Ponatinib is a third-generation tyrosine-kinase inhibitor (TKI), indicated in patients with chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML), who are ...resistant or intolerant to ≥2 prior TKIs, patients for whom subsequent treatment with imatinib is not appropriate, and patients who have a T315I mutation.
We aimed to evaluate outcomes of ponatinib treatment, including safety, with focus on cardiovascular toxicity, in real-world patients from Argentina. Data from patients with CP CML treated with ponatinib was retrospectively retrieved from 2013 to 2023 in 7 centers.
Seventy-two patients were included (median age: 44 years; male: 55.5%; T315I mutation: 32%: median treatment duration: 36 months. At baseline, 57 patients (79%) had a breakpoint cluster region–Abelson (BCR::ABL1) transcript level >10% on the international reporting scale (BCR::ABL1 IS). A molecular response (MR, BCR::ABL1 (IS) <1%) was achieved at 12 months in 51.6% of evaluable patients; 57% maintained MR at last follow-up. Overall, 43% and 25% maintained major MR (MMR) or deep MR (DMR) (MR4.0-MR5.0), respectively at last follow-up. Twelve (16.6%) ponatinib-resistant patients were rescued with allogeneic hematopoietic stem cell transplantation. The estimated 2-year progression-free survival (PFS) was 84%. Ponatinib dose was reduced during treatment in 22 patients; nevertheless, MMR was maintained in 50% of these patients. Severe arterial occlusive events (AOE) were reported in 10.9% of patients after a median treatment of 5 months.
CV toxicity was consistent with clinical trials and other real-world registries. Older age, hypercholesterolemia and a SCORE risk >2% were significantly associated with higher risk of AOEs. Controlling CV risk factors and reducing doses at optimal time points may help to optimize ponatinib use in daily practice.
We evaluate outcomes of ponatinib treatment in Argentinean real-world setting. Seventy-two patients were included. Molecular response (MR) <1% IS%BCR::ABL1 at 12 months was achieved in 51.6% of evaluable patients. Estimated 2-year progression free survival was 84%. Older age, hypercholesterolemia and a SCORE-risk >2% were significantly associated with higher risk of arterial occlusive events. Control of CV risk factors and reducing doses at optimal time-points may help to optimize ponatinib use in daily practice.
Dietary fiber supplements are a strategy to close the 'fiber gap' and induce targeted modulations of the gut microbiota. However, higher doses of fiber supplements cause gastrointestinal (GI) ...symptoms that differ among individuals. What determines these inter-individual differences is insufficiently understood. Here we analyzed findings from a six-week randomized controlled trial that evaluated GI symptoms to corn bran arabinoxylan (AX; n = 15) relative to non-fermentable microcrystalline cellulose (MCC; n = 16) at efficacious supplement doses of 25 g/day (females) or 35 g/day (males) in adults with excess weight. Self-reported flatulence, bloating, and stomach aches were evaluated weekly. Bacterial taxa involved in AX fermentation were identified by bioorthogonal non-canonical amino acid tagging. Associations between GI symptoms, fecal microbiota features, and diet history were systematically investigated. AX supplementation increased symptoms during the first three weeks relative to MCC (p < 0.05, Mann-Whitney tests), but subjects 'adapted' with symptoms reverting to baseline levels toward the end of treatment. Symptom adaptations were individualized and correlated with the relative abundance of Bifidobacterium longum at baseline (rs = 0.74, p = 0.002), within the bacterial community that utilized AX (rs = 0.69, p = 0.006), and AX-induced shifts in acetate (rs = 0.54, p = 0.039). Lower baseline consumption of animal-based foods and higher whole grains associated with less severity and better adaptation. These findings suggest that humans do 'adapt' to tolerate efficacious fiber doses, and this process is linked to their microbiome and dietary factors known to interact with gut microbes, providing a basis for the development of strategies for improved tolerance of dietary fibers.Dietary fiber supplements are a strategy to close the 'fiber gap' and induce targeted modulations of the gut microbiota. However, higher doses of fiber supplements cause gastrointestinal (GI) symptoms that differ among individuals. What determines these inter-individual differences is insufficiently understood. Here we analyzed findings from a six-week randomized controlled trial that evaluated GI symptoms to corn bran arabinoxylan (AX; n = 15) relative to non-fermentable microcrystalline cellulose (MCC; n = 16) at efficacious supplement doses of 25 g/day (females) or 35 g/day (males) in adults with excess weight. Self-reported flatulence, bloating, and stomach aches were evaluated weekly. Bacterial taxa involved in AX fermentation were identified by bioorthogonal non-canonical amino acid tagging. Associations between GI symptoms, fecal microbiota features, and diet history were systematically investigated. AX supplementation increased symptoms during the first three weeks relative to MCC (p < 0.05, Mann-Whitney tests), but subjects 'adapted' with symptoms reverting to baseline levels toward the end of treatment. Symptom adaptations were individualized and correlated with the relative abundance of Bifidobacterium longum at baseline (rs = 0.74, p = 0.002), within the bacterial community that utilized AX (rs = 0.69, p = 0.006), and AX-induced shifts in acetate (rs = 0.54, p = 0.039). Lower baseline consumption of animal-based foods and higher whole grains associated with less severity and better adaptation. These findings suggest that humans do 'adapt' to tolerate efficacious fiber doses, and this process is linked to their microbiome and dietary factors known to interact with gut microbes, providing a basis for the development of strategies for improved tolerance of dietary fibers.
Dietary fiber is an integral part of a healthy diet, but questions remain about the mechanisms that underlie effects and the causal contributions of the gut microbiota. Here, we performed a 6-week ...exploratory trial in adults with excess weight (BMI: 25-35 kg/m
) to compare the effects of a high-dose (females: 25 g/day; males: 35 g/day) supplement of fermentable corn bran arabinoxylan (AX; n = 15) with that of microbiota-non-accessible microcrystalline cellulose (MCC; n = 16). Obesity-related surrogate endpoints and biomarkers of host-microbiome interactions implicated in the pathophysiology of obesity (trimethylamine N-oxide, gut hormones, cytokines, and measures of intestinal barrier integrity) were assessed. We then determined whether clinical outcomes could be predicted by fecal microbiota features or mechanistic biomarkers.
AX enhanced satiety after a meal and decreased homeostatic model assessment of insulin resistance (HOMA-IR), while MCC reduced tumor necrosis factor-α and fecal calprotectin. Machine learning models determined that effects on satiety could be predicted by fecal bacterial taxa that utilized AX, as identified by bioorthogonal non-canonical amino acid tagging. Reductions in HOMA-IR and calprotectin were associated with shifts in fecal bile acids, but correlations were negative, suggesting that the benefits of fiber may not be mediated by their effects on bile acid pools. Biomarkers of host-microbiome interactions often linked to bacterial metabolites derived from fiber fermentation (short-chain fatty acids) were not affected by AX supplementation when compared to non-accessible MCC.
This study demonstrates the efficacy of purified dietary fibers when used as supplements and suggests that satietogenic effects of AX may be linked to bacterial taxa that ferment the fiber or utilize breakdown products. Other effects are likely microbiome independent. The findings provide a basis for fiber-type specific therapeutic applications and their personalization.
Clinicaltrials.gov, NCT02322112 , registered on July 3, 2015. Video Abstract.
Although it is noted that interpersonal sensorimotor coordination can influence several high-level socio-cognitive processes, its impact on creative collaboration is nearly unexplored. Here, we ...investigated the effects of a form of sensorimotor coordination, that is, sensorimotor synchronization, on a subsequent creative collaboration task. 60 pairs (
total = 120 participants) formed by previously unacquainted individuals performed a tower-building task either jointly or alone, followed by a dyadic creativity task. Tower building time in the joint condition was recorded through a sensorized platform and creativity performance was evaluated by two independent raters based on the quantity and quality of generated ideas. We controlled for gender composition and for the disposition to cooperate and to adopt a creative, analytical style. Results showed that male-male couples were more creative after the joint-action condition, whereas female-female and mixed-gender couples were more creative after the solo condition. Regression analyses of tower building time on creativity performance revealed that building time was a significant predictor of creativity dimensions in male-male and in mixed-gender couples but did not predict creative performance in female-female couples. Overall, these findings suggest that the manipulation of sensorimotor coordination can influence performance in a subsequent creative collaboration task, with the nature, and magnitude of this effect depending on the gender composition of the dyads. These results have potential implications for the design of sensorimotor-based strategies to enhance dyadic creative performance in several contexts, especially for the organizational settings.
SCN2A gene pathogenic variants are associated with a wide phenotypic spectrum, encompassing epilepsy, developmental delay, and autism spectrum disorder. Researches conducted in Denmark have revealed ...a disease frequency of approximately 1/78,608 (0.0012%) live births in this population. We estimated the frequency of SCN2A-related disorder in the birth cohort of Brescia and its province between 2002 and 2021.
Frequency was calculated by ratio between patients with SCN2A pathogenic variant and the total number of live births at the Regional Epilepsy Center of Brescia, between 2002 and 2021. The number of births in Brescia and province was obtained from the Italian National Institute of Statistics (ISTAT).
A frequency of 11/23,2678 births (0.0047%) was found. In comparison with Danish data, we noticed a higher frequency of the pathogenic variant in our population, even considering the same time frame (0.0035% of subjects born between 2006 and 2014).
The frequency of SCN2A pathogenic variant among live births in Brescia and its Province between 2006 and 2014 was about three times that of Danish population; this difference was about four times if we consider the period from 2002 to 2021. More studies are needed to further delineate the frequency of SCN2A pathogenic variant in Italian population.
•According to literature, there is only one article containing data on frequency of SCN2A pathogenic variants, estimated in the Danish population, which is about 1/78,608 (0.0013%) live births.•Our analysis revealed a frequency of SCN2A pathogenic variant about 0.0047% of live births in the city of Brescia and its province (11/232678).•In the timeframe between 2002 and 2021, in Brescia and its province, the frequency of this pathogenic variant was approximately four times the frequency observed in the Danish population.
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Background: Data on the safety and efficacy of copy drugs is usually unavailable. Imatinib mesylate is used to treat chronic myeloid leukemia (CML) patients in Argentina since 2002. During the last ...decade more than ten different imatinib copies are marketed by the different health-care systems in the country, usually for cost issues. In spite of the undoubted benefit of this tyrosine-kinase inhibitor indication in CML, there is no solid evidence that supports copy drug equivalent outcomes for this patient population.
Aim: To compare the clinical presentation, treatment response and outcome of a chronic phase (CP) CML patient cohort treated with branded and copy imatinib in the real-life setting.
Methods: Multicentric, retrospective trial based on data obtained from medical charts of adult CP CML patients treated with imatinib in 9 centers in Argentina from 2002 to 2020.We analyzed demographic characteristics and clinical characteristics described for branded and copy imatinib treated cohorts. Frequency of complete cytogenetic response (CCyR) at 12 months, Major molecular response or better(≥MMR) at 12, 18 and 24 months and overall MR4.0, MR4.5 and deep molecular response (MR4.0 +MR4.5 IS) were analyzed. Event was defined as failure, progression or CML related death. Kaplan Meier comparison of event free, progression free and overall survival.
Statistics: IBM SPSS version 1.
Results: A total of 568 CP CML adult patients (pt) treated with imatinib were included. Mean age at diagnosis: 45.7 years (range 18 - 85). Male 55.6% (316/568). Sokal Score was recorded in 471 pt: 57% (269/471) low, 26% (122/471) intermediate and 17% (80/471) high-risk. Median follow-up 107 months (RIQ: 36-149). Branded imatinib treatment 330 (58%) and imatinib copies 238 (42%).
For branded and copy imatinib cohorts mean age 46,1 (18-85) and 45.3(18-80), male 53% (175/330) and 59% (141/238), median follow up 102 (RIQ 101-130) and 61 (RIQ 62-146) respectively. Sokal score low 58% (164/284) and 56% (105/187), intermediate 27% (77/284) and 24% (45/187) and high 15% (43/284) and19% (37/187). Frequency of CCyR at 12 months 71% (67/94) and 69% (41/59), ≥MMR at 12 months 57% (79/138) and 43% (39/89), ≥MMR 18m 66 % (61/92) and 71% (43/60), ≥MMR 24m 65% (96/147) and 79% (58/73). Overall MR4, MR 4.5 and Deep MR with branded imatinib 62.4% (186/298), 42% (118/276) and 63% (189/300), compared to 45(97/214), 24% (50/207) and 46% (99/215) with copies. Difference in evaluation throughout the treatment periods with loss of data did not allow response rate statistical comparison in predetermined timepoints. Kaplan Meier Event free survival median 229 months vs 75 months p 0.001, Progression free survival mean 318 months vs 208 pt 0.034 and Overall Survival mean 275 months vs 206 months for branded and copy imatinib respectively.
Discussion: Several case reports have shown poor outcomes in patients treated with imatinib copy drugs, including loss of responses previously attained with branded imatinib. This study reports data from a large cohort of CP CML patients treated in daily practice during a long period of time. Treatment results at determined timepoints is comparable. Although management and treatment decisions were performed in different time periods, results show different outcomes in EFS and PFS between patients treated with branded vs copy imatinib. Overall survival in both cohorts is comparable. As studies assesing the safety and efficacy of the copy drugs compared with branded imatinib will hardly be performed this evidence calls for careful attention and strict follow up measures when managing CML patients with copy imatinib.
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Varela:Novartis: Consultancy, Speakers Bureau. Pavlovsky:Pint Pharma: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Freitas:Pfizer: Consultancy, Other: Advisory Board. Pavlovsky:Varifarma: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau. Moiraghi:Novartis: Speakers Bureau; BMS: Speakers Bureau.
Elderly patients with hemophilia have to face new challenges linked to concomitant pathologies and concurrent use of different treatments. In order to promote optimal care in the elderly hemophilia ...population, this study is aimed to analyze treatment compliance in relation to the presence of comorbidities and the role of potential determinants that can affect compliance (positively or negatively), including health-related quality of life, cognitive decline, and sociodemographic parameters (eg, living situation, partnership, presence of caregivers). This will be an observational study of elderly patients with hemophilia (aged >60 years). Patients will be interviewed during their routine medical visits. The data interview will pertaining to several dimension of treatment management. This study will detect more vulnerable patients with special care needs and will highlight psychological factors that should be considered for future psychosocial interventions.
Regulation of hematopoiesis during human development remains poorly defined. Here we applied single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin ...sequencing (scATAC-seq) to over 8,000 human immunophenotypic blood cells from fetal liver and bone marrow. We inferred their differentiation trajectory and identified three highly proliferative oligopotent progenitor populations downstream of hematopoietic stem cells (HSCs)/multipotent progenitors (MPPs). Along this trajectory, we observed opposing patterns of chromatin accessibility and differentiation that coincided with dynamic changes in the activity of distinct lineage-specific transcription factors. Integrative analysis of chromatin accessibility and gene expression revealed extensive epigenetic but not transcriptional priming of HSCs/MPPs prior to their lineage commitment. Finally, we refined and functionally validated the sorting strategy for the HSCs/MPPs and achieved around 90% enrichment. Our study provides a useful framework for future investigation of human developmental hematopoiesis in the context of blood pathologies and regenerative medicine.
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•The epigenetic and transcriptional landscape of human fetal hematopoiesis•Blood stem cells differentiate into three distinct oligopotent progenitor populations•Changes in motif accessibility in blood stem cells precede transcriptional priming•Refined sorting strategy to isolate and enrich for human fetal blood stem cells
Ranzoni et al. provide a detailed transcriptional and chromatin accessibility map of fetal liver and bone marrow hematopoietic stem cells (HSCs). Within HSCs, they revealed extensive epigenetic but not transcriptional priming. They identified transcriptional and functional differences between HSCs from liver and bone marrow.
Background:
The COVID-19 pandemic had a massive impact on health care systems, increasing the risks of psychological distress in health professionals. This study aims at assessing the prevalence of ...burnout and psychopathological conditions in health professionals working in a health institution in the Northern Italy, and to identify socio-demographic, work-related and psychological predictors of burnout.
Methods:
Health professionals working in the hospitals of the Istituto Auxologico Italiano were asked to participate to an online anonymous survey investigating socio-demographic data, COVID-19 emergency-related work and psychological factors, state anxiety, psychological distress, post-traumatic symptoms and burnout. Predictors of the three components of burnout were assessed using elastic net regression models.
Results:
Three hundred and thirty health professionals participated to the online survey. Two hundred and thirty-five health professionals (71.2%) had scores of state anxiety above the clinical cutoff, 88 (26.8%) had clinical levels of depression, 103 (31.3%) of anxiety, 113 (34.3%) of stress, 121 (36.7%) of post-traumatic stress. Regarding burnout, 107 (35.7%) had moderate and 105 (31.9%) severe levels of emotional exhaustion; 46 (14.0%) had moderate and 40 (12.1%) severe levels of depersonalization; 132 (40.1%) had moderate and 113 (34.3%) severe levels of reduced personal accomplishment. Predictors of all the three components of burnout were work hours, psychological comorbidities, fear of infection and perceived support by friends. Predictors of both emotional exhaustion and depersonalization were female gender, being a nurse, working in the hospital, being in contact with COVID-19 patients. Reduced personal accomplishment was also predicted by age.
Conclusions:
Health professionals had high levels of burnout and psychological symptoms during the COVID-19 emergency. Monitoring and timely treatment of these conditions is needed.
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