On systems and control approaches to therapeutic gain

BACKGROUND: Mathematical models of cancer relevant processes are being developed at an increasing rate. Conceptual frameworks are needed to support new treatment designs based on such models. METHODS: A modern control perspective is used to formulate two therapeutic gain strategies. RESULTS: Two conceptually distinct therapeutic gain strategies are provided. The first is direct in that its goal is to kill cancer cells more so than normal cells, the second is indirect in that its goal is to achieve implicit therapeutic gains by transferring states of cancer cells of non-curable cases to a target state defined by the cancer cells of curable cases. The direct strategy requires models that connect anti-cancer agents to an endpoint that is modulated by the cause of the cancer and that correlates with cell death. It is an abstraction of a strategy for treating mismatch repair (MMR) deficient cancers with iodinated uridine (IUdR); IU-DNA correlates with radiation induced cell killing and MMR modulates the relationship between IUdR and IU-DNA because loss of MMR decreases the removal of IU from the DNA. The second strategy is indirect. It assumes that non-curable patient outcomes will improve if the states of their malignant cells are first transferred toward a state that is similar to that of a curable patient. This strategy is difficult to employ because it requires a model that relates drugs to determinants of differences in patient survival times. It is an abstraction of a strategy for treating BCR-ABL pro-B cell childhood leukemia patients using curable cases as the guides. CONCLUSION: Cancer therapeutic gain problem formulations define the purpose, and thus the scope, of cancer process modeling. Their abstractions facilitate considerations of alternative treatment strategies and support syntheses of learning experiences across different cancers

The Neutrophil's Eye-View: Inference and Visualisation of the Chemoattractant Field Driving Cell Chemotaxis In Vivo

As we begin to understand the signals that drive chemotaxis in vivo, it is becoming clear that there is a complex interplay of chemotactic factors, which changes over time as the inflammatory response evolves. New animal models such as transgenic lines of zebrafish, which are near transparent and where the neutrophils express a green fluorescent protein, have the potential to greatly increase our understanding of the chemotactic process under conditions of wounding and infection from video microscopy data. Measurement of the chemoattractants over space (and their evolution over time) is a key objective for understanding the signals driving neutrophil chemotaxis. However, it is not possible to measure and visualise the most important contributors to in vivo chemotaxis, and in fact the understanding of the main contributors at any particular time is incomplete. The key insight that we make in this investigation is that the neutrophils themselves are sensing the underlying field that is driving their action and we can use the observations of neutrophil movement to infer the hidden net chemoattractant field by use of a novel computational framework. We apply the methodology to multiple in vivo neutrophil recruitment data sets to demonstrate this new technique and find that the method provides consistent estimates of the chemoattractant field across the majority of experiments. The framework that we derive represents an important new methodology for cell biologists investigating the signalling processes driving cell chemotaxis, which we label the neutrophils eye-view of the chemoattractant field

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Electron spin resonance characterization of calcretes from Thar desert for dating applications

Results of a study to characterize electron spin resonance (ESR) signals from naturally occurring carbonates from Thar desert are reported. Three radiation induced signals at g = 2.0071 (signal A, very weak), g = 2.0012 (signal B) and g = 2.0003 (signal C) with linewidths ranging from 0.5-2 G are seen. A broad signal (BL) with linewidth 7 G is also seen at 2,0038, Detailed ESR experiments involving (1) sensitivity of ESR signals to ionizing radiation, (2) intensity variation of ESR signals with microwave power at different temperatures, (3) analysis of acid insoluble residue to estimate the interference from ESR signals of silicate fraction, and (4) X-ray diffraction analysis (to study possible phase changes on heating), led to the choice of signal BL for dating. Experiments on acid insoluble residue revealed that signal C has a contribution from the E-1' centre of quartz and signal B is the parallel component (g(parallel to)) of the E-1' centre, Paleodose estimates based on signal BL are stratigraphically consistent. (.

Calcretes in the Thar desert: Genesis, chronology and palaeoenvironment

The calcretes in the Thar desert occur in a variety of settings, including the piedmonts, sheetwash aggraded plains; and this study adds calcretes in regolith and colluvio-alluvial plains to the group of settings in which calcretes occur in the region. Field logs, morphological details and analytical data such as petrographic, cathodoluminescence and geochemical characteristics are described along with a discussion on their implications. Sand dunes and sandy plains dating to < 20 ka have weakly developed calcretes. The better-developed calcrete horizons occur in piedmonts, interdunes or in areas that have sufficient groundwater. Deep sections in the region show pleases of calcrete development in aeolian sand aggradation at &SIM; 150, &SIM; 100, &SIM; 60 and 27-14 ka. The extensive sheetwash plains have mature calcretes and date to mid-Pleistocene. Our studies indicate that these calcretes represent a hybrid process, where carbonate enrichment of the originally calcareous host occurred due to periodically raised groundwaters, and its differentiation into nodules occurred under subaerial environment i.e., after recession of groundwater. Deep sections also show a stack of discrete calcretes that developed in individual aggradation episodes with hiatuses as indicated by ESR dating results. Nodules display a multiplicity of carbonate precipitation events and internal reorganization of calcitic groundmass. The process is accompanied by degradation and transformation of unstable minerals, particularly clays and with a neosynthesis of palygorskite. The ancient calcretes are dated front the beginning of the Quaternary to &SIM; 600 ka and show more evolved morphologies marked by brecciation, dissolution, laminar growth on brecciated surfaces, pisolites and several generations of re-cementation. Mica/chlorite schists and such other rocks are particularly vulnerable to replacement by carbonate. In an extreme case, replacement of quartzose sandstone was observed also. The presence of stretches of alluvio-colluvial plains in an area presently devoid of drainage bespeaks of occasional high-energy fluvial regime, under a semi-arid climate. The mid-Pleistocene period saw a shift towards more arid climate and this facilitated sheetwash aggradation. Finally, during the late Pleistocene, aggradation of aeolian sands indicated a progressively drier climate. However, this does not find its reflection in stable isotope data. The amount of carbonate in the form of calcretes is substantial. The present studies indicate that aeolian dust or rainwater are minor contributors to the carbonate budget. A more important source was provided by the pre-existing calcretes in the sheetwash aggraded plains and detrital carbonate in the aeolian sediments. The original source of carbonate in the region, however, remains unresolved arid will need further investigations. Electron spin resonance protocols for the dating of calcretes were developed as a part of this study and the results accorded well with geological reasoning

Realization Theory for Deterministic Boundary-Value Descriptor Systems

This paper examines the realization of acausal weighting patterns with two-point boundary-value descriptor systems (TPBVDSs). We restrict our attention to the subclass of TPBVDSs which are extendible, i.e., whose input-output weighting pattern can be extended outwards indefinitely, and stationary, so that their weighting pattern is shift-invariant. Then, given an infinite acausal shift-invariant weighting pattern, the realization problem consists in constructing a minimal TPBVDS over a fixed interval, whose extended weighting pattern matches the given pattern. The realization method which is proposed relies on a new transform, the (s,t) transform, which is used to determine the dimension of a minimal realization, and to construct a minimal realization by factoring two homogeneous rational matrices in the variables s and t. 1

When is a linear complementarity system controllable?

This paper deals with the controllability problem of a class of piecewise linear systems, known as linear complementarity, systems. it is well-known that checking certain controllability properties of very simple piecewise linear systems are undecidable problems. In an earlier paper, however, a complete characterization of the controllability of the so-called conewise linear systems has been achieved. By employing this characterization and exploiting the special structure of linear complementarity systems, we present a set of inequality-type conditions as necessary and sufficient conditions for their controllability. Our treatment is based on the ideas and the techniques from geometric control theory together with mathematical programming