Combination, Modulation and Interplay of Modern Radiotherapy with the Tumor Microenvironment and Targeted Therapies in Pancreatic Cancer: Which Candidates to Boost Radiotherapy?

Pancreatic ductal adenocarcinoma cancer (PDAC) is a highly diverse disease with low tumor immunogenicity. PDAC is also one of the deadliest solid tumor and will remain a common cause of cancer death in the future. Treatment options are limited, and tumors frequently develop resistance to current treatment modalities. Since PDAC patients do not respond well to immune checkpoint inhibitors (ICIs), novel methods for overcoming resistance are being explored. Compared to other solid tumors, the PDAC's tumor microenvironment (TME) is unique and complex and prevents systemic agents from effectively penetrating and killing tumor cells. Radiotherapy (RT) has the potential to modulate the TME (e.g., by exposing tumor-specific antigens, recruiting, and infiltrating immune cells) and, therefore, enhance the effectiveness of targeted systemic therapies. Interestingly, combining ICI with RT and/or chemotherapy has yielded promising preclinical results which were not successful when translated into clinical trials. In this context, current standards of care need to be challenged and transformed with modern treatment techniques and novel therapeutic combinations. One way to reconcile these findings is to abandon the concept that the TME is a well-compartmented population with spatial, temporal, physical, and chemical elements acting independently. This review will focus on the most interesting advancements of RT and describe the main components of the TME and their known modulation after RT in PDAC. Furthermore, we will provide a summary of current clinical data for combinations of RT/targeted therapy (tRT) and give an overview of the most promising future directions

Heliyon

Purpose: Restraint is often used when administering procedures to children. However, no metrologically scale to measure the restraint intensity had yet been validated. This study validated the metrological criteria of a scale measuring the restraint intensity, Procedural Restraint Intensity in Children (PRIC), used during procedures in children. Design and methods: The PRIC scale performance was measured by a group of 7 health professionals working in a children's hospital, by watching 20 videos of health care procedures. This group included 2 physicians, 1 pediatric resident, and 4 nurses. The intra-class correlation coefficients were calculated to evaluate the inter-rater and test-retest reliability and the construct validity with the correlation between PRIC scale and a numerical rating scale. Results: One hundred and forty measurements were made. Inter-rater and test-retest correlation coefficients were 0.98 and 0.98, respectively. The 2 scales were positively correlated with a Spearman coefficient of 0.93. Conclusions: This study validated the Procedural Restraint Intensity in Children (PRIC) scale in metrological terms with some limitation. However, there is not gold standard scale to precisely validate the reliability of this tool and this study has been conducted in "experimental" conditions. Nevertheless, this is the first scale measuring the intensity of physical restraint with a metrological validation. The next step will be to validate it in real clinical situations

Reliability and tolerance comparison in water supply networks

The final publication is available at Springer via http://dx.doi.org/10.1007/s11269-010-9753-2Urban water supply is a high priority service and so looped networks are extensively used in order to considerably reduce the number of consumers affected by a failure. Looped networks may be redundant in connectivity and capacity. The concept of reliability has been introduced in an attempt to quantitatively measure the possibility of maintaining an adequate service for a given period. Numerous researchers have considered reliability as a measure of redundancy. This concept is usually implicit, but some researchers have even stated it explicitly. This paper shows why reliability cannot be considered a measure of redundancy given that branched networks can achieve high values of reliability and this would deny the fact that a looped network is more reliable than a branched network with a similar layout and size. To this end the paper discusses two quantitative indices for measuring expected network behavior: reliability and tolerance. These indices are calculated and a comparison is made between looped, branched, and mixed networks. © 2011 Springer Science+Business Media B.V.The authors wish to acknowledge the support received from project IDAWAS, DPI2009-11591, of the Directorate-General of Research at the Spanish Ministry of Education, the grant PAID-02-09 for a stay at the Universidad Politecnica de Valencia by the first author, and a grant MAEC-AECI 0000202066 awarded to the second author by the Ministerio de Asuntos Exteriores y Cooperacion of Spain. The use of English in this paper was revised by John Rawlins; and the revision was funded by the Universidad Politecnica de Valencia, Spain.Martínez-Rodríguez, JB.; Montalvo Arango, I.; Izquierdo Sebastián, J.; Pérez García, R. (2011). Reliability and tolerance comparison in water supply networks. 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Treatment planning for MR-guided SBRT of pancreatic tumors on a 1.5 T MR-Linac: A global consensus protocol

Background and purpose: Treatment planning for MR-guided stereotactic body radiotherapy (SBRT) for pancreatic tumors can be challenging, leading to a wide variation of protocols and practices. This study aimed to harmonize treatment planning by developing a consensus planning protocol for MR-guided pancreas SBRT on a 1.5 T MR-Linac. Materials and methods: A consortium was founded of thirteen centers that treat pancreatic tumors on a 1.5 T MR-Linac. A phased planning exercise was conducted in which centers iteratively created treatment plans for two cases of pancreatic cancer. Each phase was followed by a meeting where the instructions for the next phase were determined. After three phases, a consensus protocol was reached. Results: In the benchmarking phase (phase I), substantial variation between the SBRT protocols became apparent (for example, the gross tumor volume (GTV) D99% ranged between 36.8 – 53.7 Gy for case 1, 22.6 – 35.5 Gy for case 2). The next phase involved planning according to the same basic dosimetric objectives, constraints, and planning margins (phase II), which led to a large degree of harmonization (GTV D99% range: 47.9–53.6 Gy for case 1, 33.9–36.6 Gy for case 2). In phase III, the final consensus protocol was formulated in a treatment planning system template and again used for treatment planning. This not only resulted in further dosimetric harmonization (GTV D99% range: 48.2–50.9 Gy for case 1, 33.5–36.0 Gy for case 2) but also in less variation of estimated treatment delivery times. Conclusion: A global consensus protocol has been developed for treatment planning for MR-guided pancreatic SBRT on a 1.5 T MR-Linac. Aside from harmonizing the large variation in the current clinical practice, this protocol can provide a starting point for centers that are planning to treat pancreatic tumors on MR-Linac systems

Evaluation of fungal contamination and mycotoxin production in maize silage

Agricultural activities involve daily use Of maize silage as feed for livestock, which can be contaminated by mycotoxigenic molds. To evaluate fungal contamination. and the production of mycotoxins in maize silage we propose a multi-disciplinary approach utilizing PCR methods with genes of the aflatoxin (ver-1, omt-1 and apa-2), fumonisin (FUMI) and trichothecene (TR16) biosynthesis pathways. To detect Aspergillus fumigatus, it 26S/intergenic spacer region of the rDNA complex was amplified. These specific PCR assays allowed. three major groups of toxigenic fungi-like aflatoxin-producing Aspergilli, fumonisin and trichothecene-producing Fusaria, and the ubiquitous mold A. fumigatus, to be targeted. A multimycotoxin method is also proposed to simultaneously quantify seven mycotoxins (i.e., aflatoxin B-1, citrinin, deoxynivalenol, fumonisin B-1, gliotoxin, ochratoxin A, zearalenone) in maize silage by high-perforrnance liquid chromatography coupled to mass spectrometry (HPLC-MS). These microbiological and analytical tools revealed three potentially toxigenic groups of fungi and A. fumigatus grown from mature maize silage (I I month old) that was collected in Normandy (France) and the, mycotoxins aflatoxin 13, (7.0-51.3 mu g/kg), citrinin (10.1-14.2 mu g/kg), deoxynivalenol (128.0-181.0 mu g/kg) and gliotoxin (6.6-11.9 mu g/kg). Results indicate that the combination of PCR and HPLC-MS can be used to assess fungal quality of maize silages. (C) 2008 Elsevier B.V. All rights reserved

Mycoflora and multimycotoxin detection in corn silage: Experimental study

International audienceAgricultural activities involve the use of crop preservation such as "trench-type" silo, which can sometimes be contaminated by fungi. To investigate the exposure of livestock and farm workers to fungal spores and mycotoxins, a multimycotoxin analysis method has been developed. Six mycotoxins (aflatoxin B-1, citrinin, deoxynivalenol, gliotoxin, ochratoxin A, and zearalenone) were quantified by high-performance liquid chromatography coupled to mass spectrometry after solid-phase extraction. An experimental study of fungal species and mycotoxins was conducted in corn silage (Normandy, France) during 9 months of monitoring. The results indicated the recurrence of around 20 different species, with some of them being potentially toxigenic fungi such as Aspergillus fumigatus, Aspergillus parasiticus, Fusarium verticillioides, and Monascus ruber, and the detection of aflatoxin B1 (4-34 ppb), citrinin (4-25 ppb), zearalenone (23-41 ppb), and deoxynivalenol (100-213 ppb). This suggested a possible chronic exposure to low levels of mycotoxins

A Localized Phage-Based Antimicrobial System: Effect of Alginate on Phage Desorption from β-TCP Ceramic Bone Substitutes

Tricalcium phosphate (TCP) is a prosthetic material commonly used as a bone substitute to repair osteoarticular diseases and injuries. In this type of bone reconstruction surgery, antibiotics remain the common preventive and therapeutic treatment for bacterial infection. Nevertheless, the emergence of multi-resistant strains requires complimentary or alternative treatments. Today, one of the promising alternative approaches is phage therapy. Phages are bacterial viruses that have several advantages over chemotherapy, such as the specificity of bacterial strain, the absence of side effects, and a rapid response. In this work, we studied the impact of alginate hydrogels for overlaying λvir-phage-loaded β-TCP ceramic bone substitutes, delaying the phage desorption. The results show that the use of a 1% alginate–CaCl2 hydrogel overlapping the β-TCP ceramic pellets leads to higher initial phage concentration on the material and extends the released time of phages to two weeks when compared with control pellets. These alginate-coated biomaterials also generate faster bacterial lysis kinetics and could therefore be a good practical prosthetic device for bone and joint surgeries by allowing local treatment of bacterial infections with phage therapy for a longer period of time