sFlt-1-enriched exosomes induced endothelial cell dysfunction and a preeclampsia-like phenotype in mice.

Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by maternal endothelial dysfunction and end-organ damage. Our previous work demonstrated that PE patient-derived exosomes contained higher levels of soluble FMS-like tyrosine kinase-1 (sFlt-1) and significantly induced endothelial dysfunction and PE development. However, the mechanisms underlying the effect of sFlt-1-enriched exosomes (sFlt-1-Exo) on PE development are poorly characterized. Here, we revealed that trophoblast-derived sFlt-1-Exo treatment induced significant inhibition of human umbilical vein endothelial cell (HUVEC) migration and tube formation, as well as an increase in sFlt-1 secretion. Mechanistically, we found that the increased sFlt-1 secretion in the cell culture medium was attributed to enhanced transcription of sFlt-1 in HUVECs. Importantly, we observed that treating pregnant mice with sFlt-1-Exo or recombinant mouse sFlt-1 triggered a preeclampsia-like phenotype, characterized by elevated blood pressure, proteinuria, increased plasma sFlt-1 and adverse pregnancy outcomes. These results strongly suggested that sFlt-1-Exo-induced endothelial dysfunction could be partially attributed to the upregulation of sFlt-1 in endothelial cells, potentially leading to the development of a preeclampsia-like phenotype in mice.

Rational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors.

Understanding differences in DNA double-strand break (DSB) repair between tumor and normal tissues would provide a rationale for developing DNA repair-targeted cancer therapy. Here, using knock-in mouse models for measuring the efficiency of two DSB repair pathways, homologous recombination (HR) and nonhomologous end-joining (NHEJ), we demonstrated that both pathways are up-regulated in hepatocellular carcinoma (HCC) compared with adjacent normal tissues due to altered expression of DNA repair factors, including PARP1 and DNA-PKcs. Surprisingly, inhibiting PARP1 with olaparib abrogated HR repair in HCC. Mechanistically, inhibiting PARP1 suppressed the clearance of nucleosomes at DNA damage sites by blocking the recruitment of ALC1 to DSB sites, thereby inhibiting RPA2 and RAD51 recruitment. Importantly, combining olaparib with NU7441, a DNA-PKcs inhibitor that blocks NHEJ in HCC, synergistically suppressed HCC growth in both mice and HCC patient-derived-xenograft models. Our results suggest the combined inhibition of both HR and NHEJ as a potential therapy for HCC.

Alterations in maternal plasma exosomal miRNAs revealed selective material exchange between maternal circulation and placenta.

AIM: Exosomes have emerged as important regulators in the communication between maternal peripheral blood and placenta. We aimed to compare maternal plasma exosomal miRNAs profile between healthy pregnant and nonpregnant women, screen for differential expressed miRNAs and their potential regulatory role during pregnancy. METHODS: We isolated exosomes from plasma of mid-trimester, last trimester, and nonpregnant women (n = 6 each group), analyzed the miRNA profile using next-generation sequencing. RESULTS: Several miRNA clusters were expressed in plasma exosomes, such as C19MC, C14MC, and let-7 family, miRNAs in each cluster may have synergistic effect during pregnancy. We assumed maternal circulating exosomal miRNA could be transported into placenta or selectively uptook by placenta, which was consistent with the fact that many pregnancy-associated or placenta highly expressed miRNAs reduced in exosomes during pregnancy. Some exosomal miRNAs were mainly secreted by the placenta, which could act as markers that reflect changes in the function and microenvironment of the placenta. CONCLUSIONS: Exosomal miRNAs are associated with placenta development and have potential as molecular markers.

[Free sialic acid storage disorders with fetal hydrops in a neonate]. / å”¾æ¶²é ¸è´®ç§¯ç—‡ä¼´èƒŽå„¿æ°´è‚¿1例.

A boy, aged 3 hours, was admitted due to a prenatal diagnosis of fetal hydrops at 3 hours after resuscitation for birth asphyxia. Prenatal examination at 5 months of gestation showed massive ascites in the fetus, and after birth, the boy had the manifestations of systemic hydroderma, massive ascites, coarse face, and hepatomegaly. Genetic testing revealed heterozygous mutations in the SLC17A5 gene, and there was a significant increase in urinary free sialic acid. Placental pathology showed extensive vacuolization in villous stromal cells, Hofbauer cells, cytotrophoblast cells, and syncytiotrophoblast cells in human placental chorionic villi. The boy was finally diagnosed with free sialic acid storage disorders (FSASDs). This is the first case of FSASDs with the initial symptom of fetal hydrops reported in China. The possibility of FSASDs should be considered for cases with non-immune hydrops fetalis, and examinations such as placental pathology and urinary free sialic acid may help with early diagnosis and clinical decision making.

A Feature-Encoded Physics-Informed Parameter Identification Neural Network for Musculoskeletal Systems.

Identification of muscle-tendon force generation properties and muscle activities from physiological measurements, e.g., motion data and raw surface electromyography (sEMG), offers opportunities to construct a subject-specific musculoskeletal (MSK) digital twin system for health condition assessment and motion prediction. While machine learning approaches with capabilities in extracting complex features and patterns from a large amount of data have been applied to motion prediction given sEMG signals, the learned data-driven mapping is black-box and may not satisfy the underlying physics and has reduced generality. In this work, we propose a feature-encoded physics-informed parameter identification neural network (FEPI-PINN) for simultaneous prediction of motion and parameter identification of human MSK systems. In this approach, features of high-dimensional noisy sEMG signals are projected onto a low-dimensional noise-filtered embedding space for the enhancement of forwarding dynamics prediction. This FEPI-PINN model can be trained to relate sEMG signals to joint motion and simultaneously identify key MSK parameters. The numerical examples demonstrate that the proposed framework can effectively identify subject-specific muscle parameters and the trained physics-informed forward-dynamics surrogate yields accurate motion predictions of elbow flexion-extension motion that are in good agreement with the measured joint motion data.

An HMGA2-p62-ERα axis regulates uterine leiomyomas proliferation.

Uterine leiomyomas (ULM) are a major public health issue contributing to high morbidity and poor pregnancy outcomes. However, its molecular pathogenesis is poorly understood. HMGA2-ULM is the second major subtype of human ULM and associates with large sizes, fast-growth, and high percentages of estrogen receptor α (ERα). As altered ERα expression plays a distinct role in ULM growth, here, we investigate a regulatory mechanism driving ULM growth via HMGA2 and ERα. We reveal a positive correlation of HMGA2 with ERα protein and demonstrate that HMGA2 promotes ULM cells proliferation via ERα. In addition, autophagy pathway and p62/SQSTM1 (a selective autophagy receptor) are found to participate in the regulation of HMGA2 and ERα. Moreover, HMGA2 suppresses the transcription of p62 by binding to its promoter, meanwhile, p62 interacts with ERα, and inhibition of p62 increases ERα expression and enhances cell viability in ULM, suggesting a novel mechanism of the HMGA2-p62-ERα axis in ULM proliferation. Notably, rapamycin, a familiar autophagy agonist, reduces ERα levels and the proliferation ability of ULM cells. This study demonstrates a causal role of the HMGA2-p62-ERα axis in preventing autophagy and increasing ERα expression in HMGA2-ULM. Therefore, blocking HMGA2-p62-ERα axis and targeting autophagy pathway establish a roadmap toward HMGA2-ULM medical treatment.

S100-A9 protein in exosomes derived from follicular fluid promotes inflammation via activation of NF-κB pathway in polycystic ovary syndrome.

Exosomes have recently emerged as key mediators of different physiological and pathological processes. However, there has been few report about proteomic analysis of exosomes derived from human follicular fluid and their association with the occurrence of PCOS. Herein, we used TMT-tagged quantitative proteomic approach to identify proteomic profiles in exosomes derived from follicular fluid of PCOS patients and healthy controls. We identified 662 proteins in exosomes derived from human ovarian follicular fluid. Eighty-six differently expressed proteins (P < .05) were found between PCOS and healthy women. The alterations in the proteomic profile were related to the inflammation process, reactive oxygen species metabolic process, cell migration and proliferation. Importantly, we observed that follicular fluid exosomes contain S100 calcium-binding protein A9 (S100-A9) protein. Exosome-enriched S100-A9 significantly enhanced inflammation and disrupted steroidogenesis via activation of nuclear factor kappa B (NF-κB) signalling pathway. These data demonstrate that exosomal proteins are differentially expressed in follicular fluid during disease process, and some proteins may play important roles in the regulation of granulosa cell function. These results highlight the importance of exosomes as extracellular communicators in ovarian follicular development.

Nanographite-based fluorescent biosensor for detecting microRNA using duplex-specific nuclease-assisted recycling.

The development of a nanographite (NG)-based fluorescent biosensor for detecting microRNA (miRNA) is reported. Duplex-specific nuclease (DSN)-assisted signal amplification was key to its function. In the absence of a target, with the assistance of p-stacking interactions, the NG adsorbed the double carboxyfluorescein (FAM)-labelled probe (DFP) whose surface was perfectly complementary to miRNA, leading to quenching of FAM fluorescence. In the presence of a target, double-stranded DNA/RNA hybrids were repelled by the NG and fluorescence was restored. Meanwhile, the considerable increase in signal strength and sensitivity suggests DSN-mediated target recycling as an application. The detection limit of the proposed biosensor for miRNA was 10 pmol/L; there was a linear correlation when the miRNA concentration ranged from 50 pmol/L to 5 nmol/L. Additionally, the method could distinguish let-7b from most let-7 miRNA family members and was successfully used in a sample assay. This biosensor is a novel and highly sensitive tool for miRNA detection and has great potential for biochemical research, disease diagnosis, and therapy.

A Prospective Study of Sentinel Lymph Node Mapping for Endometrial Cancer: Is It Effective in High-Risk Subtypes?

BACKGROUND: The efficacy of sentinel lymph node (SLN) mapping for high-risk endometrial cancer remains unclear. This prompted us to evaluate the sensitivity, negative predictive value (NPV), and false-negative (FN) rate of cervical injection of indocyanine green (ICG) SLN mapping in patients with endometrial cancer. MATERIALS AND METHODS: This prospective interventional study was performed at a single university teaching hospital. Consecutive patients with early-stage endometrial cancer who underwent laparoscopic surgical staging were included. Cervical injection of ICG and near-infrared SLN identification and biopsy were performed for all study patients followed by systematic pelvic lymphadenectomy, whereas para-aortic lymphadenectomy was performed in all patients with high-risk histologies. SLN detection rates, sensitivity, NPV, and FN rates were calculated. RESULTS: Between July 2016 and July 2018, 131 patients were enrolled. The overall SLN detection rate was 93.1%, with a bilateral detection rate of 61.8%. Four positive SLNs were identified in four patients. Lymph node metastasis was observed in four additional patients without positive SLNs. These four patients belonged to a group of patients with a high-risk subtype. Three of the four patients had isolated para-aortic node metastases. In low-risk endometrial cancers, the sensitivity of the SLN technique to identify nodal metastatic disease was 100% (95% confidence interval [CI] 31.0-100), with an NPV and FN rate of 100% (95% CI 95.1-100) and 0%, respectively. In high-risk endometrial cancers, the sensitivity, NPV, and FN rate were 20% (95% CI 1.0-70.1), 83.3% (95% CI 61.8-94.5), and 80%, respectively. CONCLUSION: Cervical injection of ICG and SLN mapping yielded a low sensitivity and a high FN rate for the identification of node metastasis in endometrial cancer with high-risk histologies. IMPLICATIONS FOR PRACTICE: The efficacy of sentinel lymph node (SLN) mapping for high-risk endometrial cancer remains unclear. This study enrolled 131 patients with early-stage endometrial cancer who underwent cervical injection of indocyanine green SLN mapping followed by systematic pelvic lymphadenectomy and para-aortic lymphadenectomy. The key result was that SLN mapping yielded a low sensitivity and a high false-negative rate for the identification of node metastasis in endometrial cancer with high-risk histologies. The SLN strategy in these patients may increase the risk of missed diagnosis of isolated para-aortic node metastases and seems to be unacceptable in clinical practice.

Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the leading cause of death from gynaecologic malignancies and has a poor prognosis due to metastasis. Drugs targeting the angiogenesis pathway significantly improve patient outcome. However, the key factors linking angiogenesis and metastasis have not been elucidated. In this study, we found Tie2 expressing monocytes (CD14+Tie2+, TEMs) as key contributors to angiogenesis and metastasis of EOC. METHODS: Tissue slides were evaluated by immunofluorescence for the presence of total tissue macrophages and TEMs. The correlation between microvascular density (MVD) values and the TEMs number or ratio was calculated in both ovarian cancer tissues and peritoneum. The rate of TEMs in monocytes was evaluated in the peripheral blood of female healthy donors, benign cysts patients, and EOC patients using flow cytometry. The TEMs rate in ascites from EOC patients was also evaluated by flow cytometry. The concentration of Ang2, as the ligand of Tie2, was examined by ELISA in serum samples of EOC patients, benign cysts patients, and ascites samples of EOC patients. The effects of Ang2 on the migration and the cytokine expression of TEMs were further examined. The pro- angiogenesis activity of TEMs via IGF1 was performed in both in vivo and in vitro. And the IGF1 blocking test was performed using neutralising antibody. RESULTS: TEMs were significantly higher in tumour foci, peripheral blood and ascites in EOC patients. The proportion of TEMs among total tissue macrophages was positively correlated with tumour MVD. In vivo animal results showed that TEMs promoted EOC angiogenesis and metastasis. Further functional and mechanisms studies revealed that concentration of angiopoietin 2 (Ang2), a ligand of Tie2, was elevated in EOC ascites which further recruit TEMs in a dose-dependent manner as a powerful chemokine to TEMs. Recruited TEMs promoted endothelial cell function through IGF1-activated downstream signalling. Blocking secreted IGF1 using inhibiting antibody reduced TEMs mediated angiogenesis and metastasis. CONCLUSIONS: TEMs significantly increased in EOC patients and were recruited to tumour loci by the increased Ang2. The increased TEMs have diagnostic value in ovarian cancer and were positively correlated with the MVD in ovarian cancer tissue. Furthermore, TEMs promote angiogenesis via IGF1 in both in vivo and in vitro experimental systems after stimulation by Ang2. Altogether, this study paves the way to develop novel therapy targets as the axis of Ang2-TEMs-IGF1 in EOC.

Suppression of STAT3 Signaling by Δ9-Tetrahydrocannabinol (THC) Induces Trophoblast Dysfunction.

AIMS: Marijuana is a widely used illicit drug and its consumption during pregnancy has been associated with adverse reproductive outcomes. The purpose of this study was to determine the effects of chronic intake of Δ9-tetrahydrocannabinol (THC), the major component of marijuana, on trophoblast function, placental development, and birth outcomes. METHODS: The pathological characteristics and distribution of cannabinoid receptors in placenta were observed by immunohistochemical (IHC) staining. Cell migration in response to THC was measured by transwell assays. The levels of cannabinoid receptors and Signal Transducer and Activator of Transcription 3 (STAT3) were detected by western blot. RESULTS: We found the placenta expressed two main cannabinoid receptors, suggesting that THC induced biological responses in placental cells. Supporting this hypothesis, we observed dramatic alterations of placental morphology in marijuana users. Using THC and inhibitors of cannabinoid receptors, we demonstrated that THC impaired trophoblast cell migration and invasion partly via cannabinoid receptors. Additionally, pregnant mice injected with THC showed adverse reproductive events including reduced number of fetuses, lower maternal and placental weights. Mechanistically, STAT3 signaling pathway was involved in the THC-induced suppression of trophoblast cell motility and pregnancy outcomes. CONCLUSION: Our study indicates that the STAT3 signaling pathway plays a critical role in THC-induced trophoblast dysfunction.

High expression of herpesvirus entry mediator (HVEM) in ovarian serous adenocarcinoma tissue.

PURPOSE: To explore the expression of herpesvirus entry mediator (HVEM) in ovarian serous adenocarcinoma tissues and its relationship with clinicopathological features. METHODS: Paraffin-embedded specimens from 40 patients with ovarian serous adenocarcinoma who were subjected to surgical treatment were used for the determination of HVEM expression by immunohistochemistry (IHC). Then the relationship between the expression of HVEM and the patient clinicopathological features was analyzed. RESULTS: There were 29 cases (72.5%) of HVEM/tumor necrosis factor receptor (TNFR)SF14-positive and 11 cases (27.5%) of HVEM/TNFRSF14-negative. The positive rate of HVEM was significantly correlated with TNM staging, lymph node metastasis and recurrence (p<0.05), but not with age, grade of differentiation and distant metastasis (p>0.05). CONCLUSION: HVEM is highly expressed in ovarian serous adenocarcinoma tissues and correlated with the patient clinicopathological features, such as TNM staging, lymph node metastasis and recurrence. HVEM can provide a basis in the search for a new targeting treatment for ovarian serous adenocarcinoma.

Potential Role of Hyperglycemia in Fetoplacental Endothelial Dysfunction in Gestational Diabetes Mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with structural and functional alterations in various tissues including endothelial dysfunction. The aim of this study was to explore the effects of hyperglycemia on fibroblast growth factor 2 (FGF2)- and vascular endothelial growth factor (VEGF)-stimulated placental angiogenesis and the underlying molecular signaling mechanisms. METHODS: The density of fetal placental capillaries was examined using immunohistochemistry. Human umbilical vein endothelial cells (HUVECs) derived from GDM (dHUVECs) and normal healthy patients (nHUVECs) were used as cell models in this study. Cell proliferation, migration and tube formation were measured with an MTS assay, a transwell system and a matrigel assay, respectively. The activation of ERK1/2 was analyzed with Western blot. The specific inhibitor of extracellular signal-regulated kinases 1/2 (ERK1/2) PD98059 was used to elucidate the involved signaling pathway. RESULTS: GDM did not alter the capillary density of the fetus-placenta. Both the GDM and hyperglycemic conditions inhibited the proliferation of the FGF2- but not the VEGF-stimulated HUVECs and the basal migratory capacity. Hyperglycemic condition significantly inhibited tube formation and ex vivo angiogenesis. Moreover, hyperglycemia inhibited the FGF2- but not the VEGF-induced activation of ERK1/2. PD98059 significantly inhibited the FGF2-activated ERK1/2 phosphorylation and the FGF2-stimulated cell proliferation in HUVECs. CONCLUSION: Both GDM and hyperglycemia may impair placental angiogenesis by reducing HUVEC proliferation, migration and tube formation. Hyperglycemia-inhibited cell proliferation stimulated by FGF2 probably contributed to the suppression of the MEK1/2/ERK1/2 pathways in the HUVECs.

CD34+ VEGFR-3+ progenitor cells have a potential to differentiate towards lymphatic endothelial cells.

Endothelial progenitor cells (EPCs) play an important role in postnatal neovascularization. However, it is poorly understood whether EPCs contribute to lymphangiogenesis. Here, we assessed differentiation of a novel population of EPCs towards lymphatic endothelial cells and their lymphatic formation. CD34(+) VEGFR-3(+) EPCs were isolated from mononuclear cells of human cord blood by fluorescence-activated cell sorting. These cells expressed CD133 and displayed the phenotype of the endothelial cells. Cell colonies appeared at 7-10 days after incubation. The cells of the colonies grew rapidly and could be repeatedly subcultured. After induction with VEGF-C for 2 weeks, CD34(+) VEGFR-3(+) EPCs could differentiate into lymphatic endothelial cells expressing specific markers 5'-nucleotidase, LYVE-1 and Prox-1. The cells also expressed hyaluronan receptor CD44. The differentiated cells had properties of proliferation, migration and formation of lymphatic capillary-like structures in three-dimensional collagen gel and Matrigel. VEGF-C enhanced VEGFR-3 mRNA expression. After interfering with VEGFR-3 siRNA, the effects of VEGF-C were diminished. These results demonstrate that there is a population of CD34(+) VEGFR-3(+) EPCs with lymphatic potential in human cord blood. VEGF-C/VEGFR-3 signalling pathway mediates differentiation of CD34(+) VEGFR-3(+) EPCs towards lymphatic endothelial cells and lymphangiogenesis. Cord blood-derived CD34(+) VEGFR-3(+) EPCs may be a reliable source in transplantation therapy for lymphatic regenerative diseases.

Isolation and characterization of cancer stem cells from high-grade serous ovarian carcinomas.

BACKGROUND/AIMS: In this study, a subpopulation of stem-like cells in human high grade serous ovarian carcinomas (ovarian cancer stem cells; OCSCs) were isolated and characterized. METHODS: Primary high-grade serous ovarian carcinoma (HGSC) fresh biopsies were cultured under serum-free conditions to produce floating spheres. Sphere formation assay, including self-renewal, differentiation potential, chemo-resistance, and tumorigenicity were determined in vitro or in vivo. RESULTS: OCSCs overexpressed stem cell genes (Oct-4, Nanog, Sox-2, Bmi-1, Nestin, CD133, CD44, CD24, ALDH1, CD117, and ABCG2). Immunostaining of spheres showed overexpressed Oct-4, Nanog, and Sox-2. These isolated tumor cells expanded as spheroid colonies for more than 30 passages. In contrast, adherent cells expressed high levels of CA125 and CK7. Flow cytometry analysis showed increased CSC markers (CD44, CD24, CD117, CD133, ABCG2, and ALDH1) in the spheroid cell population. OCSCs displayed higher chemoresistance to cisplatin or paclitaxel compared to adherent cells. Moreover, subcutaneous injection of 1 × 104 sphere-forming cells into NOD/SCID mice gave rise to new tumors similar to the original human tumors and could be passaged in mice. CONCLUSION: These results revealed that HGSCs are created and propagated by a small number of undifferentiated tumorigenic cells, and therapeutic targeting of these cells could be beneficial for treatment of HGSCs.

Frozen section of uterine curetting in excluding the possibility of ectopic pregnancy--a clinicopathologic study of 715 cases.

INTRODUCTION: To investigate the utility of frozen section of uterine curetting in excluding the possibility of ectopic pregnancy (EP). MATERIALS AND METHODS: A retrospective analysis of 715 curetting records in the present hospital from July 1999 to May 2009 was obtained. All specimens were processed routinely with frozen section and paraffin section. RESULTS: Of 715 cases, frozen section analyses were discordant in 33 cases (4.6%), including 32 cases under-diagnosed, and one case over-diagnosed, compared with the final diagnoses. Frozen section had a sensitivity of 92.6%, specificity of 99.6%, and frozen section accuracy rate of 95.4%. CONCLUSIONS: Frozen section is a useful and rapid method to differentiate EP from intrauterine pregnancy.

A multi-resolution physics-informed recurrent neural network: formulation and application to musculoskeletal systems.

This work presents a multi-resolution physics-informed recurrent neural network (MR PI-RNN), for simultaneous prediction of musculoskeletal (MSK) motion and parameter identification of the MSK systems. The MSK application was selected as the model problem due to its challenging nature in mapping the high-frequency surface electromyography (sEMG) signals to the low-frequency body joint motion controlled by the MSK and muscle contraction dynamics. The proposed method utilizes the fast wavelet transform to decompose the mixed frequency input sEMG and output joint motion signals into nested multi-resolution signals. The prediction model is subsequently trained on coarser-scale input-output signals using a gated recurrent unit (GRU), and then the trained parameters are transferred to the next level of training with finer-scale signals. These training processes are repeated recursively under a transfer-learning fashion until the full-scale training (i.e., with unfiltered signals) is achieved, while satisfying the underlying dynamic equilibrium. Numerical examples on recorded subject data demonstrate the effectiveness of the proposed framework in generating a physics-informed forward-dynamics surrogate, which yields higher accuracy in motion predictions of elbow flexion-extension of an MSK system compared to the case with single-scale training. The framework is also capable of identifying muscle parameters that are physiologically consistent with the subject's kinematics data.

TPD52 is a prognostic biomarker and potential therapeutic target for ER+/PR+/HER2+ breast cancer.

BACKGROUND: Breast cancer (BRCA) represents a significant health challenge for women globally, with refractory cases showing resistance to current therapeutic strategies. The discovery of novel molecular markers and therapeutic targets is critical for improving outcomes in these patients. The primary aim of this study is to elucidate the role of tumor protein D52 (TPD52) as a novel molecular marker and potential therapeutic target to improve outcomes for BRCA patients. METHODS: Using bioinformatics methods, we screened and evaluated the expression, prognosis, and associated mechanisms of TPD52 in BRCA. Two hundred and thirty-eight BRCA cases and 19 control cases were collected from Shanghai First Maternity and Infant Hospital, and the protein expression of TPD52 was detected by immunohistochemistry, and the correlation between TPD52 and the prognosis of BRCA was analyzed. RESULTS: The expression of TPD52 in BRCA tissues was significantly higher than that in the control (P<0.001), displaying a strong association with key clinical variables, concurrently indicating an unfavorable prognostic implication. The survival analysis revealed high TPD52 expression was an independent adverse prognostic factor for overall (P=0.008) and disease-specific survival (P=0.005). Gene set enrichment analysis showed that TPD52 negatively correlated with estradiol, AMP-activated protein kinase, and other responses. Immune infiltration analysis showed that TPD52 was associated with immune cell infiltration, Th-1/Th-2 cell balance, and immune defense cells such as dendritic and plasmacytoid dendritic cells. It is further found that high TPD52 expression is associated with progression-free and disease-free survival from the analysis of immunohistochemical data of the patients at our hospital. CONCLUSIONS: In summary, TPD52 may serve as an independent prognostic biomarker for BRCA, which may represent a promising novel therapeutic target, particularly for the refractory estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+)/human epidermal growth factor receptor 2-positive (HER2+) BRCA cases that have failed endocrine therapy and targeted treatment.

Phosphorylation of INF2 by AMPK promotes mitochondrial fission and oncogenic function in endometrial cancer.

Mitochondria are highly dynamic organelles capable of altering their sizes and shapes to maintain metabolic balance through coordinated fission and fusion processes. In various cancer types, mitochondrial hyperfragmentation has been frequently observed, contributing to the progression of cancer toward metastasis. Inverted formin 2 (INF2), which resides in the endoplasmic reticulum (ER), has been found to accelerate actin polymerization and drive mitochondrial fission. In this study, we demonstrate that INF2 expression is significantly upregulated in endometrial cancer (EC) and is associated with a poor prognosis in EC patients. INF2 promotes anchorage-dependent and independent EC cell growth in part by facilitating mitochondrial fission. Furthermore, in conditions of energy stress, AMP-activated protein kinase (AMPK) phosphorylates INF2 at Ser1077, leading to increased localization of INF2 to the ER and enhanced recruitment of the dynamin-related protein 1 (DRP1) to mitochondria. This AMPK-mediated phosphorylation of INF2 at Ser1077 facilitates mitochondrial division and promotes EC cell growth. Pathological examination using immunohistochemical analyses revealed a positive correlation between AMPK activity and phosphorylated INF2 (Ser1077) in EC specimens. Collectively, our findings uncover novel molecular mechanisms involving the AMPK-INF2 axis, which regulates mitochondrial dynamics and malignant cell growth in EC.

Screening and identification of serum exosomal protein ZNF587B in liquid biopsy for ovarian cancer diagnosis.

Addressing the critical challenge of early ovarian cancer (OC) detection, our study focuses on identifying novel biomarkers by analyzing preoperative peripheral blood exosomes from high-grade serous ovarian cancer (HGSC) patients and healthy controls. Utilizing high-performance liquid chromatography-mass spectrometry-based quantitative proteomics, we isolated and analyzed peripheral blood exosomes to identify differentially expressed proteins (DEPs). This comprehensive analysis, supported by gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) database assessments, revealed 28 proteins with decreased abundance and 33 with increased abundance in HGSC patients compared to controls. Notably, Zinc Finger Protein 587B (ZNF587B) exhibited a significant reduction in abundance, confirmed by decreased mRNA and protein levels in HGSC and normal ovarian tissues, consistent with omes exosomal protein expression levels. Immunohistochemical staining further confirmed reduced ZNF587B protein levels in HGSC tissues. The significant correlation between ZNF587B expression levels and tumor stage underscores its potential as a valuable biomarker for early liquid biopsy screening of OC. Our findings suggest ZNF587B plays a crucial role in early HGSC detection, highlighting the importance of further research to validate its clinical utility and improve ovarian cancer patient outcomes.