Cordon‐Cardo, Carlos

Abstract The roles of nucleoplasm-residing nucleoporins (NUP) in solid tumors, including prostate cancer, remain unknown. In this study, we reveal the clinical significance and mechanistic role of the off-pore NUP, soluble POM121 (sPOM121), as a crucial transcriptional regulator that enhances the aggressiveness of metastatic prostate cancer. Using orthogonal methodologies in human samples, sPOM121 was identified as the predominantly expressed nucleoplasmic NUP in prostate cancer. Unbiased proteomic and epigenomic studies demonstrate that sPOM121, through its C-terminus, interacts with the chromatin remodeler SMARCA5 at gene promoter sites and localizes at nuclear condensates, reprogramming gene expression. Indeed, sPOM121 regulates a distinct oncogenic gene network, including β-catenin, leading to prostate cancer progression and immune evasion. Importantly, targeting the sPOM121/β-catenin axis in patient-derived preclinical and syngeneic mouse models halts prostate cancer aggressiveness and enhances antitumor immunity. Taken together, these findings reveal previously unknown actionable reprogramming functions of off-pore NUPs in solid tumors. Significance: This study uncovers how oncogenic signaling programs are transcriptionally heightened by the NUP sPOM121 in metastatic prostate cancer. Localization of sPOM121 at active transcriptional nuclear condensates propels disease progression and immune evasion, offering novel anticancer therapeutic opportunities.

AbstractBackgroundPost‐mortem assessment remains the only option and a gold standard for a definitive diagnosis of Parkinson’s disease (PD). The antemortem diagnosis is challenging due to a variable clinical presentation and the abundance of mimicking conditions, obscuring the clinical picture and delaying the treatment. It is well established that while PD pathologically manifests in central nervous system with aggregation of α‐synuclein as Lewy bodies and Lewy neurites, this pathology is also found in the peripheral nervous system. Peripheral Lewy‐type synucleinopathy (LTS) is present in early PD, suggesting its utility as a diagnostic and prognostic biomarker. We have previously confirmed that detection of LTS in submandibular gland (SMG) biopsies is sensitive (.75) and specific (.90) for early PD. However, the assessment by a neuropathologist of multiple levels of such biopsy is laborious and time‐consuming.MethodHere work we applied two Convolutional Neural Networks (CNN) for detection of LTS on 283 digital whole slide images (WSI) from 95 unique SMG biopsies. A total number of 8,386 LTS were annotated following the interrater reliability study with kappa=.7. We used transfer learning to train a CNN model to classify image patches (40‐by‐40 pixels at 20x) with and without presence of LTS objects.ResultThe trained CNNs showed the following performance on image patches: sensitivity: .982/.988, specificity: .998/.999, precision: .852/.950, accuracy: .995/.998, and F‐1 score .912/.968 for ResNet30/InceptionV4 respectively. On test WSI the sensitivity in detecting LTS was .963/.971 respectively.ConclusionThis work is first to demonstrate the practical utility of an CNN for screening for LTS, which can further translate into a practical screening tool facilitating the antemortem diagnosis of PD. We further plan to develop neural networks for accurate and precise detection and quantification of LTS in antemortem SMG biopsies. This, altogether, would offer a screening, confirmatory, prognostic, and quantitative tool for clinical assessment of early PD.

Abstract Purpose: The eukaryotic translation initiation factor complex 4E (eIF4E) is downstream in the mammalian target of rapamycin (mTOR) pathway. This study explored expression of eIF4E and its relationship with the PTEN/AKT and RAS/MEK/ERK pathways in non–small cell lung carcinoma (NSCLC). Experimental Design: The status of phosphorylated eIF4E (p-eIF4E), phosphorylated AKT (p-AKT), PTEN, phosphorylated tuberin (p-TSC2), phosphorylated mTOR (p-mTOR), phosphorylated S6 (p-S6), and phosphorylated Erk1/2 (p-Erk1/2) was studied using immunohistochemical analysis applied to a tissue microarray containing 300 NSCLCs. Staining results for each antibody were compared with clinical and pathologic features, and the relationship between staining results was explored. Results: Overexpression of p-eIF4E, p-AKT, p-TSC2, p-mTOR, p-S6, and p-Erk1/2 in NSCLC was found in 39.9%, 78.8%, 5.1%, 46.7%, 27.1%, and 16.6% of tumors, respectively. The phenotype of p-eIF4E correlated positively with that of p-AKT, p-TSC2, and p-S6 (P < 0.001). Overall survival in NSCLC patients was significantly shorter in cases with overexpression of p-eIF4E and p-AKT alone and in combination (log-rank P < 0.001, each). Cases with underexpression of PTEN were limited (6.4%), and this phenotype did not correlate with any clinical variable. In cluster analysis, the p-AKT/p-mTOR/p-eIF4E/p-S6–positive group had significantly shorter survival compared with the survival of all cases (P < 0.001). Multivariate analysis showed that p-eIF4E overexpression is an independent prognostic factor for NSCLC (P = 0.004). Conclusions: This study shows that p-eIF4E expression in addition to p-AKT predicts poor prognosis in NSCLC. Moreover, the correlation between expression of p-eIF4E with p-AKT, as well as p-TSC2 and p-S6, indicates that eIF4E activation through the AKT pathway plays an important role in the progression of NSCLC. Clin Cancer Res; 16(1); OF1–9