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Considers the modeling and optimal control of the wafer temperatures in cylindrical resistance furnaces called diffusion furnaces. Description of the radiative heat transfer that should serve as a basis for the furnace model; Control algorithm that was designed to control wafer temperatures; Postulates that simplify the computation of the radiative exchange between surfaces.

Provides information on a study which examined the heat transfer inside cylindrical resistance diffusion and low-pressure chemical vapor deposition furnaces aimed at developing an improved temperature controller. Model of thermal behavior; Thermal behavior of the thermocouples; Model of an alternative temperature controller of the linear quadratic Gaussian type model.

This short paper argues that energy, the potential to realize change, taking place through interaction, is the essence of everything. Nonduality and emergence play a key role in explaining why energy should be conceived as the single source of everything. The very nature of space and time also follows from it. The whole universe is just energy, and everything emerges from this energy. So the essence of everything is energy. [ABSTRACT FROM AUTHOR]

A very simple, fundamental physical explanation is presented of time dilation and length contraction. This explanation is obtained from a classical model of physics that is Galilean. It assumes the existence of a medium (ether) that acts as an absolute reference in accordance with Mach's principle. Time and space are conventional, i.e., a three-dimensional space independent of time. In addition, the explanation relies on the assumption that all physics, including matter such as clocks and measuring rods, has a scalar wave structure. Matter is assumed to consist of locally stable scalar wave structures, specifically scalar standing wave structures. The scalar waves are just variations in space and time of medium density. Also, an element of special relativity is used, namely, the one taking into account the finite velocity of light. [ABSTRACT FROM AUTHOR]

The answer lies right in front of us, but we refuse to see it. Both relativity and quantum theory, the two pillars of fundamental physics, are modified in this paper to make them also explain the physical phenomena they describe. With this explanation, all current inconsistencies between the two vanish. The modifications relate to the presence of a medium, which is in fact potential energy, in three-dimensional space. This medium acts as a reference system, in accordance with Mach's principle. The speed of light, therefore, is not absolute but relative to the medium and thus to the observer. It is also dependent on medium density. Quantum waves are real scalar waves occurring in the potential energy medium, not probabilities of particles being present. Real scalar quantum waves in three-dimensional space make up the whole of physics representing manifest energy. Particles therefore do not exist; they are local manifestations of real scalar quantum waves. As a result, the Doppler effect and wave interference play a central role in physics. Moreover, the dependence of quantum wave velocity (speed of light) on medium density provides the energy exchange mechanism that is central to physics because all physical phenomena, including observation, concern energy exchange, or interaction. The conceptual simplicity of the model of physics proposed in this paper is shown to clarify a series of paradoxes and ill-understood phenomena at the fundamental level of physics such as wave-particle duality, the twins paradox, and the double slit experiment. As to entanglement, superposition, and nonlocality, the model implies that only weak versions of these properties exist. [ABSTRACT FROM AUTHOR]

Using the delta operator, the strengthened discrete-time optimal projection equations for optimal reduced-order compensation of systems with white stochastic parameters are formulated in the delta domain. The delta domain unifies discrete time and continuous time. Moreover, when formulated in this domain, the efficiency and numerical conditioning of algorithms improves when the sampling rate is high. Exploiting the unification, important theoretical results, algorithms and compensatability tests concerning finite and infinite horizon optimal compensation of systems with white stochastic parameters are carried over from discrete time to continuous time. Among others, we consider the finite-horizon time-varying compensation problem for systems with white stochastic parameters and the property mean-square compensatability (ms-compensatability) that determines whether a system with white stochastic parameters can be stabilised by means of a compensator. In continuous time, both of these appear to be new. This also holds for the associated numerical algorithms and tests to verify ms-compensatability. They are illustrated with three numerical examples that reveal several interesting theoretical and numerical issues. A fourth example illustrates the improvement of both the efficiency and numerical conditioning of the algorithms. This is of vital practical importance for digital control system design when the sampling rate is high. [ABSTRACT FROM AUTHOR]

From the state-space approach to linear systems, promoted by Kalman, we learned that minimality is equivalent with reachability together with observability. Our past research on optimal reduced-order LQG controller synthesis revealed that if the initial conditions are non-zero, minimality is no longer equivalent with reachability together with observability. In the behavioural approach to linear systems promoted by Willems, that consider systems as exclusion laws, minimality is equivalent with observability. This article describes and explains in detail these apparently fundamental differences. Out of the discussion, the system properties weak reachability or excitability, and the dual property weak observability emerge. Weak reachability is weaker than reachability and becomes identical only if the initial conditions are empty or zero. Weak reachability together with observability is equivalent with minimality. Taking the behavioural systems point of view, minimality becomes equivalent with observability when the linear system is time invariant. This article also reveals the precise influence of a possibly stochastic initial state on the dimension of a minimal realisation. The issues raised in this article become especially apparent if linear time-varying systems (controllers) with time-varying dimensions are considered. Systems with time-varying dimensions play a major role in the realisation theory of computer algorithms. Moreover, they provide minimal realisations with smaller dimensions. Therefore, the results of this article are of practical importance for the minimal realisation of discrete-time (digital) controllers and computer algorithms with non-zero initial conditions. Theoretically, the results of this article generalise the minimality property to linear systems with time-varying dimensions and non-zero initial conditions. [ABSTRACT FROM AUTHOR]

It has been observed that a stabilizing controller for the state-space-average model of a pulsewidth-modulated (PWM) DC-DC converter does not automatically imply a stabilizing controller for the DC-DC converter itself, especially in the case of the Ćuk converter. By applying multifrequency averaging as a generalization of the states-space averaging technique, the stationary periodic signals of the Ćuk converter can be obtained by solving a set of linear equations. Using these equations, we are able to analyze stability aspects of the open-loop and closed-loop PWM Ćuk converter. Simulations are included in open-and closed-loop situations. [ABSTRACT FROM AUTHOR]

The synthesis of finite-horizon digital optimal reduced-order compensators is presented, for asynchronous and aperiodically sampled continuous-time systems. The dimensions of the compensator state are a priori fixed and may be time varying. Asynchronous and aperiodic sampling refers to a deterministic sampling scheme where an arbitrary, but a priori known, number of control variables is updated, and/or an arbitrary, but a priori known, number of outputs is sampled, at arbitrary, but a priori known, time instants. This sampling scheme generalizes most deterministic sampling schemes considered in the control literature. Through the use of an integral criterion the intersample behaviour is explicitly considered in the design. As a result, frequent, synchronous and periodic sampling is no longer necessary, which can be highly relevant in practice. Also the synthesis enables comparison of the optimal performance of reduced-order compensators as a function of their dimensions and the sampling scheme. The synthesis is illustrated with a numerical example. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor prognosis even after curative resection. Responses to immunotherapy are rare and related to inadequate T-cell priming. We previously demonstrated the potency of allogeneic lysate-dendritic cell (DC) vaccination in a preclinical model. Here we translate this concept to patients. In this phase I study, patients with resected PDAC were included when they demonstrated no radiologic signs of recurrence after standard-of-care treatment. Allogeneic tumour lysate-loaded autologous monocyte-derived DCs were injected at weeks 0, 2, 4 and at months 3 and 6. Objectives are feasibility, safety and immunogenicity of allogeneic tumour-DCs. The presence of tumour antigens shared between the vaccine and patient tumours was investigated. Immunological analyses were performed on peripheral blood, skin and tumour. Ten patients were included. DC production and administration were successful. All patients experienced a grade 1 injection-site and infusion-related reaction. Two patients experienced a grade 2 fever and 1 patient experienced a grade 3 dyspnoea. No vaccine-related serious adverse events were observed. Shared tumour antigens were found between the vaccine and patient tumours. All evaluated patients displayed a vaccine-induced response indicated by increased frequencies of Ki67+ and activated PD-1+ circulating T-cells. In addition, treatment-induced T-cell reactivity to autologous tumour of study patients was detected. Seven out of ten patients have not experienced disease recurrence or progression at a median follow-up of 25 months (15–32 months). Allogeneic tumour lysate-DC treatment is feasible, safe and induces immune reactivity to PDAC expressed antigens. • Pancreatic cancer is an immune-deserted tumour and responses to immunotherapy are rare. • Allogeneic-tumour lysate-dendritic cell vaccination is feasible and safe in patients with pancreatic cancer. • Dendritic cell vaccination was immunogenic and demonstrated T-cell activation after therapy. • Therapy-induced cross-reactive T-cell responses against autologous tumour were found. [ABSTRACT FROM AUTHOR]

Across the world and within Europe, a growing number of consumers are choosing to buy gluten-free products. Motivations for a gluten-free diet and the consequences of consuming gluten are varied, from a medical necessity for those diagnosed with celiac disease to a range of health complications and discomfort for those who are gluten-intolerant. In this research, 7296 gluten-free consumers across 13 European countries responded to an online survey on the 33 types of gluten-free products purchased, how frequently they purchased them, their satisfaction with gluten-free quality and availability, the problems they have experienced, and the strategies they have employed to cope with these problems. The investigation examines whether and how these consumer attitudes and behaviors differ between those diagnosed with celiac disease, those who are gluten-intolerant, and those who are caregivers for others with a gluten-free diet. The results show that significant differences existed for all these habits and issues across the three gluten-free consumer groups. Specifically, caregivers purchased most of the gluten-free product types more frequently than the other two groups, experienced more availability problems, and were more likely to shop at multiple stores or make their own gluten-free products. Celiac-diagnosed consumers tended to buy gluten-free products more frequently than those who are gluten-intolerant, and they tended to be the most satisfied with the quality and range of gluten-free offerings. Despite purchasing frequency differences between the groups, the results suggest a similar hierarchy of gluten-free products that could provide the foundation for a European gluten-free food basket.

Introduction: The incidence of brain metastases in cancer patients is increasing, with lung and breast cancer being the most common sources. Despite advancements in targeted therapies, the prognosis remains poor, highlighting the importance to investigate the underlying mechanisms in brain metastases. The aim of this study was to investigate the differences in the molecular mechanisms involved in brain metastasis of breast and lung cancers. In addition, we aimed to identify cancer lineage-specific druggable targets in the brain metastasis., Methods: To that aim, a cohort of 44 FFPE tissue samples, including 22 breast cancer and 22 lung adenocarcinoma (LUAD) and their matched-paired brain metastases were collected. Targeted gene expression profiles of primary tumors were compared to their matched-paired brain metastases samples using nCounter PanCancer IO 360™ Panel of NanoString technologies. Pathway analysis was performed using gene set analysis (GSA) and gene set enrichment analysis (GSEA). The validation was performed by using Immunohistochemistry (IHC) to confirm the expression of immune checkpoint inhibitors., Results: Our results revealed the significant upregulation of cancer-related genes in primary tumors compared to their matched-paired brain metastases (adj. p  ≤ 0.05). We found that upregulated differentially expressed genes in breast cancer brain metastasis (BM-BC) and brain metastasis from lung adenocarcinoma (BM-LUAD) were associated with the metabolic stress pathway, particularly related to the glycolysis. Additionally, we found that the upregulated genes in BM-BC and BM-LUAD played roles in immune response regulation, tumor growth, and proliferation. Importantly, we identified high expression of the immune checkpoint VTCN1 in BM-BC, and VISTA, IDO1, NT5E, and HDAC3 in BM-LUAD. Validation using immunohistochemistry further supported these findings., Conclusion: In conclusion, the findings highlight the significance of using matched-paired samples to identify cancer lineage-specific therapies that may improve brain metastasis patients outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Najjary, de Koning, Kros and Mustafa.)

Introduction: Monitoring the therapeutic response of pancreatic ductal adenocarcinoma (PDAC) patients is crucial to determine treatment strategies. Several studies have examined the effectiveness of FOLFIRINOX as a first-line treatment in patients with locally advanced pancreatic cancer, but little attention has been paid to the immunologic alterations in peripheral blood caused by this chemotherapy regimen. Furthermore, the influence of the measurement type (e.g., flow cytometry and targeted gene expression) on the clinical discoveries is unknown. Therefore, we aimed to scrutinize the influence of using flow cytometry or targeted immune gene expression to study the immunological changes in blood samples of PDAC patients who were treated with a single-cycle FOLFIRINOX combined with lipegfilgrastim (FFX-Lipeg)., Material and Methods: Whole-blood samples from 44 PDAC patients were collected at two time points: before the first FOLFIRINOX cycle and 14 days after the first cycle. EDTA blood tubes were used for multiplex flow cytometry analyses to quantify 18 immune cell populations and for complete blood count tests as the standard clinical routine. The flow cytometry data were analyzed with FlowJo software. In addition, Tempus blood tubes were used to isolate RNA and measure 1230 immune-related genes using NanoString Technology ® . Data quality control, normalization, and analysis were performed using nSolver™ software and the Advanced Analysis module., Results: FFX-Lipeg treatment increased the number of neutrophils and monocytes, as shown by flow cytometry and complete blood count in concordance with elevated gene expression measured via targeted gene expression profiling analysis. Interestingly, flow cytometry analysis showed an increase in the number of B and T cells after treatment, while targeted gene expression analysis showed a decrease in B and T cell-specific gene expression., Conclusions: Targeted gene expression complements flow cytometry analysis to provide a comprehensive understanding of the effects of FFX-Lipeg. Flow cytometry and targeted gene expression showed increases in neutrophils and monocytes after FFX-Lipeg. The number of lymphocytes is increased after treatment; nevertheless, their cell-specific gene expression levels are downregulated. This highlights that different techniques influence clinical discoveries. Therefore, it is important to carefully select the measurement technique used to study the effect of a treatment.

Metastases in the brain are the most severe and devastating complication of cancer. The incidence of brain metastasis is increasing. Therefore, the need of finding specific druggable targets for brain metastasis is demanding. The aim of this study was to compare the brain (immune) response to brain metastases of the most common tumor lineages, viz., lung adenocarcinoma and breast cancer. Targeted gene expression profiles of 11 brain metastasis of lung adenocarcinoma (BM-LUAD) were compared to 11 brain metastasis of breast cancer (BCBM) using NanoString nCounter PanCancer IO 360™ Panel. The most promising results were validated spatially using the novel GeoMx™ Digital Spatial Profiler (DSP) Technology. Additionally, Immune cell profiles and expression of drug targets were validated by multiplex immunohistochemistry. We found a more active immune response in BM-LUAD as compared to BCBM. In the BM-LUAD, 138 genes were upregulated as compared to BCBM (adj. p ≤ 0.05). Conversely, in BCBM 28 genes were upregulated (adj. p ≤ 0.05). Additionally, genes related to CD45 + cells, T cells, and cytotoxic T cells showed to be expressed higher in BM-LUAD compared to BCBM (adj. p = 0.01, adj. p = 0.023, adj. p = 0.023, respectively). The spatial quantification of the immune cells using the GeoMx DSP technique revealed the significantly higher quantification of CD14 and CD163 in tumor regions of BM-LUAD as compared to BCBM. Importantly, the immune checkpoint VISTA and IDO1 were identified as highly expressed in the BM-LUAD. Multiplex immunohistochemistry confirmed the finding and showed that VISTA is expressed mainly in BM-LUAD tumor cells, CD3 + cells, and to fewer levels in some microglial cells in BM-LUAD. This is the first report on differences in the brain immune response between metastatic tumors of different lineages. We found a far more extensive infiltration of immune cells in BM-LUAD as compared to BCBM. In addition, we found higher expression of VISTA and IDO1 in BM-LUAD. Taken together, targeted immune therapy should be considered to treat patients with BM-LUAD., (© 2023. The Author(s).)

Background: Transcriptome analysis could be an additional diagnostic parameter in diagnosing kidney transplant (KTx) rejection. Here, we assessed feasibility and potential of NanoString nCounter analysis of KTx biopsies to aid the classification of rejection in clinical practice using both the Banff-Human Organ Transplant (B-HOT) panel and a customized antibody-mediated rejection (AMR)-specific NanoString nCounter Elements (Elements) panel. Additionally, we explored the potential for the classification of KTx rejection building and testing a classifier within our dataset., Methods: Ninety-six formalin-fixed paraffin-embedded KTx biopsies were retrieved from the archives of the ErasmusMC Rotterdam and the University Hospital Cologne. Biopsies with AMR, borderline or T cell-mediated rejections (BLorTCMR), and no rejection were compared using the B-HOT and Elements panels., Results: High correlation between gene expression levels was found when comparing the 2 chemistries pairwise (r = 0.76-0.88). Differential gene expression (false discovery rate; P  < 0.05) was identified in biopsies diagnosed with AMR (B-HOT: 294; Elements: 76) and BLorTCMR (B-HOT: 353; Elements: 57) compared with no rejection. Using the most predictive genes from the B-HOT analysis and the Element analysis, 2 least absolute shrinkage and selection operators-based regression models to classify biopsies as AMR versus no AMR (BLorTCMR or no rejection) were developed achieving an receiver-operating-characteristic curve of 0.994 and 0.894, sensitivity of 0.821 and 0.480, and specificity of 1.00 and 0.979, respectively, during cross-validation., Conclusions: Transcriptomic analysis is feasible on KTx biopsies previously used for diagnostic purposes. The B-HOT panel has the potential to differentiate AMR from BLorTCMR or no rejection and could prove valuable in aiding kidney transplant rejection classification., Competing Interests: M.C.C.v.G. has Astellas project funding paid to the Erasmus MC. J.U.B. is advisor for Sanofi. The other authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: 5-fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) is promising in treating patients with pancreatic ductal adenocarcinoma. However, many patients and physicians are reluctant to start FOLFIRINOX due to its high toxicity and limited clinical response rates. In this study, we investigated the effect of a single FOLFIRINOX cycle, in combination with a granulocyte colony-stimulating factor, on the blood immune transcriptome of patients with pancreatic ductal adenocarcinoma. We aimed to identify an early circulating biomarker to predict the lack of FOLFIRINOX response., Methods: Blood samples of 68 patients from all disease stages, who received at least four FOLFIRINOX cycles, were collected at baseline and after the first cycle. The response to treatment was radiologically evaluated following the Response Evaluation Criteria in Solid Tumours criteria 1.1. Targeted immune-gene expression profiling (GEP) was performed using NanoString technologies. To predict the lack of FOLFIRINOX response, we developed a FOLFIRINOX delta GEP (FFX-ΔGEP) score., Results: A single FOLFIRINOX cycle significantly altered 395 genes, correlating to 30 significant alterations in relative immune cell abundances and pathway activities. The eight-gene (BID, FOXP3, KIR3DL1, MAF, PDGFRB, RRAD, SIGLEC1 and TGFB2) FFX-ΔGEP score predicted the lack of FOLFIRINOX response with a leave-one-out cross-validated area under the curve (95% confidence interval) of 0.87 (0.60-0.98), thereby outperforming the predictiveness of absolute and proportional Δcarbohydrate antigen19-9 values., Conclusions: A single FOLFIRINOX cycle, combined with granulocyte colony-stimulating factor, alters the peripheral immune transcriptome indisputably. Our novel FFX-ΔGEP is, to our knowledge, the first multigene early circulating biomarker that predicts the lack of FOLFIRINOX response after one cycle. Validation in a larger independent patient cohort is crucial before clinical implementation., Competing Interests: Conflict of interest statement The authors declare that they have no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Lung tissue from COVID-19 patients shares similar histomorphological features with chronic lung allograft disease, also suggesting activation of autoimmune-related pathways in COVID-19. To more clearly understand the underlying spectrum of pathophysiology in COVID-19 pneumonia, we analysed mRNA expression of autoimmune-related genes in post-mortem lung tissue from COVID-19 patients., Methods and Results: Formalin-fixed, paraffin-embedded lung tissue samples of 18 COVID-19 patients and eight influenza patients were used for targeted gene expression profiling using NanoString technology. Multiplex immunofluorescence for tryptase and chymase was applied for validation. Genes related to mast cells were significantly increased in COVID-19. This finding was strengthened by multiplex immunofluorescence also showing a significant increase of tryptase- and chymase-positive cells in COVID-19. Furthermore, receptors for advanced glycation end-products (RAGE) and pro-platelet basic protein (PPBP) were up-regulated in COVID-19 compared to influenza. Genes associated with Type I interferon signalling showed a significant correlation to detected SARS-CoV2 pathway-related genes. The comparison of lung tissue samples from both groups based on the presence of histomorphological features indicative of acute respiratory distress syndrome did not result in finding any specific gene or pathways., Conclusion: Two separate means of measuring show a significant increase of mast cells in SARS-CoV-2-infected lung tissue compared to influenza. Additionally, several genes involved in fibrosis and thrombosis, among which are RAGE and PPBP, are up-regulated in COVID-19. As mast cells are able to induce thrombosis and fibrosis, they may play an important role in the pathogenesis of COVID-19., (© 2022 The Authors. Histopathology published by John Wiley & Sons Ltd.)