Wilson and Lippard examine the preparation of platinum anticancer complexes via synthetic methods, focusing on the structural features of ligands and the creation of thermodynamically stable platinum ...bonds.
This review summarizes the key results of recently published studies on the effects of dietary change and nutritional intervention on the human microbiome from around the world, focusing on the USA, ...Canada, Europe, Asia, and Africa. It first explores mechanisms that might explain the ability of fiber-rich foods to suppress the incidence and mortality from westernized diseases, notably cancers of the colon, breast, liver, cardiovascular, infectious, and respiratory diseases, diabetes, and obesity (O’Keefe in Lancet Gastroenterol Hepatol 4(12):984–996, 2019; Am J Clin Nutr 110:265–266, 2019). It summarizes studies from Africa which suggest that disturbance of the colonic microbiome may exacerbate chronic malnutrition and growth failure in impoverished communities and highlights the importance of breast feeding. The American section discusses the role of the microbiome in the swelling population of patients with obesity and type 2 diabetes and examines the effects of race, ethnicity, geography, and climate on microbial diversity and metabolism. The studies from Europe and Asia extoll the benefits of whole foods and plant-based diets. The Asian studies examine the worrying changes from low-fat, high-carbohydrate diets to high-fat, low-carbohydrate ones and the increasing appearance of westernized diseases as in Africa and documents the ability of high-fiber traditional Chinese diets to reverse type 2 diabetes and control weight loss. In conclusion, most of the studies reviewed demonstrate clear changes in microbe abundances and in the production of fermentation products, such as short-chain fatty acids and phytochemicals following dietary change, but the significance of the microbiota changes to human health, with the possible exception of the stimulation of butyrogenic taxa by fiber-rich foods, is generally implied and not measured. Further studies are needed to determine how these changes in microbiota composition and metabolism can improve our health and be used to prevent and treat disease.
Monofunctional platinum(II) complexes of general formula cis -Pt(NH ₃) ₂(N -heterocycle)ClCl bind DNA at a single site, inducing little distortion in the double helix. Despite this behavior, these ...compounds display significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin. To discover the most potent monofunctional platinum(II) compounds, the N -heterocycle was systematically varied to generate a small library of new compounds, with guidance from the X-ray structure of RNA polymerase II (Pol II) stalled at a monofunctional pyriplatin-DNA adduct. In pyriplatin, the N -heterocycle is pyridine. The most effective complex evaluated was phenanthriplatin, cis -Pt(NH ₃) ₂(phenanthridine)ClNO ₃, which exhibits significantly greater activity than the Food and Drug Administration-approved drugs cisplatin and oxaliplatin. Studies of phenanthriplatin in the National Cancer Institute 60-cell tumor panel screen revealed a spectrum of activity distinct from that of these clinically validated anticancer agents. The cellular uptake of phenanthriplatin is substantially greater than that of cisplatin and pyriplatin because of the hydrophobicity of the phenanthridine ligand. Phenanthriplatin binds more effectively to 5′-deoxyguanosine monophosphate than to N -acetyl methionine, whereas pyriplatin reacts equally well with both reagents. This chemistry supports DNA as a viable cellular target for phenanthriplatin and suggests that it may avoid cytoplasmic platinum scavengers with sulfur-donor ligands that convey drug resistance. With the use of globally platinated Gaussia luciferase vectors, we determined that phenanthriplatin inhibits transcription in live mammalian cells as effectively as cisplatin, despite its inability to form DNA cross-links.
Craving (a strong desire to ingest a substance or engage in an activity) is an important topic of study in the field of psychology. Along with being a key symptom of addiction, craving is a potent ...source of motivation for a wide range of appetitive behaviors. In this article, I offer a perspective regarding the nature of craving that is rooted in the theory of constructed emotion, a contemporary model of how emotions are created by the brain. According to this perspective, a state of craving emerges when the brain makes predictions that categorize sensory inputs as an instance of craving on the basis of prior experience and the context in which the inputs occur. Using the theory of constructed emotion as a guiding framework, I review various lines of evidence that provide support for this idea. In addition, I offer recommendations for future research that stem from the hypothesis that instances of craving are constructed by the brain in an experience-dependent and situation-specific manner.
Pancreatic ductal adenocarcinoma is a devastating disease, and patient outcomes have not improved in decades. Treatments that target tumor cells have largely failed. This could be because research ...has focused on cancer cells and the influence of the stroma on tumor progression has been largely ignored. The focus of pancreatic cancer research began to change with the identification of pancreatic stellate cells, which produce the pancreatic tumor stroma. There is compelling in vitro and in vivo evidence for the influence of pancreatic stellate cells on pancreatic cancer development; several recent preclinical studies have reported encouraging results with approaches designed to target pancreatic stellate cells and the stroma. We review the background and recent advances in these areas, along with important areas of future research that could improve therapy.
The 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group was coordinated and ...supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. It is designed to improve patient care and support informed decision making about asthma management in the clinical setting. This update addresses six priority topic areas as determined by the state of the science at the time of a needs assessment, and input from multiple stakeholders:•Fractional Exhaled Nitric Oxide Testing•Indoor Allergen Mitigation•Intermittent Inhaled Corticosteroids•Long-Acting Muscarinic Antagonists•Immunotherapy in the Treatment of Allergic Asthma•Bronchial ThermoplastyA rigorous process was undertaken to develop these evidence-based guidelines. The Agency for Healthcare Research and Quality's (AHRQ) Evidence-Based Practice Centers conducted systematic reviews on these topics, which were used by the Expert Panel Working Group as a basis for developing recommendations and guidance. The Expert Panel used GRADE (Grading of Recommendations, Assessment, Development and Evaluation), an internationally accepted framework, in consultation with an experienced methodology team for determining the certainty of evidence and the direction and strength of recommendations based on the evidence. Practical implementation guidance for each recommendation incorporates findings from NHLBI-led patient, caregiver, and clinician focus groups. To assist clincians in implementing these recommendations into patient care, the new recommendations have been integrated into the existing Expert Panel Report-3 (EPR-3) asthma management step diagram format.
Ensembl (http://www.ensembl.org) creates tools and data resources to facilitate genomic analysis in chordate species with an emphasis on human, major vertebrate model organisms and farm animals. Over ...the past year we have increased the number of species that we support to 77 and expanded our genome browser with a new scrollable overview and improved variation and phenotype views. We also report updates to our core datasets and improvements to our gene homology relationships from the addition of new species. Our REST service has been extended with additional support for comparative genomics and ontology information. Finally, we provide updated information about our methods for data access and resources for user training.
Anti‐IL5 therapies for asthma Farne, Hugo A; Wilson, Amanda; Powell, Colin ...
Cochrane database of systematic reviews,
09/2017, Letnik:
2017, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Background
This review is the first update of a previously published review in The Cochrane Library (Issue 7, 2015). Interleukin‐5 (IL‐5) is the main cytokine involved in the activation of ...eosinophils, which cause airway inflammation and are a classic feature of asthma. Monoclonal antibodies targeting IL‐5 or its receptor (IL‐5R) have been developed, with recent studies suggesting that they reduce asthma exacerbations, improve health‐related quality of life (HRQoL) and lung function. These are being incorporated into asthma guidelines.
Objectives
To compare the effects of therapies targeting IL‐5 signalling (anti‐IL‐5 or anti‐IL‐5Rα) with placebo on exacerbations, health‐related qualify of life (HRQoL) measures, and lung function in adults and children with chronic asthma, and specifically in those with eosinophilic asthma refractory to existing treatments.
Search methods
We searched the Cochrane Airways Trials Register, clinical trials registries, manufacturers' websites, and reference lists of included studies. The most recent search was March 2017.
Selection criteria
We included randomised controlled trials comparing mepolizumab, reslizumab and benralizumab versus placebo in adults and children with asthma.
Data collection and analysis
Two authors independently extracted data and analysed outcomes using a random‐effects model. We used standard methods expected by Cochrane.
Main results
Thirteen studies on 6000 participants met the inclusion criteria. Four used mepolizumab, four used reslizumab, and five used benralizumab. One study in benralizumab was terminated early due to sponsor decision and contributed no data. The studies were predominantly on people with severe eosinophilic asthma, which was similarly but variably defined. Eight included children over 12 years but these results were not reported separately. We deemed the risk of bias to be low, with all studies contributing data being of robust methodology. We considered the quality of the evidence for all comparisons to be high overall using the GRADE scheme, with the exception of intravenous mepolizumab because this is not currently a licensed delivery route.
All of the anti‐IL‐5 treatments assessed reduced rates of 'clinically significant' asthma exacerbation (defined by treatment with systemic corticosteroids for three days or more) by approximately half in participants with severe eosinophilic asthma on standard of care (at least medium‐dose inhaled corticosteroids (ICS)) with poorly controlled disease (either two or more exacerbations in the preceding year or Asthma Control Questionnaire (ACQ) 1.5 or more). Non‐eosinophilic participants treated with benralizumab also showed a significant reduction in exacerbation rates, but no data were available for non‐eosinophilic participants, and mepolizumab or reslizumab.
We saw modest improvements in validated HRQoL scores with all anti‐IL‐5 agents in severe eosinophilic asthma. However these did not exceed the minimum clinically important difference for ACQ and Asthma Quality of Life Questionnaire (AQLQ), with St. George's Respiratory Questionnaire (SGRQ) only assessed in two studies. The improvement in HRQoL scores in non‐eosinophilic participants treated with benralizumab, the only intervention for which data were available in this subset, was not statistically significant, but the test for subgroup difference was negative.
All anti‐IL‐5 treatments produced a small but statistically significant improvement in mean pre‐bronchodilator forced expiratory flow in one second (FEV1) of between 0.08 L and 0.11 L.
There were no excess serious adverse events with any anti‐IL‐5 treatment, and indeed a reduction in favour of mepolizumab that could be due to a beneficial effect on asthma‐related serious adverse events. There was no difference compared to placebo in adverse events leading to discontinuation with mepolizumab or reslizumab, but significantly more discontinued benralizumab than placebo, although the absolute numbers were small (36/1599 benralizumab versus 9/998 placebo).
Mepolizumab, reslizumab and benralizumab all markedly reduced blood eosinophils, but benralizumab resulted in almost complete depletion, whereas a small number remained with mepolizumab and reslizumab. The implications for efficacy and/or adverse events are unclear.
Authors' conclusions
Overall our study supports the use of anti‐IL‐5 treatments as an adjunct to standard of care in people with severe eosinophilic asthma and poor control. These treatments roughly halve the rate of asthma exacerbations in this population. There is limited evidence for improved HRQoL scores and lung function, which may not meet clinically detectable levels. There were no safety concerns regarding mepolizumab or reslizumab, and no excess serious adverse events with benralizumab, although there remains a question over adverse events significant enough to prompt discontinuation.
Further research is needed on biomarkers for assessing treatment response, optimal duration and long‐term effects of treatment, risk of relapse on withdrawal, non‐eosinophilic patients, children (particularly under 12 years), and comparing anti‐IL‐5 treatments to each other and, in people eligible for both, to anti‐immunoglobulin E. For benralizumab, future studies should closely monitor rates of adverse events prompting discontinuation.
Although the use of nondrug rewards (e.g., money) to facilitate smoking cessation is widespread, recent research has found that such rewards may be least effective when people who smoke cigarettes ...are tempted to do so. Specifically, among people who smoke, the neural response to nondrug rewards appears blunted when access to cigarettes is anticipated, and this blunting is linked to a decrease in willingness to refrain from smoking to earn a monetary incentive. Accordingly, methods to enhance the value of nondrug rewards may be theoretically and clinically important. The current proof-of-concept study tested if real-time fMRI neurofeedback training augments the ability to upregulate responses in reward-related brain areas relative to a no-feedback control condition in people who smoke. Adults (
n
= 44, age range = 20-44) who reported smoking >5 cigarettes per day completed the study. Those in the intervention group (
n
= 22, 5 females) were trained to upregulate brain responses using feedback of ongoing striatal activity (i.e., a dynamic “thermometer” that reflected ongoing changes of fMRI signal intensity in the striatum) in a single neurofeedback session with three training runs. The control group (
n
= 22, 5 females) underwent a nearly identical procedure but received no neurofeedback. Those who received neurofeedback training demonstrated significantly greater increases in striatal BOLD activation while attempting to think about something rewarding compared to controls, but this effect was present only during the first training run. Future neurofeedback research with those who smoke should explore how to make neurofeedback training more effective for the self-regulation of reward-related brain activities.
Here, we describe the discovery of a naturally occurring human antibody (Ab), FluA-20, that recognizes a new site of vulnerability on the hemagglutinin (HA) head domain and reacts with most influenza ...A viruses. Structural characterization of FluA-20 with H1 and H3 head domains revealed a novel epitope in the HA trimer interface, suggesting previously unrecognized dynamic features of the trimeric HA protein. The critical HA residues recognized by FluA-20 remain conserved across most subtypes of influenza A viruses, which explains the Ab’s extraordinary breadth. The Ab rapidly disrupted the integrity of HA protein trimers, inhibited cell-to-cell spread of virus in culture, and protected mice against challenge with viruses of H1N1, H3N2, H5N1, or H7N9 subtypes when used as prophylaxis or therapy. The FluA-20 Ab has uncovered an exceedingly conserved protective determinant in the influenza HA head domain trimer interface that is an unexpected new target for anti-influenza therapeutics and vaccines.
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•FluA-20 isolated from a healthy donor with extensive influenza vaccination history•FluA-20 protects against all major influenza A subtypes that infect humans•FluA-20 recognizes a unique conserved site in the trimer interface of the HA head•FluA-20 binds to the uncleaved form of HA trimer and disrupts trimer integrity
Antibodies targeting a novel site in the head domain of hemagglutinin afford broad protection against influenza.
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