Cabergoline treatment in acromegaly: pros

Cabergoline is an ergot-derived dopamine D2 receptor agonist which may be effective for the medical management of acromegaly. Its efficacy in reducing growth hormone and IGF-I levels, as well as its antiproliferative and pro-apoptotic effects on pituitary tumor cells, has been observed in several studies. Cabergoline may be used alone or as an add-on therapy to patients who are partially resistant to somatostatin analogs (SSA), or who do not achieve complete control with maximum doses of pegvisomant (PEG). Additionally, the convenience of its oral administration, allowing better compliance, and its lower economic cost, in comparison with SSA and PEG, favor cabergoline as an attractive option for acromegalic patients, who frequently require long-life medical treatment to achieve disease control. The few adverse events observed with prolonged DA therapy, mainly regarding cardiac valve disease, are not frequent at the doses generally used in acromegaly

Effect of Plant Growth-Promoting Rhizobacteria on Salicornia ramosissima Seed Germination under Salinity, CO2 and Temperature Stress

In a scenario of climate change and growing population, halophyte root microbiota interactions may be a sustainable solution to improve alternative crop production while combating abiotic stress. In this work, seeds of the cash crop halophyte Salicornia ramosissima were inoculated with five different plant growth-promoting rhizobacteria consortia, isolated from the rhizosphere of five halophytes in southwestern Spain salt marshes. For the first time, we recorded seed germination response to three interactive abiotic stressors, CO2 (400 and 700 ppm), temperature (25 and 29 ℃) and salinity (171, 510 and 1030 mM NaCl), all of them related to climate change. Salinity played a decisive role, as no significant differences were registered between treatments at 171 mM NaCl and no germination took place at 1030 mM NaCl. At 510 mM NaCl, one rhizobacterial consortium improved seed parameters notably, increasing up to 114% germination percentage and 65% seedlings biomass. These first findings encourage us to think that cash crop halophytes like S. ramosissima and halophyte root microbiota may be valuable resources for human or animal feeding in a future climate reality.Ministerio de Economía y Competitividad (CGL2016-75550-R)Ministerio de Educación, Cultura y Deporte (FPU014/03987

Pegvisomant-Induced Cholestatic Hepatitis in an Acromegalic Patient with UGT1A1∗ 28 Mutation

Pegvisomant (PEGv) is a growth hormone receptor antagonist approved for the treatment of acromegaly; one of its documented adverse effects is reversible elevation of hepatic enzymes. We report a 39-year-old male acromegalic patient with a pituitary macroadenoma who underwent transsphenoidal surgery. The patient’s condition improved but GH and IGF-I levels did not normalize; as a consequence, we first administered dopamine agonists and then somatostatin receptor ligands (SRLs) with poor response. PEGv 15mg every other day was added to lanreotide 120mg monthly. The patient developed a severe hepatitis five months after starting the combination therapy. Elevated ferritin, iron, and transferrin saturation suggested probable hepatitis due to haemochromatosis. We performed a liver biopsy which showed an acute cholestatic hepatitis consistent with toxic etiology. A heterozygous genotype UGT1A1∗28 polymorphism associated with Gilbert’s syndrome was also found in this Argentine patient. The predominant clinical presentation resembled an acute cholestatic hepatitis associated with severe hemosiderosis, a different and new pattern of PEGv hepatotoxicityS

Measuring urban sustainability performance through composite indicators for Spanish cities

[EN] The role that cities play in the transition to more sustainable growth is gaining increasing recognition. Measuring progress towards sustainable urban development requires quantifying this multi-dimensional phenomenon with the help of composite indicators. The purpose of this study is to propose an integrated approach to build a sustainable cities' interval of composite indicators that rely on the Sustainable Development Goals (SDGs) framework. In addition, we propose to overcome the problem of calculating a single number by constructing a strong-weak sustainability performance interval depending on the choice of the compensability level in the aggregation stage of individual indicators. One of the advantages of this interval is that it provides information on both the average performance and the worst value of the set of indicators considered for each SDG. Moreover, it also extends the analysis for the people, planet, prosperity, peace, and partnership dimensions defined by the 2030 Agenda. As an example of application, we constructed these intervals for 50 Spanish cities, which are provincial capitals. This application lets us get a more accurate vision that can serve as a valuable tool for better urban planning design.Funding for open access charge: CRUE-Universitat Politècnica de València.Lo-Iacono-Ferreira, VG.; Garcia-Bernabeu, A.; Hilario Caballero, A.; Torregrosa López, JI. (2022). Measuring urban sustainability performance through composite indicators for Spanish cities. Journal of Cleaner Production. 359:1-11. https://doi.org/10.1016/j.jclepro.2022.13198211135

PUESTA EN MARCHA DE UNA PLANTA DE FILTRACIÓN TANGENCIAL DE LEVADURA PARA LA RECUPERACIÓN DE CERVEZA

Algunos excedentes de levadura de las factorías de cerveza se utilizan para la obtención de extractos de la misma, generalmente para usos farmacéuticos o para saborizar y aromatizar algunos alimentos. Otro de los usos más generalizados es el destinado a la fabricación de piensos para el ganado, debido a los altos niveles nutricionales de la levadura fresca.El problema que encontramos con esta forma de gestionar los excedentes es que se pierde un gran volumen de producto final, puesto que la levadura que se extrae de los tanques de fermentación naturalmente se encuentra suspendida en cerveza.De modo que con el objetivo de obtener una máxima rentabilidad del proceso de producción, la compañía PALL Corporation ha diseñado una tecnología de filtración basada en una serie de membranas cerámicas que consiguen separar las células de levadura de la propia cerveza. El destino de todo este permeado recuperado será naturalmente el envasado para su normal distribución. Al tratarse de una cerveza obtenida de levadura de cosecha, posee unos aromas y un sabor no aceptados como producto final, por lo que este permeado se dosifica en línea al 3-5% en los formatos botella y lata de otras cervezas también producidas en la fábrica sin que esto afecte en absoluto a la calidad del producto final, consiguiendo así darle salida a toda la cerveza recuperada.En este trabajo se expone todo el proceso de recuperación de cerveza a partir de la levadura extraída de los tanques de fermentación y los consiguientes análisis fisico-químicos que se le realizaron tanto a la levadura filtrada como al permeado obtenido tras la filtración

Calibración de equipos en base a técnicas estadísticas. Creación de patrones

Este artículo trata de la necesidad de verificación del estado de calibración mediante técnicas estadísticas y la metodología o procedimiento utilizado por los laboratorios de calibración. Se hace mención al significado del concepto patrón de medición trazable, la verificación, y en su caso, posterior calibración en base a técnicas estadísticas. Por último, se realiza una parte experimental con objeto de comprobar las técnicas de calibración por comparación en los laboratorios de una zona de referencia.Gisbert Soler, V.; Pérez Bernabeu, E.; Cebrián Aznar, I. (2012). Calibración de equipos en base a técnicas estadísticas. Creación de patrones. 3C Tecnología. (3):6-21. http://hdl.handle.net/10251/30132S621

Pasireotide in the Personalized Treatment of Acromegaly

The delay in controlling the disease in patients who do not respond to first-line treatment with first generation somatostatin receptor ligands (first-generation SRLs) can be quantified in years, as every modification in the medical therapy requires some months to be fully evaluated. Considering this, acromegaly treatment should benefit from personalized medicine therapeutic approach by using biomarkers identifying drug response. Pasireotide has been positioned mostly as a compound to be used in first-generation SRLs resistant patients and after surgical failure, but sufficient data are now available to indicate it is a first line therapy for patients with certain characteristics. Pasireotide has been proved to be useful in patients in which hyperintensity T2 MRI signal is shown and in those depicting low SST2 and high expression of SST5, low or mutated AIP condition and sparsely granulated immunohistochemical pattern. This combination of clinical and pathological characteristics is unique for certain patients and seems to cluster in the same cases, strongly suggesting an etiopathogenic link. Thus, in this paper we propose to include this clinico-pathologic phenotype in the therapeutic algorithm, which would allow us to use as first line medical treatment those compounds with the highest potential for achieving the fastest control of GH hypersecretion as well as a positive effect upon tumor shrinkage, therefore accelerating the implementation of precision medicine for acromegaly. Moreover, we suggest the development, validation and clinical use of a pasireotide acute test, able to identify patients responsive to pasireotide LAR as the acute octreotide test is able to do for SRLs

Craniopharyngioma in the elderly: a multicenter and nationwide study in Spain

[Abstract] Background: Craniopharyngioma (CP) is a rare tumor in the elderly whose clinical features and prognosis are not well known in this population. Aim: To evaluate the clinicopathological features and therapeutic outcomes of CP diagnosed in the elderly. Patients and Methods: This was a retrospective, multicenter, national study of CP patients diagnosed over the age of 65 years and surgically treated. Results: From a total of 384 adult CP patients, we selected 53 (13.8%) patients (27 women [50.9%], mean age 72.3 ± 5.1 years [range 65–83 years]) diagnosed after the age of 65 years. The most common clinical symptoms were visual field defects (71.2%) followed by headache (45.3%). The maximum tumor diameter was 2.9 ± 1.1 cm. In most patients, the tumor was suprasellar (96.2%) and mixed (solid-cystic) (58.5%). The surgical approach most commonly used was transcranial surgery (52.8%), and more than half of the patients (54.7%) underwent subtotal resection (STR). Adamantinomatous CP and papillary CP were present in 51 and 45.1%, respectively, with mixed forms in the remaining. Surgery was accompanied by an improvement in visual field defects and in headaches; however, pituitary hormonal hypofunction increased, mainly at the expense of an increase in the prevalence of diabetes insipidus (DI) (from 3.9 to 69.2%). Near-total resection (NTR) was associated with a higher prevalence of DI compared with subtotal resection (87.5 vs. 53.6%, p = 0.008). Patients were followed for 46.7 ± 40.8 months. The mortality rate was 39.6% with a median survival time of 88 (95% CI: 57–118) months. DI at last visit was associated with a lower survival. Conclusion: CP diagnosed in the elderly shows a similar distribution by sex and histologic forms than that diagnosed at younger ages. At presentation, visual field alterations and headaches are the main clinical symptoms which improve substantially with surgery. However, surgery, mainly NTR, is accompanied by worsening of pituitary function, especially DI, which seems to be a predictor of mortality in this population

Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegaly

Background: Acromegaly is produced by excess growth hormone secreted by a pituitary adenoma of somatotroph cells (ACRO). First-line therapy, surgery and adjuvant therapy with somatostatin analogs, fails in 25% of patients. There is no predictive factor of resistance to therapy. New therapies are investigated using few dispersed tumor cells in acute primary cultures in standard conditions where the cells do not grow, or using rat pituitary cell lines that do not maintain the full somatotroph phenotype. The RET/PIT1/p14ARF/p53 pathway regulates apoptosis in normal pituitary somatotrophs whereas the RET/GDNF pathway regulates survival, controlling PIT1 levels and blocking p14ARF (ARF) and p53 expression. Methods: We investigated these two RET pathways in a prospective series of 32 ACRO and 63 non-functioning pituitary adenomas (NFPA), studying quantitative RNA and protein gene expression for molecular-clinical correlations and how the RET pathway might be implicated in therapeutic success. Clinical data was collected during post-surgical follow-up. We also established new'humanized’ pituitary cultures, allowing 20 repeated passages and maintaining the pituitary secretory phenotype, and tested five multikinase inhibitors (TKI: Vandetanib, Lenvatinib, Sunitinib, Cabozantinib and Sorafenib) potentially able to act on the GDNF-induced RET dimerization/survival pathway. Antibody arrays investigated intracellular molecular pathways. Findings: In ACRO, there was specific enrichment of all genes in both RET pathways, especially GDNF. ARF and GFRA4 gene expression were found to be opposing predictors of response to first-line therapy. ARF cut-off levels, calculated categorizing by GNAS mutation, were predictive of good response (above) or resistance (below) to therapy months later. Sorafenib, through AMPK, blocked the GDNF/AKT survival action without altering the RET apoptotic pathway. Interpretation: Tumor ARF mRNA expression measured at the time of the surgery is a prognosis factor in acromegaly. The RET inhibitor, Sorafenib, is proposed as a potential treatment for resistant ACRO. Fund: This project was supported by national grants from Agencia Estatal de Investigación (AEI) and Instituto Investigación Carlos III, with participation of European FEDER funds, to IB (PI150056) and CVA (BFU2016-76973-R). It was also supported initially by a grant from the Investigator Initiated Research (IIR) Program (WI177773) and by a non-restricted Research Grant from Pfizer Foundation to IB. Some of the pituitary acromegaly samples were collected in the framework of the Spanish National Registry of Acromegaly (REMAH), partially supported by an unrestricted grant from Novartis to the Spanish Endocrine Association (SEEN). CVA is also supported from a grant of Medical Research Council UK MR/M018539/1

Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegaly

Most of acromegaly is caused by a sporadic somatotropinoma and a couple of novel gene mutations responsible for somatotropinoma have recently been reported. To determine the cause of sporadic somatotropinoma in Japanese patients, we analyzed 61 consecutive Japanese patients with somatotropinoma without apparent family history. Comprehensive genetic analysis revealed that 31 patients harbored guanine nucleotide-binding protein, alpha stimulating (GNAS) mutations (50.8%) and three patients harbored aryl hydrocarbon receptor interacting protein (AIP) mutations (4.9%). No patients had G protein-coupled receptor 101 (GPR101) mutations. The patients in this cohort study were categorized into three groups of AIP, GNAS, and others and compared the clinical characteristics. The AIP group exhibited significantly younger age at diagnosis, larger tumor, and higher nadir GH during oral glucose tolerance test. In all patients with AIP mutation, macro- and invasive tumor was detected and repetitive surgery or postoperative medical therapy was needed. One case showed a refractory response to postoperative somatostatin analogue (SSA) but after the addition of cabergoline as combined therapy, serum IGF-I levels were controlled. The other case showed a modest response to SSA and the switching to cabergoline monotherapy was also effective. These data suggest that although resistance to SSA has been reported in patients with AIP mutations, the response to dopamine agonist (DA) may be retained. In conclusion, the cause of sporadic somatotropinoma in Japanese patients was comparable with the previous reports in Caucasians, patients with AIP mutations showed unique clinical characteristics, and DA may be a therapeutic option for patients with AIP mutations