Developing Topics.

Background: Rapamycin is currently in clinical trials for AD, yet numerous studies have suggested that rapamycin inhibits mTORC2 as well as mTORC1, which could be detrimental for AD pathology. Brain insulin resistance is a known aspect of AD pathology and mTORC2 inhibition reduces AKT phosphorylation, which is a main mediator of cellular insulin signaling, perpetuating insulin resistance and further worsening brain glucose metabolism. Here, we show that rapamycin prevents insulin-induced AKT phosphorylation in human neurons and explore the differential effects of mTORC1 and mTORC2 on neuronal insulin sensitivity.

Galectin Plasmatic Levels Reveal a Cluster Associated with Disease Aggressiveness and Kidney Damage in Multiple Myeloma Patients.

Multiple myeloma (MM) is a malignant disease characterized by the proliferation of plasma cells, primarily in the bone marrow. It accounts for approximately 1% of all cancers and 10% of hematologic malignancies. Clinical manifestations include hypercalcemia, anemia, renal failure, and bone lesions.

High-Throughput Drug Screening in Chondrosarcoma Cells Identifies Effective Antineoplastic Agents Independent of IDH Mutation.

The term chondrosarcoma refers to a rare and heterogeneous group of malignant cartilaginous tumors that are typically resistant to chemotherapy and radiotherapy. Metastatic chondrosarcoma has a poor prognosis, and effective systemic therapies are lacking. Isocitrate dehydrogenase (IDH) mutations represent a potential therapeutic target, but IDH inhibitors alone have shown limited clinical efficacy to date.

Methods for Selective Gene Expression Profiling in Single Tertiary Lymphoid Structure Using Laser Capture Microdissection.

Tertiary lymphoid structures (TLS) are de novo lymphoid formations that are induced within tissues during inflammatory episodes. TLS have been reported at various anatomic sites and in many different contexts like cancer, infections, autoimmunity, graft rejection, and idiopathic diseases. These inducible, ectopic, and transient lymphoid structures exhibit the prototypical architecture found within secondary lymphoid organs (SLO) and have been increasingly recognized as a major driver of local adaptive immune reaction.

Cocaine taking and craving produce distinct transcriptional profiles in dopamine neurons.

Dopamine (DA) signaling plays an essential role in reward valence attribution and in encoding the reinforcing properties of natural and artificial rewards. The adaptive responses from midbrain dopamine neurons to artificial rewards such as drugs of abuse are therefore important for understanding the development of substance use disorders. Drug-induced changes in gene expression are one such adaptation that can determine the activity of dopamine signaling in projection regions of the brain reward system.

Identification of targetable epigenetic vulnerabilities in uveal melanoma.

Uveal melanoma (UM) is the most prevalent primary intraocular malignancy in adults, which preferentially metastasizes to the liver in approximately half of all cases. Metastatic UM is notoriously resistant to therapy and is almost uniformly fatal. UM metastasis is most strongly associated with mutational inactivation of the tumor suppressor gene.

miRNA-21, an oncomiR that regulates cell proliferation, migration, invasion and therapy response in lung cancer.

Lung cancer is the leading cause of cancer-related death globally, with poor survival rates due mostly to a lack of early detection. The usual diagnostic technique includes a biopsy, which is frequently performed later in the disease's progression. In order to uncover processes that improve illness detection and prognosis, miRNA-21 emerges as a major miRNA identified in a variety of cancer types, including lung cancer.

Epigenetic heterogeneity shapes the transcriptional landscape of regional microglia.

Microglia, the innate immune cells in the central nervous system, exhibit distinct transcriptional profiles across brain regions that are important for facilitating their specialized function. There has been recent interest in identifying the epigenetic modifications associated with these distinct transcriptional profiles, as these may improve our understanding of the underlying mechanisms governing the functional specialization of microglia. One obstacle to achieving this goal is the large number of microglia required to obtain a genome-wide profile for a single histone modification.

Generation and Characterization of a Novel Cre Rat Model.

Activity of central amygdala (CeA) PKCδ expressing neurons has been linked to appetite regulation, anxiety-like behaviors, pain sensitivity, and addiction-related behaviors. Studies of the role that CeA PKCδ+ neurons play in these behaviors have largely been carried out in mice, and genetic tools that would allow selective manipulation of PKCδ+ cells in rats have been lacking. Here, we used a CRISPR/Cas9 strategy to generate a transgenic -cre knock-in rat and characterized this model using anatomical, electrophysiological, and behavioral approaches in both sexes.

Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug.

Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are currently no FDA-approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders.

Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood.

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts.

Kinome-Wide Virtual Screening by Multi-Task Deep Learning.

Deep learning is a machine learning technique to model high-level abstractions in data by utilizing a graph composed of multiple processing layers that experience various linear and non-linear transformations. This technique has been shown to perform well for applications in drug discovery, utilizing structural features of small molecules to predict activity. Here, we report a large-scale study to predict the activity of small molecules across the human kinome-a major family of drug targets, particularly in anti-cancer agents.

Contextualizing the Role of Osteopontin in the Inflammatory Responses of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by progressive accumulations of extracellular amyloid-beta (Aβ) aggregates from soluble oligomers to insoluble plaques and hyperphosphorylated intraneuronal tau, also from soluble oligomers to insoluble neurofibrillary tangles (NFTs). Tau and Aβ complexes spread from the entorhinal cortex of the brain to interconnected regions, where they bind pattern recognition receptors on microglia and astroglia to trigger inflammation and neurotoxicity that ultimately lead to neurodegeneration and clinical AD. Systemic inflammation is initiated by Aβ's egress into the circulation, which may be secondary to microglial activation and can confer both destructive and reparative actions.

Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug.

Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are currently no FDA-approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders.

Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure.

Background: The effects of α and ß adrenergic receptor modulation on the risk of developing heart failure (HF) remains uncertain due to a lack of randomized controlled trials. This study aimed to estimate the effects of α and ß adrenergic receptors modulation on the risk of HF and to provide proof of principle for genetic target validation studies in HF.

Methods: Genetic variants within the cis regions encoding the adrenergic receptors α1A, α2B, ß1, and ß2 associated with blood pressure in a 757,601-participant genome-wide association study (GWAS) were selected as instruments to perform a drug target Mendelian randomization study.

Low-Dose Chidamide Treatment Displays Sex-Specific Differences in the 3xTg-AD Mouse.

Epigenetic compounds have become attractive small molecules for targeting the multifaceted aspects of Alzheimer's disease (AD). Although AD disproportionately affects women, most of the current literature investigating epigenetic compounds for the treatment of AD do not report sex-specific results. This is remarkable because there is rising evidence that epigenetic compounds intrinsically affect males and females differently.

Prophylactic Mitigation of Acute Graft versus Host Disease by Novel 2-(Pyrrolidin-1-ylmethyl)pyrrole-Based Stimulation-2 (ST2) Inhibitors.

Hematopoietic cell transplantation (HCT) is a proven and potentially curable therapy for hematological malignancies and inherited hematological disease. The main risk of HCT is the development of graft versus host disease (GVHD) acquired in up to 50% of patients. Upregulation of soluble ST2 (sST2) is a key clinical biomarker for GVHD prognosis and was shown to be a potential therapeutic target for GVHD.

Nucleic acid-based therapeutics for the treatment of central nervous system disorders.

Nucleic acid-based therapeutics (NBTs) are an emerging class of drugs with potential for the treatment of a wide range of central nervous system conditions. To date, pertaining to CNS indications, there are two commercially available NBTs and a large number of ongoing clinical trials. However, these NBTs are applied directly to the brain due to very low blood brain barrier permeability.

Dopamine Transporter Knockout Rats Display Epigenetic Alterations in Response to Cocaine Exposure.

(1) Background: There is an urgent need for effective treatments for cocaine use disorder (CUD), and new pharmacological approaches targeting epigenetic mechanisms appear to be promising options for the treatment of this disease. Dopamine Transporter (DAT) transgenic rats recently have been proposed as a new animal model for studying susceptibility to CUD. (2) Methods: DAT transgenic rats were treated chronically with cocaine (10 mg/kg) for 8 days, and the expression of epigenetic modulators, Lysine Demethylase 6B (KDM6B) and Bromodomain-containing protein 4 (BRD4), was examined in the prefrontal cortex (PFC).

Long non-coding RNA-targeting therapeutics: discovery and development update.

Introduction: lncRNAs are major players in regulatory networks orchestrating multiple cellular functions, such as 3D chromosomal interactions, epigenetic modifications, gene expression and others. Due to progress in the development of nucleic acid-based therapeutics, lncRNAs potentially represent easily accessible therapeutic targets.

Areas Covered: Currently, significant efforts are directed at studies that can tap the enormous therapeutic potential of lncRNAs.

Amplifying gene expression with RNA-targeted therapeutics.

Many diseases are caused by insufficient expression of mutated genes and would benefit from increased expression of the corresponding protein. However, in drug development, it has been historically easier to develop drugs with inhibitory or antagonistic effects. Protein replacement and gene therapy can achieve the goal of increased protein expression but have limitations.

Development of Novel Small-Molecule Activators of Pyruvate Kinase Muscle Isozyme 2, PKM2, to Reduce Photoreceptor Apoptosis.

Treatment options are lacking to prevent photoreceptor death and subsequent vision loss. Previously, we demonstrated that reprogramming metabolism via the pharmacologic activation of PKM2 is a novel photoreceptor neuroprotective strategy. However, the features of the tool compound used in those studies, ML-265, preclude its advancement as an intraocular, clinical candidate.

Investigating the Synergistic Potential of Low-Dose HDAC3 Inhibition and Radiotherapy in Alzheimer's Disease Models.

We have previously shown that histone deacetylase (HDAC) inhibition and cranial radiotherapy (RT) independently improve molecular and behavioral Alzheimer's disease (AD)-like phenotypes. In the present study, we investigate the synergistic potential of using both RT and HDACi as a low-dose combination therapy (LDCT) to maximize disease modification (reduce neuroinflammation and amyloidogenic APP processing, increase neurotrophic gene expression) while minimizing the potential for treatment-associated side effects.LDCT consisted of daily administration of the HDAC3 inhibitor RGFP966 and/or bi-weekly cranial x-irradiation.