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PubMed2026

Non-invasive strategy for gastric cancer detection: Integration of cell-free DNA fragmentomics and protein biomarkers.

Gastric cancer (GC) ranks as the fifth most common cancer worldwide, however, accurate and non-invasive diagnostic modalities for GC remain limited. Cell-free DNA (cfDNA) fragmentomics has emerged as a promising tool for cancer cell detection. Here we develop a gastric cancer detection model, named GaFraD model. The GaFraD model uses four cfDNA fragmentomics features, including fragment size ratio (FSR), copy number variation (CNV), 9-bp end motif (Motif), and fragment size at transcription start sites (TF). This model achieves an area under the receiver-operating characteristic curve (AUC) of 0.970 (95% CI: 0.944 - 0.990), a sensitivity of 95.0% and a specificity of 80.9%. By combining the GaFraD model and conventional protein biomarkers CA19-9 and PG-I/PG-II, the CONFIRM model was generated. The CONFIRM model attained an AUC of 0.986 (95% CI: 0.966 - 1.000), a sensitivity of 95.0% and a specificity of 95.6% in detecting GC. Moreover, the CONFIRM model achieved remarkable performance (AUC = 0.983, sensitivity 95.6%, specificity 94.2%) in distinguishing patients with early-stage GC from controls. Our work showed the high discriminatory power in distinguishing GC patients from controls, indicating the clinical potential of using cfDNA fragmentomics combined with protein biomarkers for non-invasive GC detection. The results of the study provide a new avenue for early, accurate, and non-invasive clinical diagnosis of GC.

Cell-free DNA↗
PubMed2005

Nucleotide excision repair- and p53-deficient mouse models in cancer research.

Cancer is caused by the loss of controlled cell growth due to mutational (in)activation of critical genes known to be involved in cell cycle regulation. Three main mechanisms are known to be involved in the prevention of cells from becoming cancerous; DNA repair and cell cycle control, important to remove DNA damage before it will be fixed into mutations and apoptosis, resulting in the elimination of cells containing severe DNA damage. Several human syndromes are known to have (partially) deficiencies in these pathways, and are therefore highly cancer prone. Examples are xeroderma pigmentosum (XP) caused by an inborn defect in the nucleotide excision repair (NER) pathway and the Li-Fraumeni syndrome, which is the result of a germ line mutation in the p53 gene. XP patients develop skin cancer on sun exposed areas at a relatively early age, whereas Li-Fraumeni patients spontaneously develop a wide variety of early onset tumors, including sarcomas, leukemia's and mammary gland carcinomas. Several mouse models have been generated to mimic these human syndromes, providing us information about the role of these particular gene defects in the tumorigenesis process. In this review, spontaneous phenotypes of mice deficient for nucleotide excision repair and/or the p53 gene will be described, together with their responses upon exposure to either chemical carcinogens or radiation. Furthermore, possible applications of these and newly generated mouse models for cancer will be given.

Animals↗
PubMed1994

Properties of intracellular Ca2+ waves generated by a model based on Ca(2+)-induced Ca2+ release.

Cytosolic Ca2+ waves occur in a number of cell types either spontaneously or after stimulation by hormones, neurotransmitters, or treatments promoting Ca2+ influx into the cells. These waves can be broadly classified into two types. Waves of type 1, observed in cardiac myocytes or Xenopus oocytes, correspond to the propagation of sharp bands of Ca2+ throughout the cell at a rate that is high enough to permit the simultaneous propagation of several fronts in a given cells. Waves of type 2, observed in hepatocytes, endothelial cells, or various kinds of eggs, correspond to the progressive elevation of cytosolic Ca2+ throughout the cell, followed by its quasi-homogeneous return down to basal levels. Here we analyze the propagation of these different types of intracellular Ca2+ waves in a model based on Ca(2+)-induced Ca2+ release (CICR). The model accounts for transient or sustained waves of type 1 or 2, depending on the size of the cell and on the values of the kinetic parameters that measure Ca2+ exchange between the cytosol, the extracellular medium, and intracellular stores. Two versions of the model based on CICR are considered. The first version involves two distinct Ca2+ pools sensitive to inositol 1,4,5-trisphosphate (IP3) and Ca2+, respectively, whereas the second version involves a single pool sensitive both to Ca2+ and IP3 behaving as co-agonists for Ca2+ release. Intracellular Ca2+ waves occur in the two versions of the model based on CICR, but fail to propagate in the one-pool model at subthreshold levels of IP3. For waves of type 1, we investigate the effect of the spatial distribution of Ca(2+)-sensitive Ca2+ stores within the cytosol, and show that the wave fails to propagate when the distance between the stores exceeds a critical value on the order of a few microns. We also determine how the period and velocity of the waves are affected by changes in parameters measuring stimulation, Ca2+ influx into the cell, or Ca2+ pumping into the stores. For waves of type 2, the numerical analysis indicates that the best qualitative agreement with experimental observations is obtained for phase waves. Finally, conditions are obtained for the occurrence of "echo" waves that are sometimes observed in the experiments.

Animals↗
PubMed1999

A model for P300 generation based on responses to near-threshold visual stimuli.

Near-threshold and suprathreshold visual ERPs and their frequency components were compared with the aim to obtain further information on the generation mechanism of the P300 wave. Decrease of the stimulus energy from suprathreshold to near-threshold level resulted in an increase of the P300 amplitude specifically in the occipital region. This finding was in contrast with the P300 amplitude decrease in central and frontal regions and its constancy in parietal area. Delta and theta responses showed a similar distribution pattern, whereas alpha responses decreased in all regions as the stimulus energy decreased. We conclude that P300 wave may correspond to a delta oscillation during a widespread, transient interruption of afferent inputs from subcortical structures to the cortical neurons including those in the visual sensory area and simultaneous increase of the cortico-cortical interactions. If visual inputs are of suprathreshold strength, they override this effect specifically in the primary visual area and disrupt the cortico-cortical interactions and the emergence of P300 in the occipital cortex.

Adult↗
PubMed2005

Influence of oil type on the amounts of acrylamide generated in a model system and in French fries.

Acrylamide formation was studied by use of a new heating methodology, based on a closed stainless steel tubular reactor. Different artificial potato powder mixtures were homogenized and subsequently heated in the reactor. This procedure was first tested for its repeatability. By use of this experimental setup, it was possible to study the acrylamide formation mechanism in the different mixtures, eliminating some variable physical and chemical factors during the frying process, such as heat flux and water evaporation from and oil ingress into the food. As a first application of this optimized heating concept, the influence on acrylamide formation of the type of deep-frying oil was investigated. The results obtained from the experiments with the tubular reactor were compared with standardized French fry preparation tests. In both cases, no significant difference in acrylamide formation could be found between the various heating oils applied. Consequently, the origin of the deep-frying vegetable oils did not seem to affect the acrylamide formation in potatoes during frying. Surprisingly however, when artificial mixtures did not contain vegetable oil, significantly lower concentrations of acrylamide were detected, compared to oil-containing mixtures.

Acrylamide↗
PubMed1985

Fifth Gordon Hamilton-Fairley memorial lecture. Methotrexate resistance and gene amplification: an experimental model for the generation of cellular heterogeneity.

Gene amplification is a mechanism whereby cultured animal cells and human tumours become resistant to cancer chemotherapeutic agents. This review of studies from the authors' laboratory describes properties of the acquisition of resistance to methotrexate in cultured mammalian cells by virtue of amplification of the dihydrofolate reductase gene. These properties result in a heterogeneous cell population with respect to many cell properties, including the number and stability of the amplified genes. Gene amplification results from overreplication of DNA in a single cell cycle as a result of inhibition of DNA synthesis. The cells surviving such overreplication constitute a heterogeneous population with multiple chromosomal changes, including partial or complete endoreduplication of chromosomes, as well as a variety of chromosomal rearrangements. A similar phenomenon may underlie the generation of aneuploidy in tumours, their malignant progression, and the generation of heterogeneity in the tumour cell population.

Animals↗
PubMed1983

A strategy for generating and testing models of migration and urban growth.

"In this paper, it is argued that to identify the appropriate conditions under which the traditional gravity-type migration model should be tested, it is necessary to consider the wider demographic-economic framework in which such models play an essential part. The traditional model and attempts to make it more realistic in an ad hoc way are first sketched, and then the model is embedded in a dynamic framework based on nonlinear differential equations of the logistic kind describing the growth of population and employment. The role of the gravity model in coupling these equations is then developed." A theoretical analysis of this framework is then presented using simulation. "The simplest possible two-region case involving urban and rural regions is developed and after preliminary simulations, a more realistic version involving urban core, suburb and rural hinterland is proposed. A number of variants of this model are tested using simulation and it is concluded that in devising an appropriate test for this type of migration model, attention should be switched from spatial to temporal variation in migration using highly polarized spatial situations such as city regions." (summary in FRE, GER)

Demography↗
PubMed2005

A block-free hidden Markov model for genotypes and its application to disease association.

We present a new stochastic model for genotype generation. The model offers a compromise between rigid block structure and no structure altogether: It reflects a general blocky structure of haplotypes, but also allows for "exchange" of haplotypes at nonboundary SNP sites; it also accommodates rare haplotypes and mutations. We use a hidden Markov model and infer its parameters by an expectation-maximization algorithm. The algorithm was implemented in a software package called HINT (haplotype inference tool) and tested on 58 datasets of genotypes. To evaluate the utility of the model in association studies, we used biological human data to create a simple disease association search scenario. When comparing HINT to three other models, HINT predicted association most accurately.

Algorithms↗
PubMed1996

The Injury Severity Score is unable to differentiate between poor care and severe injury.

UNLABELLED: The Injury Severity Score (ISS) has been the most frequently used tool for stratifying injured patients. The primary hypothesis of this study was that ISS fails to differentiate between severe injury and mismanagement. METHODS: Data models were generated for mismanaged and ideally managed patients for isolated injuries for each body system. Flow charts of care, outcomes, and Abbreviated Injury Scale (AIS) and ISS scores were generated for each model. RESULTS: Multiple models demonstrated that minor injuries that were mismanaged would result in AIS and ISS scores that were the same as ideally managed severe injuries. Three examples are summarized as follows: A comparison of two patients with splenic injuries demonstrates that ISS is unable to differentiate between mismanagement of a minor splenic laceration as compared to a severely lacerated spleen. In the case of the minor injury to the spleen (initial AIS = 2) that was missed by the treating physicians and allowed to bleed into shock and near arrest because of massive hemorrhage that could have been prevented by early recognition and treatment, the final AIS is coded as 4 in this mismanaged patient, the same AIS and ISS as a severely lacerated spleen (AIS = 4) managed well. Both result in a discharge ISS of 16. Similarly, the ISS at discharge is the same for a well-managed severe head injury (AIS = 4) and a mismanaged minor head injury that is unrecognized, progresses and leads to coma (AIS = 4). Finally AIS, ISS does not differentiate between a well-managed cervical fracture with complete cord injury and a mismanaged cervical spine fracture that initially does not involve a cord injury, but because of mismanagement and lack of immobilization, progresses to complete cord injury because of poor care. Both result in the same injury severity assessment (AIS = 5, ISS = 25 in both). CONCLUSIONS: This study demonstrates a fact that should be recognized by all who rely upon the ISS for comparing quality of care: ISS fails to differentiate severe injury from mismanagement of injury. Because the ISS mixes outcome data with injury severity, ISS incorrectly assigns increased severity to the lesser injuries of mismanaged patients. These findings have important implications for use of the ISS in quality of care assessments.

Abbreviated Injury Scale↗
PubMed1991

A model for the generation of tobacco rattle virus (TRV) anomalous isolates: pea early browning virus RNA-2 acquires TRV sequences from both RNA-1 and RNA-2.

Comparison of the 5'-terminal sequences of several tobraviruses suggests that the RNA-2 molecule of the tobacco rattle virus (TRV) anomalous isolate TCM arose from pea early browning virus (PEBV) RNA-2 by acquisition of 3' and 5' sequences from TRV RNA-1 and RNA-2 molecules, respectively. We have identified a region of homology in the RNA-2 molecules of PEBV, TRV and pepper ringspot virus which could have facilitated this recombination.

Base Sequence↗