AB0565 JAK INHIBITORS AND PSORIATIC ARTHRITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Background:Despite the therapeutic armamentarium for the treatment of psoriatic arthritis (PsA) has considerably expanded over the last thirty years, there is a huge necessity of finding effective drugs for this disease. JAK inhibitors (JAKi) are small molecules able to interfere with the JAK/STAT pathway, involved in the pathogenesis of PsA (1). Up to now Tofacitinib is the only JAKi approved by the European Medicines Agency (EMA) for the treatment of PsA but in the next few years the number of approved JAKi is expected to rise significantly.Objectives:To assess the efficacy and safety of different JAKi for the treatment of PsA.Methods:A systematic review of the literature was performed to identify randomized controlled trials (RCTs), by electronic search of MEDLINE and EMBASE database until October 2020. Studies were considered eligible if they met the following criteria: I) study was a RCT; II) only patients with PsA were included; III) JAKi was compared to placebo in addition to the standard of care. Two reviewers (FC and AZ) performed study selection, with disagreements solved by the opinion of an expert reviewer (AS). The outcomes were expressed as odds ratio (OR) and 95% confidence intervals (95% CI). Statistical heterogeneity was assessed with the I2 statistic.Results:We identified 557 potentially relevant studies. A total of 554 studies were excluded based on title and/or abstract screening. Three RCTs for a total of 947 PsA patients treated with JAKi were included (2,3,4). Two were phase III studies on the efficacy and safety of Tofacitinib (OPAL Beyond and OPAL Broaden) and one was a phase II study on Filgotinib (Equator). All three studies were judged at low risk of bias according to Cochrane criteria (5). The primary efficacy outcome in all the studies was the number of patients who achieved the response rate of the American College of Rheumatology 20 score (ACR20). The outcomes evaluation was performed at 12 week for the Filgotinib trial and at 16 week for the Tofacitinib trials. We used for the main analyses the group of patients randomized to Tofacitinib 5 mg because this is the only dosage approved by the EMA for the treatment of PsA. JAKi showed a significantly higher ACR20 response rate compared to placebo (OR 3.54, 95% CI 1.76 - 7.09, I^2 = 74%). JAKi also showed a significantly higher ACR50 response rate (OR 3.36, 95% CI 2.22 - 5.09, I^2 = 0%), ACR70 response rate (OR 2.82, 95% CI 1.67 - 4.76, I^2 = 20%), PsARC response rate (OR 2.67, 95% CI 1.26 - 5.65, I^2 = 79%), PASI75 response rate (OR 3.15, 95% CI 1.61 - 6.15, I^2 = 45%) compared to placebo. JAKi were also associated with significantly better HAQ-DI (mean difference -0.23 95% CI -0.31 - -0.14) and fatigue, measured with FACIT-F (mean difference 3.54 95% CI 2.13 - 4.94). JAKi compared to placebo were associated with a non-statistically significant different risk of serious adverse events (OR 0.56, 95% CI 0.11 - 2.91, I^2 = 38%).Conclusion:This is the first published systematic review that performed a comprehensive and simultaneous evaluation of the efficacy and safety of JAKi for PsA in RCTs. Our analysis suggests a statistically significant benefit of JAKi, that appears to be effective and safe over placebo. The impact of these data on international clinical guidelines needs further investigation.References:[1]George E Fragoulis, et al. JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis, Rheumatology, Volume 58, Issue Supplement_1, February 2019, Pages i43–i54[2]Mease P, et al. Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N Engl J Med 2017; 377: 1537-50.[3]Gladman D, et al. Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors. N Engl J Med 2017; 377: 1525-36.[4]Mease P, et al. Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active psoriatic arthritis (EQUATOR): results from a randomised, placebo-controlled, phase 2 trial. Lancet 2018;392:2367–77.[5]Higgins JP, et Al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-560Figure 1.ACR20 response rate of Jaki over PlaceboDisclosure of Interests:None declared

New directional archeomagnetic data of burned cave sediments from Switzerland and geomagnetic field variations in Central Europe

This paper presents new directional archeomagnetic data from nine Meso-/Neolithic fireplaces, sampled in a cave shelter, at Arconciel, in western Switzerland. Rock magnetic measurements indicate a homogenous magnetic mineralogy in all fireplaces, with magnetite as the main magnetic carrier. The remanent magnetization is stable and generally shows one characteristic directional component. Nine new directions, which were obtained from Arconciel, are combined with 356 other archeomagnetic data from a circular area with a radius of 700km around this site, to obtain a penalized least square spline fit for the past 9000yr. We found in general good agreement with other local compilations, such as the Balkan curve, the regional SCHA.DIF.8k model and with lake sediments from UK, Fennoscandia and Switzerland. Nevertheless, a time lag of several centuries is observed for a declination maximum between the archeomagnetic spline fit and the other European data records around 5900BC. This time lag is also observed in the Swiss lake sediment record; therefore we interpret this shift as a local feature of the Earth's magnetic fiel

Evolution of the solar irradiance during the Holocene

Aims. We present a physically consistent reconstruction of the total solar irradiance for the Holocene. Methods. We extend the SATIRE models to estimate the evolution of the total (and partly spectral) solar irradiance over the Holocene. The basic assumption is that the variations of the solar irradiance are due to the evolution of the dark and bright magnetic features on the solar surface. The evolution of the decadally averaged magnetic flux is computed from decadal values of cosmogenic isotope concentrations recorded in natural archives employing a series of physics-based models connecting the processes from the modulation of the cosmic ray flux in the heliosphere to their record in natural archives. We then compute the total solar irradiance (TSI) as a linear combination of the jth and jth + 1 decadal values of the open magnetic flux. Results. Reconstructions of the TSI over the Holocene, each valid for a di_erent paleomagnetic time series, are presented. Our analysis suggests that major sources of uncertainty in the TSI in this model are the heritage of the uncertainty of the TSI since 1610 reconstructed from sunspot data and the uncertainty of the evolution of the Earth's magnetic dipole moment. The analysis of the distribution functions of the reconstructed irradiance for the last 3000 years indicates that the estimates based on the virtual axial dipole moment are significantly lower at earlier times than the reconstructions based on the virtual dipole moment. Conclusions. We present the first physics-based reconstruction of the total solar irradiance over the Holocene, which will be of interest for studies of climate change over the last 11500 years. The reconstruction indicates that the decadally averaged total solar irradiance ranges over approximately 1.5 W/m2 from grand maxima to grand minima

The Translation Factor eIF6 Is a Notch-Dependent Regulator of Cell Migration and Invasion

A growing body of evidence indicates that protein factors controlling translation play an important role in tumorigenesis. The protein known as eIF6 is a ribosome anti-association factor that has been implicated in translational initiation and in ribosome synthesis. Over-expression of eIF6 is observed in many natural tumours, and causes developmental and differentiation defects in certain animal models. Here we show that the transcription of the gene encoding eIF6 is modulated by the receptor Notch-1, a protein involved in embryonic development and cell differentiation, as well as in many neoplasms. Inhibition of Notch-1 signalling by γ-secretase inhibitors slowed down cell-cycle progression and reduced the amount of eIF6 in lymphoblastoid and ovarian cancer cell lines. Cultured ovarian cancer cell lines engineered to stably over-expressing eIF6 did not show significant changes in proliferation rate, but displayed an enhanced motility and invasive capacity. Inhibition of Notch-1 signalling in the cells over-expressing eIF6 was effective in slowing down the cell cycle, but did not reduce cell migration and invasion. On the whole, the results suggest that eIF6 is one of the downstream effectors of Notch-1 in the pathway that controls cell motility and invasiveness

Epsilon iron oxide: origin of the high coercivity stable low Curie temperature magnetic phase found in heated archeological materials

The identification of epsilon iron oxide (ɛ-Fe2O3) as the low Curie temperature high coercivity stable phase (HCSLT) carrying the remanence in heated archeological samples has been achieved in samples from two archeological sites that exhibited the clearest evidence of the presence of the HCSLT. This uncommon iron oxide has been detected by Confocal Raman Spectroscopy (CRS) and characterized by rock magnetic measurements. Large numbers of ɛ-Fe2O3 microaggregates (in CO) or isolated clusters (in HEL) could be recognized, distributed over the whole sample, and embedded within the ceramic matrix, along with hematite and pseudobrookite and with minor amounts of anatase, rutile, and maghemite. Curie temperature estimates of around 170°C for CO and 190°C for HEL are lower than for pure, synthetic ɛ-Fe2O3 (227°C). This, together with structural differences between the Raman spectra of the archeologically derived and synthetic samples, is likely due to Ti substitution in the ɛ-Fe2O3 crystal lattice. The γ-Fe2O3-ɛ-Fe2O3-α-Fe2O3 transformation series has been recognized in heated archeological samples, which may have implications in terms of their thermal history and in the factors that govern the formation of ɛ-Fe2O3

Chromosomal aberrations and aneuploidy in oral potentially malignant lesions: distinctive features for tongue

<p>Abstract</p> <p>Background</p> <p>The mucosae of the oral cavity are different at the histological level but appear all equally exposed to common genotoxic agents. As a result of this exposure, changes in the mucosal epithelia may develop giving rise to Oral Potentially Malignant Lesions (OPMLs), which with time may in turn progress to Oral Squamous Cell Carcinomas (OSCCs). Therefore, much effort should be devoted to identify features able to predict the likeliness of progression associated with an OPML. Such features may be helpful in assisting the clinician to establish both appropriate therapies and follow-up schedules. Here, we report a pilot study that compared the occurrence of DNA aneuploidy and chromosomal copy number aberrations (CNAs) in the OPMLs from different oral anatomical subsites.</p> <p>Methods</p> <p>Samples from histologically diagnosed OPMLs were processed for high resolution DNA flow cytometry (hr DNA-FCM) in order to determine the relative DNA content expressed by the DNA index (DI). Additionally, array-Comparative Genomic Hybridization (a-CGH) analysis was performed on DNA obtained from diploid nuclei suspensions directly. When aneuploid nuclei were detected, these were physically separated from diploid nuclei on the base of their DI values by means of a DNA-FCM-Sorter in order to improve the a-CGH analysis.</p> <p>Results</p> <p>Tongue OPMLs were more frequently associated with DNA aneuploidy and CNAs than OPMLs arising from all the other mucosal subsites.</p> <p>Conclusions</p> <p>We suggest that the follow-up and the management of the patients with tongue OPMLs should receive a distinctive special attention. Clearly, this hypothesis should be validated in a prospective clinical study.</p

New archaeointensity data from Italy and geomagnetic field intensity variation in the Italian Peninsula

We present new archaeointensity results from three Italian kilns situated at Ascoli Satriano, Vagnari and Fontanetto Po obtained with the Thellier modified by Coe double heating method. These data complement the directional results previously published. All sites are dated on the basis of archaeological information and/or thermoluminescence dating. The results are corrected for the anisotropy of the thermoremanent magnetization and the cooling rate effects. The new data are compared with previously published archaeointensity data from Italy and nearby countries within 900 km radius from Viterbo. An initial data set including archaeointesity data mainly coming from Italy, France, Switzerland, Czech Republic, Slovakia, Hungary, Greece and Bulgaria has been compiled. After the application of strict selection criteria, the most reliable data have been used for the calculation of a preliminary Italian intensity secular variation (SV) curve for the last 3000 yr. The new curve covers the 300 BC–400 AD and 1200–1900 AD periods. It is established by means of sliding windows of 200 yr shifted by 100 yr. The lack of reliable data for the 1000–200 BC and 400–1200 AD time intervals does not permit the calculation of a continuous curve. Clearly, more high-quality archaeointensity data from Italy and Europe are still needed to draw a robust intensity SV curve for the Italian Peninsula that could be used for archaeomagnetic dating in combination with the directional data

Tuber donnagotto, a new winter truffle species from Istria, Croatia

Tuber donnagotto is a new winter black truffle belonging to the order Pezizales and the family Tuberaceae. It grows in winter in the calcareous gravel soil (pH 7.6–7.8) near the Adriatic Sea (Rovinj, Istria, Croatia) in predominantly pine forests (Pinus halepensis). Although similar to other black truffles, it has very irregular and hard fruit bodies, lobate and knotted in form, with deep irregular cavities reaching the middle of the fruit bodies. These cavities are clearly evident in the cross-section of the fruit bodies. A distinctive characteristic of this truffle is the fact that when it is hermetically closed it can be kept in a refrigerator (2–4 °C) for more than 60 days. Tuber donnagotto has a slight but pleasant odor, reminiscent of boletus (Boletus reticulates, B. edulis). Furthermore, T. donnagotto has yellow-brownish and reticulate-alveolate spores, measuring 20–30 × 20–25 mm

D-dimer testing, with gender-specific cutoff levels, is of value to assess the individual risk of venous thromboembolic recurrence in non-elderly patients of both genders: a post hoc analysis of the DULCIS study

Male patients, especially the young, are at a higher risk of recurrent venous thromboembolism (RVTE) than females. Recent scientific reports show the use of D-dimer does not help predict RVTE risk in males. In the present report, we reviewed the data obtained in the DULCIS study (main report published in Blood 2014), focusing on D-dimer results recorded in non-elderly patients of both genders included in the study, and their relationship with RVTE events occurring during follow-up. Using specifically designed cutoff values for positive/negative interpretation, serial D-dimer measurements (performed during warfarin treatment and up to 3&nbsp;months after discontinuation of anticoagulation) in 475 patients (males 57.3%) aged 64 65&nbsp;years were obtained. D-dimer resulted positive in 46.3% and 30.5% of males and females, respectively (p = 0.001). Following management procedure, anticoagulation was stopped in 53.7% of males and 69.5% of females, who had persistently negative D-dimer results. The rate of subsequent recurrent events was 1.7% (95% CI 0.5\u20134.5%) and 0.4% (95% CI 0\u20132.5%) patient-years in males and females, respectively, with upper limits of confidence intervals always below the level of risk considered acceptable by international scientific societies for stopping anticoagulation (&lt; 5%). In conclusion, using sensitive quantitative assays with specifically designed cutoff values and serial measurements during and after discontinuation of anticoagulation, D-dimer testing is useful to predict the risk of RVTE and is of help in deciding the duration of anticoagulation in both male and female adult patients aged up to 65&nbsp;years