Search Results (281)

Multidrug resistance (MDR) remains a significant obstacle to effective cancer chemotherapy, primarily due to overexpression of P-glycoprotein (P-gp), which reduces intracellular accumulation of cytotoxic drugs. This study evaluated the pharmacological potential of the glycyrrhetinic acid derivative soloxolone N-3-(dimethylamino)propylamide (Sol-DMAP) as a biocompatible P-gp inhibitor with hepatoprotective properties. Using a murine model of P-gp-overexpressing RLS40 lymphosarcoma, we demonstrated that Sol-DMAP significantly enhanced the antitumor efficacy of doxorubicin (DOX) by increasing its intratumoral concentration 4.7-fold without enhancing systemic toxicity. Independently, Sol-DMAP exhibited direct antitumor activity, reducing tumor growth in vivo and inducing apoptosis and G1-phase arrest in RLS40 cells in vitro. In addition, Sol-DMAP mitigated DOX-induced hepatic injury by reducing necrotic and dystrophic changes in liver tissue and restoring heme oxygenase 1 (Hmox1) expression. Further studies in HepG2 cells confirmed that Sol-DMAP activated the NRF2-dependent antioxidant response, upregulating HMOX1, GCLC, GCLM, and NQO1 genes. Molecular docking revealed that Sol-DMAP can disrupt the KEAP1-NRF2 interaction, likely leading to NRF2 activation. Collectively, these findings demonstrate that Sol-DMAP effectively reverses P-gp-mediated MDR while protecting the liver from oxidative stress, highlighting its potential as a multifunctional scaffold for the development of safer and more effective chemotherapeutic adjuvants. Full article

Background: Small-cell lung cancer (SCLC) is an aggressive malignancy marked by rapid progression, early metastasis, and frequent relapse despite chemotherapy. Due to its genetic complexity, targeted therapies have limited success. Autophagy, a lysosome-dependent cellular degradation process, plays a key role in SCLC, yet effective autophagy-targeting strategies are lacking. This study evaluates Tat-SP4, an autophagy-targeting stapled peptide, for its anti-proliferative effects in SCLC. Method: We assessed Tat-SP4′s impact on autophagy in SCLC cells by measuring p62 and LC3 levels. Mitochondrial function was evaluated via mitochondrial membrane potential (Δψm) and oxygen consumption rate (OCR). Anti-proliferative effects were determined using cell viability assays in vitro and xenograft models in vivo. Cellular uptake mechanisms were investigated using Ca²⁺ imaging and pharmacological inhibitors. Result: Tat-SP4 induced a strong autophagic response and triggered autosis, a form of autophagy-dependent necrotic cell death, impairing SCLC cell proliferation. It also caused mitochondrial dysfunction with impaired oxidative phosphorylation (OXPHOS). Tat-SP4 entered cells predominantly via macropinocytosis, triggering extracellular Ca²⁺ influx measurable by live-cell imaging. Digoxin, an Na⁺, K⁺-ATPase inhibitor, partially reversed the effect of Tat-SP4 on Ca²⁺ influx, cell death, and OXPHOS activity. Lastly, Tat-SP4 inhibited tumor growth in a xenograft-based animal model for SCLC. Conclusions: The autophagy-targeting stapled peptide Tat-SP4 inhibited the proliferation of SCLC cells in vitro and inhibited the growth of the SCLC tumor in vivo. Macropinocytosis facilitates cell entry for Tat-SP4, which can be monitored by influx of extracellular Ca²⁺. By exploiting macropinocytosis for cell entry and converting the pro-survival autophagy process into a death pathway, Tat-SP4 represents a novel therapeutic strategy against SCLC. Full article

Background and Clinical Significance: Warty (condylomatous) squamous cell carcinoma (SCC) of the uterine cervix is a rare papillary variant of SCC, usually associated with good prognosis. Case Presentation: We report the clinical case of a postmenopausal woman with vaginal bleeding, anemia, and an enlarged, exophytic tumor mass protruding from the cervix. MRI showed a solid–necrotic cervical–uterine mass with invasion of bladder, rectum, both parametria, and the left ureter, with regional lymphadenopathy and FIGO IVA stage was established. Biopsies from the cervical tumor revealed invasive, well-differentiated SCC with conspicuous koilocytic atypia in superficial and deep nests, consistent with warty (condylomatous) SCC. Immunohistochemistry showed p16 overexpression, an intermediate nuclear proliferation rate, and a non-mutational pattern for p53 immunostaining. Radiotherapy was recommended but the patient’s condition deteriorated rapidly and she died three months after initial diagnosis. Due to the rarity of this type of tumor, we conducted a search on PubMed, Scopus, and Web of Science from inception to 31 July 2025 and we identified ten reports available for evaluation. A total of 32 cases were identified, usually with FIGO stage I or II, mostly with low-risk HPV infection and with good prognosis. Conclusions: The advanced stage and limited tolerance for therapy in this case emphasize the importance of HPV vaccination and HPV-based screening to prevent late, non-curable presentations. Accurate distinction from condyloma acuminatum and verrucous or papillary SCC is clinically relevant because management and outcomes differ. Since some of the cases reported in the literature had a worse clinical course, with shorter disease-free survival and overall survival, including our case, further research is mandatory in the future to unravel those features which might predict a poor outcome. Full article

Glioblastoma is one of the most aggressive and therapeutically challenging brain tumors. It is characterized by a highly immunosuppressive tumor microenvironment and poor prognosis, requiring novel treatment strategies. Along this line, ferroptosis has been proposed. To study the impact of ferroptosis on glioblastoma cells and immune cell infiltration, we established a spheroid model using LN229 glioblastoma cells and verified ferroptosis by measuring lipid peroxidation and RNA expression of ferroptosis-related genes. We then co-cultured spheroids with human peripheral blood mononuclear cells to follow the infiltration of distinct immune cell subsets by flow cytometry and immunohistochemistry. T lymphocyte infiltration into ferroptotic spheroids compared to control spheroids became apparent with the notion that ferroptotic cells attracted T cells more efficiently compared to apoptotic or necrotic cells. Mechanistically, ferroptotic glioblastoma spheroids released high amounts of ATP, which caused T cell attraction, while ATP deprivation reduced this effect. Ferroptosis appears to be an interesting therapy approach but might need co-treatments to ensure proper T cell activation. Full article

Conventional cancer treatments have limited efficacy for aggressive subtypes such as triple-negative breast cancer (TNBC), which points to the importance of new therapeutic strategies. Functionalized nanoparticles in conjunction with photodynamic therapy (PDT) represent a promising alternative. Additionally, 3D cell culture emerges as a more effective model, as it better replicates the structural and functional characteristics of the tumor microenvironment. In this study, 3D microtumors of TNBC were cultivated and treated with PDT using gold nanoparticles functionalized with Chlorin e6 (AuNPs@Ce6). Cell viability was assessed using the MTT colorimetric assay, combined with histological analysis using hematoxylin-eosin staining. The MTT assay and histological evaluation of the 3D spheroids demonstrated that PDT with AuNPs@Ce6 effectively reduced cell viability and induced necrotic morphological changes, while maintaining biocompatibility with the non-irradiated control group. These findings reinforce the potential of this approach for further investigation in TNBC models and underscore the value of 3D cultures as physiologically relevant and ethical alternatives to animal testing. Full article

Background/Objectives: The development of effective oncologic therapies with fewer adverse effects is often limited by the intrinsic and acquired resistance of tumor cells. Hybrid molecules, rationally designed to combine different pharmacophores, represent a promising strategy by providing synergistic effects, dose reduction, and a lower risk of resistance. In this study, the antitumor potential and mechanisms of action of 22 novel hybrid compounds derived from xanthene and pyran scaffolds (SJ022–SJ103) were investigated. The hybrids were initially evaluated through in vitro screening in four breast, three ovarian, and two prostate cancer cell lines, followed by the selection of T-47D, OVCAR-3, and LNCaP cells for detailed assays assessing cytotoxicity, apoptosis, cell cycle distribution, DNA damage, caspase-3/7 activity, morphology, and PI3K/AKT/mTOR pathway modulation. Methods: Cytotoxicity assays were performed in the selected cell lines, while mechanistic studies included apoptosis and cell cycle analysis by flow cytometry, γH2AX detection, Western blotting for PI3K/AKT/mTOR pathway proteins, and 3D spheroid assays. Combinatorial effects with hormone therapies (tamoxifen, fulvestrant, and letrozole) and the AKT inhibitor MK2206 were evaluated. AKT silencing by esiRNA and molecular docking was performed to confirm target engagement. Results: SJ028 demonstrated broad activity across all tested cell lines, whereas SJ064 and SJ078 exhibited higher selectivity. Treatments induced apoptosis, S/G2-M arrest, and DNA damage, accompanied by decreased phospho-AKT levels and stable PI3K and mTOR expression. In 3D models, the hybrids increased caspase-3/7 activity and necrotic core expansion. Co-administration with hormone therapies resulted in synergistic effects in breast and ovarian cancer cells, reducing IC₅₀ values by more than 50% in both parental and resistant models, while combinations with MK2206 were antagonistic across all tumor subtypes. AKT silencing abrogated cytotoxicity, and docking confirmed SJ028 binding to AKT. Conclusions: Xanthene- and pyran-based hybrids—particularly SJ028, SJ064, and SJ078—showed strong antitumor activity through apoptosis induction, cell cycle arrest, and PI3K/AKT pathway modulation. Their preserved efficacy in resistant models and synergistic interactions with hormone therapies contrasted with the antagonism observed with AKT inhibition, highlighting their potential as promising candidates for the treatment of hormone-responsive and -resistant cancers. Full article

This paper will present in vivo release profiles of Doxorubicin.HCl from halo-spun drug-loaded rubbery porous mats. For the very first time, Fluorescent Organism Bioimaging (FOBI) was used to follow drug release in a live animal model with induced tumors. A new predictive model based on apparent diffusion coefficients to simulate release profiles will also be presented and could have general applications for release profile predictions. Surprisingly, histological evaluation found that the tissue layer forming next to the drug-eluting mats had unordered morphology and only necrotic cells. This is a stunning contrast to the highly regular collagen structure next to mats without the drug, typical of an adverse foreign body type reaction. The findings suggest that this drug-eluting fiber mat can be used as a local chemotherapy approach coupled with mitigation of capsular contracture, the major complication associated with breast reconstruction following mastectomy. Full article

Introduction: Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (PCAETL) is a rare and highly aggressive subtype of cutaneous T-cell lymphoma (CTCL), accounting for less than 1% of CTCL cases. It is defined by CD8+ cytotoxic T-cell proliferation with marked epidermotropism, necrosis, and a high proliferative index. Clinically, it presents as ulcerated or necrotic lesions with rapid progression and poor response to conventional therapies. Aims: To describe a fatal case of PCAETL in a young adult female, emphasizing the diagnostic challenges, clinical progression, histopathological features, and treatment limitations. Case Presentation: A 41-year-old Venezuelan woman presented with a 10-month history of disseminated papules and nodules initially misdiagnosed as Hansen’s disease. After her arrival in Ecuador, she was re-evaluated and found to have generalized dermatosis with ulcerated nodules and tumors. Histopathological examination revealed atypical epidermotropic CD8+ T-cell infiltration with extensive necrosis. Immunohistochemistry demonstrated strong positivity for CD3, CD5, and CD8, and a Ki-67 index of 80%, confirming the diagnosis of PCAETL. The patient received methotrexate with partial response but experienced disease relapse during second-line etoposide therapy. She developed febrile neutropenia and died five months after diagnosis. Conclusions: This case highlights the rarity, diagnostic complexity, and aggressive nature of PCAETL. Early recognition and clinico-pathological correlation are essential for timely diagnosis. However, therapeutic options remain limited, and outcomes are poor despite systemic chemotherapy. Further research into targeted and personalized therapies is urgently needed to improve survival in this devastating disease. Full article

Cardiovascular diseases in dogs have diverse causes and may progress rapidly to life-threatening complications. This review outlines the relevant pathological conditions involving the cardiovascular system in dogs, especially the myocardium, including myocarditis caused by canine parvovirus (CPV-2), heartworm disease (Dirofilaria immitis), hemangiosarcoma, and polyarteritis nodosa (PAN). CPV-2 affects the myocardium of puppies during the early weeks of life, leading to necrosis, fibrosis, and congestive heart failure. Heartworm disease is caused by adult D. immitis residing mainly in the pulmonary arteries, inducing pulmonary hypertension, right ventricular overload, and vascular damage, with the severity being related to the worm burden and duration of infestation. Hemangiosarcoma is a malignant vascular tumor, most frequently originating in the spleen or right atrium, often diagnosed at an advanced stage, with widespread metastases. Polyarteritis nodosa in dogs is a necrotizing, systemic vasculitis of medium-sized arteries that may affect the coronary arteries of the heart. Its pathogenesis is still unclear, though an immune-mediated mechanism is suspected. By presenting these lesions, the review underscores the many factors that can trigger cardiovascular diseases in dogs, as well as the clinical significance and the need for further research into their pathogenesis and treatment. Full article

Pott’s Puffy Tumor (PPT) is a rare but potentially life-threatening complication of frontal sinusitis, characterized by subperiosteal abscess formation and frontal bone osteomyelitis. Although predominantly seen in adolescents, adult cases are increasingly recognized. Early diagnosis is essential to prevent severe orbital and intracranial sequelae. We present two patients with distinct clinical features: a 31-year-old female with chronic frontal sinusitis complicated by sequestrated bone extrusion through a cutaneous fistula, and a 16-year-old male with an acute presentation of subperiosteal abscess, nasal polyp-related obstruction of the osteomeatal complex (OMC), and orbital cellulitis. Both patients underwent combined surgical and medical management, including broad-spectrum intravenous antibiotics, functional endoscopic sinus surgery, and external drainage. In the adult, necrotic bone was excised, and the anterior frontal wall was reconstructed with titanium mesh to restore sinus anatomy and drainage, while in the adolescent, early abscess drainage and polyp removal ensured frontal recess patency and prevented osteomyelitis. Postoperative follow-up demonstrated complete resolution without recurrence. These cases highlight that PPT can occur in both acute and chronic settings of chronic rhinosinusitis with nasal polyps, emphasizing the importance of prompt imaging, multidisciplinary evaluation, and individualized surgical strategies to optimize outcomes and minimize life-threatening complications. Full article

Background/Objectives: We provide a framework for determining how far into the future the spatiotemporal dynamics of tumor growth can be accurately predicted using routinely available magnetic resonance imaging (MRI) data. Our analysis is applied to a coupled set of reaction-diffusion equations describing the spatiotemporal development of tumor cellularity and vascularity, initialized and constrained with diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI data, respectively. Methods: Motivated by experimentally acquired murine glioma data, the rat brain serves as the computational domain within which we seed an in silico tumor. We generate a set of 13 virtual tumors defined by different combinations of model parameters. The first parameter combination was selected as it generated a tumor with a necrotic core during our simulated ten-day experiment. We then tested 12 additional parameter combinations to study a range of high and low tumor cell proliferation and diffusion values. Each tumor is grown for ten days via our model system to establish “ground truth” spatiotemporal tumor dynamics with an infinite signal-to-noise ratio (SNR). We then systematically reduce the quality of the imaging data by decreasing the SNR, downsampling the spatial resolution (SR), and decreasing the sampling frequency, our proxy for reduced temporal resolution (TR). With each decrement in image quality, we assess the accuracy of the calibration and subsequent prediction by comparing it to the corresponding ground truth data using the concordance correlation coefficient (CCC) for both tumor and vasculature volume fractions, as well as the Dice similarity coefficient for tumor volume fraction. Results: All tumor CCC and Dice scores for each of the 13 virtual tumors are >0.9 regardless of the SNR/SR/TR combination. Vasculature CCC scores with any SR/TR combination are >0.9 provided the SNR ≥ 80 for all virtual tumors; for the special case of high-proliferating tumors (i.e., proliferation > 0.0263 day⁻¹), any SR/TR combination yields CCC and Dice scores > 0.9 provided the SNR ≥ 40. Conclusions: Our systematic evaluation demonstrates that reaction-diffusion models can maintain acceptable longitudinal prediction accuracy—especially for tumor predictions—despite limitations in the quality and quantity of experimental data. Full article

Virotherapy is a promising method for treating oncological diseases, including such aggressive and difficult-to-treat brain tumors such as glioblastoma. Recombinant vaccinia virus VV-GMCSF-Lact has previously shown high antitumor potential against tumor cells of varying histogenesis, including gliomas, and completed a Phase I clinical trial, demonstrating safety and good tolerability in patients with recurrent/refractory metastatic breast cancer. Investigating two types of VV-GMCSF-Lact delivery, intravenous and intratumoral, into orthotopically transplanted C6 glioma in rats, it was shown that intratumoral injection significantly increases tumor volumes in comparison with intravenous virus delivery and is accompanied by noticeable toxic effects. Extensive areas of necrotic decay of tumor tissue and its significant mixed-cell infiltration and peritumoral edema, affecting the tumor volume, were detected using H&E staining of C6 tumors after intratumoral injection of VV-GMCSF-Lact. However, only with intratumoral administration was a significant decrease in the level of the tumor cell proliferation marker Ki67 demonstrated by immunohistochemical staining. The observed toxic effects of VV-GMCSF-Lact with intratumoral administration revealed the need for dose selection, which was performed on a mouse GL261 glioma model. Results of the study allowed us to determine the viral dose that does not lead to toxic effects and can potentially increase life expectancy of mice. The data obtained show the need for careful selection of both the route of viral drug dose and administration. Full article

Objective: This article evaluates the reconstructive potential and functional outcomes, as well as the risks and potential perioperative complications of using free flaps in patients with advanced-stage malignant laryngeal neoplasms who require salvage surgery and reconstruction. Additionally, it assesses the effectiveness of various flap harvesting and in-setting techniques, including the performance of microvascular anastomoses. Materials and Methods: This retrospective study included 13 male patients (age range 47–76 years) diagnosed with laryngeal neoplasms, who were referred to the Department of Otolaryngology at the University of Verona between 2017 and 2022. All patients underwent salvage total laryngectomy followed by concurrent reconstructive surgery utilizing microvascular flaps. Recovery of function (phonation) and incidence of complications were evaluated in a follow-up of at least three years. Results: Only one patient experienced necrotic failure of the microvascular free flap, probably due to post-op complications. The patient required revision on the 10th day after surgery and was reconstructed using a pedicled pectoralis major muscle flap. Two patients developed a pharyngocutaneous fistula. Other three patients had pharyngoesophageal stenosis, two experienced recurrence, and one patient passed away due to septic shock. All patients achieved satisfactory functional outcomes regarding vocalization, while complete oral intake was restored in eight patients. Conclusions: Considering the limited sample size, the findings suggest that microvascular flaps represent a feasible option for reconstructing advanced laryngeal tumors, though complication rate may still be considerable. Tailoring reconstructive approaches to individual patients may enhance surgical outcomes. Full article

Current standard treatments for osteosarcoma have not been changed for decades and have limited and variable success. The advancement of precision medicine technologies, along with the drug-repurposing and fast drug-screening methodologies available, has opened new avenues for the development of more effective therapeutic strategies. In this study, we evaluated the effectiveness of halogenated boroxine (HB) and dextran-coated cerium oxide nanoparticles—DexCeNPs (SD2)—in an in vitro osteosarcoma model. Both agents were tested individually and in combination. The research encompassed assessments of treatment-related cytotoxicity and cell viability, oxidative stress, and apoptotic and necrotic responses, as well as the effects on 3D spheroid models. The results demonstrated that the effects of HB and SD2 were strongly influenced by the dose, exposure time, and cell type. Both exhibited distinguished antitumor activity through cytotoxicity and specific reactive oxygen species (ROS) induction. The combined treatment produced modulated responses that were dependent on the treatment ratio and cell line, suggesting potential synergistic or selective interactions. Notably, the outcomes of the analysis conducted in 3D models revealed reduced toxicity toward non-tumor cells. These findings suggest the improved efficacy of HB and SD2 used in combination as a selective and novel antitumor strategy and underscore the need for further mechanistic studies at the transcriptomic and proteomic levels to elucidate the underlying pathways and clarify the mechanisms of action. Full article

Background/Objectives: Breast abscesses and necrotic masses often show similar peripheral enhancement and a fluid-containing appearance on breast MRI, leading to diagnostic confusion. Accurate differentiation is critical because biopsies that fail to sample the lesion wall may yield false-negative results, may be misinterpreted as an infectious process, and delay diagnosis. Incorporating SWI into the protocol can provide additional clues to malignancy and, when warranted, prompt a second wall-targeted biopsy, thus reducing the risk of delayed cancer diagnosis. Methods: This single-center prospective diagnostic accuracy study included 42 female patients diagnosed between 2022 and 2025 with either necrotic breast tumors or abscesses, confirmed by histopathology. SWI-based Intralesional Susceptibility Score (ILSS), rim morphology, and mean ADC values were evaluated. Statistical analyses included the Mann–Whitney U test, chi-square test, ROC analysis, DeLong test for comparison of AUCs, and Cohen’s kappa for interobserver agreement. Results: SWI-based ILSS values were significantly higher in necrotic tumors compared to abscesses (mean ILSS: 2.28 vs. 0.85; 95% CI: 1.0–2.0; p < 0.001). Smooth hypointense rims were predominantly observed in abscesses (Sensitivity: 63.1%, 95% CI: 0.38–0.83; Specificity: 88.9%, 95% CI: 0.65–0.98; p = 0.001). Incomplete rim morphology was more frequent in tumors (Sensitivity: 78.9%, 95% CI: 0.54–0.93; Specificity: 77.8%, 95% CI: 0.52–0.93; p < 0.001). The double rim sign was highly specific for abscesses (Specificity: 95.2%, 95% CI: 0.76–0.99 p = 0.002). Conclusions: SWI provides valuable morphological information in differentiating abscesses from necrotic tumors on breast MRI. When used in combination with ADC values, it can enhance diagnostic accuracy. Full article