Altered Extracellular Matrix-Related Pathways Accelerate the Transition from Normal to Pre-Fibroid Myometrium in Black Women.

BACKGROUND: Black women experience a disproportionate impact of uterine fibroids compared to White women, including earlier diagnosis, higher frequency, and more severe symptoms. The etiology underlying this racial disparity remains elusive. OBJECTIVE: The aim of this study was to evaluate the molecular differences in normal myometrium (fibroid-free uteri) and at-risk myometrium (fibroid-containing uteri) tissues in Black and White women. STUDY DESIGN: We conducted whole-genome RNA-seq on normal and at-risk myometrium tissues obtained from both self-identified Black and White women (not Hispanic or Latino) to determine global gene expression profiles and to conduct enriched pathway analyses (n=3 per group). We initially assessed the differences within the same type of tissue (normal or at-risk myometrium) between races. Subsequently, we analyzed the transcriptome of normal myometrium compared to at-risk myometrium in each race and determined the differences between them. We validated our findings through real-time PCR (sample size range=5-12), western blot (sample size range=5-6), and immunohistochemistry techniques (sample size range=9-16). RESULTS: The transcriptomic analysis revealed distinct profiles between Black and White women in normal and at-risk myometrium tissues. Interestingly, genes and pathways related to extracellular matrix and mechanosensing were more enriched in normal myometrium from Black than White women. Transcription factor enrichment analysis detected greater activity of the serum response transcription factor positional motif in normal myometrium from Black compared to White women. Furthermore, we observed increased expression levels of myocardin-related transcription factor-serum response factor and the serum response factor in the same comparison. In addition, we noted increased expression of both mRNA and protein levels of vinculin, a target gene of the serum response factor, in normal myometrium tissues from Black women as compared to White women. Importantly, the transcriptomic profile of normal to at-risk myometrium conversion differs between Black and White women. Specifically, we observed that extracellular matrix-related pathways are involved in the transition from normal to at-risk myometrium and that these processes are exacerbated in Black women. We found increased levels of Tenascin C, type I collagen alpha 1 chain, fibronectin and, phospho-p38 MAPK (Thr180/Tyr182, active) protein levels in at-risk over normal myometrium tissues from Black women, whereas such differences were not observed in samples from White women. CONCLUSIONS: These findings indicate that the racial disparities in uterine fibroids may be attributed to heightened production of extracellular matrix in the myometrium in Black women, even before the tumors appear. Future research is needed to understand early life determinants of the observed racial differences.

Optimizing Trace Acetylene Removal from Acetylene/Ethylene Mixture in a Flexible Metal-Organic Framework by Crystal Downsizing.

Improving the gas separation performance of metal-organic frameworks (MOFs) by crystal downsizing is an important but often overlooked issue. Here, we report three different-sized flexible ZUL-520 MOFs (according to the crystal size from large to small, the three samples are, respectively, named ZUL-520-0, ZUL-520-1, and ZUL-520-2) with the same chemical structure for optimizing trace acetylene (C2H2) removal from acetylene/ethylene (C2H2/C2H4) mixture. The three differently sized activated ZUL-520 (denoted as ZUL-520a) exhibited almost identical C2H2 uptake of 4.8 mmol/g at 100 kPa, while the C2H2 uptake at 1 kPa increased with a downsizing crystal. The C2H2 uptake of activated ZUL-520-2 (denoted as ZUL-520-2a) at 1 kPa was ∼55% higher than that of activated ZUL-520-0 (denoted as ZUL-520-0a). The adsorption isotherms and adsorption kinetics validated that gas adsorptive separation is governed not only by adsorption thermodynamics but also by adsorption kinetics. In addition, all three different-sized ZUL-520a MOFs showed high C2H2/C2H4 selectivity. Grand canonical Monte Carlo (GCMC) simulations and dispersion-corrected density functional theory (DFT-D) computations illustrated a plausible mechanism of C2H2 adsorption in MOFs. Importantly, breakthrough experiments demonstrated that ZUL-520a can effectively separate the C2H2/C2H4 (1/99, v/v) mixture and the C2H4 productivity obtained by ZUL-520-2a was much higher than that by ZUL-520-0a. Our work may provide an easy but powerful strategy for upgrading the performance of gas adsorptive separation in MOFs.

Empowering Strategies for Lifestyle Interventions, Diet Modifications, and Environmental Practices for Uterine Fibroid Prevention; Unveiling the LIFE UP Awareness.

Uterine fibroids (UFs) are the most common prevalent benign tumor among women of reproductive age, disproportionately affecting women of color. This paper introduces an innovative management strategy for UFs, emphasizing the curbing of disease prevention and progression. Traditionally, medical intervention is deferred until advanced stages, necessitating invasive surgeries such as hysterectomy or myomectomy, leading to high recurrence rates and increased healthcare costs. The strategy, outlined in this review, emphasizes UF disease management and is named LIFE UP awareness-standing for Lifestyle Interventions, Food Modifications, and Environmental Practices for UF Prevention. These cost-effective, safe, and accessible measures hold the potential to prevent UFs, improve overall reproductive health, reduce the need for invasive procedures, and generate substantial cost savings for both individuals and healthcare systems. This review underscores the importance of a proactive UF management method, paving the way for future research and policy initiatives in this domain.

Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid Cells.

Bromodomain-containing proteins (BRDs) are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD dysfunction has been linked to many diseases, including tumorigenesis. However, the role of BRDs in the pathogenesis of uterine fibroids (UFs) is entirely unknown. The present study aimed to determine the expression pattern of BRD9 in UFs and matched myometrium and further assess the impact of a BRD9 inhibitor on UF phenotype and epigenetic/epitranscriptomic changes. Our studies demonstrated that the levels of BRD9 were significantly upregulated in UFs compared to matched myometrium, suggesting that the aberrant BRD expression may contribute to the pathogenesis of UFs. We then evaluated the potential roles of BRD9 using its specific inhibitor, I-BRD9. Targeted inhibition of BRD9 suppressed UF tumorigenesis with increased apoptosis and cell cycle arrest, decreased cell proliferation, and extracellular matrix deposition in UF cells. The latter is the key hallmark of UFs. Unbiased transcriptomic profiling coupled with downstream bioinformatics analysis further and extensively demonstrated that targeted inhibition of BRD9 impacted the cell cycle- and ECM-related biological pathways and reprogrammed the UF cell epigenome and epitranscriptome in UFs. Taken together, our studies support the critical role of BRD9 in UF cells and the strong interconnection between BRD9 and other pathways controlling the UF progression. Targeted inhibition of BRDs might provide a non-hormonal treatment option for this most common benign tumor in women of reproductive age.

Integration analysis of PLAUR as a sunitinib resistance and macrophage related biomarker in ccRCC, an in silicon and experimental study.

Sunitinib remains the preferred systemic treatment option for specific patients with advanced RCC who are ineligible for immune therapy. However, it's essential to recognize that Sunitinib fails to elicit a favourable response in all patients. Moreover, most patients eventually develop resistance to Sunitinib. Therefore, identifying new targets associated with Sunitinib resistance is crucial. Utilizing multiple datasets from public cohorts, we conducted an exhaustive analysis and identified a total of 8 microRNAs and 112 mRNAs displaying significant expression differences between Sunitinib responsive and resistant groups. A particular set of six genes, specifically NIPSNAP1, STK40, SDC4, NEU1, TBC1D9, and PLAUR, were identified as highly significant via WGCNA. To delve deeper into the resistance mechanisms, we performed additional investigations using cell, molecular, and flow cytometry tests. These studies confirmed PLAUR's pivotal role in fostering Sunitinib resistance, both in vitro and in vivo. Our findings suggest that PLAUR could be a promising therapeutic target across various cancer types. In conclusion, this investigation not only uncovers vital genes and microRNAs associated with Sunitinib resistance in RCC but also introduces PLAUR as a prospective therapeutic target for diverse cancers. The outcomes contribute to advancing personalized healthcare and developing superior therapeutic strategies.Communicated by Ramaswamy H. Sarma.

SPCS, a Novel Classifier System Based on Senescence Axis Regulators Reveals Tumor Microenvironment Heterogeneity and Guides Frontline Therapy for Clear Cell Renal Carcinoma.

RATIONALE: The emerging evidence suggested that senescence regulator genes were involved in multi cancers, which may be utilized as new targets for cancers. However, the dysregulation and clinical impact of senescence regulator genes in clear cell renal cell cancer (ccRCC) were still in foggy. METHODS: Using multiomics data from TCGA-KIRC and other datasets, we comprehensively investigated the function of senescence regulator genes in ccRCC. ccRCC patients could be remodeled into 2 significant different groups basing on senescence regulators expression: senescence-pattern cancer subtype1 (SPCS1) and subtype2 (SPCS2). We further explored clinical characteristics, functional analysis, tumor immune microenvironment, immunotherapy response, genomic mutation and drug sensitivity between the 2 subtypes. Besides, senescence-pattern related risk model was established to determine the patient's prognosis of ccRCC. Finally, the overview of MECP2 function was investigated in multi cancers. RESULTS: ccRCC patients could be divided into SPCS1 (normal aging group) and SPCS2 (Aging disorder group). The 2 subtypes showed significant different clinical characteristics and biological process in ccRCC. SPCS2, an aggressive subtype, comprised higher clinical stage and worse prognosis of ccRCC patients. SPCS2 subtype indicated activated oncogenic signaling pathway and metabolic signatures to prompt cancer expansion. SPCS2 subgroup owned immunocompromised status, which induced immune dysfunction and low ICI therapy response. The genome-copy numbers of SPCS2, including arm-gain and arm-loss was significantly more frequent than SPCS1. In addition, the 2 subtypes argue contrasting drug sensitivity profiles in clinical specimens and matched cell lines. Finally, we constructed a prognostic risk model consisted of each subtype's leading biomarkers, which exerted a satisfied performance for ccRCC patients. CONCLUSION: Senescence regulator-related signature could modify functional pathways and tumor immune microenvironment by genome mutation and pathway interaction. Senescence regulator-related molecular subtype strengthen the understanding of ccRCC' characterization and guide clinical treatment. Targeting senescence regulators may be regard as a proper way in ccRCC.

Diagnostic capability of 18F-PSMA PET-MRI and pelvic MRI plus bone scan in treatment-naive prostate cancer: a single-center paired validating confirmatory study.

BACKGROUND: Radical prostatectomy with pelvic lymph node dissection for the treatment of high-risk localized prostate cancer (PCa) results in long-term benefits in selected patients. But insufficient sensitivity of conventional examinations which are pelvic MRI and bone scan, limits the diagnosis of bone and lymph node metastasis of PCa. This affects the surgical management strategy of a large number of patients. The purpose of this study was to investigate whether 18F-prostate-specific membrane antigen (PSMA) PET-MRI could improve the clinical detection of PCa metastases compared with the conventional pelvic MRI plus bone scan. MATERIALS AND METHODS: From April 2020 to April 2023, we prospectively enroled 472 patients with histologically proven PCa in our centre, and 120 patients underwent 18F-PSMA PET-MRI, multiparametric MRI, and bone scan before laparoscopic radical prostatectomy plus lymph node dissection. The accuracy of imaging results in detecting lymph node and bone metastatic lesions was compared between PSMA PET-MRI and MRI plus bone scan. RESULTS: In diagnosing lymph node metastasis, PSMA PET-MRI had an area under the curve (AUC) of 0.844 (95% CI: 0.738-0.949, P < 0.001), sensitivity and specificity of 75% and 96%, which performed apparently better than MRI [AUC=0.615 (95% CI: 0.480-0.750, P =0.073)]. PSMA PET-MRI showed excellent expression in the diagnosis of bone metastases, with an AUC of 0.910 (95% CI: 0.840-0.981, P <0.001) compared to 0.700 (95% CI: 0.577-0.823, P =0.001) in bone scanning. PSMA PET-MRI also had higher sensitivity than bone scanning (90% vs. 43%), while lower specificity (92% vs. 97%). CONCLUSION: PSMA PET-MRI is superior to conventional imaging at diagnosing metastases in lymph nodes and bones in PCa and can provide a more accurate stagement.

Investigating the prognostic role of lncRNAs associated with disulfidptosis-related genes in clear cell renal cell carcinoma.

INTRODUCTION: Renal cell carcinoma (RCC) is a grave malignancy that poses a significant global health burden with over 400,000 new cases annually. Disulfidptosis, a newly discovered programmed cell death process, is linked to the actin cytoskeleton, which plays a vital role in maintaining cell shape and survival. The role of disulfidptosis is poorly depicted in the clear cell histologic variant of RCC (ccRCC). METHODS: Three sets of ccRCC cohorts, ICGC_RECA-EU (n = 91), GSE76207 (n = 32) and TCGA-KIRC (n = 607), were included in our study, the batch effect of which was removed using the "combat" function. Correlation was calculated using the "rcorr" function of the "Hmisc" package for Pearson analysis, which was visualized using the "pheatmap" package. Principal component analysis was performed by the "vegan" package, visualized using the "scatterplot3d" package. Long non-coding RNAs (lncRNAs) associated with disulfidptosis were screened out using least absolute shrinkage and selection operator (LASSO) and COX analysis. Tumor mutation, immune landscaping and immunotherapy prediction were performed for further characterization of two risk groups. RESULTS: A total of 1822 disulfidptosis-related lncRNAs was selected, among which 308 lncRNAs were found to be significantly associated with the clinical outcome of ccRCC patients. We retained 11 disulfidptosis-related lncRNAs, namely, AP000439.3, RP11-417E7.1, RP11-119D9.1, LINC01510, SNHG3, AC156455.1, RP11-291B21.2, EMX2OS, AC093850.2, HAGLR and RP11-389C8.2, through LASSO and COX analysis for prognosis model construction, which displayed satisfactory accuracy (area under the curve, AUC, values all above 0.6 in multiple cohorts) in stratification of ccRCC prognosis. A nomogram model was constructed by integrating clinical factors with risk score, which further enhanced the prediction efficacy (AUC values all above 0.7 in multiple cohorts). We found that patients of male gender, higher clinical stages and advanced pathological T stage were inclined to have higher risk score values. Dactinomycin_1911, Vinblastine_1004, Daporinad_1248 and Vinorelbine_2048 were identified as promising candidate drugs for treating ccRCC patients of higher risk score value. Moreover, patients of higher risk value were prone to be resistant to immunotherapy. CONCLUSION: We developed a prognosis predicting model based on 11 selected disulfidptosis-related lncRNAs, the efficacy of which was verified in different cohorts. Furthermore, we delineated an intricate portrait of tumor mutation, immune topography and pharmacosensitivity evaluations within disparate risk stratifications.

Survivin-Sodium Iodide Symporter Reporter as a Non-Invasive Diagnostic Marker to Differentiate Uterine Leiomyosarcoma from Leiomyoma.

Leiomyosarcoma (LMS) has been challenging to diagnose because of limitations in clinical and radiographic predictors, as well as the lack of reliable serum or urinary biomarkers. Most uterine masses consist of benign leiomyoma (LM). However, it is currently a significant challenge in gynecology practice to differentiate LMS from LM. This inability poses grave consequences for patients, leading to a high number of unnecessary hysterectomies, infertility, and other major morbidities and possible mortalities. This study aimed to evaluate the use of Survivin-Sodium iodide symporter (Ad-Sur-NIS) as a reporter gene biomarker to differentiate malignant LMS from benign LM by using an F18-NaBF4 PET/CT scan. The PET/CT scan images showed a significantly increased radiotracer uptake and a decreased radiotracer decay attributable to the higher abundance of Ad-Sur-NIS in the LMS tumors compared to LM (p < 0.05). An excellent safety profile was observed, with no pathological or metabolic differences detected in Ad-Sur-NIS-treated animal versus the vehicle control. Ad-Sur-NIS as a PET scan reporter is a promising imaging biomarker that can differentiate uterine LMS from LM using F18-NaBF4 as a radiotracer. As a new diagnostic method, the F18 NaBF4 PET/CT scan can provide a much-needed tool in clinical practices to effectively triage women with suspicious uterine masses and avoid unnecessary invasive interventions.

Evidence-Based Approach for Secondary Prevention of Uterine Fibroids (The ESCAPE Approach).

Uterine fibroids (UFs) are common tumors in women of reproductive age. It is imperative to comprehend UFs' associated risk factors to facilitate early detection and prevention. Simple relying on surgical/pharmacological treatment of advanced disease is not only highly expensive, but it also deprives patients of good quality of life (QOL). Unfortunately, even if the disease is discovered early, no medical intervention is traditionally initiated until the disease burden becomes high, and only then is surgical intervention performed. Furthermore, after myomectomy, the recurrence rate of UFs is extremely high with the need for additional surgeries and other interventions. This confused approach is invasive and extremely costly with an overall negative impact on women's health. Secondary prevention is the management of early disease to slow down its progression or even halt it completely. The current approach of watchful observation for early disease is considered a major missed opportunity in the literature. The aim of this article is to present an approach named the ESCAPE (Evidence-Based Approach for Secondary Prevention) of UF management. It comprises simple, inexpensive, and safe steps that can arrest the development of UFs, promote overall reproductive health, decrease the number of unnecessary surgeries, and save billions of health care systems' dollars worldwide.

Spatial Distribution of Nitrogen Binding Sites in Metal-Organic Frameworks for Selective Ethane Adsorption and One-Step Ethylene Purification.

The one-step purification of ethylene (C2 H4 ) from mixtures containing ethane (C2 H6 ) and acetylene (C2 H2 ) is an industrially important yet challenging process. In this work, we present a site-engineering strategy aimed at manipulating the spatial distribution of binding sites within a confined pore space. We realized successfully by incorporating nitrogen-containing heterocycles, such as indole-5-carboxylic acid (Ind), benzimidazole-5-carboxylic acid (Bzz), and indazole-5-carboxylic acid (Izo), into the robust MOF-808 platform via post-synthetic modification. The resulting functionalized materials, namely MOF-808-Ind, MOF-808-Bzz, and MOF-808-Izo, demonstrated significantly improved selectivity for C2 H2 and C2 H6 over C2 H4 . MOF-808-Bzz with two uniformly distributed nitrogen binding sites gave the optimal geometry for selective ethane trapping through multiple strong C-H⋅⋅⋅N hydrogen bonds, leading to the highest C2 H2 /C2 H4 and C2 H6 /C2 H4 combined selectivities among known MOFs. Column breakthrough experiments validated its ability to purify C2 H4 from ternary C2 H2 /C2 H4 /C2 H6 mixtures in a single step.

Current and Emerging Treatment Options for Uterine Fibroids.

Uterine fibroids are the most common benign neoplasm of the female reproductive tract in reproductive age women. Their prevalence is age dependent and can be detected in up to 80% of women by the age of 50 years. Patients affected by uterine fibroids may experience a significant physical, emotional, social, and financial toll as well as losses in their quality of life. Unfortunately, curative hysterectomy abolishes future pregnancy potential, while uterine-sparing surgical and radiologic alternatives are variously associated with reduced long-term reproductive function and/or high tumor recurrence rates. Recently, pharmacological treatment against uterine fibroids have been widely considered by patients to limit uterine fibroid-associated symptoms such as heavy menstrual bleeding. This hormonal therapy seemed effective through blocking the stimulatory effects of gonadal steroid hormones on uterine fibroid growth. However, they are contraindicated in women actively pursuing pregnancy and otherwise effective only during use, which is limited because of long-term safety and other concerns. Accordingly, there is an urgent unmet need for safe, durable, and fertility-compatible non-surgical treatment options for uterine fibroids. In this review article, we cover the current pharmacological treatments for uterine fibroids including their comparable efficacy and side effects as well as emerging safe natural compounds with promising anti-uterine fibroid effects.

TGFß signaling links early life endocrine-disrupting chemicals exposure to suppression of nucleotide excision repair in rat myometrial stem cells.

Environmental exposure to endocrine-disrupting chemicals (EDCs) is linked to the development of uterine fibroids (UFs) in women. UFs, non-cancerous tumors, are thought to originate from abnormal myometrial stem cells (MMSCs). Defective DNA repair capacity may contribute to the emergence of mutations that promote tumor growth. The multifunctional cytokine TGFß1 is associated with UF progression and DNA damage repair pathways. To investigate the impact of EDC exposure on TGFß1 and nucleotide excision repair (NER) pathways, we isolated MMSCs from 5-month-old Eker rats exposed neonatally to diethylstilbestrol (DES), an EDC, or to vehicle (VEH). EDC-MMSCs exhibited overactivated TGFß1 signaling and reduced mRNA and protein levels of NER pathway components compared to VEH-MMSCs. EDC-MMSCs also demonstrated impaired NER capacity. Exposing VEH-MMSCs to TGFß1 decreased NER capacity while inhibiting TGFß signaling in EDC-MMSCs restored it. RNA-seq analysis and further validation revealed decreased expression of Uvrag, a tumor suppressor gene involved in DNA damage recognition, in VEH-MMSCs treated with TGFß1, but increased expression in EDC-MMSCs after TGFß signaling inhibition. Overall, we demonstrated that the overactivation of the TGFß pathway links early life exposure to EDCs with impaired NER capacity, which would lead to increased genetic instability, arise of mutations, and fibroid tumorigenesis. We demonstrated that the overactivation of the TGFß pathway links early life exposure to EDCs with impaired NER capacity, which would lead to increased fibroid incidence.

The combination of natural compounds Crila and epigallocatechin gallate showed enhanced antiproliferative effects on human uterine fibroid cells compared with single treatments.

OBJECTIVE: To investigate the combined effects of Crila and green tea extract, epigallocatechin gallate (EGCG), compared with single treatments, on human uterine fibroid cells. DESIGN: Human uterine leiomyoma (HuLM) cells were treated with different concentrations of Crila, alone or in combination with EGCG, and several experiments were employed. SETTING: A laboratory study. PATIENTSS: N/A. INTERVENTIONS: Crila, EGCG. MAIN OUTCOME MEASURES: Cell proliferation assay, drug synergy using combination index, protein and gene expression analysis of proliferation marker proliferating cell nuclear antigen, and apoptosis marker BAX using western blotting and quantitative polymerase chain reaction, respectively. RESULTS: Results showed that tested Crila concentrations, when combined with 25 and 50 µM EGCG, exerted synergistic growth inhibitory effects on HuLM viability. This inhibitory effect on HuLM cell viability was because of decreased cell proliferation, as shown by a decrease in the proliferation marker proliferating cell nuclear antigen at messenger RNA and protein levels, rather than inducing apoptosis. CONCLUSION: Our study concludes that the utility of natural compounds may provide a safe and cost-effective alternative to currently used short-term hormonal therapies against uterine fibroids.

Prevention of Uterine Fibroids: molecular mechanisms and potential clinical application.

Uterine fibroids (UFs; leiomyoma) are the most common benign neoplastic threat to women worldwide, exacting an immense personal burden on female health and a monetary expense to the healthcare system estimated in the hundreds of billions of dollars every year globally. With no long-term non-invasive treatment option currently available to treat UFs, deeper insights regarding tumor etiology are the key for developing newer therapies. Accordingly, in this review, we discuss new mechanistic paradigm to explain UF tumor development through an exquisite model involving developmental reprogramming of myometrial stem cells due to early life endocrine disruptors exposure, inflammation, fibrosis, DNA damage, and eventually tissue stiffness. Further, we propose to utilize shear wave elastography as a potential screening tool for the early identification of women at risk for developing UFs who can benefit from several simple preventive strategies, including the consumption of natural compounds such as vitamin D and green tea as a safe fertility friendly non-hormonal modality to delay or even arrest or reverse UF progression.

Glycolysis-related biomarker TCIRG1 participates in regulation of renal cell carcinoma progression and tumor immune microenvironment by affecting aerobic glycolysis and AKT/mTOR signaling pathway.

BACKGROUND: Renal cell carcinoma (RCC) is a hypermetabolic disease. Abnormal up-regulation of glycolytic signaling promotes tumor growth, and glycolytic metabolism is closely related to immunotherapy of renal cancer. The aim of the present study was to determine whether and how the glycolysis-related biomarker TCIRG1 affects aerobic glycolysis, the tumor microenvironment (TME) and malignant progression of clear cell renal cell carcinoma (ccRCC). METHODS: Based on The Cancer Genome Atlas (TCGA, n = 533) and the glycolysis-related gene set from MSigDB, we identified the glycolysis-related gene TCIRG1 by bioinformatics analysis, analyzed its immunological properties in ccRCC and observed how it affected the biological function and glycolytic metabolism using online databases such as TIMER 2.0, UALCAN, LinkedOmics and in vitro experiments. RESULTS: It was found that the expression of TCIRG1, was significantly increased in ccRCC tissue, and that high TCIRG1 expression was associated with poor overall survival (OS) and short progression-free interval (PFI). In addition, TCIRG1 expression was highly correlated with the infiltration immune cells, especially CD4+T cell Th1, CD8+T cell, NK cell, and M1 macrophage, and positively correlated with PDCD1, CTLA4 and other immunoinhibitors, CCL5, CXCR3 and other chemokines and chemokine receptors. More importantly, TCIRG1 may regulate aerobic glycolysis in ccRCC via the AKT/mTOR signaling pathway, thereby affecting the malignant progression of ccRCC cell lines. CONCLUSIONS: Our results demonstrate that the glycolysis-related biomarker TCIRG1 is a tumor-promoting factor by affecting aerobic glycolysis and tumor immune microenvironment in ccRCC, and this finding may provide a new idea for the treatment of ccRCC by combination of metabolic intervention and immunotherapy.

Developmental reprogramming of myometrial stem cells by endocrine disruptor linking to risk of uterine fibroids.

BACKGROUND: The stage, when tissues and organs are growing, is very vulnerable to environmental influences, but it's not clear how exposure during this time causes changes to the epigenome and increases the risk of hormone-related illnesses like uterine fibroids (UFs). METHODS: Developmental reprogramming of myometrial stem cells (MMSCs), the putative origin from which UFs originate, was investigated in vitro and in the Eker rat model by RNA-seq, ChIP-seq, RRBS, gain/loss of function analysis, and luciferase activity assays. RESULTS: When exposed to the endocrine-disrupting chemical (EDC) diethylstilbestrol during Eker rat development, MMSCs undergo a reprogramming of their estrogen-responsive transcriptome. The reprogrammed genes in MMSCs are known as estrogen-responsive genes (ERGs) and are activated by mixed lineage leukemia protein-1 (MLL1) and DNA hypo-methylation mechanisms. Additionally, we observed a notable elevation in the expression of ERGs in MMSCs from Eker rats exposed to natural steroids after developmental exposure to EDC, thereby augmenting estrogen activity. CONCLUSION: Our studies identify epigenetic mechanisms of MLL1/DNA hypo-methylation-mediated MMSC reprogramming. EDC exposure epigenetically targets MMSCs and leads to persistent changes in the expression of a subset of ERGs, imparting a hormonal imprint on the ERGs, resulting in a "hyper-estrogenic" phenotype, and increasing the hormone-dependent risk of UFs.

Association of biopsy core number and location with pain in patients undergoing a transperineal prostate biopsy under local anaesthesia: a secondary analysis of the APROPOS trial.

BACKGROUND: APROPOS was a multicentre, randomized, blinded trial focus on investigating the perineal nerve block versus the periprostatic block in pain control for men undergoing a transperineal prostate biopsy. In the analysis reported here, the authors aimed to evaluate the association of biopsy core count and location with pain outcomes in patients undergoing a transperineal prostate biopsy under local anesthesia. METHODS: APROPOS was performed at six medical centers in China. Patients with suspected prostate cancer were randomized to receive either a perineal nerve block or a periprostatic block (1:1), followed by a transperineal prostate biopsy. The secondary analysis outcomes were the worst pain experienced during the prostate biopsy and postbiopsy pain at 1,6, and 24 h. RESULTS: Between 12 August 2020 and 20 July 2022, a total of 192 patients were randomized in the original trial, and 188 were involved in this analysis, with 94 patients per group. Participants had a median (IQR) age of 68 (63-72) and a median (IQR) prostate volume of 42.51 (30.04-62.84). The patient population had a median (IQR) number of biopsy cores of 15 (12-17.50), and 26.06% of patients had a biopsy cores count of more than 15. After adjusting the baseline characteristics, the number of biopsy cores was associated with the worst pain during the biopsy procedure in both the perineal nerve block group ( ß 0.19, 95% CI: 0.12-0.26, P <0.001) and the periprostatic block group ( ß 0.16, 95% CI: 0.07-0.24, P <0.001). A similar association was also evident for the postbiopsy pain at 1, 6, and 24 h. A lesser degree of pain in both groups at any time (r range -0.57 to -0.01 for both groups) was associated with biopsy cores from the peripheral zone of the middle gland, while other locations were associated with a higher degree of pain. In addition, the location of the biopsy core had less of an effect on pain during the biopsy (r range -0.01-0.25 for both groups) than it did on postbiopsy pain (r range -0.57-0.60 for both groups). CONCLUSIONS: In this secondary analysis of a randomized trial, biopsy core count and location were associated with pain in patients undergoing a transperineal prostate biopsy under local anesthesia. These results may be helpful for making clinical decisions about the anesthetic approach for scheduled transperineal prostate biopsies.

Epigenetic Modulation of Inflammatory Pathways in Myometrial Stem Cells and Risk of Uterine Fibroids.

The period during which tissue and organ development occurs is particularly vulnerable to the influence of environmental exposures. However, the specific mechanisms through which biological pathways are disrupted in response to developmental insults, consequently elevating the risk of hormone-dependent diseases, such as uterine fibroids (UFs), remain poorly understood. Here, we show that developmental exposure to the endocrine-disrupting chemical (EDC), diethylstilbestrol (DES), activates the inflammatory pathways in myometrial stem cells (MMSCs), which are the origin of UFs. Significantly, the secretome of reprogrammed MMSCs enhances the expression of critical inflammation-related genes in differentiated myometrial cells through the paracrine mechanism, which amplifies pro-inflammatory and immune suppression signaling in the myometrium. The expression of reprogrammed inflammatory responsive genes (IRGs) is driven by activated mixed-lineage leukemia protein-1 (MLL1) in MMSCs. The deactivation of MLL reverses the reprogramming of IRG expression. In addition, the inhibition of histone deacetylases (HDACs) also reversed the reprogrammed IRG expression induced by EDC exposure. This work identifies the epigenetic mechanisms of MLL1/HDAC-mediated MMSC reprogramming, and EDC exposure epigenetically targets MMSCs and imparts an IRG expression pattern, which may result in a "hyper-inflammatory phenotype" and an increased hormone-dependent risk of UFs later in life.

TGFß signaling links early-life endocrine-disrupting chemicals exposure to suppression of nucleotide excision repair in rat myometrial stem cells.

Environmental exposure to endocrine-disrupting chemicals (EDCs) is linked to the development of uterine fibroids (UFs) in women. UFs, non-cancerous tumors, are thought to originate from abnormal myometrial stem cells (MMSCs). Defective DNA repair capacity may contribute to the emergence of mutations that promote tumor growth. The multifunctional cytokine TGFß1 is associated with UF progression and DNA damage repair pathways. To investigate the impact of EDC exposure on TGFß1 and nucleotide excision repair (NER) pathways, we isolated MMSCs from 5-months old Eker rats exposed neonatally to Diethylstilbestrol (DES), an EDC, or to vehicle (VEH). EDC-MMSCs exhibited overactivated TGFß1 signaling and reduced mRNA and protein levels of NER pathway components compared to VEH-MMSCs. EDC-MMSCs also demonstrated impaired NER capacity. Exposing VEH-MMSCs to TGFß1 decreased NER capacity while inhibiting TGFß signaling in EDC-MMSCs restored it. RNA-seq analysis and further validation revealed decreased expression of Uvrag, a tumor suppressor gene involved in DNA damage recognition, in VEH-MMSCs treated with TGFß1, but increased expression in EDC-MMSCs after TGFß signaling inhibition. Overall, we demonstrated that the overactivation of the TGFß pathway links early-life exposure to EDCs with impaired NER capacity, which would lead to increased genetic instability, arise of mutations, and fibroid tumorigenesis. We demonstrated that the overactivation of the TGFß pathway links early-life exposure to EDCs with impaired NER capacity, which would lead to increased fibroid incidence.