Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.

PURPOSE Mucinous ovarian carcinomas have a distinct clinical pattern compared to other subtypes of ovarian carcinoma. Here, we evaluated (i) stage-specific clinical significance of mucinous ovarian carcinomas in a large cohort and (ii) the functional role of src kinase in pre-clinical models of mucinous ovarian carcinoma. EXPERIMENTAL DESIGN 1302 ovarian cancer patients including 122 (9.4%) cases of mucinous carcinoma were evaluated for survival analyses. Biological effects of src kinase inhibition were tested in a novel orthotopic mucinous ovarian cancer model (RMUG-S-ip2) using dasatinib-based therapy. RESULTS Patients with advanced-stage mucinous ovarian cancer had significantly worse survival compared to those with serous histology: median overall survival, 1.67 versus 3.41 years, p=0.002; and median survival time after recurrence of 0.53 versus 1.66 years, p<0.0001. Among multiple ovarian cancer cell lines, RMUG-S-ip2 mucinous ovarian cancer cells showed the highest src kinase activity. Moreover, oxaliplatin treatment induced phosphorylation of src kinase. This induced activity by oxaliplatin therapy was inhibited by concurrent administration of dasatinib. Targeting src with dasatinib in vivo showed significant anti-tumor effects in the RMUG-S-ip2 model, but not in the serous ovarian carcinoma (SKOV3-TR) model. Combination therapy of oxaliplatin with dasatinib further demonstrated significant effects on reducing cell viability, increasing apoptosis, and in vivo anti-tumor effects in the RMUG-S-ip2 model. CONCLUSIONS Our results suggest that poor survival of women with mucinous ovarian carcinoma is associated with resistance to cytotoxic therapy. Targeting src kinase with combination of dasatinib and oxaliplatin may be an attractive approach in this disease.

Asymmetric hydrogenation by using chiral transitionmetal complexes represents one of the cleanest and most environmentally benign processes available for producing optically pure organic compounds.[1] Currently, a wide variety of chiral compounds with outstanding levels of enantioselectivity has been synthesized by reduction of C=C, [1] C= O, [2,3] C=N, [4][5][6] and, more recently, heteroaromatics compounds. [7][8][9][10][11][12][13][14][15][16][17][18] Among heteroaromatics, 2-substituted quinolines have been targeted [9][10][11][12][13][14][15][16][17][18] because optically active 2-substituted-1,2,3,4-tetrahydroquinoline derivatives are key components of many bioactive natural products and drugs. [19] In contrast with the successful asymmetric hydrogenation of 2-alkyl-substituted quinolines catalyzed by chiral iridium complexes with an iodide source or iodine, [9][10][11][12][13] which dramatically enhances both catalytic activity and enantioselectivity, [5, 9a] only limited success has been achieved in the catalytic hydrogenation of 2-aryl-substituted quinolines. So far, the only known examples used 2-phenylquinoline as a unique model substrate. The first example of catalytic hydrogenation of 2-phenylquinoline (72 % ee (enantiomeric excess)), described by Zhou and co-workers, [9a] is based on anMeO-biphep/I 2 (cod = 1,5-cyclooctadiene; MeO-biphep = 6,6'-dimethoxy-2,2'-bis(diphenylphosphino)-1,1'-biphenyl) catalytic system that was recently improved to 80 % ee with a moderate yield of 41 % by using benzyl chloroformate as an activating agent, although this required an additional deprotection step on the resulting carbamate. [18] In recent years, only a few examples of the catalytic hydrogenation of 2-phenylquinoline have been reported with ee values up to 88 %. [14] We describe herein a highly enantioselective hydrogenation of the HX salts (X = Cl, Br, and I) of various 2-aryl-substituted quinolines by using cationic dinuclear iridium complexes [6,17] with [(4,4'-bi-2,2-difluoro-1,3-benzodioxole)-5,5'-diyl]bis(diphenylphosphine) (difluorphos), [20] which demonstrates an unexpected halide effect in which iridium complexes with chloro and bromo ligands serve as better catalysts than an iodo-iridium complex. The present catalyst was also effective for the hydrogenation of 2-alkyl-substituted quinolinium salts, which shows the high versatility of this new catalyst system. Furthermore, this system was applied to a formal asymmetric synthesis of selective estrogen receptor modulator (SERM) 6-hydroxy-2-(4-hydroxyphenyl)-1-{4-[2-(pyrrolidin-1-yl)ethoxy]-benzyl}-1,2,3,4-tetrahydroquinoline (1) [21] by asymmetric hydrogenation of the HCl salt of 6-methoxy-2-(4-methoxyphenyl)quinoline (2·Cl) as a key step.We recently developed cationic dinuclear triply halogen- [3][4][5][6][7][8] X= Cl, Br, and I) (Figure 1), which were conveniently prepared by adding excess aqueous HX to a mixture of [{IrClA C H T U N G T R E N N U N G (coe) 2 } 2 ] (coe = cyclooctene) and the required chiral diphosphine ligand in toluene at room...

An efficient catalytic system of a zinc cluster and tetrabutylammonium iodide (TBAI) was developed for cyclic carbonate synthesis from epoxides and carbon dioxide (CO 2 ) without the use of any organic solvents under very mild conditions (25 1C, 1 atm), even in the presence of impurities such as water and air. Electrophilicity of the central Zn(II) ion, the number of trifluoromethyl groups, nucleophilicity and leaving ability of the anion of alkylammonium salts, and various reaction parameters have a great effect on the catalytic activity of the bifunctional catalyst. Therefore, this solvent-free process represents an environmentally friendly example for the catalytic conversion of CO 2 into value-added chemicals and also has the potential to contribute towards decreasing atmospheric CO 2 emission from the burning of fossil fuels.

Adenocarcinomas arising from adenomyosis uteri are rare. This study reports four such cases and characterizes them clinically and microscopically. In all four patients, the endometrial cytology was negative, and MR imaging and ultrasound sonography did not detect the tumors preoperatively. The histological subtypes of the four tumors were endometrioid (one grade 1, one grade 3), serous, and clear cell. In three cases, the adenocarcinomas were present exclusively in the myometrium, and a transition between the carcinomas and the adenomyotic glands was observed in all cases. The eutopic endometrium was normal except in one case in which there was a small focus of invasive carcinoma. In two of four cases, pelvic or paraaortic lymph node metastases were present. In the carcinomas, ER immunoreactivity was not found in any tumor and PR positivity was found in only one tumor. In contrast, p53 immunopositivity was found in three of four carcinomas. Adenocarcinomas arising from adenomyosis are difficult to diagnose preoperatively, and their aggressive behavior in some cases seems to be related to the histological subtype.

,4-Tetrahydroisoquinolines (THIQs), a class of highly important molecular skeletons abundant in natural alkaloids and biologically active compounds, are often used as key intermediates for the synthesis of pharmaceutical drugs and drug candidates.[1] To date, synthetic efforts have focused on introducing chirality at the C1 position with configurational integrity by employing the following synthetic methodologies:[2] 1) the formation of the six-membered ring through a Bischler-Napieralski cyclization/reduction [3] or a PictetSpengler reaction, [4] 2) the C 1 -C a connectivity approach by attaching nucleophilic or electrophilic carbon units to the C1 position of tetrahydroisoquinoline derivatives, [5] and 3) the asymmetric hydrogenation of alkylidene-1,2,3,4-tetrahydroisoquinoline derivatives.[6] However, these methods have some limitations, such as a limited substrate scope and the need for stoichiometric amounts of a chiral auxiliary. In contrast to 1-substituted THIQs, the synthesis of 3-substituted THIQs has rarely been achieved, [7] although their unique structural and diverse biologic properties have been noted.[8] Accordingly, the development of more general and straightforward synthetic methods toward 1-and 3-substituted THIQs is in high demand. Although asymmetric hydrogenation of substituted isoquinolines is considered the most attractive and straightforward synthetic protocol, isoquinoline is regarded as the most challenging substrate in asymmetric hydrogenation. An efficient catalytic system has not even been found for the reduction of isoquinolines in a nonenantioselective manner. [9] Nonetheless, the recent development of an asymmetric hydrogenation of aromatic and heteroaromatic compounds was remarkable, [10][11][12][13][14][15][16][17][18][19][20] and Zhou and co-workers reported the catalytic asymmetric hydrogenation of isoquinolines, although the substrate scope is limited and an activating reagent is sometimes required (Scheme 1). [21] As part of our continuing interest in the asymmetric hydrogenation of N-heteroaromatic compounds using halogen-bridged dinuclear iridium(III) complexes, [22] we previously reported the additive effect of aryl amine derivatives in the asymmetric hydrogenation of quinoxalines, [22d] where the addition of more-basic aliphatic amines retarded the reaction, presumably because of their tight coordination to the iridium center. These findings strongly suggested that the difficulties of catalytic hydrogenation of isoquinolines upon catalysis by iridium complexes might be due to the strong basicity of the corresponding THIQs. This hypothesis prompted us to study the asymmetric hydrogenation of isoquinolinium chlorides to give the corresponding tetrahydroisoquinolinium chlorides, thus avoiding the deactivation of the iridium catalyst and providing a direct transformation of isoquinolines to THIQs in an enantioselective manner by a simple basic workup (Scheme 1).We first examined the asymmetric hydrogenation of the 3-phenylisoquinolinium salt 2 a-HCl with H 2 (30 bar) and ...

Adjuvant chemotherapy appears to be effective to control both local- and distant-recurrences in stage I UCS; adding radiotherapy to chemotherapy may be effective to control local-recurrence when the tumor exhibits multiple risk factors.

concentration in microglia, suggesting the presence of NCX activity in the reverse mode. Treatment with IFN-c (100 U/mL) caused a biphasic increase in NCX activity. The transient increase in NCX activity by IFN-c for 1 h was blocked by the protein kinase C (PKC) inhibitors, staurosporine and GF109203X, and the tyrosine kinase inhibitor, herbimycin A.The delayed increase in NCX activity by IFN-c for 24 h was blocked by the protein synthesis inhibitor cycloheximide and actinomycin D. Treatment with IFN-c for 24 h increased NCX mRNA and protein levels. The increase in NCX activity and NCX protein by IFN-c for 24 h was blocked by staurosporine, GF109203X, herbimycin A and the extracellular signal-regulated kinase inhibitor, PD98059. These findings suggest that NCX is up-regulated by IFN-c in a biphasic manner in microglia. Moreover, PKC and tyrosine kinase are involved in the upregulation of NCX and the extracellular signal-regulated protein kinase is also involved in the delayed increase in NCX activity.