Factors Associated With Stress Urinary Incontinence and Diastasis of Rectus Abdominis in Women at 6-8 Weeks Postpartum.

IMPORTANCE: In recent years, pelvic-abdominal dynamics has become a research topic in the field of pelvic floor dysfunction (PFD), and the relationship between diastasis of the rectus abdominis (DRA) and stress urinary incontinence (SUI) has been controversial. The study is helpful to further strengthen perinatal education, accurately identify the risk factors of SUI and DRA, and improve the quality of life of puerperae. OBJECTIVE: This study aimed to investigate the association of SUI and DRA in women with PFD as measured by vaginal palpation or pelvic floor biofeedback machine testing. STUDY DESIGN: A total of 301 patients diagnosed with female PFD who were 6-8 weeks postpartum at The Fifth People's Hospital of Zhuhai between May 2018 and April 2021 were enrolled. The prevalence rates and potential influencing factors of SUI and DRA were analyzed. RESULTS: A total of 29.5% (89 of 301) of the patients were diagnosed with SUI, and 31.9% (96 of 301) were diagnosed with DRA. Binary logistic regression showed that a history of delivery ( P = 0.012; odds ratio [OR], 1.982) and vaginal delivery with perineal lacerations or episiotomy ( P = 0.016; OR, 2.187) were risk factors for SUI. High birth weight (weight>4.0 kg, P < 0.001; OR, 14.507) was a risk factor for DRA. CONCLUSIONS: A history of delivery and vaginal delivery with perineal lacerations or episiotomy increased the risk of SUI, and high birth weight was an independent risk factor for DRA. Early intervention, including exercise therapy, manual therapy, and neuromuscular electrical stimulation, may be important for patients with PFD having these risk factors.

cRGD-targeted heparin nanoparticles for effective dual drug treatment of cisplatin-resistant ovarian cancer.

Resistance to the chemotherapeutic agent cisplatin (DDP) is the primary reason for invalid chemotherapy of ovarian cancer. Given the complex mechanisms underlying chemo-resistance, the design of combination therapies based on blocking multiple mechanisms is a rationale to synergistically elevate therapeutic effect for effectively overcoming cancer chemo-resistance. Herein, we demonstrated a multifunctional nanoparticle (DDP-Ola@HR), which could simultaneously co-deliver DDP and Olaparib (Ola, DNA damage repair inhibitor) using targeted ligand cRGD peptide modified with heparin (HR) as nanocarrier, enabling the concurrent tackling of multiple resistance mechanisms to effectively inhibit the growth and metastasis of DDP-resistant ovarian cancer. In combination strategy, heparin could suppress the function of multidrug resistance-associated protein 2 (MRP2) and P-glycoprotein (P-gp) to promote the intracellular accumulation of DDP and Ola by specifically binding with heparanase (HPSE) to down-regulate PI3K/AKT/mTOR signaling pathway, and simultaneously served as a carrier combined with Ola to synergistically enhance the anti-proliferation ability of DDP for resistant ovarian cancer, thus achieving great therapeutic efficacy. Our DDP-Ola@HR could provide a simple and multifunctional combination strategy to trigger an anticipated cascading effect, thus effectively overcoming the chemo-resistance of ovarian cancer.

Self-anti-angiogenesis nanoparticles enhance anti-metastatic-tumor efficacy of chemotherapeutics.

Beyond traditional endothelium-dependent vessel (EDV), vascular mimicry (VM) is another critical tumor angiogenesis that further forms in many malignant metastatic tumors. However, the existing anti-angiogenesis combined chemotherapeutics strategies are only efficient for the treatment of EDV-based subcutaneous tumors, but remain a great challenge for the treatment of in situ malignant metastatic tumor associated with EDV and VM. Here, we demonstrate a self-assembled nanoparticle (VE-DDP-Pro) featuring self-anti-EDV and -VM capacity enables to significantly enhance the treatment efficacy of cisplatin (DDP) against the growth and metastasis of ovarian cancer. The VE-DDP-Pro is constructed by patching DDP loaded cRGD-folate-heparin nanoparticles (VE) onto the surface of protamine (Pro) nanoparticle. We demonstrated the self-anti-angiogenesis capacity of VE-DDP-Pro was attributed to VE, which could significantly inhibit the formation of EDV and VM by regulating signaling pathway of MMP-2/VEGF, AKT/mTOR/MMP-2/Laminin and AKT/mTOR/EMT, facilitating chemotherapeutics to effectively suppress the development and metastasis of ovarian cancer. Thus, combing with the chemotherapeutics effectiveness of DDP, the VE-DDP-Pro can significantly enhance treatment efficacy and prolong median survival of mice with metastatic ovarian cancer. We believe our self-assembled nanoparticles integrating the anti-EDV and anti-VM capacity provide a new preclinical sight to enhance the efficacy of chemotherapeutics for the treatment malignant metastasis tumor.

A Biomimetic Drug Delivery System by Integrating Grapefruit Extracellular Vesicles and Doxorubicin-Loaded Heparin-Based Nanoparticles for Glioma Therapy.

Existing nanoparticle-mediated drug delivery systems for glioma systemic chemotherapy remain a great challenge due to poor delivery efficiency resulting from the blood brain barrier/blood-(brain tumor) barrier (BBB/BBTB) and insufficient tumor penetration. Here, we demonstrate a distinct design by patching doxorubicin-loaded heparin-based nanoparticles (DNs) onto the surface of natural grapefruit extracellular vesicles (EVs), to fabricate biomimetic EV-DNs, achieving efficient drug delivery and thus significantly enhancing antiglioma efficacy. The patching strategy allows the unprecedented 4-fold drug loading capacity compared to traditional encapsulation for EVs. The biomimetic EV-DNs are enabled to bypass BBB/BBTB and penetrate into glioma tissues by receptor-mediated transcytosis and membrane fusion, greatly promoting cellular internalization and antiproliferation ability as well as extending circulation time. We demonstrate that a high-abundance accumulation of EV-DNs can be detected at glioma tissues, enabling the maximal brain tumor uptake of EV-DNs and great antiglioma efficacy in vivo.

cRGD-functionalized nanoparticles for combination therapy of anti-endothelium dependent vessels and anti-vasculogenic mimicry to inhibit the proliferation of ovarian cancer.

Accumulating evidence has disclosed effective anti-angiogenic strategies should simultaneously inhibit endothelium-dependent vessels (EDV) and tumor cell-mediated vasculogenic mimicry (VM). The αvß3 integrin-targeting peptide cRGD has the ability to inhibit EDV and we have found cRGD can also suppress the formation of VM in ovarian cancer cells. Herein, a cRGD-based combination strategy was developed to suppress the proliferation of tumor cells by anti-EDV and anti-VM. We firstly engineered two cRGD functionalized nanoparticles (cRGD-NPs1 and cRGD-NPs2) by self-assembly using heparin conjugated with cRGD and folate. In vitro experiments demonstrated cRGD-NPs2 exhibited more significant cytotoxicity and higher intracellular uptake ability than cRGD-NPs1. Also, cRGD-NPs2 could efficiently discourage EDV, VM and proliferation in HUVECs and SKOV3 (VM+) cells. In vivo studies showed cRGD-NPs2 could specifically accumulate in ovarian cancer tissues and exerted a superior anti-tumor effect in SKOV3 xenografts. The mechanisms responsible for creating anti-EDV and anti-VM action of cRGD-NPs2 related to combined effects of cRGD, heparin and folate. The results demonstrated cRGD-NPs2 represented a versatile anti-angiogenic medicine via their combined inhibitory effect. STATEMENT OF SIGNIFICANCE: Accumulating documents indicate tumor cell-mediated vasculogenic mimicry (VM) is positively correlated with poor prognosis, occurrence of distant metastasis and low survival rate in cancer patients, suggesting VM is a potential therapeutic target for cancer treatment. Thus, effective anti-angiogenic strategies should simultaneously inhibit VM as well as endothelium-dependent vessels (EDV). Integrin αvß3 is a crucial inducer involved in the formation of both EDV and VM. In this study, we engineered αvß3 integrin-targeting peptide cRGD functionalized nanoparticles (cRGD-NPs) by self-assembly using heparin conjugated with cRGD and folate. The prepared cRGD-NPs represent a promising anti-angiogenic medicine in that they are able to inhibit endothelial sprouting angiogenesis and tumor cell-mediated VM. This work may provide useful information with which to construct effective anti-angiogenic nanomedicines.

Mir20a/106a-WTX axis regulates RhoGDIa/CDC42 signaling and colon cancer progression.

Wilms tumor gene on the X chromosome (WTX) is a putative tumor suppressor gene in Wilms tumor, but its expression and functions in other tumors are unclear. Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in women and the second leading cause in men in the United States. We demonstrated that WTX frequently lost in CRC which was highly correlated with cell proliferation, tumor invasion and metastasis. Mechanistically, WTX loss disrupts the interaction between RhoGDIα and CDC42 by losing of the binding with RhoGDIα and triggers the activation of CDC42 and its downstream cascades, which promotes CRC development and liver metastasis. The aberrant upregulation of miR-20a/miR-106a were identified as the reason of WTX loss in CRC both in vivo and in vitro. These study defined the mechanism how miR-20a/miR-106a-mediated WTX loss regulates CRC progression and metastasis, and provided a potential therapeutic target for preventing CRC progression.

Investigating MicroRNA and transcription factor co-regulatory networks in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide with poor prognosis. Studies have showed that abnormal microRNA (miRNA) expression can affect CRC pathogenesis and development through targeting critical genes in cellular system. However, it is unclear about which miRNAs play central roles in CRC's pathogenesis and how they interact with transcription factors (TFs) to regulate the cancer-related genes. RESULTS: To address this issue, we systematically explored the major regulation motifs, namely feed-forward loops (FFLs), that consist of miRNAs, TFs and CRC-related genes through the construction of a miRNA-TF regulatory network in CRC. First, we compiled CRC-related miRNAs, CRC-related genes, and human TFs from multiple data sources. Second, we identified 13,123 3-node FFLs including 25 miRNA-FFLs, 13,005 TF-FFLs and 93 composite-FFLs, and merged the 3-node FFLs to construct a CRC-related regulatory network. The network consists of three types of regulatory subnetworks (SNWs): miRNA-SNW, TF-SNW, and composite-SNW. To enhance the accuracy of the network, the results were filtered by using The Cancer Genome Atlas (TCGA) expression data in CRC, whereby we generated a core regulatory network consisting of 58 significant FFLs. We then applied a hub identification strategy to the significant FFLs and found 5 significant components, including two miRNAs (hsa-miR-25 and hsa-miR-31), two genes (ADAMTSL3 and AXIN1) and one TF (BRCA1). The follow up prognosis analysis indicated all of the 5 significant components having good prediction of overall survival of CRC patients. CONCLUSIONS: In summary, we generated a CRC-specific miRNA-TF regulatory network, which is helpful to understand the complex CRC regulatory mechanisms and guide clinical treatment. The discovered 5 regulators might have critical roles in CRC pathogenesis and warrant future investigation.