Cloning, sequencing and partial functional characterization of the 5' region of the human p75 tumor necrosis factor receptor-encoding gene (TNF-R)

A 1887-bp region at the 5' flank of the human p75 tumor necrosis factor receptor (p75 TNF-R)-encoding gene was found to be active in driving expression of the luc (luciferase-encoding) reporter gene, suggesting that it contains the promoter for the receptor. Rather unexpectedly, a 1827-bp region at the 3' end of the first intron of the p75 TNF-R gene also displayed promoter activity. This activity may be artefactual, reflecting only the presence of an enhancer in this region; yet it also raises the possibility that p75 TNF-R is controlled by more than one promoter and that it encodes various forms of the receptor, or even other proteins. We present here the nucleotide sequences of the 5' flanking and intron regions. Possible implications for the transcriptional regulation of the p75 TNF-R gene are discussed.

Elevated liver regeneration in response to pharmacological reduction of elevated portal venous pressure by terlipressin after partial hepatectomy.

BACKGROUND Liver regeneration is of crucial importance for patients undergoing living liver transplantations or extended liver resections and can be associated with elevated portal venous pressure, impaired hepatic regeneration, and postoperative morbidity. The aim of this study was to assess whether reduction of portal venous pressure by terlipressin improves postoperative liver regeneration in normal and steatotic livers after partial hepatectomy in a rodent model. METHODS Portal venous pressure was assessed after minor (30%), standard (60%), or extended (80%) partial hepatectomy (PH) in mice with and without liver steatosis. Liver regeneration was assessed by BrdU incorporation and Ki-67 immunostaining. RESULTS Portal venous pressure was significantly elevated post-PH in mice with normal and steatotic livers compared to sham-operated mice. Reduction of elevated portal pressure after 80% PH by terlipressin was associated with an increase of hepatocellular proliferation. In steatotic livers, animals treated with terlipressin had an increase in liver regeneration after 30% PH and increased survival after 60% PH. Mechanistically, terlipressin alleviated IL-6 mRNA expression following PH and down-regulated p21 and GADD45 mRNA suggesting a reduction of cell cycle inhibition and cellular stress. CONCLUSIONS Reduction of elevated portal pressure post-PH by the use of terlipressin improves liver regeneration after PH in lean and steatotic mouse livers.

Overthrowing the Tyranny of Alphabetical Ordering in Documentation Systems

Software developers are often unsure of the exact name of the API method they need to use to invoke the desired behavior. Most state-of-the-art documentation browsers present API artefacts in alphabetical order. Albeit easy to implement, alphabetical order does not help much: if the developer knew the name of the required method, he could have just searched for it in the first place. In a context where multiple projects use the same API, and their source code is available, we can improve the API presentation by organizing the elements in the order in which they are more likely to be used by the developer. Usage frequency data for methods is gathered by analyzing other projects from the same ecosystem and this data is used then to improve tools. We present a preliminary study on the potential of this approach to improve the API presentation by reducing the time it takes to find the method that implements a given feature. We also briefly present our experience with two proof-of-concept tools implemented for Smalltalk and Java.

Fully Adaptive Newton--Galerkin Methods for Semilinear Elliptic Partial Differential Equations

In this paper we develop an adaptive procedure for the numerical solution of general, semilinear elliptic problems with possible singular perturbations. Our approach combines both prediction-type adaptive Newton methods and a linear adaptive finite element discretization (based on a robust a posteriori error analysis), thereby leading to a fully adaptive Newton–Galerkin scheme. Numerical experiments underline the robustness and reliability of the proposed approach for various examples

Recommendations from GEC ESTRO Breast Cancer Working Group (I): Target definition and target delineation for accelerated or boost Partial Breast Irradiation using multicatheter interstitial brachytherapy after breast conserving closed cavity surgery

OBJECTIVE The aim was to develop a delineation guideline for target definition for APBI or boost by consensus of the Breast Working Group of GEC-ESTRO. PROPOSED RECOMMENDATIONS Appropriate delineation of CTV (PTV) with low inter- and intra-observer variability in clinical practice is complex and needs various steps as: (1) Detailed knowledge of primary surgical procedure, of all details of pathology, as well as of preoperative imaging. (2) Definition of tumour localization before breast conserving surgery inside the breast and translation of this information in the postoperative CT imaging data set. (3) Calculation of the size of total safety margins. The size should be at least 2 cm. (4) Definition of the target. (5) Delineation of the target according to defined rules. CONCLUSION Providing guidelines based on the consensus of a group of experts should make it possible to achieve a reproducible and consistent definition of CTV (PTV) for Accelerated Partial Breast Irradiation (APBI) or boost irradiation after breast conserving closed cavity surgery, and helps to define it after selected cases of oncoplastic surgery.

Interobserver variations of target volume delineation in multicatheter partial breast brachytherapy after open cavity surgery

PURPOSE To investigate interobserver variations of target volume delineations in accelerated partial breast irradiation with multicatheter brachytherapy (BT) and to assess the impact of guidelines on consistency of contouring. METHODS AND MATERIALS A contouring study with two phases in interstitial accelerated partial breast irradiation after open cavity surgery was conducted by the Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology Breast Cancer Working Group. Contours of cavity and planning target volume (PTV) on preimplant and postimplant CT images were delineated. In Phase 1, nine radiation oncologists defined the target volumes of 5 patients, whereas in Phase 2, four observers draw the contours of 4 patients applying guidelines. In Phase 1, experience in breast BT after open cavity surgery was assessed. The delineations were compared between Phase 1 and Phase 2, the impact of guidelines was assessed, and cavity visualization score was related to consistency of delineations. RESULTS Significant interobserver variability in delineations of lumpectomy cavity and PTV was observed among the participants. Observers with BT experience after open cavity surgery outlined the cavity and PTV more consistently (conformity indexgen: 0.52 vs. 0.48 and 0.59 vs. 0.55 for preimplant and postimplant cavities). For all volumes, the mean Vmax/Vmin was 2.2 vs. 2.8. Having used guidelines all conformity indices increased significantly. For cavity, the increase was 14% and 11%, whereas for the PTV, 28% and 17% on the preimplant and postimplant CT images, respectively. A strong correlation was found between consistency of contours and cavity visualization score. CONCLUSIONS Simple guidelines on defining the lumpectomy cavity significantly increased the consistency of contouring. Reliable consistency of target volume definition can be expected only for good cavity visibility.

5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial.

BACKGROUND In a phase 3, randomised, non-inferiority trial, accelerated partial breast irradiation (APBI) for patients with stage 0, I, and IIA breast cancer who underwent breast-conserving treatment was compared with whole-breast irradiation. Here, we present 5-year follow-up results. METHODS We did a phase 3, randomised, non-inferiority trial at 16 hospitals and medical centres in seven European countries. 1184 patients with low-risk invasive and ductal carcinoma in situ treated with breast-conserving surgery were centrally randomised to either whole-breast irradiation or APBI using multicatheter brachytherapy. The primary endpoint was local recurrence. Analysis was done according to treatment received. This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS Between April 20, 2004, and July 30, 2009, 551 patients had whole-breast irradiation with tumour-bed boost and 633 patients received APBI using interstitial multicatheter brachytherapy. At 5-year follow-up, nine patients treated with APBI and five patients receiving whole-breast irradiation had a local recurrence; the cumulative incidence of local recurrence was 1·44% (95% CI 0·51-2·38) with APBI and 0·92% (0·12-1·73) with whole-breast irradiation (difference 0·52%, 95% CI -0·72 to 1·75; p=0·42). No grade 4 late side-effects were reported. The 5-year risk of grade 2-3 late side-effects to the skin was 3·2% with APBI versus 5·7% with whole-breast irradiation (p=0·08), and 5-year risk of grade 2-3 subcutaneous tissue late side-effects was 7·6% versus 6·3% (p=0·53). The risk of severe (grade 3) fibrosis at 5 years was 0·2% with whole-breast irradiation and 0% with APBI (p=0·46). INTERPRETATION The difference between treatments was below the relevance margin of 3 percentage points. Therefore, adjuvant APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is not inferior to adjuvant whole-breast irradiation with respect to 5-year local control, disease-free survival, and overall survival. FUNDING German Cancer Aid.