A novel proteasome inhibitor acting in mitochondrial dysfunction, ER stress and ROS production

In cancer-treatment, potentially therapeutic drugs trigger their effects through apoptotic mechanisms. Generally, cell response is manifested by Bcl-2 family protein regulation, the impairment of mitochondrial functions, and ROS production. Notwithstanding, several drugs operate through proteasome inhibition, which, by inducing the accumulation and aggregation of misfolded or unfolded proteins, can lead to endoplasmic reticulum (ER) stress. Accordingly, it was shown that Amblyomin-X, a Kunitz-type inhibitor identified in the transcriptome of the Amblyomma cajennense tick by ESTs sequence analysis of a cDNA library, obtained in recombinant protein form, induces apoptosis in murine renal adenocarcinoma (RENCA) cells by: inducing imbalance between pro- and anti-apoptotic Bcl-2 family proteins, dysfunction/mitochondrial damage, production of reactive oxygen species (ROS), caspase cascade activation, and proteasome inhibition, all ER-stress inductive. Moreover, there was no manifest action on normal mouse-fibroblast cells (NHI3T3), suggesting an Amblyomin-X tumor-cell selectivity. Taken together, these evidences indicate that Amblyomin-X could be a promising candidate for cancer therapy.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Uniao Quimica Farmaceutica NacionalConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Inst Butantan, Lab Bioquim & Biofis, BR-05503900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Bioquim, São Paulo, BrazilInst Butantan, Programa Posgrad Interunidades Biotecnol, USP, IPT, BR-05503900 São Paulo, BrazilUniv São Paulo, Fac Med, Lab Oncol Expt LIM24, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Bioquim, São Paulo, BrazilFAPESP: FAPESP 2010/52669-3FAPESP: CAT/CEPID - 1998/14307-9Web of Scienc

The Silent Epidemic of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Children and Adolescents in Italy During the COVID-19 Pandemic in 2020

To compare the frequency of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes in Italy during the COVID-19 pandemic in 2020 with the frequency of DKA during 2017-2019

Diabetic ketoacidosis at the onset of disease during a national awareness campaign: a 2-year observational study in children aged 0-18 years

After a previous survey on the incidence of diabetic ketoacidosis (DKA) at onset of type 1 diabetes in children in 2013-2014 in Italy, we aimed to verify a possible decline in the incidence of DKA at onset during a national prevention campaign

Has COVID-19 Delayed the Diagnosis and Worsened the Presentation of Type 1 Diabetes in Children?

Objective: To evaluate whether the diagnosis of pediatric type 1 diabetes or its acute complications changed during the early phase of the coronavirus disease 2019 (COVID-19) pandemic in Italy. Research design and methods: This was a cross-sectional, Web-based survey of all Italian pediatric diabetes centers to collect diabetes, diabetic ketoacidosis (DKA), and COVID-19 data in patients presenting with new-onset or established type 1 diabetes between 20 February and 14 April in 2019 and 2020. Results: Fifty-three of 68 centers (77.9%) responded. There was a 23% reduction in new diabetes cases in 2020 compared with 2019. Among those newly diagnosed patient who presented in a state of DKA, the proportion with severe DKA was 44.3% in 2020 vs. 36.1% in 2019 (P = 0.03). There were no differences in acute complications. Eight patients with asymptomatic or mild COVID-19 had laboratory-confirmed severe acute respiratory syndrome coronavirus 2. Conclusions: The COVID-19 pandemic might have altered diabetes presentation and DKA severity. Preparing for any "second wave" requires strategies to educate and reassure parents about timely emergency department attendance for non-COVID-19 symptoms

Efficacy and safety of growth hormone treatment in children with short stature: the Italian cohort of the GeNeSIS clinical study

Purpose: We examined auxological changes in growth hormone (GH)-treated children in Italy using data from the Italian cohort of the multinational observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) of pediatric patients requiring GH treatment. Methods: We studied 711 children (median baseline age 9.6 years). Diagnosis associated with short stature was as determined by the investigator. Height standard deviation score (SDS) was evaluated yearly until final or near-final height (n = 78). Adverse events were assessed in all GH-treated patients. Results: The diagnosis resulting in GH treatment was GH deficiency (GHD) in 85.5 % of patients, followed by Turner syndrome (TS 6.6 %). Median starting GH dose was higher in patients with TS (0.30 mg/kg/week) than patients with GHD (0.23 mg/kg/week). Median (interquartile range) GH treatment duration was 2.6 (0.6\u20133.7) years. Mean (95 % confidence interval) final height SDS gain was 2.00 (1.27\u20132.73) for patients with organic GHD (n = 18) and 1.19 (0.97\u20131.40) for patients with idiopathic GHD (n = 41), but lower for patients with TS, 0.37 ( 120.03 to 0.77, n = 13). Final height SDS was > 122 for 94 % of organic GHD, 88 % of idiopathic GHD and 62 % of TS patients. Mean age at GH start was lower for organic GHD patients, and treatment duration was longer than for other groups, resulting in greater mean final height gain. GH-related adverse events occurred mainly in patients diagnosed with idiopathic GHD. Conclusions: Data from the Italian cohort of GeNeSIS showed auxological changes and safety of GH therapy consistent with results from international surveillance databases

Azimuthal anisotropy of charged jet production in root s(NN)=2.76 TeV Pb-Pb collisions

We present measurements of the azimuthal dependence of charged jet production in central and semi-central root s(NN) = 2.76 TeV Pb-Pb collisions with respect to the second harmonic event plane, quantified as nu(ch)(2) (jet). Jet finding is performed employing the anti-k(T) algorithm with a resolution parameter R = 0.2 using charged tracks from the ALICE tracking system. The contribution of the azimuthal anisotropy of the underlying event is taken into account event-by-event. The remaining (statistical) region-to-region fluctuations are removed on an ensemble basis by unfolding the jet spectra for different event plane orientations independently. Significant non-zero nu(ch)(2) (jet) is observed in semi-central collisions (30-50% centrality) for 20 <p(T)(ch) (jet) <90 GeV/c. The azimuthal dependence of the charged jet production is similar to the dependence observed for jets comprising both charged and neutral fragments, and compatible with measurements of the nu(2) of single charged particles at high p(T). Good agreement between the data and predictions from JEWEL, an event generator simulating parton shower evolution in the presence of a dense QCD medium, is found in semi-central collisions. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Forward-central two-particle correlations in p-Pb collisions at root s(NN)=5.02 TeV

Two-particle angular correlations between trigger particles in the forward pseudorapidity range (2.5 2GeV/c. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B. V.Peer reviewe

Event-shape engineering for inclusive spectra and elliptic flow in Pb-Pb collisions at root(NN)-N-S=2.76 TeV

Peer reviewe

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe