Abstract Introduction Prostate cancer (PCa) is the second most frequent malignancy in men. Genetically engineered PCa mouse models (GEMMs) do not faithfully recapitulate human PCa progression. Reasons include architectural differences between the multi-lobulated mouse prostate and the human organ, choice of gene promoter (such as probasin, Pbsn) used to regulate transgene expression in GEMMs and lobular differences in susceptibility to castration. Imaging studies showed that androgen deprivation (first line therapy for metastatic PCa) by castration leads to dramatic regression of ventral prostate (VP) by up to 70%. Hence delineating cell type equivalents between the human and mouse prostates and mapping their distribution across the distinct lobes will provide fundamental knowledge to improve GEMMs, to effectively model human PCa. Methods We performed single-cell RNA sequencing (scRNA-seq) of C57BL6 and FVB mice prostates (n=10) to delineate cell type composition. We also conducted sc multi-omics (10X Multiome gene expression+ ATAC) and spatial transcriptomics (10X Visium) of prostates from mice that were unperturbed or castrated (C57BL6) to study transcriptional module (TM) alterations and spatial gene expression among the luminal epithelial (LE) cell types upon castration. Results Analyses of scRNA-seq data from 9,439 cells identified 22 different cell types from epithelial, stromal, and immune compartments and includes 9 different LE cell types that are under-studied. The lack of a standard nomenclature describing murine prostate LE cells in previous scRNA-seq studies poses a challenge for integrative analysis. We resolved this by integrating 4 independent scRNA-seq studies with our data to arrive at unified nomenclature and simultaneously validate our findings by statistical analysis. Multi-omics data analysis revealed LE cells TM differences, suggesting that LE cell diversity is developmentally triggered. Spatial transcriptomics and matched RNA in situ hybridization captured the lobe specific distribution patterns of LE cell types. For e.g., Pbsn+ LE cells were predominantly found across the AP, dorsal and lateral prostate, while Spink1+LE cells containing stemness associated genes (e.g.Tacstd2) were enriched in the VP. Analysis of the castration model revealed susceptibility differences to androgen deprivation among LE populations. Multi-omics analysis also showed a reduction in both chromatin accessibility and transcription of androgen regulated genes upon castration. Finally, cell type enrichment analysis suggests LE cells of the mouse AP and VP as equivalents of human LE and putative cell lineage signatures were enriched in PCa profiles, possibly stratifying PCa patient population. Conclusion A comprehensive mouse prostate cell atlas was built from two mouse strains. We provide a practical reference for the transcriptional and spatial profiles of each epithelial population. LE cells from AP and VP were most sensitive to castration and best represent human LE and the cell type specific genes identified here can guide future GEMM development. Citation Format: Hanbyul Cho, Yuping Zhang, Jean Tien, Jie Luo, June E. Wilke, Saravana M. Dhanasekaran, Rahul Mannan, Lisha Wang, Fengyun Su, Rui Wang, Evan T. Keller, Xuhong Cao, Sethu Pitchaya, Arul M. Chinnaiyan. Cellular cartography reveals transcriptional specificity and spatial organization of diverse luminal epithelial cells in the murine prostate [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A067.
Studies have shown that inflammation is involved in the early pathogenesis process of cerebral small vessel disease and plays an important role in disease progression. This article reviews the possible mechanisms of inflammation in cerebral small vessel disease.
Key words:
Cerebral Small Vessel Diseases; Inflammation; Blood-Brain Barrier
<p>This file includes Supplementary Figures S1-S8. Figure S1: Inhibition of EPZ6438 and ASO-EZH2 sensitizes enzalutamide-resistant LNCaP cells to enzalutamide or ASO-AR. Figure S2: Design and validation of sgRNA targeting EZH2. Figure S3: Growth inhibitory effect of Enzalutamide in EZH2 loss-of-function CRPC cell lines. Figure S4: Knockdown efficiency of ASO-AR and ASO-EZH2 in CRPC cell lines. Figures S5: EZH2 ASOs inhibit proliferation of LNCaP-abl cells. Figure S6: EZH2 ASOs synergize with ASO-AR to inhibit growth of prostate cancer cells in soft-agar colony formation assay and Cell-titer Glo assay. Figure S7: Loss-of-function of EZH2 alters AR cistrome. Figure S8: Tumor characterization of xenografted study.</p>
FK506-binding protein 51 kDa (FKBP51), encoded by Fkbp5 gene, gained considerable attention as an important regulator of several aspects of human biology including stress response, metabolic dysfunction, inflammation, and age-dependent neurodegeneration. Its catalytic peptidyl-prolyl isomerase (PPIase) activity is mediated by the N-terminal FK506-binding (FK1) domain, whereas the C-terminal tetratricopeptide motif (TPR) domain is responsible for FKBP51 interaction with molecular chaperone heat shock protein 90 (Hsp90). To understand FKBP51-related biology, several mouse models have been created. These include Fkbp5 complete and conditional knockouts, overexpression, and humanized models. To dissect the role of FKBP51-Hsp90 interaction in FKBP51 biology, we have created an interaction-deficient mouse (Fkbp5
Pancreatic cancer is a highly devastating malignancy with a very poor survival rate of 7%. Mutations in KRAS have been identified in more than 90% of PDAC patients. Previous work from our lab has shown that KRAS directly interacts with Argonaute 2 (AGO2) to promote cellular transformation. To study the involvement of AGO2 in KRASG12D-driven cancers, AGO2 expression was ablated in the KrasG12D/+; p48 Cre model (KC) model of pancreatic cancer. AGO2 floxed mice (AGO2loxP/loxP) were crossed with KC mice, resulting in oncogenic KRAS expression along with knockout of AGO2 in pancreatic acinar cells. Survival and disease progression were compared between wild-type (AGO2+/+; KRASG12D; p48Cre), heterozygous (AGO2fl/+; KRASG12D; p48Cre), and homozygous (AGO2fl/fl; KRASG12D; p48Cre) experimental mice groups. Homozygous knockout of AGO2 in KC mice resulted in significantly increased survival as compared to wild type and heterozygous mice. Pancreatic ductal adenocarcinoma (PDAC) and metastases were restricted to the wild-type and heterozygous mice. Pancreas from AGO2fl/fl; KRASG12D; p48Cre mice develop only early pancreatic intraepithelial lesions (PanINs), which fail to progress to PDAC. Senescence-associated β-galactosidase staining showed strong and significant increase in senescence in PanIN lesions mice lacking AGO2 expression as compared to AGO2+/+; KRASG12D; p48Cre mice. This suggests that AGO2 prevents oncogene induced senescence (OIS) as a result of KRASG12D expression and allows PanIN to PDAC progression.To gain mechanistic insights of OIS due to AGO2 loss, we evaluated markers for OIS including p16, p53, p21, gamma γH2AX, and RAS-associated signaling (pERK and pAkt). Analysis of PanIN lesions lacking AGO2 showed increased p16 levels and high levels of phospho-ERK, compared to PDAC from pancreas with AGO2 expression. In order to extend these observations in cell line models, we performed AGO2 knockdown in T24 cells harboring HRASG12V. Surprisingly, cells with low AGO2 levels underwent OIS, which was similar to the pancreatic mouse model and was accompanied with increased phospho-ERK signaling and p16 expression. Further studies are underway to determine the contribution of the RAS-AGO2 interaction in the development of OIS.Additionally, we are using CRISPR/Cas9 technology to screen pancreatic cancer cell lines with AGO2 knockout for their dependence on AGO2 and their ability to undergo OIS in the absence of AGO2 expression. We will present findings from our ongoing studies involving the role of AGO2 loss in the KPC (KRASG12D; p53fl/+; Cre) model, wherein OIS will be assessed in the absence of p53, a canonical inducer of cellular senescence.Citation Format: Seema Chugh, Jean C. Tien, Ronald F. Siebenaler, Vijaya L. Dommeti, Sylvia Z. Wang, Sanjana Eyunni, Kristin M. Juckette, Lisha Wang, Sunita Shankar, Arul M. Chinnaiyan. Role of Argonaute 2 in oncogene induced senescence in a pancreatic cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 94.
The aim of the present study was to observe the temporal changes in the chest based on findings from imaging in severe patients with novel coronavirus pneumonia. A total of 33 severe confirmed cases (20 male patients and 13 female patients) were enrolled in the present study between January 31, 2020 and March 10, 2020. Chest imaging findings and clinical data were collected and analyzed. The median age was 65 years (age range, 25‑90 years). As of April 7, 2020, 24 patients were discharged, and 9 patients died. With regards to the clinical manifestations, 28 patients had fever, 17 patients had a cough and 15 patients had shortness of breath. Of these, 29 patients had underlying health conditions. Ground glass opacities, consolidation and interlobular septal thickening were the most common and typical chest computerized tomography (CT) scan abnormalities. A total of 6/33 (18.2%) patients had 1 affected lobe, 6/33 (18.2%) patients had 2 affected lobes, 5/33 (15.2%) patients had 3 affected lobes, 9/33 (27.3%) patients had 4 affected lobes and 7/33 (21.2%) patients had 5 affected lobes in the initial chest CT scan. The mean interval time between two consecutive CT examinations was 4.5 days (range, 3‑9 days). Most severe patients exhibited some degree of aggravation based on the CT findings in the 3 weeks from illness onset. After 3 weeks from illness onset, these severe survivors demonstrated improvements in the chest CT findings, which included complete absorption or only a few remaining fibrous stripes. Chest CT manifestations of patients infected with novel coronavirus pneumonia were diverse and varied. Severe patients had imaging features of rapid progression and slow absorption. Monitoring of chest imaging findings is vital to detect any changes in a timely manner.
In this article, for delayed Nicholson's blowflies equation, we propose a hybrid control nonstandard finite-difference (NSFD) scheme in which state feedback and parameter perturbation are used to control the Neimark-Sacker bifurcation. Firstly, the local stability of the positive equilibria for hybrid control delay differential equation is discussed according to Hopf bifurcation theory. Then, for any step-size, a hybrid control numerical algorithm is introduced to generate the Neimark-Sacker bifurcation at a desired point. Finally, numerical simulation results confirm that the control strategy is efficient in controlling the Neimark-Sacker bifurcation. At the same time, the results show that the NSFD control scheme is better than the Euler control method.
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