Upregulating HIF-1α to Boost the Survival of Neural Stem Cells via Functional Peptides-Complexed MRI-Visible Nanomedicine for Stroke Therapy.

Neural stem cells (NSCs) transplantation has been considered as a promising strategy for the treatment of ischemic stroke. However, the therapeutic prospect is limited by the poor control over the survival, migration, and maturation of transplanted NSCs. Upregulating hypoxia inducible factor (HIF)-1α expression in stem cells can improve the survival and migration of NSCs grafted for stroke therapy. Functional peptide drugs, which could inhibit endogenous HIF-1α ubiquitination, might be used to effectively upregulate the HIF-1α expression in NSCs, thereby to improve the therapeutic effect in ischemia stroke. Herein, a magnetic resonance imaging (MRI)-visible nanomedicine is developed to codeliver functional peptides and superparamagnetic iron oxide (SPIO) nanoparticles into NSCs. This nanomedicine not only promotes the survival and migration ability of NSCs but also allows an in vivo tracking of transplanted NSCs with MRI. The results demonstrate the great potential of the functional peptides-complexed multifunctional nanomedicine in boosting the therapeutic effect of stem cell-based therapy in stroke.

Preoperative Prediction of the Aggressiveness of Oral Tongue Squamous Cell Carcinoma with Quantitative Parameters from Dual-Energy Computed Tomography.

Objectives: To determine whether quantitative parameters derived from dual-energy computed tomography (DECT) were predictive of the aggressiveness of oral tongue squamous cell carcinoma (OTSCC) including the pathologic stages, histologic differentiation, lymph node status, and perineural invasion (PNI). Methods: Between August 2019 and March 2021, 93 patients (mean age, 54.6 ± 13.8 years; 66 men) with pathologically diagnosed OTSCC were enrolled in this prospective study. Preoperative DECT was performed and quantitative parameters (e.g., slope of the spectral Hounsfield unit curve [λHu], normalized iodine concentration [nIC], normalized effective atomic number [nZeff], and normalized electron density [nRho]) were measured on arterial phase (AP) and venous phase (VP) DECT imaging. Quantitative parameters from DECT were compared between patients with different pathologic stages, histologic differentiation, lymph node statuses, and perineural invasion statuses. Logistic regression analysis was utilized to assess independent parameters and the diagnostic performance was analyzed by the receiver operating characteristic curves (ROC). Results: λHu and nIC in AP and λHu, nZeff, and nIC in VP were significantly lower in stage III-IV lesions than in stage I-II lesions (p < 0.001 to 0.024). λHu in VP was an independent predictor of tumor stage with an odds ratio (OR) of 0.29, and area under the curve (AUC) of 0.80. λHu and nIC were higher in well-differentiated lesions than in poorly differentiated lesions (p < 0.001 to 0.021). The nIC in VP was an independent predictor of histologic differentiation with OR of 0.31, and AUC of 0.78. λHu and nIC in VP were lower in OTSCCs with lymph node metastasis than those without metastasis (p < 0.001 to 0.005). λHu in VP was the independent predictor of lymph node status with OR of 0.42, and AUC of 0.74. No significant difference was found between OTSCCs without PNI and those with PNI in terms of the quantitative DECT parameters. Conclusion: DECT can be a complementary means for the preoperative prediction of the aggressiveness of OTSCC.

Co-existing Hypertension and Hyperhomocysteinemia Increases the Risk of Carotid Vulnerable Plaque and Subsequent Vascular Event: An MR Vessel Wall Imaging Study.

Purpose: This study sought to determine the associations of co-existing hypertension and hyperhomocysteinemia (H-Hcy) with carotid vulnerable plaque features and subsequent vascular events. Methods: Symptomatic patients with carotid atherosclerosis were enrolled and underwent carotid magnetic resonance (MR) vessel wall imaging. The patients were divided into the following groups: co-existing hypertension and H-Hcy group; isolated hypertension group; isolated H-Hcy group; and control group. The morphological and compositional characteristics of carotid plaques were assessed on MR images and compared among different groups. Univariate and multivariate cox regressions were used to calculate the hazard ratio (HR) and corresponding 95% confidence interval (CI) of co-existing hypertension and H-Hcy in predicting subsequent vascular events after at least 1-year followed-up. Results: In total, 217 patients (mean age, 59.4 ± 11.9 years; 154 males) were recruited. Patients in co-existing hypertension and H-Hcy group had a significantly higher prevalence of carotid lipid-rich necrotic core (LRNC) than isolated H-Hcy and control group (73.2 vs. 43.3 vs. 50%, p = 0.015). During the median follow-up time of 12.2 ± 4.3 months, 61 (39.8%) patients experienced vascular events. After adjusting for baseline confounding factors, co-existing hypertension and H-Hcy (HR, 1.82; 95% CI, 1.01-3.27; p = 0.044), presence of carotid LRNC (HR, 2.25; 95% CI, 1.09-4.65; p = 0.029), and combination of co-existing hypertension and H-Hcy and carotid LRNC (HR, 2.39; 95% CI, 1.26-4.43; p = 0.007) were significantly associated with subsequent vascular events. Conclusions: Co-existing hypertension and H-Hcy are associated with carotid vulnerable plaque features, such as LRNC. Combining co-existing hypertension and H-Hcy with carotid vulnerable plaque features has a stronger predictive value for subsequent vascular events than each measurement alone.

Silencing of Pyruvate Kinase M2 via a Metal-Organic Framework Based Theranostic Gene Nanomedicine for Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is typically associated with poor prognosis due to its only partial response to chemotherapy and lack of clinically established targeted therapies coupled with an aggressive disease course. Aerobic glycolysis is a hallmark of reprogrammed metabolic activity in cancer cells, which can be repressed by small-interfering RNA (siRNA). However, the lack of effective carriers to deliver vulnerable siRNA restricts the clinical potentials of glycolysis-based gene therapy for TNBC. Herein, we develop a tumor-targeted, biomimetic manganese dioxide (MnO2)-shrouded metal-organic framework (MOF) based nanomedicine to deliver siRNA against pyruvate kinase muscle isozyme M2 (siPKM2), wherein PKM2 is a rate-limiting enzyme in glycolysis, to inhibit the reprogrammed glycolysis of TNBC. This MOF-based genetic nanomedicine shows excellent monodispersity and stability and protects siPKM2 against degradation by nucleases. The nanomedicine not only substantially blocks the glycolytic pathway but also improves intracellular hypoxia in TNBC cells, with a resultant O2-enhanced anticancer effect. In the mice orthotopic TNBC model, the nanomedicine shows a remarkable therapeutic effect. Meanwhile, the Mn2+ ions released from acid microenvironment-responsive MnO2 enable in vivo monitoring of the therapeutic process with magnetic resonance imaging (MRI). Our study shows great promise with this MRI-visible MOF-based nanomedicine for treating TNBC by inhibition of glycolysis via the RNA interference.