At the end of 2015, INFN formally approved a new experiment, PADME, to search for invisible decays of the A' dark photon at the DAFNE Linac in Frascati. The experiment is designed to detect the A' ...produced in positron-on-fixed target annihilation, by measuring the final state missing mass. The collaboration aims to complete the design and construction of the experiment by the end of 2017 and to collect ∼1013 positrons on target by the end of 2018, thus reaching a sensitivity on the coupling constant of ∼103 and on the dark photon mass up to ∼ 23.7 MeV/c2
Metastasis suppressors comprise a growing class of genes whose downregulation triggers metastatic progression. In contrast to tumor suppressors, metastasis suppressors are rarely mutated or deleted, ...and little is known regarding the mechanisms by which their expression is downregulated. Here, we demonstrate that the metastasis suppressor, NM23-H1, is degraded by lysosomal cysteine cathepsins (L,B), which directly cleave NM23-H1. In addition, activation of c-Abl and Arg oncoproteins induces NM23-H1 degradation in invasive cancer cells by increasing cysteine cathepsin transcription and activation. Moreover, c-Abl activates cathepsins by promoting endosome maturation, which facilitates trafficking of NM23-H1 to the lysosome where it is degraded. Importantly, the invasion- and metastasis-promoting activity of c-Abl/Arg is dependent on their ability to induce NM23-H1 degradation, and the pathway is clinically relevant as c-Abl/Arg activity and NM23-H1 expression are inversely correlated in primary breast cancers and melanomas. Thus, we demonstrate a novel mechanism by which cathepsin expression is upregulated in cancer cells (via Abl kinases). We also identify a novel role for intracellular cathepsins in invasion and metastasis (degradation of a metastasis suppressor). Finally, we identify novel crosstalk between oncogenic and metastasis suppressor pathways, thereby providing mechanistic insight into the process of NM23-H1 loss, which may pave the way for new strategies to restore NM23-H1 expression and block metastatic progression.
This work proposes a semi-pilot scale procedure for the evaluation of biogas production potential and the employment of its results for the scale-up of the process. AD tests were performed at 35 °C ...in 6 L reactors, feeding 3–6% w/w TS in a fed-batch mode. Several substrates, generated by food-processing industries, were considered in the study. Assuming solubilization as the limiting step, a theoretical model was proposed and the values of the disintegration kinetic constant (kdis) were calculated from the experimental data. The obtained model was employed as a control tool during tests afterward performed on pilot scale in a 300 L digester fed in a semi-continuous mode. Biogas yields between 0.5 and 0.9 Nm3/kgVS, and methane contents of 55–63% v/v were obtained on both scales. The model derived from the results of the proposed procedure appeared adequate for a consistent evaluation of the scale-up of the AD process.
•The experimental results derive from tests performed on 6 L and 300 L reactors.•Single-phase AD of homogenous mixtures (no co-digestion) was performed.•Good biogas yields were obtained without any pre-treatment of the substrates.•Solubilization was evaluated as the limiting step in AD of the considered substrates.•A provisional model, based on kdis and useful for the process scale-up, is proposed.
We present a new limit on the production of a light dark-force mediator with the KLOE detector at DAΦNE. This boson, called U, has been searched for in the decay ϕ→ηU, U→e+e−, analyzing the decay ...η→π0π0π0 in a data sample of 1.7 fb−1. No structures are observed in the e+e− invariant mass distribution over the background. This search is combined with a previous result obtained from the decay η→π+π−π0, increasing the sensitivity. We set an upper limit at 90% C.L. on the ratio between the U boson coupling constant and the fine structure constant of α′/α<1.7×10−5 for 30<MU<400 MeV and α′/α⩽8×10−6 for the sub-region 50<MU<210 MeV. This result assumes the Vector Meson Dominance expectations for the ϕηγ⁎ transition form factor. The dependence of this limit on the transition form factor has also been studied.
•Physical and chemical properties of crumb rubber (CR) affect its use in road pavements.•CRs change significantly as a function of materials’ source and production process.•Evaluation of CR surface ...area is needed to maximize interaction with bitumen.•Cleanliness of CR is critical in the performance of final binders and mixtures.•Organic compounds (VOCs and PAHs) in CR may affect gaseous emissions during use.
Crumb rubber (CR) derived from grinding of end-of-life tyres (ELTs) may be successfully used as a bitumen modifier or as a supplementary component in the production of bituminous mixtures employed for the construction and maintenance of road pavements. However, CRs deriving from different sources and production processes yield effects on performance of corresponding paving mixtures under traffic loading and on gaseous emissions produced during laying on site which may change considerably depending upon their physical and chemical properties. In order to quantitatively assess the possible variability of CR characteristics, 16 samples were taken from 9 Italian and 2 foreign ELT processing plants. Investigation activities included field surveys, during which plants were examined in detail, and laboratory tests, which focused on physical and chemical characterization of CR. Based on the analysis of available technical information and experimental data, it was possible to find relationships between the peculiar characteristics of treatment cycles and corresponding CR properties.
The Frascati Neutron Generator (FNG) started operations in November 1992 making available to EU fusion community 14 MeV neutrons at an emission rate of 1011 s-1. The fusion community strongly ...supported the idea of international collaboration in neutronics experiments, data base and code improvement, development of (new) experimental techniques and detectors. FNG was designed and built in ENEA that also operates the machine at its own expenses. FNG is extensively used to perform benchmarks or mock-up experiments of interest to Fusion neutronics in turn validating nuclear data and codes. A number of activities in different fields within a series of collaborations are carried out at FNG so far.
Acute failure of the Fontan circulation is rare but remains associated with high morbidity and mortality rates. Little is known about the long-term outcome of patients who underwent Fontan takedown ...to an intermediate palliative circulation and their potential candidacy for redo Fontan completion.
Patients followed up at a single institution who underwent takedown of a Fontan circulation to an intermediate palliative circulation within 2 months of extracardiac Fontan completion were reviewed.
Between October 1990 and December 2015, 18 patients underwent Fontan takedown to a superior cavopulmonary connection (with or without an additional shunt) at a median age of 3.3 years (range, 1.8 to 8.0) and median weight of 13.8 kg (range, 8.0 to 27.0 kg). Takedown was required during the Fontan procedure itself in 2 patients, and within the first 2 postoperative months in 16 patients (median time to takedown, 3 days). Seventeen patients survived the post–takedown period and 3 ultimately underwent successful redo Fontan. Four patients required heart transplantation, with 2 deaths. In patients with extended intermediate palliation, median arterial oxygen saturation was 84% (range, 76% to 92%) at a median follow-up of 6.3 years (range, 0.7 to 25.9).
Takedown to a superior cavopulmonary connection is an effective treatment option and, in some patients, acts as a bridge to subsequent redo Fontan completion or heart transplantation. An extended intermediate palliative circulation is tolerated for several years with reasonable oxygen saturation levels at rest. In our experience, an early takedown strategy to a superior cavopulmonary connection is the treatment of choice for acute Fontan failure.
Despite 35 years of clinical trials, there is little improvement in 1-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. ...The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates a dire need to develop new therapies. Here, we found a previously unrecognized role for c-Abl and Arg in melanoma progression. We demonstrate that the kinase activities of c-Abl and Arg are elevated in primary melanomas (60%), in a subset of benign nevi (33%) and in some human melanoma cell lines. Using siRNA and pharmacological approaches, we show that c-Abl/Arg activation is functionally relevant because it is requiredfor melanoma cell proliferation, survival and invasion. Significantly, we identify the mechanism by which activated c-Abl promotes melanoma invasion by showing that it transcriptionally upregulates matrix metalloproteinase-1 (MMP-1), and using rescue approaches we demonstrate that c-Abl promotes invasion through a STAT3 → MMP-1 pathway. Additionally, we show that c-Abl and Arg are not merely redundant, as active Arg drives invasion in a STAT3-independent manner, and upregulates MMP-3 and MT1-MMP, in addition to MMP-1. Most importantly, c-Abl and Arg not only promote in vitro processes important for melanoma progression, but also promote metastasis in vivo, as inhibition of c-Abl/Arg kinase activity with the c-Abl/Arg inhibitor, nilotinib, dramatically inhibits metastasis in a mouse model. Taken together, these data identify c-Abl and Arg as critical, novel, drug targets in metastatic melanoma, and indicate that nilotinib may be useful in preventing metastasis in patients with melanomas harboring active c-Abl and Arg.
Background:
Guidelines recommend adjusting therapy in patients with rheumatoid arthritis (RA) who fail to reach and sustain low disease activity (LDA) or remission (disease control). Many factors can ...affect the decision to change therapy, including the potential for improvement as well as the fear of potential worsening or loss of improvement already achieved. Although data exist on response to treatment in patients who switch therapy, data addressing the likelihood of worsening are limited.
Objectives:
The aim of this analysis was to describe the demographic, clinical characteristics, and change in clinical outcomes in patients on biologic/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) who had some improvement in clinical disease activity index (CDAI) but did not achieve LDA after ~ 6-12 months of treatment and then switched to a different b/tsDMARD.
Methods:
This study included adult inadequately responding RA patients from the CORRONA registry who: (1) started a biologic or Janus kinase inhibitor (JAKi) between January 2010 to November 2020 (V1), (2) had any CDAI improvement (i.e., decrease ≥1 unit) but were not in LDA or remission at a subsequent visit (baseline BL) occurring 3 to 15 months after V1; (3) had a third visit (follow-up F/U) 6 (±3) months after BL with a valid CDAI measure; (4) switched therapy at the BL or between BL and F/U, with the switch occurring at least 3 months prior to the F/U. CDAI >10 and ≤22 was defined as moderate disease activity (MDA) and CDAI >22 was defined as high disease activity (HDA). Two thresholds of change in CDAI (≥6 and ≥12 units) were used to define meaningful improvement and meaningful worsening after the switch. If there was no meaningful improvement or meaningful worsening, this was considered as no meaningful change (-5 to +5 for 6 units change and -11 to +11 for 12 units change). These thresholds for meaningful change were set for all switchers regardless of their pre-switch CDAI value. Descriptive statistics were generated for demographic and clinical characteristics for the switchers at BL, and the change of clinical outcomes was evaluated from BL to F/U.
Results:
Of the 1,224 patients fulfilling the inclusion criteria, 93 (7.6%) switched therapy and 1,131 (92.4%) did not switch therampy after not achieving an adequate response on the initial b/tsDMARD. At BL, 42.5% and 70.0% of patients had no meaningful improvement to their prior therapy based on ≥6 and ≥12-unit change, respectively; mean (SD) age was 53.1 (14.0) years; duration of RA 10.7 (10.4) years; CDAI 22.2 (10.8); 81.7% were female; 64.5% had MDA, 35.5% had HDA; 21.5 % reported being disabled, 24.7% were current smokers, and 50% were obese. In terms of prior biologic use 57.0%, 22.6%, and 20.4% had been on 1, 2, and 3+, respectively. From BL to F/U, meaningful worsening occurred in 30.1% and 12.9% using a threshold of 6 and 12, respectively, with the remaining patients experiencing meaningful improvement or no meaningful change (Figure 1).
Figure 1.
Meaningful Worsening, Meaningful Improvement, and No Meaningful Change Based on CDAI Change Thresholds of ≥6 and ≥12 From BL to F/U (N=93)
Conclusion:
In our analysis, a large proportion of patients who initiated a biologic/JAKi and experienced some improvement but failed to attain LDA or remission, did not switch therapy within approximately a year. This analysis consisted of many patients who did not have a meaningful response to their prior biologic/JAKi, patients who had received multiple prior biologics, and a large portion of patients with poor prognostic factors. Despite this, the proportion of patients with meaningful worsening was low compared with most patients who had either meaningful improvement or no meaningful change. Additional research is warranted to understand the reasons for not switching and whether the likelihood of a meaningful change correlates with prior response, poor prognosis, or other factors.
Acknowledgements:
Amy Praestgaard (Sanofi) contributed to the statistical analysis for this abstract. Medical writing support for this abstract was provided by Krishna Kammari (Sanofi).
Disclosure of Interests:
Jeffrey Curtis Grant/research support from: and personal fees from AbbVie, Amgen, BMS, CORRONA, Eli Lily, Janssen, Myriad, Pfizer, Roche, Regeneron, Radius, UCB, outside the submitted work, Stefano Fiore Shareholder of: Sanofi, Employee of: Sanofi. In addition, he has a patent EP 19306553.9; USPTO #s 62/799,698; 62/851,474; 62/935,395 issued, Kerri Ford Shareholder of: Sanofi, Employee of: Sanofi, Judson Janak: None declared, Hong Chang: None declared, Dimitrios A Pappas Employee of: CORRONA LLC. He has previously acted as a consultant for Sanofi, Abbvie, Gtech Roche Hellas, and Novartis. He has an equity interest in CORRONA LLC. and is on the Board of directors of the CORRONA research foundation, Taylor Blachley: None declared, Kelechi Emeanuru: None declared, Vivian Bykerk Grant/research support from: reports grants from Amgen, BMS, UCB, and Novartis were given to institution, that grants from the NIH, PCORI, and CIHR were given to institutions which whom she is affiliated, and that she has received personal fees from Amgen, Gilead, BMS, Pfizer, Sanofi Aventis, Roche, UCB and Regeneron, outside the submitted work.
PDF
