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Anaplastic thyroid cancer (ATC) is an aggressive form of thyroid cancer (TC), accounting for 50% of total TC-related deaths. Although therapeutic approaches against TC have improved in recent years, the survival rate remains low, and severe adverse effects are commonly reported. However, unexplored alternatives based on natural compounds, such as lysicamine, an alkaloid found in plants with established cytotoxicity against breast and liver cancers, offer promise. Therefore, this study aimed to explore the antineoplastic effects of lysicamine in papillary TC (BCPAP) and ATC (HTH83 and KTC-2) cells. Lysicamine treatment reduced cell viability, motility, colony formation, and AKT activation while increasing the percentage of necrotic cells. The absence of caspase activity confirmed apoptosis-independent cell death. Necrostatin-1 (NEC-1)-mediated necrosome inhibition reduced lysicamine-induced necrosis in KTC-2, suggesting necroptosis induction via a reactive oxygen species (ROS)-independent mechanism. Additionally, in silico analysis predicted lysicamine target proteins, particularly those related to MAPK and TGF-ß signaling. Our study demonstrated lysicamine's potential as an antineoplastic compound in ATC cells with a proposed mechanism related to inhibiting AKT activation and inducing cell death.

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In this study, five neolignans were isolated from Saururus cernuus-threo-dihydroguaiaretic acid (1), threo-austrobailignan-6 (2), threo-austrobailignan-5 (3), verrucosin (4), and saucernetin (5)-and have their cytotoxic effects evaluated in prostate cancer cell lines (PC3 and DU145). Initially, using an in silico approach, tested compounds were predicted to be absorbed by the gastrointestinal tract, be able to permeate the blood-brain barrier and did not show any alert in PAINS (pan-assay structures interference). In vitro assays showed that compounds 2, 4, and 5 reduced cell viability of DU145 cell line at 100 µmol/L after 48 h while compounds 1 and 3 showed to be inactive at the same conditions. Furthermore, compounds 4 and 5 reduced cell number as early as in 24 h at 50 µmol/L and compound 2 showed effects at 100 µmol/L in 24 h against both cancer cell lines PC3 and DU145. Studies using flow cytometry were conducted and indicated that compound 4 induced strong necrosis and apoptosis whereas compound 5 induced strong necrosis. Otherwise, less active compound 2 did not show evidence of induction of apoptosis or necrosis, suggesting that its mechanism of action involves inhibition of cell proliferation. In conclusion, compounds 4 and 5 have been shown to be promising cytotoxic agents against prostate cancer cell lines and can be used as a starting point for the development of new drugs for the treatment of prostate cancer.

Assuntos

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Adenovirus was first identified in the 1950s and since then this pathogenic group of viruses has been explored and transformed into a genetic transfer vehicle. Modification or deletion of few genes are necessary to transform it into a conditionally or non-replicative vector, creating a versatile tool capable of transducing different tissues and inducing high levels of transgene expression. In the early years of vector development, the application in monogenic diseases faced several hurdles, including short-term gene expression and even a fatality. On the other hand, an adenoviral delivery strategy for treatment of cancer was the first approved gene therapy product. There is an increasing interest in expressing transgenes with therapeutic potential targeting the cancer hallmarks, inhibiting metastasis, inducing cancer cell death or modulating the immune system to attack the tumor cells. Replicative adenovirus as vaccines may be even older and date to a few years of its discovery, application of non-replicative adenovirus for vaccination against different microorganisms has been investigated, but only recently, it demonstrated its full potential being one of the leading vaccination tools for COVID-19. This is not a new vector nor a new technology, but the result of decades of careful and intense work in this field.

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Metformin is the most used drug for type 2 diabetes (T2DM). Its antitumor activity has been described by clinical studies showing reduced risk of cancer development in T2DM patients, as well as management of T2DM compared with those receiving other glucose-lowering drugs. Metformin has a plethora of molecular actions in cancer cells. This review focused on in vitro data on the action mechanisms of metformin on thyroid, prostate and head and neck cancer. AMPK activation regulating specific downstream targets is a constant antineoplastic activity in different types of cancer; however, AMPK-independent mechanisms are also relevant. In vitro evidence makes it clear that depending on the type of tumor, metformin has different actions; its effects may be modulated by different cell conditions (for instance, presence of HPV infection), or it may regulate tissue-specific factors, such as the Na+/I- symporter (NIS) and androgen receptors. The hallmarks of cancer are a set of functional features acquired by the cell during malignant development. In vitro studies show that metformin regulates almost all the hallmarks of cancer. Interestingly, metformin is one of these therapeutic agents with the potential to synergize with other chemotherapeutic agents, with low cost, low side effects and high positive consequences. Some questions are still challenging: Are metformin in vitro data able to translate from bench to bedside? Does metformin affect drug resistance? Can metformin be used as a generic anticancer drug for all types of tumors? Which are the specific actions of metformin on the peculiarities of each type of cancer? Several clinical trials are in progress or have been concluded for repurposing metformin as an anticancer drug. The continuous efforts in the field and future in vitro studies will be essential to corroborate clinical trials results and to elucidate the raised questions.

Assuntos

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Differentiated thyroid carcinoma (DTC) combined with congenital hypothyroidism (CH) is a rare situation, and there is no well-established causal relationship. CH is a common congenital endocrine, while DTC occurring in childhood represents 0.4-3% of all malignancies at this stage of life. The association of CH with DTC could be related to dyshormonogenetic goiter (DHG) or developmental abnormalities. This review will explore the clinical features and the molecular mechanisms potentially associated with the appearance of DTC in CH: sporadic somatic driver mutations, chronic increase of thyroid-stimulating hormone (TSH) levels, higher concentrations of hydrogen peroxide (H2O2), cell division cycle associated 8 (Borelain/CDC8) gene mutations, and in others genes associated with CH - either alone or associated with the mechanisms involved in dyshormonogenesis. There are some pitfalls in the diagnosis of thyroid cancer in patients with CH with nodular goiter, as the proper cytological diagnosis of nodules of patients with dyshormonogenesis might be demanding due to the specific architectural and cytological appearance, which may lead to an erroneous interpretation of malignancy. The purpose of this article is to suggest an analytical framework that embraces the fundamental relationships between the various aspects of CH and CDT. In face of this scenario, the entire genetic and epigenetic context, the complex functioning, and cross talk of cell signaling may determine cellular mechanisms promoting both the maintenance of the differentiated state of the thyroid follicular cell and the disruption of its homeostasis leading to cancer. Whereas, the exact mechanisms for thyroid cancer development in CH remain to be elucidated.

Assuntos

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Introduction: It is rare for a euthyroid mother to carry a child with a fetal goiter. However, cases of congenital hypothyroidism (CH) caused by thyroid dyshormonogenesis have been reported. Even though gene mutations associated with fetal goiter have been reported in a few studies, the effects on intellectual development have not been investigated. This study aimed to characterize and investigate the underlying genetic mechanism of CH and neuropsychological development and growth of two siblings with CH-induced fetal goiters. Case report: Two male siblings from a non-consanguineous marriage with CH and fetal goiter were diagnosed by ultrasonography at 32- and 26-weeks of gestation. This condition was confirmed by cordocentesis in the first pregnancy (TSH: 135 µIU/ml). The mother was euthyroid, and no intra-amniotic levothyroxine treatment was performed. Peripheral blood DNA was screened for TPO mutations. The new deletion p.Cys296Alafs*21 and the p.Arg665Trp mutation, inherited from heterozygous parents, were identified in both patients. Functional analysis showed both mutations reduced the TPO enzyme activity and impaired the membrane localization. The p.Cys296Alafs*21 mutation produces a protein product with a drastically reduced molecular weight. Additionally, a complete clinical and neuropsychological evaluation was also performed. The WISC IV test was employed to provide an overall measure of the siblings' cognitive and intellectual abilities. No growth retardation was detected in either child. In general, both children showed normal neuropsychological development; however, they exhibited slight reduction of Processing Speed Index scores, which are sensitive to neurological and attentional factors and motor maturation activity. Notably, the younger sibling obtained significantly low scores in the Operational Memory Index, a measure of attention capacity and psychoneurological immaturity. Conclusion: We described a new TPO compound heterozygosity that severely impaired the TPO activity and membrane localization leading to severe CH and fetal goiter. This is the first report showing the neuropsychological evaluation in patients with dyshormonogenetic fetal goiter. More studies are needed to understand the neurodevelopmental outcomes of neonates with CH-induced fetal goiters.

Assuntos

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BACKGROUND: COVID-19 has stroke Brazil harshly, deaths by COVID-19 in Brazil represent almost 13% of the total deaths by COVID-19 in the world, even though Brazilian population represents only 2.6% of the world population. Our aim in this study was to evaluate death and intubation outcomes and risk factors associated with COVID-19, and treatment options focusing on diabetes patients and the use of metformin pre-admission and during hospitalization. METHODS: In this Brazilian single-center study we evaluated 1170 patients hospitalized due to COVID-19. Diabetes patients (n = 188) were divided based on their use of pre-hospital and in-hospital metformin (non-met-group and met-group). RESULTS: In the total cohort most comorbidities were risk factors for orotracheal intubation and death. The use of chloroquine/hydroxychloroquine was significantly associated with increased death and intubation risk in uni- and multivariate analysis. Diabetes patients showed worst clinical feature compared with non-diabetes patients. In-hospital non-met-group had increased mortality (20.5%) compared to met-group (3.5%) (p = 0.0002) and univariable cox proportion hazard regression indicated in-hospital metformin reduced mortality (HR = 0.325, p = 0.035). Patients that used pre-hospital metformin showed lower severity parameters at hospital admission. (met-group: 2.45 ± 2.5; non-met-group: 4.25 ± 3.4). In all the groups older patients showed more severe clinical conditions and high risk of death and intubation. CONCLUSION: Even though this is a single-center study, results from other reports have shown a similar trend, indicating that patients that used metformin during hospitalization have a better prognosis and reduced risk of death.

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This work describes the chromatographic fractionation of the aerial parts of Calea pinnatifida and the structural characterization and determination of the absolute configuration of the isolated compounds as well as their antitumor potential. The HPLC fractionation of the CH2Cl2 phase of the MeOH extract from the leaves of C. pinnatifida led to the isolation of two related sesquiterpene lactones (STLs): calein C (1) and calealactone B (2). Additionally, during the purification process, a derivative of calein C (3) was formed as a product of the Michael addition of MeOH. The structures of Compounds 1-3 were established based on spectroscopic and spectrometric data, while the absolute stereochemistry was established by vibrational circular dichroism. In order to evaluate the effect of the conjugated double bonds on the cytotoxic activity of STLs, Compounds 1-3 were tested against anaplastic (KTC-2) and papillary (TPC-1) thyroid carcinoma cells. Calein C was the most active of the STLs, and displayed activity against both KTC-2 and TPC-1. On the other hand, the calein C derivative (3) was the least cytotoxic of all the compounds tested. These results are promising and suggest the importance of studying sesquiterpene lactones isolated from C. pinnatifida in terms of antitumor activity, especially considering the effects of α,ß-unsaturated carbonyl systems.

Assuntos

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BACKGROUND: The inactivation of the tumor-suppressor homeodomain-only protein X (HOPX) usually involves promoter methylation in several cancer types. This study aimed to investigate the HOPX-ß mRNA expression and promoter methylation and their clinical relevance in differentiated thyroid cancer (DTC). PATIENTS AND METHODS: Clinicopathological data and paraffin-embedded thyroid tumor tissues from 21 patients with DTC and 6 with benign tumors (T) and their non-tumor parenchyma (NT) were investigated. Tumor cell lines (FTC238, FTC236 and WRO) were treated with demethylating agent. HOPX-ß mRNA expression was assessed by qRT-PCR and methylation status by Q-MSP. Thyroid cancer data from Cancer Genome Atlas (TCGA) was also collected. RESULTS: HOPX-ß mRNA re-expression in two cell lines treated with demethylating agent was observed concomitantly with reduced promoter methylation. Reduced mRNA expression in T group compared to their NT was observed, and reduced protein expression in T compared to NT was observed in three cases. Low mRNA expression with high methylation status was detected in 6/14 DTC samples. High methylation status was associated with older age at diagnosis, recurrent or progressive disease and with the presence of new neoplasm event post initial therapy while hyper-methylation correlated with worse overall survival, worse disease-free status and older age. CONCLUSION: A moderate coupling of downregulation of HOPX-ß mRNA expression in DTC followed by high HOPX-ß promoter methylation was observed however; high HOPX promoter methylation status was associated with the worse prognosis of DTC patients.

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Ectopic thyroid results from a migration defect of the developing gland during embryogenesis causing congenital hypothyroidism. But it has also been detected in asymptomatic individuals. This study aimed to investigate the histopathological, functional, and genetic features of human ectopic thyroids. Six samples were histologically examined, and the expression of the specific thyroid proteins was assessed by immunohistochemistry. Two samples were submitted to whole exome sequencing. An oropharynx sample showed immature fetal architecture tissue with clusters or cords of oval thyrocytes and small follicles; one sample exhibited a normal thyroid pattern while four showed colloid goiter. All ectopic thyroids expressed the specific thyroid genes and T4 at similar locations to those observed in normal thyroid. No somatic mutations associated with ectopic thyroid were found. This is the first immature thyroid fetal tissue observed in an ectopic thyroid due to the arrest of structural differentiation early in the colloid stage of development that proved able to synthesize thyroid hormone but not to respond to TSH. Despite the ability of all ectopic thyroids to synthetize specific thyroid proteins and T4, at some point in life, it may be insufficient to support body growth leading to hypothyroidism, as observed in some of the patients.