BACKGROUND: The ventricular trabeculae play a role, among others, in the impulse spreading in ectothermic hearts. Despite the morphological similarity with the early developing hearts of endotherms, this trabecular function in mammalian and avian embryos was poorly addressed. RESULTS: We simulated impulse propagation inside the looping ventricle and revealed delayed apical activation in the heart with inhibited trabecular growth. This finding was corroborated by direct imaging of the endocardial surface showing early activation within the trabeculae implying preferential spreading of depolarization along with them. Targeting two crucial pathways of trabecular formation (Neuregulin/ErbB and Nkx2.5), we showed that trabecular development is also essential for proper conduction patterning. Persistence of the slow isotropic conduction likely contributed to the pumping failure in the trabeculae-deficient hearts. CONCLUSIONS: Our results showed the essential role of trabeculae in intraventricular impulse spreading and conduction patterning in the early endothermic heart. Lack of trabeculae leads to the failure of conduction parameters differentiation resulting in primitive ventricular activation with consequent impact on the cardiac pumping function.
- Klíčová slova
- Nkx2.5, embryonic chick heart, neuregulin/ErbB, ventricular trabeculae,
- MeSH
- neureguliny MeSH
- savci MeSH
- srdce * MeSH
- srdeční komory * MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- neureguliny MeSH
INTRODUCTION: Neuregulin 1 (NRG1) gene fusion was detected in a wide range of carcinomas. It is most frequently present in lung adenocarcinomas, especially in KRAS and BRAF wild-type cases. PURPOSE: We present a newly described diverse group of NRG1 rearranged carcinomas. The paper explains basic molecular principles associated with this oncogenic driver. It consists of ERBB3 (HER3) and ERBB2 (HER2) receptor activation with downstream activation of PIK and MAPK canonical pathways. The experience with new therapeutic modalities is summarized. CONCLUSIONS: So far, the global results of cytotoxic, immune and targeted therapies were dis-appointing. Further research (including two studies in Europe) is underway, developing new therapeutic strategies and examining this cancer bio-logy. In the meantime, it is possible to dia-gnose NRG1 rearranged carcinomas in the Czech Republic since mRNA next generation sequencing (NGS) analysis is readily available.
- Klíčová slova
- ERBB 2 protein, ERBB 3 protein, NRG 1 protein, molecular targeted therapies, molecular targeted therapy, neuregulin 1, solid tumors,
- MeSH
- adenokarcinom plic farmakoterapie genetika metabolismus MeSH
- individualizovaná medicína MeSH
- lidé MeSH
- nádory plic farmakoterapie genetika metabolismus MeSH
- nádory * genetika metabolismus MeSH
- neuregulin-1 * genetika metabolismus MeSH
- protinádorové látky terapeutické užití MeSH
- receptor erbB-2 genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- neuregulin-1 * MeSH
- NRG1 protein, human MeSH Prohlížeč
- protinádorové látky MeSH
- receptor erbB-2 MeSH
The fusion genes containing neuregulin-1 (NRG1) are newly described potentially actionable oncogenic drivers. Initial clinical trials have shown a positive response to targeted treatment in some cases of NRG1 rearranged lung adenocarcinoma, cholangiocarcinoma, and pancreatic carcinoma. The cost-effective large scale identification of NRG1 rearranged tumors is an open question. We have tested a data-drilling approach by performing a retrospective assessment of a de-identified molecular profiling database of 3263 tumors submitted for fusion testing. Gene fusion detection was performed by RNA-based targeted next-generation sequencing using the Archer Fusion Plex kits for Illumina (ArcherDX Inc., Boulder, CO). Novel fusion transcripts were confirmed by a custom-designed RT-PCR. Also, the aberrant expression of CK20 was studied immunohistochemically. The frequency of NRG1 rearranged tumors was 0.2% (7/3263). The most common histologic type was lung adenocarcinoma (n = 5). Also, renal carcinoma (n = 1) and prostatic adenocarcinoma (n = 1) were found. Identified fusion partners were of a wide range (CD74, SDC4, TNC, VAMP2, UNC5D), with CD74, SDC4 being found twice. The UNC5D is a novel fusion partner identified in prostate adenocarcinoma. There was no co-occurrence with the other tested fusions nor KRAS, BRAF, and the other gene mutations specified in the applied gene panels. Immunohistochemically, the focal expression of CK20 was present in 2 lung adenocarcinomas. We believe it should be considered as an incidental finding. In conclusion, the overall frequency of tumors with NRG1 fusion was 0.2%. All tumors were carcinomas. We confirm (invasive mucinous) lung adenocarcinoma as being the most frequent tumor presenting NRG1 fusion. Herein novel putative pathogenic gene fusion UNC5D-NRG1 is described. The potential role of immunohistochemistry in tumor identification should be further addressed.
- Klíčová slova
- EGF-like domain, ERBB, ERBB3, HER, HER 3, MAPK, NRG1, PIK, carcinoma, data drilling, gene fusion, gene rearrangement, genetics, lung, mRNA sequencing, molecular, neuregulin, next-generation sequencing, receptor heterodimerization, receptor tyrosine kinase,
- MeSH
- adenokarcinom genetika patologie MeSH
- antigeny diferenciační B-lymfocytární genetika MeSH
- dospělí MeSH
- fúzní onkogenní proteiny genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránový protein 2 asociovaný s vezikuly genetika MeSH
- MHC antigeny II. třídy genetika MeSH
- nádory plic genetika patologie MeSH
- nádory prostaty genetika patologie MeSH
- neuregulin-1 genetika MeSH
- receptory buněčného povrchu genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- syndekan-4 genetika MeSH
- tenascin genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antigeny diferenciační B-lymfocytární MeSH
- fúzní onkogenní proteiny MeSH
- invariant chain MeSH Prohlížeč
- membránový protein 2 asociovaný s vezikuly MeSH
- MHC antigeny II. třídy MeSH
- neuregulin-1 MeSH
- NRG1 protein, human MeSH Prohlížeč
- receptory buněčného povrchu MeSH
- SDC4 protein, human MeSH Prohlížeč
- syndekan-4 MeSH
- tenascin MeSH
- TNC protein, human MeSH Prohlížeč
- UNC5D protein, human MeSH Prohlížeč
- VAMP2 protein, human MeSH Prohlížeč
BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited neuropathy, a debilitating disease without known cure. Among patients with CMT1A, disease manifestation, progression and severity are strikingly variable, which poses major challenges for the development of new therapies. Hence, there is a strong need for sensitive outcome measures such as disease and progression biomarkers, which would add powerful tools to monitor therapeutic effects in CMT1A. METHODS: We established a pan-European and American consortium comprising nine clinical centres including 311 patients with CMT1A in total. From all patients, the CMT neuropathy score and secondary outcome measures were obtained and a skin biopsy collected. In order to assess and validate disease severity and progression biomarkers, we performed qPCR on a set of 16 animal model-derived potential biomarkers in skin biopsy mRNA extracts. RESULTS: In 266 patients with CMT1A, a cluster of eight cutaneous transcripts differentiates disease severity with a sensitivity and specificity of 90% and 76.1%, respectively. In an additional cohort of 45 patients with CMT1A, from whom a second skin biopsy was taken after 2-3 years, the cutaneous mRNA expression of GSTT2, CTSA, PPARG, CDA, ENPP1 and NRG1-Iis changing over time and correlates with disease progression. CONCLUSIONS: In summary, we provide evidence that cutaneous transcripts in patients with CMT1A serve as disease severity and progression biomarkers and, if implemented into clinical trials, they could markedly accelerate the development of a therapy for CMT1A.
- Klíčová slova
- Charcot Marie Tooth disease 1A, biomarker, disease progression, disease severity, skin biopsy,
- MeSH
- biopsie MeSH
- Charcotova-Marieova-Toothova nemoc krev genetika terapie MeSH
- dospělí MeSH
- fosfodiesterasy genetika MeSH
- genetická transkripce genetika MeSH
- genetické markery genetika MeSH
- glutathiontransferasa genetika MeSH
- glykoproteiny genetika MeSH
- jaderné proteiny MeSH
- kathepsin A genetika MeSH
- kůže patologie MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- lidé středního věku MeSH
- lidé MeSH
- messenger RNA genetika MeSH
- neuregulin-1 genetika MeSH
- PPAR gama genetika MeSH
- prognóza MeSH
- progrese nemoci * MeSH
- pyrofosfatasy genetika MeSH
- senioři MeSH
- výsledek terapie * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- CDAN1 protein, human MeSH Prohlížeč
- CTSA protein, human MeSH Prohlížeč
- ectonucleotide pyrophosphatase phosphodiesterase 1 MeSH Prohlížeč
- fosfodiesterasy MeSH
- genetické markery MeSH
- glutathiontransferasa MeSH
- glykoproteiny MeSH
- GSTT2 protein, human MeSH Prohlížeč
- jaderné proteiny MeSH
- kathepsin A MeSH
- messenger RNA MeSH
- neuregulin-1 MeSH
- NRG1 protein, human MeSH Prohlížeč
- PPAR gama MeSH
- pyrofosfatasy MeSH
In previous studies, it has been shown that recombinant human neuregulin-1(rhNRG-1) is capable of improving the survival rate in animal models of doxorubicin (DOX)-induced cardiomyopathy; however, the underlying mechanism of this phenomenon remains unknown. In this study, the role of rhNRG-1 in attenuating doxorubicin-induce apoptosis is confirmed. Neonatal rat ventricular myocytes (NRVMs) were subjected to various treatments, in order to both induce apoptosis and determine the effects of rhNRG-1 on the process. Activation of apoptosis was determined by observing increases in the protein levels of classic apoptosis markers (including cleaved caspase-3, cytochrome c, Bcl-2, BAX and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining). The activation of Akt was detected by means of western blot analysis. The study results showed that doxorubicin increased the number of TUNEL positive cells, as well as the protein levels of cleaved caspase-3 and cytochrome c, and reduced the ratio of Bcl-2/Bax. However, all of these effects were markedly antagonized by pretreament with rhNRG-1. It was then further demonstrated that the effects of rhNRG-1 could be blocked by the phosphoinositole-3-kinase inhibitor LY294002, indicating the involvement of the Akt process in mediating the process. RhNRG-1 is a potent inhibitor of doxorubicin-induced apoptosis, which acts through the PI3K-Akt pathway. RhNRG-1 is a novel therapeutic drug which may be effective in preventing further damage from occurring in DOX-induced damaged myocardium.
- MeSH
- aktivace enzymů MeSH
- apoptóza účinky léků MeSH
- cytoprotekce MeSH
- doxorubicin toxicita MeSH
- fosforylace MeSH
- inhibitory proteinkinas farmakologie MeSH
- kardiomyocyty účinky léků enzymologie patologie MeSH
- krysa rodu Rattus MeSH
- kultivované buňky MeSH
- lidé MeSH
- neuregulin-1 farmakologie MeSH
- novorozená zvířata MeSH
- ochranné látky farmakologie MeSH
- potkani Sprague-Dawley MeSH
- proteiny regulující apoptózu metabolismus MeSH
- protinádorová antibiotika toxicita MeSH
- protoonkogenní proteiny c-akt antagonisté a inhibitory metabolismus MeSH
- rekombinantní proteiny farmakologie MeSH
- signální transdukce účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- doxorubicin MeSH
- inhibitory proteinkinas MeSH
- neuregulin-1 MeSH
- NRG1 protein, human MeSH Prohlížeč
- ochranné látky MeSH
- proteiny regulující apoptózu MeSH
- protinádorová antibiotika MeSH
- protoonkogenní proteiny c-akt MeSH
- rekombinantní proteiny MeSH
