Noms de lieux de Zélande et de Flandre occidentale composés avec <i>burg</i> (haut moyen âge)

One can find on the verge of the polders of Flanders and Zealand a series of fortified defence works dating back to the time of Norman invasions at the end of the 9th century. They look like a circular piece of land. The places here concerned are Bourbourg and Bergues-Saint-Winnoc (France, dép.Nord), Furnes (Belgium) and in the Netherlands, prov. Zealand, Oostburg, Souburg, Middelburg and Burgh. The chain of circular defence works is interrupted between Furnes and Oostburg. Here can be found however the cities of Oudenburg and Aardenburg, dating back to the Roman period. They have an approximately square shape, i.e. the shape of a Roman castellum

Geslagsaktiwiteit van Romanov-Karakoelkruisings onder ekstensiewe toestande

Gedurende 1973 is 87,5 x 12,5 en 75 x 25% Romanov-Karakoelkruisings tweekeer per dag getoets ten einde die teelseisoen, anestrus, die lengte van die estrussiklus en estrusperiode te bepaal. Die gemiddelde aantal ovulasies per ooi is d.m.v. laparotomie gedurende Mei vasgestel. Die proef is onder kraaltoestande uitgevoer waar'n onderhoudsrantsoenaan die diere verskaf is. Die proef is gedurende 1974 herhaal met 50 x 50 en 25 x 75 % Romanov-Karakoelkruisings. Puberteit is ook by die 87,5 % en 75% Romanovkruisings bepaal deur hulle vanaf 60 dae ouderdom tot aan die einde van die eerste teelseisoen tweekeer. per dag vir bronstigheid te toets. Al die kruisings wat ondersoek is, het 'n streng afgebakende teelseisoen geopenbaar wat vanaf die helfte van Januarie tot Augustus strek. Die res van die jaar kom 'n diep anestrus voor waartydens nie meer as gemiddeld 17,9% van die moontlike estrussiklusse per maand voorgekom het nie. Die gemiddelde lengte van die estrussiklus was nie verskillend van die van die Karakoel nie, maar die estrusperiode was betekenisvol langer. Die ovulasietempo (eiselle/ooi/estrusperiode) het afgeneem vanaf 2,2 in die 87,5 % Romanov's tot 1,4 in 25 % Romanov's. Puberteit het ongeveer twee maande voor die suiwer Karakoele by die Romanov-kruisings voorgekom.English Title: Sexual activity of Romanov-Karakul crosses under semi-arid conditionsEnglish AbstractDuring 1973 87,5 x 12,5 and 75 25% Romanov - Karakul crosses were tested twice daily by vasectomized rams in order to determine their breeding season, anoestrous period, the length of the oestrous cycle and the duration of oestrus. During May the ovulation rate was recorded by laporatomy. The experiment was carried out with penned ewes on a maintenance ration. The procedure was repeated during 1974 with 50 x 50 and 25 x 75 % Romanov - Karakul crosses. Puberty was also determined in the 87,5 % and 75 % Romanovs by testing them twice daily for first oestrus and determining body mass at first oestrus. This was done from 60 days of age until the end of the first breeding season. All the crosses displayed oestrous activity from middle January to August. A deep anoestrus existed from September to the first half of January during which no more than 17,9 % of the possible oestrous cycles were exhibited. The length of the oestrous cycle did not differ from the Karakul but the oestrous period was significantly longer. The ovulation rate (number of ova/ewe/oestrus&gt; decreased from 2,2 in the 85% Romanovs to 1,4 in the 25% Romanovs. Puberty occurred some two months before purebred Karakuls in the two crosses evaluated

SKY1 is involved in cisplatin-induced cell kill in Saccharomyces cerevisiae, and inactivation of its human homologue, SRPK1, induces cisplatin resistance in a human ovarian carcinoma cell line

The therapeutic potential of cisplatin, one of the most active and widely used anticancer drugs, is severely limited by the occurrence of cellular resistance. In this study, using budding yeast Saccharomyces cerevisiae as a model organism to identify novel drug resistance genes, we found that disruption of the yeast gene SKY1 (serine/arginine-rich protein-specific kinase from budding yeast) by either transposon insertion or one-step gene replacement conferred cellular resistance to cisplatin. Heterologous expression of the human SKY1 homologue SRPK1 (serine/arginine-rich protein-specific kinase) in SKY1 deletion mutant yeast cells restored cisplatin sensitivity, suggesting that SRPK1 is a cisplatin sensitivity gene, the inactivation of which could lead to cisplatin resistance. Subsequently, we investigated the role of SRPK1 in cisplatin sensitivity and resistance in human ovarian carcinoma A2780 cells using antisense oligodeoxynucleotides. Treatment of A2780 cells with antisense oligodeoxynucleotides directed against the translation initiation site of SRPK1 led to down-regulation of SRPK1 protein and conferred a 4-fold resistance to cisplatin. The human SRPK1 gene has not been associated with drug resistance before. Our new findings strongly suggest that SRPK1 is involved in cisplatin-induced cell kill and indicate that SRPK1 might potentially be of importance for studying clinical drug resistance

RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response

PURPOSE: The aim of this study was to investigate whether expression of particular drug resistance genes in primary operable breast cancer correlates with response to first-line chemotherapy in advanced disease. EXPERIMENTAL DESIGN: We determined mRNA levels of BCRP, LRP, MRP1, MRP2, and MDR1 in 59 primary breast tumor specimens of patients who

Progestogenic effects of tibolone on human endometrial cancer cells

Tibolone, a synthetic steroid acting in a tissue-specific manner and used in hormone replacement therapy, is converted into three active metabolites: a Delta(4) isomer (exerting progestogenic and androgenic effects) and two hydroxy metabolites, 3 alpha-hydroxytibolone (3 alpha-OH-tibolone) and 3beta-OH-tibolone (exerting estrogenic effects). In the present study an endometrial carcinoma cell line (Ishikawa PRAB-36) was used to investigate the progestogenic properties of tibolone and its metabolites. This cell line contains progesterone receptors A and B, but lacks estrogen and androgen receptors. When tibolone was added to the cells, complete conversion into the progestogenic/androgenic Delta(4) isomer was observed within 6 d. Furthermore, when cells were cultured with tibolone or when the Delta(4) isomer or the established progestagen medroxyprogesterone acetate was added to the medium, marked inhibition of growth was observed. Interestingly, 3 beta-OH-tibolone also induces some inhibition of growth. These growth inhibitions were not observed in progesterone receptor-negative parental Ishikawa cells, and progestagen-induced growth inhibition of PRAB-36 cells could readily be reversed using the antiprogestagen Org-31489. Upon measuring the expression of two progesterone-regulated genes (fibronectin and IGF-binding protein-3), tibolone, the Delta(4) isomer and medroxyprogesterone acetate showed similar gene expression regulation. These results indicate that tibolone, the Delta(4) metabolite, and to some extent 3 beta-OH-tibolone exert progestogenic effects. Tibolone and most likely 3 beta-OH-tibolone are converted into the Delta(4) metabolite

Final analysis from RESONATE: Up to six years of follow‐up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma

Ibrutinib, a once‐daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single‐agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high‐risk features. Here we report the final analysis from RESONATE with median follow‐up on study of 65.3 months (range, 0.3‐71.6) in the ibrutinib arm. Median progression‐free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113‐0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high‐risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080‐0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418‐0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all‐grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long‐term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high‐risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707)

Identification of quiescent, stem-like cells in the distal female reproductive tract

In fertile women, the endometrium undergoes regular cycles of tissue build-up and regression. It is likely that uterine stem cells are involved in this remarkable turn over. The main goal of our current investigations was to identify slow-cycling (quiescent) endometrial stem cells by means of a pulse-chase approach to selectively earmark, prospectively isolate, and characterize label-retaining cells (LRCs). To this aim, transgenic mice expressing histone2B-GFP (H2B-GFP) in a Tet-inducible fashion were administered doxycycline (pulse) which was thereafter withdrawn from the drinking water (chase). Over time, dividing cells progressively loose GFP signal whereas infrequently dividing cells retain H2B-GFP expression. We evaluated H2B-GFP retaining cells at different chase time points and identified long-term (LT; >12 weeks) LRCs. The LT-LRCs are negative for estrogen receptor-α and express low levels of progesterone receptors. LRCs sorted by FACS are able to form spheroids capable of self-renewal and differentiation. Upon serum stimulation spheroid cells are in

Consequences of loss of progesterone receptor expression in development of invasive endometrial cancer

PURPOSE: In endometrial cancer, loss of progesterone receptors (PR) is associated with more advanced disease. This study aimed to investigate the mechanism of action of progesterone and the loss of its receptors (PRA and PRB) in development of endometrial cancer. EXPERIMENTAL DESIGN: A 9600-cDNA microarray analysis was performed to study regulation of gene expression in the human endometrial cancer subcell line Ishikawa PRAB-36 by the progestagen medroxy progesterone acetate (MPA). Five MPA-regulated genes were selected for additional investigation. Expression of these genes was studied by Northern blot and by immunohistochemistry in Ishikawa subcell lines expressing different PR isoforms. Additionally, endometrial cancer tissue samples were immunohistochemically stained to study the in vivo protein expression of the selected genes. RESULTS: In the PRAB-36 cell line, MPA was found to regulate the expression of a number of invasion- and metastasis-related genes. On additional investigation of five of these genes (CD44, CSPG/Versican, Tenascin-C, Fibronectin-1, and Integrin-beta 1), it was observed that expression and progesterone regulation of expression of these genes varied in subcell lines expressing different PR isoforms. Furthermore, in advanced endometrial cancer, it was shown that loss of expression of both PR and E-cadherin was associated with increased expression CD44 and CSPG/Versican. CONCLUSION: The present study shows that progestagens exert a modulatory effect on the expression of genes involved in tumor cell invasion. As a consequence, loss of PR expression in human endometrial cancer may lead to development of a more invasive phenotype of the respective tumor

SPIDER: Probing the Early Universe with a Suborbital Polarimeter

We evaluate the ability of SPIDER, a balloon-borne polarimeter, to detect a divergence-free polarization pattern ("B-modes") in the Cosmic Microwave Background (CMB). In the inflationary scenario, the amplitude of this signal is proportional to that of the primordial scalar perturbations through the tensor-to-scalar ratio r. We show that the expected level of systematic error in the SPIDER instrument is significantly below the amplitude of an interesting cosmological signal with r=0.03. We present a scanning strategy that enables us to minimize uncertainty in the reconstruction of the Stokes parameters used to characterize the CMB, while accessing a relatively wide range of angular scales. Evaluating the amplitude of the polarized Galactic emission in the SPIDER field, we conclude that the polarized emission from interstellar dust is as bright or brighter than the cosmological signal at all SPIDER frequencies (90 GHz, 150 GHz, and 280 GHz), a situation similar to that found in the "Southern Hole." We show that two ~20-day flights of the SPIDER instrument can constrain the amplitude of the B-mode signal to r<0.03 (99% CL) even when foreground contamination is taken into account. In the absence of foregrounds, the same limit can be reached after one 20-day flight.Comment: 29 pages, 8 figures, 4 tables; v2: matches published version, flight schedule updated, two typos fixed in Table 2, references and minor clarifications added, results unchange

Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2.

Results of RESONATE-2 (PCYC-1115/1116) supported approval of ibrutinib for first-line treatment of chronic lymphocytic leukemia. Extended analysis of RESONATE-2 was conducted to determine long-term efficacy and safety of ibrutinib in older patients with chronic lymphocytic leukemia. A total of 269 patients aged ≥65 years with previously untreated chronic lymphocytic leukemia without del(17p) were randomized 1:1 to ibrutinib (n=136) or chlorambucil (n=133) on days 1 and 15 of a 28-day cycle for 12 cycles. Median ibrutinib treatment duration was 28.5 months. Ibrutinib significantly prolonged progression-free survival versus chlorambucil (median, not reached vs 15 months; hazard ratio, 0.12; 95% confidence interval, 0.07-0.20; P<0.0001). The 24-month progression-free survival was 89% with ibrutinib (97% and 89% in patients with del[11q] and unmutated immunoglobulin heavy chain variable region gene, respectively). Progression-free survival rates at 24 months were also similar regardless of age (<75 years [88%], ≥75 years [89%]). Overall response rate was 92% (125/136). Rate of complete response increased substantially from 7% at 12 months to 18% with extended follow up. Greater quality of life improvements occurred with ibrutinib versus chlorambucil in Functional Assessment of Chronic Illness Therapy-Fatigue (P=0.0013). The most frequent grade ≥3 adverse events were neutropenia (12%), anemia (7%), and hypertension (5%). Rate of discontinuations due to adverse events was 12%. Results demonstrated that first-line ibrutinib for elderly patients with chronic lymphocytic leukemia provides sustained response and progression-free survival benefits over chemotherapy, with depth of response improving over time without new toxicity concerns. This trial was registered at clinicaltrials.gov identifier 01722487 and 01724346