Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells.

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML

Comparison of Iron Oxide-Related MRI Artifacts in Healthy and Neuropathological Human Brain Tissue

The aim of this study is to clarify whether clinical magnetic resonance imaging data can be utilised to evaluate the pathological processes associated with disrupted iron homeostasis, such as neurodegenerative processes or cirrhosis. Although MRI has the potential to become a non-invasive biomarker of such pathology, new quantification methods must be introduced. Our findings confirmed that it is possible to detect significant difference between healthy and pathological tissue from standard T2 weighted MRI protocols

Differentiation of Native and Reconstructed Ferritin using the MRI Gradient Echo Pulse Sequence

Ferritin is a biological iron storage biomacromolecule, consisting of a spherical protein shell (apoferritin) and mineral iron core. It plays a crucial role in the pathological processes of disrupted iron homeostasis followed by iron accumulation, linked with various disorders (e.g. neuroinflammation, neurodegeneration, cirrhosis, cancer, etc.) In vitro reconstructed ferritin, with the assistance of a non-invasive magnetic resonance imaging technique, has the potential to become a suitable biomarker of these pathological processes. Through gradient echo pulse sequencing, we were able to clearly distinguish between native (physiological) and reconstructed/iron-overloaded (pathological) ferritin, which can serve as a starting point for the development of a method for their differentiation. Such method is necessary for the early diagnosis of iron-based diseases

Effect of BSA Protein on the Contrast Properties of Magnetite Nanoparticles during MRI

The aim of the study was to establish whether there is a significant change in the MRI contrast of magnetite nanoparticles, after BSA protein binding on the surface of particles. The rationale is the applicability of this feature in clinical practice for the tracking of specific proteins which are often associated with various pathologies. Contrast agents could bind to this specific marker, with the change in MRI contrast indicating the presence of pathology. We found that changes in relative contrast acquired at low-field MRI offer potential for the differentiation of magnetite nanoparticles with and without BSA protein. However, the variations in the transverse relaxation time (T₂) and transverse relaxivity (r₂), acquired at high-field MRI, were too small to be applicable for biomedical applications

Histomorphological responses after therapy with pegylated interferon α-2a in patients with essential thrombocythemia (ET) and polycythemia vera (PV)

Abstract Background Pegylated interferon alfa-2a (PEG-IFN-α-2a) is a potent immunomodulating agent capable of inducing high rate of hematologic and even complete molecular remission in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We recently reported results of a phase 2 trial of PEG-IFN-α-2a in 83 patients with ET and PV after a median follow-up of 83 months. Here we report an analysis of bone marrow (BM) responses in these patients. Methods Among 83 patients, 58 (70%, PV 25, ET 31) had evaluable BM samples. BM responses and fibrosis grading were defined according to the International Working Group for Myeloproliferative Neoplasms Research and Treatment, and the European Consensus on grading of BM fibrosis, respectively. BM was assessed prior to enrollment, and every 6–24 months while on therapy in all patients, and after therapy discontinuation in some patients. Results The median age of analyzed 58 patients was 52 years, and 29% were males. After a median follow-up of 84 months, 32 patients are still on study. Hematologic (HR) and molecular responses (MR) were seen in 93 and 69% patients, respectively. Twenty-nine patients (50%) had a BM response, including 13 (22%) with a complete BM response (BM-CR). Moreover, 13 patients (22%) have experienced complete resolution of bone marrow reticulin fibrosis. Patients with BM response had higher duration of HR and MR, and lower discontinuation rate. Furthermore, patients with BM-CR had a higher probability of complete MR. The median duration of BM-CR was 30 months, and 9 patients have maintained their BM-CR (69%), including five who have maintained their response after discontinuation of therapy. Despite this observation, the pattern of HR, MR and BM response, their durability and interrelation was heterogeneous. Conclusions Our results show the ability of PEG-IFN-α-2a to induce complete BM responses in a subset of ET and PV patients, but its correlation with durable clinically relevant treatment benefit warrants further investigation. Trial registration This study is registered with ClinicalTrials.gov (NCT00452023), and is ongoing but not enrolling new patients