Construction and validation of risk prediction models for pulmonary embolism in hospitalized patients based on different machine learning methods

ObjectiveThis study aims to apply different machine learning (ML) methods to construct risk prediction models for pulmonary embolism (PE) in hospitalized patients, and to evaluate and compare the predictive efficacy and clinical benefit of each model.MethodsWe conducted a retrospective study involving 332 participants (172 PE positive cases and 160 PE negative cases) recruited from Guangdong Medical University. Participants were randomly divided into a training group (70%) and a validation group (30%). Baseline data were analyzed using univariate analysis, and potential independent risk factors associated with PE were further identified through univariate and multivariate logistic regression analysis. Six ML models, namely Logistic Regression (LR), Decision Tree (DT), Random Forest (RF), Naive Bayes (NB), Support Vector Machine (SVM), and AdaBoost were developed. The predictive efficacy of each model was compared using the receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC). Clinical benefit was assessed using decision curve analysis (DCA).ResultsLogistic regression analysis identified lower extremity deep venous thrombosis, elevated D-dimer, shortened activated partial prothrombin time, and increased red blood cell distribution width as potential independent risk factors for PE. Among the six ML models, the RF model achieved the highest AUC of 0.778. Additionally, DCA consistently indicated that the RF model offered the greatest clinical benefit.ConclusionThis study developed six ML models, with the RF model exhibiting the highest predictive efficacy and clinical benefit in the identification and prediction of PE occurrence in hospitalized patients

Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis

EZH2, a subunit of the polycomb repressive complex 2 (PRC2) catalyzing trimethylation of histone H3 lysine 27 (H3K27), induces epithelial-mesenchymal transition (EMT) in cancers. However, whether EZH2 regulates EMT in endometriosis is unclear. Here, we show that EZH2 expression, along with its associated PRC2 proteins, is significantly elevated in ectopic and eutopic endometrium from women with endometriosis as compared with control endometrium. EZH2 knockdown or inhibition restored the epithelial phenotypes of endometriotic epithelial cells, concomitant with the upregulation of E-cadherin and downregulation of vimentin and transcription factors (Snail and Slug) as well as reduced cellular migratory and invasive propensity. Conversely, overexpression of EZH2 induced the expression of Snail, Slug and vimentin and suppresses E-cadherin expression. In vivo administration of 3-Deazaneplanocin A (DZNep), an EZH2 inhibitor, significantly inhibited the growth of endometriotic lesions and improved generalized hyperalgesia, along with attenuated EMT and reduced fibrosis in endometriosis. Notably, platelets induced EZH2 upregulation and increased H3K27 and H3K9 trimethylation levels in endometriotic epithelial cells. These data identify EZH2 as a novel driver of EMT in endometriosis, implicates the link between wound healing and epigenetic changes in the context of endometriosis, and underscore the role of platelets in the development of endometriosis

Changing prostaglandin E2 (PGE2) signaling during lesional progression and exacerbation of endometriosis by inhibition of PGE2 receptor EP2 and EP4

Abstract Purpose We investigated the change, if any, in prostaglandin E2 (PGE2) signaling in endometriotic lesions of different developmental stages in mouse. In addition, we evaluated the effect of treatment of mice with induced deep endometriosis (DE) with inhibitors of PGE2 receptor subtypes EP2 and EP4 and metformin. Methods Three mouse experimentations were conducted. In Experiment 1, female Balb/C mice were induced with endometriosis or DE and were serially sacrificed after induction. Experiments 2 and 3 evaluated the effect of treatment with EP2 and EP4 inhibitors and metformin, respectively, in mice with induced DE. Immunohistochemistry analysis of COX‐2, EP2, and EP4, along with the extent of lesional fibrosis, was evaluated. Results The immunostaining of COX‐2, EP2, and EP4 turned from activation to a stall as lesions progressed. Treatment with EP2/EP4 inhibitors in DE mice exacerbated endometriosis‐associated hyperalgesia and promoted fibrogenesis in lesions even though it suppressed the PGE2 signaling dose‐dependently. In contrast, treatment with metformin resulted in increased PGE2 signaling, concomitant with improved hyperalgesia, and retarded lesional fibrogenesis. Conclusions The PGE2 signaling diminishes as endometriotic lesions progress. Treatment with EP2/EP4 inhibitors in DE mice exacerbates endometriosis, but metformin appears to be promising seemingly through the induction of the PGE2 signaling

Perioperative Suppression of Schwann Cell Dedifferentiation Reduces the Risk of Adenomyosis Resulting from Endometrial–Myometrial Interface Disruption in Mice

We have recently demonstrated that endometrial–myometrial interface (EMI) disruption (EMID) can cause adenomyosis in mice, providing experimental evidence for the well-documented epidemiological finding that iatrogenic uterine procedures increase the risk of adenomyosis. To further elucidate its underlying mechanisms, we designed this study to test the hypothesis that Schwann cells (SCs) dedifferentiating after EMID facilitate the genesis of adenomyosis, but the suppression of SC dedifferentiation perioperatively reduces the risk. We treated mice perioperatively with either mitogen-activated protein kinase kinase (MEK)/extracellular-signal regulated protein kinase (ERK) or c-Jun N-terminal kinase (JNK) inhibitors or a vehicle 4 h before and 24 h, 48 h and 72 h after the EMID procedure. We found that EMID resulted in progressive SCs dedifferentiation, concomitant with an increased abundance of epithelial cells in the myometrium and a subsequent epithelial–mesenchymal transition (EMT). This EMID-induced change was abrogated significantly with perioperative administration of JNK or MEK/ERK inhibitors. Consistently, perioperative administration of a JNK or a MEK/ERK inhibitor reduced the incidence by nearly 33.5% and 14.3%, respectively, in conjunction with reduced myometrial infiltration of adenomyosis and alleviation of adenomyosis-associated hyperalgesia. Both treatments significantly decelerated the establishment of adenomyosis and progression of EMT, fibroblast-to-myofibroblast trans-differentiation and fibrogenesis in adenomyotic lesions. Thus, we provide the first piece of evidence strongly implicating the involvement of SCs in the pathogenesis of adenomyosis induced by EMID

Interleukin-33 Derived from Endometriotic Lesions Promotes Fibrogenesis through Inducing the Production of Profibrotic Cytokines by Regulatory T Cells

In endometriosis, it has been widely believed that the local immunological milieu is Th2-skewed. Regulatory T cells (Tregs) promote fibrogenesis of endometriosis through the transforming growth factor β1 (TGF-β1) and platelet-derived growth factor (PDGF) signaling pathways. We aimed to explore whether Tregs in endometriotic lesions acquire increased production of effector cytokines under the influence of lesion-derived interleukin (IL)-33. We extracted lymphocytes from normal endometrium and ovarian endometrioma to evaluate the expression of IL-4, IL-13, interferon-γ (IFN-γ), TGF-β1, and the IL-33 receptor (ST2) by Tregs from these tissues. Colocalization of IL-33 and FOXP3 in normal endometrium and ovarian endometrioma was evaluated by immunofluorescence. Tregs and endometriotic stromal cells were co-cultured and treated with anti-IL-33 antibody, and the cytokines produced by Tregs were analyzed by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Tregs in ovarian endometrioma produced significant amounts of IL-4, IL-13, TGF-β1, and ST2. Colocalization of IL-33 and FOXP3 was detected in ovarian endometrioma. IL-33 from endometriotic stromal cells caused the differentiation of lesional Tregs into type 2 T helper (Th2)-like cells, along with increased production of TGF-β1 by Tregs. Thus, Tregs and endometriotic lesions engage active crosstalk through IL-33 to promote fibrogenesis in endometriosis, and, as such, this finding opens up new avenues to identify novel therapeutic targets for endometriosis

A pilot study on the use of andrographolide to treat symptomatic adenomyosis

Objective: To evaluate the efficacy of andrographolide in treating adenomyosis and to test the hypothesis that its efficacy may depend on the nuclear factor-kappa-light-chain enhancer of activated B cells (NF-κB) activation status in eutopic endometrium, which may be a proxy for the status in adenomyotic foci. Materials and methods: Twenty-four patients with transvaginal ultrasound-confirmed adenomyosis (excluding ovarian endometriomas) were recruited for this study after informed consent. All patients had dysmenorrhea and/or heavy menstrual bleeding. All received andrographolide pill orally for 3 months and were followed up for an additional 3 months. The primary outcome measures included the severity of dysmenorrhea, as measured by the visual analog scale (VAS), and menstrual characteristics, such as the amount of menses, all measured before and 3 and 6 months after the drug treatment. In addition, the patients completed Clinical Global Impression rating scales at the end of the 6th month. Immunostaining of the phosphorylated NF-κB p65 (p-p65) subunit was also performed for eutopic endometrium. Results: Andrographolide treatment appeared to be well tolerated by the patients. Six months after taking andrographolide, the average dysmenorrhea VAS score was decreased from the baseline level of 5.3 to 3.5. Twelve patients (50.0%) reported “marked” or “much” improvement, seven (29.2%) reported “minimal improvement” and five (20.8%) reported “unchanged or worse”. The eutopic endometrial p-p65 staining levels were closely correlated with the satisfaction rating. Conclusion: Andrographolide is effective in some patients with symptomatic adenomyosis, who have a higher endometrial expression of the activated form of the NF-κB p65 subunit. Future independent validation studies or randomized clinical trials may be needed to more precisely evaluate the efficacy of andrographolide

Unveiling the Pathogenesis of Adenomyosis through Animal Models

Background: Adenomyosis is a common gynecological disorder traditionally viewed as “elusive”. Several excellent review papers have been published fairly recently on its pathogenesis, and several theories have been proposed. However, the falsifiability, explanatory power, and predictivity of these theories are often overlooked. Since adenomyosis can occur spontaneously in rodents and many other species, the animal models may help us unveil the pathogenesis of adenomyosis. This review critically tallies experimentally induced models published so far, with a particular focus on their relevance to epidemiological findings, their possible mechanisms of action, and their explanatory and predictive power. Methods: PubMed was exhaustively searched using the phrase “adenomyosis and animal model”, “adenomyosis and experimental model”, “adenomyosis and mouse”, and “adenomyosis and rat”, and the resultant papers were retrieved, carefully read, and the resultant information distilled. All the retrieved papers were then reviewed in a narrative manner. Results: Among all published animal models of adenomyosis, the mouse model of adenomyosis induced by endometrial–myometrial interface disruption (EMID) seems to satisfy the requirements of falsifiability and has the predictive capability and also Hill’s causality criteria. Other theories only partially satisfy Hill’s criteria of causality. In particular, animal models of adenomyosis induced by hyperestrogenism, hyperprolactinemia, or long-term exposure to progestogens without much epidemiological documentation and adenomyosis is usually not the exclusive uterine pathology consequent to those induction procedures. Regardless, uterine disruption appears to be a necessary but not sufficient condition for causing adenomyosis. Conclusions: EMID is, however, unlikely the sole cause for adenomyosis. Future studies, including animal studies, are warranted to understand how and why in utero and/or prenatal exposure to elevated levels of estrogen or estrogenic compounds increases the risk of developing adenomyosis in adulthood, to elucidate whether prolactin plays any role in its pathogenesis, and to identify sufficient condition(s) that cause adenomyosis

Identification of prognostic factors for Krukenberg tumor

Aims: A Krukenberg tumor (KT) is an uncommon type of ovarian cancer (OC) with poor prognosis. We sought to identify prognostic factors for KT originating from primary gastrointestinal (GI) tumors. Methods: Forty-four patients with KT were assessed with follow-up. The primary endpoint was overall survival (OS) after first gynecological or GI surgery. Results: The use of postoperative chemotherapy, unilaterally involved ovarian mass, resection of primary tumors, absence of metastatic residuals, and diagnosis of GI tumors synchronously with or after gynecological surgery were identified to be prognostically favorable. For OS after the first cancer-related surgery, only the resection of primary tumor and absence of metastatic residuals were found to be favorable prognostic factors. The use of postoperative chemotherapy correlated with intraoperative intraperitoneal use of chemotherapy, but not with patients’ clinicopathological characteristics, which were not found to be associated with any factors. Conclusion: The prognostic value of a factor depends on how survival is defined. Optimal cytoreductive surgery followed by aggressive chemotherapy may improve survival in KT patients. KT patients with unilaterally involved ovarian mass, resected primary tumors, and the absence of metastatic lesion residuals also seem to have a more favorable prognosis