The impact of the existence of multiple adjustable robust solutions

In this note we show that multiple solutions exist for the production-inventory example in the seminal paper on adjustable robust optimization in Ben-Tal et al. (Math Program 99(2):351–376, 2004). All these optimal robust solutions have the same worst-case objective value, but the mean objective values differ up to 21.9 % and for individual realizations this difference can be up to 59.4 %. We show via additional experiments that these differences in performance become negligible when using a folding horizon approach. The aim of this paper is to convince users of adjustable robust optimization to check for existence of multiple solutions. Using the production-inventory example and an illustrative toy example we deduce three important implications of the existence of multiple optimal robust solutions. First, if one neglects this existence of multiple solutions, then one can wrongly conclude that the adjustable robust solution does not outperform the nonadjustable robust solution. Second, even when it is a priori known that the adjustable and nonadjustable robust solutions are equivalent on worst-case objective value, they might still differ on the mean objective value. Third, even if it is known that affine decision rules yield (near) optimal performance in the adjustable robust optimization setting, then still nonlinear decision rules can yield much better mean objective values

Functional and Morphologic Analysis of the Fluid-Conducting Meshwork in Xenografted Cutaneous and Primary Uveal Melanoma

PURPOSE. In primary uveal and cutaneous melanoma lesions, extracellular matrix (ECM) is often deposited in arcs, loops, and network patterns. Based on prognostic relevance, these patterns appear to play a significant role in facilitating metastasis. It has been demonstrated that these patterns were capable of transmitting fluid. The current study was undertaken to elucidate further the functional role of these patterns in tumor perfusion and to examine the composition of the patterns by immunohistochemistry. METHODS. To study the role of these patterns in perfusion, fluorochrome-labeled bovine serum albumin, bovine insulin, and dextrans of different molecular sizes were injected intravenously into nude mice bearing subcutaneous human cutaneous melanoma xenografts. Distribution of the human melanoma cells and murine host cells was analyzed by DNA in situ hybridization. To elucidate the composition of these patterns, human uveal melanoma tissues were analyzed for expression of ECM components by immunohistochemistry. RESULTS. Small molecules (Stokes' radius Ͻ4.4 nm) crossed the vessel wall and spread along the ECM patterns within 2 to 10 minutes, whereas larger molecules (Stokes' radius ϳ5.8 nm) required 30 to 45 minutes to enter. Murine host cells were found exclusively in the ECM pattern compartment. In primary uveal melanoma, different types of collagen, ECM-associated heparan sulfate proteoglycans, and different types of cells were present in the patterns. CONCLUSIONS. The data suggest that the ECM deposited as arcs, loops, and network patterns, accommodate the transport of plasma-derived molecules, (e.g., nutrients), to the tumor lesion, thus enhancing tumor growth and progression, and facilitating infiltration of tumor tissue by host-derived cells. (Invest Ophthalmol Vis Sci. 2005;46:3013-3020

Modulation of Human Immune Responses by Bovine Interleukin-10

Cytokines can be functionally active across species barriers. Bovine IL-10 has an amino acid sequence identity with human IL-10 of 76.8%. Therefore, the aim of this study was to evaluate whether bovine IL-10 has immunomodulatory activities on human monocytes and dendritic cells. Peripheral blood monocytes were isolated from healthy donors, and used directly or allowed to differentiate to dendritic cells under the influence of IL-4 and GM-CSF. Recombinant bovine IL-10 inhibited TLR induced activation of monocytes, and dose-dependently inhibited LPS-induced activation of monocyte-derived DCs comparable to human IL-10. By using blocking antibodies to either bovine IL-10 or the human IL-10 receptor it was demonstrated that inhibition of monocyte activation by bovine IL-10 was dependent on binding of bovine IL-10 to the human IL-10R. These data demonstrate that bovine IL-10 potently inhibits the activation of human myeloid cells in response to TLR activation. Bovine IL-10 present in dairy products may thus potentially contribute to the prevention of necrotizing enterocolitis and allergy, enhance mucosal tolerance induction and decrease intestinal inflammation and may therefore be applicable in infant foods and in immunomodulatory diets

Combined CD28 and 4-1BB Costimulation Potentiates Affinity-tuned Chimeric Antigen Receptor-engineered T Cells

Purpose: Targeting nonspecific, tumor-associated antigens (TAA) with chimeric antigen receptors (CAR) requires specific attention to restrict possible detrimental on-target/off-tumor effects. A reduced affinity may direct CAR-engineered T (CART) cells to tumor cells expressing high TAA levels while sparing low expressing normal tissues. However, decreasing the affinity of the CAR-target binding may compromise the overall antitumor effects. Here, we demonstrate the prime importance of the type of intracellular signaling on the function of lowaffinity CAR-T cells. Experimental Design: We used a series of single-chain variable fragments (scFv) with five different affinities targeting the same epitope of the multiple myeloma-associated CD38 antigen. The scFvs were incorporated in three different CAR costimulation designs and we evaluated the antitumor functionality and off-tumor toxicity of the generated CAR-T cells in vitro and in vivo. Results: We show that the inferior cytotoxicity and cytokine secretion mediated by CD38 CARs of very low-affinity (K d < 1.9 × 10 -6 mol/L) bearing a 4-1BB intracellular domain can be significantly improved when a CD28 costimulatory domain is used. Additional 4-1BB signaling mediated by the coexpression of 4-1BBL provided the CD28-based CD38 CAR-T cells with superior proliferative capacity, preservation of a central memory phenotype, and significantly improved in vivo antitumor function, while preserving their ability to discriminate target antigen density. Conclusions: A combinatorial costimulatory design allows the use of very low-affinity binding domains (K d < 1 mmol/L) for the construction of safe but also optimally effective CAR-T cells. Thus, very-low-affinity scFvs empowered by selected costimulatory elements can enhance the clinical potential of TAA-targeting CARs

Assessing the prognostic value of tumor-infiltrating CD57+ cells in advanced stage head and neck cancer using QuPath digital image analysis

This study aimed to assess the prognostic value of intratumoral CD57+ cells in head and neck squamous cell carcinoma (HNSCC) and to examine the reproducibility of these analyses using QuPath. Pretreatment biopsies of 159 patients with HPV-negative, stage III/IV HNSCC treated with chemoradiotherapy were immunohistochemically stained for CD57. The number of CD57+ cells per mm2 tumor epithelium was quantified by two independent observers and by QuPath, software for digital pathology image analysis. Concordance between the observers and QuPath was assessed by intraclass correlation coefficients (ICC). The correlation between CD57 and clinicopathological characteristics was assessed; associations with clinical outcome were estimated using Cox proportional hazard analysis and visualized using Kaplan-Meier curves. The patient cohort had a 3-year OS of 65.8% with a median follow-up of 54 months. The number of CD57+ cells/mm2 tumor tissue did not correlate to OS, DFS, or LRC. N stage predicted prognosis (OS: HR 0.43, p = 0.008; DFS: HR 0.41, p = 0.003; LRC: HR 0.24, p = 0.007), as did WHO performance state (OS: HR 0.48, p = 0.028; LRC: 0.33, p = 0.039). Quantification by QuPath showed moderate to good concordance with two human observers (ICCs 0.836, CI 0.805–0.863, and 0.741, CI 0.692–0.783, respectively). In conclusion, the presence of CD57+ TILs did not correlate to prognosis in advanced stage, HPV-negative HNSCC patients treated with chemoradiotherapy. Substantial concordance between human observers and QuPath was found, confirming a promising future role for digital, algorithm driven image analysis

EMAP-II expression is associated with macrophage accumulation in primary uveal melanoma.

Contains fulltext : 144480.pdf (publisher's version ) (Open Access)PURPOSE: Primary uveal melanoma may contain arcs, loops, and networks of periodic acid-Schiff (PAS)-positive patterns, along which numerous macrophages are present. Their recruitment into tumor tissue is mediated by chemotactic cytokines, for which vascular endothelial growth factor (VEGF)-C and endothelial monocyte-activating polypeptide ((EMAP)-II are candidates. In this study, the extent of VEGF-C and EMAP-II immunoreaction was related to infiltration of macrophages. METHODS: Serial sections of 25 primary uveal melanoma lesions were analyzed by immunohistochemistry. RESULTS: The analysis showed no correlation of VEGF-C immunoreaction and localization of macrophages. However, accumulation of macrophages occurred at sites of EMAP-II expression, especially in areas containing nests of tumor cells, surrounded by arcs, loops, and network patterns. In tumors with a strong EMAP-II immunoreaction, the adhesion molecule intracellular adhesion molecule (ICAM)-1 was strongly expressed on endothelial cells. EMAP-II-positive endothelial cells did not express VEGF receptor-2. However, extensive release of von Willebrand factor was observed. Signs of apoptosis were found neither in tumor cells nor endothelial cells. CONCLUSIONS: In uveal melanoma, macrophages accumulate at sites of EMAP-II expression. Based on the results, it may be hypothesized that this process of chemotaxis is facilitated by EMAP-II-dependent expression of ICAM-1 on vascular endothelial cells and concomitantly leads to localized vascular damage, as indicated by release of von Willebrand factor

Access to evidence-based treatment among Muslim females with obsessive-compulsive disorder washing subtype: influence of religious affiliation and scrupulosity

This thesis presents the findings from three studies conducted to investigate the relationship between religiosity and Obsessive Compulsive Disorder symptom presentation in Muslim females, their help seeking pathways regarding religious OCD symptoms, and the beliefs, attitudes, experiences and behaviour of Imams regarding scrupulosity. Study 1 examined religiosity and OCD symptom manifestation in a sample of 139 high and low religious Muslim women with or without OCD washing subtype (OCD-W) in Iran. High religious Muslims with OCD-W reported being diagnosed with OCD at a later age, reported more severe OCD symptom severity at the time of diagnosis, and scored higher on self-report measures of OCD symptomatology compared to low religious Muslims with OCD-W. Study 2 employed qualitative interviews to investigate the impact of religion on OCD symptoms and the treatment-seeking experience in five Muslim women with OCD-W living in Australia. Excessive religious washing and repeating rituals before prayer were the most common compulsions reported by participants. Participants performed these rituals to prevent being punished by God and firstly sought help for OCD from Imams, not mental health professionals. There was an average of eight years between the age at which OCD onset and diagnosis of OCD by a mental health professional. Using an online survey completed by 64 Sunni and Shia Imams from Australia and Iran, Study 3 examined their attitudes, beliefs and experiences particularly concerning scrupulosity and OCD treatment. Findings revealed that the majority of Imams were unfamiliar with scrupulosity as a mental problem. Additionally, Sunni Imams were more likely to recommend suggestions inconsistent with the Exposure and Response Prevention treatment approach when asked for advice by congregation members about dealing with religious obsessions or compulsions. Research implications and limitations are discussed

‘Bowling apart?’ : Vier vragen over Nederlandse sportclubs en omgang tussen arm en rijk

‘Bowling apart?’ Four questions on poor-rich contact in Dutch sports clubs This article tests Bourdieu’s and Putnam’s competing views on sports clubs as class mixers, using crosssectional Dutch survey data for the early 1980s and late 1990s. We calculate popularity and representativity indices. Next, we develop a connectivity index, combining both measures to a frequency count variable for the number of contacts between the quartiles most distant on the income ladder. As far as prevalence of cross-class contact is concerned, our findings are most supportive of Putnam. In spite of overrepresentation of the rich, cross-class contact is common. General involvement in organized sports is widespread, while in the typical sports club the poor are far from absent, despite the fact that in some club sports they are strongly underrepresented. However, we also find that over time cross-class contact via sports clubs became less common and is about equally likely to occur via cultural clubs and cultural performances.