Summary
Background
The malignant mechanisms that control the development of cutaneous T‐cell lymphoma (CTCL) are beginning to be identified. Recent evidence suggests that disturbances in specific ...intracellular signalling pathways, such as RAS–mitogen‐activated protein kinase, T‐cell receptor (TCR)–phospholipase C gamma 1 (PLCG1)–nuclear factor of activated T cells (NFAT) and Janus kinase (JAK)–signal transducer and activator of transcription (STAT), may play an essential role in the pathogenesis of CTCL.
Objectives
To investigate the mechanisms controlling disease development and progression in mycosis fungoides (MF), the most common form of CTCL.
Methods
We collected 100 samples that were submitted for diagnosis of, or a second opinion regarding, MF between 2001 and 2018, 80% of which were in the early clinical stages of the disease. Formalin‐fixed paraffin‐embedded tissues were used for histological review and to measure the expression by immunohistochemistry of surrogate markers of activation of the TCR–PLCG1–NFAT, JAK–STAT and NF‐κB pathways. Folliculotropism and large‐cell transformation were also examined.
Results
NFAT and nuclear factor kappa B (NF‐κB) markers showed a comparable activation status in early and advanced stages, while STAT3 activation was more frequent in advanced stages and was associated with large‐cell transformation. Consistently with this observation, STAT3 activation occurred in parallel with MF progression in two initially MF‐negative cases. A significant association of NFAT with NF‐κB markers was also found, reflecting a common mechanism of activation in the two pathways. Genomic studies identified nine mutations in seven genes known to play a potential role in tumorigenesis in T‐cell leukaemia/lymphoma, including PLCG1, JAK3 and STAT3, which underlies the activation of these key cell‐survival pathways. A higher mutational allele frequency was detected in advanced stages.
Conclusions
Our results show that STAT3 is activated in advanced cases and is associated with large‐cell transformation, while the activation of NFAT and NF‐κB is maintained throughout the disease. These findings could have important diagnostic and therapeutic implications.
What's already known about this topic?
Mycosis fungoides is characterized by a clonal expansion of T cells in the skin.
The mechanisms controlling disease development and progression are not fully understood.
What does this study add?
An association of the nuclear factor of activated T cells and nuclear factor kappa B pathways was found, which could reflect a common mechanism of activation. These pathways were activated in early and advanced stages at the same level.
Signal transducer and activator of transcription 3 activation was associated with large‐cell transformation and was more frequent in advanced stages.
A genomic analysis of cutaneous T‐cell lymphoma‐associated genes was performed. Nine mutations were detected.
What is the translational message?
These results could have important implications for the treatment of MF in the near future.
Linked Comment: Ødum. Br J Dermatol 2020; 182:16–17.
Introduction
Molecular testing of Inherited bleeding coagulation disorders (IBCDs) not only offers confirmation of diagnosis but also aids in genetic counselling, prenatal diagnosis and in certain ...cases genotype–phenotype correlations are important for predicting the clinical course of the disease and to allow tailor‐made follow‐up of individuals. Until recently, genotyping has been mainly performed by Sanger sequencing, a technique known to be time consuming and expensive. Currently, next‐generation sequencing (NGS) offers a new potential approach that enables the simultaneous investigation of multiple genes at manageable cost.
Aim
The aim of this study was to design and to analyse the applicability of a 23‐gene NGS panel in the molecular diagnosis of patients with IBCDs.
Methods
A custom target enrichment library was designed to capture 31 genes known to be associated with IBCDs. Probes were generated for 296 targets to cover 86.3 kb regions (all exons and flanking regions) of these genes. Twenty patients with an IBCDs phenotype were studied using NGS technology.
Results
In all patients, our NGS approach detected causative mutations. Twenty‐one pathogenic variants were found; while most of them were missense (18), three deletions were also identified. Six novel mutations affecting F8, FGA, F11, F10 and VWF genes, and 15 previously reported variants were detected. NGS and Sanger sequencing were 100% concordant.
Conclusion
Our results demonstrate that this approach could be an accurate, reproducible and reliable tool in the rapid genetic diagnosis of IBCDs.
Summary
Background
Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline ...phosphatase ALP and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long‐term effectiveness of second‐line treatments remains uncertain.
Aims
To evaluate the long‐term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation).
Methods
We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non‐responsive PBC patients (Paris‐II criteria) from Spain and Portugal who received OCA ± fibrates.
Results
Of 255 patients, median follow‐up was 35.1 months (IQR: 20.2–53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE‐PBC and 5‐year UK‐PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension.
Conclusion
Triple therapy was superior in achieving therapeutic goals in UDCA‐nonresponsive PBC. Decompensation was linked to pre‐existing portal hypertension.
Longitudinal, real‐world study on 255 UDCA‐nonresponsive PBC patients (Per Paris II criteria); median follow‐up of 35.1 months (IQR: 20–53). All patients received obeticholic acid (OCA), with 25% receiving later add‐on fibrate treatment (triple therapy). In multivariate analysis, triple therapy outperformed dual therapy across all surrogate biochemical endpoints of outcomes.
Highlights • We report real-world data from 464 patients treated with perampanel over 1 year. • Efficacy and tolerability of perampanel were comparable with clinical trial data. • Patients ≥65 years, ...vascular aetiology or fewer prior AEDs had a superior response. • Patients with psychiatric comorbidities (hyperactivity and personality disorder) were more likely to experience psychiatric AEs. • Patients with slower titration schedules were less likely to experience an AE
The microscopic environment inside a metazoan organism is highly crowded. Whether individual cells can tailor their behavior to the limited space remains unclear. In this study, we found that cells ...measure the degree of spatial confinement by using their largest and stiffest organelle, the nucleus. Cell confinement below a resting nucleus size deforms the nucleus, which expands and stretches its envelope. This activates signaling to the actomyosin cortex via nuclear envelope stretch-sensitive proteins, up-regulating cell contractility. We established that the tailored contractile response constitutes a nuclear ruler-based signaling pathway involved in migratory cell behaviors. Cells rely on the nuclear ruler to modulate the motive force that enables their passage through restrictive pores in complex three-dimensional environments, a process relevant to cancer cell invasion, immune responses, and embryonic development.
Extreme drought events have negative effects on forest diversity and functioning. At the species level, however, these effects are still unclear, as species vary in their response to drought through ...specific functional trait combinations. We used long‐term demographic records of 21,821 trees and extensive databases of traits to understand the responses of 338 tropical dry forests tree species to ENSO2015, the driest event in decades in Northern South America. Functional differences between species were related to the hydraulic safety‐efficiency trade‐off, but unexpectedly, dominant species were characterised by high investment in leaf and wood tissues regardless of their leaf phenological habit. Despite broad functional trait combinations, tree mortality was more widespread in the functional space than tree growth, where less adapted species showed more negative net biomass balances. Our results suggest that if dry conditions increase in this ecosystem, ecological functionality and biomass gain would be reduced.
Extreme drought events have negative effects on forest diversity and functioning. We used long‐term demographic records of 21,821 trees and extensive databases of traits to understand the responses of 338 tropical dry forests tree species to an extreme. Our results indicate that irrespective of the drought adaptations, most trees will be negatively affected under drier scenarios predicted for tropical dry forests.
Toll-like receptors (TLRs) have garnered an extraordinary amount of interest in cancer research due to their role in tumor progression. By activating the production of several biological factors, ...TLRs induce type I interferons and other cytokines, which drive an inflammatory response and activate the adaptive immune system. The aim of this study was to investigate the expression and clinical relevance of TLR3, 4 and 9 in breast cancer.
The expression levels of TLR3, TLR4 and TLR9 were analyzed on tumors from 74 patients with breast cancer. The analysis was performed by immunohistochemistry.
Samples of carcinomas with recurrence exhibited a significant increase in the mRNA levels of TLR3, TLR4 and TLR9. Tumors showed high expression of TLRs expression levels by cancer cells, especially TLR4 and 9. Nevertheless, a significant percentage of tumors also showed TLR4 expression by mononuclear inflammatory cells (21.6%) and TLR9 expression by fibroblast-like cells (57.5%). Tumors with high TLR3 expression by tumor cell or with high TLR4 expression by mononuclear inflammatory cells were significantly associated with higher probability of metastasis. However, tumours with high TLR9 expression by fibroblast-like cells were associated with low probability of metastasis.
The expression levels of TLR3, TLR4 and TLR9 have clinical interest as indicators of tumor aggressiveness in breast cancer. TLRs may represent therapeutic targets in breast cancer.
The extragalactic background light (EBL) is of fundamental importance both for understanding the entire process of galaxy evolution and for γ-ray astronomy, but the overall spectrum of the EBL ...between 0.1 and 1000 μm has never been determined directly from galaxy spectral energy distribution (SED) observations over a wide redshift range. The evolving, overall spectrum of the EBL is derived here utilizing a novel method based on observations only. This is achieved from the observed evolution of the rest-frame K-band galaxy luminosity function up to redshift 4, combined with a determination of galaxy-SED-type fractions. These are based on fitting Spitzer Wide-Area Infrared Extragalactic Survey (SWIRE) templates to a multiwavelength sample of about 6000 galaxies in the redshift range from 0.2 to 1 from the All-wavelength Extended Groth Strip International Survey (AEGIS). The changing fractions of quiescent galaxies, star-forming galaxies, starburst galaxies and active galactic nucleus (AGN) galaxies in that redshift range are estimated, and two alternative extrapolations of SED types to higher redshifts are considered. This allows calculation of the evolution of the luminosity densities from the ultraviolet (UV) to the infrared (IR), the evolving star formation rate density of the Universe, the evolving contribution to the bolometric EBL from the different galaxy populations including AGN galaxies and the buildup of the EBL. Our EBL calculations are compared with those from a semi-analytic model, another observationally based model and observational data. The EBL uncertainties in our modelling based directly on the data are quantified, and their consequences for attenuation of very-high-energy γ-rays due to pair production on the EBL are discussed. It is concluded that the EBL is well constrained from the UV to the mid-IR, but independent efforts from IR and γ-ray astronomy are needed in order to reduce the uncertainties in the far-IR.
Summary
The aetiopathogenesis of hidradenitis suppurativa (HS) is not fully understood; however, increasing evidence suggests that it may be an immune‐mediated disorder. Autoimmune thyroid disease ...(AITD) has classically been considered as the ‘paradigm’ of autoimmunity, and it has been linked to a variety of skin disorders. To our knowledge, the prevalence of AITD has not been investigated in patients with HS. The aim of the present study was to assess and compare, for the first time, the prevalence of thyroid autoimmunity in 70 patients with HS and in 70 age‐ and sex‐matched controls. In all participants, thyroid autoantibodies and thyroid function tests were analysed. No statistically significant difference was detected between patients with HS and controls, either for the prevalence of thyroid antibodies or for thyroid function parameters. This lack of an association between HS and thyroid autoimmunity suggests that conventional autoimmune mechanisms may not be implicated in the pathogenesis of HS.
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