Atopic dermatitis shares a distinct T helper 2 subset with mycosis fungoides that exhibits autonomous proliferative potential.

Lichenoid-granulomatous drug reactions to dupilumab: A report of 2 cases

Dupilumab in HIV-positive patients: A case series report of 4 patients

Cutaneous T-Cell Lymphoma and Dupilumab Use: A Retrospective Matched Cohort Study of Clinical Characteristics and Treatment Outcomes

Introduction/Background With newly emerging targeted systemic therapies for atopic dermatitis (AD) there is a need to understand the evolving real-world treatment patterns and implications on AD management. Since the FDA approval of dupilumab for adults in 2017, three additional targeted therapies – the IL-13 inhibitor tralokinumab and 2 JAK inhibitors (abrocitinib and upadacitinib) – were approved for adults with moderate-to-severe AD as of January 2022. Additional treatment options are still awaiting FDA approval, including the IL-31 inhibitor nemolizumab, or undergoing clinical trials (e.g., OX40-OX40L inhibitors). Therefore, an update on real-world contemporary targeted treatment strategies for AD is warranted. Objectives To characterize current systemic treatment patterns in patients with AD. Methods A real-world retrospective observational analysis of US medical and prescription claims data (IQVIA, Durham, NC) was assessed. Individuals with an AD diagnosis were included in analysis if they initiated a modern targeted systemic AD prescription with a dermatology provider at index (patient selection event) for their first line of therapy (LOT) between January 2022 and June 2023, but had no AD systemic treatment 24 months prior to index and were continuously enrolled a minimum of six months for follow-up (n=7006). Treatment patterns, switch rates, comedications, comorbidities, and post-index events were evaluated. Results First line targeted systemic therapies for adults included dupilumab (91.2%), upadacitinib (4.3%), tralokinumab (3.9%), and abrocitinib (0.7%). Fifty-one percent of patients initiating on one of these therapies underwent a change in treatment during the follow-up period. Switch rates for monotherapy use of each of these targeted drugs to another targeted systemic therapy were 5%, 10%, 18%, and 17%, respectively. For the second LOT, dupilumab monotherapy decreased to 11% whereas upadacitinib use increased to 42%, tralokinumab to 25%, and abrocitinib to 8% of LOT-2. On average, switches to LOT-2 occurred within 5.5 months. Switches to later LOTs occurred at quicker rates, with patients switching to a third LOT at 4.6 months and to 4th and 5th LOTs at 3.1 and 3.3 months, respectively. Of patients only treated with a targeted systemic LOT-1, over one third discontinued the drug within ∼5 months and did not switch to another targeted AD therapy. These patients may have switched to other non-targeted systemic treatments, topicals, or ceased any treatment. In addition to those who switched therapies, some patients who remained on their first LOT had evidence of persisting disease burden. For instance, over half of individuals who maintained their first targeted systemic LOT also used topical therapies. Those who persisted on dupilumab treatment despite continuing pruritus (641/6001, 11%) had 2.6x higher rates of post-index biopsy (5% vs 14%, p<.001) accompanied by increased rates of other cutaneous diagnoses such as mycosis fungoides, contact dermatitis, tinea, and seborrheic dermatitis compared to those who did not. This suggests an unclear diagnosis or multiple pruritic conditions in some patients who did not achieve a robust response to targeted treatment. Post-index pruritus was suggestive of a higher level of overall disease burden and comorbidities as observed by increased proportions of patients using topical corticosteroids (61% vs 50%, p<.001) and antianxiety medications (33% vs 20%, p<.001), or seeing emergency medicine (35% vs 25%, p<.001) and cardiovascular specialists (25.9% vs 17.2%, p<.001) post index. As new therapies with different mechanisms of action are approved, there will be more options for patients with incomplete response to first-line AD therapy. Conclusions Irrespective of the index treatment for AD, >50% of patients discontinued or switched therapies. Some patients who remained on index treatment, had indicators of inadequate disease control, suggesting a need for improvement over empirical selection of therapies to support more proactive management strategies in the context of the emerging treatment landscape for AD.

Chelidonine-induced inhibition of FBP1 disrupts M2 macrophage polarization and attenuates breast cancer.

Background: Celiac Disease (CD) is a common autoimmune disorder caused by the activation of CD4+ T cells that specifically target gluten and CD8+ T cells, further causing cell death inside the epithelial layer despite no available established biomarkers of CD diagnosis. Objective: This work aimed to compare scRNA-seq and transcriptome data to find novel gene biomarkers linked to T cells that might potentially be utilized for the diagnosis and assessment of CD. Methods: Collecting the scRNA and RNAseq datasets from the NCBI database, the Seurat package of R studio, and the statistical analysis tool GREIN server were employed to identify Differentially Expressed Genes (DEGs). Then, DAVID, FunRich, STRING, and NetworkAnalyst tools were utilized to explore significant pathways, key hub proteins, and gene regulators. Results: After integrating genes and conducting a comparative analysis, a total of 115 genes were identified as DEGs. Exosomes, MHC class II receptor activity, immune response, interferon gamma signaling, and bystander B cell activation within the immune system pathways were the significant Gene Ontology (GO) and metabolic pathways identified. Besides, eleven topological algorithms discovered two hub proteins, namely HLA-DRA and HLA-DRB1, from the PPI network. Through the analysis of the regulatory network, we have identified four crucial Transcription Factors (TFs), including YY1, FOXC1, GATA2, and USF2, and seven significant miRNAs (hsa-mir-129-2-3p, and hsa-mir-155-5p, etc.) in transcriptionally and post-transcriptionally regulated. Validation of hub proteins and transcription factors using Receiver Operating Characteristic (ROC) analysis indicates the acceptable value of the Area Under the Curve (AUC). Conclusion: This study utilized single-cell RNA sequencing and transcriptomics data analysis to define unique protein biomarkers associated with T cells throughout the progression of CD. Furthermore, wet lab studies will be needed to validate the potential hub proteins, TFs, and miRNAs as clinical biomarkers. conclusion: This study utilized single cell RNA sequencing and transcriptomics data analysis to define unique protein biomarkers associated with T cells throughout the progression of CD.

Mycosis fungoides (MF) is an indolent form of cutaneous T‐cell lymphoma. Its early lesions are important to be distinguished from atopic dermatitis (AD) because of their similar immune microenvironment. We have previously demonstrated that several chemokines are involved in the pathogenesis of advanced MF. Therefore, we sought to comprehensively analyze the changes in the immune environment during the advanced phase of MF by focusing on serum cytokines and chemokines and to identify potential biomarkers for the early detection of the transition to the advanced phase of MF. Sera from 11 cases of advanced‐stage MF, 16 cases of mild AD (median EASI score = 5.75), 16 cases of severe AD (median EASI score = 28.1), and 21 healthy volunteers were analyzed using the Bio‐Plex 40 multiplex immunoassay system. The results revealed significant increases in immunosuppressive macrophage‐related factors (IL‐4, MIF, CCL3) in MF patients compared to those with AD and healthy controls. In contrast, IL‐2, CCL1, CCL7, CCL21, CCL25, and CCL26 were significantly increased in severe AD patients compared to MF patients and healthy controls. Our findings suggest that several chemokines and cytokines contribute to an immunosuppressive environment favorable for tumor growth, distinguishing MF from AD. Moreover, T‐cell proliferation and migration factors, which are mainly involved in maintaining inflammation, are elevated in severe AD compared to MF. In addition to elucidating the differences in the pathogenesis of these diseases, these factors may be important in the differential diagnosis of early MF and AD. Further studies are warranted to confirm these findings.

Integrative analysis of bulk and single-cell RNA sequencing data reveals distinct subtypes of MAFLD based on N1-methyladenosine regulator expression

Heart failure (HF) is a complex clinical syndrome resulting from various cardiac diseases and a significant medical issue worldwide. Although the role of inflammation in HF pathogenesis is well-known, the specific cell types and regulatory molecules involved remain poorly understood. Here, we identified key cell types and novel biomarkers via an analysis of single-cell and bulk RNA sequencing data obtained from patients with two major HF types of ischemic cardiomyopathy and dilated cardiomyopathy. Myeloid cells were identified as the primary cell population involved in HF through cellular fraction and gene set enrichment analysis. Additionally, differential analysis of myeloid cells revealed crosstalk between cellular communication and cytokine-regulated immune responses in HF, with the MIF pathway emerging as a crucial immune regulatory pathway. The CD74/CXCR4 receptor complex in myeloid cell subgroup Mφ2 was significantly upregulated, potentially acting as a crucial regulator in HF. Upon receiving the MIF signal molecule, the CD74/CXCR4 receptor can activate NF-κB signaling to produce chemokines and thereby enhance the inflammatory response. CD74 and CXCR4 may serve as biomarkers and treatment targets for HF.

Mycosis fungoides bullosa: An unusual presentation of a rare entity

The aim of this work was to study Toll-like receptors (TLRs) 2, 4 and 9 expression patterns in parapsoriasis and in cutaneous T-cell lymphoma (CTCL): Mycosis fungoides (MF) and Sézary syndrome (SS) at different stages of the illness. The expression of TLRs was examined by immunohistochemistry on paraffin-embedded biopsies. Normal skin, atopic dermatitis and psoriasis, were used as controls. In cutaneous lesions of inflammatory diseases (atopic dermatitis, psoriasis) the expression of TLR2, TLR4 and TLR9 was low compared to normal skin. In parapsoriasis the expression of the three TLRs was similar to control. By contrast, in MF skin we observed a strong intensity of labelling with the three TLRs in the epidermis. Concerning SS, the expression of TLR2, TLR4 and TLR9 was intermediate between inflammatory lesions and MF. Thus, the development of skin lesions in MF appears associated with an increase of TLR2, TLR4 and TLR9 expression by keratinocytes in cutaneous lesions, which could play a role in the chronic activation of T lymphocytes in the skin.

Primary cutaneous lymphomas are extranodal non-Hodgkin lymphomas of T- or B- cell origin, that predominantly affect older patients but have been reported in all age groups and as early as in the first years of life. Diagnosis of cutaneous lymphomas is challenging and requires high clinical suspicion and close collaboration between dermatologists, pediatric oncologists and pathologists. Skin involvement of non-Hodgkin lymphomas in children or adolescents can either be primary cutaneous or secondary due to an underlying nodal lymphoma. The most common primary cutaneous lymphomas encountered in children are of T-cell origin, with mycosis fungoides being the most prevalent cutaneous T-cell lymphoma, followed by CD30+ lymphoproliferative disorders. While cutaneous lymphomas share clinicopathologic characteristics between juvenile and adult forms, there are important differences in terms of clinical presentation, diagnosis and treatment. The hypopigmented variant of mycosis fungoides seems to be overrepresented in the pediatric age group. Prognosis and treatment of mycosis fungoides are stage dependent. The majority of children present with early-stage disease and respond well to topical corticosteroids and phototherapy.

Dupilumab has revolutionized atopic dermatitis (AD) treatment, but concerns arise about its potential link to cutaneous T-cell lymphomas (CTCL). This review explores CTCL occurrence post-dupilumab therapy in AD and its potential therapeutic effects. A case study of a 76-year-old patient with severe AD treated with dupilumab, developing erythroderma revealing mycosis fungoides (MF), underscores the need to understand associated mechanisms and risk factors for safe dupilumab use. This case also highlights the utility of the high-frequency ultrasound in monitoring cutaneous manifestations in patients with MF.

BackgroundLung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A deep understanding of molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs.MethodsHere, we performed integrated analyses of genomic, transcriptomic, proteomic, metabolomic, and single-cell RNA sequencing data which were derived from a total number of 154 patients with paired and unpaired primary lung cancer and LC-BrM, spanning four published and two newly generated patient cohorts on both bulk and single cell levels.ResultsWe uncovered that LC-BrMs exhibited a significantly greater intra-tumor heterogeneity. We also observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TTN, TP53, MUC16, LRP1B, RYR2, and EGFR. In addition, the genome-wide landscape of somatic copy number alterations was similar between primary lung cancers and LC-BrM lesions. Nevertheless, several regions of focal amplification were significantly enriched in LC-BrMs, including 5p15.33 and 20q13.33. Intriguingly, integrated analyses of transcriptomic, proteomic, and metabolomic data revealed mitochondrial-specific metabolism was activated but tumor immune microenvironment was suppressed in LC-BrMs. Subsequently, we validated our results by conducting real-time quantitative reverse transcription PCR experiments, immunohistochemistry, and multiplexed immunofluorescence staining of patients’ paired tumor specimens. Therapeutically, targeting oxidative phosphorylation with gamitrinib in patient-derived organoids of LC-BrMs induced apoptosis and inhibited cell proliferation. The combination of gamitrinib plus anti-PD-1 immunotherapy significantly improved survival of mice bearing LC-BrMs. Patients with a higher expression of mitochondrial metabolism genes but a lower expression of immune genes in their LC-BrM lesions tended to have a worse survival outcome.ConclusionsIn conclusion, our findings not only provide comprehensive and integrated perspectives of molecular underpinnings of LC-BrMs but also contribute to the development of a potential, rationale-based combinatorial therapeutic strategy with the goal of translating it into clinical trials for patients with LC-BrMs.

Skin is composed of diverse cell populations that cooperatively maintain homeostasis. Up-regulation of the nuclear factor κB (NF-κB) pathway may lead to the development of chronic inflammatory disorders of the skin, but its role during the early events remains unclear. Through analysis of single-cell RNA sequencing data via iterative random forest leave one out prediction, an explainable artificial intelligence method, we identified an immunoregulatory role for a unique paired related homeobox-1 (Prx1)+ fibroblast subpopulation. Disruption of Ikkb-NF-κB under homeostatic conditions in these fibroblasts paradoxically induced skin inflammation due to the overexpression of C-C motif chemokine ligand 11 (CCL11; or eotaxin-1) characterized by eosinophil infiltration and a subsequent TH2 immune response. Because the inflammatory phenotype resembled that seen in human atopic dermatitis (AD), we examined human AD skin samples and found that human AD fibroblasts also overexpressed CCL11 and that perturbation of Ikkb-NF-κB in primary human dermal fibroblasts up-regulated CCL11. Monoclonal antibody treatment against CCL11 was effective in reducing the eosinophilia and TH2 inflammation in a mouse model. Together, the murine model and human AD specimens point to dysregulated Prx1+ fibroblasts as a previously unrecognized etiologic factor that may contribute to the pathogenesis of AD and suggest that targeting CCL11 may be a way to treat AD-like skin lesions.