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Cancer Research Apr 2024Residual cancer cells persist even after targeted therapies, serving as a reservoir for the subsequent acquisition of genetic alterations that lead to acquired drug...
Residual cancer cells persist even after targeted therapies, serving as a reservoir for the subsequent acquisition of genetic alterations that lead to acquired drug resistance and tumor relapse. These initial drug-tolerant persisters (DTP) are phenotypically heterogenous with transient phenotypes attributed to epigenetic, metabolic, and cell-cycle changes. DTPs are responsible for the inevitable relapse seen in EGFR-mutant non-small cell lung cancer (NSCLC) despite high initial response to tyrosine kinase inhibitor (TKI) treatment. While past in vitro studies identified diverse drivers of drug-tolerant persistence to EGFR TKIs in NSCLC, the resultant phenotypic plasticity is not well understood and in vivo models of persistence are lacking. In this issue of Cancer Research, Hu and colleagues used patient-derived xenograft models of EGFR-mutant lung cancer treated with the third-generation TKI osimertinib to investigate mechanisms of persistence at the time of maximal response. Using bulk and single-cell RNA sequencing, the authors identified a DTP transcriptional cluster mediated by the key neuroendocrine lineage transcription factor ASCL1, which triggers an epithelial-to-mesenchymal transition transcriptional program. ASCL1 overexpression increased osimertinib tolerance in vitro as well, apparently independent of its role in neuroendocrine differentiation. Interestingly, the ability of ASCL1 to induce persistence was context dependent as this occurred only in epigenetically permissive cells. Overall, these findings contribute to our understanding of DTP heterogeneity seen after osimertinib treatment and provide insights into potential therapeutic targets. See related article by Hu et al., p. 1303.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Neoplasm Recurrence, Local; Recurrence; ErbB Receptors; Acrylamides; Aniline Compounds; Indoles; Pyrimidines
PubMed: 38616658
DOI: 10.1158/0008-5472.CAN-24-0274 -
The Eurasian Journal of Medicine Oct 2023Oleuropein is one of the main components of the antioxidant properties of olive leaves. Placental growth factor is an important regulator in angiogenesis and...
OBJECTIVE
Oleuropein is one of the main components of the antioxidant properties of olive leaves. Placental growth factor is an important regulator in angiogenesis and inflammation, its levels being variable in pathological conditions. In this study, we aimed to examine changes in placental growth factor expression and the effect of oleuropein, found in olive leaves, in rats exposed to acrylamide nephrotoxicity.
MATERIAL AND METHODS
Twenty-four male Wistar albino rats were allocated into 4 groups. The control group received saline solution only. The oleuropein group received oleuropein (4.2 mg/kg), the acrylamide group received acrylamide (5 mg/kg), and the acrylamide and oleuropein group received acrylamide (5 mg/kg) and oleuropein (4.2 mg/kg). All substances were administered via gastric gavage for 21 days. Kidney tissues were removed at the end of the study and subjected to histopathological, stereological, and immunohistochemical procedures.
RESULTS
Histopathological examination revealed dilatation, vacuolization, and degeneration in the proximal and distal tubules and increased placental growth factor immunoreactivity in the acrylamide group. Cavalieri volume analysis revealed increased cortex, distal, and proximal tubule volumes (P < .01).
CONCLUSION
Oleuropein significantly attenuated acrylamide-induced kidney injury by altering placental growth factor immunoreactivity. Placental growth factor immunoreactivity can be used as a marker of acrylamide nephrotoxicity, and oleuropein may counteract acrylamide-induced kidney injury.
PubMed: 37909193
DOI: 10.5152/eurasianjmed.2023.23043 -
Critical Reviews in Oncology/hematology Apr 2024The development of targeted therapy in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients has radically changed their clinical... (Review)
Review
The study of primary and acquired resistance to first-line osimertinib to improve the outcome of EGFR-mutated advanced Non-small cell lung cancer patients: the challenge is open for new therapeutic strategies.
The development of targeted therapy in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients has radically changed their clinical perspectives. Current first-line standard treatment for advanced disease is commonly considered third-generation tyrosine kinase inhibitors (TKI), osimertinib. The study of primary and acquired resistance to front-line osimertinib is one of the main burning issues to further improve patients' outcome. Great heterogeneity has been depicted in terms of duration of clinical benefit and pattern of progression and this might be related to molecular factors including subtypes of EGFR mutations and concomitant genetic alterations. Acquired resistance can be categorized into two main classes: EGFR-dependent and EGFR-independent mechanisms and specific pattern of progression to first-line osimertinib have been demonstrated. The purpose of the manuscript is to provide a comprehensive overview of literature about molecular resistance mechanisms to first-line osimertinib, from a clinical perspective and therefore in relationship to emerging therapeutic approaches.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Acrylamides; Aniline Compounds; ErbB Receptors; Mutation; Protein Kinase Inhibitors; Indoles; Pyrimidines
PubMed: 38382773
DOI: 10.1016/j.critrevonc.2024.104295 -
Journal of Agricultural and Food... Oct 2023Acrylamide (AA), commonly formed in carbohydrate-rich thermally processed foods, exerts harmful effects on the kidney. Allicin, from crushed garlic cloves, exhibits...
Acrylamide (AA), commonly formed in carbohydrate-rich thermally processed foods, exerts harmful effects on the kidney. Allicin, from crushed garlic cloves, exhibits strong biological activities. In the current study, the protection mechanisms of allicin against AA-caused nephrotoxicity were comprehensively examined using an rat model based on previous research that allicin plays a key role in improving renal function. The results showed that allicin attenuated histological changes of the kidney and ameliorated renal function. Damaged mitochondrial structures, upregulated voltage-dependent anion channel 1 expression, and decreased membrane potential and adenosine 5'-triphosphate levels were observed after AA treatment. Surprisingly, allicin notably reversed the adverse effects. Further, allicin effectively restored mitochondrial function via modulating mitochondrial biogenesis and dynamics, which might be associated with the upregulated expression of sirtuin 1 (SIRT1). Meanwhile, allicin dramatically activated the SIRT1 activity and subsequently inhibited p53 acetylation, prevented the translocation of cytochrome to the cytoplasm, and reduced the caspase expression, thus further inhibiting mitochondrial apoptosis caused by AA. In summary, the relieving effect of allicin on AA-caused nephrotoxicity lies in its inhibition of mitochondrial dysfunction and mitochondrial apoptosis.
Topics: Rats; Animals; Sirtuin 1; Acrylamide; Apoptosis; Sulfinic Acids; Disulfides; Kidney; Mitochondria
PubMed: 37830900
DOI: 10.1021/acs.jafc.3c04687 -
Journal of Thoracic Oncology : Official... Feb 2024Patients with metastatic EGFR-mutant NSCLC inevitably have disease progression while on tyrosine kinase inhibitor (TKI) therapy. Co-occurring tumor suppressor gene (TSG)...
INTRODUCTION
Patients with metastatic EGFR-mutant NSCLC inevitably have disease progression while on tyrosine kinase inhibitor (TKI) therapy. Co-occurring tumor suppressor gene (TSG) alterations have been associated with poor outcomes, however, detailed analyses of their impact on patient outcomes are limited.
METHODS
Patients with EGFR-mutant NSCLC treated with EGFR TKIs who had tumor genomic profiling were included. Alterations in TP53 and five additional TSGs (RB1, NF1, ARID1A, BRCA1, and PTEN) were used to stratify the cohort into the following three subgroups: patients with tumors harboring a TP53 mutation plus a mutation in at least one additional TSG (TP53/TSG), those having a TP53 mutation without additional TSG mutations (TP53/TSG), and those with TP53. Patient characteristics and clinical outcomes were assessed in two independent cohorts.
RESULTS
A total of 101 patients from the Yale Cancer Center and 182 patients from the American Association for Cancer Research Project GENIE database were included. In the Yale cohort, TP53 mutations were identified in 65 cases (64%), of which 23 were TP53/TSG and 42 were TP53/TSG. Although the presence of a TP53 mutation was associated with worse outcomes, the additional TSG alteration in TP53 tumors identified a subset of patients associated with particularly aggressive disease and inferior clinical outcome in both the Yale and the GENIE cohorts. Specifically, in the Yale cohort for patients receiving first-line TKIs, those with TP53/TSG tumors had shorter progression-free survival (PFS) and overall survival (OS) than TP53/TSG (PFS: hazard ratio [HR] = 2.03, confidence interval [CI]: 1.12-3.69, p < 0.01, OS: HR = 1.58, CI: 0.82-3.04, p = 0.12) or TP53 cases (PFS: HR 2.4, CI: 1.28-4.47, p < 0.001, OS: HR = 2.54, CI: 1.21-5.34, p < 0.005). Inferior outcomes in patients with TP53/TSG tumors were also found in those receiving osimertinib as second-line therapy. Similar findings were seen in patients in the GENIE cohort.
CONCLUSIONS
Patients with TP53/TSG tumors represent a patient subgroup characterized by an aggressive disease phenotype and inferior outcomes on EGFR TKIs. This information is important for understanding the biological underpinnings of differential outcomes with TKI treatment and has implications for identifying patients who may benefit from additional therapeutic interventions beyond osimertinib monotherapy.
Topics: Humans; Lung Neoplasms; Protein Kinase Inhibitors; ErbB Receptors; Carcinoma, Non-Small-Cell Lung; Genes, Tumor Suppressor; Mutation; Acrylamides; Aniline Compounds; Indoles; Pyrimidines
PubMed: 37806385
DOI: 10.1016/j.jtho.2023.10.001 -
Foods (Basel, Switzerland) Aug 2023This study investigated the influence of 'snackification' in Singaporean diets, leading to increased dietary acrylamide exposure. Acrylamide concentrations in commonly...
This study investigated the influence of 'snackification' in Singaporean diets, leading to increased dietary acrylamide exposure. Acrylamide concentrations in commonly consumed foods within and outside the main meals were measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS). High acrylamide concentrations were detected in vegetables cooked at high temperatures (ranging from 0.5 to 478.4 µg/kg) and potato-based crackers and chips (ranging from 81.8 to 2095.8 µg/kg). The estimated total dietary exposure for the Singapore population was 0.165 µg/kg bw/day for general consumers and 0.392 µg/kg bw/day for high consumers (95th percentile). The acrylamide exposure from outside main meals was nearly equivalent to that from within the main meals. The calculated margins of exposure (MOE) were below 10,000, indicating potential human health concern. These findings highlight the need for industry practices and consumer advisories to reduce acrylamide exposure from foods consumed both within and outside main meals.
PubMed: 37628020
DOI: 10.3390/foods12163022 -
Advanced Healthcare Materials Jul 2023Zwitterionic hydrogels have high potential for cartilage tissue engineering due to their ultra-hydrophilicity, nonimmunogenicity, and superior antifouling properties....
Zwitterionic hydrogels have high potential for cartilage tissue engineering due to their ultra-hydrophilicity, nonimmunogenicity, and superior antifouling properties. However, their application in this field has been limited so far, due to the lack of injectable zwitterionic hydrogels that allow for encapsulation of cells in a biocompatible manner. Herein, a novel strategy is developed to engineer cartilage employing zwitterionic granular hydrogels that are injectable, self-healing, in situ crosslinkable and allow for direct encapsulation of cells with biocompatibility. The granular hydrogel is produced by mechanical fragmentation of bulk photocrosslinked hydrogels made of zwitterionic carboxybetaine acrylamide (CBAA), or a mixture of CBAA and zwitterionic sulfobetaine methacrylate (SBMA). The produced microgels are enzymatically crosslinkable using horseradish peroxidase, to quickly stabilize the construct, resulting in a microporous hydrogel. Encapsulated human primary chondrocytes are highly viable and able to proliferate, migrate, and produce cartilaginous extracellular matrix (ECM) in the zwitterionic granular hydrogel. It is also shown that by increasing hydrogel porosity and incorporation of SBMA, cell proliferation and ECM secretion are further improved. This strategy is a simple and scalable method, which has high potential for expanding the versatility and application of zwitterionic hydrogels for diverse tissue engineering applications.
PubMed: 37501337
DOI: 10.1002/adhm.202301831 -
Journal of Agricultural and Food... Jul 2023The roasting process can modulate sensory and physicochemical characteristics of cocoa. This study compared the chemical characteristics of cocoa nibs roasted by a...
The roasting process can modulate sensory and physicochemical characteristics of cocoa. This study compared the chemical characteristics of cocoa nibs roasted by a convective oven [slow roasting─(SR)] vs cocoa nibs roasted in a fluidized bed roaster [fast roasting─(FR)] at two temperatures (120 and 140 °C). The contents of sugars, free amino acids (FAAs), polyphenols, acrylamide, 5-hydroxymethylfurfural, and melanoidins were monitored. Roasting reduced fructose, glucose, and sucrose contents by 95, 70, and 55%, respectively. The concentration of total FAAs was reduced up to 40% at 140 °C. The FAA profile revealed that FR favored the reactivity of some amino acids (Leu, Lys, Phe, and Val) relevant in the formation of aroma compounds and melanoidins. FR resulted in the generation of more intense brown melanoidins, a significant increase in catechin content, a higher formation of acrylamide, and a lower formation of 5-hydroxymethylfurfural in cocoa compared to SR.
Topics: Chocolate; Cacao; Amino Acids; Acrylamides
PubMed: 37352390
DOI: 10.1021/acs.jafc.3c01678 -
Critical Reviews in Food Science and... 2024Maillard reaction is a non-enzymatic thermal reaction during food processing and storage. It massively contributes to the flavor, color, health benefits and safety of... (Review)
Review
Maillard reaction is a non-enzymatic thermal reaction during food processing and storage. It massively contributes to the flavor, color, health benefits and safety of foods and could be briefly segmented into initial, intermediate and final stages with the development of a cascade of chemical reactions. During thermal reaction of food ingredients, sugar, protein and amino acids are usually the main substrates, and polyphenols co-existed in food could also participate in the Maillard reaction as a modulator. Polyphenols including flavan-3-ols, hydroxycinnamic acids, flavonoids, and tannins have shown various effects throughout the process of Maillard reaction, including conjugating amino acids/sugars, trapping α-dicarbonyls, capturing Amadori rearrangement products (ARPs), as well as decreasing acrylamide and 5-hydroxymethylfurfural (5-HMF) levels. These effects significantly influenced the flavor, taste and color of processed foods, and also decreased the hazard products' level. The chemical mechanism of polyphenols-Maillard products involved the scavenging of radicals, as well as nucleophilic addition and substitution reactions. In the present review, we concluded and discussed the interaction of polyphenols and Maillard reaction, and proposed some perspectives for future studies.
Topics: Maillard Reaction; Polyphenols; Food Handling; Furaldehyde; Acrylamide; Flavonoids; Humans; Taste; Hot Temperature; Amino Acids
PubMed: 36382683
DOI: 10.1080/10408398.2022.2146653 -
International Journal of Molecular... Jul 2023Cells produce free radicals and antioxidants when exposed to toxic compounds during cellular metabolism. However, free radicals are deleterious to lipids, proteins, and...
Cells produce free radicals and antioxidants when exposed to toxic compounds during cellular metabolism. However, free radicals are deleterious to lipids, proteins, and nucleic acids. Antioxidants neutralize and eliminate free radicals from cells, preventing cell damage. Therefore, the study aims to determine whether the antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) will ameliorate the maximum dose of acrylamide and alpha (α)-solanine synergistic toxic effects in exposed BEAS-2B cells. These toxic compounds are consumed worldwide by eating potato products. BEAS-2B cells were simultaneously treated with BHA 10 μM and BHT 20 μM and incubated in a 5% CO humidified incubator for 24 h, followed by individual or combined treatment with acrylamide (3.5 mM) and α-solanine (44 mM) for 48 h, including the controls. Cell morphology, DNA, RNA, and protein were analyzed. The antioxidants did not prevent acrylamide and α-solanine synergistic effects in exposed BEAS-2B cells. However, cell morphology was altered; polymerase chain reaction (PCR) showed reduced RNA constituents but not DNA. In addition, the toxic compounds synergistically inhibited AKT/PKB expression and its downstream genes. The study showed BHA and BHT are not protective against the synergetic toxic effects of acrylamide and α-solanine in exposed BEAS-2B cells.
Topics: Antioxidants; Solanine; Butylated Hydroxytoluene; Butylated Hydroxyanisole; Acrylamide; Proteins; DNA; RNA
PubMed: 37569330
DOI: 10.3390/ijms241511956