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Aberrant Notch signaling in gliomas: a potential landscape of actionable converging targets for combination approach in therapies resistance
No full textThe current therapeutic protocols and prognosis of gliomas still depend on clinicopathologic and radiographic characteristics. For high-grade gliomas, the standard of care is resection followed by radiotherapy plus temozolomide chemotherapy. However, treatment resistance develops due to different mechanisms, among which is the dynamic interplay between the tumor and its microenvironment. Different signaling pathways cause the proliferation of so-called glioma stem cells, a minor cancer cell population with stem cell-like characteristics and aggressive phenotype. In the last decades, numerous studies have indicated that Notch is a crucial pathway that maintains the characteristics of resistant glioma stem cells. Data obtained from preclinical models indicate that downregulation of the Notch pathway could induce multifaceted drug sensitivity, acting on the expression of drug-transporter proteins, inducing epithelial–mesenchymal transition, and shaping the tumor microenvironment. This review provides a brief overview of the published data supporting the roles of Notch in drug resistance and demonstrates how potential novel strategies targeting Notch could become an efficacious action to improve the therapy of high-grade glioma to overcome drug resistance
Tyrosine kinases in KMT2A/MLL-rearranged acute leukemias as potential therapeutic targets to overcome cancer drug resistance
No full textAim: The main goal of this study was to elucidate at the transcript level the tyrosine kinase expression profiles of primary leukemia cells from mixed lineage leukemia 1 gene rearranged (KMT2A/MLL-R+) acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients.Methods: We evaluated protein tyrosine kinase (PTK) gene expression profiles of primary leukemic cells in KMT2A/MLL-R+ AML and ALL patients using publicly available archived datasets. Results: Our studies provided unprecedented evidence that the genetic signatures of KMT2A/MLL-R+ AML and ALL cells are characterized by transcript-level overexpression of specific PTK. In infants, children and adults with KMT2A/MLL-R+ ALL, as well as pediatric patients with KMT2A/MLL-R+ AML, the gene expression levels for FLT3, BTK, SYK, JAK2/JAK3, as well as several SRC family PTK were differentially amplified. In adults with KMT2A/MLL-R+ AML, the gene expression levels for SYK, JAK family kinase TYK2, and the SRC family kinases FGR and HCK were differentially amplified. Conclusion: These results provide new insights regarding the clinical potential of small molecule inhibitors of these PTK, many of which are already FDA/EMA-approved for other indications, as components of innovative multi-modality treatment platforms against KMT2A/MLL-R+ acute leukemias
Perspectives of metal-organic framework nanosystem to overcome tumor drug resistance
No full textCancer is one of the most harmful diseases in the world, which causes huge numbers of deaths every year. Many drugs have been developed to treat tumors. However, drug resistance usually develops after a period of time, which greatly weakens the therapeutic effect. Tumor drug resistance is characterized by blocking the action of anticancer drugs, resisting apoptosis and DNA repair, and evading immune recognition. To tackle tumor drug resistance, many engineered drug delivery systems (DDS) have been developed. Metal-organic frameworks (MOFs) are one kind of emerging and promising nanocarriers for DDS with high surface area and abundant active sites that make the functionalization simpler and more efficient. These features enable MOFs to achieve advantages easily towards other materials. In this review, we highlight the main mechanisms of tumor drug resistance and the characteristics of MOFs. The applications and opportunities of MOF-based DDS to overcome tumor drug resistance are also discussed, shedding light on the future development of MOFs to address tumor drug resistance
Leveraging biomimetic synthesis strategy for next-generation dendritic cell nanovaccines
No full textThe activation of CD8+ cytotoxic T-lymphocytes (CTLs) plays the central role in cancer immunotherapy, which depends on the efficient recognition of peptide-major histocompatibility complex (pMHC) by the T cell receptor (TCR) for the first signal, and B7-CD28 co-stimulating for the second signal. To achieve the potent immune stimulatory effect, a genetically engineered cellular membrane nanovesicles platform that integrates antigen self-presentation and immunosuppression reversal (ASPIRE) for cancer immunotherapy was designed. In preclinical mouse models, ASPIRE could markedly improve antigen delivery to lymphoid organs and generate broad-spectrum T-cell responses that eliminate established tumors. This review highlights that the ASPIRE system represents a novel strategy for personalized cancer immunotherapy
Towards responsible ctDNA-based multi-cancer screening: a preliminary exploration and discussion of ethically relevant aspects
No full textWhile testing for easily accessible biomarkers in the circulation (“liquid biopsy”) has found its way to clinical cancer care, a further expected development is its use as a “universal” early detection test in population screening for cancer. A promising marker for such screening is circulating cell-free fragments of tumor DNA, shed into the circulation during tumor cell turnover. Several blood-based “multicancer early detection (MCED) tests” have recently been developed - but still need validation in large-scale studies involving non-patient populations. In this paper, we proactively explore the ethical aspects of this development. We refer to an often quoted synthesis of the internationally accepted framework of principles for responsible screening as first drawn up for the World Health Organisation (WHO) by Wilson and Junger 50 years ago and further developed and fine-tuned ever since. As our analysis suggests, some specific ethical issues and concerns about potential MCED screening connect to the fact that cancer is not just one disease. As a consequence, not all findings will have the same clinical utility. We discuss this against the background of earlier debates pertaining to broad scope forms of screening in other contexts, specifically newborn and reproductive genetic screening. We highlight the guidance provided by some of the criteria from the screening framework that seems most relevant in this connection: the need for screening objectives to be defined at the outset, the need for mechanisms to minimize potential risks, and the requirement that, for those participating in the screening, the overall benefits outweigh the harm
Leveraging the GQM+ Strategy approach and Industry 4.0 technologies for environmental sustainability in manufacturing
No full textAim: In the last years, sustainability has been identified as an enormous problem, with many facets gaining increasing attention. In this broad scenario, the availability of models for environmental sustainability constitutes a conceptual tool to guide industries towards reducing the environmental impact deriving from production. This work aims to contribute to the research on environmental sustainability in manufacturing by proposing a model that leverages the Goal Question Metrics approach and technologies of Industry 4.0.Methods: The Goal Question Metrics approach and technologies of Industry 4.0 are leveraged by proposing a model that contributes to environmental sustainability in manufacturing.Results: A model is proposed that can be used as a conceptual tool to support improvement programs in environmental sustainability.Conclusion: The application of the Goal Question Metrics+ Strategies to a case study of an automotive industry shows how the approach, combined with the implementation of Industry 4.0 technologies, contributes to the efficient use of natural resources and also reduces the emissions in the atmosphere
Exploring the causal relationship between dietary macronutrients and neurodegenerative diseases: a bi-directional two-sample Mendelian randomization study
No full textAim: The associations between dietary macronutrient intake and neurodegenerative diseases (NDDs) have been widely reported; however, the causal effect remains unclear. The current study aimed to estimate the causal relationship between dietary macronutrient intake (i.e., carbohydrate, fat, and protein) and NDDs [e.g., Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS)].Methods: Mendelian randomization (MR) was applied to evaluate the causal relationship between dietary macronutrient intake and NDDs. We used the single-nucleotide polymorphisms strongly associated (P < 5 × 10-8) with the exposures from the genome-wide association studies as instrumental variables. Inverse-variance weighted, MR-Egger, weighted median, and the MR pleiotropy residual sum and outlier were used to verify the MR assumptions.Results: Genetically predicted higher carbohydrate intake was associated with an increased risk of ALS [odds ratio (OR), 2.741, 95% confidence interval (CI): 1.419-5.293, P = 0.003). Vulnerability to PD was negatively associated with the relative intake of fat (OR, 0.976, 95%CI: 0.959-0.994, P = 0.012) and protein (OR, 0.987, 95%CI: 0.975-1.000, P = 0.042). The study also identified the causal influence of AD on dietary carbohydrate intake (OR, 1.022, 95%CI: 1.011-1.034, P = 0.001).Conclusion: We found solid evidence supporting the idea that a higher carbohydrate proportion causally increases ALS risk. Genetically predicted higher AD risk is causally associated with increased dietary carbohydrate intake. Vulnerability to PD may have a causal relationship with a decrease in the dietary intake of protein and fat
Recent advances in flexible and soft gel-based pressure sensors
No full textGels, as typical flexible and soft materials, possess the intrinsic merits of transparent bionic structures, superior mechanical properties and excellent elasticity and viscosity. Recently, gel-based materials have attracted significant attention as a result of their broad and promising applications in biomedical, energy storage, light emission, actuator, military and aerospace devices, especially the intelligent sensing for human-related applications. Among the various flexible and soft pressure sensors, gel-based ones have been gradually studied as an emerging hot research topic. This review focuses on the latest findings in the rapidly developing field of gel-based pressure sensors. Firstly, the classification and properties of the three types of gels and their corresponding fabrication methods are introduced. Secondly, the four basic working principles of pressure sensors are summarized with a comparison of their advantages and disadvantages, followed by an introduction to the construction of pressure sensors based on gel structures. Thirdly, the latest representative research on the three types of gel-based materials towards various wearable sensing applications, including electronic skin, human motion capture, healthcare and rehabilitation, physiological activity monitoring and human-machine interactions, is comprehensively reviewed. Finally, a summary of the remaining challenges and an outline of the development trend for this field are presented
Promoting healthy cardiovascular aging: emerging topics
No full textThe development of age-related cardiovascular (CV) dysfunction increases the risk of CV disease as well as other chronic age-associated disorders, including chronic kidney disease, and Alzheimer’s disease and related dementias. Major manifestations of age-associated CV dysfunction that increase disease risk are vascular dysfunction, primarily vascular endothelial dysfunction and arterial stiffening, and elevated systolic blood pressure. Declines in nitric oxide bioavailability secondary to increased oxidative stress and inflammation are established mechanisms of CV dysfunction with aging. Moreover, fundamental mechanisms of aging, termed the “hallmarks of aging” extend to the CV system and, as such, may be considered “hallmarks of CV aging”. These mechanisms represent viable therapeutic targets for treating CV dysfunction with aging. Healthy lifestyle behaviors, such as regular aerobic exercise and certain dietary patterns, are considered “first-line” strategies to prevent and/or treat age-associated CV dysfunction. Despite the well-established benefits of these strategies, many older adults do not meet the recommended guidelines for exercise or consume a healthy diet. Therefore, it is important to establish alternative and/or complementary evidence-based approaches to prevent or reverse age-related CV dysfunction. Targeting fundamental mechanisms of CV aging with interventions such as time-efficient exercise training, food-derived molecules, termed nutraceuticals, or select synthetic pharmacological agents represents a promising approach. In the present review, we will highlight emerging topics in the field of healthy CV aging with a specific focus on how exercise, nutrition/dietary patterns, nutraceuticals and select synthetic pharmacological compounds may promote healthy CV aging, in part, by targeting the hallmarks of CV aging
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