Specialized proresolving mediators (SPMs) biosynthesized from docosahexaenoic acids (DHAs) including resolvins (Rvs), protectins, and maresins are potent endogenous autacoids that actively resolve inflammation, protect organs, and stimulate tissue regeneration. Our hypothesis was that failure of resolution programs may lead to unremitting inflammation in obesity, contributing to the development of metabolic comorbidities in this condition. Obese individuals with persistent low‐grade systemic inflammation showed reduced leukocyte production of the DHA‐derived monohydroxy fatty acid 17—hydroxy‐DHA (HDHA) and unbalanced formation of SPMs (in particular d‐series Rvs) accompanied by enhanced production of proinflammatory lipid mediators such as leukotriene B4. Mechanistic studies attributed this impairment to reduced 15‐lipoxygenase (LOX) activity rather than altered DHA cellular uptake. Moreover, leukocytes from obese individuals exhibited decreased 5‐LOX levels and reduced 5‐LOX Ser271 phosphorylation and distinct intracellular 5‐LOX redistribution. However, 15‐LOX appears to be the most critical factor for the deficient production of SPMs by obese leukocytes because the formation of d‐series Rvs was completely rescued by incubation with the intermediate precursor 17‐HDHA. These data provide proof of concept that administration of intermediate precursors of SPM biosynthesis (e.g., 17‐HDHA) could be more efficient in overriding impaired formation of these proresolving lipid mediators in conditions characterized by dysfunctional LOX activity, such as obesity.—López‐Vicario, C, Titos, E., Walker, M. E., Alcaraz‐Quiles, J., Casulleras, M., Durán‐Güell, M., Flores‐Costa, R., Pérez‐Romero, N., Forné, M., Dalli, J., Clària, J. Leukocytes from obese individuals exhibit an impaired SPM signature. FASEB J. 33, 7072–7083 (2019). http://www.fasebj.org
We describe a patient with a novel WT1 pS50X germ line mutation, who developed bilateral Wilms tumours, both with stromal-type histology. Both tumours showed loss of the wild type WT1 allele (loss of heterozygosity (LOH)) and a tumour specific mutation in catenin beta1 (CTNNB1), S45P in the left and D45S in the right tumour. Molecular analysis of microdissected cells from the left tumour revealed the same S45P CTNNB1 mutation in blastema, tubuli, stroma and muscle, and a different CTNNB1 mutation (T41A) in stromal cells isolated from another area of the same slide. Microdissection of two areas of muscle cells from the right tumour revealed the same D45S mutation and no CTNNB1 mutation nor LOH of WT1 in normal kidney cells. One year later, the patient developed a new set of bilateral tumours. Both tumours showed LOH of the wild type WT1 allele, but different CTNNB1 mutations as in the first tumours: S45C on the right and S45F on the left side, demonstrating that these developed independently and are not relapses. This case demonstrates the high risk for the development of Wilms tumours in patients with germ line truncation mutations.W ilms tumour (WT) or nephroblastoma is the most frequent renal tumour of childhood. WT is thought to be derived from a renal stem cell, with impaired differentiation potential. Most tumours have a mixed histology and are composed of three elements: blastema, epithelia and stroma, recapitulating the development of the normal kidney. Tumours may also contain heterotypic cells not normally found in the kidney such as rhabdomyoblasts, fat, cartilage and bone, probably derived from an abnormal mesenchymal differentiation. This type of differentiation is mainly observed in the stromal-type variant of WT. Constitutional or somatic mutations in the WT1 gene are found in approximately 10-20% of WT, most occurring in stromal-type tumours. [1][2][3][4] In addition, approximately 75% of WT carry CTNNB1 gene mutations, mostly in or close to amino acids that are important for activity and stabilisation of the protein. [5][6][7][8][9] METHODSMutation and allelotyping analysis DNA was isolated from the tumour and blood by standard methods. WT1 gene mutation analysis was performed by the DNA-PCR SSCP method including all 10 exons and flanking intron sequences, as described. 2 CTNNB1 gene mutation analysis of exon 3 was performed as described. 5 To study the mechanism for LOH, microsatellite analysis was performed with CA-repeat markers from 11q11 (D11S1313), 11p13 (D11S1776) and 11p15.4 (D11S1323). In the PCR one marker was fluorescently labelled with IRD 800 and the products were analysed on an automatic sequencer (Li-Cor Biosciences, Lincoln, Nebraska, USA).For the molecular analysis of the different cell types the respective cells were identified after HE staining and the corresponding areas were removed from a consecutive unstained slide using a sterile scalpel. After deparaffinisation DNA was extracted with the Pico Pure DNA extraction buffer according to the manufacturer (Arcturus, Mountain Vi...
Background: Neuroblastic tumours (NBTs) represent a heterogeneous spectrum of neoplastic diseases associated with multiple genetic alterations. Structural and numerical chromosomal changes are frequent and are predictive parameters of NBTs outcome. We performed a comparative analysis of the biological entities constituted by NBTs with different ploidy status.
Background Few surgical studies have provided adjusted comparative postoperative outcome data among contemporary patients with and without COVID-19 infection and patients treated before the pandemic. The aim of this study was to determine the impact of performing emergency surgery in patients with concomitant COVID-19 infection. Methods Patients who underwent emergency general and gastrointestinal surgery from March to June 2020, and from March to June 2019 in 25 Spanish hospitals were included in a retrospective study (COVID-CIR). The main outcome was 30-day mortality. Secondary outcomes included postoperative complications and failure to rescue (mortality among patients who developed complications). Propensity score-matched comparisons were performed between patients who were positive and those who were negative for COVID-19; and between COVID-19-negative cohorts before and during the pandemic. Results Some 5307 patients were included in the study (183 COVID-19-positive and 2132 COVID-19-negative during pandemic; 2992 treated before pandemic). During the pandemic, patients with COVID-19 infection had greater 30-day mortality than those without (12.6 versus 4.6 per cent), but this difference was not statistically significant after propensity score matching (odds ratio (OR) 1.58, 95 per cent c.i. 0.88 to 2.74). Those positive for COVID-19 had more complications (41.5 versus 23.9 per cent; OR 1.61, 1.11 to 2.33) and a higher likelihood of failure to rescue (30.3 versus 19.3 per cent; OR 1.10, 0.57 to 2.12). Patients who were negative for COVID-19 during the pandemic had similar rates of 30-day mortality (4.6 versus 3.2 per cent; OR 1.35, 0.98 to 1.86) and complications (23.9 versus 25.2 per cent; OR 0.89, 0.77 to 1.02), but a greater likelihood of failure to rescue (19.3 versus 12.9 per cent; OR 1.56, 95 per cent 1.10 to 2.19) than prepandemic controls. Conclusion Patients with COVID-19 infection undergoing emergency general and gastrointestinal surgery had worse postoperative outcomes than contemporary patients without COVID-19. COVID-19-negative patients operated on during the COVID-19 pandemic had a likelihood of greater failure-to-rescue than prepandemic controls.
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