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15 pages, 1019 KiB  
Article
Diagnostic Stratification of Prostate Cancer Through Blood-Based Biochemical and Inflammatory Markers
by Donatella Coradduzza, Leonardo Sibono, Alessandro Tedde, Sonia Marra, Maria Rosaria De Miglio, Angelo Zinellu, Serenella Medici, Arduino A. Mangoni, Massimiliano Grosso, Massimo Madonia and Ciriaco Carru
Diagnostics 2025, 15(11), 1385; https://doi.org/10.3390/diagnostics15111385 - 30 May 2025
Abstract
Background: Prostate cancer (PCa) remains one of the most prevalent malignancies in men, with diagnostic challenges arising from the limited specificity of current biomarkers, like PSA. Improved stratification tools are essential to reduce overdiagnosis and guide personalized patient management. Objective: This study aimed [...] Read more.
Background: Prostate cancer (PCa) remains one of the most prevalent malignancies in men, with diagnostic challenges arising from the limited specificity of current biomarkers, like PSA. Improved stratification tools are essential to reduce overdiagnosis and guide personalized patient management. Objective: This study aimed to identify and validate clinical and hematological biomarkers capable of differentiating PCa from benign prostatic hyperplasia (BPH) and precancerous lesions (PL) using univariate and multivariate statistical methods. Methods: In a cohort of 514 patients with suspected PCa, we performed a univariate analysis (Kruskal–Wallis and ANOVA) with preprocessing via adaptive Box–Cox transformation and missing value imputation through probabilistic principal component analysis (PPCA). LASSO regression was used for variable selection and classification. An ROC curve analysis assessed diagnostic performance. Results: Five variables—age, PSA, Index %, hemoglobin (HGB), and the International Index of Erectile Function (IIEF)—were consistently significant across univariate and multivariate analyses. The LASSO regression achieved a classification accuracy of 70% and an AUC of 0.74. Biplot and post-hoc analyses confirmed partial separation between PCa and benign conditions. Conclusions: The integration of multivariate modeling with reconstructed clinical data enabled the identification of blood-based biomarkers with strong diagnostic potential. These routinely available, cost-effective indicators may support early PCa diagnosis and patient stratification, reducing unnecessary invasive procedures. Full article
(This article belongs to the Special Issue Biochemical Testing Applications in Clinical Diagnosis)
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22 pages, 2793 KiB  
Article
High Burden of Non-Clonal Chromosome Aberrations Before Onset of Detectable Neoplasia in Fanconi Anemia Bone Marrow
by Silvia Sánchez, Benilde García-de-Teresa, Marco A. Mejía-Barrera, Pedro V. Reyes-Jiménez, Antonio Paz-Martínez, Miguel A. Martínez, Moisés Ó. Fiesco-Roa, Angélica Monsiváis-Orozco, Bertha Molina, Leda Torres, Alfredo Rodríguez and Sara Frias
Cancers 2025, 17(11), 1805; https://doi.org/10.3390/cancers17111805 - 28 May 2025
Viewed by 54
Abstract
Background/objectives: Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by chromosome instability and predisposition to develop myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). Clonal chromosome aberrations (CCAs) in chromosomes 1, 3, and 7 frequently appear in the bone marrow [...] Read more.
Background/objectives: Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by chromosome instability and predisposition to develop myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). Clonal chromosome aberrations (CCAs) in chromosomes 1, 3, and 7 frequently appear in the bone marrow (BM) of patients with FA and are associated with MDS/AML progression. Given the underlying DNA repair defect that characterizes FA, non-clonal chromosomal abnormalities (NCCAs) are expected to be common events in the FA BM; in this study, we investigated the presence and significance of NCCA and CCA in the bone marrow (BM) of patients with FA. Methods: Here, we transversally examined the BM karyotypes of 43 non-transplanted patients with FA, 41 with non-clinically detectable hematologic neoplasia and two with diagnosed MDS. We searched for the presence of NCCAs, complex karyotypes (CKs), and CCAs as well as their association with the natural history of the disease, including age, degree of BM failure, and neoplastic transformation. Results: NCCAs were observed in the metaphase spreads of 41/43 FA patients; CKs were observed in 25/43 patients; CCAs were found in 15/43 patients; CCAs involving chromosomes 1, 3 and/or 7 were found in four patients; and other autosomes were found in the remaining 11 patients. Overall, we observed a baseline large karyotypic heterogeneity in the BM of FA patients, demonstrated by the ubiquitous presence of NCCA; such karyotypic heterogeneity precedes the eventual emergence of CKs and selection of cells carrying fitness-improving CCAs. Finally, CCAs involving chromosomes 1, 3 and 7, well-known drivers of hematological malignancy in FA, become established. Overall, we observed that the frequency of NCCAs and CCAs increased with age, even though a significant correlation was not found. Conclusions: These observations fit the model of evolution towards cancer that comprises a first phase of macroevolution represented by NCCAs and karyotypic heterogeneity, followed by the establishment of clones with CCAs, leading to microevolution and cancer. NCCAs are the most frequent chromosomal alterations in the bone marrow of patients with AF and constitute a genome with extensive karyotypic heterogeneity that evolves into clones with more complex genomes and can eventually progress to cancer. Full article
(This article belongs to the Special Issue The Role of Chromosomal Instability in Cancer: 2nd Edition)
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21 pages, 1612 KiB  
Review
CD300a: An Innate Immune Checkpoint Shaping Tumor Immunity and Therapeutic Opportunity
by Jei-Ming Peng and Hui-Ying Liu
Cancers 2025, 17(11), 1786; https://doi.org/10.3390/cancers17111786 - 27 May 2025
Viewed by 152
Abstract
CD300 family members are immunoglobulin superfamily receptors that regulate immune cell function through either activating or inhibitory signals. Among them, CD300a is a prototypical inhibitory receptor, highly expressed in both myeloid and lymphoid lineages, and plays a pivotal role in the pathogenesis of [...] Read more.
CD300 family members are immunoglobulin superfamily receptors that regulate immune cell function through either activating or inhibitory signals. Among them, CD300a is a prototypical inhibitory receptor, highly expressed in both myeloid and lymphoid lineages, and plays a pivotal role in the pathogenesis of inflammation and tumor immunity. CD300a transduces inhibitory signals in several immune cells—including mast cells, eosinophils, monocytes, dendritic cells (DCs), neutrophils, and natural killer (NK) cells—by recruiting SHP-1 phosphatase to immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and suppressing activation pathways such as Toll-like receptor (TLR)-MyD88 and FcεRI signaling. Recent studies suggest that tumor cells may hijack CD300a-associated pathways to establish an immunosuppressive microenvironment that facilitates immune evasion, tumor survival, and potentially metastatic spread. Proposed mechanisms include reduced DC-mediated type I interferon (IFN) production, diminished NK cell cytotoxicity, and negative regulation of mast cell– and eosinophil-dependent anti-tumor responses. Although some of these findings are derived from in vivo models, the cumulative evidence positions CD300a as a critical immune checkpoint in tumor-associated immune regulation. In addition to its established roles in hematologic malignancies—including chronic lymphocytic leukemia, acute lymphoblastic leukemia, and acute myeloid leukemia—CD300a has also been implicated in modulating tumor-associated immune responses in other pathological contexts. While most studies emphasize its immune cell–mediated effects, emerging evidence suggests that CD300a may directly influence tumor progression by regulating immune homeostasis, intracellular signaling, and tumor microenvironment interactions. Collectively, these findings establish CD300a as a pleiotropic immunoregulatory molecule in both hematologic and non-hematologic malignancies, underscoring the need to further explore its broader relevance and therapeutic potential in cancer immunology. Full article
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14 pages, 2229 KiB  
Brief Report
The Heterogenous Presentation of Hepatic Mucormycosis in Adults: A Case Report and Review of the Literature
by Hazim Allos, Rachel S. Hicklen, Takahiro Matsuo, Javier Adachi, Sebastian Wurster and Dimitrios P. Kontoyiannis
J. Fungi 2025, 11(6), 408; https://doi.org/10.3390/jof11060408 - 26 May 2025
Viewed by 233
Abstract
Hepatic mucormycosis is a rare but often fatal opportunistic fungal infection, primarily affecting immunocompromised patients. Herein, we report such a case from MD Anderson Cancer Center (Houston, TX, USA) and systematically review published cases in patients ≥ 19 years of age to better [...] Read more.
Hepatic mucormycosis is a rare but often fatal opportunistic fungal infection, primarily affecting immunocompromised patients. Herein, we report such a case from MD Anderson Cancer Center (Houston, TX, USA) and systematically review published cases in patients ≥ 19 years of age to better characterize clinical presentation, diagnostic challenges, and treatment outcomes of hepatic mucormycosis. Among the 40 identified cases (including ours), hematologic malignancies (55%) and solid organ transplantation (30%) were the most common underlying conditions. Fever (70%) and abdominal pain (63%) were the predominant symptoms. Imaging revealed multiple hepatic lesions in 72% of cases. Diagnosis was primarily based on histopathology (73%), whereas culture positivity was low (36%), underscoring the difficulty of pathogen isolation. Mucorales-active antifungal therapy was often delayed but eventually used in 85% of cases (all amphotericin B +/− Mucorales-active triazoles), while 45% underwent additional surgical intervention. Despite treatment, 1-year all-cause mortality remained high at 46%, with a trend towards lower mortality for those who underwent surgery compared to non-surgical management (35% vs. 55%, p = 0.334). These findings highlight the aggressive nature of hepatic mucormycosis and the importance of early recognition as well as the need for non-culture-based diagnostics and multimodal treatment approaches. Improved awareness and further research into optimized management strategies are crucial to improve the outcomes of this challenging infection. Full article
(This article belongs to the Special Issue Multidrug-Resistant Fungi, 2nd Edition)
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13 pages, 2244 KiB  
Review
Hiding in Plain Sight: Cell Biomimicry for Improving Hematological Cancer Outcomes
by Laura A. Weinstein and Bingqing Wei
Nanomaterials 2025, 15(10), 739; https://doi.org/10.3390/nano15100739 - 15 May 2025
Viewed by 176
Abstract
The field of nanomedicine has been fruitful in creating novel drug delivery ideas to battle hematologic cancers. However, one persistent barrier to efficient nanoparticle treatment is phagocytic uptake or the clearance of nanoparticles by immune cells. To prevent this immune uptake, scientists have [...] Read more.
The field of nanomedicine has been fruitful in creating novel drug delivery ideas to battle hematologic cancers. However, one persistent barrier to efficient nanoparticle treatment is phagocytic uptake or the clearance of nanoparticles by immune cells. To prevent this immune uptake, scientists have utilized biomimicry, the emulation of natural structures for engineered applications, to create particles that are able to remain unrecognized by immune cells. This method aims to improve the overall circulation time of nanoparticles by decreasing the amount of particles filtered out of the blood. It can even lead to homotypic cancer cell targeting, decreasing cancer cell vitality. This review summarizes recent in vivo and in vitro studies to prove that biomimetic cargo delivery is a unique and tenable way of increasing survival outcomes in patients with hematologic cancers. Full article
(This article belongs to the Section Biology and Medicines)
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23 pages, 2218 KiB  
Review
Epigenetic Therapies in Melanoma—Targeting DNA Methylation and Histone Modification
by Adrian Bogdan Tigu, Andrei Ivancuta, Andrada Uhl, Alexandru Cristian Sabo, Madalina Nistor, Ximena-Maria Mureșan, Diana Cenariu, Tanase Timis, Doru Diculescu and Diana Gulei
Biomedicines 2025, 13(5), 1188; https://doi.org/10.3390/biomedicines13051188 - 13 May 2025
Viewed by 436
Abstract
Skin cancer prevalence has increased during the last decades, with the last years serving as a pivotal moment for comprehending its epidemiological patterns and its impact on public health. Melanoma is one of the most frequently occurring malignancies, arising from a complex interplay [...] Read more.
Skin cancer prevalence has increased during the last decades, with the last years serving as a pivotal moment for comprehending its epidemiological patterns and its impact on public health. Melanoma is one of the most frequently occurring malignancies, arising from a complex interplay of genetic factors, environmental factors, lifestyle and socio-economic conditions. Epigenetic changes play a critical role in tumor development, influencing progression and aggressiveness. Epigenetic therapies could represent novel therapeutic options, while drug repositioning may serve as a viable strategy for cancer treatment. Demethylating agents, commonly used in hematological malignancies, show promising results on solid tumors, including melanoma. Methylation patterns are responsible for tumor development by modulating gene expression, while histone acetylation influences DNA processes such as transcription, replication, repair, and recombination. This review aims to identify existing potential therapeutical approaches using therapeutic agents that can modulate DNA methylation and histone modification, which can lead to tumor inhibition, cell death initiation and reactivation of tumor suppressor genes. Full article
(This article belongs to the Special Issue Feature Reviews in Cell Death)
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37 pages, 1634 KiB  
Review
Assessing the Effects of Pesticides on Aquacultured Fish and Ecosystems: A Comprehensive Environmental Health Review
by Emily Burch, Mohamed Ali Hussein, Manar Zaki, Lereen T. Kamal, Ghada Zaki, Tamer Shoeib, Mahmoud Dawood, Hani Sewilam and Anwar Abdelnaser
Fishes 2025, 10(5), 223; https://doi.org/10.3390/fishes10050223 - 13 May 2025
Viewed by 532
Abstract
Aquaculture has been rapidly growing during the past decade to accommodate the increasing need for seafood as a vital source of nutrients for human beings. The nutritional benefits of incorporating fish into one’s diet are paramount in promoting overall health, bolstering immunity and [...] Read more.
Aquaculture has been rapidly growing during the past decade to accommodate the increasing need for seafood as a vital source of nutrients for human beings. The nutritional benefits of incorporating fish into one’s diet are paramount in promoting overall health, bolstering immunity and warding off diseases. Nonetheless, farm-raised aquatic species are frequently subjected to elevated contamination levels due to pesticides, antibiotics, and heavy metals in the marine environment. Pesticides affect fish differently based on species, class, dosage, and exposure duration. They can induce histological damage or neurobehavioral changes by inhibiting acetylcholinesterase production. This can promote liver dysfunction, metabolism deregulation, oxidative stress, and hematological imbalances, impair immune responses, and adversely affect fish reproduction. Furthermore, pesticides negatively affect the nutritional composition of fish by reducing the total protein levels in muscle, liver, gills, and kidney tissues. They disrupt lipid metabolism, resulting in lipid accumulation in the liver and a decrease in polyunsaturated fatty acids. Additionally, pesticides interfere with metabolism by altering carbohydrate levels in the gills, muscles, and kidneys while decreasing glycogen storage in the liver. Pesticide exposure has been linked to severe health impacts in humans, such as non-communicable diseases, reproductive issues, cognitive dysfunction, and cancer. The current review comprehensively emphasizes the harmful effects of pesticides on fish and human health, urging the establishment of environmental monitoring programs and biomonitoring studies. It accentuates the need for risk assessment models to evaluate pesticide impacts on marine ecosystems and advocates for stricter safety standards and lower pesticide residue limits in aquaculture products. Full article
(This article belongs to the Section Welfare, Health and Disease)
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45 pages, 15230 KiB  
Article
The Transcription Axes ERK-Elk1, JNK-cJun, and JAK-STAT Promote Autophagy Activation and Proteasome Inhibitor Resistance in Prostate Cancer Cells
by Georgios Kalampounias, Kalliopi Zafeiropoulou, Theodosia Androutsopoulou, Spyridon Alexis, Argiris Symeonidis and Panagiotis Katsoris
Curr. Issues Mol. Biol. 2025, 47(5), 352; https://doi.org/10.3390/cimb47050352 - 12 May 2025
Viewed by 326
Abstract
The rapid emergence of resistance limits the application of proteasome inhibitors against solid tumors, despite their effectiveness in the treatment of hematological malignancies. Resistant phenotypes are complex and multifaceted, and, thus, the mechanisms involved have not been adequately described. In this study, a [...] Read more.
The rapid emergence of resistance limits the application of proteasome inhibitors against solid tumors, despite their effectiveness in the treatment of hematological malignancies. Resistant phenotypes are complex and multifaceted, and, thus, the mechanisms involved have not been adequately described. In this study, a Bortezomib-resistant prostate cancer cell line is created by using the PC-3 cell as a prostate carcinoma model of high metastatic potential. The main biochemical differences and adaptations exhibited by the resistant cells revolve around apoptosis evasion, autophagy induction (functioning as a ubiquitin-proteasome system substitute), expression of epithelial-to-mesenchymal transition markers, and increased aggressiveness. Broad-spectrum signaling pathway analyses also reveal an upregulation and activation of Nf-κB, STAT3, cJun, and Elk1 transcription factors in the resistant cells. Additionally, intracellular reactive oxygen species assays reveal a downregulation in resistant cells, which is theorized to be a consequence of metabolic changes, increased autophagic flux, and antioxidative enzyme action. These findings expand our understanding of proteasome inhibitor resistance and highlight key kinases and transcription factors as novel potential therapeutic targets. Effective inhibition of resistance-specific pathways could re-sensitize the cells to proteasome inhibitors, thus surpassing current therapeutic limitations. Full article
(This article belongs to the Special Issue Molecular Research of Urological Diseases)
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13 pages, 394 KiB  
Article
Our Experience and Literature Update Regarding Concomitant Radiotherapy with CDK4/6 Inhibitors and Hormonal Therapy in Metastatic Breast Cancer
by Laura-Florentina Rebegea, Dorel Firescu, Oana-Gabriela Trifanescu, Roxana-Andreea Rahnea-Nita, Liviu Bilteanu, Mihaela Dumitru, Florentina Lacatus and Gabriela Rahnea-Nita
J. Mind Med. Sci. 2025, 12(1), 33; https://doi.org/10.3390/jmms12010033 - 12 May 2025
Viewed by 199
Abstract
Background and Objectives: Standard treatment in metastatic breast cancer with positive estrogen receptors and negative HER2neu is represented by CDK4 inhibitors combined with aromatase inhibitors or fulvestrant. Palliative radiotherapy is indicated for symptoms or local–regional control. Multiple preclinical data suggest a potential synergistic [...] Read more.
Background and Objectives: Standard treatment in metastatic breast cancer with positive estrogen receptors and negative HER2neu is represented by CDK4 inhibitors combined with aromatase inhibitors or fulvestrant. Palliative radiotherapy is indicated for symptoms or local–regional control. Multiple preclinical data suggest a potential synergistic effect when CDK4/6 inhibitors and radiotherapy are administered concurrently. We are trying to address some questions and/or to establish correlations within a subgroup of patients with unusual toxicities, the safety of combined treatments, the correlation with radiotherapy techniques and fractionation schemas. Also, we are aware that some organs at risk of a rapid turnover are more vulnerable to the occurrence of acute toxicities. Materials and Methods: This retrospective study includes 20 patients with metastatic breast cancer, treated with CDK4 inhibitors and radiotherapy on 29 disease sites; we followed the compliance and toxicities of combined treatments. Results: Regarding the recorded hematological toxicities, grade 1 associated with CDK4 inhibitors, occurring anterior radiotherapy was recorded; grade 2, leucopenia during radiotherapy presented in three cases without radiotherapy interrupting and leucopenia with neutropenia grade 3 presented in one case after pleural secondary lesion’s irradiation. Non-hematological grade 3 toxicities occurred in two cases: one case with grade 3 enteritis, at 2 weeks from bone metastases irradiation—iliac bone (in field toxicity) and one case with radiodermitis during radiotherapy on the breast and lymph node level, in the second week of external radiotherapy (RTE). Conclusions: In all analyzed cases, we obtained control of irradiated lesions. Secondary toxicities occurred only in irradiated areas. A close monitoring of patients during combined treatment must be considered and we are confident that in the future it will be possible to identify the subgroup of patients with a high risk of unusual toxicities occurring; additionally, we hope that using more conforming radiotherapy techniques minimizes the organ being at risk from radiation doses. Full article
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16 pages, 810 KiB  
Review
Bruton’s Tyrosine Kinase: A Double-Edged Sword in Cancer and Aging
by Zahraa Qusairy and Miran Rada
Kinases Phosphatases 2025, 3(2), 10; https://doi.org/10.3390/kinasesphosphatases3020010 - 7 May 2025
Viewed by 216
Abstract
Bruton’s tyrosine kinase (BTK) is a key signaling molecule involved in both hematological malignancies and solid tumors. In B-cell malignancies such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), BTK mediates B-cell receptor signaling, promoting tumor survival and proliferation, leading to the [...] Read more.
Bruton’s tyrosine kinase (BTK) is a key signaling molecule involved in both hematological malignancies and solid tumors. In B-cell malignancies such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), BTK mediates B-cell receptor signaling, promoting tumor survival and proliferation, leading to the development of BTK inhibitors like ibrutinib that improve patient outcomes. In solid tumors, BTK isoforms, particularly p65BTK, contribute to tumor growth and therapy resistance, with inhibition showing promise in cancers like colorectal, ovarian, and non-small cell lung cancer. BTK also influences the tumor microenvironment by modulating immune cells such as myeloid-derived suppressor cells and tumor-associated macrophages, aiding immune evasion. BTK inhibition can enhance anti-tumor immunity and reduce inflammation-driven tumor progression. Additionally, BTK contributes to tumor angiogenesis, with inhibitors like ibrutinib showing anti-angiogenic effects. Beyond cancer, BTK is linked to aging, where its modulation may reduce senescent cell accumulation and preserve cognitive function. This review explores BTK’s dual role, focusing on its oncogenic effects and potential impact on aging processes. We also discuss the use of BTK inhibitors in cancer treatment and their potential to address age-related concerns, providing a deeper understanding of BTK as a therapeutic target and mediator in the complex relationship between cancer and aging. Full article
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15 pages, 1334 KiB  
Systematic Review
Treatment-Related Adverse Events in Extended Stage Small Cell Lung Cancer Patients Receiving First-Line Chemoimmunotherapy Versus Chemotherapy Alone: A Systematic Review and Meta-Analysis
by Elsa Vitale, Alessandro Rizzo, Lorenza Maistrello, Deniz Can Guven, Omar Cauli, Domenico Galetta and Vito Longo
Cancers 2025, 17(9), 1571; https://doi.org/10.3390/cancers17091571 - 5 May 2025
Viewed by 419
Abstract
Introduction: Nowadays the prognosis of extended stage (ES) small cell lung cancer (SCLC) patients is poor. However, a high response rate to first-line chemotherapy (CT) and the addition of immune checkpoint inhibitors (ICIs) have notably ameliorated the outcome of these patients. The aim [...] Read more.
Introduction: Nowadays the prognosis of extended stage (ES) small cell lung cancer (SCLC) patients is poor. However, a high response rate to first-line chemotherapy (CT) and the addition of immune checkpoint inhibitors (ICIs) have notably ameliorated the outcome of these patients. The aim of our study is to compare treatment-related adverse events (TRAEs) between ES- SCLC patients receiving first-line ICIs adding CT and those receiving only CT. Methods: All phase III clinical trials published between 15 June 2008, and 30 June 2024, likenessing ICIs adding systemic CT and only CT in treatment-naïve ES-SCLC patients were retrieved. Results: Twenty-six types of adverse events were included, grouped into ten categories, for a total of 43,391 observations (observations in immune group n = 22,643 and in placebo group n = 20,748) and 9831 events. Our analysis suggested a statistically significant increase in hematological events in patients receiving ICIs plus CT compared with CT alone. Conversely, blood pressure alterations such as hypertension were more frequent in patients treated with CT alone. Conclusions: Despite our analysis confirming the manageable safety profile of chemoimmunotherapy, this remains an issue to be further investigated. Full article
(This article belongs to the Special Issue New Perspectives in the Treatment of Thoracic Cancers)
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14 pages, 2244 KiB  
Article
CDK4/6 Inhibitors-Induced Macrocytosis Is Not Associated with Hemolysis and Does Not Impact Hemoglobin Homeostasis
by Tiago Barroso, Leila Costa, Lisa Gonçalves, Vanessa Patel, João Araújo, Inês Pinho, Carolina Monteiro, Miguel Esperança-Martins, Catarina Abreu, Rita Teixeira de Sousa, Helena Pais, Gonçalo Nogueira-Costa, Sofia Torres, Leonor Abreu Ribeiro and Luís Marques da Costa
Cancers 2025, 17(9), 1567; https://doi.org/10.3390/cancers17091567 - 5 May 2025
Viewed by 354
Abstract
Background: CDK 4/6 inhibitors (CDK4/6is) are the first-line treatment for metastatic luminal-like breast cancer (BC). These drugs induce macrocytosis without anemia in most patients. The mechanism for the red blood cell (RBC) changes is unknown. In vitro and animal studies show that RBCs [...] Read more.
Background: CDK 4/6 inhibitors (CDK4/6is) are the first-line treatment for metastatic luminal-like breast cancer (BC). These drugs induce macrocytosis without anemia in most patients. The mechanism for the red blood cell (RBC) changes is unknown. In vitro and animal studies show that RBCs from CDK6-knockout mice have increased membrane fragility, but the clinical impact of CDK4/6is on human RBC lifespan is not known. We sought to determine the impact of CDK4/6is on RBC lifespan and detect changes in the regulation of hemoglobin production. Using the mean corpuscular volume (MCV) measurements at several time points, we can study the evolution of MCV, mean corpuscular hemoglobin concentration (MCHC), and RBC count over time. From this, one can estimate the RBC lifespan under CDK4/6is. Methods: We performed a unicentric retrospective study. Based on published models of RBC population dynamics, we have coded a biologically inspired model which allowed us to extract values for biological parameters, including the RBC lifespan. Results: A total of 122 patients were identified, and 1959 laboratory measurements were analyzed. After the pre-treatment RBCs were replaced, the mean MCV increased by 12.6 femtoliter (fL) (95% Bayesian credible interval [CdI] 13–14), the MCHC increased slightly by 0.69 g/dL (95% CdI 0.42–0.96), and the RBC count decreased by 0.77 × 109/L (95% CdI 0.42 × 109/L–0.96 × 109/L). The net result was a 0.64 g/dL (95% CdI 0.48–0.80) rise in hemoglobin. The mean total RBC lifetime was 118 days (95% CdI 114–122), similar to the value measured in healthy persons. Discussion and Conclusions: These findings suggest that, despite changes in RBC volume, CDK4/6is do not predispose patients to RBC destruction and do not impair regulation of hemoglobin homeostasis. We show that CDK4/6is do not decrease the RBC lifespan in pre-treatment erythrocytes. Unfortunately, this method cannot determine the lifespan of post-treatment RBCs, but further research could help answer this question. Full article
(This article belongs to the Special Issue The Role of Aromatase Inhibitors in Breast Cancer Treatment)
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16 pages, 2702 KiB  
Review
Harnessing Azelaic Acid for Acute Myeloid Leukemia Treatment: A Novel Approach to Overcoming Chemoresistance and Improving Outcomes
by Silvia Di Agostino, Anna Di Vito, Annamaria Aloisio, Giovanna Lucia Piazzetta, Nadia Lobello, Jessica Bria and Emanuela Chiarella
Int. J. Mol. Sci. 2025, 26(9), 4362; https://doi.org/10.3390/ijms26094362 - 3 May 2025
Viewed by 396
Abstract
Azelaic acid (AZA), an aliphatic dicarboxylic acid (HOOC-(CH2)7-COOH), is widely used in dermatology. It functions as an inhibitor of tyrosinase, mitochondrial respiratory chain enzymes, and DNA synthesis, while also scavenging free radicals and reducing reactive oxygen species (ROS) production by neutrophils. [...] Read more.
Azelaic acid (AZA), an aliphatic dicarboxylic acid (HOOC-(CH2)7-COOH), is widely used in dermatology. It functions as an inhibitor of tyrosinase, mitochondrial respiratory chain enzymes, and DNA synthesis, while also scavenging free radicals and reducing reactive oxygen species (ROS) production by neutrophils. AZA has demonstrated anti-proliferative and cytotoxic effects on various cancer cells. However, its therapeutic potential in acute myeloid leukemia (AML) remains largely unexplored. AML is a complex hematologic malignancy characterized by the clonal transformation of hematopoietic precursor cells, involving chromosomal rearrangements and multiple gene mutations. The disease is associated with poor prognosis and high relapse rates, primarily due to its propensity to develop resistance to treatment. Recent studies indicate that AZA suppresses AML cell proliferation by inducing apoptosis and arresting the cell cycle at the G1 phase, with minimal cytotoxic effects on healthy cells. Additionally, AZA exerts antileukemic activity by modulating the ROS signaling pathway, enhancing the total antioxidant capacity in both AML cell lines and patient-derived cells. AZA also sensitizes AML cells to Ara-C chemotherapy. In vivo, AZA has been shown to reduce leukemic spleen infiltration and extend survival. As our understanding of AML biology progresses, the development of new molecularly targeted agents, in combination with traditional chemotherapy, offers the potential for improved treatment outcomes. This review aims to provide a comprehensive synthesis of preclinical evidence on the therapeutic potential of AZA in AML, consolidating current knowledge and identifying future directions for its clinical application. Full article
(This article belongs to the Special Issue Molecular Mechanism of Acute Myeloid Leukemia)
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26 pages, 1707 KiB  
Review
Doxorubicin-Induced Cardiotoxicity and the Emerging Role of SGLT2 Inhibitors: From Glycemic Control to Cardio-Oncology
by Iacob-Daniel Goje, Greta-Ionela Goje, Valentin Laurențiu Ordodi, Valentina Gabriela Ciobotaru, Vlad Sabin Ivan, Roxana Buzaș, Oana Tunea, Florina Bojin and Daniel-Florin Lighezan
Pharmaceuticals 2025, 18(5), 681; https://doi.org/10.3390/ph18050681 - 3 May 2025
Viewed by 511
Abstract
Cancer remains the second leading cause of death worldwide. Doxorubicin (DOX) is a cornerstone of hematologic malignancy treatment, but it is limited by its dose-dependent cardiotoxicity, leading to systolic and diastolic cardiac dysfunction and, ultimately, dilated hypokinetic cardiomyopathy. Cardio-oncology has emerged as a [...] Read more.
Cancer remains the second leading cause of death worldwide. Doxorubicin (DOX) is a cornerstone of hematologic malignancy treatment, but it is limited by its dose-dependent cardiotoxicity, leading to systolic and diastolic cardiac dysfunction and, ultimately, dilated hypokinetic cardiomyopathy. Cardio-oncology has emerged as a subspecialty addressing cardiovascular complications in cancer patients, highlighting preventive and therapeutic strategies to reduce cancer therapy-related cardiac dysfunction (CTRCD). Current approaches, including beta-blockers, renin–angiotensin system (RAS) inhibitors, and statins, offer partial cardioprotection. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, initially developed for type 2 diabetes mellitus (T2DM), demonstrate pleiotropic cardioprotective effects beyond glycemic control, including reduced oxidative stress, inflammation, and myocardial remodeling. This review explores the interplay between anthracycline therapy, particularly DOX, and cardiotoxicity while evaluating SGLT2 inhibitors as novel agents in cardio-oncology. Preclinical studies suggest SGLT2 inhibitors attenuate CTRCD by preserving mitochondrial function and inhibiting apoptosis, while clinical trials highlight their efficacy in reducing heart failure (HF) hospitalizations and cardiovascular (CV) mortality. Integrating SGLT2 inhibitors into cardio-oncology protocols could revolutionize the management of CTRCD, enhancing patient outcomes in oncology and cardiovascular care. Considering the emerging evidence, SGLT2 inhibitors may provide significant benefits to patients undergoing anthracycline therapy, particularly those with elevated cardiovascular risk profiles. We recommend that future prospective, large-scale clinical trials further evaluate the efficacy and safety of these agents as cardioprotective therapy to optimize individualized treatment strategies. Full article
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24 pages, 7003 KiB  
Article
Preclinical Toxicological Characterization of Porphyrin-Doped Conjugated Polymer Nanoparticles for Photodynamic Therapy
by Matías Daniel Caverzan, Ana Belén Morales Vasconsuelo, Laura Cerchia, Rodrigo Emiliano Palacios, Carlos Alberto Chesta and Luis Exequiel Ibarra
Pharmaceutics 2025, 17(5), 593; https://doi.org/10.3390/pharmaceutics17050593 - 1 May 2025
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Abstract
Background: Photodynamic therapy (PDT) utilizing nano-based photosensitizers (PSs) offers promising cancer treatment potential but requires rigorous safety evaluation. Conjugated polymer nanoparticles (CPNs) doped with porphyrins, such as platinum porphyrin–doped poly(9,9-dioctylfluorene-alt-benzothiadiazole) (F8BT), exhibit enhanced photodynamic efficiency but lack comprehensive preclinical toxicity data. This study [...] Read more.
Background: Photodynamic therapy (PDT) utilizing nano-based photosensitizers (PSs) offers promising cancer treatment potential but requires rigorous safety evaluation. Conjugated polymer nanoparticles (CPNs) doped with porphyrins, such as platinum porphyrin–doped poly(9,9-dioctylfluorene-alt-benzothiadiazole) (F8BT), exhibit enhanced photodynamic efficiency but lack comprehensive preclinical toxicity data. This study aimed to evaluate the biocompatibility, biodistribution, and acute/subacute toxicity of these CPNs to establish their safety profile for clinical translation. Methods: CPNs were synthesized via nanoprecipitation using amphiphilic stabilizers (PSMA or PS-PEG-COOH) and characterized for colloidal stability in parenteral solutions. Hemolysis assays were used to assess blood compatibility. Single-dose (0.3 and 1 mg/kg, intravenous) and repeated-dose (0.1–1 mg/kg, intraperitoneal, every 48 h for 28 days) toxicity studies were conducted in BALB/c mice. Hematological, biochemical, histopathological, and biodistribution analyses (via ICP-MS) were performed to evaluate systemic and organ-specific effects. Results: CPNs demonstrated excellent colloidal stability in 5% dextrose, with minimal aggregation. No hemolytic activity was observed at concentrations up to 50 mg/L. Single and repeated administrations revealed no significant changes in body/organ weights, hematological parameters (except transient fibrinogen elevation), or liver/kidney function markers (ALT, AST, BUN, Cr). Histopathology showed preserved tissue architecture in major organs, with mild hepatocyte vacuolation at 30 days. Biodistribution indicated hepatic/splenic accumulation and rapid blood clearance, suggesting hepatobiliary elimination. Conclusions: Platinum porphyrin–doped F8BT CPNs exhibited minimal acute and subacute toxicity, favorable biocompatibility, and no systemic adverse effects in murine models. These findings support their potential as safe PS candidates for PDT. However, chronic toxicity studies are warranted to address long-term organ accumulation and metabolic impacts. This preclinical evaluation provides a critical foundation for advancing CPNs toward clinical applications in oncology. Full article
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