scholarly journals Somatic Variant Analysis Identifies Targets for Tailored Therapies in Patients with Vascular Malformations

2020 ◽  
Vol 9 (11) ◽  
pp. 3387
Author(s):  
Stefano Paolacci ◽  
Raul Ettore Mattassi ◽  
Giuseppe Marceddu ◽  
Elena Manara ◽  
Alessandra Zulian ◽  
...  
Keyword(s):  
Vascular Malformations ◽  
Mammalian Target Of Rapamycin ◽  
Sequencing Analysis ◽  
Somatic Variant ◽  
Activating Mutations ◽  
Pathogenic Variants ◽  
Next Generation Sequencing Analysis ◽  
Variant Analysis ◽  
Phosphoinositide 3 Kinase

Vascular malformations include various disorders characterized by morphological, structural and/or functional alterations of blood and lymph vessels. Most are sporadic, due to somatic mutations. Here, we report a cohort of patients with sporadic and/or unifocal vascular malformations, in whom we carried out next generation sequencing analysis of a panel of genes associated with vascular malformations. The 115 patients analyzed were from different clinical centres. In 37 patients (32%), we found pathogenic mutations: most of these were gain–of–function mutations in PIK3CA (18%, 21/115) and TEK (13/115, 11%). We also found mutations in GNAQ, CCM2 and PTEN. Identifying pathogenic variants in patients with vascular malformations can help improve management, particularly in cases with activating mutations that cause an increase in cell proliferation. Personalized pharmacological treatment, if possible, is now considered preferable to surgery and can help prevent recurrences, i.e., long–term complications of residual malformation or regrowth of tumors. For instance, rapamycin is currently being investigated for the treatment of various vascular malformations associated with hyperactivation of the phosphoinositide 3–kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway.

scholarly journals An Unusually Short Latent Period of Therapy-Related Myeloid Neoplasm Harboring a Rare MLL-EP300 Rearrangement: Case Report and Literature Review

2019 ◽  
Vol 2019 ◽  
pp. 1-6
Author(s):  
Reina Takeda ◽  
Kazuaki Yokoyama ◽  
Seiichiro Kobayashi ◽  
Toyotaka Kawamata ◽  
Sousuke Nakamura ◽  
...  
Keyword(s):  
Chromosomal Translocation ◽  
Acute Type ◽  
Sequencing Analysis ◽  
Hematopoietic Stem ◽  
Adult T Cell Leukemia ◽  
Myeloid Neoplasm ◽  
Dismal Prognosis ◽  
Short Latent Period ◽  
Next Generation Sequencing Analysis

Therapy-related myeloid neoplasm (t-MN) is a late and lethal complication induced by chemotherapy and/or radiation therapy. Hematological malignancy is one of the most common primary diseases in patients with t-MN. However, the occurrence of t-MN in adult T-cell leukemia/lymphoma (ATL) patients is rarely reported, possibly due to the dismal prognosis of ATL per se. Here, we report a 62-year-old female who developed t-MN only three months after the completion of conventional chemotherapy and anti-CCR4 antibody for ATL acute type. The patient presented with persistent fever and monocytosis without any evidence of infectious diseases. Bone marrow examinations revealed chronic myelomonocytic leukemia-like disease with a chromosomal translocation of t(11;22)(q23;q13) as a solo cytogenetic abnormality, resulting in the diagnosis of t-MN. Next-generation sequencing analysis identified a rare chimeric transcript, MLL-EP300, without any additional somatic mutations. Although the patient underwent allogenic hematopoietic stem cell transplantation, she died of viral encephalomyelitis at 7 months after diagnosis of t-MN. Since recent therapeutic advances have extended the survival of patients with ATL, further evaluation of the long-term risks of developing t-MN in these patients is warranted.

Germline RET variants underlie a subset of paediatric osteosarcoma

2020 ◽  
Vol 58 (1) ◽  
pp. 20-24
Author(s):  
Michal Kovac ◽  
Connor Woolley ◽  
Sebastian Ribi ◽  
Claudia Blattmann ◽  
Eva Roth ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Kinase Activity ◽  
Preventive Measures ◽  
Malignant Tumour ◽  
Sequencing Analysis ◽  
Considerable Effort ◽  
Medullary Thyroid ◽  
Activating Mutations ◽  
Pathogenic Variants

BackgroundAlthough considerable effort has been put into decoding of the osteosarcoma genome, very little is known about germline mutations that underlie this primary malignant tumour of bone.Methods and resultsWe followed here a coincidental finding in a multiple endocrine neoplasia family in which a 32-year-old patient carrying a germline pathogenic RET mutation developed an osteosarcoma 2 years after the resection of a medullary thyroid carcinoma. Sequencing analysis of additional 336 patients with osteosarcoma led to the identification of germline activating mutations in the RET proto-oncogene in three cases and somatic amplifications of the gene locus in five matched tumours (4%, n=5/124 tumours). Functional analysis of the pathogenic variants together with an integrative analysis of osteosarcoma genomes confirmed that the mutant RET proteins couple functional kinase activity to dysfunctional ligand binding. RET mutations further co-operated with alterations in TP53 and RB1, suggesting that osteosarcoma pathogenesis bears reminiscence to the stepwise model of medullary thyroid carcinoma.ConclusionsAfter Li-Fraumeni-predisposing mutations in TP53, RET becomes the second most mutated cancer-predisposing gene in the germline of patients with osteosarcoma. Hence, early identification of RET mutation carriers can help to identify at-risk family members and carry out preventive measures.

scholarly journals Analysis of 29 Targeted Genes for Non-obstructive Azoospermia: the Relationship Between Genetic Testing and Testicular Histology

2021 ◽  
Author(s):  
Rossella Cannarella ◽  
Matteo Bertelli ◽  
Rosita A. Condorelli ◽  
Marija Vilaj ◽  
Sandro La Vignera ◽  
...  
Keyword(s):  
Klinefelter Syndrome ◽  
Testicular Biopsy ◽  
University Hospital ◽  
Testicular Sperm Extraction ◽  
Obstructive Azoospermia ◽  
Sequencing Analysis ◽  
Pathogenic Variants ◽  
Next Generation Sequencing Analysis ◽  
Testicular Histology ◽  
The Relationship

Abstract BACKGROUND. Few studies have evaluated the relationship between testicular histology and pathogenic variations of genes regulating spermatogenesis.AIM. To analyze the presence of potentially pathogenic variants of 29 candidate genes known to cause spermatogenic failure (SPGF) in patients with non-obstructive azoospermia (NOA) who underwent testicular histology.PATIENTS AND METHODS. Sixty patients with NOA referred to the Department of Transfusion Medicine and Transplantation Biology, University Hospital Center Zagreb, Croatia, for testicular biopsy were consecutively assessed for eligibility. Twelve patients were excluded from the study because they had Klinefelter syndrome (n=1), Yq microdeletions (n=6), testicular trauma (n=2), or in-situ germ cell neoplasia (n=3). Therefore, 48 patients were considered eligible and included in this study. They were divided into three groups: those who had cryptorchidism (n=9), those with varicocele (n=14), and those with idiopathic NOA (n=25). All included patients underwent blood withdrawal for next-generation sequencing analysis and gene sequencing.RESULTS. We found a possible genetic cause in 4 patients with idiopathic NOA (16%) and in 2 with cryptorchidism (22%). No pathogenic or possibly pathogenic mutations were identified in patients with varicocele. Variants of undetermined significance (VUS) were found in 11 patients with idiopathic NOA (44%), 3 with cryptorchidism (33%), and 8 patients with varicocele (57%). VUSs of the USP9Y gene were the most frequently as they were found in 14 out of 48 patients (29%). In particular, the VUS USP9Y c.7434+14del was found in 11 patients. They showed varied histological pictures, including Sertoli cell-only syndrome, mixed atrophy, and hypospermatogenesis, regardless of cryptorchidism or varicocele. No direct correlation was found between the gene mutation/variant and the testicular histological picture. CONCLUSION. Different mutations of the same gene cause various testicular histological pictures. These results suggest that it is not the gene itself but the type of mutation/variation that determines the testicular histology picture. Based on the data presented above, it remains challenging to design a genetic panel with prognostic value for the outcome of testicular sperm extraction in patients with NOA.

scholarly journals Novel STAG1 Frameshift Mutation in a Patient Affected by a Syndromic Form of Neurodevelopmental Disorder

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1116
Author(s):  
Ester Di Muro ◽  
Pietro Palumbo ◽  
Mario Benvenuto ◽  
Maria Accadia ◽  
Marilena Carmela Di Giacomo ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Sequencing Analysis ◽  
Cohesin Complex ◽  
Mild Intellectual Disability ◽  
Pathogenic Variants ◽  
Core Proteins ◽  
Next Generation Sequencing Analysis ◽  
Cornelia De Lange

The cohesin complex is a large evolutionary conserved functional unit which plays an essential role in DNA repair and replication, chromosome segregation and gene expression. It consists of four core proteins, SMC1A, SMC3, RAD21, and STAG1/2, and by proteins regulating the interaction between the complex and the chromosomes. Mutations in the genes coding for these proteins have been demonstrated to cause multisystem developmental disorders known as “cohesinopathies”. The most frequent and well recognized among these distinctive clinical conditions are the Cornelia de Lange syndrome (CdLS, OMIM 122470) and Roberts syndrome (OMIM 268300). STAG1 belongs to the STAG subunit of the core cohesin complex, along with five other subunits. Pathogenic variants in STAG1 gene have recently been reported to cause an emerging syndromic form of neurodevelopmental disorder that is to date poorly characterized. Here, we describe a 5 year old female patient with neurodevelopmental delay, mild intellectual disability, dysmorphic features and congenital anomalies, in which next generation sequencing analysis allowed us to identify a novel pathogenic variation c.2769_2770del p.(Ile924Serfs*8) in STAG1 gene, which result to be de novo. The variant has never been reported before in medical literature and is absent in public databases. Thus, it is useful to expand the molecular spectrum of clinically relevant alterations of STAG1 and their phenotypic consequences.

Lupeol Inhibits Proliferation and Promotes Apoptosis of Ovarian Cancer Cells by Inactivating Phosphoinositide-3-Kinase/Protein Kinase B/ Mammalian Target of Rapamycin Pathway

2020 ◽  
Vol 19 (2) ◽  
pp. 206-210
Author(s):  
Feng Chen ◽  
Bei Zhang
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Protein Kinase ◽  
Cell Viability ◽  
Cancer Cells ◽  
Protein Kinase B ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Ovarian Cancer Cells ◽  
Phosphoinositide 3 Kinase

Lupeol exhibits multiple pharmacological activities including, anticancerous, anti-inflammatory, and antioxidant. The aim of this study was to explore the anticancerous activity of lupeol on ovarian cancer cells and examine its mechanism of action. To this end, increasing concentrations of lupeol on cell viability, cell cycle, and apoptosis in Caov-3 cells were evaluated. Lupeol inhibited cell viability, induced G1 phase arrest in cell cycle, increased cell apoptosis, and inhibited the ratio of phospho-Akt/protein kinase B and phospho-mammalian target of rapamycin/mammalian target of rapamycin. In conclusion, these data suggest that lupeol may play a therapeutic role in ovarian cancer.

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

scholarly journals Changes in Bacterial and Fungal Soil Communities in Long-Term Organic Cropping Systems

Agriculture ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 445
Author(s):  
Jessica Cuartero ◽  
Onurcan Özbolat ◽  
Virginia Sánchez-Navarro ◽  
Marcos Egea-Cortines ◽  
Raúl Zornoza ◽  
...  
Keyword(s):  
Microbial Community ◽  
Crop Yield ◽  
Soil Microbial Community ◽  
Cropping Systems ◽  
Sequencing Analysis ◽  
Soil Microbial Community Structure ◽  
Soil Microbial ◽  
Network Analyses ◽  
Organic Cultivation

Long-term organic farming aims to reduce synthetic fertilizer and pesticide use in order to sustainably produce and improve soil quality. To do this, there is a need for more information about the soil microbial community, which plays a key role in a sustainable agriculture. In this paper, we assessed the long-term effects of two organic and one conventional cropping systems on the soil microbial community structure using high-throughput sequencing analysis, as well as the link between these communities and the changes in the soil properties and crop yield. The results showed that the crop yield was similar among the three cropping systems. The microbial community changed according to cropping system. Organic cultivation with manure compost and compost tea (Org_C) showed a change in the bacterial community associated with an improved soil carbon and nutrient content. A linear discriminant analysis effect size showed different bacteria and fungi as key microorganisms for each of the three different cropping systems, for conventional systems (Conv), different microorganisms such as Nesterenkonia, Galbibacter, Gramella, Limnobacter, Pseudoalteromonas, Pantoe, and Sporobolomyces were associated with pesticides, while for Org_C and organic cultivation with manure (Org_M), other types of microorganisms were associated with organic amendments with different functions, which, in some cases, reduce soil borne pathogens. However, further investigations such as functional approaches or network analyses are need to better understand the mechanisms behind this behavior.

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