Exploratory comparative transcriptomic analysis reveals potential gene targets associated with Cry1A.105 and Cry2Ab2 resistance in fall armyworm (Spodoptera frugiperda).

Genetically modified (GM) crops, expressing Bacillus thuringiensis (Bt) insecticidal toxins, have substantially transformed agriculture. Despite rapid adoption, their environmental and economic benefits face scrutiny due to unsustainable agricultural practices and the emergence of resistant pests like Spodoptera frugiperda, known as the fall armyworm (FAW). FAW's adaptation to Bt technology in corn and cotton compromises the long-term efficacy of Bt crops. To advance the understanding of the genetic foundations of resistance mechanisms, we conducted an exploratory comparative transcriptomic analysis of two divergent FAW populations. One population exhibited practical resistance to the Bt insecticidal proteins Cry1A.105 and Cry2Ab2, expressed in the genetically engineered MON-89Ø34 - 3 maize, while the other population remained susceptible to these proteins. Differential expression analysis supported that Cry1A.105 and Cry2Ab2 significantly affect the FAW physiology. A total of 247 and 254 differentially expressed genes were identified in the Cry-resistant and susceptible populations, respectively. By integrating our findings with established literature and databases, we underscored 53 gene targets potentially involved in FAW's resistance to Cry1A.105 and Cry2Ab2. In particular, we considered and discussed the potential roles of the differentially expressed genes encoding ABC transporters, G protein-coupled receptors, the P450 enzymatic system, and other Bt-related detoxification genes. Based on these findings, we emphasize the importance of exploratory transcriptomic analyses to uncover potential gene targets involved with Bt insecticidal proteins resistance, and to support the advantages of GM crops in the face of emerging challenges.

Safety and Pharmacokinetics of a Combined Antioxidant Therapy against Myocardial Reperfusion Injury: A Phase 1 Randomized Clinical Trial in Healthy Humans.

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.

A review of dose escalation for FDA-approved products treating solid tumors and hematological malignancies in first-in-human trials.

First-in-human (FIH) dose-escalation trials on oncology should prioritize safety and emphasize efficacy. We reviewed the FIH trials of 67 anti-tumor products approved by the Food and Drug Administration between 2018 and 2023 and found that the "3 + 3" design remains the predominant dose-escalation method (66.2%). The number of patients receiving sub-therapeutic doses is positively correlated with the maximum tolerated dose (MTD) or maximum dose (MD) to starting dose ratio (P = 0.056) and the number of dose levels in trials (P < 0.001). In addition, the proportion of products with a high ratio in antibody drugs is higher than that in small molecules (P < 0.001). The MTD or MD exceeded the label dose by three or more doses in 22.03% of the products. In conclusion, optimizing the starting dose selection method, refining the way of determining doses, and finding alternative indicators to replace toxicity as the endpoints will increase the effectiveness and broaden the beneficiary scope.

A Phase I Dose-Escalation Clinical Trial to Assess the Safety and Efficacy of Umbilical Cord-Derived Mesenchymal Stromal Cells in Knee Osteoarthritis.

Osteoarthritis (OA) is the most common degenerative joint disease. Mesenchymal stromal cells (MSC) are promising cell-based therapy for OA. However, there is still a need for additional randomized, dose-dependent studies to determine the optimal dose and tissue source of MSC for improved clinical outcomes. Here, we performed a dose-dependant evaluation of umbilical cord (UC)-derived MSC (Celllistem) in a murine model and in knee OA patients. For the preclinical study, a classical dose (200.000 cells) and a lower dose (50.000 cells) of Cellistem were intra-articularly injected into the mice knee joints. The results showed a dose efficacy response effect of Cellistem associated with a decreased inflammatory and degenerative response according to the Pritzker OARSI score. Following the same approach, the dose-escalation phase I clinical trial design included 3 sequential cohorts: low-dose group (2 × 106 cells), medium-dose group (20 × 106), and high-dose group (80 × 106). All the doses were safe, and no serious adverse events were reported. Nonetheless, 100% of the patients injected with the high-dose experienced injection-related swelling in the knee joint. According to WOMAC total outcomes, patients treated with all doses reported significant improvements in pain and function compared with baseline after 3 and 6 months. However, the improvements were higher in patients treated with both medium and low dose as compared to high dose. Therefore, our data demonstrate that the intra-articular injection of different doses of Cellistem is both safe and efficient, making it an interesting therapeutic alternative to treat mild and symptomatic knee OA patients. Trial registration ClinicalTrials.gov NCT03810521.

Consideraciones bioéticas sobre los incentivos a participantes voluntarios sanos en investigaciones Fase I

Los ensayos clínicos en Fase I se realzan con la participación de voluntarios sanos de prueban la seguridad y tolerabilidad de los productos farmacéuticos en investigación. En ellos, los participantes están expuestos a riesgos de medicamentos del estudio sin la posibilidad de un beneficio médico directo y, por lo general, deben pasar días o semanas en un centro de investigación. Los incentivos, como pagos monetarios se utilizan para incentivar la inscripción y compensar a los participantes por su tiempo. Estas características de los ensayos voluntarios sanos de fase I crean un contexto de investigación que difiere notablemente de la mayoría de las otras investigaciones clínicas, pues la mayoría de ellos son personas vulnerables económicamente. Este artículo presenta el objetivo de analizar factores bioéticos que inciden en el otorgamiento de incentivos a participantes voluntarios sanos en investigaciones Fase I.

Phase I Clinical Trials are conducted with the participation of healthy volunteers to test the safety and tolerability of pharmaceutical products. In them, participants are exposed to study drug risks without the possibility of direct medical benefit and usually must spend days or weeks at a research site. Incentives such as monetary payments are used to encourage enrollment and compensate participants for their time. These characteristics of Phase I healthy volunteer trials create a research context that differs markedly from most other clinical research, as most of them are financially vulnerable individuals. This paper aims to analyze bioethical factors that influence the granting of incentives to healthy volunteer participants in Phase I research.

Identification and cross-species comparison of in vitro phase I brevetoxin (BTX-2) metabolites in northern Gulf of Mexico fish and human liver microsomes by UHPLC-HRMS(/MS).

Brevetoxins (BTX) are a group of marine neurotoxins produced by the harmful alga Karenia brevis. Numerous studies have shown that BTX are rapidly accumulated and metabolized in shellfish and mammals. However, there are only limited data on BTX metabolism in fish, despite growing evidence that fish serve as vectors for BTX transfer in marine food webs. In this study, we aimed to investigate the in vitro biotransformation of BTX-2, the major constituent of BTX profiles in K. brevis, in several species of northern Gulf of Mexico fish. Metabolism assays were performed using hepatic microsomes prepared in-house as well as commercially available human microsomes for comparison, focusing on phase I reactions mediated by cytochrome P450 monooxygenase (CYP) enzymes. Samples were analyzed by UHPLC-HRMS(/MS) to monitor BTX-2 depletion and characterize BTX metabolites based on MS/MS fragmentation pathways. Our results showed that both fish and human liver microsomes rapidly depleted BTX-2, resulting in a 72-99% reduction within 1 h of incubation. We observed the simultaneous production of 22 metabolites functionalized by reductions, oxidations, and other phase I reactions. We were able to identify the previously described congeners BTX-3 and BTX-B5, and tentatively identified BTX-9, 41,43-dihydro-BTX-2, several A-ring hydrolysis products, as well as several novel metabolites. Our results confirmed that fish are capable of similar BTX biotransformation reactions as reported for shellfish and mammals, but comparison of metabolite formation across the tested species suggested considerable interspecific variation in BTX-2 metabolism potentially leading to divergent BTX profiles. We additionally observed non-enzymatic formation of BTX-2 and BTX-3 glutathione conjugates. Collectively, these findings have important implications for determining the ecotoxicological fate of BTX in marine food webs.

Self-management to promote physical activity after discharge from in-patient stroke rehabilitation: a feasibility study.

OBJECTIVES: To investigate the feasibility of a self-management program aimed at increasing physical activity in community-dwelling ambulators after stroke in a middle-income country with high income inequality. METHODS: A Phase 1, pre-post intervention study was conducted with 20 sub-acute stroke participants. The self-management program was delivered in six home-based sessions over 3 months. Feasibility of recruitment, intervention, and measurement was determined. Physical activity, cardiovascular risk, depression, walking speed, self-efficacy for exercise, participation, and quality of life were measured at baseline, 3, and 6 months. RESULTS: 16% of eligible participants were recruited. 90% completed the program and were measured at 3 months, and 65% at 6 months. The most common reasons for withdrawal were return to work, lack of interest/motivation and surgery. 92% of the sessions were delivered for 59 (SD 23) minutes per session. Participants did not increase physical activity at 3 months (MD 364 steps/day, 95% CI -282 to 1010) or 6 months (MD 312 steps/day, 95% CI -881 to 1504). Post-hoc analysis showed that sedentary participants increased their step count at 3 months by 1,300 (95% CI 152 to 2447) and at 6 months by 1,701 (95% CI -556 to 3959) more steps than non-sedentary participants. CONCLUSIONS: A Phase 2 study of the self-management program appears to be feasible in a middle-income country with high income inequality and has the potential to increase physical activity levels in sedentary individuals with mild disability after stroke. TRIAL REGISTRATION: RBR-6bdmsk.

Remediation of endosulfan-contaminated water by hairy roots: removal and phytometabolization assessment.

Although many countries banned the insecticide endosulfan, it is still an environmental pollutant. Plants metabolize the two diastereomers of the formulations known as technical grade endosulfan (TGE) by two phase I pathways: hydrolysis leading to less toxic derivatives and oxidation giving endosulfan sulfate which is as toxic as endosulfan itself. We assessed the removal, bioaccumulation and phase I metabolization of TGE from water matrices using hairy root clones (HRs) of three edible species, Brassica napus, Raphanus sativus and Capsicum annuum. B. napus and C. annuum HRs removed 86% of TGE from the bioreaction media in 2 and 96 h, respectively, whereas R. sativus HRs removed 91% of TGE within 6 h of biotreatment. In the experiments with B. napus, only endosulfan sulfate was detected in both biomass and medium, whereas R. sativus and C. annuum accumulated endosulfan sulfate and endosulfan alcohol. Besides, endosulfan lactone was detected in C. annuum reaction medium. Acute ichthyotoxicity assays toward Poecilia reticulata showed that media contaminated with TGE lethal levels did not produce mortality after the phytotreatments. This research highlights the feasibility of using HRs to evaluate plant enzymatic abilities toward xenobiotics and their potential for the design of ex situ decontamination processes.

Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022.

In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.

Comparative Colorimetric Sensor Based on Bi-Phase γ-/α-Fe2O3 and γ-/α-Fe2O3/ZnO Nanoparticles for Lactate Detection.

This work reports on Fe2O3 and ZnO materials for lactate quantification. In the synthesis, the bi-phase γ-/α-Fe2O3 and γ-/α-Fe2O3/ZnO nanoparticles (NPs) were obtained for their application in a lactate colorimetric sensor. The crystalline phases of the NPs were analyzed by XRD and XPS techniques. S/TEM images showed spheres with an 18 nm average and a needle length from 125 to 330 nm and 18 nm in diameter. The γ-/α-Fe2O3 and γ-/α-Fe2O3/ZnO were used to evaluate the catalytic activity of peroxidase with the substrate 3,3,5,5-tetramethylbenzidine (TMB), obtaining a linear range of 50 to 1000 µM for both NPs, and a 4.3 µM and 9.4 µM limit of detection (LOD), respectively. Moreover, γ-/α-Fe2O3 and γ-/α-Fe2O3/ZnO/lactate oxidase with TMB assays in the presence of lactate showed a linear range of 50 to 1000 µM, and both NPs proved to be highly selective in the presence of interferents. Finally, a sample of human serum was also tested, and the results were compared with a commercial lactometer. The use of ZnO with Fe2O3 achieved a greater response toward lactate oxidation reaction, and has implementation in a lactate colorimetric sensor using materials that are economically accessible and easy to synthesize.

Modeling synergism in early phase cancer trials with drug combination with continuous dose levels: is there an added value?

In parametric Bayesian designs of early phase cancer clinical trials with drug combinations exploring a discrete set of partially ordered doses, several authors claimed that there is no added value in including an interaction term to model synergism between the two drugs. In this paper, we investigate these claims in the setting of continuous dose levels of the two agents. Parametric models will be used to describe the relationship between the doses of the two agents and the probability of dose limiting toxicity and efficacy. Trial design proceeds by treating cohorts of two patients simultaneously receiving different dose combinations and response adaptive randomization. We compare trial safety and efficiency of the estimated maximum tolerated dose (MTD) curve between models that include an interaction term with models without the synergism parameter with extensive simulations. Under a selected class of dose-toxicity models and dose escalation algorithm, we found that not including an interaction term in the model can compromise the safety of the trial and reduce the pointwise reliability of the estimated MTD curve.

Contemporary dose-escalation methods for early phase studies in the immunotherapeutics era.

Phase 1 dose-escalation trials are crucial to drug development by providing a framework to assess the toxicity of novel agents in a stepwise and monitored fashion. Despite widely adopted, rule-based dose-escalation methods (such as 3 + 3) are limited in finding the maximum tolerated dose (MTD) and tend to treat a significant number of patients at subtherapeutic doses. Newer methods of dose escalation, such as model-based and model-assisted designs, have emerged and are more accurate in finding MTD. However, these designs have not yet been broadly embraced by investigators. In this review, we summarise the advantages and disadvantages of contemporary dose-escalation methods, with emphasis on model-assisted designs, including time-to-event designs and hybrid methods involving optimal biological dose (OBD). The methods reviewed include mTPI, keyboard, BOIN, and their variations. In addition, the challenges of drug development (and dose-escalation) in the era of immunotherapeutics are discussed, where many of these agents typically have a wide therapeutic window. Fictional examples of how the dose-escalation method chosen can alter the outcomes of a phase 1 study are described, including the number of patients enrolled, the trial's timeframe, and the dose level chosen as MTD. Finally, the recent trends in dose-escalation methods applied in phase 1 trials in the immunotherapeutics era are reviewed. Among 856 phase I trials from 2014 to 2019, a trend towards the increased use of model-based and model-assisted designs over time (OR = 1.24) was detected. However, only 8% of the studies used non-rule-based dose-escalation methods. Increasing familiarity with such dose-escalation methods will likely facilitate their uptake in clinical trials.

Xenobiotic transport and metabolism in the human brain.

Organisms have metabolic pathways responsible for eliminating endogenous and exogenous toxicants. Generally, we associate the liver par excellence as the organ in charge of detoxifying the body; however, this process occurs in all tissues, including the brain. Due to the presence of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), the Central Nervous System (CNS) is considered a partially isolated organ, but similar to other organs, the CNS possess xenobiotic transporters and metabolic pathways associated with the elimination of xenobiotic agents. In this review, we describe the different systems related to the detoxification of xenobiotics in the CNS, providing examples in which their association with neurodegenerative processes is suspected. The CNS detoxifying systems include carrier-mediated, active efflux and receptor-mediated transport, and detoxifying systems that include phase I and phase II enzymes, as well as those enzymes in charge of neutralizing compounds such as electrophilic agents, reactive oxygen species (ROS), and free radicals, which are products of the bioactivation of xenobiotics. Moreover, we discuss the differential expression of these systems in different regions of the CNS, showing the different detoxifying needs and the composition of each region in terms of the cell type, neurotransmitter content, and the accumulation of xenobiotics and/or reactive compounds.

A first-in-class, first-in-human, phase I trial of CIGB-552, a synthetic peptide targeting COMMD1 to inhibit the oncogenic activity of NF-κB in patients with advanced solid tumors.

CIGB-552 is a synthetic peptide that interacts with COMMD1 and upregulates its protein levels. The objectives of this phase I study were safety, pharmacokinetic profile, evaluation of the lymphocytes CD4+ and CD8+ and preliminary activity in patients with advanced tumors. A 3 + 3 dose-escalation design with seven dose levels was implemented. Patients were included until a grade 3 related adverse event occurred and the maximum tolerated dose was reached. The patients received subcutaneous administration of CIGB-552 three times per week for 2 weeks. Single-dose plasma pharmacokinetics was characterized at two dose levels, and tumor responses were classified by RECIST 1.1. Twenty-four patients received CIGB-552. Dose-limiting toxicity was associated with a transient grade 3 pruritic maculopapular rash at a dose of 7.0 mg. The maximum tolerated dose was defined as 4.7 mg. Ten patients were assessable for immunological status. Seven patients had significant changes in the ratio CD4/CD8 in response to CIGB-552 treatment; three patients did not modify the immunological status. Stable disease was observed in five patients, including two metastatic soft sarcomas. We conclude that CIGB-552 at dose 4.7 mg was well tolerated with no significant adverse events and appeared to provide some clinical benefits.

Safety and immunogenicity evaluation of recombinant BCG vaccine against respiratory syncytial virus in a randomized, double-blind, placebo-controlled phase I clinical trial.

BACKGROUND: Respiratory syncytial virus (RSV) is responsible for most respiratory tract infections and hospitalizations in infants and represents a significant economic burden for public health. The development of a safe, effective, and affordable vaccine is a priority for the WHO. METHODS: We conducted a double-blinded, escalating-dose phase 1 clinical trial in healthy males aged 18-50 years to evaluate safety, tolerability, and immunogenicity of a recombinant Mycobacterium bovis BCG vaccine expressing the nucleoprotein of RSV (rBCG-N-hRSV). Once inclusion criteria were met, volunteers were enrolled in three cohorts in an open and successive design. Each cohort included six volunteers vaccinated with 5 × 103, 5 × 104, or 1 × 105 CFU, as well as two volunteers vaccinated with the full dose of the standard BCG vaccine. This clinical trial (clinicaltrials.gov NCT03213405) was conducted in Santiago, Chile. FINDINGS: The rBCG-N-RSV vaccine was safe, well-tolerated, and no serious adverse events related to the vaccine were recorded. Serum IgG-antibodies directed against Mycobacterium and the N-protein of RSV increased after vaccination, which were capable of neutralizing RSV in vitro. Additionally, all volunteers displayed increased cellular response consisting of IFN-γ and IL-2 production against PPD and the N-protein, starting at day 14 and 30 post-vaccination respectively. INTERPRETATION: The rBCG-N-hRSV vaccine had a good safety profile and induced specific cellular and humoral responses. FUNDING: This work was supported by Millennium Institute on Immunology and Immunotherapy from Chile (P09/016), FONDECYT 1190830, and FONDEF D11E1098.

Intravaginal administration of gelatine capsules containing freeze-dried autochthonous lactobacilli: a double-blind, randomised clinical trial of safety.

Vaginal lactobacilli (LAB) in probiotic formulas constitute a promising alternative for microbiome reconstitution and for the prevention and treatment of urogenital infections. A double-blind, randomised clinical trial was conducted to assess the safety of LAB-gelatine capsules vaginally administered to healthy sexually active women. Participants were randomised into three groups: intervention A: Lactobacillus reuteri CRL1324, Lactobacillus gasseri CRL1263 and CRL1307; intervention B: Lactobacillus rhamnosus CRL1332, L. gasseri CRL1256 and CRL1320; and intervention C: placebo. In a survey and clinical evaluation, participants received a blister with 7 capsules to be administered 1 per day. A second sampling and a new survey were conducted 3-10 days after completing application. Colposcopy was performed to assess adverse effects on vaginal-cervical mucosa. Vaginal swabs were taken for Gram staining to determine the Nugent score, and obtainment of viable-cell cultures to quantify cultivable lactic acid bacteria and pathogens. The main outcomes evaluated were overall satisfaction and secondary effects, including discomfort, urogenital infection, inflammatory response or other symptoms. No significant differences were found in Nugent score or in leukocyte numbers in vaginal samples either before or after the three interventions. However, a tendency to decrease in both the Nugent score and in leukocyte numbers was observed after interventions A and B, though not after C. A significant increase in cultivable lactobacilli was determined after LAB interventions. No severe adverse events were detected. LAB-containing capsules were well tolerated by subjects, so they could be proposed as an adequate alternative to restore vaginal lactobacilli in sexually active women.

Referral pattern of periodontal disease among general dental practitioners in Iraq / Padrão de referência da doença periodontal entre os clínicos odontológicos gerais no Iraque

Objectives: To evaluate the type of "periodontal treatment" performed by general dental practitioners and the referral patterns of periodontists in Iraq. Material and methods: A total of 201 general dentists were asked to complete a self-administered questionnaire consisting of nine questions regarding periodontal treatment and the referral patterns of periodontists. Results: The study showed that 91.1% of general dental practitioners (GDPs) performed "phase-I therapy", and most of them done "scaling". Regarding surgical periodontal therapy, only 12.9% of them performed surgical periodontal therapy, half of the GDPs did gingivectomy, and less than 30% performed crown lengthening. When evaluating maintenance therapy after periodontal treatment, it was found that 77.9% of the GDPs scheduled appointments for patients in the maintenance phase, 49.4% of them after one month, 24.7% after three months, and 15.6% after six months. Using TRUF analysis, most general dentists believed that the patient and periodontal factors were responsible for the recurrence of periodontal disease. Conclusions: There is still a lack of awareness of periodontal surgical procedures among the "general dental practitioners". Thus, it is essential to increase the comprehension of periodontal treatment among general dentists. (AU)

Objetivo: Avaliar o tipo de "tratamento periodontal" realizado por dentistas generalistas e os padrões de encaminhamento aos periodontistas, no Iraque. Material e métodos: Um total de 201 dentistas generalistas preencheram um questionário autoaplicável que consistiu em nove perguntas sobre o tratamento periodontal e os padrões de encaminhamento para periodontistas. Resultados: O estudo mostrou que 91,1% dos dentistas gerais (DG) realizavam "terapia fase I" e a maioria realizava "raspagem". Em relação à terapia periodontal cirúrgica, apenas 12,9% deles realizavam, sendo que metade dos DG realizavam gengivectomia e menos de 30% realizavam aumento de coroa clínica. Ao avaliar a terapia de manutenção após o tratamento periodontal, constatou-se que 77,9% dos DGs agendaram consultas para pacientes em fase de manutenção, sendo 49,4% após um mês, 24,7% após três meses e 15,6% após seis meses. Usando a análise TRUF, a maioria dos dentistas gerais acredita que o paciente e os fatores periodontais são responsáveis pela recorrência da doença periodontal. Conclusões: Ainda existe um desconhecimento dos procedimentos cirúrgicos periodontais entre os "dentistas generalistas". Assim, é essencial aumentar a compreensão do tratamento periodontal entre os cirurgiões-dentistas gerais (AU)

Does VEGF-targeted active immunotherapy induce complete abrogation of platelet VEGF levels?

OBJECTIVES: Vascular endothelial growth factor (VEGF) is involved in physiological angiogenesis, but also is considered one of the key factors that promotes tumor angiogenesis. CIGB-247 is a VEGF-based vaccine that has been evaluated in phase I clinical trial patients with advanced solid tumors. This specific active immunotherapy is able to reduce platelet VEGF levels; however it is unknown whether this effect leads to a decrease in VEGF below the levels that can be observed in healthy individuals. The objective of the present study is to investigate platelet VEGF levels in cancer patients vaccinated with CIGB-247, and then compare these values with those obtained in healthy individuals. To achieve this, platelet VEGF levels of 62 cancer patients and 93 healthy individuals were compared. Cancer patients were those individuals recruited in CENTAURO and CENTAURO-2 clinical trials. RESULTS: Before vaccination, platelets of cancer patients carried more VEGF than the levels seen in platelet of healthy individuals. However, after vaccination, cancer patients had platelet VEGF values within the range established by healthy individuals, indicating that the antibody response elicited by CIGB-247 is not able to induce a complete suppression of VEGF. Vaccination with CIGB-247 helps to normalize VEGF levels within platelets.

Usnic Acid Potassium Salt: Evaluation of the Acute Toxicity and Antinociceptive Effect in Murine Model.

To obtain usnic acid potassium salt (PS-UA), the usnic acid (UA) was extracted and purified from the lichen Cladonia substellata, and modified to produce PS-UA. The structure was determined by 1H-NMR, IR and elemental analysis, ratified through computational models, as well as identification the site of K+ insertion in the molecule. Antinociceptive activity was detected through contortions in mice induced by acetic acid and formalin (phases I and II) after treatments with 10 and 20 mg/kg of PS-UA, indicating interference in both non-inflammatory and inflammatory pain. After oral administration at doses of 500, 1000 and 2000 mg/kg, no deaths of mice with treatments below 2000 mg/kg were observed. Except for body weight gain, food and water consumption decreased with treatments of 1000 and 2000 mg/kg, and the number of segmented leukocytes was higher for both treatments. Regarding serum levels, cholesterol and triglycerides decreased, however, there was an increase in hepatic transaminases with both treatments. Liver and kidney histological changes were detected in treatments of 2000 mg/kg, while the spleen was preserved. The PS-UA demonstrated antinociceptive activity while the acute toxicity at the concentration of 2000 mg/kg was the only dose that presented morphological changes in the liver and kidney.

Serological evidence of Coxiella burnetii infection in cattle and farm workers: is Q fever an underreported zoonotic disease in Ecuador?

Background: Q fever is an underreported zoonotic disease of cattle and men in most countries of the world. Very little information about the prevalence of Coxiella burnetii infection in animals and humans comes from South and Central America and systematic studies are lacking. Methods: A seroprevalence survey for Q fever amongst cattle, farm workers and students was conducted in Ecuador using a commercial ELISA kit. Results: Survey results showed an unexpectedly high prevalence of Coxiella burnetii antibodies in dairy cattle (43%) and in farm workers (34%). In addition, a clinical case in a human of acute Q fever in the convalescent stage was detected. Conclusion: We conclude that the disease is endemic in Ecuador but is overlooked by medical and laboratory personnel. Q fever should be considered a public health issue in Ecuador and further research into the clinical relevance of this infection is recommended.