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Pharmacogenomics and Personalized... 2024Lung cancer is the leading cause of cancer deaths worldwide, primarily due to lung adenocarcinoma (LUAD). However, the heterogeneity of programmed cell death results in...
BACKGROUND
Lung cancer is the leading cause of cancer deaths worldwide, primarily due to lung adenocarcinoma (LUAD). However, the heterogeneity of programmed cell death results in varied prognostic and predictive outcomes. This study aimed to develop an LUAD evaluation marker based on cuproptosis-related lncRNAs.
METHODS
First, transcriptome data and clinical data related to LUAD were downloaded from the Cancer Genome Atlas (TCGA), and cuproptosis-related genes were analyzed to identify cuproptosis-related lncRNAs. Univariate, LASSO, and multivariate Cox regression analyses were conducted to construct cuproptosis-associated lncRNA models. LUAD patients were categorized into high-risk and low-risk groups using prognostic risk values. Kaplan-Meier analysis, PCA, GSEA, and nomograms were employed to evaluate and validate the results.
RESULTS
7 cuproptosis-related lncRNAs were identified, and a risk model was created. High-risk tumors exhibited cuproptosis-related gene alterations in 95.54% of cases, while low-risk tumors showed alterations in 85.65% of cases, mainly involving TP53. The risk value outperformed other clinical variables and tumor mutation burden as a predictor of 1-, 3-, and 5-year overall survival. The cuproptosis-related lncRNA-based risk model demonstrated high validity for LUAD evaluation, potentially influencing individualized treatment approaches. Expression analysis of four candidate cuproptosis-related lncRNAs (AL606834.1, AL161431.1, AC007613.1, and LINC02835) in LUAD tissues and adjacent normal tissues revealed significantly higher expression levels of AL606834.1 and AL161431.1 in LUAD tissues, positively correlating with tumor stage, lymph node metastasis, and histopathological grade. Conversely, AC007613.1 and LINC02835 exhibited lower expression levels, negatively correlating with these factors. High expression of AL606834.1 and AL161431.1 indicated poor prognosis, while low expression of AC007613.1 and LINC02835 was associated with unfavorable outcomes. Univariate and multivariate analyses confirmed these lncRNAs as independent risk factors for LUAD prognosis.
CONCLUSION
The 4 cuproptosis-related (lncRNAsAL606834.1, AL161431.1, AC007613.1, and LINC02835) can accurately predict the prognosis of patients with LUAD and may provide new insights into clinical applications and immunotherapy.
PubMed: 38952778
DOI: 10.2147/PGPM.S452625 -
Frontiers in Genetics 2024Developmental Dysplasia of the Hip (DDH) is a skeletal disorder where late-presenting forms often escape early diagnosis, leading to limb and pain in adults. The genetic...
BACKGROUND
Developmental Dysplasia of the Hip (DDH) is a skeletal disorder where late-presenting forms often escape early diagnosis, leading to limb and pain in adults. The genetic basis of DDH is not fully understood despite known genetic predispositions.
METHODS
We employed Whole Genome Sequencing (WGS) to explore the genetic factors in late-presenting DDH in two unrelated families, supported by phenotypic analyses and validation.
RESULTS
In both cases, a novel heterozygous missense mutation in (c.193A>G [p.Lys65Glu]) was identified. This mutation impacted protein structure and function, altering downstream signaling in the Ras/ERK pathway, as demonstrated by bioinformatics, molecular dynamics simulations, and validations.
CONCLUSION
This study contributes to our understanding of the genetic factors involved in DDH by identifying a novel mutation in . The identification of the mutation suggests a possible involvement of the Ras/ERK pathway in the pathogenesis of late-presenting DDH, indicating its potential role in skeletal development.
PubMed: 38952713
DOI: 10.3389/fgene.2024.1375736 -
Frontiers in Oncology 2024Breast cancer is the leading cause of cancer death among women worldwide. Studies about the genomic landscape of metastatic breast cancer (MBC) have predominantly...
BACKGROUND
Breast cancer is the leading cause of cancer death among women worldwide. Studies about the genomic landscape of metastatic breast cancer (MBC) have predominantly originated from developed nations. There are still limited data on the molecular epidemiology of MBC in low- and middle-income countries. This study aims to evaluate the prevalence of mutations in the PI3K-AKT pathway and other actionable drivers in estrogen receptor (ER)+/HER2- MBC among Brazilian patients treated at a large institution representative of the nation's demographic diversity.
METHODS
We conducted a retrospective observational study using laboratory data (OC Precision Medicine). Our study included tumor samples from patients with ER+/HER2- MBC who underwent routine tumor testing from 2020 to 2023 and originated from several Brazilian centers within the Oncoclinicas network. Two distinct next-generation sequencing (NGS) assays were used: GS Focus (23 genes, covering , , , , , , , , but not ) or GS 180 (180 genes, including PTEN, tumor mutation burden [TMB] and microsatellite instability [MSI]).
RESULTS
Evaluation of tumor samples from 328 patients was undertaken, mostly (75.6%) with GS Focus. Of these, 69% were primary tumors, while 31% were metastatic lesions. The prevalence of mutations in the PI3K-AKT pathway was 39.3% (95% confidence interval, 33% to 43%), distributed as 37.5% in and 1.8% in . Stratification by age revealed a higher incidence of mutations in this pathway among patients over 50 (44.5% vs 29.1%, p=0.01). Among the mutations, 78% were canonical (included in the alpelisib companion diagnostic non-NGS test), while the remaining 22% were characterized as non-canonical mutations (identifiable only by NGS test). mutations were detected in 6.1%, exhibiting a higher frequency in metastatic samples (15.1% vs 1.3%, p=0.003). Additionally, mutations in , or were identified in 3.9% of cases, while mutations in were found in 2.1%. No mutations were detected, nor were TMB high or MSI cases.
CONCLUSION
We describe the genomic landscape of Brazilian patients with ER+/HER2- MBC, in which the somatic mutation profile is comparable to what is described in the literature globally. These data are important for developing precision medicine strategies in this scenario, as well as for health systems management and research initiatives.
PubMed: 38952553
DOI: 10.3389/fonc.2024.1372947 -
Frontiers in Oncology 2024The substantial heterogeneity exhibited by head and neck cancer (HNC), encompassing diverse cellular origins, anatomical locations, and etiological contributors,... (Review)
Review
The substantial heterogeneity exhibited by head and neck cancer (HNC), encompassing diverse cellular origins, anatomical locations, and etiological contributors, combined with the prevalent late-stage diagnosis, poses significant challenges for clinical management. Genomic sequencing endeavors have revealed extensive alterations in key signaling pathways that regulate cellular proliferation and survival. Initiatives to engineer therapies targeting these dysregulated pathways are underway, with several candidate molecules progressing to clinical evaluation phases, including FDA approval for agents like the EGFR-targeting monoclonal antibody cetuximab for K-RAS wild-type, EGFR-mutant HNSCC treatment. Non-coding RNAs (ncRNAs), owing to their enhanced stability in biological fluids and their important roles in intracellular and intercellular signaling within HNC contexts, are now recognized as potent biomarkers for disease management, catalyzing further refined diagnostic and therapeutic strategies, edging closer to the personalized medicine desideratum. Enhanced comprehension of the genomic and immunological landscapes characteristic of HNC is anticipated to facilitate a more rigorous assessment of targeted therapies benefits and limitations, optimize their clinical deployment, and foster innovative advancements in treatment approaches. This review presents an update on the molecular mechanisms and mutational spectrum of HNC driving the oncogenesis of head and neck malignancies and explores their implications for advancing diagnostic methodologies and precision therapeutics.
PubMed: 38952548
DOI: 10.3389/fonc.2024.1373821 -
Frontiers in Oncology 2024Phosphoinositide 3-kinase (PI3K) inhibitors have shown synergistic anticancer effects with endocrine therapy against ER+/PIK3CA-mutated breast cancer. PI3K inhibitors...
Phosphoinositide 3-kinase (PI3K) inhibitors have shown synergistic anticancer effects with endocrine therapy against ER+/PIK3CA-mutated breast cancer. PI3K inhibitors for cancer therapy are becoming more common. There is an increasing need to understand their cardiac adverse events. In this report, we describe the features of near-fatal mixed arrhythmias in a patient who was undergoing a phase Ib clinical study of PI3Kα inhibitor with fulvestrant. Subsequently, the patient survived by cardiopulmonary resuscitation and therefore did not die. This case highlights that PI3K inhibitors can induce QT/QTc prolongation and predispose patients to TdP. The combination of QT/QTc prolongation in combination with prolonged cardiac repolarization, such as an AV block during treatment with PI3Kα inhibitor, may aggravate the occurrence of TdP. It is likely to be a safer strategy to adjust the standard of discontinuing drugs and continuing drugs (QTc interval was <500 and <60 ms at baseline) or choose other types of alternative treatment options. This report provided some ideas for clinicians to identify early and prevent the occurrence of fatal arrhythmias during anticancer treatment.
PubMed: 38952547
DOI: 10.3389/fonc.2024.1331472 -
Frontiers in Neurology 2024Xanthomatosis is a genetic disease inherited in an autosomal recessive manner. The specific phenotypic features are associated with patient's genetic profile. The result... (Review)
Review
Xanthomatosis is a genetic disease inherited in an autosomal recessive manner. The specific phenotypic features are associated with patient's genetic profile. The result of the mutation is disorder of cholesterol synthesis and the accumulation of its precursors in tissues. The characteristic symptoms are progressive cerebellar ataxia, cataract, diarrhea, and the deposition of cholesterol in the tendons. Our objective is to follow-up information to treatment efficacy of 22-year-old patient diagnosed with cerebrotendinous xanthomatosis through 1.5 year observation. In 2012, an 11-year-old patient with a long history of deformed feet and frequent yellowing of the skin, was admitted to the Department of Neurology due to seizures. In 2013, the patient began to suffer from diarrhea, and its frequency was correlated with the concentration of bilirubin in the blood. In the same year cataract was diagnosed. Gradually, the patient starts to complain about progressive difficulties in moving. In 2019, genetic tests confirmed the diagnosis of cerebrotendinous xanthomatosis. Since July 2021, the patient has been treated with chenodeoxycholic acid. The deterioration of patient's mobility has been significantly inhibited, consequently his quality of life has improved. The presented case report underscores the efficacy of CDCA supplementation in halting the progression of CTX, resulting in marked improvements in the patient's quality of life.
PubMed: 38952472
DOI: 10.3389/fneur.2024.1409138 -
Molecular Therapy. Nucleic Acids Sep 2024p47 -deficient chronic granulomatous disease (p47-CGD) is a primary immunodeficiency caused by mutations in the neutrophil cytosolic factor 1 () gene, resulting in...
p47 -deficient chronic granulomatous disease (p47-CGD) is a primary immunodeficiency caused by mutations in the neutrophil cytosolic factor 1 () gene, resulting in defective NADPH oxidase function in phagocytes. Due to its complex genomic context, the locus is not suited for safe gene editing with current genome editing technologies. Therefore, we developed a targeted coding sequence knock-in by CRISPR-Cas9 ribonucleoprotein and viral vector template delivery, to restore p47 expression under the control of the endogenous locus. encodes for p67 , an NADPH oxidase subunit that closely interacts with p47 and is predominantly expressed in myeloid cells. This approach restored p47 expression and NADPH oxidase function in p47-CGD patient hematopoietic stem and progenitor cells (HSPCs) and in p47 -deficient mouse HSPCs, with the transgene expression following a myeloid differentiation pattern. Adeno-associated viral vectors performed favorably over integration-deficient lentiviral vectors for template delivery, with fewer off-target integrations and higher correction efficacy in HSPCs. Such myeloid-directed gene editing is promising for clinical CGD gene therapy, as it leads to the co-expression of p47 and p67 , ensuring spatiotemporal and near-physiological transgene expression in myeloid cells.
PubMed: 38952440
DOI: 10.1016/j.omtn.2024.102229 -
Clinical, Cosmetic and Investigational... 2024Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that influences structures of ectodermal origin, such as teeth, hair, and sweat glands. Compared with...
INTRODUCTION
Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that influences structures of ectodermal origin, such as teeth, hair, and sweat glands. Compared with autosomal recessive and dominant modes of inheritance, the X-linked HED (XLHED) characterized by Hypodontia/Oligodontia teeth, Absent/sparse hair, Anhidrosis/hypohidrosis, and characteristic facial features, is the most frequent and its primary cause is the mutation of ectodysplasin A (EDA) gene. This research aimed to expound the clinical and molecular features of a Chinese male with XLHED and to summarize and compare several previous findings.
METHODS
Genomic DNA was obtained from the peripheral blood of the proband and his family members, then Sanger sequencing was used to perform a mutational analysis of . Real-time quantitative PCR and Western blotting were used to detect EDA expression. The transcriptional activity of NF-κB was detected using a luciferase assay.
RESULTS
The probandwith XLHED was identified a novel mutation, c.1119G>C(p.M373I), that affected the molecular analysis of transmembrane protein exon8 mutations, inherited from the mother. He showed a severe multiple-tooth loss, with over 20 permanent teeth missing and sparse hair and eyebrows, dry, thin, and itching skin. Furthermore, his sweating function was abnormal to a certain extent.
DISCUSSION
The functional study showed that this novel mutant led to a significant decrease in the EDA expression level and transcriptional activity of NF-κB. Our findings extend the range of mutations in XLHED patients, which provides the basis and idea for further exploring the pathogenesis of XLHED.
PubMed: 38952411
DOI: 10.2147/CCID.S451125 -
Heliyon Jun 2024Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the gene encoding the lysosomal enzyme -acetylgalactosamine-6-sulfate sulfatase...
Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the gene encoding the lysosomal enzyme -acetylgalactosamine-6-sulfate sulfatase (GALNS), resulting in the accumulation of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). Previously, it was reported the production of an active human recombinant GALNS (rGALNS) in BL21(DE3). However, this recombinant enzyme was not taken up by HEK293 cells or MPS IVA skin fibroblasts. Here, we leveraged a glyco-engineered strain to produce a recombinant human GALNS bearing the eukaryotic trimannosyl core glycan, ManGlcNAc (rGALNSGly). The glycosylated GALNS was produced at 100 mL and 1.65 L scales, purified and characterized with respect to pH stability, enzyme kinetic parameters, cell uptake, and KS clearance. The results showed that the addition of trimannosyl core glycans enhanced both protein stability and substrate affinity. rGALNSGly was capture through a mannose receptor-mediated process. This enzyme was delivered to the lysosome, where it reduced KS storage in human MPS IVA fibroblasts. This study demonstrates the potential of a glyco-engineered for producing a fully functional GALNS enzyme. It may offer an economic approach for the biosynthesis of a therapeutic glycoprotein that could prove useful for MPS IVA treatment. This strategy could be extended to other lysosomal enzymes that rely on the presence of mannose N-glycans for cell uptake.
PubMed: 38952373
DOI: 10.1016/j.heliyon.2024.e32555 -
Heliyon Jun 2024Ovarian cancer (OC) ranks as the fifth most prevalent neoplasm in women and exhibits an unfavorable prognosis. To improve the OC patient's prognosis, a pioneering risk...
BACKGROUND
Ovarian cancer (OC) ranks as the fifth most prevalent neoplasm in women and exhibits an unfavorable prognosis. To improve the OC patient's prognosis, a pioneering risk signature was formulated by amalgamating disulfidptosis-related genes.
METHODS
A comparative analysis of OC tissues and normal tissues was carried out, and differentially expressed disulfidptosis-related genes (DRGs) were found using the criteria of |log2 (fold change) | > 0.585 and adjusted P-value <0.05. Subsequently, the TCGA training set was utilized to create a prognostic risk signature, which was validated by employing both the TCGA testing set and the GEO dataset. Moreover, the immune cell infiltration, mutational load, response to chemotherapy, and response to immunotherapy were analyzed. To further validate these findings, QRT-PCR analysis was conducted on ovarian tumor cell lines.
RESULTS
A risk signature was created using fourteen differentially expressed genes (DEGs) associated with disulfidptosis, enabling the classification of ovarian cancer (OC) patients into high-risk group (HRG) and low-risk group (LRG). The HRG exhibited a lower overall survival (OS) compared to the LRG. In addition, the risk score remained an independent predictor even after incorporating clinical factors. Furthermore, the LRG displayed lower stromal, immune, and estimated scores compared to the HRG, suggesting a possible connection between the risk signature, immune cell infiltration, and mutational load. Finally, the QRT-PCR experiments revealed that eight genes were upregulated in the human OC cell line SKOV3 compared with the human normal OC line IOSE80, while six genes were down-regulated.
CONCLUSIONS
A fourteen-biomarker signature composed of disulfidptosis-related genes could serve as a valuable risk stratification tool in OC, facilitating the identification of patients who may benefit from individualized treatment and follow-up management.
PubMed: 38952356
DOI: 10.1016/j.heliyon.2024.e32273