New control mechanisms of the tumor suppressor protein FBXW7 mediated by DYRK2 kinase

The systems responsible for protein homeostasis play a fundamental role in the development of tumors. These systems recognize and degrade incomplete, misfolded proteins or act as control mechanisms for cellular processes. Specifically, protein degradation by the ubiquitination proteasome system (UPS) controls a wide range of them. This ubiquitination-mediated proteolysis is rapid, irreversible, highly regulated, and plays a key role in cell division, growth, and differentiation. With almost total certainty, the protein that is part of a UPS most widely studied to date is FBXW7 ubiquitin ligase, which also has among its substrates key oncoproteins in tumor development involved in cell cycle control, proliferation, migration and tumorigenesis. Furthermore, FBXW7 is among the most mutated genes associated with the development of cancer. Given the high prevalence of FBXW7 mutations, the development of therapies targeting FBXW7 pathway is of great interest. All these data make the scientific community consider FBXW7 a key and fundamental candidate for the search for regulatory mechanisms that can open new anticancer therapies. However, the few known mechanisms for regulating the expression or activity of FBXW7 and, therefore, those signaling pathways vulnerable to being altered using drugs make it necessary to describe new pathways or ways capable of regulating this tumor suppressor. In this work, a new regulatory mechanism for FBXW7 dependent on the serine/threonine protein kinase DYRK2 is described for the first time. We show that DYRK2 interacts with and phosphorylates FBXW7, resulting in its proteasome-mediated degradation. DYRK2-mediated destabilization of FBXW7 is independent of its ubiquitin ligase activity. Furthermore, functional analysis demonstrates the existence of DYRK2- dependent regulatory mechanisms for key substrates of FBXW7. Finally, we provide evidence indicating that DYRK2-dependent regulation of FBXW7 protein accumulation contributes to cytotoxic effects in response to chemotherapeutic agents such as doxorubicin or paclitaxel in colorectal cancer cell lines and to BET inhibitors in T-cell acute lymphoblastic leukemia cell lines. Taken together, this work reveals a new regulatory axis, DYRK2/FBXW7, which provides insight into the role of these two proteins in tumor progression and the response to DNA damage.Los sistemas encargados de la homeostasis de las proteínas juegan un papel fundamental en el desarrollo de tumores. Estos sistemas reconocen y degradan proteínas incompletas, mal plegadas o actúan como mecanismos de control de procesos celulares. Concretamente, la degradación de proteínas por el sistema del proteosoma mediante ubiquitinación (UPS) controla un amplio abanico de ellos. Esta proteólisis mediada por ubiquitinación es rápida, irreversible y está altamente regulada, y cumple un rol determinante en la división, el crecimiento y la diferenciación celular. Con casi total seguridad, la proteína que forma parte de un UPS más ampliamente estudiada hasta la fecha es la ubiquitina ligasa FBXW7, la cual además tiene entre sus sustratos a oncoproteínas clave en el desarrollo tumoral implicados en el control ciclo celular, proliferación, migración y tumorigénesis. Además, FBXW7 se encuentra entre los genes más mutados y asociados al desarrollo de cáncer. Dada la alta prevalencia de mutaciones de FBXW7, el desarrollo de terapias dirigidas a la vía de FBXW7 tiene un gran interés. Todos estos datos hacen que la comunidad científica considere a FBXW7 una candidata clave y fundamental para la búsqueda de mecanismos reguladores que puedan abrir nuevas terapias anticancerígenas. No obstante, los pocos mecanismos de regulación de la expresión o actividad de FBXW7 conocidos y, por lo tanto, aquellas rutas de señalización vulnerables a ser alteradas mediante el uso de fármacos hacen necesario describir nuevas vías o formas capaces de regular a este supresor tumoral. En este trabajo se describe por primera vez, un nuevo mecanismo regulador para FBXW7 dependiente de la serina/treonina proteína quinasa DYRK2. Mostramos que DYRK2 interactúa con FBXW7 y la fosforila, lo que resulta en su degradación mediada por el proteasoma. La desestabilización de FBXW7 mediad por DYRK2 es independiente de su actividad ubiquitina ligasa. Además, el análisis funcional demuestra la existencia de mecanismos reguladores dependientes de DYRK2 para sustratos clave de FBXW7. Finalmente, proporcionamos evidencia que indica que la regulación dependiente de DYRK2 de la acumulación de proteína FBXW7 contribuye a los efectos citotóxicos en respuesta a agentes quimioterapéuticos como la doxorrubicina o el paclitaxel en líneas celulares de cáncer colorrectal y a los inhibidores BET en líneas celulares de leucemia linfoblástica aguda de células T. En conjunto, este trabajo revela un nuevo eje regulador, DYRK2/FBXW7, que permite comprender el papel de estas dos proteínas en la progresión tumoral y la respuesta al daño del ADN

Myxofibroma of the maxilla. Reconstruction with iliac crest graft and dental implants after tumor resection

Odontogenic fibromyxomas are benign odontogenic tumors of mesenchymal origin of rare presentation in the oral cavity, which exhibit locally aggressive behavior and are prone to local recurrence. The controversy has mainly been on therapeutic management with recommendations varying, depending on the clinical cases, from simple curettage of lesion to segmental bone resection. We present a case report describing the reconstruction of an osseous defect in the maxilla and the restoration with dental implants in a 32 year old female patient after radical surgical excision due to an odontogenic fibromyxoma with locally aggressive behavior. The primary reconstruction of maxillary discontinuity defect was carried out by an immediate non-vascularized cortico-cancellous iliac crest graft. Using a computer-guided system for the implant treatment-planning, three dental implants were secondary placed in the bone graft by means of flapless implant surgery. The patient was subsequently restored with an implant-supported fixed prosthesis that has remained in continuous function for a period of three years. The surgical, reconstructive and restorative treatment sequence and techniques are discussed. © Medicina Oral S. L

Engineering of III-Nitride Semiconductors on Low Temperature Co-fired Ceramics

This work presents results in the feld of advanced substrate solutions in order to achieve high crystalline quality group-III nitrides based heterostructures for high frequency and power devices or for sensor applications. With that objective, Low Temperature Co-fred Ceramics has been used, as a noncrystalline substrate. Structures like these have never been developed before, and for economic reasons will represent a groundbreaking material in these felds of Electronic. In this sense, the report presents the characterization through various techniques of three series of specimens where GaN was deposited on this ceramic composite, using diferent bufer layers, and a singular metal-organic chemical vapor deposition related technique for low temperature deposition. Other single crystalline ceramic-based templates were also utilized as substrate materials, for comparison purposes

Recent Changes in Breast Cancer Incidence in Spain, 1980–2004

BACKGROUND: Since the 1980s, Spain experienced two decades of sharply increasing breast cancer incidence. Declines in breast cancer incidence have recently been reported in many developed countries. We examined whether a similar downturn might have taken place in Spain in recent years. METHODS: Cases of invasive female breast cancer were drawn from all population-based Spanish cancer registries that had at least 10 years of uninterrupted registration over the period 1980-2004. Overall and age-specific changes in incidence rates were evaluated using change-point Poisson models, which allow for accurate detection and estimation of trend changes. All statistical tests were two-sided. RESULTS: A total of 80,453 incident cases of invasive breast cancer were identified. Overall age- and registry-adjusted incidence rates rose by 2.9% (95% confidence interval [CI] = 2.7% to 3.1%) annually during the 1980s and 1990s; there was a statistically significant change in this trend in 2001 (95% CI = 1998 to 2004; P value for the existence of a change point <.001), after which incidence declined annually by 3.0% (95% CI = 1.8% to 4.1%). This trend differed by age group: There was a steady increase in incidence for women younger than 45 years, an abrupt downturn in 2001 for women aged 45-64 years, and a gradual leveling off in 1995 for women aged 65 years or older. Separate analyses for registries that had at least 15 years of uninterrupted registration detected a statistically significant interruption of the previous upward trend in breast cancer incidence in provinces that had aggressive breast cancer screening programs and high screening participation rates, including Navarra (change point = 1991, P < .001), Granada (change point = 2002, P = .003), Bizkaia (change point = 1998, P < .001), Gipuzkoa (change point = 1998, P = .001), and Araba (change point = 1997, P = .002). CONCLUSIONS: The recent downturn in breast cancer incidence among Spanish women older than 45 years is best explained by a period effect linked to screening saturation.Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP) (AC07-005 to M.P., PM07-004 to R.P-B.) and Carlos III Institute of Health (ISCIII-CIBERESP collaborative agreement “Acción Transversal del Cancer”).S

Criterios de diseño para locales de Primaria y Secundaria polidocentes completos y usos compartidos

Provee criterios y herramientas para diseño de la infraestructura educativa de este tipo de locales, agrupados por características técnicas (instalaciones, materiales, acabados, u otras) y procesos pedagógicos similares, con el objetivo de definir modelos de espacios mínimos aceptables que respondan también de manera adecuada a las condiciones climáticas de cada zona del país en aras del mejoramiento del servicio educativo, que no depende solamente de estos temas, sino que también está directamente relacionado con el mejoramiento de las prácticas pedagógicas, y con el mejoramiento de la organización y gestión

Predictors of Response to Exclusive Enteral Nutrition in Newly Diagnosed Crohn´s Disease in Children: PRESENCE Study from SEGHNP

Exclusive enteral nutrition (EEN) has been shown to be more effective than corticosteroids in achieving mucosal healing in children with Crohn´s disease (CD) without the adverse effects of these drugs. The aims of this study were to determine the efficacy of EEN in terms of inducing clinical remission in children newly diagnosed with CD, to describe the predictive factors of response to EEN and the need for treatment with biological agents during the first 12 months of the disease. We conducted an observational retrospective multicentre study that included paediatric patients newly diagnosed with CD between 2014–2016 who underwent EEN. Two hundred and twenty-two patients (140 males) from 35 paediatric centres were included, with a mean age at diagnosis of 11.6 ± 2.5 years. The median EEN duration was 8 weeks (IQR 6.6–8.5), and 184 of the patients (83%) achieved clinical remission (weighted paediatric Crohn’s Disease activity index [wPCDAI] 15 mg/L and ileal involvement tended to respond better to EEN. EEN administered for 6–8 weeks is effective for inducing clinical remission. Due to the high response rate in our series, EEN should be used as the first-line therapy in luminal paediatric Crohn’s disease regardless of the location of disease and disease activityS

Sympathetic nervous activation, mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: the metabolomic prognostic models (CLIF-C MET)

Background and aims Current prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those with acute-on-chronic liver failure (ACLF), underestimate the risk of mortality. This is probably because systemic inflammation (SI), the major driver of AD/ACLF, is not reflected in the scores. SI induces metabolic changes, which impair delivery of the necessary energy for the immune reaction. This investigation aimed to identify metabolites associated with short-term (28-day) death and to design metabolomic prognostic models. Methods Two prospective multicentre large cohorts from Europe for investigating ACLF and development of ACLF, CANONIC (discovery, n=831) and PREDICT (validation, n=851), were explored by untargeted serum metabolomics to identify and validate metabolites which could allow improved prognostic modelling. Results Three prognostic metabolites strongly associated with death were selected to build the models. 4-Hydroxy-3-methoxyphenylglycol sulfate is a norepinephrine derivative, which may be derived from the brainstem response to SI. Additionally, galacturonic acid and hexanoylcarnitine are associated with mitochondrial dysfunction. Model 1 included only these three prognostic metabolites and age. Model 2 was built around 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, bilirubin, international normalised ratio (INR) and age. In the discovery cohort, both models were more accurate in predicting death within 7, 14 and 28 days after admission compared with MELDNa score (C-index: 0.9267, 0.9002 and 0.8424, and 0.9369, 0.9206 and 0.8529, with model 1 and model 2, respectively). Similar results were found in the validation cohort (C-index: 0.940, 0.834 and 0.791, and 0.947, 0.857 and 0.810, with model 1 and model 2, respectively). Also, in ACLF, model 1 and model 2 outperformed MELDNa 7, 14 and 28 days after admission for prediction of mortality. Conclusions Models including metabolites (CLIF-C MET) reflecting SI, mitochondrial dysfunction and sympathetic system activation are better predictors of short-term mortality than scores based only on organ dysfunction (eg, MELDNa), especially in patients with ACLF

Safety and immunogenicity of the protein-based PHH-1V compared to BNT162b2 as a heterologous SARS-CoV-2 booster vaccine in adults vaccinated against COVID-19 : a multicentre, randomised, double-blind, non-inferiority phase IIb trial

A SARS-CoV-2 protein-based heterodimer vaccine, PHH-1V, has been shown to be safe and well-tolerated in healthy young adults in a first-in-human, Phase I/IIa study dose-escalation trial. Here, we report the interim results of the Phase IIb HH-2, where the immunogenicity and safety of a heterologous booster with PHH-1V is assessed versus a homologous booster with BNT162b2 at 14, 28 and 98 days after vaccine administration. The HH-2 study is an ongoing multicentre, randomised, active-controlled, double-blind, non-inferiority Phase IIb trial, where participants 18 years or older who had received two doses of BNT162b2 were randomly assigned in a 2:1 ratio to receive a booster dose of vaccine-either heterologous (PHH-1V group) or homologous (BNT162b2 group)-in 10 centres in Spain. Eligible subjects were allocated to treatment stratified by age group (18-64 versus ≥65 years) with approximately 10% of the sample enrolled in the older age group. The primary endpoints were humoral immunogenicity measured by changes in levels of neutralizing antibodies (PBNA) against the ancestral Wuhan-Hu-1 strain after the PHH-1V or the BNT162b2 boost, and the safety and tolerability of PHH-1V as a boost. The secondary endpoints were to compare changes in levels of neutralizing antibodies against different variants of SARS-CoV-2 and the T-cell responses towards the SARS-CoV-2 spike glycoprotein peptides. The exploratory endpoint was to assess the number of subjects with SARS-CoV-2 infections ≥14 days after PHH-1V booster. This study is ongoing and is registered with , . From 15 November 2021, 782 adults were randomly assigned to PHH-1V (n = 522) or BNT162b2 (n = 260) boost vaccine groups. The geometric mean titre (GMT) ratio of neutralizing antibodies on days 14, 28 and 98, shown as BNT162b2 active control versus PHH-1V, was, respectively, 1.68 (p < 0.0001), 1.31 (p = 0.0007) and 0.86 (p = 0.40) for the ancestral Wuhan-Hu-1 strain; 0.62 (p < 0.0001), 0.65 (p < 0.0001) and 0.56 (p = 0.003) for the Beta variant; 1.01 (p = 0.92), 0.88 (p = 0.11) and 0.52 (p = 0.0003) for the Delta variant; and 0.59 (p ≤ 0.0001), 0.66 (p < 0.0001) and 0.57 (p = 0.0028) for the Omicron BA.1 variant. Additionally, PHH-1V as a booster dose induced a significant increase of CD4 + and CD8 + T-cells expressing IFN-γ on day 14. There were 458 participants who experienced at least one adverse event (89.3%) in the PHH-1V and 238 (94.4%) in the BNT162b2 group. The most frequent adverse events were injection site pain (79.7% and 89.3%), fatigue (27.5% and 42.1%) and headache (31.2 and 40.1%) for the PHH-1V and the BNT162b2 groups, respectively. A total of 52 COVID-19 cases occurred from day 14 post-vaccination (10.14%) for the PHH-1V group and 30 (11.90%) for the BNT162b2 group (p = 0.45), and none of the subjects developed severe COVID-19. Our interim results from the Phase IIb HH-2 trial show that PHH-1V as a heterologous booster vaccine, when compared to BNT162b2, although it does not reach a non-inferior neutralizing antibody response against the Wuhan-Hu-1 strain at days 14 and 28 after vaccination, it does so at day 98. PHH-1V as a heterologous booster elicits a superior neutralizing antibody response against the previous circulating Beta and the currently circulating Omicron BA.1 SARS-CoV-2 variants in all time points assessed, and for the Delta variant on day 98 as well. Moreover, the PHH-1V boost also induces a strong and balanced T-cell response. Concerning the safety profile, subjects in the PHH-1V group report significantly fewer adverse events than those in the BNT162b2 group, most of mild intensity, and both vaccine groups present comparable COVID-19 breakthrough cases, none of them severe. HIPRA SCIENTIFIC, S.L.U

Patients receiving a high burden of antibiotics in the community in Spain: a cross-sectional study.

Some patients in the community receive a high burden of antibiotics. We aimed at describing the characteristics of these patients, antibiotics used, and conditions for which they received antibiotics. We carried out a cross-sectional study. Setting: Thirty Health Primary Care Areas from 12 regions in Spain, covering 5,960,191 inhabitants. Patients having at least 30 packages of antibacterials for systemic use dispensed in 2017 were considered. Main outcome measures: Prevalence of antibiotic use, conditions for which antibiotics were prescribed, clinical characteristics of patients, comorbidities, concomitant treatments, and microbiological isolates. Patient's average age was 70 years; 52% were men; 60% smokers/ex-smokers; 54% obese. Overall, 93% of patients had, at least, one chronic condition, and four comorbidities on average. Most common comorbidities were cardiovascular and/or hypertension (67%), respiratory diseases (62%), neurological/mental conditions (32%), diabetes (23%), and urological diseases (21%); 29% were immunosuppressed, 10% were dead at the time of data collection. Patients received three antibiotic treatments per year, mainly fluoroquinolones (28%), macrolides (21%), penicillins (19%), or cephalosporins (12%). Most frequently treated conditions were lower respiratory tract (infections or prophylaxis) (48%), urinary (27%), and skin/soft tissue infections (11%). Thirty-five percent have been guided by a microbiological diagnosis, being Pseudomonas aeruginosa (30%) and Escherichia coli (16%) the most frequent isolates. In conclusion, high antibiotic consumers in the community were basically elder, with multimorbidity and polymedication. They frequently received broad-spectrum antibiotics for long periods of time. The approach to infections in high consumers should be differentiated from healthy patients receiving antibiotics occasionally

Spanish Pediatric Inflammatory Bowel Disease Diagnostic Delay Registry: SPIDER Study From Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátrica

Background and Aims: Diagnostic delay (DD) is especially relevant in children with inflammatory bowel disease, leading to potential complications. We examined the intervals and factors for DD in the pediatric population of Spain. Methods: We conducted a multicentric prospective study, including 149 pediatric inflammatory bowel disease patients, obtaining clinical, anthropometric, and biochemical data. Time to diagnosis (TD) was divided into several intervals to identify those where the DD was longer and find the variables that prolonged those intervals. Missed opportunities for diagnosis (MODs) were also identified. Results: Overall TD was 4.4 months (interquartile range [IQR] 2.6–10.4), being significantly higher in Crohn’s disease (CD) than in ulcerative colitis (UC) (6.3 [IQR 3.3–12.3] vs. 3 [IQR 1.6–5.6] months, p = 0.0001). Time from the visit to the first physician until referral to a pediatric gastroenterologist was the main contributor to TD (2.4 months [IQR 1.03–7.17] in CD vs. 0.83 months [IQR 0.30–2.50] in UC, p = 0.0001). One hundred and ten patients (78.3%) visited more than one physician (29.9% to 4 or more), and 16.3% visited the same physician more than six times before being assessed by the pediatric gastroenterologist. The number of MODs was significantly higher in CD than that in UC patients: 4 MODs (IQR 2–7) vs. 2 MODs ([IQR 1–5], p = 0.003). Referral by pediatricians from hospital care allowed earlier IBD diagnosis (odds ratio 3.2 [95% confidence interval 1.1–8.9], p = 0.025). Conclusions: TD and DD were significantly higher in CD than those in UC. IBD patients (especially those with CD) undergo a large number of medical visits until the final diagnosis.Jiménez Treviño S, Pujol Muncunill G, Martín-Masot R, Rodríguez Martínez A, Segarra Cantón O, Peña Quintana L, Armas Ramos H, Eizaguirre Arocena FJ, Barrio Torres J, García Burriel JI, Ortigosa Castillo L, Donat Aliaga E, Crujeiras Martínez V, Barros García P, Botija Arcos G, Bartolomé Porro JM, Juste Ruiz M, Ochoa Sangrador C, García Casales Z, Galicia Poblet G, Oliver Goicolea P, Lorenzo Garrido H, García Romero R, La Orden Izquierdo E, Pérez Solis D, Navas-López VM, Díaz Martin JJ and Martín de Carpi J (2020) Spanish Pediatric Inflammatory Bowel Disease Diagnostic Delay Registry: SPIDER Study From Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátrica. Front. Pediatr. 8:584278. doi: 10.3389/fped.2020.58427