Development of a multiparametric model for predicting the response to neoadjuvant chemotherapy in breast cancer.

Background: Choosing the appropriate treatment early and predicting the efficacy of neoadjuvant chemotherapy (NAC) for locally advanced breast cancer patients are of particular importance for clinicians. Developing and validating a multiparametric model for predicting NAC would be very meaningful for clinical practice. Methods: This study included 91 patients with locally advanced breast cancer treated from 2016 to 2020. The correlation between multiparametric characteristics and the efficacy of NAC was examined. The data were randomly divided into training and validation sets. A least absolute shrinkage and selection operator (LASSO) regression analysis was used for the variable screening. A multivariable logistic regression analysis was used to construct the model. Calibration and decision curves were used to assess the performance of the established model. Results: Lymph node metastasis, the first standard apparent diffusion coefficient (ADC) at the baseline, the change in the standard ADC at the first follow-up, the change in tumor volume at the first follow-up, and the clinical stage of the tumor at the baseline were selected for inclusion in the model. In the receiver operating characteristic (ROC) analysis, the areas under the curve (AUCs) were 0.984 [95% confidence interval (CI): 0.958-1] and 0.815 (95% CI: 0.509-1) for the primary and validation cohorts, respectively. The utility of the established model was confirmed by calibration and decision curves, and a nomogram was obtained. Conclusions: A multiparametric model based on clinical-pathological-magnetic resonance imaging (MRI) features was established to predict the effect of NAC in patients with locally advanced breast cancer.

Exercise-induced myocardial hypertrophy preconditioning promotes fibroblast senescence and improves myocardial fibrosis through Nrf2 signaling pathway.

This study aims to investigate how exercise-induced myocardial hypertrophy preconditioning affects cardiac fibroblasts in the context of myocardial fibrosis, a chronic disease that can cause cardiac arrhythmia and heart failure. Heart failure was induced in male C57BL/6 mice via Transverse aortic constriction, and some mice were given swimming exercise before surgery to test the effects of exercise-induced myocardial hypertrophy preconditioning on myocardial fibrosis. Myocardial tissue was evaluated for fibrosis, senescent cells, and apoptotic cells. Myocardial fibroblasts from rats were cultured and treated with norepinephrine to induce fibrosis which were then treated with si-Nrf2 and analyzed for markers of fibrosis, senescence, apoptosis, and cell proliferation. Exercise-induced myocardial hypertrophy preconditioning reduced myocardial fibrosis in mice, as shown by decreased mRNA expression levels of fibrosis-related indicators and increased cell senescence. In vitro data indicated that norepinephrine (NE) treatment increased fibrosis-related markers and reduced apoptotic and senescent cells, and this effect was reversed by pre-conditioning in PRE+NE group. Preconditioning activated Nrf2 and downstream signaling genes, promoting premature senescence in cardiac fibroblasts and tissues isolated from preconditioned mice. Moreover, Nrf2 knockdown reversed proapoptotic effects, restored cell proliferation, reduced senescence-related protein expression, and increased oxidative stress markers and fibrosis-related genes, indicating Nrf2's crucial role in regulating oxidative stress response of cardiac fibroblasts. Exercise-induced myocardial hypertrophy preconditioning improves myocardial fibrosis which is Nrf2-dependent, indicating the protective effect of hypertrophy preconditioning. These findings may contribute to the development of therapeutic interventions to prevent or treat myocardial fibrosis.

Synthesis of Vanadium Doped Lanthanum Bismuthate Nanorods for Enhanced Photocatalytic Activity.

Vanadium doped lanthanum bismuthate nanorods with vanadium ratio of 1%, 3%, 5% and 10 wt.% were fabricated through the hydrothermal method using sodium orthovanadate as vanadium source. Vanadium doped lanthanum bismuthate nanorod products were analyzed by scanning electron microscopy, X-ray diffraction pattern and diffuse reflection spectrum. X-ray diffraction patterns show that vanadium in the vanadium doped lanthanum bismuthate nanorods exists as triclinic Bi23V4O44.5 and monoclinic LaVO4 phases. Scanning electron microscopy observations show that the size and micro-morphology of the vanadium doped products are closely relative to the vanadium mass ratio. The length of the vanadium doped nanorods decreases and the morphology changes from nanorods to irregular nanoparticles with increasing the vanadium mass ratio. Solid UV-vis diffuse reflectance measurement shows that the bandgap value of the doped lanthanum bismuthate nanorods is narrowed from 2.37 eV to 2.25 eV after the vanadium doping ratio is increased from 1% to 10%. The doped lanthanum bismuthate nanorods illustrate enhanced photocatalytic performance for methylene orange (MO) removal with the irradiation of sunlight. The catalytic performance for MO removal depends on the irradiation time, vanadium content and dosage of the nanorods. The doped lanthanum bismuthate nanorods with the vanadium mass ratio of 10% possess the best MO catalytic degradation performance.

Nanoparticle-Mediated Delivery of Pitavastatin to Monocytes/Macrophages Inhibits Left Ventricular Remodeling After Acute Myocardial Infarction by Inhibiting Monocyte-Mediated Inflammation.

Left ventricular (LV) remodeling after myocardial infarction (MI) causes heart failure. Although medical therapies including angiotensin converting enzyme inhibitors show inhibitory effects on post-infarct LV remodeling, the prognosis of patients with post-infarct heart failure is still poor. Accumulating evidence suggests that an inflammatory response is implicated in the process of post-infarct LV remodeling. Therefore, we hypothesized that anti-inflammatory therapy by nanoparticle-mediated monocyte/macrophage-targeting delivery of pitavastatin may protect the heart from post-infarct LV remodeling.Male C57BL/6 mice were subjected to permanent coronary ligation and pitavastatin-incorporating nanoparticles (Pitavastatin-NPs) were intravenously injected for 3 to 5 consecutive days. Pitavastatin-NPs were delivered to CD11b+ monocytes/macrophages, but not to cardiomyocytes. Treatment with Pitavastatin-NPs after establishment of MI attenuated post-infarct LV remodeling accompanied by a reduction of monocytes/macrophages in the heart, whereas pitavastatin solution treatment did not. Pitavastatin-NPs inhibited mobilization of monocytes from the spleen after MI. In mice after splenectomy, Pitavastatin-NPs still decreased the number of monocytes/macrophages in the infarcted heart and inhibited post-infarct LV remodeling.Nanoparticle-mediated delivery of pitavastatin to monocytes/macrophages may be a novel therapeutic strategy to protect the heart from post-infarct LV remodeling. Inhibition of monocyte mobilization from the bone marrow is one of the major mechanisms by which Pitavastatin-NPs attenuated post-infarct LV remodeling.

Nanoparticle-Mediated Delivery of Mitochondrial Division Inhibitor 1 to the Myocardium Protects the Heart From Ischemia-Reperfusion Injury Through Inhibition of Mitochondria Outer Membrane Permeabilization: A New Therapeutic Modality for Acute Myocardial Infarction.

BACKGROUND: Mitochondria-mediated cell death plays a critical role in myocardial ischemia-reperfusion (IR) injury. We hypothesized that nanoparticle-mediated drug delivery of mitochondrial division inhibitor 1 (Mdivi1) protects hearts from IR injury through inhibition of mitochondria outer membrane permeabilization (MOMP), which causes mitochondrial-mediated cell death. METHODS AND RESULTS: We formulated poly (lactic-co-glycolic acid) nanoparticles containing Mdivi1 (Mdivi1-NP). We recently demonstrated that these nanoparticles could be successfully delivered to the cytosol and mitochondria of cardiomyocytes under H2O2-induced oxidative stress that mimicked IR injury. Pretreatment with Mdivi1-NP ameliorated H2O2-induced cell death in rat neonatal cardiomyocytes more potently than Mdivi1 alone, as indicated by a lower estimated half-maximal effective concentration and greater maximal effect on cell survival. Mdivi1-NP treatment of Langendorff-perfused mouse hearts through the coronary arteries at the time of reperfusion reduced infarct size after IR injury more effectively than Mdivi1 alone. Mdivi1-NP treatment also inhibited Drp1-mediated Bax translocation to the mitochondria and subsequent cytochrome c leakage into the cytosol, namely, MOMP, in mouse IR hearts. MOMP inhibition was also observed in cyclophilin D knockout (CypD-KO) mice, which lack the mitochondrial permeability transition pore (MPTP) opening. Intravenous Mdivi1-NP treatment in vivo at the time of reperfusion reduced IR injury in wild-type and CypD-KO mice, but not Bax-KO mice. CONCLUSIONS: Mdivi1-NP treatment reduced IR injury through inhibition of MOMP, even in the absence of a CypD/MPTP opening. Thus, nanoparticle-mediated drug delivery of Mdivi1 may be a novel treatment strategy for IR injury.

A New Therapeutic Modality for Acute Myocardial Infarction: Nanoparticle-Mediated Delivery of Pitavastatin Induces Cardioprotection from Ischemia-Reperfusion Injury via Activation of PI3K/Akt Pathway and Anti-Inflammation in a Rat Model.

AIM: There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction (AMI), for which the effectiveness of interventional reperfusion therapy is hampered by myocardial ischemia-reperfusion (IR) injury. Pretreatment with statins before ischemia is shown to reduce MI size in animals. However, no benefit was found in animals and patients with AMI when administered at the time of reperfusion, suggesting insufficient drug targeting into the IR myocardium. Here we tested the hypothesis that nanoparticle-mediated targeting of pitavastatin protects the heart from IR injury. METHODS AND RESULTS: In a rat IR model, poly(lactic acid/glycolic acid) (PLGA) nanoparticle incorporating FITC accumulated in the IR myocardium through enhanced vascular permeability, and in CD11b-positive leukocytes in the IR myocardium and peripheral blood after intravenous treatment. Intravenous treatment with PLGA nanoparticle containing pitavastatin (Pitavastatin-NP, 1 mg/kg) at reperfusion reduced MI size after 24 hours and ameliorated left ventricular dysfunction 4-week after reperfusion; by contrast, pitavastatin alone (as high as 10 mg/kg) showed no therapeutic effects. The therapeutic effects of Pitavastatin-NP were blunted by a PI3K inhibitor wortmannin, but not by a mitochondrial permeability transition pore inhibitor cyclosporine A. Pitavastatin-NP induced phosphorylation of Akt and GSK3ß, and inhibited inflammation and cardiomyocyte apoptosis in the IR myocardium. CONCLUSIONS: Nanoparticle-mediated targeting of pitavastatin induced cardioprotection from IR injury by activation of PI3K/Akt pathway and inhibition of inflammation and cardiomyocyte death in this model. This strategy can be developed as an innovative cardioprotective modality that may advance currently unsatisfactory reperfusion therapy for AMI.