Radiotherapy for tumors of the stomach and gastroesophageal junction - a review of its role in multimodal therapy

There is broad consensus on surgical resection being the backbone of curative therapy of gastric- and gastroesophageal junction carcinoma. Nevertheless, details on therapeutic approaches in addition to surgery, such as chemotherapy, radiotherapy or radiochemotherapy are discussed controversially; especially whether external beam radiotherapy should be applied in addition to chemotherapy and surgery is debated in both entities and differs widely between regions and centers. Early landmark trials such as the Intergroup-0116 and the MAGIC trial must be interpreted in the context of potentially insufficient lymph node resection. Despite shortcomings of both trials, benefits on overall survival by radiochemotherapy and adjuvant chemotherapy were confirmed in populations of D2-resected gastric cancer patients by Asian trials. Recent results on junctional carcinoma patients strongly suggest a survival benefit of neoadjuvant radiochemotherapy in curatively resectable patients. An effect of chemotherapy in the perioperative setting as given in the MAGIC study has been confirmed by the ACCORD07 trial for junctional carcinomas; however both the studies by Stahl et al. and the excellent outcome in the CROSS trial as compared to all other therapeutic approaches indicate a superiority of neoadjuvant radiochemotherapy as compared to perioperative chemotherapy in junctional carcinoma patients. Surgery alone without neoadjuvant or perioperative therapy is considered suboptimal in patients with locally advanced disease. In gastric carcinoma patients, perioperative chemotherapy has not been compared to adjuvant radiochemotherapy in a randomized setting. Nevertheless, the results of the recently published ARTIST trial and the Chinese data by Zhu and coworkers, indicate a superiority of adjuvant radiochemotherapy as compared to adjuvant chemotherapy in terms of disease free survival in Asian patients with advanced gastric carcinoma. The ongoing CRITICS trial is supposed to provide reliable conclusions about which therapy should be preferred in Western patients with gastric carcinoma. If radiotherapy is performed, modern approaches such as intensity-modulated radiotherapy and image guidance should be applied, as these methods reduce dose to organs at risk and provide a more homogenous coverage of planning target volumes

Machined Versus Cast Abutments for Dental Implants: a 1-year Within-patient Multicentre Randomized Controlled Trial Assessing Marginal Seal Capacity and Outcomes

PURPOSE To compare clinical outcomes of machined titanium abutments (machined group) versus cast cobalt-chrome abutments (cast group) and to evaluate in vitro their implant fit. MATERIALS AND METHODS This study comprised two parts. In the in vitro part, the im-plant–abutment fit of 5 cast abutments and 5 machined abutments screwed on with a torque of 30 Ncm was qualitatively and quantitatively evaluated using micro-computed tomography (µ-CT) and AgNO3 to reveal connection gaps. In the clinical part, 31 partially edentulous subjects received two single non-adjacent implant-supported crowns at three centres. At impression taking, three and a half months after implant placement, implants were randomized to receive a machined or cast abutment according to a wi-thin-patient study design. Unfortunately, four patients dropped out and one patient lost one implant before randomization, so only 26 patients had their implants randomized. Outcome measures were: prosthesis and implant failures, any complications, and radiographic peri-implant marginal bone level changes. Patients were followed up to 1 year after loading. RESULTS The fit of the implant–abutment connection was assessed in vitro using µ-CT scans. No gaps were revealed at any of the machined or cast abutments tested. In the clinical part, after randomization, three patients dropped out, no implant failed, but one crown on a cast abutment was replaced. The between-group difference in prosthesis failure was not statistically different (McNemar chi-square test P = 1.0; difference in proportions = 0.039). One complication occurred in each group, the difference not being statistically different (McNemar test P = 1.000; difference in proportions = 0; 95% CI 0.06 to 15.99). Both groups presented statistically significant peri-implant marginal bone loss from implant placement to 1 year after loading, respectively-0.76 ± 1.01 mm for machined and-0.69 ± 0.82 mm for cast abutments, with no statistically significant differences between the two groups (mean difference 0.07 mm; 95% CI-0.54 to 0.67; P = 0.828). Both groups gradually lost marginal peri-implant bone from loading to 1 year after loading but this was not significantly different, respectively-0.06 ± 0.56 mm for machined and-0.10 ± 0.29 mm for cast abutments, with no statistically significant differences between the two groups (P = 0.739; mean difference 0.07 mm; 95% CI-0.12 to 0.16; P = 0.739). CONCLUSIONS Our clinical data suggests that implant prognosis up to 1 year after loading is not affected by using machined or cast abutments. In support of these findings, in vitro analysis proved that both types of abutments allow a tight fit with no gaps. The-refore, for the time being dentists should feel free to choose whichever type they prefer. However, these preliminary results need to be confirmed by larger trials with at least 10 years of follow-up

Estimation of synthetic accessibility score of drug-like molecules based on molecular complexity and fragment contributions

<p>Abstract</p> <p>Background</p> <p>A method to estimate ease of synthesis (synthetic accessibility) of drug-like molecules is needed in many areas of the drug discovery process. The development and validation of such a method that is able to characterize molecule synthetic accessibility as a score between 1 (easy to make) and 10 (very difficult to make) is described in this article.</p> <p>Results</p> <p>The method for estimation of the synthetic accessibility score (SAscore) described here is based on a combination of fragment contributions and a complexity penalty. Fragment contributions have been calculated based on the analysis of one million representative molecules from PubChem and therefore one can say that they capture historical synthetic knowledge stored in this database. The molecular complexity score takes into account the presence of non-standard structural features, such as large rings, non-standard ring fusions, stereocomplexity and molecule size. The method has been validated by comparing calculated SAscores with ease of synthesis as estimated by experienced medicinal chemists for a set of 40 molecules. The agreement between calculated and manually estimated synthetic accessibility is very good with <it>r</it>²= 0.89.</p> <p>Conclusion</p> <p>A novel method to estimate synthetic accessibility of molecules has been developed. This method uses historical synthetic knowledge obtained by analyzing information from millions of already synthesized chemicals and considers also molecule complexity. The method is sufficiently fast and provides results consistent with estimation of ease of synthesis by experienced medicinal chemists. The calculated SAscore may be used to support various drug discovery processes where a large number of molecules needs to be ranked based on their synthetic accessibility, for example when purchasing samples for screening, selecting hits from high-throughput screening for follow-up, or ranking molecules generated by various <it>de novo </it>design approaches.</p

A formally exact field theory for classical systems at equilibrium

We propose a formally exact statistical field theory for describing classical fluids with ingredients similar to those introduced in quantum field theory. We consider the following essential and related problems : i) how to find the correct field functional (Hamiltonian) which determines the partition function, ii) how to introduce in a field theory the equivalent of the indiscernibility of particles, iii) how to test the validity of this approach. We can use a simple Hamiltonian in which a local functional transposes, in terms of fields, the equivalent of the indiscernibility of particles. The diagrammatic expansion and the renormalization of this term is presented. This corresponds to a non standard problem in Feynman expansion and requires a careful investigation. Then a non-local term associated with an interaction pair potential is introduced in the Hamiltonian. It has been shown that there exists a mapping between this approach and the standard statistical mechanics given in terms of Mayer function expansion. We show on three properties (the chemical potential, the so-called contact theorem and the interfacial properties) that in the field theory the correlations are shifted on non usual quantities. Some perspectives of the theory are given.Comment: 20 pages, 8 figure

Molecular Modelling Guided Experimental Study for Isotopic Enrichment of Gadolinium

Abstract Molecular modelling and experimental studies were performed to predict the feasibility of Gd isotope separation using crown ether grafted resin. ) were found to be 6.3, 3.4, 9.7 and 11.1 for the isotopic pair of 155/158, 157/158, 155/160 and 157/160 respectively and shows promise for future study

Adsorption of CO on a Platinum (111) surface - a study within a four-component relativistic density functional approach

We report on results of a theoretical study of the adsorption process of a single carbon oxide molecule on a Platinum (111) surface. A four-component relativistic density functional method was applied to account for a proper description of the strong relativistic effects. A limited number of atoms in the framework of a cluster approach is used to describe the surface. Different adsorption sites are investigated. We found that CO is preferably adsorbed at the top position.Comment: 23 Pages with 4 figure

Interobserver agreement on definition of the target volume in stereotactic radiotherapy for pancreatic adenocarcinoma using different imaging modalities

PURPOSE The aim of this study was to evaluate interobserver agreement (IOA) on target volume definition for pancreatic cancer (PACA) within the Radiosurgery and Stereotactic Radiotherapy Working Group of the German Society of Radiation Oncology (DEGRO) and to identify the influence of imaging modalities on the definition of the target volumes. METHODS Two cases of locally advanced PACA and one local recurrence were selected from a large SBRT database. Delineation was based on either a planning 4D CT with or without (w/wo) IV contrast, w/wo PET/CT, and w/wo diagnostic MRI. Novel compared to other studies, a combination of four metrics was used to integrate several aspects of target volume segmentation: the Dice coefficient (DSC), the Hausdorff distance (HD), the probabilistic distance (PBD), and the volumetric similarity (VS). RESULTS For all three GTVs, the median DSC was 0.75 (range 0.17-0.95), the median HD 15 (range 3.22-67.11) mm, the median PBD 0.33 (range 0.06-4.86), and the median VS was 0.88 (range 0.31-1). For ITVs and PTVs the results were similar. When comparing the imaging modalities for delineation, the best agreement for the GTV was achieved using PET/CT, and for the ITV and PTV using 4D PET/CT, in treatment position with abdominal compression. CONCLUSION Overall, there was good GTV agreement (DSC). Combined metrics appeared to allow a more valid detection of interobserver variation. For SBRT, either 4D PET/CT or 3D PET/CT in treatment position with abdominal compression leads to better agreement and should be considered as a very useful imaging modality for the definition of treatment volumes in pancreatic SBRT. Contouring does not appear to be the weakest link in the treatment planning chain of SBRT for PACA

The use of 2D fingerprint methods to support the assessment of structural similarity in orphan drug legislation.

In the European Union, medicines are authorised for some rare disease only if they are judged to be dissimilar to authorised orphan drugs for that disease. This paper describes the use of 2D fingerprints to show the extent of the relationship between computed levels of structural similarity for pairs of molecules and expert judgments of the similarities of those pairs. The resulting relationship can be used to provide input to the assessment of new active compounds for which orphan drug authorisation is being sought

Rab2 promotes autophagic and endocytic lysosomal degradation

Rab7 promotes fusion of autophagosomes and late endosomes with lysosomes in yeast and metazoan cells, acting together with its effector, the tethering complex HOPS. Here we show that another small GTPase, Rab2, is also required for autophagosome and endosome maturation and proper lysosome function in Drosophila melanogaster. We demonstrate that Rab2 binds to HOPS, and that its active, GTP-locked form associates with autolysosomes. Importantly, expression of active Rab2 promotes autolysosomal fusions unlike that of GTP-locked Rab7, suggesting that its amount is normally rate limiting. We also demonstrate that RAB2A is required for autophagosome clearance in human breast cancer cells. In conclusion, we identify Rab2 as a key factor for autophagic and endocytic cargo delivery to and degradation in lysosomes