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Clinics (Sao Paulo, Brazil) 2024The present study aimed to investigate FOXO3a deregulation in Uterine Smooth Muscle Tumors (USMT) and its potential association with cancer development and prognosis.
OBJECTIVE
The present study aimed to investigate FOXO3a deregulation in Uterine Smooth Muscle Tumors (USMT) and its potential association with cancer development and prognosis.
METHODS
The authors analyzed gene and protein expression profiles of FOXO3a in 56 uterine Leiomyosarcomas (LMS), 119 leiomyomas (comprising conventional and unusual leiomyomas), and 20 Myometrium (MM) samples. The authors used techniques such as Immunohistochemistry (IHC), FISH/CISH, and qRT-PCR for the present analyses. Additionally, the authors conducted an in-silico analysis to understand the interaction network involving FOXO3a and its correlated genes.
RESULTS
This investigation revealed distinct expression patterns of the FOXO3a gene and protein, including both normal and phosphorylated forms. Expression levels were notably elevated in LMS, and Unusual Leiomyomas (ULM) compared to conventional Leiomyomas (LM) and Myometrium (MM) samples. This upregulation was significantly associated with metastasis and Overall Survival (OS) in LMS patients. Intriguingly, FOXO3a deregulation did not seem to be influenced by EGF/HER-2 signaling, as there were minimal levels of EGF and VEGF expression detected, and HER-2 and EGFR were negative in the analyzed samples. In the examination of miRNAs, the authors observed upregulation of miR-96-5p and miR-155-5p, which are known negative regulators of FOXO3a, in LMS samples. Conversely, the tumor suppressor miR-let7c-5p was downregulated.
CONCLUSIONS
In summary, the outcomes of the present study suggest that the imbalance in FOXO3a within Uterine Smooth Muscle Tumors might arise from both protein phosphorylation and miRNA activity. FOXO3a could emerge as a promising therapeutic target for individuals with Unusual Leiomyomas and Leiomyosarcomas (ULM and LMS), offering novel directions for treatment strategies.
Topics: Humans; Female; Forkhead Box Protein O3; Uterine Neoplasms; Middle Aged; Leiomyoma; Adult; Immunohistochemistry; Gene Expression Regulation, Neoplastic; Leiomyosarcoma; Smooth Muscle Tumor; Up-Regulation; MicroRNAs; Prognosis; Aged; Myometrium
PubMed: 38636197
DOI: 10.1016/j.clinsp.2024.100350 -
Protein & Cell Jul 2024Adenomyosis is a poorly understood gynecological disorder lacking effective treatments. Controversy persists regarding "invagination" and "metaplasia" theories. The...
Adenomyosis is a poorly understood gynecological disorder lacking effective treatments. Controversy persists regarding "invagination" and "metaplasia" theories. The endometrial-myometrial junction (EMJ) connects the endometrium and myometrium and is important for diagnosing and classifying adenomyosis, but its in-depth study is just beginning. Using single-cell RNA sequencing and spatial profiling, we mapped transcriptional alterations across eutopic endometrium, lesions, and EMJ. Within lesions, we identified unique epithelial (LGR5+) and invasive stromal (PKIB+) subpopulations, along with WFDC1+ progenitor cells, supporting a complex interplay between "invagination" and "metaplasia" theories of pathogenesis. Further, we observed endothelial cell heterogeneity and abnormal angiogenic signaling involving vascular endothelial growth factor and angiopoietin pathways. Cell-cell communication differed markedly between ectopic and eutopic endometrium, with aberrant signaling in lesions involving pleiotrophin, TWEAK, and WNT cascades. This study reveals unique stem cell-like and invasive cell subpopulations within adenomyosis lesions identified, dysfunctional signaling, and EMJ abnormalities critical to developing precise diagnostic and therapeutic strategies.
Topics: Humans; Female; Adenomyosis; Single-Cell Analysis; Transcriptome; Endometrium; Sequence Analysis, RNA; Myometrium
PubMed: 38486356
DOI: 10.1093/procel/pwae012 -
Reproduction (Cambridge, England) Aug 2023Inappropriate uterine contractions are a matter of concern during pregnancy or menses. We identified the transient receptor potential melastatin 4 (TRPM4) ion channel as...
IN BRIEF
Inappropriate uterine contractions are a matter of concern during pregnancy or menses. We identified the transient receptor potential melastatin 4 (TRPM4) ion channel as a new actor in mouse uterine contractions highlighting this protein as a potential pharmacological target for a better control of myometrial activity.
ABSTRACT
Control of uterine contractions is of interest in the context of inappropriate myometrial activity during pregnancy and at time of delivery, but it is also a matter for menstrual pain. While several molecular determinants of myometrial contractions have been described, the complete distribution of roles to the various actors is far from understood. A key phenomenon is a variation in cytoplasmic Ca2+ which leads to the activation of calmodulin in smooth muscle and also in the phosphorylation of myosin allowing contraction. The Ca2+ - TRPM4 channel which is known to modulate Ca2+- fluxes in several cell types was shown to participate in vascular as well as detrusor muscle contraction. We thus designed a study to determine whether it also participates in myometrial contraction. Uterine rings were isolated from Trpm4+/+ and Trpm4-/- non-pregnant adult mice and contractions were recorded using an isometric force transducer. In basal conditions, spontaneous contractions were similar in both groups. Application of 9-phenanthrol, a pharmacological TRPM4 inhibitor, dose-dependently reduced contraction parameters in Trpm4+/+ rings with an IC50 around 2.10-6 mol/L. The effect of 9-phenanthrol was significantly reduced in Trpm4-/- rings. The effect of oxytocin was tested and was found to be stronger in Trpm4+/+ rings compared to Trpm4-/-. Under a constant stimulation by oxytocin, 9-phenanthrol still reduced contraction parameters in Trpm4+/+ rings with a smaller effect on Trpm4-/-. Altogether it indicates that TRPM4 participates in uterine contractions in mice and may thus be evaluated as a new target to control such contractions.
Topics: Female; Pregnancy; Mice; Animals; Uterine Contraction; Calcium; Oxytocin; TRPM Cation Channels; Myometrium
PubMed: 37204208
DOI: 10.1530/REP-22-0484 -
Cureus Sep 2023Formation of a uterine niche following a C-section can predispose the patient to future obstetric complications such as dehiscence, uterine rupture, ectopic pregnancy,... (Review)
Review
Formation of a uterine niche following a C-section can predispose the patient to future obstetric complications such as dehiscence, uterine rupture, ectopic pregnancy, and placenta accreta. The significant morbidity and mortality of these complications along with increasing C-section rates emphasizes the importance of prevention. However, there are no clear guidelines on intra-operative protocol to prevent postpartum niche formation. Besides surgical technique, the novel use of platelet-rich plasma (PRP) and mesenchymal stem cell (MSC) injections has demonstrated promising potential and may have applications in hysterotomy closures. The objective is to examine current research on optimal C-section procedures to prevent uterine niche formation and subsequent obstetric complications. A systematic review was conducted using PubMed and Google Scholar. Initial searches yielded 827 results. Inclusion criteria were human, animal, and in-vitro studies, peer-reviewed sources, and outcomes pertinent to the uterine niche. Exclusion criteria applied to articles with outcomes unrelated to myometrium and interventions outside of the intra-operative and immediate pre-/post-operative period. Based on the criteria, 41 articles were cited. Pathophysiology of uterine niche formation was associated with incisions through cervical tissue, adhesion formation, and poor approximation. Significant risk factors were low uterine incisions, advanced cervical dilatation, low station, non-closure of the peritoneum, and creation of a bladder flap. There was no consensus on uterine closure as it likely depends on surgical proficiency with the given technique, but a double-layered non-locking suture appears reliable to reduce niche severity. Recent trials indicate that intra-operative PRP/MSC injections may decrease niche incidence and severity, but more research is needed. If prevention or minimization of uterine niche is desired, the optimal C-section protocol should avoid low uterine incisions, choose uterine closure technique based on the surgeon's proficiency (double-layered non-locking is reliable), and close the peritoneum, and myometrial injection of PRP/MSC may be a useful adjunct intervention pending further clinical evidence.
PubMed: 37790067
DOI: 10.7759/cureus.44521 -
Nature Communications Jan 2024Age-associated myometrial dysfunction can prompt complications during pregnancy and labor, which is one of the factors contributing to the 7.8-fold increase in maternal...
Age-associated myometrial dysfunction can prompt complications during pregnancy and labor, which is one of the factors contributing to the 7.8-fold increase in maternal mortality in women over 40. Using single-cell/single-nucleus RNA sequencing and spatial transcriptomics, we have constructed a cellular atlas of the aging myometrium from 186,120 cells across twenty perimenopausal and postmenopausal women. We identify 23 myometrial cell subpopulations, including contractile and venous capillary cells as well as immune-modulated fibroblasts. Myometrial aging leads to fewer contractile capillary cells, a reduced level of ion channel expression in smooth muscle cells, and impaired gene expression in endothelial, smooth muscle, fibroblast, perivascular, and immune cells. We observe altered myometrial cell-to-cell communication as an aging hallmark, which associated with the loss of 25 signaling pathways, including those related to angiogenesis, tissue repair, contractility, immunity, and nervous system regulation. These insights may contribute to a better understanding of the complications faced by older individuals during pregnancy and labor.
Topics: Pregnancy; Humans; Female; Myometrium; Labor, Obstetric; Muscle, Smooth; Aging; Muscle Contraction
PubMed: 38296945
DOI: 10.1038/s41467-024-45143-z -
The Journal of Maternal-fetal &... Dec 2023Describe the clinical-surgical results of patients with PAS in the low-posterior cervical-trigonal space associated with fibrosis (PAS type 4) compared with PAS types in...
OBJECTIVE
Describe the clinical-surgical results of patients with PAS in the low-posterior cervical-trigonal space associated with fibrosis (PAS type 4) compared with PAS types in other locations (Types 1, upper bladder, 2 in upper parametrium) and in particular with PAS type 3, corresponding to dissectible cervical-trigonal invasion. The clinical-surgical results of using a standard hysterectomy were analyzed with a modified subtotal hysterectomy (MSTH) in patients with PAS type 4.
MATERIAL AND METHODS
A descriptive, retrospective, multicenter study included 337 patients of PAS; thirty-two corresponding to PAS type 4, from three PAS reference hospitals, CEMIC, Buenos Aires, Argentina, Fundación Valle de Lili, Cali, Colombia, and Dr. Soetomo General Hospital, Surabaya, Indonesia, between January 2015 and December 2020. PAS was diagnosed by abdominal and transvaginal ultrasound and topographically characterized by ultrafast T2 weighted MRI. In persistent macroscopic hematuria after MSTH, the surgeon performs an intentional cystotomy and uses a square compression suture to achieve the hemostasis inside the bladder wall.According to a PAS topographical classification, the patients with low-vesical cervical involvement compared with PAS located in relation with the upper blader (type1), upper parametrium (type 2 upper), and also with PAS situated in the lower vesical-trigon space (type 3). PAS 3 and 4 are located in identical area, but in type 3, group A, the vesicouterine space was dissectible, and in type 4, group B, significant fibrosis made surgical dissection extremely challenging. Furthermore, group B was divided into patients treated with total hysterectomy (HT) and those treated with a modified subtotal hysterectomy (MSTH). The surgical requirements to perform an MSHT included the availability of proximal vascular control at the aortic level (internal manual aortic compression, aortic endovascular balloon, aortic loop, or aortic cross-clamping). Then surgeon performed an upper segmental hysterotomy, avoiding the abnormal placenta invasion area; after that, the fetus was delivered, and the umbilical cord was ligated.After uterine exteriorization, the surgeon applies a continuous circular suture with number 2 polyglactin 910, taking some portions of the myometrium -to avoid unintentional slipping- around the lower uterine segment and a 3-4 cm proximal to the abnormal adhesion of the placenta. After tightening hard the circular suture, the uterine segment was circumferentially cut, three centimeters proximal to the circular hemostatic sutures. Next, the surgery follows the upper steps of conventional hysterectomy without changes. Additionally, the histological presence of fibrosis was examined in all samples.
RESULTS
Modified subtotal hysterectomy in patients with PAS type 4 (cervical-trigonal fibrosis) resulted in a significant clínico-surgical improvement over total hysterectomy. The median operative time and intraoperative bleeding were 140 min (IQR 90--240) and 1895 mL (IQR 1300-2500) in patients undergoing modified subtotal hysterectomy, and 260 min (IQR 210-287) and 2900 mL (IQR 2150-5500) in patients treated with total hysterectomy, respectively. The complication rate was 20% for MSHT and 82.3% for patients with a total hysterectomy.
CONCLUSIONS
PAS in the cervical trigonal area associated with fibrosis implies a greater risk of complications due to uncontrollable bleeding and organ damage. MSTH is associated with lower morbidity and difficulties in PAS type 4. Prenatal or intrasurgical diagnosis is essential to plan surgical alternatives to improve the results.
Topics: Pregnancy; Female; Humans; Placenta Accreta; Retrospective Studies; Uterus; Hysterectomy; Morbidity; Fibrosis; Placenta
PubMed: 37193605
DOI: 10.1080/14767058.2023.2183741 -
International Journal of Gynaecology... Aug 2023An accessory cavitated uterine mass (or malformation) (ACUM) is an isolated cystic uterine lesion located at the lateral aspect of the myometrium just below the... (Review)
Review
An accessory cavitated uterine mass (or malformation) (ACUM) is an isolated cystic uterine lesion located at the lateral aspect of the myometrium just below the insertion of the round ligament. Often the source of severe dysmenorrhea and pelvic pain, this condition is classified as a Müllerian abnormality. Understanding ACUMs, recognizing their clinical appearance, diagnosing an ACUM with ultrasound or magnetic resonance imaging, and advising patients about conservative, medicinal, and surgical treatment options is important to all clinicians. Although ACUM primarily presents with severe dysmenorrhea but can have other clinical symptoms, we have provided a few sample cases to help clinicians prepare for ACUM encounters. We also reviewed the other published literature available on ACUM regarding clinical presentation, etiology, and management. Last but not least, based on our research and the work of others, we offer a set of characteristics that will be useful in diagnosing and treating ACUM. ACUM diagnosis is crucial in clinically suspicious circumstances, and early treatment significantly enhances patients' quality of life.
Topics: Female; Humans; Dysmenorrhea; Quality of Life; Uterus; Pelvic Pain
PubMed: 36656754
DOI: 10.1002/ijgo.14681 -
Reproductive Sciences (Thousand Oaks,... Feb 2024Adenomyosis is associated with pelvic pain, abnormal uterine bleeding, and infertility. Several ultrasound-based classifications have been reported, but it is not clear... (Review)
Review
Adenomyosis is associated with pelvic pain, abnormal uterine bleeding, and infertility. Several ultrasound-based classifications have been reported, but it is not clear which criteria reflect the severity of symptoms. The aim of this review is to summarize the ultrasound features that correlate with clinical manifestations of adenomyosis and to discuss diagnostic methods for predicting disease severity. A literature search of PubMed and Google Scholar published up to March 2022 was performed. A consensus-based classification was determined primarily by defining the mapping or topography of the lesion. Ultrasound features can be classified into direct (i.e., the presence of ectopic endometrial tissue within the myometrium) and indirect findings (i.e., changes in the myometrial structure and translesional vascularity secondary to myometrial invasion). There are some reports that symptoms are positively correlated with the location and spread of the disease. Indeed, the lesion thickness, diffuse or internal adenomyosis, and focal adenomyosis may be associated with increased risks of dysmenorrhea, abnormal uterine bleeding, and infertility, respectively. Two ultrasound markers (i.e., the presence of heterogeneous myometrium and myometrial cysts) appear to be the criteria most clinicians focus on. However, decision-making on treatment necessity is determined by symptom severity rather than the topography of the lesions. There is currently no consensus that symptom severity can be predicted based on ultrasound features, but the ultrasound-based criteria may be helpful in diagnosing adenomyosis.
Topics: Female; Humans; Adenomyosis; Uterine Diseases; Ultrasonography; Myometrium; Infertility; Uterine Hemorrhage
PubMed: 37584856
DOI: 10.1007/s43032-023-01318-5 -
Biomolecules Apr 2024Hydrogen sulfide (HS), previously regarded as a toxic exhaust and atmospheric pollutant, has emerged as the third gaseous signaling molecule following nitric oxide (NO)... (Review)
Review
Hydrogen sulfide (HS), previously regarded as a toxic exhaust and atmospheric pollutant, has emerged as the third gaseous signaling molecule following nitric oxide (NO) and carbon monoxide (CO). Recent research has revealed significant biological effects of HS in a variety of systems, such as the nervous, cardiovascular, and digestive systems. Additionally, HS has been found to impact reproductive system function and may have therapeutic implications for reproductive disorders. This paper explores the relationship between HS and male reproductive disorders, specifically erectile dysfunction, prostate cancer, male infertility, and testicular damage. Additionally, it examines the impact of HS regulation on the pathophysiology of the female reproductive system, including improvements in preterm birth, endometriosis, pre-eclampsia, fetal growth restriction, unexplained recurrent spontaneous abortion, placental oxidative damage, embryo implantation, recovery of myometrium post-delivery, and ovulation. The study delves into the regulatory functions of HS within the reproductive systems of both genders, including its impact on the NO/cGMP pathway, the activation of K channels, and the relaxation mechanism of the spongy smooth muscle through the ROCK pathway, aiming to broaden the scope of potential therapeutic strategies for treating reproductive system disorders in clinical settings.
Topics: Hydrogen Sulfide; Humans; Female; Male; Pregnancy; Animals; Nitric Oxide; Reproduction
PubMed: 38785947
DOI: 10.3390/biom14050540 -
Radiology Aug 2023Background The Ovarian-Adnexal Reporting and Data System (O-RADS) has limited specificity for malignancy. Contrast-enhanced US can help distinguish malignant from benign...
Background The Ovarian-Adnexal Reporting and Data System (O-RADS) has limited specificity for malignancy. Contrast-enhanced US can help distinguish malignant from benign lesions, but its added value to O-RADS has not yet been assessed. Purpose To establish a diagnostic model combining O-RADS and contrast-enhanced US and to validate whether O-RADS plus contrast-enhanced US has a better diagnostic performance than O-RADS alone. Materials and Methods This prospective study included participants from May 2018 to March 2021 who underwent contrast-enhanced US before surgery and had lesions categorized as O-RADS 3, 4, or 5 by US, with a histopathologic reference standard. From April 2021 to July 2022, participants with pathologically confirmed ovarian-adnexal lesions were recruited for the validation group. In the pilot group, the initial enhancement time and enhancement intensity in comparison with the uterine myometrium, contrast agent distribution pattern, and dynamic changes in enhancement of lesions were assessed. Contrast-enhanced US features were used to calculate contrast-enhanced US scores for benign (score ≤2) and malignant (score ≥4) lesions. Lesions were then re-rated according to O-RADS category plus contrast-enhanced US scores. Receiver operating characteristic curves were constructed and compared using the DeLong method. The combined system was validated in an independent group. Results The pilot group included 76 women (mean age, 44 years ± 13 [SD]), and the validation group included 46 women (mean age, 42 years ± 14). Differences in initial enhancement time ( < .001), enhancement intensity ( < .001), and dynamic changes in enhancement ( < .001) between benign and malignant lesions were observed in the pilot group. Contrast-enhanced US scores were calculated using these features. The O-RADS risk stratification was upgraded one level for contrast-enhanced US scores of 4 or more and downgraded one level for contrast-enhanced US scores of 2 or less. In the validation group, the diagnostic performance of O-RADS plus contrast-enhanced US score was higher (area under the receiver operating characteristic curve [AUC] = 0.93) than O-RADS (AUC = 0.71, < .001). Conclusion Contrast-enhanced US improved the diagnostic performance for malignancy of the O-RADS categories 3-5. © RSNA, 2023 See also the editorial by Grant in this issue.
Topics: Humans; Female; Adult; Prospective Studies; Retrospective Studies; ROC Curve; Neoplasms; Risk Assessment; Sensitivity and Specificity; Ultrasonography
PubMed: 37552073
DOI: 10.1148/radiol.223003