Prognostic Role of Tumor Immune Microenvironment in Pleural Epithelioid Mesothelioma

BackgroundPleural mesothelioma (MPM) is an aggressive malignancy with an average patient survival of only 10 months. Interestingly, about 5%-10% of the patients survive remarkably longer. Prior studies have suggested that the tumor immune microenvironment (TIME) has potential prognostic value in MPM. We hypothesized that high-resolution single-cell spatial profiling of the TIME would make it possible to identify subpopulations of patients with long survival and identify immunophenotypes for the development of novel treatment strategies. MethodsWe used multiplexed fluorescence immunohistochemistry (mfIHC) and cell-based image analysis to define spatial TIME immunophenotypes in 69 patients with epithelioid MPM (20 patients surviving >= 36 months). Five mfIHC panels (altogether 21 antibodies) were used to classify tumor-associated stromal cells and different immune cell populations. Prognostic associations were evaluated using univariate and multivariable Cox regression, as well as combination risk models with area under receiver operating characteristic curve (AUROC) analyses. ResultsWe observed that type M2 pro-tumorigenic macrophages (CD163(+)pSTAT1(-)HLA-DRA1(-)) were independently associated with shorter survival, whereas granzyme B+ cells and CD11c(+) cells were independently associated with longer survival. CD11c(+) cells were the only immunophenotype increasing the AUROC (from 0.67 to 0.84) when added to clinical factors (age, gender, clinical stage, and grade). ConclusionHigh-resolution, deep profiling of TIME in MPM defined subgroups associated with both poor (M2 macrophages) and favorable (granzyme B/CD11c positivity) patient survival. CD11c positivity stood out as the most potential prognostic cell subtype adding prediction power to the clinical factors. These findings help to understand the critical determinants of TIME for risk and therapeutic stratification purposes in MPM.Peer reviewe

High tumor cell platelet-derived growth factor receptor beta expression is associated with shorter survival in malignant pleural epithelioid mesothelioma

Malignant pleural mesothelioma (MPM) has a rich stromal component containing mesenchymal fibroblasts. However, the properties and interplay of MPM tumor cells and their surrounding stromal fibroblasts are poorly characterized. Our objective was to spatially profile known mesenchymal markers in both tumor cells and associated fibroblasts and correlate their expression with patient survival. The primary study cohort consisted of 74 MPM patients, including 16 patients who survived at least 60 months. We analyzed location-specific tissue expression of seven fibroblast markers in clinical samples using multiplexed fluorescence immunohistochemistry (mfIHC) and digital image analysis. Effect on survival was assessed using Cox regression analyses. The outcome measurement was all-cause mortality. Univariate analysis revealed that high expression of secreted protein acidic and cysteine rich (SPARC) and fibroblast activation protein in stromal cells was associated with shorter survival. Importantly, high expression of platelet-derived growth factor receptor beta (PDGFRB) in tumor cells, but not in stromal cells, was associated with shorter survival (hazard ratio [HR] = 1.02, p <0.001). A multivariable survival analysis adjusted for clinical parameters and stromal mfIHC markers revealed that tumor cell PDGFRB and stromal SPARC remained independently associated with survival (HR = 1.01, 95% confidence interval [CI] = 1.00-1.03 and HR = 1.05, 95% CI = 1.00-1.11, respectively). The prognostic effect of PDGFRB was validated with an artificial intelligence-based analysis method and further externally validated in another cohort of 117 MPM patients. In external validation, high tumor cell PDGFRB expression associated with shorter survival, especially in the epithelioid subtype. Our findings suggest PDGFRB and SPARC as potential markers for risk stratification and as targets for therapy.Peer reviewe

The implications of autonomy: Viewed in the light of efforts to uphold patients dignity and integrity

This article focuses on Danish patients’ experience of autonomy and its interplay with dignity and integrity in their meeting with health professionals. The aim is to chart the meanings and implications of autonomy for persons whose illness places them in a vulnerable life situation. The interplay between autonomy and personal dignity in the meeting with health care staff are central concepts in the framework. Data collection and findings are based on eight qualitative semi-structured interviews with patients. Patients with acute, chronic, and life threatening diseases were represented including surgical as well as medical patients. The values associated with autonomy are in many ways vitalising, but may become so dominant, autonomy seeking, and pervasive that the patient's dignity is affected. Three types of patient behaviour were identified. (1) The proactive patient: Patients feel that they assume responsibility for their own situation, but it may be a responsibility that they find hard to bear. (2) The rejected patient: proactive patients take responsibility on many occasions but very active patients are at risk of being rejected with consequences for their dignity. (3) The knowledgeable patient: when patients are health care professionals, the patient's right of self-determination was managed in a variety of ways, sometimes the patient's right of autonomy was treated in a dignified way but the opposite was also evident. In one way, patients are active and willing to take responsibility for themselves, and at the same time they are “forced” to do so by health care staff. Patients would like health professionals to be more attentive and proactive

Response to letter on use of functional imaging by 11C-metomidate PET for primary aldosteronism subtyping

Non peer reviewe

Longest Common Prefixes with kk-Errors and Applications

Although real-world text datasets, such as DNA sequences, are far from being uniformly random, average-case string searching algorithms perform significantly better than worst-case ones in most applications of interest. In this paper, we study the problem of computing the longest prefix of each suffix of a given string of length $n$ over a constant-sized alphabet that occurs elsewhere in the string with $k$-errors. This problem has already been studied under the Hamming distance model. Our first result is an improvement upon the state-of-the-art average-case time complexity for non-constant $k$ and using only linear space under the Hamming distance model. Notably, we show that our technique can be extended to the edit distance model with the same time and space complexities. Specifically, our algorithms run in $\mathcal{O}(n \log^k n \log \log n)$ time on average using $\mathcal{O}(n)$ space. We show that our technique is applicable to several algorithmic problems in computational biology and elsewhere

Solving Weighted Least Squares (WLS) problems on ARM-based architectures

TheWeighted Least Squares algorithm (WLS) is applied to numerous optimization problems, but requires the use of high computational resources, especially when complex arithmetic is involved. This work aims to accelerate the resolution of a WLS problem by reducing the computational cost (relaying on BLAS/LAPACK routines) and the computational precision from double to single. As a test case, we design an IIR filter for a Graphic Equalizer, where the numerical errors due to single precision are easily visualized. In addition, given the importance of low power architectures for this kind of implementations, we evaluate the performance, scalability, and energy efficiency of each method on two different processors implementing the ARMv7 architecture, widely used in current mobile devices with power constraints. Results show that the method that exhibits a high theoretical computational cost overcomes in efficiency other methods with lower theoretical cost in architectures of this type.This work started in spring 2016 when Jose A. Belloch was a visiting postdoctoral researcher at Budapest University of Technology and Economics thanks to the European Network COST Action IC1305 inside the program Short Term Scientific Mission with the following reference: COST-SPASM-ECOST-STSM-IC1305-020416-072431. Dr. Jose A. Belloch is supported by GVA contract APOSTD/2016/069. The researchers from Universitat Jaume I are supported by the CICYT projects TIN2014-53495-R of MINECO and FEDER. The authors from the Universitat Politecnica de Valencia are supported by MINECO Projects TEC2015-67387-C4-1-R, PROMETEOII/2014/003 and CAPAP-H5 network TIN2014-53522-REDT. The researcher from UCM is supported by the EU (FEDER) and the Spanish MINECO, under Grants TIN 2015-65277-R and TIN2012-32180. The work of Balazs Bank was supported by the UNKP-16-4-III New National Excellence Program of the Ministry of Human Capacities, Hungary.Belloch Rodríguez, JA.; Bank, B.; Igual Peña, FD.; Quintana Ortí, ES.; Vidal Maciá, AM. (2017). Solving Weighted Least Squares (WLS) problems on ARM-based architectures. Journal of Supercomputing. 73(1):530-542. https://doi.org/10.1007/s11227-016-1910-9S530542731Smith TM, van de Geijn RA, Smelyanskiy M, Hammond JR, Van Zee FG (2014) Anatomy of high-performance many-threaded matrix multiplication. In: 28th IEEE International Parallel and Distributed Processing Symposium (IPDPS 2014)Burrus CS (2012) Iterative reweighted least squares. OpenStax-CNC document, May 2012, module m45285. http://cnx.org/content/m45285/1.12 . Accessed 2 Nov 2016Khang SW (1972) Best $$L_p$$ L p approximation. Math Comput 26(118):505–508Jackson LB (2008) Frequency-domain Steiglitz-McBride method for least-squares filter design, ARMA modeling, and periodogram smoothing. IEEE Signal Process Lett 15:49–52Bank B (2012) Magnitude-priority filter design for audio applications. In: Proceedings of $$132^{{\rm nd}}$$ 132 nd AES Convention, Preprint No. 8591, Budapest, Hungary, May 2012Daubechies I, Devire R, Fornasier M, Gntrk CS (2010) Iteratively reweighted least squares minimization for sparse recovery. Comput Music J 23(2):52–69Rämö J, Välimäki V, Bank B (2014) High-precision parallel graphic equalizer. IEEE/ACM Trans Audio Speech Lange Proc 22(12):1894–1904Perez Gonzales E, Reiss J (2009) Automatic equalization of multi-channel audio using cross-adaptive methods. In: Proceedings of AES 127th Convention, New York, Oct. 2009Rämö J, Välimäki V (2013) Live sound equalization and attenuation with a headset. In: Proceedings of AES 51st International Conference, Helsinki, Finland, Aug. 2013Mäkivirta A, Antsalo P, Karjalainen M, Välimäki V (2003) Modal equalization of loudspeaker-room responses at low frequencies. J Audio Eng Soc 51(5):324–343Holters M, Zölzer U (2006) Graphic equalizer design using higher-order recursive filters. In: Proceedings of International Conference Digital Audio Effects, Montreal, QC, pp 37–40Tassart S (2013) Graphical equalization using interpolated filter banks. J Audio Eng Soc 61(5):263–279Chen Z, Geng GS, Yin FL, Hao J (2014) A pre-distortion based design method for digital audio graphic equalizer. Digital Signal Process 25:296–302Välimäki V, Reiss J (2016) All about audio equalization: solutions and frontiers. Appl Sci 6(5):129–145Belloch JA, Välimäki V (2016) Efficient target-response interpolation for a graphic equalizer. In: 2016 IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP), March 2016, pp 564–568Belloch JA, Alventosa FJ, Alonso P, Quintana-Ortí ES, Vidal AM (2016) Accelerating multi-channel filtering of audio signal on arm processors. J Supercomput, pp 1–12. doi: 10.1007/s11227-016-1689-8Belloch JA, Gonzalez A, Igual FD, Mayo R, Quintana-Ortí ES (2015)Vectorization of binaural sound virtualization on the ARM cortex-A15 architecture. In: Proceedings of 23rd European Signal Processing Conference, (EUSIPCO), Nize, France, September 2015Mitra G, Johnston B, Rendell A, McCreath E, Zhou J (2013) Use of simd vector operations to accelerate application code performance on low-powered arm and intel platforms. In: IEEE 27th International Parallel and Distributed Processing Symposium Workshops PhD Forum (IPDPSW), May 2013, pp 1107–1116Tomov S, Dongarra J, Baboulin M (2008) Towards dense linear algebra for hybrid gpu accelerated manycore systems. LAPACK Working Note, Tech. Rep. 210, Oct. 2008. http://www.netlib.org/lapack/lawnspdf/lawn210.pdf . Accessed 2 Nov 2016Dongarra JJ, DuCroz J, Hammarling S, Hanson RJ (1985) A proposal for an extended set of fortran basic linear algebra subprograms. ACM Signum Newsletter, New York, pp 2–18Golub GH, Loan CFV (2013) Matrix Comput, 4th edn. The John Hopkins University Press, BaltimoreAlonso P, Badia RM, Labarta J, Barreda M, Dolz MF, Mayo R, Quintana-Ortí ES, Reyes R (2012) Tools for power-energy modelling and analysis of parallel scientific applications. In: 41st International Conference on Parallel Processing—ICPP, 2012, pp 420–42

Decreased Bone Mineral Density in Adults Born with Very Low Birth Weight: A Cohort Study

Petteri Hovi and colleagues evaluate skeletal health in 144 adults born preterm with very low birth weight and show that as adults these individuals have significantly lower bone mineral density than do their term-born peers

No selection for change in polyandry under experimental evolution

What drives mating system variation is a major question in evolutionary biology. Female multiple mating (polyandry) has diverse evolutionary consequences, and there are many potential benefits and costs of polyandry. However, our understanding of its evolution is biased towards studies enforcing monandry in polyandrous species. What drives and maintains variation in polyandry between individuals, genotypes, populations and species remains poorly understood. Genetic variation in polyandry may be actively maintained by selection, or arise by chance if polyandry is selectively neutral. In Drosophila pseudoobscura, there is genetic variation in polyandry between and within populations. We used isofemale lines to found replicate populations with high or low initial levels of polyandry and tracked polyandry under experimental evolution over seven generations. Polyandry remained relatively stable, reflecting the starting frequencies of the experimental populations. There were no clear fitness differences between high versus low polyandry genotypes, and there was no signature of balancing selection. We confirmed these patterns in direct comparisons between evolved and ancestral females and found no consequences of polyandry for female fecundity. The absence of differential selection even when initiating populations with major differences in polyandry casts some doubt on the importance of polyandry for female fitness