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Introduction: There is an urgent clinical need to accurately predict the risk for disease progression in post‐treatment NSCLC patients, yet current ctDNA mutation profiling approaches are limited by low sensitivity. We represent a non‐invasive liquid biopsy assay utilizing cfDNA neomer profiling for predicting disease progression in 44 inoperable localized NSCLC patients. Methods: A total of 97 plasma samples were collected at various time points during or post‐treatments (TP1: 39, TP2: 33, TP3: 25). cfDNA neomer profiling, generated based on target sequencing data, was used to fit survival support vector machine models for each time point. Leave‐one‐out cross‐validation (LOOCV) was performed to evaluate the models' predictive performances. Results: Our cfDNA neomer profiling assay showed excellent performance in detecting patients with a high risk for disease progression. At TP1, the high‐risk patients detected by our model showed an increased risk of 3.62 times (hazard ratio [HR] = 3.62, p = 0.0026) for disease progression, compared to 3.91 times (HR = 3.91, p = 0.0022) and 4.00 times (HR = 4.00, p = 0.019) for TP2 and TP3. These neomer profiling determined HRs were higher than the ctDNA mutation‐based results (HR = 2.08, p = 0.074; HR = 1.49, p = 0.61) at TP1 and TP3. At TP1, the predictive model reached 40% sensitivity at 92.9% specificity, outperforming the mutation‐based method (40% sensitivity at 78.6% specificity), while the combination results reached a higher sensitivity (60%). Finally, the longitudinal analysis showed that the combination of neomer and ctDNA mutation‐based results could predict disease progression with an excellent sensitivity of 88.9% at 80% specificity. Conclusion: In conclusion, we developed a cfDNA neomer profiling assay for predicting disease progression in inoperable NSCLC patients. This assay showed increased predicting power during and post‐treatment compared to the ctDNA mutation‐based method, thus illustrating a great clinical potential to guide treatment decisions in inoperable NSCLC patients. Trial Registration: ClinicalTrials.gov: NCT04014465 [ABSTRACT FROM AUTHOR]

BackgroundThis article describes a pilot study evaluating a novel liquid biopsy system for non-small cell lung cancer (NSCLC) patients. The electric field-induced release and measurement (EFIRM) method utilizes an electrochemical biosensor for detecting oncogenic mutations in biofluids.MethodsSaliva and plasma of 17 patients were collected from three cancer centers prior to and after surgical resection. The EFIRM method was then applied to the collected samples to assay for exon 19 deletion and p.L858 mutations. EFIRM results were compared with cobas results of exon 19 deletion and p.L858 mutation detection in cancer tissues.ResultsThe EFIRM method was found to detect exon 19 deletion with an area under the curve (AUC) of 1.0 in both saliva and plasma samples in lung cancer patients. For L858R mutation detection, the AUC of saliva was 1.0, while the AUC of plasma was 0.98. Strong correlations were also found between presurgery and post-surgery samples for both saliva (0.86 for exon 19 and 0.98 for L858R) and plasma (0.73 for exon 19 and 0.94 for L858R).ConclusionOur study demonstrates the feasibility of utilizing EFIRM to rapidly, non-invasively, and conveniently detect epidermal growth factor receptor mutations in the saliva of patients with NSCLC, with results corresponding perfectly with the results of cobas tissue genotyping.

This article discusses a prospective cohort study that examined the use of circulating tumor DNA (ctDNA) as a biomarker to predict failure patterns and the efficacy of consolidation immunotherapy in patients with locally advanced non-small-cell lung cancer (LA-NSCLC) who received chemoradiotherapy (CRT). The study found that dynamic ctDNA levels could predict failure patterns and identify patients who may benefit from consolidation immunotherapy. Patients with decreased ctDNA levels after CRT had a higher risk of distant metastasis but showed more benefit from immunotherapy, while patients with increased ctDNA levels had a higher risk of both local-regional and distant failure and also showed benefit from immunotherapy. The study suggests that ctDNA testing could be used to personalize treatment decisions and improve outcomes for LA-NSCLC patients. [Extracted from the article]

Lysosomes are degradative organelles and play vital roles in a variety of cellular processes. Ion channels on the lysosomal membrane are key regulators of lysosomal function. TMEM175 has been identified as a lysosomal potassium channel, but its modulation and physiological functions remain unclear. Here, we show that the apoptotic regulator Bcl‐2 binds to and inhibits TMEM175 activity. Accordingly, Bcl‐2 inhibitors activate the channel in a caspase‐independent way. Increased TMEM175 function inhibits mitophagy, disrupts mitochondrial homeostasis, and increases production of reactive oxygen species (ROS). ROS further activates TMEM175 and thus forms a positive feedback loop to augment apoptosis. In a 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), knockout (KO) of TMEM175 mitigated motor impairment and dopaminergic (DA) neuron loss, suggesting that TMEM175‐mediated apoptosis plays an important role in Parkinson's disease (PD). Overall, our study reveals that TMEM175 is an important regulatory site in the apoptotic signaling pathway and a potential therapeutic target for Parkinson's disease (PD). Synopsis: The anti‐apoptotic mitochondrial protein Bcl‐2 regulates lysosomal K+ channel TMEM175. TMEM175 forms a positive feedback loop with ROS to augment apoptosis and promote the death of DA neurons in Parkinson's disease. Anti‐apoptotic mitochondrial protein Bcl‐2 binds to and regulates lysosomal potassium channel TMEM175.TMEM175 inhibits mitophagy, impairs mitochondrial function, and consequently increases ROS production.ROS activates TMEM175 through a positive feedback loop to augment apoptosis.TMEM175‐mediated apoptosis promotes the death of dopaminergic neurons in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Two new lanostanoids, 7-oxo-ganoderic acid Z (1) and 15-hydroxy-ganoderic acid S (2), were isolated from a lipophilic extract of the fruiting body of Ganoderma lucidum. The structures of both compounds were established by interpretation of their spectroscopic data. Compounds 1 and 2 both exhibited inhibitory activities against the HMG-CoA reductase and acyl CoA acyltransferase. [ABSTRACT FROM AUTHOR]