Search Results (190)

Background: Breast cancer (BC), one of the most common cancers, has increased in Mexico during the past decade, along with other chronic and metabolic diseases. Methods: Herein, we analyzed 121 SNPs (85 SNPs related to BC and/or glucose-associated metabolic pathways and 36 SNP classified as ancestry markers) in 92 confirmed BC cases and 126 unaffected BC women from Northeastern Mexico. The relationship of these 121 SNPs with BC, considering BMI, menopause status, and age as cofactors, was explored using a gene–environment (G × E) interaction multi-locus model. Results: Twelve gene variants were significantly associated with BC: three located in exome (rs3856806 PPARG, rs12792229 MMP8, and rs5218 KCNJ11-ABCC8), and nine in non-coding regions, which are involved in accelerated decay of the mRNA transcripts, regulatory regions, and flanking regions (rs3917542 PON1; rs3750804 and rs3750805 TCF7L2; rs1121980 and rs3751812 FTO; rs12946618 RPTOR; rs2833483 SCAF4; rs11652805 AMZ2P1-GNA13; and rs1800955 SCT-DEAF1-DRD4). Conclusions: This study identified an association between BC and menopause, age (above 45), obesity, and overweight status with gene variants implicated in diabetes mellitus, obesity, insulin resistance, inflammation, and remodeling of the extracellular matrix. Full article

Graphene nanoplatelet aggregates (GNAs) are a low-cost, low-quality alternative to graphene nanoplatelets (GNPs), characterized by their three-dimensional stacked structure and porous surface morphology. Despite their affordability, limited research has been conducted on the effects of GNAs in cementitious systems. This study investigates the impact of GNAs on hydration kinetics, phase assemblage, mortar consistency, mechanical strength, bulk electrical resistivity, water absorption, and pore solution pH. Mortar mixtures with 0%, 0.05%, and 1% GNAs by cement weight were prepared using a water-to-cement ratio of 0.42 and cured for 28 days. The results showed that GNAs had minimal influence on hydration kinetics, with no significant changes in hydration products detected by XRD and TGA analyses. Mortar consistency consistently decreased with increasing GNA content. At 0.05%, GNAs had no significant effect on compressive strength or bulk electrical resistivity, whereas 1% GNAs reduced compressive strength by 10%. Water absorption was significantly lower in specimens with 1% GNAs as well, while pore solution pH increased at this dosage. The findings of this study indicate that the incorporation of GNAs at a 0.05% replacement level does not inherently enhance cementitious properties but can influence specific behaviors, such as workability and water absorption, when used at 1% dosages. Full article

Introduction: Non-small cell lung cancer (NSCLC) is a lethal type of lung cancer (LC) with a 5-year survival rate of 19%. Because drug resistance typically develops following chemotherapy, radiotherapy, and immunotherapy, a novel NSCLC therapeutic strategy is urgently demanded. Gambogenic acid (GNA), a major bioactive ingredient isolated from gamboge, has multipotent antitumor effects, although activity against NSCLC is unknown. Methods: CCK8, ethynyl deoxyuridine (EdU), the plate colony formation assay, and the transwell and wound healing (WH) assay were used to study the effect of GNA on the proliferation and migration ability of NSCLC. Flow cytometry was used to detect apoptosis and the cell cycle. Proteomic analysis and LiP-SMap were used to detect the downstream target of GNA. Ferroptosis inhibitor ferrostatin-1 was used to detect the effect of GNA on NSCLC ferroptosis. Overexpressing GCH1 was used for a rescue experiment. Subcutaneous tumor and pulmonary metastasis in a mouse model were used to study the effect of GNA on NSCLC growth and metastasis. Results: The results of the present study showed that GNA inhibited the proliferation and migration of NSCLC cells in a dose- and time-dependent manner, which arrested the cell cycle in the G0/G1 phase. In vivo data revealed that GNA inhibited tumor growth and lung metastasis. Proteomic analysis found that GNA significantly inhibited the expression of GTP cyclohydrolase 1 (GCH1). LiP-SMap analysis showed that GNA interacted with ILE248 and ARG249 of GCH1. GCH1 overexpression had a similar role to the ferroptosis inhibitor ferrostatin-1 and restored cell proliferation and migration after GNA treatment. Also, GNA promoted reactive oxygen species (ROS) accumulation, which reduced mitochondrial membrane potential. GCH1 overexpression or ferrostatin-1 treatment reversed GNA regulation of ROS accumulation and mitochondrial membrane potential inhibition. Conclusions: Taken together, these findings confirmed that GNA suppressed the malignant progression of NSCLC by inducing GCH1-mediated ferroptosis. Full article

Introduction: Liposclerosing myxofibrous tumors (LSMFTs) have been described as an infrequent and peculiar fibrous dysplasia variant with a predilection for the intertrochanteric femoral region and are not globally considered a distinct tumor. Given their features, they may be confused with a variety of entities. Our aim is to analyze the clinical, radiological, histopathological and molecular features of LSMFTs. Material and Methods: We report 15 new LSMFT cases managed in our tertiary referral hospital and compare our findings with those of the 241 previous LSMFT cases published in the English medical literature. Results: In plain radiography and computerized tomography, LSMFTs are well-defined intraosseous lytic masses with peripheral sclerotic rims and variable amounts of internal calcifications. Histopathologically, LSFMTs consist of variable amounts of spindle cells, bone matrix, adipose tissue, and cystic spaces embedded in a predominantly fibromyxoid stroma. Molecular tests reveal GNAS and TP53 mutations. Conclusions: Knowledge of LSMFT and its typical radiological appearance with heterogeneous histopathological findings—especially in small biopsies—are key to preventing the misdiagnosis and overtreatment of affected patients. Full article

Background: Intraductal papillary mucinous neoplasms (IPMNs) are pre-malignant pancreatic lesions that may progress to invasive pancreatic ductal adenocarcinoma (PDAC). IPMN-associated invasive carcinoma (iIPMN) has been associated with more favorable survival outcomes compared to non-iIPMN-derived PDAC. Here, we aim to investigate the genetic landscape of IPMNs to assess their relevance to oncologic outcomes. Methods: This retrospective study used a large single-institution prospectively maintained database. Patients who underwent curative-intent pancreatic resection between 2016 and 2022 with histologically confirmed diagnosis of IPMN were included. Demographic, pathologic, molecular, and oncologic outcome data were recorded. Kaplan–Meier survival analyses were performed. PDAC data from public genetic databases were used for mutational correlation analysis. p-value ≤ 0.05 was considered as significant. Results: A total of thirty-nine patients with resected IPMN with complete clinical and sequencing data were identified and included in the final cohort. The male-to-female distribution was 21:18, and the mean age was 70.1 ± 9.1 years. GNAS mutations occurred in 23.1% of patients, and 89.7% of patients had iIPMN. In iIPMN patients, GNAS mutation was strongly associated with improved disease-free survival: all GNAS-mutant patients survived to follow-up with significantly fewer recurrences than in GNAS wild-type (WT) patients (p = 0.013). Mutated GNAS closely co-occurred with wild-type KRAS (p < 0.001), and further analysis of large genomic PDAC datasets validated this finding (OR 3.47, p < 0.0001). Conclusions: Our study suggests prognostic value of mutational status in malignant resected IPMNs. WT GNAS, mutant P53, and mutant KRAS each correlate with recurrence and decreased survival. Further studies are required to validate these preliminary observations. Full article

Hidradenitis suppurativa (HS) is a chronic skin condition that primarily affects areas with dense hair follicles and apocrine sweat glands, such as the underarms, groin, buttocks, and lower breasts. Intense pain and discomfort in HS have been commonly noted, primarily due to the lesions’ effects on nearby tissues. Pain is a factor that can influence DNA methylation patterns, though its exact role in HS is not fully understood. We aim to identify molecular markers of chronic pain in HS patients. We performed DNA methylome of peripheral blood DNA derived from a group of 24 patients with HS and 24 healthy controls, using Illumina methylation array chips. We identified 253 significantly differentially methylated CpG sites across 253 distinct genes regulating pain sensitization in HS, including 224 hypomethylated and 29 hypermethylated sites. Several genes with pleiotropic roles include transporters (ABCC2, SLC39A8, SLC39A9), wound healing (MIR132, FGF2, PDGFC), ion channel regulators (CACNA1C, SCN1A), oxidative stress mediators (SCN8A, DRD2, DNMT1), cytochromes (CYP19A, CYP1A2), cytokines (TGFB1, IL4), telomere regulators (CSNK1D, SMAD3, MTA1), circadian rhythm (IL1R2, ABCG1, RORA), ultradian rhythms (PHACTR1, TSC2, ULK1), hormonal regulation (PPARA, NR3C1, ESR2), and the serotonin system (HTR1D, HTR1E, HTR3C, HTR4, TPH2). They also play roles in glucose metabolism (POMC, IRS1, GNAS) and obesity (DRD2, FAAH, MMP2). Gene ontology and pathway enrichment analysis identified 43 pathways, including calcium signaling, cocaine addiction, and nicotine addiction. This study identified multiple differentially methylated genes involved in chronic pain in HS, which may serve as biomarkers and therapeutic targets. Understanding their epigenetic regulation is crucial for personalized pain management and could enhance the identification of high-risk patients, leading to better preventative therapies and improved maternal and neonatal outcomes. Full article

Background: Despite advances in uveal melanoma (UM) diagnosis and treatment, about 50% of patients develop distant metastases, thereby displaying poor overall survival. Molecular profiling has identified several genetic alterations that can stratify patients with UM into different risk categories. However, these genetic alterations are currently dispersed over multiple studies and several methodologies, emphasizing the need for a defined workflow that will allow standardized and reproducible molecular analyses. Methods: Following the findings published by “The Cancer Genome Atlas–UM” (TCGA-UM) study, we developed an NGS-based gene panel (called the UMpanel) that classifies mutation sets in four categories: initiating alterations (CYSLTR2, GNA11, GNAQ and PLCB4), prognostic alterations (BAP1, EIF1AX, SF3B1 and SRSF2), emergent biomarkers (CDKN2A, CENPE, FOXO1, HIF1A, RPL5 and TP53) and chromosomal abnormalities (imbalances in chromosomes 1, 3 and 8). Results: Employing commercial gene panels, reference mutated DNAs and Sanger sequencing, we performed a comparative analysis and found that our methodological approach successfully predicted survival with great specificity and sensitivity compared to the TCGA-UM cohort that was used as a validation group. Conclusions: Our results demonstrate that a reproducible NGS-based workflow translates into a reliable tool for the clinical stratification of patients with UM. Full article

N6-methyladenosine (m6A) modification is a key methylation modification involved in reproductive processes. Myostatin gene editing (MT) in cattle is known to enhance muscle mass and productivity. However, the changes in m6A modification in MT bull sperm remain poorly understood. In the MT and wild-type (WT) groups, we identified 25,542 and 22,253 m6A peaks, respectively, mainly concentrated in the coding sequence (CDS) and 3′ untranslated region (UTR) of genes. The MT group showed an increase in gene transcription, but there was no significant difference in the overall m6A peaks pattern. There was also no significant difference in m6A motif and chromosome distribution between MT and WT groups. Most genes had less m6A modification sites. A total of 1120 m6A peaks were significantly different, corresponding to 1053 differentially m6A-methylated genes (DMMGs). These DMMGs are mainly associated with G protein-coupled receptor signaling pathways and the overall composition of the cell membrane. Furthermore, an MCL clustering analysis of 111 differentially m6A-methylated and expressed genes identified seven key genes (RHOA, DAAM1, EXOC4, GNA12, PRICKLE1, SCN1A, and STXBP5L), with the cytoskeleton and migration-related gene, RHOA, being the most important gene located at the center of the gene network. However, the analysis of sperm morphology and motility indicated no significant changes in semen volume, sperm count, sperm viability, plasma membrane integrity, acrosome membrane integrity, or mitochondrial membrane integrity. This study provides a map of m6A methylation in spermatozoa from MT and WT bulls, identifies key differential m6A genes that are affected by the myostatin gene but do not affect sperm morphology and viability in MT bulls, and provides a theoretical basis for the breeding quality of MT bulls. Full article

Immune checkpoint inhibitors (ICIs) are effective in treating recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but only 20% of patients achieve durable responses. This study evaluated circulating tumor DNA (ctDNA) as a real-time biomarker for monitoring treatment response in HNSCC. The SHIZUKU-HN study prospectively collected and analyzed serial plasma samples (n = 27) from HNSCC patients undergoing ICIs, using Guardant360 to assess ctDNA variant allele frequency (VAF) and genetic mutations. Tumor volumes were quantified using 3D reconstruction of CT scans, and data from Japan’s C-CAT database (n = 2255) provided insights into ctDNA testing in HNSCC. C-CAT data showed that ctDNA testing was underutilized, performed in only 7% of head and neck cancer cases. In SHIZUKU-HN, mean VAF significantly correlated with tumor volume (Spearman’s ρ = 0.70, p = 0.001), often preceding radiographic progression. BRAF and APC mutations disappeared in partial responders, while GNAS mutations varied. EGFR and PIK3CA amplifications, detectable via ctDNA but missed in tissue biopsies, indicated emerging resistance mechanisms. The SHIZUKU-HN study demonstrates the potential of ctDNA as a dynamic biomarker in HNSCC, offering early insights into treatment efficacy and informing personalized ICI therapy. Full article

Days open (DO) is a critical economic and reproductive trait that is commonly employed in genetic selection. Making improvements using conventional genetic techniques is exceedingly challenging. Therefore, new techniques are required to improve the accuracy of genetic selection using genomic data. This study examined the genetic approaches of traditional AIREML and single-step genomic AIREML (ssGAIREML) to assess genetic parameters and the accuracy of estimated breeding values while also investigating SNP regions associated with DO and identifying candidate genes through a genome-wide association study (GWAS). The dataset included 59415 DO records from 36368 Thai–Holstein crossbred cows and 882 genotyped animals. The cows were classified according to their Holstein genetic proportion (breed group, BG) as follows: BG1 (>93.7% Holstein genetics), BG2 (87.5% to 93.6% Holstein genetics), and BG3 (<87.5% Holstein genetics). AIREML was utilized to estimate genetic parameters and variance components. The results of this study reveal that the average DO values for BG1, BG2, and BG3 were 97.64, 97.25, and 96.23 days, respectively. The heritability values were estimated to be 0.02 and 0.03 for the traditional AIREML and ssGAIREML approaches, respectively. Depending on the dataset, the ssGAIREML method produced more accurate estimated breeding values than the traditional AIREML method, ranging from 40.5 to 45.6%. The highest values were found in the top 20% of the dam dataset. For the GWAS, we found 12 potential candidate genes (DYRK1A, CALCR, MIR489, MIR653, SLC36A1, GNA14, GNAQ, TRNAC-GCA, XYLB, ACVR2B, SLC22A14, and EXOC2) that are believed to have a significant influence on days open. In summary, the ssGAIREML method has the potential to enhance the accuracy and heritability of reproductive values compared to those obtained using conventional AIREML. Consequently, it is a viable alternative for transitioning from conventional methodologies to the ssGAIREML method in the breeding program for dairy cattle in Thailand. Moreover, the 12 identified potential candidate genes can be utilized in future studies to select markers for days open in regard to dairy cattle. Full article

Malignant proliferating trichilemmal tumors (MPTTs), arising from the external root sheath of hair follicles, are exceptionally rare, with limited documentation of their genetic alterations. We present a case of a 64-year-old African American woman who initially presented with a gradually enlarging nodule on her posterior scalp. An initial biopsy at an outside hospital suggested metastatic adenocarcinoma or squamous cell carcinoma (SCC) of an uncertain origin. A subsequent wide local excision revealed a 2.0 cm tumor demonstrating characteristic trichilemmal keratinization, characterized by an abrupt transition from the nucleated epithelium to a laminated keratinized layer, confirming MPTT. Immunohistochemistry demonstrated diffuse p53 expression, patchy CD 34 expression, focal HER2 membranous expression, and patchy p16 staining (negative HPV ISH). A molecular analysis identified TP53 mutation and amplifications in the ERBB2 (HER2), BRD4, and TYMS. Additional gene mutations of uncertain significance included HSPH1, ATM, PDCD1 (PD-1), BARD1, MSH3, LRP1B, KMT2C (MLL3), GNA11, and RUNX1. Assessments for the homologous recombination deficiency, PD-L1 expression, gene rearrangement, altered splicing, and DNA mismatch repair gene expression were negative. The confirmation of ERBB2 (HER2) amplification in the MPTT through a molecular analysis suggests potential therapeutic avenues involving anti-HER2 monoclonal antibodies. The presence of the TP53 mutation, without the concurrent gene mutations typically observed in SCC, significantly aided in this differential diagnosis. Full article

Immune checkpoint blockade (ICB), radiotherapy, chemotherapy and surgery are currently used as therapeutic strategies against melanoma, lung, bladder and renal cancers, but their efficacy is limited. Thus, I need to predict treatment response and resistance to address this challenge. In this study, I analyzed 350 lung cancer, 320 melanoma, 215 bladder cancer, 139 head and neck cancer and 151 renal carcinoma patients treated with ICB to identify tumor mutations associated with response and resistance to treatment. I identified several tumor mutations linked with a difference in survival outcomes following ICB. In lung cancer, missense mutations in ABL1, ASXL1, EPHA3, EPHA5, ERBB4, MET, MRE11A, MSH2, NOTCH1, PAK7, PAX5, PGR, ZFHX3, PIK3C3 and REL genes were indicative of favorable responses to ICB. Conversely, mutations in TGFBR2, ARID5B, CDKN2C, HIST1H3I, RICTOR, SMAD2, SMAD4 and TP53 genes were associated with shorter overall survival post-ICB treatment. In melanoma, mutations in FBXW7, CDK12, CREBBP, CTNNB1, NOTCH1 and RB1 genes predict resistance to ICB, whereas missense mutations in FAM46C and RHOA genes are associated with extended overall survival. In bladder cancer, mutations in HRAS genes predict resistance to ICB, whereas missense mutations in ERBB2, GNAS, ATM, CDKN2A and LATS1 genes, as well as nonsense mutations in NCOR1 and TP53 genes, are associated with extended overall survival. In head and neck cancer, mutations in genes like PIK3CA and KRAS correlated with longer survival, while mutations in genes like TERT and TP53 were linked to shorter survival. In renal carcinoma, mutations such as EPHA5, MGA, PIK3R1, PMS1, TSC1 and VHL were linked to prolonged overall survival, while others, including total splice mutations and mutations in B2M, BCOR, JUN, FH, IGF1R and MYCN genes were associated with shorter overall survival following ICB. Then, I developed predictive survival models by machine learning that correctly forecasted cancer patient survival following ICB within an error between 5 and 8 months based on their distinct tumor mutational attributes. In conclusion, this study advocates for personalized immunotherapy approaches in cancer patients. Full article

GNAS (Guanine Nucleotide-Binding Protein, Alpha Stimulating) is a complex gene that encodes the alpha subunit of the stimulatory G protein (G_sα), critical for signaling through various G protein-coupled receptors. Inactivating genetic and epigenetic changes in GNAS, resulting in G_sα deficiency, cause different variants of pseudohypoparathyroidism, which may manifest features of Albright hereditary osteodystrophy (AHO, a syndrome characterized by early-onset obesity and other developmental defects). Recent findings have linked G_sα deficiency with isolated, severe, early-onset obesity, suggesting it as a potential, underrecognized cause of monogenic, non-syndromic obesity. This study was prompted by identifying several GNAS variants of uncertain significance (VUSs) in pediatric patients presenting with unexplained, severe, early-onset obesity at Sidra Medicine in Qatar. To functionally characterize these variants, we developed the first zebrafish model of G_sα deficiency, offering numerous advantages over other model systems. This was achieved by knockdown of the ortholog through microinjection of translation-blocking Morpholino antisense oligonucleotides into the yolks of 1-8-cell-stage zebrafish embryos. The morphant larvae displayed an obese phenotype, marked by significantly enlarged yolk sacs, increased neutral lipid accumulation, and reduced metabolic rates, among other developmental abnormalities resembling those in AHO. This zebrafish model lays the foundation for efficient functional characterization of GNAS VUSs and paves the way for enhancing our understanding of G_sα deficiency-associated early-onset obesity. Full article

Diminished ovarian reserve (DOR) and primary ovarian insufficiency (POI) are major causes of female infertility. We recently found a monogenic etiology in 29.3% of POI, leading to personalized medicine. The genetic landscape of DOR is unknown. A prospective study (2018–2023) of an international cohort of 120 patients with unexplained DOR was performed using a large custom targeted next-generation sequencing panel including all known POI-causing genes. The diagnostic yield, based on the American College of Medical Genetics, was 24, 2%. Genes belong to different pathways: metabolism and mitochondria (29.7%), follicular growth (24.3%), DNA repair/meiosis (18.9%), aging (16.2%), ovarian development (8.1%), and autophagy (2.7%). Five genes were recurrently found: LMNA, ERCC6, SOX8, POLG, and BMPR1B. Six genes identified in single families with POI were involved in DOR, GNAS, TGFBR3, XPNPEP2, EXO1, BNC1, ATG, highlighting their role in maintaining ovarian reserve. In our cohort, 26 pregnancies were recorded, but no pregnancy was observed when meiosis/DNA repair genes were involved, suggesting severely impaired oocyte quality. Additional studies should confirm these preliminary results. This study with a large NGS panel defines the genetic landscape of a large cohort of DOR. It supports routine genetic diagnosis. Genetics could be a biomarker predicting infertility and progression to POI. Full article

Uveal melanoma (UM), recognized as the most prevalent primary intraocular malignancy in adults, is primarily driven by mutations in the GNAQ and GNA11 genes. These genetic alterations are also implicated in other conditions, which exhibit distinct morphological characteristics. In this article, we investigate the role of GNAQ and GNA11 mutations across varied disorders (e.g., UM, skin blue nevi, and hemangiomas), emphasizing the shared pathogenic mechanisms that connect them despite their differing clinical manifestations. By investigating the molecular pathways affected by these mutations, we provide insights into the potential for targeted therapies that could address not only UM but also other disorders associated with GNAQ/GNA11 mutations. Moreover, we discuss the role of SOX10-positive perivascular cells that may be implicated in the complex pathophysiology of GNAQ/GNA11-related entities. Understanding the common molecular foundation of these conditions opens new ways for research and treatment opportunities, potentially leading to more effective, personalized therapeutic strategies. Full article