scholarly journals Expression of BARD1 β Isoform in Selected Pediatric Tumors

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 168
Author(s):  
Anna Jasiak ◽  
Natalia Krawczyńska ◽  
Mariola Iliszko ◽  
Katarzyna Czarnota ◽  
Kamil Buczkowski ◽  
...  
Keyword(s):  
Pediatric Cancer ◽  
Genome Stability ◽  
Cell Cycle Control ◽  
Reverse Transcriptase Gene ◽  
Neoplastic Tissue ◽  
Adult Type ◽  
Qpcr Method ◽  
New Treatments ◽  
First Time ◽  
Work Supports

Currently, many new possible biomarkers and mechanisms are being searched and tested to analyse pathobiology of pediatric tumours for the development of new treatments. One such candidate molecular factor is BARD1 (BRCA1 Associated RING Domain 1)—a tumour-suppressing gene involved in cell cycle control and genome stability, engaged in several types of adult-type tumours. The data on BARD1 significance in childhood cancer is limited. This study determines the expression level of BARD1 and its isoform beta (β) in three different histogenetic groups of pediatric cancer—neuroblastic tumours, and for the first time in chosen germ cell tumours (GCT), and rhabdomyosarcoma (RMS), using the qPCR method. We found higher expression of beta isoform in tumour compared to healthy tissue with no such changes concerning BARD1 full-length. Additionally, differences in expression of BARD1 β between histological types of neuroblastic tumours were observed, with higher levels in ganglioneuroblastoma and ganglioneuroma. Furthermore, a higher expression of BARD1 β characterized yolk sac tumours (GCT type) and RMS when comparing with non-neoplastic tissue. These tumours also showed a high expression of the TERT (Telomerase Reverse Transcriptase) gene. In two RMS cases we found deep decrease of BARD1 β in post-chemotherapy samples. This work supports the oncogenicity of the beta isoform in pediatric tumours, as well as demonstrates the differences in its expression depending on the histological type of neoplasm, and the level of maturation in neuroblastic tumours.

scholarly journals Phosphorylation of the RB C-terminus regulates condensin II release from chromatin

2020 ◽  
pp. jbc.RA120.016511
Author(s):  
Seung J Kim ◽  
James I MacDonald ◽  
Frederick A. Dick
Keyword(s):  
Cell Cycle ◽  
Genome Stability ◽  
Cell Cycle Control ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Biologically Relevant ◽  
C Terminus ◽  
Independent Functions ◽  
Phosphorylation Event ◽  
Rb Phosphorylation

The retinoblastoma tumour suppressor protein (RB) plays an important role in biological processes such as cell cycle control, DNA damage repair, epigenetic regulation, and genome stability. The canonical model of RB regulation is that cyclin-CDKs phosphorylate, and render RB inactive in late G1/S, promoting entry into S phase. Recently, mono-phosphorylated RB species were described to have distinct cell-cycle independent functions, suggesting that a phosphorylation code dictates diversity of RB function. However, a biologically relevant, functional role of RB phosphorylation at non-CDK sites has remained elusive. Here, we investigated S838/T841 dual phosphorylation, its upstream stimulus, and downstream functional output.  We found that mimicking T-cell receptor activation in Jurkat leukemia cells induced sequential activation of downstream kinases including p38 MAPK, and RB S838/T841 phosphorylation.  This signaling pathway disrupts RB and condensin II interaction with chromatin.  Using cells expressing a WT or S838A/T841A mutant RB fragment, we present evidence that deficiency for this phosphorylation event prevents condensin II release from chromatin.

scholarly journals SIRT7 is a deacetylase of N4-acetylcytidine on ribosomal RNA

2021 ◽  
Author(s):  
Chenzhong Xu ◽  
Jin Zhang ◽  
Jie Zhang ◽  
Baohua Liu
Keyword(s):  
Circadian Rhythms ◽  
Ribosomal Rna ◽  
Genome Stability ◽  
Rna Stability ◽  
Translation Efficiency ◽  
Dependent Protein ◽  
First Time ◽  
Protein Deacetylase

AbstractN-acetyltransferase 10 catalyzes RNA N4-acetylcytidine (ac4C) modifications and thus regulates RNA stability and translation efficiency. However, the deacetylase for ac4C is unknown. SIRT7 was initially identified as an NAD+-dependent protein deacetylase and plays essential roles in genome stability, circadian rhythms, metabolism, and aging. In this study, we identified SIRT7 as a deacetylase of the ac4C of ribosomal (r)RNA for the first time and found it to be NAD+-independent. Our data highlight the important role of SIRT7 in rRNA ac4C modification and suggest an additional epitranscriptional regulation of aging.

scholarly journals Therapeutic Approaches Targeting Nucleolus in Cancer

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1090 ◽  
Author(s):  
Pietro Carotenuto ◽  
Annalisa Pecoraro ◽  
Gaetano Palma ◽  
Giulia Russo ◽  
Annapina Russo
Keyword(s):  
Stress Responses ◽  
Ribosome Biogenesis ◽  
Genome Stability ◽  
Cell Cycle Control ◽  
Therapeutic Interventions ◽  
Main Function ◽  
Therapeutic Approaches ◽  
Functional Studies ◽  
Cellular Processes ◽  
Histopathological Studies

The nucleolus is a distinct sub-cellular compartment structure in the nucleus. First observed more than 200 years ago, the nucleolus is detectable by microscopy in eukaryotic cells and visible during the interphase as a sub-nuclear structure immersed in the nucleoplasm, from which it is not separated from any membrane. A huge number of studies, spanning over a century, have identified ribosome biogenesis as the main function of the nucleolus. Recently, novel functions, independent from ribosome biogenesis, have been proposed by several proteomic, genomic, and functional studies. Several works have confirmed the non-canonical role for nucleoli in regulating important cellular processes including genome stability, cell-cycle control, the cellular senescence, stress responses, and biogenesis of ribonucleoprotein particles (RNPs). Many authors have shown that both canonical and non-canonical functions of the nucleolus are associated with several cancer-related processes. The association between the nucleolus and cancer, first proposed by cytological and histopathological studies showing that the number and shape of nucleoli are commonly altered in almost any type of cancer, has been confirmed at the molecular level by several authors who demonstrated that numerous mechanisms occurring in the nucleolus are altered in tumors. Recently, therapeutic approaches targeting the nucleolus in cancer have started to be considered as an emerging “hallmark” of cancer and several therapeutic interventions have been developed. This review proposes an up-to-date overview of available strategies targeting the nucleolus, focusing on novel targeted therapeutic approaches. Finally, a target-based classification of currently available treatment will be proposed.

Time trends in incidence, comorbidity, and mortality of ischemic stroke in Denmark (1996–2016)

Neurology ◽  
2020 ◽  
Vol 95 (17) ◽  
pp. e2343-e2353
Author(s):  
Adelina Yafasova ◽  
Emil Loldrup Fosbøl ◽  
Mia Nielsen Christiansen ◽  
Naja Emborg Vinding ◽  
Charlotte Andersson ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cox Regression ◽  
Initial Level ◽  
Age Groups ◽  
Incidence Rates ◽  
Lipid Lowering ◽  
Mortality Risks ◽  
Rate Ratios ◽  
New Treatments ◽  
First Time

ObjectiveTo examine whether the incidence, comorbidity, and mortality of first-time ischemic stroke changed in Denmark between 1996 and 2016 overall and according to age and sex using a nationwide cohort design.MethodsIn this cohort study, 224,617 individuals ≥18 years of age admitted with first-time ischemic stroke between 1996 and 2016 were identified through Danish nationwide registries. We calculated annual age-standardized incidence rates and absolute 30-day and 1-year mortality risks. Furthermore, we calculated annual incidence rate ratios using Poisson regression, odds ratios for 30-day mortality using logistic regression, and hazard ratios for 1-year mortality using Cox regression.ResultsThe overall age-standardized incidence rates of ischemic stroke per 1,000 person-years increased from 1996 (2.70 [95% confidence interval [CI] 2.65–2.76]) to 2002 (3.25 [95% CI 3.20–3.31]) and then gradually decreased to below the initial level until 2016 (1.99 [95% CI 1.95–2.02]). Men had higher incidence rates than women in all age groups except 18 to 34 and ≥85 years. Absolute mortality risk decreased between 1996 and 2016 (30-day mortality from 17.1% to 7.6% and 1-year mortality from 30.9% to 17.3%). Women between 55 and 64 and ≥85 years of age had higher mortality than men. Similar trends were observed for all analyses after multivariable adjustment. The prevalence of atrial fibrillation, hypertension, diabetes mellitus, and use of lipid-lowering medication increased during the study period.ConclusionsThe age-standardized incidence of first-time hospitalization for ischemic stroke increased from 1996 to 2002 and then gradually decreased to below the initial level until 2016. Absolute 30-day and 1-year mortality risks decreased between 1996 and 2016. These findings correspond to increased stroke prevention awareness and introduction of new treatments during the study period.

scholarly journals Update Breast Cancer 2020 Part 2 – Advanced Breast Cancer: New Treatments and Implementation of Therapies with Companion Diagnostics

2020 ◽  
Vol 80 (04) ◽  
pp. 391-398
Author(s):  
Diana Lüftner ◽  
Andreas Schneeweiss ◽  
Andreas D. Hartkopf ◽  
Volkmar Müller ◽  
Achim Wöckel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Targeted Therapy ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Companion Diagnostics ◽  
Molecular Tests ◽  
New Treatments ◽  
First Time

AbstractFor patients with locally advanced or metastatic breast cancer, new and effective therapies such as CDK4/6 inhibitors, PARP inhibitors and a PD-L1 inhibitor have been introduced in recent years. This review presents an update on the available studies with their data. In addition, two innovative anti-HER2 therapies are presented (trastuzumab-deruxtecan and tucatinib) for which the results from new studies have been reported. Molecular tests offer the possibility of defining patient populations or also monitoring courses of therapy. This can help identify patients with specific characteristics in order to provide them with individually targeted therapy within the framework of studies. In a large study, the benefit of such a biomarker study was able to be described for the first time.

scholarly journals Will the RACE for Children Act lead to new treatments for pediatric cancer?

Cancer ◽  
2017 ◽  
Vol 123 (2) ◽  
pp. 189-189
Author(s):  
Jennifer L. W. Fink
Keyword(s):  
Pediatric Cancer ◽  
New Treatments

scholarly journals HIF-1α is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2α–induced excessive erythropoiesis

Blood ◽  
2013 ◽  
Vol 121 (8) ◽  
pp. 1436-1445 ◽  
Author(s):  
Kristin Franke ◽  
Joanna Kalucka ◽  
Soulafa Mamlouk ◽  
Rashim Pal Singh ◽  
Antje Muschter ◽  
...  
Keyword(s):  
Protective Factor ◽  
Hypoxia Inducible Factor ◽  
The Body ◽  
Entire System ◽  
Mouse Line ◽  
Prolyl Hydroxylases ◽  
Oxygen Sensitive ◽  
New Treatments ◽  
First Time ◽  
Deficient Mice

Abstract Erythropoiesis must be tightly balanced to guarantee adequate oxygen delivery to all tissues in the body. This process relies predominantly on the hormone erythropoietin (EPO) and its transcription factor hypoxia inducible factor (HIF). Accumulating evidence suggests that oxygen-sensitive prolyl hydroxylases (PHDs) are important regulators of this entire system. Here, we describe a novel mouse line with conditional PHD2 inactivation (cKO P2) in renal EPO producing cells, neurons, and astrocytes that displayed excessive erythrocytosis because of severe overproduction of EPO, exclusively driven by HIF-2α. In contrast, HIF-1α served as a protective factor, ensuring survival of cKO P2 mice with HCT values up to 86%. Using different genetic approaches, we show that simultaneous inactivation of PHD2 and HIF-1α resulted in a drastic PHD3 reduction with consequent overexpression of HIF-2α-related genes, neurodegeneration, and lethality. Taken together, our results demonstrate for the first time that conditional loss of PHD2 in mice leads to HIF-2α–dependent erythrocytosis, whereas HIF-1α protects these mice, providing a platform for developing new treatments of EPO-related disorders, such as anemia.

scholarly journals Collection and Reporting of National Cancer Stage at Diagnosis Data in Australia (STaR Project)

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 67s-67s
Author(s):  
R. Long ◽  
A. Woods ◽  
C. Biondi ◽  
J. Luzuriaga ◽  
C. Anderiesz ◽  
...  
Keyword(s):  
Pediatric Cancer ◽  
Cancer Registries ◽  
Population Based ◽  
National Standard ◽  
Cancer Stage ◽  
Stage At Diagnosis ◽  
Business Rules ◽  
Cancer Outcomes ◽  
National Data ◽  
First Time

Background: Stage at diagnosis is an important prognostic factor for cancer, providing contextual information for interpreting population health indicators such as mortality from cancer and cancer survival. Australian population-based cancer registries (PBCRs) routinely collect information on cancer incidence and mortality. The need for high quality, comprehensive national data on stage at diagnosis to supplement these data are widely recognized in Australia. The collection and dissemination of quality national stage data will enhance the: • ability to better monitor cancer outcomes, inform cancer control policy; • understand variations across different populations; and • identify where further research and targeted strategies may be required to improve cancer outcomes. Linking data on cancer stage at diagnosis with other administrative cancer data will also allow for a better understanding of the relationship between stage at diagnosis, treatments received, patterns of cancer recurrence, and survival outcomes. Aim: To strengthen national data capacity by collecting and reporting cancer stage at diagnosis for Cancer Australia's Stage, Treatment and Recurrence (STaR) project. Methods: Working with state and territory population-based cancer registries (PBCRs) and the Australian Pediatric Cancer Registry, Cancer Australia supported the development and testing of Business Rules for the collection of national cancer stage at diagnosis for: • The top 5 incident cancers based on the Tumor, Node, and Metastasis (TNM) staging system. These rules were endorsed by the Australasian Association of Cancer Registries (AACR) as a national standard in May 2016; and • Childhood cancers, with a separate set of Business Rules for 16 childhood cancer types based on the Toronto Pediatric Cancer Stage Guidelines. These rules were supported by the AACR as a national standard. Results: Using the AACR-endorsed Business Rules, comprehensive national cancer stage at diagnosis data for the top 5 incident cancers (for 2011) have been collected in Australia for the first time. Over 90% of incidence cases were able to be assigned a value for registry-derived (RD) stage at diagnosis for melanoma (97%), prostate (97%), and female breast (94%) cancers. Lower staging completeness was found for colorectal cancers (88%), and for lung cancers (72%). Business Rules for the collection of stage at diagnosis data for pediatric cancers have also been developed; 93% of sample cases diagnosed in the period 2006-2010 were able to be staged, ranging from 84% for nonrhabdomyosarcoma to 100% for hepatoblastoma. Conclusion: The Business Rules enabled the uniform collection of cancer stage at diagnosis data for the first time in Australia. The collection of these data will allow for the linkage of stage at diagnosis to other sources of information, including patterns of treatments applied, and enable reporting of survival and recurrence outcomes by stage.

A reconfigurable microscale assay enables insights into cancer-associated fibroblast modulation of immune cell recruitment

2021 ◽  
Vol 13 (4) ◽  
pp. 87-97
Author(s):  
Jiaquan Yu ◽  
Amber Piazza ◽  
Sidney Sparks ◽  
Laurel E Hind ◽  
David J Niles ◽  
...  
Keyword(s):  
Immune Cell ◽  
Neutrophil Infiltration ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Neoplastic Tissue ◽  
Cell Recruitment ◽  
Cancer Associated Fibroblast ◽  
First Time ◽  
Immune Cell Recruitment

Abstract Innate immune cell infiltration into neoplastic tissue is the first line of defense against cancer and can play a deterministic role in tumor progression. Here, we describe a series of assays, using a reconfigurable microscale assay platform (i.e. Stacks), which allows the study of immune cell infiltration in vitro with spatiotemporal manipulations. We assembled Stacks assays to investigate tumor–monocyte interactions, re-education of activated macrophages, and neutrophil infiltration. For the first time in vitro, the Stacks infiltration assays reveal that primary tumor-associated fibroblasts from specific patients differ from that associated with the benign region of the prostate in their ability to limit neutrophil infiltration as well as facilitate monocyte adhesion and anti-inflammatory monocyte polarization. These results show that fibroblasts play a regulatory role in immune cell infiltration and that Stacks has the potential to predict individual patients’ cancer-immune response.

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