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Objectives: To summarize the clinicopathological and genetic features of malignant paragangliomas in head and neck cancer and to explore the appropriate treatment options for this rare lesion. Methods: Six patients harboring head and neck malignant paraganglioma from Beijing Tongren Hospital were retrospectively reviewed. The clinicopathological characteristics, gene mutations, and prognosis of these patients were analyzed. Results: Of these 6 patients, 3 were male and 3 were female; 4 patients harbored malignant carotid body tumors, and two had malignant vagal paragangliomas. Three patients had cervical lymph node metastasis, two presented with lung and bone metastasis, and 1 had lung and liver metastasis. Of the 6 patients, four underwent surgical resection, and the other two patients denied surgery and instead received chemotherapy with paclitaxel, ifosfamide, and dacarbazine. These 2 patients with vagal paraganglioma received postoperative radiotherapy. All 6 patients are still alive at the present time, with a median follow-up time of 66 months. Positive Ki-67 expression in tumor tissue ranged from 1% to 40%. Genetic mutations in SDHD, SDHB, ATR, and MAP3K13 were identified in 4 patients. Conclusions: After comprehensive treatment, head and neck malignant paraganglioma can attain a favorable prognosis. Genetic mutations are commonly detected in patients with malignant paragangliomas. This study also identified mutations in ATR and MAP3K13 in these patients. [ABSTRACT FROM AUTHOR]

Purpose: To elucidate the anticancer mechanism and molecular targets of the aqueous fraction from Cotinus coggygria leaf extract in A375 malignant melanoma cells. Methods: Aqueous ethanol extract from the leaves of C. coggygria was fractionated into the aqueous and chloroform fractions by solvent-solvent partition. A375 cells were treated with the aqueous fraction at various concentrations and incubated for 72 h. The effect of the aqueous fraction on programmed cell death by staining with Annexin V/Propidium iodide ias well as on cell viability and adhesion through labeling with fluorescein diacetate were determined under fluorescence microscopy. In addition, the clonogenicity assessment, comet assay evaluation of genotoxic properties, characterization of thermodynamic behavior of cells by differential scanning calorimetry, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on the expression of genes involved in processes of apoptosis and cell cycle control were determined. Results: The number of viable adherent cells was reduced by 38.00 and 85.06 % at 20 and 80 µg/mL, respectively compared to untreated cells. In addition, a significant, dose-dependent reduction in the clonogenicity of melanoma cells was observed, culminating in an almost complete inhibition of cancer cells colony-forming ability at 40 and 60 µg/mL of the fraction. Treatment with the fraction increased comets of Classes 3 and 4 to 35 %, while comets of Class 5, which corresponds to the highest level of DNA fragmentation, increased to 2.25 %. Also, the gene damage index (GDI) was highest (1.2) at the concentration of 40 µg/mL. Furthermore, the expression levels of BAX, CASP8 and CDKN1A were upregulated and MYC expression decreased after treatment with the aqueous fraction. Conclusion: Cotinus coggygria possesses significant in vitro anti-melanoma potential. Future studies will be focused on the in vivo assessment of its therapeutic qualities in experimental animals. [ABSTRACT FROM AUTHOR]

Dacarbazine (DTIC) and its oral counterpart temozolomide (TMZ) have been the most used agents in advanced malignant melanoma (MM) patients and they are still used routinely. The preferred first line treatment, immune checkpoint inhibitors (CPIs) might shape the tumor and the tumor microenvironment, possibly affecting the response to subsequent therapies. The aim of this study was to investigate the treatment effect of DTIC/TMZ in MM patients after CPI therapy in a consecutive patient cohort and through systematic literature review and meta‐analysis. Thirty‐five patients with advanced MM treated with DTIC/TMZ after previous CPI therapy in three Swedish regions between 2017 and 2021 were recognized and seven case series studies were identified through systematic database review. Pooled data from all 345 patients showed a median real‐world progression‐free survival (rwPFS) of 1.9 months and overall survival (OS) of 6.0 months. Three of these studies were included in a meta‐analysis comparing DTIC/TMZ after CPI treatment, versus no previous immunotherapy, showing no statistically significant differences in rwPFS or OS but higher real‐world response rate to chemotherapy for the prior‐CPI treated group (Odds Ratio: 2.24; 95% Confidence Interval: 1.04–4.86). The current study supports consideration of DTIC/TMZ in later line of treatment in the immunotherapy era. [ABSTRACT FROM AUTHOR]

In this research, the potential applicability of fullerene (C60), boron nitride cage (B12N12), and (Al/Si)-doped fullerene as an efficient sensing substance for the detection of dacarbazine (DAC) has been explored using density functional theory. The adsorption of DAC on nanocages surface was evaluated by using adsorption energy, quantum theory of atoms in molecule, natural bond orbital (NBO), and frontier molecular orbital (FMOs) analysis. The Al-doped BNNCs exhibit the greatest adsorption energy, while the C60 clusters have the least. B12N11Si and C60 cannot be suitable adsorbents for potential sensor due to the positive free energy. The DAC drug molecule prefers to be adsorbed on boron nitride cage with the aid of its carbonyl group and nitrogen head with an adsorption energy of about − 27.4171 and − 14.3520 kcal/mol, respectively. The large reduction of the HOMO–LUMO gaps of the B12N12 and AlB11N12 after the adsorption of drug reflects not only good selectivity but also easy recovery of the sensor, which suggests them as suitable sensors for DAC detection. [ABSTRACT FROM AUTHOR]

The current study analyzes the possibility of determining the drug location in electrospun polymeric matrices and forecasting the release kinetics of drug delivery systems. Electrospun membranes made of polycaprolactone (PCL) loaded with dacarbazine (the drug of choice for the treatment of melanoma) and with AuM1 (a promising synthetic Au‐based complex recently proposed for antitumoral treatments) are successfully prepared. Atomic force microscopy (AFM) analysis is performed on various membranes, highlighting the relevance of investigating the three‐dimensional topology of the membranes for understanding the release kinetic. The produced mats are similar for all membranes, but significant differences in the microscopic roughness wall between the systems loaded with AuM1 and dacarbazine are observed. For AuM1, which has a low affinity with the PCL matrix, the complex aggregates on the nanofibers' external walls, consequently increasing the roughness and causing a high burst in the first hours of release. On the other hand, dacarbazine is successfully included in the bulk core of the PCL nanofibers. Thus, the release kinetics is diffusive and well described by the Fick model. [ABSTRACT FROM AUTHOR]

Little is known about the outcome for HIV-associated Hodgkin lymphoma (HIV-HL) as this is less common than HIV-negative lymphoma. Therefore, we performed a multi-center study to analyze the clinical characteristics and outcomes of HIV-HL patients in China. Nineteen cases of HIV-HL were diagnosed and treated at three center and including the sixth people's hospital of Zhengzhou, Peking union medical college hospital, and Chongqing university cancer hospital, between December 2013 and June 2022. Data on the clinical features, laboratory results, response, and prognosis were collected and analyzed. The median age at diagnosis was 43(22–74) years. All patients were infected with HIV through sexual transmission, with ten cases transmitted through man having sex with man (MSM) and nine cases transmitted through heterosexual transmission. Seven patients were diagnosed with lymphoma and found to be infected with HIV. Four cases were in stage III, and fifteen cases were in stage IV. After a median follow up of 46.8(4.0-112.9) months, 17 cases were alive after ABVD regimen chemotherapy combined with combination antiretroviral therapy (cART). The 5-year progression-free survival (PFS) and overall survival (OS) rate were 83.9% and 89.5%,respectively. HIV-HL exhibits an invasive process in clinical practice, and cART combined with ABVD regimen chemotherapy can achieve long-term survival for patients. [ABSTRACT FROM AUTHOR]

Chalcones are polyphenols that belong to the flavonoids family, known for their broad pharmacological properties. They have thus attracted the attention of chemists for their obtention and potential activities. In our study, a library of compounds from 2′-hydroxychalcone's family was first synthesized. A one-step mechanochemical synthesis via Claisen–Schmidt condensation reaction under ball mill conditions was studied, first in a model reaction between a 5′-fluoro-2′-hydroxyacetophenone and 3,4-dimethoxybenzaldehyde. The reaction was optimized in terms of catalysts, ratio of reagents, reaction time, and influence of additives. Among all assays, we retained the best one, which gave the highest yield of 96% when operating in the presence of 1 + 1 eq. of substituted benzaldehyde and 2 eq. of KOH under two grinding cycles of 30 min. Thus, this protocol was adopted for the synthesis of the selected library of 2′-hydroxychalcones derivatives. The biological activities of 17 compounds were then assessed against Plasmodium falciparum, Leishmania donovani parasite development, as well as IGR-39 melanoma cell lines by inhibiting their viability and proliferation. Compounds 6 and 11 are the most potent against L. donovani, exhibiting IC50 values of 2.33 µM and 2.82 µM, respectively, better than the reference drug Miltefosine (3.66 µM). Compound 15 presented the most interesting antimalarial activity against the 3D7 strain, with IC50 = 3.21 µM. Finally, chalcone 12 gave the best result against IGR-39 melanoma cell lines, with an IC50 value of 12 µM better than the reference drug Dacarbazine (IC50 = 25 µM). [ABSTRACT FROM AUTHOR]

Up to 80% of patients under immune checkpoint inhibitors (ICI) face resistance. In this context, stereotactic ablative radiotherapy (SABR) can induce an immune or abscopal response. However, its molecular determinants remain unknown. We present early results of a translational study assessing biomarkers of response to combined ICI and SABR (I-SABR) in liquid biopsy from oligoprogressive patients in a prospective observational multicenter study. Cohort A includes metastatic patients in oligoprogression to ICI maintaining the same ICI due to clinical benefit and who receive concomitant SABR. B is a comparative group of oligometastatic patients receiving only SABR. Blood samples are extracted at baseline (T1), after the first (T2) and last (T3) fraction, two months post-SABR (T4) and at further progression (TP). Response is evaluated by iRECIST and defined by the objective response rate (ORR)—complete and partial responses. We assess peripheral blood mononuclear cells (PBMCs), circulating cell-free DNA (cfDNA) and small RNA from extracellular vesicles. Twenty-seven patients could be analyzed (cohort A: n = 19; B: n = 8). Most were males with non-small cell lung cancer and one progressing lesion. With a median follow-up of 6 months, the last ORR was 63% (26% complete and 37% partial response). A decrease in cfDNA from T2 to T3 correlated with a good response. At T2, CD8+PD1+ and CD8+PDL1+ cells were increased in non-responders and responders, respectively. At T2, 27 microRNAs were differentially expressed. These are potential biomarkers of response to I-SABR in oligoprogressive disease. [ABSTRACT FROM AUTHOR]

This study investigates the distinctive characteristics of iron oxide magnetic nanoparticles (mNPs) and their potential application in cancer therapy, focusing on melanoma. Three types of mNPs, pre-validated for safety, underwent molecular analysis to uncover the activated signaling pathways in melanoma cells. Using the Western blot technique, the study revealed that mNPs induce cytotoxicity, hinder proliferation through ERK1/2 dephosphorylation, and prompt proapoptotic effects, including DNA damage by inducing H2AX phosphorylation. Additionally, in vitro magnetic hyperthermia notably enhanced cellular damage in melanoma cells. Moreover, the quantification of intracellular iron levels through Inductively Coupled Plasma Mass Spectrometry (ICP-MS) analysis unveils the precise dosage required to induce cellular damage effectively. These compelling findings not only shed light on the therapeutic potential of mNPs in melanoma treatment but also open exciting avenues for future research, heralding a new era in the development of targeted and effective cancer therapies. Indeed, by discerning the effective dose, our approach becomes instrumental in optimizing the therapeutic utilization of iron oxide magnetic nanoparticles, enabling the induction of precisely targeted and controlled cellular responses. [ABSTRACT FROM AUTHOR]

In the present work, five series of new 2,3‐disubstituted quinazolin‐4(3H)‐ones 4a–c, 5a–d, 6a–g, 7a,b, and 9a–c were designed, synthesized, and screened in vitro for their cytotoxic activity against 60 cancer cell lines by the National Cancer Institute, USA. Five candidates 4c, 6a, 6b, 6d, and 6g revealed promising cytotoxicity with significant percentage growth inhibition in the range of 81.98%–96.45% against the central nervous system (CNS) (SNB‐19), melanoma (MDA‐MB‐435), and non‐small cell lung cancer (HOP‐62) cell lines. The in vitro cytotoxic half maximal inhibitory concentration (IC50) values for the most active compounds 4c, 6a, 6b, 6d, and 6g against the most sensitive cell lines were evaluated. Additionally, screening their cyclin‐dependent kinase 2 (CDK2) inhibitory activity was performed. Ortho‐chloro‐benzylideneamino derivative 6b emerged as the most potent compound with IC50 = 0.67 µM compared to Roscovitine (IC50 = 0.64 µM). The most active candidates arrested the cell cycle at G1, S phases, or both, leading to cell death and inducing apoptosis against CNS (SNB‐19), melanoma (MDA‐MB‐435), and non‐small cell lung cancer (HOP‐62) cell lines. The molecular docking study verified the resulting outcomes for the most active candidates in the CDK2‐binding pocket. Finally, physicochemical, and pharmacokinetic properties deduced that compounds 4c, 6a, 6b, 6d, and 6g displayed significant drug‐likeness properties. According to the obtained results, the newly targeted compounds are regarded as promising scaffolds for the continued development of novel CDK2 inhibitors. [ABSTRACT FROM AUTHOR]

Background: Malignant melanoma is the most aggressive form of skin cancer with a rather poor prognosis. Standard chemotherapy often results in severe side effects on normal (healthy) cells finally being difficult to tolerate for the patients. Shown by us earlier, cerium oxide nanoparticles (CNP, nanoceria) selectively killed A375 melanoma cells while not being cytotoxic at identical concentrations on non-cancerous cells. In conclusion, the redox-active CNP exhibited both prooxidative as well as antioxidative properties. In that context, CNP induced mitochondrial dysfunction in the studied melanoma cells via generation of reactive oxygene species (primarily hydrogen peroxide (H2O2)), but that does not account for 100% of the toxicity. Aim: Cancer cells often show an increased glycolytic rate (Warburg effect), therefore we focused on CNP mediated changes of the glucose metabolism. Results: It has been shown before that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) activity is regulated via oxidation of a cysteine in the active center of the enzyme with a subsequent loss of activity. Upon CNP treatment, formation of cellular lactate and GAPDH activity were significantly lowered. The treatment of melanoma cells and melanocytes with the GAPDH inhibitor heptelidic acid (HA) decreased viability to a much higher extent in the cancer cells than in the studied normal (healthy) cells, highlighting and supporting the important role of GAPDH in cancer cells. Conclusion: We identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a target protein for CNP mediated thiol oxidation. [ABSTRACT FROM AUTHOR]

Background: Despite the higher sensitivity of melanoma towards ferroptosis and photodynamic therapy (PDT), the lack of efficient ferroptosis inducers and the poor solubility of photosensitizers restrict their synergistic strategies. With unique advantages, carbon dots (CDs) are expected to serve as innovative building blocks for combination therapy of cancers. Results: Herein, an ferroptosis/PDT integrated nanoplatform for melanoma therapy is constructed based on chlorin e6-modified Fe ions-doped carbon dots (Fe-CDs@Ce6). As a novel type of iron-carbon hybrid nanoparticles, the as-prepared Fe-CDs can selectively activate ferroptosis, prevent angiogenesis and inhibit the migration of mouse skin melanoma cells (B16), but have no toxicity to normal cells. The nano-conjugated structures facilitate not only the aqueous dispersibility of Ce6, but also the self-accumulation ability of Fe-CDs@Ce6 within melanoma area without requiring extra targets. Moreover, the therapeutic effects of Fe-CDs@Ce6 are synergistically enhanced due to the increased GSH depletion by PDT and the elevated singlet oxygen (1O2) production efficiency by Fe-CDs. When combined with laser irradiation, the tumor growth can be significantly suppressed by Fe-CDs@Ce6 through cyclic administration. The T2-weighted magnetic resonance imaging (MRI) capability of Fe-CDs@Ce6 also reveals their potentials for cancer diagnosis and navigation therapy. Conclusions: Our findings indicate the multifunctionality of Fe-CDs@Ce6 in effectively combining ferroptosis/PDT therapy, tumor targeting and MRI imaging, which enables Fe-CDs@Ce6 to become promising biocompatible nanoplatform for the treatment of melanoma. [ABSTRACT FROM AUTHOR]

Introduction: Uterine leiomyosarcoma is a rare gynecological malignancy, the limited literature indicated that doxorubicin alone or gemcitabine/docetaxel combination is the preferred chemotherapy regimen. Given the rarity of the disease and the lack of high-level clinical evidence, there is no consensus on the best treatment. Case report: We report a case of a patient with uterine leiomyosarcoma who recurred after adjustment treatment with doxorubicin, gemcitabine, docetaxel, and anlotinib; and required a new chemotherapy regimen. Management and outcomes: The follow-up chemotherapy regimen was doxorubicin-liposome 40 mg/m2 on one day in combination with dacarbazine 250 mg/m2 on one to five days of intravenous infusion every 21 days. We monitored adverse effects during chemotherapy and the process was smooth. Discussion: It is important to comprehensively consider the patient's condition, and fully consider the efficacy, dosage, and adverse reactions of the chemotherapy regimen to determine the appropriate plan, in order to achieve the best therapeutic benefits for patients. [ABSTRACT FROM AUTHOR]

Elevated genomic instability in cancer cells suggests a possible model-scenario for their selective killing via the therapeutic delivery of well-defined levels of further DNA damage. To examine this scenario, this study investigated the potential for redox modulation of oxidatively-induced DNA damage by ascorbate in malignant melanoma (MM) cancer cells, to selectively enhance both DNA damage and MM cell killing. DNA damage was assessed by Comet and ɣH2AX assays, intracellular oxidising species by dichlorofluorescein fluorescence, a key antioxidant enzymatic defence by assessment of catalase activity and cell survival was determined by clonogenic assay. Comet revealed that MM cells had higher endogenous DNA damage levels than normal keratinocytes (HaCaT cells); this correlated MM cells having higher intracellular oxidising species and lower catalase activity, and ranked with MM cell melanin pigmentation. Comet also showed MM cells more sensitive towards the DNA damaging effects of exogenous H 2 O 2 , and that ascorbate further enhanced this H 2 O 2 -induced damage in MM cells; again, with MM cell sensitivity to induced damage ranking with degree of cell pigmentation. Furthermore, cell survival data indicated that ascorbate enhanced H 2 O 2 -induced clonogenic cell death selectively in MM cells whilst protecting HaCaT cells. Finally, we show that ascorbate serves to enhance the oxidising effects of the MM therapeutic drug Elesclomol in both established MM cells in vitro and primary cell cultures ex vivo. Together, these results suggest that ascorbate selectively enhances DNA damage and cell-killing in MM cells. This raises the option of incorporating ascorbate into clinical oxidative therapies to treat MM. [Display omitted] • Malignant melanoma cells, MM: elevated oxidising species & endogenous DNA damage. • Levels of oxidising species and DNA damage correlate with MM cellular pigmentation. • Ascorbate enhances the generation of oxidatively induced DNA damage in MM. • Ascorbate leads to the selective killing of MM cells. • Ascorbate enhances the oxidising effects of Elesclomol in both in vitro and ex vivo. [ABSTRACT FROM AUTHOR]

In this research, ZIF-8 was synthesized and subsequently functionalized by 3-aminopropyltrimethoxysilane (APTES) as a carrier (ZIF-8@APTES) for montelukast sodium (MS). One of the aggressive cancers with a high fatality rate is melanoma. This study aimed to determine the potential cytotoxic effects of montelukast sodium (MS) on the B16F10 murine melanoma cell line as well as the therapeutic effects of MS combined with ZIF-8@APTES as a carrier. B16F10 cells were treated with different doses of ZIF-8@APTES-MS for 24, 48, and 72 h, and then the cytotoxic effect and antioxidant activity of these treatments were studied. Results indicated that after 48 and 72 h, B16F10 cell proliferation was reduced in a dose-dependent manner by MS and/or ZIF-8@APTES-MS. When MS is combined with ZIF-8@APTES, the IC50 concentration is lower than when MS is used alone. Furthermore, receiving 32 μg/ml ZIF-8@APTES-MS after 72 h significantly improved the total antioxidant activity (TAC) of B16F10 cells. In this research, the treatment of melanoma cells with MS and ZIF-8@APTES-MS was investigated. [ABSTRACT FROM AUTHOR]

Background: Cutaneous melanoma arises from skin melanocytes and has a high risk of metastatic spread. Despite better prevention, earlier detection, and the development of innovative therapies, melanoma incidence and mortality increase annually. Major clinical risk factors for melanoma include fair skin, an increased number of nevi, the presence of dysplastic nevi, and a family history of melanoma. However, several external inducers seem to be associated with melanoma susceptibility such as environmental exposure, primarily unprotected sun experience, alcohol consumption, and heavy metals. In recent years, epidemiological studies have highlighted a potential risk of β-hexachlorocyclohexane (β-HCH), the most studied organochlorine pesticide, causing cancer induction including melanoma. Methods: We evaluated in vitro the impact of this pollutant on epidermal and dermal cells, attempting to describe mechanisms that could render cutaneous cells more prone to oncogenic transformation. Results: We demonstrated that β-HCH impacts melanocyte biology with a highly cell-type specific signature that involves perturbation of AKT/mTOR and Wnt/β-catenin signaling, and AMPK activation, resulting in lowering energy reserve, cell proliferation, and pigment production. Conclusions: In conclusion, long-term exposure to persistent organic pollutants damages melanocyte metabolism in its function of melanin production with a consequent reduction of melanogenesis indicating a potential augmented skin cancer risk. [ABSTRACT FROM AUTHOR]

Upon conducting an investigation, the functionality of the smallest fullerene (C20) as a nano-carrier for the dacarbazine anticancer drug was thoroughly examined using density functional theory simulations. The adsorption energies obtained from the simulations indicate that the interaction of dacarbazine with C20 is indeed feasible under experimental conditions. Furthermore, the Natural Bond Orbital (NBO) analysis revealed that no chemical bond is formed between dacarbazine and the nanostructure, indicating that the interaction is purely a result of physisorption. Additionally, the results from the frontier molecular orbital analysis demonstrated a significant decrease in the bandgap of the fullerene by 44.469% to 4.967 eV. This reduction in bandgap suggests that C20 has the potential to serve as an ideal nanocarrier for the delivery of dacarbazine. Moreover, the values obtained for the dipole moment and chemical hardness further support the suitability of C20 as a nano-carrier for the delivery of dacarbazine. In conclusion, the findings from the density functional theory simulations provide compelling evidence for the potential use of C20 as an effective nano-carrier for the delivery of the dacarbazine anticancer drug. These results pave the way for further exploration and development of C20-based nanomaterials for drug delivery applications. [ABSTRACT FROM AUTHOR]

The coordination compounds of antineoplastic chemotherapy drug of dacarbazine (DAC) with Zn(II) ([Zn(DAC)2] 3H2O; NGDCM1) and Cu(II) ([Cu(DAC)ClH2O]; NGDCM2) were synthesized and characterized using analytical and spectroscopic techniques. The electrochemical behaviors of the obtained new compounds and the starting active substance DAC were examined in detail. The interaction of all compounds with fish sperm double-stranded deoxyribonucleic acid (FSdsDNA) was investigated by measuring their binding constant (Kb) to FSdsDNA. Also, the competitive binding fluorescence spectroscopy studies with ethidium bromide (EtBr) were carried out. Furthermore, both compound's anticancer activities were investigated on human lung cancer (A549) cells, and their effects were compared to other metals possessing antineoplastic drugs, including oxaliplatin and cisplatin. [ABSTRACT FROM AUTHOR]

Melanoma is the most aggressive and lethal type of skin cancer due to its characteristics such as high metastatic potential and low response rate to existing treatment modalities. In this way, new drug prototypes are being studied to solve the problem of treating patients with melanoma. Among these, ruthenium-based metallopharmaceuticals may be promising alternatives due to their antitumor characteristics and low systemic toxicity. In this context, the present study evaluated the antineoplastic effect of the ruthenium complex [Ru(mtz)(dppe)2]PF6-2-mercaptothiazoline-di-1,2-bis(diphenylphosphine) ethaneruthenium(II), namely RuMTZ, on human melanoma (A-375) and murine (B16-F10) cells, considering different approaches. Through XTT colorimetric and clonogenic efficiency assays, the complex revealed the selective cytotoxic activity, with the lowest IC50 (0.4 µM) observed for A375 cells. RuMTZ also induced changes in cell morphology, increased cell population in the sub-G0 phase and inhibiting cell migration. The levels of γH2AX and cleaved caspase 3 proteins were increased in both cell lines treated with RuMTZ. These findings indicated that the cytotoxic activity of RuMTZ on melanoma cells is related, at least in part, to the induction of DNA damage and apoptosis. Therefore, RuMTZ exhibited promising antineoplastic activity against melanoma cells. [ABSTRACT FROM AUTHOR]

This article, published in the Journal of Neurological Surgery, explores the presence of pigment incontinence in sinonasal mucosal melanoma (SNMM). The study conducted a retrospective chart review of patients diagnosed with SNMM at Thomas Jefferson University Hospital from 2007 to 2023. The results showed that pigment incontinence was present in 65% of patients, and regression was observed in 15 out of 17 patients. The study suggests that pigment incontinence can be a part of the natural tumor life cycle and may be mistaken for melanoma, especially after neoadjuvant therapy. Understanding these findings is important for diagnosis and clinical management of SNMM. [Extracted from the article]

This study explores the impact of antiretroviral administration on the expression of human endogenous retroviruses (HERVs), cell growth, and invasive capability of human melanoma cell lines in culture. We investigated three antiretrovirals—lamivudine, doravirine, and cabotegravir—in A375, FO-1, and SK-Mel-28, BRAF-mutated, and in MeWo, P53-mutated, melanoma cell lines. The findings indicate a general capability of these drugs to downregulate the expression of HERV-K Pol and Env genes and hinder cell viability, mobility, and colony formation capacity of melanoma cells. The antiretroviral drugs also demonstrate selectivity against malignant cells, sparing normal human epithelial melanocytes. The study reveals that the integrase inhibitor cabotegravir is particularly effective in inhibiting cell growth and invasion across different cell lines in comparison with lamivudine and doravirine, which are inhibitors of the viral reverse transcriptase enzyme. The investigation further delves into the molecular mechanisms underlying the observed effects, highlighting the potential induction of ferroptosis, apoptosis, and alterations in cell cycle regulatory proteins. Our findings showed cytostatic effects principally revealed in A375, and SK-Mel-28 cell lines through a downregulation of retinoblastoma protein phosphorylation and/or cyclin D1 expression. Signs of ferroptosis were detected in both A375 cells and FO-1 cells by a decrease in glutathione peroxidase 4 and ferritin expression, as well as by an increase in transferrin protein levels. Apoptosis was also detected in FO-1 and SK-Mel-28, but only with cabotegravir treatment. Moreover, we explored the expression and activity of the stimulator of interferon genes (STING) protein and its correlation with programmed death-ligand 1 (PD-L1) expression. Both the STING activity and PD-L1 expression were decreased, suggesting that the antiretroviral treatments may counteract the detrimental effects of PD-L1 expression activation through the STING/interferon pathway triggered by HERV-K. Finally, this study underscores the potential therapeutic significance of cabotegravir in melanoma treatment. The findings also raise the prospect of using antiretroviral drugs to downregulate PD-L1 expression, potentially enhancing the therapeutic responses of immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Unesbulin is being investigated in combination with dacarbazine (DTIC) as a potential therapeutic agent in patients with advanced leiomyosarcoma (LMS). This paper reports the pharmacokinetics (PK) of unesbulin, DTIC, and its unreactive surrogate metabolite 5‐aminoimidazole‐4‐carboxamide (AIC) in 29 patients with advanced LMS. Drug interactions between DTIC (and AIC) and unesbulin were evaluated. DTIC (1000 mg/m2) was administered to patients with LMS via 1‐h intravenous (i.v.) infusion on day 1 of every 21‐day (q21d) cycle. Unesbulin dispersible tablets were administered orally twice weekly (b.i.w.), starting on day 2 of every cycle, except for cycle 2 (C2), where unesbulin was dosed either on day 1 together with DTIC or on day 2, 1 day after DTIC administration. The PK of DTIC, AIC, and unesbulin in cycle 1 (C1) and C2 were estimated using noncompartmental analysis. DTIC and AIC were measurable immediately after the start of infusion and reached maximum plasma concentration (Cmax) immediately or shortly after end of infusion at 1.0 and 1.4 h (time to Cmax), respectively. Co‐administration of unesbulin orally at 200 mg or above with DTIC inhibited cytochrome P450 (CYP)1A2‐mediated DTIC metabolism, resulting in 66.7% reduction of AIC exposures. Such inhibition could be mitigated when unesbulin was dosed the day following DTIC infusion. Repeated unesbulin dosing demonstrated evidence of clinical CYP1A2 induction and increased AIC Cmax by 69.4% and area under concentration‐time curve to infinity by 57.9%. No meaningful difference in unesbulin PK was observed between C2 and C1. The combination therapy of 1000 mg/m2 i.v. DTIC q21d and 300 mg unesbulin b.i.w. in a staggered regimen is well‐tolerated in patients with LMS. [ABSTRACT FROM AUTHOR]

Betulinic acid is a naturally occurring pentacyclic triterpene belonging to the lupane-group that exhibits a wide range of pharmacological activities. BA derivatives are continuously being researched due to their improved anticancer efficacy and bioavailability. The current research was conducted in order to determine the antiproliferative potential of three synthesized BA fatty esters using palmitic, stearic and butyric acids and their liposomal nanoformulations. The cytotoxic potential of BA fatty esters (Pal-BA, St-BA, But-BA) and their respective liposomal formulations (Pal-BA-Lip, St-BA-Lip, But-BA-Lip) has been assessed on HaCaT immortalized human keratinocytes and A375 human melanoma cells. Both the esters and their liposomes acted as cytotoxic agents against melanoma cells in a time- and dose-dependent manner. The butyryl ester But-BA outperformed BA in terms of cytotoxicity (IC50 60.77 μM) while the nanoformulations St-BA-Lip, But-BA-Lip and BA-Lip also displayed IC50 values (60.11, 50.71 and 59.01 μM) lower compared to BA (IC50 65.9 μM). The morphological evaluation revealed that the A375 cells underwent morphological changes consistent with apoptosis following 48 h treatment with the tested compounds, while the HaCaT cells' morphology remained unaltered. Both the esters and their liposomal formulations were able to inhibit the migration of the melanoma cells, suggesting a significant antimetastatic effect. The quantitative real-time PCR revealed that all tested samples were able to significantly increase the expression of the pro-apoptotic Bax and inhibit the anti-apoptotic Bcl-2 proteins. This effect was more potent in the case of liposomal nanoformulations versus non-encapsulated compounds, and overall, But-BA and its formulation exhibited the best results in this regard. [ABSTRACT FROM AUTHOR]

AbstractCancer, the biggest cause of death globally, remains a tough illness despite enormous advances in therapy. In the present study, 1,3-benzodioxole-tagged dacarbazine derivates were investigated as microtubule inhibitors in order to control cancer as microtubules are involved in cell proliferation. The tubulin protein was analyzed and its structure was validated by various protein validation tools. The binding potential of 1,3-benzodioxole-based dacarbazine-tagged derivatives with tubulin was checked using molecular docking software HEX 8.0 CUDA and AutoDock Vina. Swiss ADME online Web server and pkCSM are used for studying pharmacokinetic and pharmacological studies of compounds. The docking analysis ADME studies displayed that Compounds 1 and 2 bind effectively with the tubulin protein and showed potential properties to use as a potent anticancer drug.

Transdermal drug delivery has been regarded as an alternative to oral delivery and subcutaneous injection. However, needleless transdermal delivery of biomacromolecules remains a challenge. Herein, a transdermal delivery platform based on biocompatible fluorocarbon modified chitosan (FCS) is developed to achieve highly efficient non-invasive delivery of biomacromolecules including antibodies and antigens. The formed nanocomplexes exhibits effective transdermal penetration ability via both intercellular and transappendageal routes. Non-invasive transdermal delivery of immune checkpoint blockade antibodies induces stronger immune responses for melanoma in female mice and reduces systemic toxicity compared to intravenous injection. Moreover, transdermal delivery of a SARS-CoV-2 vaccine in female mice results in comparable humoral immunity as well as improved cellular immunity and immune memory compared to that achieved with subcutaneous vaccine injection. Additionally, FCS-based protein delivery systems demonstrate transdermal ability for rabbit and porcine skins. Thus, FCS-based transdermal delivery systems may provide a compelling opportunity to overcome the skin barrier for efficient transdermal delivery of bio-therapeutics. Different approaches have been described for the transdermal delivery of drugs. Here the authors report the design of a fluorocarbon modified chitosan-based non-invasive transdermal platform for the delivery of biomacromolecules, such as viral antigens for vaccines or immune checkpoint inhibitors for melanoma immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Advanced soft tissue sarcomas (aSTSs) have scarce treatment options due to their low incidence, being considered by the World Health Organization as a rare disease; low investment by principal actors in trial designs; and high variability in treatment responses. The combination of gemcitabine and dacarbazine has been demonstrated to be effective in aSTSs in terms of progression-free survival and overall survival in three phase I–II clinical trials. Some pathological, clinical, and analytical variables have been analyzed as possible prognostic and predictive factors, providing a clue for clinicians to select the most optimal treatment in this setting. Background: The combination of gemcitabine and dacarbazine has exhibited efficacy in terms of progression-free survival (PFS) and overall survival (OS) for aSTSs, albeit without robust confirmation from larger clinical trials. Methods: We conducted a retrospective study in a single institution involving aSTS patients treated with gemcitabine and dacarbazine. Results: 95 patients were assessed, pointing to a benefit in PFS of 3.5 months and an OS of 14.2 months. Patients with translocated histotypes had better PFS, while those with platelet–lymphocyte ratios (PLRs) surpassing a specific threshold or lower albumin levels had poorer overall survival. Conclusions: This study validates previous findings from three phase I–II trials, affirming the utility of this treatment approach in routine clinical practice. [ABSTRACT FROM AUTHOR]

Background: Melanoma, the most lethal skin cancer type, occurs more frequently in Parkinson's disease (PD), and PD is more frequent in melanoma patients,suggesting disease mechanisms overlap. α-synuclein, a protein that accumulates in PD brain, and the oncogene DJ-1, which is associated with PD autosomal recessive forms, are both elevated in melanoma cells. Whether this indicates melanoma progression or constitutes a protective response remains unclear. We hereby investigated the molecular mechanisms through which α-synuclein and DJ-1 interact, suggesting novel biomarkers and targets in melanoma. Methods: The Cancer Genome Atlas (TCGA) expression profiles derived from UCSC Xena were used to obtain α-synuclein and DJ-1 expression and correlated with survival in skin cutaneous melanoma (SKCM). Immunohistochemistry determined the expression in metastatic melanoma lymph nodes. Protein–protein interactions (PPIs) and molecular docking assessed protein binding and affinity with chemotherapeutic drugs. Further validation was performed using in vitro cellular models and ELISA immunoassays. Results: α-synuclein and DJ-1 were upregulated in primary and metastatic SKCM. Aggregated α-synuclein was selectively detected in metastatic melanoma lymph nodes. α-synuclein overexpression in SK-MEL-28 cellsinduced the expression of DJ-1, supporting PPI and a positive correlation in melanoma patients. Molecular docking revealed a stable protein complex, with differential binding to chemotherapy drugs such as temozolomide, dacarbazine, and doxorubicin. Parallel reduction of both proteins in temozolomide-treated SK-MEL-28 spheroids suggests drug binding may affect protein interaction and/or stability. Conclusion: α-synuclein, together with DJ-1, may play a role in melanoma progression and chemosensitivity, constituting novel targets for therapeutic intervention, and possible biomarkers for melanoma. [ABSTRACT FROM AUTHOR]

Non-invasive image-guided precise photothermal/photodynamic therapy (PTT/PDT) has been proven to be an effective local treatment modality but incompetent against metastases. Hence, the combination of local PTT/PDT and systemic immunotherapy would be a promising strategy for tumor eradication. Herein, a magnetic resonance imaging (MRI)-visualized PTT/PDT agent (SIDP NMs) was constructed, and the efficacy of its multimodal combination with a programmed cell death 1 (PD-1) inhibitor in the treatment of melanoma and metastases was studied. Due to the hydrophobic encapsulation of indocyanine green within the micellar core, SIDP NMs exhibited excellent photothermal/photodynamic properties and stability under an 808 nm near-infrared laser. In vitro cell experiments showed that SIDP NMs had a good killing effect. After incubating with B16-F10 cells for 24 h and irradiating with an 808-nm laser for 10 min, cell viability decreased significantly. Magnetic resonance imaging experiments in melanoma-bearing mice have shown that the dynamic distribution of SIDP NMs in tumor tissue could be monitored by T 2WI and T 2-MAP non-invasively due to the presence of superparamagnetic iron oxide nanocrystal in SIDP NMs. When the 808 nm laser was irradiated at the maximum focusing time point shown by MRI, the temperature of the tumor area rapidly increased from 32°C to 60.7°C in 5 min. In mouse melanoma ablation and distant tumor immunotherapy studies, SIDP NMs provided excellent MRI-guided PTT/PDT results and, when combined with PD-1 inhibitor, have great potential to cure primary tumors and eradicate metastases. [ABSTRACT FROM AUTHOR]

Background: The causation of Glycemic Traits and risks of Melanoma remains unknown. We used Mendelian Randomization (MR) to assess the links between Glycemic Traits and Melanoma. Method: Pooled data from Genome-Wide Association Studies (GWAS) were utilized to examine the relationships that exist between Fasting Insulin (n = 26), 2-h Glucose (n = 10), Fasting Glucose (n = 47), HbA1c (n = 68), and Type-2 Diabetes (n = 105) and Melanoma. We evaluated the correlation of these variations with melanoma risk using Two-Samples MR. Result: In the IVW model, Fasting Glucose (OR = 0.99, 95%CI = 0.993-0.998, p < 0.05, IVW), Type-2 Diabetes (OR = 0.998, 95%CI = 0.998-0.999, p < 0.01, IVW) and HbA1c (OR = 0.19, 95%CI = 0.0415-0.8788, p < 0.05, IVW) was causally associated with a lower risk of Melanoma. In all models analyzed, there was no apparent causal relationship between Fasting Insulin and Melanoma risk. There was no obvious causal difference in the IVW analysis of 2-h Glucose and Melanoma, but its p < 0.05 in MR Egger (OR = 0.99, 95%CI = 0.9883-0.9984, p < 0.05, MR Egger), and the direction was consistent in other MR analyses, suggesting that there may be a causal relationship. Conclusion: The results of this study suggest that a higher risk of Fasting Glucose, Type-2 Diabetes, 2-h Glucose, and HbA1c may be associated with a lower risk of Melanoma. However, no causal relationship between fasting insulin and melanoma was found. These results suggest that pharmacological or lifestyle interventions that regulate plasma glucose levels in the body may be beneficial in the prevention of melanoma. [ABSTRACT FROM AUTHOR]

Skin cancer, ranked as the fifth most prevalent cancer, is a rising health threat, emphasizing the need for innovative treatments. Genetic mutations cause skin cell abnormalities leading to various cancers, especially melanoma. Current treatments, such as radiation therapy and chemotherapy, have limitations, necessitating advancements in technology and therapy. Early detection is crucial for effective intervention, and diagnostic methods encompass blood tests, imaging, biopsies, and genetic tests, followed by staging to determine disease severity. This review focuses on herbal remedies from medicinal plants like ursolic acid, genistic acid, luteolin, curcumin, and others, demonstrating anti-cancer properties in inhibiting proliferation and modulating molecular processes. Studies, primarily in vitro and animals, offer insights into their potential for skin cancer prevention. The review synthesizes diverse literature, providing nuanced insights into herbal remedies' molecular mechanisms for innovative therapeutic approaches. Emphasizing the importance of human trials, particularly for compounds like ursolic acid and genistic acid, is crucial for validating efficacy and safety. Herbal remedies align with WHO recommendations, holding promise for more effective and holistic skin cancer treatments. Ongoing research supports the integration of these compounds into treatment protocols, marking a hopeful frontier in combatting this pervasive disease. [ABSTRACT FROM AUTHOR]

Gold nanostars (GNSs) as a photothermal agent have shown great potential for the treatment of cancers like melanoma. Irradiation of the photothermal agents with light of a suitable wavelength generates heat that induces cellular stress and protein denaturation in cancer cells. The delivery of GNSs to skin using fast dissolving microneedles (MNs) presents a promising approach for painless and convenient administration of the therapy. In this study, polyethylene glycol (PEG) stabilized GNSs able to absorb light in the near‐infra red region and release heat (up to 65 °C, room temperature) are developed. The cytotoxicity of these nanoparticles is assessed before and after exposure to laser irradiation. GNSs show an instant lethal photothermal effect when tested on B16F10 melanoma cells upon irradiation with 808 nm at a power of 800 mW for 10 min. Loading the GNSs in polyvinylpyrrolidone (PVP) MNs preserves the photothermal effect of GNS and the mechanical properties of MNs. GNS‐loaded PVP MNs show efficient piercing in excised porcine skin, fast dissolution in 3 min after insertion and elevation of the skin temperature after laser irradiation (808 nm, 800 mW, 10 min) to 63 °C. Consequently, PEG‐stabilized GNSs and PVP MNs are a promising platform for photothermal therapy in melanoma treatment. [ABSTRACT FROM AUTHOR]

Quaternary ammonium surfactants, due to their diverse chemical structure and their biological properties, can be used in medicine as DNA carriers, disinfectants, and antimicrobial and antitumor agents. In this study, using melanoma A375, colon adenocarcinoma HT-29 and normal human dermal fibroblast (NHDF) cells, we tested the hypothesis that the quaternary ammonium surfactants 2-dodecanoyloxyethyl)trimethylammonium bromide (DMM-11), 2-dodecanoyloxypropyl)trimethylammonium bromide (DMPM-11) and 2-pentadecanoyloxymethyl)trimethylammonium bromide (DMGM-14) act selectively against cancer cells. The results showed that these compounds led to the initiation of the apoptotic process of programmed cell death, as evidenced by the ratio of the relative expression of Bax protein to Bcl-2. The encapsulation of surfactants in liposomes allowed lower concentrations to be used. Moreover, encapsulation reduced their toxicity towards non-cancerous cells. The anticancer efficiency and apoptotic effect of the liposomal formulations with surfactants (DMM-11, DMPM-11 and DMGM-14) were higher than those of surfactant-free liposomes. Therefore, quaternary ammonium surfactant-loaded liposomes show significant potential as delivery vehicles for the treatment of melanoma and colon cancers. The use of nano-formulations offers the advantage of optimizing quaternary ammonium surfactant delivery for improved anticancer therapy. [ABSTRACT FROM AUTHOR]

Plant proteins have become attractive for biomedical applications such as wound dressing and drug delivery. In this research, nanofibers from pristine zein (plant protein) and zein loaded with tungsten oxide (WO3) were prepared (WO3@zein) using less toxic solvents (ethanol and acetic acid). Morphological and biological properties of the zein nanofiber were determined. Prepared nanofibers were defined by thermogravimetric analysis (TGA), X-ray diffraction (X-RD), Fourier-transform infrared spectroscopy (FT-IR), and scanning electron microscopy. The average fiber diameter was unchanged with an increase in WO3 concentration from 0.001 to 0.008%. FT-IR spectroscopy and X-RD indicated the presence of WO3 in WO3@zein nanofibers. In comparison to WO3-free, WO3@zein nanofibers showed higher safety and preserved the anticancer effect of WO3 against human melanoma cell line (A375) melanoma cells compared to WO3-free. Moreover, both WO3-free and WO3@zein caused a fourfold increase in the cellular proliferation of reactive oxygen species (ROS) in the treated A375 cells compared to untreated cells. ROS elevation led to apoptosis-dependent cell death of A375 cells as evidenced by up-regulating the expression of p53-downstream genes (p21 and Bax) (tumor-suppressor gene) while down-regulating the expression of key oncogenes (BCL2 and cyclin D). In conclusion, the prepared nanofiber represents a promising and safe candidate for anticancer applications. [ABSTRACT FROM AUTHOR]

Enzyme‐prodrug therapies have shown unique advantages in efficiency, selectivity, and specificity of in vivo prodrug activation. However, precise spatiotemporal control of both the enzyme and its substrate at the target site, preservation of enzyme activity, and in situ substrate depletion due to low prodrug delivery efficiency continue to be great challenges. Here, we propose a novel core–shell reactor partitioning enzyme and prodrug by ZIF‐8, which integrates an enzyme with its substrate and increases the drug loading capacity (DLC) using a prodrug as the building ligand to form a Zn‐prodrug shell. Cytochrome P450 (CYP450) is immobilized in ZIF‐8, and the antitumor drug dacarbazine (DTIC) is coordinated and deposited in its outer layer with a high DLC of 43.6±0.8 %. With this configuration, a much higher prodrug conversion efficiency of CYP450 (36.5±1.5 %) and lower IC50 value (26.3±2.6 μg/mL) are measured for B16‐F10 cells with a higher NADPH concentration than those of L02 cells and HUVECs. With the tumor targeting ability of hyaluronic acid, this core–shell enzyme reactor shows a high tumor suppression rate of 96.6±1.9 % and provides a simple and versatile strategy for enabling in vivo biocatalysis to be more efficient, selective, and safer. [ABSTRACT FROM AUTHOR]