Precision medicine informatics is a field of research that incorporates learning systems that generate new knowledge to improve individualized treatments using integrated data sets and models. Given the ever-increasing volumes of data that are relevant to patient care, artificial intelligence (AI) pipelines need to be a central component of such research to speed discovery. Applying AI methodology to complex multidisciplinary information retrieval can support efforts to discover bridging concepts within collaborating communities. This dovetails with precision medicine research, given the information rich multi-omic data that are used in precision medicine analysis pipelines. In this perspective article we define a prototype AI pipeline to facilitate discovering research connections between bioinformatics and clinical researchers. We propose building knowledge representations that are iteratively improved through AI and human-informed learning feedback loops supported through crowdsourcing. To illustrate this, we will explore the specific use case of nonalcoholic fatty liver disease, a growing health care problem. We will examine AI pipeline construction and utilization in relation to bench-to-bedside bridging concepts with interconnecting knowledge representations applicable to bioinformatics researchers and clinicians.
The article aims at giving a comprehensive overview on controlling communicable diseases (CCD) and discusses the implications of providing CCD as a global public good (GPG).After a short introductory summary of the history of CCD, Sections "PUBLIC (COMMON) GOODS" and "GLOBAL PUBLIC GOODS" offer a concise definition of the concepts of "public goods" and "global public goods".Sections "INTERNATIONAL HEALTH REGULATIONS (1969-2005) AS A GPG" and "IHR (2005) AND CCD"critically analyse the International Health Regulations (IHR) (2005) as a means to provide CCD as a GPG, and argues that it falls short of that goal as (a) many countries are not able to provide the "Core Capacity Requirements for Surveillance and Response" because of severe deficits of their health systems, (b) the IHR do not include HIV/AIDS, tuberculosis, malaria, etc. which are a constant threat in infested regions (and to international transmission) and may be called "chronic infectious diseases" and (c) ignore the issue of fighting antimicrobial resistance.Therefore, full global health security (accepting the highest attainable standard of health as a human right) needs an integrated CCD which implied that CCD is provided as a GPG, including minimal standards of health everywhere, a "One-Health" approach, and the perspective of "Health in All Policies" (Section "TOWARDS AN INTEGRATED CONTROL OF COMMUNICABLE DISEASES AS A GPG").Section "FINANCE OF CCD" discusses the dimension of financing CCD as a GPG and poses the question whether an enhanced transnational norm-building and solidarity can be expected.Improving CCD is not only one step towards the goal of "one healthy world", but also depends on a comprehensive improvement of health services.
Background: GAS5 is expressed in growth arrested cells as a result of nutrient deprivation or growth factor withdrawal. Besides its roles in metabolism, GAS5 has been studied in a variety of human cancers. The aim of the present work was to review the literature and report all recent findings of the roles of GAS5 in a variety of tumors. Methods: An electronic literature search was conducted by the authors using the keywords âGAS5â and âcancerâ, and then individually searched for each type of cancer that was brought up by the first search. Original articles and systematic reviews were selected, and the titles and abstracts of the papers were screened to determine whether they met the eligibility criteria. In addition, we performed computer-based structural analysis on the human GAS5 RNA for extending our understanding on its biological and/or pathological actions. Results: We have found that the majority of studies, irrespectively of tumor types, confirm the role of GAS5 as a tumor suppressor gene. Especially, more recent findings have also highlighted GAS5 interaction with miRNAs contributing even more to its tumor inhibiting role. In particular, we could outline two miRNAs, which came up throughout our review; miR-222 and miR-21. GAS5, miR-222 and miR-21 could pose potential prognostic and diagnostic biomarkers for a variety of tumors, making them quite useful in cancer clinic. Conclusions: For certain, more studies are required in order to better understand the role of GAS5 in tumor biology, and in particular the signaling pathways in which the gene participates.
Due to the abundance and conserved role of tRNAs, fragments thereof were considered as mere degradation products for a long time. Lately, however, it was unveiled that these 15â35 nucleotides-long tRNA (-precursor) -derived small RNAs (tsRNAs) can modulate gene expression by different mechanisms and act in a variety of contexts. While some tsRNAs inhibit translation globally by impeding the formation of the translation initiation complex, many studies find tsRNAs to silence target genes in a sequence-specific manner that is potentially mediated by Argonaute proteins. This function plays a role in transposon control, but was also found to be exploited by viruses and trypanosoma to regulate host genes. Beyond their involvement in infectious disease, aberrant tsRNA expression is linked to several other diseases such as cancer or neurological disorders. Furthermore, it was recently shown that tsRNAs residing in sperm of high-fat or low-protein diet mice can act as transgenerational transmitters that induce metabolic disorders and addictive behavior in the offspring. A better understanding of tsRNA-mediated gene regulation pathways, will not only expand our knowledge on how parental lifestyle influences the epigenome of the progeny, but may also enable the development of new drugs and biomarkers.
Microbial transglutaminase (mTG) is a survival factor for bacteria that is heavily used as a protein glue in the processed food industries. Despite the manufacturers’ claims for it safe usage, scientific observations are accumulating for its unwanted effects on human health. The enzyme can cross link proteins, imitating its family member, tissue transglutaminase, the autoantigen of celiac disease. Its gliadin cross-linked complexes are immunogenic in celiac disease. In the intestinal lumen, mTG exerts anti protease activity and forms resistant isopeptide bonds, it is anti-phagocytic, thus suppressing luminal protective pathways. It increases intestinal permeability, is trans-epithelialy transported and faces the enteric mucosal immune cells. Finally, mTG-containing products can react as emulsifiers and mucolytic agents thus compromising barriers’ integrities. The present review summarizes and updates on the potential detrimental effects of mTG, aiming to protect the public from the enzyme’s unwanted effects.
BACKGROUND:People with Huntington's disease (HD) struggle to maintain regular physical activity despite evidence of the benefits of exercise. This study aimed to evaluate the experiences of people who co-produced a walking group for people with HD. METHODS:Three people with HD, a specialist HD advisor (sHDA), two project officers from Let's Walk Cymru (LWC) and the research team co-produced and participated in a walking group for people with HD. A walking group for people with HD was supported weekly by LWC for eight weeks and fortnightly for a further 12 weeks. Semi-structured interviews were undertaken with three people with HD, a sHDA and two project LWC project officers. Interviews were transcribed verbatim and analysed using thematic analysis. FINDINGS:Interviews identified six themes across participants: "organisation and planning"; "purpose of the walks"; "benefits"; "barriers", "the group" and "the future". People with HD enjoyed participating in the walks and reported increased confidence to be more active outside the home. All participants noted challenges including apathy, diminished planning skills, social stigma and motor problems specific to HD; people with HD perceived a lack of influence in relation to co-planning and co-execution of the walking group. CONCLUSIONS:The walking group was perceived as enjoyable, beneficial, and motivational. This is the first study to report co-production of a walking group with people with HD and the findings suggest that further research is needed to adapt models of co-production for people with a long-term complex condition.
As a nascent and emerging field that holds great potential for precision oncology, nanotechnology has been envisioned to improve drug delivery and imaging capabilities through precise and efficient tumor targeting, safely sparing healthy normal tissue. In the clinic, nanoparticle formulations such as the first-generation Abraxane® in breast cancer, Doxil® for sarcoma, and Onivyde® for metastatic pancreatic cancer, have shown advancement in drug delivery while improving safety profiles. However, effective accumulation of nanoparticles at the tumor site is sub-optimal due to biological barriers that must be overcome. Nanoparticle delivery and retention can be altered through systematic design considerations in order to enhance passive accumulation or active targeting to the tumor site. In tumor niches where passive targeting is possible, modifications in the size and charge of nanoparticles play a role in their tissue accumulation. For niches in which active targeting is required, precision oncology research has identified targetable biomarkers, with which nanoparticle design can be altered through bioconjugation using antibodies, peptides, or small molecule agonists and antagonists. This review is structured to provide a better understanding of nanoparticle engineering design principles with emphasis on overcoming tumor-specific biological barriers.
Stem cell therapy has emerged as one of the topics in tissue engineering where undifferentiated and multipotent cells are strategically placed/ injected in tissue structure for cell regeneration. Over the years, stem cells have shown promising results in skin repairs for non-healing and/or chronic wounds. The addition of the stem cells around the wound site promotes signaling pathways for growth factors that regulate tissue reconstruction. However, injecting stem cells around the wound site has its drawbacks, including cell death due to lack of microenvironment cues. This particular issue is resolved when biomaterial scaffolds are involved in the cultivation and mechanical support of the stem cells. In this review, we describe the current models of stem cell therapy by injections and those that are done through cell cultures using electrospun fiber scaffolds. Electrospun fibers are considered as an ideal candidate for cell cultures due to their surface properties. Through the control of fiber morphology and fiber structure, cells are able to proliferate and differentiate into keratinocytes for skin tissue regeneration. Furthermore, we provide another perspective of using electrospun fibers and stem cells in a layer-by-layer structure for skin substitutes (dressing). Finally, electrospun fibers have the potential to incorporate bioactive agents to achieve controlled release properties, which is beneficial to the survival of the delivered stem cells or the recruitment of the cells. Overall, our work illustrates that electrospun fibers are ideal for stem cell cultures while serving as cell carriers for wound dressing materials.
Peroxynitrite (ONOO-, PN) has long been considered a potent nitrating agent implicated in numerous inflammation-mediated diseases. The current work highlights an unexplored oxidation chemistry initiated under conditions of sustained PN exposure. Impetus for this investigation developed from mass spectral results that suggested dimerization of a model peptide with a single tyrosine residue that was first nitrated following extended exposure to PN generated in situ. In attempts to substantiate this dimerization event and divulge the possible mode of linkage between the tyrosine derivatives of the peptide monomers, 3-nitrotyrosine (3-NT) was exposed to sustained fluxes of PN in a two-component PN-generating platform developed in this laboratory. Such exposure afforded products with tandem mass spectrometry and fluorescence spectroscopy profiles indicative of C-O coupling between 3-NT moieties. Synthesis and comparative analysis of the C-C coupled 3-NT isomer corroborated these findings. Most notably, the mass spectral data of the C-C coupled 3-NT dimer displayed a 226.80 m/z peak following exposure to high collision energy, corresponding to symmetric cleavage of the parent dimer peak (m/z = 453) along with a fragmentation product at m/z = 180.04 (-NO2 species). This fragmentation profile was distinct from the C-O coupled 3-NT dimer that exhibited a predominant 209.14 m/z peak with a small secondary 226.15 m/z peak indicative of asymmetric cleavage of the parent dimer. Results of this study indicate that formation of C-O coupled 3-NT dimer is promoted by elevated levels of 3-NT formed under high and sustained flux of PN.
Traditional vaccines have seen spectacular successes in eradicating smallpox and have come close to eradicating poliomyelitis also. However, they have been short in combating viral epidemics which are now occurring with increasing frequency; the reasons are primarily due to rapid mutations in RNA viruses. Alternative procedures are to be found in the new science of vaccinomics where peptide vaccines have come to be recognized as a strong alternative strategy. While several issues still need to be resolved, and no license has yet been released for human use of peptide vaccines, such vaccines have found ready acceptance in cancer therapeutics where personalized vaccines are of necessity the de facto norm. This knowledge gives us the opportunity in the event of viral epidemics to tailor making vaccines for different communities for maximum efficiency and for immunocompromised individuals. We give a brief perspective on the current status and future prospects of new trends in vaccine research, specifically peptide vaccines development, in this paper.
Background: To investigate the influence of systemic inflammation on dynamic cerebral autoregulation and vascular tone during experimental human endotoxemia and sepsis. Methods: Healthy volunteers received 3 h continuous infusion of LPS (c-LPS, 4 ng/kg, n = 11, Clinicaltrials.gov NCT02922673) or a bolus of LPS (b-LPS, 2 ng/kg, n = 8, Clinicaltrials.gov NCT02675868) and 10 sepsis patients were studied. Mean arterial pressure (MAP) and cerebral blood flow velocity (CBFV) were monitored simultaneously. Cerebral autoregulation was analysed by transfer function analysis (TFA). Critical closing pressure (CrCP) was estimated as a measure of cerebral vascular tone. Results: c-LPS resulted in a more pronounced and prolonged plasma cytokine response compared with b-LPS. MAP decreased from 89 ± 3 to 75 ± 2 mmHg (p < 0.05) and from 91 ± 2 to 77 ± 3 mmHg (p < 0.001) in the c-LPS and b-LPS groups, respectively. MAP in sepsis patients was 65 ± 4 mmHg. TFA in both LPS groups showed no significant changes over time in coherence, gain and phase. Phase in sepsis patients was lower compared with both LPS groups (7 (2 to 33) [median (interquartile range)] in sepsis versus 57 (36 to 74) in the c-LPS (p = 0.02) and 53 (43 to 64) degrees in the b-LPS group (p = 0.01)). CrCP decreased from 49 ± 2 to 41 ± 2 mmHg (p = 0.16) in the c-LPS and from 50 ± 2 to 42 ± 2 mmHg in the b-LPS group (p < 0.01), and was 36 ± 2 mmHg in sepsis patients. Conclusions: Dynamic cerebral autoregulation is impaired in sepsis patients, but remains intact during experimental human endotoxemia. CrCP decreased during endotoxemia and was low in sepsis, reflecting decreased vascular tone. This indicates activation of a cerebrovascular adaptive process, also during experimental endotoxemia with intact cerebral autoregulation. Trial Registration: Clinicaltrials.gov NCT02922673 and Clinicaltrials.gov NCT02675868
One of the most common solutions to treat ischemic heart disease nowadays is the implantation of drug eluting stents. Currently, new strategies are being developed to improve healing process, which includes pharmacological treatments or gene therapy. In this paper, we presented a proposal based on the use of poly(β-amino ester) (pBAE) nanoparticles. To enhance the release method, we used an approach based on attaching these nanoparticles on a polymeric coating. The process includes coating metallic cardiovascular stents with a thin and highly functionalized layer of pentafluorophenyl methacrylate (PFM) to which loaded nanoparticles are chemically bonded. Through this design, when a stent is expanded during its implantation, nanoparticles will stay attached to the polymer matrix. Nanocarriers will penetrate target adjacent cells, guaranteeing effective drug delivery. Results obtained show that this work opens a pathway for pharmacological and/or gene delivery systems based on the adhesion of pBAE nanoparticles prior to stent implantation.
Small cell lung cancer (SCLC) is an invasive and high-grade neuroendocrine malignant tumor. It is characterized by short doubling time, high proliferation rate, and early extensive metastasis. SCLC is sensitive to radiotherapy and chemotherapy in the initial stage; however, it can easily relapse and develop drug resistance. In the past five years, there has been a resurgence of research on SCLC worldwide, including the establishment of SCLC cells, the development of related genetically engineered mouse models (GEMMs) and the establishment of patient-derived xenograft models (PDXs). These studies have identified new potential therapeutic vulnerabilities for SCLC, leading to new clinical trials. In this perspective, the establishment, application, and advantages and disadvantages of three preclinical research models of SCLC are systematically summarized.
Background: The integration of inhalation drug delivery and nanotechnology offers exciting potentials to enhance the targeting, release, diagnostic, and therapeutic outcomes of drugs. Human lungs provide many advantages over other routers such as noninvasive delivery, a large surface area for absorption, avoiding the first-pass metabolism, and quick therapeutic onset. It is crucial to understand nanoparticle dosimetry in the acinar region to reliably evaluate the therapeutic outcomes of nanomedicines. However, an acinus unit comprises up to 10,000 alveoli and to model a complete acinus is still a prohibitive task. Besides, the presence of inter-alveolar septa creates a labyrinth pathway for inhaled airflow and particles. Methods: The objective of this study is to numerically investigate nanoparticle deposition in three alveolar models with varying physical complexities, which retain 1, 4, and 45 alveoli, respectively. A discrete-phase Lagrangian model was implemented to track nanoparticle trajectories under the influence of rhythmic wall expansion and contraction. Both temporal and spatial dosimetry in the alveoli were computed. Results: Strikingly different behaviors were observed in the dynamic alveolar model between micron particles and nanoparticles. Minimal deposition rates were predicted for 500â600 nm particles for all the three models considered. Consistently lower deposition rates were found in the 45-alveoli model than the other two simplified models for all particles ranging from 1 nm to 1000 nm. Considering the gravitational orientation effect, nanoparticles smaller than 200 nm appears insensitive to the alveolar orientation and only becomes perceivable around 500 nm. For nanoparticles larger than 500 nm, lower doses were predicted in the horizontal alveoli than in the vertical alveoli, regardless of the model complexity. Conclusions: The magnitude of the airflow velocity (depending on ventilated volume) is an essential factor in determining the deposition of inhaled nanoparticles. Future correlation development for acinar deposition should consider the velocity distribution in different regions of the acinus.
One of the key areas in nanomedicine is the use of nanometer-sized materials as nanocarriers for therapeutic and diagnostic (theranostic) purposes. In particular, nanoparticles (NPs) have attracted a considerable attention due to their small size that confers the ability to be transported more easily through the body. Ideally, nanocarriers would be biocompatible and biodegradable so the involvement of soft matter-based NPs is an interesting approach. Folding individual polymer chains to single-chain nanoparticles (SCNPs) endows the resulting soft nano-objects with promising prospects for drug encapsulation and subsequent controlled delivery. In this work, we report on the preparation and preliminary (in vitro) evaluation of Povidone SCNPs as potential drug delivery nanocarriers. We select Povidone (polyvinylpyrrolidone) as a water-soluble polymer with a large commercial use in medicine, which is biocompatible and non-antigenic as well as safe for oral and topical applications. For evaluation of Povidone SCNPs as drug delivery nanocarriers, we select two drugs with reported anti-cancer activity: (i) Cisplatin, a widely used hydrophilic anticancer agent for treatment of a variety of cancer cells; and (ii) Lovastatin, a lipophilic compound with in vitro anti-proliferative, pro-apoptotic and anti-invasive effects in different cancer cell lines. After showing release of these drugs from Povidone SCNPs, we demonstrate that these nanoparticles can be rendered fluorescent in combination with functional aggregation-induced emission (AIE) fluorophore molecules paving the way to the potential development of theranostic Povidone SCNPs.
Foodborne pathogens especially bacteria cause a vast number of diseases which leads to a high mortality rate in humans. Conventional antibiotics have been employed in an attempt to eradicate these pathogens and this has led to the evolution of a multidrug resistant bacteria strain. Thus, a new genre of antibiotics is prepared by using nanoparticles as they show effective antibacterial capabilities. Biosynthesized nanoparticles are less toxic to humans as compared to chemically synthesized nanoparticles which are prepared using toxic precursors. They also exhibit enhanced antibacterial action along with the biomolecules that help in their formation. Among most metal oxides, magnesium oxide (MgO) nanoparticles show unique antibacterial properties due to their exclusive oxide vacancies and crystalline structure. The antibacterial activity of MgO nanoparticles synthesized using leaf extract is further enhanced by the presence of phytochemicals. The present work is a comparative study of the antibacterial activity of MgO nanoparticles synthesized using three different leaf extracts: (1) Amaranthus tricolor, (2) Amaranthus blitum and (3) Andrographis paniculata and their reaction towards Escherichia coli which is a gram negative, food borne pathogen. The results showed that the ~78 nm spherical shaped MgO nanoparticles synthesized from A. blitum, exhibited the highest antibacterial activity at 60 µL dosage. In addition, the effects of the characteristics of the MgO nanoparticles such as size, morphology, concentration, surface charge and phytochemicals on antibacterial mechanism were also discussed.
Cancer biology has long been characterised by definitive hallmarks [1,2]; acquired traits that inevitably footprint the mutational history of its transformation. It is only recently that molecular profiling techniques have offered us the opportunity to chart the sequence of these mutations—allowing us to perceive these traits, not simply as hallmarks, but as milestones in the evolution of cancer. Squamous cell carcinoma of the lung accounts for approximately 30 percent of lung cancers and remains a world-wide health problem. Mascaux et al. [3] contribute to our growing understanding of carcinogenesis by demonstrating the crucial role of immune evasion in the pre-invasive stages of squamous cell carcinoma of the lung, building on previous studies implying that a breakdown in immune surveillance underpins this process [4,5]. Key to their report is the temporal information gleaned by analysing 9 distinct morphological stages in the development of this disease; from which arises the suggestion that escape from host immunity occurs prior to the cancer’s capability to metastasise. Crucially, the directionality of this sequence may have important implications for detection and early prevention of lung cancer—a condition which remains largely incurable because of its presentation mainly at advanced stages. This comes at an opportune moment in efforts centred on early detection. In terms of macroscopic disease, the NELSON trial is a randomised, controlled population-based screening study exploring volume computed-tomography in at-risk groups for lung cancer. Recently, the investigators reported a 26% reduction in lung cancer mortality in men and 39%–61% in women at 10 years of follow-up [6]—a clear indication that targeted screening is of substantial benefit. Such are the implications, that the United Kingdom National Health Service has recently invested Open Access
