MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2^{Kip2} targeting

Rhabdomyosarcomas (RMS) are pediatric mesenchymal-derived malignancies encompassing PAX3/7-FOXO1 Fusion Positive (FP)-RMS, and Fusion Negative (FN)-RMS with frequent RAS pathway mutations. RMS express the master myogenic transcription factor MYOD that, whilst essential for survival, cannot support differentiation. Here we discover SKP2, an oncogenic E3-ubiquitin ligase, as a critical pro-tumorigenic driver in FN-RMS. We show that SKP2 is overexpressed in RMS through the binding of MYOD to an intronic enhancer. SKP2 in FN-RMS promotes cell cycle progression and prevents differentiation by directly targeting p27$^{Kip1}$ and p57$^{Kip2}$, respectively. SKP2 depletion unlocks a partly MYOD-dependent myogenic transcriptional program and strongly affects stemness and tumorigenic features and prevents in vivo tumor growth. These effects are mirrored by the investigational NEDDylation inhibitor MLN4924. Results demonstrate a crucial crosstalk between transcriptional and post-translational mechanisms through the MYOD-SKP2 axis that contributes to tumorigenesis in FN-RMS. Finally, NEDDylation inhibition is identified as a potential therapeutic vulnerability in FN-RMS

Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care

Introduction: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. Methods: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. Results: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42%  60% of patients, and more often than sitagliptin or empagliflozin. Conclusion: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management

The social construction process of geographical indication: sustainable territorial development in the Planalto Norte Catarinense

Different initiatives civil society and the state have emerged with the aim of inducing sustainable development in rural territories where family farming predominates. This paper aims to evaluate the potential of the processes of constitution of Geographical Indications (GI) in promoting Sustainable Territorial Development (STD), based on the analysis of the trajectory of the construction of the GI Erva-Mate, from Planalto Norte Catarinense (PNC). The research combined bibliographic and documentary review with semi-structured interviews. The model of the Basket of Territorial Goods and Services is presented as a theoretical-methodological approach that can be adopted by local actors, aiming for a more comprehensive and articulated model of STD process. From this approach, it appears that, despite the long trajectory of the construction of mate tea GI, doubts remain regarding its functioning among the actors of the production chain. At the same time, it is notable the governance structure established in the PNC, which enables the integration of other initiatives. Thus, based on the case analyzed, it can be seen that development strategies need to be adapted to the socio-cultural, economic and environmental specificities of Brazil.Diferentes iniciativas da sociedade civil e do Estado surgiram com o objetivo de induzir o desenvolvimento sustentável em territórios rurais onde predomina a agricultura familiar. O presente artigo visa avaliar o potencial dos processos de constituição de Indicações Geográficas (IG) em promover o Desenvolvimento Territorial Sustentável (DTS), tomando por base a análise da trajetória de construção da IG Erva-Mate do Planalto Norte Catarinense. A pesquisa combinou revisão bibliográfica e documental com a realização de entrevistas semiestruturadas. O modelo da Cesta de Bens e Serviços Territoriais é apresentado como um enfoque teórico-metodológico que pode ser adotado pelos atores locais, visando um modelo mais abrangente e articulado do processo de DTS. A partir desse enfoque, constata-se que, apesar da longa trajetória de construção da IG da erva-mate, persistem dúvidas quanto ao seu funcionamento entre os atores da cadeia produtiva. Paralelamente, é notória a estrutura de governança constituída no PNC, que possibilita a integração de outras iniciativas. Assim, com base no caso analisado, percebe-se que estratégias de desenvolvimento precisam ser adaptadas às especificidades socioculturais, econômicas e ambientais do Brasil

Reliability of two smartphone applications for radiographic measurements of hallux valgus angles

The objective of the present study was to assess the reliability of 2 smartphone applications compared with the traditional goniometer technique for measurement of radiographic angles in hallux valgus and the time required for analysis with the different methods. The radiographs of 31 patients (52 feet) with a diagnosis of hallux valgus were analyzed. Four observers, 2 with >10 years' experience in foot and ankle surgery and 2 in-training surgeons, measured the hallux valgus angle and intermetatarsal angle using a manual goniometer technique and 2 smartphone applications (Hallux Angles and iPinPoint). The interobserver and intermethod reliability were estimated using intraclass correlation coefficients (ICCs), and the time required for measurement of the angles among the 3 methods was compared using the Friedman test. A very good or good interobserver reliability was found among the 4 observers measuring the hallux valgus angle and intermetatarsal angle using the goniometer (ICC 0.913 and 0.821, respectively) and iPinPoint (ICC 0.866 and 0.638, respectively). Using the Hallux Angles application, a very good interobserver reliability was found for measurements of the hallux valgus angle (ICC 0.962) and intermetatarsal angle (ICC 0.935) only among the more experienced observers. The time required for the measurements was significantly shorter for the measurements using both smartphone applications compared with the goniometer method. One smartphone application (iPinPoint) was reliable for measurements of the hallux valgus angles by either experienced or nonexperienced observers. The use of these tools might save time in the evaluation of radiographic angles in the hallux valgus562230233sem informaçã

DNA damage, salivary cortisol levels, and cognitive parameters in a nursing team

In a cross-sectional study of women in a nursing team at a university hospital in southern Brazil, we studied DNA damage, salivary cortisol levels, and cognition. DNA damage was measured in blood leukocytes with the comet assay and the micronucleus test. Salivary cortisol levels were determined upon waking, 30 min later, and at bedtime. Cognition was evaluated according to the Stroop, Digit span and Word span tests. Cortisol levels on waking up were associated negatively with the number of years the employee worked at the institution and positively with the DNA damage in comet assay. Cognitive scores were lower when the cortisol levels were low at awakening and high at bedtime; and were associated positively with educational level. Cortisol status may influence overall health as well as essential work skills, such as attention

De novo partial 13q22-q34 trisomy with typical neurological and immunological findings: A case report with new genetic insights

The partial trisomy 13q encompasses an extensive variability of phenotypic and radiolog-ical findings including leukoencephalopathy and brain malformations such as holoprosencephaly, callosal dysgenesis, hippocampal hypoplasia, olfactory hypoplasia, and vermian hypoplasia. We report for the first time a case of a 23-year-old patient affected by de novo partial 13q22.1q34 trisomy (41.7 Mb, 72,365,975-114,077,122x3) presenting with hemiparesis related to both ischemic and haem-orrhagic cerebral lesions compatible with cerebral vasculitis due to a possible combination of genetic and immunological interaction

Establishment and Characterization of a Cell Line (S-RMS1) Derived from an Infantile Spindle Cell Rhabdomyosarcoma with SRF-NCOA2 Fusion Transcript

Background: Spindle cell rhabdomyosarcoma (S-RMS) is a rare tumor that was previously considered as an uncommon variant of embryonal RMS (ERMS) and recently reclassified as a distinct RMS subtype with NCOA2, NCOA1, and VGLL2 fusion genes. In this study, we established a cell line (S-RMS1) derived from a four-month-old boy with infantile spindle cell RMS harboring SRF-NCOA2 gene fusion. Methods: Morphological and molecular characteristics of S-RMS1 were analyzed and compared with two RMS cell lines, RH30 and RD18. Whole genome sequencing of S-RMS1 and clinical exome sequencing of genomic DNA were performed. Results: S-RMS1 showed cells small in size, with a fibroblast-like morphology and positivity for MyoD-1, myogenin, desmin, and smooth muscle actin. The population doubling time was 3.7 days. Whole genome sequencing demonstrated that S-RMS1 retained the same genetic profile of the tumor at diagnosis. A Western blot analysis showed downregulation of AKT-p and YAP-p while RT-qPCR showed upregulation of endoglin and GATA6 as well as downregulation of TGFßR1 and Mef2C transcripts. Conclusion: This is the first report of the establishment of a cell line from an infantile spindle cell RMS with SRF-NCOA2 gene fusion. S-RMS1 should represent a useful tool for the molecular characterization of this rare and almost unknown tumor