"ATAD3C regulates ATAD3A assembly and function in the mitochondrial membrane".

Mitochondrial ATAD3A is an ATPase Associated with diverse cellular Activities (AAA) domain containing enzyme, involved in the structural organization of the inner mitochondrial membrane and of increasing importance in childhood disease. In humans, two ATAD3A paralogs arose by gene duplication during evolution: ATAD3B and ATAD3C. Here we investigate the cellular activities of the ATAD3C paralog that has been considered a pseudogene. We detected unique ATAD3C peptides in HEK 293T cells, with expression similar to that in human tissues, and showed that it is an integral membrane protein that exposes its carboxy-terminus to the intermembrane space. Overexpression of ATAD3C, but not of ATAD3A, in fibroblasts caused a decrease in cell proliferation and oxygen consumption rate, and an increase of cellular ROS. This was due to the incorporation of ATAD3C monomers in ATAD3A complex in the mitochondrial membrane reducing its size. Consistent with a negative regulation of ATAD3A function in mitochondrial membrane organization, ATAD3C expression led to increased accumulation of respiratory chain dimeric CIII in the inner membrane, to the detriment to that assembled in respiratory supercomplexes. Our results demonstrate a negative dominant role of the ATAD3C paralog with implications for mitochondrial OXPHOS function and suggest that its expression regulates ATAD3A in the cell.

How virtual and mechanical coupling impact bimanual tracking.

Bilateral training systems look to promote the paretic hand's use in individuals with hemiplegia. Although this is normally achieved using mechanical coupling (i.e., a physical connection between the hands), a virtual reality system relying on virtual coupling (i.e., through a shared virtual object) would be simpler to use and prevent slacking. However, it is not clear whether different coupling modes differently impact task performance and effort distribution between the hands. We explored how 18 healthy right-handed participants changed their motor behaviors in response to the uninstructed addition of mechanical coupling, and virtual coupling using a shared cursor mapped to the average hands' position. In a second experiment, we then studied the impact of connection stiffness on performance, perception, and effort imbalance. The results indicated that both coupling types can induce the hands to actively contribute to the task. However, the task asymmetry introduced by using a cursor mapped to either the left or right hand only modulated the hands' contribution when not mechanically coupled. The tracking performance was similar for all coupling types, independent of the connection stiffness, although the mechanical coupling was preferred and induced the hands to move with greater correlation. These findings suggest that virtual coupling can induce the hands to actively contribute to a task in healthy participants without hindering their performance. Further investigation on the coupling types' impact on the performance and hands' effort distribution in patients with hemiplegia could allow for the design of simpler training systems that promote the affected hand's use.NEW & NOTEWORTHY We showed that the uninstructed addition of a virtual and/or a mechanical coupling can induce both hands to actively contribute in a continuous redundant bimanual tracking task without impacting performance. In addition, we showed that the task asymmetry can only alter the effort distribution when the hands are not connected, independent of the connection stiffness. Our findings suggest that virtual coupling could be used in the development of simpler VR-based training devices.

Medium/long term evaluation of lipid profile after bariatric surgery (gastric bypass versus sleeve gastrectomy).

INTRODUCTION: Bariatric surgery aims to reduce weight and resolve the comorbidities associated with obesity. Few studies have assessed mid/long-term changes in lipid profile with sleeve gastrectomy versus gastric bypass. This study was conducted to assess and compare changes in lipid profile with each procedure after 60 months. METHODS: This was an observational, retrospective study of analytical cohorts enrolling 100 patients distributed into two groups: 50 had undergone gastric bypass (GBP) surgery and 50 sleeve gastrectomy (SG) surgery. Total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels were measured before surgery and at 1, 6, 12, 24, 36, 48, and 60 months. Weight loss and the resolution of dyslipidemia with each of the procedures were also assessed. RESULTS: Ninety-five of the 100 patients completed follow-up. At 60 months, TC and LDL levels had significantly decreased in the BPG group (167.42 ±â€¯31.22 mg/dl and 88.06 ±â€¯31.37 mg/dl, respectively), while there were no differences in the SG group. Increased HDL levels were seen with both procedures (BPG: 62.69 ±â€¯16.3 mg/dl vs. SG: 60.64 ±â€¯18.73 mg/dl), with no difference between the procedures. TG levels decreased in both groups (BPG: 86.06 ±â€¯56.57 mg/dl vs. SG: 111.09 ±â€¯53.08 mg/dl), but values were higher in the BPG group (P < .05). The percentage of overweight lost (PSP) was higher in the BPG group: 75.65 ±â€¯22.98 mg/dl vs. the GV group: 57.83 ±â€¯27.95 mg/dl. CONCLUSION: Gastric bypass achieved better mid/long-term results in terms of weight reduction and the resolution of hypercholesterolemia as compared to sleeve gastrectomy. While gastric bypass improved all lipid profile parameters, sleeve gastrectomy only improved HDL and triglyceride levels.

Efficacy and safety of preoperative preparation with Lugol's iodine solution in euthyroid patients with Graves' disease (LIGRADIS Trial): Study protocol for a multicenter randomized trial.

BACKGROUND: Currently, both the American Thyroid Association and the European Thyroid Association recommend preoperative preparation with Lugol's Solution (LS) for patients undergoing thyroidectomy for Graves' Disease (GD), but their recommendations are based on low-quality evidence. The LIGRADIS trial aims to provide evidence either to support or refute the systematic use of LS in euthyroid patients undergoing thyroidectomy for GD. METHODS: A multicenter randomized controlled trial will be performed. Patients ≥18 years of age, diagnosed with GD, treated with antithyroid drugs, euthyroid and proposed for total thyroidectomy will be eligible for inclusion. Exclusion criteria will be prior thyroid or parathyroid surgery, hyperparathyroidism that requires associated parathyroidectomy, thyroid cancer that requires adding a lymph node dissection, iodine allergy, consumption of lithium or amiodarone, medically unfit patients (ASA-IV), breastfeeding women, preoperative vocal cord palsy and planned endoscopic, video-assisted or remote access surgery.Between January 2020 and January 2022, 270 patients will be randomized for either receiving or not preoperative preparation with LS. Researchers will be blinded to treatment assignment. The primary outcome will be the rate of postoperative complications: hypoparathyroidism, recurrent laryngeal nerve injury, hematoma, surgical site infection or death. Secondary outcomes will be intraoperative events (Thyroidectomy Difficulty Scale score, blood loss, recurrent laryngeal nerve neuromonitoring signal loss), operative time, postoperative length of stay, hospital readmissions, permanent complications and adverse events associated to LS. CONCLUSIONS: There is no conclusive evidence supporting the benefits of preoperative treatment with LS in this setting. This trial aims to provide new insights into future Clinical Practice Guidelines recommendations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03980132.

Usefulness of the Wisconsin and CaPTHUS indices for predicting multiglandular disease in patients with primary hyperparathyroidism in a southern European population.

BACKGROUND: Focused parathyroidectomy is a safe technique for the treatment of primary hyperparathyroidism. The CaPTHUS score and the Wisconsin index are preoperative diagnostic tools designed to distinguish between single- and multigland disease. The aim of the study is to evaluate the usefulness of these models for predicting multiglandular disease in a European population. METHODS: Retrospective review of a database of patients operated upon for primary hyperparathyroidism at a referral center. The sensitivity, specificity, positive and negative predictive values, and reliability of both scores for the prediction of multiglandular disease, were calculated. Receiver operating characteristic (ROC) curves were constructed to assess the sensitivity and specificity of CaPTHUS score and Wisconsin Index for predicting single-gland disease. A level of P<0.05 was accepted as significant. RESULTS: Two hundred and eighty-one patients who underwent successful surgery from January 2001 to December 2018 were included. Single-gland disease was detected in 92.5%, and 73.7% had a CaPTHUS score of ≥3. The sensitivity, specificity, positive and negative predictive values of this model for predicting single-gland disease with a score of ≥3 were 76.9%, 66.7%, 96.6%, and 18.9% respectively. The area under the curve value of the CaPTHUS score for predicting single-gland disease was 0.74. A Wisconsin Index >2,000 and an excised gland weight above one gram presented a positive predictive value for single-gland disease of 92.5%. CONCLUSIONS: Despite the good performance of both scales, the established cut-off points did not definitively rule out parathyroid multiglandular disease in our population. In cases with a minimal suspicion of this condition, additional intraoperative techniques must be used, or bilateral neck explorations should be performed.

Development and validation of a new model for predicting hypocalcaemia after total thyroidectomy: the NuGra model.

BACKGROUND: Hypocalcaemia is the most frequent complication after total thyroidectomy. Finding a method for its early detection has become a priority. A single-center prospective cohort study was conducted to identify risk factors for postoperative hypocalcaemia, develop an early detection model, and test its validity in a different group of patients. METHODS: The sample was composed of patients who underwent a total thyroidectomy between May 2012 and September 2015. Demographic, clinical, laboratory, and surgical data were collected. The incidence of hypocalcaemia and permanent hypoparathyroidism was calculated. Bivariate and multivariate analysis identified several independent predictors of hypocalcaemia, which were used to design a predictive model. The validity of the model was subsequently tested in a different cohort. Area under the ROC curve (AUROC) was calculated to determine its predictive power. RESULTS: The study and validation groups included 352 and 118 patients, respectively. Seventy-three patients developed laboratory-confirmed hypocalcaemia (20.7%), and symptomatic in 43 (12.2%). Multivariate analysis confirmed as independent predictors of hypocalcaemia the higher number of parathyroid glands identified [OR 1.41(0.98, 2.02); p = 0.063] and pre-to-postoperative gradient of parathormone decline [OR 1.06(1.04, 1.08); p < 0.001]. Based on these variables, the NuGra (Number of parathyroid glands identified-Gradient of decline) model was developed for predicting laboratory-confirmed hypocalcaemia. Its predictive power was high (AUROC 0.902, CI 0.857-0.947) for the study and the validation group (AUROC 0.956, CI 0.919-0.993). CONCLUSIONS: A higher number of parathyroid glands identified and a higher gradient of parathormone decline are risk factors for post-thyroidectomy hypocalcaemia. The NuGra model is useful for early prediction of individual risk for hypocalcaemia.

Prophylaxis of venous thromboembolism in general surgery in Spain. Analysis of a national survey. / Profilaxis del tromboembolismo venoso en cirugía general en España. Análisis de una encuesta nacional.

INTRODUCTION: Venous thromboembolism (VTE) represents a serious postoperative complication that can be prevented by adequate thromboprophylaxis. Surveys provide relevant information about clinician's attitudes and preferences regarding VTE prophylaxis. METHODS: Transversal, descriptive study based on a survey sent to general surgeons members of the Spanish Association of Surgeons (AEC), that included 31 questions regarding postoperative VTE and its prevention, as well as three clinical scenarios. RESULTS: 530 surgeons, 21.8% of the 2,429 invited by electronic mail to participate, completed the survey. Most of the answering clinicians work on in big teaching hospitals, and 28.5% are residents. VTE represents a serious problem for 28% of participants. Although 81% consider that their knowledge on the prevention of postoperative VTE is adequate, a similar percentage recognizes the need for further education. The vast majority (98.7%) use low molecular weight heparins, which are considered the most effective and safe modality, followed by mechanical methods. The Caprini risk assessment score is used by 81% of surgeons, who usually start pharmacological prophylaxis preoperatively. However, there are remarkable differences in the dosing of heparins, timing of initiation, and duration, especially in non-oncologic surgical patients. CONCLUSIONS: Most Spanish surgeons are interested in the prevention of postoperative VTE. Overall, the level of knowledge on thromboprophylaxis is adequate. However, our results indicate that there is a need for better education on relevant practical aspects of prophylaxis that could be achieved by incorporating recommendations from recent guidelines to local hospital-based protocols.

Oxidative Phosphorylation Dysfunction Modifies the Cell Secretome.

Mitochondrial oxidative phosphorylation disorders are extremely heterogeneous conditions. Their clinical and genetic variability makes the identification of reliable and specific biomarkers very challenging. Until now, only a few studies have focused on the effect of a defective oxidative phosphorylation functioning on the cell's secretome, although it could be a promising approach for the identification and pre-selection of potential circulating biomarkers for mitochondrial diseases. Here, we review the insights obtained from secretome studies with regard to oxidative phosphorylation dysfunction, and the biomarkers that appear, so far, to be promising to identify mitochondrial diseases. We propose two new biomarkers to be taken into account in future diagnostic trials.

Genetic and phenotypic associations between root architecture, arbuscular mycorrhizal fungi colonisation and low phosphate tolerance in strawberry (Fragaria × ananassa).

BACKGROUND: Phosphate is an essential plant macronutrient required to achieve maximum crop yield. Roots are able to uptake soil phosphate from the immediate root area, thus creating a nutrient depletion zone. Many plants are able to exploit phosphate from beyond this root nutrient depletion zone through symbiotic association with Arbuscular Mycorrhizal Fungi (AMF). Here we characterise the relationship between root architecture, AMF association and low phosphate tolerance in strawberries. The contrasting root architecture in the parental strawberry cultivars 'Redgauntlet' and 'Hapil' was studied through a mapping population of 168 progeny. Low phosphate tolerance and AMF association was quantified for each genotype to allow assessment of the phenotypic and genotypic relationships between traits. RESULTS: A "phosphate scavenging" root phenotype where individuals exhibit a high proportion of surface lateral roots was associated with a reduction in root system size across genotypes. A genetic correlation between "root system size" traits was observed with a network of pleiotropic QTL found to represent five "root system size" traits. By contrast, average root diameter and the distribution of roots appeared to be under two discrete methods of genetic control. A total of 18 QTL were associated with plant traits, 4 of which were associated with solidity that explained 46% of the observed variation. Investigations into the relationship between AMF association and root architecture found that a higher root density was associated with greater AMF colonisation across genotypes. However, no phenotypic correlation or genotypic association was found between low phosphate tolerance and the propensity for AMF association, nor root architectural traits when plants are grown under optimal nutrient conditions. CONCLUSIONS: Understanding the genetic relationships underpinning phosphate capture can inform the breeding of strawberry varieties with better nutrient use efficiency. Solid root systems were associated with greater AMF colonisation. However, low P-tolerance was not phenotypically or genotypically associated with root architecture traits in strawberry plants. Furthermore, a trade-off was observed between root system size and root architecture type, highlighting the energetic costs associated with a "phosphate scavenging" root architecture.

KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study.

KRAS mutation is a confirmed predictive biomarker for anti-EGFR monoclonal antibody therapy response for metastatic colorectal cancer. However, its prognosis impact and the predictive potential for first-line standard chemotherapy remains unclear. On the other hand, V600E mutation is the most frequent and studied mutation in the BRAF gene, and it has been associated with a poor outcome of patients and a low response to anti-EGFR treatment. Thus, the aim of this study is to evaluate the role of KRAS and BRAF mutations as prognosis factors and predictive biomarkers for 1st line standard chemotherapy in metastatic colorectal cancer. KRAS mutations and BRAF V600E mutations exhibited a poor outcome (p = 0.021 and p < 0.0001, respectively). Cox multivariate analysis showed that the presence of liver metastasis (HR = 1.595; 95% CI: 1.086-2.343; p = 0.017), KRAS mutation (HR = 1.643; 95% CI: 1.110-2.431; p = 0.013) and BRAF V600E mutation (HR = 5.861; 95% CI: 2.531-13.570; p < 0.0001) were statistically significant co-variables for progression-free survival. Interestingly, patients with KRAS mutations were associated with a poor response to first line standard chemotherapy (p = 0.008). In contrast, the BRAF V600E mutation did not have any impact on the first line standard chemotherapy response (p = 0.540). Therefore, in the present study, we provide new insight on the role of KRAS and BRAF, not only as prognosis biomarkers, but also as first line standard chemotherapy response biomarkers in metastatic colorectal cancer.

Fasting ghrelin levels after gastric bypass and vertical sleeve gastrectomy: An analytic cohort study. / Comportamiento de ghrelina en ayunas después de bypass gástrico y gastrectomía vertical: estudio de cohortes analítico.

BACKGROUND AND OBJECTIVE: Neuronal populations involved in the regulation of food intake, particularly the orexigenic (appetite-stimulating) hormone ghrelin, are found in the hypothalamus. Changes in plasma ghrelin levels have been observed following different bariatric surgery procedures, but the results from different studies are contradictory. Much remains unknown regarding the role of ghrelin in the weight loss process following bariatric surgery. Our objective was to describe the behaviour of fasting ghrelin levels, comparing the changes occurring between 2 different surgical techniques (gastric bypass versus vertical sleeve gastrectomy) and their correlation with weight loss. PATIENTS AND METHOD: A prospective, observational, analytic cohort study of 54 patients (27 for each surgical technique) with a 12-month follow-up period. We analysed demographic data, anthropometric data, comorbidities, weight loss and evolution of fasting ghrelin. RESULTS: The behaviour of acylated ghrelin was similar with the 2 surgical techniques, with no significant differences between gastric bypass and vertical sleeve gastrectomy. With both procedures, there was an increase in acylated ghrelin on day 5 and a subsequent decrease, and levels then gradually increased to reach values at 12 months that were higher than those reported preoperatively. This increase in ghrelin levels did not affect weight loss, since one year post-surgery, 30% weight loss was achieved with both types of surgery. CONCLUSIONS: We observed an increase in fasting acylated ghrelin levels at one year of follow-up with both surgical techniques, with 30% weight loss.

Accreditation of endocrine surgery units.

BACKGROUND/PURPOSE: A key measure to maintain and improve the quality of healthcare is the formal accreditation of provider units. The European Society of Endocrine Surgeons (ESES) therefore proposes a system of accreditation for endocrine surgical centers in Europe to supplement existing measures that promote high standards in the practice in endocrine surgery. METHODS: A working group analyzed the current healthcare situation in the field of endocrine surgery in Europe. Two surveys were distributed to ESES members to acquire information about the structure, staffing, caseload, specifications, and technology available to endocrine surgery units. Further data were sought on tracer diagnoses for quality standards, training provision, and research activity. Existing accreditation models related to endocrine surgery were included in the analysis. RESULTS: The analysis of existing accreditation models, available evidence, and survey results suggests that a majority of ESES members aspire to a two-level model (termed competence and reference centers), sub-divided into those providing neck endocrine surgery and those providing endocrine surgery. Criteria for minimum caseload, number and certification of staff, unit structure, on-site collaborating disciplines, research activities, and training capacity for competence center accreditation are proposed. Lastly, quality indicators for distinct tracer diagnoses are defined. CONCLUSIONS: Differing healthcare structures, existing accreditation models, training models, and varied case volumes across Europe are barriers to the conception and implementation of a pan-European accreditation model. However, there is consensus on accepted standards required for accrediting an ESES competence center. These will serve as a basis for first-stage accreditation of endocrine surgery units.

Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood.

AIM: To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations. METHOD: A multi-gene panel of childhood-onset basal ganglia neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts. RESULTS: Three siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Brain magnetic resonance showed symmetric and bilateral cytotoxic lesions in the putamen and proliferation of the lenticular-striate arteries, latter spreading to the caudate and progressing to cavitation and volume loss. We identified a frameshift novel change (c.554_558delTTCTT; p.Tyr187AsnfsTer65) and a pathogenic missense change (c.371T>C; p.Ile124Thr) in the NDUFAF6 gene, which segregated with an autosomal recessive inheritance within the family. Patient mutations were associated with the absence of the NDUFAF6 protein and reduced activity and assembly of mature complex I in fibroblasts. By functional complementation assay, the mutant phenotype was rescued by the canonical version of the NDUFAF6. A literature review of 14 NDUFAF6 patients showed a consistent phenotype of an early childhood insidious onset neurological regression with prominent dystonia associated with basal ganglia degeneration and long survival. INTERPRETATION: NDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis. By genetic complementation, we could demonstrate the pathogenicity of novel genetic variants in NDUFAF6.

Molecular Characterization of New FBXL4 Mutations in Patients With mtDNA Depletion Syndrome.

Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is a rare genetic disorder caused by defects in F-box leucine-rich repeat protein 4 (FBXL4). Although FBXL4 is essential for the bioenergetic homeostasis of the cell, the precise role of the protein remains unknown. In this study, we report two cases of unrelated patients presenting in the neonatal period with hyperlactacidemia and generalized hypotonia. Severe mtDNA depletion was detected in muscle biopsy in both patients. Genetic analysis showed one patient as having in compound heterozygosis a splice site variant c.858+5G>C and a missense variant c.1510T>C (p.Cys504Arg) in FBXL4. The second patient harbored a frameshift novel variant c.851delC (p.Pro284LeufsTer7) in homozygosis. To validate the pathogenicity of these variants, molecular and biochemical analyses were performed using skin-derived fibroblasts. We observed that the mtDNA depletion was less severe in fibroblasts than in muscle. Interestingly, the cells harboring a nonsense variant in homozygosis showed normal mtDNA copy number. Both patient fibroblasts, however, demonstrated reduced mitochondrial transcript quantity leading to diminished steady state levels of respiratory complex subunits, decreased respiratory complex IV (CIV) activity, and finally, low mitochondrial ATP levels. Both patients also revealed citrate synthase deficiency. Genetic complementation assays established that the deficient phenotype was rescued by the canonical version of FBXL4, confirming the pathological nature of the variants. Further analysis of fibroblasts allowed to establish that increased mitochondrial mass, mitochondrial fragmentation, and augmented autophagy are associated with FBXL4 deficiency in cells, but are probably secondary to a primary metabolic defect affecting oxidative phosphorylation.

Human Endometrial Reconstitution From Somatic Stem Cells: The Importance of Niche-Like Cells.

Endometrial regeneration has long been proposed to be mediated by stem cells, but the isolation of endometrial stem cells has been hampered by a lack of validated markers. Specific markers would enable isolation of these stem cells, thereby promoting advancements in regenerative medicine for the treatment of endometrial diseases and dysfunctions. We sought to investigate the regenerative ability of human endometrial positive for sushi domain containing 2/intercellular adhesion molecule 1 (SUSD2+/ICAM1+) cells and Side Population cell lines in a xenograft mice model. The injection of total endometrial cell suspensions and Side Population cell lines under kidney capsules induced neoformation of human endometrium verified by the presence of typical endometrial markers (vimentin, cytokeratin 18, and progesterone receptor) by immunofluorescence. Total endometrial cell types promoted a better reconstitution in comparison to injecting ICAM1+ and SUSD2+ cells alone. The endometrial fraction is probably acting as a niche, resulting in increased reconstruction efficiency of pure fractions. Human engrafted cells were localized near blood vessels and induced the proliferation of surrounding cells. Our results suggest that human endometrial Side Population, a heterogeneous population possibly harboring endometrial stem cells, has the optimum capacity to regenerate endometrial-like tissue. In contrast, cells positive for single stem cell markers SUSD2 and ICAM1 have minimally functional regenerative capacities in the absence of niche-like cells.

Clinical Implications of NRAS Overexpression in Resectable Pancreatic Adenocarcinoma Patients.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, and its incidence is rising worldwide. Although survival can be improved by surgical resection, when detected at an early stage, this type of cancer is usually asymptomatic, and disease becomes only apparent after metastasis. Adjuvant treatment does not improve survival, thus after surgery there is a lack of predictive and prognosis biomarkers to predict treatment response and survival. The mitogen-activated protein-kinase and phosphoinositide 3-kinase signalling pathways play a crucial role in cancer development and progression. Especially, activated RAS proteins promote cell proliferation through constitutive stimulation of the downstream effectors RAF-MEK-ERK and PI3K-AKT. Mutational status of NRAS is required in several types of cancer like colorectal or cutaneous melanoma. However, mutations in this gene are very scarce in PDAC patients, and NRAS determination is not usually performed in clinical practice for this kind of tumor. In this study, we analyse the association between NRAS protein expression and progression-free survival and overall survival of an homogenous cohort of pancreatic ductal adenocarcinoma patients from a single-centre. Interestingly, we found that patients with high expression not only showed longer progression-free survival than those patients with low expression (22 versus 9 months, respectively) (P = 0.013), but also longer overall survival (43 versus 19 months, respectively) (P = 0.020). These results confirm NRAS expression could be used to differentiate patients according to their prognosis. Proportional hazard model revealed NRAS expression together with grade of differentiation as pathological variables to predict patient's outcome.

UNR/CDSE1 expression as prognosis biomarker in resectable pancreatic ductal adenocarcinoma patients: A proof-of-concept.

Pancreatic ductal adenocarcinoma is an aggressive form of pancreatic cancer and the fourth leading cause of cancer-related death. When possible, curative approaches are based on surgical resection, though not every patient is a candidate for surgery. There are clinical guidelines for the management of these patients that offer different treatment options depending on the clinical and pathologic characteristics. However, the survival rates seen in this kind of patients are still low. The CDSE1 gene is located upstream of NRAS and encodes an RNA-binding protein termed UNR. The aim of this study was to analyze UNR expression and its correlation with outcome in patients with resectable pancreatic ductal adenocarcinoma (PDAC). For this, samples from resectable PDAC patients who underwent duodenopancreatectomy were used to evaluate UNR protein expression by immunohistochemistry using a tissue microarray. Here, we observed that low UNR expression was significantly associated with shorter progression-free survival after surgery (P = 0.010). Moreover, this prognostic marker remained significant after Cox proportional hazards model (P = 0.036). We further studied the role of CDSE1 expression in patient's prognosis using data from public repositories (GEO and TGCA), confirming our results. Interestingly, CDSE1 expression correlated with that of genes characteristic of an immunogenic molecular subtype of pancreatic cancer. Based on these findings, UNR may be considered a potential prognostic biomarker for resectable PDAC and may serve to guide subsequent adjuvant treatment decisions.

De- and recellularization of the pig uterus: a bioengineering pilot study.

Absolute uterine factor infertility, or the absence of a functional uterus, has a prevalence of 3%-5% in the general population. Despite the great strides being made in reproductive medicine, patients diagnosed with absolute uterine factor infertility remain untreatable. The only available solution has been gestational surrogacy, but recently the Brannström group presented a viable alternative by reporting the first successful live birth after uterus transplantation. Similar to other transplantations, this approach has inherent limitations such as the paucity of donor organs and the need for long-term immunosuppression. Whole organ de- and recellularization, a novel tissue engineering approach within the field of regenerative medicine, could eventually provide another solution. Several groups have described animal models in which they have performed decellularization of whole uteri, while maintaining the extracellular matrix to enable recellularization attempts. Our work offers a new perspective; in decellularizing the porcine uterus, this constitutes the first pilot study using large whole reproductive organs. We demonstrated the preservation of a reusable/functional extracellular matrix while maintaining its vascular network. Furthermore, we report the first use of human side population stem cells in the successful recellularization of small acellular disk scaffolds procured from the decellularized organs. To conclude, this research opens new avenues in whole uterus bioengineering, opening the way towards the transplantation of functional bioengineered uteri into humans.