Prognostic relevance of tumor-infiltrating lymphocytes and immune checkpoints in pediatric medulloblastoma

Pediatric medulloblastomas are the most frequently diagnosed embryonal tumors of the central nervous system. Current therapies cause severe neurological and cognitive side effects including secondary malignancies. Cellular immunotherapy might be key to improve survival and to avoid morbidity. Efficient killing of tumor cells using immunotherapy requires to overcome cancer-associated strategies to evade cytotoxic immune responses. Here, we examined the immune response and immune evasion strategies in pediatric medulloblastomas. Cytotoxic T-cells, infiltrating medulloblastomas with variable activation status, showed no correlation with overall survival of the patients. We found limited numbers of PD1+T-cells and complete absence of PD-L1 on medulloblastomas. Medulloblastomas downregulated immune recognition molecules MHC-I and CD1 d. Intriguingly, expression of granzyme inhibitors SERPINB1 and SERPINB4 was acquired in 23% and 50% of the tumors, respectively. Concluding, pediatric medulloblastomas exploit multiple immune evasion strategies to overcome immune surveillance. Absence of PD-L1 expression in medulloblastoma suggest limited or no added value for immunotherapy with PD1/PD-L1 blockers

Expressions of E2 and E7-HPV16 proteins in pre-malignant and malignant lesions of the uterine cervix

Continuous production of the E7 protein from different types of high risk human papilloma virus (HPV) is required for progression of malignancy. We developed antibodies against HPV type 16 E7 and E2 proteins to evaluate their utility as markers for diagnosis during early stages of cervical cancer. Forty biopsies from uterine cervices were diagnosed as low grade intraepithelial lesion (LSIL), high grade intraepithelial lesion (HSIL), squamous carcinoma (SC), in situ adenocarcinoma (ISA) and invasive adenocarcinoma (AC), all of which were infected with HPV 16. Immunohistochemistry was used to investigate the expressions of E7 and E2 (both from HPV 16) and p16. P16 was expressed in eight of 12 LSILs, in all HSILs, in 16 of 18 SC and in all ACs. E2 was expressed in six of 12 LSILs. E7 was positive in eight of 12 LSILs and in all HSIL and carcinomas. The expressions of E2 and E7 of HPV16 related to p16 expression confirmed the value of the viral oncogenic proteins as complementary to histology and support the carcinogenic model of the uterine cervix, because HPVDNA integration into cellular DNA implies the destruction of the gene encoding E2, which suppresses the expression of the E6 and E7 oncoproteins. E2 from HPV16 could be marker for LSILs, while E7 could be a marker for progression of LSILs to HSILs in patients infected by HPV16, because viral typing has little positive predictive value.Fil: Ramírez, N.. Furtwangen University; AlemaniaFil: Guerra, Fernando Andres. Universidad de Buenos Aires. Hospital de Clínicas; ArgentinaFil: Camporeale, Gabriela. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; ArgentinaFil: Quintana, S.. Instituto Fares Taie. Laboratorio de Biología Molecular; ArgentinaFil: Diaz, L. B.. Universidad de Buenos Aires. Hospital de Clínicas; ArgentinaFil: Cuneo, N.. Hospital de Oncología María Curie; ArgentinaFil: Villacorta Hidalgo, J.. Universidad de Buenos Aires. Hospital de Clínicas; ArgentinaFil: Tatti, S. A.. Universidad de Buenos Aires. Hospital de Clínicas; ArgentinaFil: Alonso, Leonardo Gabriel. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; ArgentinaFil: Borkosky, Silvia Susana. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; ArgentinaFil: de Prat Gay, Gonzalo. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; ArgentinaFil: Palaoro, L.. Universidad de Buenos Aires. Hospital de Clínicas; Argentin

Differences between familial and sporadic dilated cardiomyopathy: ESC EORP Cardiomyopathy & Myocarditis registry

Aims: Dilated cardiomyopathy (DCM) is a complex disease where genetics interplay with extrinsic factors. This study aims to compare the phenotype, management, and outcome of familial DCM (FDCM) and non-familial (sporadic) DCM (SDCM) across Europe. Methods and results: Patients with DCM that were enrolled in the prospective ESC EORP Cardiomyopathy & Myocarditis Registry were included. Baseline characteristics, genetic testing, genetic yield, and outcome were analysed comparing FDCM and SDCM; 1260 adult patients were studied (238 FDCM, 707 SDCM, and 315 not disclosed). Patients with FDCM were younger (P\ua0<\ua00.01), had less severe disease phenotype at presentation (P\ua0<\ua00.02), more favourable baseline cardiovascular risk profiles (P\ua0 64\ua00.007), and less medication use (P\ua0 64\ua00.042). Outcome at 1\ua0year was similar and predicted by NYHA class (HR 0.45; 95% CI [0.25\u20130.81]) and LVEF per % decrease (HR 1.05; 95% CI [1.02\u20131.08]. Throughout Europe, patients with FDCM received more genetic testing (47% vs. 8%, P\ua0<\ua00.01) and had higher genetic yield (55% vs. 22%, P\ua0<\ua00.01). Conclusions: We observed that FDCM and SDCM have significant differences at baseline but similar short-term prognosis. Whether modification of associated cardiovascular risk factors provide opportunities for treatment remains to be investigated. Our results also show a prevalent role of genetics in FDCM and a non-marginal yield in SDCM although genetic testing is largely neglected in SDCM. Limited genetic testing and heterogeneity in panels provides a scaffold for improvement of guideline adherence

Pediatric Primitive Neuroectodermal Tumors of the Central Nervous System Differentially Express Granzyme Inhibitors

BACKGROUND: Central nervous system (CNS) primitive neuroectodermal tumors (PNETs) are malignant primary brain tumors that occur in young infants. Using current standard therapy, up to 80% of the children still dies from recurrent disease. Cellular immunotherapy might be key to improve overall survival. To achieve efficient killing of tumor cells, however, immunotherapy has to overcome cancer-associated strategies to evade the cytotoxic immune response. Whether CNS-PNETs can evade the immune response remains unknown. METHODS: We examined by immunohistochemistry the immune response and immune evasion strategies in pediatric CNS-PNETs. RESULTS: Here, we show that CD4+, CD8+, γδ-T-cells, and Tregs can infiltrate pediatric CNS-PNETs, although the activation status of cytotoxic cells is variable. Pediatric CNS-PNETs evade immune recognition by downregulating cell surface MHC-I and CD1d expression. Intriguingly, expression of SERPINB9, SERPINB1, and SERPINB4 is acquired during tumorigenesis in 29%, 29%, and 57% of the tumors, respectively. CONCLUSION: We show for the first time that brain tumors express direct granzyme inhibitors (serpins) as a potential mechanism to overcome cellular cytotoxicity, which may have consequences for cellular immunotherapy

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10−8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD. © 2020, The Author(s).Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10-8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD