Elevated LAMTOR4 Expression Is Associated with Lethal Prostate Cancer and Its Knockdown Decreases Cell Proliferation, Invasion, and Migration In Vitro.

Late endosomal/lysosomal adaptor, MAPK and mTOR, or LAMTOR, is a scaffold protein complex that senses nutrients and integrates growth factor signaling. The role of LAMTOR4 in tumorigenesis is still unknown. However, there is a considerable possibility that LAMTOR4 is directly involved in tumor cell proliferation and metastasis. In the current study, we investigated the protein expression of LAMTOR4 in a cohort of 314 men who were undergoing transurethral resection of prostate (TURP) consisting of incidental, advanced and castration-resistant cases. We also correlated the data with ERG and PTEN genomic status and clinicopathological features including Gleason score and patients' outcome. Additionally, we performed in vitro experiments utilizing knockdown of LAMTOR4 in prostate cell lines, and we performed mRNA expression assessment using TCGA prostate adenocarcinoma (TCGA-PRAD) to explore the potential differentially expressed genes and pathways associated with LAMTOR4 overexpression in PCa patients. Our data indicate that high LAMTOR4 protein expression was significantly associated with poor overall survival (OS) (HR: 1.44, CI: 1.01-2.05, p = 0.047) and unfavorable cause-specific survival (CSS) (HR: 1.71, CI: 1.06-2.77, p = 0.028). Additionally, when high LAMTOR4 expression was combined with PTEN-negative cases (score 0), we found significantly poorer OS (HR: 2.22, CI: 1.37-3.59, p = 0.001) and CSS (HR: 3.46, CI: 1.86-6.46, p < 0.0001). Furthermore, ERG-positive cases with high LAMTOR4 exhibited lower OS (HR: 1.98, CI: 1.18-3.31, p = 0.01) and CSS (HR: 2.54, CI: 1.32-4.87, p = 0.005). In vitro assessment showed that knockdown of LAMTOR4 decreases PCa cell proliferation, migration, and invasion. Our data further showed that knockdown of LAMTOR4 in the LNCaP cell line significantly dysregulated the ß catenin/mTOR pathway and tumorigenesis associated pathways. Inhibiting components of the mTOR pathway, including LAMTOR4, might offer a strategy to inhibit tumor progression and metastasis in prostate cancer.

Undervaluing nondrug rewards or overvaluing cocaine? Cocaine demand relates to cocaine use severity more strongly than anhedonia in individuals with cocaine use disorder.

Cocaine use disorder (CUD) is a major public health issue, and greater cocaine use severity has been associated with worse treatment retention and outcomes. Therefore, greater understanding of processes that influence cocaine use is needed. Both anhedonia (i.e., undervaluation of nondrug rewards) and cocaine demand (i.e., cocaine valuation) are related to cocaine use severity and thematically related to each other at face value, but no studies have directly compared these outcomes to our knowledge. The present study represents a secondary analysis from a two-phase sequential, multiple assignment, randomized trial aimed at developing adaptive interventions for CUD. We examined the relationship between anhedonia and cocaine demand and how these measures were related to cocaine use severity. Participants (N = 116) were treatment-seeking adults with CUD. All measures were taken at baseline before treatment initiation. Analyses revealed (a) moderate and very strong evidence of relationships between cocaine demand factors (i.e., persistence, amplitude) and anhedonia (PP values ≥ 77.8%); (b) positive association between cocaine demand (both persistence and amplitude) and measures of cocaine use severity, with the exception of one relationship, which was in the opposite direction; and (c) demand amplitude continued to be positively related to cocaine use severity, even when considering anhedonia. Overall, findings from this study indicate cocaine demand relates to cocaine use severity more strongly than anhedonia. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Assessing cocaine motivational value: Comparison of brain reactivity bias toward cocaine cues and cocaine demand.

The behavioral economic measure drug demand and the neural measure late positive potential (LPP) are two measures of motivational value that have been associated with drug relapse risk and treatment outcomes. Despite having overlapping themes, no studies have directly compared drug demand and LPP. Participants (N = 59) included treatment-seeking individuals with cocaine use disorder that had completed both a baseline cocaine demand task and an electroencephalogram (EEG) picture-viewing task of drug-related and pleasant picture cues. Associations between the LPP difference score amplitude (drug-pleasant) and five demand indices (Q0, essential value [EV], Omax, Pmax, and breakpoint [BP]) were evaluated via Bayesian generalized linear modeling. Positive associations (posterior probabilities ≥ 75%) were found between LPP amplitude and four demand indices (Q0, EV, Omax, BP). These results suggest that individuals who attach greater relevance to cocaine cues also exhibit greater valuation of cocaine reward. Implications for incorporating methodology from behavioral science and brain imaging are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).