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.
Insulin resistance in hidradenitis suppurativa: a case–control study Vilanova, I.; Hernández, J.L.; Mata, C. ...
JEADV. Journal of the European Academy of Dermatology and Venereology/Journal of the European Academy of Dermatology and Venereology,
20/May , Letnik:
32, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Background
The association between chronic inflammatory diseases, such as rheumatoid arthritis and psoriasis, and insulin resistance (IR) has been well established. Hidradenitis suppurativa (HS) is a ...chronic inflammatory cutaneous disease that affects the apocrine gland‐bearing areas of the body.
Objective
We aimed to determine the prevalence of IR in patients with HS.
Methods
This cross‐sectional, case–control study enrolled 137 subjects, 76 patients with HS and 61 age‐ and gender‐matched controls. Demographic data, clinical examination of HS patients, anthropometric measures, cardiovascular risk factors and laboratory studies were recorded. The homeostasis model assessment of IR (HOMA‐IR) was calculated in all participants by measuring fasting plasma glucose and insulin levels.
Results
The median (IQR) HOMA‐IR value in HS patients was significantly higher 2.0 (1.0–3.6) than in controls 1.5 (0.9–2.3) (P = 0.01). The prevalence of IR was significantly higher in cases (43.4%) compared with controls (16.4%) (P = 0.001). In the linear regression multivariable analysis after adjusting for age, sex and body mass index (BMI), HS remained as a significant factor for a higher HOMA‐IR 2.51 (0.18) vs 1.92(0.21); P = 0.04. The HOMA‐IR value and the prevalence of IR did not differ significantly among HS patients grouped by severity of the disease.
Conclusion
Our results show an increased frequency of IR in HS. Thus, we suggest HS patients to be evaluated for IR and managed accordingly.
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.
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.
Ecological Genomics of Marine Roseobacters MORAN, M. A; BELAS, R; HOWARD, E. C ...
Applied and Environmental Microbiology,
07/2007, Letnik:
73, Številka:
14
Journal Article
There is substantial inter-individual diversity in the susceptibility of alcoholics to liver injury. Alterations of intestinal microbiota (IM) have been reported in alcoholic liver disease (ALD), but ...the extent to which they are merely a consequence or a cause is unknown. We aimed to demonstrate that a specific dysbiosis contributes to the development of alcoholic hepatitis (AH).
We humanised germ-free and conventional mice using human IM transplant from alcoholic patients with or without AH. The consequences on alcohol-fed recipient mice were studied.
A specific dysbiosis was associated with ALD severity in patients. Mice harbouring the IM from a patient with severe AH (sAH) developed more severe liver inflammation with an increased number of liver T lymphocyte subsets and Natural Killer T (NKT) lymphocytes, higher liver necrosis, greater intestinal permeability and higher translocation of bacteria than mice harbouring the IM from an alcoholic patient without AH (noAH). Similarly, CD45+ lymphocyte subsets were increased in visceral adipose tissue, and CD4(+)T and NKT lymphocytes in mesenteric lymph nodes. The IM associated with sAH and noAH could be distinguished by differences in bacterial abundance and composition. Key deleterious species were associated with sAH while the Faecalibacterium genus was associated with noAH. Ursodeoxycholic acid was more abundant in faeces from noAH mice. Additionally, in conventional mice humanised with the IM from an sAH patient, a second subsequent transfer of IM from an noAH patient improved alcohol-induced liver lesions.
Individual susceptibility to ALD is substantially driven by IM. It may, therefore, be possible to prevent and manage ALD by IM manipulation.
Summary
Background
Frontal fibrosing alopecia (FFA) is a chronic cicatricial alopecia with an increasing incidence and unknown aetiology.
Aim
To identify possible environmental and hormonal factors ...related to FFA.
Methods
We conducted a multicentre case–control study paired by sex and age, and recruited 664 women (335 cases and 329 controls) and 106 men (20 cases and 86 controls). Study subjects completed an exhaustive questionnaire enquiring about pharmacological, environmental, hormonal, social, job exposure, lifestyle, drugs and diet factors to which they were exposed at least 5 years prior to the onset of the disease.
Results
For women, there was a statistical association between alopecia and history of pregnancy (OR = 1.6; 95% CI 1.06–2.41), use of facial sunscreen (OR = 1.6; 95% CI 1.06–2.41) and hormone replacement therapy (HRT) (OR = 1.76; 95% CI 1.11–2.8) or raloxifene (no controls exposed therefore OR was not calculated), exposure to alkylphenolic compounds (OR = 1.48; 95% CI 1.05–2.08), and presence of rosacea (OR = 1.91; 95% CI 1.07–3.39), lichen planus pigmentosus (LPP) (OR = 5.14; 95% CI 1.11–23.6) or hypothyroidism (OR = 1.73; 95% CI 1.11–2.69). For men, there was a statistical association between alopecia and use of facial sunscreens (OR = 11.6; 95% CI 1.7–80.9) or antiageing creams (OR = 1.84; 95% CI 1.04–3.23).
Conclusions
FFA seems to be associated with hormonal exposure (pregnancy, HRT and raloxifene), comorbidities (hypothyroidism, LPP and rosacea) and environmental factors (facial sunscreens, antiageing creams and occupational exposure). Further research is required to analyse the exact mechanism in which these environmental factors participate in the development of this alopecia.
Bone Regeneration represents a clinical need, related to bone defects such as congenital anomalies, trauma with bone loss, and/or some pathologies such as cysts or tumors This is why a polymeric ...biomaterial that mimics the osteogenic composition and structure represents a high potential to face this problem. The method of obtaining these materials was first to prepare a stabilized hydrogel by means of physical bonds and then to make use of the lyophilization technique to obtain the 3D porous scaffolds with temperature conditions of −58 °C and pressure of 1 Pa for 16 h. The physicochemical and bioactive properties of the scaffolds were studied. FTIR and TGA results confirm the presence of the initial components in the 3d matrix of the scaffold. The scaffolds exhibited a morphology with pore size and interconnectivity that promote good cell viability. Together, the cell viability and proliferation test, Alamar Blue
TM
and the differentiation test: alizarin staining, showed the ability of physically stabilized scaffolds to proliferate and differentiate swine dental pulp stem cell (DPSCs) followed by mineralization. Therefore, the Cs-PCL-PVA-HA scaffold stabilized by physical bonds has characteristics that suggest great utility for future complementary in vitro tests and in vivo studies on bone defects. Likewise, this biomaterial was enhanced with the addition of HA, providing a scaffold with osteoconductive properties necessary for good regeneration of bone tissue.
Graphical abstract
Poor adhesion is a recurrent problem for the wider use of diamond-like carbon (DLC) coatings in industrial applications. In this work, we investigate the effectiveness of high-power impulse magnetron ...sputtering (HiPIMS) metal ion etching to improve the adhesion of DLC coatings on high speed steel substrates. The influence of HiPIMS pretreatment parameters, the metal ion selection for the process and the addition of bonding layers on the adhesion properties were studied. Daimler-Benz and nanoscratch test methods were used to evaluate the adhesion. The elemental composition, morphology and microstructure of the samples were evaluated by EELS, SEM, AFM and HRTEM. In general, samples pretreated with HiPIMS metal ion etching withstand larger critical loads than those pretreated by conventional Ar+ glow discharge and bonding layers. The pretreatment is proven to be very effective at removing surface contaminants and providing a gradual interface. The selection of Cr over Ti contributes to a significant improvement on the adhesion due to the reduction of the oxygen level at the interface thus ensuring an optimal coating-substrate contact and a more compliant structure, which prevents the delamination failure.
•HiPIMS pretreatment method for enhanced DLC adhesion on steel substrates is proposed.•HiPIMS metal ion etching process parameters are optimized for Cr and Ti.•Improved adhesion relates to substrate oxides removal and a gradual interface.•Superior DLC adhesion with Cr due to lower O2 gettering and more compliant interface
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