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Keywords = ETS factor inhibitor

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2 pages, 143 KiB  
Correction
Correction: Ssengonzi et al. Inhibitor of DNA Binding Protein 2 (ID2) Mediates the Anti-Proliferative and Pro-Differentiation Effects of Insulin-like Growth Factor-1 (IGF-1). Life 2024, 14, 1663
by Rebecca Ssengonzi, Yuye Wang, Jiayi Zhou, Yukako Kayashima, W. H. Davin Townley-Tilson, Balaji Rao, Qing Ma, Nobuyo Maeda-Smithies and Feng Li
Life 2025, 15(7), 1016; https://doi.org/10.3390/life15071016 - 26 Jun 2025
Viewed by 254
Abstract
In the original publication [...] Full article
27 pages, 7392 KiB  
Article
Skin-Whitening, Antiwrinkle, and Moisturizing Effects of Astilboides tabularis (Hemsl.) Engl. Root Extracts in Cell-Based Assays and Three-Dimensional Artificial Skin Models
by Nam Ho Yoo, Hyun Sook Lee, Sung Min Park, Young Sun Baek and Myong Jo Kim
Int. J. Mol. Sci. 2025, 26(12), 5725; https://doi.org/10.3390/ijms26125725 - 15 Jun 2025
Viewed by 530
Abstract
This study investigated the potential cosmetic properties of the ethyl acetate (EtOAc) fraction obtained from the roots of Astilboides tabularis (Hemsl.) Engl., focusing on skin-whitening, antiwrinkle, and moisturizing effects using cell-based assays and three-dimensional (3D) artificial skin models (Neoderm-ED and Neoderm-ME). The EtOAc [...] Read more.
This study investigated the potential cosmetic properties of the ethyl acetate (EtOAc) fraction obtained from the roots of Astilboides tabularis (Hemsl.) Engl., focusing on skin-whitening, antiwrinkle, and moisturizing effects using cell-based assays and three-dimensional (3D) artificial skin models (Neoderm-ED and Neoderm-ME). The EtOAc fraction showed significant dose-dependent inhibitory activity against tyrosinase (TYR) (72.0% inhibition at 50 µg/mL), comparable to that of kojic acid. In α-melanocyte-stimulating hormone (α-MSH)-stimulated Neoderm-ME artificial skin containing melanocytes, the EtOAc fraction reduced melanin synthesis at concentrations of 50 and 75 µg/mL and decreased melanogenesis-related gene expression, including TYR, microphthalmia-associated transcription factor (MITF), tyrosinase-related protein-1 (TRP-1) and TRP-2. In the antiwrinkle assays, the EtOAc fraction effectively inhibited elastase activity (41.5% inhibition at 10 µg/mL), exceeding the efficacy of ursolic acid. In the Neoderm-ED artificial skin model, the EtOAc fraction reversed structural damage induced by particulate matter (PM10), restoring epidermal thickness and dermal density. This improvement was supported by the increased expression of skin barrier and antiwrinkle genes, including filaggrin, hyaluronic acid synthase-1 (HAS-1), HAS-2, aquaporin-3 (AQP-3), collagen type I alpha 1 chain (COL1A1), elastin, tissue inhibitor of metalloproteinases-1 (TIMP-1), and TIMP-2, as well as decreased expression of matrix metalloproteinases (MMP-1, MMP-3, and MMP-9). Our results indicate that the EtOAc fraction from A. tabularis root has considerable potential as a multifunctional cosmetic. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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15 pages, 1289 KiB  
Systematic Review
Continuing Cyclin-Dependent Kinase 4/6 Inhibitors Beyond Progression in Advanced Breast Cancer: A Meta-Analysis
by Neha Pathak, Sudhir Kumar, Diego Malon Gimenez, Massimo Di Iorio, Jacqueline Savill, Yael Berner-Wygoda, Meredith Li, Consolacion Molto Valiente, Danielle Cuthbert, Aarushi Gupta, Diana P. Arteaga, Atul Batra, Eitan Amir and Abhenil Mittal
Cancers 2025, 17(10), 1609; https://doi.org/10.3390/cancers17101609 - 9 May 2025
Viewed by 775
Abstract
Background: The use of cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i) with endocrine therapy (ET) is a first-line standard treatment for hormone receptor-positive (ER+) Human Epidermal Growth factor Receptor-2-negative (HER2-) advanced breast cancer. The data supporting incorporation of CDK 4/6i + ET beyond progression [...] Read more.
Background: The use of cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i) with endocrine therapy (ET) is a first-line standard treatment for hormone receptor-positive (ER+) Human Epidermal Growth factor Receptor-2-negative (HER2-) advanced breast cancer. The data supporting incorporation of CDK 4/6i + ET beyond progression are variable. Here, we report a pooled analysis of this strategy. Methods: A systematic review identified reports of both observational and clinical studies, which evaluated the continuation of CDK4/6i beyond progression. The mean overall response rate (ORR) and progression-free survival (PFS) weighted by the study sample size were calculated. Meta-regression comprising linear regression weighted by the sample size (mixed effects) was performed to explore the association between disease and treatment-related factors and the benefit from continuing CDK4/6i. Quantitative significance was assessed using the Burnand criteria. Results: Thirteen studies comprising 1530 patients were included. The median age was 58 years, 50.8% had visceral metastases, and 48% had ESR1 mutations; the median lines of prior therapies were 1 (range 1–5), and 96.3% received palbociclib as the initial CDK4/6i. Eight studies tested a CDK4/6i switch as the intervention. The median PFS was 5.3 months, and the ORR was 14%. In randomized studies, statistically significant differences were observed between CDK4/6i continuation and control, although it is uncertain whether the magnitude of the effect is clinically meaningful. Increasing age, lack of prior chemotherapy, no visceral metastasis or ESR1 mutations, and a switch to a non-palbociclib CDK4/6i were associated with better outcomes. Conclusion: Continuing a CDK 4/6i + ET beyond progression yields modest benefits. Switching CDK4/6i likely results in improved ORR and PFS. Continuing palbociclib beyond progression is likely ineffectual. Full article
(This article belongs to the Section Clinical Research of Cancer)
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16 pages, 3142 KiB  
Article
Effect of Tasurgratinib as an Orally Available FGFR1–3 Inhibitor on Resistance to a CDK4/6 Inhibitor and Endocrine Therapy in ER+/HER2 Breast Cancer Preclinical Models
by Satoshi Kawano, Sayo Fukushima, Kyoko Nishibata, Ryu Gejima and Saori Watanabe Miyano
Cancers 2025, 17(7), 1084; https://doi.org/10.3390/cancers17071084 - 24 Mar 2025
Viewed by 744
Abstract
Background: Fibroblast growth factor (FGF) signaling plays a crucial role in several cellular functions in cancer cells. Tasurgratinib, formerly known as E7090, is an orally available FGF receptor (FGFR)1–3 selective inhibitor. Here, we present the effects of tasurgratinib on the resistance to CDK4/6 [...] Read more.
Background: Fibroblast growth factor (FGF) signaling plays a crucial role in several cellular functions in cancer cells. Tasurgratinib, formerly known as E7090, is an orally available FGF receptor (FGFR)1–3 selective inhibitor. Here, we present the effects of tasurgratinib on the resistance to CDK4/6 inhibitors and endocrine therapy (ET) in a preclinical model. Methods: Estrogen receptor (ER)+ breast cancer (BC) patient-derived xenograft (PDX) models harboring ESR1 wild-type or ESR1 mutation were used as animal models. An in vitro cell proliferation assay of ER+ BC cell lines treated with fulvestrant or palbociclib + fulvestrant was conducted in the presence of FGF2 and FGF10, with or without tasurgratinib. Results: Among five ER+ BC PDX models, OD-BRE-0438 and OD-BRE-0704 showed higher sensitivities to tasurgratinib with prior palbociclib + fulvestrant than without it. In these models, palbociclib + fulvestrant treatment upregulated the expression of several FGF ligand mRNAs. In vitro, FGF2 and FGF10 decreased the sensitivity to both fulvestrant and palbociclib + fulvestrant, which was restored by co-treatment with tasurgratinib. Consistently, fulvestrant + tasurgratinib and elacestrant + tasurgratinib showed antitumor activity in ER+ BC PDX models harboring ESR1 wild-type and ESR1 mutation, respectively. In these models, fulvestrant or elacestrant upregulated the expression of several FGF ligand mRNAs. Conclusions: FGF signaling plays a role in resistance to CDK4/6 inhibitors and ET in ER+ BC. Tasurgratinib has the potential to exhibit significant antitumor activity in combination with ET against ER+ BC via FGF signaling inhibition. These findings indicate the therapeutic potential of tasurgratinib in treating ER+ BC. Full article
(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer (Volume II))
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18 pages, 1134 KiB  
Article
Evaluating the Effectiveness of Cyclin-Dependent Kinase 4/6 Inhibitors in Early- and Very Early-Onset Metastatic Breast Cancer: A Multicenter Study
by Akif Doğan, Nurullah İlhan, Goncagül Akdağ, Sedat Yıldırım, Mustafa Seyyar, Zeynep Yüksel Yaşar, Hande Nur Erölmez, Heves Sürmeli, Buğra Öztosun, Özlem Nuray Sever, Hatice Odabaş, Mahmut Emre Yıldırım, Devrim Çabuk, Nedim Turan and Mahmut Gümüş
Medicina 2025, 61(1), 154; https://doi.org/10.3390/medicina61010154 - 17 Jan 2025
Viewed by 1320
Abstract
Background and Objectives: Early-onset breast cancer (EOBC), particularly in patients under 40, presents with distinct biological characteristics and worse survival outcomes compared to late-onset cases. Despite intensive treatments, EOBC patients, especially those with hormone receptor-positive, HER2-negative (HR+/HER2-) subtypes, show poorer prognosis. CDK4/6 inhibitors, combined [...] Read more.
Background and Objectives: Early-onset breast cancer (EOBC), particularly in patients under 40, presents with distinct biological characteristics and worse survival outcomes compared to late-onset cases. Despite intensive treatments, EOBC patients, especially those with hormone receptor-positive, HER2-negative (HR+/HER2-) subtypes, show poorer prognosis. CDK4/6 inhibitors, combined with endocrine therapy (ET) have become the standard for HR+/HER2- metastatic breast cancer, yet younger patients are underrepresented in clinical trials. This study aims to evaluate the efficacy of ribociclib and palbociclib with ET in HR+/HER2- metastatic breast cancer, addressing the critical gap in understanding treatment outcomes in younger patient populations. Materials and Methods: This multicenter, retrospective study evaluated the efficacy and safety of cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors, ribociclib, and palbociclib, in combination with endocrine therapy in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer. Results: A total of 198 patients treated between 2019 and 2023 were analyzed for progression-free survival, overall survival, and prognostic factors. Very early-onset breast cancer, which is diagnosed before the age of 35, was identified as an independent prognostic factor for poor progression-free survival. Additional factors associated with poorer outcomes included liver metastasis, progesterone receptor negativity, high tumor grade, and the concurrent use of fulvestrant with CDK4/6 inhibitors. Both ribociclib and palbociclib demonstrated similar efficacy, and dose reductions due to treatment-related adverse events did not compromise therapeutic outcomes. Conclusions: This study is the first to focus specifically on the treatment of early-onset breast cancer with CDK4/6 inhibitors, providing critical insights into the unique challenges faced by this patient population. The findings underscore the urgent need for personalized treatment strategies, routine genetic testing, and dedicated clinical trials designed to address the specific needs of these high-risk subgroups. By advancing our understanding of the clinical and molecular landscape of early-onset breast cancer and very early-onset breast cancer, this study lays the groundwork for improving outcomes in these underserved patients through tailored therapeutic approaches. Full article
(This article belongs to the Section Oncology)
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18 pages, 1939 KiB  
Article
Root-Knot Nematode Early Infection Suppresses Immune Response and Elicits the Antioxidant System in Tomato
by Sergio Molinari, Anna Carla Farano and Paola Leonetti
Int. J. Mol. Sci. 2024, 25(23), 12602; https://doi.org/10.3390/ijms252312602 - 23 Nov 2024
Cited by 1 | Viewed by 1924
Abstract
The immune response in plants is regulated by several phytohormones and involves the overexpression of defense genes, including the pathogenesis-related (PR-) genes. The data reported in this paper indicate that nematodes can suppress the immune response by inhibiting the expression of [...] Read more.
The immune response in plants is regulated by several phytohormones and involves the overexpression of defense genes, including the pathogenesis-related (PR-) genes. The data reported in this paper indicate that nematodes can suppress the immune response by inhibiting the expression of defense genes. Transcripts from nine defense genes were detected by qRT-PCR in the roots of tomato plants at three and seven days post-inoculation (dpi) with living juveniles (J2s) of Meloidogyne incognita (root-knot nematodes, RKNs). All the salicylic acid (SA)-responsive genes tested (PR-1, PR-2, PR-4b, PR-5) were down-regulated in response to nematode infection. On the contrary, the expression of jasmonic acid (JA)-responsive genes, including ACO (encoding the enzyme 1-aminocyclopropane-1-carboxylic acid oxidase, which catalyzes the last step of ethylene (ET) biosynthesis) and JERF3 (Jasmonate Ethylene Response Factor 3), was unaffected by the infection. Conversely, the effect of nematode attack on the activities of the defense enzymes endoglucanase and endochitinase, encoded by PR-2 and PR-3, respectively, changed depending on the tested dpi. At 5 dpi, both enzymes were inhibited in inoculated plants compared to healthy controls. The genes encoding glutathione peroxidase (GPX) and catalase (CAT), both part of the antioxidant plant system, were highly overexpressed. Additionally, the activity of the antioxidant enzymes superoxide dismutase (SOD), CAT, and ascorbate peroxidase (APX) was enhanced in infected roots. Isoelectrofocusing of root extracts revealed novel SOD isoforms in samples from inoculated plants. Furthermore, plants were pre-treated with an array of key compounds, including hormone generators, inhibitors of SA or JA-mediated defense pathways, reactive oxygen species (ROS) scavengers and generators, inhibitors of ROS generation, and compounds that interfere with calcium-mediated metabolism. After treatments, plants were inoculated with RKNs, and nematodes were allowed to complete their life cycle. Factors of plant growth and infection level in treated plants were compared with those from untreated inoculated plants. Generally, compounds that decreased SA and/or ROS levels increased infection severity, while those that reduced JA/ET levels did not affect infection rates. ROS generators induced resistance against the pests. Compounds that silence calcium signaling by preventing its intake augmented infection symptoms. The data shown in this paper indicate that SA-mediated plant immune responses are consistently suppressed during the early stages of nematode infection, and this restriction is associated with the activation of the antioxidant ROS-scavenging system. Full article
(This article belongs to the Special Issue Molecular Interactions between Plants and Pests)
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17 pages, 4942 KiB  
Article
Anti-Inflammatory Effects and Metabolomic Analysis of Ilex Rotunda Extracted by Supercritical Fluid Extraction
by Duc Dat Le, Young Su Jang, Vinhquang Truong, Thientam Dinh, Thinhulinh Dang, Soojung Yu and Mina Lee
Int. J. Mol. Sci. 2024, 25(22), 11965; https://doi.org/10.3390/ijms252211965 - 7 Nov 2024
Cited by 3 | Viewed by 1423
Abstract
Ilex rotunda is a famous medicinal plant with many ethnopharmacological uses. It is traditionally employed for treating inflammation and cardiovascular diseases. In this study, we established green technology to extract the leaves and twigs of I. rotunda. The obtained extracts and [...] Read more.
Ilex rotunda is a famous medicinal plant with many ethnopharmacological uses. It is traditionally employed for treating inflammation and cardiovascular diseases. In this study, we established green technology to extract the leaves and twigs of I. rotunda. The obtained extracts and their fractions were evaluated for their anti-inflammatory potential. In cytokine assays, the extract, n-hexane (H), methylene chloride (MC), and EtOAc (E) fractions of the twigs of I. rotunda significantly inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO), interleukin (IL)-6, and tumor necrosis factor (TNF)-α production in RAW264.7 macrophages. Furthermore, the extract, H, and MC fractions of the leaves of I. rotunda modulated cytokine expression by downregulating LPS-induced NO, IL-6, and TNF-α production in RAW264.7 macrophages. Western blotting analysis revealed that the extracts and fractions of the leaves and twigs of I. rotunda inhibited inflammatory cytokines by inactivating nuclear factor kappa B (NFκB) action by reducing the phosphorylation of transcript factor (p65) and nuclear factor-kappa B inhibitor alpha (IκBα) degradation, or by inactivating mitogen-activated protein kinase (MAPK) through the p38 or ERK signaling pathways via the active ingredients of the leaves and twigs of I. rotunda. Ultra-high-resolution liquid chromatography–Orbitrap mass analysis (UHPLC–ESI-Orbitrap-MS/MS)-based molecular networking, in cooperation with social open platform-guided isolation and dereplication, led to the identification of metabolites in this plant. Our findings indicate that the leaves and twigs of I. rotunda could be promising candidates for developing therapeutic strategies to treat anti-inflammatory diseases. Full article
(This article belongs to the Special Issue Molecular Pharmacology of Medicinal Plants)
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20 pages, 7902 KiB  
Article
Analysis of the Setomimycin Biosynthetic Gene Cluster from Streptomyces nojiriensis JCM3382 and Evaluation of Its α-Glucosidase Inhibitory Activity Using Molecular Docking and Molecular Dynamics Simulations
by Kyung-A Hyun, Xuhui Liang, Yang Xu, Seung-Young Kim, Kyung-Hwan Boo, Jin-Soo Park, Won-Jae Chi and Chang-Gu Hyun
Int. J. Mol. Sci. 2024, 25(19), 10758; https://doi.org/10.3390/ijms251910758 - 6 Oct 2024
Cited by 2 | Viewed by 1908
Abstract
The formation of atroposelective biaryl compounds in plants and fungi is well understood; however, polyketide aglycone synthesis and dimerization in bacteria remain unclear. Thus, the biosynthetic gene cluster (BGC) responsible for antibacterial setomimycin production from Streptomyces nojiriensis JCM3382 was examined in comparison with [...] Read more.
The formation of atroposelective biaryl compounds in plants and fungi is well understood; however, polyketide aglycone synthesis and dimerization in bacteria remain unclear. Thus, the biosynthetic gene cluster (BGC) responsible for antibacterial setomimycin production from Streptomyces nojiriensis JCM3382 was examined in comparison with the BGCs of spectomycin, julichromes, lincolnenins, and huanglongmycin. The setomimycin BGC includes post-polyketide synthase (PKS) assembly/cycling enzymes StmD (C-9 ketoreductase), StmE (aromatase), and StmF (thioesterase) as key components. The heterodimeric TcmI-like cyclases StmH and StmK are proposed to aid in forming the setomimycin monomer. In addition, StmI (P-450) is predicted to catalyze the biaryl coupling of two monomeric setomimycin units, with StmM (ferredoxin) specific to the setomimycin BGC. The roles of StmL and StmN, part of the nuclear transport factor 2 (NTF-2)-like protein family and unique to setomimycin BGCs, could particularly interest biochemists and combinatorial biologists. α-Glucosidase, a key enzyme in type 2 diabetes, hydrolyzes carbohydrates into glucose, thereby elevating blood glucose levels. This study aimed to assess the α-glucosidase inhibitory activity of EtOAc extracts of JCM 3382 and setomimycin. The JCM 3382 EtOAc extract and setomimycin exhibited greater potency than the standard inhibitor, acarbose, with IC50 values of 285.14 ± 2.04 μg/mL and 231.26 ± 0.41 μM, respectively. Molecular docking demonstrated two hydrogen bonds with maltase-glucoamylase chain A residues Thr205 and Lys480 (binding energy = −6.8 kcal·mol−1), two π–π interactions with Trp406 and Phe450, and one π–cation interaction with Asp542. Residue-energy analysis highlighted Trp406 and Phe450 as key in setomimycin’s binding to maltase-glucoamylase. These findings suggest that setomimycin is a promising candidate for further enzymological research and potential antidiabetic therapy. Full article
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15 pages, 3436 KiB  
Systematic Review
Cyclin-Dependent Kinase 4/6 Inhibitors Plus Endocrine Therapy versus Endocrine Therapy Alone for HR-Positive, HER-2-Negative Early Breast Cancer: Meta-Analysis of Phase III Randomized Clinical Trials
by Francisco Cezar Aquino de Moraes, Gustavo de Oliveira Almeida, Vinícius Freire Costa Alves, Jonathan N. Priantti, Giovanna da Conceição Gomes, Sarah Vitória Bristot Carnevalli, Thiago Madeira, Maysa Vilbert, Carlos Stecca, Maria Cristina Figueroa Magalhães, Marianne Rodrigues Fernandes and Ney Pereira Carneiro dos Santos
J. Pers. Med. 2024, 14(5), 464; https://doi.org/10.3390/jpm14050464 - 27 Apr 2024
Cited by 8 | Viewed by 2444
Abstract
Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for advanced breast cancer combined with endocrine therapy (ET). The efficacy of CDK4/6 inhibitors plus ET in hormone estrogen-positive, human epidermal growth factor 2-negative (HR+/HER2−) early-stage breast cancer (esBC) is still to be confirmed. Methods: [...] Read more.
Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for advanced breast cancer combined with endocrine therapy (ET). The efficacy of CDK4/6 inhibitors plus ET in hormone estrogen-positive, human epidermal growth factor 2-negative (HR+/HER2−) early-stage breast cancer (esBC) is still to be confirmed. Methods: We performed a systematic review and a meta-analysis to investigate the efficacy of CDK4/6i plus ET in esBC. Main outcomes included invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), and overall survival (OS). We included only phase III randomized controlled trials. We used RStudio version 4.2.3, and we considered p < 0.05 to be statistically significant. Results: Four studies were selected, including 14,168 patients, of which 7089 were treated with CDK4/6i plus ET and 7079 received ET monotherapy. Regarding patient characteristics, 6828 (48.2%) were premenopausal. Compared with ET alone, iDFS rates (HR 0.81; 95% CI: 0.67, 0.98; p = 0.034) were significantly in favor of CDK4/6 inhibitors plus ET. However, there were no significant differences in DRFS (HR 0.79; 95% CI: 0.58, 1.07; p = 0.132) nor OS (HR 0.96; 95% CI: 0.69, 1.35; p = 0.829). Conclusions: Our results show that the addition of CDK4/6 inhibitors is associated with a significant benefit for HR+/HER2− esBC patients in iDFS. More studies and longer follow-up are needed to assess overall survival benefits. Full article
(This article belongs to the Section Personalized Therapy and Drug Delivery)
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13 pages, 1087 KiB  
Article
Real-World Treatment Patterns and Clinical Outcomes among Patients Receiving CDK4/6 Inhibitors for Metastatic Breast Cancer in a Canadian Setting Using AI-Extracted Data
by Ruth Moulson, Guillaume Feugère, Tracy S. Moreira-Lucas, Florence Dequen, Jessica Weiss, Janet Smith and Christine Brezden-Masley
Curr. Oncol. 2024, 31(4), 2172-2184; https://doi.org/10.3390/curroncol31040161 - 9 Apr 2024
Cited by 2 | Viewed by 3313
Abstract
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are widely used in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 negative (HER2−) advanced/metastatic breast cancer (ABC/MBC) in first line (1L), but little is known about their real-world use and clinical outcomes long-term, in Canada. [...] Read more.
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are widely used in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 negative (HER2−) advanced/metastatic breast cancer (ABC/MBC) in first line (1L), but little is known about their real-world use and clinical outcomes long-term, in Canada. This study used Pentavere’s previously validated artificial intelligence (AI) to extract real-world data on the treatment patterns and outcomes of patients receiving CDK4/6i+endocrine therapy (ET) for HR+/HER2− ABC/MBC at Sinai Health in Toronto, Canada. Between 1 January 2016 and 1 July 2021, 48 patients were diagnosed with HR+/HER2− ABC/MBC and received CDK4/6i + ET. A total of 38 out of 48 patients received CDK4/6i + ET in 1L, of which 34 of the 38 (89.5%) received palbociclib + ET. In 2L, 12 of the 21 (57.1%) patients received CDK4/6i + ET, of which 58.3% received abemaciclib. In 3L, most patients received chemotherapy (10/12, 83.3%). For the patients receiving CDK4/6i in 1L, the median (95% CI) time to the next treatment was 42.3 (41.2, NA) months. The median (95% CI) time to chemotherapy was 46.5 (41.4, NA) months. The two-year overall survival (95% CI) was 97.4% (92.4, 100.0), and the median (range) follow-up was 28.7 (3.4–67.6) months. Despite the limitations inherent in real-world studies and a limited number of patients, these AI-extracted data complement previous studies, demonstrating the effectiveness of CDK4/6i + ET in the Canadian real-world 1L, with most patients receiving palbociclib as CDK4/6i in 1L. Full article
(This article belongs to the Topic Artificial Intelligence in Cancer, Biology and Oncology)
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25 pages, 2070 KiB  
Review
Transcription Factors in Prostate Cancer: Insights for Disease Development and Diagnostic and Therapeutic Approaches
by Karla C. S. Silva, Nadine Tambwe, Dalia H. Mahfouz, Martha Wium, Stefano Cacciatore, Juliano D. Paccez and Luiz F. Zerbini
Genes 2024, 15(4), 450; https://doi.org/10.3390/genes15040450 - 2 Apr 2024
Cited by 5 | Viewed by 3781
Abstract
Transcription factors (TFs) are proteins essential for the regulation of gene expression, and they regulate the genes involved in different cellular processes, such as proliferation, differentiation, survival, and apoptosis. Although their expression is essential in normal physiological conditions, abnormal regulation of TFs plays [...] Read more.
Transcription factors (TFs) are proteins essential for the regulation of gene expression, and they regulate the genes involved in different cellular processes, such as proliferation, differentiation, survival, and apoptosis. Although their expression is essential in normal physiological conditions, abnormal regulation of TFs plays critical role in several diseases, including cancer. In prostate cancer, the most common malignancy in men, TFs are known to play crucial roles in the initiation, progression, and resistance to therapy of the disease. Understanding the interplay between these TFs and their downstream targets provides insights into the molecular basis of prostate cancer pathogenesis. In this review, we discuss the involvement of key TFs, including the E26 Transformation-Specific (ETS) Family (ERG and SPDEF), NF-κB, Activating Protein-1 (AP-1), MYC, and androgen receptor (AR), in prostate cancer while focusing on the molecular mechanisms involved in prostate cancer development. We also discuss emerging diagnostic strategies, early detection, and risk stratification using TFs. Furthermore, we explore the development of therapeutic interventions targeting TF pathways, including the use of small molecule inhibitors, gene therapies, and immunotherapies, aimed at disrupting oncogenic TF signaling and improving patient outcomes. Understanding the complex regulation of TFs in prostate cancer provides valuable insights into disease biology, which ultimately may lead to advancing precision approaches for patients. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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9 pages, 4225 KiB  
Case Report
ETV6::ABL1-Positive Myeloid Neoplasm: A Case of a Durable Response to Imatinib Mesylate without Additional or Previous Treatment
by Maria Teresa Bochicchio, Giovanni Marconi, Carmen Baldazzi, Lorenza Bandini, Francesca Ruggieri, Alessandro Lucchesi, Claudio Agostinelli, Elena Sabattini, Agnese Orsatti, Anna Ferrari, Giorgia Capirossi, Chiara Servili, Andrea Ghelli Luserna di Rorà, Giovanni Martinelli, Giorgia Simonetti and Gianantonio Rosti
Int. J. Mol. Sci. 2024, 25(1), 118; https://doi.org/10.3390/ijms25010118 - 21 Dec 2023
Cited by 2 | Viewed by 1656
Abstract
ETV6::ABL1 rearranged neoplasms are rare hematological diseases. To date, about 80 cases have been reported, including myeloid and lymphoid leukemias. The ETV6 gene codes for an ETS family transcription factor and several fusion partners have been described. When translocated, ETV6 causes the constitutive [...] Read more.
ETV6::ABL1 rearranged neoplasms are rare hematological diseases. To date, about 80 cases have been reported, including myeloid and lymphoid leukemias. The ETV6 gene codes for an ETS family transcription factor and several fusion partners have been described. When translocated, ETV6 causes the constitutive activation of the partner genes. Here, we report the case of a 54-year-old woman with a cryptic insertion of the 3′ region of ABL1 in the ETV6 gene. The patient was first diagnosed with idiopathic hypereosinophilic syndrome, according to the clinical history, conventional cytogenetics, standard molecular analyses and pathologist description. Next generation sequencing of diagnosis samples unexpectedly detected both ETV6::ABL1 type A and B fusion transcripts, which were then confirmed by FISH. The diagnosis was Myeloid/Lymphoid neoplasm with ETV6::ABL1 fusion, and the patient received imatinib mesylate treatment. In a follow-up after more than one year, the patient still maintained the molecular and complete hematological responses. This case highlights the importance of timely and proper diagnostics and prompt tyrosine kinase inhibitor treatment. Full article
(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy)
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28 pages, 4728 KiB  
Article
Biomarkers of Affective Dysregulation Associated with In Utero Exposure to EtOH
by Nune Darbinian, Nana Merabova, Gabriel Tatevosian, Mary Morrison, Armine Darbinyan, Huaqing Zhao, Laura Goetzl and Michael Edgar Selzer
Cells 2024, 13(1), 2; https://doi.org/10.3390/cells13010002 - 19 Dec 2023
Cited by 5 | Viewed by 2864
Abstract
Introduction: Children with fetal alcohol spectrum disorders (FASD) exhibit behavioral and affective dysregulation, including hyperactivity and depression. The mechanisms are not known, but they could conceivably be due to postnatal social or environmental factors. However, we postulate that, more likely, the affective dysregulation [...] Read more.
Introduction: Children with fetal alcohol spectrum disorders (FASD) exhibit behavioral and affective dysregulation, including hyperactivity and depression. The mechanisms are not known, but they could conceivably be due to postnatal social or environmental factors. However, we postulate that, more likely, the affective dysregulation is associated with the effects of EtOH exposure on the development of fetal serotonergic (5-HT) and/or dopaminergic (DA) pathways, i.e., pathways that in postnatal life are believed to regulate mood. Many women who use alcohol (ethanol, EtOH) during pregnancy suffer from depression and take selective serotonin reuptake inhibitors (SSRIs), which might influence these monoaminergic pathways in the fetus. Alternatively, monoaminergic pathway abnormalities might reflect a direct effect of EtOH on the fetal brain. To distinguish between these possibilities, we measured their expressions in fetal brains and in fetal brain-derived exosomes (FB-Es) isolated from the mothers’ blood. We hypothesized that maternal use of EtOH and/or SSRIs during pregnancy would be associated with impaired fetal neural development, detectable as abnormal levels of monoaminergic and apoptotic biomarkers in FB-Es. Methods: Fetal brain tissues and maternal blood were collected at 9–23 weeks of pregnancy. EtOH groups were compared with unexposed controls matched for gestational age (GA). The expression of 84 genes associated with the DA and 5-HT pathways was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) on microarrays. FB-Es also were assayed for serotonin transporter protein (SERT) and brain-derived neurotrophic factor (BDNF) by enzyme-linked immunosorbent assay (ELISA). Results: Six EtOH-exposed human fetal brain samples were compared to SSRI- or polydrug-exposed samples and to unexposed controls. EtOH exposure was associated with significant upregulation of DA receptor D3 and 5-HT receptor HTR2C, while HTR3A was downregulated. Monoamine oxidase A (MAOA), MAOB, the serine/threonine kinase AKT3, and caspase-3 were upregulated, while mitogen-activated protein kinase 1 (MAPK1) and AKT2 were downregulated. ETOH was associated with significant upregulation of the DA transporter gene, while SERT was downregulated. There were significant correlations between EtOH exposure and (a) caspase-3 activation, (b) reduced SERT protein levels, and (c) reduced BDNF levels. SSRI exposure independently increased caspase-3 activity and downregulated SERT and BDNF. Early exposure to EtOH and SSRI together was associated synergistically with a significant upregulation of caspase-3 and a significant downregulation of SERT and BDNF. Reduced SERT and BDNF levels were strongly correlated with a reduction in eye diameter, a somatic manifestation of FASD. Conclusions: Maternal use of EtOH and SSRI during pregnancy each was associated with changes in fetal brain monoamine pathways, consistent with potential mechanisms for the affective dysregulation associated with FASD. Full article
(This article belongs to the Special Issue Signaling Pathways in Pregnancy)
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17 pages, 3754 KiB  
Article
The Protective Effect of Marsdenia tenacissima against Cisplatin-Induced Nephrotoxicity Mediated by Inhibiting Oxidative Stress, Inflammation, and Apoptosis
by Zhiguang Zhang, Boya Liang, Wugemo Jike, Runtian Li, Xinxin Su, Jie Yu and Tongxiang Liu
Molecules 2023, 28(22), 7582; https://doi.org/10.3390/molecules28227582 - 14 Nov 2023
Cited by 5 | Viewed by 2019
Abstract
Cisplatin (Cis) is considered to be one of the most effective drugs for killing cancer cells and remains a first-line chemotherapeutic agent. However, Cis’s multiple toxicities (especially nephrotoxicity) have limited its clinical use. Marsdenia tenacissima (Roxb.) Wight et Arn. (MT), a traditional Chinese [...] Read more.
Cisplatin (Cis) is considered to be one of the most effective drugs for killing cancer cells and remains a first-line chemotherapeutic agent. However, Cis’s multiple toxicities (especially nephrotoxicity) have limited its clinical use. Marsdenia tenacissima (Roxb.) Wight et Arn. (MT), a traditional Chinese medicine (TCM) employed extensively in China, not only enhances the antitumor effect in combination with Cis, but is also used for its detoxifying effect, as it reduces the toxic side effects of chemotherapy drugs. The aim of this study was to explore the therapeutic effect of MT on Cis-induced nephrotoxicity, along with its underlying mechanisms. In this study, liquid–mass spectrometry was performed to identify the complex composition of the extracts of MT. In addition, we measured the renal function, antioxidant enzymes, and inflammatory cytokines in mice with Cis-induced nephrotoxicity and conducted renal histology evaluations to assess renal injury. The expressions of the proteins related to antioxidant, anti-inflammatory, and apoptotic markers in renal tissues was detected by Western blotting (WB). MT treatment improved the renal function, decreased the mRNA expression of the inflammatory factors, and increased the antioxidant enzyme activity in mice. A better renal histology was observed after MT treatment. Further, MT inhibited the expression of the phospho-NFκB p65 protein/NFκB p65 protein (p-p65)/p65, phospho-inhibitor of nuclear factor kappa B kinase beta subunit/inhibitor of nuclear factor kappa B kinase beta subunit (p-IKKβ/IKKβ), Bcl-2-associated X (Bax), and Cleaved Caspase 3/Caspase 3 proteins, while the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Recombinant NADH Dehydrogenase, Quinone 1 (NQO1), and B-cell lymphoma-2 (Bcl-2) was increased. The present study showed that MT ameliorated renal injury, which mainly occurs through the regulation of the Nrf2 pathway, the NF-κB pathway, and the suppression of renal tissue apoptosis. It also suggests that MT can be used as an adjuvant to mitigate the nephrotoxicity of Cis chemotherapy. Full article
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14 pages, 2945 KiB  
Article
The Small-Molecule E26-Transformation-Specific Inhibitor TK216 Attenuates the Oncogenic Properties of Pediatric Leukemia
by Ritul Sharma, Chunfen Zhang and Aru Narendran
Genes 2023, 14(10), 1916; https://doi.org/10.3390/genes14101916 - 8 Oct 2023
Cited by 1 | Viewed by 2074
Abstract
The E26-transformation-specific (ETS) transcription factors regulate multiple aspects of the normal hematopoietic system. There is an increasing body of evidence suggesting aberrant ETS activity and its contribution to leukemia initiation and progression. In this study, we evaluated the small-molecule ETS inhibitor TK216 and [...] Read more.
The E26-transformation-specific (ETS) transcription factors regulate multiple aspects of the normal hematopoietic system. There is an increasing body of evidence suggesting aberrant ETS activity and its contribution to leukemia initiation and progression. In this study, we evaluated the small-molecule ETS inhibitor TK216 and demonstrated its anti-tumor activity in pediatric leukemia. We found TK216 induced growth inhibition, cell cycle arrest and apoptosis and inhibited the migratory capability of leukemic cells, without significantly inhibiting the cell viability of normal blood mononuclear cells. Priming the leukemic cells with 5-Azacitidine enhanced the cytotoxic effects of TK216 on pediatric leukemia cells. Importantly, we found purine-rich box1 (PU.1) to be a potential target of TK216 in myeloid and B-lymphoid leukemic cells. In addition, TK216 sharply decreased Mcl-1 protein levels in a dose-dependent manner. Consistent with this, TK216 also potentiated the cytotoxic effects of Bcl-2 inhibition in venetoclax-resistant cells. The sustained survival benefit provided to leukemic cells in the presence of bone-marrow-derived conditioned media is also found to be modulated by TK216. Taken together, our data indicates that TK216 could be a promising targeted therapeutic agent for the treatment of acute myeloid and B-lymphoid leukemia. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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