Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation.

T and NK lymphocytes express CD137 (4-1BB), a costimulatory receptor of the TNFR family whose function is exploitable for cancer immunotherapy. Mitochondria regulate the function and survival of T lymphocytes. Herein, we show that CD137 costimulation provided by agonist mAb and CD137L (4-1BBL) induced mitochondria enlargement that resulted in enhanced mitochondrial mass and transmembrane potential in human and mouse CD8+ T cells. Such mitochondrial changes increased T-cell respiratory capacities and were critically dependent on mitochondrial fusion protein OPA-1 expression. Mass and function of mitochondria in tumor-reactive CD8+ T cells from cancer-bearing mice were invigorated by agonist mAb to CD137, whereas mitochondrial baseline mass and function were depressed in CD137-deficient tumor reactive T cells. Tumor rejection induced by the synergistic combination of adoptive T-cell therapy and agonistic anti-CD137 was critically dependent on OPA-1 expression in transferred CD8+ T cells. Moreover, stimulation of CD137 with CD137 mAb in short-term cultures of human tumor-infiltrating lymphocytes led to mitochondria enlargement and increased transmembrane potential. Collectively, these data point to a critical link between mitochondrial morphology and function and enhanced antitumor effector activity upon CD137 costimulation of T cells. Cancer Immunol Res; 6(7); 798-811. ©2018 AACR.This project was supported by imCORE Network (Roche Genentech), MINECO (SAF2014-52361-R, 2017-83267-C2-1-R; I. Melero), European Commission VII Framework and Horizon 2020 programs (IACT and PROCROP), Fundacion de la Asociaci on Espa nola Contra el C ~ ancer (AECC), and Fundacion BBVA. A. Teijeira receives support from a Juan de la Cierva contract, MINECO. Electron and light microscopy CIMA services as well as Flow Cytometry CIMA facilities (Diego Alignani) and personnel at blood bank of Navarra are acknowledged for their technical support. We are also grateful to Drs. Lasarte and HervasStubbs for scientific discussion and to Dr. Paul Miller for editing the manuscript. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.S

Longitudinal association of dietary acid load with kidney function decline in an older adult population with metabolic syndrome

Background: Diets high in acid load may contribute to kidney function impairment. This study aimed to investigate the association between dietary acid load and 1-year changes in glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (UACR). Methods: Older adults with overweight/obesity and metabolic syndrome (mean age 65 ± 5 years, 48% women) from the PREDIMED-Plus study who had available data on eGFR (n = 5,874) or UACR (n = 3,639) at baseline and after 1 year of follow-up were included in this prospective analysis. Dietary acid load was estimated as potential renal acid load (PRAL) and net endogenous acid production (NEAP) at baseline from a food frequency questionnaire. Linear and logistic regression models were fitted to evaluate the associations between baseline tertiles of dietary acid load and kidney function outcomes. One year-changes in eGFR and UACR were set as the primary outcomes. We secondarily assessed ≥ 10% eGFR decline or ≥10% UACR increase. Results: After multiple adjustments, individuals in the highest tertile of PRAL or NEAP showed higher one-year changes in eGFR (PRAL, β: -0.64 ml/min/1.73 m2; 95% CI: -1.21 to -0.08 and NEAP, β: -0.56 ml/min/1.73 m2; 95% CI: -1.13 to 0.01) compared to those in the lowest category. No associations with changes in UACR were found. Participants with higher levels of PRAL and NEAP had significantly higher odds of developing ≥10% eGFR decline (PRAL, OR: 1.28; 95% CI: 1.07-1.54 and NEAP, OR: 1.24; 95% CI: 1.03-1.50) and ≥10 % UACR increase (PRAL, OR: 1.23; 95% CI: 1.04-1.46) compared to individuals with lower dietary acid load. Conclusions: Higher PRAL and NEAP were associated with worse kidney function after 1 year of follow-up as measured by eGFR and UACR markers in an older Spanish population with overweight/obesity and metabolic syndrome. Keywords: albuminuria; chronic kidney disease (CKD); dietary acid load; glomerular filtration rate (GFR); kidney function; net endogenous acid production (NEAP); potential renal acid load (PRAL); renal nutrition

Repurposing infectious disease vaccines for intratumoral immunotherapy

Intratumoral delivery of viruses and virus-associated molecular patterns can achieve antitumor effects that are largely mediated by the elicitation or potentiation of immune responses against the malignancy. Attenuated vaccines are approved and marketed as good manufactiring practice (GMP)-manufactured agents whose administration might be able to induce such effects. Recent reports in mouse transplantable tumor models indicate that the rotavirus, influenza and yellow fever vaccines can be especially suitable to elicit powerful antitumor immunity against cancer following intratumoral administration. These results highlight that intratumoral anti-infectious vaccines can turn cold tumors into hot, and underscore the key role played by virus-induced type I interferon pathways to overcome resistance to immune checkpoint-targeted antibodies

Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells

UNLABELLED: Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-) mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti-PD-1 mAbs. Batf3(-/-) mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti-CD137- and anti-PD-1-mediated immunostimulation in tumor therapy against B16-ovalbumin-derived melanomas, whereas this function was lost in Batf3(-/-) mice. These experiments show that cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects. SIGNIFICANCE: Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical responses in different types of cancer. We show that cross-priming of tumor antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory mAbs.Work at the I. Melero lab is funded by MICINN (SAF200803294 and SAF2011-22831), Departamento de salud del Gobierno de Navarra, Redes temáticas de investigación cooperativa RETIC (RD06/0020/0065), and the European commission 7th framework program (ENCITE and IACT). Work in the D. Sancho laboratory is funded by the CNIC and grants from the Spanish Ministry of Economy and Competitiveness (SAF-2013-42920R) and the European Research Council (ERC Starting Independent Researcher Grant 2010, ERC-2010-StG 260414). The CNIC is supported by the Spanish Ministry of Economy and Competitiveness and the Pro-CNIC Foundation. I. Melero and D. Sancho are funded by the European Commission (635122-PROCROP H2020).S

Repurposing the yellow fever vaccine for intratumoral immunotherapy

Abstract Live 17D is widely used as a prophylactic vaccine strain for yellow fever virus that induces potent neutralizing humoral and cellular immunity against the wild‐type pathogen. 17D replicates and kills mouse and human tumor cell lines but not non‐transformed human cells. Intratumoral injections with viable 17D markedly delay transplanted tumor progression in a CD8 T‐cell‐dependent manner. In mice bearing bilateral tumors in which only one is intratumorally injected, contralateral therapeutic effects are observed consistent with more prominent CD8 T‐cell infiltrates and a treatment‐related reduction of Tregs. Additive efficacy effects were observed upon co‐treatment with intratumoral 17D and systemic anti‐CD137 and anti‐PD‐1 immunostimulatory monoclonal antibodies. Importantly, when mice were preimmunized with 17D, intratumoral 17D treatment achieved better local and distant antitumor immunity. Such beneficial effects of prevaccination are in part explained by the potentiation of CD4 and CD8 T‐cell infiltration in the treated tumor. The repurposed use of a GMP‐grade vaccine to be given via the intratumoral route in prevaccinated patients constitutes a clinically feasible and safe immunotherapy approach

LMO2 expression reflects the different stages of blast maturation and genetic features in B-cell acute lymphoblastic leukemia and predicts clinical outcome

BACKGROUND: LMO2 is highly expressed at the most immature stages of lymphopoiesis. In T-lymphocytes, aberrant LMO2 expression beyond those stages leads to T-cell acute lymphoblastic leukemia, while in B cells LMO2 is also expressed in germinal center lymphocytes and diffuse large B-cell lymphomas, where it predicts better clinical outcome. The implication of LMO2 in B-cell acute lymphoblastic leukemia must still be explored. DESIGN AND METHODS: We measured LMO2 expression by real time RT-PCR in 247 acute lymphoblastic leukemia patient samples with cytogenetic data (144 of them also with survival and immunophenotypical data) and in normal hematopoietic and lymphoid cells. RESULTS: B-cell acute lymphoblastic leukemia cases expressed variable levels of LMO2 depending on immunophenotypical and cytogenetic features. Thus, the most immature subtype, pro-B cells, displayed three-fold higher LMO2 expression than pre-B cells, common-CD10+ or mature subtypes. Additionally, cases with TEL-AML1 or MLL rearrangements exhibited two-fold higher LMO2 expression compared to cases with BCR-ABL rearrangements or hyperdyploid karyotype. Clinically, high LMO2 expression correlated with better overall survival in adult patients (5-year survival rate 64.8% (42.5%–87.1%) vs. 25.8% (10.9%–40.7%), P= 0.001) and constituted a favorable independent prognostic factor in B-ALL with normal karyotype: 5-year survival rate 80.3% (66.4%–94.2%) vs. 63.0% (46.1%–79.9%) (P= 0.043). CONCLUSIONS: Our data indicate that LMO2 expression depends on the molecular features and the differentiation stage of B-cell acute lymphoblastic leukemia cells. Furthermore, assessment of LMO2 expression in adult patients with a normal karyotype, a group which lacks molecular prognostic factors, could be of clinical relevance

Disseminated Histoplasmosis in HIV-Infected Patients in South America: A Neglected Killer Continues on Its Rampage.

International audienc

A Pharmacovigilance Study in First Episode of Psychosis : Psychopharmacological Interventions and Safety Profiles in the PEPs Project

The characterization of the first episode of psychosis and how it should be treated are principal issues in actual research. Realistic, naturalistic studies are necessary to represent the entire population of first episode of psychosis attended in daily practice. Sixteen participating centers from the PEPs project recruited 335 first episode of psychosis patients, aged 7 to 35 years. This article describes and discusses the psychopharmacological interventions and safety profiles at baseline and during a 60-day pharmacovigilance period. The majority of first episode of psychosis patients received a second-generation antipsychotic (96.3%), orally (95%), and in adjusted doses according to the product specifications (87.2%). A total of 24% were receiving an antipsychotic polytherapy pattern at baseline, frequently associated with lower or higher doses of antipsychotics than the recommended ones. Eight patients were taking clozapine, all in monotherapy. Males received higher doses of antipsychotic (P=.043). A total of 5.2% of the patients were being treated with long-acting injectable antipsychotics; 12.2% of the patients received anticholinergic drugs, 12.2% antidepressants, and 13.7% mood stabilizers, while almost 40% received benzodiazepines; and 35.52% reported at least one adverse drug reaction during the pharmacovigilance period, more frequently associated with higher antipsychotic doses and antipsychotic polytherapy (85.2% vs 45.5%, P<.001). These data indicate that the overall pharmacologic prescription for treating a first episode of psychosis in Spain follows the clinical practice guideline recommendations, and, together with security issues, support future research of determinate pharmacological strategies for the treatment of early phases of psychosis, such as the role of clozapine, long-acting injectable antipsychotics, antipsychotic combination, and the use of benzodiazepines

Improving equity in access to early diagnosis of cancer in different healthcare systems of Latin America: protocol for the EquityCancer-LA implementation-effectiveness hybrid study

Introduction Healthcare fragmentation, a main cause for delay in cancer diagnosis and treatment, contributes to high mortality in Latin America (LA), particularly among disadvantaged populations. This research focuses on integrated care interventions, which have been limitedly implemented in the region. The objective is to evaluate the contextual effectiveness of scaling-up an integrated care intervention to improve early diagnosis of frequent cancers in healthcare networks of Chile, Colombia and Ecuador.Methods and analysis This research is two pronged: (A) quasi-experimental design (controlled before and after) with an intervention and a control healthcare network in each LA country, using an implementation-effectiveness hybrid approach to assess the intervention process, effectiveness and costs; and (B) case study design to analyse access to diagnosis of most frequent cancers. Focusing on the most vulnerable socioeconomic population, it develops in four phases: (1) analysis of delays and barriers to early diagnosis (baseline); (2) intervention adaptation and implementation (primary care training, fast-track referral pathway and patient information); (3) intracountry evaluation of intervention and (4) cross-country analysis. Baseline and evaluation studies adopt mixed-methods qualitative (semistructured individual interviews) and quantitative (patient questionnaire survey) methods. For the latter, a sample size of 174 patients with cancer diagnosis per healthcare network and year was calculated to detect a proportions difference of 15%, before and after intervention (α=0.05; β=0.2) in a two-sided test. A participatory approach will be used to tailor the intervention to each context, led by a local steering committee (professionals, managers, policy makers, patients and researchers).Ethics and dissemination This study complies with international and national legal stipulations on ethics. It was approved by each country’s ethical committee and informed consent will be obtained from participants. Besides the coproduction of knowledge with key stakeholders, it will be disseminated through strategies such as policy briefs, workshops, e-tools and scientific papers

Impact of SARS-CoV-2 pandemic on vascular liver diseases

Vascular liver diseases (VLD) are represented mainly by portosinusoidal vascular disease (PSVD), non-cirrhotic splanchnic vein thrombosis (SVT) and Budd Chiari syndrome (BCS). It is unknown whether patients with VLD constitute a high-risk population for complications and greater COVID-19-related mortality from SARS-CoV-2 infection. Our objective was to assess the prevalence and severity of SARS-CoV-2 infection among patients with VLD, as well as to assess its impact on hepatic decompensation and survival.This is a observational international study analyzing the prevalence and severity of SARS-CoV-2 infection in VLD between March 2020-March 2021 comparing with the general population (GP). Patients from Spain (5 centers, n = 493) and France (1 center, n = 475) were included.Nine hundred and sixty-eight patients were included: 274 PSVD, 539 SVT and 155 BCS. Among them, 138 (14%) were infected with SARS-CoV-2: 53 PSVD, 77 SVT and 8 BCS. The prevalence of SARS-CoV-2 infection in PSVD (19%) and SVT (14%) was significantly higher than in GP (6.5%, p < 0.05), while it was very similar in BCS (5%). In terms of infection severity, patients with VLD also presented a higher need of hospital admission (14% vs 7.3%, p<0.01), ICU admission (2% vs 0.7%, p< 0.01) and mortality (4% vs 1.5%, p < 0.05) than GP. Previous history of ascites (50% vs 8%, p < 0.05) and post-COVID-19 hepatic decompensation (50% vs 4%, p < 0.05) were associated to COVID-19 mortality.PSVD and SVT patients could be at higher risk of infection by SARS-CoV-2 and at higher risk of severe COVID-19 disease.Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved