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The REarranged during Transfection (RET) receptor tyrosine kinase plays a crucial role in the development of various anatomical structures during embryogenesis and it is involved in many physiological cellular processes. This protein is also associated with the initiation of various cancer types, such as thyroid cancer, non-small cell lung cancer, and multiple endocrine neoplasms. In breast cancer, and especially in the estrogen receptor-positive (ER+) subtype, the activity of RET is of notable importance. Indeed, RET seems to be involved in tumor progression, resistance to therapies, and cellular proliferation. Nevertheless, the ways RET alterations could impact the prognosis of breast cancer and its response to treatment remain only partially elucidated. Several inhibitors of RET kinase have been developed thus far, with various degrees of selectivity toward RET inhibition. These molecules showed notable efficacy in the treatment of RET-driven tumors, including some breast cancer cases. Despite these encouraging results, further investigation is needed to fully understand the potential role RET inhibition in breast cancer. This review aims to recapitulate the existing evidence about the role of RET oncogene in breast cancer, from its pathogenic and potentially prognostic role, to the clinical applications of RET inhibitors.

In this work, we study a Mediterranean cyclone, Helios, which took place during 9–11 February 2023 in the southeastern part of Sicily and Malta, by a multiparametric approach combining microseism results with sea state and meteorological data provided by wavemeter buoy, HF radar, hindcast maps and satellite SEVIRI images. The sub-tropical system Helios caused heavy rainfall, strong wind gusts and violent storm surges with significant wave heights greater than 5 m. We deal with the relationships between such a system and the features of microseism (the most continuous and ubiquitous seismic signal on Earth) in terms of spectral content, space–time variation of the amplitude and source locations tracked by means of two methods (amplitude-based grid search and array techniques). By comparing the location of the microseism sources and the area affected by significant storm surges derived from sea state data, we note that the microseism location results are in agreement with the real position of the storm surges. In addition, we are able to obtain the seismic signature of Helios using a method that exploits the coherence of continuous seismic noise. Hence, we show how an innovative monitoring system of the Mediterranean cyclones can be designed by integrating microseism information with other techniques routinely used to study meteorological phenomena.

Background: Hydroxyurea (HU), also known as hydroxycarbamide, is an oral ribonucleotide reductase inhibitor. In 1999, the United States Food and Drug Administration (FDA) approved HU for the treatment of sickle cell disease (SCD). Since then, it has become the cornerstone in the management of SCD patients, helping to reduce vaso-occlusive crises, acute chest syndrome, the need for blood transfusions, hospitalizations and mortality. There is considerable variability among individuals in HU pharmacokinetic (Pk) parameters that can influence treatment efficacy and toxicity. The objective of this work is part of a clinical study aimed at investigating HU Pk and determining the optimal sampling time to estimate the Area Under the Curve (AUC) in SCD patients. Methods: HU plasma concentration in 80 patients at various time points (2, 4, 6, 24 h) following a 48-h drug washout was quantified using High-Pressure Liquid Chromatography (HPLC) coupled with an ultraviolet (UV) detection method previously described in the literature and adapted to new conditions with partial modifications. Results: The mean HU administered dose was 19.5 ± 5.1 mg/kg (range: 7.7–37.5 mg/kg). The median AUC quantified in plasma patients was 101.3 mg/L/h (Interquartile Range (IQR): 72.5–355.9) and it was not influenced by the weight-based dose. However, there was a strong positive correlation between AUC and Body Mass Index (BMI) as well as dose per Body Surface Area (BSA). Along with a three-point approach for AUC determination present in the literature, we show results obtained from a four-point sampling strategy, which is more useful and effective for better optimizing dose escalation to the maximum tolerated dose (MTD). Moreover, we observed that most patients achieved the maximum HU plasma concentration two hours after drug administration, regardless of age differences. Conclusions: HU treatment, which represents a milestone in the treatment of SCD due to its ability to reduce disease complications and improve patients’ quality of life, requires careful monitoring to optimize the individual dose for saving potential side effects and/or adverse events.

We have learned that the story of COVID-19 is not so simple [...]

Comparar os resultados clínico-funcional pré e pós-operatório de artroplastia total do tornozelo para tratamento de artrose tíbio-talar com a aplicação dos American Orthopaedic Foot and Ankle Society Score, e do Foot and Ankle Outcome Score, além destes foi aplicado o Questionário da Qualidade de Vida SF-36 e Escala Visual Analógica da Dor. Métodos: Estudo clínico retrospectivo com nível de evidência 4, com quinze pacientes submetidos à artroplastia total do tornozelo para tratamento de artrose tíbio-talar. Resultados: Este trabalho possui um nível de significância de 0,05 (5%) e todos os intervalos de confiança construídos ao longo do trabalho foram planejados com 95% de confiança estatística. O teste T-Student Pareado foi utilizado para comparar o American Orthopaedic Foot and Ankle Society Score e o Foot and Ankle Outcome Score entre os momentos pré e pós-operatório. Constatou-se que a média aumentou de forma significativa, no American Orthopaedic Foot and Ankle aumentou de 25,8 para 79,8 e no Foot and Ankle Outcome Score dor de 7,2 para 69,8. Ao correlacionar a Escala Visual Analógica de Dor e o Foot and Ankle Outcome Score Esportes, notou-se que quanto maior for o escore do Foot and Ankle Outcome Score no momento pós, menor será o Escala Visual Analógica da Dor e vice e versa. E ao realizar a correlação positiva, entre o Questionário da Qualidade de Vida SF-36 (Saúde Mental) com o Foot and Ankle Outcome Score Qualidade de Vida em relação ao pé e tornozelo, foi observado que quanto maior o escore do Questionário da Qualidade de Vida SF-36 Saúde Mental maior também será o escore do Foot and Ankle Outcome Score Qualidade de Vida do pé e tornozelo. Conclusão: A artroplastia total de tornozelo apresenta-se como uma opção segura e com melhores resultados no que diz respeito à funcionalidade do membro para pacientes em estágios avançados de artrose tíbio-társica, podendo significar grandes melhorias na qualidade de vida desses pacientes.

We studied the incidence of acute graft versus host disease (GvHD) and its outcome in three consecutive time frames (year 2010), in 3,120 patients allografted in two transplant Centers between 1976 and 2020. The median age increased over the three periods from 32 to 42 to 54 years (p 0.001); post-transplant cyclophosphamide (PTCY) (RR 0.41, p

Teachers of the Computer Science course of the School of Dentistry of the University of Florence have accepted the many invites from academic organizations, health and non-health related, to propose the teaching methodology of updating Wikipedia pages to the students. This study describes the educational strategy that was tested in a class of students attending the Computer Science course of the School of Dentistry. The used approach was analyzed from a qualitative and quantitative point of view, respectively through the administration of a satisfaction survey and the examination of the whole activity carried out by the students. Editing Wikipedia pages was globally appreciated by students who expressed satisfaction in participating in a shared knowledge production process that spreads beyond the academic sphere to address a real audience. The modified Wikipedia pages have aroused interest, receiving many visits from Internet users. The Computer Science course program includes a part related to Evidence Based Medicine, which transfers competencies that are propedeutic to update Wikipedia pages. Aggiornamento di Wikipedia nel Corso di Laurea in odontoiatria e Protesi Dentaria dell’Università di Firenze. I docenti del corso di Informatica del Corso di Laurea in Odontoiatria e Protesi Dentaria (CLOPD) dell’Università di Firenze hanno accolto le numerose istanze provenienti da organizzazioni accademiche, sanitarie e non, che invitano a proporre la metodologia didattica di aggiornamento di Wikipedia agli studenti. In questo studio viene descritta la strategia formativa che è stata sperimentata in una classe di studenti frequentanti l’insegnamento di Informatica di CLOPD. L’approccio utilizzato è stato analizzato da un punto di vista qualitativo e quantitativo, rispettivamente attraverso la somministrazione di un questionario di gradimento e l’esame dell’attività svolta dagli studenti. L’aggiornamento di Wikipedia è stato globalmente apprezzato dagli studenti che hanno espresso soddisfazione nella partecipazione a un processo di produzione di conoscenza condivisa che si diffonde oltre l’ambito accademico per rivolgersi alla popolazione. Le pagine di Wikipedia modificate hanno destato interesse, ricevendo numerosi accessi dagli utenti della rete. Il programma del corso di Informatica prevede una parte relativa alla Evidence Based Medicine, che trasferisce competenze che risultano propedeutiche all’aggiornamento di Wikipedia.

Abstract CRC cells evolve a variety of strategies to limit or circumvent apoptosis cell death. RNA binding proteins (RBPs) regulate many of the molecular mechanisms that underlie the development of cancer. The insulin-like growth factor II mRNA-binding proteins (IMP) family are oncofoetal RBPs, consisting of IMP1, IMP2 and IMP3, which have an important role in RNA metabolism. IMP3 is highly expressed in colorectal cancer (CRC) tissue, where its expression often correlates with poor prognosis. However, the role of IMP3 in CRC is not fully understood. IMP3 expression was analysed using a public database and by Western blotting and immunohistochemistry in human colon samples derived from patients with sporadic CRC and healthy subjects. To address whether IMP3 controls cancer cell survival, we analysed cell death pathways in in vitro and in vivo experiments after IMP3 downregulation by siRNA or an antisense oligonucleotide. IMP3 was highly expressed in CRC samples compared to normal control tissues. The knockdown of IMP3 enhanced a caspase-independent cell death in CRC cell lines. Furthermore, the treatment of CRC cells with IMP3 siRNA did not alter the expression of GSDMD, GPX-4 and the activated form of RIP3, three key molecules that govern pyroptosis, ferroptosis and necroptosis, respectively. Abrogation of IMP3 in CRC significantly reduced Bcl-2 and Bcl-xL mRNA and was associated with an altered mitochondrial membrane potential that allowed the nuclear migration of the apoptosis-inducing factor (AIF). Moreover, specific immunoprecipitation experiments on CRC human cell lines indicated that IMP3 binds Bcl-2 and Bcl-xL mRNA, suggesting that IMP3 acts as a regulator of the intrinsic apoptotic pathway through the surveillance of anti-apoptotic Bcl mRNA metabolism. Finally, we showed that IMP3 block inhibited the growth of CRC cell lines in vivo after transplantation into immunodeficient mice. Altogether, these data support a novel role for IMP3 in controlling the intrinsic caspase-independent apoptotic pathway in CRC.

Alfredo Berrettini,1 Irene Paraboschi,1 Massimo Di Grazia,1 Michele Gnech,1 Guglielmo Mantica,2 Dario Guido Minoli,1 Erika Adalgisa De Marco,1 Gianantonio Manzoni,1 Marco Capece,3 Alessandro Palmieri,3 David Ralph,3 Vincenzo Mirone3 1Department of Pediatric Urology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy; 2Department of Urology, IRCCS Ospedale Policlinico San Martino, Genova, Italy; 3Department of Urology, Azienda Ospedaliera Universitaria “Federico II”, Napoli, ItalyCorrespondence: Irene Paraboschi, Department of Pediatric Urology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, Milano, Italy, Tel +393313229495, Email irene.paraboschi01@gmail.comAbstract: We present the first case of a patient born with congenital fusiform megalourethra who underwent the successful placement of an inflatable penile prosthesis (IPP) and mesh phalloplasty due to primary erectile dysfunction (ED). After an extensive psychosexual assessment and a preoperative MRI scan, an IPP was successfully implanted. The procedure was carried out through a penoscrotal approach, which offered excellent exposure to the crura and the proximal ends of the corpora cavernosa. Following the incision and the dilatation of both corpora cavernosa, the penile cylinders were inserted and a mesh phalloplasty was performed, to replace the erectile tissues lacking in the distal corpora cavernosa. After reservoir and pump placement, the device was tested, and no mechanical issues were recorded. The postoperative course was uneventful, and, at the 2-year follow-up, the patient reported highly satisfactory results, with valid functional erections.Keywords: congenital fusiform megalourethra, inflatable penile prosthesis, phalloplasty, erectile dysfunction

Solar energy is growing rapidly thanks to reduced implementation costs; European development plans foresee a significant increase in installed capacity in the coming years. In this scenario, new identifiable areas on water surfaces are needed. This would lead to the development of floating photovoltaic (FPV) systems, which would mitigate the environmental impacts of terrestrial installations. Therefore, it is necessary to develop and propose a methodology to identify suitable sites for the installation of such plants. This study is useful to demonstrate the potential benefits that can be achieved using the methods of GIS for the optimal siting of FPVs in combination with the use of MCDA in areas such as Sicily, which are characterised by high summer temperatures. Seven watersheds were studied and the best site for FPV allocation selected using MCDA is San Giovanni Dam.

The demand for electrical energy is constantly growing. Power generation from renewable sources will play a role in meeting the electricity demand. Floating photovoltaics is a solution that still needs to be explored in the design and construction phases. The floating system has important characteristics: it reduces evaporation of water and algae growth in the basins, it does not occupy land and has a high efficiency due to the evaporative cooling effect. Multi-criteria decision analysis is used to determine the best technology, between fixed or tracked structure, on a system in Sicily. Analysis provided results regarding the superiority of horizontal axis tracking systems; the Levelized Cost Of Electricity is 64.37 USD/MWh and the avoided CO2 emissions are 23,491.60 tonnes.

Objective: The percutaneous nephrolithotomy (PCNL) in Horseshoe kidneys (HSK) is usually performed in the prone position, allowing entry through the upper pole and providing good access to the collecting system. However, in patients with normal kidney anatomy, the supine position is reliable and safe in most cases, but it is unknown whether the supine position is adequate in patients with HSK. The purpose of this study was to describe the results of PCNL in HSK in three different surgical institutions and to evaluate the impact of supine position during surgery, comparing pre-operative and post-operative data, complications, and stone status after surgery. Material and Methods: Between 2017 and 2022, a total of 10 patients underwent percutaneous renal surgery for stone disease in HSK. All patients were evaluated pre- and post- operatively with non-contrast CT. we evaluated patients (age and gender), stones characteristics (size, number, side, site and density ), and outcomes. The change in haemoglobin, hematocrit, creatinine and eGFr were assessed between the most recent preoperative period and the first postoperative day. Procedure success was defined as stone-free or presence of ≤4 mm fragments (Clinically Insignificant residual Fragments – CIrF). Complications were registered and classified according to Clavien-dindo Grading System, during the 30 - day postoperative period and Clavien scores ≥ 3 were considered as major complications. Statistical analysis was performed using “r 4.2.1” software, with a 5% significance level. we also compared pre-operative and post-operative data using “wilcoxon signedrank test”. Results: No statistical difference was observed between preoperative and post-operative renal function data. At one post operative day CT scan, an overall success rate of 100% was registered. 9/10 patients were completely free from urolithiasis (stone-free rate: 90%), while 1/10 patients had ≤4 mm residual stone fragments (CIrF rate: 10%). No cases of intraoperative complications were registered. Post-operative complications were reported in 1/10 patients. A patient developed urosepsis (defined as SIrS with clinical signs of bacterial infections involving urogenital organs - Clavien-dindo Grade II) after procedure, and was treated with intravenous antibiotic therapy successfully. Conclusions: This study shows that in patients with HSK mini- PCNL in supine position allows to achieve good stone free rate with a very low morbidity. According to our series, the described technique for PCNL in HSK should be an option. Nevertheless these results must be confirmed by further studies.

A genome-wide association study on classic bladder exstrophy reveals eight genome-wide significant loci, most of which contained genes expressed in embryonic developmental bladder stages.