Platelet RNA enables accurate detection of ovarian cancer: an intercontinental, biomarker identification study.

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.

Elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation.

Finely tuned mitogen-activated protein kinase (MAPK) signaling is important for cancer cell survival. Perturbations that push cells out of the MAPK fitness zone result in cell death. Previously, in a screen of the North China Pharmaceutical Group Corporation's pure compound library of microbial origin, we identified elaiophylin as an autophagy inhibitor. Here, we demonstrated a new role for elaiophylin in inducing excessive endoplasmic reticulum (ER) stress, ER-derived cytoplasmic vacuolization, and consequent paraptosis by hyperactivating the MAPK pathway in multiple cancer cells. Genome-wide CRISPR/Cas9 knockout library screening identified SHP2, an upstream intermediary of the MAPK pathway, as a critical target in elaiophylin-induced paraptosis. The cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) assay further confirmed the direct binding between the SHP2 and elaiophylin. Inhibition of the SHP2/SOS1/MAPK pathway through SHP2 knockdown or pharmacological inhibitors distinctly attenuated elaiophylin-induced paraptosis and autophagy inhibition. Interestingly, elaiophylin markedly increased the already-elevated MAPK levels and preferentially killed drug-resistant cells with enhanced basal MAPK levels. Elaiophylin overcame drug resistance by triggering paraptosis in multiple tumor-bearing mouse models resistant to platinum, taxane, or PARPi, suggesting that elaiophylin might offer a reasonable therapeutic strategy for refractory ovarian cancer.

The small molecule chemical compound cinobufotalin attenuates resistance to DDP by inducing ENKUR expression to suppress MYH9-mediated c-Myc deubiquitination in lung adenocarcinoma.

The small molecule chemical compound cinobufotalin (CB) is reported to be a potential antitumour drug that increases cisplatin (DDP) sensitivity in nasopharyngeal carcinoma. In this study, we first found that CB decreased DDP resistance, migration and invasion in lung adenocarcinoma (LUAD). Mechanistic studies showed that CB induced ENKUR expression by suppressing PI3K/AKT signalling to downregulate c-Jun, a negative transcription factor of ENKUR. Furthermore, ENKUR was shown to function as a tumour suppressor by binding to ß-catenin to decrease c-Jun expression, thus suppressing MYH9 transcription. Interestingly, MYH9 is a binding protein of ENKUR. The Enkurin domain of ENKUR binds to MYH9, and the Myosin_tail of MYH9 binds to ENKUR. Downregulation of MYH9 reduced the recruitment of the deubiquitinase USP7, leading to increased c-Myc ubiquitination and degradation, decreased c-Myc nuclear translocation, and inactivation of epithelial-mesenchymal transition (EMT) signalling, thus attenuating DDP resistance. Our data demonstrated that CB is a promising antitumour drug and may be a candidate chemotherapeutic drug for LUAD patients.

PD-L1 expression in megakaryocytes and its clinicopathological features in primary myelofibrosis patients.

Myeloproliferative neoplasms (MPNs) are characterized by upregulation of proinflammatory cytokines and immune dysregulation, which provide a reasonable basis for immunotherapy in patients. Megakaryocytes are crucial in the pathogenesis of primary myelofibrosis (PMF), the most clinically aggressive subtype of MPN. In this study, we aimed to explore PD-L1 (programmed death-ligand 1) expression in megakaryocytes and its clinical implications in PMF. We analyzed PD-L1 expression on megakaryocytes in PMF patients by immunohistochemistry and correlated the results with clinicopathological features and molecular aberrations. We employed a two-tier grading system considering both the proportion of cells positively stained and the intensity of staining. Among the 85 PMF patients, 41 (48%) showed positive PD-L1 expression on megakaryocytes with the immune-reactive score ranging from 1 to 12. PD-L1 expression correlated closely with higher white blood cell count (p = 0.045), overt myelofibrosis (p = 0.010), JAK2V617F mutation (p = 0.011), and high-molecular risk mutations (p = 0.045), leading to less favorable overall survival in these patients (hazard ratio 0.341, 95% CI 0.135-0.863, p = 0.023). Our study provides unique insights into the interaction between immunologic and molecular phenotypes in PMF patients. Future work to explore the translational potential of PD-L1 in the clinical setting is needed.

Electromagnetized-Nanoparticle-Modulated Neural Plasticity and Recovery of Degenerative Dopaminergic Neurons in the Mid-Brain.

The degeneration of dopaminergic neurons is a major contributor to the pathogenesis of mid-brain disorders. Clinically, cell therapeutic solutions, by increasing the neurotransmitter dopamine levels in the patients, are hindered by low efficiency and/or side effects. Here, a strategy using electromagnetized nanoparticles to modulate neural plasticity and recover degenerative dopamine neurons in vivo is reported. Remarkably, electromagnetic fields generated by the nanoparticles under ultrasound stimulation modulate intracellular calcium signaling to influence synaptic plasticity and control neural behavior. Dopaminergic neuronal functions are reversed by upregulating the expression tyrosine hydroxylase, thus resulting in ameliorating the neural behavioral disorders in zebrafish. This wireless tool can serve as a viable and safe strategy for the regenerative therapy of the neurodegenerative disorders.

Folate-Modified Photoelectric Responsive Polymer Microarray as Bionic Artificial Retina to Restore Visual Function.

A high-optical-resolution artificial retina system that accurately communicates with the optic nerve is the main challenge in the modern biological science and bionic field. Here, we developed a bionic artificial retina possessing phototransduction "cells" with measurements even smaller than that of the neural cells. Using the technique of micrometer processing, we constructed a pyramid-shape periodic microarray of a photoreceptor. Each "sensing cell" took advantage of polythiophene derivative/fullerene derivative (PCBM) as a photoelectric converter. Because folic acid played an essential role in eye growth, we particularly modified the polythiophene derivatives with folic acid tags. Therefore, the artificial retina could enlarge the contact area and even recognize the nerve cells to improve the consequence of nerve stimulation. We implanted the artificial retina into blinded rats' eyes. Electrophysiological analysis revealed its recovery of photosensitive function 3 months after surgery. Our work provides an innovative idea for fabricating a high-resolution bionic artificial retina system. It shows great potential in artificial intelligence and biomedicine.

Light-Induced ROS Generation and 2-DG-Activated Endoplasmic Reticulum Stress by Antitumor Nanosystems: An Effective Combination Therapy by Regulating the Tumor Microenvironment.

A multimodal cancer therapeutic nanoplatform is reported. It demonstrates a promising approach to synergistically regulating the tumor microenvironment. The combination of intracellular reactive oxygen species (ROS) generated by irradiation of photosensitizer and endoplasmic reticulum (ER) stress induced by 2-deoxy-glucose (2-DG) has a profound effect on necrotic or apoptotic cell death. Especially, targeting metabolic pathway by 2-DG is a promising strategy to promote the effect of photodynamic therapy and chemotherapy. The nanoplatform can readily release its cargoes inside cancer cells and combines the advantages of ROS-sensitive releasing chemotherapeutic drugs, upregulating apoptosis pathways under ER stress, light-induced generation of cytotoxic ROS, achieving tumor accumulation, and in vivo fluorescence imaging capability. This work highlights the importance of considering multiple intracellular stresses as design parameters for nanoscale functional materials in cell biology, immune response, as well as medical treatments of cancer, Alzheimer's disease, etc.

Anti-oxidative Responses on Hepatic Tissue of Zebrafish (Danio rerio) in a Short Duration of Sub-lethal Concentrations of Cadmium Exposure.

The aim of the present study was to identify whether the responses of oxidative stress in zebrafish liver are similar to those in mammalians upon low doses of Cd2+ exposure in short durations. Fish were exposed to 1.78 µM Cd2+ (treatment) and 0.0 µM Cd2+ (control) for 0, 1, 3, and 6 h. The reactive oxygen species (ROS) and lipid peroxidation (LPO) of hepatic tissues significantly increased after 3 and 6 h of Cd2+ exposure, respectively. Antioxidants glutathione peroxidase (gpx1a), superoxide dismutase (sod), and catalase (cat) were up regulated after 1-3 h, and metallothionein isoforms (smtB and mt2) increased after 3-6 h of Cd2+ exposure. The caspase-3 and p53 mRNA expressions significantly increased threefolds after 1 h of Cd2+ exposure. Results confirmed that oxidative stress in the hepatic tissue was induced by Cd2+ within 3 h. However, anti-oxidative functions immediately up regulated, causing cell apoptosis levels to decrease after 6 h of Cd2+ exposure.

Bioinspired Ferroelectric Polymer Arrays as Photodetectors with Signal Transmissible to Neuron Cells.

A bioinspired photodetector with signal transmissible to neuron cells is fabricated. Photoisomerization of the dye molecules embedded in the ferroelectric polymer membrane achieves electric polarization change under visible light. The photodetector realizes high sensitivity, color recognition, transient response, and 3D visual detection with resolution of 25 000 PPI, and, impressively, directly transduces the signal to neuron cells.

Anti-oxidative functions of mt2 and smtB mRNA expression in the gills and brain of zebrafish (Danio rerio) upon cadmium exposure.

There were not any past studies about metallothionein isoforms (smtB and mt2) having anti-oxidative functions on zebrafish after Cd2+ exposure. On the other hand, the anti-oxidative enzymatic factors such as superoxide dismutase (sod), glutathione peroxidase (gpx1a), and catalase (cat) are used as references to investigate whether the smtB and mt2 have anti-oxidative responses on the gills and brain of zebrafish after 1-6 h of 0 and 1.78 µM Cd2+ exposure. The anti-oxidative system such as sod, cat, and gpx1a mRNA expressions demonstrated a cascade response upon Cd2+-induced oxidative stress in the present study. Interestingly, the smtB mRNA expression levels increased by 3.2- to 6.1-fold, and mt2 raised by 4.1- to 11.3-fold in gills at 1 and 3 h after exposure to Cd2+, respectively. On the other hand, the smtB mRNA levels increased by 10.6- to 58.6-fold, but mt2 mRNA levels increased by 2.3- to 11.1-fold in brain at 1 and 3 h after exposure to Cd2+, respectively. In addition, both tissues showed increased apoptosis levels at 3 h, and recovery after 6 h of Cd2+ exposure. From the results, we suggest that both mt2 and smtB play a role in anti-oxidation responses within 6 h after exposure to Cd2+. In conclusion, the smtB mRNA levels have a higher response than mt2 in the brain, but both mRNA expressions appear to have a similar pattern in the gill. We suggest that smtB plays an important role to defend oxidative stress in the brain of adult zebrafish upon acute Cd2+ exposure.