Background: Although multiple studies have assessed molecular changes in chronic atopic dermatitis (AD) lesions, little is known about the transition from acute to chronic disease stages, and the factors and mechanisms that shape chronic inflammatory activity. Objectives: We sought to assess the global transcriptome changes that characterize the progression from acute to chronic stages of AD. Methods: We analyzed transcriptome changes in paired nonlesional skin, acute and chronic AD lesions from 11 patients and 38 healthy controls by RNA-sequencing, and conducted in vivo and histological assays to evaluate findings. Results: Our data demonstrate that approximately 74% of the genes dysregulated in acute lesions remain or are further dysregulated in chronic lesions, whereas only 34% of the genes dysregulated in chronic lesions are altered already in the acute stage. Nonlesional AD skin exhibited enrichment of TNF, T H 1, T H 2, and T H 17 response genes. Acute lesions showed marked dendritic-cell signatures and a prominent enrichment of T H 1, T H 2, and T H 17 responses, along with increased IL-36 and thymic stromal lymphopoietin expression, which were further heightened in chronic lesions. In addition, genes involved in skin barrier repair, keratinocyte proliferation, wound healing, and negative regulation of T-cell activation showed a significant dysregulation in the chronic versus acute comparison. Furthermore, our data show progressive changes in vasculature and maturation of dendritic-cell subsets with chronicity, with FOXK1 acting as immune regulator. Conclusions: Our results show that the changes accompanying the transition from nonlesional to acute to chronic inflammation in AD are quantitative rather than qualitative, with chronic AD having heightened T H 2, T H 1, T H 17, and IL36 responses and skin barrier repair mechanisms. These findings provide novel insights and highlight underappreciated pathways in AD pathogenesis that may be amenable to therapeutic targeting. (J

MicroRNAs have emerged as critical modulators of immune responses, but little is known about their transcriptional regulation and tissue specificity. MicroRNA-142 is specifically expressed in hematopoietic tissues and it plays an important role in regulating immunity. Herein we identified the key transcriptional elements for regulation of miR-142 and its impact on TLR-4 mediated expression of IL-6. The PU-1, C/EBPβ and Runx1 transcription factor (TF) binding sites are conserved and constitutively occupied by the respective transcription factors in the miR-142 gene promoter only in the hematopoietic cells. Specific knock-down experiments in hematopoietic cells and rescue experiments in non-hematopoietic cells show that PU-1 is critical for miR-142 gene expression and that it synergizes with Runx1, C/EBPβ and CBFβ. Furthermore TLR4 stimulation enhanced miR-155 while experiments with knock-down and mimic expression of miR-155 demonstrated that miR-155 negatively regulates miR-142-3p expression by targeting PU-1. Thus TLR4 stimulation represses PU-1 resulting in resulting in down-regulation of miR-142 and increased expression of IL-6. These results collectively reveal the direct cis acting sequences of miR-142 specific promoter and that transcription factor PU-1 is necessary for its exclusive expression in hematopoietic cells and regulation of IL-6.

Cutaneous T cell lymphoma (CTCL) represents a heterogeneous group of non-Hodgkin lymphoma distinguished by the presence of clonal malignant T cells. The heterogeneity of malignant T cells and the complex tumor microenvironment remain poorly characterized. With single-cell RNA analysis and bulk whole-exome sequencing on 19 skin lesions from 15 CTCL patients, we decipher the intra-tumor and inter-lesion diversity of CTCL patients and propose a multi-step tumor evolution model. We further establish a subtyping scheme based on the molecular features of malignant T cells and their pro-tumorigenic microenvironments: the TCyEM group, demonstrating a cytotoxic effector memory T cell phenotype, shows more M2 macrophages infiltration, while the TCM group, featured by a central memory T cell phenotype and adverse patient outcome, is infiltrated by highly exhausted CD8+ reactive T cells, B cells and Tregs with suppressive activities. Our results establish a solid basis for understanding the nature of CTCL and pave the way for future precision medicine for CTCL patients.

No abstract

Typhoon Nuri (2008) was 1 of approximately 120 typhoons in the past 60 years that passed through a narrow gap, the Luzon Strait, connecting the western North Pacific and the South China Sea (SCS). In total 70% of these storms, including Nuri, reached their maximum intensities over the warm waters east of Luzon and in the Kuroshio, then rapidly weakened in the SCS. Numerical experiments were conducted to understand the intensity change of Nuri. Westward across the Kuroshio in the Luzon Strait, the 26°C isotherm shallows rapidly by half. This and stronger mixing by wind–ocean resonance preferentially cooled sea surface temperature and weakened the typhoon in SCS. A positive-feedback mechanism is then described to explain the intensification of Nuri over the western North Pacific.

Primary cutaneous anaplastic T-cell lymphoma, characterized by the CD30þ anaplastic large T cells, comprises the second most common group of cutaneous T-cell lymphoma. Little is known about the mechanisms of disease progression. Here we report that enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 that mediates histone H3 lysine 27 trimethylation, is overexpressed in CD30þ anaplastic cells in primary cutaneous anaplastic T-cell lymphoma and large-cell transformed cutaneous T-cell lymphoma. Silencing EZH2 or inhibiting its histone methyltransferase activity conferred increased apoptosis and G1 cell-cycle arrest in primary cutaneous anaplastic T-cell lymphoma cells in vitro and a xenograft model in vivo. This was mediated by the de-repression of thioredoxin-interacting protein, a major redox control molecule, and consequent formation of reactive oxygen species. Silencing thioredoxin-interacting protein abrogated reactive oxygen species accumulation in EZH2 suppressed cells and rescued cell growth disadvantage. Moreover, EZH2 suppression de-repressed C-X-C motif chemokine ligand 10 and facilitated the recruitment of effector CD4þ and CD8þ T cells into the tumor microenvironment via a C-X-C motif chemokine ligand 10/receptor 3 interaction. These results demonstrate a dual role for polycomb repressive complex 2-mediated epigenetic silencing in tumor progression and antitumor immunity in primary cutaneous anaplastic T-cell lymphoma, and provide a rationale for the pharmacologic inhibition of EZH2 activity in large-cell transformed cutaneous T-cell lymphoma.

Interdecadal variability of tropical cyclone (TC) genesis in the South China Sea (SCS) during 1982–2015 is investigated using observations and atmospheric reanalysis data. TC genesis primarily occurs in the northern SCS (north of 13 °N) in July–September (summer), while in the southern SCS (south of 13 °N) in October–December (autumn). The TC genesis location is consistent with the climatological distribution of TC genesis potential index. Noticeably, the TC genesis frequency (TCGF) is relatively low in 1982–1993 and 2003–2015 while relatively high in 1994–2002 in summer in the SCS. In autumn, the TCGF shows an abrupt transition from high to low in the early 2000s in the SCS. It is found that such interdecadal change of TCGF is closely related to the east‐westward movement of the subtropical high (SH). When the SH is close to the SCS, large‐scale air subsidence, low‐level divergence, negative vorticity, and high pressure are prominent and inhabit TC genesis in the SCS. On the contrary, when the SH moves away from the SCS, environmental conditions become more favorable for TC genesis. In addition, the localized atmospheric intraseasonal variability can affect TCGF at interdecadal time scales as well.

Cutaneous CD30 lymphoproliferative disorders (LPDs), including lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma, comprise the second most common group of cutaneous T-cell lymphomas. Previously, we reported that special SATB1, a thymocyte-specific chromatin organizer, was overexpressed and promoted malignant T-cell proliferation in a portion of CD30 LPDs. Here, we investigated the expression pattern of SATB1 in CD30 LPDs with a large cohort of patient samples, and examined the potential of SATB1 as a molecular marker to classify CD30 LPDs with differential clinicopathological behaviors. SATB1 expression was identified in the CD30 anaplastic T cells in 11 of 12 (91.7%) lymphomatoid papulosis and 16 of 42 (38.1%) primary cutaneous anaplastic large-cell lymphoma cases. SATB1 cases showed T-helper 17 polarization, together with more prominent epidermal hyperplasia and granulocytic infiltration. SATB1 lesions responded better to combined treatment of methotrexate and interferon. SATB1 activated the expression of T-helper 17 cytokines while repressing T-helper 1-related genes. The heterogeneity in SATB1 expression across CD30 LPDs was associated with the extent of promoter DNA methylation. Hence, SATB1 expression defines a subtype of CD30 LPDs with characteristic pathobiology and prognosis. These data provide valuable insights into the heterogeneity of cutaneous T-cell malignancies, which may lead to individualized therapy in the future.