Clinical trials of Crohn's disease generally use the Crohn's Disease Activity Index to assess disease activity; these calculations are complex, time-consuming, and impracticable. We investigated ...whether a simpler tool, the Harvey-Bradshaw Index, was equally effective in assessing disease severity.
Crohn's Disease Activity and Harvey-Bradshaw Index scores were collected from 2 large multicenter Crohn's disease studies. The PEGylated antibody fragment evaluation in Crohn's disease: safety and efficacy (PRECiSE) 1 and 2 trials assessed efficacy and tolerability of certolizumab pegol (PEGylated, humanized, Fab' fragment of an antitumor necrosis factor alpha antibody). PRECiSE 1 and 2 data were analyzed to determine if results from the Crohn's Disease Activity Index correlated with those from the Harvey-Bradshaw Index criteria for defining response and remission.
Analysis of almost 1000 data pairs showed a positive correlation between scores. The correlation between the indices for pooled data from PRECiSE 1 and PRECiSE 2 was 0.800 (Spearman correlation coefficient). The correlations between indices for the PRECiSE 1 or PRECiSE 2 were 20.698 and 0.716, respectively (Kronecker product variance). A 3-point change in the Harvey-Bradshaw Index score corresponded to a 100-point change in the Crohn's Disease Activity Index (clinical response); scores < or =4 points corresponded to a Crohn's Disease Activity Index score < or =150 points (clinical remission).
Results from the Crohn's Disease Activity Index correlate with those from the Harvey-Bradshaw Index; use of the Harvey-Bradshaw Index might permit simpler Crohn's disease activity assessment in long-term clinical trials, and facilitate standardized disease activity measurements and cross-center comparisons.
High-hydrostatic pressure is an alternative perturbation method that can be used to destabilize globular proteins. Generally perfectly reversible, pressure exerts local effects on regions or domains ...of a protein containing internal voids, contrary to heat or chemical denaturant that destabilize protein structures uniformly. When combined with NMR spectroscopy, high pressure (HP) allows one to monitor at a residue-level resolution the structural transitions occurring upon unfolding and to determine the kinetic properties of the process. The use of HP-NMR has long been hampered by technical difficulties. Owing to the recent development of commercially available high-pressure sample cells, HP-NMR experiments can now be routinely performed. This review summarizes recent advances of HP-NMR techniques for the characterization at a quasi-atomic resolution of the protein folding energy landscape.
For patients presenting with an aneurysmal subarachnoid hemorrhage (aSAH), delayed cerebral ischemia (DCI) is a significant cause of morbidity and mortality. The REACT study is designed to assess the ...safety and efficacy of clazosentan in preventing clinical deterioration due to DCI in patients with aSAH.
REACT is a prospective, multicenter, randomized phase 3 study that is planned to enroll 400 patients with documented aSAH from a ruptured cerebral aneurysm, randomized 1:1 to 15 mg/hour intravenous clazosentan vs. placebo, in approximately 100 sites and 15 countries. Eligible patients are required to present at hospital admission with CT evidence of significant subarachnoid blood, defined as a thick and diffuse clot that is more than 4 mm in thickness and involves 3 or more basal cisterns. The primary efficacy endpoint is the occurrence of clinical deterioration due to DCI up to 14 days post-study drug initiation. The main secondary endpoint is the occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation. Other secondary endpoints include the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) score at Week 12 post-aSAH, dichotomized into poor and good outcome. Radiological results and clinical endpoints are centrally evaluated by independent committees, blinded to treatment allocation. Exploratory efficacy endpoints comprise the assessment of cognition status at 12 weeks and quality of life at 12 and 24 weeks post aSAH.
In the REACT study, clazosentan is evaluated on top of standard of care to determine if it reduces the risk of clinical deterioration due to DCI after aSAH. The selection of patients with thick and diffuse clots is intended to assess the benefit/risk profile of clazosentan in a population at high risk of vasospasm-related ischemic complications post-aSAH. TRIAL REGISTRATION (ADDITIONAL FILE 1): ClinicalTrials.gov (NCT03585270). EU Clinical Trial Register (EudraCT Number: 2018-000241-39).
Emission of ionizing radiation (IR) in the environment is a natural phenomenon which can be enhanced by human activities. Ecosystems are then chronically exposed to IR. But environmental risk ...assessment of chronic exposure suffers from a lack of knowledge. Extrapolation of data from acute to chronic exposure is not always relevant, and can lead to uncertainties as effects could be different between the two irradiation modes, especially regarding reproduction endpoint, which is an ecologically relevant parameter. In the present study, we decided to refine the understanding of the molecular mechanisms involved in response to acute and chronic γ-irradiation by a global proteome label free LC-MS/MS analysis. C. elegans were exposed to 3 common cumulated radiation doses for acute or chronic exposure condition and global modification of the proteome was studied. This analysis of protein expression has demonstrated the modulation of proteins involved in regulatory biological processes such as lipid transport, DNA replication, germ cell development, apoptosis, ion transport, cuticle development, and aging at lower doses than those for which individual effects on reproduction have been previously observed. Thus, these proteins could constitute early and sensitive markers of radio-induced reprotoxicity; more specifically HAT-1, RPS-19 in acute and VIT-3 for chronic conditions that are expressed in a dose-dependent manner. Finally, to focus on reproduction process, this analysis showed either repression or overexpression of 12 common proteins in organisms exposed to acute or chronic irradiation, respectively. These proteins include the vitellogenin cluster notably involved in lipid transport and oocyte maturation and proteins involved in cuticle development and molting i.e. COL-14, GLF-1, NOAH-1, NOAH-2, ACN-1. These results show that protein expression modulation is a sensitive and predictive marker of radio-induced reproductive effects, but also highlight limitation of data extrapolation from acute to chronic exposure for environmental risk assessment.
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•Opposite modulation of some key proteins after acute vs. chronic exposure to γ-rays.•Chronic BP GO terms include lipid transport, DNA replication, germ cell development.•Acute BP GO terms include hatching success, embryo development, apoptotic processes.•Some reproduction process proteins are mis-regulated from 0.5 Gy chronic exposure.•Proteome modification is a sensitive marker of the gamma radiation effects.
Life is thought to have appeared in the depth of the sea under high hydrostatic pressure. Nowadays, it is known that the deep biosphere hosts a myriad of life forms thriving under high-pressure ...conditions. However, the evolutionary mechanisms leading to their adaptation are still not known. Here, we show the molecular bases of these mechanisms through a joint structural and dynamical study of two orthologous proteins. We observed that pressure adaptation involves the decoupling of protein–water dynamics and the elimination of cavities in the protein core. This is achieved by rearranging the charged residues on the protein surface and using bulkier hydrophobic residues in the core. These findings will be the starting point in the search for a complete genomic model explaining high-pressure adaptation.
Abstract
Background and Aims
Besides bananas belonging to the AAA triploid Mutika subgroup, which predominates in the Great Lakes countries, other AAA triploids as well as edible AA diploids, locally ...of considerable cultural weight, are cultivated in East Africa and in the nearby Indian Ocean islands as far as Madagascar. All these varieties call for the genetic identification and characterization of their interrelations on account of their regional socio-economic significance and their potential for banana breeding strategies.
Methods
An extensive sampling of all traditional bananas in East Africa and near Indian Ocean islands was genotyped with simple sequence repeat (SSR) markers, with particular emphasis on the diploid forms and on the bananas of the Indian Ocean islands, which remain poorly characterized.
Key Results
All the edible AA varieties studied here are genetically homogeneous, constituting a unique subgroup, here called ‘Mchare’, despite high phenotypic variation and adaptions to highly diverse ecological zones. At triploid level, and besides the well-known AAA Mutika subgroup, at least two other genetically related AAA subgroups specific to this region are identified. Neither of these East African AAA genotypes can be derived directly from the local AA Mchare diploids. However, it is demonstrated that the East African diploids and triploids together belong to the same genetic complex. The geographical distribution of their wild acuminata relatives allowed identification of the original area of this complex in a restricted part of island South-East Asia. The inferred origin leads to consideration of the history of banana introduction in Africa. Linked to biological features, documentation on the embedding of bananas in founding legends and myths and convincing linguistic elements were informative regarding the period and the peoples who introduced these Asian plants into Africa. The results point to the role of Austronesian-speaking peoples who colonized the Indian Ocean islands, particularly Madagascar, and reached the East African coasts.
Conclusions
Understanding of the relations between the components of this complex and identifying their Asian wild relatives and related cultivars will be a valuable asset in breeding programmes and will boost the genetic improvement of East African bananas, but also of other globally important subgroups, in particular the AAA Cavendish.
Living species are chronically exposed to environmental ionizing radiations from sources that can be overexpressed by nuclear accidents. In invertebrates, reproduction is the most radiosensitive ...studied endpoint, likely to be connected with aging. Surprisingly, aging is a sparsely investigated endpoint after chronic ionizing radiation, whereas understanding it is of fundamental interest in biology and medicine. Indeed, aging and aging-related diseases (e.g., cancer and degenerative diseases) cause about 90% of deaths in developed countries. Therefore, glp-1 sterile Caenorhabditis elegans nematode was used to assess the impact of chronic gamma irradiation on the lifespan. Analyses were performed, at the individual level, on aging and, in order to delve deeper into the mechanisms, at the molecular level, on oxidative damage (carbonylation), biomolecules (lipids, proteins and nucleic acids) and their colocalization. We observed that ionizing radiation accelerates aging (whatever the duration (3–19 days)/dose (0.5–24 Gy)/dose rate (7 and 52 mGy h−1) tested) leading to a longevity value equivalent to that of wt nematode (∼25–30 days). Moreover, the level of protein oxidative damage (carbonylation) turned out to be good cellular biomarker of aging, since it increases with age. Conversely, chronic radiation treatments reduced carbonylation levels and induced neutral lipid catabolism whatever the dose rate and the final delivered dose. Finally, under some conditions a lipid-protein colocalization without any carbonyl was observed; this could be linked to yolk accumulation in glp-1 nematodes. To conclude, we noticed through this study a link between chronic gamma exposure, lifespan shortening and lipid level decrease associated with a decrease in the overall carbonylation.
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•Chronic γ-radiation shortens glp-1 C. elegans lifespan without linear dose-response.•Carbonylation turned out to be a good biomarker of aging.•γ-radiation yields lipid and carbonylation catabolism whatever dose and dose rate.•Radiation-induced lipid catabolism is associated with reduced C. elegans longevity.•Lipid-protein colocalization with no carbonyls could be linked to accumulated yolk.
When combined with NMR spectroscopy, high hydrostatic pressure is an alternative perturbation method used to destabilize globular proteins that has proven to be particularly well suited for exploring ...the unfolding energy landscape of small single-domain proteins. To date, investigations of the unfolding landscape of all-β or mixed-α/β protein scaffolds are well documented, whereas such data are lacking for all-α protein domains. Here we report the NMR study of the unfolding pathways of GIPC1-GH2, a small α-helical bundle domain made of four antiparallel α-helices. High-pressure perturbation was combined with NMR spectroscopy to unravel the unfolding landscape at three different temperatures. The results were compared to those obtained from classical chemical denaturation. Whatever the perturbation used, the loss of secondary and tertiary contacts within the protein scaffold is almost simultaneous. The unfolding transition appeared very cooperative when using high pressure at high temperature, as was the case for chemical denaturation, whereas it was found more progressive at low temperature, suggesting the existence of a complex folding pathway.
Despite advances in experimental and computational methods, the mechanisms by which an unstructured polypeptide chain regains its unique three-dimensional structure remains one of the main puzzling ...questions in biology. Single-molecule techniques, ultra-fast perturbation and detection approaches and improvement in all-atom and coarse-grained simulation methods have greatly deepened our understanding of protein folding and the effects of environmental factors on folding landscape. However, a major challenge remains the detailed characterization of the protein folding landscape. Here, we used high hydrostatic pressure 2D NMR spectroscopy to obtain high-resolution experimental structural information in a site-specific manner across the polypeptide sequence and along the folding reaction coordinate. We used this residue-specific information to constrain
calculations, in order to obtain a topological description of the entire folding landscape. This approach was used to describe the conformers populating the folding landscape of two small globular proteins, AVR-Pia and AVR-Pib, that belong to the structurally conserved but sequence-unrelated MAX effectors superfamily. Comparing the two folding landscapes, we found that, in spite of their divergent sequences, the folding pathway of these two proteins involves a similar, inescapable, folding intermediate, even if, statistically, the routes used are different.
•3 important comorbidities could be correctly identified in health insurance data.•Good agreement between prevalence based on medical files and health insurance data.•Renal insufficiencies could not ...be defined properly.•Health insurance data can be used to measure comorbidities in lung cancer.
Identifying comorbidities in lung cancer patients is a complex process in population-based studies and no gold standard exists. The current study aims to identify and measure the main comorbidities using administrative health insurance data, which were available on a population-based level.
A literature search was conducted to identify comorbidities in lung cancer patients and to select Anatomical Therapeutic Chemical codes to measure them. For each patient, the volume of delivered relevant drugs for each comorbidity in the year preceding the diagnosis of lung cancer was computed, based on the Defined Daily Doses reimbursed. Case definition rules were set by comparing the identification of comorbidities via health insurance data with the reporting of them in the medical files in a sample of hospitals.
Four comorbidities were identified: chronic respiratory diseases, chronic cardiovascular diseases, diabetes mellitus and renal diseases. A very good to moderate agreement between the prevalence based on medical files versus health insurance data was obtained for diabetes mellitus (kappa = 0.83), chronic cardiovascular diseases (kappa = 0.64), chronic respiratory diseases (kappa = 0.48) but not for renal diseases (kappa = 0.22). Because only 27% of patients having renal diseases recorded in the medical files were identified using health insurance data, this comorbidity was not withheld. Among 12,839 lung cancer patients diagnosed in 2010–2011 in Belgium, 29.7% had chronic respiratory diseases, 57.5% had chronic cardiovascular diseases and 14.1% had diabetes mellitus.
This study showed that it was possible to capture three major comorbidities in lung cancer patients using administrative health data, namely, diabetes mellitus, chronic cardiovascular diseases, and chronic respiratory diseases. However, the agreement was only moderate for the last one. A prerequisite for using this methodology is that administrative health data are available for all patients.
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