Daniel Augusto Barnabé Nobre

Targeted therapies have substantially advanced cancer treatment; however, therapeutic resistance remains a major challenge, particularly in lung cancer. Polo-like kinase 1 (PLK-1), a key regulator of mitosis, is frequently overexpressed in lung tumors and has emerged as an attractive anticancer target. Although PLK-1 inhibition induces robust antitumor effects in preclinical models, its translation into clinical benefit has been limited, particularly when used as monotherapy. Previous in vitro work from our group demonstrated that combining PLK-1 inhibition with the pro-apoptotic agent Navitoclax markedly enhanced cancer cell death by reducing mitotic slippage and promoting post-mitotic apoptosis. Here, we investigated whether this combinatorial strategy translates into therapeutic benefit in vivo. Using Lewis lung carcinoma (LLC1) cells, we evaluated the effects of BI2536 (a PLK-1 inhibitor) and Navitoclax, alone or in combination, in vitro and in male C57BL/6J mice using three lung cancer models: subcutaneous, intranasal, and intrapulmonary. The in vitro results corroborated the findings of our previous work, demonstrating synergistic effects. In the murine models, tumor progression, body weight, survival, and histopathological features were assessed to evaluate therapeutic efficacy and systemic toxicity. In the subcutaneous model, BI2536 monotherapy significantly reduced tumor volume compared with vehicle-treated controls, while Navitoclax alone and the combination therapy also produced tumor growth inhibition. In contrast, in the intranasal model, no significant differences were observed in body weight or survival among groups. Nonetheless, treatment with BI2536 alone or in combination with Navitoclax significantly reduced tumor cell proliferative activity. In the aggressive intrapulmonary (orthotopic) model, rapid disease progression and high mortality were observed across all groups. Notably, BI2536 treatment was associated with improved survival compared with Navitoclax monotherapy, whereas the combination therapy did not confer additional survival benefit. Histological analyses revealed highly proliferative tumors with pronounced cellular and nuclear atypia. Moreover, the BI2536 monotherapy group exhibited significantly greater necrosis/apoptosis than the other treatment groups, while diffuse and focal hepatic steatosis was observed exclusively in the combination group. Together, these findings indicate that while PLK-1 inhibition exerts antitumor effects in certain in vivo contexts, the therapeutic synergy observed in vitro with Navitoclax does not consistently translate to in vivo lung cancer models. This study highlights the challenges of translating combinatorial mitotic and apoptotic targeting strategies into effective in vivo therapies and underscores the importance of model selection and tumor microenvironment in preclinical drug evaluation.

This study aimed to investigate the clinicopathological characteristics of thrombi in the oral and maxillofacial region. A cross-sectional study was conducted in nine reference centers for oral and maxillofacial pathology diagnosis in Brazil, from which biopsy records were obtained. The data were analyzed descriptively. A total of 93,036 biopsies from the oral and maxillofacial region were evaluated, 187 (0.2%) of which were diagnosed as thrombi. The highest occurrence was in females, with a mean age of 52.4 ± 17.7 years. The lip was the most frequently affected anatomical location. A clinical diagnostic hypothesis of thrombus was considered in 4.2% of cases. Oral thrombi were uncommon lesions in the studied population, with a higher occurrence among females in the seventh decade of life. This study provides a clinicopathological profile of oral and maxillofacial thrombi and offers information that may assist clinicians in establishing a diagnosis.

Background: This study evaluated the presence of Epstein-Barr virus type 1 (EBV-1) DNA in patients living with HIV, before and after three different topical therapy protocols for oral hairy leukoplakia (OHL). Methods: The sample consisted of five patients treated with topical solution of 25% podophyllin resin; six with 25% podophyllin resin plus 5% acyclovir cream; and four with 25% podophyllin resin plus 1% penciclovir cream. DNA was extracted from OHL scrapings and amplified by the PCR using specific primers for EBV-1 (EBNA-1). Results: Clinical healing of OHL lesions was observed across all treatment groups over time. At baseline, EBNA-1 was detected in all OHL lesions. After treatment, OHL samples from three patients treated with 25% podophyllin resin plus 5% acyclovir cream and from one patient treated with 25% podophyllin resin plus 1% penciclovir cream exhibited negative EBNA-1 viral gene encoding. Despite the clinical resolution of OHL, 11 patients (73.3%) showed EBNA-1 positivity immediately after the lesion disappeared. Three patients (20%) treated with podophyllin resin displayed both EBNA-1 positivity and a recurrence of OHL, in contrast to no recurrence in the other two groups. Conclusions: These findings suggest potential associations between treatment formulations, EBNA-1 persistence, and the recurrence of OHL lesions.

For the first time, compounds developed from the 1,2,3‐triazole scaffold were evaluated as novel drugs to treat triple‐negative breast cancer (TNBC). Four organic salts were idealized as nonclassical bioisosteres of miltefosine, which is used in the topical treatment for skin metastasizing breast carcinoma. Among them, derivative dhmtAc displayed better solubility and higher cytotoxicity against the human breast adenocarcinoma cell line and mouse 4T1 cell lines, which are representatives of TNBC. In vitro assays revealed that dhmtAc interferes with cell integrity, confirmed by lactate dehydogenase leakage. Due to its human peripheral blood mononuclear cell (PBMC) toxicity, dhmtAc in vivo studies were carried out with the drug incorporated in a long‐circulating and pH‐sensitive liposome (SpHL‐dhmtAc), and the acute toxicity in BALB/c mice was determined. Free dhmtAc displayed cardiac and pulmonary toxicity after the systemic administration of 5 mg/kg doses. On the other hand, SpHL‐dhmtAc displayed no toxicity at 20 mg/kg. The in vivo antitumor effect of SpHL‐dhmtAc was investigated using the 4T1 heterotopic murine model. Intravenous administration of SpHL‐dhmtAc reduced the tumor volume and weight, without interfering with the body weight, compared with the control group and the dhmtAc free form. The incorporation of the triazole compound in the liposome allowed the demonstration of its anticancer potential. These findings evidenced 1,3,4‐trisubstituted‐1,2,3‐triazole as a promising scaffold for the development of novel drugs with applicability for the treatment of patients with TNBC.