Differential Response of Mycosis Fungoides Cells to Vorinostat.

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and is characterized by epidermotrophism of malignant CD4+ T-lymphocytes. When MF advances to a recurrent stage, patients require treatment with systemic therapies such as vorinostat, a histone deacetylase inhibitor. While vorinostat has been shown to exhibit anti-tumor activity in MF, its exact molecular mechanism has yet to be fully discerned. In the present study, we examined the transcriptomic and proteomic profiles of vorinostat treatment in two MF cell lines, Myla 2059 and HH. We find that vorinostat downregulates CTLA-4, CXCR4, and CCR7 in both cell lines, but its effect on several key pathways differs between the two MF cell lines. For example, vorinostat upregulates CCL5, CCR5, and CXCL10 expression in Myla cells but downregulates CCL5 and CXCL10 expression in HH cells. Furthermore, vorinostat upregulates IFN-γ and IL-23 signaling and downregulates IL-6, IL-7, and IL-15 signaling in Myla cells but does not affect these pathways in HH cells. Although Myla and HH represent established MF cell lines, their distinct tumor origin from separate patients demonstrates that inherent phenotypic variations within the disease persist, underscoring the importance of using a variety of MF cells in the preclinical development of MF therapeutics.

GZ17-6.02 Inhibits the Growth of EGFRvIII+ Glioblastoma.

Epidermal Growth Factor Receptor (EGFR) is amplified in over 50% of glioblastomas and promotes tumor formation and progression. However, attempts to treat glioblastoma with EGFR tyrosine kinase inhibitors have been unsuccessful thus far. The current standard of care is especially poor in patients with a constitutively active form of EGFR, EGFRvIII, which is associated with shorter survival time. This study examined the effect of GZ17-6.02, a novel anti-cancer agent undergoing phase 1 studies, on two EGFRvIII+ glioblastoma stem cells: D10-0171 and D317. In vitro analyses showed that GZ17-6.02 inhibited the growth of both D10-0171 and D317 cells with IC50 values of 24.84 and 28.28 µg/mL respectively. RNA sequencing and reverse phase protein array analyses revealed that GZ17-6.02 downregulates pathways primarily related to steroid synthesis and cell cycle progression. Interestingly, G17-6.02's mechanism of action involves the downregulation of the recently identified glioblastoma super-enhancer genes WSCD1, EVOL2, and KLHDC8A. Finally, a subcutaneous xenograft model showed that GZ17-6.02 inhibits glioblastoma growth in vivo. We conclude that GZ17-6.02 is a promising combination drug effective at inhibiting the growth of a subset of glioblastomas and our data warrants further preclinical studies utilizing xenograft models to identify patients that may respond to this drug.

Sleep disturbance in adults with chronic pruritic dermatoses is associated with increased C-reactive protein levels.

BACKGROUND: Pruritus is a common symptom that can significantly reduce quality of life through sleep disruption. OBJECTIVE: To examine features of disturbed sleep in patients with chronic pruritic dermatoses and test the hypothesis that systemic inflammation may serve as a biomarker for impaired sleep in these patients. METHODS: Cross-sectional analysis of the National Health and Nutrition Examination Survey investigating systemic inflammation using C-reactive protein (CRP) levels. Logistic regression was used to compare patients with and without sleep disturbances, adjusting for demographics (model 1) and medical comorbidities (model 2). RESULTS: Chronic pruritic dermatoses were associated with multiple sleep disturbances, including nighttime awakenings (model 1: odds ratio [OR], 1.646; 95% confidence interval [CI], 1.031-2.627; model 2: OR, 1.329; 95% CI, 0.888-1.989) and early morning awakening (model 1: OR, 1.669, 95% CI, 1.118-2.493; model 2: OR, 1.582; 95% CI, 1.008-2.481). Mean CRP levels were 52.8% higher among patients with pruritic dermatoses reporting trouble sleeping compared with those who did not (0.663 vs 0.434 mg/dL; P = .034). Trouble sleeping was also positively correlated with CRP levels (ß = 0.142, P = .025). LIMITATIONS: Potential recall bias among participants. CONCLUSIONS: In addition to confirming sleep disturbances with pruritic dermatoses, we found these disturbances are more likely to present with elevated CRP levels. Clinicians should consider the potential risk for sleep-related and cardiac comorbidities in patients diagnosed with itchy skin conditions.

Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development.

The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR. The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. We validated proteomic profiles using patient-derived glioblastoma xenografts (PDGX), characterizing 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. Proteins found to be associated with high EGFR activity represent potential biomarkers for GBM monitoring.

Obstructive sleep apnea and delirium: exploring possible mechanisms.

INTRODUCTION: Obstructive sleep apnea (OSA) is a medical disorder strongly associated with multiple comorbidities and postoperative complications. Current evidence suggests that OSA disturbs fundamental biochemical processes, leading to low-grade systemic inflammation and oxidative stress. Animal models have shown that OSA may lead to apoptosis of central neurons. In clinical studies, oxygen desaturation index and sleep fragmentation have been shown to be independently associated with cognitive dysfunction. Moreover, in several studies, patients with OSA were shown to have decreased brain activation in multiple brain areas. OSA AND DELIRIUM: The possibility of an association between OSA and delirium has been highlighted in several case reports. The first prospective study of the possible link between apnea and delirium showed that the presence of OSA was independently associated with the occurrence of delirium after knee replacement surgery. CONCLUSIONS: Therefore, we suggest that OSA should be considered as a risk factor for delirium, and clinicians should assess patients for OSA and related risk factors prior to surgery. However, further research is required to shed light on the mechanisms connecting these disorders and on whether the treatment of OSA affects the incidence of delirium.

Integrated plasma metabolomic and cytokine analysis reveals a distinct immunometabolic signature in atopic dermatitis.

Importance: Disease models for atopic dermatitis (AD) have primarily focused on understanding underlying environmental, immunologic, and genetic etiologies. However, the role of metabolic mechanisms in AD remains understudied. Objective: To investigate the circulating blood metabolomic and cytokine profile of AD as compared to healthy control patients. Design: This study collected plasma from 20 atopic dermatitis with moderate-to-severe itch (score of ≥5 on the itch Numeric Rating Scale and IGA score ≥3) and 24 healthy control patients. Mass-spectrometry based metabolite data were compared between AD and healthy controls. Unsupervised and supervised machine learning algorithms and univariate analysis analyzed metabolic concentrations. Metabolite enrichment and pathway analyses were performed on metabolites with significant fold change between AD and healthy control patients. To investigate the correlation between metabolites levels and cytokines, Spearman's rank correlation coefficients were calculated between metabolites and cytokines. Setting: Patients were recruited from the Johns Hopkins Itch Center and dermatology outpatient clinics in the Johns Hopkins Outpatient Center. Participants: The study included 20 atopic dermatitis patients and 24 healthy control patients. Main outcomes and measures: Fold changes of metabolites in AD vs healthy control plasma. Results: In patients with AD, amino acids isoleucine, tyrosine, threonine, tryptophan, valine, methionine, and phenylalanine, the amino acid derivatives creatinine, indole-3-acrylic acid, acetyl-L-carnitine, L-carnitine, 2-hydroxycinnamic acid, N-acetylaspartic acid, and the fatty amide oleamide had greater than 2-fold decrease (all P-values<0.0001) compared to healthy controls. Enriched metabolites were involved in branched-chain amino acid (valine, leucine, and isoleucine) degradation, catecholamine biosynthesis, thyroid hormone synthesis, threonine metabolism, and branched and long-chain fatty acid metabolism. Dysregulated metabolites in AD were positively correlated cytokines TARC and MCP-4 and negatively correlated with IL-1a and CCL20. Conclusions and relevance: Our study characterized novel dysregulated circulating plasma metabolites and metabolic pathways that may be involved in the pathogenesis of AD. These metabolic pathways serve as potential future biomarkers and therapeutic targets in the treatment of AD.

Efficacy and Safety of Abrocitinib in Prurigo Nodularis and Chronic Pruritus of Unknown Origin: A Nonrandomized Controlled Trial.

Importance: Prurigo nodularis (PN) and chronic pruritus of unknown origin (CPUO) are chronic pruritic diseases that dramatically impair quality of life, but therapeutic options are limited. Abrocitinib, a Janus kinase 1 inhibitor, represents a promising therapy for both conditions. Objective: To assess the efficacy and safety of 200-mg oral abrocitinib administered once daily in adults with moderate to severe PN or CPUO. Design, Setting, and Participants: This phase 2, open-label, nonrandomized controlled trial conducted between September 2021 and July 2022 took place at a single center in the US. A total of 25 adult patients with moderate to severe PN or CPUO were screened. Ten patients with PN and 10 patients with CPUO were enrolled. All 20 patients completed the 12-week treatment period, 18 of whom completed the 4-week follow-up period. Intervention: Abrocitinib, 200 mg, by mouth once daily for 12 weeks. Main Outcomes and Measures: The primary efficacy end point was the percent change in weekly Peak Pruritus Numerical Rating Scale (PP-NRS) scores from baseline to week 12. Key secondary end points included the percentage of patients achieving at least a 4-point reduction in weekly PP-NRS score from baseline to week 12 and the percent change in Dermatology Life Quality Index (DLQI) scores. Results: A total of 10 patients with PN (mean [SD] age, 58.6 [13.1] years; all were female) and 10 patients with CPUO (mean [SD] age, 70.7 [5.6] years; 2 were female) enrolled in the study. The mean (SD) baseline PP-NRS score was 9.2 (1.0) for PN and 8.2 (1.2) for CPUO. PP-NRS scores decreased by 78.3% in PN (95% CI, -118.5 to -38.1; P < .001) and 53.7% in CPUO (95% CI, -98.8 to -8.6; P = .01) by week 12. From baseline to week 12, 8 of 10 patients with PN and 6 of 10 patients with CPUO achieved at least a 4-point improvement on the PP-NRS. Both groups experienced significant improvement in quality of life as demonstrated by percent change in DLQI scores (PN: -53.2% [95% CI, -75.3% to -31.1%]; P = .002; CPUO: -49.0% [95% CI, -89.6% to -8.0%]; P = .02). The most common adverse event among patients was acneiform eruption in 2 of 20 patients (10%). No serious adverse events occurred. Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that abrocitinib monotherapy may be effective and tolerated well in adults with PN or CPUO. Randomized, double-blind, placebo-controlled trials are warranted to validate these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT05038982.

Transcriptomic and proteomic analysis of tumor suppressive effects of GZ17-6.02 against mycosis fungoides.

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL). Despite having a wide variety of therapeutic agents available for the treatment of MF, patients often suffer from a significant decrease in quality of life and rarely achieve long-term remission or complete cure, highlighting a need to develop novel therapeutic agents for this disease. The present study was undertaken to evaluate the efficacy of a novel anti-tumor agent, GZ17-6.02, which is composed of curcumin, harmine, and isovanillin, against MF in vitro and in murine models. Treatment of HH and MyLa cells with GZ17-6.02 inhibited the growth of both cell lines with IC50 ± standard errors for growth inhibition of 14.37 ± 1.19 µg/mL and 14.56 ± 1.35 µg/mL, respectively, and increased the percentage of cells in late apoptosis (p = .0304 for HH; p = .0301 for MyLa). Transcriptomic and proteomic analyses revealed that GZ17-6.02 suppressed several pathways, including tumor necrosis factor (TNF)-ɑ signaling via nuclear factor (NF)-kB, mammalian target of rapamycin complex (mTORC)1, and Pi3K/Akt/mTOR signaling. In a subcutaneous tumor model, GZ17-6.02 decreased tumor volume (p = .002) and weight (p = .009) compared to control conditions. Proteomic analysis of tumor samples showed that GZ17-6.02 suppressed the expression of several proteins that may promote CTCL growth, including mitogen-activated protein kinase (MAPK)1, MAPK3, Growth factor receptor bound protein (GRB)2, and Mediator of RAP80 interactions and targeting subunit of 40 kDa (MERIT)40.

Spatial Mass Cytometry-Based Single-Cell Imaging Reveals a Disrupted Epithelial-Immune Axis in Prurigo Nodularis.

Prurigo nodularis (PN) is a chronic, inflammatory skin condition that disproportionately affects African Americans and features intensely pruritic, hyperkeratotic nodules on the extremities and trunk. PN is understudied compared with other inflammatory skin diseases, with the spatial organization of the cutaneous infiltrate in PN yet to be characterized. In this work, we employ spatial imaging mass cytometry to visualize PN lesional skin inflammation and architecture with single-cell resolution through an unbiased machine learning approach. PN lesional skin has increased expression of caspase 3, NF-kB, and phosphorylated signal transducer and activator of transcription 3 compared with healthy skin. Keratinocytes in lesional skin are subdivided into CD14+CD33+, CD11c+, CD63+, and caspase 3-positive innate subpopulations. CD14+ macrophage populations expressing phosphorylated extracellular signal-regulated kinase 1/2 correlate positively with patient-reported itch (P = .006). Hierarchical clustering reveals a cluster of patients with PN with greater atopy, increased NF-kB+ signal transducer and activator of transcription 3-positive phosphorylated extracellular signal-regulated kinase 1/2-positive monocyte-derived myeloid dendritic cells, and increased vimentin expression (P < .05). Neighborhood analysis finds interactions between CD14+ macrophages, CD3+ T cells, monocyte-derived myeloid dendritic cells, and keratinocytes expressing innate immune markers. These findings highlight phosphorylated extracellular signal-regulated kinase-positive CD14+ macrophages as contributors to itch and suggest an epithelial-immune axis in PN pathogenesis.

Immune stimulus exposure as a trigger for the development of chronic pruritus and circulating blood type 2 inflammation.

Background: Chronic pruritus (CP) is a poorly characterized condition associated with intense pruritus without a primary skin eruption. This condition tends to emerge more commonly in older adults, and there is limited research on triggering factors. Objective: To explore the clinical characteristics and pathophysiology of CP following exposure to an immune stimulus. Methods: Clinical characteristics and plasma samples were collected from 15 patients who developed CP following an immune stimulus such as checkpoint inhibitors or vaccination. A multiplex panel was used to analyze plasma cytokine concentrations within these patients. Results: Most immunotherapy-treated patients experienced CP during treatment or after 21 to 60 days of receiving treatment, while vaccine-stimulated patients developed pruritus within a week of vaccination. Plasma cytokine analysis revealed elevated levels of 12 cytokines in patients with immune-stimulated CP compared to healthy controls. Notably, T helper 2 (Th2) related cytokines interleukin (IL)-5 (fold change 2.65; q < 0.25) and thymic stromal lymphopoietin (fold change 1.61 q < 0.25) were upregulated. Limitations: Limitations of this study include limited sample size, particularly in the plasma cytokine assay. Conclusions and Relevance: This study reveals triggers of CP development and describes alterations in blood Th2 markers in patients with CP, including IgE, increased blood eosinophils, and cytokines IL-5 and thymic stromal lymphopoietin.

Comprehensive plasma cytokine and chemokine profiling in prurigo nodularis reveals endotypes in Type 2 inflammation.

Prurigo nodularis (PN) is a chronic inflammatory skin disease that is associated with variability in peripheral blood eosinophil levels and response to T-helper 2 targeted therapies (Th2). Our objective was to determine whether circulating immune profiles with respect to type 2 inflammation differ by race and peripheral blood eosinophil count. Plasma from 56 PN patients and 13 matched healthy controls was assayed for 54 inflammatory biomarkers. We compared biomarker levels between PN and HCs, among PN patients based on absolute eosinophil count, and across racial groups in PN. Eleven biomarkers were elevated in PN versus HCs including interleukin (IL)-12/IL-23p40, tumor necrosis factor-alpha (TNF-α), Thymic stromal lymphopoietin (TSLP), and macrophage-derived chemokine (MDC/CCL22). Additionally, PN patients with AEC > 0.3 K cells/µL had higher Th2 markers (eotaxin, eotaxin-3, TSLP, MCP-4/CCL13), and African American PN patients had lower eosinophils, eotaxin, and eotaxin-3 versus Caucasian and Asian PN patients (p < 0.05 for all). Dupilumab responders had higher AEC (p < 0.01), were more likely to be Caucasian (p = 0.02) or Asian (p = 0.05) compared to African Americans, and more often had a history of atopy (p = 0.08). This study suggests that blood AEC > 0.3 K and Asian and Caucasian races are associated with Th2 skewed circulating immune profiles and response to Th2 targeted therapies.

Single-Cell RNA Sequencing Reveals Dysregulated POSTN+WNT5A+ Fibroblast Subclusters in Prurigo Nodularis.

Prurigo nodularis (PN) is an intensely pruritic, inflammatory skin disease with a poorly understood pathogenesis. We performed single-cell transcriptomic profiling of 28,695 lesional and nonlesional PN cells. Lesional PN has increased dysregulated fibroblasts (FBs) and myofibroblasts. FBs in lesional PN were shifted toward a cancer-associated FB-like phenotype, with POSTN+WNT5A+ cancer-associated FBs increased in PN and similarly so in squamous cell carcinoma. A multicenter cohort study revealed an increased risk of squamous cell carcinoma and cancer-associated FB-associated malignancies (breast and colorectal) in patients with PN. Systemic fibroproliferative diseases (renal sclerosis and idiopathic pulmonary fibrosis) were upregulated in patients with PN. Ligand-receptor analyses demonstrated an FB neuronal axis with FB-derived WNT5A and periostin interactions with neuronal receptors melanoma cell adhesion molecule and ITGAV. These findings identify a pathogenic and targetable POSTN+WNT5A+ FB subpopulation that may predispose cancer-associated FB-associated malignancies in patients with PN.

Revisiting the prehypertension debate: increasing evidence for treatment yet randomized clinical trials are lacking.

In 2009, Blood Pressure featured a debate about whether to treat patients with prehypertension (Kiely et al., Blood Press. 2009;18:300-303; McInnes GT, Blood Press. 2009;18:304-307). Our group supported pharmacotherapy for this condition at that time. Since then, additional evidence linking prehypertension with associated morbidities has emerged. These studies are detailed below and provide further evidence for the treatment of prehypertension.

Modulation of Neuroimmune and Epithelial Dysregulation in Patients With Moderate to Severe Prurigo Nodularis Treated With Nemolizumab.

Importance: Prurigo nodularis (PN) is a debilitating skin disease characterized by intense pruritus and hyperkeratotic skin nodules. Nemolizumab, a monoclonal antibody targeting interleukin 31 receptor α, is a promising novel therapy for the treatment of moderate to severe PN. The biological mechanisms by which nemolizumab promotes improvement of itch and skin lesions in PN are unknown. Objective: To characterize changes in plasma protein biomarkers associated with clinical response to nemolizumab in patients with PN. Design, Setting, and Participants: This multicenter cohort study included patients recruited from Austria, France, Germany, Poland, and the US from a phase 2 clinical trial. Adults diagnosed with moderate to severe PN with severe pruritus for at least 6 months were included in the original trial. Patients in the nemolizumab group were included in the present study if they achieved at least a 4-point decrease in the Peak Pruritus Numerical Rating Scale (PP-NRS) from baseline to week 12 during nemolizumab treatment. Placebo controls did not experience a 4-point decrease in PP-NRS. Mass spectrometry with tandem mass tags to enrich skin-specific protein detection was used to characterize changes in plasma protein expression in nemolizumab and placebo groups. Data were collected from November 2, 2017, to September 26, 2018, and analyzed from December 6, 2019, to April 8, 2022. Intervention: As part of the clinical trial, patients were treated with 3 doses of nemolizumab or placebo at 0, 4, and 8 weeks. Main Outcomes and Measures: Changes in plasma and epidermal protein expression in nemolizumab-treated patients compared with the placebo group at 0, 4, and 12 weeks. Results: Among the 38 patients included in the analysis (22 women and 16 men; mean [SD] age, 55.8 [15.8] years), enrichment analysis of canonical pathways, biological functions, and upstream regulators showed downregulation of terms involving inflammation (IL-6, acute-phase response, signal transducer and activator of transcription 3, and interferon γ), neural processes (synaptogenesis signaling and neuritogenesis), tissue remodeling and fibrosis (transforming growth factor ß1 and endothelin-1), and epidermal differentiation (epithelial mesenchymal transition) in the plasma of nemolizumab group. Conclusions and Relevance: In this cohort study, differences between nemolizumab and placebo groups included modulation of inflammatory signaling, neural development, and epithelial differentiation, suggesting a promising potential approach for clinical management of PN.

Construction of a Secondary Enclosure for UVB Irradiation of Mice.

UV irradiation is commonly used in murine models of skin cancers. Despite the popularity of using UVB rays to model photocarcinogenesis in animals, there is a lack of standardization in the secondary enclosures used to administer radiation. An appraisal of the literature also shows a general lack of details regarding the materials and procedures utilized in the fabrication of such enclosures. We present in this study a detailed overview of the construction of a UVB exposure chamber that successfully induces lesions in hairless mice. A standardized protocol for producing a UVB enclosure may reduce methodological variation in future studies seeking to investigate photocarcinogenesis in animals.

Somatic mutations reveal hyperactive Notch signaling and racial disparities in prurigo nodularis.

Prurigo nodularis (PN) is a chronic inflammatory skin disease that disproportionately affects African Americans and is characterized by pruritic skin nodules of unknown etiology. Little is known about genetic alterations in PN pathogenesis, especially relating to somatic events which are often implicated in inflammatory conditions. We thus performed whole-exome sequencing on 54 lesional and nonlesional skin biopsies from 17 PN patients and 10 atopic dermatitis (AD) patients for comparison. Somatic mutational analysis revealed that PN lesional skin harbors pervasive somatic mutations in fibrotic, neurotropic, and cancer-associated genes. Nonsynonymous mutations were most frequent in NOTCH1 and the Notch signaling pathway, a regulator of cellular proliferation and tissue fibrosis, and NOTCH1 mutations were absent in AD. Somatic copy-number analysis, combined with expression data, showed that recurrently deleted and downregulated genes in PN lesional skin are associated with axonal guidance and extension. Follow-up immunofluorescence validation demonstrated increased NOTCH1 expression in PN lesional skin fibroblasts and increased Notch signaling in PN lesional dermis. Finally, multi-center data revealed a significantly increased risk of NOTCH1-associated diseases in PN patients. In characterizing the somatic landscape of PN, we uncover novel insights into its pathophysiology and identify a role for dysregulated Notch signaling in PN.

Single-cell RNA sequencing reveals dysregulated fibroblast subclusters in prurigo nodularis.

Prurigo nodularis (PN) is an intensely pruritic, chronic inflammatory skin disease that disproportionately affects black patients. However, the pathogenesis of PN is poorly understood. We performed single-cell transcriptomic profiling, ligand receptor analysis and cell trajectory analysis of 28,695 lesional and non-lesional PN skin cells to uncover disease-identifying cell compositions and genetic characteristics. We uncovered a dysregulated role for fibroblasts (FBs) and myofibroblasts as a key pathogenic element in PN, which were significantly increased in PN lesional skin. We defined seven unique subclusters of FBs in PN skin and observed a shift of PN lesional FBs towards a cancer-associated fibroblast (CAF)-like phenotype, with WNT5A+ CAFs increased in the skin of PN patients and similarly so in squamous cell carcinoma (SCC). A multicenter PN cohort study subsequently revealed an increased risk of SCC as well as additional CAF-associated malignancies in PN patients, including breast and colorectal cancers. Systemic fibroproliferative diseases were also upregulated in PN patients, including renal sclerosis and idiopathic pulmonary fibrosis. Ligand receptor analyses demonstrated increased FB1-derived WNT5A and periostin interactions with neuronal receptors MCAM and ITGAV, suggesting a fibroblast-neuronal axis in PN. Type I IFN responses in immune cells and increased angiogenesis/permeability in endothelial cells were also observed. As compared to atopic dermatitis (AD) and psoriasis (PSO) patients, increased mesenchymal dysregulation is unique to PN with an intermediate Th2/Th17 phenotype between atopic dermatitis and psoriasis. These findings identify a pathogenic role for CAFs in PN, including a novel targetable WNT5A+ fibroblast subpopulation and CAF-associated malignancies in PN patients.

Topical GZ21T Inhibits the Growth of Actinic Keratoses in a UVB-Induced Model of Skin Carcinogenesis.

Actinic keratoses (AKs) are premalignant intraepidermal neoplasms that occur as a result of cumulative sun damage. AKs commonly relapse, and up to 16% undergo malignant transformation into cutaneous squamous cell carcinoma. There is a need for novel therapies that reduce the quantity and surface area of AKs as well as prevent malignant transformation to cutaneous squamous cell carcinomas. We recently showed that GZ17-6.02, an anticancer agent composed of curcumin, haramine, and isovanillin, inhibited the growth of H297.T cells. This study evaluated the efficacy of a topical formulation of GZ17-6.02, known as GZ21T, in a murine model of AK generated by exposing SKH1 mice to UVR. Treatment of mice with topical GZ21T inhibited the growth of AKs by decreasing both lesion count (P = 0.012) and surface area occupied by tumor (P = 0.002). GZ21T also suppressed the progression of AKs to cutaneous squamous cell carcinoma by decreasing the count (P = 0.047) and surface area (P = 0.049) of lesions more likely to represent cutaneous squamous cell carcinoma. RNA sequencing and proteomic analyses revealed that GZ21T suppressed several pathways, including MAPK (P = 0.025), phosphoinositide 3-kinase-protein kinase B (P = 0.04), HIF-1α (P = 0.016), Wnt (P = 0.025), insulin (P = 0.018), and ERBB (P = 0.016) signaling. GZ21T also upregulated the autophagy-promoting protein AMPK while suppressing proteins such as PD-L1, glutaminase, pAkt1 S473, and eEF2K.

A Polygenic Risk Score for Predicting Racial and Genetic Susceptibility to Prurigo Nodularis.

Prurigo nodularis (PN) is an understudied inflammatory skin disease characterized by pruritic, hyperkeratotic nodules. Identifying the genetic factors underlying PN could help to better understand its etiology and guide the development of therapies. In this study, we developed a polygenic risk score that predicts a diagnosis of PN (OR = 1.41, P = 1.6 × 10-5) in two independent and continentally distinct populations. We also performed GWASs, which uncovered genetic variants associated with PN, including one near PLCB4 (rs6039266: OR = 3.15, P = 4.8 × 10-8) and others near TXNRD1 (rs34217906: OR = 1.71, P = 6.4 × 10-7; rs7134193: OR = 1.57, P = 1.1 × 10-6). Finally, we discovered that Black patients have over a two-times greater genetic risk of developing PN (OR = 2.63, P = 7.8 × 10-4). Combining the polygenic risk score and self-reported race together was significantly predictive of PN (OR = 1.32, P = 4.7 × 10-3). Strikingly, this association was more significant with race than after adjusting for genetic ancestry. Because race is a sociocultural construct and not a genetically bound category, our findings suggest that genetics, environmental influence, and social determinants of health likely affect the development of PN and may contribute to clinically observed racial disparities.

Obstructive sleep apnea and incidence of postoperative delirium after elective knee replacement in the nondemented elderly.

BACKGROUND: Postoperative delirium, a common complication in the elderly, can occur following any type of surgery and is associated with increased morbidity and mortality; it may also be associated with subsequent cognitive problems. Effective therapy for postoperative delirium remains elusive because the causative factors of delirium are likely multiple and varied. METHODS: Patients 65 yr or older undergoing elective knee arthroplasty were prospectively evaluated for postoperative Diagnostic and Statistical Manual of Mental Disorders-IV delirium. Exclusion criteria included dementia, mini-mental state exam score less than 24, delirium, clinically significant central nervous system/neurologic disorder, current alcoholism, or any serious psychiatric disorder. Delirium was assessed on postoperative days 2 and 3 using standardized scales. Patients' preexisting medical conditions were obtained from medical charts. The occurrence of obstructive sleep apnea was confirmed by contacting patients to check their polysomnography records. Data were analyzed using Pearson chi-square or Wilcoxon rank sum tests and multiple logistic regressions adjusted for effects of covariates. RESULTS: Of 106 enrolled patients, 27 (25%) developed postoperative delirium. Of the 15 patients with obstructive sleep apnea, eight (53%) experienced postoperative delirium, compared with 19 (20%) of the patients without obstructive sleep apnea (P = 0.0123, odds ratio: 4.3). Obstructive sleep apnea was the only statistically significant predictor of postoperative delirium in multivariate analyses. CONCLUSIONS: This is the first prospective study employing validated measures of delirium to identify an association between preexisting obstructive sleep apnea and postoperative delirium.