SEOM-GEINO clinical guidelines for high-grade gliomas of adulthood (2022)

High-grade gliomas (HGG) are the most common primary brain malignancies and account for more than half of all malignant primary brain tumors. The new 2021 WHO classification divides adult HGG into four subtypes: grade 3 oligodendroglioma (1p/19 codeleted, IDH-mutant); grade 3 IDH-mutant astrocytoma; grade 4 IDH-mutant astrocytoma, and grade 4 IDH wild-type glioblastoma (GB). Radiotherapy (RT) and chemotherapy (CTX) are the current standard of care for patients with newly diagnosed HGG. Several clinically relevant molecular markers that assist in diagnosis and prognosis have recently been identified. The treatment for recurrent high-grade gliomas is not well defined and decision-making is usually based on prior strategies, as well as several clinical and radiological factors. Whereas the prognosis for GB is grim (5-year survival rate of 5-10%) outcomes for the other high-grade gliomas are typically better, depending on the molecular features of the tumor. The presence of neurological deficits and seizures can significantly impact quality of life

Novel Variant in the CNNM2 Gene Associated with Dominant Hypomagnesemia

The maintenance of magnesium (Mg2+) homeostasis is essential for human life. The Cystathionine-beta-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) have been described to be involved in maintaining Mg2+ homeostasis. Among these CNNMs, CNNM2 is expressed in the basolateral membrane of the kidney tubules where it is involved in Mg2+ reabsorption. A total of four patients, two of them with a suspected disorder of calcium metabolism, and two patients with a clinical diagnosis of primary tubulopathy were screened for mutations by Next-Generation Sequencing (NGS). We found one novel likely pathogenic variant in the heterozygous state (c.2384C>A; p.(Ser795*)) in theCNNM2gene in a family with a suspected disorder of calcium metabolism. In this family, hypomagnesemia was indirectly discovered. Moreover, we observed three novel variants of uncertain significance in heterozygous state in the other three patients (c.557G>C; p.(Ser186Thr), c.778A>T; p.(Ile260Phe), and c.1003G>A; p.(Asp335Asn)). Our study shows the utility of Next-Generation Sequencing in unravelling the genetic origin of rare diseases. In clinical practice, serum Mg2+ should be determined in calcium and PTH-related disorders.This study was supported by three grants from the Department of Health (2017111014, 2018111097 and 2019111052) and one grant from the Department of Education (IT1281-19) of the Basque Government. This work is generated within the Endocrine European Reference Network (Project ID number of Endo-ERN: 739527). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Supporting central nervous system neuroprotection and remyelination by specific TLR4 antagonism

ApTOLL is an aptamer specifically designed to antagonize toll-like receptor 4 (TLR4), which is involved in the innate immunity that promotes inflammatory responses in several diseases, including multiple sclerosis (MS). MS is a chronic, immune, demyelinating and neurodegenerative disease of the central nervous system that represents the second most important cause of neurological disability in young adults. The drugs currently available to treat this disease are immunomodulators and, to date, there are no therapeutic remyelinating drugs available to manage MS. In this study, we show that TLR4 is located in post-mortem cortical lesions of MS patients and as a result, we evaluated the effect of its inhibition by ApTOLL in two different animal models of MS, that of experimental autoimmune encephalomyelitis (EAE) and the cuprizone model. ApTOLL administration ameliorated the clinical symptomatology of the affected mice, which was associated with better preservation and restoration of myelin and oligodendrocytes in the demyelinated lesions of these animals. This revealed not only an immunomodulatory but also a remyelinating effect of the treatment with ApTOLL which was corroborated on purified cultures of rodent and adult human oligodendrocyte precursor cells (OPCs). In summary, the molecular nature of ApTOLL and its mechanism of action strongly supports its further study and use in novel strategies to treat MS and eventually, other demyelinating diseases.This work was supported by grant IND2018/BMD-9751 (Programa de Doctorados Industriales, Comunidad de Madrid, Spain), SAF2016-77575-R (Spanish Ministerio de Economía, Industria y Competitividad-MINECO), and the contract for technological support ApTLR2019-PC-MS-001 (AptaTargets, S.L., Spain) to FdC. BF-G is currently hired by Aptatargets S.L., PG-M is hired under PEJ-2020-AI/BMD-18541 de la Comunidad de Madrid, Spain (associated with the youth guarantee fund to FdC), SN had a predoctoral contract from the UCLM and was hired under SAF2012-40023, SAF2016- 77575-R, RD12-0032/0012 and RD16-0015/0019 (Spanish Ministerio de Economía, Industria y Competitividad-MINECO) and IND2018/BMD-9751, YL has been contracted under ReTics and SAF (to FdC). We thank David Segarra and Mª Eugenia Zarabozo (AptaTargets S.L.) for their constant technological support, Laude Garmendia for her indispensable constant help at the animal facility (Instituto Cajal-CSIC), including the extra effort during Covid-19 pandemics, Profs María Ángeles Moro (Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid and Universidad Complutense de Madrid, Spain) and Ignacio Lizasoaín (Universidad Complutense de Madrid, Spain) for lending us the TLR4 knockout mice, and the former GNDe member Dr. Carolina MeleroJerez (currently working at JazzPharma, Spain) for the initial training of BF-G on EAE animal model and different techniques at the laboratory. Human samples were supplied by the UK Multiple Sclerosis Tissue Bank, funded by the Multiple Sclerosis Society of Great Britain and Northern Ireland (registered charity 207495).N

Five Patients with Disorders of Calcium Metabolism Presented with GCM2 Gene Variants

The GCM2 gene encodes a transcription factor predominantly expressed in parathyroid cells that is known to be critical for development, proliferation and maintenance of the parathyroid cells. A cohort of 127 Spanish patients with a disorder of calcium metabolism were screened for mutations by Next-Generation Sequencing (NGS). A targeted panel for disorders of calcium and phosphorus metabolism was designed to include 65 genes associated with these disorders. We observed two variants of uncertain significance (p.(Ser487Phe) and p.Asn315Asp), one likely pathogenic (p.Val382Met) and one benign variant (p.Ala393_Gln395dup) in the GCM2 gene in the heterozygous state in five families (two index cases had hypocalcemia and hypoparathyroidism, respectively, and three index cases had primary hyperparathyroidism). Our study shows the utility of NGS in unravelling the genetic origin of some disorders of the calcium and phosphorus metabolism, and confirms the GCM2 gene as an important element for the maintenance of calcium homeostasis. Importantly, a novel variant in the GCM2 gene (p.(Ser487Phe)) has been found in a patient with hypocalcemia.This study was supported by three grants from the Department of Health (2017111014, 2018111097 and 2019111052) and one grant from the Department of Education (IT1281-19) of the Basque Government. This work is generated within the Endocrine European Reference Network (Project ID number of Endo-ERN: 739527). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip

Rare Germline DICER1 Variants in Pediatric Patients With Cushing's Disease: What Is Their Role?

Context: The DICER1 syndrome is a multiple neoplasia disorder caused by germline mutations in the DICER1 gene. In DICER1 patients, aggressive congenital pituitary tumors lead to neonatal Cushing's disease (CD). The role of DICER1 in other corticotropinomas, however, remains unknown. Objective: To perform a comprehensive screening for DICER1 variants in a large cohort of CD patients, and to analyze their possible contribution to the phenotype. Design, setting, patients, and interventions: We included 192CD cases: ten young-onset (age <30 years at diagnosis) patients were studied using a next generation sequencing panel, and 182 patients (170 pediatric and 12 adults) were screened via whole-exome sequencing. In seven cases, tumor samples were analyzed by Sanger sequencing. Results: Rare germline DICER1 variants were found in seven pediatric patients with no other known disease-associated germline defects or somatic DICER1 second hits. By immunohistochemistry, DICER1 showed nuclear localization in 5/6 patients. Variant transmission from one of the parents was confirmed in 5/7 cases. One patient had a multinodular goiter; another had a family history of melanoma; no other patients had a history of neoplasms. Conclusions: Our findings suggest that DICER1 gene variants may contribute to the pathogenesis of non-syndromic corticotropinomas. Clarifying whether DICER1 loss-of-function is disease-causative or a mere disease-modifier in this setting, requires further studies.This work was supported by the Intramural Research Programs of Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Institute for Neurological Diseases and Stroke, National Institutes of Health, a grant from the Basque Department of Education (IT795-13), a grant from the Basque Department of Health (GV2018111082), the Merck Serono Research award from Fundacion Salud 2000 (15-EP-004) and the Jose Igea 2018 grant, sponsored by Pfizer, from Fundacion Sociedad Espanola de Endocrinologia Pediatrica (SEEP)

Liver osteopontin is required to prevent the progression of age-related nonalcoholic fatty liver disease

[EN] Osteopontin (OPN), a senescence-associated secretory phenotype factor, is increased in patients with nonalcoholic fatty liver disease (NAFLD). Cellular senescence has been associated with age-dependent hepatosteatosis. Thus, we investigated the role of OPN in the age-related hepatosteatosis. For this, human serum samples, animal models of aging, and cell lines in which senescence was induced were used. Metabolic fluxes, lipid, and protein concentration were determined. Among individuals with a normal liver, we observed a positive correlation between serum OPN levels and increasing age. This correlation with age, however, was absent in patients with NAFLD. In wild-type (WT) mice, serum and liver OPN were increased at 10 months old (m) along with liver p53 levels and remained elevated at 20m. Markers of liver senescence increased in association with synthesis and concentration of triglycerides (TG) in 10m OPN-deficient (KO) hepatocytes when compared to WT hepatocytes. These changes in senescence and lipid metabolism in 10m OPN-KO mice liver were associated with the decrease of 78 kDa glucose-regulated protein (GRP78), induction of ER stress, and the increase in fatty acid synthase and CD36 levels. OPN deficiency in senescent cells also diminished GRP78, the accumulation of intracellular TG, and the increase in CD36 levels. In 20m mice, OPN loss led to increased liver fibrosis. Finally, we showed that OPN expression in vitro and in vivo was regulated by p53. In conclusion, OPN deficiency leads to earlier cellular senescence, ER stress, and TG accumulation during aging. The p53-OPN axis is required to inhibit the onset of agerelated hepatosteatosis.This work was supported by Ayudas para apoyar grupos de investigación del sistema Universitario Vasco (IT971‐16 to P.A.), MINECO‐FEDER (SAF2017‐87301‐R to M.L.M‐Ch) MCIU/AEI/FEDER, UE (RTI2018‐095134‐B‐100 to P.A. and RTI2018‐099413‐B‐I00 to RN, Asociación Española contra el Cáncer, Canceres raros (M.L.M‐Ch), La Caixa Foundation (to M.L.M‐Ch), Ayudas Fundación BBVA a equipos de Investigación Científica 2018 (to M.L.M‐Ch), Xunta de Galicia (RN: 2015‐CP080 and 2016‐ PG057), Fundación BBVA (RN), and European Foundation for the Study of Diabetes (RN). ISCIII‐FEDER PI17/00535 (to C.G‐M.), ISCIII‐FEDER CP14/00181 and PI16/00823 (to A.G‐ R.), and Francisco Cobos Foundation (to A.G‐R.). CiC bioGUNE thanks MINECO for the Severo Ochoa Excellence Accreditation (SEV‐2016‐ 0644

Use of non-steroidal anti-inflammatory drugs and risk of breast cancer: The Spanish Multi-Case-control (MCC) study

Background: The relationship between non-steroidal anti-inflammatory drug (NSAID) consumption and breast cancer has been repeatedly studied, although the results remain controversial. Most case-control studies reported that NSAID consumption protected against breast cancer, while most cohort studies did not find this effect. Most studies have dealt with NSAIDs as a whole group or with specific drugs, such aspirin, ibuprofen, or others, but not with NSAID subgroups according to the Anatomical Therapeutic Chemical Classification System; moreover, scarce attention has been paid to their effect on different tumor categories (i.e.: ductal/non-ductal, stage at diagnosis or presence of hormonal receptors). Methods: In this case-control study, we report the NSAID – breast cancer relationship in 1736 breast cancer cases and 1895 healthy controls; results are reported stratifying by the women’s characteristics (i.e.: menopausal status or body mass index category) and by tumor characteristics. Results: In our study, NSAID use was associated with a 24 % reduction in breast cancer risk (Odds ratio [OR] = 0.76; 95 % Confidence Interval [CI]: 0.64–0.89), and similar results were found for acetic acid derivatives, propionic acid derivatives and COXIBs, but not for aspirin. Similar results were found in postmenopausal and premenopausal women. NSAID consumption also protected against hormone + or HER2+ cancers, but not against triple negative breast cancers. The COX-2 selectivity showed an inverse association with breast cancer (i.e. OR < 1), except in advanced clinical stage and triple negative cancers. Conclusion: Most NSAIDs, but not aspirin, showed an inverse association against breast cancer; this effect seems to be restricted to hormone + or HER2+ cancers. Keywords: Breast cancer, Non-steroidal anti-inflammatory drug, Hormone receptor positive breast cancer, HER2 positive breast cancer, Triple negative breast cance

Persistent Pulmonary Hypertension in Corrected Valvular Heart Disease: Hemodynamic Insights and Long-Term Survival.

Background The determinants and consequences of pulmonary hypertension after successfully corrected valvular heart disease remain poorly understood. We aim to clarify the hemodynamic bases and risk factors for mortality in patients with this condition. Methods and Results We analyzed long-term follow-up data of 222 patients with pulmonary hypertension and valvular heart disease successfully corrected at least 1 year before enrollment who had undergone comprehensive hemodynamic and imaging characterization as per the SIOVAC (Sildenafil for Improving Outcomes After Valvular Correction) clinical trial. Median (interquartile range) mean pulmonary pressure was 37 mm Hg (32-44 mm Hg) and pulmonary artery wedge pressure was 23 mm Hg (18-26 mm Hg). Most patients were classified either as having combined precapillary and postcapillary or isolated postcapillary pulmonary hypertension. After a median follow-up of 4.5 years, 91 deaths accounted for 4.21 higher-than-expected mortality in the age-matched population. Risk factors for mortality were male sex, older age, diabetes mellitus, World Health Organization functional class III and higher pulmonary vascular resistance-either measured by catheterization or approximated from ultrasound data. Higher pulmonary vascular resistance was related to diabetes mellitus and smaller residual aortic and mitral valve areas. In turn, the latter correlated with prosthetic nominal size. Six-month changes in the composite clinical score and in the 6-minute walk test distance were related to survival. Conclusions Persistent valvular heart disease-pulmonary hypertension is an ominous disease that is almost universally associated with elevated pulmonary artery wedge pressure. Pulmonary vascular resistance is a major determinant of mortality in this condition and is related to diabetes mellitus and the residual effective area of the corrected valve. These findings have important implications for individualizing valve correction procedures. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00862043.This study was funded by the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spain, the European Union–European Regional Development Fund (EC07/90772 and PI19/00649), and the Consorcio de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV).S

Alternativas de desarrollo agropecuario con proyección sostenible para el distrito de riego del Zulia y su zona de influencia

La asociación de usuarios del Distrito de Adecuación de Tierras de Gran Escala del Río Zulia (ASOZULIA) Norte de Santander, con un área de influencia de 45.536 hectáreas, está interesada en la planificación productiva de su territorio. Dentro de sus actividades agropecuarias se encuentran el arroz (12.000 a 17.000 ha), la palma de aceite (1.534 ha), cítricos (limón, naranja; 346 ha), caña de azúcar (100 ha) y la ganadería. Su principal sistema de producción durante más de 50 años es el cultivo de arroz, sistema que presenta reducción de la productividad (7 a 3 tha), degradación del suelo y problemas de plagas y enfermedades, debido entre otros al uso continuo del fangueo como sistema de preparación de suelos. Adicionalmente, a pesar de tener el distrito de riego del río Zulia una concesión de 13,5 m3.s1, en épocas de verano la oferta hidrica es mucho menor como, por ejemplo, la correspondiente a los meses de febrero a marzo de 2016, con un caudal en la bocatoma del distrito de 10,8 m3s'y una captación real del distrito de solo 6 m.s' Asimismo, la construcción del nuevo acueducto para el área metropolitana de la ciudad de Cúcuta tomará 2,95 m3s del caudal antes de la bocatoma que provee agua al distrito, lo que disminuirá aún más la disponibilidad de agua para riego en esa región. Por lo anterior, se requiere la recuperación de los suelos para el establecimiento de nuevos sistemas productivos que demanden un menor consumo de agua y sean una alternativa viable para los productores.Acelga-Remolacha de hoja, Beta vulgaris var. Cicl

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality