ΔNp73 and its effector targets promote colorectal peritoneal carcinosis and predict survival.

Peritoneal metastasis of colorectal origin appears in ~10-15% of patients at the time of diagnosis and in 30-40% of cases with disease progression. Locoregional spread through the peritoneum is considered stage IVc and is associated with a poor prognosis. The development of a regional therapeutic strategy based on cytoreductive surgery, and hyperthermic intra-abdominal chemotherapy has significantly altered the course of the disease. Although recent evidence supports the benefits of cytoreductive surgery, the benefits of hyperthermic intra-abdominal chemotherapy are, however, still a matter of debate. Understanding the molecular alterations underlying the disease is crucial for developing new therapeutic strategies. Here, we evaluated the involvement in peritoneal dissemination of the oncogenic isoform of TP73, ΔNp73, and its effector targets in in vitro and mouse models, and in 30 patients diagnosed with colorectal peritoneal metastasis. In an orthotopic mouse model, we observed that tumor cells overexpressing ΔNp73 present a higher avidity for the peritoneum and that extracellular vesicles secreted by ΔNp73-upregulating tumor cells enhance their dissemination. In addition, we identified that tumor cells overexpressing ΔNp73 present with dysregulation of genes associated with an epithelial/mesothelial-to-mesenchymal transition (MMT) and that mesothelial cells exposed to the conditioned medium of tumor cells with upregulated ΔNp73 present a mesenchymal phenotype. Lastly, ΔNp73 and its effector target RNAs were dysregulated in our patient series, there were positive correlations between ΔNp73 and its effector targets, and MSN and ITGB4 (ΔNp73 effectors) predicted patient survival. In conclusion, ΔNp73 and its effector targets are involved in the peritoneal dissemination of colorectal cancer and predict patient survival. The promotion of the EMT/MMT and modulation of the adhesion capacity in colorectal cancer cells might be the mechanisms triggered by ΔNp73. Remarkably, ΔNp73 protein is a druggable protein and should be the focus of future studies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

ß-Catenin Drives Butyrophilin-like Molecule Loss and γδ T-cell Exclusion in Colon Cancer.

Intraepithelial lymphocytes (IEL) expressing γδ T-cell receptors (γδTCR) play key roles in elimination of colon cancer. However, the precise mechanisms by which progressing cancer cells evade immunosurveillance by these innate T cells are unknown. Here, we investigated how loss of the Apc tumor suppressor in gut tissue could enable nascent cancer cells to escape immunosurveillance by cytotoxic γδIELs. In contrast with healthy intestinal or colonic tissue, we found that γδIELs were largely absent from the microenvironment of both mouse and human tumors, and that butyrophilin-like (BTNL) molecules, which can critically regulate γδIEL through direct γδTCR interactions, were also downregulated in tumors. We then demonstrated that ß-catenin activation through loss of Apc rapidly suppressed expression of the mRNA encoding the HNF4A and HNF4G transcription factors, preventing their binding to promoter regions of Btnl genes. Reexpression of BTNL1 and BTNL6 in cancer cells increased γδIEL survival and activation in coculture assays but failed to augment their cancer-killing ability in vitro or their recruitment to orthotopic tumors. However, inhibition of ß-catenin signaling via genetic deletion of Bcl9/Bcl9L in either Apc-deficient or mutant ß-catenin mouse models restored Hnf4a, Hnf4g, and Btnl gene expression and γδ T-cell infiltration into tumors. These observations highlight an immune-evasion mechanism specific to WNT-driven colon cancer cells that disrupts γδIEL immunosurveillance and furthers cancer progression.

Dysfunction of programmed embryo senescence is linked to genetic developmental defects.

Developmental senescence is a form of programmed senescence that contributes to morphogenesis during embryonic development. We showed recently that the SIX1 homeoprotein, an essential regulator of organogenesis, is also a repressor of adult cellular senescence. Alterations in the SIX/EYA pathway are linked to the human branchio-oto-renal (BOR) syndrome, a rare congenital disorder associated with defects in the ears, kidneys and branchial arches. Here, we have used Six1-deficient mice, an animal model of the BOR syndrome, to investigate whether dysfunction of senescence underpins the developmental defects associated with SIX1 deficiency. We have focused on the developing inner ear, an organ with physiological developmental senescence that is severely affected in Six1-deficient mice and BOR patients. We show aberrant levels and distribution of senescence markers in Six1-deficient inner ears concomitant with defective morphogenesis of senescent structures. Transcriptomic analysis and ex vivo assays support a link between aberrant senescence and altered morphogenesis in this model, associated with deregulation of the TGFß/BMP pathway. Our results show that misregulation of embryo senescence may lead to genetic developmental disorders, significantly expanding the connection between senescence and disease.

A Phase I-II multicenter trial with Avelumab plus autologous dendritic cell vaccine in pre-treated mismatch repair-proficient (MSS) metastatic colorectal cancer patients; GEMCAD 1602 study.

BACKGROUND: Immune check-point blockade (ICB) has shown clinical benefit in mismatch repair-deficient/microsatellite instability high metastatic colorectal cancer (mCRC) but not in mismatch repair-proficient/microsatellite stable patients. Cancer vaccines with autologous dendritic cells (ADC) could be a complementary therapeutic approach to ICB as this combination has the potential to achieve synergistic effects. METHODS: This was a Phase I/II multicentric study with translational sub-studies, to evaluate the safety, pharmacodynamics and anti-tumor effects of Avelumab plus ADC vaccine in heavily pre-treated MSS mCRC patients. Primary objective was to determine the maximum tolerated dose and the efficacy of the combination. The primary end-point was 40% progression-free survival at 6 months with a 2 Simon Stage. RESULTS: A total of 28 patients were screened and 19 pts were included. Combined therapy was safe and well tolerated. An interim analysis (Simon design first-stage) recommended early termination because only 2/19 (11%) patients were disease free at 6 months. Median PFS was 3.1 months [2.1-5.3 months] and overall survival was 12.2 months [3.2-23.2 months]. Stimulation of immune system was observed in vitro but not clinically. The evaluation of basal RNA-seq noted significant changes between pre and post-therapy liver biopsies related to lipid metabolism and transport, inflammation and oxidative stress pathways. CONCLUSIONS: The combination of Avelumab plus ADC vaccine is safe and well tolerated but exhibited modest clinical activity. Our study describes, for the first-time, a de novo post-therapy metabolic rewiring, that could represent novel immunotherapy-induced tumor vulnerabilities.

Shewanella sp. T2.3D-1.1 a Novel Microorganism Sustaining the Iron Cycle in the Deep Subsurface of the Iberian Pyrite Belt.

The Iberian Pyrite Belt (IPB) is one of the largest deposits of sulphidic minerals on Earth. Río Tinto raises from its core, presenting low a pH and high metal concentration. Several drilling cores were extracted from the IPB's subsurface, and strain T2.3D-1.1 was isolated from a core at 121.8 m depth. We aimed to characterize this subterranean microorganism, revealing its phylogenomic affiliation (Average Nucleotide Identity, digital DNA-DNA Hybridization) and inferring its physiology through genome annotation, backed with physiological experiments to explore its relationship with the Fe biogeochemical cycle. Results determined that the isolate belongs to the Shewanella putrefaciens (with ANI 99.25 with S. putrefaciens CN-32). Its genome harbours the necessary genes, including omcA mtrCAB, to perform the Extracellular Electron Transfer (EET) and reduce acceptors such as Fe3+, napAB to reduce NO3- to NO2-, hydAB to produce H2 and genes sirA, phsABC and ttrABC to reduce SO32-, S2O32- and S4O62-, respectively. A full CRISPR-Cas 1F type system was found as well. S. putrefaciens T2.3D-1.1 can reduce Fe3+ and promote the oxidation of Fe2+ in the presence of NO3- under anaerobic conditions. Production of H2 has been observed under anaerobic conditions with lactate or pyruvate as the electron donor and fumarate as the electron acceptor. Besides Fe3+ and NO3-, the isolate also grows with Dimethyl Sulfoxide and Trimethyl N-oxide, S4O62- and S2O32- as electron acceptors. It tolerates different concentrations of heavy metals such as 7.5 mM of Pb, 5 mM of Cr and Cu and 1 mM of Cd, Co, Ni and Zn. This array of traits suggests that S. putrefaciens T2.3D-1.1 could have an important role within the Iberian Pyrite Belt subsurface participating in the iron cycle, through the dissolution of iron minerals and therefore contributing to generate the extreme conditions detected in the Río Tinto basin.

Vitrification and in-straw warming do not affect pregnancy rates of biopsied bovine embryos.

In the cattle industry, in vivo or in vitro embryo production combined with genotyping and cryopreservation technologies allows the selection and conservation of embryos carrying genes for desirable traits. This study aimed to assess the efficiency of a vitrification method suitable for in-straw warming of biopsied in vivo derived (IVD) bovine embryos. Three experiments were carried out using two methodologies: the Cryotop®, the gold standard vitrification and 3-step warming methodology, or the VitTrans, a vitrification/in-straw 1-step warming method that enables direct embryo transfer to the uterus. In experiment 1, intact and biopsied in vitro produced (IVP) day 7 expanded blastocysts were vitrified using the Cryotop® and warmed in 1- or 3-steps. No differences in survival rates were recorded at 24 h after warming for intact or biopsied IVP blastocysts irrespective of the warming procedure. In experiment 2, the effect of the time from trophectoderm (TE) biopsy to vitrification/in-straw warming on post-warming survival rate was assessed. No significant differences in survival were observed when blastocysts were vitrified/in-straw warmed immediately after biopsy or after 3 h in culture when compared to intact blastocysts. In experiment 3, IVD embryos were vitrified 3 h after biopsy using the Cryotop® or the VitTrans method and pregnancy rates were assessed at day 60 after transfer. Fresh, biopsied embryos served as control. Similar pregnancy rates were observed when IVD biopsied embryos were transferred fresh or vitrified/warmed by the Cryotop® or VitTrans method. No significant effect of the embryo quality or developmental stage was detected on the percentage of pregnant recipients when IVD biopsied embryos were transferred fresh or after vitrification. While fresh female IVD embryos produced significantly higher pregnancy rates than male embryos, there were no differences in pregnancy rates when male or female vitrified/warmed embryos were transferred. About 81% from the biopsies analyzed successfully determined the embryo sex, confirming that DNA was there, and it was efficiently amplified. To conclude, our findings indicate that both vitrification methodologies produced similar post-warming outcomes for both intact and biopsied IVP embryos. Besides, vitrification/in-straw warming of biopsied IVD bovine embryos did not affect the viability to originate pregnancy, being a useful option for their direct transfer in field conditions.

In-depth proteomics characterization of ∆Np73 effectors identifies key proteins with diagnostic potential implicated in lymphangiogenesis, vasculogenesis and metastasis in colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. Alterations in proteins of the p53-family are a common event in CRC. ΔNp73, a p53-family member, shows oncogenic properties and its effectors are largely unknown. We performed an in-depth proteomics characterization of transcriptional control by ∆Np73 of the secretome of human colon cancer cells and validated its clinical potential. The secretome was analyzed using high-density antibody microarrays and stable isotopic metabolic labeling. Validation was performed by semiquantitative PCR, ELISA, dot-blot and western blot analysis. Evaluation of selected effectors was carried out using 60 plasma samples from CRC patients, individuals carrying premalignant colorectal lesions and colonoscopy-negative controls. In total, 51 dysregulated proteins were observed showing at least 1.5-foldchange in expression. We found an important association between the overexpression of ∆Np73 and effectors related to lymphangiogenesis, vasculogenesis and metastasis, such as brain-derived neurotrophic factor (BDNF) and the putative aminoacyl tRNA synthase complex-interacting multifunctional protein 1 (EMAP-II)-vascular endothelial growth factor C-vascular endothelial growth factor receptor 3 axis. We further demonstrated the usefulness of BDNF as a potential CRC biomarker able to discriminate between CRC patients and premalignant individuals from controls with high sensitivity and specificity.

Validation of 3D printing materials for high dose-rate brachytherapy using ionisation chamber and custom phantom.

Methods.Measurements were taken with the Exradin A20 (Standard Imaging) ionisation chamber, and the 'homemade' MARM phantom was made with the 3D Ultimaker 2+ printer using PLA material. The material used for validation was ABS Medical from Smart Materials 3D. The irradiation was undertaken with a192Ir source by means of Varian's GammaMed Plus iX HDR equipment. EBT3 films were used to run additional tests. We compared different measurements for PLA, ABS Medical, and water. Additional validation methods, described in the bibliography, were also compared.Results.The measurements with the ionisation chamber that we obtained using the MARM phantom with PLA and ABS within the clinically relevant range (0.5-1.5 cm) differ with respect to the measures in the water reference, by 2.3% and 0.94%, respectively.Discussion.The literature describes highly heterogeneous validation methods, complicating the performance of systematic reviews and comparisons between materials. Thus, creating a phantom represents a single effort that will quickly pay off. This system enables comparisons, ensuring that geometric conditions remain stable-something that is not always possible with radiochromic films. The use of a calibrated ionisation chamber in the corresponding energy range, combined with the 'homemade' MARM phantom applied according to the proposed methodology, allows a differentiation between the attenuation of the material itself and the drop in the dose due to distance.Conclusion.The validation method for 3D printing materials, using an ionisation chamber and the MARM PLA phantom, represents an accessible, standardisable solution for manufacturing brachytherapy applicators.

Metastatic Malignant Peritoneal Mesothelioma Mimicking an Autoinflammatory Syndrome in a 12-Year-Old Boy.

A case of a malignant peritoneal mesothelioma mimicking an autoinflammatory syndrome in a 12-year-old boy is reported. The patient initially presented with lymphadenopathy and weight loss but without abdominal pain. Three things confounded the initial diagnosis: a positive test result for a gene related to cryopyrin-associated periodic syndrome, a positive response to the autoinflammatory syndrome treatment, and a lymph node biopsy which showed "hyperplastic mesothelial cells in the lymph sinuses." His symptoms relapsed several years later, and a peritoneal biopsy confirmed the final diagnosis. Complete morphological, immunohistochemical, and molecular diagnoses are described. A translocation in the TERT gene involving the truncation of the promoter was found in the mesothelioma. The translocation has never been described in mesotheliomas and is of an unknown significance.

Multiplexed monitoring of a novel autoantibody diagnostic signature of colorectal cancer using HaloTag technology-based electrochemical immunosensing platform.

Background and Purpose: The humoral immune response in cancer patients can be used for early detection of the disease. Autoantibodies raised against tumor-associated antigens (TAAs) are promising clinical biomarkers for reliable cancer diagnosis, prognosis, and therapy monitoring. In this study, an electrochemical disposable multiplexed immunosensing platform able to integrate difficult- and easy-to-express colorectal cancer (CRC) TAAs is reported for the sensitive determination of eight CRC-specific autoantibodies. Methods: The electrochemical immunosensing approach involves the use of magnetic microcarriers (MBs) as solid supports modified with covalently immobilized HaloTag fusion proteins for the selective capture of specific autoantibodies. After magnetic capture of the modified MBs onto screen-printed carbon working electrodes, the amperometric responses measured using the hydroquinone (HQ)/H2O2 system were related to the levels of autoantibodies in plasma. Results: The biosensing platform was applied to the analysis of autoantibodies against 8 TAAs described for the first time in this work in plasma samples from healthy asymptomatic individuals (n=3), and patients with high-risk of developing CRC (n=3), and from patients already diagnosed with colorectal (n=3), lung (n=2) or breast (n=2) cancer. The developed bioplatform demonstrated an improved discrimination between CRC patients and controls (asymptomatic healthy individuals and breast and lung cancer patients) compared to an ELISA-like luminescence test. Conclusions: The proposed methodology uses a just-in-time produced protein in a simpler protocol, with low sample volume, and involves cost-effective instrumentation, which could be used in a high-throughput manner for reliable population screening to facilitate the detection of early CRC patients at affordable cost.

Identification of tumor-associated antigens with diagnostic ability of colorectal cancer by in-depth immunomic and seroproteomic analysis.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer related death worldwide. Its diagnosis at early stages would significantly improve the survival of CRC patients. The humoral immune response has been demonstrated useful for cancer diagnosis, predating clinical symptoms up to 3 years. Here, we employed an in-depth seroproteomic approach to identify proteins that elicit a humoral immune response in CRC patients. The seroproteomic approach relied on the immunoprecipitation with patient-derived autoantibodies of proteins from CRC cell lines with different metastatic properties followed by LC-MS/MS. After bioinformatics, we focused on 31 targets of CRC autoantibodies. After WB and IHC validation, ERP44 and TALDO1 showed potential to discriminate disease-free and metastatic CRC patients, and time to recurrence of CRC patients in stage II. Using plasma samples of 30 healthy individuals, 28 premalignant individuals, and 32 CRC patients, nine out of 13 selected targets for seroreactive analysis showed significant diagnostic ability to discriminate either CRC patients or premalignant subjects from controls. Our results suggest that the here defined panel of CRC autoantibodies and their target proteins should be included in CRC blood-based biomarker panels to get a clinically useful blood-based diagnostic signature for CRC detection. SIGNIFICANCE: Colorectal cancer is one of the deadliest cancer types mainly due to its late diagnosis. Its early diagnosis, therefore, is of great importance since it would significantly improve the survival of CRC patients. In our work, the in-depth seroproteomic analysis of colorectal cancer using isolated IgGs from colorectal cancer patients and controls and protein extract of colorectal cancer cells provide the identification of valuable biomarkers with diagnostic and prognostic ability of the disease.

Valoración de la efectividad de un protocolo de estimulación sensorial de la mano hemiparésica para la rehabilitación del control postural en pacientes con ictus crónico. Estudio piloto / Evaluation of the effectiveness of a hemiparesis hand sensory stimulation protocol for postural control rehabilitation in patients with chronic stroke. Pilot study

Introducción. Uno de los objetivos principales de la neurorrehablitación en pacientes con ictus es el reentrenamiento del equilibrio. Se ha estudiado la influencia de la función motora del miembro superior en el control postural, pero desconocemos si la estimulación somatosensorial de la mano afecta puede influirlo. Objetivo. Estudiar si un protocolo de estimulación somatosensorial de la mano afecta, podía modificar, en pacientes con ictus crónico, la posición del centro de masa y su desplazamiento en bipedestación. Pacientes y métodos. 5 pacientes con ictus crónico con capacidad de bipedestación autónoma completaron este estudio piloto prospectivo y longitudinal, con valoración pretratamiento, post-primer tratamiento y post-intervención final. La intervención consistió en estimulación somatosensorial de la mano afecta, de 20 minutos de duración durante 5 días consecutivos. Se midieron Timed Up and GO Test (TUG), Performance Oriented Mobility Assessment (POMA), Limits Of Stability (LOS) y Modified Clinical Test of Sensory Interaction on Balance (mCTSIB). Resultados. Se observaron cambios estadísticamente significativos en TUG (p=0,043), en mCTSIB en los máximos desplazamientos del centro de presiones para la condición ojos abiertos (p=0,043) y en LOS para el tiempo de reacción en la diagonal posterior afecta(p꞊0,043), máximas excursiones en las diagonales anterior menos afecta, afecta y posterior afecta (p=0,043) y el control direccional en la anterior menos afecta y anterior afecta. Conclusiones. La estimulación somatosensensorial propuesta puede ser positiva para el reentrenamiento del equilibrio a la luz de los resultados obtenidos. Son necesarias investigaciones a este nivel a gran escala y a largo plazo con muestras más grandes.

Introduction. One of the main objectives of neurorehablitation in stroke patients is balance retraining. The influence of upper limb motor function on postural control has been studied, but we do not know whether somatosensory stimulation of the affected hand can influence it. Objective. To study whether a protocol of somatosensory stimulation of the affected hand could modify, in patients with chronic stroke, the position of the center of mass and its displacement in standing. Patients and methods. Five patients with chronic stroke who were able to stand independently completed this prospective and longitudinal pilot study, with pre-treatment, post-first treatment and final post-intervention assessment. The intervention consisted of somatosensory stimulation of the affected hand, lasting 20 minutes for 5 consecutive days. Timed Up and GO Test (TUG), Performance Oriented Mobility Assessment (POMA), Limits Of Stability (LOS) and Modified Clinical Test of Sensory Interaction on Balance (mCTSIB) were measured. Results. Statistically significant changes were observed in TUG (p=0.043), in mCTSIB for maximum center of pressures displacements for the eyes open condition (p=0.043) and in LOS for reaction time in the posterior diagonal affect(p꞊0.043), maximum excursions in the anterior least affect, affect and posterior affect diagonals (p=0.043) and directional control in the anterior least affect and anterior affect. Conclusions. The proposed somatosensory stimulation may be positive for balance retraining in light of the results obtained. Large-scale and long-term investigations at this level with larger samples are necessary.

The specific seroreactivity to ∆Np73 isoforms shows higher diagnostic ability in colorectal cancer patients than the canonical p73 protein.

The p53-family is tightly regulated at transcriptional level. Due to alternative splicing, up to 40 different theoretical proteoforms have been described for p73 and at least 20 and 10 for p53 and p63, respectively. However, only the canonical proteins have been evaluated as autoantibody targets in cancer patients for diagnosis. In this study, we have cloned and expressed in vitro the most upregulated proteoforms of p73, ΔNp73α and ΔNp73ß, for the analysis of their seroreactivity by a developed luminescence based immunoassay test using 145 individual plasma from colorectal cancer, premalignant individuals and healthy controls. ∆Np73α seroreactivity showed the highest diagnostic ability to discriminate between groups. The combination of ∆Np73α, ∆Np73ß and p73 proteoforms seroreactivity were able to improve their individual diagnostic ability. Competitive inhibition experiments further demonstrated the presence of unique specific epitopes in ΔNp73 isoforms not present in p73, with several colorectal patients showing unique and specific seroreactivity to the ΔNp73 proteoforms. Overall, we have increased the complexity of the humoral immune response to the p53-family in cancer patients, showing that the proteoforms derived from the alternative splicing of p73 possess a higher diagnostic ability than the canonical protein, which might be extensive for p53 and p63 proteins.

Evaluation of integrated care services in Catalonia: population-based and service-based real-life deployment protocols.

BACKGROUND: Comprehensive assessment of integrated care deployment constitutes a major challenge to ensure quality, sustainability and transferability of both healthcare policies and services in the transition toward a coordinated service delivery scenario. To this end, the manuscript articulates four different protocols aiming at assessing large-scale implementation of integrated care, which are being developed within the umbrella of the regional project Nextcare (2016-2019), undertaken to foster innovation in technologically-supported services for chronic multimorbid patients in Catalonia (ES) (7.5 M inhabitants). Whereas one of the assessment protocols is designed to evaluate population-based deployment of care coordination at regional level during the period 2011-2017, the other three are service-based protocols addressing: i) Home hospitalization; ii) Prehabilitation for major surgery; and, iii) Community-based interventions for frail elderly chronic patients. All three services have demonstrated efficacy and potential for health value generation. They reflect different implementation maturity levels. While full coverage of the entire urban health district of Barcelona-Esquerra (520 k inhabitants) is the main aim of home hospitalization, demonstration of sustainability at Hospital Clinic of Barcelona constitutes the core goal of the prehabilitation service. Likewise, full coverage of integrated care services addressed to frail chronic patients is aimed at the city of Badalona (216 k inhabitants). METHODS: The population-based analysis, as well as the three service-based protocols, follow observational and experimental study designs using a non-randomized intervention group (integrated care) compared with a control group (usual care) with a propensity score matching method. Evaluation of cost-effectiveness of the interventions using a Quadruple aim approach is a central outcome in all protocols. Moreover, multi-criteria decision analysis is explored as an innovative method for health delivery assessment. The following additional dimensions will also be addressed: i) Determinants of sustainability and scalability of the services; ii) Assessment of the technological support; iii) Enhanced health risk assessment; and, iv) Factors modulating service transferability. DISCUSSION: The current study offers a unique opportunity to undertake a comprehensive assessment of integrated care fostering deployment of services at regional level. The study outcomes will contribute refining service workflows, improving health risk assessment and generating recommendations for service selection. TRIALS REGISTRATION: NCT03130283 (date released 04/06/2018), NCT03768050 (date released 12/05/2018), NCT03767387 (date released 12/05/2018).

Availability of specific tools to assess patient reported outcomes in hip arthroplasty in Spain. Identifying the best candidates to incorporate in an arthroplasty register. A systematic review and standardized assessment.

PURPOSE: 1) To systematically review the available scientific literature regarding specific instruments developed and/or tested in a Spanish population, to assess these PROMs in hip arthroplasty; 2) to carry out a standardized assessment of their measurement properties; and 3) to identify the best tools for use in Spain in an arthroplasty registry context. METHODS: A systematic review of PubMed/MEDLINE and EMBASE and CINHAL was done. Furthermore, a standardized assessment of the questionnaires identified using the Evaluating the Measurement of Patient-Reported Outcomes (EMPRO) tool was performed. All developments, validation and studies aiming to assess the measurement properties of PROMs in hip arthroplasty in the Spanish population were included. Data from the questionnaires on metric properties was taken into account to identify the best candidates for inclusion in a register. RESULTS: A total of 853 documents were found. After screening title and abstract, 13 full text documents were reviewed and 8 questionnaires adapted and validated to assess some of the aspects of hip arthroplasty in the Spanish population were identified. After the EMPRO assessment, 4 questionnaires showed suitable properties (WOMAC, OAKHQOL, mini-OAKHQOL and PFH). CONCLUSIONS: In Spain, there are a few suitable hip-specific questionnaires currently available to assess PROMs in hip arthroplasty surgery. Some of the more widely used questionnaires, like the OHS and HOOS, have not been validated in the Spanish population until now. Identified tools are suitable for use in a clinical context, however their use in an arthroplasty register is more questionable due to the lack of validation studies of the widely used tools in other registers.

Lipase-catalyzed glycerolysis of anchovy oil in a solvent-free system: Simultaneous optimization of monoacylglycerol synthesis and end-product oxidative stability.

The production of mono- and diacylglycerols rich in polyunsaturated fatty acids is achieved in this study, by solvent-free glycerolysis of anchovy oil with lipase PS-DI from Burkholderia cepacia. Attention is focused on the oxidative stability of the reaction products, determined in terms of induction time (It). The effects of glycerol/triacylglycerol molar ratio, enzyme concentration, and reaction temperature on mono- and diacylglycerol production and It are all assessed. The operating conditions that optimized monoacylglycerol yields and oxidative stability were a glycerol/triacylglycerol ratio of 3/1, 9.0% (w/w) Lipase PS-DI, a stirring rate of 200 rpm, and a reaction time of 4 h, at 45.8 °C, producing a content of 24.8% and 51.9% of mono- and diacylglycerols, respectively, over an It of 1.41 h. The glycerolysis conditions determined by simultaneous optimization strategy increased the oxidative stability of the glycerolysis products by 68%, which rose from 0.84 h (individual optimization) to 1.41 h.

Determination of Cadherin-17 in Tumor Tissues of Different Metastatic Grade Using a Single Incubation-Step Amperometric Immunosensor.

This paper reports the development of an amperometric immunosensing platform for the determination of cadherin-17 (CDH-17), an atypical adhesion protein involved in the progression, metastatic potential, and survival of high prevalence gastric, hepatocellular, and colorectal tumors. The methodology developed relies on the efficient capture and enzymatic labeling of the target protein on the magnetic microparticles (MBs) surface using commercial antibodies and amperometric transduction at screen-printed carbon electrodes (SCPEs) through the HRP/H2O2/HQ system. The developed immunosensing platform allows the selective determination of the target protein at low ng mL-1 level (LOD of 1.43 ng mL-1) in 45 min and using a single incubation step. The electrochemical immunosensor was successfully used for the accurate determination of the target protein in a small amount (0.5 µg) of raw lysates of colon cancer cells with different metastatic potential as well as in extracts from paraffin embedded cancer colon tissues of different metastatic grade.

Once-Weekly Hypofractionated Radiotherapy for Breast Cancer in Elderly Patients: Efficacy and Tolerance in 486 Patients.

PURPOSE: Radiation therapy is a key treatment of breast cancer. Elderly patients with associated diseases that modify their performance status do not tolerate long periods of daily irradiation. The objective of this study is to analyze the results of weekly hypofractionated treatment in these patients. MATERIAL AND METHODS: Between 1992 and 2016, we included 486 elderly patients presenting concomitant pathology or sociofamilial problems in which it was not feasible to propose conventional treatment. They were treated with conservative surgery or mastectomy and then adjuvant hypofractionated irradiation, administering 5 Gy or 6.25 Gy in 6 fractions, once a week (total dose 30-37.5 Gy) over 6 weeks. RESULTS: Breast cancer overall survival according to the Kaplan-Meier method at 5 years was 74.2% ± 2.3%; breast cancer disease-free survival was 90% ± 1.6%; local relapse-free survival was 96.5% ± 1% showing that patients die more from other causes and not from their neoplasia. Acute dermatitis was mild (75.6% of the patients grades I-III) and 30.6% had moderate chronic fibrosis. CONCLUSIONS: The once-weekly hypofractionated radiotherapy is a feasible and convenient option for elderly patients with breast cancer. It is a safe treatment modality with similar survival and local control results compared to standard fractionation, while the side effects are acceptable.

Influence of a 100-M Simulated In-Water Rescue on Cardiopulmonary Parameters.

OBJECTIVE: Cardiopulmonary resuscitation (CPR) after a drowning episode is performed under fatigue conditions. However, the characterization of CPR in this context is still unknown. Our purpose was to investigate the effect of a 100-m simulated in-water rescue on CPR and physiological parameters in trained certified lifeguards. METHODS: Thirty trained certified lifeguards (age 24.6 ± 3.8 yrs; height 178.2 ± 7.4 cm and weight 76.9 ± 10.6 kg) completed two protocols using an adult manikin: (i) 4-min CPR after 4-min baseline conditions (CPR), and (ii) 4-min CPR after a 100-m simulated in-water rescue in the sea (CPR Rescue), both with a compression-ventilation ratio of 30:2. Physiological parameters of the subjects were continuously measured (breath-by-breath) during baseline and CPR conditions, using a telemetric portable gas analyzer (K4b 2 , Cosmed, Rome, Italy) and CPR techniques analyzed using two HD video cameras (Sony, HDR PJ30VE, Japan). RESULTS: The 100-m simulated in-water rescue induced higher values of physiological related parameters all over the 4-min CPR exercise (e.g. Tidal Volume: 1.5 ± 0.4 and 2.4 ± 0.5 L; VO2: 15.9 ± 3.9 and 22.8 ± 3.2 ml.kg-1.min-1; R: 0.9 ± 0.1 and 1.2 ± 0.1, for CPR and CPR Rescue, respectively). However, the compression rate was higher in CPR Rescue compared to the CPR in the first (cycle 3: 85 ± 12 vs. 78 ± 9 s) and last three complete cycles (cycle 12: 100 ± 12 and 85 ± 12 s), and, in both conditions, it increased from the first to the last CPR complete cycle. CONCLUSIONS: Fatigue induced by the 100-m simulated in-water rescue had a strong physiological expression but a minimal impact on CPR performance. Key words: CPR; fatigue; lifeguards; VO2.

Toward Liquid Biopsy: Determination of the Humoral Immune Response in Cancer Patients Using HaloTag Fusion Protein-Modified Electrochemical Bioplatforms.

Autoantibodies raised against tumor-associated antigens have shown high promise as clinical biomarkers for reliable diagnosis, prognosis, and therapy monitoring of cancer. An electrochemical disposable biosensor for the specific and sensitive determination of p53-specific autoantibodies has been developed for the first time in this work. This biosensor involves the use of magnetic microcarriers (MBs) modified with covalently immobilized HaloTag fusion p53 protein as solid supports for the selective capture of specific autoantibodies. After magnetic capture of the modified MBs onto screen-printed carbon working electrodes, the amperometric signal using the system hydroquinone/H2O2 was related to the levels of p53-autoantibodies in the sample. The biosensor was applied for the analysis of sera from 24 patients with high-risk of developing colorectal cancer and 6 from patients already diagnosed with colorectal (4) and ovarian (2) cancer. The developed biosensor was able to determine p53 autoantibodies with a sensitivity higher than that of a commercial standard ELISA using a just-in-time produced protein in a simpler protocol with less sample volume and easily miniaturized and cost-effective instrumentation.