scholarly journals Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 506 ◽  
Author(s):  
Emilia Modolo Pinto ◽  
Fabio R. Faucz ◽  
Luana Z. Paza ◽  
Gang Wu ◽  
Elizabeth S. Fernandes ◽  
...  
Keyword(s):  
Critical Role ◽  
Cell Cancer ◽  
Uniparental Disomy ◽  
Camp Signaling ◽  
Endocrine Tumors ◽  
Chromosome 11P15 ◽  
Germline Variants ◽  
Adrenocortical Tumors ◽  
Cyclic Monophosphate ◽  
Pediatric Adrenocortical Tumors

Phosphodiesterases (PDEs) form a superfamily of enzymes that catalyze the hydrolysis of cyclic nucleotides adenosine 3′5′-cyclic monophosphate (cAMP) and guanosine 3′5′-cyclic monophosphate (cGMP) to their inactive 5′ monophosphates. cAMP plays a critical role as a second messenger in endocrine tissues, and activation of cAMP signaling has been reported in endocrine tumors. Germline variants in PDEs have been associated with benign cortisol-secreting adrenocortical adenomas and testicular germ cell cancer but not adrenocortical carcinoma. We performed whole genome sequencing (WGS) and whole exome sequencing (WES) of paired blood and tumor samples from 37 pediatric adrenocortical tumors (ACTs). Germline inactivating variants in PDEs were observed in 9 of 37 (24%) patients. Tumor DNA analysis revealed loss of heterozygosity, with maintenance of the mutated allele in all cases. Our results suggest that germline variants in PDEs and other regulators of the cAMP-signaling pathway may contribute to pediatric adrenocortical tumorigenesis, perhaps by cooperating with germline hypomorphic mutant TP53 alleles and uniparental disomy of chromosome 11p15 (Beckwith–Wiedemann syndrome).

Glucocorticoid regulation of epithelial sodium channel genes in human fetal lung

1997 ◽  
Vol 273 (1) ◽  
pp. L227-L233 ◽  
Author(s):  
V. C. Venkatesh ◽  
H. D. Katzberg
Keyword(s):  
Rna Polymerase Ii ◽  
Actinomycin D ◽  
Critical Role ◽  
Fetal Lung ◽  
Explant Culture ◽  
Late Gestation ◽  
Na Channel ◽  
Second Trimester ◽  
Cyclic Monophosphate ◽  
Human Fetal Lung

Pulmonary epithelial Na+ channels (ENaC), composed of three distinct subunits (alpha, beta, and gamma), play a critical role in the regulation of fluid reabsorption from airspaces of late-gestation fetal lung. We studied the expression of ENaC subunit genes in cultured human fetal lung. All three mRNAs were expressed at low levels in second trimester lung (13-32% of adult values at 24 wk gestation). There was a spontaneous increase of approximately threefold over preculture values of all three subunits within 24 h of explant culture in serum-free Waymouth's medium. Dexamethasone (Dex) induced all three mRNAs by two- to threefold. Maximal induction was noted by 8 h with 30-100 nM Dex and half-maximal stimulation with 3-10 nM Dex. Cycloheximide decreased basal expression of all three subunits by 8 h but did not alter the response to Dex. Actinomycin D and 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), inhibitors of RNA polymerase II, decreased the basal and the Dex-induced expression of all three subunits with a more marked effect on human hENaC-gamma than on hENaC-alpha or hENaC-beta. Under conditions where transcription was blocked by actinomycin D or DRB, Dex did not alter the stability of the three mRNAs. Triiodothyronine (T3) at low (2 nM) or high (100 nM) concentrations had no effect on the expression of the three subunits in the presence or absence of low (10 nM) or high (100 nM) concentrations of Dex for 8 or 24 h. Similarly, 8-bromoadenosine 3',5'-cyclic monophosphate (2 microM) had no effect on basal or Dex-induced increase in the three subunits. We conclude that the three Na+ channel subunit genes are expressed in second trimester human fetal lung and are coordinately upregulated by glucocorticoid hormones but not by T3 or adenosine 3',5'-cyclic monophosphate. Glucocorticoid induction is receptor mediated, is primarily transcriptional, and does not require the induction of an intermediate protein for transcriptional enhancement. We speculate that induction of lung ENaC may contribute to the beneficial effects of antenatal glucocorticoids in premature babies.

scholarly journals Critical Role of PDE4D in β2-Adrenoceptor-dependent cAMP Signaling in Mouse Embryonic Fibroblasts

2008 ◽  
Vol 283 (33) ◽  
pp. 22430-22442 ◽  
Author(s):  
Matthew D. Bruss ◽  
Wito Richter ◽  
Kathleen Horner ◽  
S.-L. Catherine Jin ◽  
Marco Conti
Keyword(s):  
Critical Role ◽  
Camp Signaling ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts

Stimulation of Ca2+ influx in αT3–1 gonadotrophs via the cAMP/PKA signaling system

1997 ◽  
Vol 273 (5) ◽  
pp. E850-E858 ◽  
Author(s):  
Marjan Hezareh ◽  
Werner Schlegel ◽  
Stephen R. Rawlings
Keyword(s):  
Adenylate Cyclase ◽  
Calcium Concentration ◽  
Cytosolic Calcium ◽  
Camp Signaling ◽  
Signaling System ◽  
Cyclic Monophosphate ◽  
Pituitary Adenylate Cyclase ◽  
Inositol 1,4,5 Trisphosphate ◽  
Made In ◽  
Stimulation Of

To investigate the regulation of free cytosolic calcium concentration ([Ca2+]i) by the adenosine 3′,5′-cyclic monophosphate (cAMP) signaling system in clonal gonadotrophs, microfluorimetric recordings were made in single indo 1-loaded αT3–1 cells. Forskolin, 8-bromoadenosine 3′,5′-cyclic monophosphate, or a low concentration (100 pM) of the hypothalamic factor pituitary adenylate cyclase-activating polypeptide (PACAP) stimulated Ca2+ step responses or repetitive Ca2+ transients, which were blocked by the removal of extracellular Ca2+ by the dihydropyridine (DHP) (+)PN 200–110 or by preincubation with the protein kinase A (PKA) antagonist H-89 (10 μM). Thus activation of the cAMP/PKA system in αT3–1 gonadotrophs stimulates Ca2+ influx through DHP-sensitive (L-type) Ca2+ channels. In contrast, high PACAP concentrations (100 nM) stimulated biphasic Ca2+ spike-plateau responses. The Ca2+ spike was independent of extracellular Ca2+, and similar responses were observed by microperfusion of individual cells withd- myo-inositol 1,4,5-trisphosphate, suggesting the involvement of the phospholipase C (PLC) signaling pathway. The Ca2+plateau depended on Ca2+ influx, was blocked by (+)PN 200–110, but was only partially blocked by H-89 pretreatment. In conclusion, PACAP stimulates [Ca2+]iincreases in αT3–1 gonadotrophs through both the PLC and adenylate cyclase signaling pathways. Furthermore, this is the first clear demonstration that the cAMP/PKA system can mediate changes in [Ca2+]iin gonadotroph-like cells.

Low expression ofHLA-DRA, HLA-DPA1, andHLA-DPB1is associated with poor prognosis in pediatric adrenocortical tumors (ACT)

2014 ◽  
Vol 61 (11) ◽  
pp. 1940-1948 ◽  
Author(s):  
Fabíola A. Leite ◽  
Regia C. P. Lira ◽  
Paola F. Fedatto ◽  
Sonir R. R. Antonini ◽  
Carlos E. Martinelli ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Adrenocortical Tumors ◽  
Low Expression ◽  
Pediatric Adrenocortical Tumors

Correlation between selected angiogenic markers and prognosis in pediatric adrenocortical tumors

2015 ◽  
Vol 50 (8) ◽  
pp. 1323-1328 ◽  
Author(s):  
André Ivan Bradley dos Santos Dias ◽  
Camila Girardi Fachin ◽  
Lucimar Retto Silva Avó ◽  
Caio Vinicius Gonçalves Frazão ◽  
Eliana Maria Monteiro Caran ◽  
...  
Keyword(s):  
Adrenocortical Tumors ◽  
Angiogenic Markers ◽  
Pediatric Adrenocortical Tumors

Talactoferrin alfa is an anti-cancer agent with activity in renal cell cancer (RCC) patients and a novel immunomodulatory mechanism of action

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14648-14648
Author(s):  
A. Varadhachary ◽  
M. Spadaro ◽  
J. Engelmayer ◽  
P. Blezinger ◽  
T. Valli ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Cytotoxic T Lymphocyte ◽  
Critical Role ◽  
Cell Cancer ◽  
Single Agent ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Cd8 Cells ◽  
Anti Cancer ◽  
Cancer Activity

14648 Background: Talactoferrin alfa (talactoferrin) is a novel, orally administered immunomodulatory protein with demonstrated anti-cancer activity in preclinical experiments. Methods: Talactoferrin’s safety and efficacy in cancer patients was evaluated in a Phase I/II trial. Patients with metastatic disease who had failed standard therapy were treated with single-agent oral talactoferrin. Tumors were measured by CT scan using RECIST criteria. Talactoferrin’s mechanism of action was evaluated in preclinical experiments in tumor-bearing immunocompetent BALB/c and knockout mice. Cytokine levels were measured by ELISA. Cellular changes were measured by FACS analysis and immunofluorescence. Results: Seven patients with metastatic RCC who had failed previous systemic therapy were treated with oral, single-agent talactoferrin. Talactoferrin was safe and very well tolerated without a single drug-related SAE. All seven patients achieved at least Stable Disease, with one patient showing a deep and sustained partial response (71% shrinkage by RECIST two years after start of therapy). There was an apparent increase in median PFS to 7.3 months, with two patients still progression free after two years. Median OS has not yet been reached. In experiments conducted to define its anti-cancer mechanism, orally administered talactoferrin was found to act at the gut and the Gut Associated Lymphoid Tissue (GALT). Talactoferrin induced the chemotaxis of immune cells to intestinal Peyer’s Patches in mice, initiating an immunostimulatory cascade in the GALT and activating both innate and adaptive immunity. We observed significantly increased numbers of Dendritic Cells, NK-T cells and CD8+ T-lymphocytes in small intestinal Peyer’s patches, a systemic increase in Natural Killer (NK) and Cytotoxic T-lymphocyte (CTL) activity, activation of tumor draining lymph nodes, and cellular infiltration of distant tumors. The critical role of NK-T and CD8+ cells was demonstrated in knockout and depletion experiments. Conclusions: Talactoferrin, a first-in-class molecule with apparent clinical anti-cancer activity in RCC, acts through a novel immunomodulatory mechanism of action. [Table: see text]

Association of genetic markers in angiogenesis- or exposure-related genes with overall survival in pazopanib (P) treated patients (Pts) with advanced renal cell carcinoma.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 303-303 ◽  
Author(s):  
C. Xu ◽  
H. A. Ball ◽  
N. Bing ◽  
C. N. Sternberg ◽  
Z. Xue ◽  
...  
Keyword(s):  
Overall Survival ◽  
Renal Cell ◽  
Proportional Hazards Model ◽  
Kinase Inhibitor ◽  
Cell Cancer ◽  
Cox Proportional Hazards Model ◽  
Phase Iii ◽  
Wild Type ◽  
Germline Variants ◽  
Functional Polymorphisms

303 Background: Pazopanib, an oral tyrosine kinase inhibitor of VEGFR, PDGFR and c-Kit, has been approved for the treatment of advanced renal cell cancer (RCC). Interindividual variability in response and survival is observed among advanced RCC pts treated with P. Our previous analyses showed that germline variants in angiogenesis (IL8, HIF1A, VEGFA)- and exposure (NR1IR)-related genes may predict progression free survival and/or response rate to P monotherapy (ASCO 2010 abstract 4520). This study sought to test the hypothesis that differences in overall survival (OS) can be explained, at least in part, by germline genetic variants in angiogenesis- and/or exposure-related genes. Methods: Twenty-seven functional polymorphisms within 13 genes were evaluated in 241 P treated pts with advanced RCC from a phase III study (ESMO 2010 abstract LBA22) and a single arm Phase II study. Genetic association with OS was analyzed using the Cox proportional hazards model. Results: Six polymorphisms in IL8, FGFR2, VEGFA, FLT4, and NR1I2 showed nominally significant association with OS (p≤0.05). A median OS of 29.6 months was observed in pts carrying wild-type IL8 2767 AA genotype (n=68, 31%), compared to 14.8 months in those with the TT variant genotype (n=36, 16%) (HR (95%CI) = 2.3 (1.4, 3.9) for TT vs. AA, p=0.002]. The median OS for pts who were heterozygous for this IL8 polymorphism was 23.9 months (n=119, 53%). The FGFR2 IVS2 + 906C>T variant TT genotype was associated with inferior OS compared with the wild-type CC genotype (median OS, 21.4 vs. 28.0 months, HR (95%CI) = 2.0 (1.2, 3.2), p=0.009). Similarly, shorter OS was observed for the VEGFA −1154G>A variant AA genotype compared with the wild-type GG genotype [median OS, 16.7 vs. 25.3 months, HR (95%CI) = 2.2 (1.3, 3.6), p=0.004]. The variant genotypes of the NR1IR (−25385C>T) and FLT4 (1480A>G) polymorphisms were also associated with reduced OS (p<0.05). Conclusions: Germline variants in angiogenesis- and exposure-related genes may be associated with survival outcome for P monotherapy in pts with advanced RCC. These associations are considered exploratory and require confirmation in an independent dataset. [Table: see text]

scholarly journals Newborn Screening for the Detection of the TP53 R337H Variant and Surveillance for Early Diagnosis of Pediatric Adrenocortical Tumors: Lessons Learned and Way Forward

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6111
Author(s):  
Karina C. F. Tosin ◽  
Edith F. Legal ◽  
Mara A. D. Pianovski ◽  
Humberto C. Ibañez ◽  
Gislaine Custódio ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Lessons Learned ◽  
Disease Stage ◽  
Tumor Weight ◽  
Adrenocortical Tumors ◽  
Screening Cost ◽  
Screening And Surveillance ◽  
Improved Outcomes ◽  
Age Of Diagnosis ◽  
Pediatric Adrenocortical Tumors

The incidence of pediatric adrenocortical tumors (ACT) is high in southern Brazil due to the founder TP53 R337H variant. Neonatal screening/surveillance (NSS) for this variant resulted in early ACT detection and improved outcomes. The medical records of children with ACT who did not participate in newborn screening (non-NSS) were reviewed (2012–2018). We compared known prognostic factors between the NSS and non-NSS cohorts and estimated surveillance and treatment costs. Of the 16 non-NSS children with ACT carrying the R337H variant, the disease stages I, II, III, and IV were observed in five, five, one, and five children, respectively. The tumor weight ranged from 22 to 608 g. The 11 NSS children with ACT all had disease stage I and were alive. The median tumor weight, age of diagnosis, and interval between symptoms and diagnosis were 21 g, 1.9 years, and two weeks, respectively, for the NSS cohort and 210 g, 5.2 years, and 15 weeks, respectively, for the non-NSS cohort. The estimated surveillance/screening cost per year of life saved is US$623/patient. NSS is critical for improving the outcome of pediatric ACT in this region. Hence, we strongly advocate for the inclusion of R337H in the state-mandated universal screening and surveillance.

Sign in / Sign up

Export Citation Format

Share Document