Immunohistochemical Expression of Immune Regulatory Proteins in Interface Dermatoses.

Cutaneous immune-related adverse events (irAEs) of immunotherapies, such as anti-programmed cell death protein-1 (PD-1), suggest that immune checkpoint factors may contribute to the pathobiology of lichenoid interface dermatitis in immunotherapy-naïve patients. Our study aimed to describe innate and adaptive immune markers via immunohistochemical (IHC) staining of lichenoid interface dermatoses. We studied the staining patterns of PD-L1, STING, IL-36 gamma, CD8, PD-1, and LAG-3 in five interface dermatoses: oral lichen planus (LP) (n = 10), cutaneous LP (n = 10), chronic cutaneous lupus erythematosus (CLE) (n = 11), erythema multiforme (EM) (n = 11), and toxic epidermal necrolysis (TEN) (n = 13), by immunohistochemistry (IHC) analysis.

Differential type I and type III interferon expression profiles in rheumatoid and juvenile idiopathic arthritis.

Background: The role of type I and type III interferons (IFNs) in rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) is still poorly understood. The objective of this study was to examine the hypothesis that IFN expression profiles in the peripheral blood differ between subsets of arthritic subjects. Multiple type I and type III IFNs were examined in patients with RA and JIA, as well as among subtypes of JIA.

Two Cases of Cutaneous Sarcomatoid Squamous Cell Carcinoma Resembling Cutaneous Giant Cell Tumor of Soft Tissue.

Cutaneous sarcomatoid squamous cell carcinoma is well-described with histology resembling pleomorphic undifferentiated sarcoma featuring collagenous or myxoid stroma with or without elements of keratinizing squamous carcinoma. This report presents 2 cases of dedifferentiated squamous cell carcinoma (SCC) composed of sheets of malignant mononuclear cells with malignant osteoclast-like multinucleated giant cells, extravasated blood, and hemosiderin resembling cutaneous giant cell tumor (cGCT). In the first case, an exophytic facial mass of a 96-year-old woman removed by shave showing extensive cGCT-like tumor but with microscopic elements of SCC in situ and positivity for cytokeratin 5/6 in the malignant spindle cells and SCC.

Autoimmune blistering diseases treated with glucocorticoids: An international study of steroid-induced myopathy.

Background: Patients with autoimmune blistering diseases (AIBDs) are often exposed to chronic glucocorticoid (GC) treatment with many side effects. Glucocorticoid-induced myopathy (GIM) is a well-established side effect, which particularly affects the proximal muscles. The Glucocorticoid Toxicity Index (GTI) is a validated global assessment tool which quantifies GC toxicity over time.

Impact of potassium test sample rejections on routine laboratory service, South Africa.

Background: Accurate potassium measurements are necessary for effective clinical management of hyperkalaemia. Pre-analytical factors may affect laboratory measurements, leading to erroneous results and inappropriate patient management and negatively impact the efficiency and finances of laboratories and hospitals.

Objective: This study evaluated the impact of rejected potassium test requests on laboratory service.

MicroRNA-27a-3p enhances the inflammatory phenotype of Juvenile Idiopathic Arthritis fibroblast-like synoviocytes.

Background: Juvenile Idiopathic Arthritis (JIA) is the most prevalent chronic pediatric rheumatic disorder. In joints of JIA patients, aggressive phenotypic changes in fibroblast-like synoviocytes (FLS) of the synovial lining play a key role in inflammation. MicroRNAs are dysregulated in rheumatoid arthritis and JIA, including miR-27a-3p.

Differentially Expressed Inflammation-Regulating MicroRNAs in Oligoarticular Juvenile Idiopathic Arthritis.

Objective: To evaluate microRNA expression in synovial fluid (SF), plasma, and leukocytes from patients with juvenile idiopathic arthritis (JIA).

Methods: MicroRNA expression in pooled JIA plasma and SF was assessed by absolute quantitative droplet digital PCR array. The results were validated in individual patient samples.

Delivering hydrophilic peptide inhibitors of heat shock protein 70 into cancer cells.

Heat shock protein 70 (Hsp70) plays a major role in protein folding and has emerged as an attractive target in a wide range of cancers. Here we used a polymer nanogel to deliver two hydrophilic peptide inhibitors that block the interaction between the C-terminus of Hsp70 and heat shock organizing protein (HOP). The nanogels are able to load ∼200 wt% of the peptide inhibitors from solution via simple agitation at pH 7, and release them after cell uptake.

Prolidase deficiency, a rare inborn error of immunity, clinical phenotypes, immunological features, and proposed treatments in twins.

Background: Prolidase deficiency (PD) is an autosomal recessive inborn multisystemic disease caused by mutations in the PEPD gene encoding the enzyme prolidase D, leading to defects in turnover of proline-containing proteins, such as collagen. PD is categorized as a metabolic disease, but also as an inborn error of immunity. PD presents with a range of findings including dysmorphic features, intellectual disabilities, recurrent infections, intractable skin ulceration, autoimmunity, and splenomegaly.

High Dose Intravenous IgG Therapy Modulates Multiple NK Cell and T Cell Functions in Patients With Immune Dysregulation.

Intravenous immunoglobulin (IVIG) is an effective immunomodulatory treatment for immune dysregulation diseases. However, the mechanisms by which it reduces systemic inflammation are not well understood. NK cell cytotoxicity is decreased by IVIG in women with reduced fertility, but IVIG effects on NK cells in immune dysregulation are less clear.

De Novo Design, Synthesis, and Mechanistic Evaluation of Short Peptides That Mimic Heat Shock Protein 27 Activity.

We report the first small molecule peptides based on the N-terminal sequence of heat shock protein 27 (Hsp27, gene HSPB1) that demonstrates chaperone-like activity. The peptide, comprising the SWDPF sequence located at Hsp27's amino (N)-terminal domain, directly regulates protein aggregation events, maintaining the disaggregated state of the model protein, citrate synthase. While traditional inhibitors of protein aggregation act via regulation of a protein that facilitates aggregation or disaggregation, our molecules are the first small peptides between 5 and 8 amino acids in length that are based on the N-terminus of Hsp27 and directly control protein aggregation.

Using NMR to identify binding regions for N and C-terminal Hsp90 inhibitors using Hsp90 domains.

We present the first NMR study of the interaction between heat shock protein 90 (Hsp90) and amino (N)-terminal inhibitors 17-AAG, and AUY922, and carboxy (C)-terminal modulators SM253, and LB51. We show that the two ATP mimics, 17-AAG and AUY922, bind deeply within the ATP binding pocket of the N-terminal domain, consistent with the crystal structures. In contrast, SM253, a C-terminal Hsp90 modulator, binds to the linker region between the N and middle domains.

Dual-Stage Picolinic Acid-Derived Inhibitors of .

causes a prevalent human infection for which only the acute stage has an FDA-approved therapy. To find inhibitors of both the acute stage parasites and the persistent cyst stage that causes a chronic infection, we repurposed a compound library containing known inhibitors of parasitic hexokinase, the first step in the glycolysis pathway, along with a larger collection of new structural derivatives. The focused screen of 22 compounds showed a 77% hit rate (>50% multistage inhibition) and revealed a series of aminobenzamide-linked picolinic acids with submicromolar potency against both parasite forms.

Cyclic Peptides as Drugs for Intracellular Targets: The Next Frontier in Peptide Therapeutic Development.

Developing macrocyclic peptides that can reach intracellular targets is a significant challenge. This review discusses the most recent strategies used to develop cell permeable cyclic peptides that maintain binding to their biological target inside the cell. Macrocyclic peptides are unique from small molecules because traditional calculated physical properties are unsuccessful for predicting cell membrane permeability.

Association of a Type 2-Polarized T Cell Phenotype With Methotrexate Nonresponse in Patients With Rheumatoid Arthritis.

Objective: Rheumatoid arthritis (RA) is a chronic inflammatory disease mediated through complex immunologic pathways. Among RA patients receiving low-dose methotrexate (MTX) monotherapy, approximately one-half exhibit a meaningful clinical response within the first 6 months of starting treatment. Whether baseline immune phenotypes differ between subsequent MTX responders and nonresponders is unknown.

C-Terminal HSP90 Inhibitors Block the HIF-1 Hypoxic Response by Degrading HIF-1α through the Oxygen-Dependent Degradation Pathway.

Background/aims: Hypoxia Inducible Factor-1α (HIF-1α) is involved in cancer progression and is stabilized by the chaperone HSP90 (Heat Shock Protein 90), preventing degradation. Previously identified HSP90 inhibitors bind to the N-terminal pocket of HSP90, which blocks binding to HIF-1α and induces HIF-1α degradation. N-terminal inhibitors have failed in the clinic as single therapy treatments partially because they induce a heat shock response.

Polymer mediated transport of the Hsp90 inhibitor LB76, a polar cyclic peptide, produces an Hsp90 cellular phenotype.

LB76 is a cyclic peptide that shows great promise as a selective heat shock protein 90 (Hsp90) inhibitor. However despite strong binding to and inhibition of Hsp90 in cell lysate its polar structure prevents it from crossing the cell membrane. We have developed a pH responsive polymer nanoparticle that effectively encapsulates LB76 from solution without need for purification.

Nanoparticles for Bioapplications: Study of the Cytotoxicity of Water Dispersible CdSe(S) and CdSe(S)/ZnO Quantum Dots.

Semiconductor nanocrystals or quantum dots (QDs) have unique optical and physical properties that make them potential imaging tools in biological and medical applications. However, concerns over the aqueous dispersivity, toxicity to cells, and stability in biological environments may limit the use of QDs in such applications. Here, we report an investigation into the cytotoxicity of aqueously dispersed CdSe(S) and CdSe(S)/ZnO core/shell QDs in the presence of human colorectal carcinoma cells (HCT-116) and a human skin fibroblast cell line (WS1).

Delivering bioactive cyclic peptides that target Hsp90 as prodrugs.

The most challenging issue facing peptide drug development is producing a molecule with optimal physical properties while maintaining target binding affinity. Masking peptides with protecting groups that can be removed inside the cell, produces a cell-permeable peptide, which theoretically can maintain its biological activity. Described are series of prodrugs masked using: (a) O-alkyl, (b) N-alkyl, and (c) acetyl groups, and their binding affinity for Hsp90.

Protein-protein inhibitor designed de novo to target the MEEVD region on the C-terminus of Hsp90 and block co-chaperone activity.

Protein-protein interactions control all cellular functions. Presented is the first de novo designed protein-protein inhibitor that targets the C-terminus of heat shock protein 90 (Hsp90) and blocks co-chaperones from binding. Compound LB76, which was created from an Hsp90 co-chaperone, selectively pulls down Hsp90 from cell lysates, binds to Hsp90's C-terminal domain, and blocks the interactions between Hsp90 and TPR-containing co-chaperones.

Synthesis and Structure-Activity Relationships of Inhibitors That Target the C-Terminal MEEVD on Heat Shock Protein 90.

Herein, we describe the synthesis and structure-activity relationships of cyclic peptides designed to target heat shock protein 90 (Hsp90). Generating 19 compounds and evaluating their binding affinity reveals that increasing electrostatic interactions allows the compounds to bind more effectively with Hsp90 compared to the lead structure. Exchanging specific residues for lysine improves binding affinity for Hsp90, indicating some residues are not critical for interacting with the target, whereas others are essential.

Estimating Recent Local Impacts of Sea-Level Rise on Current Real-Estate Losses: A Housing Market Case Study in Miami-Dade, Florida.

Sea-Level Rise (SLR) Projections from the National Oceanic and Atmospheric Administration (NOAA) and the U.S. Army Corp of Engineers (USACE) indicate increasing, and imminent, risk to coastal communities from tidal flooding and hurricane storm surge.

Designing de Novo Small Molecules That Control Heat Shock Protein 70 (Hsp70) and Heat Shock Organizing Protein (HOP) within the Chaperone Protein-Folding Machinery.

Protein-protein interactions (PPIs) regulate all signaling pathways for cellular function. Developing molecules that modulate PPIs through the interface of their protein surfaces has been a significant challenge and there has been little success controlling PPIs through standard molecular library screening approaches. PPIs control the cell's protein-folding machinery, and this machinery relies on a multiprotein complex formed with heat shock protein 70 (Hsp70).