Identifying Candidate Gene Drivers Associated with Relapse in Pediatric T-Cell Acute Lymphoblastic Leukemia Using a Gene Co-Expression Network Approach.

Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) relapses are still associated with a dismal outcome, justifying the search for new therapeutic targets and relapse biomarkers. Using single-cell RNA sequencing (scRNAseq) data from three paired samples of pediatric T-ALL at diagnosis and relapse, we first conducted a high-dimensional weighted gene co-expression network analysis (hdWGCNA). This analysis highlighted several gene co-expression networks (GCNs) and identified relapse-associated hub genes, which are considered potential driver genes. Shared relapse-expressed genes were found to be related to antigen presentation (HLA, B2M), cytoskeleton remodeling (TUBB, TUBA1B), translation (ribosomal proteins, EIF1, EEF1B2), immune responses (MIF, EMP3), stress responses (UBC, HSP90AB1/AA1), metabolism (FTH1, NME1/2, ARCL4C), and transcriptional remodeling (NF-κB family genes, FOS-JUN, KLF2, or KLF6). We then utilized sparse partial least squares discriminant analysis to select from a pool of 481 unique leukemic hub genes, which are the genes most discriminant between diagnosis and relapse states (comprising 44, 35, and 31 genes, respectively, for each patient). Applying a Cox regression method to these patient-specific genes, along with transcriptomic and clinical data from the TARGET-ALL AALL0434 cohort, we generated three model gene signatures that efficiently identified relapsed patients within the cohort. Overall, our approach identified new potential relapse-associated genes and proposed three model gene signatures associated with lower survival rates for high-score patients.

Collective memory in the digital age.

The digital transformation of our societies particulary driven by information and communication technologies have revolutionized how we generate, communicate, and acquire information. Collective memory as a core and unifying force in our societies has not been an exception among many societal concepts which have been revolutionized through this digital transformation. In this chapter, we have distinguished between "digitalized collective memory" and "collective memory in the digital age". In addition to discussing these two main concepts, we discuss how digital tools and trace data can open doorways into the study of collective memory that is formed inside and outside of the digital space.

Safety and Tolerability of the Potassium Binder Patiromer From a Global Pharmacovigilance Database Collected Over 4 Years Compared with Data from the Clinical Trial Program.

INTRODUCTION: The availability of the sodium-free potassium binder patiromer opens new opportunities for hyperkalemia management. OBJECTIVE: Our objective was to compare data from a 4-year global pharmacovigilance database of adverse events (AEs) reported in patients prescribed patiromer in clinical practice compared with data obtained from the clinical trial program. METHODS: Postmarketing safety data regarding patiromer (Veltassa®; Vifor Pharma, Inc.), collected and recorded in the company's global pharmacovigilance database, were analyzed for the period from January 2016 through September 2019. These data were both solicited (i.e., via an organized data-collection method such as a patient-support program) and unsolicited (i.e., voluntarily reported by healthcare professionals, consumers, and competent authorities worldwide). The cumulative annualized mortality rate (events per 100 patient-years [PYs]) for the pharmacovigilance database analysis period were compared with the rate obtained in the longest patiromer clinical trial to date (up to 52 weeks of treatment). For individual AEs, reporting rates (% of events/100 PYs) for events collected in the global pharmacovigilance database were compared with the frequencies (% of patients with event/patients exposed) of events collected in the clinical trial program (N = 666). RESULTS: Over 4 years, the global pharmacovigilance database contained an estimated 45,000 PYs of exposure (17,823 individual case reports and 38,109 AEs), with most cases (95%) from the USA; > 85% of cases utilized 8.4 g/day. In total, 1214 deaths were reported, with a cumulative annualized mortality rate of 2.69/100 PYs (vs. 5.70 deaths/100 PYs in the 52-week clinical trial). Global pharmacovigilance reporting rates for the two most common AEs, constipation and diarrhea, were 6.90 and 3.48%, respectively. Respective frequencies were 7.2 and 4.8% in the clinical trial program. The pharmacovigilance reporting rate for AEs of decreased blood potassium was 0.45%; serum potassium < 3.5 mmol/L was reported in 4.7% of patients in the clinical trial program. For hypomagnesemia or decreased blood magnesium, reporting rates in the postmarketing setting were 0.02 and 0.16%, respectively, and they were observed in 5.3 and 0.8% of patients, respectively, in the clinical trial program. CONCLUSIONS: Global pharmacovigilance data over 4 years confirmed that the tolerability and safety of patiromer in clinical practice is predictable and consistent with clinical trial data, with no evidence of any new safety signals to date.

Trends in summer presence of fin whales in the Western Mediterranean Sea Region: new insights from a long-term monitoring program.

BACKGROUND: The Mediterranean subpopulation of fin whale Balaenoptera physalus (Linnaeus, 1758) has recently been listed as Vulnerable by the IUCN Red List of threatened species. The species is also listed as species in need of strict protection under the Habitat Directive and is one of the indicators for the assessment of Good Environmental Status under the MSFD. Reference values on population abundance and trends are needed in order to set the threshold values and to assess the conservation status of the population. METHODS: Yearly summer monitoring using ferries as platform of opportunity was performed since 2008 within the framework of the FLT Med Network. Data were collected along several fixed transects crossing the Western Mediterranean basin and the Adriatic and Ionian region. Species presence, expressed by density recorded along the sampled transects, was inspected for assessing interannual variability together with group size. Generalized Additive Models were used to describe density trends over a 11 years' period (2008-2018). A spatial multi-scale approach was used to highlight intra-basin differences in species presence and distribution during the years. RESULTS: Summer presence of fin whales in the western Mediterranean area showed a strong interannual variability, characterized by the alternance of rich and poor years. Small and large groups of fin whales were sighted only during rich years, confirming the favorable feeding condition influencing species presence. Trends highlighted by the GAM can be summarized as positive from 2008 to 2013, and slightly negative from 2014 to 2018. The sub-areas analysis showed a similar pattern, but with a more stable trend during the second period in the Pelagos Sanctuary sub-area, and a negative one in the other two sub-areas. Our findings further confirm the need for an integrated approach foreseeing both, large scale surveys and yearly monitoring at different spatial scales to correct and interpret the basin wide abundance estimates, and to correlate spatial and temporal trends with the ecological and anthropogenic drivers.

Assessing cetacean surveys throughout the Mediterranean Sea: a gap analysis in environmental space.

Heterogeneous data collection in the marine environment has led to large gaps in our knowledge of marine species distributions. To fill these gaps, models calibrated on existing data may be used to predict species distributions in unsampled areas, given that available data are sufficiently representative. Our objective was to evaluate the feasibility of mapping cetacean densities across the entire Mediterranean Sea using models calibrated on available survey data and various environmental covariates. We aggregated 302,481 km of line transect survey effort conducted in the Mediterranean Sea within the past 20 years by many organisations. Survey coverage was highly heterogeneous geographically and seasonally: large data gaps were present in the eastern and southern Mediterranean and in non-summer months. We mapped the extent of interpolation versus extrapolation and the proportion of data nearby in environmental space when models calibrated on existing survey data were used for prediction across the entire Mediterranean Sea. Using model predictions to map cetacean densities in the eastern and southern Mediterranean, characterised by warmer, less productive waters, and more intense eddy activity, would lead to potentially unreliable extrapolations. We stress the need for systematic surveys of cetaceans in these environmentally unique Mediterranean waters, particularly in non-summer months.