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Uncovering the Molecular Mechanisms and Therapeutic Vulnerabilities of t(6;9)-driven Acute Myeloid Leukaemia
Full text linkThe t(6;9)(p22.3;q34.1) translocation/DEK::NUP214 fusion protein defines a distinct subgroup of younger AML patients classified as a separate disease entity by the World Health Organization. DEK is a nuclear factor with multifunctional roles, including gene regulation, while its fusion partner, NUP214, plays a pivotal role in nuclear export by interacting with transport receptors such as XPO1. However, the precise mechanism by which DEK::NUP214 drives leukaemia remains unclear. A comprehensive multi-omics comparison of 57 AML primary samples (including whole genome sequencing, targeted sequencing, transcriptomics and drug screening with > 500 compounds) revealed that t(6;9) cases display a selective response to XPO1 inhibitors (Selinexor & Eltanexor) and a distinct transcriptomic signature characterised by the overexpression of FOXC1 and HOX genes that are key leukaemia mediators. CUT&RUN experiments demonstrated the direct binding of DEK::NUP214 to the promoters of FOXC1 and HOXA/B clusters. Strikingly, the expression of these genes and the binding of DEK::NUP214 to their regulatory regions were selectively reduced upon XPO1 inhibition in t(6;9) cells. Altogether, these results identified a novel function of DEK::NUP214 as an XPO1-dependent transcriptional activator of key leukaemia drivers and provide a rationale to explore the use of XPO1 inhibitors in this patient population
Hidden costs and propped-up profits: unraveling the economics of Europe’s purse-seine tuna fishing industry
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Three Essays on Monetary Policy, Bank Lending, Gender Diversity and Systemic Risk in the Banking Sector
No full textThis dissertation examines the effects of quantitative easing (QE) on U.S. banking behavior and systemic stability during two major crises of distinct origins: the Global Financial Crisis (GFC) and the COVID-19 pandemic. Using detailed bank-level data and robust econometric techniques, the study investigates how QE influenced bank lending, systemic risk, and the role of internal governance in shaping financial stability under different financial conditions. Chapter 2 analyzes QE's transmission through the bank lending channel. Results show that QE stimulated lending during both crises, with stronger effects during the pandemic, especially via Treasury purchases. Real estate lending exhibited a muted and nonlinear response. Notably, QE alleviated liquidity constraints during the GFC, while during the pandemic, improved credit demand drove lending. Endogeneity concerns are addressed using the Federal Reserve's total assets as an instrument. Chapter 3 evaluates QE’s impact on systemic risk using the ΔCoVaR framework. QE reduced banks’ systemic risk contributions in both crises, more significantly during the GFC. Treasury purchases contributed to stability, whereas mortgage-backed securities (MBS) heightened systemic vulnerability. A Two-Stage Least Squares (2SLS) approach using Excess Reserves as an instrument is employed to mitigate endogeneity concerns, confirming the causal effect of QE. Chapter 4 investigates the relationship between board gender diversity and systemic risk. Findings reveal that systemic risk increases when female board representation reaches 30–40%, particularly during crisis periods and QE-induced liquidity expansions. The effect varies by board structure and bank characteristics. A Difference-in-Differences strategy using California’s Senate Bill 826 and Propensity Score Matching support the results. Collectively, the findings underscore that QE’s effectiveness is crisis-contingent, asset composition matters for financial stability, and governance structures play a crucial role in shaping systemic outcomes. These insights carry important implications for the design of unconventional monetary policy and regulatory frameworks in future crises
European Code Against Cancer, 5th edition - organised cancer screening programmes.
Full text linkThe 5th edition of the European Code Against Cancer (ECAC5) recommends sustainable, organised screening programmes for: (a) colorectal cancer using biennial quantitative faecal immunochemical test (FIT) for individuals aged 50-74 years. As an alternative strategy, once-only endoscopy may be considered within the same age range; (b) breast cancer using biennial digital mammography for women aged 50-69 years. Implementing this strategy for women aged 45-49 years and 70-74 years can be considered. Other screening strategies or additional examinations could be considered for women with high mammographic density; (c) cervical cancer using human papillomavirus (HPV) screening at intervals no shorter than 5 years for women aged 30-65 years. It is recommended to adapt policies according to vaccination status and screening history; and (d) lung cancer using annual low-dose computed tomography (LDCT) for individuals considered to be at increased risk of lung cancer based on age, history of smoking or validated risk models, with biennial screening as an alternative. Screening should incorporate smoking cessation interventions
Understanding the role of YTHDF2 in Acute Myeloid Leukaemia through its yeast homologue Pho92
No full textThe N6-methyladenosine modification (m6A) is the most common internal modification and has widespread molecular and biological functions in regulating gene expression. The modification is evolutionarily conserved. It is deposited by a methyltransferase complex onto RRACH motifs on mRNAs and read by a group of YTH domain-containing reader proteins. One of the main functions of m6A is to regulate the rate of m6A-modified transcript turnover. In budding yeast, the only YTH domain reader protein, Pho92, is known to turnover m6A-transcripts. Exactly how Pho92 initiated m6A-transcript degradation was not fully characterised. Pho92 is also the likely yeast homologue of human YTHDF2, which is known to associate with the CCR4-NOT complex. Through various experimental approaches, I initially characterised the Pho92 interactome and defined two possible interaction sites with the Caf40 subunit of the Ccr4-Not complex. Both within Pho92’s intrinsically disordered N-terminus, W5/W18 and an α-helix. Next, I demonstrated that Caf40 had a functional effect on disrupting m6A-dependent transcript stability and identified that the α-helix mediating the interaction with Caf40 was sufficient for degradation and could be disrupted by the point mutation L35A. I then assessed conserved regions in YTHDF2 and demonstrated tryptophan-mediated interactions with Caf40 homologue, CNOT9, via W75 and W134 and isolated 1-250aa to be sufficient for degradation. The mechanism of YTHDF2 in acute myeloid leukaemia (AML) initiation and propagation involves its regulation of m6A-modified transcripts, likely through the CCR4-NOT complex. Therefore, I characterised the effects of CNOT9 knockdown (KD) in THP1 AML cell lines and found that it disrupted cellular proliferation, increased apoptosis, increased myeloid differentiation and reduced colony formation. Based on these findings, I propose CNOT9 as a promising therapeutic target that should undergo further cellular and molecular characterisation in AML
The impact of subject weight and activity level on over-inserted cemented acetabular cups after Total HIP Arthroplasty (THA).
No full textIn cemented Total Hip Arthroplasty (THA), several risk factors have been identified with the failure of the acetabular component, including body mass index (BMI), exercise, femoral head size, cup placement, and cement mantle integrity. Elevated BMI and larger femoral heads increase bone and cement stresses, accelerating wear and predisposing to aseptic loosening. This study evaluates the effect of over-inserted acetabular cups on cement mantle interfaces and pelvic bone stresses using two femoral head sizes (28 mm and 36 mm), four body weights (normal, overweight, obese, and morbidly obese), and three activities (one-leg stand, stair descent, and stumbling). Results show that von Mises stresses rise with increasing body weight, activity intensity, and femoral head size, with the highest values observed in the superior periacetabular region of the pelvic bone for the morbidly obese subject during stumbling with the 36 mm head. Stresses at the bone-cement interface exceeded those at the cement-cup interface, particularly in the superior quadrant of over-inserted cups. Our findings suggest that morbidly obese subjects are at a higher risk of aseptic loosening due to the stresses induced in the bone-cement interface during physical activities, resulting in higher peak hip reaction forces. This risk is increased in the case of over-insertion of the acetabular cup, leading to a thinner cement layer. These findings highlight the combined influence of implant design, patient characteristics, and surgical technique on long-term THA performance
Circulating HBV RNA and hepatitis B core-related antigen as determinants of HBsAg loss in persons with HIV in Europe.
Get PDFBACKGROUND & AIMS: HBsAg loss improves clinical outcomes in persons with HIV and HBV coinfection. We aimed to evaluate if hepatitis B core-related antigen and circulating HBV RNA levels were associated with HBsAg loss in Euro-B, a multi-cohort collaboration including data from the Swiss HIV Cohort Study, EuroSIDA, and the French HIV/HBV cohort. METHODS: We included persons with HIV, a positive HBsAg, and ≥6 months of follow-up on tenofovir-containing antiretroviral therapy. We evaluated quantitative HBsAg, HBV DNA, hepatitis B core-related antigen, and HBV RNA levels over time and assessed HBsAg loss (i.e. quantitative HBsAg <0.05 IU/ml) during tenofovir therapy. RESULTS: Among 599 participants median age was 41 years (IQR 35-47), 18.4% were female and 47.3% HBeAg-positive. We observed HBsAg loss in 12.9% of participants after 2 years and in 18.2% during a median follow-up of 8.2 years (IQR 3.6-13.1). Individuals who were HBeAg-negative were more likely to have a negative hepatitis B core-related antigen and HBV RNA below the detection limit than participants who were HBeAg-positive. Quantitative HBsAg ≤1,000 IU/ml at baseline was the strongest predictor of HBsAg loss regardless of HBeAg status. Additionally, HBsAg loss was associated with lower baseline HBV RNA levels (odds ratio 0.66, 95% CI 0.49-0.88) and higher baseline HBV DNA levels in participants who were HBeAg-positive. CONCLUSIONS: In this European cohort of persons with HIV/HBV, 18% experienced HBsAg loss during tenofovir-containing antiretroviral therapy. In addition to low baseline quantitative HBsAg levels, HBV RNA may predict HBsAg loss in individuals who are HBeAg-positive. IMPACT AND IMPLICATIONS: The present study builds on a multi-cohort collaboration including persons with HIV/HBV from Europe. It provides estimates on the probability of HBsAg loss during long-term tenofovir-containing antiretroviral therapy and describes the potential of the novel biomarkers HBV RNA and hepatitis B core-related antigen as its predictors. The discrepancies regarding HBV RNA and HBcrAg levels before and during therapy observed between persons who were HBeAg-negative and HBeAg-positive with HIV/HBV may influence treatment decisions and the development of new treatment strategies. CLINICAL TRIALS REGISTRATION: The study is registered at ClinicalTrials.gov (NCT04984772)