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International Journal of Molecular... Jun 2024The genomic analyses of pediatric acute lymphoblastic leukemia (ALL) subtypes, particularly T-cell and B-cell lineages, have been pivotal in identifying potential...
The genomic analyses of pediatric acute lymphoblastic leukemia (ALL) subtypes, particularly T-cell and B-cell lineages, have been pivotal in identifying potential therapeutic targets. Typical genomic analyses have directed attention toward the most commonly mutated genes. However, assessing the contribution of mutations to cancer phenotypes is crucial. Therefore, we estimated the cancer effects (scaled selection coefficients) for somatic substitutions in T-cell and B-cell cohorts, revealing key insights into mutation contributions. Cancer effects for well-known, frequently mutated genes like and in B-ALL were high, which underscores their importance as therapeutic targets. However, less frequently mutated genes , , and also demonstrated high cancer effects, suggesting pivotal roles in the development of leukemia when present. In T-ALL, and are less frequently mutated than in B-ALL. However, their cancer effects when present are high in both subtypes. Mutations in and were not at high prevalence, yet exhibited some of the highest cancer effects in individual T-cell ALL patients. Even , with a low prevalence and relatively modest cancer effect, is potentially highly relevant for the epistatic effects that its mutated form exerts on other mutations. Prioritizing investigation into these moderately frequent but potentially high-impact targets not only presents novel personalized therapeutic opportunities but also enhances the understanding of disease mechanisms and advances precision therapeutics for pediatric ALL.
Topics: Humans; Child; Mutation; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; B-Lymphocytes
PubMed: 38928295
DOI: 10.3390/ijms25126589 -
International Journal of Molecular... Jun 2024Activation of neural stem cells (NSCs) correlates with improved functional outcomes in mouse models of injury. In the murine brain, NSCs have been extensively...
Activation of neural stem cells (NSCs) correlates with improved functional outcomes in mouse models of injury. In the murine brain, NSCs have been extensively characterized and comprise (1) primitive NSCs (pNSCs) and (2) definitive NSCs (dNSCs). pNSCs are the earliest cells in the NSC lineage giving rise to dNSCs in the embryonic and adult mouse brain. pNSCs are quiescent under baseline conditions and can be activated upon injury. Herein, we asked whether human pNSCs and dNSCs can be isolated during the maturation of human cerebral organoids (COs) and activated by drugs known to regulate mouse NSC behavior. We demonstrate that self-renewing, multipotent pNSC and dNSC populations are present in human COs and express genes previously characterized in mouse NSCs. The drug NWL283, an inhibitor of apoptosis, reduced cell death in COs but did not improve NSC survival. Metformin, a drug used to treat type II diabetes that is known to promote NSC activation in mice, was found to expand human NSC pools. Together, these findings are the first to identify and characterize human pNSCs, advancing our understanding of the human NSC lineage and highlighting drugs that enhance their activity.
Topics: Humans; Neural Stem Cells; Organoids; Animals; Mice; Cell Differentiation; Metformin; Cells, Cultured; Brain
PubMed: 38928255
DOI: 10.3390/ijms25126549 -
International Journal of Molecular... Jun 2024While the genomics era has allowed remarkable advances in understanding the mechanisms driving the biology and pathogenesis of numerous blood cancers, including acute...
While the genomics era has allowed remarkable advances in understanding the mechanisms driving the biology and pathogenesis of numerous blood cancers, including acute lymphoblastic leukemia (ALL), metabolic studies are still lagging, especially regarding how the metabolism differs between healthy and diseased individuals. T-cell ALL (T-ALL) is an aggressive hematological neoplasm deriving from the malignant transformation of T-cell progenitors characterized by frequent NOTCH1 pathway activation. The aim of our study was to characterize tumor and plasma metabolomes during T-ALL development using a NOTCH1-induced murine T-ALL model (ΔE-NOTCH1). In tissue, we found a significant metabolic shift with leukemia development, as metabolites linked to glycolysis (lactic acid) and Tricarboxylic acid cycle replenishment (succinic and malic acids) were elevated in NOTCH1 tumors, while metabolites associated with lipid oxidation (e.g., carnitine) as well as purine and pyrimidine metabolism were elevated in normal thymic tissue. Glycine, serine, and threonine metabolism, glutathione metabolism, as well as valine, leucine, and isoleucine biosynthesis were enriched pathways in tumor tissue. Phenylalanine and tyrosine metabolism was highly enriched in plasma from leukemia-bearing mice compared to healthy mice. Further, we identified a metabolic signature consisting of glycine, alanine, proline, 3-hydroxybutyrate, and glutamic acid as potential biomarkers for leukemia progression in plasma. Hopefully, the metabolic differences detected in our leukemia model will apply to humans and contribute to the development of metabolism-oriented therapeutic approaches.
Topics: Animals; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Mice; Receptor, Notch1; Metabolomics; Biomarkers, Tumor; Metabolome; Disease Models, Animal
PubMed: 38928249
DOI: 10.3390/ijms25126543 -
International Journal of Molecular... Jun 2024Breast cancer stands as one of the foremost cause of cancer-related deaths globally, characterized by its varied molecular subtypes. Each subtype requires a distinct...
Breast cancer stands as one of the foremost cause of cancer-related deaths globally, characterized by its varied molecular subtypes. Each subtype requires a distinct therapeutic strategy. Although advancements in treatment have enhanced patient outcomes, significant hurdles remain, including treatment toxicity and restricted effectiveness. Here, we explore the anticancer potential of novel 1,4-naphthoquinone/4-quinolone hybrids on breast cancer cell lines. The synthesized compounds demonstrated selective cytotoxicity against Luminal and triple-negative breast cancer (TNBC) cells, which represent the two main molecular types of breast cancer that depend most on cytotoxic chemotherapy, with potency comparable to doxorubicin, a standard chemotherapeutic widely used in breast cancer treatment. Notably, these derivatives exhibited superior selectivity indices (SI) when compared to doxorubicin, indicating lower toxicity towards non-tumor MCF10A cells. Compounds 11a and 11b displayed an improvement in IC values when compared to their precursor, 1,4-naphthoquinone, for both MCF-7 and MDA-MB-231 and a comparable value to doxorubicin for MCF-7 cells. Also, their SI values were superior to those seen for the two reference compounds for both cell lines tested. Mechanistic studies revealed the ability of the compounds to induce apoptosis and inhibit clonogenic potential. Additionally, the irreversibility of their effects on cell viability underscores their promising therapeutic utility. In 3D-cell culture models, the compounds induced morphological changes indicative of reduced viability, supporting their efficacy in a more physiologically relevant model of study. The pharmacokinetics of the synthesized compounds were predicted using the SwissADME webserver, indicating that these compounds exhibit favorable drug-likeness properties and potential as antitumor agents. Overall, our findings underscore the promise of these hybrid compounds as potential candidates for breast cancer chemotherapy, emphasizing their selectivity and efficacy.
Topics: Humans; Naphthoquinones; Antineoplastic Agents; Female; Breast Neoplasms; Cell Line, Tumor; MCF-7 Cells; Quinolones; Apoptosis; Cell Culture Techniques, Three Dimensional; Doxorubicin; Cell Proliferation; Cell Survival
PubMed: 38928197
DOI: 10.3390/ijms25126490 -
International Journal of Molecular... Jun 2024β C-S lyases (β-CSLs; EC 4.4.1.8) are enzymes catalyzing the dissociation of β carbon-sulfur bonds of cysteine S-conjugates to produce odorant metabolites with a free... (Review)
Review
β C-S lyases (β-CSLs; EC 4.4.1.8) are enzymes catalyzing the dissociation of β carbon-sulfur bonds of cysteine S-conjugates to produce odorant metabolites with a free thiol group. These enzymes are increasingly studied for their role in flavor generation in a variety of food products, whether these processes occur directly in plants, by microbial β-CSLs during fermentation, or in the mouth under the action of the oral microbiota. Microbial β-CSLs react with sulfur aroma precursors present in beverages, vegetables, fruits, or aromatic herbs like hop but also potentially with some precursors formed through Maillard reactions in cooked foods such as meat or coffee. β-CSLs from microorganisms like yeasts and lactic acid bacteria have been studied for their role in the release of polyfunctional thiols in wine and beer during fermentation. In addition, β-CSLs from microorganisms of the human oral cavity were shown to metabolize similar precursors and to produce aroma in the mouth with an impact on retro-olfaction. This review summarizes the current knowledge on β-CSLs involved in flavor generation with a focus on enzymes from microbial species present either in the fermentative processes or in the oral cavity. This paper highlights the importance of this enzyme family in the food continuum, from production to consumption, and offers new perspectives concerning the utilization of β-CSLs as a flavor enhancer.
Topics: Humans; Flavoring Agents; Fermentation; Carbon-Sulfur Lyases; Bacteria; Taste
PubMed: 38928118
DOI: 10.3390/ijms25126412 -
International Journal of Molecular... Jun 2024Neural precursor cells (NPCs) that persist in the postnatal/adult subventricular zone (SVZ) express connexins that form hemichannels and gap junctions. Gap junctional...
Neural precursor cells (NPCs) that persist in the postnatal/adult subventricular zone (SVZ) express connexins that form hemichannels and gap junctions. Gap junctional communication plays a role in NPC proliferation and differentiation during development, but its relevance on postnatal age remains to be elucidated. In this work we aimed to evaluate the effect of the blockade of gap junctional communication on proliferation and cell fate of NPCs obtained from the SVZ of postnatal rats. NPCs were isolated and expanded in culture as neurospheres. Electron microscopy revealed the existence of gap junctions among neurosphere cells. Treatment of cultures with octanol, a broad-spectrum gap junction blocker, or with Gap27, a specific blocker for gap junctions formed by connexin43, produced a significant decrease in bromodeoxyuridine incorporation. Octanol treatment also exerted a dose-dependent antiproliferative effect on glioblastoma cells. To analyze possible actions on NPC fate, cells were seeded in the absence of mitogens. Treatment with octanol led to an increase in the percentage of astrocytes and oligodendrocyte precursors, whereas the percentage of neurons remained unchanged. Gap27 treatment, in contrast, did not modify the differentiation pattern of SVZ NPCs. Our results indicate that general blockade of gap junctions with octanol induces significant effects on the behavior of postnatal SVZ NPCs, by reducing proliferation and promoting glial differentiation.
Topics: Animals; Gap Junctions; Neural Stem Cells; Cell Proliferation; Cell Differentiation; Rats; Octanols; Neuroglia; Cells, Cultured; Lateral Ventricles; Connexin 43; Rats, Wistar; Astrocytes; Animals, Newborn; Humans
PubMed: 38927995
DOI: 10.3390/ijms25126288 -
Cancers Jun 2024Exposure to ionizing radiation is associated with an increased risk of hematologic malignancies in myeloid and lymphoid lineages in humans and experimental mice. Given... (Review)
Review
Exposure to ionizing radiation is associated with an increased risk of hematologic malignancies in myeloid and lymphoid lineages in humans and experimental mice. Given that substantial evidence links radiation exposure with the risk of hematologic malignancies, it is imperative to deeply understand the mechanisms underlying cellular and molecular changes during the latency period between radiation exposure and the emergence of fully transformed malignant cells. One experimental model widely used in the field of radiation and cancer biology to study hematologic malignancies induced by radiation exposure is mouse models of radiation-induced thymic lymphoma. Murine radiation-induced thymic lymphoma is primarily driven by aberrant activation of Notch signaling, which occurs frequently in human precursor T-cell lymphoblastic lymphoma (T-LBL) and T-cell lymphoblastic leukemia (T-ALL). Here, we summarize the literature elucidating cell-autonomous and non-cell-autonomous mechanisms underlying cancer initiation, progression, and malignant transformation in the thymus following total-body irradiation (TBI) in mice.
PubMed: 38927929
DOI: 10.3390/cancers16122224 -
Bioengineering (Basel, Switzerland) May 2024Esophageal carcinoma is the sixth-leading cause of cancer death worldwide. A precursor to esophageal adenocarcinoma (EAC) is Barrett's Esophagus (BE). Early-stage...
Design and Evaluation of ScanCap: A Low-Cost, Reusable Tethered Capsule Endoscope with Blue-Green Illumination Imaging for Unsedated Screening and Early Detection of Barrett's Esophagus.
Esophageal carcinoma is the sixth-leading cause of cancer death worldwide. A precursor to esophageal adenocarcinoma (EAC) is Barrett's Esophagus (BE). Early-stage diagnosis and treatment of esophageal neoplasia (Barrett's with high-grade dysplasia/intramucosal cancer) increase the five-year survival rate from 10% to 98%. BE is a global challenge; however, current endoscopes for early BE detection are costly and require extensive infrastructure for patient examination and sedation. We describe the design and evaluation of the first prototype of ScanCap, a high-resolution optical endoscopy system with a reusable, low-cost tethered capsule, designed to provide high-definition, blue-green illumination imaging for the early detection of BE in unsedated patients. The tethered capsule (12.8 mm diameter, 35.5 mm length) contains a color camera and rotating mirror and is designed to be swallowed; images are collected as the capsule is retracted manually via the tether. The tether provides electrical power and illumination at wavelengths of 415 nm and 565 nm and transmits data from the camera to a tablet. The ScanCap prototype capsule was used to image the oral mucosa in normal volunteers and ex vivo esophageal resections; images were compared to those obtained using an Olympus CV-180 endoscope. Images of superficial capillaries in intact oral mucosa were clearly visible in ScanCap images. Diagnostically relevant features of BE, including irregular Z-lines, distorted mucosa, and dilated vasculature, were clearly visible in ScanCap images of ex vivo esophageal specimens.
PubMed: 38927792
DOI: 10.3390/bioengineering11060557 -
Genes Jun 2024Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid...
Multifactor Analyses of Frontal Cortex Lipids in the APP/PS1 Model of Familial Alzheimer's Disease Reveal Anomalies in Responses to Dietary n-3 PUFA and Estrogenic Treatments.
Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid alterations are linked to neurodegenerative diseases, especially Alzheimer's disease (AD). The complexity of the brain lipidome and its metabolic regulation has hampered the identification of critical processes associated with the onset and progression of AD. While most experimental studies have focused on the effects of known factors on the development of pathological hallmarks in AD, e.g., amyloid deposition, tau protein and neurofibrillary tangles, neuroinflammation, etc., studies addressing the causative effects of lipid alterations remain largely unexplored. In the present study, we have used a multifactor approach combining diets containing different amounts of polyunsaturated fatty acids (PUFAs), estrogen availabilities, and genetic backgrounds, i.e., wild type (WT) and APP/PS1 (FAD), to analyze the lipid phenotype of the frontal cortex in middle-aged female mice. First, we observed that severe n-3 PUFA deficiency impacts the brain n-3 long-chain PUFA (LCPUFA) composition, yet it was notably mitigated by hepatic de novo synthesis. n-6 LCPUFAs, ether-linked fatty acids, and saturates were also changed by the dietary condition, but the extent of changes was dependent on the genetic background and hormonal condition. Likewise, brain cortex phospholipids were mostly modified by the genotype (FAD>WT) with nuanced effects from dietary treatment. Cholesterol (but not sterol esters) was modified by the genotype (WT>FAD) and dietary condition (higher in DHA-free conditions, especially in WT mice). However, the effects of estrogen treatment were mostly observed in relation to phospholipid remodeling in a genotype-dependent manner. Analyses of lipid-derived variables indicate that nerve cell membrane biophysics were significantly affected by the three factors, with lower membrane microviscosity (higher fluidity) values obtained for FAD animals. In conclusion, our multifactor analyses revealed that the genotype, diet, and estrogen status modulate the lipid phenotype of the frontal cortex, both as independent factors and through their interactions. Altogether, the outcomes point to potential strategies based on dietary and hormonal interventions aimed at stabilizing the brain cortex lipid composition in Alzheimer's disease neuropathology.
Topics: Alzheimer Disease; Animals; Fatty Acids, Omega-3; Mice; Frontal Lobe; Female; Disease Models, Animal; Amyloid beta-Protein Precursor; Estrogens; Mice, Transgenic; Presenilin-1; Lipid Metabolism; Humans
PubMed: 38927745
DOI: 10.3390/genes15060810 -
Genes Jun 2024Previous studies have demonstrated the essential role of the Kisspeptin/Neurokinin B/Dynorphin A (KNDy) pathway in female reproductive biology by regulating the activity...
Previous studies have demonstrated the essential role of the Kisspeptin/Neurokinin B/Dynorphin A (KNDy) pathway in female reproductive biology by regulating the activity of the hypothalamic-pituitary-gonadal axis. Identified loss-of-function mutations in these genes are linked to various reproductive disorders. This study investigated genetic disorders linked to mutations in the genes related to premature ovarian insufficiency (POI). A cohort of 14 Mexican POI patients underwent genetic screening using PCR-SSCP and Sanger sequencing, assessing the genetic variations' impact on protein function thereafter using multiple in silico tools. The PCR excluded extensive deletions, insertions, and duplications, while SSCP detected five genetic variants. Variations occurred in the (c.58G>A and c.242C>G), (c.1091A>T), (c.600C>T), and (c.36G>T) genes, whereas no genetic anomalies were found in genes. Each single-nucleotide variant underwent genotyping using PCR-SSCP in 100 POI-free subjects. Their allelic frequencies paralleled the patient group. These observations indicate that allelic variations in the genes may not contribute to POI etiology. Hence, screening for mutations in genes should not be a part of the diagnostic protocol for POI.
Topics: Humans; Female; Primary Ovarian Insufficiency; Mexico; Adult; Neurokinin B; Kisspeptins; Cohort Studies; Polymorphism, Single Nucleotide; Receptors, Kisspeptin-1; Enkephalins; Protein Precursors
PubMed: 38927724
DOI: 10.3390/genes15060788