Characterization of gene expression in the kidney of renal tubular cell-specific NFAT5 knockout mice.

Nuclear factor of activated T cells 5 (NFAT5; also called TonEBP/OREBP) is a transcription factor that is activated by hypertonicity and induces osmoprotective genes to protect cells against hypertonic conditions. In the kidney, renal tubular NFAT5 is known to be involved in the urine concentration mechanism. Previous studies have suggested that NFAT5 modulates the immune system and exerts various effects on organ damage, depending on organ and disease states. Pathophysiological roles of NFAT5 in renal tubular cells, however, still remain obscure. We conducted comprehensive analysis by performing transcription start site (TSS) sequencing on the kidney of inducible and renal tubular cell-specific NFAT5 knockout (KO) mice. Mice were subjected to unilateral ureteral obstruction to examine the relevance of renal tubular NFAT5 in renal fibrosis. TSS sequencing analysis identified 722 downregulated TSSs and 1,360 upregulated TSSs, which were differentially regulated ≤-1.0 and ≥1.0 in log2 fold, respectively. Those TSSs were annotated to 532 downregulated genes and 944 upregulated genes, respectively. Motif analysis showed that sequences that possibly bind to NFAT5 were enriched in TSSs of downregulated genes. Gene Ontology analysis with the upregulated genes suggested disorder of innate and adaptive immune systems in the kidney. Unilateral ureteral obstruction significantly exacerbated renal fibrosis in the renal medulla in KO mice compared with wild-type mice, accompanied by enhanced activation of immune responses. In conclusion, NFAT5 in renal tubules could have pathophysiological roles in renal fibrosis through modulating innate and adaptive immune systems in the kidney.NEW & NOTEWORTHY TSS-Seq analysis of the kidney from renal tubular cell-specific NFAT5 KO mice uncovered novel genes that are possibly regulated by NFAT5 in the kidney under physiological conditions. The study further implied disorders of innate and adaptive immune systems in NFAT5 KO mice, thereby exacerbating renal fibrosis at pathological states. Our results may implicate the involvement of renal tubular NFAT5 in the progression of renal fibrosis. Further studies would be worthwhile for the development of novel therapy to treat chronic kidney disease.

Chemical Bonding, 10Dq Parameter and Superexchange in the Model Compound KNiF3.

The cubic field splitting parameter, 10Dq, plays a central role in the ligand field theory on insulating transition metal compounds. Experimental data obtained in the last 50 years prove that 10Dq is highly dependent on changes of the metal-ligand distance, R, induced by chemical or applied pressures. Despite this fact has important consequences on optical and magnetic properties of such compounds, its actual origin is still controversial. Seeking to clarify that crucial issue, this work is focused on KNiF3, a reference system among insulating transition metal compounds. By means of first principles calculations we show that, contrary to what is usually thought, the R-dependence of 10Dq arises neither from the crystal field contribution nor from the covalent admixture of 3d(Ni) with valence 2p(F) orbitals. Indeed, we prove that it is mainly due to the residual covalency with deep 2s(F) orbitals, highly sensitive to R variations. As a salient feature the present calculations show that the 3d-2pσ and 3d-2pπ admixtures raise practically equal the energy of antibonding eg and t2g orbitals of NiF6 4- units in KNiF3 thus leading to a null contribution to 10Dq. This conclusion is not significantly altered when considering the change of covalency on passing from the ground state 3A2(t2g 6eg 2) to the excited state 3T2(t2g 5eg 3). The different influence of chemical bonding on the superexchange constant, J, and 10Dq is also discussed in a second step. It is pointed out that the strong dependence of J upon R can hardly be explained through the behavior of the 3d-2pσ covalency derived for a single NiF6 4- unit. For the sake of clarity, the meaning of 10Dq is also briefly analyzed.

Understanding Pressure Effects on Structural, Optical, and Magnetic Properties of CsMnF4 and Other 3dn Compounds.

The pressure dependence of structural, optical, and magnetic properties of the layered compound CsMnF4 are explored through first-principles calculations. The structure at ambient pressure does not arise from a Jahn-Teller effect but from an orthorhombic instability on MnF63- units in the tetragonal parent phase, while there is a P4/n → P4 structural phase transition at P = 40 GPa discarding a spin crossover transition from S = 2 to S = 1. The present results reasonably explain the evolution of spin-allowed d-d transitions under pressure, showing that the first transition undergoes a red-shift under pressure following the orthorhombic distortion in the layer plane. The energy of such a transition at zero pressure is nearly twice that observed in Na3MnF6 due to the internal electric field and the orthorhombic distortion also involved in K2CuF4. The reasons for the lack of orthorhombic distortion in K2MF4 (M = Ni, Mn) or CsFeF4 are also discussed in detail. The present calculations confirm the ferromagnetic ordering of layers in CsMnF4 at zero pressure and predict a shift to an antiferromagnetic phase for pressures above 15 GPa consistent with the reduction of the orthorhombicity of the MnF63- units. This study underlines the usefulness of first-principles calculations for a right interpretation of experimental findings.

Red Shift in Optical Excitations on Layered Copper Perovskites under Pressure: Role of the Orthorhombic Instability.

The red shift under pressure in optical transitions of layered compounds with CuCl6 4- units is explored through first-principles calculations and the analysis of available experimental data. The results on Cu2+ -doped (C2 H5 NH3 )2 CdCl4 , that is taken as a guide, show the existence of a highly anisotropic response to pressure related to a structural instability, driven by a negative force constant, that leads to an orthorhombic geometry of CuCl6 4- units but with a hole displaying a dominant 3z2 -r2 character (z being the direction perpendicular to the layer plane). As a result of such an instability, a pressure of only 3 GPa reduces by 0.21 Šthe longest Cu2+ -Cl- distance, lying in the layer plane, while leaving unmodified the two other metal-ligand distances. Owing to this fact, it is shown that the lowest d-d transition would experience a red shift of 0.34 eV while the first allowed charge transfer transition is also found to be red shifted but only by 0.11 eV that reasonably concurs with the experimental value. The parallel study on Jahn-Teller systems CdCl2 :Cu2+ and NaCl:Cu2+ involving tetragonal elongated CuCl6 4- units shows that the reduction of the long axis by a pressure of 3 GPa is three times smaller than that for the layered (C2 H5 NH3 )2 CdCl4 :Cu2+ compound. Accordingly, the optical transitions of such systems, which involve a positive force constant, are much less sensitive to pressure than in layered compounds. The origin of the red shift under pressure undergone by the lowest d-d and charge transfer transitions of (C2 H5 NH3 )2 CdCl4 :Cu2+ is discussed in detail.

NFAT5 Amplifies Antipathogen Responses by Enhancing Chromatin Accessibility, H3K27 Demethylation, and Transcription Factor Recruitment.

The ability of innate immune cells to respond to pathogen-associated molecular patterns across a wide range of intensities is fundamental to limit the spreading of infections. Studies on transcription responses to pathogen-activated TLRs have often used relatively high TLR ligand concentrations, and less is known about their regulation under mild stimulatory conditions. We had shown that the transcription factor NFAT5 facilitates expression of antipathogen genes under TLR stimulation conditions corresponding to low pathogen loads. In this study, we analyze how NFAT5 optimizes TLR-activated responses in mouse macrophages. We show that NFAT5 was required for effective recruitment of central effectors p65/NF-κB and c-Fos to specific proinflammatory target genes, such as Nos2, Il6, and Tnf in primary macrophages responding to low doses of the TLR4 ligand LPS. By contrast, NFAT5 was not required for p65/NF-κB recruitment in response to high LPS doses. Using the transposase-accessible chromatin with high-throughput sequencing assay, we show that NFAT5 facilitated chromatin accessibility mainly at promoter regions of multiple TLR4-responsive genes. Analysis of various histone marks that regulate gene expression in response to pathogens identified H3K27me3 demethylation as an early NFAT5-dependent mechanism that facilitates p65 recruitment to promoters of various TLR4-induced genes. Altogether, these results advance our understanding about specific mechanisms that optimize antipathogen responses to limit infections.

Pressure Effects on 3dn (n=4, 9) Insulating Compounds: Long Axis Switch in Na3 MnF6 not Due to the Jahn-Teller Effect.

The pressure-induced switch of the long axis of MnF6 3- units in the monoclinic Na3 MnF6 compound and Mn3+ -doped Na3 FeF6 is explored with the help of first principles calculations. Although the switch phenomenon is usually related to the Jahn-Teller effect, we show that, due to symmetry reasons, it cannot take place in 3dn (n=4, 9) systems displaying a static Jahn-Teller effect. By contrast, we prove that in Na3 MnF6 the switch arises from the anisotropic response of the low symmetry lattice to hydrostatic pressure. Indeed, while the long axis of a MnF6 3- unit at ambient pressure corresponds to the Mn3+ -F3 - direction, close to the crystal c axis, at 2.79 GPa the c axis is reduced by 0.29 Šwhile b is unmodified. This fact is shown to force a change of the HOMO wavefunction favoring that the long axis becomes the Mn3+ -F2 - direction, not far from crystal b axis, after the subsequent relaxation process. The origin of the different d-d transitions observed for Na3 MnF6 and CrF2 at ambient pressure is also discussed together with changes induced by pressure in Na3 MnF6 . The present work opens a window for understanding the pressure effects upon low symmetry insulating compounds containing d4 or d9 ions.

New Ideas for Understanding the Structure and Magnetism in AgF2 : Prediction of Ferroelasticity.

In the search for new high-temperature superconductors, it has been proposed that there are strong similarities between the fluoroargentate AgF2 and the cuprate La2 CuO4 . We explored the origin of the possible layered structure of AgF2 by studying its parent high-symmetry phase and comparing these results with those of a seemingly analogous cuprate, CuF2 . Our findings first stress the large differences between CuF2 and AgF2 . Indeed, the parent structure of AgF2 is found to be cubic, naturally devoid of any layering, even though Ag2+ ions occupy trigonal sites that, nevertheless, allow the existence of a Jahn-Teller effect. The observed Pbca orthorhombic phase is found when the system is cooperatively distorted by a local E⊗e trigonal Jahn-Teller effect around the silver sites that creates both geometrical and magnetic layering. While the distortion implies that two Ag2+ -F- bonds increase their distance by 15 % and become softer, our simulations indicate that covalent bonding and interlayer electron hopping is strong, unlike the situation in cuprate superconductors, and that, in fact, exfoliation of individual planes might be a harder task than previously suggested. As a salient feature, these results prove that the actual magnetic structure in AgF2 is a direct consequence of vibronic contributions involved in the Jahn-Teller effect. Finally, our findings show that, due to the multiple minima intrinsic to the Jahn-Teller energy surface, the system is ferroelastic, a property that is strongly coupled to magnetism in this argentate.

Ground State and Optical Excitations in Compounds with Tetragonal CuF64- Units: Insight into KAlCuF6 and CuFAsF6.

It has been argued that AAlCuF6 (A = K, Cs) and CuFAsF6 are the only known crystals that exhibit compressed CuF64- units due to the Jahn-Teller effect. However, no grounds for this singular behavior have yet been reported. By means of first-principles calculations on such compounds and the isomorphous compounds involving Zn2+ ions instead of Cu2+, we prove that neither the ground state nor the equilibrium geometry of CuF64- complexes in KAlCuF6 and CuFAsF6 is the result of a Jahn-Teller effect. In contrast, it is shown that the internal electric field, ER(r), created by the rest of the lattice ions upon the localized electrons in the complex, plays an important role in understanding this matter as well as the d-d transitions of these two compounds. The energy of an optical transition is shown to involve two contributions: the intrinsic contribution derived for the isolated CuF64- unit at equilibrium and the extrinsic contribution coming from the ER(r) field. Aside from reproduction of the experimental d-d transitions observed for KAlCuF6, it is found that in CuFAsF6 the b1g(x2 - y2) → a1g(3z2 - r2) transition is not the lowest one due to the stronger effects from the internal field. Interestingly, the intrinsic contribution corresponding to that transition can simply be written as ß(Req - Rax) where Req and Rax are the equatorial and axial Cu2+-F- distances and ß = 2.7 eV/Å is the same for all systems involving tetragonal CuF64- units and an average metal-ligand distance close to 2.03 Å. This shows the existence of a common point shared by the Jahn-Teller system KZnF3:Cu2+ and other non-Jahn-Teller systems such as KAlCuF6, CuFAsF6, K2ZnF4:Cu2+, and Ba2ZnF6:Cu2+. Although most Jahn-Teller systems display an elongated geometry, there are however many Cu2+ compounds with a compressed geometry but hidden by an additional orthorhombic instability. The lack of that instability in KAlCuF6 and CuFAsF6 is also discussed.

NFAT5-Regulated Macrophage Polarization Supports the Proinflammatory Function of Macrophages and T Lymphocytes.

Macrophages are exquisite sensors of tissue homeostasis that can rapidly switch between pro- and anti-inflammatory or regulatory modes to respond to perturbations in their microenvironment. This functional plasticity involves a precise orchestration of gene expression patterns whose transcriptional regulators have not been fully characterized. We had previously identified the transcription factor NFAT5 as an activator of TLR-induced responses, and in this study we explore its contribution to macrophage functions in different polarization settings. We found that both in classically and alternatively polarized macrophages, NFAT5 enhanced functions associated with a proinflammatory profile such as bactericidal capacity and the ability to promote Th1 polarization over Th2 responses. In this regard, NFAT5 upregulated the Th1-stimulatory cytokine IL-12 in classically activated macrophages, whereas in alternatively polarized ones it enhanced the expression of the pro-Th1 mediators Fizz-1 and arginase 1, indicating that it could promote proinflammatory readiness by regulating independent genes in differently polarized macrophages. Finally, adoptive transfer assays in vivo revealed a reduced antitumor capacity in NFAT5-deficient macrophages against syngeneic Lewis lung carcinoma and ID8 ovarian carcinoma cells, a defect that in the ID8 model was associated with a reduced accumulation of effector CD8 T cells at the tumor site. Altogether, detailed analysis of the effect of NFAT5 in pro- and anti-inflammatory macrophages uncovered its ability to regulate distinct genes under both polarization modes and revealed its predominant role in promoting proinflammatory macrophage functions.

Understanding the Structure and Ground State of the Prototype CuF2 Compound Not Due to the Jahn-Teller Effect.

Insulating CuF2 is considered a prototype compound displaying a Jahn-Teller effect (JTE) which gives rise to elongated CuF64- units. By means of first-principles calculations together with an analysis of experimental data of both CuF2 and Cu2+-doped ZnF2, we demonstrate that such an idea is not correct. For ZnF2:Cu2+, we find that CuF64- units are compressed always along the Z local axis with a hole essentially in a 3 z2- r2 antibonding orbital, in agreement with experimental EPR data that already underline the absence of a JTE. The structure of the monoclinic CuF2 crystal also comes from compressed CuF64- complexes, although hidden by an additional orthorhombic instability due to a negative force constant of b2g and b3g local modes. The associated distortion, similar to that involved in K2CuF4 and other layered Cu2+ compounds, is also shown to be developed for ZnF2:Cu2+ upon increasing the copper concentration. The origin of this cooperative effect is discussed together with the differences between non-Jahn-Teller systems like ZnF2:Cu2+ and CuF2 and true Jahn-Teller systems like KZnF3:Cu2+. From present results and those on layered compounds, the usual assumption of a JTE for explaining the properties of d9 ions in low-symmetry lattices can hardly be right.

Context-dependent regulation of Th17-associated genes and IFNγ expression by the transcription factor NFAT5.

Stress-activated transcription factors influence T-cell function in different physiopathologic contexts. NFAT5, a relative of nuclear factor κB and the calcineurin-activated NFATc transcription factors, protects mammalian cells from hyperosmotic stress caused by the elevation of extracellular sodium levels. In T cells exposed to hypernatremia, NFAT5 not only induces osmoprotective gene products but also cytokines and immune receptors, which raises the question of whether this factor could regulate other T-cell functions in osmostress-independent contexts. Here we have used mice with a conditional deletion of Nfat5 in mature T lymphocytes to explore osmostress-dependent and -independent functions of this factor. In vitro experiments with CD4 T cells stimulated in hyperosmotic medium showed that NFAT5 enhanced the expression of IL-2 and the Th17-associated gene products RORγt and IL-23R. By contrast, NFAT5-deficient CD4 T cells activated in vivo by anti-CD3 antibody exhibited a different activation profile and were skewed towards enhanced interferon γ (IFNγ) and IL-17 expression and attenuated Treg responses. Using a model of experimental colitis, we observed that mice lacking NFAT5 in T cells exhibited exacerbated intestinal colitis and enhanced expression of IFNγ in draining lymph nodes and colon. These results show that NFAT5 can modulate different T-cell responses depending on stress conditions and stimulatory context.

Significant HLA class I type associations with aromatic antiepileptic drug (AED)-induced SJS/TEN are different from those found for the same AED-induced DRESS in the Spanish population.

Aromatic antiepileptic drugs (AEDs) are among the drugs most frequently involved in severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). This study investigated the associations between the genetic polymorphisms of HLA class-I and AED-induced SCARs in the Spanish population. HLA class-I genotypes were determined in AED (phenytoin[PHT],lamotrigine[LTG],carbamazepine[CBZ],phenobarbital[PB])-induced SJS/TEN (n=15) or DRESS (n=12) cases included in the Spanish SCAR registry, PIELenRed. There were 3 control groups: (A)tolerant to a single AED, (B)tolerant to any AED, and (C)Spanish population controls. For SJS/TEN, concomitant HLA-A*02:01/Cw15:02 alleles were significantly associated with PHT-cases compared to control groups B and C [(B)odds ratio(OR):14.75, p=0.009;(C)OR:27.50, p<0.001], and were close to significance with respect to control group A (p=0.060). The genotype frequency of the HLA-B*38:01 was significantly associated with PHT-LTG-cases compared with the 3 groups of controls [(A)OR:12.86, p=0.012;(B)OR:13.81; p=0.002;(C)OR:14.35, p<0.001], and with LTG-cases [(A)OR:147.00, p=0.001;(B)OR:115.00, p<0.001;(C)OR:124.70, p<0.001]. We found the HLA-B*15:02 allele in a Spanish Romani patient with a CBZ-case. The HLA-A*11:01 was significantly associated with CBZ-cases [(A)OR:63.89, p=0.002;(B)OR:36.33, p=0.005;(C)OR:28.29, p=0.007]. For DRESS, the HLA-A*24:02 genotype frequency was statistically significant in the PHT-LTG-cases [(A)OR:22.56, p=0.003;(B)OR:23.50. p=0.001; (C)OR:33.25, p<0.001], and in the LTG-cases [(A),OR:49.00, p=0.015;(B)OR:27.77, p=0.005; (C)OR:34.53, p=0.002]. HLA-A*31:01 was significantly associated with the CBZ-cases [(A)OR:22.00, p=0.047;(B)OR:29.50, p=0.033;(C)OR:35.14, p=0.006]. In conclusion, we identified several significant genetic risk factors for the first time in the Spanish Caucasian population: HLA-A*02:01/Cw*15:02 combination as a risk factor for PHT-induced SJS/TEN, HLA-B*38:01 for LTG- and PHT- induced SJS/TEN, HLA-A*11:01 for CBZ-induced SJS/TEN, and HLA-A*24:02 for LTG- and PHT- induced DRESS. The strong association between HLA*31:01 and CBZ-DRESS in Europeans was confirmed in this study.

Large Differences in the Optical Spectrum Associated with the Same Complex: The Effect of the Anisotropy of the Embedding Lattice.

Transition-metal complexes with a well-defined geometry are usually considered to display almost the same properties independently of the system where they are embedded. Here we show that the above statement is not true depending on the anisotropy of the host lattice, which is revealed in the form of the electric field created by the rest of lattice ions over the complex. To illustrate this concept we analyze the origin of the surprisingly large differences in the d-d optical transitions of two systems containing square-planar CuF42- complexes, CaCuF4, and center II in Cu2+-doped Ba2ZnF6, even though the Cu2+-F-distance difference is just found to be 1%. Using a minimalist first-principles model we show that the different morphology of the host lattices creates an anisotropic field that red-shifts the in vacuo complex transitions to the 1.25-1.70 eV range in CaCuF4, while it blue-shifts them to the 1.70-3.0 eV region in Ba2ZnF6:Cu2+. This particular example shows how the lattice anisotropy strongly alters the optical properties of a given transition-metal complex. This knowledge opens a new path to tune the spectra of this large family of systems.

Immunodeficiency and autoimmune enterocolopathy linked to NFAT5 haploinsufficiency.

The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.

Predictors of diffuse alveolar damage in patients with acute respiratory distress syndrome: a retrospective analysis of clinical autopsies.

BACKGROUND: Although diffuse alveolar damage (DAD) is considered the typical histological pattern of acute respiratory distress syndrome (ARDS), only half of patients exhibit this morphological hallmark. Patients with DAD may have higher mortality than those without DAD. Therefore, we aimed to identify the factors associated with DAD in patients with ARDS. METHODS: We analyzed autopsy samples of 356 patients who had ARDS at the time of death. DAD was assessed by two pathologists, and ARDS criteria were evaluated by two intensivists. Criteria for severe ARDS included the degree of hypoxemia and the ancillary variables of the current Berlin definition assessed within 48 h before death: radiographic severity, high positive end-expiratory pressure (PEEP) level, and physiological variables (i.e., altered respiratory system compliance and large anatomic dead space). RESULTS: After multivariable analysis, high PEEP levels, physiological variables, and opacities involving only three quadrants on chest radiographs were not associated with DAD. The four markers independently associated with DAD were (1) duration of evolution (OR 3.29 [1.95-5.55] for patients with ARDS ≥ 3 days, p < 0.001), (2) degree of hypoxemia (OR 3.92 [1.48-10.3] for moderate ARDS and 6.18 [2.34-16.3] for severe ARDS, p < 0.01 for both), (3) increased dynamic driving pressure (OR 1.06 [1.04-1.09], p = 0.007), and (4) radiographic severity (OR 2.91 [1.47-5.75] for patients with diffuse opacities involving the four quadrants, p = 0.002). DAD was found in two-thirds of patients with a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ≤ 100 mmHg and opacities involving the four quadrants. CONCLUSIONS: In addition to severe hypoxemia, diffuse opacities involving the four quadrants were a strong marker of DAD.

A Genuine Jahn-Teller System with Compressed Geometry and Quantum Effects Originating from Zero-Point Motion.

First-principle calculations together with analysis of the experimental data found for 3d(9) and 3d(7) ions in cubic oxides proved that the center found in irradiated CaO:Ni(2+) corresponds to Ni(+) under a static Jahn-Teller effect displaying a compressed equilibrium geometry. It was also shown that the anomalous positive g∥ shift (g∥ -g0 =0.065) measured at T=20 K obeys the superposition of the |3 z(2) -r(2) ⟩ and |x(2) -y(2) ⟩ states driven by quantum effects associated with the zero-point motion, a mechanism first put forward by O'Brien for static Jahn-Teller systems and later extended by Ham to the dynamic Jahn-Teller case. To our knowledge, this is the first genuine Jahn-Teller system (i.e. in which exact degeneracy exists at the high-symmetry configuration) exhibiting a compressed equilibrium geometry for which large quantum effects allow experimental observation of the effect predicted by O'Brien. Analysis of the calculated energy barriers for different Jahn-Teller systems allowed us to explain the origin of the compressed geometry observed for CaO:Ni(+) .

Pleomorphic dermal sarcoma: a more aggressive neoplasm than previously estimated.

BACKGROUND: Pleomorphic dermal sarcoma (PDS) is a rare neoplasm sharing pathological features with atypical fibroxanthoma, but adding tumor necrosis, invasion beyond superficial subcutis or vascular or perineural infiltration. Although its metastatic risk has been estimated to be less than 5%, its real outcome is presently uncertain because of its rarity and to the lack of homogeneous criteria used in reported cases. METHODS: Retrospective clinicopathological study of 18 cases of PDS. RESULTS: The lesions presented as tumors or plaques (size: 7-70 mm) on the head of elderly patients (median: 81 years), without a gender predominance. Histopathologically, they consisted of spindle cells arranged in a fascicular pattern, containing pleomorphic epithelioid and giant multinucleated cells in varying proportions, and usually exhibiting numerous mitotic figures and infiltrative tumor margins. No immunoexpression for cytokeratins, S100 protein, desmin or CD34 was observed. Necrosis and venous invasion were found in three tumors each (17%). Follow-up was available in 15 cases (median: 33 months). Three patients (20%) had local recurrences, all with incomplete primary surgical resections. Three patients (20%) developed distant metastases in the skin, regional lymph nodes and/or lungs and died from the disease. CONCLUSION: Our data suggest that PDS may be a more aggressive neoplasm than previously estimated.

Transcription factors and target genes of pre-TCR signaling.

Almost 30 years ago pioneering work by the laboratories of Harald von Boehmer and Susumo Tonegawa provided the first indications that developing thymocytes could assemble a functional TCRß chain-containing receptor complex, the pre-TCR, before TCRα expression. The discovery and study of the pre-TCR complex revealed paradigms of signaling pathways in control of cell survival and proliferation, and culminated in the recognition of the multifunctional nature of this receptor. As a receptor integrated in a dynamic developmental process, the pre-TCR must be viewed not only in the light of the biological outcomes it promotes, but also in context with those molecular processes that drive its expression in thymocytes. This review article focuses on transcription factors and target genes activated by the pre-TCR to drive its different outcomes.

Clear Cell Atypical Fibroxanthoma: Clinicopathological Study of 6 Cases and Review of the Literature With Special Emphasis on the Differential Diagnosis.

Atypical fibroxanthoma (AFX) is an uncommon dermal-based neoplasm arising on the sun-damaged skin of elderly people. Clear cell AFX is a rare variant with only 12 cases reported until the present date, all of them as case reports, except for 1 small series of 3 cases. The authors report 6 new cases and review the literature with special emphasis on the differential diagnosis. The clear cell variant represents 5% of AFX from their files. Histopathologically, it consists of sheets of epithelioid, pleomorphic cells, intermixed with a varying number of giant multinucleated and spindle cells, the latter arranged in a fascicular pattern. All cell types predominantly exhibit a clear, microvacuolated cytoplasm with well-demarcated cell borders. The clinical and immunohistochemical features of this variant are similar to those of the classic type. Clear cell AFX must be differentiated from other cutaneous clear cell neoplasms, some of them with an aggressive clinical behavior, including clear cell melanoma, primary cutaneous and metastatic clear cell carcinomas, clear cell sarcoma, pleomorphic liposarcoma, tumor of perivascular epithelioid cells, and distinctive dermal clear cell mesenchymal neoplasm. The clinical presentation and immunohistochemical profile play a key role in the differential diagnosis.

NFAT5 induction by the pre-T-cell receptor serves as a selective survival signal in T-lymphocyte development.

The Rel-like transcription factors nuclear factor kappa B (NF-κB) and the calcineurin-dependent nuclear factor of activated T cells (NFATc) control specific points of thymocyte maturation. Thymocytes also express a distinct member of the Rel family, the calcineurin-independent, osmostress response regulator NFAT5. Here we show that IKKß regulates the expression of NFAT5 in thymocytes, which in turn contributes to the survival of T-cell receptor αß thymocytes and the transition from the ß-selection checkpoint to the double-positive stage in an osmostress-independent manner. NFAT5-deficient thymocytes had normal expression and proximal signaling of the pre-T-cell receptor but exhibited a partial defect in ß-chain allelic exclusion and increased apoptosis. Further analysis showed that NFAT5 regulated the expression of the prosurvival factors A1 and Bcl2 and attenuated the proapoptotic p53/Noxa axis. These findings position NFAT5 as a target of the IKKß/NF-κB pathway in thymocytes and as a downstream effector of the prosurvival role of the pre-T-cell receptor.