SUPREME-HN: a retrospective biomarker study assessing the prognostic value of PD-L1 expression in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck

Biomarcador; Carcinoma de células escamosas de cabeza y cuello; PD-L1Biomarker; Head and neck squamous cell carcinoma; PD-L1Biomarcador; Carcinoma de cèl·lules escamoses de cap i coll; PD-L1Background Programmed cell death ligand-1 (PD-L1) expression on tumor cells (TCs) is associated with improved survival in patients with head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy, although its role as a prognostic factor is controversial. This study investigates whether tumoral expression of PD-L1 is a prognostic marker in patients with recurrent and/or metastatic (R/M) HNSCC treated with standard chemotherapy. Methods This retrospective, multicenter, noninterventional study assessed PD-L1 expression on archival R/M HNSCC tissue samples using the VENTANA PD-L1 (SP263) Assay. PD-L1 high was defined as PD-L1 staining of ≥ 25% TC, with exploratory scoring at TC ≥ 10% and TC ≥ 50%. The primary objective of this study was to estimate the prognostic value of PD-L1 status in terms of overall survival (OS) in patients with R/M HNSCC. Results 412 patients (median age, 62.0 years; 79.9% male; 88.2% Caucasian) were included from 19 sites in seven countries. 132 patients (32.0%) had TC ≥ 25% PD-L1 expression; 199 patients (48.3%) and 85 patients (20.6%) had TC ≥ 10% and ≥ 50%, respectively. OS did not differ significantly across PD-L1 expression (at TC ≥ 25% cutoff median OS: 8.2 months vs TC < 25%, 10.1 months, P = 0.55) or the ≥ 10% and ≥ 50% cutoffs (at TC ≥ 10%, median OS: 9.6 months vs TC < 10%, 9.4 months, P = 0.32, and at TC ≥ 50%, median OS 7.9 vs TC < 50%, 10.0 months, P = 0.39, respectively). Conclusions PD-L1 expression, assessed using the VENTANA PD-L1 (SP263) Assay, was not prognostic of OS in patients with R/M HNSCC treated with standard of care chemotherapies.This study was sponsored by AstraZeneca. The protocol for this study was developed by the sponsor (AstraZeneca) and advisors. Data were collected collaboratively by the sponsor and clinical investigators. Statisticians employed by the sponsor analyzed the data. All authors participated in the preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication

Evidence for a novel neuronal mechanism driving Alzheimer's disease, upstream of amyloid

This perspective offers an alternative to the amyloid hypothesis in the etiology of Alzheimer's disease (AD). We review evidence for a novel signaling mechanism based on a little‐known peptide, T14. T14 could drive neurodegeneration as an aberrantly activated process of plasticity selective to interconnecting subcortical nuclei, the isodendritic core, where cell loss starts at the pre‐symptomatic stages of the disease. Each of these cell groups has the capacity to form T14, which can stimulate production of p‐Tau and β‐amyloid, suggestive of an upstream driver of neurodegeneration. Moreover, results in an animal AD model show that antagonism of T14 with a cyclated variant, NBP14, prevents formation of β‐amyloid, and restores cognitive function to that of wild‐type counterparts. Any diagnostic and/or therapeutic strategy based on T14‐NBP14 awaits validation in clinical trials. However, an understanding of this novel signaling system could bring much‐needed fresh insights into the progression of cell loss underlying AD. Highlights: The possible primary mechanism of neurodegeneration upstream of amyloid. Primary involvement of selectively vulnerable subcortical nuclei, isodendritic core. Bioactive peptide T14 trophic in development but toxic in context of mature brain. Potential for early‐stage biomarker to detect Alzheimer's disease. Effective therapeutic halting neurodegeneration, validated already in 5XFAD mice

A Multi-isotopic approach to investigate the influence of land use on nitrate removal in a highly saline lake-aquifer system

Endorheic or closed drainage basins in arid and semi-arid regions are vulnerable to pollution. Nonetheless, in the freshwater-saltwater interface of endorheic saline lakes, oxidation-reduction (redox) reactions can attenuate pollutants such as nitrate (NO3- ). This study traces the ways of nitrogen (N) removal in the Pétrola lake- aquifer system (central Spain), an endorheic basin contaminated with NO3- (up to 99.2 mg/L in groundwater). This basin was declared vulnerable to NO3- pollution in 1998 due to the high anthropogenic pressures (mainly agriculture and wastewaters). Hydrochemical, multi-isotopic (δ18ONO3, δ15NNO3, δ13CDIC, δ18OH2O, and δ2HH2O) and geophysical techniques (electrical resistivity tomography) were applied to identify the main redox processes at the freshwater-saltwater interface. The results showed that the geometry of this interface is influenced by land use, causing spatial variability of nitrogen biogeochemical processes over the basin. In the underlying aquifer, NO3- showed an average concentration of 38.5 mg/L (n = 73) and was mainly derived from agricultural inputs. Natural attenuation of NO3- was observed in dryland farming areas (up to 72%) and in irrigation areas (up to 66%). In the Pétrola Lake, mineralization and organic matter degradation in lake sediment play an important role in NO3- reduction. Our findings are a major step forward in understanding freshwater-saltwater interfaces as reactive zones for NO3- attenuation. We further emphasize the importance of including a land use perspective when studying water quality-environmental relationships in hydrogeological systems dominated by density- driven circulation

Tribocorrosion behavior of new martensitic stainless steels in sodium chloride solution

The tribo-electrochemical behavior of two new martensitic stainless steels in a 3% NaCI solution has been investigated. Different electrochemical and surface analysis techniques (Scanning Electron Microscopy, Focused Ion Beam) were discussed to analyze the influence of the effect of the electrochemical conditions on friction and wear, and to elucidate involved wear mechanisms (plastic deformation, plastic shakedown and low-cycle fatigue). The selected stainless steels degrade through a delamination type of wear mechanism. The effects of the applied potential on wear are related to the formation of a passive film which alters the mechanical behavior of the surface and subsurface of the materials to promote wear. A coefficient of friction below 0.6 promotes nanowear, and a transition was observed when the coefficient of friction exceeded that value. (C) 2016 Elsevier B.V. All rights reserved.The authors would like to thank to BPI, Region Centre and Tours Plus for support of this research. This work is done under the project FUI 11 Mekinox.Dalmau Borrás, A.; Rmili, W.; Richard, C.; Igual Muñoz, AN. (2016). Tribocorrosion behavior of new martensitic stainless steels in sodium chloride solution. Wear. 368:146-155. doi:10.1016/j.wear.2016.09.002S14615536

Anti-trbc1 antibody-based flow cytometric detection of t-cell clonality: Standardization of sample preparation and diagnostic implementation

© 2021 by the authors.A single antibody (anti-TRBC1; JOVI-1 antibody clone) against one of the two mutually exclusive T-cell receptor β-chain constant domains was identified as a potentially useful flow-cytometry (FCM) marker to assess Tαβ-cell clonality. We optimized the TRBC1-FCM approach for detecting clonal Tαβ-cells and validated the method in 211 normal, reactive and pathological samples. TRBC1 labeling significantly improved in the presence of CD3. Purified TRBC1+ and TRBC1− monoclonal and polyclonal Tαβ-cells rearranged TRBJ1 in 44/47 (94%) and TRBJ1+TRBJ2 in 48 of 48 (100%) populations, respectively, which confirmed the high specificity of this assay. Additionally, TRBC1+/TRBC1− ratios within different Tαβ-cell subsets are provided as reference for polyclonal cells, among which a bimodal pattern of TRBC1-expression profile was found for all TCRVβ families, whereas highly-variable TRBC1+/TRBC1− ratios were observed in more mature vs. naïve Tαβ-cell subsets (vs. total T-cells). In 112/117 (96%) samples containing clonal Tαβ-cells in which the approach was validated, monotypic expression of TRBC1 was confirmed. Dilutional experiments showed a level of detection for detecting clonal Tαβ-cells of ≤10−4 in seven out of eight pathological samples. These results support implementation of the optimized TRBC1-FCM approach as a fast, specific and accurate method for assessing T-cell clonality in diagnostic-FCM panels, and for minimal (residual) disease detection in mature Tαβ+ leukemia/lymphoma patients.This work was supported by the CB16/12/00400 (CIBERONC) and PI20-01346 grants, from the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (Madrid, Spain) and FONDOS FEDER, and by the EuroFlow Foundation (Leiden, The Netherlands). N. Muñoz-García is supported by a pre-doctoral grant (Ref. IBPredoc17/00012) from IBSAL (Salamanca, Spain). M. Lima, N. Villamor, A.W. Langerak, J.J.M. van Dongen, A. Orfao, and J. Almeida are members of the EuroFlow Consortiu

Impact of cortical and subcortical atrophy in the diagnosis and prognosis of bvFTD: A multicenter longitudinal study

AbstractBackgroundThe behavioral variant of frontotemporal dementia (bvFTD) presents with variable patterns of cortical and subcortical atrophy on Magnetic Resonance Imaging (MRI). We aimed to assess the clinical utility of two reproducible measurements of cerebral atrophy (Harper's visual atrophy scale [HVAS], and the Magnetic Resonance Parkinsonism Index [MRPI]) in a large multicenter sample of bvFTD with longitudinal follow‐up.MethodsWe included 466 participants from three centers: 241 bvFTD (according to the International bvFTD Criteria Consortium), and 225 healthy controls (HC). Clinical deterioration was assessed with Mini‐Mental State Examination (MMSE) and the Clinical Deterioration Scale Sum‐of‐boxes (CDR‐sb). bvFTD participants were considered to have an increased certainty of underlying Frontotemporal Lobar Degeneration (+FTLD) when: (i) FTLD was confirmed at autopsy (n=72); (ii) a secondary FTLD‐related phenotype was identified during follow‐up (n=47) or (iii) a FTLD‐related mutation was found (n=49). Six raters blinded to clinical data were first asked to dichotomize participants according to the presence of "a clear pattern of atrophy suggestive of probable bvFTD", and then applied the HVAS (ICC(2,k)=.86 to .96). The MRPI was calculated with a fully automated algorithm.ResultsMean age of bvFTD participants was 63.3 ± 10, 68% were male (MMSE=23 ± 7 and CDR‐sb=6.7 ± 3.5). Blinded raters had 52% sensitivity and 97% specificity for the identification of bvFTD participants (AUC=.74, p=.001). All HVAS measures with the exception of posterior atrophy discriminated between bvFTD and HC (AUC=.77 to .83, p<.001). The composite bvFTD score (average score of orbitofrontal, anterior cingulate, anterior temporal, medial temporal lobe and frontal insula regions) showed the best diagnostic accuracy for the differentiation of bvFTD from HC (AUC=.91, p<.001 in +FTLD). This composite score also differentiated between bvFTD participants that were not considered to have a clear pattern of atrophy suggestive of probable bvFTD (blinded raters) and HC (p<.001). We hypothesized that HVAS and MRPI scores may be independent predictors of clinical deterioration and survival in bvFTD (definitive results pending).ConclusionThe combination of HVAS and MRPI may provide valuable diagnostic and prognostic information in the behavioral syndromes verifying bvFTD criteria. These measures represent reliable, reproducible and affordable imaging biomarkers

Classical operators on the Hörmander algebras

We study the integration operator, the differentiation operator and more general differential operators on radial Fr´echet or (LB) H¨ormander algebras of entire functions. We analyze when these operators are power bounded, hypercyclic and (uniformly) mean ergodic.This research was partially supported by MEC and FEDER Project MTM2010-15200. The research of M. J. Beltran was also supported by grant F.P.U. AP2008-00604 and Programa de Apoyo a la Investigacion y Desarrollo de la UPV PAID-06-12, and the research of J. Bonet and C. Fernandez, by GVA under Project PROMETEOII/2013/013.Beltrán Meneu, MJ.; Bonet Solves, JA.; Fernández, C. (2015). Classical operators on the Hörmander algebras. Discrete and Continuous Dynamical Systems - Series A. 35(2):637-652. https://doi.org/10.3934/dcds.2015.35.637S63765235