The FOSSIL Study: FLAG or standard 7+3 induction therapy in secondary acute myeloid leukemia

Patients with secondary acute myeloid leukemia (sAML) have poor outcomes, with CR/CRi rates of 25-35% with standard 7 + 3 induction chemotherapy, while single center non-comparative analyses suggest promising outcomes with FLAG. We conducted a single-center, retrospective cohort study assessing outcomes in treatment-naïve patients with sAML treated with fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (FLAG, n = 40) compared with 7 + 3 (n = 66). Median patient age was 63 years (range: 27-82) in the FLAG group and 60 years (range: 21-76) in the 7 + 3 group (P = 0.968). Patients treated with FLAG achieved higher overall response rates (CR + CRi + MLFS) compared to 7 + 3 (70% vs. 48%, P = 0.043). FLAG was well tolerated, with only one induction death (30-day mortality rate, 3% vs. 8%, P = 0.405) and no cases of cerebellar toxicity. Duration of neutropenia was significantly shorter with FLAG (median 16 vs. 23 days, P \u3c 0.001). Half of the FLAG-treated patients proceeded to consolidative therapy compared with only 27% of those who received 7 + 3 (P = 0.022). Overall survival was comparable between groups (8.5 mos, FLAG vs. 9.1 mos, 7 + 3; P = 0.798). Thus, FLAG may represent a low-cost treatment strategy in sAML that produces higher response rates and promising survival outcomes with minimal treatment-related toxicity. Further studies are required to prospectively compare FLAG to the newly FDA-approved CPX-351 in sAML

Apolipoprotein A-I proteolysis in aortic valve stenosis: role of cathepsin S

Aortic valve stenosis (AVS) is the most common valvular heart disease in the Western world. Therapy based on apolipoprotein A-I (apoA-I), the major protein component of high-density lipoproteins, results in AVS regression in experimental models. Nevertheless, apoA-I degradation by proteases might lead to suboptimal efficacy of such therapy. An activatable probe using a quenched fluorescently labeled full-length apoA-I protein was generated to assess apoA-I-degrading protease activity in plasma derived from 44 men and 20 women with severe AVS (age 65.0 ± 10.4 years) as well as from a rabbit model of AVS. In human and rabbit AVS plasma, apoA-I-degrading protease activity was significantly higher than in controls (humans: 0.038 ± 0.009 vs 0.022 ± 0.005 RFU/s, p < 0.0001; rabbits: 0.033 ± 0.016 vs 0.017 ± 0.005 RFU/s, p = 0.041). Through the use of protease inhibitors, we identified metalloproteinases (MMP) as exerting the most potent proteolytic effect on apoA-I in AVS rabbits (67%, p < 0.05 vs control), while the cysteine protease cathepsin S accounted for 54.2% of apoA-I degradation in human plasma (p < 0.05 vs control) with the maximum effect seen in women (68.8%, p < 0.05 vs men). Accordingly, cathepsin S activity correlated significantly with mean transaortic pressure gradient in women (r = 0.5, p = 0.04) but not in men (r = - 0.09, p = 0.60), and was a significant independent predictor of disease severity in women (standardized beta coefficient 0.832, p < 0.001) when tested in a linear regression analysis. ApoA-I proteolysis is increased in AVS. Targeting circulating cathepsin S may lead to new therapies for human aortic valve disease

Beneficial Effects of High-Density Lipoproteins on Acquired von Willebrand Syndrome in Aortic Valve Stenosis

BACKGROUND Infusions of apolipoprotein A-I (apoA-I), the major protein component of high-density lipoproteins (HDL), result in aortic valve stenosis (AVS) regression in experimental models. Severe AVS can be complicated by acquired von Willebrand syndrome, a haemorrhagic disorder associated with loss of high-molecular-weight von Willebrand factor (vWF) multimers (HMWM), the latter being a consequence of increased shear stress and enhanced vWF-cleaving protease (ADAMTS-13) activity. Although antithrombotic actions of HDL have been described, its effects on ADAMTS-13 and vWF in AVS are unknown. METHODS AND RESULTS We assessed ADAMTS-13 activity in plasma derived from a rabbit model of AVS ( = 29) as well as in plasma collected from 64 patients with severe AVS (age 65.0 ± 10.4 years, 44 males) undergoing aortic valve replacement (AVR). In both human and rabbit AVS plasma, ADAMTS-13 activity was higher than that in controls ( < 0.05). Accordingly, AVS patients had less HMWM than controls (66.3 ± 27.2% vs. 97.2 ± 24.1%,  < 0.0001). Both ADAMTS-13 activity and HMWM correlated significantly with aortic transvalvular gradients, thereby showing opposing correlations ( = 0.3,  = 0.018 and  = -0.4,  = 0.003, respectively). Administration of an apoA-I mimetic peptide reduced ADAMTS-13 activity in AVS rabbits as compared with the placebo group (2.0 ± 0.5 RFU/sec vs. 3.8 ± 0.4 RFU/sec,  < 0.05). Similarly, a negative correlation was found between ADAMTS-13 activity and HDL cholesterol levels in patients with AVS ( = -0.3,  = 0.045). CONCLUSION Our data indicate that HDL levels are associated with reduced ADAMTS-13 activity and increased HMWM. HDL-based therapies may reduce the haematologic abnormalities of the acquired von Willebrand syndrome in AVS

Young Adult Unemployment Through the Lens of Social Media: Italy as a Case Study

Youth unemployment rates are still in alerting levels for many countries, among which Italy. Direct consequences include poverty, social exclusion, and criminal behaviours, while negative impact on the future employability and wage cannot be obscured. In this study, we employ survey data together with social media data, and in particular likes on Facebook Pages, to analyse personality, moral values, but also cultural elements of the young unemployed population in Italy. Our findings show that there are small but significant differences in personality and moral values, with the unemployed males to be less agreeable while females more open to new experiences. At the same time, unemployed have a more collectivist point of view, valuing more in-group loyalty, authority, and purity foundations. Interestingly, topic modelling analysis did not reveal major differences in interests and cultural elements of the unemployed. Utilisation patterns emerged though; the employed seem to use Facebook to connect with local activities, while the unemployed use it mostly as for entertainment purposes and as a source of news, making them susceptible to mis/disinformation. We believe these findings can help policymakers get a deeper understanding of this population and initiatives that improve both the hard and the soft skills of this fragile population