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Human immunodeficiency virus (HIV) infections are typically accompanied by high levels of secreted inflammatory cytokines and generation of high levels of reactive oxygen species (ROS). To elucidate how HIV-1 alters the cellular redox environment during viral replication, we used human HIV-1 infected CD4+T lymphocytes and uninfected cells as controls. ROS and nitric oxide (NO) generation, antioxidant enzyme activity, protein phosphorylation, and viral and proviral loads were measured at different times (2–36 h post-infection) in the presence and absence of the NO donor S-nitroso-N-acetylpenicillamine (SNAP). HIV-1 infection increased ROS generation and decreased intracellular NO content. Upon infection, we observed increases in copper/zinc superoxide dismutase (SOD1) and glutathione peroxidase (GPx) activities, and a marked decrease in glutathione (GSH) concentration. Exposure of HIV-1 infected CD4+T lymphocytes to SNAP resulted in an increasingly oxidizing intracellular environment, associated with tyrosine nitration and SOD1 inhibition. In addition, SNAP treatment promoted phosphorylation and activation of the host's signaling proteins, PKC, Src kinase and Akt. Inhibition of PKC leads to inhibition of Src kinase strongly suggesting that PKC is the upstream element in this signaling cascade. Changes in the intracellular redox environment after SNAP treatment had an effect on HIV-1 replication as reflected by increases in proviral and viral loads. In the absence or presence of SNAP, we observed a decrease in viral load in infected CD4+T lymphocytes pre-incubated with the PKC inhibitor GF109203X. In conclusion, oxidative/nitrosative stress conditions derived from exposure of HIV-1-infected CD4+T lymphocytes to an exogenous NO source trigger a signaling cascade involving PKC, Src kinase and Akt. Activation of this signaling cascade appears to be critical to the establishment of HIV-1 infection. Image 1 • Redox regulation during HIV infection increased ROS generation and decreased intracellular NO. • The oxidizing cellular environment, Src kinase, PKC and AKT were phosphorylated and SOD1 expression was increased. • SNAP treatment of CD4+T lymphocytes increased the proviral DNA and RNA viral loads. [ABSTRACT FROM AUTHOR]

Abstract Rice is a significant source of arsenic (As) exposure. The accumulation of the plant depends on several factors, including environmental conditions and genetic factors. The differences in As uptake, translocation, and grains filling in different cultivars are a focus on studies to mitigate the grains contamination. This study assessed the pattern of As species accumulation in different Brazilian rice cultivars (Oryza sativa L.). Thus, pot experiments were conducted with 6 different cultivars (white rice: EPAGRI 109, EPAGRI 108, BRS Tiotaka SCS, and SCS 114 Andosan and red rice: Maranhão and Cáqui) cultivated in soils at low (As-) (0.65 mg kg−1) and high (As+) (12.1 mg kg−1) As levels. All cultivars in As+ group presented total As (t-As) in grains more elevated than the maximum limit of inorganic arsenic (i-As) recommended by Codex Alimentarius Commission. The As speciation disclose that Maranhão, Caqui, and SCS 114 Andosan cultivars presented the lowest % i-As (27%, 25% and 31%, respectively) at the highest As exposure condition. On the other hand, higher i-As concentration and % i-As (91%) were observed in EPAGRI 108. Moreover, EPAGRI 108 and EPAGRI 109 had the highest transference factor soil-to-grain (TFsoil-grain = 0.22 and 0.20, respectively). Interestingly, for the cultivars EPAGRI 108 and Maranhão, the levels of some essential elements (Co and Mn) in grains were modulated by the levels of As in the soil. This study shows that levels of i-As were modulated by the type of Brazilian rice cultivar, the range of As levels in soil, As phytotoxicity and the transference factor of As from soil to root straw and grains. Moreover, SCS 114 Andosan is the promising cultivar that exhibits low t-As and % i-As in grains and low TF soil-grain. Graphical abstract fx1 Highlights • Percentage of i-As in grains were affected by rice cultivars and As levels in soil. • As phytotoxicity to plant height decrease the percentage i-As in grains. • Low transference factor was observed in the high As exposure. • Andosan had the lowest t-As, percentage of i-As in grains and low TF soil-grain. • Co and Mn in grains were modulated by the levels of As in the soil. [ABSTRACT FROM AUTHOR]

The small GTP-binding proteins Ras and Rac1 are molecular switches exchanging GDP for GTP and converting external signals in response to a variety of stimuli. Ras and Rac1 play an important role in cell proliferation, cell differentiation, and cell migration. Rac1 is directly involved in the reorganization and changes in the cytoskeleton during cell motility. Nitric oxide (NO) stimulates the Ras – ERK1/2 MAP kinases signaling pathway and is involved in the interaction between Ras and the phosphatidyl-inositol-3 Kinase (PI3K) signaling pathway and cell migration. This study utilizes bradykinin (BK), which promotes endogenous production of NO, in an investigation of the role of NO in the activation of Rac1 in rabbit aortic endothelial cells (RAEC). NO-derived from BK stimulation of RAEC and incubation of the cells with the s-nitrosothiol S-nitrosoglutathione (GSNO) activated Rac1. NO-derived from BK stimulation promoted RAEC migration over a period of 12 h. The use of RAEC permanently transfected with the dominant negative mutant of Ras (Ras N17 ) or with the non-nitrosatable mutant of Ras (Ras C118S ); and the use of specific inhibitors of: Ras, PI3K, and Rac1 resulted in inhibition of NO-mediated Rac1 activation. BK-stimulated s-nitrosylation of Ras in RAEC mediates Rac1 activation and cell migration. Inhibition of NO-mediated Rac1 activation resulted in inhibition of endothelial cell migration. In conclusion, the NO indirect activation of Rac1 involves the direct participation of Ras and PI3K in the migration of endothelial cells stimulated with BK. [ABSTRACT FROM AUTHOR]

Abstract: Glycoprotein gp70 is an important intracellular antigen from Paracoccidioides brasiliensis that elicits both humoral and cellular immune responses. Herein, the PbGP70 gene cloning from isolate Pb18 using internal peptide sequence information is reported. The deduced protein sequence bears two N-glycosylation sites, antigenic sites and two mouse T-cell epitopes. Anti-recombinant gp70 (rPbgp70) polyclonal antibodies reacted with a 70-kDa component in total cell extract of P. brasiliensis, while MAbC5F11 and paracoccidioidomycosis patients’ sera recognized rPbgp70. Confocal microscopy with anti-rPbgp70 and MAbC5F11 showed intense staining and cytoplasmatic co-localization. The protein sequence belongs to the flavoprotein monooxygenase family which groups important anti-oxidative bioactive compounds. We found increased PbGP70 transcript accumulation under oxidative stress induced by H2O2, during fungal growth and in macrophage phagocyted/bound yeasts. Therefore, gp70 might play a dual role in P. brasiliensis by both eliciting immune cellular and humoral responses in the host and protecting the fungus from oxidative stress generated by phagocytic cells. [Copyright &y& Elsevier]

Abstract: p21Ras protein plays a critical role in cellular signaling that induces either cell cycle progression or apoptosis. Nitric oxide (NO) has been consistently reported to activate p21Ras through the redox sensitive cysteine residue (118). In this study, we demonstrated that the p21Ras–ERK pathway regulates THP-1 monocyte/macrophage apoptosis induced by S-nitrosoglutathione (SNOG). This was apparent from studies in THP-1 cells expressing NO-insensitive p21Ras (p21RasC118S) where the pro-apoptotic action of SNOG was almost abrogated. Three major MAP kinase pathways (ERK, JNK, and p38) that are downstream to p21Ras were investigated. It was observed that only the activation of ERK1/2 MAP kinases by SNOG in THP-1 cells was attributable to p21Ras. The inhibition of the ERK pathway by PD98059 markedly attenuated apoptosis in SNOG-treated THP-1 cells, but had a marginal effect on SNOG-treated THP-1 cells expressing NO-insensitive p21Ras. The inhibition of the JNK and p38 pathways by selective inhibitors had no marked effects on the percentage of apoptosis. The induction of p21Waf1 expression by SNOG was observed in THP-1 cells harboring mutant and wild-type p21Ras, however in cells expressing mutant Ras, the expression of p21Waf1 was significantly attenuated. The treatment of THP-1 cells expressing wild-type p21Ras with PD98059 resulted in significant attenuation of p21Waf1 expression. These results indicate that the redox sensitive p21Ras–ERK pathway plays a critical role in sensing and delivering the pro-apoptotic signaling mediated by SNOG. [Copyright &y& Elsevier]

Abstract: The MDJ1/LON locus is conserved among pathogenic dimorphic fungi. We have mapped using DNase I footprinting and mobility shift assays three putative heat shock elements and one AP-1 binding domain (ARE) in the 5′ intergenic region shared by PbMDJ1and PbLON (ML) from Paracoccidioides brasiliensis. The region bearing an ARE-like towards PbLON also has an opposite skn-1-like element. We studied genetically and pathogenically distinct isolates Pb18 and Pb3, where ML is polymorphic and the number of elements detected was higher. The functionality of the elements was suggested by the stimulatory response of both genes to heat shock and oxidative stress. Co-regulation occurred upon heat shock from 36 to 42°C and, only in Pb3, also during mycelium to yeast transformation (26–36°C). In Pb18, PbMDJ1 seemed to be preferentially expressed in yeast. Our study might help understand regulation of genes involved in fungal adaptation to the host. [Copyright &y& Elsevier]

This study presents the degradation of fipronil in sewage treatment plant (STP) effluent by photo-Fenton at near neutral pH (pH 6.0) using Fe3+/Citrate complex. 83% of fipronil degradation was reached using a molar iron/citrate ratio of 1:3 (192 μmol L−1 of Fe3+/576 μmol L−1 of citrate). Photo-Fenton reduced the toxicity of treated solutions as according to the survival of Drosophila melanogaster exposed to non-treated and treated samples. Control experiments performed in distilled water using 32 μmol L−1 of Fe3+/96 μmol L−1 of citrate achieved 98% of fipronil degradation within 100 kJ m−2 (UV-A radiation, k = 30 × 10−3 kJ−1 m2 and t 1/2 = 23 kJ m−2), thus indicating that fipronil degradation is impaired by natural organic matter and inorganic ions present in STP effluent. Degradation was faster under solar radiation, as the same efficiency (98%) was obtained after 75 kJ m−2 (k = 63 × 10−3 kJ−1 m2 and t 1/2 = 11 kJ m−2). In addition, pathways of fipronil degradation using Fe3+/Citrate under solar and UV-A radiation were investigated and transformation products proposed. Results revealed that the HO• attack occurred preferentially in the pyrazole ring. Eight transformation products were identified by UHPLC-Q-TOF-MS and four are unprecedented in the literature. Control experiments in distilled water demonstrated that toxicity reduction is related to fipronil degradation and that transformation products are less toxic than fipronil. Furthermore, toxicity of STP fortified with fipronil was reduced after photo-Fenton. These results demonstrate the feasibility of applying this process using Fe3+/Citrate complex for fipronil degradation in a real matrix. Image 1 • Degradation of fipronil in seweage treatment plant effluent by photo-Fenton at pH 6. • Matrix composition affected operational parameters and treatment efficiency. • Eight transformation products were identified, and four of them are unprecedented. • A degradation mechanism is proposed for fipronil and transformation products. • Toxicity toward Drosophila melanogaster was reduced after photo-Fenton. [ABSTRACT FROM AUTHOR]

Aim: To investigate gene and protein inflammasome components expression in the liver of rats during the development of cachexia induced by Walker 256 carcinosarcoma. Methods: Eight-weeks old male rats were subcutaneously inoculated with a Walker 256 carcinosarcoma cell suspension (2×107 cells in 1.0mL; tumour-bearing, TB) or PBS control (C). The liver was excised on days 0, 7 and 14 after tumour cell injection. Cytokine mRNA analysis was performed by real time PCR and protein content evaluated with ELISA (normalized for total protein in the samples). Results: NLR family, pyrin domain containing (Nlrp 1 and 3) gene expression was increased already on day 7 (2.1 and 3.2-fold; p <0.05) and suffered further augment on day 14 (2.5 and 3.5-fold; p <0.05) in TB when compared C. IL-β gene expression followed the same pattern increased on day 7 (5.2-fold; p <0.05) and more dramatically, on day 14 (9.5-fold; p <0.01). While IL-β protein expression increased on day 14 (2-fold; p <0.05). Triacylglycerol (TG) levels were augmented in liver levels (1.7-fold; p <0.05) on day 7 (1.4-fold; p <0.5) on day 14 when compared C, suggesting a steatosis hepatic induced by cancer-cachexia. To further explore the mechanism involved with TG accumulation, we evaluated metabolism-related gene, such as carnitine palmitoyltransferase 1 (Cpt1) and AMP-activated (AMPK). We showed an up-regulation in Cpt1 and AMPK on day 7 (1.6 and 1.4-fold, respectively; p <0.05), but it was not restore accumulating TG and, we observed a down-regulation in CptI and AMPK on day 14. Conclusion: These results showed metabolism-related genes not to be able restore triacylglycerol liver during tumour progression and, in final stage of the cachexia the increased of the inflammasome components were inversely with metabolism gene, it is suggesting a modulation these gene for pathway inflammasome. [Copyright &y& Elsevier]

Spatial confinement and temporal regulation of signaling by nitric oxide (NO) and reactive oxygen species (ROS) occurs in cancer cells. Signaling mediated by NO and ROS was investigated in two sub clones of the murine melanoma B16F10-Nex2 cell line, Nex10C and Nex8H treated or not with bradykinin (BK). The sub clone Nex10C, similar to primary site cells, has a low capacity for colonizing the lungs, whereas the sub clone Nex8H, similar to metastatic cells, corresponds to a highly invasive melanoma. BK-treated Nex10C cells exhibited a transient increase in NO and an inhibition in basal O 2 − levels. Inhibition of endogenous NO production by l -NAME resulted in detectable levels of O 2 −. l -NAME promoted Rac1 activation and enhanced Rac1–PI3K association. l -NAME in the absence of BK resulted in Nex10C cell migration and invasion, suggesting that NO is a negative regulator of O 2 − mediated cell migration and cell invasion. BK-treated Nex8H cells sustained endogenous NO production through the activation of NOS3. NO activated Rac1 and promoted Rac1–PI3K association. NO stimulated cell migration and cell invasion through a signaling axis involving Ras, Rac1 and PI3K. In conclusion, a role for O 2 − and NO as positive regulators of Rac1–PI3K signaling associated with cell migration and cell invasion is proposed respectively for Nex10C and Nex8H murine melanoma cells. • NO and O 2 - signaling was investigated in murine melanoma treated with bradykinin. • Nex10C are primary site melanoma cells and Nex8H are metastatic melanoma cells. • In Nex10C O 2 − regulates Rac1-PI3K signaling mediating cell migration and invasion. • In Nex8H NO regulates Rac1-PI3K signaling mediating cell migration and invasion. • NO and O 2 − regulate migration and invasion depending on melanoma development. [ABSTRACT FROM AUTHOR]

[Display omitted] • Electrochemical online ICP-MS is used to assess time and potential resolved Pd dissolution. • Accelerated stress tests are developed to test catalyst stability in RDE. • The catalysts containing Sn and Fe demonstrate improved activity and maintain good stability. • PdSn/C and PdFe 3 O 4 /C are suitable for fuel cell applications, Nb dissolution destabilizes Pd. • Additional metals and oxides can improve the alcohol oxidation kinetics of Pd. This study evaluates the dissolution of the supported electrocatalysts Pd/C, PdSn/C, PdNb/C, and PdFe 3 O 4 /C during ethanol oxidation reaction for Alkaline Direct Liquid Fuel Cells (ADLFC) applications. A scanning flow cell (SFC) combined to an inductively coupled plasma mass spectrometry (online ICP-MS) is used to assess the dissolution stability in a broad potential window. Accelerated stress tests with and without ethanol are developed using a rotating disk electrode (RDE) with dissolution products analysis by ex-situ ICP-MS. Potential profiles simulating those experienced by the catalyst during regular fuel cell operation were used. Sn and Fe catalysts demonstrate improved activity and stability compared with the material with Pd alone. For these reasons, PdSn/C and PdFe 3 O 4 /C are suitable for ADLFC applications. Severe Nb dissolution destabilizes Pd, increasing its leaching. This work demonstrates that while additional metals and oxides can improve the alcohol oxidation kinetics of Pd, these additives' dissolution stability must already be considered at the catalyst design stage. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is a rare lysosomal storage disorder, characterized by a reduction in α-galactosidase A enzyme activity and the progressive accumulation of globotriaosylceramide (GL3) and its metabolites in the cells of various organs. Agalsidase beta, an enzyme replacement therapy (ERT), is approved for use in patients with FD in Europe, Canada, Australia, South America, and Asia, and is the only ERT approved for use in the United States. In this review, we discuss the clinical relevance of GL3 accumulation, the effect of agalsidase beta on GL3 in target tissues, and the association between treatment-related tissue GL3 clearance and long-term structure, function, or clinical outcomes. Accumulation of GL3 in the kidney, heart, vasculature, neurons, skin, gastrointestinal tract and auditory system correlates to cellular damage and irreversible organ damage, as a result of sclerosis, fibrosis, apoptosis, inflammation, and endothelial dysfunction. Damage leads to renal dysfunction and end-stage renal disease; myocardial hypertrophy with heart failure and arrhythmias; ischemic stroke; neuropathic pain; skin lesions; intestinal ischemia and dysmotility; and hearing loss. Treatment with agalsidase beta is effective in substantially clearing GL3 in a range of cells from the tissues affected by FD. Agalsidase beta has also been shown to slow renal decline and lower the overall risk of clinical progression, demonstrating an indirect link between treatment-related GL3 clearance and stabilization of FD. • Fabry disease is associated with the accumulation of globotriaosylceramide (GL3). • Lysosomal GL3 accumulation is correlated with structural damage and functional loss. • Enzyme replacement therapy with agalsidase beta clears GL3 from affected tissues. • A link between GL3 clearance and clinical benefit is supported by the data. • Early treatment is crucial to prevent GL3-related organ damage. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is involved in angiogenesis and stimulates the EGF-R signaling pathway. Stimulation of different endothelial cell lines with bradykinin (BK) activates the endothelial NO synthase (eNOS) and promotes EGF-R tyrosine phosphorylation. Increase in NO production correlated with enhanced phosphorylation of tyrosine residues and S-nitrosylation of the EGF-R. NO-mediated stimulatory effects on tyrosine phosphorylation of the EGF-R, where cGMP independent. Inhibition of soluble guanylyl cyclase followed by BK stimulation of human umbilical vein endothelial cells (HUVECs) did not change tyrosine phosphorylation levels of EGF-R. BK-stimulation of HUVEC promoted S-nitrosylation of the phosphatase SHP-1 and of p21Ras. Phosphorylation and activation of the ERK1/2 MAP kinases mediated by BK was dependent on the activation of the B2 receptor, of the EGF-R, and of p21 Ras. Inhibition of BK-stimulated S-nitrosylation prevented the activation of the ERK1/2 MAP kinases. Furthermore, activated ERK1/2 MAP kinases inhibited internalization of EGF-R by phosphorylating specific Thr residues of its cytoplasmic domain. BK-induced proliferation of endothelial cells was partially inhibited by the NOS inhibitor (L-NAME) and by the MEK inhibitor (PD98059). BK stimulated the expression of vascular endothelial growth factor (VEGF). VEGF expression was dependent on the activation of the EGF-R, the B2 receptor, p21Ras, and on NO generation. A Matrigel®-based in vitro assay for angiogenesis showed that BK induced the formation of capillary-like structures in HUVEC, but not in those cells expressing a mutant of the EGF-R lacking tyrosine kinase activity. Additionally, pre-treatment of BK-stimulated HUVEC with L-NAME, PD98059, and with SU5416, a specific inhibitor of VEGFR resulted in inhibition of in vitro angiogenesis. Our findings indicate that BK-mediated angiogenesis in endothelial cells involves the induction of the expression of VEGF associated with the activation of the NO/EGF-R/p21Ras/ERK1/2 MAP kinases signaling pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] Gold nanoparticles (AuNPs) can be used in diagnostic and therapeutic applications. The development of facile and fast synthetic approaches is accordingly desirable towards ready-to-use biomedical materials. We report a practical one-pot method for the synthesis in aqueous media and room temperature of surface-decorated AuNPs with enhanced biological responses. The gold ions could be reduced using only polyethyleneimine (PEI) derivatives containing sugar and-or alkyl chains acting simultaneously as reducing and stabilizing agent, without the aid of any other mediator. The process is possibly potentialized by the presence of the amino groups in the polymer chains which further confer colloidal stability. The kinetics of AuNPs nucleation and growth depends on the chemical nature of the polymer chains. Particularly, the presence of lactose moieties conjugated to the PEI chains conducted to surface-decorated AuNPs with low cytotoxicity that are remarkably faster uptaken by HepG2 cells. These cells overexpress asialoglycoprotein (ASGP-R), a galactose receptor. These findings may kick off significant advances towards the practical and ready-to-use manufacturing of functionalized AuNPs towards cell-targeting since the methodology is applicable for a large variety of other ligands that can be conjugated to the same polymer chains. [ABSTRACT FROM AUTHOR]

Abstract: Accumulating evidence indicates that post-translational protein modifications by nitric oxide and its derived species are critical effectors of redox signaling in cells. These protein modifications are most likely controlled by intracellular reductants. Among them, the importance of the 12 kDa dithiol protein thioredoxin-1 (TRX-1) has been increasingly recognized. However, the effects of TRX-1 in cells exposed to exogenous nitrosothiols remain little understood. We investigated the levels of intracellular nitrosothiols and survival signaling in HeLa cells over-expressing TRX-1 and exposed to S-nitrosoglutahione (GSNO). A role for TRX-1 expression on GSNO catabolism and cell viability was demonstrated by the concentration-dependent effects of GSNO on decreasing TRX-1 expression, activation of caspase-3, and increasing cell death. The over-expression of TRX-1 in HeLa cells partially attenuated caspase-3 activation and enhanced cell viability upon GSNO treatment. This was correlated with reduction of intracellular levels of nitrosothiols and increasing levels of nitrite and nitrotyrosine. The involvement of ERK, p38 and JNK pathways were investigated in parental cells treated with GSNO. Activation of ERK1/2 MAP kinases was shown to be critical for survival signaling. In cells over-expressing TRX-1, basal phosphorylation levels of ERK1/2 MAP kinases were higher and further increased after GSNO treatment. These results indicate that the enhanced cell viability promoted by TRX-1 correlates with its capacity to regulate the levels of intracellular nitrosothiols and to up-regulate the survival signaling pathway mediated by the ERK1/2 MAP kinases. [Copyright &y& Elsevier]

Abstract Paracoccidioides brasiliensis is a temperature-dependent dimorphic fungus that cause paracoccidioidomycosis (PCM), the major systemic mycosis in Latin America. The capacity to evade the innate immune response of the host is due to P. brasiliensis ability to respond and to survive the nitrosative stress caused by phagocytic cells. However, the regulation of signal transduction pathways associated to nitrosative stress response are poorly understood. Ras GTPase play an important role in the various cellular events in many fungi. Ras, in its activated form (Ras-GTP), interacts with effector proteins and can initiate a kinase cascade. In this report, we investigated the role of Ras GTPase in P. brasiliensis after in vitro stimulus with nitric oxide (NO). We observed that low concentrations of NO induced cell proliferation in P. brasiliensis , while high concentrations promoted decrease in fungal viability, and both events were reversed in the presence of a NO scavenger. We observed that high levels of NO induced Ras activation and its S -nitrosylation. Additionally, we showed that Ras modulated the expression of antioxidant genes in response to nitrosative stress. We find that the Hog1 MAP kinase contributed to nitrosative stress response in P. brasiliensis in a Ras-dependent manner. Taken together, our data demonstrate the relationship between Ras-GTPase and Hog1 MAPK pathway allowing for the P. brasiliensis adaptation to nitrosative stress. Highlights • Nitric oxide can act as a signal transducer in P. brasiliensis. • Depending on NO concentration, different events are modulated in P. brasiliensis. • High concentrations of NO can switch the Ras-GDP to Ras-GTP with consequent activation and triggering a response to nitrosative stress. • Ras is involved in the Hog1 pathway required for nitrosative stress. [ABSTRACT FROM AUTHOR]

Fabry disease (FD, α-galactosidase A deficiency) is a rare, progressive, complex lysosomal storage disorder affecting multiple organ systems with a diverse spectrum of clinical phenotypes, particularly among female patients. Knowledge of its clinical course was still limited in 2001 when FD-specific therapies first became available and the Fabry Registry (NCT00196742 ; sponsor: Sanofi) was initiated as a global observational study. The Fabry Registry has now been operational for over 20 years, overseen by expert Boards of Advisors, and has collected real-world demographic and longitudinal clinical data from more than 8000 individuals with FD. Leveraging the accumulating evidence base, multidisciplinary collaborations have resulted in the creation of 32 peer-reviewed scientific publications, which have contributed to the greatly expanded knowledge on the onset and progression of FD, its clinical management, the role of sex and genetics, the outcomes of enzyme replacement therapy with agalsidase beta, and prognostic factors. We review how the Fabry Registry has evolved from its inception to become the largest global source of real-world FD patient data, and how the generated scientific evidence has helped to better inform the medical community, individuals living with FD, patient organizations, and other stakeholders. The patient-centered Fabry Registry fosters collaborative research partnerships with the overarching goal of optimizing the clinical management of patients with FD and is well positioned to add to its past achievements. • Fabry disease is a rare, progressive, complex lysosomal storage disorder. • Over 20 years of real-world patient data are available in the Fabry Registry. • More than 8000 patients from 219 participating sites have contributed data. • 32 publications contributed to optimization of clinical management of patients. • Fostering of partnerships with the Fabry community remains a key priority. [ABSTRACT FROM AUTHOR]

In Gaucher disease (GD), deficiency of lysosomal acid β-glucosidase results in a broad phenotypic spectrum that is classified into three types based on the absence (type 1 [GD1]) or presence and severity of primary central nervous system involvement (type 2 [GD2], the fulminant neuronopathic form, and type 3 [GD3], the milder chronic neuronopathic form). Enzyme replacement therapy (ERT) with imiglucerase ameliorates and prevents hematological and visceral manifestations in GD1, but data in GD3 are limited to small, single-center series. The effects of imiglucerase ERT on hematological, visceral and growth outcomes (note: ERT is not expected to directly impact neurologic outcomes) were evaluated during the first 5 years of treatment in 253 children and adolescents (< 18 years of age) with GD3 enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry. The vast majority of GBA mutations in this diverse global population consisted of only 2 mutations: L444P (77%) and D409H (7%). At baseline, GD3 patients exhibited early onset of severe hematological and visceral disease and growth failure. During the first year of imiglucerase treatment, hemoglobin levels and platelet counts increased and liver and spleen volumes decreased, leading to marked decreases in the number of patients with moderate or severe anemia, thrombocytopenia, and hepatosplenomegaly. These improvements were maintained through Year 5. There was also acceleration in linear growth as evidenced by increasing height Z-scores. Despite devastating disease at baseline, the probability of surviving for at least 5 years after starting imiglucerase was 92%. In this large, multinational cohort of pediatric GD3 patients, imiglucerase ERT provided a life-saving and life-prolonging benefit for patients with GD3, suggesting that, with proper treatment, many such severely affected patients can lead productive lives and contribute to society. [ABSTRACT FROM AUTHOR]

Aim: To investigate Cytokine gene expression in different anatomical sites of adipose tissue during the progression of cancer cachexia in a rodent model. Methods: Eight week old male rats were subcutaneously inoculated with a Walker 256 carcinosarcoma cell suspension (2×107 cells in 1.0mL; Tumour-bearing, TB) or NaCl2 control (C). The retroperitoneal (RPAT), mesenteric (MES) and epididymal (EPI) adipose depots were excised on days 0, 7 and 14 after tumour cell injection. Cytokine mRNA analysis was performed by real time PCR. Additionally, adipocytes were isolated from the various pads and examined for cytokine express. Results: Interleukins 6 and 10 (IL-6, IL-10) were found to be augmented on day 14 in the RPAT and EPI (4.7; 26.7-fold and 18.6; 34.8-fold p <0.05, respectively), as compared with control. TNF-α mRNA expression was increased on day 14 in all adipose pads of TB, in relation to controls, while on day 7 it was already enhanced in MES from TB (23.7-fold p <0.05). While IL-6 gene expression did not present a different pattern in the adipocytes from the studied groups, that of TNF-α mimicked the results obtained for the whole tissue. RPAT adipocytes, solely, demonstrated enhanced IL-10 expression in TB, as compared with control (2.9-fold p <0.05). Conclusions: The WAT is known to be an important source of inflammatory and anti-inflammatory cytokines in cancer cachexia. We show that there is a heterogeneous response by adipose depots according to anatomical localisation and degree of cachexia. Additionally, adipocyites seem to contribute to the final tissue content of TNF-α, while, as no correlation was found for IL-10 and IL-6 between adipocytes and whole tissue expression, the stromal–vascular fraction is suggested to play a relevant role for the final concentration of these factors in WAT. [Copyright &y& Elsevier]