Summary
Icatibant is used to treat acute hereditary angioedema with C1 inhibitor deficiency types I/II (C1‐INH‐HAE types I/II) and has shown promise in angioedema due to acquired C1 inhibitor ...deficiency (C1‐INH‐AAE). Data from the Icatibant Outcome Survey (IOS) were analysed to evaluate the effectiveness of icatibant in the treatment of patients with C1‐INH‐AAE and compare disease characteristics with those with C1‐INH‐HAE types I/II. Key medical history (including prior occurrence of attacks) was recorded upon IOS enrolment. Thereafter, data were recorded retrospectively at approximately 6‐month intervals during patient follow‐up visits. In the icatibant‐treated population, 16 patients with C1‐INH‐AAE had 287 attacks and 415 patients with C1‐INH‐HAE types I/II had 2245 attacks. Patients with C1‐INH‐AAE versus C1‐INH‐HAE types I/II were more often male (69 versus 42%; P = 0·035) and had a significantly later mean (95% confidence interval) age of symptom onset 57·9 (51·33–64·53) versus 14·0 (12·70–15·26) years. Time from symptom onset to diagnosis was significantly shorter in patients with C1‐INH‐AAE versus C1‐INH‐HAE types I/II (mean 12·3 months versus 118·1 months; P = 0·006). Patients with C1‐INH‐AAE showed a trend for higher occurrence of attacks involving the face (35 versus 21% of attacks; P = 0·064). Overall, angioedema attacks were more severe in patients with C1‐INH‐HAE types I/II versus C1‐INH‐AAE (61 versus 40% of attacks were classified as severe to very severe; P < 0·001). Median total attack duration was 5·0 h and 9·0 h for patients with C1‐INH‐AAE versus C1‐INH‐HAE types I/II, respectively.
Real‐world data from the Icatibant Outcome Survey was used to evaluate the effectiveness of icatibant in the treatment of 16 patients with C1‐INH‐AAE (experiencing 287 attacks) and 415 patients with C1‐INH‐HAE types I/II (experiencing 2245 attacks), and to compare disease characteristics. Time from symptom onset to diagnosis was significantly shorter in patients with C1‐INH‐AAE versus C1‐INH‐HAE types I/II. Angioedema attacks were significantly less severe, and median total attack duration was significantly shorter in patients with C1‐INH‐AAE vs patients with C1‐INH‐HAE types I/II.
Icatibant, a bradykinin B2 receptor antagonist, is an established treatment for acute attacks of hereditary angioedema (HAE) with C1‐inhibitor (C1‐INH) deficiency. We describe our experience with ...icatibant in eight patients with angioedema because of acquired C1‐INH deficiency (AAE). Forty‐eight moderate‐to‐severe attacks were treated with subcutaneous icatibant 30 mg; two moderate attacks resolved without treatment. The median (range) duration of treated attacks (onset to complete resolution) was 9.33 (1.67–39.00) h; durations of the untreated attacks were 72 and 96 h. Symptom improvement following icatibant treatment occurred in 0.5 (0.25–2.10) h and complete resolution in 6.75 (0.50–30.75) h. A single icatibant injection achieved complete symptom resolution in 47 attacks; one facial attack required a second injection. One peripheral attack responded less quickly than other treated attacks. Five patients reported transient injection site reactions. Icatibant appeared to provide effective symptom relief and was generally well tolerated.
Background
Hereditary angioedema due to C1 inhibitor deficiency (HAE‐1/2) is a chronic and debilitating disease. The unpredictable clinical course represents a significant patient burden.
Objective
...To analyse longitudinal registry data from the Icatibant Outcome Survey (IOS) in order to characterize temporal changes in disease activity in patients with HAE‐1/2.
Methods
Icatibant Outcome Survey (NCT01034969) is an international observational registry monitoring the clinical outcomes of patients eligible for icatibant treatment. The current analyses are based on data collected between July 2009 and July 2019. Retrospective data for attacks recorded in the 12 months prior to IOS enrolment and for each 12‐month period up to 7 years were analysed.
Results
Included patients reported angioedema attacks without long‐term prophylaxis (LTP; n = 315) and with LTP (n = 292) use at the time of attack onset. Androgens were the most frequently used LTP option (80.8%). At the population level, regardless of LTP use, most patients (52–80%) reporting <5 attacks in Year 1 continued experiencing this rate; similarly, many patients (25–76%) who reported high attack frequency continued reporting ≥10 attacks/year. However, year on year, 31–51% of patients experienced notable changes (increase/decrease of ≥5 attacks) in annual attack frequency. Of patients who reported an absolute change of ≥10 attacks from Year 1 to 2, 17–50% continued to experience a change of this magnitude in subsequent years.
Conclusion
At the population level, attack frequency was generally consistent over 7 years. At the small group level, 28.8–34.5% of patients reported a change in attack frequency of ≥5 attacks from Year 1 to Year 2; up to half of these patients continued to experience this magnitude of variation in disease activity in later years, reflecting high intra‐patient variability.
Tumor necrosis factor-related apoptosis-inducing ligand-TNFSF10 (TRAIL), a member of the TNF-α family and a death receptor ligand, was shown to selectively kill tumor cells. Not surprisingly, TRAIL ...is downregulated in a variety of tumor cells, including BCR-ABL-positive leukemia. Although we know much about the molecular basis of TRAIL-mediated cell killing, the mechanism responsible for TRAIL inhibition in tumors remains elusive because (a) TRAIL can be regulated by retinoic acid (RA); (b) the tumor antigen preferentially expressed antigen of melanoma (PRAME) was shown to inhibit transcription of RA receptor target genes through the polycomb protein, enhancer of zeste homolog 2 (EZH2); and (c) we have found that TRAIL is inversely correlated with BCR-ABL in chronic myeloid leukemia (CML) patients. Thus, we decided to investigate the association of PRAME, EZH2 and TRAIL in BCR-ABL-positive leukemia. Here, we demonstrate that PRAME, but not EZH2, is upregulated in BCR-ABL cells and is associated with the progression of disease in CML patients. There is a positive correlation between PRAME and BCR-ABL and an inverse correlation between PRAME and TRAIL in these patients. Importantly, knocking down PRAME or EZH2 by RNA interference in a BCR-ABL-positive cell line restores TRAIL expression. Moreover, there is an enrichment of EZH2 binding on the promoter region of TRAIL in a CML cell line. This binding is lost after PRAME knockdown. Finally, knocking down PRAME or EZH2, and consequently induction of TRAIL expression, enhances Imatinib sensibility. Taken together, our data reveal a novel regulatory mechanism responsible for lowering TRAIL expression and provide the basis of alternative targets for combined therapeutic strategies for CML.
We present an analysis of the stellar mass growth over the last 10 Gyr ($z\le 2$) using a unique large sample of galaxies selected at $3.6~\mu$m. We have assembled accurate photometric and ...spectroscopic redshifts for ~21 200 and 1500 galaxies, respectively, with F(3.6 μm) ≥ 9.0 μJy by combining data from Spitzer-SWIRE IRAC, the VIMOS VLT Deep Survey (VVDS), UKIDSS and very deep optical CFHTLS photometry. We split our sample into quiescent (red) and active (blue) galaxies on the basis of an SED fitting procedure that we have compared with the strong rest-frame color bimodality $(NUV-r')_{\rm ABS}$. The present sample contains ~ 4400 quiescent galaxies. Our measurements of the K-rest frame luminosity function and luminosity density evolution support the idea that a large fraction of galaxies is already assembled at z ~ 1.2, with almost 80% and 50% of the active and quiescent populations already in place, respectively. Based on the analysis of the evolution of the stellar mass-to-light ratio (in K-band) for the spectroscopic sub-sample, we derive the stellar mass density for the entire sample. We find that the global evolution of the stellar mass density is well reproduced by the star formation rate derived from UV based measurements when an appropriate dust correction is applied, which supports the idea of an initial mass function that is on average universal. Over the last 8 Gyr (z ≤ 1.2) we observe that the stellar mass density of the active population shows a modest mass growth rate ($\dot{\rho}$ ~ 0.005(±0.005) $M_{\odot}$/Mpc3/yr), consistent with a constant stellar mass density, $\rho_{\star}^{\rm active}$ ~ 3.1 $\times$ 108 $M_{\odot}$/Mpc3. In contrast, an increase by a factor of ~2 for the quiescent population over the same timescale is observed. As a consequence, the growth of the stellar mass in the quiescent population must be due to the shutoff of star formation in active galaxies that migrate into the quiescent population. We estimate this stellar mass flux to be $\dot{\rho}_{A\rightarrow Q}$ ~ 0.017(±0.004) $M_{\odot}$/Mpc3/yr, which balances the major fraction of new stars born according to our best SFR estimate ($\dot{\rho}$ = 0.025(±0.003) $M_{\odot}$/Mpc3/yr). From $z = 2$ to $z = 1.2$, we observe a major build-up of the quiescent population with an increase by a factor of ~10 in stellar mass (a mass growth rate of ~ 0.063 $M_{\odot}$/Mpc3/yr). This rapid evolution suggests that we are observing the epoch when, for the first time in the history of the universe, an increasing fraction of galaxies end their star formation activity and start to build up the red sequence.
INFN is developing at the LASA lab (Milano, Italy) the High Order (HO) corrector magnets for the High Luminosity-LHC (HL-LHC) project, which will equip the new interaction regions. All the HO ...correctors, from skew quadrupole to dodecapole, are based on a novel superferric design, never used so far in high energy colliders, which allows a relatively simple, modular, and easy way to construct a magnet. The series production is ongoing after the completion of the five prototypes program; all the 54 series magnets have been produced in the industry and the testing at LASA is ongoing. The delivery to CERN also started. We discuss the design optimizations introduced and the lessons learned during the first half of the series production. We also focus on the quality assurance plan, which allowed us to early detect non-conformities and monitor the learning curve. The testing station at LASA is fully operational, four magnets per cool down are tested. Each magnet is powered individually, and the magnetic measurement system, supplied by CERN, provides field quality and transfer function. We provide an overview of the performed tests and measurements, focusing on the test station's performance and quality of the measurements. Finally, we provide an outlook of the production completion, test plan and delivery to CERN.
INFN has developed at the LASA lab (Milano, Italy) the High Order (HO) corrector magnets for the High Luminosity-LHC (HL-LHC) project, which will equip the new interaction regions. All the HO ...correctors, from skew quadrupole to dodecapole, are based on a novel superferric design, never used so far in high energy colliders, which allows a relatively simple, modular, and easy way to construct a magnet. After the completion of the production of the 54 series magnets in industry, the powering of all the produced magnets has been achieved. The delivery to CERN and the assembly of the first cold mass started. Each magnet has been powered individually and most of them have also been magnetically characterized, the aggregate results are presented and discussed. The lessons learned during the production and the testing of the magnets are reported. The quality assurance and the procedures developed in during development and production in industry proved to be key points of the successful experience of the HO correctors development, together with the solid design. We also report the lessons learned during the experience of the series production of the HO correctors.
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