History of the rare cancer network and past research.

Approximately, twenty years ago, the Rare Cancer Network (RCN) was formed in Lausanne, Switzerland, to support the study of rare malignancies. The RCN has grown over the years and now includes 130 investigators from twenty-four nations on six continents. The network held its first international symposium in Nice, France, on March 21-22, 2014. The proceedings of that meeting are presented in two companion papers. This manuscript reviews the history of the growth of the RCN and contains the abstracts of fourteen oral presentations made at the meeting of prior RCN studies. From 1993 to 2014, 74 RCN studies have been initiated, of which 54 were completed, 10 are in progress or under analysis, and 9 were stopped due to poor accrual. Forty-four peer reviewed publications have been written on behalf of the RCN

Improving quality of care and clinical outcomes for rectal cancer through clinical audits in a multicentre cancer care organisation

Introduction: Colorectal cancer treatment requires a complex, multidisciplinary approach. Because of the potential variability, monitoring through clinical audits is advisable. This study assesses the effects of a quality improvement action plan in patients with locally advanced rectal cancer and treated with radiotherapy. Methods: Comparative, multicentre study in two cohorts of 120 patients each, selected randomly from patients diagnosed with rectal cancer who had initiated radiotherapy with a curative intent. Based on the results from a baseline clinical audit in 2013, a quality improvement action plan was designed and implemented; a second audit in 2017 evaluated its impact. Results: Standardised information was present on 77.5% of the magnetic resonance imaging (MRI) staging reports. Treatment strategies were similar in all three study centres. Of the patients whose treatment was interrupted, just 9.7% received a compensation dose. There was an increase in MRI re-staging from 32.5 to 61.5%, and a significant decrease in unreported circumferential resection margins following neoadjuvant therapy (ypCRM), from 34.5 to 5.6% (p < 0.001). Conclusions: The comparison between two clinical audits showed improvements in neoadjuvant radiotherapy in rectal cancer patients. Some indicators reveal areas in need of additional efforts, for example to reduce the overall treatment time

Methylglyoxal Produced by Amyloid- Peptide-Induced Nitrotyrosination of Triosephosphate Isomerase Triggers Neuronal Death in Alzheimer’s Disease

Amyloid-β peptide (Aβ) aggregates induce nitro-oxidative stress, contributing to the characteristic neurodegeneration found in Alzheimer's disease (AD). One of the most strongly nitrotyrosinated proteins in AD is the triosephosphate isomerase (TPI) enzyme which regulates glycolytic flow, and its efficiency decreased when it is nitrotyrosinated. The main aims of this study were to analyze the impact of TPI nitrotyrosination on cell viability and to identify the mechanism behind this effect. In human neuroblastoma cells (SH-SY5Y), we evaluated the effects of Aβ42 oligomers on TPI nitrotyrosination. We found an increased production of methylglyoxal (MG), a toxic byproduct of the inefficient nitro-TPI function. The proapoptotic effects of Aβ42 oligomers, such as decreasing the protective Bcl2 and increasing the proapoptotic caspase-3 and Bax, were prevented with a MG chelator. Moreover, we used a double mutant TPI (Y165F and Y209F) to mimic nitrosative modifications due to Aβ action. Neuroblastoma cells transfected with the double mutant TPI consistently triggered MG production and a decrease in cell viability due to apoptotic mechanisms. Our data show for the first time that MG is playing a key role in the neuronal death induced by Aβ oligomers. This occurs because of TPI nitrotyrosination, which affects both tyrosines associated with the catalytic center

Memory in low-grade glioma patients treated with radiotherapy or temozolomide: a correlative analysis of EORTC study 22033-26033

Background: EORTC study 22033-26033 showed no difference in progression-free survival between high-risk low-grade glioma receiving either radiotherapy (RT) or temozolomide (TMZ) chemotherapy alone as primary treatment. Considering the potential long-term deleterious impact of RT on memory functioning, this study aims to determine whether TMZ is associated with less impaired memory functioning. Methods: Using the Visual Verbal Learning Test (VVLT), memory functioning was evaluated at baseline and subsequently every 6 months. Minimal compliance for statistical analyses was set at 60%. Conventional indices of memory performance (VVLT Immediate Recall, Total Recall, Learning Capacity, and Delayed Recall) were used as outcome measures. Using a mixed linear model, memory functioning was compared between treatment arms and over time. Results: Neuropsychological assessment was performed in 98 patients (53 RT, 46 TMZ). At 12 months, compliance had dropped to 66%, restricting analyses to baseline, 6 months, and 12 months. At baseline, patients in either treatment arm did not differ in memory functioning, sex, age, or educational level. Over time, patients in both arms showed improvement in Immediate Recall (P = 0.017) and total number of words recalled (Total Recall; P < 0.001, albeit with delayed improvement in RT patients (group by time; P = 0.011). Memory functioning was not associated with RT gross, clinical, or planned target volumes. Conclusion: In patients with high-risk low-grade glioma there is no indication that in the first year after treatment, RT has a deleterious effect on memory function compared with TMZ chemotherapy. Keywords: chemotherapy; low-grade glioma; memory functioning; radiotherapy

The Alkaline Hydrolysis of Sulfonate Esters: Challenges in Interpreting Experimental and Theoretical Data

Sulfonate ester hydrolysis has been the subject of recent debate, with experimental evidence interpreted in terms of both stepwise and concerted mechanisms. In particular, a recent study of the alkaline hydrolysis of a series of benzene arylsulfonates (Babtie et al., Org. Biomol. Chem. 10, 2012, 8095) presented a nonlinear Brønsted plot, which was explained in terms of a change from a stepwise mechanism involving a pentavalent intermediate for poorer leaving groups to a fully concerted mechanism for good leaving groups and supported by a theoretical study. In the present work, we have performed a detailed computational study of the hydrolysis of these compounds and find no computational evidence for a thermodynamically stable intermediate for any of these compounds. Additionally, we have extended the experimental data to include pyridine-3-yl benzene sulfonate and its N-oxide and N-methylpyridinium derivatives. Inclusion of these compounds converts the Brønsted plot to a moderately scattered but linear correlation and gives a very good Hammett correlation. These data suggest a concerted pathway for this reaction that proceeds via an early transition state with little bond cleavage to the leaving group, highlighting the care that needs to be taken with the interpretation of experimental and especially theoretical data

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Multiscale molecular dynamics of protein aggregation

The 60's gave birth to the practical implementation of classical mechanics to unravel the dynamics and energetics of biomolecules. In the 70's the use of generalized force fields and more advanced integrative solutions to the microscopic understanding of nature (like hybrid QM/MM) were introduced. During the 80's, algorithms to obtain free energy values were further developed and in the 90's practical integration schemes of molecular mechanics force fields with other levels of detail (QM on one extreme and advances in implicit solvation on the other) were implemented in widely spread software. In the first decade of the XXIst century a considerable effort has been put in two seemingly discordant models for the simulation of biomolecules. On the one hand, extraordinary advances in computing technologies (both in terms of processor power and of new efficient parallel and distributed computing schemas) have allowed researchers to deal with bigger systems and longer simulations, reaching molecular processes including millions of particles or lying in the milisecond scale. On the other hand, the realization that the relevant answers to many biomolecular problems are not homogeneously distributed through the molecular structure, something already envisioned by the QM/MM pioneers more than three decades ago, has led researchers to find smart ways of putting different emphases on different ranges of the spatial or system time scale. In this context, e.g., molecular aggregation represents a paradigm for multiscalability, as molecular recognition can be understood with simple (semi-)macroscopic electrostatic terms when the two fragments are far apart, while the atomic interactions need to be considered in full detail upon close distances. In this manuscript the current status of the techniques that use multiple scale representations of biomolecules are reviewed, and the findings are synthesized in a modular schema that can be extensively used when studying aggregation processes. It is shown that a smart alternative to brute force and massive computation of uninteresting regions in the all atom potential energy surface is the consideration of a simplified reference potential, explored thoroughly in the relevant regions, combined with a free energy perturbation approach that transforms this simple representation to a full atom representation.Fil: Avila, Cesar Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Dreschel, Nils J. D.. Universitat Pompeu Fabra; EspañaFil: Alcántara, Raúl. Universitat Pompeu Fabra; EspañaFil: Villà Freixa, Jordi. Universitat Pompeu Fabra; Españ