Heterochromatin protein 1α mediates development and aggressiveness of neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer (PCa) arising mostly from adenocarcinoma via NE transdifferentiation following androgen deprivation therapy. Mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei are a distinguishing histopathological feature of NEPC, we utilized transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models to identify 36 heterochromatin-related genes that are significantly enriched in NEPC. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression increased early and steadily during NEPC development and remained elevated in the developed NEPC tumor. Its elevated expression was further confirmed in multiple PDX and clinical NEPC samples. HP1α knockdown in the NCI-H660 NEPC cell line inhibited proliferation, ablated colony formation, and induced apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promoted NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduced expression of androgen receptor (AR) and RE1 silencing transcription factor (REST) and enriched the repressive trimethylated histone H3 at Lys9 (H3K9me3) mark on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and management

Rabies virus pseudotyped with CVS-N2C glycoprotein as a powerful tool for retrograde neuronal network tracing

Abstract Background: Efficient viral vectors for mapping and manipulating long projection neuronal circuits are crucial in brain structural and functional studies. The glycoprotein gene-deleted SAD strain rabies virus pseudotyped with the N2C glycoprotein (SAD-RV(ΔG)-N2C(G)) shows high neuro-tropism in cell culture, but its in vivo retrograde infection efficiency and neuro-tropism have not been systematically characterized. Methods: SAD-RV(ΔG)-N2C(G) and two other broadly used retrograde tracers, SAD-RV(ΔG)-B19(G) and rAAV2-retro were respectively injected into the VTA or DG in C57BL/6 mice. The neuron numbers labeled across the whole brain regions were counted and analyzed by measuring the retrograde infection efficiencies and tropisms of these viral tools. The labeled neural types were analyzed using fluorescence immunohistochemistry or GAD67-GFP mice. Result: We found that SAD-RV (ΔG)-N2C (G) enhanced the infection efficiency of long-projecting neurons by ~ 10 times but with very similar neuro-tropism, compared with SAD-RV (ΔG)-B19(G). On the other hand, SAD-RV(ΔG)-N2C(G) showed comparable infection efficiency with rAAV2-retro, but had a more restricted diffusion range, and broader tropism to different types and regions of long-projecting neuronal populations. Conclusions: These results demonstrate that SAD-RV(ΔG)-N2C(G) can serve as an effective retrograde vector for studying neuronal circuits. Key words：Viral vector, N2C Glycoprotein, Neuronal circuits, Retrograde tracin

The evolutionarily conserved long non‐coding RNA <i>LINC00261</i> drives neuroendocrine prostate cancer proliferation and metastasis <i>via</i> distinct nuclear and cytoplasmic mechanisms

Metastatic neuroendocrine prostate cancer (NEPC) is a highly aggressive disease, whose incidence is rising. Long noncoding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, most of which are still functionally uncharacterized. Thus, we set out to identify the highly conserved lncRNAs that play a central role in NEPC pathogenesis. To this end, we performed transcriptomic analyses of donor-matched patient-derived xenograft models (PDXs) with immunohistologic features of prostate adenocarcinoma (AR+/PSA+) or NEPC (AR-/SYN+/CHGA+ ) and through differential expression analyses identified lncRNAs that were upregulated upon neuroendocrine transdifferentiation. These genes were prioritized for functional assessment based on the level of conservation in vertebrates. Here, LINC00261 emerged as the top gene with over 3229-fold upregulation in NEPC. Consistently, LINC00261 expression was significantly upregulated in NEPC specimens in multiple patient cohorts. Knockdown of LINC00261 in PC-3 cells dramatically attenuated its proliferative and metastatic abilities, which are explained by parallel downregulation of CBX2 and FOXA2 through distinct molecular mechanisms. In the cell cytoplasm, LINC00261 binds to and sequesters miR-8485 from targeting the CBX2 mRNA, while inside the nucleus, LINC00261 functions as a transcriptional scaffold to induce SMAD-driven expression of the FOXA2 gene. For the first time, these results demonstrate hyperactivation of the LINC00261-CBX2-FOXA2 axes in NEPC to drive proliferation and metastasis, and that LINC00261 may be utilized as a therapeutic target and a biomarker for this incurable disease

Immune phenotypes of prostate cancer cells: Evidence of epithelial immune cell-like transition?

Prostate cancers (PCa) have been reported to actively suppress antitumor immune responses by creating an immune-suppressive microenvironment. There is mounting evidence that PCas may undergo an ‘‘Epithelial Immune Cell-like Transition’’ (EIT) by expressing molecules conventionally associated with immune cells (e.g., a variety of cytokines/receptors, immune transcription factors, Ig motifs, and immune checkpoint molecules), which subsequently results in the suppression of anti-cancer immune activity within the tumor microenvironment. Recent progress within the field of immune therapy has underscored the importance of immune checkpoint molecules in cancer development, thus leading to the development of novel immunotherapeutic approaches. Here, we review the expression of select immune checkpoint molecules in PCa epithelial and associated immune cells, with particular emphasis on clinical data supporting the concept of an EIT-mediated phenotype in PCa. Furthermore, we summarize current advances in anti-immune checkpoint therapies, and provide perspectives on their potential applicability. Keywords: Prostate cancer, Immune checkpoint, Epithelial immune cell-like transition, Immune suppression, Immune therap

Molecular events in neuroendocrine prostate cancer development

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. NEPC arises de novo only rarely; the disease predominantly develops from adenocarcinoma in response to drug-induced androgen receptor signalling inhibition, although the mechanisms behind this transdifferentiation are a subject of debate. The survival of patients with NEPC is poor, and few effective treatment options are available. To improve clinical outcomes, understanding of the biology and molecular mechanisms regulating NEPC development is crucial. Various NEPC molecular drivers make temporal contributions during NEPC development, and despite the limited treatment options available, several novel targeted therapeutics are currently under research

Gelatinase Responsive Nanogel for Antibacterial Phototherapy and Wound Healing

The unique bactericidal mechanism of metal nanoparticles (MNPs) is considered to be an effective strategy to deal with antibiotic resistance, but the oxidative stress damage caused by excessive accumulation of MNPs to normal cells cannot be ignored. Achieving on-demand release of nano-drugs in specific infection environments is highly attractive. Herein, we constructed a “core-shell” nanogel (G@CuS) based on a copper sulfide (CuS) antimicrobial agent and gelatin for targeted drug release and bacterial clearance in a gelatinase infected microenvironment. G@CuS produced heat and reactive oxygen species (ROS) under the irradiation of a laser, which together with the released Cu2+ cause irreversible and efficient physical damage to the bacteria. Moreover, the encapsulation of gelatin not only limits the biotoxicity of CuS nanodots (NDs), but also effectively promotes the proliferation of mammalian cells. Under the synergy of multiple mechanisms, G@CuS eradicated the colonized bacteria in the wound of mice infected with Staphylococcus aureus (S. aureus) and accelerated wound healing. The proposed application strategy of nanogel is expected to provide a new idea for clinical transformation

Experimental study on seismic behaviour of an innovative composite shear wall

To improve the strength and ductility of the core walls in high-rise buildings which would be subjected to combined high axial compressive force and bending moment during the earthquake, an innovative concrete filled double-skin steel-plate composite (CFDSC) wall is proposed. The CFDSC wall is composed of the concrete filled double-skin steel-plate wall body with transverse stiffeners, vertical diaphragms and distributed batten plates welding on the internal surface of the double steel plates, and the concrete filled steel tube (CFST) columns including a pair of CFST columns positioned at the end of the cross section as boundary elements and an additional one located in the central section of the wall. Five CFDSC wall specimens were tested under constant axial compressive force and lateral reversed cyclic loading to investigate the seismic behaviour of the wall considering the effect of axial force ratio and shear span ratio. The favourable seismic performance of the CFDSC walls was demonstrated in the test. No serious pinching effect was observed on the hysteresis curves of all the specimens. The drift ratios corresponding to the ultimate stage were recorded as being in the range from 1/67 to 1/30 and the ductility coefficients were varied from 4.50 to 8.22. The experimental results manifest that the CFDSC walls have great energy dissipation capacity. Formulae for calculating the lateral load-carrying capacity of the CFDSC wall, taking the confinement effects from steel plates into account, were proposed. The results calculated by the proposed method show good agreement with the experimental results

Novel spontaneous myelodysplastic syndrome mouse model

Abstract Background Myelodysplastic syndrome (MDS) is a group of disorders involving hemopoietic dysfunction leading to leukemia. Although recently progress has been made in identifying underlying genetic mutations, many questions still remain. Animal models of MDS have been produced by introduction of specific mutations. However, there is no spontaneous mouse model of MDS, and an animal model to simulate natural MDS pathogenesis is urgently needed. Methods In characterizing the genetically diverse mouse strains of the Collaborative Cross (CC) we observed that one, designated JUN, had abnormal hematological traits. This strain was thus further analyzed for phenotypic and pathological identification, comparing the changes in each cell population in peripheral blood and in bone marrow. Results In a specific‐pathogen free environment, mice of the JUN strain are relatively thin, with healthy appearance. However, in a conventional environment, they become lethargic, develop wrinkled yellow hair, have loose and light stools, and are prone to infections. We found that the mice were cytopenic, which was due to abnormal differentiation of multipotent bone marrow progenitor cells. These are common characteristics of MDS. Conclusions A mouse strain, JUN, was found displaying spontaneous myelodysplastic syndrome. This strain has the advantage over existing models in that it develops MDS spontaneously and is more similar to human MDS than genetically modified mouse models. JUN mice will be an important tool for pathogenesis research of MDS and for evaluation of new drugs and treatments

Single-cell RNA-sequencing of cellular heterogeneity and pathogenic mechanisms in paraquat-induced Parkinson's disease with depression

Parkinson's disease (PD) is among the most prevalent neurodegenerative diseases, and approximately one third of patients with PD are estimated to have depression. Paraquat (PQ) exposure is an important environmental risk factor for PD. In this study, we established a mouse model of PQ-induced PD with depression to comprehensively investigate cellular heterogeneity and the mechanisms underlying the progression of depression in the context of PD. We utilized single-cell RNA-seq (scRNA-seq) to acquire the transcriptomic atlas of individual cells from model mice and characterize the gene expression profiles in each differentially expressed cell type. We identified a specific glutamatergic neuron cluster responsible for the development of heterogeneous depression-associated changes and established a comprehensive gene expression atlas. Furthermore, functional enrichment and cell trajectory analyses revealed that the mechanisms underlying the progression of PD with depression were associated with specific glutamatergic neurons. Together, our findings provide a valuable resource for deciphering the cellular heterogeneity of PD with depression. The suggested connection between intrinsic transcriptional states of neurons and the progression of depression can provide insight into potential biomarkers and specific targets for anti-depression treatment in patients with PD. Synopsis: Our results obtained using model mice confirm the core effects of PQ exposure on glutamatergic neurons and their potential role in the development of PD with depression

Ultra-Steep-Slope High-Gain MoS2 Transistors with Atomic Threshold-Switching Gate.

The fundamental Boltzmann limitation dictates the ultimate limit of subthreshold swing (SS) to be 60 mV dec-1 , which prevents the continued scaling of supply voltage. With atomically thin body, 2D semiconductors provide new possibilities for advanced low-power electronics. Herein, ultra-steep-slope MoS2 resistive-gate field-effect transistors (RG-FETs) by integrating atomic-scale-resistive filamentary with conventional MoS2 transistors, demonstrating an ultra-low SS below 1 mV dec-1 at room temperature are reported. The abrupt resistance transition of the nanoscale-resistive filamentary ensures dramatic change in gate potential, and switches the device on and off, leading to ultra-steep SS. Simultaneously, RG-FETs demonstrate a high on/off ratio of 2.76 × 107 with superior reproducibility and reliability. With the ultra-steep SS, the RG-FETs can be readily employed to construct logic inverter with an ultra-high gain ≈2000, indicating exciting potential for future low-power electronics and monolithic integration