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PubMed2006

Hormesis outperforms threshold model in National Cancer Institute antitumor drug screening database.

Which dose-response model best explains low-dose responses is a critical issue in toxicology, pharmacology, and risk assessment. The present paper utilized the U.S. National Cancer Institute yeast screening database that contains 56,914 dose-response studies representing the replicated effects of 2189 chemically diverse possible antitumor drugs on cell proliferation in 13 different yeast strains. Multiple evaluation methods indicated that the observed data are inconsistent with the threshold model while supporting the hormetic model. Hormetic response patterns were observed approximately four times more often than would be expected by chance alone. The data call for the rejection of the threshold model for low-dose prediction, and they support the hormetic model as the default model for scientific interpretation of low-dose toxicological responses.

Animals↗

PubMed1990

Effects of the training of integrity--promoting care on the interaction at a long-term ward. Analysis of video-recorded social activities.

A training programme in integrity-promoting care was given the staff of a long-term ward and practised during a three months intervention period. The effects were analysed in different parameters and compared with a control ward. This report describes analysis of video-recorded interactions (12 hs) during social activities between demented patients and caregivers and changes induced by the programme. The video-recorded episodes, containing mainly music and coffee sessions were interpreted from a model on interaction with demented patients suggested by Athlin & Norberg. The results indicate that the training programme and the guidance during the intervention resulted in increased understanding of demented patients' situation among the staff. They became more sensitive, adapted their cues and made the environment easier to interpret for the patients. This in turn led to the fact that the patients appeared more sensitive and clear in their cues. A positive circle developed.

Aged↗

PubMed2003

Influence of CO2 on the micro-structural properties of spider dragline silk: X-ray microdiffraction results.

The mechanical properties of spider dragline fibres are altered by CO(2) exposure under anaesthetizing conditions during the spinning process. In order to relate these macroscopic changes to a microscopic model, the extrusion of dragline silk was studied by synchrotron radiation microdiffraction. A brief exposure of a female Nephila senigalensis spider to CO(2 )results after an incubation time of less than 7 min in the extrusion of a thread (two fibres) swollen with water. The data are interpreted for a model of crystalline beta-sheet domains containing nanofibrils, which reinforce a network of protein chains. The protein network absorbs water, leaving the nanofibrils unaffected. A continuous flow of CO(2) results in a co-extrusion of a dragline thread and an isotropic silk fraction, which probably has a glycine-rich sequence. Long CO(2) exposure reduces the axial alignment of nanofibrils, presumably due to a partial destruction of the amorphous network.

Animals↗

PubMed2006

QSPR models for the prediction of apparent volume of distribution.

An estimate of volume of distribution (V(d)) is of paramount importance both in drug choice as well as maintenance and loading dose calculations in therapeutics. It can also be used in the prediction of drug biological half life. This study employs quantitative structure-pharmacokinetic relationship (QSPR) techniques for the prediction of volume of distribution. Values of V(d) for 129 drugs were collated from the literature. Structural descriptors consisted of partitioning, quantum mechanical, molecular mechanical, and connectivity parameters calculated by specialized software and pK(a) values obtained from ACD labs/log D database. Genetic algorithm and stepwise regression analyses were used for variable selection and model development. Models were validated using a leave-many-out procedure. QSPR analyses resulted in a number of significant models for acidic and basic drugs separately, and for all the drugs. Validation studies showed that mean fold error of predictions for the selected models were between 1.79 and 2.17. Although separate QSPR models for acids and bases resulted in lower prediction errors than models for all the drugs, the external validation study showed a limited applicability for the equation obtained for acids. Therefore, the universal model that requires only calculated structural descriptors was recommended. The QSPR model is able to predict the volume of distribution of drugs belonging to different chemical classes with a prediction error similar to that of the other more complicated prediction methods including the commonly practiced interspecies scaling. The structural descriptors in the model can be interpreted based on the known mechanisms of distribution and the molecular structures of the drugs.

Algorithms↗

PubMed1978

The spatiotemporal transfer function of the Limulus lateral eye.

The dynamics of the Limulus retina may be well described by the spatiotemporal transfer function, which measures the response of the eye to moving sinusoidal gratings. We consider a model for this system, which incorporates an excitatory generator potential, and self- and lateral inhibitory processes. Procedures are described which allow estimation of parameters for the model consistent with the empirical transfer function data. Transfer functions calculated from the model show good agreement with laboratory measurements, and may be used to predict accurately the response of the eye to arbitrary moving stimuli. The model allows convenient interpretation of the transfer function measurements in terms of physiological processes which underly the response of the Limulus retina.

Animals↗

PubMed2005

Long time-constant behavior of the oculomotor plant in barbiturate-anesthetized primate.

The mechanics of the extraocular muscles and orbital tissue ("oculomotor plant") can be approximated by a small number of viscoelastic (Voigt) elements in series. Recent analysis of the eye's return from displacement in lightly anesthetized rhesus monkeys has suggested a four-element plant model with time constants (TCs) of approximately 0.01, 0.1, 1, and 10 s. To demonstrate directly the presence of long (1,10 s) TC elements and to assess their contribution quantitatively, horizontal eye displacement was induced in Cynomolgus monkeys under deep barbiturate anesthesia that prevented interference from spontaneous eye movements. The displacement was maintained for either a prolonged (30 s) or brief (0.2 s) period before release. Return to resting position took 20-30 s after prolonged displacement but only 1-2 s after brief displacement, consistent with the presence of long TC elements that would only be substantially stretched in the former condition. Quantitative fitting of the release curves after prolonged displacement indicated that the two long TC elements contribute a substantial proportion (approximately 30%) of the total plant compliance. A model based on the estimated compliance values is shown to account quantitatively both for our release data and for Goldstein and Robinson's data on hysteresis of ocular motoneuron firing rates measured after centripetal saccades following prolonged eccentric fixation. Long time-constant elements in the plant thus make a substantial contribution to some types of eye movement, and their inclusion in plant models can help interpret the firing patterns of single units in the oculomotor system.

Animals↗

PubMed2001

Preeclampsia: from epidemiological observations to molecular mechanisms.

Preeclampsia is the main cause of maternal mortality and is associated with a five-fold increase in perinatal mortality in developing countries. In spite of this, the etiology of preeclampsia is unknown. The present article analyzes the contradictory results of the use of calcium supplementation in the prevention of preeclampsia, and tries to give an explanation of these results. The proposal of an integrative model to explain the clinical manifestations of preeclampsia is discussed. In this proposal we suggest that preeclampsia is caused by nutritional, environmental and genetic factors that lead to the creation of an imbalance between the free radicals nitric oxide, superoxide and peroxynitrate in the vascular endothelium. The adequate interpretation of this model would allow us to understand that the best way of preventing preeclampsia is the establishment of an adequate prenatal control system involving adequate antioxidant vitamin and mineral supplementation, adequate diagnosis and early treatment of asymptomatic urinary and vaginal infections. The role of infection in the genesis of preeclampsia needs to be studied in depth because it may involve a fundamental change in the prevention and treatment of preeclampsia.

Calcium, Dietary↗

PubMed2006

[Precursors to pancreatic cancer].

BACKGROUND: Pancreatic adenocarcinoma is a relatively frequent cancer with an extremely poor prognosis. Until recently, the natural history of pancreatic adenocarcinoma has not been possible to study, but the identification of precursor lesions (pancreatic intraepithelial neoplasia, PanIN) has lead to a better understanding of the stepwise morphological and genetic alterations involved in the development of invasive adenocarcinoma. MATERIAL AND METHODS: Relevant literature from the period of 1996-2005 was found by searching the Medline database, combining the terms "pancreas", "cancer", "PanIN" and "neoplasia". Principal original and review papers were extracted and used as background for a presentation of the PanIN cancer progression model. RESULTS AND INTERPRETATION: PanINs are established as designation of histological precursor lesions to pancreatic adenocarcinoma. PanIN grade I to III represent stepwise morphological alterations in the pancreatic ductal epithelium, from early neoplasia (PanIN I and II), via carcinoma in situ (PanIN III) to the development of invasive ductal adenocarcinoma. This model allows for the investigation of sequential molecular changes such as activation of oncogenes and inactivation of tumour suppressor genes. Increased knowledge about pancreatic carcinogenesis may pave the way for prevention strategies, early detection, and new treatment options, thus ultimately improving the prognosis of the patients.

Adenocarcinoma↗

PubMed1994

[Effects of the training in integrity-promoting care on the interactions in a long-term ward].

A training programme in integrity-promoting care was given the staff of a long-term ward and practised during a three months intervention period. The effects were analysed in different parameters and compared with a control ward. This report describes analysis of video-recorded interactions (12 hs) during social activities between demented patients and caregivers and changes induced by the programme. The video-recorded episodes, containing mainly music and coffee sessions were interpreted from a model on interaction with demented patients suggested by Athlin and Norberg. The results indicate that the training programme and the guidance during the intervention resulted in increased understanding of demented patients' situation among the staff. They became more sensitive, adapted their cues and made the environment easier to interpret for the patients. This in turn led to the fact that the patients appeared more sensitive and clear in their cues. A positive circle developed.

Empathy↗

PubMed2006

A method for patient-specific evaluation of vertebral cancellous bone strength: in vitro validation.

BACKGROUND: In the context of osteoporosis, important determinants of the fracture risk are the apparent strength and stiffness of cancellous bone, as well as its brittleness and energy absorption capacity. Standard medical imaging, however, cannot measure these mechanical properties directly. Consequently, an estimation of the risk for fracture is made by correlating relative density or mineral density at a skeletal site with statistics of fracture occurrence, which provides limited and partial indications on fracture risks. A better method for evaluating the patient-specific mechanical properties of cancellous bone is therefore required. METHODS: In order to asses the mechanical properties of vertebral cancellous bone, we developed a finite element parametric model of lattice trabecular architecture that, in the future, will be suitable for use with bone imaging modalities. The model inputs are apparent morphological parameters (trabecular thickness and trabecular separation) and the bone mineral density. We conducted uniaxial compression tests on 36 canine vertebral cancellous bone specimens (C7 and L1) to validate model predictions of strength and stiffness in vitro. FINDINGS: Predictions of strength and stiffness matched the experimental results within relative absolute errors of 17.7% and 12.8%, respectively (average of differences between model-predicted and measured values, divided by the average of measured values). We also employed the model for evaluation of strength and stiffness of human L1 and L5 vertebrae and found mean strength of 1.67 MPa (confidence interval 0.42 MPa) and mean elastic modulus of 190 MPa (confidence interval 50 MPa), which are well within the range of previously reported apparent strength and stiffness properties. INTERPRETATION: The present model can be used to improve medical imaging-based evaluation of the spine in osteoporotic individuals by providing more specific information on the individual bone's susceptibility to fracture once clinical bone scans will be able to provide more reliable measures of trabecular thickness and separation.

Animals↗

PubMed2003

Toward cell replacement therapy: promises and caveats.

Studies in animal models have suggested a role for stem cells in repair and regeneration of the nervous system. Human equivalents of stem and precursor cells have been isolated and their efficacy is being evaluated in rodent and primate models. Difficulties exist in translating results of these preclinical models to therapy in humans. Evolutionary differences among rodents, primates, and humans; fundamental differences in the anatomy and physiology; differences in immune responses in xenotransplant models; the paucity of good transplant models of chronic disease; and allelic variability in the cells themselves make any study evaluating the efficacy of cells in transplant models difficult to interpret. As no better alternatives to testing in animals exist, we suggest that at this early stage a considered step-by-step approach to testing and comparison of different transplant strategies in isolation will prepare us better for clinical trials than simple evaluation of functional outcomes in various models of disease. We emphasize that we do not recommend delaying or abandoning clinical trials; rather, we suggest that one anticipate failures and design experiments and data collection such that we learn from these failures to ensure future success in as rapid a time frame as possible.

Alleles↗

PubMed2026

Artificial intelligence-based tumour infiltrating lymphocyte quantification in patients with triple-negative breast cancer: an independent validation study.

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) are a robust prognostic marker in patients with triple-negative breast cancer. Artificial intelligence (AI)-derived computational tools assessing TILs could improve efficiency, but require independent validation against clinical outcomes. We aimed to compare the prognostic performance of AI-derived TIL scores with pathologist-scored TILs in a large, prospectively collected dataset pooled from randomised controlled trials. METHODS: CATALINA was an independent, external validation study using prospectively collected long-term clinical outcome data pooled from seven randomised clinical trials conducted at multiple sites. We independently evaluated two previously validated AI pipelines that generate five computationally assessed tumour-infiltrating lymphocyte (cTIL) scores by masked, independent deployment of locked models. cTIL scores were correlated with the mean of the pathologist-scored stromal TILs (sTILs) in 220 digitised haematoxylin and eosin whole slide images in a cohort of patients with early-stage triple-negative or HER-2 positive breast cancer, previously scored by trained pathologists in a TIL-reproducibility study. Prognostic performance was assessed in a separate cohort of patients with early triple-negative breast cancer pooled from seven prospective, randomised adjuvant trials. Multivariable Cox regression models adjusted for clinicopathological factors and study heterogeneity assessed associations of cTIL score and sTIL score with invasive disease-free survival, distant disease-free survival, and overall survival. 5-year discrimination was estimated using time-dependent area under the receiver operating characteristic curve (AUC). FINDINGS: Individual data were collated from 1759 patients, of whom 1356 had complete clinicopathological data, pathologist sTIL scores, and cTIL scores available. Modest correlation (r 0·375-0·473) was observed between cTIL scores and the mean pathologist sTIL score. Both sTIL and cTIL were independently associated with 5-year invasive disease-free survival, distant disease-free survival, and overall survival after adjustment for clinicopathological factors (hazard ratio for invasive disease-free survival was 0·73 [95% CI 0·66-0·82]; q<0·0001, distant disease-free survival was 0·70 [0·61-0·79]; q<0·0001, and overall survival was 0·72 [0·63-0·82]; q<0·0001 for sTIL scores and 0·80 [0·73-0·89]; q<0·0001, 0·77 [0·69-0·86]; q<0·0001, and 0·79 [0·70-0·88]; q=0·0002, respectively, for percentage_lymphocyte scores). In models adjusted for clinicopathological variables and sTIL score, cTIL score did not maintain a statistically significant prognostic association. Both sTIL and cTIL scores improved the 5-year AUC over clinicopathological variables alone, while cTIL score did not significantly further improve AUC when combined with clinicopathological variables and sTIL score. INTERPRETATION: Two cTIL models deployed entirely without retraining or modification provided statistically significant prognostic information and improved risk discrimination compared with clinicopathological variables alone in this large, platform-based, independent validation study. Although cTIL score did not incrementally improve prognostication compared with models combining clinicopathological variables with sTIL score, these findings support the application of cTILs as a reproducible prognostic biomarker, particularly in settings where routine or widespread pathologist assessment is unavailable. FUNDING: Breast Cancer Research Foundation (USA).

Humans↗

PubMed1979

Interaction of permeant ions with channels activated by acetylcholine in Aplysia neurones.

1. Aplysia neurones with an excitatory response to acetylcholine (ACh) were voltage-clamped, and the ACh-induced currents were studied using noise and relaxation techniques. The mean channel open time, tau, and the amplitude of the elementary current, iel, were determined from these experiments, and the variation of these parameters with the ionic content of the extracellular solution was analysed. The goal of this work was to test whether permeant ions may bind in a voltage-dependent manner to channel sites and thereby hinder channel closing, as has been proposed before (Ascher, Marty & Neild, 1978a). 2. The relation between tau and the membrane potential V has a similar shape in normal sea water and after total replacement of Na ions with Li or Cs. In contrast, the shape of the tau(V) relation is modified if Na is replaced by Mg, Sr, or Ba. 3. Replacing the divalent cations (Mg and Ca) present in normal sea water with Na results in a decrease of tau and an increase of iel. Both effects are enhanced by cell hyperpolarization. 4. Similarly partial replacement of Na by Sr causes a voltage-dependent decrease of iel. 5. Experiments were performed in solutions containing Na and sucrose, or Mg and mannitol. In both cases tau was smaller than in an isotonic Na or Mg solution. 6. None of the above observations can be accounted for on the sole basis of outer surface potential changes. 7. A quantitative model of the interaction between permeant ions and ACh-sensitive channels is proposed. The possible relevance of this model for the interpretation of tau(V) curves in other systems is discussed.

Acetylcholine↗

PubMed2025

Assessing individual genetic susceptibility to metabolic syndrome: interpretable machine learning method.

BACKGROUND: Genome-wide association studies have provided profound insights into the genetic aetiology of metabolic syndrome (MetS). However, there is a lack of machine-learning (ML)-based predictive models to assess individual genetic susceptibility to MetS. This study utilized single-nucleotide polymorphisms (SNPs) as variables and employed ML-based genetic risk score (GRS) models to predict the occurrence of MetS, bringing it closer to clinical application. METHODS: Feature selection was performed using Least Absolute Shrinkage and Selection Operator. Six ML algorithms were employed to construct GRS models. A fivefold cross-validation was utilized to aid in the internal validation of models. The receiver operating characteristic (ROC) curve was used to select the better-performing GRS model. The SHapley Additive exPlanations (SHAP) was then applied to interpret the model. After extracting GRS, stratified analysis of BMI, age and gender was performed. Finally, these conventional risk factors and GRS were integrated through multivariate logistic regression to establish a combined model. RESULTS: A total of 17 SNPs were selected for analysis. Among the GRS models, the extreme gradient boosting (XGBoost) model demonstrated superior discriminative performance (AUC = 0.837). The XGBoost's optimal robustness was also validated through five-fold cross-validation (mean ROC-AUC = 0.706). The XGBoost-based SHAP algorithm not only elucidated the global effects of 17 SNPs across all samples, but also described the interaction between SNPs, providing a visual representation of how SNPs impact the prediction of MetS in an individual. There was a strong correlation between GRS and MetS risk, particularly observed among young individuals, males and overweight individuals. Furthermore, the model combining conventional risk factors and GRS exhibited excellent discriminative performance (AUC = 0.962) and outstanding robustness (mean ROC-AUC = 0.959). CONCLUSION: This study established a reliable XGBoost-based GRS model and a GRS prediction platform (https://metabolicsyndromeapps.shinyapps.io/geneticriskscore/) to assess individual genetic susceptibility to MetS. This model has high interpretability and can provide personalized reference for determining the necessity of primary prevention measures for MetS. Additionally, there may be interactions between traditional risk factors and GRS, and the integration of both in a comprehensive model is useful in the prediction of MetS occurrence.

Humans↗

PubMed1994

A possible interpretation of some colony forming assays: 'developmental tree' model.

The characteristic form of the probability distributions of in vitro grown colonies is analysed and experimental results are shown to be well approximated by an exponential dependence. It is argued that this type of dependence is very frequent in nature and does not provide sufficient evidence to resolve the dilemma whether the development of haemopoietic lineages proceeds according to a schema of 'progressive and stochastic restriction' or more limiting 'developmental tree' with some random control process involved. Detailed analysis of the experimental conditions and results is needed to provide insight into collective phenomena in cellular proliferation and differentiation. At present, the complexity of the phenomena involved prevents unique interpretation of the experimental distributions. Nevertheless, one particular quantitative model, based on a developmental tree concept, yields a set of the theoretical probability distributions, which are in a very good agreement with the experimental results.

Animals↗

PubMed1992

Site-specific binding constants for actinomycin D on DNA determined from footprinting studies.

We report site-specific binding constants for the intercalating anticancer drug actinomycin D (Act-D), binding to a 139-base-pair restriction fragment from pBR 322 DNA. The binding constants are derived from analysis of footprinting experiments, in which the radiolabeled 139-mer is cleaved using DNase I, the cleavage products undergo gel electrophoresis, and, from the gel autoradiogram, spot intensities, proportional to amounts of cleaved fragments, are measured. A bound drug prevents DNase I from cleaving at approximately 7 bonds, leading to decreased amounts of corresponding fragments. With the radiolabel on the 3' end of the noncoding strand (A-label), we measured relative amounts of 54 cleavage products at 25 Act-D concentrations. For cleavage of the 139-mer with the label on the 3' end of the coding strand (G-label), relative amounts of 43 cleavage products at 11 Act-D concentrations were measured. These measurements give information about approximately 120 base pairs of the restriction fragment (approximately 12 turns of the DNA helix); in this region, 14 strong and weak Act-D binding sites were identified. The model used to interpret the footprinting plots is derived in detail. Binding constants for 14 sites on the fragment are obtained simultaneously. It is important to take into account the effect of drug binding at its various sites on the local concentration of probe elsewhere. It is also necessary to include in the model weak as well as strong Act-D sites on the carrier DNA which is present, since the carrier DNA controls the free-drug concentration. As expected, the strongest sites are those with the sequence (all sequences are 5'----3') GC, with TGCT having the highest binding constant, 6.4 x 10(6) M-1. Sites having the sequence GC preceded by G are weak binding sites, having binding constants approximately 1 order of magnitude lower than those of the strong sites. Also, the non-GC-containing sequences CCG and CCC bind Act-D with a binding constant comparable to those of the weak GGC sites. The analysis may reveal drug-induced structural changes on the DNA, which are discussed in terms of the mechanism of Act-D binding.

Base Sequence↗

PubMed1987

3-D graphics modelling of the tRNA-like 3'-end of turnip yellow mosaic virus RNA: structural and functional implications.

The tRNA-like structure of the aminoacylatable 3'-end of turnip yellow mosaic virus (TYMV) RNA was submitted to 3-D graphics modelling. A model of this structure has been inferred previously from both biochemical results and sequence comparisons which presents a new RNA folding feature, the "pseudoknot". It has been verified that this structure can be constructed without compromising accepted RNA stereochemical rules, namely base stacking and preferential 3'-endo sugar pucker. The model has aided interpretation of previous structural mapping experiments using chemical and enzymatic probes, and new accessibilities of residues could be predicted and tested. Pseudoknots have been considered as potential splice sites because they form antiparallel helical segments in a single RNA molecule. We have examined this possibility with the constructed 3-D model and could verify the hypothesis on a structural basis. The model presents a striking similarity with canonical tRNA and allows a valuable comparison between the protection patterns of yeast tRNA(Val) and tRNA-like viral RNA by cognate yeast valyl-tRNA synthetase against structural probes.

Base Sequence↗

PubMed1990

[Seroepidemiologic evaluation of malaria in Mayotte (Comoro archipelago) 1984-1988].

In the context of a research programme on the immunology of malaria in the islands of the south-west of the Indian Ocean, seroepidemiological studies by means of sampling surveys have been carried out annually in Mayotte Island (Comoro Archipelago) from 1984 to 1988. Apart from the transient character of the increases in rates in the wake of the epidemic outbreak of 1984, the evolution of the antibody geometric mean reciprocal titre (GMRT) by age reveals a negativation of population at large, fast only in the younger age-group. At such a high level of negativation, the GMRT does not lend itself to interpretation. In the older age-groups the negativation becomes so slow as to render a yearly periodicity too short to show differences. The correlation between GMRT and age that persisted over the five-year period suggests that the evolution of the rates according to age follows a predetermined model. The epidemiological interpretation of purely serological data, except for a general indication of the trend, is however difficult, specially in an archipelago where the levels of malaria transmission are not the same in the different islands, but where inter-island migration is quite important.

Adolescent↗