Gene Expression Analyses in Non Muscle Invasive Bladder Cancer Reveals a Role for Alternative Splicing and Tp53 Status

Non-muscle invasive bladder cancer (NMIBC) represents a crucial problem for the national health care systems due to its high rates of recurrence and the consequent need of frequent follow-ups. Here, gene expression analyses in patients diagnosed as NMIBC were performed to determine those molecular pathways involved in tumor initiation, finding that both MYC and E2F are up regulated and helps to tumor initiation and progression. Our results also support an important involvement of alternative splicing events, modifying key pathways to favour bladder tumor evolution. Finally, since MDM2 showed differential exon usage, mutations in TP53 and its protein expression have been also studied in the same patients. Our data support that recurrence is epigenetically mediated and favoured by an increase protein expression of TP53, which appears more frequently mutated in advanced stages and grades, being associated to a worse prognosis. Therefore, TP53 mutational status could be used as a potential biomarker in the first stages of NMIBC to predict recurrence and prognosis.We express our deepest acknowledgement to patients and their families. The authors also acknowledge the computing resources and technical support provided by Abel Paz-Gallardo and Alfonso Pardo from Extremadura Research Centre for Advanced Technologies (CETA−CIEMAT). This work was supported FEDER cofounded MINECO grant SAF2015-66015-R, ISCIII-RETIC RD12/0036/0009, and PIE15/00076 and CB/16/00228 (to J.M. Paramio); MMF was supported by a Jose Castillejo Fellowship (CAS16/00115)

Genomic landscape and immune-related gene expression profiling of epithelial ovarian cancer after neoadjuvant chemotherapy

Ovarian cancerCàncer d'ovariCáncer de ovarioPlatinum-based neoadjuvant chemotherapy followed by interval debulking surgery is an accepted treatment for patients with stage III or IV epithelial ovarian cancer who are not suitable for primary debulking surgery. The identification of suitable adjuvant treatments in these patients is an unmet need. Here, we explore potential genomic characteristics (mutational and immune-associated expression profiles) in a series of patients undergoing neoadjuvant chemotherapy. Tumor samples from biopsy and interval debulking surgery were analyzed for mutational landscape and immune profiling, together with detailed immunohistochemistry using different immune cell markers, and correlated with clinicopathological characteristics and potential response to neoadjuvant chemotherapy. No major differences in the mutational landscape were observed in paired biopsy and surgery samples. Genomic loss of heterozygosity was found to be higher in patients with total/near-total tumor response. The immune gene expression profile after neoadjuvant chemotherapy revealed activation of several immune regulation-related pathways in patients with no/minimal or partial response. In parallel, neoadjuvant therapy caused a significant increase of tumor-infiltrating lymphocyte population abundance, primarily due to an augmentation of the CD8+ T cell population. Remarkably, these changes occurred irrespective of potential homologous recombination defects, such as those associated with BRCA1/2 mutations. Our study strengthens the use of loss of heterozygosity as a biomarker of homologous repair deficiency. The changes of immune states during neoadjuvant chemotherapy reveal the dynamic nature of tumor-host immune interactions and suggest the potential use of immune checkpoint inhibitors or their combination with poly-ADP polymerase inhibitors in high stage and grade epithelial ovarian cancer patients undergoing neoadjuvant therapy.This study was funded by GlaxoSmithKline (GSK). I.L. position is funded by Fundación Científica Asociación Española Contra el Cáncer (AECC), Predoctoral AECC 2019 grant number PRDMA19024LODE. L. Morales position is funded by AECC, Postdoctoral AECC 2019 grant number POSTD19036MORA. This study was partially co-funded by European Regional Development Fund (FEDER) grants from Science and Innovation (SAF2015-66015-R and PID2019-110758RB-I00 to J.M.P.) and Instituto de Salud Carlos III (CIBERONC no. CB16/12/00228 to J.M.P.)

Relationship between anthropometric parameters, physiological responses, routes and competition results in formula windsurfing

Formula windsurfing is faster than the Olympic version, due to anumber of unique differences. This study was designed to identify the importance of anthropometric and cardiac factors on the final result of the European Formula Windsurf Championships (2007). We selected 45 competitors (30 amateurs and 15 professionals) of 30±9.77 years of age, a height of 182.6±0.06 cm, a weight of 81.67±7.35 kg and a BMIof 24.7±2.1 kg. They were divided into three groups (PG: 15; TG: 45and GPSG: 12). We followed the recommendations of Carter and Marfell-Jones for the anthropometric measurements. The route, speed, distance and heart rate were recorded using an FRWD W600 GPS (Global Positioning System) unit. The anthropometric measurements indicate a professional profile with 2.3±0.4 endomorphy 5±0.8 mesomorphy and 2.4±0.6 ectomorphy. Arm span and fat mass show a significant (p≤0.02) and very significant (p≤0.005) correlation with the final classification. The average speed was 11.84±2.38 km·h–1, the heart rate varied from 128 to 180 b·min–1 and the average was 127.62±13.73 b·min–1. The distances covered (12784.77±5522.19 m) and the times used for the races (2049.3±989.68 s) were very variable. This will assist not only in initial selection for the sport, but also in the design of training programmes which further develop that morphology, where possible, in the pursuit of improved performance

Stray-light contamination and spatial deconvolution of slit-spectrograph observations

Stray light caused by scattering on optical surfaces and in the Earth's atmosphere degrades the spatial resolution of observations. We study the contribution of stray light to the two channels of POLIS. We test the performance of different methods of stray-light correction and spatial deconvolution to improve the spatial resolution post-facto. We model the stray light as having two components: a spectrally dispersed component and a component of parasitic light caused by scattering inside the spectrograph. We use several measurements to estimate the two contributions: observations with a (partly) blocked FOV, a convolution of the FTS spectral atlas, imaging in the pupil plane, umbral profiles, and spurious polarization signal in telluric lines. The measurements allow us to estimate the spatial PSF of POLIS and the main spectrograph of the German VTT. We use the PSF for a deconvolution of both spectropolarimetric data and investigate the effect on the spectra. The parasitic contribution can be directly and accurately determined for POLIS, amounting to about 5%. We estimate a lower limit of about 10% across the full FOV for the dispersed stray light. In quiet Sun regions, the stray-light level from the close surroundings (d< 2") of a given spatial point is about 20%. The stray light reduces to below 2% at a distance of 20" from a lit area for both POLIS and the main spectrograph. A two-component model of the stray-light contributions seems to be sufficient for a basic correction of observed spectra. The instrumental PSF obtained can be used to model the off-limb stray light, to determine the stray-light contamination accurately for observation targets with large spatial intensity gradients such as sunspots, and also allows one to improve the spatial resolution of observations post-facto.Comment: 14 pages, 16 figures, accepted by A&A. Version V2 revised for language editin

Fijación interna en la fractura expuesta del tobillo. Presentación de dos casos

La fractura expuesta de tobillo se presenta de forma esporádica en la práctica de la traumatología. Su evolución clínica está sujeta a múltiples factores, con una propensión hacia la osteoartritis del tobillo con el transcurso de los años. Se presentan dos casos atendidos en el Hospital General Universitario Dr. Gustavo Aldereguía Lima, de Cienfuegos, a los que se les realizó el tratamiento quirúrgico de urgencia consistente en la limpieza quirúrgica de la lesión expuesta, reducción de la luxación y la fijación interna de la fractura. Por la poca frecuencia en la presentación de este tipo de lesión del tobillo y por el interés que puede presentar para el personal médico, en especial para los médicos traumatólogos, se decidió la presentación de estos casos

IKKβ overexpression together with a lack of tumour suppressor genes causes ameloblastic odontomas in mice

Odontogenic tumours are a heterogeneous group of lesions that develop in the oral cavity region and are characterized by the formation of tumoural structures that differentiate as teeth. Due to the diversity of their histopathological characteristics and clinical behaviour, the classification of these tumours is still under debate. Alterations in morphogenesis pathways such as the Hedgehog, MAPK and WNT/β-catenin pathways are implicated in the formation of odontogenic lesions, but the molecular bases of many of these lesions are still unknown. In this study, we used genetically modified mice to study the role of IKKβ (a fundamental regulator of NF-κB activity and many other proteins) in oral epithelial cells and odontogenic tissues. Transgenic mice overexpressing IKKβ in oral epithelial cells show a significant increase in immune cells in both the oral epithelia and oral submucosa. They also show changes in the expression of several proteins and miRNAs that are important for cancer development. Interestingly, we found that overactivity of IKKβ in oral epithelia and odontogenic tissues, in conjunction with the loss of tumour suppressor proteins (p53, or p16 and p19), leads to the appearance of odontogenic tumours that can be classified as ameloblastic odontomas, sometimes accompanied by foci of secondary ameloblastic carcinomas. These tumours show NF-κB activation and increased β-catenin activity. These findings may help to elucidate the molecular determinants of odontogenic tumourigenesis and the role of IKKβ in the homoeostasis and tumoural transformation of oral and odontogenic epitheliaThis work was funded by project PI17/00578, from the “Instituto de Salud Carlos III” (Ministry of Science, Innovation and Universities) and co-funded by the European Regional Development Fund, and approved by the Ethics Committee of our Institution. It has been founded also by projects CB16/12/00228, PI16/00161, RD16/0011/0011, RD12/0019/0023 and SAF2017–84248-PS

Gene Expression Analyses in Non Muscle Invasive Bladder Cancer Reveals a Role for Alternative Splicing and Tp53 Status

Non-muscle invasive bladder cancer (NMIBC) represents a crucial problem for the national health care systems due to its high rates of recurrence and the consequent need of frequent follow-ups. Here, gene expression analyses in patients diagnosed as NMIBC were performed to determine those molecular pathways involved in tumor initiation, finding that both MYC and E2F are up regulated and helps to tumor initiation and progression. Our results also support an important involvement of alternative splicing events, modifying key pathways to favour bladder tumor evolution. Finally, since MDM2 showed differential exon usage, mutations in TP53 and its protein expression have been also studied in the same patients. Our data support that recurrence is epigenetically mediated and favoured by an increase protein expression of TP53, which appears more frequently mutated in advanced stages and grades, being associated to a worse prognosis. Therefore, TP53 mutational status could be used as a potential biomarker in the first stages of NMIBC to predict recurrence and prognosis