Ruthenium(II) complex with 2-mercaptothiazoline ligand induces selective cytotoxicity involving DNA damage and apoptosis in melanoma cells.

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.

Efficacy and safety of guttiferone E in melanoma-bearing mice.

Melanoma, an aggressive and potentially fatal skin cancer, is constrained by immunosuppression, resistance, and high toxicity in its treatment. Consequently, there is an urgent need for innovative antineoplastic agents. Therefore, this study investigated the antimelanoma potential of guttiferone E (GE). In an allogeneic murine B16 melanoma model, GE was administered subcutaneously and intraperitoneally. Antitumor evaluation included tumor volume/weight measurements and histopathological and immunohistochemical analysis. Furthermore, the toxicity of the treatments was evaluated through body/organ weights, biochemical parameters, and genotoxicity. Subcutaneous administration of 20 mg/kg of GE resulted in a significant reduction in both tumor volume and weight, effectively suppressing melanoma cell proliferation as evidenced by a decrease in mitotic figures. The tumor growth inhibition rate was equivalent to 54%. This treatment upregulated cleaved caspase-3, indicating apoptosis induction. On the other hand, intraperitoneal administration of GE showed no antimelanoma effect. Remarkably, GE treatments exhibited no toxicity, evidenced by non-significant differences in body weight gain, as well as organ weight, biochemical parameters of nephrotoxicity and hepatotoxicity, and genotoxic damage. This study revealed, for the first time, the efficacy of subcutaneous administration of GE in reducing melanoma, in the absence of toxicity. Furthermore, it was observed that the apoptotic signaling pathway is involved in the antimelanoma property of GE. These findings offer valuable insights for further exploring GE's therapeutic applications in melanoma treatment.

Analise de custo por resposta de adalimumabe, etanercepte, guselcumabe, infliximabe, ixequizumabe, secuquinumabe e ustequinumabe para tratamento de psoríase em placas moderada a grave sob a perspectiva do Sistema de Saúde Suplementar brasileiro / Cost per response analysis of adalimumab, etanercept, guselkumab, infliximab, ixekizumab, secukinumab and ustekinumab for the treatment of moderate to severe plaque psoriasis from the Brazilian private health care system perspective

O OBJETIVO: deste estudo é avaliar o custo por resposta das terapias biológicas disponíveis no Brasil para o tratamento da psoríase em placas moderada a grave na perspectiva do Sistema de Saúde Suplementar. MÉTODOS: A resposta PASI 90 foi o desfecho avaliado neste estudo. Dados clíni-cos foram calculados com base na razão de risco de uma metanálise em rede, comparando adalimu-mabe, etanercepte, infliximabe, ixequizumabe, secuquinumabe e ustequinumabe a guselcumabe, cujo dado foi obtido no estudo clínico. Foram considerados apenas os custos de medicamentos. O caso-base avaliou o custo por resposta do ano de indução do tratamento. Além disso, conduziu-se uma análise de orçamento fixo. Em um cenário alternativo, analisou-se o custo por resposta do ano de manutenção. Uma análise de sensibilidade avaliou incertezas dos dados clínicos. RESULTADOS: O menor custo por resposta foi de guselcumabe (R$ 98.643), seguido de ixequizumabe (R$ 112.549), ustequinumabe (R$ 124.078), secuquinumabe (R$ 160.930), infliximabe (R$ 208.039), adalimumabe (R$ 208.686) e etanercepte (R$ 639.124). Resultados similares foram observados no cenário alterna-tivo, considerando os custos no ano de manutenção. Guselcumabe demonstrou ser a terapia que tratou mais pacientes com sucesso, considerando um cenário de orçamento fixo. Conclusão: O presente estudo demonstrou que, na perspectiva do Sistema de Saúde Suplementar brasileiro, gu-selcumabe possui o menor custo por resposta entre as terapias biológicas para psoríase em placas moderada a grave, além de tratar com sucesso mais pacientes em um cenário de orçamento fixo.

Objective: This study aims to evaluate the cost per response of the biologic therapies available for moderate to severe plaque psoriasis treatment in Brazil from a private payer perspective Methods: Treatment response evaluated in this study was the achievement of PASI 90. Clinical data was calculated based on the risk ratio of a network meta-analysis comparing adalimumab, etanercept, infliximab, ixekizumab, secukinumab and ustekinumab to guselkumab, which data was extracted from clinical trials. Only drug acquisition cost were considered. Base case analysis evaluated the first year of treatment cost per response Besides that, a fixed budget analysis was conducted. An alternative scenario analysis considered the maintenance year cost per response. A sensitivity analysis evaluated the clinical data uncertainties. Results: The lowest cost per response was obtained with guselkumab (R$98.643), followed by ixekizumab (R$ 112.549), ustekinumab (R$ 124.078), secukinumab (R$ 160.930), infliximab (R$ 208.039), adalimumab (R$ 208.686), and etanercept (R$ 639.124). Similar results were found in the alternative scenario, with maintenance year costs. Guselkumab demonstrated to be the therapy which successfully treats more patients with a fixed budget. Conclusion: In conclusion, this study demonstrated that, from the Brazilian private payer perspective, guselkumab presents the lowest cost per response among the avail-able biologic therapies for moderate to severe plaque psoriasis, and is able to successfully treat more patients in a limited budget scenario.

Screw loosening of different UCLA-type abutments after mechanical cycling

AIM: To evaluate the loss of applied torque (detorque) values in cast and pre-machined abutments for external hex abutment/implant interface of single implant-supported prostheses subjected to mechanical cycling. METHODS: Ten metal crowns were fabricated using two types of UCLA abutments: cast and pre-machined with metal base in NiCrTi alloy and tightened to regular external hex implants with a titanium alloy screw, with an insertion torque of 32 N.cm, measured with a digital torque gauge. Samples were embedded with autopolymerizing acrylic resin in a stainless steel cylindrical matrix, and positioned in an electromechanical machine. Dynamic oblique loading of 120 N was applied during 5 x 10(5) cycles. Then, each sample was removed from the resin and detorque values were measured using the same digital torque gauge. The difference of the initial (torque) and final (detorque) measurement was registered and the results were expressed as percentage of initial torque. The results of torque loss were expressed as percentage of the initial torque and subjected to statistical analysis by the Student's t-test (p<0.05) for comparisons between the test groups. RESULTS: Statistical analysis demonstrated that mechanical cycling reduced the torque of abutments without significant difference between cast or pre-machined UCLA abutments (p=0.908). CONCLUSIONS: Within the limitations of this in vitro study, it may be concluded that the mechanical cycling, corresponding to one-year use, reduced the torque of the samples regardless if cast or pre-machined UCLA abutments were used.

Abutment rotational freedom evaluation of external hexagon single-implant restorations after mechanical cycling.

PURPOSE: The purpose of this study was to evaluate the rotational freedom between implant and abutment counterpart of two abutments types over external hexagon implants submitted to mechanical cycling. MATERIALS AND METHODS: Ten implants with external hexagon (3.75 mm × 13 mm), five cast abutments, and five premachined abutments both with 4.1 mm plataform size were used in this study. Ten metallic crowns were fabricated using the two types of abutments and were fixed to each implant using titanium screws (Ti6Al4V). Rotational freedom measurements were made before and after the cast procedure and after the mechanical cycling. Groups were classified according to the rotational misfit register using University of California, Los Angeles abutment and implants as new (group 1 = G1); using crowns and implants after crown casting (group 2 = G2); and using crowns and implants after mechanical cycling (group 3 = G3). Oblique loading of 120N at 1.8 Hz and 5 × 10(5) cycles was applied on specimen. RESULTS: Statistical analysis (p < .05) showed that no significant difference was observed when cast abutment was compared with premachined abutment after casting (p = .390) and mechanical cycling (p = .439); however, significant difference was noted before the casting (p = .005) with higher values for the cast abutments. CONCLUSIONS: Within the limitations of this in vitro study, it could be concluded that the abutment type used do not influenced the rotational freedom after casting and the amount of applied cycles (500,000 cycles) was not sufficient to significantly alter the values of rotational freedom at the implant/abutment joint.

Bone response to three different chemical compositions of fluorcanasite glass-ceramic.

The aim of this study was to evaluate the bone response to three fluorcanasite glass-ceramic compositions with different solubilities (K3, K5, and K8) after implantation in a femur rabbit model. Fluorcanasite glass-ceramic rods were implanted bilaterally in the mid-shafts rabbit femurs. Implants were harvested at 8 and 12 weeks and prepared for histological and histomorphometric analyses at the light microscope level. Bioglass 45S5 rods were used as a control material. At 8 weeks, all fluorcanasite glass-ceramics were entirely surrounded by a nonmineralized connective tissue. At 12 weeks, reduced areas of bone tissue were observed in the cortical area in direct contact with the K3 and K5 fluorcanasite glass-ceramics compared to Bioglass 45S5, whereas no bone tissue was observed in direct contact with the K8 surface. Bone-to-implant contact in the cortical area was affected by the material chemical composition and ranked as follows: Bioglass 45S5>K3>K5>K8 (p=0.001). In the bone marrow, a layer of fibrous connective tissue formed in direct contact with the fluorcanasite glass-ceramics and Bioglass 45S5, and only rarely exhibited contact osteogenesis. All the fluorcanasite glass-ceramics appeared to degrade in the biological environment. The solubility ratio did not alter significantly the biological reply of the fluorcanasite glass-ceramics in vivo. Further modifications of the chemical composition of the fluorcanasite glass-ceramic are required to increase the stability of the material in vivo.