scholarly journals Sructural rearrangements of NTRK genes: characteristics, methods of detection and targeted therapy for cancer

2022 ◽  
Vol 20 (6) ◽  
pp. 120-133
Author(s):  
A. A. Kechin ◽  
A. I. Andriyanova ◽  
M. L. Filipenko
Keyword(s):  
First Generation ◽  
Protein Product ◽  
Cellular Level ◽  
Targeted Drugs ◽  
Secretory Carcinoma ◽  
Development Of Resistance ◽  
Congenital Mesoblastic Nephroma ◽  
Different Types ◽  
Trk Inhibitors ◽  
Structure And Functions

Background. The first-generation trk inhibitors, larotrectinib and entrectinib, were approved by the u.s. Food and drug administration (Fda) for the treatment of advanced solid tumors harboring NTRK gene fusions in November 2018 and in august 2019, respectively. The purpose of the study was to present upto-date data on the structure and functions of ntrk genes, the frequency of occurrence of rearrangements with their participation, the consequences of their occurrence at the cellular level, methods of detecting such rearrangements, as well as targeted drugs used in the presence of chimeric NTRK genes. Material and methods. A systemic literature search was conducted in pubmed ncbi, Web of science, scopus databases. Results. The products of NTRK genes are receptors for neurotrophins, and their high expression is normally observed only in a narrow range of tissue types. Intrachromosomal or interchromosomal rearrangements lead to a significant increase in the level of expression of the chimeric gene regulated by the strong promoter of the partner gene. The high transcriptional activity of such a gene, along with the constant activation of the kinase activity of the protein product, leads to the activation of metabolic pathways responsible for cell escape from apoptosis and disruption of the regulation of the cell cycle. The occurrence of chimeric NTRK genes varies between different types of tumors, with the highest (up to 90 %) in rare cancers (secretory carcinoma of the breast, secretory carcinoma of the salivary glands, congenital mesoblastic nephroma, children’s fibrosarcoma). Larotrectinib and entrectinib are highly effective targeted drugs in suppressing the growth of a tumor carrying NTRK rearrangements, regardless of the type of tumor. In this regard, the introduction of new high-precision methods for the detection of chimeric NTRK genes, as well as the study of the mechanisms of the development of resistance with the assumption of ways to overcome it, seems relevant. Conclusion. Rearrangements of NTRK genes are quite common in various types of oncology and are an effective target for modern targeted drugs.

The Multimedia Classroom

1976 ◽  
Vol 35 (2) ◽  
pp. 173-177
Author(s):  
Stuart McRae
Keyword(s):  
Community College ◽  
Student Teacher ◽  
Alternative Model ◽  
First Generation ◽  
Learning Experience ◽  
Learning Center ◽  
Santa Fe ◽  
Different Types ◽  
First Generation College

We need an alternative model to education that will turn students on to learning. Such a model must recognize the ability each student brings to the learning experience. At the Learning Center for Anthropology at Santa Fe Community College in Gainesville, Florida, a smorgasbord of experiences using different types of media was substituted for the traditional academic menu. Early studies show several definite trends for the multimedia classroom: increased student-teacher contact; increased performance by students who are first generation college participants; decreased course costs per student-hour; and greater individualization of instruction.

scholarly journals Új célzott terápiás lehetőség az onkológiában: tropomiozin receptor-tirozin-kináz gátlók

2021 ◽  
Vol 162 (34) ◽  
pp. 1362-1369
Author(s):  
Edina Kiss ◽  
Zsuzsanna Pápai
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
First Generation ◽  
Kinase Inhibitor ◽  
Disease Free Survival ◽  
Diagnostic Methods ◽  
Molecular Diagnostic ◽  
Precision Oncology ◽  
Gene Fusions ◽  
Trk Inhibitors

Összefoglaló. A molekuláris diagnosztikai módszerek folyamatos fejlődésének köszönhetően egyre több onkogén genetikai eltérést azonosítanak. A neurotrofikus tropomiozin receptor-tirozin-kináz (NTRK-) génfúziók fontos precíziós onkológiai célpontok, melyek mindhárom NTRK-génben előfordulhatnak, onkogén-hajtóerőként viselkednek. A génfúziók különböző molekuláris diagnosztikai módszerekkel azonosíthatók, melyek közül a legpontosabb, legköltségesebb és legidőigényesebb meghatározást az újgenerációs szekvenálási technika jelenti. A tropomiozin receptor-tirozin-kináz (TRK-) fúziós fehérjék szelektív gátlása személyre szabott onkológiai kezelési lehetőséget jelent a tumor típusától, lokalizációjától és a beteg életkorától függetlenül. Az első generációs TRK-gátlók gyors, hatékony és tartós daganatellenes hatást biztosítanak kimutatott NTRK-fúzió-pozitív daganatok esetén, alacsony mellékhatásprofil mellett. Az első generációs TRK-gátlók mellett jelentkező ’on target’ rezisztenciát a második generációs TRK-gátlók oldják fel. Szekvenciális tirozin-kináz-inhibitor-kezeléssel tartós betegségmentes túlélés érhető el. Orv Hetil. 2021; 162(34): 1362–1369. Summary. Due to the continuous development of molecular diagnostic methods, more and more oncogenic genetic abnormalities are being identified. Neurotrophic tropomyosin receptor tyrosine kinase (NTRK) gene fusions are important precision oncology targets that can occur in all three NTRK genes and act as oncogenic drivers. Gene fusions can be identified by a variety of molecular diagnostic technologies, of which next-generation sequencing is the most accurate, costly and time-consuming determination. Selective inhibition of tropomyosin receptor tyrosine kinase (TRK) fusion proteins represents a personalized oncology treatment option regardless of tumour type, localization and patient age. First-generation TRK inhibitors provide rapid, efffective and long-lasting antitumor activity in NTRK fusion-positive tumors with a low side-effect profile. On target resistance to first-generation TRK inhibitors is resolved by second-generation TRK inhibitors. Durable disease-free survival can be achieved with sequential tyrosine kinase inhibitor therapies. Orv Hetil. 2021; 162(34): 1362–1369.

scholarly journals Impact of Disdrometer Types on Rainfall Erosivity Estimation

Water ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 963
Author(s):  
Lisbeth Lolk Johannsen ◽  
Nives Zambon ◽  
Peter Strauss ◽  
Tomas Dostal ◽  
Martin Neumann ◽  
...  
Keyword(s):  
Drop Size ◽  
First Generation ◽  
Rainfall Intensity ◽  
Measurement Instrument ◽  
Rainfall Erosivity ◽  
Data Handling ◽  
Rainfall Characteristics ◽  
Different Types ◽  
Spatial Differences ◽  
Soil Erosion By Water

Soil erosion by water is affected by the rainfall erosivity, which controls the initial detachment and mobilization of soil particles. Rainfall erosivity is expressed through the rainfall intensity (I) and the rainfall kinetic energy (KE). KE–I relationships are an important tool for rainfall erosivity estimation, when direct measurement of KE is not possible. However, the rainfall erosivity estimation varies depending on the chosen KE–I relationship, as the development of KE–I relationships is affected by the measurement method, geographical rainfall patterns and data handling. This study investigated how the development of KE–I relationships and rainfall erosivity estimation is affected by the use of different disdrometer types. Rainfall data were collected in 1-min intervals from six optical disdrometers at three measurement sites in Austria, one site in Czech Republic and one site in New Zealand. The disdrometers included two disdrometers of each of the following types: the PWS100 Present Weather Sensor from Campbell Scientific, the Laser Precipitation Monitor from Thies Clima and the first generation Parsivel from OTT Hydromet. The fit of KE–I relationships from the literature varied among disdrometers and sites. Drop size and velocity distributions and developed KE–I relationships were device-specific and showed similarities for disdrometers of the same type across measurement sites. This hindered direct comparison of results from different types of disdrometers, even when placed at the same site. Thus, to discern spatial differences in rainfall characteristics the same type of measurement instrument should be used.

scholarly journals Protective Roles of Cytosolic and Plastidal Proteasomes on Abiotic Stress and Pathogen Invasion

Plants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 832
Author(s):  
Md. Sarafat Ali ◽  
Kwang-Hyun Baek
Keyword(s):  
Abiotic Stress ◽  
Cell Survival ◽  
Plant Cells ◽  
Cellular Level ◽  
26S Proteasome ◽  
Pathogen Invasion ◽  
Cellular Environment ◽  
Abiotic Stressors ◽  
Different Types ◽  
Clp Proteases

Protein malfunction is typically caused by abiotic stressors. To ensure cell survival during conditions of stress, it is important for plant cells to maintain proteins in their respective functional conformation. Self-compartmentalizing proteases, such as ATP-dependent Clp proteases and proteasomes are designed to act in the crowded cellular environment, and they are responsible for degradation of misfolded or damaged proteins within the cell. During different types of stress conditions, the levels of misfolded or orphaned proteins that are degraded by the 26S proteasome in the cytosol and nucleus and by the Clp proteases in the mitochondria and chloroplasts increase. This allows cells to uphold feedback regulations to cellular-level signals and adjust to altered environmental conditions. In this review, we summarize recent findings on plant proteolytic complexes with respect to their protective functions against abiotic and biotic stressors.

Immunolocalization of PTCH Protein in Odontogenic Cysts and Tumors

2002 ◽  
Vol 81 (11) ◽  
pp. 757-760 ◽  
Author(s):  
D.C. Barreto ◽  
A.E. Bale ◽  
L. De Marco ◽  
R.S. Gomez
Keyword(s):  
Basal Cell ◽  
Tumor Suppression ◽  
Protein Product ◽  
Odontogenic Tumors ◽  
Odontogenic Cysts ◽  
Odontogenic Keratocysts ◽  
Basal Cell Carcinomas ◽  
Different Types ◽  
Embryologic Development

The human patched gene ( PTCH) functions in both embryologic development and tumor suppression. PTCH mutations have been found in odontogenic keratocysts. However, the expression and localization of the protein product of the gene have not been determined in odontogenic tumors and cysts. We investigated 68 odontogenic lesions by immunohistochemistry, and compared their PTCH expression with that in basal cell carcinomas. All odontogenic lesions, including two keratocysts with truncating mutations, were positive for PTCH. Different types of lesions had different amounts of staining. Lack of staining was noted in the majority of basal cell carcinomas. Taken together, these data suggest that odontogenic keratocysts arise with heterozygous mutations of the PTCH gene.

scholarly journals Nuclear and mitochondrial inheritance in yeast depends on novel cytoplasmic structures defined by the MDM1 protein.

1992 ◽  
Vol 118 (2) ◽  
pp. 385-395 ◽  
Author(s):  
S J McConnell ◽  
M P Yaffe
Keyword(s):  
Indirect Immunofluorescence ◽  
Protein Product ◽  
Cellular Level ◽  
Yeast Cells ◽  
Temperature Sensitive ◽  
Nonpermissive Temperature ◽  
Animal Cells ◽  
Keratin Gene ◽  
Reading Frame ◽  
Cytoplasmic Structures

The mdml mutation causes temperature-sensitive growth and defective transfer of nuclei and mitochondria into developing buds of yeast cells at the nonpermissive temperature. The MDM1 gene was cloned by complementation, and its sequence revealed an open reading frame encoding a potential protein product of 51.5 kD. This protein displays amino acid sequence similarities to hamster vimentin and mouse epidermal keratin. Gene disruption demonstrated that MDM1 is essential for mitotic growth. Antibodies against the MDM1 protein recognized a 51-kD polypeptide that was localized by indirect immunofluorescence to a novel pattern of spots and punctate arrays distributed throughout the yeast cell cytoplasm. These structures disappeared after shifting mdm1 mutant cells to the nonpermissive temperature, although the cellular level of MDM1 protein was unchanged. Affinity-purified antibodies against MDM1 also specifically recognized intermediate filaments by indirect immunofluorescence of animal cells. These results suggest that novel cytoplasmic structures containing the MDM1 protein mediate organelle inheritance in yeast.

Contribution of aerobic step and Pilates exercises to life quality increase

2014 ◽  
Vol 7 (13) ◽  
pp. 99-104 ◽  
Author(s):  
Ancuța Lupău ◽  
Mihaela-Liana Faur ◽  
Corina Pantea
Keyword(s):  
Physical Exercise ◽  
Life Quality ◽  
Muscular Tissue ◽  
Everyday Activities ◽  
Different Types ◽  
Body Weight Index ◽  
Functional Deterioration ◽  
Structure And Functions ◽  
Life Work ◽  
Muscular Tissues

Abstract Physical activity practiced on a constant, regular basis contributes directly to the improvement of the structure and functions of different organs and body systems. It can also counteract the appearance of some anatomic and functional deterioration and contribute to the correction of certain deficiencies caused by improper conditions of life/work in people’s life. This study analyses two forms of physical exercise - Aerobic Step and Pilates. The goal of the study is to identify the effects of practicing Aerobic Step and Pilates exercises on the bodies of those who practice these forms of physical exercise. The hypothesis of the research is that practicing on constant/regular basis different types of aerobic exercises combined with efficient nutrition ensures optimum physical condition for everyday activities. The activity was carried out at the “Beauty Centre” aerobic hall from Timisoara, Romania. The study was carried out between February and May 2013 on a sample of 25 people subjected to anthropometric and functional measurements (size, weight, hip perimeter and body weight index, percentage of muscular tissue) both before (initial test - It) and after (final test - Ft) Aerobic Step and Pilates programmes. Results show the efficiency of these programmes as pointed out by the diminution of hip perimeter, by normal IMC, and by the increase of the active muscular tissues.

scholarly journals The p38 MAPK Components and Modulators as Biomarkers and Molecular Targets in Cancer

2021 ◽  
Vol 23 (1) ◽  
pp. 370
Author(s):  
Laura García-Hernández ◽  
María Belén García-Ortega ◽  
Gloria Ruiz-Alcalá ◽  
Esmeralda Carrillo ◽  
Juan Antonio Marchal ◽  
...  
Keyword(s):  
Molecular Targets ◽  
Mechanisms Of Action ◽  
Cellular Level ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Therapies ◽  
Intracellular Signals ◽  
Extracellular Signal ◽  
Different Types ◽  
Mitogen Activated Protein ◽  
Different Tissues

The mitogen-activated protein kinase (MAPK) family is an important bridge in the transduction of extracellular and intracellular signals in different responses at the cellular level. Within this MAPK family, the p38 kinases can be found altered in various diseases, including cancer, where these kinases play a fundamental role, sometimes with antagonistic mechanisms of action, depending on several factors. In fact, this family has an immense number of functionalities, many of them yet to be discovered in terms of regulation and action in different types of cancer, being directly involved in the response to cancer therapies. To date, three main groups of MAPKs have been identified in mammals: the extracellular signal-regulated kinases (ERK), Jun N-terminal kinase (JNK), and the different isoforms of p38 (α, β, γ, δ). In this review, we highlight the mechanism of action of these kinases, taking into account their extensive regulation at the cellular level through various modifications and modulations, including a wide variety of microRNAs. We also analyze the importance of the different isoforms expressed in the different tissues and their possible role as biomarkers and molecular targets. In addition, we include the latest preclinical and clinical trials with different p38-related drugs that are ongoing with hopeful expectations in the present/future of developing precision medicine in cancer.

scholarly journals THE PROVISION OF PASTURE LEGUMES FOR DIFFICULT ENVIRONMENTS

1987 ◽  
pp. 83-88
Author(s):  
R.L. Burt ◽  
M.B. Forde
Keyword(s):  
New Species ◽  
New Zealand ◽  
South America ◽  
First Generation ◽  
Plant Introduction ◽  
Simple Approach ◽  
European Species ◽  
Pasture Legumes ◽  
Different Types ◽  
A New Species

Early plant introduction in Australia and NZ involved familiar European species and simple general principles. 'First-generation' pasture cultivars in both countries were based on naturalized or cultivated material originally brought by colonists. Later, imported material was systematically used to improve these established varieties and produce 'second-generation' cultivars more closely adapted to local ecological conditions and agronomic systems. This simple approach proved inadequate for new and difficult environments which required different types of plant, and new species were sometimes tried and discarded prematurely because their potential was not fully displayed in the limited material initially available. Experience with Sfylosanthes in Australia shows that full suites of germplasm are necessary to evaluate a new species properly, and that such material should be deliberately and systematically collected from areas of similar or more extreme climate, particular attention being paid to edaphic characteristics. To obtain suitable legumes for the cold dry high country of the South Island collections from homologous regions in places such as Chile, Argentina, Kashmir, and the USSR may be useful. Keywords: plant introduction, Stylosanthes, Lotus, South America, Australia, New Zealand

scholarly journals Diamond-Blackfan anemia: heterogenous response of hematopoietic progenitor cells in vitro to the protein product of the steel locus

Blood ◽  
1991 ◽  
Vol 78 (9) ◽  
pp. 2211-2215
Author(s):  
NF Olivieri ◽  
T Grunberger ◽  
Y Ben-David ◽  
J Ng ◽  
DE Williams ◽  
...  
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Macrocytic Anemia ◽  
Protein Product ◽  
Cellular Level ◽  
Cellular Heterogeneity ◽  
Hematopoietic Growth Factors ◽  
Erythroid Progenitor ◽  
Diamond Blackfan Anemia

Diamond-Blackfan anemia is a congenital disorder of erythropoiesis in humans, characterized by a macrocytic anemia often associated with physical anomalies. Mutations at either the W or Steel loci in the mouse also leads to a severe macrocytic anemia, as well as other developmental abnormalities. The W locus encodes the proto-oncogene c- kit, a member of the receptor tyrosine kinase family, while the Steel locus encodes a potent hematopoietic growth factor that is the ligand for c-kit. Growth of clonogenic marrow erythroid progenitor cells in vitro in the presence of the recombinant hematopoietic growth factors interleukin-3 (IL-3) and Steel was used to characterize this disease at the cellular level. Three patterns of in vitro marrow response to both recombinant IL-3 or Steel were observed among 10 Diamond-Blackfan patients: those that responded quantitatively and qualitatively almost as well as cells from normal marrow, those that responded at an intermediate level, and those that did not respond at all. These results provide evidence for cellular heterogeneity underlying the pathogenesis of this disorder and therefore raise the possibility that there may be more than one underlying molecular basis for the disease. No gross abnormalities in the structure of either the c-kit or Steel loci were observed in these patients. The normal response in culture of the progenitor cells from at least some patients to Steel with or without IL-3 raises the possibility of using this novel growth factor as a therapeutic agent in Diamond-Blackfan anemia.

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