Prediction of 90 day readmission in heart failure with preserved ejection fraction by interpretable machine learning.

AIMS: Certain critical risk factors of heart failure with preserved ejection fraction (HFpEF) patients were significantly different from those of heart failure with reduced ejection fraction (HFrEF) patients, resulting in the limitations of existing predictive models in real-world situations. This study aimed to develop a machine learning model for predicting 90 day readmission for HFpEF patients. METHODS AND RESULTS: Data were extracted from electronic health records from 1 August 2020 to 1 August 2021 and follow-up records of patients with HFpEF within 3 months after discharge. Feature extraction was performed by univariate analysis combined with the least absolute shrinkage and selection operator (LASSO) algorithms. Machine learning models like eXtreme Gradient Boosting (XGBoost), random forest, neural network and logistic regression were adopted to construct models. The discrimination and calibration of each model were compared, and the Shapley Additive exPlanations (SHAP) method was used to explore the interpretability of the model. The cohort included 746 patients, of whom 103 (13.8%) were readmitted within 90 days. XGBoost owned the best performance [area under the curve (AUC) = 0.896, precision-recall area under the curve (PR-AUC) = 0.868, sensitivity = 0.817, specificity = 0.837, balanced accuracy = 0.827]. The Kolmogorov-Smirnov (KS) statistic was 0.694 at 0.468 in the XGBoost model. SHAP identified the top 12 risk features, including activities of daily living (ADL), left atrial dimension (LAD), left ventricular end-diastolic diameter (LVDD), shortness, nitrates, length of stay, nutritional risk, fall risk, accompanied by other symptoms, educational level, anticoagulants and edema. CONCLUSIONS: Our model could help medical agencies achieve the early identification of 90 day readmission risk in HFpEF patients and reveal risk factors that provide valuable insights for treatments.

Exosome-derived miR-372-5p promotes stemness and metastatic ability of CRC cells by inducing macrophage polarization.

Colorectal cancer (CRC) is the most common malignancy in the digestive system, and tumor metastasis is the main cause of death in clinical patients with CRC. It has been shown that exosomes promote phenotypic changes in macrophages and tumor metastasis in the CRC tumor microenvironment. In this study, we used miRNA-seq technology to screen out the highly expressed miR-372-5p among the miRNAs differentially expressed in plasma exosomes of clinical CRC patients. It was found that miR-372-5p highly expressed in HCT116 exosomes could be phagocytosed by macrophages and promote their polarization into M2 macrophages by regulating the PTEN/AKT pathway. Meanwhile, co-culture of CRC cells with conditioned medium (CM) of macrophages enhanced the EMT, stemness and metastasis of CRC cells. Mechanistically, CRC cells exosome-derived miR-372-5p induced polarized M2 macrophages to secrete chemokine C-X-C-Motif Ligand 12 (CXCL12), which activated the WNT/ß-catenin pathway to promote the EMT, stemness and metastatic ability of CRC cells. In summary, this study elucidated the molecular mechanism of exosomal miR-372-5p promoting metastasis and stemness in CRC, which may provide new therapeutic targets for CRC metastasis and prognosis assessment.

Colorectal cancer tumor cell-derived exosomal miR-203a-3p promotes CRC metastasis by targeting PTEN-induced macrophage polarization.

(1) Background: Tumor-associated macrophages (TAMs) are important immunocytes associated with liver metastasis of colorectal cancer (CRLM). However, the molecular processes underpinning the interaction between the TME and the tumour-derived exosomal miRNAs in CRLM are not being fully understood; (2) Methods: Transmission electron microscopy was utilized to confirm the existence of exosomes after differential ultracentrifugation. To determine the roles of exosomal miR-203a-3p, an in vivo and in vitro investigation was conducted. The mechanism by which exosomal miR-203a-3p governs the interaction between CRC cells and M2 macrophages was investigated using a dual-luciferase reporter assay, western blot, and other techniques; (3) Results: Overexpression of miR-203a-3p was associated with poor prognosis and liver metastasis in CRC patients. Exosomal miR-203a-3p was upregulated in the plasma of CRC patients and highly metastatic CRC cells HCT116, and it could be transported to macrophages via exosomes. Exosomal miR-203a-3p induced M2 polarization of macrophages by controlling PTEN and activating the PI3K/Akt signaling pathway. M2-polarized macrophages secreted the CXCL12, which increased cancer metastasis and resulted in pre-metastatic niches in CRLM by CXCL12/CXCR4/NF-κB signaling pathway. Co-culture of macrophages with miR-203a-3p-transfected or exosome-treated cells increased the ability of HCT116 cells to metastasize both in vitro and in vivo; (4) Conclusions: Exosomes produced by highly metastatic CRC cells and rich in miR-203a-3p may target PTEN and alter the TME, promoting liver metastasis in CRC patients. These findings offer fresh understanding of the liver metastatic process in CRC.

Layered Double Hydroxide-Loaded miR-30a for the Treatment of Breast Cancer In Vitro and In Vivo.

MicroRNAs (miRNAs) play an essential role in cancer therapy, but the disadvantages of its poor inherent stability, rapid clearance, and low delivery efficiency affect the therapeutic efficiency. Loading miRNAs by nanoformulations can improve their bioavailability and enhance therapeutic efficiency, which is an effective miRNA delivery strategy. In this study, we synthesized layered double hydroxides (LDH), which are widely used as carriers of drugs or genes due to the characteristics of good biocompatibility, high loading capacity, and pH sensitivity. We loaded the suppressor oncogene miR-30a on LDH nanomaterials (LDH@miR-30a) and determined the mass ratio of miRNA binding to LDH by agarose gel electrophoresis. LDH@miR-30a was able to escape the lysosomal pathway and was successfully phagocytosed by breast cancer SKBR3 cells and remained detectable in the cells after 24 h of co-incubation. In vitro experiments showed that LDH@miR-30a-treated SKBR3 cells showed decreased proliferation and cell cycle arrest in the G0/G1 phase and LDH@miR-30a was able to regulate the epithelial-mesenchymal transition (EMT) process and inhibit cell migration and invasion by targeting SNAI1. Meanwhile, in vivo experiments showed that nude mice treated with LDH@miR-30a showed a significant reduction in their solid tumors and no significant impairment of vital organs was observed. In conclusion, LDH@miR-30a is an effective drug delivery system for the treatment of breast cancer.

Exosomal lncRNA NEAT1 induces paclitaxel resistance in breast cancer cells and promotes cell migration by targeting miR-133b.

The lncRNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1) has been associated with the development, metastasis and drug resistance of breast cancer (BC). However, the mechanisms underlying NEAT1-induced paclitaxel resistance in the microenvironment of BC remain unclear. In this study, NEAT1 expression was found to be high in paclitaxel-resistant BC cells (SKBR3/PR cells) and exosomes derived from these cells. NEAT1 promoted the migration of BC cells and their resistance to paclitaxel, whereas its downregulation reduced the drug resistance. In addition, downregulation of NEAT1 decreased the migration and proliferation of BC cells by inhibiting the expression of CXCL12 by reducing the adsorption of miR-133b. Furthermore, inhibition of miR-133b reversed the interference of NEAT1 and CXCL12 in paclitaxel resistance, migration and proliferation of BC cells. Knockdown of NEAT1 in a xenograft-bearing mouse model remarkably inhibited cancer progression and improved the response to paclitaxel. Altogether, this study revealed that SKBR3/PR cell-derived exosomal lncRNA NEAT1 can induce paclitaxel resistance and cell migration and growth in the tumour microenvironment of BC and may serve as a new target for the clinical treatment of BC.

miR-142-3p improves paclitaxel sensitivity in resistant breast cancer by inhibiting autophagy through the GNB2-AKT-mTOR Pathway.

Breast cancer has overtaken lung cancer as the most prevalent cancer worldwide. The development of advanced drug resistance inhibits the efficacy of paclitaxel(PTX)as a first-line chemotherapeutic agent for breast cancer. Autophagy and microRNAs (miRNAs) play a key role in chemoresistance. This study investigated the miR-142-3p effect on PTX resistance by regulating autophagy. A PTX-resistant breast cancer cell line was constructed, and miR-142-3p and G protein beta polypeptide 2 (GNB2) were filtered out using RNA sequencing and protein microarray analysis. The study revealed that miR-142-3p expression was lower in drug-resistant cells compared parental cells. Higher miR-142-3p expression inhibited the viability, migration, and autophagic flux of drug-resistant cells, while promoting apoptosis and sensitivity to PTX treatment. Mechanistically, miR-142-3p was found to amend PTX resistance by targeting GNB2, further revealing that the knockdown of GNB2 expression could activate the AKT-mTOR pathway. This study suggests that GNB2 is an essential target for miR-142-3p to restrain autophagy, providing a new reference value for improving breast cancer PTX treatment.

[Clinical study of ultrathin flap LASIK and LASEK for the treatment of high myopia with thin cornea].

OBJECTIVE: To explore the efficacy and safety of the ultrathin flap LASIK and LASEK for the treatment of high myopia with central corneal thickness below 500 microm. METHODS: Ultrathin flap LASIK and LASEK were randomly selected to treat high myopic patients with corneal thickness between 450 and 500 microm. 39 cases of 23 patients with average spherical equivalent of -7.51D (range from -6.00 to -9.50D) were treated with ultra thin flap LASIK, and 37 cases of 19 patients with average SE of -7.50D (range from -6.00 to -10.75D) were treated with LASEK. The uncorrected visual acuity, best corrected visual acuity, spherical equivalent, intraocular pressure, haze were examined and recorded 1, 3, 6 and 12 months postoperatively. RESULTS: Postoperative reaction was mild in LASIK patients, who showed a quick recovery in UCVA, whereas LASEK patients needed average 4 days to re-epithelization. At 1, 3, 6, 12 months postoperatively, the percentage of UCVA above 1.0 was 64.1%, 87.2%, 87.2% and 79.3% in LASIK patients and 37.8%, 75.7%, 67.6% and 71.4% in LASEK patients respectively. The percentage of spherical equivalent between +/- 0.50D was 48.7%, 51.3%, 61.5%, 82.8% in LASIK patients and 51.4%, 45.9%, 45.9%, 57.1% in LASEK respectively. There was no severe complications that implicate the BSCVA occurred in-operation and postoperatively. The main complications in LASIK group was corneal flap striae and overcorrection, regression and mild haze in LASEK group. CONCLUSION: Ultrathin flap LASIK had the similar efficacy and safety with LASEK in the treatment of high myopia with thin CCT, but the stability of results and satisfaction from the patients was superior to LASEK.

[Comparison of laser subepithelial keratomileusis and photorefractive keratectomy for the correction of myopia].

OBJECTIVE: To compare the effectiveness and difference between laser subepithelial keratomileusis (LASEK) and conventional photorefractive keratectomy (PRK) for the treatment of myopia up to -8.00 diopter. METHODS: In this prospective study, 46 patients with a manifest refactiion of -1.75 to -8.00 diopters were treated and followed up for 6 months. In each case, PRK was performed in one eye and LASEK in the other eye. The first eye treated and surgical method used in the first eye was randomized. Epithelial healing time, postoperative pain, uncorrected visual acuity (UCVA), manifest refraction, corneal HAZE were followed and compared in PRK and LASEK treated eyes. RESULTS: LASEK eyes took a mean time of 3.49 days to heal the epithelium, whereas PRK eyes took 2.45 days, which is statistically significant (P <0.05). Postoperative pain index was 2.04 and 2.45 in LASEK eyes and PRK eyes respectively (P <0.05). There were no significant differences between eyes in UCVA and manifest refraction during the follow time (P >0.05). However, LASEK-treated eyes showed less corneal haze than PRK eyes. CONCLUSIONS: LASEK can effectively and safely treat myopia up to -8.00 diopters as PRK did, and can diminish early pain after surgery and prevent corneal Haze from happening.