-
Scientific Reports Jun 2024Gallbladder cancer (GBC) is a rare but very aggressive most common digestive tract cancer with a high mortality rate due to delayed diagnosis at the advanced stage....
Gallbladder cancer (GBC) is a rare but very aggressive most common digestive tract cancer with a high mortality rate due to delayed diagnosis at the advanced stage. Moreover, GBC progression shows asymptomatic characteristics making it impossible to detect at an early stage. In these circumstances, conventional therapy like surgery, chemotherapy, and radiotherapy becomes refractive. However, few studies reported some molecular markers like KRAS (Kirsten Rat Sarcoma) mutation, upregulation of HER2/neu, EGFR (Epidermal Growth Factor Receptor), and microRNAs in GBC. However, the absence of some specific early diagnostic and prognostic markers is the biggest hurdle for the therapy of GBC to date. The present study has been designed to identify some specific molecular markers for precise diagnosis, and prognosis, for successful treatment of the GBC. By In Silico a network-centric analysis of two microarray datasets; (GSE202479) and (GSE13222) from the Gene Expression Omnibus (GEO) database, shows 50 differentially expressed genes (DEGs) associated with GBC. Further network analysis revealed that 12 genes are highly interconnected based on the highest MCODE (Molecular Complex Detection) value, among all three genes; TRIP13 (Thyroid Receptor Interacting Protein), NEK2 (Never in Mitosis gene-A related Kinase 2), and TPX2 (Targeting Protein for Xklp2) having highest network interaction with transcription factors and miRNA suggesting critically associated with GBC. Further survival analysis data corroborate the association of these genes; TRIP13, NEK2, and TPX2 with GBC. Thus, TRIP13, NEK2, and TPX2 genes are significantly correlated with a greater risk of mortality, transforming them from mere biomarkers of the GBC for early detections and may emerge as prognostic markers for treatment.
Topics: Gallbladder Neoplasms; Humans; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; NIMA-Related Kinases; Computer Simulation; Microtubule-Associated Proteins; Cell Cycle Proteins; Gene Regulatory Networks; Gene Expression Profiling; Prognosis; Carcinogenesis; Nuclear Proteins
PubMed: 38914609
DOI: 10.1038/s41598-024-61762-4 -
Discover Oncology Jun 2024Hepatocellular carcinoma (HCC) is the most common form of liver cancer globally and remains a major cause of cancer-related deaths. HCC exhibits significant...
INTRODUCTION
Hepatocellular carcinoma (HCC) is the most common form of liver cancer globally and remains a major cause of cancer-related deaths. HCC exhibits significant intra-tumoral and interpatient heterogeneity, impacting treatment efficacy and patient prognosis.
METHODS
We acquired transcriptome data from the TCGA and ICGC databases, as well as liver cancer chip data from the GEO database, and processed the data for subsequent analysis. We also obtained single cell data from the GEO database and performed data analysis using the Seurat package. To further investigate epithelial cell subgroups and their copy number variations, we used the Seurat workflow for subgroup classification and the InferCNV software for CNV analysis, utilizing endothelial cells as a reference. Pseudo-time analysis and transcription factor analysis of epithelial cells were performed using the monocle2 and SCENIC software, respectively. To assess intercellular communication, we employed the CellChat package to identify potential ligand-receptor interactions. We also analyzed gene expression differences and conducted enrichment analysis using the limma and clusterProfiler packages. Additionally, we established tumor-related risk characteristics using Cox analysis and Lasso regression, and predicted immunotherapy response using various datasets.
RESULTS
The samples were classified into 23 clusters, with malignant epithelial cells being the majority. Trajectory analysis revealed the differentiation states of the malignant epithelial cells, with cluster 1 being in the terminal state. Functional analysis revealed higher aggressiveness and epithelial-mesenchymal transition (EMT) scores in cluster 1, indicating a higher propensity for metastasis. RBP4+ tumor cells were highly enriched with hypoxia process and intensive cell-to-cell communication. A prognostic model was established, and immune infiltration analysis showed increased infiltration in the high-risk group. TP53 demonstrated significant differences in mutation rate between the two risk groups. Validation analysis confirmed the up-regulation of model genes, including AKR1B10, ARL6IP4, ATP6V0B, and BSG in tumor tissues.
CONCLUSION
A prognostic model was established based on HCC malignant cell associated gene signature, displaying decent prognosis guiding effectiveness in the multiple cohorts. The study provided comprehensive insights into the heterogeneity and potential therapeutic targets of LIHC.
PubMed: 38913193
DOI: 10.1007/s12672-024-01115-9 -
Annals of Translational Medicine Jun 2024The somatic mutation of fms-like tyrosine kinase 3 () in acute myeloid leukemia (AML) is associated with increased risk of relapse and lower survival rates. FLT3i as...
BACKGROUND
The somatic mutation of fms-like tyrosine kinase 3 () in acute myeloid leukemia (AML) is associated with increased risk of relapse and lower survival rates. FLT3i as maintenance after allogeneic hematopoietic stem cell transplant (allo-HSCT) are under study to prevent disease relapse, but real-world data are lacking.
METHODS
We performed a single center, retrospective cohort study and analyzed patients who had -mutated AML and underwent allogeneic-HSCT between January 2011 to June 2022 at the University of Chicago. We identified 23 patients who received FLT3i maintenance therapy post-allo-HSCT and compared their outcomes against 57 patients who did not. Primary outcome was disease-free survival (DFS). Secondary outcomes include overall survival (OS) and relapse rate.
RESULTS
FLT3i maintenance therapy was started at a median 59 days (range, 29-216 days) after allo-HSCT with median duration of 287 days (range, 15-1,194 days). Maintenance therapy was well tolerated. Overall, the improvement in DFS rates for patients after they were placed on FLT3i maintenance therapy was not significant [hazard ratio (HR) for relapse or death =0.65, 95% confidence interval (CI): 0.32-1.31, P=0.23]. However, when adjusted for the conditioning regimen and donor status, the differences were statistically significant with improvement in DFS and OS for patients on FLT3i maintenance (HR for OS =0.42, 95% CI: 0.18-0.95, P=0.04).
CONCLUSIONS
When adjusting for conditioning regimen and donor status, there was a significant improvement in DFS and OS for patients who received FLT3i maintenance therapy compared to those who did not. Randomized prospective studies may provide more insight.
PubMed: 38911560
DOI: 10.21037/atm-23-1941 -
Blood Science (Baltimore, Md.) Jul 2024Ivosidenib, an isocitrate dehydrogenase 1 () inhibitor, has demonstrated clinical benefits in a pivotal study (AG120-C-001) in patients with -mutated (m) acute myeloid...
Ivosidenib, an isocitrate dehydrogenase 1 () inhibitor, has demonstrated clinical benefits in a pivotal study (AG120-C-001) in patients with -mutated (m) acute myeloid leukemia (AML). A registry study (CS3010-101: NCT04176393) was conducted to assess the pharmacokinetic (PK) characteristics, safety, and efficacy of ivosidenib in Chinese patients with relapsed or refractory (R/R) m AML. Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression. Ten subjects underwent intensive PK/progressive disease (PD) assessments. All subjects had the clinical response assessed at screening, every 28 days through month 12, and then every 56 days. Between November 12, 2019, and April 2, 2021, 30 patients were enrolled; 26 (86.7%) had de novo AML and 18 (60.0%) were transfusion-dependent at baseline. Following single and repeated doses of ivosidenib, median time to maximum plasma concentration ( ) was 4.0 and 2.0 hours, respectively. The inter-individual variability of pharmacokinetic exposure was moderate to high (coefficient of variation [CV], 25%-53%). No obvious accumulation was observed after repeated doses at cycle 2 day 1. Regarding the clinical response, the CR + CRh rate was 36.7% (95% confidence interval [CI]: 19.9%-56.1%), the median duration of CR + CRh was 19.7 months (95% CI: 2.9 months-not reached [NR]), and median duration of response (DoR) was 14.3 months (95% CI: 6.4 months-NR). Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months, as compared with primary data cutoff, and the data from Chinese R/R m AML patients were also consistent with results from pivotal study.
PubMed: 38911469
DOI: 10.1097/BS9.0000000000000196 -
Evolutionary Applications Jun 2024There are two primary measures of the amount of genetic variation in a population at a locus: heterozygosity and the number of alleles. Effective population size ( )...
There are two primary measures of the amount of genetic variation in a population at a locus: heterozygosity and the number of alleles. Effective population size ( ) provides both an expectation of the amount of heterozygosity in a population at drift-mutation equilibrium and the rate of loss of heterozygosity because of genetic drift. In contrast, the number of alleles in a population at drift-mutation equilibrium is a function of both and census size ( ). In addition, populations with the same can lose allelic variation at very different rates. Allelic variation is generally much more sensitive to bottlenecks than heterozygosity. Expressions used to adjust for the effects of violations of the ideal population on do not provide good predictions of the loss of allelic variation. These effects are much greater for loci with many alleles, which are often important for adaptation. We show that there is a linear relationship between the reduction of and the corresponding reduction of the expected number of alleles at drift-mutation equilibrium. This makes it possible to predict the expected effect of a bottleneck on allelic variation. Heterozygosity provides good estimates of the rate of adaptive change in the short-term, but allelic variation provides important information about long-term adaptive change. The guideline of long-term being greater than 500 is often used as a primary genetic metric for evaluating conservation status. We recommend that this guideline be expanded to take into account allelic variation as well as heterozygosity.
PubMed: 38911263
DOI: 10.1111/eva.13733 -
Journal For Immunotherapy of Cancer Jun 2024Previous studies have suggested the potential synergistic antitumor activity when combining immune checkpoint inhibitors with anti-angiogenic agents in various solid...
BACKGROUND
Previous studies have suggested the potential synergistic antitumor activity when combining immune checkpoint inhibitors with anti-angiogenic agents in various solid tumors. We aimed to assess the efficacy and safety of camrelizumab (a humanized programmed cell death-1 antibody) plus apatinib (a vascular endothelial growth factor receptor tyrosine kinase inhibitor) for patients with advanced mucosal melanoma (MM), and explore-related biomarkers.
METHODS
We conducted a single-center, open-label, single-arm, phase II study. Patients with unresectable or recurrent/metastatic MM received camrelizumab and apatinib. The primary endpoint was the confirmed objective response rate (ORR).
RESULTS
Between April 2019 and June 2022, 32 patients were enrolled, with 50.0% previously received systemic therapy. Among 28 patients with evaluable response, the confirmed ORR was 42.9%, the disease control rate was 82.1%, and the median progression-free survival (PFS) was 8.05 months. The confirmed ORR was 42.9% (6/14) in both treatment-naïve and previously treated patients. Notably, treatment-naïve patients had a median PFS of 11.89 months, and those with prior treatment had a median PFS of 6.47 months. Grade 3 treatment-related adverse events were transaminase elevation, rash, hyperbilirubinemia, proteinuria, hypertension, thrombocytopenia, hand-foot syndrome and diarrhea. No treatment-related deaths were observed. Higher tumor mutation burden (TMB), increased T-cell receptor (TCR) diversity, and altered receptor tyrosine kinase (RTK)/RAS pathway correlated with better tumor response.
CONCLUSION
Camrelizumab plus apatinib provided promising antitumor activity with acceptable toxicity in patients with advanced MM. TMB, TCR diversity and RTK/RAS pathway genes were identified as potential predictive biomarkers and warrant further validation.
TRIAL REGISTRATION NUMBER
Chinese Clinical Trial Registry, ChiCTR1900023277.
Topics: Humans; Male; Female; Melanoma; Pyridines; Middle Aged; Antibodies, Monoclonal, Humanized; Aged; Adult; Antineoplastic Combined Chemotherapy Protocols; Mucous Membrane
PubMed: 38908858
DOI: 10.1136/jitc-2023-008611 -
International Immunopharmacology Jun 2024Severe combined immunodeficiency (SCID) is the most fatal form of inherited primary immunodeficiency disease. Known molecular defect mutations occur in most children...
BACKGROUND
Severe combined immunodeficiency (SCID) is the most fatal form of inherited primary immunodeficiency disease. Known molecular defect mutations occur in most children with SCID.
METHODS
Herein, we report Adenosine Deaminase-SCID (ADA-SCID) using whole-exome sequencing (WES), explore exome mutational landscape and significance for 17 SCID samples, and verify the mutated exon genes using the Gene Expression Omnibus (GEO) datasets. A total of 250 patients, who were hospitalized at the Neonatal Intensive Care Unit (NICU) of The Seventh Medical Center of the PLA General Hospital for 3 years (from 2017 to 2020), were screened for SCID. We collected mutated genes from the WES data of 17 SCID children. GSE609 and GSE99176 cohorts were used to identify the expressions of mutated exon genes and molecular features in SCID. Gene set variation analyses (GSVA) and correlation analyses were performed.
RESULTS
The detection rate with approximately 6.8 % (17/250) of SCID is high in the NICU. A total of 16 genes were identified among 17 SCID samples, of which the Top 2 genes (MUC6 and RP11-683L23.1) might be crucial in the progression of SCID with 94 % mutation frequency. Furthermore, CNN2 and SCGB1C1 had significant co-mutations and may cooperate to affect SCID development. Importantly, the phylogenetic tree classification results of 17 SCID samples are more correlated to MUC6 with the most significant mutations. Expression profiles of seven mutated genes and five mutated genes were documented in GSE609 and GSE99176 cohorts based on microarray, respectively. Several immune-related pathways were significantly enriched, and Foxd4, differing from the other four mutated genes, was inversely correlated with the GSVA-enriched pathway.
CONCLUSION
Due to its high detection rate (6.8%) and fatality rate (100%), the inclusion of SCID in newborn screening (NBS) is urgent for children in China. The WES successfully identified several common exonic variants (e.g., MUC6) and depicted the feature of mutations and evolution, which will help develop new diagnostic methods for SCID.
PubMed: 38908084
DOI: 10.1016/j.intimp.2024.112402 -
Medicine Jun 2024Breast invasive carcinoma (BRCA) is one of the most common cancers in women, with its malignant progression significantly influenced by intracellular fatty acid (FA)...
Breast invasive carcinoma (BRCA) is one of the most common cancers in women, with its malignant progression significantly influenced by intracellular fatty acid (FA) desaturation. Stearoyl-coenzyme A desaturase (SCD) and fatty acid desaturase 2 (FADS2) are two key rate-limiting enzymes that catalyze the FA desaturation process and cooperate to accelerate lipid metabolic activities. In this study, we investigated the potential functions of SCD and FADS2 in BRCA using bioinformatic analysis and experimental validation. The gene expression profiling interactive analysis database showed that the expression of SCD or FADS2 genes was positively linked to worse overall survival and disease-free survival in the Cancer Genome Atlas database-BRCA. The University of Alabama at Birmingham cancer data analysis portal database indicates that the expression and methylation levels of SCD or FADS2 are associated with various clinicopathological factors in patients with BRCA. Moreover, the tumor immune estimation resource and TISCH databases showed a significant positive correlation between the expression of SCD and the abundance of CD8+ T cells and macrophage cell infiltration, while the expression of FADS2 was positively correlated with the abundance of B cells. Meanwhile, SCD or FADS2 had a higher expression in monocytes/macrophages analyzed the BRCA_GSE143423 and BRCA_GSE114727_inDrop datasets. Mechanistically, the Search Tool for the Retrieval of Distant Genes and CancerSEA databases showed that SCD and FADS2 were upregulated in several cell biology signaling pathways, particularly in inflammation, apoptosis, and DNA repair. Finally, SCD or FADS2 knockdown inhibited the proliferation of MCF-7 and MDA-MB-231 cells. In summary, SCD and FADS2 play significant roles in BRCA development, suggesting that they may serve as potential therapeutic targets for BRCA treatment.
Topics: Humans; Fatty Acid Desaturases; Breast Neoplasms; Female; Tumor Microenvironment; Prognosis; Stearoyl-CoA Desaturase; Mutation; Gene Expression Regulation, Neoplastic
PubMed: 38905386
DOI: 10.1097/MD.0000000000038597 -
Frontiers in Endocrinology 2024Thyroid cancer rarely occurs in children and adolescents. Molecular markers such as , , and have been widely used in adult PTC. It is currently unclear whether these...
OBJECTIVES
Thyroid cancer rarely occurs in children and adolescents. Molecular markers such as , , and have been widely used in adult PTC. It is currently unclear whether these molecular markers have equivalent potential for application in pediatric patients. This study aims to explore the potential utility of a multi-gene conjoint analysis based on next-generation targeted sequencing for pediatric papillary thyroid carcinoma (PTC).
MATERIALS AND METHODS
The patients diagnosed with PTC (aged 18 years or younger) in the pediatrics department of Lishui District Hospital of Traditional Chinese Medicine were retrospectively screened. A targeted enrichment and sequencing analysis of 116 genes associated with thyroid cancer was performed on paraffin-embedded tumor tissues and paired paracancerous tissue of fifteen children (average age 14.60) and nine adults (average age 49.33) PTC patients. Demographic information, clinical indicators, ultrasonic imaging information and pathological data were collected. The Kendall correlation test was used to establish a correlation between molecular variations and clinical characteristics in pediatric patients.
RESULTS
A sample of 15 pediatric PTCs revealed a detection rate of 73.33% (11/15) for driver gene mutations and fusion. Compared to adult PTCs, the genetic mutation landscape of pediatric PTCs was more complex. Six mutant genes overlap between the two groups, and an additional seventeen unique mutant genes were identified only in pediatric PTCs. There was only one unique mutant gene in adult PTCs. The tumor diameter of pediatric PTCs tended to be less than 4cm (p<0.001), and the number of lymph node metastases was more than five (p<0.001). Mutations in specific genes unique to pediatric PTCs may contribute to the onset and progression of the disease by adversely affecting hormone synthesis, secretion, and action mechanisms, as well as the functioning of thyroid hormone signaling pathways. But, additional experiments are required to validate this hypothesis.
CONCLUSION
mutation and fusion are involved in the occurrence and development of adolescent PTC. For pediatric thyroid nodules that cannot be determined as benign or malignant by fine needle aspiration biopsy, multiple gene combination testing can provide a reference for personalized diagnosis and treatment by clinical physicians.
Topics: Humans; Female; Adolescent; Thyroid Cancer, Papillary; Male; Child; Thyroid Neoplasms; Mutation; Retrospective Studies; Proto-Oncogene Proteins B-raf; Adult; Middle Aged; Biomarkers, Tumor; Proto-Oncogene Proteins c-ret; High-Throughput Nucleotide Sequencing; DNA Mutational Analysis
PubMed: 38904052
DOI: 10.3389/fendo.2024.1405142 -
Frontiers in Public Health 2024To comprehensively investigate the molecular transmission patterns of HIV-1 genotypes among men who have sex with men (MSM) in Chongqing, we employed 392 pol sequences...
To comprehensively investigate the molecular transmission patterns of HIV-1 genotypes among men who have sex with men (MSM) in Chongqing, we employed 392 pol sequences of MSM to construct a phylogenetic tree and gene transmission network. Among the viral subtypes, CRF07_BC accounted for 73.2% (287/392) and CRF01_AE accounted for 20.7% (81/392), emerging as the predominant subtypes in this investigation. Additionally, we observed the presence of CRF55_01B, subtype B, CRF08_BC and other circulating recombinant forms. The HIV-1 molecular network was constructed with a gene distance threshold of 1.5%, resulting in an entry rate of 61.4% (241/392). Within the network, we identified a total of 23 molecular clusters, with the largest cluster being the CRF07_BC molecular cluster comprising 148 node values. Transmitted drug-resistance (TDR) mutations were found in 4.34% of the cases, with 1.79% associated with protease inhibitors (PIs), 0.51% with nucleoside reverse transcriptase inhibitors (NRTIs), and 2.55% with non-nucleoside reverse transcriptase inhibitors (NNRTIs). Statistical analysis indicated a higher enrollment rate in the HIV-1 molecular network among infected individuals with the CRF07_BC subtype, those identifying with same-sex sexual roles as "vers," and individuals with higher education levels. This suggests the need for strengthened investigation and intervention in this population to prevent the formation of larger transmission clusters. Furthermore, continuous monitoring of the HIV-1 molecular dynamics network is necessary to promptly and accurately track changes in molecular epidemic characteristics.
Topics: Humans; Male; China; Homosexuality, Male; HIV-1; Drug Resistance, Viral; Adult; Phylogeny; HIV Infections; Genotype; Acquired Immunodeficiency Syndrome; Middle Aged; Mutation
PubMed: 38903589
DOI: 10.3389/fpubh.2024.1308784