Colloid-Forming Prodrug-Hydrogel Composite Prolongs Lower Intraocular Pressure in Rodent Eyes after Subconjunctival Injection.

Colloidal drug aggregates (CDAs) are challenging in drug discovery due to their unpredictable formation and interference with screening assays. These limitations are turned into a strategic advantage by leveraging CDAs as a drug delivery platform. This study explores the deliberate formation and stabilization of CDAs for local ocular drug delivery, using a modified smallmolecule glaucoma drug.

Constitutional MLH1 Methylation Is a Major Contributor to Mismatch Repair-Deficient, MLH1-Methylated Colorectal Cancer in Patients Aged 55 Years and Younger.

Background: Most mismatch repair-deficient (MMRd) colorectal cancer (CRC) cases arise sporadically, associated with somatic MLH1 methylation, whereas approximately 20% have germline mismatch repair pathogenic variants causing Lynch syndrome (LS). Universal screening of incident CRC uses presence of MLH1 methylation in MMRd tumors to exclude sporadic cases from germline testing for LS. However, this overlooks rare cases with constitutional MLH1 methylation (epimutation), a poorly recognized mechanism for LS.

POLE-Mutant Colon Cancer Treated with PD-1 Blockade Showing Clearance of Circulating Tumor DNA and Prolonged Disease-Free Interval.

Colon cancer with high microsatellite instability is characterized by a high tumor mutational burden and responds well to immunotherapy. Mutations in polymerase ɛ, a DNA polymerase involved in DNA replication and repair, are also associated with an ultra-mutated phenotype. We describe a case where a patient with POLE-mutated and hypermutated recurrent colon cancer was treated with pembrolizumab.

MLH1-methylated endometrial cancer under 60 years of age as the "sentinel" cancer in female carriers of high-risk constitutional MLH1 epimutation.

Objective: Universal screening of endometrial carcinoma (EC) for mismatch repair deficiency (MMRd) and Lynch syndrome uses presence of MLH1 methylation to omit common sporadic cases from follow-up germline testing. However, this overlooks rare cases with high-risk constitutional MLH1 methylation (epimutation), a poorly-recognized mechanism that predisposes to Lynch-type cancers with MLH1 methylation. We aimed to determine the role and frequency of constitutional MLH1 methylation among EC cases with MMRd, MLH1-methylated tumors.

Rapid culture of human keratinocytes in an autologous, feeder-free system with a novel growth medium.

Background Aims: The ability to culture human keratinocytes is beneficial in the treatment of skin injury and disease, as well as for testing chemicals in vitro as a substitute for animal testing.

Results: We have identified a novel culture medium for the rapid growth of keratinocytes from human skin. "Kelch's medium" supports keratinocyte growth that is as rapid as in the classical Rheinwald and Green method, but without the need for cholera toxin or xenogeneic feeder cells.

Sugar-sugar interactions in oil suspensions containing surfactants and effects on macroscopic phenomena.

Surfactants are used in confectionery production to control the viscosity and yield value of molten chocolate. To develop a deeper understanding of the structure-function relationship of surfactants in food-related particle suspensions, the apparent viscosity, yield value, sedimentation, and particle interactions of 10 wt% confectioner's sugar-in-canola oil suspensions were investigated in the presence of up to 1 wt% commercial soy lecithin, polyglycerol polyricinoleate (PGPR), citric acid esters of monoacylglycerols (CITREM) or ammonium phosphatides (AMP). Atomic force microscopy (AFM) was used to measure attractive forces at the nano-Newton scale between a sugar substrate and a sugar crystal-functionalized AFM cantilever in an oil environment.

Role of methylated septin 9 as an adjunct diagnostic and prognostic biomarker in hepatocellular carcinoma.

Background: Methylated septin 9 (mSEPT9) has a role in hepatocarcinogenesis. We evaluated mSEPT9 performance in patients with hepatocellular carcinoma (HCC) and those at risk of HCC METHODS: Using Epi-proColon® V2.0 assay adapted for 1 mL plasma, we investigated mSEPT9 sensitivity, specificity, associations with influential covariates and relation to death.

Multi-omic comparison of Alzheimer's variants in human ESC-derived microglia reveals convergence at APOE.

Variations in many genes linked to sporadic Alzheimer's disease (AD) show abundant expression in microglia, but relationships among these genes remain largely elusive. Here, we establish isogenic human ESC-derived microglia-like cell lines (hMGLs) harboring AD variants in CD33, INPP5D, SORL1, and TREM2 loci and curate a comprehensive atlas comprising ATAC-seq, ChIP-seq, RNA-seq, and proteomics datasets. AD-like expression signatures are observed in AD mutant SORL1 and TREM2 hMGLs, while integrative multi-omic analysis of combined epigenetic and expression datasets indicates up-regulation of APOE as a convergent pathogenic node.

Soluble SORLA Enhances Neurite Outgrowth and Regeneration through Activation of the EGF Receptor/ERK Signaling Axis.

SORLA is a transmembrane trafficking protein associated with Alzheimer's disease risk. Although SORLA is abundantly expressed in neurons, physiological roles for SORLA remain unclear. Here, we show that cultured transgenic neurons overexpressing SORLA feature longer neurites, and accelerated neurite regeneration with wounding.

Chinese Herbal Medicine Interventions in Neurological Disorder Therapeutics by Regulating Glutamate Signaling.

Glutamate is the major excitatory neurotransmitter in the central nervous system, and its signaling is critical for excitatory synaptic transmission. The well-established glutamate system involves glutamate synthesis, presynaptic glutamate release, glutamate actions on the ionotropic glutamate receptors (NMDA, AMPA, and kainate receptors) and metabotropic glutamate receptors, and glutamate uptake by glutamate transporters. When the glutamate system becomes dysfunctional, it contributes to the pathogenesis of neurodegenerative and neuropsychiatric diseases such as Alzheimer's disease, Parkinson's disease, depression, epilepsy, and ischemic stroke.

The proteomic skin profile of moderate-to-severe atopic dermatitis patients shows an inflammatory signature.

Background: Moderate-to-severe atopic dermatitis (AD) is increasingly recognized as a systemic disease, largely due to proteomic blood studies. There are growing efforts to develop AD biomarkers using minimal tissues.

Objective: To characterize the AD skin proteomic signature and its relationship with the blood proteome and genomic skin profile in the same individuals.

Increased cardiovascular and atherosclerosis markers in blood of older patients with atopic dermatitis.

Background: Atopic dermatitis (AD) is associated with increased systemic inflammation and cardiovascular risk. Although previous studies have found increased inflammatory proteins in the blood of patients with AD, detailed comparison among patients with AD of different ages is unavailable.

Objective: To characterize the blood proteomic signature of patients with AD as a function of age.

Stroke Induces a BDNF-Dependent Improvement in Cognitive Flexibility in Aged Mice.

Stroke remains a leading cause of disability worldwide. Recently, we have established an animal model of stroke that results in delayed impairment in spatial memory, allowing us to better investigate cognitive deficits. Young and aged brains show different recovery profiles after stroke; therefore, we assessed aged-related differences in poststroke cognition.

Membralin deficiency dysregulates astrocytic glutamate homeostasis leading to ALS-like impairment.

Mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) are yet unclear. Specific deletion of the ER-component membralin in astrocytes manifested postnatal motor defects and lethality in mice, causing the accumulation of extracellular glutamate through reducing the glutamate transporter EAAT2. Restoring EAAT2 levels in membralin KO astrocytes limited astrocyte-dependent excitotoxicity in motor neurons.

The skin as an immune organ: Tolerance versus effector responses and applications to food allergy and hypersensitivity reactions.

Skin is replete with immunocompetent cells that modulate signaling pathways to maintain a salubrious immunogenic/tolerogenic balance. This fertile immune environment plays a significant role in the development of allergic responses and sensitivities, but the mechanisms underlying these pathways have been underappreciated and underused with respect to developing therapeutics. Among the complex repertoire of cells that promote tolerogenic pathways in the periphery, 2 key classes include dendritic cells and regulatory T (Treg) cells.

Characteristics of patients with myeloproliferative neoplasms with lymphoma, with or without JAK inhibitor therapy.

There is a Commentary on this article in this issue.

GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis.

Background: GBR 830 is a humanized mAb against OX40, a costimulatory receptor on activated T cells. OX40 inhibition might have a therapeutic role in T cell-mediated diseases, including atopic dermatitis (AD).

Objective: This exploratory phase 2a study investigated the safety, efficacy, and tissue effects of GBR 830 in patients with AD.

Age-specific changes in the molecular phenotype of patients with moderate-to-severe atopic dermatitis.

Background: Atopic dermatitis (AD) shows differential clinical presentation in older compared with younger patients. Nevertheless, changes in the AD molecular profile with age are unknown.

Objective: We sought to characterize age-related changes in the AD profile.

A Phase 2 Randomized Trial of Apremilast in Patients with Atopic Dermatitis.

A phase 2, double-blind, placebo-controlled trial evaluated apremilast efficacy, safety, and pharmacodynamics in adults with moderate to severe atopic dermatitis. Patients were randomly assigned to receive placebo, apremilast 30 mg twice daily (APR30), or apremilast 40 mg twice daily (APR40) for 12 weeks. During weeks 12-24, all patients received APR30 or APR40.

Effect of short-term liver X receptor activation on epidermal barrier features in mild to moderate atopic dermatitis: A randomized controlled trial.

Background: Liver X receptors (LXRs) are involved in maintaining epidermal barrier and suppressing inflammatory responses in model systems. The LXR agonist VTP-38543 showed promising results in improving barrier function and inflammatory responses in model systems.

Objective: To assess the safety, tolerability, cellular and molecular changes, and clinical efficacy of the topical VTP-38543 in adults with mild to moderate atopic dermatitis (AD).