RESUMO
The activation of the maternal immune system by a prenatal infection is considered a risk factor for developing psychiatric disorders in the offspring. Toxoplasma gondii is one of the pathogenic infections associated with schizophrenia. Recent studies have shown an association between high levels of IgG anti-T. gondii from mothers and their neonates, with a higher risk of developing schizophrenia. The absence of the parasite and the levels of IgGs found in the early stages of life suggest a transplacental transfer of the anti-T. gondii IgG antibodies, which could bind fetal brain structures by molecular mimicry and induce alterations in neurodevelopment. This study aimed to determine the maternal pathogenic antibodies formation that led to behavioral impairment on the progeny of rats immunized with T. gondii. Female rats were immunized prior to gestation with T. gondii lysate (3 times/once per week). The anti-T. gondii IgG levels were determined in the serum of pregestational exposed females' previous mating. After this, locomotor activity, cognitive and social tests were performed. Cortical neurotransmitter levels for dopamine and glutamate were evaluated at 60 PND in the progeny of rats immunized before gestation (Pregestational group). The maternal pathogenic antibodies were evidenced by their binding to fetal brain mimotopes in the Pregestational group and the reactivity of the serum containing anti-T. gondii IgG was tested in control fetal brains (non-immunized). These results showed that the Pregestational group presented impairment in short and long-term memory, hypoactivity and alteration in social behavior, which was also associated with a decrease in cortical glutamate and dopamine levels. We also found the IgG antibodies bound to brain mimotopes in fetuses from females immunized with T. gondii, as well as observing a strong reactivity of the serum females immunized for fetal brain structures of fetuses from unimmunized mothers. Our results suggest that the exposure to T. gondii before gestation produced maternal pathogenic antibodies that can recognize fetal brain mimotopes and lead to neurochemical and behavioral alterations in the offspring.
Assuntos
Dopamina , Toxoplasma , Gravidez , Animais , Feminino , Ratos , Ácido Glutâmico , Imunoglobulina G , EncéfaloRESUMO
Spinal cord injury (SCI) refers to the damage suffered in the spinal cord by any trauma or pathology. The purpose of this work was to determine whether 99mTc-GA-5, a radiotracer targeting Glial Fibrillary Acidic Protein (GFAP), can reveal in vivo the reactivation of astrocytes in a murine model with SCI. A method for the 99mTc radiolabeling of the mouse anti-GFAP monoclonal antibody GA-5 was implemented. Radiochemical characterization was performed, and radioimmunohistochemistry assays were used to evaluate the integrity of 99mTc-GA-5. MicroSPECT/CT was used for in vivo imaging to trace SCI in the rats. No alterations in the GA-5's recognition/specificity ability were observed after the radiolabeling. The GA-5's radiolabeling procedure implemented in this work offers a practical method to allow the in vivo following of this monoclonal antibody to evaluate its biodistribution and specificity for GFAP receptors using SPECT/CT molecular imaging.
Assuntos
Proteína Glial Fibrilar Ácida/genética , Traumatismos da Medula Espinal/diagnóstico por imagem , Medula Espinal/diagnóstico por imagem , Tecnécio/química , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/imunologia , Proteína Glial Fibrilar Ácida/farmacologia , Humanos , Radioquímica , Compostos Radiofarmacêuticos/farmacologia , Ratos , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Medula Espinal/patologia , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/patologia , Tecnécio/farmacologia , Distribuição Tecidual/efeitos da radiaçãoRESUMO
The FDA's approval of peptide drugs such as Ziconotide or Exendin for pain relief and diabetes treatment, respectively, enhanced the interest to explore novel conotoxins from Conus species venom. In general, conotoxins can be used in pathologies where voltage-gated channels, membrane receptors, or ligands alter normal physiological functions, as in metabolic diseases such as Type 2 diabetes. In this study, the synthetic cal14.2b (s-cal14.2b) from the unusual Californiconus californicus demonstrated bioactivity on NIT-1 insulinoma cell lines stimulating insulin secretion detecting by high performance liquid chromatography (HPLC). Accordingly, s-cal14.2b increased the CaV1.2/1.3 channel-current by 35 ± 4% with a recovery τ of 10.3 ± 4 s in primary cell culture of rat pancreatic ß-cells. The in vivo results indicated a similar effect of insulin secretion on mice in the glucose tolerance curve model by reducing the glucose from 500 mg/dL to 106 mg/dL in 60 min, compared to the negative control of 325 mg/dL at the same time. The PET-SCAN with radiolabeling 99mTc-s-cal14.2b demonstrated biodistribution and accumulation in rat pancreas with complete depuration in 24 h. These findings show the potential therapeutic use of s-cal14.2b in endocrinal pathologies such as early stages of Type 2 Diabetes where the pancreas's capability to produce insulin is still effective.
RESUMO
BACKGROUND: Malignant Pleural Mesothelioma (MPM) is a rare but aggressive neoplasia that usually presents at advanced stages. Even though some advances have been achieved in the management of patients with MPM, this malignancy continuous to impose a deleterious prognosis for affected patients (12-18 months as median survival, and 5-10% 5-year survival rate), accordingly, the recognition of biomarkers that allow us to select the most appropriate therapy are necessary. METHODS: Immunohistochemistry semi-quantitative analysis was performed to evaluate four different biomarkers (ERCC1, RRM1, RRM2, and hENT-1) with the intent to explore if any of them was useful to predict response to treatment with continuous infusion gemcitabine plus cisplatin. Tissue biopsies from patients with locally advanced or metastatic MPM were analyzed to quantitatively asses the aforementioned biomarkers. Every included patient received treatment with low-dose gemcitabine (250 mg/m2) in a 6-h continuous infusion plus cisplatin 35 mg/m2 on days 1 and 8 every 3 weeks as first-line therapy. RESULTS: From the 70 eligible patients, the mean and standard deviation (SD) for ERCC1, RRM1, RRM2 and hENT-1 were 286,178.3 (± 219, 019.8); 104,647.1 (± 65, 773.4); 4536.5 (± 5, 521.3); and 2458.7 (± 4, 983.4), respectively. Patients with high expression of RRM1 had an increased median PFS compared with those with lower expression (9.5 vs 4.8 months, p = < 0.001). Furthermore, high expression of RRM1 and ERCC1 were associated with an increased median OS compared with their lower expression counterparts; [(23.1 vs 7.2 months for RRM1 p = < 0.001) and (17.4 vs 9.8 months for ERCC1 p = 0.018)]. CONCLUSIONS: ERCC1 and RRM1 are useful biomarkers that predict better survival outcomes in patients with advanced MPM treated with continuous infusion of gemcitabine plus cisplatin.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Mesotelioma Maligno/tratamento farmacológico , Mesotelioma Maligno/metabolismo , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/metabolismo , Ribonucleosídeo Difosfato Redutase/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Cisplatino/administração & dosagem , Proteínas de Ligação a DNA/genética , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Endonucleases/genética , Feminino , Humanos , Imuno-Histoquímica , Masculino , Mesotelioma Maligno/mortalidade , Mesotelioma Maligno/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/patologia , Prognóstico , Ribonucleosídeo Difosfato Redutase/genética , GencitabinaRESUMO
BACKGROUND: Malignant pleural mesothelioma (MPM) is rare and aggressive neoplasia, with a poor prognosis; furthermore, the monetary cost of its treatment represents a major challenge for many patients. The economic burden this malignancy imposes is underscored by the fact that asbestos exposure, which is the most frequent risk factor, is much more prevalent in the lower socioeconomic population of developing countries. The aims of the present study were to evaluate the efficacy, safety, and cost of continuous infusion of low-dose Gemcitabine plus Cisplatin (CIGC) as a treatment strategy for patients with unresectable MPM. METHODS: We performed a prospective cohort study to determine efficacy and safety of continuous infusion gemcitabine at a dose of 250 mg/m2 in a 6-h continuous infusion plus cisplatin 35 mg/m2 on days 1 and 8 of a 21-day cycle in patients with unresectable MPM. We also performed a cost-minimization analysis to determine if this chemotherapy regimen is less expensive than other currently used regimens. RESULTS: The median number of chemotherapy cycles was six (range 1-11 cycles); objective response rate was documented in 46.2%, and disease control rate was seen in 81.2%. Median PFS was 8.05 months (CI 95% 6.97-9.13); median OS was 16.16 months (CI 95% 12.5-19.9). The cost minimization analysis revealed savings of 66.4, 61.9, and 97.7% comparing CIGC with short-infusion gemcitabine plus cisplatin (SIGC), cisplatin plus pemetrexed (CP), and cisplatin plus pemetrexed and bevacizumab (CPB), respectively. Furthermore, this chemotherapy regimen proved to be safe at the administered dosage. CONCLUSION: CIGC is an effective and safe treatment option for patients with unresectable MPM; besides, this combination is a cost-saving option when compared with other frequently used chemotherapy schemes. Therefore, this treatment scheme should be strongly considered for patients with unresectable MPM and limited economic resources.
RESUMO
Toxoplasmosis is a zoonotic disease caused by the apicomplexa protozoan parasite Toxoplasma gondii. This disease is a health burden, mainly in pregnant women and immunocompromised individuals. Dehydroepiandrosterone (DHEA) has proved to be an important molecule that could drive resistance against a variety of infections, including intracellular parasites such as Plasmodium falciparum and Trypanozoma cruzi, among others. However, to date, the role of DHEA on T. gondii has not been explored. Here, we demonstrated for the first time the toxoplasmicidal effect of DHEA on extracellular tachyzoites. Ultrastructural analysis of treated parasites showed that DHEA alters the cytoskeleton structures, leading to the loss of the organelle structure and organization as well as the loss of the cellular shape. In vitro treatment with DHEA reduces the viability of extracellular tachyzoites and the passive invasion process. Two-dimensional (2D) SDS-PAGE analysis revealed that in the presence of the hormone, a progesterone receptor membrane component (PGRMC) with a cytochrome b5 family heme/steroid binding domain-containing protein was expressed, while the expression of proteins that are essential for motility and virulence was highly reduced. Finally, in vivo DHEA treatment induced a reduction of parasitic load in male, but not in female mice.
RESUMO
Retinol plays a significant role in several physiological processes through their nuclear receptors, whose expression depends on retinol cytoplasmic concentration. Loss of expression of nuclear receptors and low retinol levels have been correlated with lung cancer development. Stimulated by retinoic acid 6 (STRA6) is the only described cell membrane receptor for retinol uptake. Some chronic diseases have been linked with specific polymorphisms in STRA6. This study aimed to evaluate four STRA6 single nucleotide polymorphisms (SNPs) (rs4886578, rs736118, rs351224, and rs97445) among 196 patients with locally-advanced and metastatic non-small cell lung cancer (NSCLC) patients. Genotyping, through a validated SNP assay and determined using real time-PCR, was correlated with clinical features and outcomes. NSCLC patients with a TT SNP rs4886578 and rs736118 genotype were more likely to be >60 years, non-smokers, and harboring EGFR mutations. Patients with a TT genotype compared with a CC/CT SNP rs974456 genotype had a median progression-free survival (PFS) of 3.2 vs. 4.8 months, p = 0.044, under a platinum-based regimen in the first-line. Furthermore, patients with a TT rs351224 genotype showed a prolonged overall survival (OS), 47.5 months vs. 32.0 months, p = 0.156. This study showed a correlation between clinical characteristics, such as age, non-smoking history, and EGFR mutational status and oncological outcomes depending on STRA6 SNPs. The STRA6 TT genotype SNP rs4886578 and rs736118 might be potential biomarkers in locally-advanced and metastatic NSCLC patients.
RESUMO
Malignant pleural mesothelioma (MPM) is the most common tumor of the pulmonary pleura. It is a rare and aggressive malignancy, generally associated with continuous occupational exposure to asbestos. Only a multimodal-approach to treatment, based on surgical resection, chemotherapy and/or radiation, has shown some benefits. However, the survival rate remains low. Nimotuzumab (h-R3), an anti-EGFR (epidermal growth factor receptor) humanized antibody, is proposed as a promising agent for the treatment of MPM. The aim of this research was to implement a procedure for nimotuzumab radiolabeling to evaluate its biodistribution and affinity for EGF (epidermal growth factor) receptors present in a mesothelioma xenograft. Nimotuzumab was radiolabeled with 67Ga; radiolabel efficiency, radiochemical purity, serum stability, and biodistribution were evaluated. Biodistribution and tumor uptake imaging studies by microSPECT/CT in mesothelioma xenografts revealed constant nimotuzumab uptake at the tumor site during the first 48 h after drug administration. In vivo studies using MPM xenografts showed a significant uptake of this radioimmunoconjugate, which illustrates its potential as a biomarker that could promote its theranostic use in patients with MPM.
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Radioisótopos de Gálio/farmacocinética , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Neoplasias Pleurais/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Fluordesoxiglucose F18/química , Humanos , Imageamento Tridimensional , Fígado/metabolismo , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Mesotelioma/diagnóstico por imagem , Mesotelioma Maligno , Camundongos Nus , Neoplasias Pleurais/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Epidermal growth factor receptor (EGFR) is overexpressed in >60% of non-small cell lung cancer (NSCLC) cases. In combination with radiotherapy or chemotherapy, first-line treatments with antibodies against EGFR, including cetuximab and necitumumab, have demonstrated benefits by increasing overall survival (OS), particularly in patients who overexpress EGFR. The present study evaluated the interobserver agreement among three senior pathologists, who were blinded to the clinical outcomes and assessed tumor samples from 85 patients with NSCLC using the H-score method. EGFR immunohistochemistry was performed using a qualitative immunohistochemical kit. The reported (mean ± standard deviation) H-scores from each pathologist were 111±102, 127±103 and 128.53±104.03. The patients with average H-scores ≥1, ≥100, ≥200 and between 250-300 were 85.9, 54.1, 28.2 and 12.9, respectively. Patients who had an average H-score >100 had a shorter OS time compared with those with lower scores. Furthermore, patients with EGFR mutations who were treated with EGFR-tyrosine kinase inhibitors (TKIs) and had an average H-score >100 had a longer OS time compared with those with an average H-score <100. The interobserver concordance for the total H-scores were 0.982, 0.980 and 0.988, and for a positive H-score ≥200, the interobserver concordance was 0.773, 0.710 and 0.675, respectively. The determination of EGFR expression by the H-score method is highly reproducible among pathologists and is a prognostic factor associated with a poor OS in all patients. Additionally, the results of the present study suggest that patients with EGFR mutations that are treated with EGFR-TKIs and present with a high H-score have a longer OS time.
RESUMO
BACKGROUND: Previous population-based studies have demonstrated an association between metformin use and improved survival among diabetic patients with cancer. We sought to analyze the effects of diabetes and its treatment in terms of the survival of patients with lung cancer. METHODS: Overall, 1106 patients with non-small cell lung cancer (94.3 % with stage IV disease) were included. The outcomes were compared between the patients with (n = 186) and without diabetes (n = 920). The characteristics associated with antidiabetic treatment and proper glycemic control (defined as a mean plasma glucose <130 mg/dL) were examined at diagnosis. The overall survivals (OSs) of the different patient populations were analyzed using Kaplan-Meier curves, and a multivariate Cox proportional hazard model was used to determine the influences of the patient and tumor characteristics on survival. RESULTS: The OS for the entire population was 18.3 months (95 % CI 16.1-20.4). There was no difference in the OSs of the diabetic and non-diabetic patients (18.5 vs 16.4 months, p = 0.62). The diabetic patients taking metformin exhibited a superior OS than did those on other antidiabetic treatments (25.6 vs 13.2 months, p = 0.017). Those with proper glycemic control had a better OS than did those without proper glycemic control and the non-diabetics (40.5 vs 13.2 and 18.5 months, respectively, p < 0.001). Both the use of metformin (HR 0.53, p < 0.0001 and HR 0.57, p = 0.017, respectively) and proper glycemic control (HR 0.49, p < 0.0001 and HR 0.40, p = 0.002, respectively) were significant protective factors in all and only diabetic patients, respectively. CONCLUSIONS: The diabetic patients with proper glycemic control exhibited a better OS than did those without proper glycemic control and even exhibited a better OS than did the patients without diabetes mellitus. Metformin use was independently associated with a better OS.