Gareth Forde

Theoretical ab Initio study of the effects of methylation on structure and stability of G:C watson-crick base pair

Abstract Methylation of DNA occurs most readily at N(3), N(7), and O(6) of purine bases and N(3) and O(2) of pyrimidines. Methylated bases are continuously formed through endogenous and exogenous mechanisms. The results of a theoretical ab initio study on the methylation of G:C base pair components are reported. The geometries of the local minima were optimized without symmetry restrictions by the gradient procedure at DFT level of theory and were verified by energy second derivative calculations. The standard 6–31G(d) basis set was used. The single-point calculations have been performed at the MP2/6–31G(d,p), MP2/6–31++G(d,p), and MP2/6–311++G(2d,2p) levels of theory. The geometrical parameters, relative stability and counterpoise corrected interaction energies are reported. Also, using a variation-perturbation energy decomposition scheme we have found the vital contributions to the total interaction energy.

A quality process study of lymph node evaluation in endometrial cancer.

Our objective was to analyze the reported lymph node counts between surgeons, histology prosectors, and pathologists using a cohort of patients enrolled on a national protocol that standardized surgical intent.This is a retrospective review of patients with uterine cancer who underwent a standardized formal staging procedure as dictated by a National Cancer Institute sponsored protocol. Patients were staged using the International Federation of Gynecology and Obstetrics 1988 guidelines. All patients required a hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymphadenectomy. Lymphadenectomy specimens were separated by the following regions: external iliac, obturator, common iliac, and periaortic. Lymph node counts were analyzed by region, surgeon, histology prosector, and pathologist.There were 78 patients enrolled in the protocol during the study period. Of them, 72 (92%) patients met the inclusion criteria. A total of 2397 lymph nodes were counted, with an average total number of 33 (SD=9) lymph nodes dissected per patient. Surgeons A, B, and C had an average lymph node count of 32, 33, and 35, respectively, with no significant difference in mean node count (P=0.66). Prosectors 1 to 4 dissected an average of 34, 33, 28, and 35 lymph nodes, respectively (P=0.091). There were 2 pathologists with ≥ 10 cases. Their mean lymph node counts were 35 and 30, respectively, with no significant difference in mean node count (P=0.079).This systematic review did not identify a discrepancy in nodal count among surgeons, prosectors, or pathologists at our institution. The methods used may be helpful in structuring interdepartmental reviews for completeness of nodal dissections in cases where surgical intent has been standardized.

Molecular Structure and Properties of Protonated and Methylated Derivatives of Cytosine

Abstract Ab initio techniques were used to determine the effects of protonation and methylation on cytosines molecular geometry, molecular affinities, relative stability, and structural rigidity. The geometries of local minima were fully optimized by the gradient procedure at DFT and MP2 levels of theory with the medium size 6–31G(d,p) basis set. The results of energetic analysis indicate that N(3)-methyl-cytosine and C(5)-methyl-cytosine are the most stable derivatives for monocationic and neutral species, respectively. The structural rigidity of each species was assessed by an analysis of normal out-of-plane frequencies, the amplitudes, and by the contribution of internal coordinates to the potential energy distributions. The obtained evidence suggests that methylation increases the overall structural flexibility of cytosine and that all molecules in this study populate a non-planar conformation 50% of the time.

cis-Diamminodichloronickel and Its Interaction with Guanine and Guanine–Cytosine Base Pair

Comprehensive ab initio calculations are performed on cis-diamminodichloronickel (cisni) at the HF, DFT, and MP2 levels of theory. The results are compared to those obtained for cisplatin. The characteristics of the interactions of cisni with guanine (G) and guanine–cytosine (GC) base pair are also evaluated and compared to the interactions of cisplatin. Cisni causes similar geometric changes of the base as cis-platinum when complexed to guanine. The nickel, palladium and platinum complexes also show similar characteristics when complexed to GC base pair. However, this study predicts higher dissociation energy of the cisni chlorine ligands that indicate areas of differences between the title Ni and Pt and Pd complexes. Comparison of the G-cisni interaction energy to that of cisplatin and cispd indicate differences between the Ni and Pd complexes, but also reveals its closer similarities to cisplatin.

Theoretical Ab Initio Study of the Effects of Methylation on the Nature of Hydrogen Bonding in A:T Base Pair

Abstract We report the results of a theoretical ab initio study of methylation in Watson-Crick A:T base pairs. Equilibrium geometries were obtained without symmetry restrictions by the gradient procedure at DFT level of theory with the standard 6–31G(d) basis set. Each local minima was verified by energy second derivative calculations. Single-point calculations for the DFT geometries have been performed at the MP2/6–31G(d,p), MP2/6–31++G(d,p), and MP2/6–311++G(2d,2p) levels of theory. The geometrical parameters, relative stabilities and counterpoise corrected interaction energies are reported. In addition, using a variation-perturbation energy decomposition scheme, we have found the important contributions to the total interaction energy.

Bilateral and Multinodular Signet-Ring Stromal Tumor of the Ovary

BACKGROUND: Signet-ring stromal tumor of the ovary is a rare, benign sex cord stromal tumor that is typically unilateral. Its distinction from malignant signet-ring cell adenocarcinoma metastatic to the ovary (Krukenberg tumor), is critical. CASE: A 69-year-old gravida 5 woman presented with a 1-week history of right lower abdominal pain. Ultrasonography revealed a 4-cm right adnexal mass. Serum CA 125 and carcinoembryonic antigen were within normal limits. An exploratory laparotomy, partial omentectomy, bilateral salpingo-oophorectomy and peritoneal washing were performed. Solid multinodular masses in both ovaries were identified that histologically corresponded to bilateral signet-ring stromal tumors. CONCLUSION: We report a rare example of signet-ring stromal tumor that is bilateral and multinodular mimicking a Krukenberg tumor. Awareness of this unusual presentation can help prevent incorrect diagnosis.

Targeted Treatment of a Rare Vaginal Sarcoma With an Anaplastic Lymphoma Kinase Inhibitor.

BACKGROUND: Anaplastic lymphoma kinase is a tyrosine kinase receptor that can become oncogenic. Crizotinib is a tyrosine kinase inhibitor that shows activity in patients with anaplastic lymphoma kinase rearrangements that have failed conventional therapies. CASE: A 34-year-old woman presented with a painful 3-cm left vulvar–vaginal mass, which was excised and determined to be a sarcoma with positive surgical margins. Fluorescence in situ hybridization testing of her tumor was conducted and demonstrated anaplastic lymphoma kinase gene rearrangements. A 3-cm mass recurred 1 month later. Treatment with 250 mg crizotinib orally twice daily resulted in complete regression of all visible or palpable tumor within 3 weeks. CONCLUSION: Molecular evaluation techniques can be used to direct targeted therapy for select malignancies. Future technologic advances will expand the number of malignancies for which these treatment approaches can be used.