-
Oncology Research 2024Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with intermediate malignancy characterized by a propensity for recurrence but a low metastatic rate.... (Review)
Review
Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with intermediate malignancy characterized by a propensity for recurrence but a low metastatic rate. Diagnostic challenges arise from the diverse pathological presentation, variable symptomatology, and lack of different imaging features. However, IMT is identified by the fusion of the anaplastic lymphoma kinase (ALK) gene, which is present in approximately 70% of cases, with various fusion partners, including ran-binding protein 2 (RANBP2), which allows confirmation of the diagnosis. While surgery is the preferred approach for localized tumors, the optimal long-term treatment for advanced or metastatic disease is difficult to define. Targeted therapies are crucial for achieving sustained response to treatment within the context of genetic alteration in IMT. Crizotinib, an ALK tyrosine kinase inhibitor (TKI), was officially approved by the US Food and Drug Administration (FDA) in 2020 to treat IMT with ALK rearrangement. However, most patients face resistance and disease progression, requiring consideration of sequential treatments. Combining radiotherapy with targeted therapy appears to be beneficial in this indication. Early promising results have also been achieved with immunotherapy, indicating potential for combined therapy approaches. However, defined recommendations are still lacking. This review analyzes the available research on IMT, including genetic disorders and their impact on the course of the disease, data on the latest targeted therapy regimens and the possibility of developing immunotherapy in this indication, as well as summarizing general knowledge about prognostic and predictive factors, also in terms of resistance to systemic therapy.
Topics: Humans; Neoplasms, Muscle Tissue; Anaplastic Lymphoma Kinase; Molecular Targeted Therapy; Protein Kinase Inhibitors
PubMed: 38948020
DOI: 10.32604/or.2024.050350 -
Drug Design, Development and Therapy 2024Activating mutations in epidermal growth factor receptor (EGFR) have been identified as key predictive biomarkers for the customized treatment with EGFR tyrosine kinase...
PURPOSE
Activating mutations in epidermal growth factor receptor (EGFR) have been identified as key predictive biomarkers for the customized treatment with EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), aiding in improving patient response rates and survival. However, resistance challenges the efficacy of these treatments, with limited understanding of post-resistance therapeutic strategies. A deep understanding of the biology and resistance mechanisms of EGFR-mutant NSCLC is crucial for developing new treatment approaches. This study, through bibliometric analysis, summarizes the trends in research on resistance to EGFR-TKIs.
METHODS
Research papers on NSCLC with EGFR inhibitor resistance were collected from the Web of Science Core Collection (WoSCC). The analysis utilized bibliometric tools like CiteSpace, VOSviewer, and other platforms for comprehensive analysis and visualization of the outcomes.
RESULTS
The WoSCC database contains a total of 5866 documents on resistance to EGFR-TKIs treatment, including 4727 articles (93.48%) and 1139 reviews (6.52%), spanning 81 countries and regions, 4792 institutions, with the involvement of 23,594 authors. Since 2016, there has been a significant increase in publications in this field. China has the highest publication output, while the United States has the highest citation count for papers. Harvard University leads in terms of the number of publications. Among the top ten journals with the highest output, Clinical Cancer Research has the highest impact factor at 11.5, with 90% of the journals classified in Q1 or Q2. Rafael Rosell is one of the most influential authors in this field, ranking second in publication volume and fourth in citation count. Research on EGFR-TKIs resistance mainly focuses on genetic testing, resistance mechanisms, and post-resistance treatment strategies.
CONCLUSION
This study provides researchers with a reliable basis and guidance for finding authoritative references, understanding research trends, and exploring potential directions.
Topics: Humans; Antineoplastic Agents; Bibliometrics; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Lung Neoplasms; Mutation; Protein Kinase Inhibitors
PubMed: 38947223
DOI: 10.2147/DDDT.S465238 -
CNS Neuroscience & Therapeutics Jul 2024Glycogen synthase kinase-3 (GSK3), consisting of GSK3α and GSK3β subtypes, is a complex protein kinase that regulates numerous substrates. Research has observed... (Review)
Review
Glycogen synthase kinase-3 (GSK3), consisting of GSK3α and GSK3β subtypes, is a complex protein kinase that regulates numerous substrates. Research has observed increased GSK3 expression in the brains of Alzheimer's disease (AD) patients and models. AD is a neurodegenerative disorder with diverse pathogenesis and notable cognitive impairments, characterized by Aβ aggregation and excessive tau phosphorylation. This article provides an overview of GSK3's structure and regulation, extensively analyzing its relationship with AD factors. GSK3 overactivation disrupts neural growth, development, and function. It directly promotes tau phosphorylation, regulates amyloid precursor protein (APP) cleavage, leading to Aβ formation, and directly or indirectly triggers neuroinflammation and oxidative damage. We also summarize preclinical research highlighting the inhibition of GSK3 activity as a primary therapeutic approach for AD. Finally, pending issues like the lack of highly specific and affinity-driven GSK3 inhibitors, are raised and expected to be addressed in future research. In conclusion, GSK3 represents a target in AD treatment, filled with hope, challenges, opportunities, and obstacles.
Topics: Humans; Alzheimer Disease; Animals; Glycogen Synthase Kinase 3; tau Proteins; Amyloid beta-Protein Precursor
PubMed: 38946682
DOI: 10.1111/cns.14818 -
Gynecological Endocrinology : the... Dec 2024Telomeres maintain chromosome stability, while telomerase counteracts their progressive shortening. Telomere length varies between cell types, with leukocyte telomere...
BACKGROUND
Telomeres maintain chromosome stability, while telomerase counteracts their progressive shortening. Telomere length varies between cell types, with leukocyte telomere length (LTL) decreasing with age. Reduced telomerase activity has been linked to reproductive issues in females, such as low pregnancy rates and premature ovarian failure, with recent studies indicating correlations between telomere length in granulosa cells and IVF outcomes.
OBJECTIVES
The study aims to explore the relationship between telomere length, telomerase activity, and euploid blastocyst rate in infertile women undergoing IVF/ICSI PGT-A cycles.
METHODS
This prospective study involves 108 patients undergoing controlled ovarian stimulation and PGT-A. Telomere length and telomerase activity were measured in peripheral mononuclear cells and granulosa cells (GC), respectively.
RESULTS
The telomere repeat copy number to single gene copy number ratio (T/S) results respectively 0.6 ± 0.8 in leukocytes and 0.7 ± 0.9 in GC. An inverse relationship was found between LTL and the patient's age ( < .01). A higher aneuploid rate was noticed in patients with short LTL, with no differences in ovarian reserve markers ( = .15), number of oocytes retrieved ( = .33), and number of MII ( = 0.42). No significant association was noticed between telomere length in GC and patients' age ( = 0.95), in ovarian reserve markers ( = 0.32), number of oocytes retrieved ( = .58), number of MII ( = .74) and aneuploidy rate ( = .65).
CONCLUSION
LTL shows a significant inverse correlation with patient age and higher aneuploidy rates. Telomere length in GCs does not correlate with patient age or reproductive outcomes, indicating differential telomere dynamics between leukocytes and granulosa cells.
Topics: Humans; Female; Adult; Telomerase; Telomere; Prospective Studies; Pregnancy; Aneuploidy; Fertilization in Vitro; Granulosa Cells; Infertility, Female; Ovulation Induction; Blastocyst; Telomere Homeostasis; Sperm Injections, Intracytoplasmic
PubMed: 38946430
DOI: 10.1080/09513590.2024.2373742 -
Journal of Nutritional Science and... 2024L-Theanine is contained in green tea at 1-3% per dry matter as an amino acid with an umami taste, and the antidepressant effect and protective effect against...
L-Theanine is contained in green tea at 1-3% per dry matter as an amino acid with an umami taste, and the antidepressant effect and protective effect against stress-induced brain atrophy in mice, as well as the related mechanism have been reported. However, effects of theanine on the hippocampus from the proteome analysis and the action mechanism have not been examined. In this study, we mainly investigated the possibility of theanine's cognitive impairment-preventing function and the action mechanism by proteomics in the hippocampus of SAMP8 administered with theanine. In addition to improvement in the aging score with theanine administration, in proteomics, significant suppressions in the expressions of synapsin 2, α-synuclein, β-synuclein, and protein tau were observed by theanine administration, and the expression of CAM kinase II beta and alpha exhibited a significant increase and increasing tendency with theanine administration, respectively. The expression of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein tended to increase by theanine administration. On the other hand, serotonin/tryptophan, GABA/glutamic acid and glutamine/glutamic acid ratios in the hippocampus showed an increasing tendency, a significant increase, and an increasing tendency with theanine administration, respectively. These results suggested that theanine might have been involved in the improvement of neurodegeneration or cognitive impairment by suppressing the productions of synapsin, synuclein and protein tau which are considered to be produced along with aging and oxidation, and by enhancing the production of serotonin by increasing the expression of CAM kinase II, and further by affecting the metabolism of glutamate.
Topics: Animals; Glutamates; Hippocampus; Mice; Male; Aging; Synapsins; Glutamic Acid; alpha-Synuclein; tau Proteins; Proteomics; Dietary Supplements; Serotonin; Diet; gamma-Aminobutyric Acid; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cognitive Dysfunction
PubMed: 38945886
DOI: 10.3177/jnsv.70.210 -
The Journal of Toxicological Sciences 2024Dihydropyrazines (DHPs) are formed by non-enzymatic glycation reactions in vivo and in food. We recently reported that 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), which...
Dihydropyrazines (DHPs) are formed by non-enzymatic glycation reactions in vivo and in food. We recently reported that 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), which is a methyl-substituted DHP, caused severe oxidative stress and cytotoxicity. However, the molecular mechanisms underlying the cytotoxic pathways of the DHP response remain elusive. Because oxidative stress induces endoplasmic reticulum (ER) stress and autophagy, we investigated the ability of DHP-3 to modulate the ER stress and autophagy pathways. DHP-3 activated the ER stress pathway by increasing inositol-requiring enzyme 1 (IRE1) and PKR-like ER kinase (PERK) phosphorylation and transcription factor 6 (ATF6) expression. Moreover, DHP-3 increased the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), which are downstream targets of PERK. In addition, DHP-3 inhibited the autophagy pathway by increasing the accumulation of microtubule-associated protein 1 light chain 3 alpha-phosphatidylethanolamine conjugate (LC3-II) and p62/sequestosome 1 (p62), while decreasing autophagic flux. Taken together, these results indicate that DHP-3 activates the ER stress pathway and inhibits the autophagy pathway, suggesting that the resulting removal of damaged organelles is inadequate.
Topics: Humans; Autophagy; Endoplasmic Reticulum Stress; Pyrazines; Hep G2 Cells; Activating Transcription Factor 4; eIF-2 Kinase; Activating Transcription Factor 6; Protein Serine-Threonine Kinases; Transcription Factor CHOP; Endoribonucleases; Phosphorylation; Carcinoma, Hepatocellular; Liver Neoplasms; Oxidative Stress; Sequestosome-1 Protein; Signal Transduction; Microtubule-Associated Proteins
PubMed: 38945842
DOI: 10.2131/jts.49.313 -
Nature Communications Jun 2024JNK signaling is a critical regulator of inflammation and regeneration, but how it is controlled in specific tissue contexts remains unclear. Here we show that, in the...
JNK signaling is a critical regulator of inflammation and regeneration, but how it is controlled in specific tissue contexts remains unclear. Here we show that, in the Drosophila intestine, the TNF-type ligand, Eiger (Egr), is expressed exclusively by intestinal stem cells (ISCs) and enteroblasts (EBs), where it is induced by stress and during aging. Egr preferentially activates JNK signaling in a paracrine fashion in differentiated enterocytes (ECs) via its receptor, Grindelwald (Grnd). N-glycosylation genes (Alg3, Alg9) restrain this activation, and stress-induced downregulation of Alg3 and Alg9 correlates with JNK activation, suggesting a regulatory switch. JNK activity in ECs induces expression of the intermembrane protease Rhomboid (Rho), driving secretion of EGFR ligands Keren (Krn) and Spitz (Spi), which in turn activate EGFR signaling in progenitor cells (ISCs and EBs) to stimulate their growth and division, as well as to produce more Egr. This study uncovers an N-glycosylation-controlled, paracrine JNK-EGFR-JNK feedforward loop that sustains ISC proliferation during stress-induced gut regeneration.
Topics: Animals; Drosophila Proteins; ErbB Receptors; Intestines; MAP Kinase Signaling System; Drosophila melanogaster; Enterocytes; Stem Cells; Intestinal Mucosa; Drosophila; Glycosylation; Receptors, Invertebrate Peptide; Cell Proliferation; JNK Mitogen-Activated Protein Kinases; Signal Transduction; Cell Communication; Cell Differentiation; Epidermal Growth Factor; Membrane Proteins
PubMed: 38944657
DOI: 10.1038/s41467-024-49786-w -
Cancer Genomics & Proteomics 2024BRCA1/2 mutations in breast cancer cells impair homologous recombination and promote alternative end joining (Alt-EJ) for DNA-damage repair. DNA polymerase theta,...
BACKGROUND/AIM
BRCA1/2 mutations in breast cancer cells impair homologous recombination and promote alternative end joining (Alt-EJ) for DNA-damage repair. DNA polymerase theta, encoded by POLQ, plays a crucial role in Alt-EJ, making it a potential therapeutic target, particularly in BRCA1/2-mutant cancers. Methionine restriction is a promising approach to target cancer cells due to their addiction to this amino acid. The present study investigated the expression of POLQ in BRCA1/2 wild-type and BRCA1-mutant breast cancer cells under methionine restriction.
MATERIALS AND METHODS
POLQ mRNA expression was measured using qRT-PCR in BRCA1/2 wild-type (MDA-MB-231) and BRCA1- mutant (HCC1937 and MDA-MB-436) breast-cancer cells under normal, or serum-restricted, or serum- and methionine-restricted conditions.
RESULTS
Compared to BRCA1/2 wild-type cells, BRCA1-mutant cells displayed significantly higher basal POLQ expression in normal medium. Methionine restriction further increased POLQ expression in the BRCA1-mutant cells but decreased it in the BRCA1/2 wild-type cells.
CONCLUSION
The present findings suggest that methionine restriction showed differential effects on POLQ expression, potentially impacting Alt-EJ activity, in BRCA1/2 wild-type and BRCA1-mutant breast-cancer cells. Further investigation is needed to explore the potential of combining methionine restriction with DNA-repair inhibitors, such as PARP inhibitors, to overcome drug resistance in BRCA1/2 mutant cancers.
Topics: Humans; Methionine; Breast Neoplasms; Female; BRCA1 Protein; Mutation; DNA Polymerase theta; DNA-Directed DNA Polymerase; DNA Repair; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; BRCA2 Protein
PubMed: 38944428
DOI: 10.21873/cgp.20458 -
Cancer Genomics & Proteomics 2024Breast cancer (BC) is the most common malignant disease worldwide. Localized stages of BC can be successfully treated by surgery. However, local recurrence occurs in...
BACKGROUND/AIM
Breast cancer (BC) is the most common malignant disease worldwide. Localized stages of BC can be successfully treated by surgery. However, local recurrence occurs in about 4-10% of patients, requiring systemic treatments that impair the patients' quality of life and shortens life expectancy. Therefore, new therapeutic options are needed, which can be used intraoperatively and contribute to the complete removal of residual tumor cells in the surgical area. In the present study, we describe a cysteine-modified variant of the anti-HER2 antibody trastuzumab, that was coupled to the silicon phthalocyanine photosensitizer dye WB692-CB1 for the photoimmunotherapy (PIT) of BC.
MATERIALS AND METHODS
The cysteine modified trastuzumab variant was cloned and expressed in Expi293F cells. After purification via immobilized affinity chromatography, the antibody was coupled to the dye. Cell binding of the antibody and the antibody dye conjugate was measured by flow cytometry. After incubation of BC cells with the conjugate and activation of the dye by irradiation with red light, cell viability was determined.
RESULTS
The antibody and the conjugate showed specific binding to HER2-expressing BC cells. Treatment of the HER2 BC cell line SK-BR-3 with the conjugate followed by irradiation with a red light dose of 32 J/cm led to complete cell killing within 24 h.
CONCLUSION
Our novel antibody dye conjugate represents a promising candidate for intraoperative treatment of localized BC, aiming to eliminate residual tumor cells in the surgical area and potentially reduce local recurrence, thereby improving recovery prospects for BC patients.
Topics: Humans; Breast Neoplasms; Female; Receptor, ErbB-2; Immunotherapy; Trastuzumab; Phototherapy; Photosensitizing Agents; Cell Line, Tumor
PubMed: 38944426
DOI: 10.21873/cgp.20453 -
Journal of Orthopaedic Surgery and... Jun 2024Tendon stem/progenitor cell (TSPC) senescence contributes to tendon degeneration and impaired tendon repair, resulting in age-related tendon disorders. Ferroptosis, a...
Platelet-derived exosomes alleviate tendon stem/progenitor cell senescence and ferroptosis by regulating AMPK/Nrf2/GPX4 signaling and improve tendon-bone junction regeneration in rats.
BACKGROUND
Tendon stem/progenitor cell (TSPC) senescence contributes to tendon degeneration and impaired tendon repair, resulting in age-related tendon disorders. Ferroptosis, a unique iron-dependent form of programmed cell death, might participate in the process of senescence. However, whether ferroptosis plays a role in TSPC senescence and tendon regeneration remains unclear. Recent studies reported that Platelet-derived exosomes (PL-Exos) might provide significant advantages in musculoskeletal regeneration and inflammation regulation. The effects and mechanism of PL-Exos on TSPC senescence and tendon regeneration are worthy of further study.
METHODS
Herein, we examined the role of ferroptosis in the pathogenesis of TSPC senescence. PL-Exos were isolated and determined by TEM, particle size analysis, western blot and mass spectrometry identification. We investigated the function and underlying mechanisms of PL-Exos in TSPC senescence and ferroptosis via western blot, real-time quantitative polymerase chain reaction, and immunofluorescence analysis in vitro. Tendon regeneration was evaluated by HE staining, Safranin-O staining, and biomechanical tests in a rotator cuff tear model in rats.
RESULTS
We discovered that ferroptosis was involved in senescent TSPCs. Furthermore, PL-Exos mitigated the aging phenotypes and ferroptosis of TSPCs induced by t-BHP and preserved their proliferation and tenogenic capacity. The in vivo animal results indicated that PL-Exos improved tendon-bone healing properties and mechanical strength. Mechanistically, PL-Exos activated AMPK phosphorylation and the downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway, leading to the suppression of lipid peroxidation. AMPK inhibition or GPX4 inhibition blocked the protective effect of PL-Exos against t-BHP-induced ferroptosis and senescence.
CONCLUSION
In conclusion, ferroptosis might play a crucial role in TSPC aging. AMPK/Nrf2/GPX4 activation by PL-Exos was found to inhibit ferroptosis, consequently leading to the suppression of senescence in TSPCs. Our results provided new theoretical evidence for the potential application of PL-Exos to restrain tendon degeneration and promote tendon regeneration.
Topics: Animals; Ferroptosis; Exosomes; NF-E2-Related Factor 2; Cellular Senescence; Rats; Signal Transduction; Phospholipid Hydroperoxide Glutathione Peroxidase; Regeneration; AMP-Activated Protein Kinases; Stem Cells; Tendons; Male; Blood Platelets; Rats, Sprague-Dawley; Rotator Cuff Injuries; Disease Models, Animal
PubMed: 38943181
DOI: 10.1186/s13018-024-04869-8