The integrity of thalamo-dorsolateral prefrontal cortex tract: a key factor in residual consciousness in disorders of consciousness patients.

Background: The mesocircuit model describes a complex network that includes the prefrontal cortical-striatopallidal-thalamo-cortical loop systems and is involved in the mechanism underlying consciousness in patients with disorders of consciousness (DoC). Inhibitory signals to the thalamus become hyperactive in DoC patients, leading to a loss of consciousness. Reactivating this mesocircuit system is important for recovering consciousness in these patients.

Improvement of Therapeutic Effect via Inducing Non-Apoptotic Cell Death Using mRNA-Protection Nanocage.

Necroptosis, a cell death mechanism with the characteristics of both apoptosis and necrosis, is proposed as a promising therapeutic approach for cancer therapy. Induction of necroptosis for cancer therapy may be possible through the regulation of the expression of a key factor gene receptor-interacting protein kinase-3 (RIPK3) via in vitro transcription (IVT) mRNA delivery. However, mRNA is susceptible to degradation and has a low delivery efficiency, which highlights the requirement of a proper delivery vehicle for intracellular delivery.

Exploration of Immune-Modulatory Effects of Amivantamab in Combination with Pembrolizumab in Lung and Head and Neck Squamous Cell Carcinoma.

Unlabelled: Immune checkpoint inhibitors are effective first-line therapy for solid cancers. However, low response rate and acquired resistance over time has led to the need for additional therapeutic options. Here, we evaluated synergistic antitumor efficacy of EGFR × MET targeting bispecific antibody, amivantamab with PD-L1 immunotherapy, pembrolizumab in head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma tumor-bearing humanized patient-derived xenograft (PDX) models.

Human Bone Marrow-Derived Mesenchymal Stem Cell Applications in Neurodegenerative Disease Treatment and Integrated Omics Analysis for Successful Stem Cell Therapy.

Neurodegenerative diseases (NDDs), which are chronic and progressive diseases, are a growing health concern. Among the therapeutic methods, stem-cell-based therapy is an attractive approach to NDD treatment owing to stem cells' characteristics such as their angiogenic ability, anti-inflammatory, paracrine, and anti-apoptotic effects, and homing ability to the damaged brain region. Human bone-marrow-derived mesenchymal stem cells (hBM-MSCs) are attractive NDD therapeutic agents owing to their widespread availability, easy attainability and in vitro manipulation and the lack of ethical issues.

Bioreducible polymer-mediated delivery of oncolytic adenovirus can attenuate antiviral immune response and concurrently enhance the induction of antitumor immune response to effectively prevent metastasis.

Oncolytic virotherapy is a highly promising and novel treatment modality for cancer. Several clinical trials with oncolytic viruses have illustrated that the potent antitumor efficacy of these viruses may rely on the efficient induction of antitumor immune response. In contrast, antiviral immune response is attributed to adverse side defects and diminishing therapeutic efficacy.

Continuous centrifugal microfluidics (CCM) isolates heterogeneous circulating tumor cells via full automation.

Understanding cancer heterogeneity is essential to finding diverse genetic mutations in metastatic cancers. Thus, it is critical to isolate all types of CTCs to identify accurate cancer information from patients. Moreover, full automation robustly capturing the full spectrum of CTCs is an urgent need for CTC diagnosis to be routine clinical practice.

High-Precision RTT-Based Indoor Positioning System Using RCDN and RPN.

Wi-Fi round-trip timing (RTT) was applied to indoor positioning systems based on distance estimation. RTT has a higher reception instability than the received signal strength indicator (RSSI)-based fingerprint in non-line-of-sight (NLOS) environments with many obstacles, resulting in large positioning errors due to multipath fading. To solve these problems, in this paper, we propose high-precision RTT-based indoor positioning system using an RTT compensation distance network (RCDN) and a region proposal network (RPN).

Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR-MET Bispecific Antibody, in Diverse Models of Exon 20 Insertion-Driven NSCLC.

exon 20 insertion driver mutations (Exon20ins) in non-small cell lung cancer (NSCLC) are insensitive to EGFR tyrosine kinase inhibitors (TKI). Amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR-MET, has shown preclinical activity in TKI-sensitive -mutated NSCLC models and in an ongoing first-in-human study in patients with advanced NSCLC. However, the activity of amivantamab in Exon20ins-driven tumors has not yet been described.

A Helical Polypeptide-Based Potassium Ionophore Induces Endoplasmic Reticulum Stress-Mediated Apoptosis by Perturbing Ion Homeostasis.

Perturbation of potassium homeostasis can affect various cell functions and lead to the onset of programmed cell death. Although ionophores have been intensively used as an ion homeostasis disturber, the mechanisms of cell death are unclear and the bioapplicability is limited. In this study, helical polypeptide-based potassium ionophores are developed to induce endoplasmic reticulum (ER) stress-mediated apoptosis.

Development of apoptosis-inducing polypeptide via simultaneous mitochondrial membrane disruption and Ca delivery.

Mitochondria are the primary organelle of regulating apoptosis, and intracellular calcium ions are a key component of pro-apoptosis induction. Herein, we report an artificial apoptosis-inducing polypeptide that destabilizes the mitochondrial membrane and transports calcium ions into the cytosol, thereby synergistically creating severe oxidative conditions. The oxidative stress highly activates an apoptotic signaling cascade, and also inhibits cell migration and invasion in vitro and in vivo.

Synergistic antitumor effect mediated by a paclitaxel-conjugated polymeric micelle-coated oncolytic adenovirus.

Combination treatment consisting of oncolytic adenovirus (Ad) and paclitaxel (PTX) is a promising strategy to achieve synergistic antitumor effect. However, a co-administration approach is subject to inherent limitations due to the poor solubility of PTX and chemoresistance of tumor cells. In order to overcome these limitations, an oncolytic Ad expressing a p53 variant (oAd-vp53) that is resistant to p53 inactivation in the tumor microenvironment was complexed with PEGylated and PTX-conjugated polymeric micelle (APP).

Jak kinase 3 signaling in microgliogenesis from the spinal nestin+ progenitors in both development and response to injury.

During spinal cord development, endogenous progenitors expressing nestin can migrate into the target and differentiate into neurons and other glial cells. Microglial cells can also be derived from nestin progenitor cells, even in the adult brain. Knockdown of Jak kinase 3 (Jak3) signaling can increase neurogenesis with longer neurite outgrowth in cortical progenitor cells.

Conformation-switchable helical polypeptide eliciting selective pro-apoptotic activity for cancer therapy.

Artificial cationic helical peptides possess an enhanced cell-penetrating property. However, their cell-penetrability is not converted by cellular environmental changes resulting in nonspecific uptake. In this study, pH-sensitive anion-donating groups were added to a helical polypeptide to simultaneously achieve tumor targeting and pro-apoptotic activity.

Glutamate dehydrogenase as a neuroprotective target against brain ischemia and reperfusion.

Deregulation of glutamate homeostasis is associated with degenerative neurological disorders. Glutamate dehydrogenase (GDH) is important for glutamate metabolism and plays a central role in expanding the pool of tricarboxylic acid (TCA) cycle intermediate alpha-ketoglutarate (α-KG), which improves overall bioenergetics. Under high energy demand, maintenance of ATP production results in functionally active mitochondria.

Silica-coated magnetic nanoparticles impair proteasome activity and increase the formation of cytoplasmic inclusion bodies in vitro.

The potential toxicity of nanoparticles, particularly to neurons, is a major concern. In this study, we assessed the cytotoxicity of silica-coated magnetic nanoparticles containing rhodamine B isothiocyanate dye (MNPs@SiO2(RITC)) in HEK293 cells, SH-SY5Y cells, and rat primary cortical and dopaminergic neurons. In cells treated with 1.

Enhanced anti-tumor efficacy and safety profile of tumor microenvironment-responsive oncolytic adenovirus nanocomplex by systemic administration.

Unlabelled: Oncolytic adenovirus (Ad) holds great promise as a potential gene therapy for cancer. However, intravenously administered Ad may encounter difficulties due to unfavorable host responses, non-specific interactions, and the heterogeneity of the tumor cell population. As an approach to combine the advantages of oncolytic Ad and synthetic polymers and to address the associated difficulties, Ad was physically complexed with a pH-sensitive block copolymer, methoxy poly(ethylene glycol)-b-poly(l-histidine) (mPEG-b-pHis).

Fructose-1,6-bisphosphate suppresses lipopolysaccharide-induced expression of ICAM-1 through modulation of toll-like receptor-4 signaling in brain endothelial cells.

Fructose-1,6-bisphosphate (FBP) is a glycolytic intermediate with salutary effects in various brain injury models, but its neuroprotective mechanism is incompletely understood. In this study, we examined the effects of FBP on the expression of adhesion molecules in cerebrovascular endothelial cells and explored the possible mechanisms therein involved. FBP significantly down-regulated lipopolysaccharide (LPS)-induced expression of adhesion molecules and leukocyte adhesion to brain endothelial cells and inhibited NF-κB activity, which is implicated in the expression of adhesion molecules.

Isobavachalcone attenuates lipopolysaccharide-induced ICAM-1 expression in brain endothelial cells through blockade of toll-like receptor 4 signaling pathways.

Inflammation has been implicated in the pathogenesis of various cerebral diseases. Thus, control of brain inflammation is regarded as one of the important therapeutic strategies for the treatment of neurodegenerative diseases such as Alzheimer׳s disease and stroke. Isobavachalcone, a flavonoid from Psoralea corylifolia, is known to possess a wide spectrum of biological activities and is expected to be useful in preventing or treating neurodegenerative diseases.

Safety profiles and antitumor efficacy of oncolytic adenovirus coated with bioreducible polymer in the treatment of a CAR negative tumor model.

Adenovirus (Ad) vectors show promise as cancer gene therapy delivery vehicles, but immunogenic safety concerns and coxsackie and adenovirus receptor (CAR)-dependency have limited their use. Alternately, biocompatible and bioreducible nonviral vectors, including arginine-grafted cationic polymers, have been shown to deliver nucleic acids through a cell penetration peptide (CPP) and protein transduction domain (PTD) effect. We utilized the advantages of both viral and nonviral vectors to develop a hybrid gene delivery vehicle by coating Ad with mPEG-PEI-g-Arg-S-S-Arg-g-PEI-mPEG (Ad/PPSA).

NDRG2 controls COX-2/PGE₂-mediated breast cancer cell migration and invasion.

N-myc downstream-regulated gene 2 (NDRG2), which is known to have tumor suppressor functions, is frequently down-regulated in breast cancers and potentially involved in preventing the migration and invasion of malignant tumor cells. In the present study, we examined the inhibitory effects of NDRG2 overexpression, specifically focusing on the role of cyclooxygenase-2 (COX-2) in the migration of breast cancer cells. NDRG2 overexpression in MDA-MB-231 cells inhibited the expression of the COX-2 mRNA and protein, the transcriptional activity of COX-2, and prostaglandin E2 (PGE2) production, which were induced by a treatment with phorbol-12-myristate-13-acetate (PMA).

A high-fat diet increases oxidative renal injury and protein glycation in D-galactose-induced aging rats and its prevention by Korea red ginseng.

Declining renal function is commonly observed with age. Obesity induced by a high-fat diet (HFD) may reduce renal function. Korean red ginseng (KRG) has been reported to ameliorate oxidative tissue injury and have an anti-aging effect.

Seizure susceptibility in immature brain due to lack of COX-2-induced PGF2α.

The immature brain is prone to seizure; however, the mechanism underlying this vulnerability has not been clarified. Febrile seizure is common in young children, and the use of non-steroidal anti-inflammatory drugs for febrile seizure is not recommended. In previous studies, we established that prostaglandin (PG) F2α, a product of cyclooxygenase (COX), acts as an endogenous anticonvulsant in the adult mouse.

Fructose-1,6-bisphosphate ameliorates lipopolysaccharide-induced dysfunction of blood-brain barrier.

Fructose-1,6-bisphosphate (FBP), a glycolytic intermediate, has neuroprotective effects in various brain injury models. However, its effects on blood-brain barrier (BBB) are largely unknown. In this study, we investigated the effects of FBP on lipopolysaccharide (LPS)-induced BBB dysfunction in in vitro BBB model comprising co-culture of mouse brain endothelial cell line, bEnd.

Genomic copy number alterations with transcriptional deregulation at 6p identify an aggressive HCC phenotype.

Genomic analyses have revealed the enormous heterogeneity in essentially all cancer types. However, the identification of precise subtypes, which are biologically informative and clinically useful, remains a challenge. The application of integrative analysis of multilayered genomic profiles to define the chromosomal regions of genomic copy number alterations with concomitant transcriptional deregulation is posited to provide a promising strategy to identify driver targets.

Prostaglandin E₂-induced intercellular adhesion molecule-1 expression is mediated by cAMP/Epac signalling modules in bEnd.3 brain endothelial cells.

Background And Purpose: Prostaglandin E₂ (PGE₂) has been implicated in the regulation of adhesion molecules, leukocyte adhesion and infiltration into inflamed site. However, the underlying mechanism therein involved remains ill-defined. In this study, we explored its cellular mechanism of action in the regulation of the intercellular adhesion molecule-1 (ICAM-1) expression in the brain endothelial cells.