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.
Background
The clinical and pathological features of primary melanoma are not sufficiently sensitive to accurately predict which patients are at a greater risk of relapse. Recently, a 31‐gene ...expression profile (DecisionDx‐Melanoma) test has shown promising results.
Objectives
To evaluate the early prognostic performance of a genetic signature in a multicentre prospectively evaluated cohort.
Methods
Inclusion of patients with AJCC stages IB and II conducted between April 2015 and December 2016. All patients were followed up prospectively to assess their risk of relapse. Prognostic performance of this test was evaluated individually and later combined with the AJCC staging system. Prognostic accuracy of disease‐free survival was determined using Kaplan–Meier curves and Cox regression analysis. Results of the gene expression profile test were designated as Class 1 (low risk) and Class 2 (high risk).
Results
Median follow‐up time was 26 months (IQR 22–30). The gene expression profile test was performed with 86 patients; seven had developed metastasis (8.1%) and all of them were in the Class 2 group, representing 21.2% of this group. Gene expression profile was an independent prognostic factor for relapse as indicated by multivariate Cox regression analysis, adjusted for AJCC stages and age.
Conclusions
This prospective multicentre cohort study, performed in a Spanish Caucasian cohort, shows that this 31‐gene expression profile test could correctly identify patients at early AJCC stages who are at greater risk of relapse. We believe that gene expression profile in combination with the AJCC staging system could well improve the detection of patients who need intensive surveillance and optimize follow‐up strategies.
Stimulation of the dorsolateral periaqueductal grey matter (dlPAG) in rats evokes an active defensive behaviour together with a cardiorespiratory response characterised by tachypnoea, tachycardia and ...hypertension. The dlPAG neurons involved in these responses are excitatory, presumably glutamatergic, due to the presence of vesicular glutamate transporter VGLUT2 within their axon terminals. Previously, our group described a functional interaction between dlPAG and the pontine A5 region. Accordingly, in the present work, in order to characterize the role of glutamate within this interaction, experiments were carried out in spontaneously breathing anaesthetized rats (sodium pentobarbitone 60 mg/kg i.p., suplemented with 20 mg/kg i.p.). The cardiorespiratory response evoked by electrical stimulation of the dlPAG (1 ms pulses, 20–50 μA, given at 100 Hz, during 5 s) was analysed before and after the microinjection, within the A5 region, of either kynurenic acid (non-specific glutamate receptor antagonist; 5–10 nmol), DAP-5 (NMDA antagonist; 1 pmol), CNQX (non-NMDA antagonist; 1 pmol) or MCPG (metabotropic antagonist; 0,1 nmol). Kynurenic acid decreased the intensity of both the tachypnoea (
p
< 0,001) and tachycardia (
p
< 0,001) induced by dl-PAG stimulation. Blockade of no-NMDA receptors reduced the increase of respiratory frequency, heart rate and pressor response to dl-PAG stimulation (
p
< 0,01,
p
< 0,001,
p
< 0,05 respectively). Blockade of either NMDA or metabotropic receptors reduced the dlPAG-evoked tachycardia and pressor response (
p
< 0,01;
p
< 0,05 respectively). These results suggest a neuromodulatory role for A5 region via glutamate neurotransmission of the dlPAG-evoked cardiorespiratory response, confirming the role of the ventrolateral pons in the neuronal circuits involved in respiratory and heart rate control.
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.
This paper analyzes how the regulative, normative, and cultural dimensions of institutions exert pressure both on companies' decisions to voluntarily disclose environmental information and on the ...quality of the information disclosed. Prior research has focused on the influence of economic, disclosure, and generic institutional determinants, although little attention has been paid to the analysis of the influence exerted by climate change‐related institutional pillars. The results show that the three institutional pillars have different effects as regards both the decision to respond and the quality of disclosure. The regulative pillar positively influences the response decision but does not influence disclosure quality. The normative pillar positively affects both the propensity of companies to disclose and the quality of the information reported. Meanwhile, the cultural pillar positively influences disclosure quality, but it has no effect on firms' decisions to disclose environmental information. This paper is the first to analyze whether the institutional profile of climate change in different countries influences voluntary environmental disclosures.
The origin of the unification model for active galactic nuclei (AGN) was the detection of broad hydrogen recombination lines in the optical polarized spectrum of the Seyfert 2 galaxy (Sy2) NGC 1068. ...Since then, a search for the hidden broad-line region (HBLR) of nearby Sy2s started, but polarized broad lines have only been detected in ∼30–40 per cent of the nearby Sy2s observed to date. Here we present new VLT/FORS2 optical spectropolarimetry of a sample of 15 Sy2s, including Compton-thin and Compton-thick sources. The sample includes six galaxies without previously published spectropolarimetry, some of them normally treated as non-hidden BLR (NHBLR) objects in the literature, four classified as NHBLR, and five as HBLR based on previous data. We report ≥4σ detections of a HBLR in 11 of these galaxies (73 per cent of the sample) and a tentative detection in NGC 5793, which is Compton-thick according to the analysis of X-ray data performed here. Our results confirm that at least some NHBLRs are misclassified, bringing previous publications reporting differences between HBLR and NHBLR objects into question. We detect broad Hα and Hβ components in polarized light for 10 targets, and just broad Hα for NGC 5793 and NGC 6300, with line widths ranging between 2100 and 9600 km s−1. High bolometric luminosities and low column densities are associated with higher polarization degrees, but not necessarily with the detection of the scattered broad components.
The expansion on the use of Electric Vehicles demands new mechanisms to ease the charging process, making it autonomous and with a reduced user intervention. This paper reviews the technologies ...applied to the wireless charge of Electric Vehicles. In particular, it focuses on the technologies based on the induction principle, the capacitive-based techniques, those that use radiofrequency waves and the laser powering. As described, the convenience of each technique depends on the requirements imposed on the wireless power transfer. Specifically, we can state that the power level, the distance between the power source and the electric vehicle or whether the transfer is executed with the vehicle on the move or not or the cost are critical parameters that need to be taken into account to decide which technology to use. In addition, each technique requires some complementary electronics. This paper reviews the main components that are incorporated into these systems and it provides a review of their most relevant configurations.
One of the main issues in the medical field and clinical practice is the development of novel and effective treatments against infections caused by antibiotic-resistant bacteria. One avenue that has ...been approached to develop effective antimicrobials is the use of silver nanoparticles (Ag-NPs), since they have been found to exhibit an efficient and wide spectrum of antimicrobial properties. Among the main drawbacks of using Ag-NPs are their potential cytotoxicity against eukaryotic cells and the latent environmental toxicity of their synthesis methods. Therefore, diverse green synthesis methods, which involve the use of environmentally friendly plant extracts as reductive and capping agents, have become attractive to synthesize Ag-NPs that exhibit antimicrobial effects against resistant bacteria at concentrations below toxicity thresholds for eukaryotic cells.
In this study, we report a green one-pot synthesis method that uses
extract as a reducing and capping agent, to produce Ag-NPs with applications as therapeutic agents to treat infections in vivo.
The Ag-NPs were characterized using transmission electron microscopy (TEM), high-resolution TEM, selected area electron diffraction, energy-dispersive spectroscopy, ultraviolet-visible, and Fourier transform infrared.
We show that Ag-NPs are spherical with a narrow size distribution. The Ag-NPs show antimicrobial activities in vitro against Gram-negative (
,
, and a clinical multidrug-resistant strain of
) and Gram-positive (
) bacteria. Moreover, antimicrobial effects of the Ag-NPs, against a resistant
clinical strain, were tested in a murine skin infection model. The results demonstrate that the Ag-NPs reported in this work are capable of eradicating pathogenic resistant bacteria in an infection in vivo. In addition, skin, liver, and kidney damage profiles were monitored in the murine infection model, and the results demonstrate that Ag-NPs can be used safely as therapeutic agents in animal models.
Together, these results suggest the potential use of Ag-NPs, synthesized by green chemistry methods, as therapeutic agents against infections caused by resistant and nonresistant strains.
Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics and are unaffected by clinically available β-lactamase inhibitors (βLIs). Active-site architecture divides MBLs into three ...classes (B1, B2, and B3), complicating development of βLIs effective against all enzymes. Bisthiazolidines (BTZs) are carboxylate-containing, bicyclic compounds, considered as penicillin analogs with an additional free thiol. Here, we show both L- and D-BTZ enantiomers are micromolar competitive βLIs of all MBL classes in vitro, with K
is of 6–15 μM or 36–84 μM for subclass B1 MBLs (IMP-1 and BcII, respectively), and 10–12 μM for the B3 enzyme L1. Against the B2 MBL Sfh-I, the L-BTZ enantiomers exhibit 100-fold lower K
is (0.26–0.36 μM) than D-BTZs (26–29 μM). Importantly, cell-based time-kill assays show BTZs restore β-lactam susceptibility of Escherichia coli-producing MBLs (IMP-1, Sfh-1, BcII, and GOB-18) and, significantly, an extensively drug-resistant Stenotrophomonas maltophilia clinical isolate expressing L1. BTZs therefore inhibit the full range of MBLs and potentiate β-lactam activity against producer pathogens. X-ray crystal structures reveal insights into diverse BTZ binding modes, varying with orientation of the carboxylate and thiol moieties. BTZs bind the di-zinc centers of B1 (IMP-1; BcII) and B3 (L1) MBLs via the free thiol, but orient differently depending upon stereochemistry. In contrast, the L-BTZ carboxylate dominates interactions with the monozinc B2 MBL Sfh-I, with the thiol uninvolved. D-BTZ complexes most closely resemble β-lactam binding to B1 MBLs, but feature an unprecedented disruption of the D120–zinc interaction. Cross-class MBL inhibition therefore arises from the unexpected versatility of BTZ binding.
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