0.54-0.89; P = 0.0020) in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32; 95% CI, 0.17-0.63; nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair proficient/microsatellite stable (MMRp/MSS) population (HR = 0.79; 95% CI, 0.60-1.04; nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis.
CONCLUSIONS
Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful overall survival benefit in the overall population of patients with primary advanced or recurrent endometrial cancer while demonstrating an acceptable safety profile.
PubMed: 38866180
DOI: 10.1016/j.annonc.2024.05.546 -
Aging Jun 2024SMARCD3 has recently been shown to be an important gene affecting cancer, playing an important role in medulloblastoma and pancreatic ductal adenocarcinoma. Therefore,...
BACKGROUND
SMARCD3 has recently been shown to be an important gene affecting cancer, playing an important role in medulloblastoma and pancreatic ductal adenocarcinoma. Therefore, we conducted this research to investigate the potential involvement of SMARCD3 across cancers and to offer recommendations for future studies.
METHODS
Utilizing information on 33 malignancies in the UCSC Xena database, SMARCD3 expression and its prognostic value were assessed. The tumor microenvironment was evaluated with the "CIBERSORT" and "ESTIMATE" algorithms. SMARCD3 and immune-related genes were analyzed using the TISIDB website. The pathways related to the target genes were examined using GSEA. MSI (microsatellite instability), TMB (tumor mutational burden), and immunotherapy analysis were used to evaluate the impact of target genes on the response to immunotherapy.
RESULTS
There is heterogeneity in terms of the expression and prognostic value of SMARCD3 among various cancers, but it is a risk factor for many cancers including uterine corpus endometrial cancer (UCEC), renal clear cell carcinoma (KIRC), and gastric adenocarcinoma (STAD). GSEA revealed that SMARCD3 is related to chromatin remodeling and transcriptional activation, lipid metabolism, and the activities of various immune cells. The TMB and MSI analyses suggested that SMARCD3 affects the immune response efficiency of KIRC, LUAD and STAD. Immunotherapy analysis suggested that SMARCD3 may be a potential immunotherapy target. RT-qPCR demonstrated the variation in SMARCD3 expression in KIRC, LUAD, and STAD.
CONCLUSION
Our study revealed that SMARCD3 affects the prognosis and immunotherapy response of some tumors, providing a direction for further research on this gene.
Topics: Humans; Biomarkers, Tumor; Prognosis; Tumor Microenvironment; Immunotherapy; Neoplasms; Microsatellite Instability; Gene Expression Regulation, Neoplastic; Chromosomal Proteins, Non-Histone
PubMed: 38862250
DOI: 10.18632/aging.205921 -
Discover Oncology Jun 2024CD74 is a non-polymorphic type II transmembrane glycoprotein. It is involved in the regulation of T and B cell development, and dendritic cell (DC) motility. Numerous...
BACKGROUND
CD74 is a non-polymorphic type II transmembrane glycoprotein. It is involved in the regulation of T and B cell development, and dendritic cell (DC) motility. Numerous studies have found that CD74 exerts an essential role in tumor immunity, but the expression profile of CD74 is still not systematically reported, and its value in human pan-cancer analysis is unknown. In this study, we analyzed the expression pattern of CD74 in 33 cancers, and evaluated the significance of CD74 in prognosis prediction and cancer immunity.
METHODS
Pan-cancer dataset from UCSC Xena.We used the Sangerbox website combined with R software' Timer, CIBERSORT method and IOBR package to analyze and plot the data. Survival was assessed using the Kaplan-Meier method and log-rank test for 33 cancer types (p < 0.05). In addition, to explore the relationship between CD74 expression and immune checkpoints, immune cell infiltration, tumor mutational burden (TMB) and microsatellite instability (MSI), Spearman correlation analysis was performed.
RESULTS
This study comprehensively analyzed CD74 expression in 33 different tumor types, revealing that CD74 play an crucial role in cancer formation and development.
CONCLUSIONS
CD74 gene expression in different cancers is associated with immune cell infiltration and immunomodulators and may provide a promising target for survival and immunotherapy. Our study shows that CD74 has an essential role as a biomarker of prognosis during tumor development, which highlights the possibility of new targeted therapies.
PubMed: 38861249
DOI: 10.1007/s12672-024-01081-2