Salvage Therapy with Second-Generation Inhibitors for FLT3 Mutated Acute Myeloid Leukemia: A Real-World Study by the CETLAM and PETHEMA Groups.

Background/objectives: Patients with relapsed/refractory (R/R) AML with mutation () have a dismal prognosis. offers a target for therapy in these patients. Gilteritinib (gilter) and quizartinib (quizar) have demonstrated efficacy as single agents in two phase 3 clinical trials.

From Lipid Signatures to Cellular Responses: Unraveling the Complexity of Melanoma and Furthering Its Diagnosis and Treatment.

Recent advancements in mass spectrometry have significantly enhanced our understanding of complex lipid profiles, opening new avenues for oncological diagnostics. This review highlights the importance of lipidomics in the comprehension of certain metabolic pathways and its potential for the detection and characterization of various cancers, in particular melanoma. Through detailed case studies, we demonstrate how lipidomic analysis has led to significant breakthroughs in the identification and understanding of cancer types and its potential for detecting unique biomarkers that are instrumental in its diagnosis.

Beyond the MEP Pathway: A novel kinase required for prenol utilization by malaria parasites.

A proposed treatment for malaria is a combination of fosmidomycin and clindamycin. Both compounds inhibit the methylerythritol 4-phosphate (MEP) pathway, the parasitic source of farnesyl and geranylgeranyl pyrophosphate (FPP and GGPP, respectively). Both FPP and GGPP are crucial for the biosynthesis of several essential metabolites such as ubiquinone and dolichol, as well as for protein prenylation.

Plasmodium falciparum COQ2 gene encodes a functional 4-hydroxybenzoate polyprenyltransferase.

Ubiquinone (UQ) is a fundamental mitochondrial electron transport chain component. This compound is synthesized as the condensation of a p-substituted benzoic acid and a polyisoprenic moiety catalyzed by the enzyme 4-hydroxybenzoate polyprenyltransferase (EC 2.5.

The Biomedical Importance of the Missing Pathway for Farnesol and Geranylgeraniol Salvage.

Isoprenoids are the output of the polymerization of five-carbon, branched isoprenic chains derived from isopentenyl pyrophosphate (IPP) and its isomer, dimethylallyl pyrophosphate (DMAPP). Isoprene units are consecutively condensed to form longer structures such as farnesyl and geranylgeranyl pyrophosphate (FPP and GGPP, respectively), necessary for the biosynthesis of several metabolites. Polyprenyl transferases and synthases use polyprenyl pyrophosphates as their natural substrates; however, it is known that free polyprenols, such as farnesol (FOH), and geranylgeraniol (GGOH) can be incorporated into prenylated proteins, ubiquinone, cholesterol, and dolichols.

Mathematical expressions describing enzyme velocity and inhibition at high enzyme concentration.

Enzyme behaviour is characterised in the laboratory using diluted solutions of enzyme. However, processes usually occur at [ ] ≈ [ ] ≈  . Furthermore, the study of enzyme action involves characterisation of inhibitors and their mechanisms.

Abnormal sterol-induced cell wall glucan deficiency in yeast is due to impaired glucan synthase transport to the plasma membrane.

Abnormal sterols disrupt cellular functions through yet unclear mechanisms. In Saccharomyces cerevisiae, accumulation of Δ8-sterols, the same type of sterols observed in patients of Conradi-Hünermann-Happle syndrome or in fungi after amine fungicide treatment, leads to cell wall weakness. We have studied the influence of Δ8-sterols on the activity of glucan synthase I, the protein synthetizing the main polymer in fungal cell walls, its regulation by the Cell Wall Integrity (CWI) pathway, and its transport from the endoplasmic reticulum to the plasma membrane.

Interpretation of Domain Scores on the EPIC-How Does the Domain Score Translate into Functional Outcomes?

Purpose: The EPIC-26 (Expanded Prostate Cancer Index Composite-Short Form) is a validated questionnaire for measuring health related quality of life. However, the relationship between domain scores and functional outcomes remains unclear, leading to potential confusion about expectations after treatment. For instance, does a sexual function domain score of 80 mean that a patient can achieve erection sufficient for intercourse? Consequently we sought to determine the relationship between the domain score and the response to obtaining the best possible outcome for each question.

Nuclear proteasomal degradation of Saccharomyces cerevisiae inorganic pyrophosphatase Ipp1p, a nucleocytoplasmic protein whose stability depends on its subcellular localization.

Inorganic pyrophosphate (PPi) is an abundant by-product of cellular metabolism. PPi-producing reactions take place in the nucleus concurrently with reactions that use PPi as a substrate. Saccharomyces cerevisiae possesses two soluble pyrophosphatases (sPPases): Ipp1p, an essential and allegedly cytosolic protein, and Ipp2p, a mitochondrial isoenzyme.

The glutamine synthetase of Trypanosoma cruzi is required for its resistance to ammonium accumulation and evasion of the parasitophorous vacuole during host-cell infection.

Trypanosoma cruzi, the etiological agent of Chagas disease, consumes glucose and amino acids depending on the environmental availability of each nutrient during its complex life cycle. For example, amino acids are the major energy and carbon sources in the intracellular stages of the T. cruzi parasite, but their consumption produces an accumulation of NH4+ in the environment, which is toxic.

Vacuolar H(+)-Pyrophosphatase AVP1 is Involved in Amine Fungicide Tolerance in Arabidopsis thaliana and Provides Tridemorph Resistance in Yeast.

Amine fungicides are widely used as crop protectants. Their success is believed to be related to their ability to inhibit postlanosterol sterol biosynthesis in fungi, in particular sterol-Δ(8),Δ(7)-isomerases and sterol-Δ(14)-reductases, with a concomitant accumulation of toxic abnormal sterols. However, their actual cellular effects and mechanisms of death induction are still poorly understood.

8-Dehydrosterols induce membrane traffic and autophagy defects through V-ATPase dysfunction in Saccharomyces cerevisae.

8-Dehydrosterols are present in a wide range of biologically relevant situations, from human rare diseases to amine fungicide-treated fungi and crops. However, the molecular bases of their toxicity are still obscure. We show here that 8-dehydrosterols, but not other sterols, affect yeast vacuole acidification through V-ATPases.

Biochemical and structural characterization of Cryptosporidium parvum Lactate dehydrogenase.

The protozoan parasite Cryptosporidium parvum causes waterborne diseases worldwide. There is no effective therapy for C. parvum infection.

Inorganic pyrophosphatase defects lead to cell cycle arrest and autophagic cell death through NAD+ depletion in fermenting yeast.

Inorganic pyrophosphatases are required for anabolism to take place in all living organisms. Defects in genes encoding these hydrolytic enzymes are considered inviable, although their exact nature has not been studied at the cellular and molecular physiology levels. Using a conditional mutant in IPP1, the Saccharomyces cerevisiae gene encoding the cytosolic soluble pyrophosphatase, we show that respiring cells arrest in S phase upon Ipp1p deficiency, but they remain viable and resume growth if accumulated pyrophosphate is removed.

Intracellular proton pumps as targets in chemotherapy: V-ATPases and cancer.

Cancer cells show a metabolic shift that makes them overproduce protons; this has the potential to disturb the cellular acid-base homeostasis. However, these cells show cytoplasmic alkalinisation, increased acid extrusion and endosome-dependent drug resistance. Vacuolar type ATPases (V-ATPases), together with other transporters, are responsible to a great extent for these symptoms.

A plant proton-pumping inorganic pyrophosphatase functionally complements the vacuolar ATPase transport activity and confers bafilomycin resistance in yeast.

V-ATPases (vacuolar H+-ATPases) are a specific class of multi-subunit pumps that play an essential role in the generation of proton gradients across eukaryotic endomembranes. Another simpler proton pump that co-localizes with the V-ATPase occurs in plants and many protists: the single-subunit H+-PPase [H+-translocating PPase (inorganic pyrophosphatase)]. Little is known about the relative contribution of these two proteins to the acidification of intracellular compartments.

Intraorganellar acidification by V-ATPases: a target in cell proliferation and cancer therapy.

Vacuolar-type ATPases are multicomponent proton pumps involved in the acidification of single membrane intracellular compartments such as endosomes and lysosomes. They couple the hydrolysis of ATP to the translocation of one to two protons across the membrane. Acidification of the lumen of single membrane organelles is a necessary factor for the correct traffic of membranes and cargo to and from the different internal compartments of a cell.

Mutants of the Arabidopsis thaliana cation/H+ antiporter AtNHX1 conferring increased salt tolerance in yeast: the endosome/prevacuolar compartment is a target for salt toxicity.

Mutants of the plant cation/H(+) antiporter AtNHX1 that confer greater halotolerance were generated by random mutagenesis and selected in yeast by phenotypic complementation. The amino acid substitutions that were selected were conservative and occurred in the second half of the membrane-associated N terminus. AtNHX1 complemented the lack of endogenous ScNHX1 in endosomal protein trafficking assays.

HDAC and Hsp90 inhibitors down-regulate PTTG1/securin but do not induce aneuploidy.

Human securin regulates correct chromatid separation. However, there are conflicting reports on the aneugenic effects of its gene deletion. Here we show that PTTG1/securin gene expression is dramatically repressed when Hsp90 or histone deacetylases are inhibited.

Dicoumarol down-regulates human PTTG1/Securin mRNA expression through inhibition of Hsp90.

Securin, the natural inhibitor of sister chromatid untimely separation, is a protooncogene overexpressed in tumors. Its protein levels correlate with malignancy and metastatic proneness. Dicoumarol, a long-established oral anticoagulant, is a new Hsp90 inhibitor that represses PTTG1/Securin gene expression and provokes apoptosis through a complex trait involving both intrinsic and extrinsic pathways.

p53 stabilization can be uncoupled from its role in transcriptional activation by loss of PTTG1/securin.

HCT116 cells devoid of PTTG1/securin (sec(-/-) HCT116) show a stabilized yet transcriptionally latent form of p53 protein in the absence of DNA damage. Ser15, Ser20 phosphorylation and other post-transcriptional modifications of p53 resolved by 2D gel electrophoresis are comparable to that observed in sec(+/+) HCT116 cells. The difference in degradation was also shown to be independent of the ubiquitin system but reliant on calpains.