Biomedical subjects

A G Michel

Publications and source records attributed to A G Michel.

15 recordsLinked to original sources

PubMed1996

Breast preservation in stage I and II carcinoma of the breast. The University of Chicago experience.

BACKGROUND: Although breast conservation has received increased acceptance, there are still unresolved issues regarding local treatment techniques, such as the extent of surgery, in relation to the final margins of excision and the use of tumor bed boost radiation. The goal of this study was to determine the local control and breast preservation with particular emphasis on the importance of the final microscopic margins in patients receiving tumor bed boost therapy. METHODS: The authors analyzed 869 cases of Stage I and II breast carcinoma in 852 women who were treated with breast-conserving surgery and radiation therapy between 1984 and 1994. The median follow-up was 43 months. Final microscopic margins were negative in 762 (88%), microscopically positive in 82 (9%), and unknown in 25 (3%) of the patients. Negative margins were defined as no tumor cells at the surgical margin. The patients were treated with external beam radiation therapy to the entire breast to a median dose of 46 Gray (Gy). A boost to the tumor bed was delivered to 863 (99%) of the patients. The median tumor bed dose was 60 Gy. A multivariate analysis of factors impacting on the local control and overall survival was performed. Variables introduced into the model included size, age, lymph node status, microscopic margins, nuclear grade, histologic grade, and estrogen and progesterone receptor status. RESULTS: The actuarial 5-year local control rate was 97%. The median time to local failure was 32 months (range, 14-69 months). In multivariate analysis, the only significant factor affecting local control was the status of margins. In patients receiving boost radiation to the excision site, the local control rate at 5 years was 98% and 89%, respectively, if the margins were negative or positive (P < 0.01). This resulted in 5-year actuarial breast preservation rates of 98% and 92% (P = 0.03). In the patients in whom the margins of excision were microscopically positive, the local control rate was 91% if the total dose to the tumor bed was > 60 Gy compared with 76% for a dose < or = 60 Gy (P = 0.05). The 5-year actuarial overall survival rate was 89%. Approximately 94% of the women considered their cosmetic outcome good to excellent. CONCLUSIONS: By obtaining microscopically negative margins and using tumor bed boost therapy, excellent local control, breast preservation, and cosmesis can be achieved. In patients with microscopically positive margins, an acceptable local control rate can be achieved if a tumor bed boost is given.

Adult↗

PubMed1992

Structural aspects of Ca2+ binding by acyclic peptides: low-energy conformational domains and molecular dynamics of N-acetyl-L-prolyl-D-alanyl-L-alanine-N'-methylamide.

We have applied random-search, energy minimization and molecular dynamics simulations to investigate the structural aspects of the interaction of N-acetyl-L-prolyl-D-alanyl-L-alanine-N'-methylamide with Ca2+. Spectral data on related peptides had suggested that the beta-turn conformation might be a prerequisite for the binding of cation ion by such short linear peptides. In order to relate the conformational characteristics with the Ca(2+)-binding affinities of these peptides, the molecular events involved in cation binding need to be understood. We have addressed this problem in this study by using a systematic approach that involved the following steps. First, a random search technique was used to generate a large population of conformers for the free peptide in the absence of Ca2+. Next, the energies of these conformers were computed. Conformations with energies within 4 kcal/mol of the global minimum were analysed and found to fall into four main groups characterized by the presence of different types of hydrogen-bonded structures including single and consecutive beta-turns. The energies for interconversion of conformers from one group to another were computed and found to be relatively small (< 10 kcal/mol). Finally, molecular dynamics of the peptide at 300K in the presence of Ca2+ were used to simulate the cation binding process. Starting points for these simulations were generated by placing the ion in the vicinity of two molecules of the peptide. The simulation results showed that the conformers with two consecutive beta-turns led to the formation of a stable 2:1 (peptide:Ca2+) sandwich complex in agreement with earlier experimental observations on similar linear peptides. While the starting conformation of the peptide in the consecutive beta-turn structure allowed for the proper orientation of three carbonyl oxygen atoms for chelation to the metal ion, the dynamics of complex formation rearranged the peptide structure substantially, leading to the formation of an 8-coordinated Ca2+ complex in a dodecahedral spatial arrangement. Thus, based on the energetics of the structures and processes involved, the present study demonstrates that: a) peptide-Ca2+ complex formation is initiated by conformers adopting consecutive beta-turn structures which subsequently go over to a significantly different conformation found in the complex; and, b) The facile interconversion between the low-energy conformers in the different groups would help shift the equilibrium population towards the consecutive beta-turn structure during the complex formation.

Amino Acid Sequence↗

PubMed1992

Crystal structure of tert.-butyloxycarbonyl-L-prolyl-D-alanyl-D-alanyl-N-methylamide. Dimeric beta-sheet formation.

The crystal structure of the tripeptide t-Boc-L-Pro-D-Ala-D-Ala-NHCH3, monohydrate, (C17H30N4O5.H2O, molecular weight = 404.44) has been determined by single crystal X-ray diffraction. The crystals are monoclinic, space group P2(1), a = 9.2585(4), b = 9.3541(5), c = 12.4529(4)A, beta = 96.449(3) degrees, Z = 2. The peptide units are in the trans and the tBoc-Pro bond in the cis orientation. The first and third peptide units show significant deviations from planarity (delta omega = 5.2 degrees and delta omega = 3.7 degrees, respectively). The backbone torsion angles are: phi 1 = -60 degrees, psi 1 = 143.3 degrees, omega 1 = -174.8 degrees, phi 2 = 148.4 degrees, psi 2 = -143.1 degrees, omega 2 = -179.7 degrees, phi 3 = 151.4 degrees, psi 3 = -151.9 degrees, omega 3 = -176.3 degrees. The pyrrolidine ring of the proline residue adopts the C2-C gamma conformation. The molecular packing gives rise to an antiparallel beta-sheet structure formed of dimeric repeating units of the peptide. The surface of the dimeric beta-sheet is hydrophobic. Water molecules are found systematically at the edges of the sheets interacting with the urethane oxygen and terminal amino groups. Surface catalysis of an L-Ala to D-Ala epimerization process by water molecules adsorbed on to an incipient beta-sheet is suggested as a mechanism whereby crystals of the title peptide were obtained from a solution of tBoc-Pro-D-Ala-Ala-NHCH3.

Amino Acid Sequence↗

PubMed1991

Non-natural 14-hydroxy steroids. II. 13 alpha,14 alpha and 13 beta,14 beta isomers of methyl 14-hydroxy-1,7,17-trioxo-5 beta-androst-8-ene-19-oate.

C20H24O6, Mr = 360.41 lambda (Cu K alpha) = 1.54056 A, room temperature. (I) (5 beta,10 beta,13 alpha,14 alpha)-Methyl 14-hydroxy-1,7,17-trioxoandrost-8-ene-19-oate, triclinic, P1, a = 7.9514 (5), b = 9.2892 (5), c = 12.8534 (12) A, alpha = 81.256 (6), beta = 75.796 (6), gamma = 77.908 (5) degrees, V = 894.85 (11) A3, Z = 2, Dx = 1.338 Mg m-3, mu = 0.77 mm-1, F(000) = 383.96, final R = 0.043 for 2912 observed reflections. (II) (5 beta, 10 beta, 13 beta,14 beta)-Methyl 14-hydroxy-1,7,17-trioxoandrost-8-ene-19-oate, monoclinic, P21/n, a = 12.8704 (9), b = 10.4481 (9), c = 13.1482 (5) A, beta = 104.103 (5) degrees, V = 1714.77 (20) A3, Z = 4, Dx = 1.396 Mg m-3, mu = 0.81 mm-1, F(000) = 767.92, final R = 0.055 for 2516 observed reflections. These two non-natural steroids bear a methoxycarbonyl group at C(10). In both molecules the relative stereo-chemistry is cis for the A/B ring junction and cis for the C/D ring junction. The relative orientations of MeO2C--C(10) and HO--C(14) are anti for (I) and syn for (II). The methoxycarbonyl group lies at the axial position for (I) and equatorial for (II), relative to ring A. The energies of possible conformations for (I) and (II) are evaluated, wherein the A rings adopt a chair conformation.

Androstenols↗

PubMed1990

Functionalized hydrocarbons with condensed ring skeletons. X. A methyltricyclo[7.4.0.0(2,6)]tetradec-7-ene.

(1) 1,9-trans-1,2-cisoid-2,6-cis-4,11,11-Tris(methoxycarbonyl)-6- methyltricyclo[7.4.0.0(2,6)]-tridec-7-ene-4,2-carbolacton e+ ++, C21H26O8, Mr = 406.43, monoclinic, P1, a = 6.0774 (2), b = 12.3784 (5), c = 14.2565 (4) A, alpha = 72.906 (3), beta = 86.361 (3), gamma = 78.181 (3) degrees, V = 1003.38 (6) A3, Dx = 1.345 Mg m-3, Z = 2, lambda (Cu K alpha) = 1.54056 A, mu = 0.82 mm-1, F(000) = 432, room temperature, final R = 0.043 for 2841 observed reflections. The tricyclic compound (1) has the same carbon framework as in the BCD rings in a steroid nucleus. Ring B adopts a chair while ring C has a half-chair conformation. A trans relative stereochemistry is observed at the BC ring junction while a cis hydrinclane is observed for the CD junction, the lactone bridge being cis to the angular methyl group at C(6) and to the hydrogen at C(1).

Bridged-Ring Compounds↗

PubMed1990

Molecular structure of opiate alkaloids. IV. Structure of two thioniamorphinans.

(I) S(equatorial)-Allyl-3-hydroxy-17-thioniamorphinan perchlorate, C19H25OS+.C1O4-, Mr = 400.91, monoclinic, P2(1)/n, a = 9.4171 (8), b = 10.7425 (10), c = 19.096 (2) A, beta = 95.666 (7) degrees, V = 1922.4 (3) A3, Z = 4, Dx = 1.385 Mg m-3, lambda (Mo K alpha) = 0.70930 A, mu = 0.33 mm-1, F(000) = 847.92, room temperature, final R = 0.052 for 1742 observed reflections. (II) S(axial)-Allyl-3-hydroxy-17-thioniamorphinan perchlorate, C19H25OS+.C1O4-, Mr = 400.91, monoclinic, P2(1), a = 8.4554 (10), b = 11.658 (3), c = 9.5831 (21) A, beta = 95.620 (10) degrees, V = 940.1 (3) A 3, Z = 2, Dx = 1.416 Mg m-3, lambda (Mo K alpha) = 0.70930 A, mu = 0.33 mm-1, F(000) = 423.96, room temperature, final R = 0.054 for 1015 observed reflections. The molecular structures of (I) and (II) are differentiated only by the orientation of the S-allyl substituent: the S-allyl group is equatorial in (I) and axial in (II). It has been shown that the activities as potent and selective blockers of kappa opioid receptors (kappa 2 subtype) are to be attributed to the alpha-thiamorphinan isomer (I). The inactive compound (II) is the beta-isomer. The fused ring systems are almost identical in the two molecules.

Alkaloids↗

PubMed1990

Crystal and molecular structure of two geometrically restricted chemotactic tripeptides, analogues of formyl-methionine-leucine-phenylalanine.

The crystal structures of HCO-Met-Leu-Phe-OC(CH3)3, (CH25H39N3O5S), fMLP-OtBu, and HCO-Met psi [CSNH]-Leu-Phe-OCH3, (C22H33N3O4S2), fMS LP-OMe, have been determined by single crystal X-ray diffraction, and their conformational properties investigated by molecular mechanics energy calculations. Crystals of fMLP-OtBu are monoclinic, space group P2(1), a = 12.027(4), b = 9.492(3), c = 12.660(4) A, beta = 101.99(3) degrees, Z = 2; those of fMS LP-OMe are orthorhombic, space group P2(1)2(1)2(1), a = 7.130(1), b = 12.097(2), c = 31.060(5) A, Z = 4. The first compounds fMLP-OtBu is the t-butyl ester of the tripeptide fMLP that represents one of the most potent compounds in inducing the lysozyme release from human neutrophils that reflects the chemotactic activity. From the crystal structure, it is shown that the orientation of the phenylalanine side chain is largely affected by the presence of the bulky group. fMSLP-OMe was shown to be inactive after thionation of the methionine residue in the original tripeptide. Nevertheless, the crystal structure does not reveal any influence of the presence of the thionated peptidic bond on the backbone conformation. The X-ray results have been used to generate parameters for empirical energy calculations. Subsequently, a strategy based on random generation of conformations followed by energy-minimization was applied to investigate the conformational space of thiopeptides, in comparison with normal peptides. From molecular free energy calculations, it is shown that the main influence of the introduction of a thioamide bond on the molecular structure is to prevent the existence of C7(eq) conformations involving the thiomethionine residue. Consequently, a larger number of conformers are found to form intramolecular hydrogen bonds involving the formyl group, reducing its availability to interact with the receptor. For the first time, the theoretical prediction of the existence of C7eq conformations for fMLP is made. The resulting conformers are compared to previously active structures of these chemotactic agents.

Amino Acid Sequence↗

PubMed1989

Breast conserving surgery and definitive irradiation for early stage breast cancer.

Breast conserving surgery and postoperative breast radiotherapy were used to treat 219 cases of AJCC Stage I and II breast carcinoma at the Michael Reese and University of Chicago Hospitals. Most patients were treated with lumpectomy and axillary sampling followed by breast irradiation to a dose of 46 Gy followed by a boost dose of 14-16 Gy to the surgical bed. The 5-year actuarial local control is 92%. Follow-up is 1 to 10 years and the median follow-up is 36 months. Of the seven patients who recurred in the breast, three failed in the boost site and three failed adjacent to the boost site. The seventh patient recurred diffusely in the breast and skin. Four of the seven recurrences were in patients with positive surgical margins. The 5-year actuarial relapse-free survival is 80%. Factors which had an adverse affect on the cosmetic results were a scar length greater than 8 cm and a volume of resected breast tissue greater than 100 cm3. Treatment related complications were minor and infrequent. Breast conserving surgery followed by radiation therapy is effective in achieving local control with good to excellent cosmetic results.

Adult↗

PubMed1978