Predictors of Lung Adenocarcinoma With Leptomeningeal Metastases: A 2022 Targeted-Therapy-Assisted molGPA Model.

Objective: To explore prognostic indicators of lung adenocarcinoma with leptomeningeal metastases (LM) and provide an updated graded prognostic assessment model integrated with molecular alterations (molGPA). Methods: A cohort of 162 patients was enrolled from 202 patients with lung adenocarcinoma and LM. By randomly splitting data into the training (80%) and validation (20%) sets, the Cox regression and random survival forest methods were used on the training set to identify statistically significant variables and construct a prognostic model. The C-index of the model was calculated and compared with that of previous molGPA models. Results: The Cox regression and random forest models both identified four variables, which included KPS, LANO neurological assessment, TKI therapy line, and controlled primary tumor, as statistically significant predictors. A novel targeted-therapy-assisted molGPA model (2022) using the above four prognostic factors was developed to predict LM of lung adenocarcinoma. The C-indices of this prognostic model in the training and validation sets were higher than those of the lung-molGPA (2017) and molGPA (2019) models. Conclusions: The 2022 molGPA model, a substantial update of previous molGPA models with better prediction performance, may be useful in clinical decision making and stratification of future clinical trials.

ß-Methylphenylalanine exerts neuroprotective effects in a Parkinson's disease model by protecting against tyrosine hydroxylase depletion.

We evaluated the neuroprotective effects of ß-methylphenylalanine in an experimental model of rotenone-induced Parkinson's disease (PD) in SH-SY5Y cells and rats. Cells were pre-treated with rotenone (2.5 µg/mL) for 24 hours followed by ß-methylphenylalanine (1, 10 and 100 mg/L) for 72 hours. Cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), mitochondrial fragmentation, apoptosis, and mRNA and protein levels of tyrosine hydroxylase were determined. In a rat model of PD, dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels, bradykinesia and tyrosine hydroxylase expression were determined. In rotenone-pre-treated cells, ß-methylphenylalanine significantly increased cell viability and MMP, whereas ROS levels, apoptosis and fragmented mitochondria were reduced. ß-Methylphenylalanine significantly increased the mRNA and protein levels of tyrosine hydroxylase in SH-SY5Y cells. In the rotenone-induced rat model of PD, oral administration of ß-methylphenylalanine recovered DA and DOPAC levels and bradykinesia. ß-Methylphenylalanine significantly increased the protein expression of tyrosine hydroxylase in the striatum and substantia nigra of rats. In addition, in silico molecular docking confirmed binding between tyrosine hydroxylase and ß-methylphenylalanine. Our experimental results show neuroprotective effects of ß-methylphenylalanine via the recovery of mitochondrial damage and protection against the depletion of tyrosine hydroxylase. We propose that ß-methylphenylalanine may be useful in the treatment of PD.