RLIM inhibits functional activity of LIM homeodomain transcription factors via recruitment of the histone deacetylase complex.

LIM domains are required for both inhibitory effects on LIM homeodomain transcription factors and synergistic transcriptional activation events. The inhibitory actions of the LIM domain can often be overcome by the LIM co-regulator known as CLIM2, LDB1 and NLI (referred to hereafter as CLIM2; refs 2-4). The association of the CLIM cofactors with LIM domains does not, however, improve the DNA-binding ability of LIM homeodomain proteins, suggesting the action of a LIM-associated inhibitor factor. Here we present evidence that LIM domains are capable of binding a novel RING-H2 zinc-finger protein, Rlim (for RING finger LIM domain-binding protein), which acts as a negative co-regulator via the recruitment of the Sin3A/histone deacetylase corepressor complex. A corepressor function of RLIM is also suggested by in vivo studies of chick wing development. Overexpression of the gene Rnf12, encoding Rlim, results in phenotypes similar to those observed after inhibition of the LIM homeodomain factor LHX2, which is required for the formation of distal structures along the proximodistal axis, or by overexpression of dominant-negative CLIM1. We conclude that Rlim is a novel corepressor that recruits histone deacetylase-containing complexes to the LIM domain.

Distal Transradial Access in the Anatomic Snuffbox for Diagnostic Cerebral Angiography.

The aim of this study was to describe the feasibility, technique, and safety of distal transradial access in the anatomic snuffbox for diagnostic cerebral angiography. A retrospective review of diagnostic cerebral angiograms obtained during a 6-month period with distal transradial access was performed. Thirty-four successful procedures were performed via distal transradial access. There were 4 failed attempts. This single-center experience using distal transradial access suggests that this technique is safe and effective.

Combination of bleomycin, etoposide, and cisplatin for the treatment of advanced ovarian granulosa cell tumors.

The objective is to investigate the activity and toxicity of bleomycin, etoposide, and cisplatin (BEP) regimen in ovarian granulosa cell tumors (OGCTs). Twenty consecutive patients with initial metastatic (5 patients) or recurrent (15 patients) OGCT were treated; BEP regimen: B: 30 mg intravenously or intramurally on days 1, 8, and 15; E: 100 mg/m2/day on days 1-5; and P: 20 mg/m2/day on days 1-5. Median age: 42 years (range: 17-60); median follow-up: 45 months (range: 3-112). The overall response rate is 90% (nine clinical complete response [CR], nine clinical partial response) with a median duration of 24 months (range: 4-77). A second-look laparotomy performed in 11 patients showed a pathologic CR in 7 cases and microscopic disease in 1 case. Seven patients remain free of disease (at 4-84 months); 11 patients relapsed (median: 24 months, range: 13-58), 12 patients are still alive, and 9 patients are without disease (2 patients in second CR). At 4 years, overall survival and event-free survival are respectively 58% and 30%. Toxicity is evaluable for 19 patients (48 cycles). A grade 4 neutropenia occurred in 15% of cycles (in seven patients) with a febrile neutropenia in four patients. Five patients experienced a low bleomycin pulmonary toxicity. BEP regimen appears to be an active regimen for OGCT in first-line chemotherapy.

Results of a prospective dose-intensive regimen in 27 patients with small cell carcinoma of the ovary of the hypercalcemic type.

BACKGROUND: The evaluation of first-line intensive combination therapy in small cell carcinoma of the ovary (SCCO). PATIENTS AND METHODS: Debulking surgery; four to six cycles of chemotherapy with cisplatin (P) 80 mg/m(2) day 1, adriamycin (A) 40 mg/m(2) day 1, vepeside (V) 75 mg/m(2)/day days 1-3, cyclophosphamide (EP) 300 mg/m(2)/day days 1-3, every 3 weeks and granulocyte colony-stimulating factor with, in case of a complete remission, high-dose chemotherapy with carboplatin, vepeside, cyclophosphamide and stem-cell support. RESULTS: Twenty-seven patients (median age 25 years); International Federation of Gynecology and Obstetrics stage: five I, four IIC, 17 IIIC-IV and one unknown. Twenty patients underwent complete surgery. Eight patients progressed under chemotherapy. Among 18 patients in complete response (CR), 10 received high-dose chemotherapy (CT) (three stem-cell collection failures, two protocol violations, two disease progression and one refusal). The main grade 3-4 toxic effects were hematologic. There were eight relapses among the 18 CR, four of which were pelvic alone. Among the 27 patients, 13 died and 10 patients are in CR1, three in CR2. The median follow-up is 37 months (8-166) and the median duration of the 18 CR is 30 months (5-111). Overall survival at 1 and 3 years is 58% [confidence interval (CI) 40% to 75%] and 49% (CI 30% to 67%). CONCLUSIONS: Initial dose-intensive therapy achieves interesting overall survival in SCCO.

The rat albumin promoter: cooperation with upstream elements is required when binding of APF/HNF1 to the proximal element is partially impaired by mutation or bacterial methylation.

We have characterized in the accompanying paper (P. Herbomel, A. Rollier, F. Tronche, M.-O. Ott, M. Yaniv, and M. C. Weiss, Mol. Cell. Biol. 9:4750-4758, 1989) six different elements in the albumin promoter. One of them, the proximal element (PE), is the binding site for a strictly liver specific factor, APF/HNF1. This binding site contains a bacterial DAM DNA methylase methylation target sequence which, when methylated, decreases the affinity of the protein for this element. When the different albumin promoter constructions were prepared in an Escherichia coli deoxyadenosine methylase-negative strain, the respective contributions of the elements to the overall promoter activity were strikingly different. An intact proximal element plus the TATA box gave almost full transcriptional activity in transient transfection experiments and only in differentiated hepatoma cells of line H4II, whereas the distal elements (distal element III [DEIII], the NF1-binding site DEII, and the E/CBP-binding site DEI) had become essentially dispensable. Mutations affecting the CCAAT box showed only a two- to threefold decrease. When PE was methylated, mutated, or replaced by the homologous element from the alpha-fetoprotein gene, activity in the context of the short promoter (PE plus the TATA box) was abolished. However, activity was restored in the presence of the upstream elements, showing that cooperation with factors binding to the CCAAT box and distal elements favors the functional interaction of the liver-specific APF/HNF1 factor with lower-affinity binding sites.

The LIM domain: regulation by association.

The LIM domain is a zinc finger structure that is present in several types of proteins, including homeodomain transcription factors, kinases and proteins that consist of several LIM domains. Proteins containing LIM domains have been discovered to play important roles in a variety of fundamental biological processes including cytoskeleton organization, cell lineage specification and organ development, but also for pathological functions such as oncogenesis, leading to human disease. The LIM domain has been demonstrated to be a protein-protein interaction motif that is critically involved in these processes. The recent isolation and analysis of more LIM domain-containing proteins from several species have confirmed and broadened our knowledge about LIM protein function. Furthermore, the identification and characterization of factors that interact with LIM domains illuminates mechanisms of combinatorial developmental regulation.

Tumor parameters, clinical and pathological responses, medical management, and survival through time on 710 operable breast cancers.

The aim of the current study is an analysis of tumor parameters, clinical and pathological responses, medical management, and survival on 710 operable breast cancer patients who received neoadjuvant chemotherapy from 1982 to 2004 and were grouped into four successive periods according to diagnosis date: (1) 1982-1989; (2) 1990-1994; (3) 1995-1999; and (4) 2000-2004. Patients were treated by different neoadjuvant chemotherapies combinations: AVCF/M, TNCF, NEM, NET, TAXOTERE, FEC 50, 75, 100, FAC 50, and TAXOTERE-TNCF, mainly in successive prospective phase II trials. They received a median number of six cycles (range, 1-9). After primary chemotherapy, patients underwent a surgery and a radiotherapy. In case of significant residual disease, some patients received additional courses of chemotherapy. In addition, menopausal patients with hormonal receptor-positive tumors received tamoxifen for 5 yr. Clinical factors had some remarkable variations with time. The median age of the patients was 49.5 yr (range, 26-81). The size of the tumor was significantly greater from 1995; conversely, clinical lymph-node involvement was lower in period 4 than in the first period. The percentage of invasive ductal carcinoma and of SBR III tumors increased about 20% from 1982-1989 to 2000-2004. The number of positive hormonal receptors increased from 38.3% in period 1 to 74% in period 4. The clinical response rate improved recently from before 1990. The pathological response rate was greater in periods 2 and 3 than in periods 1 and 4. An adjuvant hormonotherapy became progressively more frequently given (44.7 for period 1 and 73.3% for period 4). Finally, no significant difference was found when we compared overall and disease-free survival through the four periods. It appears that the progressive increase of tumor burden was compensated by more effective treatments.

Radical radiotherapy alone in non-operable breast cancer: the major impact of tumor size and histological grade on prognosis.

This retrospective study involved 319 non-operable breast cancer patients treated by radiotherapy alone with doses of 65 Gy at the Institut Gustave-Roussy (IGR). These patients either had operable tumors but were unfit for general anesthesia or had inoperable tumors due to local contraindications. Most of them had advanced tumors: 21% less than 7 cm; 30% N2 or N3; 30% with inflammatory carcinomas. The 5- and 10-year survival was 40 and 19%, respectively. The local and distant relapse-free rate was 56 and 33% at 5 years and 44 and 28% at 10 years respectively. Results were analyzed according to tumor size, clinical node involvement, histologic grade, age, skin invasion and tumor dose. A multivariate analysis demonstrated that tumor size (p = 10(-3)) and histological grade (HG) (p = 10(-2)) were both significant factors predicting local relapse. Histological grade (p = 10(-3)), tumor size (p = 10(-2)) and clinical node involvement (p = 10(-2)) were the most significant factors predicting distant relapses. An individual risk (IR) of local recurrence and of distant recurrence was defined according to the above factors and was demonstrated to be good prognostic index. Tumor doses above 80 Gy did not increase local control. We recommend the general use of histological grading as it seems important for prediction of local and distant control in patients treated by radiotherapy alone.

Sequences of DNA fragments contacting the nuclear lamina in vivo.

To study the DNA sequences contacting the nuclear lamina (NL) in vivo, Ehrlich ascites tumor cells were UV-irradiated. The NL was purified, and the DNA fragments covalently linked to the lamina proteins in vivo were cloned and sequenced. Although heterogeneous in length and composition, the sequences displayed homology to the introns and/or flanking regions of different genes, suggesting that functionally distinct regions are organized in a topologically defined manner at the nuclear periphery.

[Sequential chemotherapy and radiotherapy in inoperable squamous cell lung cancer (author's transl)]. / Association de chimiothérapie et de radiothérapie séquentielles dans le traitement des carcinomes épidermoïdes bronchiques inopérables.

Thirteen patients with inoperable squamous cell lung cancer were treated by a protocol combining multiple chemotherapy with radiotherapy. Chemotherapy with Adriamycine, Vinblastine, Cyclophamide, Methotrexate and Cis-platinum was administered every month, followed by two radiotherapy sessions with doses of mediastinum. Six cycles were programmed. In 11 non-metastatic patients, 8 responses were obtained (4 objective remissions). Three developed distant metastases. However, mean survival (27 weeks) and 1 year survival (2/10) rates were disappointing. Multiple chemotherapy could be useful in decreasing tumoral size before radiotherapy, modalities of combined treatment should be studied.

[Fibrinolysis of deep venous thrombosis on implantable perfusion devices. Apropos of a consecutive series of 57 cases of thrombosis and 32 cases of fibrinolysis]. / Fibrinolyse des thromboses veineuses profondes sur dispositifs de perfusion implantables. A propos d'une série consécutive de 57 thromboses et de 32 fibrinolyses.

The main complication of totally implantable venous access devices is deep venous thrombosis on catheter. It may dramatically reduce the already limited venous capacity of patients undergoing chemotherapy and obturate catheters, causing pulmonary embolism or functional disorders. These thromboses usually involve veins of the superior vena cava system where the catheters are implanted. Generally, they occur early, are extensive and often asymptomatic. Doppler ultrasonography is the diagnostic investigation of choice, phlebography being reserved for particular cases or to specify the limits of the thrombus. In a series of 412 vein access devices implanted and systematically monitored by Doppler ultrasonography, we found 57 thromboses (13.8%), 15 partial and 42 complete. The lowest thrombosis rate was observed in the right internal jugular vein (10% vs 20 to 23%, p = 0.006). Thirty-two patients received a systemic fibrinolytic treatment, 16 with streptokinase (SK), five with urokinase (UK), four with tissue plasminogen activator (rt-PA) and seven with SK/UK association. No serious side effects were observed. Sixteen repermeabilizations (50% of fibrinolysis) were obtained. There were no significant differences with respect to the fibrinolytic, the initial characteristics of thrombosis or the patients. Patients without fibrinolysis received 3 weeks of low molecular weight heparin (curative doses) then warfarin. Only one patient was repermeabilized with this treatment (significative difference with fibrinolysis: p = 0.009). Fibrinolysis is indicated in symptomatic thrombosis and/or in cases of extension to the innominate vein or the superior vena cava. Systematic monitoring by Doppler ultrasonography and prophylactic anti-thrombotic treatment are recommended in patients with implantable venous access devices in order to decrease the occurrence of thromboses, to detect asymptomatic patients at an early stage and to increase the effectiveness of fibrinolysis.

[Deep venous thrombosis on implantable infusion devices. A prospective study of 72 patients with Doppler ultrasonography of veins of the neck (jugular, subclavian and brachiocephalic trunk)]. / Thromboses veineuses profondes sur dispositifs de perfusion implantables. Etude prospective de 72 patients par échotomographie-Doppler des veines du cou (jugulaire, sous-clavière et tronc brachio-céphalique veineux).

Seventy-two consecutive patients with totally implanted catheters for administration of chemotherapy for solid tumours or lymphomas were studied prospectively to assess the prevalence of venous thrombosis. During the follow-up period of 343 (6-1,177) days, 11 cases of venous thrombosis (15.2%), of which 45% were partial and only 36% symptomatic were observed. Venous thrombosis was an early complication, 6/11 cases being observed within 1 month of implantation. No clinical or biological predisposing factor, apart from the presence of malignant disease, could be identified. Doppler ultrasonography is a good method of following-up these patients. This method should become an essential diagnostic tool in this field.

[Carl Wunibalt Otto--communist, pharmacist and chemist]. / Carl Wunibald Otto--Kommunist, Pharmazeut und Chemiker.

Along with the cigarette factory worker P. Röser, the tailors P. J. Nothjung und F. Lessner, the editor H. Bürgers, the publisher H. Becker, the clerk J. Ehrhardt and the doctors R. Daniels, J. Klein, A. Jacobi and W. Reiff, the 1852 Cologne communist trial also tried the pharmacist and chemist C. W. Otto. His life and his work for the German revolutionary worker's movement in the ninetieth century, up till now hardy mentioned, is discussed with the aid of archive sources.

[Experimental prevention of deep venous thrombosis with low-molecular-weight heparin using implantable infusion devices]. / Essai de prévention des thromboses veineuses profondes sur dispositifs de perfusion implantables par une héparine de bas poids moléculaire.

We studied the effect of a fractionated heparin, Dalteparine Sodium, on the prevention of thrombosis of veins of the superior vena cava system catheterized by implantable infusion devices. Forty-six patients with solid or lympho-proliferative tumors, whose clinical condition required installation of a such device, were successively included into the study in 1991. The anticoagulant was administered for one month following implantation at the dosage of 2,500 anti-Xa units per day. The development of deep vein thrombosis was investigated by systematic Doppler ultrasound before the first and third months and at 1 year. Three early (D9, D12 and D16) and asymptomatic thrombosis were diagnosed (6.5%). This rate, although clearly more favourable, was not significantly different (p = 0.254) from the rate of 15.2% previously reported in a group of 72 comparable patients, but who did not receive preventive treatment. These results demonstrate the necessity and feasibility of a randomized study on a larger number of patients testing several protocols, before concluding on the efficacy of this type of preventive treatment.