Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
1.
Ann Thorac Surg ; 114(4): 1367-1375, 2022 10.
Article in English | MEDLINE | ID: mdl-34416226

ABSTRACT

BACKGROUND: Guidelines for sinus of Valsalva (SOV)-thoracic aortic aneurysms in Marfan syndrome recommend size-based criteria for elective surgical repair. Biomechanics may provide a better prediction of dissection risk than diameter. Our aim was to determine magnitudes of wall stress in the aortic root of Marfan patients using finite element analyses. METHODS: Forty-six Marfan patients underwent patient-specific 3-dimensional SOV-thoracic aortic aneurysm geometry reconstruction using imaging data. Finite element analyses were performed to determine wall stress distributions at SOV, sinotubular junction (STJ), and ascending aorta (AscAo) at systole. RESULTS: Peak circumferential stresses were 432.8 ± 111 kPa, 408.1 ± 88.3 kPa, and 321.9 ± 83.8 kPa at the SOV, STJ, and AscAo, respectively, with significant differences between SOV and AscAo (P < 3.08E-07), and STJ and AscAo (P < 2.26E-06). Peak longitudinal wall stresses were 352 ± 73.9 kPa, 277.5 ± 89.5 kPa, and 200.6 ± 81 kPa at SOV, STJ, and AscAo, respectively, with significant differences between SOV and STJ (P < 6.01E-06), SOV and AscAo (P < 9.79E-13), and STJ and AscAo (P < 3.34E-07). Diameter was not correlated to wall stresses. Comparison of wall stresses in aneurysm <5 cm vs ≥5 cm and <4.5 cm vs ≥4.5 cm showed no significant differences in wall stresses in the circumferential or longitudinal direction. CONCLUSIONS: Peak wall stresses in Marfan SOV- thoracic aortic aneurysm were greatest in SOV than STJ than AscAo. Diameter was poorly correlated to peak stresses such that current guidelines with 5 cm cutoff had significant overlap in peak stresses in patients with <5 cm vs ≥5 cm. Use of patient-specific Marfan aneurysm models may identify patients with high wall stresses and small aneurysms who could benefit from earlier surgical repair to prevent aortic dissection.


Subject(s)
Aortic Aneurysm, Thoracic , Marfan Syndrome , Aorta/surgery , Aortic Aneurysm, Thoracic/etiology , Biomechanical Phenomena , Finite Element Analysis , Humans , Marfan Syndrome/complications
2.
Mutat Res ; 821: 111702, 2020.
Article in English | MEDLINE | ID: mdl-32422468

ABSTRACT

We report the mutational spectra in a segment of the E. coli rpoB gene of bleomycin (BLEO), 4-nitroquinoline-1-oxide (NQO), and hydrogen peroxide (H2O2). We compare these spectra with those of other mutagens and repair deficient strains in the same rpoB system, and review the key elements determining mutational hotspots and outline the questions that remain unanswered. We consider three tiers of hotspots that derive from 1) the nature of the sequence change at a specific base, 2) the direct nearest neighbors and 3) some aspect of the larger sequence context or the local 3D-structure of segments of DNA. This latter tier can have a profound effect on mutation frequencies, even among sites with identical nearest neighbor sequences. BLEO is dependent on the SOS-induced translesion Pol V for mutagenesis, and has a dramatic hotspot at a single mutational site in rpoB. NQO is not dependent on any of the translesion polymerases, in contrast to findings with plasmids treated in vitro and transformed into E. coli. The rpoB system allows one to monitor both G:C -> A:T transitions and G:C -> T:A transversions at the same site in 11 cases, each site having the identical sequence context for each of the two mutations. The combined preference for G:C -> A:T transitions at these sites is 20-fold. Several of the favored sites for hydrogen peroxide mutagenesis are not seen in the spectra of BLEO and NQO mutations, indicating that mutagenesis from reactive oxygen species is not a major cause of BLEO or NQO mutagenesis, but rather specific adducts. The variance in mutation rates at sites with identical nearest neighbors suggests that the local structure of different DNA segments is an important factor in mutational hotspots.


Subject(s)
4-Nitroquinoline-1-oxide/toxicity , Bleomycin/toxicity , DNA-Directed RNA Polymerases/genetics , Escherichia coli Proteins/genetics , Escherichia coli/genetics , Gene Expression Regulation, Bacterial/radiation effects , Hydrogen Peroxide/toxicity , Mutation , Antibiotics, Antineoplastic/toxicity , DNA-Directed RNA Polymerases/radiation effects , Escherichia coli/radiation effects , Escherichia coli Proteins/radiation effects , Mutagens/toxicity , Oxidants/toxicity
3.
Article in English | MEDLINE | ID: mdl-30509944

ABSTRACT

We show that trimethoprim (TMP), an antibiotic in current use, displays a strong synergistic effect on mutagenesis in Escherichia coli when paired with the base analog 2-aminopurine (2AP), resulting in a 35-fold increase in mutation frequencies in the rpoB-Rifr system. Combination therapies are often employed both as antibiotic treatments and in cancer chemotherapy. However, mutagenic effects of these combinations are rarely examined. An analysis of the mutational spectra of TMP, 2AP, and their combination indicates that together they trigger a response via an alteration in deoxynucleoside triphosphate (dNTP) ratios that neither compound alone can trigger. A similar, although less strong, response is seen with the frameshift mutagen ICR191 and 2AP. These results underscore the need for testing the effects on mutagenesis of combinations of antibiotics and chemotherapeutics.


Subject(s)
2-Aminopurine/pharmacology , Anti-Bacterial Agents/pharmacology , Escherichia coli/genetics , Mutagenesis/drug effects , Mutagens/pharmacology , Trimethoprim/pharmacology , DNA-Directed RNA Polymerases/drug effects , Drug Synergism , Escherichia coli/drug effects , Escherichia coli Proteins/drug effects
4.
J Bacteriol ; 198(20): 2776-83, 2016 10 15.
Article in English | MEDLINE | ID: mdl-27457718

ABSTRACT

UNLABELLED: We tested pairwise combinations of classical base analog mutagens in Escherichia coli to study possible mutagen synergies. We examined the cytidine analogs zebularine (ZEB) and 5-azacytidine (5AZ), the adenine analog 2-aminopurine (2AP), and the uridine/thymidine analog 5-bromodeoxyuridine (5BrdU). We detected a striking synergy with the 2AP plus ZEB combination, resulting in hypermutability, a 35-fold increase in mutation frequency (to 53,000 × 10(-8)) in the rpoB gene over that with either mutagen alone. A weak synergy was also detected with 2AP plus 5AZ and with 5BrdU plus ZEB. The pairing of 2AP and 5BrdU resulted in suppression, lowering the mutation frequency of 5BrdU alone by 6.5-fold. Sequencing the mutations from the 2AP plus ZEB combination showed the predominance of two new hot spots for A·T→G·C transitions that are not well represented in either single mutagen spectrum, and one of which is not found even in the spectrum of a mismatch repair-deficient strain. The strong synergy between 2AP and ZEB could be explained by changes in the dinucleoside triphosphate (dNTP) pools. IMPORTANCE: Although mutagens have been widely studied, the mutagenic effects of combinations of mutagens have not been fully researched. Here, we show that certain pairwise combinations of base analog mutagens display synergy or suppression. In particular, the combination of 2-aminopurine and zebularine, analogs of adenine and cytidine, respectively, shows a 35-fold increased mutation frequency compared with that of either mutagen alone. Understanding the mechanism of synergy can lead to increased understanding of mutagenic processes. As combinations of base analogs are used in certain chemotherapy regimens, including those involving ZEB and 5AZ, these results indicate that testing the mutagenicity of all drug combinations is prudent.


Subject(s)
Azacitidine/toxicity , Base Pairing/drug effects , Bromodeoxyuridine/toxicity , Cytidine/analogs & derivatives , Escherichia coli/drug effects , Mutagens/toxicity , Mutation/drug effects , Azacitidine/chemistry , Bromodeoxyuridine/chemistry , Cytidine/chemistry , Cytidine/toxicity , Drug Synergism , Escherichia coli/genetics , Escherichia coli/metabolism , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Mutagens/chemistry
6.
Antimicrob Agents Chemother ; 60(3): 1515-20, 2015 Dec 28.
Article in English | MEDLINE | ID: mdl-26711761

ABSTRACT

We used classical mutagens in Gram-negative Escherichia coli to study synergies with different classes of antibiotics, test models of antibiotic mechanisms of action, and examine the basis of synergy. We used 4-nitroquinoline 1-oxide (4NQO), zebularine (ZEB), 5-azacytidine (5AZ), 2-aminopurine (2AP), and 5-bromodeoxyuridine (5BrdU) as mutagens (with bactericidal potency of 4NQO > ZEB > 5AZ > 2AP > 5BrdU) and vancomycin (VAN), ciprofloxacin (CPR), trimethoprim (TMP), gentamicin (GEN), tetracycline (TET), erythromycin (ERY), and chloramphenicol (CHL) as antibiotics. We detected the strongest synergies with 4NQO, an agent that oxidizes guanines and ultimately results in double-strand breaks when paired with the bactericidal antibiotics VAN, TMP, CPR, and GEN, but no synergies with the bacteriostatic antibiotics TET, ERY, and CHL. Each of the other mutagens displays synergies with the bactericidal antibiotics to various degrees that reflect their potencies, as well as with some of the other mutagens. The results support recent models showing that bactericidal antibiotics kill bacteria principally by ultimately generating more double-strand breaks than can be repaired. We discuss the synergies seen here and elsewhere as representing dose effects of not the proximal target damage but rather the ultimate resulting double-strand breaks. We also used the results of pairwise tests to place the classic mutagens into functional antibacterial categories within a previously defined drug interaction network.


Subject(s)
Anti-Bacterial Agents/pharmacology , DNA Breaks, Double-Stranded/drug effects , Drug Synergism , Escherichia coli/drug effects , Mutagens/pharmacology , 2-Aminopurine/pharmacology , 4-Nitroquinoline-1-oxide/pharmacology , Azacitidine/pharmacology , Bromodeoxyuridine/pharmacology , Chloramphenicol/pharmacology , Ciprofloxacin/pharmacology , Cytidine/analogs & derivatives , Cytidine/pharmacology , Erythromycin/pharmacology , Gentamicins/pharmacology , Microbial Sensitivity Tests , Tetracycline/pharmacology , Trimethoprim/pharmacology , Vancomycin/pharmacology
SELECTION OF CITATIONS
SEARCH DETAIL
...