2,698 research outputs found

    Antiretroviral therapy of HIV infection using a novel optimal type-2 fuzzy control strategy

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    Abstract The human immunodeficiency virus (HIV), as one of the most hazardous viruses, causes destructive effects on the human bodies' immune system. Hence, an immense body of research has focused on developing antiretroviral therapies for HIV infection. In the current study, we propose a new control technique for a fractional-order HIV infection model. Firstly, a fractional model of the HIV model is investigated, and the importance of the fractional-order derivative in the modeling of the system is shown. Afterward, a type-2 fuzzy logic controller is proposed for antiretroviral therapy of HIV infection. The developed control scheme consists of two individual controllers and an aggregator. The optimal aggregator modifies the output of each individual controller. Simulations for two different strategies are conducted. In the first strategy, only reverse transcriptase inhibitor (RTI) is used, and the superiority of the proposed controller over a conventional fuzzy controller is demonstrated. Lastly, in the second strategy, both RTI and protease inhibitors (PI) are used simultaneously. In this case, an optimal type-2 fuzzy aggregator is also proposed to modify the output of the individual controllers based on optimal rules. Simulations results demonstrate the appropriate performance of the designed control scheme for the uncertain system

    Vive la radiorésistance!: converging research in radiobiology and biogerontology to enhance human radioresistance for deep space exploration and colonization.

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    While many efforts have been made to pave the way toward human space colonization, little consideration has been given to the methods of protecting spacefarers against harsh cosmic and local radioactive environments and the high costs associated with protection from the deleterious physiological effects of exposure to high-Linear energy transfer (high-LET) radiation. Herein, we lay the foundations of a roadmap toward enhancing human radioresistance for the purposes of deep space colonization and exploration. We outline future research directions toward the goal of enhancing human radioresistance, including upregulation of endogenous repair and radioprotective mechanisms, possible leeways into gene therapy in order to enhance radioresistance via the translation of exogenous and engineered DNA repair and radioprotective mechanisms, the substitution of organic molecules with fortified isoforms, and methods of slowing metabolic activity while preserving cognitive function. We conclude by presenting the known associations between radioresistance and longevity, and articulating the position that enhancing human radioresistance is likely to extend the healthspan of human spacefarers as well

    Improving clinical outcomes for patients with locally advanced non-small cell lung cancer treated with photon and proton radiotherapy

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    Objectives To identify mechanisms improving clinical outcomes for patients with unresectable locally advanced non-small-cell lung cancer (LA-NSCLC) treated with photon and proton radiotherapy. Strategies explored include 1. Investigating using routine healthcare datasets to estimate survival outcomes for patients with LA-NSCLC treated with definitive radiotherapy, in order to assess the effectiveness of current strategies; 2. Assessing the physical advantages of protons by conducting a retrospective planning study comparing volumetric modulated arc therapy (VMAT) and pencil beam scanning (PBS) proton plans of superior sulcus tumours (SSTs), a rare subset of LA-NSCLC; 3. Exploring potential biological advantages of protons by examining major cell death pathways following XRT, high and low linear energy transfer (LET) proton irradiation of NSCLC cells. Methods Workflow 1: LA-NSCLC patients receiving definitive radiotherapy were identified. For each, key time points (date of diagnosis, recurrence, death or last clinical encounter) were used to calculate overall survival (OS) and progression free survival (PFS) from manual-data (hospital notes) and compared to estimated OS and PFS from routine-data (electronic databases). Dataset correlations were then tested to establish if routine-data were a reliable proxy measure for manual-data. Workflow 2: Patients with SSTs treated with 4D radiotherapy were identified. Tumour motion was assessed and excluded if >5 mm. Comparative VMAT and PBS plans were generated retrospectively. Robustness analysis was assessed for both plans involving: 1. 5 mm geometric uncertainty scenarios, with an additional 3.5% range uncertainty for proton plans; 2. verification plans at breathing extremes. Comparative dosimetric and robustness analyses were carried out. Workflow 3: Human NSCLC cell lines were irradiated with single doses of 2-15 Gy photon radiotherapy, high- or low-linear energy transfer (LET) protons (12 keV/µm and 1 keV/µm, respectively) and analysed 24-144 hours post-irradiation. DNA damage foci and cell death mechanisms were investigated. Results Workflow 1: In forty-three patients, routine data underestimated PFS by 0.09 months (p=0.86; 95% CI -0.86-1.03) and OS by 1.02 months (p=0.00; 95% CI 0.34-1.69) but there was good correlation with a Pearson correlation coefficient of 0.94 (p=0.00, 95% CI 0.90-0.97) for PFS and 0.97 (p= 0.00, 95% CI 0.95-0.98) for OS. Workflow 2: In ten patients, both modalities achieved similar target coverage with mean clinical target volume D95 of 98.1% + 0.4 (97.5-98.8) and 98.4% + 0.2 (98.1-98.9) for PBS and VMAT plans, respectively. The same four PBS and VMAT plans failed robustness. Proton plans significantly reduced mean lung dose (by 21.9%), lung V5, V10, V20 (by 47.9%, 36.4%, 12.1%, respectively), mean heart dose (by 21.4%) and vertebra dose (by 29.2%) (p<0.05). Workflow 3: XRT predominantly induced mitotic catastrophe, autophagy and senescence. Senescence, established via the p53/p21 pathway, was the major cell death pathway by which protons more effectively reduce clonogenic potential compared to XRT in NSCLC cell lines. High LET protons at a dose of 10 Gy(RBE) resulted in the lowest cell survival. The mechanisms driving the LET- and dose-dependent senescence was unclear but did not appear to be related to differential DNA repair machineries. Conclusions Proton radiotherapy could be pivotal in improving outcomes in select cases of LA-NSCLC. These studies demonstrate that 1. survival-outcomes are reliably estimated by routine data and such a methodology could enable rapid outcomes analysis to keep pace with trial development; 2. robust PBS plans are achievable in carefully selected patients and considerable dose reductions to the lung, heart and thoracic vertebra are possible without compromising target coverage; 3. Identification of LET- and dose-dependent proton-induced cellular senescence may guide radiotherapy optimisation and drug-radiotherapy combinations, maximising tumour cell kill. This work contributes to important preliminary research required to understand the physical and biological strengths and weaknesses prior to trials

    Advances in immunotherapy for cervical cancer

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    Cervical cancer; Immunotherapy; RadiotherapyCáncer de cuello uterino; Inmunoterapia; RadioterapiaCàncer de coll uterí; Immunoteràpia; RadioteràpiaCervical cancer still represents a major public health problem, being the fourth most common cancer in incidence and mortality in women worldwide. These figures are unacceptable since cervical cancer, an human papillomavirus-related malignancy, is a largely preventable disease by means of well-established screening and vaccination programs. Patients with recurrent, persistent, or metastatic disease unsuitable for curative therapeutic approaches represent a dismal prognosis population. Until recently, these patients were only candidates for cisplatin-based chemotherapy plus bevacizumab. However, the introduction of immune checkpoint inhibitors has revolutionized the treatment landscape of this disease achieving historical overall survival improvements in both the post-platinum and frontline settings. Interestingly, the clinical development of immunotherapy in cervical cancer is currently advancing to earlier stages of the disease, as the locally advanced setting, whose standard of care has not changed in the last decades with still modest outcomes. As more innovative immunotherapy approaches are in clinical early development in advanced cervical cancer, promising efficacy data are emerging that may shape the future of this disease. This review summarizes the main treatment advances carried out in the field of immunotherapy throughout the past years

    The Role of Costimulatory Receptors of the Tumour Necrosis Factor Receptor Family in Atherosclerosis

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    Atherosclerosis is a chronic inflammatory disease that is mediated by both the innate and adaptive immune responses. T lymphocytes, that together with B cells are the cellular effectors of the adaptive immune system, are currently endowed with crucial roles in the development and progression of atherosclerosis. Costimulatory receptors are a class of molecules expressed by T lymphocytes that regulate the activation of T cells and the generation of effector T-cell responses. In this review we present the roles of costimulatory receptors of the tumour necrosis factor receptor (TNFR) superfamily in atherosclerosis and discuss the implications for future therapies that could be used to specifically modulate the immune response of pathogenic T cells in this disease

    A new fuzzy reinforcement learning method for effective chemotherapy

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    A key challenge for drug dosing schedules is the ability to learn an optimal control policy even when there is a paucity of accurate information about the systems. Artificial intelligence has great potential for shaping a smart control policy for the dosage of drugs for any treatment. Motivated by this issue, in the present research paper a Caputo–Fabrizio fractional-order model of cancer chemotherapy treatment was elaborated and analyzed. A fix-point theorem and an iterative method were implemented to prove the existence and uniqueness of the solutions of the proposed model. Afterward, in order to control cancer through chemotherapy treatment, a fuzzy-reinforcement learning-based control method that uses the State-Action-Reward-State-Action (SARSA) algorithm was proposed. Finally, so as to assess the performance of the proposed control method, the simulations were conducted for young and elderly patients and for ten simulated patients with different parameters. Then, the results of the proposed control method were compared with Watkins’s Q-learning control method for cancer chemotherapy drug dosing. The results of the simulations demonstrate the superiority of the proposed control method in terms of mean squared error, mean variance of the error, and the mean squared of the control action—in other words, in terms of the eradication of tumor cells, keeping normal cells, and the amount of usage of the drug during chemotherapy treatment
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