Increasing evidence implicates the tumor microbiota as a factor that can influence cancer progression. In patients with colorectal cancer (CRC), we found that pre-resection antibiotics targeting anaerobic bacteria substantially improved disease-free survival by 25.5%. For mouse studies, we designed an antibiotic silver-tinidazole complex encapsulated in liposomes (LipoAgTNZ) to eliminate tumor-associated bacteria in the primary tumor and liver metastases without causing gut microbiome dysbiosis. Mouse CRC models colonized by tumor-promoting bacteria (Fusobacterium nucleatum spp.) or probiotics (Escherichia coli Nissle spp.) responded to LipoAgTNZ therapy, which enabled more than 70% long-term survival in two F. nucleatum-infected CRC models. The antibiotic treatment generated microbial neoantigens that elicited anti-tumor CD8⁺ T cells. Heterologous and homologous bacterial epitopes contributed to the immunogenicity, priming T cells to recognize both infected and uninfected tumors. Our strategy targets tumor-associated bacteria to elicit anti-tumoral immunity, paving the way for microbiome–immunotherapy interventions.
Today's challenge for precision medicine involves the integration of the impact of molecular clocks on drug pharmacokinetics, toxicity, and efficacy, toward personalized chronotherapy. Meaningful improvements of tolerability and/or efficacy of medications through proper administration timing have been confirmed over the past decade for immunotherapy and chemotherapy against cancer, as well as for commonly used pharmacological agents in cardiovascular, metabolic, inflammatory, and neurological conditions. Experimental and human studies have recently revealed sexually dimorphic circadian drug responses. Dedicated randomized clinical trials should now aim to issue personalized circadian timing recommendations for daily medical practice, integrating innovative technologies for remote longitudinal monitoring of circadian metrics, statistical prediction of molecular clock function from single-timepoint biopsies, and multiscale biorhythmic mathematical modelling. Importantly, chronofit patients with a robust circadian function, who would benefit most from personalized chronotherapy, need to be identified. Conversely, nonchronofit patients could benefit from the emerging pharmacological class of chronobiotics targeting the circadian clock. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Solar‐powered vehicles have the potential to reduce CO 2 emissions, operational costs and charging frequency needs of electric vehicles. This potential will depend on the local solar irradiation but also shadowing conditions, a relevant issue for urban contexts. The potential of solar‐powered vehicles in the urban context is modelled for 100 cities across the world showing that the median solar extended driving range is 18 and 8 km/day/kWp for driving and parked vehicles, respectively. The most favourable geographies include Africa, the Middle East and Southeast Asia; nonetheless, solar‐powered mobility has relevant potential across the full sample, including China, Europe, North America and Australia. Highlights Urban VIPV potential is assessed for 100 cities across the world. Solar extended driving range varies between 11 and 29 km/day/kWp. Charging frequency ratio ranges from 0% to 80%, with a median of 57%. Urban shadowing reduces driving range by about 25% for driving vehicles.
The advancement of microelectromechanical systems (MEMS) and the Internet of Things (IoT) have enabled a wide range of applications based on smartphones. However, the existing navigation methods using these low-cost MEMS sensors cannot provide acceptable information for location-based applications in various environments. Their technical limitations, such as severe signal attenuation, reflections, blockages, error accumulation, and low quality of images degrade the performance of GNSS, INS, and camera. To mitigate these limitations, especially in indoor vehicle navigation, we first analyze the performance of the existing fusion algorithm, then we propose Semantic Proximity Update (SPU) based on a pre-trained model of real-time object detection to enhance the integration of Global Navigation Satellite System (GNSS), Inertial Navigation System (INS) and Visual Inertial Navigation System (VINS). SPU consists of the detection of geo-referenced objects and the relative movement to infer the absolute position. The proposed INS/GNSS/VINS/SPU can maintain long-term acceptable accuracy regardless of the indoor/outdoor environment. It only requires the use of smartphone sensors; thus, this scheme has no additional cost for users. Experimental results indicated that the errors of this scheme in horizontal positioning and three-dimensional positioning were 51.6% and 86.8% lower, respectively than those of a conventional integration.
Replication of vertebrate genomes is tightly regulated to ensure accurate duplication, but our understanding of the interplay between genetic and epigenetic factors in this regulation remains incomplete. Here, we investigated the involvement of three elements enriched at gene promoters and replication origins: guanine-rich motifs potentially forming G-quadruplexes (pG4s), nucleosome-free regions (NFRs), and the histone variant H2A.Z, in the firing of origins of replication in vertebrates. We show that two pG4s on the same DNA strand (dimeric pG4s) are sufficient to induce the assembly of an efficient minimal replication origin without inducing transcription in avian DT40 cells. Dimeric pG4s in replication origins are associated with formation of an NFR next to precisely-positioned nucleosomes enriched in H2A.Z on this minimal origin and genome-wide. Thus, our data suggest that dimeric pG4s are important for the organization and duplication of vertebrate genomes. It supports the hypothesis that a nucleosome close to an NFR is a shared signal for the formation of replication origins in eukaryotes.
This study represents a pioneering endeavor in estimating the biodegradability of dissolved organic carbon (DOC) in river systems thanks to high-frequency dissolved oxygen (DO) data. Indeed, the first implementation of a particle filter algorithm in a hydro-biogeochemical model had improved DO simulation in river systems. Yet, mismatches between observed and simulated oxygen remain during summer low-flow periods. To address this issue, a sensitivity analysis was conducted, revealing the influence of biodegradable dissolved organic carbon (BDOC) during non-bloom low-flow periods in summer when bacterial net growth activity is high. Therefore, in this study, BDOC is parameterized in ProSe-PA data assimilation software by integrating an organic carbon partitioning model. As a proof of concept, several case studies are developed which demonstrate that the incorporation of the parameter representing BDOC in the data assimilation scheme of ProSe-PA i) improves DO simulation during low-flow periods, ii) helps identify the posterior distribution of bacterial parameters, and iii) for the first time quantifies the biodegradability of DOC in a river given oxygen data. Next, it is shown that at least two DO monitoring stations are necessary to identify model parameters whose locations are controlled by BDOC and bacterial activity. Finally, ProSe-PA is configured to detect changes in bacteria physiology and DOC biodegradability by evaluating the role of data assimilation configuration parameters such as the assimilation time step and the amount of perturbation of model parameter values. The study also verifies that ProSe-PA is capable of detecting abrupt and gradual changes in the biodegradability of DOC.
Deep geological repository is widely considered as the preferred solution for the final disposal of high-level radioactive waste. Investigation representative of the Hungarian disposal concept was conducted using mock-up diffusion cells to study the chemical changes of S235JR carbon canister and CEM II/B PURAM concrete under anerobic and water saturated conditions at 80°C. Micro-Raman, SEM-EDX, fluid and potentiometric analysis were performed over a period of 12 months. The discussion was supported by thermodynamic and reactive transport modeling. The findings revealed that a uniform corrosion process occurred, leading to rapid passivation of the C-steel with magnetite as the primary corrosion product. Modeling demonstrated that the increase in temperature to 80°C and the chemical evolution of the concrete did not significantly affect the corrosion passivation process. Although the formation of Fe-siliceous hydrogarnets is thermodynamically possible at 80°C, it did not jeopardize magnetite passivation. Overall, the results suggest that the containers would have a long lifespan under the studied disposal conditions.
We are pleased to present this Special Issue of IEEE Transactions on Automation Science and Engineering (TASE), which includes 11 extended articles selected from the technical program of the 17th International Conference on Automation Science and Engineering (CASE 2021). CASE 2021, held on August 23–27, 2021, at the Congress Center of Lyon, France, was primarily a face-to-face conference with online participation for those who could not travel to the beautiful and lively city of Lyon. CASE, as an offspring of TASE, is the flagship automation conference of the IEEE Robotics and Automation Society and constitutes the primary forum for cross-industry and multidisciplinary research in automation. Its goal is to provide a broad coverage and dissemination of foundational research in automation among researchers, academics, and practitioners. The theme of CASE 2021 was Data-Driven Automation.
Purpose Research about ethical, legal, and social implications (ELSI) of assisted reproductive technologies (ART) is influenced by cultural and value-based perspectives. It impacts regulations, funding, and clinical practice, and shapes the perception of ART in society. We analyze trends in the global literature on ELSI of ART between 1999 and 2019. As most output is produced by North America, Western Europe, and Australia, we focus on international research, i.e., academic articles studying a different country than that of the corresponding author. Methods The corpus, extracted from PubMed, Web of Science, and Scopus, includes 7714 articles, of which 1260 involved international research. Analysis is based on titles, abstracts and keywords, classification into ART fields and Topic Modeling, the countries of corresponding author, and countries mentioned in abstracts. Results An absolute increase in the number of international studies, and their relative proportion. Trends of decentralization are apparent, yet geographic centralization remains, which reflects an unequal distribution of research funds across countries and may result in findings that do not reflect global diversity of norms and values. Preference for studying conceptual challenges through philosophical analysis, and for fields that concern only a portion of ART cycles. Less attention was dedicated to economic analysis and barriers to access, or to knowledge of and attitudes. International studies provide an opportunity to expand and diversify the scope of ELSI research. Conclusion We call on the research community to promote international collaborations, focus on less explored regions, and divert more attention to questions of cost, access, knowledge, and attitudes.
Concurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 trial (NCT03298893) is designed to determine the safety/tolerance profile and the recommended phase-II dose of nivolumab with and following concurrent CRT in 16 women with locally advanced cervical cancer. Secondary endpoints include objective response rate (ORR), progression free survival (PFS), disease free survival, and immune correlates of response. Three patients experience grade 3 dose-limiting toxicities. The pre-specified endpoints are met, and overall response rate is 93.8% [95%CI: 69.8–99.8%] with a 2-year PFS of 75% [95% CI: 56.5–99.5%]. Compared to patients with progressive disease (PD), progression-free (PF) subjects show a brisker stromal immune infiltrate, higher proximity of tumor-infiltrating CD3⁺ T cells to PD-L1⁺ tumor cells and of FOXP3⁺ T cells to proliferating CD11c⁺ myeloid cells. PF show higher baseline levels of PD-1 and ICOS-L on tumor-infiltrating EMRA CD4⁺ T cells and tumor-associated macrophages, respectively; PD instead, display enhanced PD-L1 expression on TAMs, higher peripheral frequencies of proliferating Tregs at baseline and higher PD-1 levels at week 6 post-treatment initiation on CD4 and CD8 T cell subsets. Concomitant nivolumab plus definitive CRT is safe and associated with encouraging PFS rates. Further validation in the subset of locally advanced cervical cancer displaying pre-existing, adaptive immune activation is warranted.
Introduction Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. Patients and methods An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. Results In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04–1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m², 95% CI 0.66–0.84) and BRCA2 (HR 0.76, 95% CI 0.65–0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m², 95% CI 1.02–1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01–1.19, respectively). Conclusion Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.
The advancement in vehicle connectivity and autonomy has fostered the development of eco-driving technology, aimed at optimizing driving behaviors to reduce vehicle energy consumption. This study proposed a real-time deep reinforcement learning based hierarchical eco-driving control strategy to optimally control a connected and automated hybrid electric vehicle in a traffic scenario with multiple constraints. The speed optimization layer of the proposed strategy employs a twin-delayed deep deterministic policy gradient (TD3) based reference speed planning strategy to compute the optimized speed, based on a pre-trained optimal policy and observed environmental states. Specifically, to learn the optimal policy, a multi-objective reward function is designed that integrates fuel consumption reward and shaping reward involving car-following and road speed limit. Additionally, a rule-based competition-decision model is embedded within the speed optimization layer to ensure compliance with traffic light rules. In the vehicle controller layer, a real-time controller is implemented to specify appropriate actuator variables for the hybrid powertrain to track the reference speed and conduct energy management control. Simulation results show that the proposed TD3 based eco-driving strategy achieves remarkable energy saving performance by optimizing the speed. Besides, the proposed eco-driving strategy is capable of satisfying the constraint of diverse traffic scenarios, including car-following and traffic light, while also being computationally lightweight.
546 Background: Circadian rhythms regulate the cellular and molecular processes that determine treatment effects. Scarce data suggest that daily timing could influence endocrine therapy (ET) pharmacology. We prospectively tested this hypothesis within the UNIRAD adjuvant phase III trial (NCT01805271) in patients (pts) with hormone receptors positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC). Methods: Between June 2013 and March 2020, 1,278 pts with high-risk HR+/HER2- primary BC were randomly assigned to adjuvant ET combined with EVE or placebo. Pts were stratified according to lymph node involvement, progesterone receptor status, ET (tamoxifen or aromatase inhibitors (AI)), prior neoadjuvant or adjuvant chemotherapy, and duration of ET before randomization. Throughout their participation in the trial, patients were asked to declare prospectively in a daily diary the timing of ET intake within four 6-h slots (06:00 to11:59 (morning), 12:00 to 17:59 (afternoon), 18:00 to 23:59 (evening), or 24:00 to 05:59 (night). The prognostic impact of the timing of ET and EVE/placebo on DFS was a prespecified secondary endpoint. Results: A total of 855 patients (67%) recorded ET intake daily timings (n = 401 in the EVE arm, n = 454 in the placebo arm). Morning intake was preferred by 465 pts (54%), whilst 344 pts (40%) chose evening intake, and minor proportions took ET in the afternoon (49 patients, 5%) or at night (5 patients, 1%). Pts choosing morning or afternoon intake were significantly older than those preferring evening or night intakes (mean age: morning: 56.4 y.o.; afternoon: 58.4 y.o; evening: 53.1 y.o ; night : 50.8 y.o.; p < 0.001). Only 10 patients (1.1%) reported changing ET timing during the study. With a median follow-up of 72.5 months, 118 patients relapsed (locally n = 30, metastases n = 84), and 41 patients died. In the whole population, ET intake timing was not associated with DFS (HR 0.77 [95%CI, 0.53-1.12], p = 0.17). ET intake timing effects according to the stratification factors revealed a significant interaction between its prognostic impact and ET agent (tamoxifen versus AI, p for interaction = 0.01). DFS was prolonged in those pts taking tamoxifen in the evening/night rather than in the morning/afternoon (HR = 0.43 [0.22 - 0.85], p = 0.015), while no such effect was found for those on AI (HR = 1.07 [0.68 - 1.7], p = 0.761). Such interaction remained statistically significant at multivariate analysis (HR 0.38, p = 0.003). Conclusions: Tamoxifen intake in the evening was associated with an improved DFS in high-risk HR+/HER2- breast cancer pts and could be recommended at no cost in the adjuvant setting. Clinical trial information: NCT01805271 .
Reactive transport modeling has become widely used to help improve understanding of hydrogeochemical processes from the pore scale to the watershed scale. In recent years, the scope of reactive transport applications has increased toward a higher level of complexity and process coupling. For example, the production and consumption of water as well as porosity evolution associated with the dissolution and precipitation of hydrated minerals can impact system evolution. Waste rock weathering, carbon sequestration, or the degradation of engineered barriers in radioactive waste repositories all constitute applications in which geochemistry and hydrodynamics can strongly influence each other. For these purposes, the traditional formulation of reactive transport simulators, which decouples groundwater flow and reactive transport processes, is limited. We present a global implicit compositional approach, which integrates the flow processes directly into the reactive transport and geochemical framework. This approach solves the flow field implicitly with the reactive transport equations, simultaneously accounting for water consumption and production due to geochemical reactions. Applications show that the model allows tackling complex reactive transport problems while accounting for intra‐aqueous reactions, redox reactions, and reactions involving mass transfer with the gas and solid phases. The presented simulations also demonstrate that the compositional and traditional approaches yield similar results for complex geochemical systems with relatively low reactivity.
Driven by shorter innovation and product life cycles as well as economic volatility, the demand for reconfiguration of production systems is increasing. Thus, a systematic literature review on reconfiguration management in manufacturing is conducted within this work in order to determine by which degree this is addressed by the literature. To approach this, a definition of reconfiguration management is provided and key aspects of reconfigurable manufacturing systems as well as shortcomings of today’s manufacturing systems reconfiguration are depicted. These provide the basis to derive the requirements for answering the formulated research question. Consequently, the methodical procedure of the literature review is outlined, which is based on the assessment of the derived requirements. Finally, the obtained results are provided and noteworthy insights are given.
We consider the problem of computing a Gaussian approximation to the posterior distribution of a parameter given a large number N of observations and a Gaussian prior when the dimension of the parameter d is also large. To address this problem we build on a recently introduced recursive algorithm for variational Gaussian approximation of the posterior, called recursive variational Gaussian approximation (RVGA), which is a single pass algorithm, free of parameter tuning. In this paper, we consider the case where the parameter dimension d is high, and we propose a novel version of RVGA that scales linearly in the dimension d (as well as in the number of observations N), and which only requires linear storage capacity in d. This is afforded by using a novel recursive expectation maximization (EM) algorithm applied for factor analysis introduced herein, to approximate at each step the covariance matrix of the Gaussian distribution conveying the uncertainty in the parameter. The approach is successfully illustrated on the problems of high dimensional least-squares and logistic regression, and generalized to a large class of nonlinear models.
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