Abstract
Objective
To evaluate role of genetic factors (polymorphisms of ADRB1 gene (Arg389Gly, rs1801253) and ACE gene (I/D, rs4343) for effectiveness assessment of β-blocker (carvedilol) and ...angiotensin-converting enzyme inhibitor (enalapril) therapy in women with anthracycline- induced cardiotoxicity during 12-month follow-up period.
Methods
A total of 82 women, median age of 45.0 (42.0; 50.0) years with anthracycline-induced cardiotoxicity and without prior cardiovascular diseases were enrolled in the study. All patients received chemotherapy for the treatment of breast cancer included a combination of doxorubicin and cyclophosphamide, or combination of doxorubicin, cyclophosphamide and docetaxel. The cumulative dose of doxorubicin was 300–360 mg/m2. Criteria for the development of cardiotoxicity were a decrease in the left ventricle ejection fraction (LVEF) at the 12 months after chemotherapy completion by >10%, the development of heart failure (HF) with symptoms and clinical signs, and NT-proBNP levels ≥125 pg/mL. Echocardiography and serum levels of NT-proBNP were performed at baseline and at 12 months after enrollment. Average up-titrated dosage of carvedilol was 50 (25; 50) mg per day and enalapril was 10 (10; 20) mg per day. Evaluation of gene polymorphisms of ADRB1 gene and ACE gene were carried out by polymerase chain reaction at baseline before treatment initiation.
Results
The baseline LVEF, end-systolic and end-diastolic dimension indexes, NT-proBNP levels, 6-minute walk test distance did not differ among patients with different genotypes of ADRB1 and ACE genes. However, carriers of T/T genotype of ADRB1 gene had a significant increasing in LVEF (<0.001) by 11% from 50.0 (48.0; 51.0) to 56.0 (53.0; 57.0)% and decreasing in end-systolic dimension index (p<0.001) by 27.7% and end-systolic dimension index (p<0.001) by 6% within 12 months of follow-up period. The levels of NT-proBNP decreased (p=0.001) by 34.2% from 327.5 (260.1; 381.8) to 213.5 (195.3; 256.7) pg/mL and 6-minute walk test distance increased (0.008) by 10%. Carriers of G/G genotype of ACE gene had the same benefits from this therapy: LVEF (<0.001) increased by 6.5% from 50.5 (47.0; 51.0) to 54.0 (50.0; 57.0)%, end-systolic dimension index (p<0.001) decreased by 5.3% and end-systolic dimension index (p<0.001) by 3% within 12 months of follow-up period. The levels of NT-proBNP decreased (p=0.005) by 20.3 from 314.1 (279.6; 372.9) to 249.9 (197.3; 267.8) pg/mL and 6-minute walk test distance increased (0.008) by 5%. Carriers of other genotypes had decreasing in LVEF, increasing in LV dimensions and NT-proBNP, and further progression of HF.
Conclusion
Our data suggest that evaluation of gene polymorphisms of ADRB1 (Arg389Gly, rs1801253) and ACE gene (I/D, rs4343) can be recommended before treatment initiation of anthracycline- induced cardiotoxicity in women without prior cardiovascular diseases to determine who will benefit of carvedilol and enalapril therapy.
Funding Acknowledgement
Type of funding sources: None.
Context:
Current methods of preoperative diagnostics frequently fail to discriminate between benign and malignant thyroid neoplasms. In encapsulated follicular-patterned tumors (EnFPT), this ...discrimination is challenging even using histopathological analysis. Autoantibody response against tumor-associated antigens is a well-documented phenomenon with prominent diagnostic potential; however, autoantigenicity of thyroid tumors remains poorly explored.
Objectives:
Objectives were exploration of tumor-associated antigen repertoire of thyroid tumors and identification of candidate autoantibody biomarkers capable of discrimination between benign and malignant thyroid neoplasms.
Design, Setting, and Patients:
Proteins isolated from FTC-133 cells were subjected to two-dimensional Western blotting using pooled serum samples of patients originally diagnosed with either papillary thyroid carcinoma (PTC) or EnFPT represented by apparently benign follicular thyroid adenomas, as well as healthy individuals. Immunoreactive proteins were identified using liquid chromatography-tandem mass-spectrometry. Pathological reassessment of EnFPT was performed applying nonconservative criteria for capsular invasion and significance of focal PTC nuclear changes (PTC-NCs). Recombinant T-complex protein 1 subunitζ (TCP-1ζ) was used to examine an expanded serum sample set of patients with various thyroid neoplasms (n = 89) for TCP-1ζ autoantibodies. All patients were included in tertiary referral centers.
Results:
A protein demonstrating a distinct pattern of EnFPT-specific seroreactivity was identified as TCP-1ζ protein. A subsequent search for clinicopathological correlates of TCP-1ζ seroreactivity revealed nonclassical capsular invasion or focal PTC-NC in all TCP-1ζ antibody-positive cases. Further studies in an expanded sample set confirmed the specificity of TCP-1ζ autoantibodies to malignant EnFPT.
Conclusions:
We identified TCP-1ζ autoantibodies as a potential biomarker for presurgical discrimination between benign and malignant encapsulated follicular-patterned thyroid tumors. Our results suggest the use of nonconservative morphological criteria for diagnosis of malignant EnFPT in biomarker identification studies and provide a peculiar example of uncovering the diagnostic potential of a candidate biomarker using incorporation of pathological reassessment in the pipeline of immunoproteomic research.
Aim of investigation - to study effect of angiotensin-converting enzyme (ACE) gene polymorphism as a dominant risk factor of development of chronic heart failure (CHF) and target for effective ...therapy with ACE inhibitor enalapril in patients with ischemic heart disease. We followed 226 patients with CHF on stable permanent basic therapy comprising -adrenoblocker, diuretic, aldosterone antagonist, digoxin, and ACE inhibitor. Seventy eight patients received enalapril (starting dose 2.5 mg twice daily with subsequent titration up to 10-20 mg twice daily). Control group comprised 136 patients without cardiovascular abnormalities. Allele D of polymorphic locus I/D of ACE gene in homozygous state was associated with high risk of development and severity of clinical manifestations of CHF. In patients with D/D genotype of ACE gene at the background of therapy with enelapril we noted more pronounced lowering of CHF functional class and augmentation of left ventricular ejection fraction compared with patients having I/I and I/D genotypes. We revealed associative interrelationships of ACE gene polymorphism (polymorphic locus I/D) with development and severity of CHF as well as effectiveness of therapy with an ACE inhibitor enalapril.
Cytochrome
c
is an indispensable electron carrier in the mitochondrial respiratory chain and also an important mediator of the internal pathway triggering apoptosis. Mice with a complete deficiency ...of the
Cycs
gene encoding the somatic cytochrome
c
die during the embryogenesis. Using the technology of LoxP-cre-dependent tissue-specific recombination, we obtained some mouse strains with significantly reduced expression of cytochrome
c
in certain cell types (“conditional genetic knockdown”). This knockdown was achieved by abrogation of the normal splicing of the
Cycs
locus pre-mRNA due to an additional acceptor site inside the stop-cassette neor. Previously, we observed embryonic lethality in homozygous mice with the same knockdown of cytochrome
c
in all cells of the organism. In the present work we studied two novel mouse strains with conditional knockdown of the
Cycs
gene in T lymphocytes and macrophages. Somewhat surprisingly, the mice of these two strains under normal conditions were not phenotypically different from the wild-type mice, either on the whole organism level or on the level of activity of individual target cells. Thus, the amount of cytochrome
c
in lymphomyeloid cells does not affect their development and normal functioning.
Regional higher pedagogical educational institutions in Russia need to use new techniques in preparing students for new social and economic needs, including providing more opportunities for ...engagement in practical research experiences.
Performance of the ATLAS hadronic end-cap calorimeter in beam tests Dowler, B; Pinfold, J; Soukup, J ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
04/2002, Letnik:
482, Številka:
1-2
Journal Article
Recenzirano
Odprti dostop
Modules of the ATLAS liquid argon Hadronic End-cap Calorimeter (HEC) were exposed to beams of electrons, muons and pions in the energy range 6⩽E⩽200GeV at the CERN SPS. A description of the HEC and ...of the beam test setup are given. Results on the energy response and resolution are presented and compared with simulations. The ATLAS energy resolution for jets in the end-cap region is inferred and meets the ATLAS requirements.
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