Search Results (5,619)

Background/Objectives: Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo tumor models. While OVs are known to mediate systemic anti-tumor immune responses, the detailed characterization of local and systemic immune responses to fusogenic oncolytic virotherapy remains unexplored. Methods and Results: We analyzed immune cell compartments in the spleen, blood, tumor-draining lymph nodes (TDLNs), and tumors over the course of VSV-NDV therapy in a bilateral syngeneic melanoma mouse model. Our results revealed significant local infiltration and activation of T lymphocytes in tumors and globally in the blood and spleen. Notably, in vivo CD8⁺ T cell depletion led to complete abrogation of the tumor response, highlighting the crucial role of T cells in promoting the therapeutic effects of oncolytic VSV-NDV. In vitro co-culture experiments enabled the interrogation of human immune cell responses to VSV-NDV-mediated oncolysis. Human peripheral blood mononuclear cells (PBMCs) were efficiently stimulated by exposure to VSV-NDV-infected cancer cells, which recapitulates the in vivo murine findings. Conclusions: Taken together, these data characterize a broad anti-tumor immune cell response to oncolytic VSV-NDV therapy and suggest that CD8⁺ T cells play a decisive role in therapeutic outcome, which supports the further development of this chimeric vector as a multimechanistic immunotherapy for solid cancers. Full article

The Tunisian Health Technology Assessment (HTA) body, INEAS, conducted a cost-effectiveness analysis (CEA) of vemurafenib in the treatment of locally advanced or metastatic BRAF V600-mutated melanoma. The objective of this analysis was to enable the use of value-based pricing as a new approach to price negotiation. This study was part of a broader HTA report that was prepared in response to a joint request from the regulatory authorities and the CNAM, Tunisia’s compulsory insurance scheme. Our analysis was based on a probabilistic Markov cohort model that calculated the costs and quality-adjusted life years (QALY) associated with vemurafenib compared to the standard of care from a public payer perspective. The CEA indicated that vemurafenib provides a gain of 0.38 life years (1.78 vs. 1.4) for an incremental cost of USD 101,106.62 from the perspective of the main public payer (CNAM). This study revealed an incremental cost-effectiveness ratio (ICER) of 163,311.40 USD/QALY and 163,911.46 USD/QALY, respectively, from the CNAM and public health facilities’ perspectives. Vemurafenib cannot be considered cost-effective in terms of what has normally been considered a reasonable willingness to pay (WTP) in Tunisia. A significant price reduction would be necessary to bring the incremental cost-effectiveness ratio to an acceptable level. Full article

The presented study depicts the synthesis of 11 carborane–thiazole conjugates with anticancer activity, as well as an evaluation of their biological activity as inhibitors of two enzymes: tyrosinase and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The overexpression of tyrosinase results in the intracellular accumulation of melanin and can be observed in melanoma. The overexpression of 11β-HSD1 results in an elevation of glucocorticoid levels and has been associated with the aggravation of metabolic disorders such as type II diabetes mellitus and obesity. Recently, as the comorbidity of melanomas and metabolic disorders is being recognized as an important issue, the search for new therapeutic options has intensified. This study demonstrates that carborane–thiazole derivatives inhibit both enzymes, exerting beneficial effects. The antiproliferative action of all newly synthesized compounds was evaluated using three cancer cell lines, namely A172 (human brain glioblastoma), B16F10 (murine melanoma) and MDA-MB-231 (human breast adenocarcinoma), as well as a healthy control cell line of HUVEC (human umbilical vein endothelial cells). The results show that 9 out of 11 newly synthesized compounds demonstrated similar antiproliferative action against the B16F10 cell line to the reference drug, and three of these compounds surpassed it. To the best of our knowledge, this study is the first to demonstrate dual inhibitory action of carborane–thiazole derivatives against both tyrosinase and 11β-HSD1. Therefore, it represents the first step towards the simultaneous treatment of melanoma and comorbid diseases such as type II diabetes mellitus. Full article

Background: When monotherapy with PD-1 inhibitors in metastatic melanoma fails, there are currently no standard second-line choices. In case of the unavailability of clinical trials, ipilimumab represents a possible alternative treatment. Methods: We collected data of 44 patients who received ipilimumab after the failure of PD-1 inhibitors from July 2017 to May 2023 at our Institute. Overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS) based on BRAF or NRAS mutation status, sex, and the presence of brain metastases were estimated using the Kaplan–Meier method. Cox regression was used to evaluate independence in multivariate analysis. The objective response rate (ORR) was estimated based on RECIST 1.1. Results: Among the 44 patients enrolled in this study, 28 BRAF-wildtype, 9 BRAF-mutated, and 7 NRAS-mutated patients were identified. OS analysis showed a significant difference between wildtype and BRAF- or NRAS-mutated patients: 23.2 months vs 5.3 and 4.59, respectively, p = 0.017. The presence of brain metastases and BRAF or NRAS mutation were independent factors for mortality in multivariate analysis. Conclusions: In case of failure to enroll patients in innovative clinical trials, second-line ipilimumab still represents an effective therapy in patients with metastatic wildtype melanoma and in the absence of brain metastases. Full article

Genome instability relies on preserving the chromatin structure, with any histone imbalances threating DNA integrity. Histone synthesis occurs in the cytoplasm, followed by a maturation process before their nuclear translocation. This maturation involves protein folding and the establishment of post-translational modifications. Disruptions in this pathway hinder chromatin assembly and contribute to genome instability. JMJD1B, a histone demethylase, not only regulates gene expression but also ensures a proper supply of histones H3 and H4 for the chromatin assembly. Reduced JMJD1B levels lead to the cytoplasmic accumulation of histones, causing defects in the chromatin assembly and resulting in DNA damage. To investigate the role of JMJD1B in regulating genome stability and the malignancy of melanoma tumors, we used a JMJD1B/KDM3B knockout in B16F10 mouse melanoma cells to perform tumorigenic and genome instability assays. Additionally, we analyzed the transcriptomic data of human cutaneous melanoma tumors. Our results show the enhanced tumorigenic properties of JMJD1B knockout melanoma cells both in vitro and in vivo. The γH2AX staining, Micrococcal Nuclease sensitivity, and comet assays demonstrated increased DNA damage and genome instability. The JMJD1B expression in human melanoma tumors correlates with a lower mutational burden and fewer oncogenic driver mutations. Our findings highlight JMJD1B’s role in maintaining genome integrity by ensuring a proper histone supply to the nucleus, expanding its function beyond gene expression regulation. JMJD1B emerges as a crucial player in preserving genome stability and the development of melanoma, with a potential role as a safeguard against oncogenic mutations. Full article

Numerous gene therapy drugs for cancer have received global approval, yet their efficacy against solid tumors remains inadequate. Our previous research indicated that the fiber protein, a component of the adenovirus capsid, can propagate from infected cells to neighboring cells that express the adenovirus receptor. We hypothesize that merging this fiber protein with an anti-cancer protein could enable the anti-cancer protein to disseminate around the transfected cells, presenting a novel approach to cancer gene therapy. In our study, we discovered that the knob region of the adenovirus type 5 fiber protein is the smallest unit capable of spreading to adjacent cells in a receptor-specific manner. We also showed that the recombinant knob protein infiltrates cells after dispersing to surrounding cells. To assess the potential of the knob protein to augment gene therapy for solid tumors in mice, we expressed a fusion gene of the A subunit of cytotoxic cholera toxin and the knob region in mouse tumors. We found that this fusion protein only inhibited tumor growth in receptor-expressing mouse melanomas, and this inhibitory effect persisted even in mice with anti-knob antibodies. Our study’s findings propose a novel cancer gene therapy strategy that enhances therapeutic effects by specifically delivering therapeutic proteins, expressed from in vivo administered genes, to target molecules. This outcome offers a fresh perspective on gene therapy for solid cancers, and we anticipate that knob proteins will serve as a platform for this method. Full article

Background: Telenursing comprises a set of tools and interventions enabling nurses to provide remote care. This study aims to assess the impact of telenursing interventions on the supportive care needs of patients with melanoma and lung cancer who are receiving targeted therapies. Methods: This six-month monocentric, double-arm, randomised, controlled trial study protocol will assess the effect of telenursing on the supportive care needs (primary outcome) in 40 patients (20 in each group) after one month. The secondary outcomes will be monitored at baseline, one, three and six months: supportive care needs (at three and six months), therapeutic adherence, quality of life, usability and satisfaction, performance status, patient-reported outcomes and main adverse events. The SPIRIT guidelines will be used for the reporting. Results: The results from this trial will assess the impact of a telenursing intervention on cancer care. Conclusions: This trial could be a starting point for more extensive studies on telenursing interventions to promote nurses’ skills, as well as the quality and safety of care in patients with cancer, highlighting the impact of more outstanding nursing contributions on cancer care. Trial and Protocol Registration: The study protocol was approved by the relevant Italian Ethics Committee Lazio Area 5 (RS1851/23, 2773; 6 September 2023) and was registered on ClinicalTrials.gov (trial registry number NCT06254196). Full article

Melanoma is one of the most aggressive forms of skin cancer. While most melanomas have a discernible primary site, a small subset, approximately 3.2%, present as a metastatic disease without an identifiable primary origin, a condition known as melanoma of unknown primary (MUP). Unusual cases of primary melanoma have also been previously reported in the respiratory, gastrointestinal, and urogenital tracts. MUP typically is found in lymph nodes, subcutaneous sites, and visceral organs, with hypotheses about its origin including spontaneous primary tumor regression and ectopic melanocytes. MUP presents unique challenges in diagnosis and treatment due to the absence of a detectable primary tumor. Understanding its genetic and molecular features, epidemiology, prognostic factors, and treatment options is crucial for optimizing patient care and outcomes in this subset of melanoma patients. We conducted an extensive literature review triggered by a case report of a patient with suspected MUP. A 51-year-old woman was transferred from another hospital where an incision was performed for a suspected superinfected hematoma of the left thigh. Since the patient showed high leukocytosis and redness and swelling of the thigh, local debridement, drainage, and excisional biopsy of the tumor mass were performed in our unit in the emergency setting, and the tumor was taken for histopathology evaluation. Intraoperatively, the mass appeared nonspecific. The permanent histopathology report established a diagnosis of melanoma, with tumor proliferation also involving lymphoid tissue, and despite broad clinical and imagistic assessments, the primary melanoma could not be identified. Clinicians must be aware of the varied clinical manifestations of malignant melanoma, especially in cases of occult melanoma where the primary site is not evident. Full article

Plaque radiotherapy is an effective treatment modality for medium-sized ocular tumors such as uveal melanoma. The authors review the available literature and concisely summarize the current state of the art of ophthalmic plaque brachytherapy. The choice of radioisotope, which includes Ruthenium-106 and Iodine-125, depends on the intended treatment duration, tumor characteristics, and side effect profiles. Ophthalmic plaques may be customized to allow for the delivery of a precise radiation dose by adjusting seed placement and plaque shape to minimize collateral tissue radiation. High dose rate (HDR) brachytherapy, using beta (e.g., Yttrium-90) and photon-emitting sources (e.g., Ytterbium-169, Selenium-75), allows for rapid radiation dose delivery, which typically lasts minutes, compared to multiple days with low-dose plaque brachytherapy. The efficacy of Ruthenium-106 brachytherapy for uveal melanoma varies widely, with reported local control rates between 59.0% and 98.0%. Factors influencing outcomes include tumor size, thickness, anatomical location, and radiation dose at the tumor apex, with larger and thicker tumors potentially exhibiting poorer response and a higher rate of complications. Plaque brachytherapy is effective for selected tumors, particularly uveal melanoma, providing comparable survival rates to enucleation for medium-sized tumors. The complications of plaque brachytherapy are well described, and many of these are treatable. Full article

Undaria pinnatifida is a temperate brown alga known to exert free radical-scavenging and anti-inflammatory effects. In this study, we investigated the skin-whitening effects of U. pinnatifida sporophyll extracts (UPEs) in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16F10 melanoma cells. The crude polysaccharide fraction (UPF) was obtained via ethanol precipitation. Four polysaccharide fractions (UPF1–4) were isolated and purified using ion-exchange column chromatography, and their anti-melanogenic activity was evaluated. UPF3 exhibited the highest anti-melanogenic activity, showing the highest sulfate (39.79%), fucose (143 μg/mg), and galactose (208 μg/mg) contents. UPF3 significantly inhibited intracellular tyrosinase activity in B16F10 cells. We also evaluated the melanogenic signaling pathway to determine the mechanism of action of UPF3 in melanongenesis. UPF3 reduced the expression of tyrosinase-related protein-1 (TRP-1), tyrosinase-related protein-2 (TRP-2), and tyrosinase, which play important roles in melanin production. Therefore, UPF3 has high potential for use in skin-whitening functional pharmaceuticals and cosmetics. Full article

Non-melanoma skin cancers (NMSC), including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC), are increasingly common and present significant healthcare challenges. Neutrophil extracellular traps (NETs), chromatin fibers expulsed by neutrophil granulocytes, can promote immunotherapy resistance via an impairment of CD8⁺ T cell-mediated cytotoxicity. Here, to identify a potential therapeutic target, we investigate the expulsion of NETs and their relation to CD8⁺ T cell infiltration in NMSC. Immunofluorescence staining for neutrophils (CD15) and NETs (H3cit), as well as immunohistochemistry for cytotoxic T cells (CD8⁺) on human cSCCs (n = 24), BCCs (n = 17) and MCCs (n = 12), revealed a correlation between neutrophil infiltration and ulceration diameter in BCC and MCC, but not in cSCC. In BCC and cSCC, neutrophil infiltration also correlated with the cross-sectional area (CSA). NETs were not associated with established risk factors but with the presence of an ulceration, and, in cSCC, with abscess-like structures. CD8⁺ T cell infiltration was not reduced in tumors that were NET-positive nor in those with a denser neutrophil infiltration. This study is the first to report and characterize NETs in NMSC. Thus, it gives an incentive for further research in this relevant yet understudied topic. Full article

The aim of this study was to investigate the qualitative and quantitative fruit profiles of ten cultivars (cvs.) of haskap berry (Lonicera caerulea var. kamtschatica Sevast.) to determine their antioxidant activity (ABTS test, CUPRAC test, ability to capture superoxide (O₂˙⁻) and hydroxyl radicals (OH˙)), cytotoxic activity (against cancer cell lines breast, MCF-7; colon, HT-29; and melanoma, SK-Mel-28) and physicochemical properties. Most of the selected cultivars had not previously been analyzed for these properties. A total of 19 polyphenolic compounds were identified in the fruits of the tested genotypes, with a quantitative range of 2166.3–3597.0 µg/g. The polyphenol profile was dominated by anthocyanins (90.0–92.4%), and the remaining classes occurred in the following order: phenolic acids > flavonols > flavan-3-ols. The highest concentrations of these polyphenol groups were found in the cultivars ‘Honeybee’, ‘Sinij Uties’ and ‘Usłada’. The fruits of these cultivars were also characterized by the highest antioxidant activity (546.6–683.5 µg/mL for O₂˙⁻ and 541.2–652.1 µg/mL for OH˙) and cytotoxic activity (103.6–649.2 µg/mL). The data obtained indicate that the fruits of the new haskap cultivars are a good source of bioactive compounds with possible health-promoting properties. Full article

The landscape of clinical management for metastatic melanoma (MM) and other solid tumors has been modernized by the advent of immune checkpoint inhibitors (ICI), including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. While these agents demonstrate efficacy in suppressing tumor growth, they also lead to immune-related adverse events (irAEs), resulting in the exacerbation of autoimmune diseases such as rheumatoid arthritis (RA), ulcerative colitis (UC), and Crohn’s disease (CD). The immune checkpoint inhibitors offer promising advancements in the treatment of melanoma and other cancers, but they also present significant challenges related to irAEs and autoimmune diseases. Ongoing research is crucial to better understand these challenges and develop strategies for mitigating adverse effects while maximizing therapeutic benefits. In this manuscript, we addressed this challenge using network-based approaches by constructing and analyzing the molecular and signaling networks associated with tumor-immune crosstalk. Our analysis revealed that IL6 is the key regulator responsible for irAEs during ICI therapies. Furthermore, we conducted an integrative network and molecular-level analysis, including virtual screening, of drug libraries, such as the Collection of Open Natural Products (COCONUT) and the Zinc15 FDA-approved library, to identify potential IL6 inhibitors. Subsequently, the compound amprenavir was identified as the best molecule that may disrupt essential interactions between IL6 and IL6R, which are responsible for initiating the signaling cascades underlying irAEs in ICI therapies. Full article

Carpesium macrocephalum, a species native to China, Korea, Japan, and Russia, has been used medicinally in the countries of its origin. Though mono- and sesquiterpenoids are known constituents of C. macrocephalum, the complete analysis of essential oils produced by the roots and aerial parts of the plant has not been published until now. The present study discloses considerable differences in the composition and cytotoxic activity of essential oils distilled from roots and shoots of C. macrocephalum. The GC-MS-FID analyses have led to the identification of 131 compounds in all, of which 114 were found in aerial parts and 110 in the roots of the plants. The essential oil distilled from shoots contained a mixture of nerol and thymol methyl ether (c. 26%), neryl isobutyrate (c. 12%) and linalool (c. 9%) as major constituents, whereas alantolactone (c. 29%), thymol methyl ether (c. 7%) and 2,5-dimethoxy-p-cymene (thymohydroquinone dimethyl ether, c. 7%) predominated in the essential oil obtained from the roots. The oils demonstrated weak antibacterial activity against Staphylococcus aureus and, at concentrations up to 2.08 mg/mL (oil from the aerial parts) and up to 3.38 mg/mL (oil from roots), were inactive against Gram-negative bacteria. The essential oil from the roots of the plant demonstrated strong but not selective cytotoxic activity. Full article

Background/Objectives: This study investigated the anticancer potential of an aqueous extract of the fungus Fomitopsis betulina. Methods: The study assessed the effect of the extract on nine cancer cell lines, including melanoma (LM-MEL-75), lung cancer (A549), and colorectal cancer (HT29, LoVo), and four normal cell lines. The cytotoxicity of the extract was evaluated using MTT, sulforhodamine-B (SRB), and clonogenic viability assays. Additionally, the study examined the effect of the extract on plant model organisms, garden cress (Lepidium sativum) and common onion (Allium cepa), to further investigate its biological activity. Results: The assays demonstrated selective cytotoxicity of the extract toward cancer cells, while sparing normal cells. The extract induced significant cytotoxic effects at lower concentrations in lung cancer, melanoma, and colon cancer cells, showing promise as a potential anticancer agent. The results also revealed that the extract inhibited seed germination and root growth, suggesting its potential to disrupt cell cycles and induce apoptosis. Conclusions: This study highlights the therapeutic potential of F. betulina and highlights the need for further research to identify the active ingredients and mechanisms underlying its anticancer effects. Full article