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The prognosis of AML patients with adverse genetics, such as a complex, monosomal karyotype and TP53 lesions, is still dismal even with standard chemotherapy. DNA-hypomethylating agent monotherapy induces an encouraging response rate in these patients. When combined with decitabine (DAC), all-trans retinoic acid (ATRA) resulted in an improved response rate and longer overall survival in a randomized phase II trial (DECIDER; NCT00867672). The molecular mechanisms governing this in vivo synergism are unclear. We now demonstrate cooperative antileukemic effects of DAC and ATRA on AML cell lines U937 and MOLM-13. By RNA-sequencing, derepression of >1200 commonly regulated transcripts following the dual treatment was observed. Overall chromatin accessibility (interrogated by ATAC-seq) and, in particular, at motifs of retinoic acid response elements were affected by both single-agent DAC and ATRA, and enhanced by the dual treatment. Cooperativity regarding transcriptional induction and chromatin remodeling was demonstrated by interrogating the HIC1, CYP26A1, GBP4, and LYZ genes, in vivo gene derepression by expression studies on peripheral blood blasts from AML patients receiving DAC + ATRA. The two drugs also cooperated in derepression of transposable elements, more effectively in U937 (mutated TP53) than MOLM-13 (intact TP53), resulting in a “viral mimicry” response. In conclusion, we demonstrate that in vitro and in vivo, the antileukemic and gene-derepressive epigenetic activity of DAC is enhanced by ATRA.

Metastatic clear cell renal cell carcinomas (ccRCCs) are resistant to DNA-damaging chemotherapies, limiting therapeutic options for patients whose tumors are resistant to tyrosine kinase inhibitors and/or immune checkpoint therapies. Here we show that mouse and human ccRCCs were frequently characterized by high levels of endogenous DNA damage and that cultured ccRCC cells exhibited intact cellular responses to chemotherapy-induced DNA damage. We identify that pharmacological inhibition of the DNA damage–sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) with the orally administered, potent, and selective drug M4344 (gartisertib) induced antiproliferative effects in ccRCC cells. This effect was due to replication stress and accumulation of DNA damage in S phase. In some cells, DNA damage persisted into subsequent G 2 /M and G 1 phases, leading to the frequent accumulation of micronuclei. Daily single-agent treatment with M4344 inhibited the growth of ccRCC xenograft tumors. M4344 synergized with chemotherapeutic drugs including cisplatin and carboplatin and the poly(ADP-ribose) polymerase inhibitor olaparib in mouse and human ccRCC cells. Weekly M4344 plus cisplatin treatment showed therapeutic synergy in ccRCC xenografts and was efficacious in an autochthonous mouse ccRCC model. These studies identify ATR inhibition as a potential novel therapeutic option for ccRCC.

Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic disease with unresolved pathophysiology and limited diagnostic options. Extracellular vesicles (EVs) carry disease-specific protein and miRNA signatures and may enable improved disease profiling. We aimed to identify novel protein and miRNA markers as potential biomarkers in plasma EVs from female ME/CFS patients, including post-COVID-19 ME/CFS and post-infectious ME/CFS of other origins, compared with healthy controls. EVs were isolated from plasma by size-exclusion chromatography and characterized for number, size, morphology, and surface marker expression. Flow cytometry showed that small EVs strongly expressed tetraspanins, with only minor differences between ME/CFS patients and healthy donors. Proteomic profiling of EVs from ME/CFS patients identified altered cargo proteins, including hemoglobin subunit alpha and insulin-like growth factor-binding protein acid labile subunit compared with healthy controls (n ≤ 10/cohort). Small RNA sequencing followed by qPCR revealed significant downregulation of hsa-let-7b-5p in EVs from post-COVID-19 ME/CFS patients (n = 12) versus healthy controls (n = 15). Reduced hsa-let-7b-5p expression correlated with impaired physical functioning and increased fatigue, pain, and immune activation. These findings indicate that EV cargo differences, particularly hemoglobin subunit alpha and insulin-like growth factor-binding protein acid labile subunit, as well as hsa-let-7b-5p, represent promising candidates for ME/CFS diagnosis and patient stratification.

Background/Objectives: Despite multimodal therapeutic concepts, treatment of recurrent malignant gliomas remains challenging. Stereotactic radiosurgery (SRS) may be a possible safe and effective non-invasive salvage treatment. In this study, we aim to investigate the SRS treatment outcomes using partly 18F-Fluorethylthyrosine (FET)-PET-imaging sequences for SRS treatment planning focusing on overall survival, event-free survival, and the incidence and factors influencing radiation necrosis (RN) occurrence. Additionally, we evaluated the potential application of AI-based tumor segmentation. Methods: We conducted a retrospective analysis of patients with recurrent malignant glioma treated with single-fraction or hypofractionated SRS at our institution. The outcomes assessed included local control, overall survival (OS), and local event-free survival (LEFS, defined as the interval until tumor recurrence or the onset of RN). We also performed a simulation analysis to assess the potential of AI-based tumor segmentation. Results: The study included 27 patients with a median age of 57 years and 41 lesions. The median OS post-SRS was 9.6 months and an LEFS of 5.2 months. Factors positively influencing OS and LEFS included the gross tumor volume (GTV) of the lesions before SRS therapy, presence of an IDH mutation, and lomustine treatment post-SRS. The incidence of RN post-SRS was 31.7%. RN was confirmed histopathologically in 15.4%, based on MRI in 46.2% and by FET-PET in 38.5% of lesions. In a simulation analysis, AI-based tumor segmentation reliably delineated all lesions, requiring only minimal manual adjustments to define target volumes. Conclusions: High-dose SRS is a feasible salvage treatment for small-volume recurrent high-grade gliomas, achieving local control and survival outcomes comparable to other re-irradiation strategies. IDH mutation, smaller tumor volume, and lomustine therapy were associated with improved survival. RN occurred frequently, particularly in periventricular lesions. AI-based tumor segmentation showed promise in well-defined satellite recurrences, but remains limited in cavity-adjacent lesions, underlining the need for expert review and 18FET-PET imaging.