N-methyl-D-aspartate Receptors and Depression: Linking Psychopharmacology, Pathology and Physiology in a Unifying Hypothesis for the Epigenetic Code of Neural Plasticity.

Uncompetitive NMDAR (N-methyl-D-aspartate receptor) antagonists restore impaired neural plasticity, reverse depressive-like behavior in animal models, and relieve major depressive disorder (MDD) in humans. This review integrates recent findings from in silico, in vitro, in vivo, and human studies of uncompetitive NMDAR antagonists into the extensive body of knowledge on NMDARs and neural plasticity. Uncompetitive NMDAR antagonists are activity-dependent channel blockers that preferentially target hyperactive GluN2D subtypes because these subtypes are most sensitive to activation by low concentrations of extracellular glutamate and are more likely activated by certain pathological agonists and allosteric modulators.

Therapeutic Keratoplasty for Keratitis.

: This study evaluates the effectiveness of therapeutic keratoplasty for fungal keratitis and explores the diagnosis and management challenges of this infectious corneal disease. We retrospectively analyzed therapeutic keratoplasty cases at a tertiary hospital for keratitis when standard treatments failed. : Five cases of keratitis, unresponsive to typical antifungal treatments, required keratoplasty due to fast progression and diagnostic difficulties.

Comparative Analysis on Polyphenolic Composition of Different Olive Mill Wastewater and Related Extra Virgin Olive Oil Extracts and Evaluation of Nutraceutical Properties by Cell-Based Studies.

This study reports a comparative analysis of the polyphenolic composition and nutraceutical properties of different olive mill wastewater (OMWW) and corresponding extra virgin olive oil (EVOO) extracts. Specifically, four OMWWs and corresponding EVOOs from cultivars Frantoio (A) and Leccino (B) obtained from different crushing seasons (early-stage (A1 and B1) and later-stage (A2 and B2)) were analyzed. Employing HPLC-DAD and LC-MS methods, the primary polyphenol content was identified and quantified.

Telehealth vs In-Person Early Palliative Care for Patients With Advanced Lung Cancer: A Multisite Randomized Clinical Trial.

Importance: Numerous studies show that early palliative care improves quality of life and other key outcomes in patients with advanced cancer and their caregivers, although most lack access to this evidence-based model of care.

Objective: To evaluate whether delivering early palliative care via secure video vs in-person visits has an equivalent effect on quality of life in patients with advanced non-small cell lung cancer (NSCLC).

Design, Setting, And Participants: Randomized, multisite, comparative effectiveness trial from June 14, 2018, to May 4, 2023, at 22 US cancer centers among 1250 patients within 12 weeks of diagnosis of advanced NSCLC and 548 caregivers.

Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage.

Aneuploidy is a hallmark of human cancer, yet the molecular mechanisms to cope with aneuploidy-induced cellular stresses remain largely unknown. Here, we induce chromosome mis-segregation in non-transformed RPE1-hTERT cells and derive multiple stable clones with various degrees of aneuploidy. We perform a systematic genomic, transcriptomic and proteomic profiling of 6 isogenic clones, using whole-exome DNA, mRNA and miRNA sequencing, as well as proteomics.

Increased RNA and Protein Degradation Is Required for Counteracting Transcriptional Burden and Proteotoxic Stress in Human Aneuploid Cells.

Aneuploidy results in a stoichiometric imbalance of protein complexes that jeopardizes cellular fitness. Aneuploid cells thus need to compensate for the imbalanced DNA levels by regulating their RNA and protein levels, but the underlying molecular mechanisms remain unknown. In this study, we dissected multiple diploid versus aneuploid cell models.

Micronuclear collapse from oxidative damage.

Chromosome-containing micronuclei are a hallmark of aggressive cancers. Micronuclei frequently undergo irreversible collapse, exposing their enclosed chromatin to the cytosol. Micronuclear rupture catalyzes chromosomal rearrangements, epigenetic abnormalities, and inflammation, yet mechanisms safeguarding micronuclear integrity are poorly understood.

A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements.

Chromosomal instability (CIN) generates micronuclei-aberrant extranuclear structures that catalyze the acquisition of complex chromosomal rearrangements present in cancer. Micronuclei are characterized by persistent DNA damage and catastrophic nuclear envelope collapse, which exposes DNA to the cytoplasm. We found that the autophagic receptor p62/SQSTM1 modulates micronuclear stability, influencing chromosome fragmentation and rearrangements.

Pharmacokinetics, Tolerability, and Safety of Esmethadone in Subjects with Chronic Kidney Disease or Hepatic Impairment.

Background And Objectives: Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is a low potency N-methyl--aspartate (NMDA) receptor channel blocker that showed a rapid and sustained adjunctive antidepressant effects in patients with major depressive disorder with inadequate response to ongoing serotonergic antidepressant treatment. Previous studies indicated that esmethadone is partially excreted by the kidney (53.9% of the dose) and by the liver (39.

Facing Life in Old Age: Exploring Resilience in Older Adults with Bipolar Disorder.

Older adults with bipolar disorder (OABD) are individuals aged 50 years and older with bipolar disorder (BD). People with BD may have fewer coping strategies or resilience. A long duration of the disease, as seen in this population, could affect the development of resilience strategies, but this remains under-researched.

Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants: A Phase 3 Randomized Controlled Trial.

To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants. In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD () were randomized to daily oral esmethadone (75 mg on day 1, followed by 25 mg daily on days 2 through 28) or placebo between December 2020 and December 2022. The primary efficacy measure was change from baseline (CFB) to day 28 in the Montgomery-Asberg Depression Rating Scale (MADRS) score.

Patient Perceptions of Specialist Palliative Care Intervention in Surgical Oncology Care.

Introduction: Surgical oncology patients have a high symptom burden and increased risk of morbidity. The aim of palliative care is to evaluate and treat the patient in a holistic manner focusing on the unique attributes of each patient. This goal-concordant approach could help surgical patients cope with the stress and uncertainty that often accompany serious illness and surgery, improving overall outcomes.

Effect of Time From Onset of Major Depressive Disorder on the Therapeutic Response to Esmethadone (REL-1017).

The relationship between the duration of major depressive disorder (MDD) and therapeutic response to standard antidepressant treatment (SAT) is unknown. -methyl-D-aspartate receptor uncompetitive antagonists are emerging drugs for MDD. We investigated whether the antidepressant effect of esmethadone (REL-1017) could be related to the duration of depression.

Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice.

Introduction: The pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the demise of motor neurons has been linked to excitotoxicity caused by excessive calcium influx via N-methyl-D-aspartate receptors (NMDARs), suggesting that uncompetitive NMDAR antagonism could be a strategy to attenuate motor neuron degeneration. REL-1017, the dextro-isomer of racemic methadone, is a low-affinity uncompetitive NMDAR antagonist. Importantly, in humans REL-1017 has shown excellent tolerability in clinical trials for major depression.

Insights into Hepatocellular Carcinoma: From Pathophysiology to Novel Therapies.

Hepatocellular carcinoma (HCC), the most common primary liver cancer, accounts for 830,180 related deaths worldwide in 2020, according to GLOBOCAN, representing the fourth leading cause of cancer-related death, with a five-year survival rate of about 18% for advanced stage, and the second leading cause in men of cancer-related mortality worldwide [...

Are Gender Differences Important for Autoimmune Liver Diseases?

Gender Medicine has had an enormous expansion over the last ten years. Autoimmune liver diseases include several conditions, i.e.

Tyrosol attenuates NASH features by reprogramming the hepatic immune milieu.

Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease, and no drugs have been approved for its therapy. Among plant-derived molecules, phenolic compounds of extra virgin olive oil like tyrosol (Tyr) had demonstrated multiple beneficial actions for liver health, including the modulation of inflammation in fibrosis. This study aims at assessing the protective effect and mechanism of Tyr in invitro and in vivo models of NASH, with a focus on the hepatic immune microenvironment and extrahepatic manifestations.

Current Perspectives on the Molecular and Clinical Relationships between Primary Biliary Cholangitis and Hepatocellular Carcinoma.

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterised by the immune-mediated destruction of small and medium intrahepatic bile ducts, with variable outcomes and progression. This review summarises the state of the art regarding the risk of neoplastic progression in PBC patients, with a particular focus on the molecular alterations present in PBC and in hepatocellular carcinoma (HCC), which is the most frequent liver cancer in these patients. Major risk factors are male gender, viral infections, e.

Nonlinear elasticity and short-range mechanical coupling govern the rate and symmetry of mouth opening in .

has a tubular bilayered epithelial body column with a dome-shaped head on one end and a foot on the other. lacks a permanent mouth: its head epithelium is sealed. Upon neuronal activation, a mouth opens at the apex of the head which can exceed the body column diameter in seconds, allowing to ingest prey larger than itself.

Adipocyte Precursor-Derived NRG1 Promotes Resistance to FGFR Inhibition in Urothelial Carcinoma.

Unlabelled: Aberrations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic urothelial cancer (mUC), and blocking the FGF/FGFR signaling axis is used as a targeted therapeutic strategy for treating patients. Erdafitinib is a pan-FGFR inhibitor, which has recently been approved by the FDA for mUC with FGFR2/3 alterations. Although mUC patients show initial response to erdafitinib, acquired resistance rapidly develops.

Targeting the Adipose Tissue-Liver-Gut Microbiota Crosstalk to Cure MASLD.

The gut microbiota is a complex system, playing a peculiar role in regulating innate and systemic immunity. Increasing evidence links dysfunctional gut microbiota to metabolic dysfunction-associated steatotic liver disease (MASLD) due to the activation of multiple pathways in the gut and in the liver, including those mediated by Toll-like receptors (TLRs), that sustain hepatic inflammation. Thus, many efforts have been made to unravel the role of microbiota-associated dysfunction in MASLD, with the final aim of finding novel strategies to improve liver steatosis and function.

Position statement on infection screening, prophylaxis, and vaccination of pediatric patients with rheumatic diseases and immunosuppressive therapies, part 3: precautions in situations of surgery, fever, and opportunistic infections.

The objective of this study is to provide practical recommendations on the management of pediatric patients with immune-mediated rheumatic diseases receiving immunosuppressive therapies. The recommendations specifically address the cases of surgery, fever, and opportunistic infections (varicella, herpes-zoster, tuberculosis, invasive fungal disease). A qualitative approach was applied.

Drug-Drug Interaction Studies of Esmethadone (REL-1017) Involving CYP3A4- and CYP2D6-Mediated Metabolism.

Background And Objective: Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is the opioid inactive dextro-isomer of racemic methadone. Esmethadone is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker with higher affinity for GluN2D subtypes. Esmethadone showed robust, rapid, and sustained antidepressant effects in patients with major depressive disorder (MDD) with inadequate response to ongoing serotonergic antidepressant treatment.