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

The Custodial Randall-Sundrum Model: From Precision Tests to Higgs Physics

We reexamine the Randall-Sundrum (RS) model with enlarged gauge symmetry SU(2)_L x SU(2)_R x U(1)_X x P_LR in the presence of a brane-localized Higgs sector. In contrast to the existing literature, we perform the Kaluza-Klein (KK) decomposition within the mass basis, which avoids the truncation of the KK towers. Expanding the low-energy spectrum as well as the gauge couplings in powers of the Higgs vacuum expectation value, we obtain analytic formulas which allow for a deep understanding of the model-specific protection mechanisms of the T parameter and the left-handed Z-boson couplings. In particular, in the latter case we explain which contributions escape protection and identify them with the irreducible sources of P_LR symmetry breaking. We furthermore show explicitly that no protection mechanism is present in the charged-current sector confirming existing model-independent findings. The main focus of the phenomenological part of our work is a detailed discussion of Higgs-boson couplings and their impact on physics at the CERN Large Hadron Collider. For the first time, a complete one-loop calculation of all relevant Higgs-boson production and decay channels is presented, incorporating the effects stemming from the extended electroweak gauge-boson and fermion sectors.Comment: 74 pages, 13 figures, 3 tables. v2: Matches version published in JHE

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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The Fermion Mass Hierarchy in Models with Warped Extra Dimensions and a Bulk Higgs

The phenomenological implications of allowing the Higgs to propagate in both AdS${}_5$ and a class of asymptotically AdS spaces are considered. Without tuning, the vacuum expectation value (VEV) of the Higgs is peaked towards the IR tip of the space and hence such a scenario still offers a potential resolution to the gauge-hierarchy problem. When the exponent of the Higgs VEV is approximately two and one assumes order one Yukawa couplings, then the fermion Dirac mass term is found to range from $\sim 10^{-5}$ eV to $\sim 200$ GeV in approximate agreement with the observed fermion masses. However, this result is sensitive to the exponent of the Higgs VEV, which is a free parameter. This paper offers a number of phenomenological and theoretical motivations for considering an exponent of two to be the optimal value. In particular, the exponent is bounded from below by the Breitenlohner-Freedman bound and the requirement that the dual theory resolves the gauge hierarchy problem. While, in the model considered, if the exponent is too large, electroweak symmetry may not be broken. In addition, the holographic method is used to demonstrate, in generality, that the flatter the Higgs VEV, the smaller the contribution to the electroweak $T$ parameter. In addition, the constraints from a large class of gauge mediated and scalar mediated flavour changing neutral currents, will be at minimal values for flatter Higgs VEVs. Some initial steps are taken to investigate the physical scalar degrees of freedom that arise from a mixing between the $W_5/Z_5$ components and the Higgs components.Comment: 34 pages, 20 figures, 1 table; v3: matches version to be published in JHE

Phenomenology of a light gluon resonance in top-physics at Tevatron and LHC

We present a phenomenological analysis of the recent Tevatron results on the $t \bar t$ forward-backward asymmetry and invariant-mass spectrum assuming a new contribution from an s-channel gluon resonance with a mass in the range from 700 to 2500 GeV. In contrast to most of the previous works, this analysis shows that for masses below ~1 TeV resonant New Physics could accommodate the experimental data. In general, we find that axial-like couplings are preferred for light and top quark couplings, and that only top quark couples strongly to New Physics. We find that composite model scenarios arise naturally from only phenomenological analyses of the experimental results. We show that our results are compatible with recent LHC limits in dijet and $t \bar t$ production, and find some tension for large resonance mass ~2.5 TeV. We indicate as best observables for discriminating a relatively light new gluon a better resolution in CDF forward-backward asymmetry, as well as the $t \bar t$ charge asymmetry and invariant-mass spectrum at the LHC.Comment: 22 pages with 5 figure