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PubMed2025

Reconsidering the definition of triple-negative breast cancer in the immune checkpoint inhibitor era: an optimal cut-off value for hormone receptor percentage of HER2-negative invasive breast cancer.

The optimal cut-off values of estrogen receptor (ER) and progesterone receptor (PgR) expression to define the positivity of ER and PgR have been under discussion for over a decade but remain controversial. The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) and the St. Gallen International Expert Consensus recommended that breast cancers with ≥1% of ER or PgR expression should be considered hormone receptor (HR)-positive tumors but ER/PR expression of 1% to 10% should be reported as HR-low positive; however, among HER2-negative disease, data on the overall benefit of adjuvant endocrine therapies for patients with HR-low positive disease is limited, resulting in the revisiting of the definition of triple-negative breast cancer (TNBC). Defining HR-low positive disease by better understanding the biology is essential because of the recent advancement of neoadjuvant and adjuvant systemic therapy strategies, including immune checkpoint inhibitors (ICIs) for TNBC. Additionally, identifying who should be treated with adjuvant endocrine therapy, particularly those who have HR-low HER2-negative disease, which is currently treated as TNBC without adjuvant endocrine therapy, is a clinical unmet need. In clinical practice, treating physicians have tailored systemic treatment strategies using other clinical and pathological factors (i.e., age, grade, Ki-67, tumor size, lymph node involvement). There is no universal practice to treat patients with HR-low HER2-negative breast cancer. This review summarized the currently available data to define the clinically relevant optimal cut-off values of ER/PgR in neoadjuvant- and adjuvant-setting. We recommend considering creating a novel category of triple-negative like breast cancer (TN-like BC), which will require a therapeutic strategy different from conventional TNBC.

Humans↗

PubMed2026

Genomic hallmarks of depot medroxyprogesterone acetate-associated meningiomas.

BACKGROUND: Population-based studies have linked progestin exposure to increased meningioma risk. However, the molecular basis of meningiomas associated with depot medroxyprogesterone acetate (DMPA)-a common injectable contraceptive-remains undefined. METHODS: We performed an integrated clinicopathologic and genomic analysis of meningiomas from 10 women with long-term DMPA exposure. Tumors underwent histopathological analysis, targeted sequencing, and DNA methylation profiling. Data were integrated with reference cohorts (Baylor and Heidelberg) and analyzed through classifier assignment, consensus clustering, copy number analysis, differential methylation testing, and dimensionality reduction. RESULTS: Depot medroxyprogesterone acetate-associated meningiomas were all newly diagnosed, World Health Organization grade 1 tumors with a predilection for the anterior and central skull base (n = 6). Nine patients harbored multiple meningiomas. Four experienced regression of untreated meningiomas following DMPA cessation, while 5 demonstrated stabilization. Histopathology demonstrated relative overrepresentation of metaplastic morphology, an uncommon meningioma subtype. All DMPA-associated meningiomas mapped to benign molecular groups, and most exhibited low copy number alteration burden. Targeted sequencing revealed enrichment for TRAF7 mutations (n = 5), with no NF2 mutations detected. Eight tumors shared consensus cluster identity, with cohesive grouping on principal component analysis and t-distributed stochastic neighbor embedding. No differential methylation was identified at the progesterone receptor locus. CONCLUSIONS: Depot medroxyprogesterone acetate-associated meningiomas represent a recognizable phenotype within the broader NF2-wildtype/TRAF7-enriched spectrum of benign meningiomas, characterized by chromosomal stability, a shared methylation profile, tumor multiplicity, and regression or stabilization following DMPA cessation. While derived from a small single-institution cohort, these findings provide a molecular framework for understanding progestin-associated meningioma biology, reinterpreting epidemiologic literature, and informing population-level risk stratification.

Humans↗

PubMed2026

Treatment of Hot Flashes in Men With Prostate Cancer Undergoing Androgen Deprivation Therapy.

BACKGROUND: Hot flashes are common and often debilitating side effects of castration therapy; a cornerstone in the treatment of metastatic prostate cancer (PCa) as well as in localized or locally advanced PCa when combined with radiotherapy. The evidence for relieving vasomotor symptoms is limited. This systematic review presents both pharmacological and non-pharmacological interventions for treating hot flashes in men with PCa undergoing castration therapy, primarily androgen deprivation therapy (ADT). METHODS: a systematic literature search was conducted in PubMed using ("hot flash*" OR "hot flush*" OR "vasomotor*") AND ("prostate") as keywords. Studies with intervention for hot flashes due to castration therapy, estimation of treatment response (e.g., reduction in frequency or impact on quality of life) and patients with PCa (any stage) were eligible. RESULTS: Of 469 papers, 35 were included in the review. The included studies evaluated cyproterone acetate, estrogen or estrogen derivatives, progesterone derivatives, selective serotonin reuptake inhibitors (SSRIs), gabapentin, oxybutynin, and clonidine, as well as non-pharmacological interventions such as acupuncture, cognitive behavioral therapy (CBT), and dietary supplements (e.g., Dong Quai/Angelica Sinensis, Serelys Homme, soy protein, and Salvia officinalis). Across all blinded pharmacological interventions, the relative reduction in hot flash frequency ranged from -21% to -84%, and the placebo effect was between -19% and -30%. CONCLUSION: Hormonal agents such as cyproterone acetate and estrogen appear to be the most effective treatments, although they are associated with side effects. Non-pharmacological options like acupuncture and CBT may offer some benefit, while dietary supplements seem to be ineffective. Future studies are needed also to evaluate newer treatments, such as fezolinetant, in this patient population.

Humans↗

PubMed2026

Altered reproductive hormone profiles in systemic lupus erythematosus - A systematic review and meta-analysis.

BACKGROUND: Systemic lupus erythematosus (SLE) shows a marked female predominance during reproductive years, possibly suggesting hormonal factors in its pathogenesis. However, evidence regarding reproductive hormone alterations in SLE remains inconsistent. OBJECTIVES: To systematically review studies assessing reproductive hormone levels in adult SLE patients compared with healthy controls and across disease activity states. METHODS: Following PRISMA guidelines and a pre-registered protocol (PROSPERO CRD42024544730), PubMed and Scopus were searched (May 2024). Eligible observational studies reported estradiol, testosterone, progesterone, prolactin, FSH, LH, DHEA-S, DHEA or androstenedione in SLE patients versus controls or by disease activity. Random-effects meta-analyses were conducted. RESULTS: Eighty-three studies were included (5389 individuals for SLE vs. controls; 2067 for active vs. inactive SLE). Prolactin was consistently higher in SLE (MD 8.07 ng/mL; 95% CI 4.69-11.45; p < 0.001) and even more during flare (MD 5.83 ng/mL; 95% CI 3.88-7.78; p < 0.001). Estradiol showed non-significant overall elevations but was significantly higher in women with active disease (MD 8.55 pg/mL; 95% CI 1.37-15.73; p = 0.03). DHEA-S was found to be significantly lower in SLE (MD -1.00 μg/mL; 95% CI -1.5 to -0.50; p = 0.002) but too few studies evaluated its dynamics during flares. FSH and LH were significantly higher in men with SLE. Other hormones were inconsistent. Only three small heterogeneous studies evaluated hormonal changes during flares. CONCLUSIONS: Prolactin excess and androgen deficiency are consistent features of SLE, particularly in women, while elevated gonadotropins are mainly seen in men. Estradiol is higher during active disease but other data are inconsistent. Longitudinal studies are limited, with prolactin the only hormone consistently linked to disease activity and full hormonal profiles during flares are largely unstudied.

Humans↗

PubMed2026

Targeting TP53 in triple-negative breast cancer: Molecular pathogenesis, therapeutic implications, and emerging pharmacological strategies.

Triple-negative breast cancer (TNBC) remains a highly aggressive and therapeutically challenging subtype, defined by the absence of oestrogen, progesterone, and HER2 expression. Tumour Protein 53 (TP53) mutations represent the most frequent genetic alteration, occurring in over 80% of cases and driving tumour initiation, progression, and therapeutic resistance. Mutant p53 proteins not only lose canonical tumour-suppressive functions but also often acquire gain-of-function (GOF) oncogenic properties that promote metastasis, genomic instability, and resistance to mechanisms like ferroptosis. This review examines the biological role of TP53 in TNBC pathogenesis and evaluates emerging pharmacological strategies aimed at targeting these vulnerabilities. Key approaches include the pharmacological reactivation of mutant p53 using small molecules such as APR-246, COTI-2, and the mutation-specific reactivator rezatapopt (PC14586), which has shown significant clinical tumour reduction in Y220C-mutant patients. Other strategies involve targeted protein degradation, the exploitation of synthetic lethal interactions (e.g., Chk1 or Aurora kinase B inhibition), and the use of natural products like cryptolepine or piperine derivatives. Recent clinical evidence further highlights the potential of combining epigenetic agents like decitabine with chemotherapy in TP53-mutant populations. Integrating TP53 mutation status into biomarker-driven treatment paradigms is a pivotal step toward achieving precision oncology and improving clinical outcomes for patients with TNBC.

Precision oncology↗

PubMed2026

Exploring hormonal influences on nicotine craving and use across the perinatal period: A prospective longitudinal study.

INTRODUCTION: Perinatal nicotine use is common despite well-documented adverse consequences. We examined associations between reproductive-related hormones with nicotine craving and use during the perinatal period to identify potential novel intervention points. METHODS: All participants reported use of nicotine during the perinatal period. Participants were enrolled at gestational week ≥ 36 and followed to postpartum week 12 via daily surveys (i.e., nicotine craving via 100-point scale, dichotomous use) and weekly hormone measurement in saliva (cortisol, oxytocin) or dried blood spots (progesterone, estradiol, testosterone, dehydroepiandrosterone sulfate). Bayesian mixed-effects models accounted for within-person correlation while estimating hormone effects. RESULTS: Participants (n = 46) were 28.9 ± 4.9 years old. During follow-up, exclusive combustible cigarettes (n = 20), electronic nicotine delivery systems (ENDS; n = 13), or dual (n = 2) use was observed, with variability in use and craving across participants and over time. During pregnancy, higher oxytocin was linked to greater craving (β=16.31, 95% CI: 3.71, 28.83). Greater peripartum declines in oxytocin were associated with more craving (β=8.71, 95% CI: 0.75, 16.93) and use (β=1.13, 95% CI: 0.05, 2.43). During postpartum, lower estradiol was linked to more craving (β=-1.17, 95% CI: -2.15, -0.18) and use (β=-0.40, 95% CI: -0.76, -0.03). In models simultaneously evaluating all postpartum hormones, the lone meaningful association was between estradiol and craving (β=-1.66, 95% CI: -2.84, -0.48). CONCLUSIONS: The results of this study suggest that oxytocin and estradiol may contribute to the risk of perinatal nicotine use. Additional research is needed to replicate our observations in more diverse study samples and explore implications for clinical intervention.

Bayesian↗

PubMed2025

Deciphering Pseudoendocrine Sarcoma: A Clinicopathological, Molecular, and Epigenetic Study Suggesting Biological Links With Solid Pseudopapillary Neoplasm of the Pancreas.

Pseudoendocrine sarcoma (PS) is a recently described neoplasm of uncertain differentiation, characterized by recurrent CTNNB1 mutations, frequent paravertebral location, and a neuroendocrine-like histomorphology. In this study, we report the clinicopathologic, immunohistochemical, transcriptomic, and epigenetic findings of 12 PS cases. The tumors affected 7 men and 5 women with a median age of 66 years and were located in the paraspinal/paravertebral region (n = 11) and the thigh (n = 1). Median tumor size was 82 mm (range, 32-170 mm). Histologically, the tumors comprised sheets and nests of epithelioid-to-ovoid cells with uniform nuclei and speckled chromatin, frequently associated with extracellular hyaline globules and fibrovascular cords/septa. Uncommon findings included microcalcifications, myxoid stroma, pseudopapillary, pseudoglandular, microcystic or corded architecture, and lumen and rosette-like structures. Necrosis was absent, and mitotic activity was low. On immunohistochemistry, the tumors showed aberrant nuclear staining for beta-catenin (8/8) and expression of CD56 (7/7), S100 (8/8), desmin (2/6), and androgen receptor (1/4). Pankeratin (AE1/AE3), progesterone receptor, synaptophysin, chromogranin, and INSM1 were negative. All tested cases harbored CTNNB1 mutations. Using a customized cohort, methylation profiling revealed that PS formed a common cluster with solid pseudopapillary neoplasm of the pancreas (SPNP), distinct from all methylation classes from the Heidelberg sarcoma classifier and a subset of paragangliomas. Transcriptomic analysis showed that PS formed an independent cluster from a control group of tumors (including SPNP). Differential gene expression analysis showed enrichment in genes of the Wnt signaling pathway (HALLMARK gene sets) and biological processes related to sensory perception, among others (gene ontology - biological process [GO-BP]). Additionally, upregulated genes were related to various fetal cell types from the cell type signature data set (MSigDB), particularly of neuronal and epithelial lineage. Immunohistochemical assessment of potential markers identified through gene expression analysis revealed focal-to-diffuse expression of GLUT1 (6/6) and focal/multifocal expression of Brachyury (4/9) and HuD (3/7). Follow-up information, available for 10 cases (median duration of 18 months; range, 7-69 months), showed local recurrences and metastatic spread in 2 patients each. Evidence of response to radiotherapy was documented in one tumor. Altogether, this study expands knowledge on PS and suggests biological links with SPNP, including a potential shared cell of origin.

Humans↗

PubMed2026

Time-varying hazard rates reveal patterns of progression in HR+/HER2- metastatic breast cancer: Towards risk-adapted monitoring.

BACKGROUND: optimal imaging intervals for patients with hormone receptor-positive/HER2-negative metastatic breast cancer (MBC) remains undefined. Aim of this study was to analyze the temporal patterns of disease progression to identify high risk subgroups that may benefit from intensified monitoring. METHODS: we analyzed 149 hormone receptor-positive/HER2-negative MBC patients prospectively enrolled in the MAGNETIC.1 trial (NCT05814224) and treated with first line endocrine therapy. Hazard rates (HR) for disease progression were determined according to clinico-pathological and liquid biopsy features. RESULTS: in the overall population, two distinct progression-risk peaks emerged at 2-3 months (32.9/1000 person-months) and at 24 months (28.0/1000). Higher risk of progression was observed in lobular carcinoma (61.1) [HR 61.12 per 1000 person month (pm)], progesterone receptor-negative status (HR 39.07), fulvestrant-based treatment (HR 46.88), liver metastases (HR 59.00), and presence of ≥ 3 metastatic sites (HR 40.10). CONCLUSIONS: Hazard distribution in hormone receptor-positive/HER2-negative MBC is biphasic and modulated by readily available clinical variables. High-risk subgroups may benefit from intensified radiologic and liquid-biopsy surveillance during the first three months and around two years after treatment start.

Breast cancer↗

PubMed2026

Epigenetic modulators in triple-negative breast cancer: epigenetic modifications and future treatment perspectives.

Triple Negative Breast Cancer (TNBC), an aggressive type of Breast Cancer (BC) characterized by the loss of expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal growth factor Receptor 2 (HER2) protein. TNBC is quite heterogenous in nature with limited available therapeutic options due to the lack of defined molecular targets. Epigenetic abnormalities have been implicated in the onset, progression, immune escape, and resistance to treatment in TNBC. Important epigenetic modulations, include DNA methylation, histone lactylation, histone modifications, and chromatin remodeling. Global hypomethylation contributes to genomic instability, while promoter hypermethylation inhibits tumor suppressor genes, by dysregulating their expression, thereby promoting uncontrolled proliferation, EMT, metastasis, and immune evasion in TNBC. Targeting epigenetic modulators, have the potential to develop novel therapeutic interventions have been developed and being explored. These epidrugs have proven to be effective in preclinical and clinical trials when used in combination with chemotherapy, immunotherapy, or targeted therapy, reducing drug resistance and aberrant proliferation. Despite of the advancements, challenges like target specificity, precise biomarkers and treatment related toxicity are the major hurdles. The review comprehensively summarized the important epigenetic alterations as well as novel treatment strategies with potential clinical applications in TNBC.

Humans↗

PubMed2025

Clinical and molecular landscape of metastatic extramammary Paget's disease.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignancy without established systemic therapy. EMPD shares molecular features with breast cancer, such as human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) expression, but their clinical relevance remains unclear. MATERIALS AND METHODS: Tumors from 20 metastatic invasive EMPD cases were analyzed for molecular and biological features. Genomic features, transcriptomic profiles, and HER2 and HR expression status were investigated using immunohistochemistry, fluorescence in situ hybridization, and targeted-genome next-generation sequencing and nCounter BC360 panels. Metastatic breast cancer samples were used as a comparison to clarify metastatic EMPD's clinical relevance. RESULTS: Estrogen receptor expression was observed in 45% of EMPD tumors, while only 10% expressed progesterone receptor. HER2 was overexpressed in 30% of cases, and HER2-directed therapies were durably effective. Among 8 patients with NGS data, 63% (5/8) harbored oncogenic ERBB2 alterations independent of HER2 expression. BC360 profiling revealed biological differences between EMPD and breast cancer, particularly poor biological compatibility for HR-positive tumors. Immune profiling showed that a subset of EMPD tumors exhibited CD8+ T-cell signatures and PD-1/PD-L1 gene expression comparable to triple-negative breast cancer. The median overall survival was 22.1 months (95% CI, 12.0-42.2), with 16 patients (80%) treated with systemic therapy, including anti-HER2 therapy, hormonal therapy, or cytotoxic therapies based on their molecular features. CONCLUSIONS: This study highlights the unique molecular and biological features of metastatic EMPD, emphasizing the need for tailored treatment approaches. This information should be used to guide future clinical strategies for metastatic EMPD.

Humans↗

PubMed2026

Uterine Leiomyomas Presenting During Pregnancy and Delivery: Comprehensive Characterization of Features Helpful in the Distinction From Malignant Mimics.

A subset of uterine leiomyomas becomes clinically apparent during pregnancy/delivery and is typically excised during Cesarean section. Although benign, these leiomyomas excised during pregnancy and/or delivery (LEPs) can pose diagnostic challenges due to morphologic changes that mimic malignant mesenchymal neoplasms, such as leiomyosarcoma. This study analyzed 97 LEPs to characterize their histopathologic and immunohistochemical features. Histologic examination revealed predominantly low mitotic activity (mean: 0.5 mitoses/10 HPFs) and mild (87.6% of tumors) to at most focal moderate (9.3% of tumors) nuclear atypia. Ischemic necrosis occurred in 57.7% of tumors. Features attributed to coagulative necrosis were common, including sharp viable-nonviable transition (22.7%), perivascular tumor preservation (9.3%), and ghost outlines of tumor cell nuclei (50.5%). Focal myxoid changes, affecting ≤30% of tumor volume, were seen in 42.3% of tumors. Rare, bizarre cells were identified in 48.5% of tumors. Immunohistochemistry demonstrated the absence of estrogen receptor staining in 65% of tumors, with focal staining in 35.2%, and progesterone receptor expression in 97.7%. Caldesmon (98.9%) and desmin (100%) were positive, with the majority diffuse. CD10 (100%) showed variable staining intensity. Wild-type p53 expression was seen in all tumors tested. Expression of ATRX, MTAP, RB1, and PTEN was predominantly retained with equivocal staining in 35.3% (ATRX) and 3.4% (RB1) of tumors. Although Cyclin D1 expression was common (97.4%), it was always focal, with no diffuse (≥70%) strong nuclear staining. FH loss occurred in 3.2% of tumors. All tumors were negative for MelanA, and 92.4% were negative for HMB45. Calretinin expression was observed in 39% of tumors, typically focal and strong, while only 1 tumor showed positive inhibin staining in <5% of cells. ALK expression was focally positive or equivocal in 9.6% of cases, but no gene rearrangements were identified by in situ hybridization. Follow-up data were available for 71 patients (mean: 56 mo), with no malignant transformation or recurrence. These findings confirm that LEPs exhibit distinct morphologic and immunophenotypic alterations, including features typically attributed to coagulative tumor cell necrosis. However, given benign clinical outcomes, low mitotic activity, and lack of significant atypia, such a finding does not warrant designation as leiomyosarcoma or smooth muscle tumor of uncertain malignant potential in the context of concurrent pregnancy.

Female↗

PubMed2026

Bridging the gap: multi-omic insights into exercise responses in postmenopausal women.

Postmenopausal women represent the fastest-growing demographic at risk of sarcopenia and cardiometabolic disease, yet exercise biology research remains disproportionately derived from male or hormone-replete phenotypes. Menopause constitutes a chronic endocrine perturbation characterized by sustained reductions in estrogen and progesterone, and altered androgen balance, superimposed on the acute and chronic perturbations induced by exercise. This hormonal shift modifies substrate metabolism, inflammation, redox balance, and recovery capacity, factors that shape molecular responses to exercise across tissues and time. Here, we synthesize current evidence on exercise responses in postmenopausal females across genomics, epigenomics, transcriptomics, proteomics, and metabolomics/lipidomics. Across omics layers, direct data in postmenopausal cohorts remain limited, with frequent underreporting of menopausal status, hormone therapy exposure, circulating hormone concentrations, medication use, and biosampling timing relative to exercise and hormone dosing. We outline a menopause-aware framework for exercise-omics that prioritizes endocrine stratification, repeated sampling across exercise and recovery, and integrative multi-omics approaches linking molecular responses to functional outcomes. We also outline minimum reporting standards to improve reproducibility, inclusivity, and translational relevance. Advancing menopause-aware exercise-omics will be essential for developing precision exercise strategies that improve health span and functional independence in later life.

Humans↗

PubMed2025

Investigating the molecular mechanisms, drug prediction, and validation of CCNA2 and MAD2L1 in esophageal squamous cell carcinoma based on bioinformatics.

OBJECTIVE: Aims to comprehensively investigate the expression patterns of CCNA2 and MAD2L1 in esophageal squamous cell carcinoma using bioinformatics methods. METHODS: Based on WGCNA analysis of gene mutation expression, methylation level distribution, mRNA expression and ESCC-related genes in public databases, were employed for investigating potential biomarkers for prognosis of esophageal squamous cell carcinoma(ESCC).Finally,. performing qRT-PCR and immunohistochemistry to validate. RESULTS: Ultimately identified 4 hub genes: CDK1, CCNA2,TOP2A and MAD2L1. Bioinformatics analysis showed high expression of these four genes in ESCC (P < 0.05). CCNA2 and MAD2L1 were selected for subsequent analysis based on literature.3.Single gene enrichment analysis revealed significant enrichment of CCNA2 and MAD2L1 in pathways related to splicing, bladder cancer, non-homologous end joining and homologous recombination, glycosaminoglycan biosynthesis chondroitin sulfate, progesterone-mediated oocyte maturation and mismatch repair. PASTAA database indicated the involvement of transcription factors such as Roralpha1, Pou6f1, Roralpha2, Atf-1, Pax-3, C/ebpalpha, Nkx2-1 in the regulation of CCNA2, while no transcription factors were predicted for MAD2L1..Immune infiltration analysis revealed a close association between ESCC and plasma cells, CD8 + T cells, monocytes, M0 macrophages, M1 macrophages, dendritic cells, and resting mast cells.Drug prediction for CCNA2 included 7 drugs such as ETHINYL ESTRADIOL, Seliciclib and TAMOXIFEN, while no drugs were predicted for MAD2L1.qRT-PCR and immunohistochemistry demonstrated high expression of CCNA2 in ESCC, while MAD2L1 showed no significant difference between ESCC and normal esophageal squamous epithelial tissues. CONCLUSION: CCNA2 and MAD2L1 may be potential biomarkers for ESCC, providing a novel basis for understanding the molecular mechanisms underlying ESCC pathogenesis.Additionally, the potential drugs predicted for CCNA2 may emerge as a new hope for ESCC patients in the future.

Humans↗

PubMed2025

The causal relationship between steroid hormones and risk of stroke: evidence from a two-sample Mendelian randomization study.

It is unclear how steroid hormones contribute to stroke, and conducting randomized controlled trials to obtain related evidence is challenging. Therefore, Mendelian randomization (MR) technique was employed in this study to examine this association. Through genome-wide association meta-analysis, the genetic variants of steroid hormones, including testosterone/17β-estradiol (T/E2) ratio, aldosterone, androstenedione, progesterone, and hydroxyprogesterone, were acquired as instrumental variables. Analysis was done on the impact of these steroid hormones on the risk of stroke subtypes. The T/E2 ratio was associated to an elevated risk of small vessel stroke (SVS) according to the inverse variance weighted approach which was the main MR analytic technique (OR, 1.23, 95% CI: 1.05-1.44, p = 0.009). These findings were solid since no heterogeneity nor horizontal pleiotropy were found. The causal association between T/E2 and SVS was also confirmed in the replication study (p = 0.009). Nevertheless, there was no proof that other steroid hormones increased the risk of stroke. According to this study, T/E2 ratio and SVS are causally related. However, strong evidence for the impact of other steroid hormones on stroke subtypes is still lacking. These findings may be beneficial for developing stroke prevention strategies from steroid hormones levels.

Mendelian Randomization Analysis↗

PubMed2026

Multi-omics integration uncovers epigenetic control of metabolic reprogramming in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen, progesterone, and HER2 receptors, limiting effective targeted therapies. Increasing evidence suggests that metabolic reprogramming, a hallmark of TNBC progression, is driven by underlying epigenetic mechanisms such as DNA methylation. The represented study performed an integrative analysis of transcriptomic (RNA-seq) and methylome data to uncover the metabolic-epigenetic interplay in TNBC. Differential gene expression analysis using DESeq2 revealed significant dysregulation of key metabolic genes, including upregulation of genes encoding glycolytic and serine biosynthesis enzymes and downregulation of metabolic tumor suppressors. Genome-wide methylation profiling identified extensive cytosine-phosphate-guanine (CpG) hypermethylation events associated with transcriptional repression, particularly in promoter regions. Integrative analysis pinpointed a subset of metabolism-related genes exhibiting both differential expression and methylation, such as FBP1, RASSF1A, and PHGDH. Pathway enrichment analysis highlighted aberrations in glycolysis/gluconeogenesis, fatty acid metabolism, and one-carbon pathways (adjusted p < 0.01). Importantly, TNBC patients with hypermethylated metabolic gene signatures displayed significantly shorter overall survival (log-rank p < 0.05). These findings reveal that DNA methylation-driven metabolic dysregulation contributes to TNBC aggressiveness and may provide novel biomarkers and therapeutic targets at the metabolic-epigenetic interface.

Humans↗

PubMed2026

Novel compound heterozygous POR variants in a neonate with Antley-Bixler syndrome and 46,XY DSD: a case report and literature review.

BACKGROUND: Cytochrome P450 oxidoreductase deficiency (PORD) is an ultra-rare autosomal recessive disorder within the congenital adrenal hyperplasia (CAH) spectrum, characterized by a broad clinical spectrum involving steroidogenesis defects, genital anomalies, and skeletal abnormalities. CASE PRESENTATION: We report a phenotypically female neonate with a 46,XY karyotype whose postnatal diagnostic evaluation was initiated after newborn screening revealed elevated 17-hydroxyprogesterone (17-OHP) concentration. The patient presented with mild hypertelorism, mild nasal hypoplasia, and low-set bilateral ears, along with female external genitalia consistent with disorder of sex development (DSD) and anal atresia. Radiological evaluation revealed femoral bowing and subsequent fracture. The craniofacial and skeletal abnormalities were consistent with the features of Antley-Bixler syndrome (ABS). Endocrine evaluation revealed elevated progesterone, markedly reduced testosterone, and secondary hyperaldosteronism. Genetic analysis identified three novel variants in the POR gene (NM_001395413.1): the patient harbored a paternal c.1187_1195dup (p.Pro396_Glu398dup) variant and two maternally inherited variants in cis, c.1447G>A (p.Gly483Ser) and c.1806 + 4_1806 + 28del. Protein structural modeling predicted that the p.Pro396_Glu398dup and p.Gly483Ser may disrupt the flavin adenine dinucleotide (FAD)-binding domain. RNA sequencing (RNA-seq) confirmed that the intronic variant c.1806 + 4_1806 + 28del caused aberrant splicing, resulting in partial intron retention and predicted impairment of the nicotinamide adenine dinucleotide phosphate (NADPH)-binding domain. According to American College of Medical Genetics and Genomics (ACMG) guidelines and incorporating functional evidence, c.1187_1195dup and c.1806 + 4_1806 + 28del were reclassified as likely pathogenic (LP), whereas c.1447G>A remained a variant of uncertain significance (VUS). CONCLUSIONS: This study describes a neonate with PORD caused by three novel POR variants and expands the known clinical spectrum of PORD by identifying rare manifestations including anal atresia and hearing loss. RNA-seq provided valuable functional evidence for variant interpretation and facilitated accurate molecular diagnosis. These findings highlight the importance of integrating genetic phasing, transcript-level functional analysis, and comprehensive clinical evaluation for precise diagnosis and counseling in rare endocrine disorders.

Humans↗

PubMed2026

[Study of a patient with azoospermia due to variant of MOV10L1 gene].

OBJECTIVE: To explore the clinical and genotypic characteristics of a patient with Sertoli cell-only syndrome (SCOS) due to variants of MOV10L1 gene. METHODS: A 27-year-old patient with Non-obstructive azoospermia (NOA) underwent routine semen analysis. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), estradiol (E2), prolactin (PRL), and testosterone (T) were determined by chemiluminescence assays. Peripheral blood samples were collected for G-banded karyotyping analysis. Multiplex PCR fluorescence detection was used to screen for AZF gene microdeletions. Whole exome sequencing (WES) and Sanger sequencing were performed simultaneously. Testicular biopsy tissues were subjected to Hematoxylin-Eosin (HE) staining to assess seminiferous tubule cell composition, and MOV10L1 protein expression was detected by immunohistochemical staining. Bioinformatics tools were employed to predict the pathogenicity of variants and their impact on protein structure and function. This study was approved by the Medical Ethics Committee of the Guangdong Institute of Reproductive Sciences [Ethics No.: 2023(01)]. RESULTS: The patient's two semen analyses had failed to detect any sperm. Hormone tests indicated elevated FSH (22.32 mIU/mL) and PRL (397.6 mIU/mL), while T (3.68 nmol/L) and E2 (38.32 pmol/L) were reduced. Chromosomal karyotyping revealed 46,XY, and no AZF gene deletion was detected. WES and Sanger sequencing detected compound heterozygous variants of the MOV10L1 gene, including a c.345C>A (p.C115X) nonsense variant and a c.3323C>T (p.T1108I) missense variant, with the former being unreported previously. HE staining showed only Sertoli cells in the seminiferous tubules, confirming the diagnosis of SCOS. Immunohistochemical staining revealed absent MOV10L1 protein expression in the testicular tissue. Based on the guidelines from American College of Medical Genetics and Genomics (ACMG), the c.345C>A (p.C115X) was classified as a pathogenic variant (PVS1+PM2_Supporting+PP4), while the c.3323C>T (p.T1108I) was deemed variant of uncertain significance (PM2_Supporting+PP3_Supporting+PP4). Bioinformatics analysis demonstrated that c.345C>A (p.C115X) may cause premature termination of protein translation, while c.3323C>T (p.T1108I) may disrupt the hydrophobicity of the RNA helicase domain, reducing the active pocket volume and decreasing its affinity for MILI protein. CONCLUSION: This study has diagnosed a case of SCOS due to compound heterozygous variants of the MOV10L1 gene, which also enriched its mutational spectrum.

Humans↗

PubMed2026

PGR expression as a pharmacogenomic companion biomarker to GENE70-derived genomic risk in ER-positive/HER2-negative breast cancer.

BACKGROUND: The biology of the estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancers is heterogeneous even when they are categorized by their risk via genomics. Transcriptomic PGR expression reflects endocrine pathway activity and may provide complementary biological information within established GENE70-derived genomic-risk categories. Whether this molecular marker improves the biological interpretation of genomic-risk stratification beyond conventional clinicopathological assessment remains uncertain. OBJECTIVES: The aim of this study was to determine whether transcriptomic PGR expression provides complementary biological and prognostic information within reconstructed GENE70-derived genomic-risk categories and refines the characterization of endocrine-related tumour biology in ER-positive/HER2-negative breast cancer. METHODS: This study analysed publicly available transcriptomic and clinical data from three cohorts: METABRIC (discovery cohort), GSE96058/SCAN-B cohort (validation cohort) and TCGA-BRCA cohort (molecular validation cohort). The GENE70-derived genomic-risk score was reconstructed for each cohort using matched genes. Cox regression, Kaplan-Meier analysis and subgroup comparisons were used to assess relationships between PGR expression, clinicopathologic variables, molecular features and survival outcomes. RESULTS: Across the three independent cohorts, low transcriptomic PGR expression was consistently associated with higher GENE70-derived genomic risk, increased MKI67 expression, reduced ESR1 expression and enrichment of the Luminal B subtype. Survival findings differed between cohorts. In the discovery METABRIC cohort, transcriptomic PGR expression showed heterogeneous associations with survival, particularly within GENE70-derived high-risk subgroups, whereas the external GSE96058/SCAN-B validation cohort demonstrated consistent associations between low PGR expression and poorer overall survival in both the overall ER-positive/HER2-negative population and GENE70-derived high-risk subgroups. CONCLUSION: These findings suggest that transcriptomic PGR provides complementary biological and prognostic information within GENE70-derived genomic-risk categories. However, because treatment response was not evaluated in the present study, the findings should not be interpreted as evidence of predictive or pharmacogenomic utility and prospective studies incorporating treatment-response analyses are required before such applications can be established.

Humans↗