Cytological nuclear atypia classification can predict prognosis in patients with endometrial cancer.

OBJECTIVE: Endometrial cancer is one of the leading causes of malignancy in females. Nuclear findings are important for patients with cancer, and can provide valuable information to treating oncologists. We investigated whether nuclear findings were a useful prognostic factor in patients with endometrial cancer. METHOD: We investigated 71 cases of endometrial carcinoma with paired histology and cytology at Kurume University Hospital. We classified endometrial endometrioid adenocarcinoma (EEC) G1 and G2 as type I carcinomas, and uterine papillary serous carcinoma (UPSC), clear cell carcinoma (CC) and EEC G3 as type II carcinomas. For the establishment of the cytological nuclear atypia classification, we examined the following nuclear factors on the cytological smears: mitotic figures, prominent nucleoli, nuclear area and anisonucleosis. RESULTS: There was a significant difference in mitotic figures (P < 0.001) and anisonucleosis (P = 0.026) in cytological smears between type I and type II carcinomas. Based on these findings, we categorized cytological nuclear atypia into three groups, nuclear atypia-1 (57.7%), nuclear atypia-2 (19.7%) and nuclear atypia-3 (22.5%), and this classification system correlated well with prognosis in patients with endometrial cancer (P < 0.001). Furthermore, this classification system was able to extract patients with a good prognosis from those with high-grade carcinomas, such as UPSC+CC+EEC G3, and patients with a poor prognosis from those with EEC G1. CONCLUSIONS: Our system of cytological nuclear atypia classification based on endometrial cytology can predict patient prognosis. Cytological nuclear atypia classification and histological typing may be useful for the treatment and follow-up of patients with endometrial cancer, and should be routinely incorporated into cytological reports.

Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102).

BACKGROUND: A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival. METHODS: Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1-5, vincristine 0.7 mg m(-2) day 5, mitomycin 7 mg m(-2) day 5, cisplatin 14 mg m(-2) days 1-5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival. RESULTS: A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80%; P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85). CONCLUSION: Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.

Efficacy of neoadjuvant chemotherapy in patients with FIGO stage IB1 to IIA cervical cancer: an international collaborative meta-analysis.

BACKGROUND: The efficacy of neoadjuvant chemotherapy before surgery (NCS) has not been well-established in FIGO stage IB1 to IIA cervical cancer when compared with primary surgical treatment (PST). Thus, we performed a meta-analysis to determine the efficacy of NCS in patients with FIGO stage IB1 to IIA cervical cancer when compared with PST. METHODS: We searched Pubmed, Embase and the Cochrane Library between January 1987 and September 2010. Since there was a relative lack of relevant randomized controlled trials (RCTs), we included 5 RCTs and 4 observational studies involving 1784 patients among 523 potentially relevant studies. RESULTS: NCS was related with lower rates of large tumor size (≥4 cm) (ORs, 0.22 and 0.10; 95% CI, 0.13-0.39 and 0.02-0.37) and lymph node metastasis (ORs, 0.61 and 0.38; 95% CI, 0.37-0.99 and 0.20-0.73) than PST in all studies and RCTs. Furthermore, NCS reduced the need of adjuvant radiotherapy (RT) in all studies (OR, 0.57; 95% CI, 0.33-0.98), and distant metastasis in all studies and RCTs (ORs, 0.61 and 0.61; 95% CI, 0.42-0.89 and 0.38-0.97). However, overall and loco-regional recurrences and progression-free survival were not different between the 2 treatments. On the other hand, NCS was associated with poorer overall survival in observational studies when compared with PST (HR, 1.68; 95% CI, 1.12-2.53). CONCLUSIONS: Although NCS reduced the need of adjuvant RT by decreasing tumor size and lymph node metastasis, and distant metastasis, it failed to improve survival when compared with PST in patients with FIGO stage IB1 to IIA cervical cancer.

Dynamics of placental ghrelin production and its receptor expression in a Dahl salt-sensitive rat model of intrauterine growth restriction.

BACKGROUND: Ghrelin, a peptide hormone produced mainly in the stomach, is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). The existence of placental ghrelin and its receptor has been confirmed in normal pregnancy. However, few reports have so far referred to placental ghrelin and its receptor in intrauterine growth restriction (IUGR). OBJECTIVES: The dynamics of ghrelin production and its receptor expression was investigated to clarify the role of placental ghrelin in an IUGR pregnancy using pregnant Dahl salt-sensitive (Dahl S) rats as a model for IUGR. METHODS: Pregnant Dahl S rats were fed a high-salt diet to develop hypertensive pregnancy with IUGR (IUGR-preg). The levels of ghrelin peptide in the placenta, stomach and plasma of the dams, together with the expression levels of mRNAs for ghrelin and its functional receptor (GHS-R1a) in the placenta, were measured in the IUGR-preg rats at 2 and 3 weeks of gestation, and compared to those in the control pregnant Dahl S rats fed standard chow (Normal-preg). RESULTS: The levels of placental ghrelin peptide at 2 weeks of gestation and placental ghrelin mRNA at each gestational week in IUGR-preg were significantly higher than those in Normal-preg. The level of GHS-R1a mRNA in the placenta of IUGR-preg, which was lower at 2 weeks of gestation in comparison to Normal-preg, significantly increased from 2 to 3 weeks of gestation. No significant difference was observed in the level of ghrelin peptide in the plasma or stomach of the dams between the two groups. CONCLUSION: The profile of placental ghrelin production and the expression of its receptor using Dhal S rats in the IUGR-preg was different from that in the control. The placental ghrelin-ghrelin receptor system thus continues to work until the term of pregnancy in the IUGR-preg in contrast to Normal-preg, which might act as a compensational mechanism for fetal growth.

Expression of activated signal transducer and activator of transcription-3 predicts poor prognosis in cervical squamous-cell carcinoma.

BACKGROUND: Stat3 is a member of the Janus-activated kinase/STAT signalling pathway. It normally resides in the cytoplasm and can be activated through phosphorylation. Activated Stat3 (p-Stat3) translocates to the nucleus to activate the transcription of several molecules involved in cell survival and proliferation. The constitutive activation of Stat3 has been shown in various types of malignancies, and its expression has been reported to indicate a poor prognosis. However, the correlation between the constitutive activation of Stat3 and the prognosis of cervical cancer patients has not been reported. METHODS: The immunohistochemical analysis of p-Stat3 expression was performed on tissues from 125 cervical squamous-cell carcinoma patients who underwent extended hysterectomy and pelvic lymphadenectomy, and the association of p-Stat3 expression with several clinicopathological factors and survival was investigated. RESULTS: Positive p-Stat3 expression was observed in 71 of 125 (56.8%) cases and was significantly correlated with lymph node metastasis, lymph vascular space invasion, and large tumour diameter (>4 cm) by Fisher's exact test. Kaplan-Meier survival analysis showed that p-Stat3 expression was statistically indicative of a poor prognosis for overall survival (P=0.006) and disease-free survival (P=0.010) by log-rank test. CONCLUSION: These data showed that p-Stat3 expression in cervical cancer acts as a predictor of poor prognosis.

Magnetic resonance T1 gradient-echo imaging in hepatolithiasis.

BACKGROUND: We examined the role of magnetic resonance T1-weighted gradient-echo (MRT1-GE) imaging in hepatolithiasis. METHODS: MRT1-GE, precontrast computed tomography (CT), and magnetic resonance cholangiopancreatography (MRCP) of 10 patients with hepatolithiasis were compared for their diagnostic accuracies in the detection and localization of intrahepatic calculi. The diagnosis of hepatolithiasis was confirmed by surgery. For localization of the stone, we divided the bile ducts into six areas: right and left hepatic ducts and bile ducts of the lateral, medial, right anterior, and right posterior segments of the liver. Chemical analysis of the stones was performed in eight patients. RESULTS: The total number of segments proved by surgery to contain stones was 18. Although not significantly different, the sensitivity of MRT1-GE was 77.8% (14 of 18 segments), higher than that of MRCP (66.7%, 12 of 18 segments) and that of CT (50%, nine of 18 segments). The sensitivity of magnetic resonance imaging (MRCP + MRT1) was significantly higher than that of CT (p < 0.01). Multiple logistic regression analysis showed that the result of surgery was significantly affected only by the result of magnetic resonance imaging. On MRT1-GE, all the depicted stones appeared as high-intensity signal areas within the low-intensity bile duct irrespective of their chemical composition. CONCLUSION: MRT1-GE imaging provides complementary information concerning hepatolithiasis.

Prenatal diagnosis of sustained bradycardia with 1 : 1 atrioventricular conduction.

OBJECTIVES: The aims of this study were to elucidate the clinical course of fetal bradycardia with 1 : 1 atrioventricular conduction, and to discuss the optimal management of affected fetuses in the second and third trimesters of pregnancy. METHODS: The hospital records of five fetuses with the diagnosis of bradycardia (100 bpm) with 1 : 1 atrioventricular conduction between 1981 and 2000 in our institution were reviewed. Atrioventricular conduction was evaluated by simultaneous M-mode echocardiographic tracing of the atria and the ventricles. RESULTS: The gestational ages at referral ranged from 19 to 36 (median, 25) weeks, and fetal heart rates ranged from 60 to 80 (median, 80) bpm. Postnatal electrocardiography revealed sinus bradycardia in four (two of which were siblings) of the five cases, and junctional rhythm in the remaining case. Two fetuses with congenital heart defects (CHDs) were delivered by Cesarean section but died postnatally. The three fetuses without CHDs were delivered vaginally and have survived to date for 6, 8 and 15 years. CONCLUSIONS: Fetal bradycardia with 1 : 1 atrioventricular conduction caused by sustained sinus bradycardia or wandering pacemaker is an important type of fetal arrhythmia. Further investigations with a larger number of cases are required to determine the risk factors for predicting the outcome of affected fetuses.

Enlarged bronchial arteries in a fetus with transposition of the great arteries and intact ventricular septum.

Enlarged bronchial arteries are associated in some patients with transposition of the great arteries and intact ventricular septum. The etiology of these enlarged bronchial arteries is not yet known. In this report, we describe a case of TGA/IVS in which enlarged bronchial arteries were demonstrated from the prenatal period. The arteriogram at one year after arterial switch repair demonstrated enlarged bronchial arteries. This prenatal information may be useful for deciding on a strategy for postnatal treatment and counseling the family members.

Recognition of ADP-ribosylation factor 4-like by HLA-A2-restricted and tumor-reactive cytotoxic T lymphocytes from patients with brain tumors.

Although specific immunotherapy is one candidate treatment of brain tumor, the molecular basis of T-cell-mediated recognition of brain tumors has not yet been elucidated. In this study, we tried to identify brain tumor antigens using HLA-A2-restricted and tumor-reactive cytotoxic T lymphocytes (CTLs). As an HLA-A2-restricted OK-CTL line contained CTLs capable of responding to HLA-A2+ malignant glioma cells, this cell line was used for identification of brain tumor antigens. After screening a cDNA library from brain tumor cells, this CTL line was found to produce interferon (IFN)-gamma when cultured with COS-7 cells, which were cotransfected with both a cDNA clone (clone 1) and HLA-A0207 cDNA. Data base searches indicated that the clone 1 was 98% identical to that of the human ADP-ribosylation factor 4-like (ARF4L). Two peptides, ARF4L 15-24 and ARF4L 69-77, possessed the ability to induce HLA-A2-restricted and tumor-reactive CTLs from peripheral blood mononuclear cells of patients with brain tumors. Although ARF4L seemed to be ubiquitously expressed at the mRNA level, ARF4L-reactive CTLs failed to exhibit cytotoxicity against normal lymphoid blasts. These results indicate that these two ARF4L peptides could be targets for immunotherapy of HLA-A2+ patients with brain tumors.

UDP-Gal: betaGlcNAc beta1, 3-galactosyltransferase, polypeptide 3 (GALT3) is a tumour antigen recognised by HLA-A2-restricted cytotoxic T lymphocytes from patients with brain tumour.

Patient prognosis in the case of malignant brain tumours is generally poor, despite significant improvements in the early detection of the tumours, and thus the development of new treatment modalities is needed. One of the most prominent modalities is specific immunotherapy, for which the elucidation of antigenic molecules of malignant brain tumours recognized by T cells is essential. We report here a gene, UDP-Gal: betaGlcNAc beta1, 3-galactosyltransferase, polypeptide 3, encoding three epitope peptides recognised by tumor-reactive cytotoxic T lymphocytes in an HLA-A2-restricted manner. Two of the three peptides possessed an ability to induce HLA-A2-restricted and tumour-reactive cytotoxic T lymphocytes from peripheral blood mononuclear cells of patients with brain tumours. These peptides may be useful in the peptide-based specific immunotherapy for patients with malignant brain tumours.

The possible intraspousal transmission of HCV in terms of lichen planus.

Lichen planus (LP), common mucocutaneous disorder, involves not only oral mucosa and skin but genitalia membrane. LP is frequently seen in patients with HCV infection. This study evaluated patients with HCV-associated oral lichen planus (OLP) for vulvar and vaginal LP involvement, and the possible intraspousal transmission of HCV. We examined a total of 24 female Japanese patients with OLP for genitalia LP: 14 OLP-HCV positive and 10 OLP-HCV negative. All subjects were evaluated for genital LP by a gynecologist. All 24 subjects and 10 of the husbands were tested for anti-HCV and serum HCV RNA. Vulvar LP was observed in 10 (41.7%) of 24 patients with OLP. Vulvar LP in 14 (OLP-HCV positive) and 10 patients (OLP-HCV negative) were observed in 42.9 and 40%, respectively. There were no significant differences (age, sites of OLP, blood transfusion, HCV infection, and degree of liver diseases) between the vulvar LP and non-vulvar LP patients. Two spouses of 10 married couples were shown to be infected with HCV. In one couple with HCV infection, the wife and husband had also erosive OLP, the wife had erosive vulvar LP. In conclusion, the majority of OLP patients suffered from genitalia LP in Japan. Clinicians should follow the OLP patients with sufficient attention to the presence of extraoral manifestations. These data may suggest the occurrence of intraspousal transmission of HCV through erosive vulvar LP.

Detection of peptide-specific CTL-precursors in peripheral blood lymphocytes of cancer patients.

Development of therapeutic vaccines is one of the major areas of tumour immunotherapy today. However, clinical trials of peptide-based cancer vaccines have rarely resulted in tumour regression. This failure might be due to an insufficient induction of cytotoxic T lymphocytes in the current regimes, in which cytotoxic T lymphocytes-precursors in pre-vaccination peripheral blood mononuclear cells are not measured. Initiation of immune-boosting through vaccination could be better than that of immune-priming with regard to induction of prompt and strong immunity. If this is also the case for therapeutic vaccines, pre-vaccination measurement of peptide-specific cytotoxic T lymphocytes-precursors will be important. In the present study, we investigated whether cytotoxic T lymphocytes-precursors reacting to 28 kinds of peptides of vaccine candidates (13 and 15 peptides for HLA-A24(+) and HLA-A2(+) patients, respectively) were detectable in pre-vaccination peripheral blood mononuclear cells of 80 cancer patients. Peptide-specific cytotoxic T lymphocytes-precursors were found to be detectable in peripheral blood mononuclear cells of the majority of cancer patients (57 out of 80 cases, 71%). The mean numbers of positive peptides were 2.0 peptides per positive case. Peripheral blood mononuclear cells incubated with positive peptides, not with negative peptides, showed significant levels of HLA-class-I-restricted cytotoxicity to cancer cells. The profiles of positive peptides entirely varied among patients, and were not influenced by the cancer origin. These results may provide a scientific basis for the development of a new approach to cancer immunotherapy, e.g.) cytotoxic T lymphocytes-precursor-oriented peptide vaccine.

Small hypervascular hepatocellular carcinoma versus hypervascular pseudolesions: differential diagnosis on MRI.

BACKGROUND: We wanted to differentiate small hypervascular hepatocellular carcinoma (HCC) from hypervascular pseudolesion (HPL) on magnetic resonance imaging (MRI). METHODS: We reviewed small hypervascular foci (< or = 2 cm in diameter) on dynamic MRI in patients with chronic liver disease, which were followed-up with serial MRI examinations. RESULTS: Twenty of 34 hypervascular foci were larger at follow-up; 19 of 20 foci had characteristics suggesting HCC; and 14 foci did not grow or disappeared and were judged to be HPLs. There were no differences in the initial sizes and follow-up periods between HCCs and HPLs. On initial MRI, nine of 19 HCCs (47%) and one of 14 HPLs (7%) appeared hyperintense on T2-weighted images. The difference between HCCs and HPLs on T2-weighted images was statistically significant (p = 0.039). CONCLUSION: HPLs are seen frequently as small hypervascular foci on dynamic MRI in patients with chronic liver disease. Hyperintensity of the foci on T2-weighted images differentiates HCCs from HPLs.

Degradation of p53 by adenovirus E4orf6 and E1B55K proteins occurs via a novel mechanism involving a Cullin-containing complex.

Although MDM2 plays a major role in regulating the stability of the p53 tumor suppressor protein, other poorly understood MDM2-independent pathways also exist. Human adenoviruses have evolved strategies to regulate p53 function and stability to permit efficient viral replication. One mechanism involves adenovirus E1B55K and E4orf6 proteins, which collaborate to target p53 for degradation. To determine the mechanism of this process, a multiprotein E4orf6-associated complex was purified and shown to contain a novel Cullin-containing E3 ubiquitin ligase that is (1) composed of Cullin family member Cul5, Elongins B and C, and the RING-H2 finger protein Rbx1(ROC1); (2) remarkably similar to the von Hippel-Lindau tumor suppressor and SCF (Skp1-Cul1/Cdc53-F-box) E3 ubiquitin ligase complexes; and (3) capable of stimulating ubiquitination of p53 in vitro in the presence of E1/E2 ubiquitin-activating and -conjugating enzymes. Cullins are activated by NEDD8 modification; therefore, to determine whether Cullin complexes are required for adenovirus-induced p53 degradation, studies were conducted in ts41 Chinese hamster ovary cells that are temperature sensitive for the NEDD8 pathway. E4orf6/E1B55K failed to induce the degradation of p53 at the nonpermissive temperature. Thus, our results identify a novel role for the Cullin-based machinery in regulation of p53.

Degradation of p27(Kip1) at the G(0)-G(1) transition mediated by a Skp2-independent ubiquitination pathway.

Targeting of the cyclin-dependent kinase inhibitor p27(Kip1) for proteolysis has been thought to be mediated by Skp2, the F-box protein component of an SCF ubiquitin ligase complex. Degradation of p27(Kip1) at the G(0)-G(1) transition of the cell cycle has now been shown to proceed normally in Skp2(-/-) lymphocytes, whereas p27(Kip1) proteolysis during S-G(2) phases is impaired in these Skp2-deficient cells. Degradation of p27(Kip1) at the G(0)-G(1) transition was blocked by lactacystin, a specific proteasome inhibitor, suggesting that it is mediated by the ubiquitin-proteasome pathway. The first cell cycle of stimulated Skp2(-/-) lymphocytes appeared normal, but the second cycle was markedly inhibited, presumably as a result of p27(Kip1) accumulation during S-G(2) phases of the first cell cycle. Polyubiquitination of p27(Kip1) in the nucleus is dependent on Skp2 and phosphorylation of p27(Kip1) on threonine 187. However, polyubiquitination activity was also detected in the cytoplasm of Skp2(-/-) cells, even with a threonine 187 --> alanine mutant of p27(Kip1) as substrate. These results suggest that a polyubiquitination activity in the cytoplasm contributes to the early phase of p27(Kip1) degradation in a Skp2-independent manner, thereby promoting cell cycle progression from G(0) to G(1).

Weekly 1 hour paclitaxel infusion in patients with recurrent gynecological tumors: a pilot study.

BACKGROUND: Intensifying the dose of paclitaxel given in a weekly schedule is useful towards improving the therapeutic index of paclitaxel in treating a variety of advanced and recurrent malignancies and is suitable for outpatient administration. This pilot study was carried out to evaluate the safety of weekly paclitaxel administration by 1 h infusion in the outpatient setting. METHODS: Eleven patients with recurrent gynecological tumors who had previously been treated with at least one platinum-based chemotherapy regimen participated in the study between May 1999 and March 2000. Paclitaxel was given at a dose of 70 mg/m(2 ) as a 1 h infusion every week for at least 20 consecutive weeks unless lesions became progressive. Intravenous dexamethasone and cimetidine and oral diphenhydramine were administered 30 min before paclitaxel infusion. RESULTS: The 11 patients received a total of 166 cycles of therapy. All patients received 70 mg/m(2 ) doses of paclitaxel without treatment delay. No hypersensitivity reactions were elicited. Grade 3 or 4 leukopenia and neutropenia occurred in 9 and 36% of the patients, respectively. Granulocyte colony-stimulating factor was required for only one patient and no patients experienced febrile neutropenia. Neurotoxicity was the most serious adverse effect and all patients experienced grade 1 or 2 peripheral neuropathy. Grade 1 or 2 myalgias were observed in 45% of the patients. Alopecia was universal. No Grade 3 or higher non-hematological toxicities were observed. CONCLUSION: Weekly 1 h paclitaxel administration is considered safe as a salvage therapy for recurrent gynecological tumors, making its use more convenient and easier in the outpatient setting. The current results support further evaluation.

Relationship between age, histological type, and size of ovarian tumors.

OBJECTIVE: To clarify the relationship between age, histological type, and size of ovarian tumors. METHOD: A review was made of 1648 cases of histopathologically diagnosed ovarian tumors and tumor-like lesions, and information on the age of the patients and size of the tumor was obtained. Statistical analysis was performed using Kruskal-Wallis tests or Mann-Whitney U-tests. RESULTS: There were 840 (51%) cases of benign tumors, 73 (4%) cases of tumors of low malignant potential (LMP), 268 (16%) cases of malignant tumors and 467 (28%) cases of tumor-like lesions. The age of the patients was significantly different among tumor-like lesions (34.6+/-8.1 years), benign tumors (39.8+/-16.4 years), LMP tumors (45.2+/-18.3 years) and malignant tumors (51.9+/-13.0 years) (P<0.0001). The maximum diameter of the tumors was significantly different among tumor-like lesions (7.1+/-3.3 cm), benign tumors (10.9+/-5.6 cm), malignant tumors (13.6+/-6.5 cm) and LMP tumors (18.5+/-6.8 cm) (P<0.0001). CONCLUSION: The distribution of tumor histological type (tumor-like lesions, benign, LMP and malignant) was correlated against patient age and lesion diameter, with tumors in older patients or larger tumors more likely to be malignant.

[A modified administrated schedule for combination therapy with irinotecan and cisplatin as a neoadjuvant chemotherapy in locally advanced cervical cancer--a report of 2 cases as a pilot study].

To shorten the treatment term of neoadjuvant chemotherapy (NAC) for locally advanced cervical cancer, a combination of irinotecan (CPT-11) and cisplatin was administered on a modified administrated schedule for 2 eligible patients as a pilot study. CPT-11 70 mg/m2 was administered (div) on days 1 and 8, followed by cisplatin 70 mg/m2 given (div) on day 1. Treatment was repeated every 3 weeks for a total of two cycles. Both patients showed a complete clinical response. No severer toxicities were observed than with the usual regimen, and both cases could undergo radical hysterectomy after NAC. The results suggest that this modified regimen of combination of CPT-11 and cisplatin can be effective as an NAC in cases of locally advanced cervical cancer, especially in terms of shortening treatment term. This regimen is worthy of further study.

Muf1, a novel Elongin BC-interacting leucine-rich repeat protein that can assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase.

The heterodimeric Elongin BC complex has been shown to interact in vitro and in mammalian cells with a conserved BC-box motif found in a growing number of proteins including RNA polymerase II elongation factor Elongin A, SOCS-box proteins, and the von Hippel-Lindau (VHL) tumor suppressor protein. Recently, the VHL-Elongin BC complex was found to interact with a module composed of Cullin family member Cul2 and RING-H2 finger protein Rbx1 to reconstitute a novel E3 ubiquitin ligase that activates ubiquitylation by the E2 ubiquitin-conjugating enzymes Ubc5 and Cdc34. In the context of the VHL ubiquitin ligase, Elongin BC functions as an adaptor that links the VHL protein to the Cul2/Rbx1 module, raising the possibility that the Elongin BC complex could function as an integral component of a larger family of E3 ubiquitin ligases by linking alternative BC-box proteins to Cullin/Rbx1 modules. In this report, we describe identification and purification from rat liver of a novel leucine-rich repeat-containing BC-box protein, MUF1, which we demonstrate is capable of assembling with a Cullin/Rbx1 module containing the Cullin family member Cul5 to reconstitute ubiquitin ligase activity. In addition, we show that the additional BC-box proteins Elongin A, SOCS1, and WSB1 are also capable of assembling with the Cul5/Rbx1 module to reconstitute potential ubiquitin ligases. Taken together, our findings identify MUF1 as a new member of the BC-box family of proteins, and they predict the existence of a larger family of Elongin BC-based E3 ubiquitin ligases.

Remission of metastatic cervical adenocarcinoma with weekly paclitaxel.

We report the use of paclitaxel in the successful treatment of a patient with recurrent adenocarcinoma of the cervix. Paclitaxel, 70 mg/m2 by 1-h infusion weekly, was administered to a 59-year-old patient with cervical adenocarcinoma showing lung metastasis. She showed partial clinical response after seven cycles, and at the completion of 20 cycles she showed complete response, which was confirmed by chest X-ray and computed tomography scan. Toxicities including neurotoxicity were mild. She showed an objective response to treatment for over 8 months, and she enjoyed a favorable quality of life during and after treatment. Weekly paclitaxel was very well tolerated, yet was effective for recurrent cervical adenocarcinoma.