Fas (TNFRSF6/Apo-1/CD95) is a type I transmembrane receptor, which mediates apoptosis. Fas gene mutations, aberrant transcripts, and abundant expression of Fas have been reported in adult T cell leukemia (ATL). To further elucidate the role of Fas in ATL pathogenesis, we investigated whether the -670 FAS promoter A/G polymorphism (STAT1-binding site) might contribute to susceptibility and clinical outcome in ATL. Thirty-one patients with ATL, 33 healthy, human T lymphotropic virus type 1-infected individuals, and 70 healthy, uninfected controls were genotyped for the FAS -670 polymorphism by PCR-restriction fragment-length polymorphism. The AA genotype was significantly over-represented in ATL patients in comparison with healthy controls (P=0.006), as well as asymptomatics (P=0.037), corresponding to an odds ratio (OR) of 3.79 [95% confidence intervals (CI; 1.28-11.41)] and 4.58 [95% CI (1.13-20.03)], respectively. The AA group also comprised significantly more aggressive (acute and lymphoma) clinical subtypes [P=0.012; OR=8.40; 95% CI (1.60-44.12)]. In addition, we observed a statistically significant association between GG genotype and survival (log rank test, P=0.032). Finally, IFN-gamma-induced but not basal FAS mRNA levels were increased significantly (P=0.049) in PBMCs from AA versus GG individuals, demonstrating the IFN-dependent functionality of the -670 polymorphism. In conclusion, our results demonstrate that a functional Fas promoter polymorphism is significantly associated to susceptibility, clinical manifestation, and survival in ATL.

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Background: Despite the number of empirical studies that assess Aspect-Oriented Software Development (AOSD) techniques, more research is required to investigate, for example, how software maintainability is impacted when these techniques are employed. One way to minimize the effort and increase the reliability of results in further research is to systematize empirical studies in Aspect-Oriented Software Maintainability (AOSM). In this context, metrics are useful as indicators to quantify software quality attributes, such as maintenance. Currently, a high number of metrics have been used throughout the literature to measure software maintainability. However, there is no comprehensive catalogue showing which metrics can be used to measure AOSM. Aim: To identify an AOSM metrics suite to be used by researchers in AOSM research. Method: We performed a systematic mapping study based on Kitchenham and Charters' guidelines, which derived a research protocol, and used well known digital libraries engines to search the literature. Conclusions: A total of 138 primary studies were selected. They describe 67 aspect-oriented (AO) maintainability metrics. Also, out of the 575 object-oriented maintainability metrics that we analyzed, 469 can be adapted to AO software. This catalogue provides an objective guide to researchers looking for maintainability metrics to be used as indicators in their quantitative and qualitative assessments. We provide information such as authors, metrics description, and studies that used the metric. Researchers can use this information to decide which metrics are more suited for their studies.#Papers Authors 1All the others.

Systemic sclerosis (SSc) is a multisystemic, complex, and rare disease of connective tissue, with high morbidity and mortality, and without specific treatment. The disease is characterized by three main principles: vascular disease, autoantibody production and inflammation, and fibrosis. Since it is well defined that SSc is characterized by elevated production of TGF-β, IL-6, and IL-1, all of them cytokines related to Th17 differentiation, the hypothesis is that this disease may be strongly related to a polarization of the immune response towards the Th17 pathway. Considering the importance of a better understanding of the pathophysiology of Th17 pathway in SSc, this article aims to propose an update for a better understanding of current knowledge on main cytokines secreted by the Th17 cells (IL-17 A, IL-21, and IL-22) and the future prospects in the current disease.

We first showed raised IFN-λ1 levels in SSc patients. Furthermore, we found a correlation between IFN-λ1 and IFN-γ levels and an association between IFN-γ and myositis. Additional in vitro and in vivo studies are needed to understand IFN-λ1 role in SSc.

Objective. To determine active TGF-β1 (aTGF-β1) levels in serum, skin, and peripheral blood mononuclear cell (PBMC) culture supernatants and to understand their associations with clinical parameters in systemic sclerosis (SSc) patients. Methods. We evaluated serum samples from 56 SSc patients and 24 healthy controls (HC). In 20 SSc patients, we quantified spontaneous or anti-CD3/CD28 stimulated production of aTGF-β1 by PBMC. The aTGF-β1 levels were measured by ELISA. Skin biopsies were obtained from 13 SSc patients and six HC, and TGFB1 expression was analyzed by RT-PCR. Results. TGF-β1 serum levels were significantly higher in SSc patients than in HC (p < 0.0001). Patients with increased TGF-β1 serum levels were more likely to have diffuse subset (p = 0.02), digital ulcers (p = 0.02), lung fibrosis (p < 0.0001), positive antitopoisomerase I (p = 0.03), and higher modified Rodnan score (p = 0.046). Most of our culture supernatant samples had undetectable levels of TGF-β1. No significant difference in TGFB1 expression was observed in the SSc skin compared with HC skin. Conclusion. Raised active TGF-β1 serum levels and their association with clinical manifestations in scleroderma patients suggest that this cytokine could be a marker of fibrotic and vascular involvement in SSc.

Although several cytokines and chemokines have been investigated as possible mediators of fibrosis in systemic sclerosis (SSc), specific correlation between cytokines and organ involvement have not been found yet, and a cytokine profile characteristic of SSc is far to be identified. We studied the profile of antifibrotic and profibrotic transcripts involved in skin of SSc patients. The mRNA expression was detected by fluorescence‐based quantitative real‐time PCR (qPCR) in skin's biopsies from 14 patients with SSc and 5 healthy controls. PDGF‐A, CTGF, CCL3, IL‐6, IL‐13, IL‐7, IFNγ, IL‐17, IL‐22 and RORc were analysed in these samples. CCL3, IL‐7, IL‐13 and IFN‐γ were more expressed in skin's biopsy of patients with SSc (P = 0.0002, P = 0.0082, P = 0.0243, P = 0.0335, respectively) when compared with healthy controls. We also found a positive correlation between CCL3 and IL‐7 transcripts (P = 0.0050 r = 0.7187). Furthermore, we observed that patients with lung involvement had lower expression of PDGF‐A (P = 0.0385). We found an increase in IL‐7, IFN‐γ, CCL3 and IL‐13 relative mRNA expressions on the skin's biopsy of patients with SSc, and a positive correlation between IL‐7 and CCL3. These molecules are involved in the pathogenesis of SSc, and how their interactions occur should be the subject of further studies.

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