Journal of translational science最新文献

The current COVID-19 pandemic has presented unprecedented challenges to the world community. No effective therapies or vaccines have yet been established. Upon the basis of homologies to similar coronaviruses, several potential drug targets have been identified and are the focus of both laboratory and clinical investigation. The rationale for several of these drug candidates is presented in this review. Emerging clinical data has revealed that severe COVID-19 disease is associated with heightened inflammatory responses and a procoagulant state, suggesting that patient treatment strategies must extend beyond antiviral agents. Effective approaches to the treatment of vulnerable patients with comorbidities will render COVID-19 substantially more manageable.

Rationale and objective: Despite contribution of dyslipidemia to ischemic stroke, plasma lipidomic correlates of stroke in CKD is not studied. This study is aimed to identify plasma lipid alterations associated with stroke.

Study design: Cross sectional.

Setting and population: 214 participants of Clinical Phenotyping and Resource Biobank Core (CPROBE). Clinical data and plasma samples at the time of recruitment were obtained and used to generate lipidomic data by liquid chromatography/mass-spectrometry-based untargeted platform.

Predictors: Various levels of free fatty acids, acylcarnitines and complex lipids.

Outcome: Stroke.

Analytic approach: includes compound by compound comparison of lipids using t-test adjusted by false discovery rate in patients with and without stroke, and application of logistic regression analysis to identify independent lipid predictors of stroke and to estimate the odds associated with their various levels.

Results: Overall, we identified 330 compounds. Enrichment analysis revealed overrepresentation of differentially regulated phosphatidylcholines (PC)s and phosphatidylethanolamines (PE)s were overrepresented in stroke (P<0.001). Abundance of PC38:4, PE36:4, PC34:0, and palmitate were significantly higher, but those of plasmenyl-PE (pPE)38:2, and PE 32:2 was significantly lower in patients with stroke (p≤0.0014). After adjusting, each 1-SD increase in palmitate and PC38:4 was independently associated with 1.84 fold (95% CI: 1.06-3.20, p=0.031) and 1.84 fold (1.11-3.05, p=0.018) higher risk of stroke, respectively. We observed a significant trend toward higher abundance of PCs, PEs, pPEs, and sphingomyelins in stroke (p≤0.046).

Limitations: Small sample size; unclear, if similar changes in the same or opposite direction preceded stroke, as the cross-sectional nature of the observation does not allow determining the effect of time course on lipid alterations.

Conclusion: Differential regulation of palmitate, PCs, and PEs in patients with CKD and a history of stroke may represent a previously unrecognized risk factor and might be a target of risk stratification and modification.

Objective: Obesity has reached epidemic proportions and is a strong risk factor for obstructive sleep apnea (OSA). However, the underlying mechanisms are poorly understood and current treatment strategies for OSA and obesity have critical limitations. Thus, establishment of an obesity-related large animal model with spontaneous OSA is imperative.

Materials and methods: Natural and sedated sleep were monitored and characterized in 4 obese (body mass index - BMI>48) and 3 non-obese (BMI<40) minipigs. These minipigs were instrumented with the BioRadio system under sedation for the wireless recording of respiratory airflow, snoring, abdominal and chest respiratory movements, electroencephalogram, electrooclulogram, electromyogram, and oxygen saturation. After instrumentation, the minipigs were placed in a dark room with a remote night-vision camera for monitoring all behaviors. Wakefulness and different sleep stages were classified, and episodes of apneas and/or hypopneas were identified during natural and/or sedated sleep.

Results: No hypopnea episodes were observed in two of the non-obese minipigs, but one non-obese minipig had 5 hypopnea events. Heavy snoring and 27-58 apnea and/or hypopnea episodes were identified in all 4 obese minipigs. Most of these episodes occurred in the rapid eye movement stage during natural sleep and/or sedated sleep in Yucatan minipigs.

Conclusions: Obese minipigs can experience naturally occurring OSA, thus are an ideal large animal model for obese-related OSA studies.

Human cancers emerge from cancer stem cells (CSCs), which are resistant to cancer chemotherapeutic agents, radiation, and cell death. Moreover, autophagy provides the cytoprotective effect which contributes to drug resistance in these cells. Furthermore, much evidence shows that CSCs cause tumor initiation, progression, metastasis, and cancer recurrence. Various signaling pathways including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), maternal embryonic leucine zipper kinase (MELK), NOTCH1, and Wnt/β-catenin as well as the CSC markers maintain CSC properties. Several mechanisms including overexpression of ABC multidrug resistance transporters, a deficiency in mitochondrial-mediated apoptosis, upregulation of c-FLIP, overexpression of anti-apoptotic Bcl-2 family members and inhibitors of apoptosis proteins (IAPs), and PI3K/AKT signaling contribute to enhancing resistance to chemotherapeutic drugs and cell death induction in CSCs in various cancers. Studying such pathways may help provide detailed understanding of CSC mechanisms of resistance to chemotherapeutic agents and apoptosis and may lead to the development of effective therapeutics to eradicate CSCs.