The Biologics Revolution and Endotoxin Test Concerns
Ontology highlight
ABSTRACT:
SUBMITTER: Williams K
PROVIDER: S-EPMC7123716 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
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Project description:The Ganga basin includes some of the most densely populated areas in the world, in a region characterized by extremely high demographic and economic growth rates. Although anthropogenic pressure in this area is increasing, the pollution status of the Ganga is still poorly studied and understood. In the light of this, we have carried out a systematic literature review of the sources, levels and spatiotemporal distribution of organic pollutants in surface water and sediment of the Ganga basin, including for the first time emerging contaminants (ECs). We have identified 61 publications over the past thirty years, with data on a total of 271 organic compounds, including pesticides, industrial chemicals, and by-products, artificial sweeteners, pharmaceuticals, and personal care products (PPCPs). The most studied organic contaminants are pesticides, whereas knowledge of industrial compounds and PPCPs, among which some of the major ECs, is highly fragmentary. Most studies focus on the main channel of the Ganga, the Yamuna, the Gomti, and the deltaic region, while most of the Ganga's major tributaries, and the entire southern part of the catchment, have not been investigated. Hotspots of contamination coincide with major urban agglomerations, including Delhi, Kolkata, Kanpur, Varanasi, and Patna. Pesticides levels have decreased at most of the sites over recent decades, while potentially harmful concentrations of polychlorinated biphenyls (PCBs), organotin compounds (OTCs), and some PPCPs have been detected in the last ten years. Considering the limited geographical coverage of sampling and number of analyzed compounds, this review highlights the need for a more careful selection of locations, compounds and environmental matrices, prioritizing PPCPs and catchment-scale, source-to-sink studies.
| S-EPMC7900350 | biostudies-literature
Project description: Not available
| S-EPMC525755 | biostudies-literature
Project description:BackgroundNanomaterials can be contaminated with endotoxin (lipopolysaccharides, LPS) during production or handling. In this study, we searched for a convenient in vitro method to evaluate endotoxin contamination in nanoparticle samples. We assessed the reliability of the commonly used limulus amebocyte lysate (LAL) assay and an alternative method based on toll-like receptor (TLR) 4 reporter cells when applied with particles (TiO(2), Ag, CaCO(3) and SiO(2)), or after extraction of the endotoxin as described in the ISO norm 29701.ResultsOur results indicate that the gel clot LAL assay is easily disturbed in the presence of nanoparticles; and that the endotoxin extraction protocol is not suitable at high particle concentrations. The chromogenic-based LAL endotoxin detection systems (chromogenic LAL assay and Endosafe-PTS), and the TLR4 reporter cells were not significantly perturbed.ConclusionWe demonstrated that nanoparticles can interfere with endotoxin detection systems indicating that a convenient test method must be chosen before assessing endotoxin contamination in nanoparticle samples.
| S-EPMC3546036 | biostudies-literature
Project description:Accurate protein-protein docking remains challenging, especially for artificial biologics not coevolved naturally against their protein targets, like antibodies and other engineered scaffolds. We previously developed ProPOSE, an exhaustive docker with full atomistic details, which delivers cutting-edge performance by allowing side-chain rearrangements upon docking. However, extensive protein backbone flexibility limits its practical applicability as indicated by unbound docking tests. To explore the usefulness of ProPOSE on systems with limited backbone flexibility, here we tested the engineered scaffold DARPin, which is characterized by its relatively rigid protein backbone. A prospective screening campaign was undertaken, in which sequence-diversified DARPins were docked and ranked against a directed epitope on the target protein BCL-W. In this proof-of-concept study, only a relatively small set of 2,213 diverse DARPin interfaces were selected for docking from the huge theoretical library from mutating 18 amino-acid positions. A computational selection protocol was then applied for enrichment of binders based on normalized computed binding scores and frequency of binding modes against the predefined epitope. The top-ranked 18 designed DARPin interfaces were selected for experimental validation. Three designs exhibited binding affinities to BCL-W in the nanomolar range comparable to control interfaces adopted from known DARPin binders. This result is encouraging for future screening and engineering campaigns of DARPins and possibly other similarly rigid scaffolds against targeted protein epitopes. Method limitations are discussed and directions for future refinements are proposed.
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Project description:Some people with cancer suffer from muscle wasting, lose weight and feel tired. This process, termed cachexia, is a significant problem and can lead to a reduction in both quality and quantity of life.
Cachexia is caused by interactions between the tumour and the patient. Historically, it was considered to be a purely end-stage phenomenon of advanced cancer, however, it is now known that early signs of cachexia can even influence the outcomes of patients with potentially curative pathology, including those planned for a surgical resection.
This study aims to collect information, from patients who are at risk of cachexia, about body composition, physical activity, quality of life and the body’s immune response to cancer. Previously these measures have been most frequently studied in isolation, or at one single time-point, and are therefore likely to give an incomplete picture. A more holistic characterisation of surgical patients at risk of cancer cachexia, across their treatments, is currently lacking.
Participants with cancer will be recruited to the study from surgical services in the United Kingdom (UK). A small number of ‘control’ patients without cancer, who are undergoing surgery for a benign condition, will also be recruited for comparison. Those recruited will have their height and weight measured, answer questionnaires about quality of life, undergo assessment of their physical function and levels of activity, have blood taken to analyse markers of inflammation and have their body composition measured by a variety of methods. A subgroup of patients will also undergo an additional magnetic resonance imaging (MRI) scan of their abdomen and thighs. At the time of their operation, participants will also have small biopsies of muscle, fat, tumour and urine taken for biochemical analysis. Patients with cancer, will be asked to return for three follow up appointments during the year after their operation where these assessments will be repeated.
| 1784 | ecrin-mdr-crc
Project description:Progress in science relies in part on generating hypotheses with existing observations and testing hypotheses with new observations. This distinction between postdiction and prediction is appreciated conceptually but is not respected in practice. Mistaking generation of postdictions with testing of predictions reduces the credibility of research findings. However, ordinary biases in human reasoning, such as hindsight bias, make it hard to avoid this mistake. An effective solution is to define the research questions and analysis plan before observing the research outcomes-a process called preregistration. Preregistration distinguishes analyses and outcomes that result from predictions from those that result from postdictions. A variety of practical strategies are available to make the best possible use of preregistration in circumstances that fall short of the ideal application, such as when the data are preexisting. Services are now available for preregistration across all disciplines, facilitating a rapid increase in the practice. Widespread adoption of preregistration will increase distinctiveness between hypothesis generation and hypothesis testing and will improve the credibility of research findings.
| S-EPMC5856500 | biostudies-other
Project description:The perspective of using messenger RNA (mRNA) as a therapeutic molecule first faced some uncertainties due to concerns about its instability and the feasibility of large-scale production. Today, given technological advances and deeper biomolecular knowledge, these issues have started to be addressed and some strategies are being exploited to overcome the limitations. Thus, the potential of mRNA has become increasingly recognized for the development of new innovative therapeutics, envisioning its application in immunotherapy, regenerative medicine, vaccination, and gene editing. Nonetheless, to fully potentiate mRNA therapeutic application, its efficient production, stabilization and delivery into the target cells are required. In recent years, intensive research has been carried out in this field in order to bring new and effective solutions towards the stabilization and delivery of mRNA. Presently, the therapeutic potential of mRNA is undoubtedly recognized, which was greatly reinforced by the results achieved in the battle against the COVID-19 pandemic, but there are still some issues that need to be improved, which are critically discussed in this review.
| S-EPMC8707022 | biostudies-literature
Project description:The ability to sense the environment is essential to survival and is the primary purpose of the somatosensory nervous system. However, despite its highly conserved nature, the sensation of itch has been historically overlooked, and its importance in medicine underappreciated. Herein, we highlight how fundamental discoveries, coupled to rapid successes of new therapeutics, have placed itch biology at the forefront of a translational revolution in the field of somatosensation and beyond.
| S-EPMC9308644 | biostudies-literature
Project description:Skin and subcutaneous diseases affect millions of people worldwide, causing significant morbidity. Biologics are becoming increasingly useful for the treatment of many skin diseases, particularly as alternatives for patients who have failed to tolerate or respond to conventional systemic therapies. Biological therapies provide a targeted approach to treatment through interaction with specific components of the underlying immune and inflammatory disease processes. This review article examines the increasing evidence base for biologics in dermatology, including well-established treatments and novel agents.
| S-EPMC3816698 | biostudies-literature
Project description:BackgroundThis multi-center, retrospective study aimed to clarify retention rates and reasons for discontinuation of 7 biological disease-modifying antirheumatic drugs (bDMARDs) and tofacitinib (TOF), one of the janus kinase inhibitors, in bDMARDs-naïve and bDMARDs-switched patients with rheumatoid arthritis (RA).MethodsThis study assessed 3897 patients and 4415 treatment courses with bDMARDs and TOF from 2001 to 2019 (2737 bDMARDs-naïve courses and 1678 bDMARDs-switched courses [59.5% of switched courses were their second agent], female 82.3%, baseline age 57.4 years, disease duration 8.5 years; rheumatoid factor positivity 78.4%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate 4.3; concomitant prednisolone [PSL] dose 6.1 mg/day [usage 42.4%], and methotrexate [MTX] dose 8.5 mg/week [usage 60.9%]). Treatment courses included abatacept (ABT; n = 663), adalimumab (ADA; n = 536), certolizumab pegol (CZP; n = 226), etanercept (ETN; n = 856), golimumab (GLM; n = 458), infliximab (IFX; n = 724), tocilizumab (TCZ; n = 851), and TOF (n = 101/only bDMARDs-switched cases). Drug discontinuation reasons (categorized into lack of effectiveness, toxic adverse events, non-toxic reasons, or remission) and rates were estimated at 36 months using Gray's test and statistically evaluated after adjusted by potential clinical confounders (age, sex, disease duration, concomitant PSL and MTX usage, starting date, and number of switched bDMARDs) using the Fine-Gray model.ResultsCumulative incidence of drug discontinuation for each reason was as follows: lack of effectiveness in the bDMARDs-naïve group (from 13.7% [ABT] to 26.9% [CZP]; P < 0.001 between agents) and the bDMARDs-switched group (from 18.9% [TCZ] to 46.1% [CZP]; P < 0.001 between agents); toxic adverse events in the bDMARDs-naïve group (from 4.6% [ABT] to 11.2% [ETN]; P < 0.001 between agents) and the bDMARDs-switched group (from 5.0% [ETN] to 15.7% [TOF]; P = 0.004 between agents); and remission in the bDMARDs-naïve group (from 2.9% [ETN] to 10.0% [IFX]; P < 0.001 between agents) and the bDMARDs-switched group (from 1.1% [CZP] to 3.3% [GLM]; P = 0.9 between agents).ConclusionsRemarkable differences were observed in drug retention of 7 bDMARDs and TOF between bDMARDs-naïve and bDMARDs-switched cases.
| S-EPMC7296929 | biostudies-literature