Search

p53 is a crucial tumor suppressor in vertebrates that is frequently mutated in human cancers. Most mutations are missense mutations that render p53 inactive in suppressing tumor initiation and progression. Developing small-molecule drugs to convert mutant p53 into an active, wild-type-like conformation is a significant focus for personalized cancer therapy. Prior research indicates that reactivating p53 suppresses cancer cell proliferation and tumor growth in animal models. Early clinical evidence with a compound selectively targeting p53 mutants with substitutions of tyrosine 220 suggests potential therapeutic benefits of reactivating p53 in patients. This study identifies and examines the UCI-1001 compound series as a potential corrector for several p53 mutations. The findings indicate that UCI-1001 treatment in p53 mutant cancer cell lines inhibits growth and reinstates wild-type p53 activities, including DNA binding, target gene activation, and induction of cell death. Cellular thermal shift assays, conformation-specific immunofluorescence staining, and differential scanning fluorometry suggest that UCI-1001 interacts with and alters the conformation of mutant p53 in cancer cells. These initial results identify pyrimidine trione derivatives of the UCI-1001 series as candidates for p53 corrector drug development.

Abstract Animal pollination plays a key role in global agricultural production and especially of monoecious crops, which are essentially dependent on pollinators. The West Indian gherkin fruit (Cucumis anguria L., Cucurbitaceae) is a monoecious vegetable adaptable to adverse abiotic conditions, resistant to diseases, and rich in minerals and vitamins, thus being a relevant alternative for improving nutritional security of socioeconomically vulnerable populations. The knowledge on the influence of pollination and of specific pollinators on chemical characteristics of fruits would help pollinators’ management, but it is still poorly understood. In this study we investigated the influence of pollination on quantitative and qualitative aspects of fruits fruits of West Indian gherkin fruits (Cucumis anguria L., Cucurbitaceae) in the Brazilian semi-arid region. Data on pollination biology and on fruits resulted from controlled crosses (open-OP, cross-CP and Apis mellifera Linnaeus, 1758 pollinations) were compared among crosses: number, length, weight, number of seeds, firmness and chemical traits related to flavor and shelf life. Flowers were pollinated by four bee species, and Apis mellifera was the most frequent. followed by two native bee species. OP and A. mellifera resulted in more fruits than CP. Fruits resulting from OP were heavier than CP and had similar weight when compared to A. mellifera. The other variables did not differ between treatments. The better performance of OP and A. mellifera when compared to CP is probably related to the xenia, i.e., the influence of tissues bearing paternal genes (pollen and pollen tube) in maternal tissues. OP and A. mellifera experiments apparently resulted in the deposition of a greater genotypic diversity of the pollen loads when compared to CP. This result is also explained by the higher functional diversity of pollinators related to OP when compared to CP. This study not only elucidates immediate impacts on yield but also emphasizes the deeper connections between floral biology, pollinator diversity, and sustainable crop production, once West Indian gherkin profit was enhanced by bee pollination.

The tumor suppressor p53 is the most frequently mutated protein in human cancer. The majority of these mutations are missense mutations in the DNA binding domain of p53. Restoring p53 tumor suppressor function could have a major impact on the therapy for a wide range of cancers. Here we report a virtual screening approach that identified several small molecules with p53 reactivation activities. The UCI-LC0023 compound series was studied in detail and was shown to bind p53, induce a conformational change in mutant p53, restore the ability of p53 hotspot mutants to associate with chromatin, reestablish sequence-specific DNA binding of a p53 mutant in a reconstituted in vitro system, induce p53-dependent transcription programs, and prevent progression of tumors carrying mutant p53, but not p53null or p53WT alleles. Our study demonstrates feasibility of a computation-guided approach to identify small molecule corrector drugs for p53 hotspot mutations.

Background/Objectives: Levothyroxine (L-T4) is available for use in congenital hypothyroidism (CH) in three formulations: tablets, drops, and oral solution. This study aims to compare the efficacy and safety of all three L-T4 formulations. Methods: We enrolled 63 children born between January 2019 and April 2023 in the Emilia-Romagna Region (Italy) and diagnosed with CH by newborn screening. They were divided according to the L-T4 formulation used: drops (Group D), oral solution (Group S), and tablets (Group T). Clinical and laboratory data were collected up to 3 years after the start of replacement therapy. Results: Serum-free thyroxine (sFT4) and thyroid stimulating hormone (sTSH) normalization occurred within the first month of treatment in most patients of all groups. No negative effects on growth and cognitive development were observed. At 7–15 days we found higher median sTSH levels (p = 0.031) and a greater percentage of patients with sTSH > 5 µU/mL (p = 0.011) in Group S than in Group T, but comparable sFT4 levels. At 12 months, a greater percentage of patients of Group D showed sFT4 values below the normal range than Group S (p = 0.011) and Group T (p = 0.038); Conclusions: Overall, our study reported an equal efficacy of the L-T4 oral solution compared to drops and tablets in CH treatment. A larger series of patients and a long-term follow-up are needed.

Rickets results from impaired mineralization of growing bone due to alterations in calcium and phosphate homeostasis. Clinical signs of rickets are related to the age of the patient, the duration of the disease, and the underlying disorder. The most common signs of rickets are swelling of the wrists, knees or ankles, bowing of the legs (knock-knees, outward bowing, or both) and inability to walk. However, clinical features alone cannot differentiate between the various forms of rickets. Rickets includes a heterogeneous group of acquired and inherited diseases. Nutritional rickets is due to a deficiency of vitamin D, dietary calcium or phosphate. Mutations in genes responsible for vitamin D metabolism or function, the production or breakdown of fibroblast growth factor 23, renal phosphate regulation, or bone mineralization can lead to the hereditary form of rickets. This position paper reviews the relevant literature and presents the expertise of the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology (SIEDP). The aim of this document is to provide practical guidance to specialists and healthcare professionals on the main criteria for diagnosis, treatment, and management of patients with rickets. The various forms of rickets are discussed, and detailed references for the discussion of each form are provided. Algorithms to guide the diagnostic approach and recommendations to manage patients with rare forms of hereditary rickets are proposed.

Summary: Here, we present a protocol for lentiviral delivery of CRISPR-Cas9 to human induced pluripotent stem cell (iPSC)-derived macrophages using co-incubation with VPX virus-like particles (VPX-VLPs). We describe steps for producing polybrene and puromycin kill curves, VPX viral production, and VPX-VLP titration by western blotting. We then detail procedures for iPSC macrophage precursor lentiviral transduction and lentiviral CRISPR-Cas9-based knockout in iPSC-derived macrophages. This protocol uses efficient genome-editing techniques to explore macrophage involvement in immune response, chronic inflammation, neurodegenerative disease, and cancer progression.For complete details on the use and execution of this protocol, please refer to Navarro-Guerrero et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

p53 is a crucial tumor suppressor in vertebrates that is frequently mutated in human cancers. Most mutations are missense mutations that render p53 inactive in suppressing tumor initiation and progression. Developing small-molecule drugs to convert mutant p53 into an active, wild-type-like conformation is a significant focus for personalized cancer therapy. Prior research indicates that reactivating p53 suppresses cancer cell proliferation and tumor growth in animal models. Early clinical evidence with a compound selectively targeting p53 mutants with substitutions of tyrosine 220 suggests potential therapeutic benefits of reactivating p53 in patients. This study identifies and examines the UCI-1001 compound series as a potential corrector for several p53 mutations. The findings indicate that UCI-1001 treatment in p53 mutant cancer cell lines inhibits growth and reinstates wild-type p53 activities, including DNA binding, target gene activation, and induction of cell death. Cellular thermal shift assays, conformation-specific immunofluorescence staining, and differential scanning fluorometry suggest that UCI-1001 interacts with and alters the conformation of mutant p53 in cancer cells. These initial results identify pyrimidine trione derivatives of the UCI-1001 series as candidates for p53 corrector drug development.

Congenital adrenal hyperplasia (CAH) is a recessive condition t hat affects the adrenal glands. Despite life-long replacement therapy with glucocorticoids and mineralocorticoids, adult patients with CAH often experience impaired gonadal function. In pubertal boys and in men with CAH, circulating testosterone is produced by the adrenal glands as well as the testicular, steroidogenic cells. In this European two-center study, we evaluated the function of Leydig and Sertoli cells in 61 boys and men with CAH, primarily due to 21-hydroxylase deficiency. Despite conventional hormone replacement therapy, our results indicated a significant reduction in serum concentrations of both Leydig cel l-derived hormones (i.e. insulin-like factor 3 (INSL3) and testosterone) and Sertoli cell-derived hormones (i.e. inhibin B and anti-Müllerian hormone) in adult males with CAH. Serum concentrations of INSL3 were particularly reduced in those with testicular adrenal rest tumors. To our knowledge, this is the first study to evaluate circulating INSL3 as a candi date biomarker to monitor Leydig cell function in patients with CAH.

Summary: Background: Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained. Methods: We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/SF-1 variants, identified through the I-DSD registry and a research network. Findings: Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF-1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with

Abstract Ceratitis capitata (Wiedemann, 1824) is an insect of major economic importance in the mango orchards of the submedium of the São Francisco River Valley, the main area of mango production and exportation in Brazil. To provide alternatives for the management of C. capitata, toxic baits based on alpha-cypermethrin (Gelsura®) and spinosad (Success® 0.02 CB) were evaluated in three commercial mango experiments during two consecutive harvests: 2016/2017 (experiment 1 - area 1) and 2017/2018 (experiment 2 -area 2 and experiment 3 - area 3). According to the results, there was a large reduction in the infestation of C. capitata after five sequential applications of the alpha-cypermethrin (6 g.ha-1) and spinosad (0.38 g.ha-1) toxic baits performed at seven-day intervals during mango fruit ripening in all experiments and years (harvest) evaluated. Compared with the untreated plots, the plots with alpha-cypermethrin and spinosad applications showed a significant reduction in the damage induced (fallen fruits and/or on trees) by C. capitata. The management of C. capitata in mango orchards can include the use of the toxic bait based on alpha-cypermethrin, which represents an alternative to rotate with spinosad toxic bait in the São Francisco River Valley.

Background: Information on clinical outcomes of coronavirus disease 19 (COVID-19) infection in patients with adrenal disorders is scarce. Methods: A collaboration between the European Society of Endocrinology (ESE) Rare Disease Committee and European Reference Network on Rare Endocrine Conditions via the European Registries for Rare Endocrine Conditions allowed the collection of data on 64 cases (57 adrenal insufficiency (AI), 7 Cushing’s syndrome) th at had been reported by 12 centres in 8 European countries between January 2020 and Dec ember 2021. Results: Of all 64 patients, 23 were males and 41 females (13 of those children) with a median age of 37 and 51 years. In 45/57 (95%) AI cases, COVID -19 infection was confirmed by testing. Primary insufficiency was present in 45/57 p atients; 19 were affected by Addison’s disease, 19 by congenital adrenal hyperpla sia and 7 by primary AI (PAI) due to other causes. The most relevant comorbidities w ere hypertension (12%), obesity (n = 14%) and diabetes mellitus (9%). An increase by a median of 2. 0 (IQR 1.4) times the daily replacement dose was reported in 42 (74%) patie nts. Two patients were administered i.m. injection of 100 mg hydrocortisone, and 11/64 were admitted to the hospital. Two patients had to be transferred to the intensive care unit, one with a fatal outcome. Four patients reported persistent SARS-CoV-2 inf ection, all others complete remission. Conclusion: This European multicentre questionnaire is the first to collect data on the outcome of COVID-19 infection in patients with adrenal gland disorders. It suggests good clinical outcomes in case of duly dose adjustments and emphasiz es the importance of patient education on sick day rules.

Venous leg ulcers are one of the most common nonhealing conditions and represent an important clinical problem. The application of pulsed radiofrequency electromagnetic fields (PRF-EMFs), already applied for pain, inflammation, and new tissue formation, can represent a promising approach for venous leg ulcer amelioration. This study aims to evaluate the effect of PRF-EMF exposure on the inflammatory, antioxidant, cell proliferation, and wound healing characteristics of human primary dermal fibroblasts collected from venous leg ulcer patients. The cells’ proliferative and migratory abilities were evaluated by means of a BrdU assay and scratch assay, respectively. The inflammatory response was investigated through TNFα, TGFβ, COX2, IL6, and IL1β gene expression analysis and PGE2 and IL1β production, while the antioxidant activity was tested by measuring GSH, GSSG, tGSH, and GR levels. This study emphasizes the ability of PRF-EMFs to modulate the TGFβ, COX2, IL6, IL1β, and TNFα gene expression in exposed ulcers. Moreover, it confirms the improvement of the proliferative index and wound healing ability presented by PRF-EMFs. In conclusion, exposure to PRF-EMFs can represent a strategy to help tissue repair, regulating mediators involved in the wound healing process.

Background and Objectives: bLH is considered an excellent biochemical predictor of CPP. However, its utilization in clinical practice shows some uncertainties. This study aims to evaluate the diagnostic power of bLH and propose a diagnostic algorithm for CPP. Materials and Methods: We conducted a monocentric cohort retrospective study evaluating all females referred for suspicion of CPP between 1 January 2017 and 31 December 2020 who underwent a GnRH test. Auxological, hormonal, and instrumental data were collected, including pelvic ultrasonography and bone age (BA) assessment. Simple linear regression, t-test, and ROC tests were utilized to study the diagnostic value of basal hormone levels. Two hundred thirteen girls were included in the study. They were subdivided into two groups according to the results of the GnRH test: Group 1, with LH peak > 5 IU/L (pubertal) and 79 patients (37%), and Group 2, with an LH peak ≤ 5 IU/L (prepubertal) and 134 patients (63%). Results: The ROC curve showed that bLH level > 1.5 Ul/L best predicts a pubertal response to the GnRH test (AUC 0.8821, accuracy 82%), with low sensitivity (34%). The multivariate analysis found that bLH > 0.5 IU/L, basal FSH (bFSH) > 3.5 IU/L, bLH/bFSH ratio > 0.16, BA advancement > 1.7 years, uterine volume > 3.6 mL, longitudinal uterine diameter > 41 mm, and the presence of endometrial rhyme were significantly associated with a pubertal response at the GnRH test. An algorithm based on these features was created, and its application would reduce the number of GnRH tests by 34%. Overall, 96.2% of Group 1 patients reached the LH peak at the 30th minute of the GnRH test, supporting the hypothesis that the GnRH test duration could be reduced to 30 min. Conclusions: Morning bLH > 1.5 IU/L could be carefully used as a diagnostic predictor of CPP. The GnRH test, even reduced to 30 min, could be reserved for girls who show low intermediate morning bLH and specific clinical signs of pubertal development.

Background Complications are frequently reported after hypospadias repair and there is a need to understand the factors that influence their occurrence.Methods Data from boys with hypospadias born between 2000 and 2020 were obtained from the International Disorders of Sex Development (I-DSD) Registry. Logistic regressions, fisher’s exact tests and spearman’s correlation tests were performed on the data to assess associations between clinical factors and complication rates.Results Of the 551 eligible boys, data were available on 160 (29%). Within the cohort, the median (range) External Masculinization Score (EMS) was 6 (2, 9). All presented with one or more additional genital malformation and 61 (38%) presented with additional extragenital malformations. Disorders of androgen action, androgen synthesis and gonadal development were diagnosed in 28 (18%), 22 (14%) and 9 (6%) boys, respectively. The remaining 101 (62%) patients were diagnosed as having non-specific 46,XY Disorders of Sex Development. Eighty (50%) boys had evidence of abnormal biochemistry, and gene variants were identified in 42 (26%). Median age at first hypospadias surgery was 2 years (0, 9), and median length of follow-up was 5 years (0, 17). Postsurgical complications were noted in 102 (64%) boys. There were no significant associations with postsurgical complications.Conclusions Boys with proximal hypospadias in the I-DSD Registry have high rates of additional comorbidities and a high risk of postoperative complications. No clinical factors were significantly associated with complication rates. High complication rates with no observable cause suggest the involvement of other factors which need investigation.

In topological physics, the bulk-boundary correspondence is of great interest in both Hermitian and non-Hermitian systems. This work unveils a similar universal modulation instability-rogue wave correspondence in integrable models, which may offer a way of better understanding the physics of nonlinear waves as well as of obtaining exact rogue wave solutions.

Differences of sex development and maturation (SDM) represent a heterogeneous puzzle of rare conditions with a large genetic component whose management and treatment could be improved by an accurate classification of underlying molecular conditions, and next-generation sequencing (NGS) should represent the most appropriate approach. Therefore, we conducted a survey dedicated to the use and potential outcomes of NGS for SDM disorders diagnosis among the 53 health care providers (HCP) of the European Reference Network for rare endocrine conditions. The response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except 1, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with differences of sex development (DSD), including 811 unexplained primary ovarian insufficiency, and 2956 (44%) with congenital hypogonadotropic hypogonadism (CHH). The approaches varied from targeted analysis of custom gene panels (range: 11–490 genes) in 81.5% of cases or whole exome sequencing with the extraction of a virtual panel in the remaining cases. These analyses were performed for diagnostic purposes in 21 HCPs, supported by the National Health Systems in 16 cases. The likelihood of finding a variant ranged between 7 and 60%, mainly depending upon the number of analysed genes or criteria used for reporting, most HCPs also reporting variants of uncertain significance. These data illustrate the status of genetic diagnosis of DSD and CHH across Europe. In most countries, these analyses are performed for diagnostic purposes, yielding highly variable results, thus suggesting the need for harmonization and general improvements of NGS approaches.

En este trabajo se presenta un análisis exploratorio de la heterogeneidad temporal de la performance económica de la economía argentina para el período 1960-2020, a partir de datos de frecuencia anual. El objetivo es proponer tres grupos de desempeño –que representan años de buena, mala y muy mala performance económica– y caracterizarlos a partir de un amplio conjunto de variables. La metodología utilizada es exploratoria y está basada en el Análisis de Componentes Principales (ACP), una técnica que permite resumir la información de un conjunto de datos multivariados y caracterizar a los grupos obtenidos a partir de un pequeño número de ellas. Los resultados obtenidos permiten evidenciar las características principales de cada uno de los grupos. El primero de ellos, que representa a los años de buena performance económica corresponde al crecimiento económico, el consumo de bienes finales y la formación bruta de capital. El grupo dos, que incluye los años de desempeño económico deficiente, no presenta variables que lo caractericen, pero se encuentran ausentes en ellos las variables que caracterizan al primer grupo. Finalmente, el tercer grupo, abarca los años de crisis económicas severas y disruptivas, siendo las variables que mejor lo representan la abrupta tasa de crecimiento del ratio deuda/PBI del gobierno central, la tasa de crecimiento del crédito interno –tanto al sector privado como al sector financiero, la tasa de crecimiento del comercio y la tasa de crecimiento de las exportaciones.

Synthesis of a stable, well ordered honeycomb borophene (hB) phase has been achieved to date by exploiting Al(111) as a growth substrate, which provides the necessary charge doping to compensate the high hexagonal-holes density. However, B/Al(111) is governed by a strong B–Al interaction so to yield the actual formation of an AlB _2 hB phase. Dilution of aluminum by alloying could then in principle weaken the boron-support bonding. By means of a combined spectroscopy and microscopy experimental approach, we find instead that the growth of boron layers on the Ni _3 Al(111) alloy termination is driven by B dissolution into the bulk and surface segregation mechanisms. While no long-range ordered boron-induced phase is observed, locally ordered superstructural units with triangular appearance are stabilized by substrate pinning, following the chemical p (2 × 2) surface order. Oxidation involves both boron and aluminum, inducing surface segregation of B, while nickel remains in its metallic form.

Optical rogue waves are the optical counterpart of sudden and dramatic oceanic wave formations the underlying physics of which are thought to be connected with solitons. Here, the authors report the observation of a 2D spatial twin spotlight beam in anisotropic crystals with quadratic nonlinearity, that spontaneously appears and disappears as a function of laser beam in intensity.

During the main COVID-19 global pandemic lockdown period of 2020 an impromptu set of pollination ecologists came together via social media and personal contacts to carry out standardised surveys of the flower visits and plants in gardens. The surveys involved 67 rural, suburban and urban gardens, of various sizes, ranging from 61.18° North in Norway to 37.96° South in Australia, resulting in a data set of 25,174 rows, with each row being a unique interaction record for that date/site/plant species, and comprising almost 47,000 visits to flowers, as well as records of flowers that were not visited by pollinators, for over 1,000 species and varieties belonging to more than 460 genera and 96 plant families. The more than 650 species of flower visitors belong to 12 orders of invertebrates and four of vertebrates. In this first publication from the project, we present a brief description of the data and make it freely available for any researchers to use in the future, the only restriction being that they cite this paper in the first instance. The data generated from these global surveys will provide scientific evidence to help us understand the role that private gardens (in urban, rural and suburban areas) can play in conserving insect pollinators and identify management actions to enhance their potential.

X-linked hypophosphatemic rickets (XLH) is an X-linked dominant disease caused by mutations in the Phosphate-Regulating Endopeptidase X-Linked (PHEX) gene. Due to its rarity and the wide range of clinical manifestations, management of the disease can be challenging due to several associated clinical implications that may arise during follow-up. The neurological complications associated with XLH are the most severe and often less known, which lead to important comorbidities. With the aim of summarizing the available knowledge on neurosurgical intervention in patients with XLH, we present four emblematic cases with disorders requiring neurosurgical evaluation. Relevant diagnostic delay was seen in two of these cases, with another case demonstrating that complications requiring neurosurgery may be present even in patients with few symptoms. The last case stresses the need for care of adult patients who can present with undiagnosed comorbidities. We also carried out a narrative review on neurosurgical interventions in patients with XLH. Through case reports and a review of the literature, focus is placed on the role of the neurosurgeon in the management of patients with XLH. In fact, neurosurgical intervention can often provide stable outcomes for craniosynostosis and clinical improvement for symptoms related to spinal stenosis. Thus, the neurosurgeon can aid in optimizing management of patients with XLH and should be a member of both adult and pediatric multidisciplinary teams. Lastly, additional studies are needed to determine if the early use of burosumab in infants can help to avoid complications in the long term.

BackgroundDespite the optimization of replacement therapy, adrenal crises still represent life-threatening emergencies in many children with adrenal insufficiency.ObjectiveWe summarized current standards of clinical practice for adrenal crisis and investigated the prevalence of suspected/incipient adrenal crisis, in relation to different treatment modalities, in a group of children with adrenal insufficiency.ResultsFifty-one children were investigated. Forty-one patients (32 patients 4 yrs) used quartered non-diluted 10 mg tablets. Two patients 4 yrs used crushed non-diluted 10 mg tablets. The overall number of episodes of adrenal crisis was 7.3/patient/yr in patients 4 yrs. The mean number of hospital admissions was 0.5/patient/yr in children 4 yrs. There was a wide variability in the individual number of events reported. Both children on therapy with a micronized weighted formulation reported no episode of suspected adrenal crisis during the 6-month observation period.ConclusionParental education on oral stress dosing and switching to parenteral hydrocortisone when necessary are the essential approaches to prevent adrenal crisis in children.

O presente estudo trata de forma crítica e reflexiva acerca da formação de professores para a Educação Profissional e Tecnológica (EPT). Tem por objetivo demonstrar a centralidade do professor no processo de ensino e aprendizagem, de modo a destacar a importância de uma formação para a docência na EPT. A metodologia empregada fundamenta-se em uma pesquisa de abordagem qualitativa, pautada no método do materialismo histórico dialético e nos objetivos exploratórios. Ainda, utilizou-se da técnica bibliográfica narrativa, concentrada em obras de autores e comentadores que investigam a formação docente para atuar na EPT. Apresenta uma estrutura que pode ser assim descrita: a) aborda o contexto em que está inserida a formação docente para a EPT no Brasil; b) discute os desafios históricos e perspectivas contemporâneas no cenário da formação de professores para a EPT no Brasil. Por fim, trata das considerações finais. Conclui-se que há especificidades que devem ser consideradas na formação de professores para a EPT. A tônica dessa inferência encontra-se no preceito teórico, conceitual e ideológico de tomar os processos formativos e educativos sob o tripé: ensino, pesquisa e extensão. Palavras-chave: Educação profissional; formação de professores; trabalho como princípio educativo.

Abstract Background Cancer stem cells (CSC) have been implicated in tumor progression. In ovarian carcinoma (OC), CSC drive tumor formation, dissemination and recurrence, as well as drug resistance, thus contributing to the high death-to-incidence ratio of this disease. However, the molecular basis of such a pathogenic role of ovarian CSC (OCSC) has been elucidated only to a limited extent. In this context, the functional contribution of the L1 cell adhesion molecule (L1CAM) to OC stemness remains elusive. Methods The expression of L1CAM was investigated in patient-derived OCSC. The genetic manipulation of L1CAM in OC cells provided gain and loss-of-function models that were then employed in cell biological assays as well as in vivo tumorigenesis experiments to assess the role of L1CAM in OC cell stemness and in OCSC-driven tumor initiation. We applied antibody-mediated neutralization to investigate L1CAM druggability. Biochemical approaches were then combined with functional in vitro assays to study the molecular mechanisms underlying the functional role of L1CAM in OCSC. Results We report that L1CAM is upregulated in patient-derived OCSC. Functional studies showed that L1CAM promotes several stemness-related properties in OC cells, including sphere formation, tumor initiation and chemoresistance. These activities were repressed by an L1CAM-neutralizing antibody, pointing to L1CAM as a druggable target. Mechanistically, L1CAM interacted with and activated fibroblast growth factor receptor-1 (FGFR1), which in turn induced the SRC-mediated activation of STAT3. The inhibition of STAT3 prevented L1CAM-dependent OC stemness and tumor initiation. Conclusions Our study implicate L1CAM in the tumorigenic function of OCSC and point to the L1CAM/FGFR1/SRC/STAT3 signaling pathway as a novel driver of OC stemness. We also provide evidence that targeting this pathway can contribute to OC eradication.

Abstract Objective Recently, we observed some cases of Precocious Puberty (PP) with a partial central activation of hypothalamic-pituitary-gonadal (HPG) axis that tended to normalized in 6–12 months. To evaluate the frequency of this form within the spectrum of forms of PP, we retrospectively assessed the clinical, hormonal and ultrasound characteristics of patients attending to our Center for signs of PP, between 2007 and 2017. To hypothesize some causes of this “pubertal poussée” a questionnaire about environmental data was provided to patients. Methods 96 girls were recruited for the study and divided into three Groups. Group 1: 56 subjects with Central PP (CPP) requiring treatment with GnRH analogue; Group 2: 22 subjects with transient activation of pubertal axis, that tended to normalize, “Transient CPP”(T-CPP); Group 3: 18 subjects with Isolated Thelarche (IT). Results Mean age at diagnosis was 6.8 ± 1.0 years in Group 1, 5.9 ± 1.3 years in Group 2 and 5.6 ± 1.5 years in Group 3. A significant increase of diagnosis of T-CPP was observed over the study period. Significantly higher use of some homeopathic medicines and potential exposure to pesticides was reported in Group 2 vs Group 1. Conclusions To our knowledge, we first reported a form defined as T-CPP, characterized by partial activation in the HPG axis normalizing over time. An increased use of homeopathic medicines and exposure to environmental pollutants in these patients was evidenced.

Testicular adrenal rest tumors (TARTs) are a common complication in male patients with congenital adrenal hyperplasia (CAH). The aim of our cross-sectional cohort study is to estimate the frequency of TARTs with the correlation of genotype and disease control on tumor development. Thirty-five male patients, aged 14–26 years, were included in the study, all followed by the same center of pediatric endocrinology in Bologna. We studied genotypes, hormonal profiles at different time intervals and testicular ultrasound. A logistic regression model with multivariant analysis was developed for the statistical analysis. TARTs were detected in 31.4% of the cases, 90.9% of them had a classic form with salt wasting, while 9.1% had a non-classic form. Additionally, a significant correlation between the incidence of TARTs and severity of genotype was detected. Patients with TARTs had markedly worse metabolic control on average (p = 0.027), reflected by high ACTH, 17OH progesterone, and overall delta4-androstenedione. In conclusion, a screening tool is mandatory, especially (but not exclusively) in patients with the most severe forms of CAH and poor endocrine control of the disease.

An infant with a prenatal diagnosis of citrullinemia, who started standard treatment at birth (L-arginine; sodium benzoate and a personalized diet characterized by a low protein intake and supplementation of essential nutrients and amino acids), presented at 4 months of age with extended, progressive, and severe skin lesions consistent with acrodermatitis dysmetabolica. Guidelines for the diagnosis and management of urea cycle disorders underline that a low-protein diet places patients at risk of essential fatty acids, trace elements, and vitamin deficiency. At hospital admission, our patient had normal levels of zinc and alkaline phosphatases. The plasmatic amino acid profile revealed a severe and generalized deficiency. In particular, the serum levels of arginine, valine, and isoleucine were very low and the dermatitis did not improve until the blood levels of these amino acids increased. In our patient, skin lesions happened despite an early diagnosis of citrullinemia and timely treatment due to compliance issues as a consequence of linguistic barriers.