Search Results (570)

Triple-negative breast cancer (TNBC) accounts for about 10–15% of all breast cancers and is an aggressive disease with a poor prognosis. There is currently no standard treatment regimen for TNBC patients; thus, chemotherapy remains the main treatment. Anthracycline- and taxane-based regimens are the most widely used in a clinical setting, either alone or in combination with other chemotherapeutic agents, including poly (ADP-ribose) polymerase (PARP) inhibitors and platinum drugs. Platinum drugs have been used particularly in patients with BRCA1-mutated TNBC. Preclinical and clinical trials revealed that the response to PARP inhibition was directly correlated to the sensitivity to platinum chemotherapies. Inhibition of PARP enzymes has been shown to specifically target BRCA1 dysfunctional cells. Therefore, targeting breast cancer cells that possess genetic alterations that are absent in normal cells could be attained by the exploitation of synthetic lethality for the discovery of other candidate metals, i.e., ruthenium-derived compounds, as next-generation drugs for the treatment of TNBC. This prospective approach provides new insight into alternative treatments for breast cancers with BRCA1-associated TNBC. Full article

Adult patients affected by acute myeloid leukemia who fail to achieve remission after two cycles of intensive chemotherapy based on a combination of anthracyclines and cytarabine are considered chemorefractory and are unlikely to benefit from further induction attempts. Characterized by a poor prognosis, they may still benefit from allogeneic hematopoietic stem cell transplantation, even if long-term survival rarely exceeds 20–30%. Still, the use of sequential high-dose chemotherapy followed by reduced-intensity conditioning, with transplantation performed during aplasia, and the optimization of the alloreactivity of donor leukocytes against leukemia (i.e., the graft-versus-leukemia effect) may ameliorate these results. Optimization of alloreactivity against leukemic cells can be achieved by proper donor selection, by the early withdrawal of immunosuppressive therapy, by post-transplant administration of donor lymphocyte infusions as prophylaxis of leukemia relapse, and by several other maintenance and preemptive therapies. Far from being the final stage of consolidation therapy, allogeneic hematopoietic stem cell transplantation is now considered as the moment when a unique immunological platform can be established in these patients, to be used for additional post-transplant measures. In this study we will critically review the different pre- and post-transplant strategies used in clinical trials to improve long-term survival in adult patients transplanted with chemorefractory leukemia. Full article

The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function (“OXPHOS-high” cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling, suggestive of increased mitochondrial fusion. A genome-wide CRISPR editing screen in doxorubicin-persistent OXPHOS-high TNBC cells revealed the BCL-XL gene as the top survival dependency in these quiescent tumor cells, but not in their untreated proliferating counterparts. Quiescent OXPHOS-high TNBC cells were highly sensitive to BCL-XL inhibitors, but not to inhibitors of BCL2 and MCL1. Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis-targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy. Full article

Background: Doxorubicin (Dox)-induced cardiotoxicity is the most important side effect of the drug and significantly limits its use in susceptible patients. Therefore, preventive measures are required to alleviate the Dox-induced cardiac failure. In this study, curcumin, a strong antioxidant agent, was investigated for its potential protective effect on dox-induced cardiotoxicity with its effect on Apelin expression as a mediator of cardiac function. Methods: Wistar albino rats were equally divided into four groups as Control, DOX, CUR, and CUR+DOX. Dox was administered a single dose of 20 mg/kg bw intraperitoneally while 100 mg/kg bw curcumin was given orally for 14 days before the Dox use. Results: DOX group showed a prolonged QT interval on an electrocardiogram and elevated cardiac troponin levels. In biochemical analyses, decreased Superoxide Dismutase activity and increased Malondialdehyde level and Catalase activity were detected in DOX group. Gene expression of Apelin decreased significantly while NF-κB increased in DOX group. Degenerative changes in histopathology, and increased iNOS and nitrotyrosine immunoreactivity were detected in DOX group. However, no significant changes were observed at reduced Glutathione, TNF-, and IL-1β levels. Curcumin use in Dox-given rats altered most of the disturbed parameters investigated in this study, indicating an alleviating effect on Dox-induced cardiotoxicity. Serum and heart Apelin levels and mRNA expression in heart tissue were detected to significantly increase in CUR+DOX group as compared to DOX group. Furthermore, NF-κB mRNA expression was significantly decreased in heart tissue of CUR+DOX group compared with the DOX group. Conclusions: The results suggest that Apelin acts as an important mediator in Dox cardiotoxicity and may be used as a target for treatment of certain cardiomyopathies. By regulating Apelin expression, curcumin may serve as a potential adjunct in cardioprotective approaches. Full article

Cancer-induced cardiac dysfunction has become a major clinical challenge as advances in cancer therapies continue to extend patient survival. Once regarded as a secondary concern, cardiotoxicity is now recognized as a leading contributor to morbidity and mortality among cancer patients and survivors. Its pathophysiology is multifactorial, involving systemic inflammation (e.g., TNF-α, IL-6), oxidative stress driven by reactive oxygen species (ROS), neurohormonal imbalances (e.g., angiotensin II, endothelin-1), and metabolic disturbances. These mechanisms collectively promote cardiomyocyte apoptosis, atrophy, mitochondrial dysfunction, and impaired cardiac output. Cardiac complications may arise directly from cancer itself or as adverse effects of oncologic therapies such as anthracyclines, trastuzumab, and immune checkpoint inhibitors. These agents have been linked to heart failure (HF), systolic dysfunction, and cardiac atrophy, often progressing insidiously and underscoring the importance of early detection and careful monitoring. Current preventive and therapeutic strategies include pharmacological interventions such as ACE inhibitors, beta-blockers, statins, dexrazoxane, and endothelin receptor antagonists like atrasentan. Emerging compounds, particularly Withaferin A (WFA), have shown potential through their anti-inflammatory and cardiac protective properties. In addition, antioxidants and lifestyle modifications may provide supplementary cardioprotective benefits, while interventional cardiology procedures are increasingly considered in selected patients. Despite encouraging progress, standardized treatment protocols and robust long-term outcome data remain limited. Given the heterogeneity of cancer types and cardiovascular responses, a personalized and multidisciplinary approach is essential. Continued research and close collaboration between oncologists, cardiologists, and basic scientists will be the key to advancing care, reducing treatment-related morbidity, and ensuring that improvements in cancer survival are matched by preservation of cardiovascular health. Full article

Background: There are no comparative trials between the two most common schemes in HER2-positive early breast cancer treatment; BERENICE (with anthracyclines) and TRAIN-2 (without anthracyclines). In this study, we investigated the pathological complete response (pCR) and safety events achieved with each. Methods: This analytical retrospective observational study included 111 patients with early and locally advanced HER-2-positive breast cancer who initiated neoadjuvant treatment with an anthracycline-based scheme (four cycles of doxorubicin and cyclophosphamide, followed by four cycles of taxane, trastuzumab, and pertuzumab = AC-THP) and a non-anthracycline scheme (carboplatin, weekly paclitaxel, trastuzumab, and pertuzumab for six–nine cycles = TCbHP) at the National Cancer Institute in Colombia, between April 2020 and December 2024. The primary endpoint was the pCR. Safety was analyzed in patients who received at least one treatment cycle. Results: A total of 51 patients received AC-THP and 60 TCbHP (89.6% of which received six cycles). The pCR was 58.3% in ACHTP and 60.4% in TCbHP (p = 0.84). As a descriptive analysis, with the anthracycline-based scheme, there was a trend toward a higher pCR in patients with T3-T4, positive nodal involvement (N+), and positive hormone receptor (HR+). Cardiac toxicity events during the neoadjuvant phase were 9.8% in ACTHP and 3.3% in TCbHP. Grade 2 neuropathy events were higher in patients with the TCbHP scheme, at 23.3%, versus 9.8% in ACTHP. Conclusions: We found similar pCR rates between the schemes with anthracyclines and without anthracyclines. It is still pertinent to discuss the risk–benefit of using anthracycline-based regimens in patients with HR+, T3-T4, and N+. The cardiac adverse events reported in our patients were similar to those reported in the BERENICE trial. Full article

Oxidative stress and mitochondrial dysfunction play a key role in the early stage of Doxorubicin (Doxo)-induced cardiotoxicity. Our study investigated the potential cardioprotective role of Simvastatin (Sim), widely known for its antioxidant properties, in an in vitro model of Doxo-induced acute cardiotoxicity. Human Cardiomyocytes (HCMs) were treated with Sim (10 µM, 4 h) and then co-exposed to Doxo (1 µM) and Sim for 20 h. Our data showed that Sim co-treatment significantly (p < 0.05) reduced both cytosolic and mitochondrial Doxo-induced reactive oxygen species overproduction. In Sim co-treated cells, significant reductions in nuclear factor erythroid 2-related factor 2 (Nrf2) gene expression (p < 0.01) and catalase (CAT), heme-oxygenase 1 (HO-1), and superoxide dismutase 2 (SOD2) levels (p < 0.05) compared to Doxo-treated cells were also demonstrated, suggesting a decreased need for compensatory antioxidant defense responses. Moreover, significant reductions in Doxo-induced mitochondrial calcium overload, mitochondrial membrane depolarization (p < 0.005), and apoptosis (p < 0.005) confirmed the protective effects of Sim co-treatment on cardiomyocytes. These data confirm that Sim could be a valuable therapeutic strategy for reducing Doxo-induced HCM damage, preventing the development of dilated cardiomyopathy and long-term heart damage, which are the main limitations of anthracycline use. Finally, real-time PCR analysis revealed that Sim co-treatment significantly reduced (p < 0.001) the Doxo-induced overexpression of MAP4K4, a mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) involved in oxidative stress-induced cell death, thus suggesting the involvement of other molecular mechanisms in Sim-mediated cardioprotection. Full article

Background: Anthracycline-based chemotherapy, while highly effective for breast cancer, poses a significant risk for chemotherapy-related cardiac dysfunction (CTRCD), mainly determined by left ventricular ejection fraction (LVEF) reduction. Objectives: We aimed to evaluate the diagnostic utility of speckle tracking analysis (STA) and Diastolic Stress Test Echocardiography (DSTE) for the early detection of cardiac dysfunction either CTRCD or heart failure with preserved ejection fraction (HFpEF) in women undergoing chemotherapy for breast cancer and developed exertional dyspnea and/or fatigue during follow-up. Methods: In this prospective case–control study, 133 women receiving anthracycline-based chemotherapy (with or without anti-HER2 therapy) (chemotherapy group-CTG) and 65 age-matched healthy women as the control group (CG) underwent resting echocardiographic assessment, including LVEF, global longitudinal strain (GLS), myocardial work indices, biomarkers assay (NT-proBNP, troponin, galectin-3) and DSTE at baseline. That assessment was repeated after 12 months in CTG. Results: In this prospective case—control study, 133 women receiving anthracycline-based chemotherapy (with or without anti-HER2 therapy) were included. Based on the presence of CTRCD, they were further subdivided into a CTRCD subgroup (n = 37) and a CTRCD-free subgroup (n = 88). At the end of this study, CTG showed worse values of LVEF, GLS, myocardial work indices than baseline and CG (p < 0.05). Subgroup comparison (CTRCD vs. CTRCD-free) showed significant impairment in LVEF (53.60% vs. 62.60%, p < 0.001), GLS (–16.68% vs. −20.31%, p < 0.001), DSTE-derived tricuspid regurgitation maximum velocity (TRVmax) (3.05 vs. 2.31 m/s, p < 0.001) and elevated biomarkers (NT-proBNP: 200.06 vs. 61.49 pg/mL; troponin: 12.42 vs. 3.95 ng/L, p < 0.001) in the former subgroup. Regression analysis identified GLS, NT-proBNP, troponin, and TRVmax as independent predictors of CTRCD. Notably, a subgroup of CTRCD-free patients (n = 16) showed a high probability for HFpEF based on the HFA-PEFF score, with elevated GLS, NT-proBNP and DSTE-derived TRVmax compared to the rest of CTRCD-free patients and the CG (p < 0.001). Conclusions: STA and DSTE significantly outperform conventional LVEF in detecting subclinical cardiac dysfunction among women with breast cancer receiving chemotherapy. The combination of novel echocardiographic techniques and biomarkers may enable the detection of early CTRCD, including the under-estimated presence of HFpEF among breast cancer women with HF symptoms. Full article

Background: Systemic therapy for soft tissue sarcoma (STS) provides modest survival benefit but carries clinically relevant toxicity. Published trials report adverse events (AEs) of varying quality and extension. Poor toxicity reporting hampers balanced risk–benefit appraisal. Methods: A PRISMA-2020 systematic review was registered in PROSPERO CRD420251087366. PubMed, CENTRAL, and Google Scholar were searched from 16 December 2024 to 16 April 2025 for randomized controlled trials (RCTs) evaluating chemotherapy, kinase inhibitors, or immune checkpoint inhibitors in STS. AE terms were harmonized to CTCAE v5.0; event rates were normalized to patients evaluable for safety. Pooled proportions used DerSimonian–Laird random-effects models; between-group comparisons employed unpaired t-tests. Risk of bias (RoB 2) was assessed with the Cochrane RoB 2 tool. Results: Ten RCTs (1079 treated, 979 control patients; 1994–2024) met the inclusion criteria, although two lacked sufficient presentation of toxicity data and seven failed to report parallel control-arm AEs. Pooled normalized incidences for treated patients were as follows: grade ≥ 3 hematological AEs, 17% (95% CI 14–20); severe gastrointestinal AEs, 9% (8–11); and grade 4 AEs, ≤6%. Anthracycline-based and kinase-inhibitor regimens displayed comparable composite grade ≥ 3 burdens (58% vs. 84%, p = 0.64). Between-study heterogeneity was considerable for gastrointestinal and hematological events (I² > 60%), driven by differing AE scales and denominators. Late-effect toxicities (cardiac, hepatic, neurological, and nephrological) were rarely reported, occurring in <1% of the patients. Across the three RCTs with control-arm data, experimental therapy increased common grade 3 AEs by 4–12 percentage points (p = 0.001). RoB 2 flagged serious concerns in 4/10 trials. Conclusions: Severe AEs in STS systemic therapy are moderately frequent; while the toxicity spectrum differs across drug classes (e.g., hematological for anthracyclines vs. neuropathic or fatigue-related for agents such as eribulin), the aggregate burden of severe AEs has not been lower for newer agents. Confidence in these estimates is limited by incomplete and non-standardized AE reporting. Future sarcoma trials must adopt CTCAE v5.0, specify explicit safety denominators, and publish full AE matrices to enable high-certainty risk–benefit assessment. Full article

Cardiotoxicity is one of the most important adverse events of chemotherapy regimens, especially of anthracyclines. Different mechanisms are associated with chemotherapy-related cardiac dysfunction (CTRCD): oxidative stress, mitochondrial dysfunction, inhibition of topoisomerase 2 beta, abnormal iron metabolism, apoptosis, and fibrosis. Even after years of investigation, the early detection and prevention of cardiac impairment after chemotherapy through biomarkers remains an unmet need. The differential expression of microRNAs (miRs) in plasma at different timepoints (baseline, stable intervals during and at the end of chemotherapy) has been associated with CTRCD. Namely, some miRs, such as let-7, miR-29 and miR-30 family, miR-1 clusters, miR-34a, miR-126, miR-130a, miR-140, miR-320a, and miR-499, could play prognostic and/or diagnostic roles in CTRCD. Key miRs involved in apoptosis and oxidative stress include miR-1, miR-21, miR-30 and miR-130a, while let-7 family, miR-34a, miR-29b and miR-499 are associated with fibrosis and extracellular matrix remodeling. Additionally, mitochondrial function is regulated by miR-30, miR-130a and miR-499. Expanding its role, miR-130a could act as a therapeutic agent of CTRCD through its inhibition. This narrative review focuses on the current understanding of miRs’ involvement in CTRCD pathophysiology, summarizes the evidence linking miRs with cardiotoxicity risk, and explores the potential of miRs as biomarkers and therapeutic targets to improve early detection, risk stratification, and management of CTRCD. Full article

Antimicrobial resistance represents a critical global health challenge, intensifying the urgency of discovering novel antibiotics. Actinomycetota species, the most prolific source of clinical antibiotics, remain underexplored in unique ecosystems. In this study, we isolated 340 Actinomycetota strains from soils of the Brazilian semiarid Caatinga biome. Screening revealed that 122 isolates (35.9%) exhibited antimicrobial activity against clinically relevant pathogens (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans). Notably, 19 isolates showed activity against Mycobacterium tuberculosis H37Ra. MALDI-TOF MS analysis successfully provided genus-level identification for a subset of isolates, with approximately 32% assigned to the Streptomyces genus. However, the limited resolution of the database for the majority of the strains indicates high phylogenetic diversity and suggests the presence of potentially novel species. Metabolomic profiling via LC-MS/MS and GNPS molecular networking suggested the production of known antibiotics such as actinomycins, cyclomarins and anthracyclines and unveiled distinct molecular families putatively assigned to undescribed metabolites. Our work establishes the Caatinga biome as a valuable reservoir of bioactive Actinomycetota, encoding both known and potentially novel antimicrobial compounds. These results underscore the potential of underexplored and extreme environments in the quest to overcome antibiotic resistance. Full article

In addition to killing malignant cells, effective cancer therapies must also promote the development of an immunostimulatory tumor microenvironment (TME). Macrophages are the most abundant immune cell population within the TME. These highly plastic cells play key roles in tumor progression, chronic inflammation, immunosuppression, and metastasis. Although increasing research efforts focus on manipulating macrophage functions, relatively little is known about how standard anticancer strategies, especially chemotherapeutic agents, influence the composition, polarization state, and functional behavior of macrophage subpopulations. Chemotherapeutic agents remain a primary treatment option for many types of cancer, including breast and cervical cancers. In this study, we used epirubicin and doxorubicin at near-therapeutic concentrations and examined their effects on macrophage functions in co-culture with MDA-MB-231 breast cancer and HeLa cervical cancer cell lines. We demonstrated that the presence of tumor cells led to increased expression of the M2 macrophage marker CD206, a change that was reduced by both chemotherapeutic agents. The production of macrophage-derived chemokines, such as IP-10 and IL-8, was also altered by tumor presence and drug exposure. A striking finding was that the co-presence of chemotherapeutic agents and MDA-MB-231 cells synergistically altered macrophage motility. This effect was not observed in monocultures. Furthermore, the presence of tumor cells reduced the susceptibility of pro-inflammatory M1 macrophages to drug-induced cell death. These results indicate that chemotherapy can reshape the macrophage landscape in the TME. We highlight that the combined effects of tumor cell presence and chemotherapy modulate the composition, phenotype, and migration of macrophage subtypes differently than either factor alone. Full article

Anthracyclines are widely used chemotherapeutic agents with proven efficacy against a broad range of malignancies, but their clinical utility is limited by a well-documented, dose-dependent cardiotoxicity. While this toxicity has traditionally been attributed to direct cardiomyocyte injury, emerging evidence highlights the pivotal role of cardiac fibroblasts (CFs) in the development and progression of anthracycline-induced cardiotoxicity. This review examines the diverse effects of anthracycline focusing on doxorubicin (DOX) and CFs across the temporal phases of cardiac injury. DOX activates fibroblast-driven extracellular matrix remodeling and promotes fibrosis through enhanced collagen production and the induction of cellular senescence, thereby exacerbating early myocardial inflammation and dysfunction. Clinically, anthracycline cardiotoxicity may present as acute (within days), subacute (within weeks), or chronic progressive forms manifesting either early (within one year) or late (up to decades post-treatment). While early manifestations may be reversible with timely detection and management, late-phase cardiotoxicity is often irreversible, characterized by declining left ventricular ejection fraction and heart failure. A deeper understanding of the molecular and cellular contributions of CFs may uncover novel therapeutic targets to prevent or attenuate anthracycline-related cardiac damage. Full article

Background/Objectives: The study describes the elaboration and evaluation of thermosensitive niosomes intended for the systemic application of daunorubicin hydrochloride. The attained stimulus sensitivity would determine the release of the chemotherapeutic predominantly at the target site, which ensures a higher drug concentration and leads to reduced systemic toxicity. The latter is highly beneficial, as the anthracycline antibiotic is known for its dose-dependent cardiotoxic effects. Methods: Conventional and copolymer-modified niosomes were prepared via thin-film hydration and the transmembrane ammonium gradient method, allowing us to assess the impacts of copolymer type-DHP-PiPOX (1,3-dihexadecyl-propane-2-ol-poly(2-isopropyl-2-oxazoline)) or DHP-PETEGA (1,3-dihexadecyl-propane-2-ol-poly(ethoxytriethylene glycol acrylate)) and their concentrations (0.5, 1, and 2.5 mol%), as well as the method of preparation, on the main physicochemical properties of the vesicles. Niosomes were characterized in terms of their size, polydispersity index (PDI), zeta potential, entrapment efficiency, morphology, and drug release properties. Thermosensitivity was evaluated by fluorescence studies, and the antiproliferative activity of optimized formulations was assessed against the acute myelocyte leukemia-derived HL-60 cell line. Results: Daunorubicin-loaded niosomes modified with DHP-PiPOX and DHP-PETEGA at 2.5 mol% exhibited suitable physicochemical properties for systemic application, with sizes below 200 nm (155 and 158 nm respectively), low PDI values of 0.25 and 0.29, spherical morphology, and high daunorubicin entrapment efficiency (68.6 and 66.5% respectively). The vesicles showed temperature-dependent drug release properties and superior antiproliferative activity compared to the free daunorubicin (IC₅₀ values of 6.91 and 8.54 vs. 12.14). Conclusions: The obtained results indicate that the developed thermosensitive nanovesicles may serve as a suitable drug delivery system for the systemic application of daunorubicin hydrochloride. Full article

Background: Spinal solitary fibrous tumors (SFTs) are a rare oncological entity, almost anecdotal in the pediatric population. They have a high relapse rate and represent an ongoing oncological challenge. Methods: In this article, we conducted a systematic review starting from a case report to highlight the current state of the art in managing these tumors. Results: Spinal solitary fibrous tumors (SFTs) are rare, slow-growing neoplasms that can be either intra- or extramedullary. Only a limited number of studies focus on primary pediatric spinal cord localization. Five pediatric cases of spinal SFT have been documented in the literature. On MRI, they typically present as highly vascularized, contrast-enhancing masses. Histologically, they are composed of spindle-shaped cells within a collagenous stroma featuring staghorn-shaped blood vessels. More aggressive subtypes, such as dedifferentiated SFTs, resemble high-grade sarcomas. The NAB2–STAT6 fusion is a key marker, driving EGFR signaling, collagen production, and fibrosis. Additional diagnostic markers include CD34, CD99, and Bcl-2. Surgical resection remains the primary treatment. In metastatic cases, chemotherapy—mainly with anthracyclines, dacarbazine, or temozolomide—is employed, although no standardized pediatric protocols exist. Anti-angiogenic agents, including tyrosine kinase inhibitors, have shown promise. Radiotherapy is used postoperatively for local disease control, but its impact on survival is still under investigation. Conclusions: Surgery remains the cornerstone of treatment, significantly impacting the natural history of the disease and symptom control. While clinical trials exploring radiotherapy and chemotherapy are ongoing in adults, no specific treatment protocol has been established for pediatric patients. Full article