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Chapagai, D.

Publications and source records attributed to Chapagai, D..

2 recordsLinked to original sources

Childhood Trauma and Cortical Thickness in Bipolar Disorder with and without Psychosis: Effects by Diagnostic Group and Trauma Subtype

Abstract Background Bipolar disorder affects about 2-3% of the population and is associated with cortical abnormalities, with bipolar disorder with psychosis (BDP) reported to show more pronounced changes. It remains unclear whether childhood trauma is associated with cortical thickness differences across bipolar disorder subgroups, particularly in BDP. Methods Using the publicly available PARDIP (Psychosis and Affective Research Domains and Intermediate Phenotypes) data set, we examined whether childhood trauma was associated with cortical thickness differences among 120 individuals: 33 with bipolar disorder without psychosis (BD; 36% male), 38 with bipolar disorder with psychosis (BDP; 47% male), and 49 healthy controls (HC; 61% male). Participants completed the Childhood Trauma Questionnaire-Short Form (CTQ-SF), and T1-weighted MRI scans were processed with FreeSurfer to extract cortical thickness across the 68 Desikan-Killiany regions. Linear mixed effects models tested associations between CTQ subtype scores and cortical thickness and trauma-by-diagnosis interactions, with sensitivity analyses for medication class and illness duration following the ENIGMA guidelines. Results No cortical thickness difference survived correction for multiple testing. At the nominal level, BD showed reduced thickness relative to HC in cingulate, frontal and occipital regions, whereas BDP showed greater superior temporal thickness relative to BD. Sexual abuse was nominally associated with reduced temporal thickness. Exploratory trauma-by-diagnosis interactions suggested region- and subtype-specific patterns that did not survive correction. Medication class and illness duration showed no significant effects after FDR correction. Conclusions These exploratory findings suggest nominal, region-specific associations between childhood trauma subtypes and cortical thickness in bipolar disorder. However, no findings survived correction for multiple comparisons, so they should be read as preliminary and need replication in larger samples.

neuroscience↗

Abbapolin inhibitors of the PLK1 PBD as Prostate Cancer Therapeutics, in vivo activity and synergy with androgen therapy

Polo-like kinase 1 (PLK1) is an established therapeutic target in cancer; however, ATP-competitive kinase inhibitors have shown limited clinical success because of toxicity, acquired resistance, and incomplete inhibition of non-catalytic PLK1 functions. Targeting the Polo-box domain (PBD), which regulates PLK1 localization and substrate recognition, represents an alternative therapeutic strategy but has been hindered by the lack of selective, cell-active small molecules. Here, the optimization and biological characterization of abbapolins, a series of non-peptidic PLK1 PBD inhibitors developed using the REPLACE strategy are described. Structure-guided optimization and screening across the NCI-60 cancer cell panel identified compounds with preferential activity against prostate cancer cells. Proteomic analyses demonstrated that cellular sensitivity correlated with PLK1 protein abundance, supporting an on-target mechanism of action. Abbapolins directly engaged PLK1 in cells, induced selective degradation of endogenous PLK1, and suppressed long-term clonogenic growth. Lead compounds demonstrated favorable pharmacokinetic properties and significantly inhibited prostate tumor growth in xenograft models without detectable systemic toxicity. PLK1 abundance was significantly reduced in treated tumors and correlated with tumor response, identifying PLK1 degradation as a potential pharmacodynamic biomarker. Abbapolins also synergized with enzalutamide in castration- resistant prostate cancer cells, supporting their potential as combination therapies for advanced disease. Collectively, these studies establish selective inhibition of the PLK1 Polo-box domain as a viable therapeutic strategy, provide in vivo proof-of-concept for the REPLACE approach, and identify abbapolins as promising leads for advanced prostate cancer.

cancer biology↗