Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia

Hypophosphatasia (HPP) features low tissue-nonspecific alkaline phosphatase (TNSALP) isoenzyme activity resulting in extracellular accumulation of its substrates including pyridoxal 5\u27-phosphate (PLP), the principal circulating form of vitamin B6, and inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. Asfotase alfa is an enzyme replacement therapy developed to treat HPP. This multinational, randomized, open-label study (NCT01163149; EudraCT 2010-019850-42) evaluated the efficacy and safety of asfotase alfa in adults and adolescents 13-66 years of age with HPP. The study comprised a 6-month primary treatment period and a 4.5-year extension phase. In the primary treatment period, 19 patients were randomized to receive asfotase alfa 0.3 mg/kg/d subcutaneously (SC; n = 7), asfotase alfa 0.5 mg/kg/d SC (n = 6), or no treatment (control; n = 6) for 6 months. In the extension phase, patients received asfotase alfa (0.5 mg/kg/d for 6 mo-1 y, then 1 mg/kg/d 6 d/wk). During the primary treatment period, changes from Baseline to Month 6 in plasma PLP and PPi concentrations (coprimary efficacy measure) were greater in the combined asfotase alfa group compared with the control group, reaching statistical significance for PLP (P = 0.0285) but not for PPi (P = 0.0715). However, for the total cohort, the within subject changes in both PLP and PPi after 6 months and over 5 years of treatment with asfotase alfa were significant (P \u3c 0.05). Secondary efficacy measures included transiliac crest histomorphometry, dual-energy X-ray absorptiometry (DXA), and the 6-Minute Walk Test (6MWT). A significant decrease from Baseline in mineralization lag time was observed in the combined asfotase alfa group at Year 1. There were no significant differences between treated and control patients in DXA mean bone mineral density results at 6 months; Z-scores and T-scores were within the expected range for age at Baseline and remained so over 5 years of treatment. On the 6MWT, median (min, max) distance walked increased from 355 (10, 620; n = 19) meters before treatment to 450 (280, 707; n = 13) meters at 5 years (P \u3c 0.05). Results for the exploratory outcome measures suggested improvements in gross motor function, muscle strength, and patient-reported functional disability over 5 years of treatment. There were no deaths during this study. Asfotase alfa was generally well tolerated; the most common adverse events were mild to moderate injection site reactions. This study suggests that in adults and adolescents with pediatric-onset HPP, treatment with asfotase alfa is associated with normalization of circulating TNSALP substrate levels and improved functional abilities

HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes

Histone deacetylases (HDACs) regulate the acetylation of histones in the control of gene expression. Many non-histone proteins are also targeted for acetylation, including TGF-ß signalling pathway components such as Smad2, Smad3 and Smad7. Our studies in mouse C3H10T1/2 fibroblasts suggested that a number of TGF-ß-induced genes that regulate matrix turnover are selectively regulated by HDACs. Blockade of HDAC activity with trichostatin A (TSA) abrogated the induction of a disintegrin and metalloproteinase 12 (Adam12) and tissue inhibitor of metalloproteinases-1 (Timp-1) genes by TGF-ß, whereas plasminogen activator inhibitor-1 (Pai-1) expression was unaffected. Analysis of the activation of cell signalling pathways demonstrated that TGF-ß induced robust ERK and PI3K activation with delayed kinetics compared to the phosphorylation of Smads. The TGF-ß induction of Adam12 and Timp-1 was dependent on such non-Smad signalling pathways and, importantly, HDAC inhibitors completely blocked their activation without affecting Smad signalling. Analysis of TGF-ß-induced Adam12 and Timp-1 expression and ERK/PI3K signalling in the presence of semi-selective HDAC inhibitors valproic acid, MS-275 and apicidin implicated a role for class I HDACs. Furthermore, depletion of HDAC3 by RNA interference significantly down-regulated TGF-ß-induced Adam12 and Timp-1 expression without modulating Pai-1 expression. Correlating with the effect of HDAC inhibitors, depletion of HDAC3 also blocked the activation of ERK and PI3K by TGF-ß. Collectively, these data confirm that HDACs, and in particular HDAC3, are required for activation of the ERK and PI3K signalling pathways by TGF-ß and for the subsequent gene induction dependent on these signalling pathways

A gravitational-wave standard siren measurement of the Hubble constant

The detection of GW170817 (ref. 1) heralds the age of gravitational-wave multi-messenger astronomy, with the observations of gravitational-wave and electromagnetic emission from the same transient source. On 17 August 2017 the network of Advanced Laser Interferometer Gravitational-wave Observatory (LIGO)2 and Virgo3 detectors observed GW170817, a strong signal from the merger of a binary neutron-star system. Less than two seconds after the merger, a γ-ray burst event, GRB 170817A, was detected consistent with the LIGO–Virgo sky localization region4–6). The sky region was subsequently observed by optical astronomy facilities7, resulting in the identification of an optical transient signal within about 10 arcseconds of the galaxy NGC 4993 (refs 8–13). GW170817 can be used as a standard siren14–18, combining the distance inferred purely from the gravitational-wave signal with the recession velocity arising from the electromagnetic data to determine the Hubble constant. This quantity, representing the local expansion rate of the Universe, sets the overall scale of the Universe and is of fundamental importance to cosmology. Our measurements do not require any form of cosmic ‘distance ladder’19; the gravitational-wave analysis directly estimates the luminosity distance out to cosmological scales. Here we report H0 = kilometres per second per megaparsec, which is consistent with existing measurements20,21, while being completely independent of them

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

The Beatings Will Continue Until Morale Improves

Political decisions about higher education and organizational decision-making within higher educational institutions reflect the acceptance of academic capitalist discourse, placing financial burdens on students, stress upon faculty, and the obliteration of trust between faculty and administration. In this critical layered narrative account, a tenure-track faculty member examines the impacts and influences of academic capitalism, including how this neoliberal discourse disregards the idea of higher education as a public good, creates an atmosphere of fear among faculty, and affects faculty-student relationships. This account illustrates how academic capitalism, with its emphasis on money and power, influenced decisions regarding a partnership with a software company, and of course, a rebooted football program