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Due to the clonal nature of human leukemia evolution, all leukemic cells carry the same leukemia-initiating genetic lesions, independently of the intrinsic tumoral cellular heterogeneity. However, the latest findings have shown that the mode of action of oncogenes is not homogeneous throughout the developmental history of leukemia. Studies on different types of hematopoietic tumors have shown that the contribution of oncogenes to leukemia is mainly mediated through the epigenetic reprogramming of the leukemia-initiating target cell. This driving of cancer by a malignant epigenetic stem cell rewiring is, however, not exclusive of the hematopoietic system, but rather represents a common tumoral mechanism that is also at work in epithelial tumors. Tumoral epigenetic reprogramming is therefore a new type of interaction between genes and their target cells, in which the action of the oncogene modifies the epigenome to prime leukemia development by establishing a new pathological tumoral cellular identity. This reprogramming may remain latent until it is triggered by either endogenous or environmental stimuli. This new view on the making of leukemia not only reveals a novel function for oncogenes, but also provides evidence for a previously unconsidered model of leukemogenesis, in which the programming of the leukemia cellular identity has already occurred at the level of stem cells, therefore showing a role for oncogenes in the timing of leukemia initiation.

ETV6-RUNX1 is almost exclusively associated with childhood B-cell acute lymphoblastic leukemia (B-ALL), but the consequences of ETV6-RUNX1 expression on cell lineage decisions during B-cell leukemogenesis are completely unknown. Clinically silent ETV6-RUNX1 preleukemic clones are frequently found in neonatal cord blood, but few carriers develop B-ALL as a result of secondary genetic alterations. The understanding of the mechanisms underlying the first transforming steps could greatly advance the development of non-toxic prophylactic interventions. Using genetic lineage tracing, we examined the capacity of ETV6-RUNX1 to instruct a malignant phenotype in the hematopoietic lineage by cell-specific Cre-mediated activation of ETV6-RUNX1 from the endogenous Etv6 gene locus. Here we show that, while ETV6-RUNX1 has the propensity to trigger both T- and B-lymphoid malignancies, it is the second hit that determines tumor cell identity. To instigate leukemia, both oncogenic hits must place early in the development of hematopoietic/precursor cells, not in already committed B-cells. Depending on the nature of the second hit, the resulting B-ALLs presented distinct entities that were clearly separable based on their gene expression profiles. Our findings give a novel mechanistic insight into the early steps of ETV6-RUNX1+ B-ALL development and might have major implications for the potential development of ETV6-RUNX1+ B-ALL prevention strategies.

Since their discovery, cis-spliced epitopes have been studied in relation to tumor immunology, as alternative sources for attacking cancer cells through adoptive T cell therapies. The mutations often occur in the KRAS G12 and G13 residues, which impair the KRAS GTPase activity and render the mutants persistently in the GTP-bound active form, thereby driving carcinogenesis (33). Through the application of various in vitro techniques, we and others demonstrated that this tumor-specific cis-spliced neoepitope candidate can efficiently (i) be produced by proteasomes in in vitro kinetics experiments, (ii) be transported by Transporters Associated with antigen Processing (TAP) heterodimers into the endoplasmic reticulum (ER) lumen, and (iii) bind HLA-A*02:01 complex (11). In Vitro Digestions and MS Measurements In our original study (11), the synthetic KRAS2-35 G12V polypeptide (sequence: TEYKLVVVGAVGVGKSALTIQLIQN HFVDEYDPT; 40 µM final concentration) was digested by 3 µg 20S proteasomes (purified from peripheral blood) in 100 µl TEAD (20 mM Tris/KOH-pH 7.2, 1 mM EDTA, 1 mM DTT, 0.02% Sodium azide) buffer for different time points (0-4 h and 20 h) at 37°C. We performed three independent experiments, each of them measured either 3 times (for the 0-4 h kinetics) or 2 times (for 20h digestions) by MS. In the present study, the synthetic KRAS2-35 G12V polypeptide (40 µM final concentration) was digested by 1.6 µg 20S proteasomes (purified from human erythrocytes) for different time points (0-4 h) at 37°C in 40 µl HMDA buffer (20 mM Hepes/KOH-pH 7.2, 5 mM MgCl2, 1 mM DTT, 0.02% sodium azide; samples “MF”) or TMDA (20 mM Tris/KOH-pH 7.2, 5 mM MgCl2, 1 mM DTT, 0.02% Sodium azide; samples “MG”), as previously described (37).

Noncanonical epitopes presented by Human Leucocyte Antigen class I (HLA-I) complexes to CD8 + T cells attracted the spotlight in the research of novel immunotherapies against cancer, infection and autoimmunity. Proteasomes, which are the main producers of HLA-I-bound antigenic peptides, can catalyze both peptide hydrolysis and peptide splicing. The prediction of proteasome-generated spliced peptides is an objective that still requires a reliable (and large) database of non-spliced and spliced peptides produced by these proteases. Here, we present an extended database of proteasome-generated spliced and non-spliced peptides, which was obtained by analyzing in vitro digestions of 80 unique synthetic polypeptide substrates, measured by different mass spectrometers. Peptides were identified through invitroSPI method, which was validated through in silico and in vitro strategies. The peptide product database contains 16,631 unique peptide products (5,493 non-spliced, 6,453 cis -spliced and 4,685 trans -spliced peptide products), and a substrate sequence variety that is a valuable source for predictors of proteasome-catalyzed peptide hydrolysis and splicing. Potential artefacts and skewed results due to different identification and analysis strategies are discussed.

This article presents the framework of a mathematical formulation for modelling and evaluating natural gas (NG) pipeline networks under hydrogen injection. The model development is based on gas transport through pipelines and compressors which compensate for the pressure drops by implying mainly the mass and energy balances on the basic elements of the network. The model was initially implemented for natural gas transport and the principle of extension for hydrogen-natural gas mixtures is presented. A published pipeline network is revisited here for the case of hydrogen-natural gas mixtures. Typical quantitative results are presented, showing that the addition of hydrogen to natural gas decreases significantly the transmitted power: the maximum fraction of hydrogen that can be added to natural gas is around 6% mass for this example.

Leukemic stem cells (LSCs) are defined as cells that possess the ability to self-renew and give rise to the differentiated cancer cells that comprise the tumor. These LSCs seem to show chemo-resistance and radio-resistance leading to the failure of conventional cancer therapies. Current therapies are directed at the fast growing tumor mass leaving the LSC fraction untouched. Eliminating LSCs, the root of cancer origin and recurrence, is considered to be a hopeful approach to improve survival or even to cure cancer patients. In order to achieve this, the characterization of LSCs is a prerequisite in order to develop LSC-based therapies to eliminate them. Here we review if vitamin D analogues may allow an avenue to target the LSCs.

Aflatoxin B1 (AFB1) exhibits the most potent mutagenic and carcinogenic activity among aflatoxins. For this reason, AFB1 is recognized as a human group 1 carcinogen by the International Agency of Research on Cancer. Consequently, it is essential to determine its properties and behavior in different chemical systems. The chemical properties of AFB1 can be explored using computational chemistry, which has been employed complementarily to experimental investigations. The present review includes in silico studies (semiempirical, Hartree–Fock, DFT, molecular docking, and molecular dynamics) conducted from the first computational study in 1974 to the present (2022). This work was performed, considering the following groups: (a) molecular properties of AFB1 (structural, energy, solvent effects, ground and the excited state, atomic charges, among others); (b) theoretical investigations of AFB1 (degradation, quantification, reactivity, among others); (c) molecular interactions with inorganic compounds (Ag+, Zn2+, and Mg2+); (d) molecular interactions with environmentally compounds (clays); and (e) molecular interactions with biological compounds (DNA, enzymes, cyclodextrins, glucans, among others). Accordingly, in this work, we provide to the stakeholder the knowledge of toxicity of types of AFB1-derivatives, the structure–activity relationships manifested by the bonds between AFB1 and DNA or proteins, and the types of strategies that have been employed to quantify, detect, and eliminate the AFB1 molecule.

Glioblastoma is one of the most common brain tumors in adult populations, usually carrying a poor prognosis. While several studies have researched the impact of anti-angiogenic therapies, especially anti-VEFG treatments in glioblastoma, few have attempted to assess its progress using imaging studies. We attempted to analyze whether relative cerebral blood volume (rCBV) from dynamic susceptibility-weighted contrast-enhanced MRI (DSC-MRI) could predict response in patients with glioblastoma undergoing Bevacizumab (BVZ) treatment. We performed a retrospective study evaluating patients with recurrent glioblastoma receiving anti-angiogenic therapy with BVZ between 2012 and 2017 in our institution. Patients were scheduled for routine MRIs at baseline and first-month follow-up visits. Studies were processed for DSC-MRI, cT1, and FLAIR images, from which relative cerebral blood volume measurements were obtained. We assessed patient response using the Response Assessment in Neuro-Oncology (RANO) working group criteria and overall survival. 40 patients were included in the study and were classified as Bevacizumab responders and non-responders. The average rCBV before treatment was 4.5 for both groups, and average rCBV was 2.5 for responders and 5.4 for non-responders. ROC curve set a cutoff point of 3.7 for rCBV predictive of response to BVZ. Cox Multivariate analysis only showed rCBV as a predictive factor of OS. A statistically significant difference was found in rCBV between patients who responded and those who did not respond to BVZ treatment. rCBV may be a low-cost and effective marker to assess response to Bevacizumab treatment in GBM. •rCBV is an indirect value of the cerebral blood volume using contrast material.•rCBV can identify patients who benefit from antiangiogenic therapy in a cost-effective way.•Pretreatment rCBV is a potential predicting imaging biomarker in BVZ-treated rGB.