Synthesis and properties of PNA containing a dicationic nucleobase based on N4-benzoylated cytosine.

We report the synthesis of a peptide nucleic acid (PNA) monomer containing N4-bis(aminomethyl)benzoylated cytosine (BzC2+ base). The BzC2+ monomer was incorporated into PNA oligomers using Fmoc-based solid-phase synthesis. The BzC2+ base in PNA had two positive charges and exhibited greater affinity for DNA G base than the natural C base. The BzC2+ base stabilized PNA-DNA heteroduplexes through electrostatic attractions, even in high salt conditions. The two positive charges on the BzC2+ residue did not compromise the sequence specificity of PNA oligomers. These insights will aid the future design of cationic nucleobases.

Atropodiastereoselective 5N-Acylation of 1,5-Benzodiazepin-2-ones with (S)-2-Phenylpropanoyl and (S)-2-Phenylbutanoyl Chlorides.

5N-Acylation of 1N-methyl-1,5-benzodiazepin-2-ones with (S)-2-phenylpropanoyl and (S)-2-phenylbutanoyl chlorides afforded the (a1S,a2S,S)-atropisomer (I) diastereoselectively over the (a1R,a2R,S)-isomer (II) in the ratio of 1:0.06-0.15. The preferential formation of I may be explained by the thermodynamically preferable π-π stacking interaction between two benzene rings in the benzodiazepine ring and the acyl chloride during the reaction. Analysis using ab initio calculations (RI-MP2/6-31+G(d) level of theory) for the acylation reaction indicated the π-π stacking interaction in the transition state. Furthermore, isomer I was shown to be thermodynamically more stable than II. The higher stability of I may be caused by the folded form of the two benzene rings, which was revealed by NMR, X-ray, and computational analyses.

Elucidation of the Active Conformation of Antiproliferative Sulfonamides, 5N-Arylsulfonyl-1,5-benzodiazepin-2-ones.

The 5N-arylsulfonyl-1,5-benzodiazepin-2-ones with antiproliferative activity were prepared and successfully separated into the (a1R,a2R)- and (a1S,a2S)-atropisomers with extraordinary stability (ΔG⧧ = ∼130 kJ/mol) by freezing the conformation around the sp2-sp2 axis in an Ar-N(SO2) moiety with a C6-methyl group. Also, by introducing a C3-methyl group (central chirality) into the 1,5-benzodiazepine nucleus, the stereochemistry at the axis was biased to take solely one diastereomer with a relative stereochemistry of (a1R*,a2R*,3R*). The (a1S) stereochemistry was crucial for exerting the antiproliferative activity.

Giant cystic leiomyoma of the uterus occupying the retroperitoneal space.

A 31-year-old nulliparous woman visited our hospital complaining of abdominal distension. Abdominal ultrasonography and computed tomography revealed a 40 × 40 × 30-cm, multilocular cystic mass extending from the upper abdomen to the pelvis. Magnetic resonance imaging (MRI) revealed a cystic tumor that was hypointense on T1-weighted images and was heterogeneously hyperintense on T2-weighted images. The final diagnosis was an 8 kg leiomyoma with cystic degeneration. Uterine leiomyomas are common benign tumors in females of reproductive age. However, subserosal leiomyomas with complete cystic degeneration of the retroperitoneal space are rare, and they are difficult to accurately diagnosis without pathological examination.

Adenomyosis with extensive glandular proliferation simulating infiltrating malignancy on magnetic resonance imaging.

We report a case of multicystic adenomyosis, which is an exceedingly rare benign tumor. The patient complained of an irregular menstrual cycle and abnormal genital bleeding that gradually increased in amount and frequency. The patient finally became severely anemic, and a hysterectomy was therefore performed. T2-weighted magnetic resonance imaging (MRI) indicated hyperplasia of the endometrium, with a myometrial lesion, where a high signal intensity multicystic mass was observed. The preoperative diagnosis was complicated by confusing MRI results. Postoperative macroscopic examination revealed a villous endometrium and a myometrium thickened with multiple small cysts containing serous transparent fluid. The final diagnosis, based on the hysterectomy specimen, was adenomyosis coexisting with simple endometrial hyperplasia. The MRI and positron emission tomography images are presented.

Early results of magnetic resonance-guided focused ultrasound surgery of adenomyosis: analysis of 20 cases.

STUDY OBJECTIVE: To evaluate the thermal ablative effects of magnetic resonance-(MR) guided focused ultrasound surgery (MRgFUS) on adenomyosis and to assess improvement in clinical parameters. DESIGN: Twenty patients with adenomyosis were treated with MRgFUS. Extensive adenomyosis (6 cases) was treated with 2 applications. Uterine volume was evaluated by MR imaging before and immediately after MRgFUS. Ablation of adenomyosis and the architecture of nonperfused areas were evaluated immediately after MRgFUS. Improvement in patient symptoms was assessed through the symptom severity score questionnaire (Canadian Task Force classification II-3). SETTING: Department of gynecology at a Japanese general hospital. PATIENTS: Premenopausal women at least 18 years of age with symptomatic adenomyosis. INTERVENTIONS: Thermal ablation by MRgFUS. MEASUREMENTS AND MAIN RESULTS: We classified the nonperfused lesions on contrast-enhanced MR images immediately after MRgFUS into 3 types: lesions with round margins (type R), serrated margins (type S), and honeycomb architecture (type H). Type R was the most common (16/20 patients). Most adenomyosis lesions could be sufficiently ablated close to the serosal surface or to the endometrium by MRgFUS. The mean uterine volume 6 months after therapy was decreased by 12.7%. Symptom severity score improved significantly during 6 months of follow-up. No serious complications were observed. CONCLUSION: These early results indicate the safe and effective ablation of adenomyosis tissue by MRgFUS. The procedure also resulted in the improvement in clinical symptoms during the 6 months of follow-up.

Subjective effect of magnetic resonance-guided focused ultrasound surgery for uterine fibroids.

AIM: We treated 69 patients with symptomatic uterine fibroids using a magnetic resonance-guided focused ultrasound surgery (MRgFUS) system. Our objective was to determine the clinical outcome of MRgFUS, focusing on symptom improvement, with emphasis on the time and extent of improvement. METHODS: Patients who would have been otherwise offered conventional surgery were considered for eligibility. They were asked to report their symptom severities before and after treatment on the same query form. The questionnaire, given 6 months after treatment, included a question asking when the patients' symptoms started to improve. Their fibroids were classified into three types according to the signal intensity on T2-weighted magnetic resonance images: type 1, low intensity as skeletal muscle, type 2, intermediate intensity, lower than myometrium but higher than skeletal muscle; and type 3, high intensity, the same as or higher than myometrium. RESULTS: No severe adverse events occurred in any of the patients. Seven patients required alternative treatment after MRgFUS, with five of them having type 3 fibroids. Mean symptom scores were all reduced after MRgFUS, regardless of the symptom types. Frequent urination improved first, while heavy bleeding took longer to resolve than the other symptoms. CONCLUSION: MRgFUS is an effective and safe method for treating symptomatic uterine fibroids, especially for type 1 and type 2 fibroids. Type 3 fibroids, however, are difficult to treat using the current MRgFUS system.

Mid-term outcome of magnetic resonance-guided focused ultrasound surgery for uterine myomas: from six to twelve months after volume reduction.

STUDY OBJECTIVE: To clarify the volume change ratio of uterine myomas treated with magnetic resonance-guided focused ultrasound surgery (MRgFUS), in relation to the signal intensity of T(2)-weighted magnetic resonance (MR) images. DESIGN: Prospective study (Canadian Task Force classification II-3). SETTING: Department of Gynecology, Shinsuma General Hospital, Kobe, Japan. PATIENTS: Forty-eight myomas in 35 patients were followed up with MR images 6 months after MRgFUS, and 23 myomas in 17 patients were followed up 12 months after MRgFUS. Before treatment, the myomas were classified into 3 types on the basis of the signal intensity of T(2)-weighted MR images as follows: Type 1, low intensity; type 2, intermediate intensity; type 3, high intensity. INTERVENTIONS: Thermal ablation therapy was performed with an MRgFUS system (ExAblate 2000). MEASUREMENTS AND MAIN RESULTS: MRgFUS produced a greater volume reduction in type 1 and type 2 myomas than in type 3 myomas. Nonperfused areas always diminished in the period after MRgFUS; however, the volume change was affected by the volume change ratio of perfused areas inside the treated myomas. CONCLUSION: At present, type 3 myomas should be exempted from the application of MRgFUS, because the nonperfused ratio immediately after the procedure was small compared with that in type 1 and type 2 myomas, and the subsequent volume change was unfavorable.

Magnetic resonance-guided focused ultrasound surgery for uterine fibroids: relationship between the therapeutic effects and signal intensity of preexisting T2-weighted magnetic resonance images.

OBJECTIVE: This study was undertaken to clarify the relationship between the signal intensity of T2-weighted magnetic resonance images and the therapeutic effect of magnetic resonance-guided focused ultrasound surgery (MRgFUS) on uterine fibroids. STUDY DESIGN: Ninety-five fibroids in 63 patients were classified into 3 types based on the signal intensity of T2-weighted magnetic resonance images as follows: type 1, low intensity; type 2, intermediate intensity; type 3, high intensity. The treated area ratio of MRgFUS and the volume reduction ratio 6 months after treatment were used as the indices of therapeutic effect. RESULTS: The treated area ratio of type 3 fibroids was the lowest among the 3 types (P < .01). The volume reduction ratio correlated with the treated area ratio (r = 0.64; P < .01). CONCLUSION: The efficacy of MRgFUS correlates with the signal intensity of T2-weighted magnetic resonance images. Type 1 and type 2 fibroids are suitable candidates for MRgFUS, whereas type 3 fibroids are not.