Targeting Glutaminolysis Shows Efficacy in Both Prednisolone-Sensitive and in Metabolically Rewired Prednisolone-Resistant B-Cell Childhood Acute Lymphoblastic Leukaemia Cells.

The prognosis for patients with relapsed childhood acute lymphoblastic leukaemia (cALL) remains poor. The main reason for treatment failure is drug resistance, most commonly to glucocorticoids (GCs). The molecular differences between prednisolone-sensitive and -resistant lymphoblasts are not well-studied, thereby precluding the development of novel and targeted therapies. Therefore, the aim of this work was to elucidate at least some aspects of the molecular differences between matched pairs of GC-sensitive and -resistant cell lines. To address this, we carried out an integrated transcriptomic and metabolomic analysis, which revealed that lack of response to prednisolone may be underpinned by alterations in oxidative phosphorylation, glycolysis, amino acid, pyruvate and nucleotide biosynthesis, as well as activation of mTORC1 and MYC signalling, which are also known to control cell metabolism. In an attempt to explore the potential therapeutic effect of inhibiting one of the hits from our analysis, we targeted the glutamine-glutamate-α-ketoglutarate axis by three different strategies, all of which impaired mitochondrial respiration and ATP production and induced apoptosis. Thereby, we report that prednisolone resistance may be accompanied by considerable rewiring of transcriptional and biosynthesis programs. Among other druggable targets that were identified in this study, inhibition of glutamine metabolism presents a potential therapeutic approach in GC-sensitive, but more importantly, in GC-resistant cALL cells. Lastly, these findings may be clinically relevant in the context of relapse-in publicly available datasets, we found gene expression patterns suggesting that in vivo drug resistance is characterised by similar metabolic dysregulation to what we found in our in vitro model.

miRNAs in Lymphocytic Leukaemias-The miRror of Drug Resistance.

Refractory disease and relapse remain the main causes of cancer therapy failure. Refined risk stratification, treatment regimens and improved early diagnosis and detection of minimal residual disease have increased cure rates in malignancies like childhood acute lymphoblastic leukaemia (ALL) to 90%. Nevertheless, overall survival in the context of drug resistance remains poor. The regulatory role of micro RNAs (miRNAs) in cell differentiation, homeostasis and tumorigenesis has been under extensive investigation in different cancers. There is accumulating data demonstrating the significance of miRNAs for therapy outcomes in lymphoid malignancies and some direct demonstrations of the interplay between these small molecules and drug response. Here, we summarise miRNAs' impact on chemotherapy resistance in adult and paediatric ALL and chronic lymphocytic leukaemia (CLL). The main focus of this review is on the modulation of particular signaling pathways like PI3K-AKT, transcription factors such as NF-κB, and apoptotic mediators, all of which are bona fide and pivotal elements orchestrating the survival of malignant lymphocytic cells. Finally, we discuss the attractive strategy of using mimics, antimiRs and other molecular approaches pointing at miRNAs as promising therapeutic targets. Such novel strategies to circumvent ALL and CLL resistance networks may potentially improve patients' responses and survival rates.

Gordonia sputi as an Arising Causative Agent of Bacteremia in Immunocompromised Comorbid Dialysis Patients-A Case Report.

Improvements in medical care have turned severe diseases into chronic conditions, but often their treatment and the use of medical devices are related to specific complications. Here, we present a clinical case of a long-term dialysis patient who was infected with a rare opportunistic infectious agent-Gordonia sputi. In recent years, the incidence of Gordonia spp. infections in immunocompromised patients with central venous catheters (CVC) has appeared to rise. The isolation and identification of Gordonia spp. are challenging and require modern techniques. In addition, the treatment is usually persistent and often results in CVC extraction, which is associated with further risk and costs for the patient. We also studied the alterations in the immune status of the patient caused by long-term renal replacement therapy and persistent hepatitis C virus infection. Antibiotic therapy and immunostimulation with Inosine pranobex lead to successful eradication of the infection without the need for CVC replacement.