Adenomas hipofisarios no funcionantes: valoración de la invasión, persistencia, recurrencia y del índice de proliferación celular Ki-67

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ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity

Pancreatic cancer stem cells (PaCSCs) drive pancreatic cancer tumorigenesis, chemoresistance and metastasis. While eliminating this subpopulation of cells would theoretically result in tumor eradication, PaCSCs are extremely plastic and can successfully adapt to targeted therapies. In this study, we demonstrate that PaCSCs increase expression of interferon-stimulated gene 15 (ISG15) and protein ISGylation, which are essential for maintaining their metabolic plasticity. CRISPR-mediated ISG15 genomic editing reduces overall ISGylation, impairing PaCSCs self-renewal and their in vivo tumorigenic capacity. At the molecular level, ISG15 loss results in decreased mitochondrial ISGylation concomitant with increased accumulation of dysfunctional mitochondria, reduced oxidative phosphorylation (OXPHOS) and impaired mitophagy. Importantly, disruption in mitochondrial metabolism affects PaCSC metabolic plasticity, making them susceptible to prolonged inhibition with metformin in vivo. Thus, ISGylation is critical for optimal and efficient OXPHOS by ensuring the recycling of dysfunctional mitochondria, and when absent, a dysregulation in mitophagy occurs that negatively impacts PaCSC stemness

Allogeneic stem cell transplantation as a curative option in relapse/refractory diffuse large B cell lymphoma: Spanish multicenter GETH/GELTAMO study

Grupo Español de Trasplante Hematopoyético (GETH) and Grupo Español de Linfoma y Trasplante Autólogo (GELTAMO).We performed a retrospective multicenter study including 140 patients with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) who underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) from March 1995 to November 2018. Our objective was to analyze long term outcomes. Seventy-four percent had received a previous auto-SCT (ASCT) and the median number of lines pre-allo-SCT was 3 (range 1–9). Three year-event free survival (EFS) and overall survival (OS) were 38% and 44%, respectively. Non-relapse mortality (NRM) at day 100 was 19%. Cumulative incidence of grade III–IV acute graft versus host disease (GVHD) at day 100 was 16% and moderate/severe chronic GVHD at 3 years 34%. Active disease at allo-SCT (HR 1.95, p = 0.039) (HR 2.19, p = 0.019), HCT-CI ≥ 2 (2.45, p = 0.002) (HR 2.33, p = 0.006) and donor age >37 years (HR 2.75, p = 0.014) (HR 1.98, p = 0.043) were the only independent variables both for PFS and OS, respectively. NRM was significantly modified by HCT-CI ≥ 2 (HR 4.8, p = 0.008), previous ASCT (HR 4.4, p = 0.048) and grade III–IV acute GVHD on day 100 (HR 6.13, p = 0.016). Our data confirmed that allo-SCT is a curative option for patients with R/R DLBCL, displaying adequate results for fit patients with chemosensitive disease receiving an allo-SCT from a young donor

Sera from Patients with NMOSD Reduce the Differentiation Capacity of Precursor Cells in the Central Nervous System

Introduction: AQP4 (aquaporin-4)–immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve; remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of AQP4–IgG in cell differentiation. Material and Methods: We included three groups—a group of patients with AQP4–IgG-positive neuromyelitis optica, a healthy group, and a sham group. We analyzed differentiation capacity in cultures of neurospheres from the subventricular zone of mice by adding serum at two different times: early and advanced stages of differentiation. We also analyzed differentiation into different cell lines. Results and Conclusions: The effect of sera from patients with NMOSD on precursor cells differs according to the degree of differentiation, and probably affects oligodendrocyte progenitor cells from NG2 cells to a lesser extent than cells from the subventricular zone; however, the resulting oligodendrocytes may be compromised in terms of maturation and possibly limited in their ability to generate myelin. Furthermore, these cells decrease in number with age. It is very unlikely that the use of drugs favoring the migration and differentiation of oligodendrocyte progenitor cells in multiple sclerosis would be effective in the context of neuromyelitis optica, but cell therapy with oligodendrocyte progenitor cells seems to be a potential alternative

Open-label, phase 2 study of blinatumomab after frontline R-chemotherapy in adults with newly diagnosed, high-risk DLBCL

This open-label, multicenter, single-arm, phase 2 study assessed the safety and efficacy of blinatumomab consolidation therapy in adult patients with newly diagnosed, high-risk diffuse large B-cell lymphoma (DLBCL; International Prognostic Index 3–5 and/or double-/triple-hit or double MYC/BCL-2 expressors) who achieved complete response (CR), partial response (PR), or stable disease (SD) following run-in with 6 cycles of R-chemotherapy (NCT03023878). Of the 47 patients enrolled, 28 received blinatumomab. Five patients (17.9%) experienced grade 4 treatment-emergent adverse events of interest (neutropenia, n = 4; infection, n = 1). Two deaths reported at the end of the study were unrelated to treatment with blinatumomab (disease progression, n = 1; infection, n = 1). 3/4 patients with PR and 4/4 patients with SD after R-chemotherapy achieved CR following blinatumomab. Consolidation with blinatumomab in patients with newly diagnosed, high-risk DLBCL who did not progress under R-chemotherapy was better tolerated than in previous studies where blinatumomab was used for treatment of patients with lymphoma

Metabolic-associated fatty liver disease: from simple steatosis towards liver cirrhosis and potential complications. Proceedings of the Third Translational Hepatology Meeting, endorsed by the Spanish Association for the Study of the Liver (AEEH)

This is a meeting report of the 3rd Translational Hepatology Meeting held in Alicante, Spain, in October 2021. The meeting, which was organized by the Spanish Association for the Study of the Liver (AEEH), provided an update on the recent advances in the field of basic and translational hepatology, with a particular focus on the molecular and cellular mechanisms and therapeutic targets involved in metabolic-associated fatty liver disease (MAFLD), metabolic-associated steatohepatitis (MASH), cirrhosis and end-stage hepatocellular carcinoma (HCC).S

2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Actualización del Documento Sevilla

La transfusión de sangre alogénica (TSA) no es inocua, y como consecuencia han surgido múltiples alternativas a la misma (ATSA). Existe variabilidad respecto a las indicaciones y buen uso de las ATSA. Dependiendo de la especialidad de los médicos que tratan a los pacientes, el grado de anemia, la política transfusional, la disponibilidad de las ATSA y el criterio personal, estas se usan de forma variable. Puesto que las ATSA tampoco son inocuas y pueden no cumplir criterios de coste-efectividad, la variabilidad en su uso es inaceptable. Las sociedades españolas de Anestesiología y Reanimación (SEDAR), Hematología y Hemoterapia (SEHH), Farmacia Hospitalaria (SEFH), Medicina Intensiva y Unidades Coronarias (SEMICYUC), Trombosis y Hemostasia (SETH) y Transfusiones Sanguíneas (SETS) han elaborado un documento de consenso para el buen uso de la ATSA. Un panel de expertos de las 6 sociedades ha llevado a cabo una revisión sistemática de la literatura médica y elaborado el 2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Solo se contempla las ATSA dirigidas a disminuir la transfusión de concentrado de hematíes. Se definen las ATSA como toda medida farmacológica y no farmacológica encaminada a disminuir la transfusión de concentrado de hematíes, preservando siempre la seguridad del paciente. La cuestión principal que se plantea en cada ítem se formula, en forma positiva o negativa, como: «La ATSA en cuestión reduce/no reduce la tasa transfusional». Para formular el grado de recomendación se ha usado la metodología Grades of Recommendation Assessment, Development and Evaluation (GRADE)

The Integration of Cell Therapy and Biomaterials as Treatment Strategies for Remyelination

Multiple sclerosis (MS) is a chronic degenerative autoimmune disease of the central nervous system that causes inflammation, demyelinating lesions, and axonal damage and is associated with a high rate of early-onset disability. Disease-modifying therapies are used to mitigate the inflammatory process in MS but do not promote regeneration or remyelination; cell therapy may play an important role in these processes, modulating inflammation and promoting the repopulation of oligodendrocytes, which are responsible for myelin repair. The development of genetic engineering has led to the emergence of stable, biocompatible biomaterials that may promote a favorable environment for exogenous cells. This review summarizes the available evidence about the effects of transplantation of different types of stem cells reported in studies with several animal models of MS and clinical trials in human patients. We also address the advantages of combining cell therapy with biomaterials

Diastereoselective Synthesis of C60/Steroid Conjugates

The design and synthesis of fullerene–steroid hybrids by using Prato’s protocol has afforded new fullerene derivatives endowed with epiandrosterone, an important naturally occurring steroid hormone. Since the formation of the pyrrolidine ring resulting from the 1,3-dipolar cyloaddition reaction takes place with generation of a new stereogenic center on the C2 of the five-membered ring, the reaction proceeds with formation of a diastereomeric mixture [compounds 6 and 7 in 70:30 ratio, 8 and 9 in 26:74 ratio (HPLC)] in which the formation of the major diasteroisomers 6 and 9 is consistent with an electrophilic attack of [60]fullerene on the Re face of the azomethine ylide directed by the steroidic unit. The chiroptical properties of these conjugates reveal typical Cotton effects in CD spectra that have been used to assign the absolute configuration of the new fulleropyrrolidines. The electrochemical study of the new compounds reveals the presence of four quasi-reversible reduction waves which are cathodically shifted in comparison with the parent C60, thus ascertaining the proposed structures.Financial support by the Ministerio de Ciencia e Innovación (MINECO) of Spain (CTQ2011-24652, CTQ2011-27253, PIB2010JP-00196, and CSD2007-00010 projects) and CAM (Madrisolar-2) is acknowledged; A.R. thanks UCM for financial support; M.S. is indebted to Programa del Grupo Santander 2012

Therapeutic effect of all-trans-retinoic acid (at-RA) on an autoimmune nephritis experimental model: role of the VLA-4 integrin

BACKGROUND: Mercuric chloride (HgCl(2)) induces an autoimmune nephritis in the Brown Norway (BN) rats characterized by anti-glomerular basement membrane antibodies (anti-GBM Ab) deposition, proteinuria and a severe interstitial nephritis, all evident at day 13 of the disease. We assessed the effects of all-trans retinoic acid (at-RA) in this experimental model. At-RA is a vitamin A metabolite which has shown beneficial effects on several nephropathies, even though no clear targets for at-RA were provided. METHODS: We separated animals in four different experimental groups (HgCl(2), HgCl(2)+at-RA, at-RA and vehicle). From each animal we collected, at days 0 and 13, numerous biological samples: urine, to measure proteinuria by colorimetry; blood to determine VLA-4 expression by flow citometry; renal tissue to study the expression of VCAM-1 by Western blot, the presence of cellular infiltrates by immunohistochemistry, the IgG deposition by immunofluorescence, and the cytokines expression by RT-PCR. Additionally, adhesion assays to VCAM-1 were performed using K562 α4 transfectant cells. ANOVA tests were used for statistical significance estimation. RESULTS: We found that at-RA significantly decreased the serum levels of anti-GBM and consequently its deposition along the glomerular membrane. At-RA markedly reduced proteinuria as well as the number of cellular infiltrates in the renal interstitium, the levels of TNF-α and IL-1β cytokines and VCAM-1 expression in renal tissue. Moreover, we reported here for the first time in an in vivo model that at-RA reduced, to basal levels, the expression of VLA-4 (α4β1) integrin induced by mercury on peripheral blood leukocytes (PBLs). In addition, using K562 α4 stable transfectant cells, we found that at-RA inhibited VLA-4 dependent cell adhesion to VCAM-1. CONCLUSION: Here we demonstrate a therapeutic effect of at-RA on an autoimmune experimental nephritis model in rats. We report a significant reduction of the VLA-4 integrin expression on PBLs as well as the inhibition of the VLA4/VCAM1-dependent leukocyte adhesion by at-RA treatment. Thereby we point out the VLA-4 integrin as a target for at-RA in vivo