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Clinical and Translational... Jun 2024The characteristics of gastric carcinoma in young individuals differ from that in older individuals. We conducted a systematic review and meta-analysis to explore the... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
The characteristics of gastric carcinoma in young individuals differ from that in older individuals. We conducted a systematic review and meta-analysis to explore the clinicopathological features and risk factors associated with young-onset (younger than 50 years) gastric carcinoma.
METHODS
We searched for studies published between January 1, 1990, and September 1, 2023, on patients with young-onset gastric carcinoma in PubMed, EMBASE, Web of Science, and MEDLINE to explore clinicopathological characteristics among this specific patient group. Extracted information included the proportion of patients with symptoms or family history of gastric cancer, tumor location, and histological features such as Lauren or World Health Organization histological classification and degree of differentiation. Additional analyses were conducted on risk factors such as positive family history, Helicobacter pylori infection, or high-risk nutritional or behavioral factors. The estimates were derived using random or fixed-effect models and included subgroup analyses based on different sex and age groups. This study was registered in PROSPERO (CRD42023466131).
RESULTS
We identified 5,696 records, 1,292 were included in the quality assessment stage. Finally, 84 studies from 18 countries or regions including 89,447 patients with young-onset gastric carcinoma were included. Young-onset gastric carcinoma has slight female predominance (53.7%, 95% confidence interval [CI]: 51.6-55.7%), with most having symptoms (87.0%, 95% CI: 82.4%-91.7%). Family history was reported in 12.1% (95% CI: 9.5%-14.7%). H. pylori infection was detected in 60.0% of cases (95% CI: 47.1%-72.8%). Most of these carcinomas were in the non-cardia region (89.6%, 95% CI: 82.4%-96.8%), exhibiting Lauren diffuse-type histology (71.1%, 95% CI: 66.8%-75.3%) and poor/undifferentiated features (81.9%, 95% CI%: 79.7-84.2%). A positive family history of gastric cancer was the most important risk factor associated with the development of gastric carcinoma in young individuals (pooled odds ratios 4.0, 95% CI: 2.8-5.2), followed by H. pylori infection (odds ratio 2.3; 95% CI: 1.4-3.2) and dietary and other lifestyle risk factors.
DISCUSSION
Young-onset gastric carcinoma exhibits specific clinicopathological characteristics, with positive family history being the most important risk factor. Most of the patients were symptomatic at diagnosis. These findings could help to inform future strategies for the early detection of gastric carcinoma among young individuals.
Topics: Humans; Stomach Neoplasms; Risk Factors; Age of Onset; Helicobacter Infections; Helicobacter pylori; Adult; Middle Aged; Male; Female
PubMed: 38717039
DOI: 10.14309/ctg.0000000000000714 -
Nature Communications May 2024Mammalian sex determination is controlled by antagonistic gene cascades operating in embryonic undifferentiated gonads. The expression of the Y-linked gene SRY is...
Mammalian sex determination is controlled by antagonistic gene cascades operating in embryonic undifferentiated gonads. The expression of the Y-linked gene SRY is sufficient to trigger the testicular pathway, whereas its absence in XX embryos leads to ovarian differentiation. Yet, the potential involvement of non-coding regulation in this process remains unclear. Here we show that the deletion of a single microRNA cluster, miR-17~92, induces complete primary male-to-female sex reversal in XY mice. Sry expression is delayed in XY knockout gonads, which develop as ovaries. Sertoli cell differentiation is reduced, delayed and unable to sustain testicular development. Pre-supporting cells in mutant gonads undergo a transient state of sex ambiguity which is subsequently resolved towards the ovarian fate. The miR-17~92 predicted target genes are upregulated, affecting the fine regulation of gene networks controlling gonad development. Thus, microRNAs emerge as key components for mammalian sex determination, controlling Sry expression timing and Sertoli cell differentiation.
Topics: Animals; MicroRNAs; Female; Male; Sertoli Cells; Mice; Ovary; Testis; Sex-Determining Region Y Protein; Cell Differentiation; Sex Determination Processes; Gene Expression Regulation, Developmental; Mice, Knockout; Sex Differentiation; Disorders of Sex Development; Gonads
PubMed: 38714644
DOI: 10.1038/s41467-024-47658-x -
BioRxiv : the Preprint Server For... Apr 2024Global and site-specific changes in DNA methylation and gene expression are associated with cardiovascular aging and disease, but how toxicant exposures during early...
BACKGROUND
Global and site-specific changes in DNA methylation and gene expression are associated with cardiovascular aging and disease, but how toxicant exposures during early development influence the normal trajectory of these age-related molecular changes, and whether there are sex differences, has not yet been investigated.
OBJECTIVES
We used an established mouse model of developmental exposures to investigate the effects of perinatal exposure to either lead (Pb) or diethylhexyl phthalate (DEHP), two ubiquitous environmental contaminants strongly associated with CVD, on age-related cardiac DNA methylation and gene expression.
METHODS
Dams were randomly assigned to receive human physiologically relevant levels of Pb (32 ppm in water), DEHP (25 mg/kg chow), or control water and chow. Exposures started two weeks prior to mating and continued until weaning at postnatal day 21 (3 weeks of age). Approximately one male and one female offspring per litter were followed to 3 weeks, 5 months, or 10 months of age, at which time whole hearts were collected (n ≥ 5 per sex per exposure). Enhanced reduced representation bisulfite sequencing (ERRBS) was used to assess the cardiac DNA methylome at 3 weeks and 10 months, and RNA-seq was conducted at all 3 time points. MethylSig and edgeR were used to identify age-related differentially methylated regions (DMRs) and differentially expressed genes (DEGs), respectively, within each sex and exposure group. Cell type deconvolution of bulk RNA-seq data was conducted using the MuSiC algorithm and publicly available single cell RNA-seq data.
RESULTS
Thousands of DMRs and hundreds of DEGs were identified in control, DEHP, and Pb-exposed hearts across time between 3 weeks and 10 months of age. A closer look at the genes and pathways showing differential DNA methylation revealed that the majority were unique to each sex and exposure group. Overall, pathways governing development and differentiation were most frequently altered with age in all conditions. A small number of genes in each group showed significant changes in DNA methylation and gene expression with age, including several that were altered by both toxicants but were unchanged in control. We also observed subtle, but significant changes in the proportion of several cell types due to age, sex, and developmental exposure.
DISCUSSION
Together these data show that perinatal Pb or DEHP exposures deflect normal age-related gene expression, DNA methylation programs, and cellular composition across the life course, long after cessation of exposure, and highlight potential biomarkers of developmental toxicant exposures. Further studies are needed to investigate how these epigenetic and transcriptional changes impact cardiovascular health across the life course.
PubMed: 38712146
DOI: 10.1101/2024.04.25.591125 -
Journal of Central Nervous System... 2024Patients with Multiple Sclerosis (pwMS) treated with anti-CD20 (cluster of differentiation) monoclonal antibodies (mAbs) such as ocrelizumab (OCR) and ofatumumab (OFA)...
INTRODUCTION
Patients with Multiple Sclerosis (pwMS) treated with anti-CD20 (cluster of differentiation) monoclonal antibodies (mAbs) such as ocrelizumab (OCR) and ofatumumab (OFA) show a reduction mainly of B-lymphocytes, but also other lymphocyte subsets can be affected by these treatments. There is limited data on differences between lymphocyte subset counts of pwMS after treatment initiation with OCR or OFA.
OBJECTIVE
To compare lymphocyte subset counts after treatment initiation in pwMS treated with OCR and OFA.
METHODS
We analyzed 22 pwMS initiated on OFA and 56 sex-, age- and MS course matched pwMS initiated on OCR from 2 prospectively collected observational MS databases (Bern [n: OFA 14, OCR 44] and Vienna [n: OFA 8, OCR 12]) statistically comparing lymphocyte subset counts (Mann Whitney Test).
RESULTS
We found that pwMS treated with OCR showed a stronger reduction of CD20 B-lymphocytes ( = .001), and a trend towards lower counts of CD8 T cells ( = .056) compared to pwMS treated with OFA, whereas reduction of total lymphocyte, CD4 lymphocyte and NK cell count was equally distributed between both treatments.
CONCLUSION
Different effects on lymphocyte subpopulations appear to be present in pwMS after treatment initiation with different anti-CD20 mAbs. Further studies are needed to determine potential effects on anti-CD20 treatment efficacy as well as treatment associated risks such as failed vaccinations and infections.
PubMed: 38711956
DOI: 10.1177/11795735241249644 -
Scientific Reports May 2024Depression is a serious psychiatric illness that causes great inconvenience to the lives of elderly individuals. However, the diagnosis of depression is somewhat...
Depression is a serious psychiatric illness that causes great inconvenience to the lives of elderly individuals. However, the diagnosis of depression is somewhat subjective. Nontargeted gas chromatography (GC)/liquid chromatography (LC)-mass spectrometry (MS) was used to study the plasma metabolic profile and identify objective markers for depression and metabolic pathway variation. We recruited 379 Chinese community-dwelling individuals aged ≥ 65. Plasma samples were collected and detected by GC/LC‒MS. Orthogonal partial least squares discriminant analysis and a heatmap were utilized to distinguish the metabolites. Receiver operating characteristic curves were constructed to evaluate the diagnostic value of these differential metabolites. Additionally, metabolic pathway enrichment was performed to reveal metabolic pathway variation. According to our standard, 49 people were included in the depression cohort (DC), and 49 people age- and sex-matched individuals were included in the non-depression cohort (NDC). 64 metabolites identified via GC‒MS and 73 metabolites identified via LC‒MS had significant contributions to the differentiation between the DC and NDC, with VIP values > 1 and p values < 0.05. Three substances were detected by both methods: hypoxanthine, phytosphingosine, and xanthine. Furthermore, 1-(sn-glycero-3-phospho)-1D-myo-inositol had the largest area under the curve (AUC) value (AUC = 0.842). The purine metabolic pathway is the most important change in metabolic pathways. These findings show that there were differences in plasma metabolites between the depression cohort and the non-depression cohort. These identified differential metabolites may be markers of depression and can be used to study the changes in depression metabolic pathways.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Biomarkers; China; Chromatography, Liquid; Depression; East Asian People; Gas Chromatography-Mass Spectrometry; Metabolic Networks and Pathways; Metabolome; Metabolomics; ROC Curve
PubMed: 38705886
DOI: 10.1038/s41598-024-60836-7 -
Journal of Evolutionary Biology May 2024Molluscs have undergone many transitions between separate sexes and hermaphroditism, which is of interest for studying the evolution of sex determination and...
Molluscs have undergone many transitions between separate sexes and hermaphroditism, which is of interest for studying the evolution of sex determination and differentiation. Here we combined multi-locus genotypes obtained from RAD sequencing with anatomical observations of the gonads for three deep-sea hydrothermal vent gastropods of the genus Alviniconcha living in the southwest Pacific. We found that all three species (A. boucheti, A. strummeri, and A. kojimai) share the same male-heterogametic XY sex determination system, but that the gonads of XX A. kojimai individuals are invaded by a variable proportion of male reproductive tissue. The identification of Y-specific RAD loci (found only in A. boucheti) and the phylogenetic analysis of three sex-linked loci shared by all species suggested that X-Y recombination has evolved differently within each species. This situation of three species showing variation in gonadal development around a common sex determination system provides new insights into the reproductive mode of poorly known deep-sea species and opens up an opportunity to study the evolution of recombination suppression on sex chromosomes and its association with mixed or transitory sexual systems.
PubMed: 38699972
DOI: 10.1093/jeb/voae051 -
Frontiers in Endocrinology 2024In mammals, gonadal somatic cell lineage differentiation determines the development of the bipotential gonad into either the ovary or testis. Sertoli cells, the only... (Review)
Review
In mammals, gonadal somatic cell lineage differentiation determines the development of the bipotential gonad into either the ovary or testis. Sertoli cells, the only somatic cells in the spermatogenic tubules, support spermatogenesis during gonadal development. During embryonic Sertoli cell lineage differentiation, relevant genes, including , , , , , , , and , are expressed at specific times and in specific locations to ensure the correct differentiation of the embryo toward the male phenotype. The dysregulated development of Sertoli cells leads to gonadal malformations and male fertility disorders. Nevertheless, the molecular pathways underlying the embryonic origin of Sertoli cells remain elusive. By reviewing recent advances in research on embryonic Sertoli cell genesis and its key regulators, this review provides novel insights into sex determination in male mammals as well as the molecular mechanisms underlying the genealogical differentiation of Sertoli cells in the male reproductive ridge.
Topics: Sertoli Cells; Male; Humans; Animals; Cell Differentiation; Cell Lineage; Reproduction; Spermatogenesis; Sex Determination Processes
PubMed: 38699384
DOI: 10.3389/fendo.2024.1357594 -
Environment International May 2024Combined oral contraceptives, comprising of both an oestrogen and a progestin component, are released in aquatic environments and potentially pose a risk to aquatic...
Estetrol/drospirenone versus 17α-ethinylestradiol/drospirenone: An extended one generation test to evaluate the endocrine disruption potential on zebrafish (Danio rerio).
Combined oral contraceptives, comprising of both an oestrogen and a progestin component, are released in aquatic environments and potentially pose a risk to aquatic wildlife by their capacity to disrupt physiological mechanisms. In this study, the endocrine disruptive potential of two mixtures, 17α-ethinylestradiol (EE2), a synthetic oestrogen, or estetrol (E4), a natural oestrogen, with the progestin drospirenone (DRSP) have been characterised in three generations of zebrafish, according to an adapted Medaka Extended One Generation Reproduction Test. Zebrafish (Danio rerio) were exposed to a range of concentrations of EE2/DRSP and E4/DRSP (∼1×, ∼3×, ∼10× and ∼30× predicted environmental concentration, PEC). Survival, growth, hatching success, fecundity, fertilisation success, vitellogenin (VTG), gonad histopathology, sex differentiation, and transcriptional analysis of genes related to gonadal sex steroid hormones synthesis were assessed. In the F0 generation, exposure to EE2/DRSP at ∼10 and ∼30× PEC decreased fecundity and increased male VTG concentrations. The highest concentration of EE2/DRSP also affected VTG concentrations in female zebrafish and the expression of genes implicated in steroid hormones synthesis. In the F1 generation, sex determination was impaired in fish exposed to EE2/DRSP at concentrations as low as ∼3× PEC. Decreased fecundity and fertility, and abnormal gonadal histopathology were also observed. No effects were observed in the F2 generation. In contrast, E4/DRSP induced only minor histopathological changes and an increase in the proportion of males, at the highest concentration tested (∼30× PEC) in the F1 generation and had no effect on hatching success of F2 generation. Overall, this study suggests that the combination E4/DRSP has a more favourable environmental profile than EE2/DRSP.
Topics: Animals; Zebrafish; Ethinyl Estradiol; Androstenes; Endocrine Disruptors; Female; Male; Water Pollutants, Chemical; Vitellogenins; Reproduction
PubMed: 38678935
DOI: 10.1016/j.envint.2024.108702 -
Animals : An Open Access Journal From... Apr 2024The mechanism of sex determination and differentiation in animals remains a central focus of reproductive and developmental biology research, and the regulation of sex...
The mechanism of sex determination and differentiation in animals remains a central focus of reproductive and developmental biology research, and the regulation of sex differentiation in amphioxus remains poorly understood. Cytochrome P450 Family 19 Subfamily A member 1 () is a crucial sex differentiation gene that catalyzes the conversion of androgens into estrogens. In this study, we identified two aromatase-like genes in amphioxus: and . The is more primitive and may represent the ancestral form of in zebrafish and other vertebrates, while the is likely the result of gene duplication within amphioxus. To gain further insights into the expression level of these two , we examined their expression in different tissues and during different stages of gonad development. While the expression level of the two genes differs in tissues, both are highly expressed in the gonad primordium and are primarily localized to microsomal membrane systems. However, as development proceeds, their expression level decreases significantly. This study enhances our understanding of sex differentiation mechanisms in amphioxus and provides valuable insights into the formation and evolution of sex determination mechanisms in vertebrates.
PubMed: 38672288
DOI: 10.3390/ani14081140 -
World Journal of Gastroenterology Apr 2024Population of patients with inflammatory bowel disease (IBD) is burdened by various extraintestinal manifestations which substantially contribute to greater morbidity...
BACKGROUND
Population of patients with inflammatory bowel disease (IBD) is burdened by various extraintestinal manifestations which substantially contribute to greater morbidity and mortality. Growth-differentiation factor-15 (GDF-15) is often over-expressed under stress conditions, such as inflammation, malignancies, heart failure, myocardial ischemia, and many others.
AIM
To explore the association between GDF-15 and IBD as serum concentrations of GDF-15 were shown to be an independent predictor of poor outcomes in multiple diseases. An additional aim was to determine possible associations between GDF-15 and multiple clinical, anthropometric and laboratory parameters in patients with IBD.
METHODS
This cross-sectional study included 90 adult patients diagnosed with IBD, encompassing both Crohn's disease (CD) and ulcerative colitis (UC), and 67 healthy age- and sex-matched controls. All patients underwent an extensive workup, including colonoscopy with subsequent histopathological analysis. Disease activity was assessed by two independent gastroenterology consultants specialized in IBD, employing well-established clinical and endoscopic scoring systems. GDF-15 serum concentrations were determined following an overnight fasting, using electrochemiluminescence immunoassay.
RESULTS
In patients with IBD, serum GDF-15 concentrations were significantly higher in comparison to the healthy controls [800 (512-1154) pg/mL 412 (407-424) pg/mL, < 0.001], whereas no difference in GDF-15 was found between patients with CD and UC [807 (554-1451) pg/mL 790 (509-956) pg/mL, = 0.324]. Moreover, multiple linear regression analysis showed that GDF-15 levels predict CD and UC severity independent of age, sex, and C-reactive protein levels ( = 0.016 and = 0.049, respectively). Finally, an association between GDF-15 and indices of anemia was established. Specifically, negative correlations were found between GDF-15 and serum iron levels ( = -0.248, = 0.021), as well as GDF-15 and hemoglobin ( = -0.351, = 0.021). Accordingly, in comparison to IBD patients with normal hemoglobin levels, GDF-15 serum levels were higher in patients with anemia (1256 (502-2100) pg/mL 444 (412-795) pg/mL, < 0.001).
CONCLUSION
For the first time, we demonstrated that serum concentrations of GDF-15 are elevated in patients with IBD in comparison to healthy controls, and the results imply that GDF-15 might be involved in IBD pathophysiology. Yet, it remains elusive whether GDF-15 could serve as a prognostic indicator in these patients.
Topics: Adult; Female; Humans; Male; Middle Aged; Young Adult; Anemia; Biomarkers; Case-Control Studies; Colitis, Ulcerative; Colonoscopy; Crohn Disease; Cross-Sectional Studies; Growth Differentiation Factor 15; Inflammatory Bowel Diseases; Patient Acuity
PubMed: 38659482
DOI: 10.3748/wjg.v30.i13.1899