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PubMed2001

Marginal likelihood estimation for proportional odds models with right censored data.

One major aspect in medical research is to relate the survival times of patients with the relevant covariates or explanatory variables. The proportional hazards model has been used extensively in the past decades with the assumption that the covariate effects act multiplicatively on the hazard function, independent of time. If the patients become more homogeneous over time, say the treatment effects decrease with time or fade out eventually, then a proportional odds model may be more appropriate. In the proportional odds model, the odds ratio between patients can be expressed as a function of their corresponding covariate vectors, in which, the hazard ratio between individuals converges to unity in the long run. In this paper, we consider the estimation of the regression parameter for a semiparametric proportional odds model at which the baseline odds function is an arbitrary, non-decreasing function but is left unspecified. Instead of using the exact survival times, only the rank order information among patients is used. A Monte Carlo method is used to approximate the marginal likelihood function of the rank invariant transformation of the survival times which preserves the information about the regression parameter. The method can be applied to other transformation models with censored data such as the proportional hazards model, the generalized probit model or others. The proposed method is applied to the Veteran's Administration lung cancer trial data.

Antineoplastic Agents↗
PubMed2025

scPlantLLM: A Foundation Model for Exploring Single-cell Expression Atlases in Plants.

Single-cell RNA sequencing (scRNA-seq) provides unprecedented insights into plant cellular diversity by enabling high-resolution analyses of gene expression at the single-cell level. However, the complexity of scRNA-seq data, including challenges in batch integration, cell type annotation, and gene regulatory network (GRN) inference, demands advanced computational approaches. To address these challenges, we developed scPlantLLM, a Transformer model trained on millions of plant single-cell data points. Using a sequential pretraining strategy incorporating masked language modeling and cell type annotation tasks, scPlantLLM generates robust and interpretable single-cell data embeddings. When applied to Arabidopsis thaliana datasets, scPlantLLM excels in clustering, cell type annotation, and batch integration, achieving an accuracy of up to 0.91 in zero-shot learning scenarios. Furthermore, the model demonstrates an ability to identify biologically meaningful GRNs and subtle cellular subtypes, showcasing its potential to advance plant biology research. Compared to traditional methods, scPlantLLM outperforms in key metrics such as adjusted rand index (ARI), normalized mutual information (NMI), and silhouette score (SIL), highlighting its superior clustering accuracy and biological relevance. scPlantLLM represents a foundation model for exploring plant single-cell expression atlases, offering unprecedented capabilities to resolve cellular heterogeneity and regulatory dynamics across diverse plant systems. The code used in this study is available at https://github.com/compbioNJU/scPlantLLM.

Single-Cell Analysis↗
PubMed2006

Asymmetric time-dependent model for the dynamic finger arterial pressure-volume relationship.

The volumetric pulses in the finger PPG signal appear as an information source for several indirect measurement methods. In this study we modelled transformation of pressure pulses into volume pulses in a wide transmural pressure range. The noninvasive finger arterial pressure and photoplethysmographic (PPG) signals were simultaneously registered in 13 healthy subjects while the pressure in the PPG cuff ramped up and down. The nonlinearity of the pressure-volume (P-V) relationship was modelled by an asymmetric function, consisting of two arctangents, each for a different pressure region. The time dependency was described by the first order lag. The disturbing effect of slow creeps in the PPG signal was suppressed by an equal filtering of the measured and model-predicted signal. The differences between the two estimates of the subject's P-V relationship for the increasing and decreasing cuff pressure were small thus showing the repeatability of this method, which can be used for the characterization of individual finger arterial behaviour as well as its changes.

Adult↗
PubMed2006

Automatic elastic image registration by interpolation of 3D rotations and translations from discrete rigid-body transformations.

We present an algorithm for automatic elastic registration of three-dimensional (3D) medical images. Our algorithm initially recovers the global spatial mismatch between the reference and floating images, followed by hierarchical octree-based subdivision of the reference image and independent registration of the floating image with the individual subvolumes of the reference image at each hierarchical level. Global as well as local registrations use the six-parameter full rigid-body transformation model and are based on maximization of normalized mutual information (NMI). To ensure robustness of the subvolume registration with low voxel counts, we calculate NMI using a combination of current and prior mutual histograms. To generate a smooth deformation field, we perform direct interpolation of six-parameter rigid-body subvolume transformations obtained at the last subdivision level. Our interpolation scheme involves scalar interpolation of the 3D translations and quaternion interpolation of the 3D rotational pose. We analyzed the performance of our algorithm through experiments involving registration of synthetically deformed computed tomography (CT) images. Our algorithm is general and can be applied to image pairs of any two modalities of most organs. We have demonstrated successful registration of clinical whole-body CT and positron emission tomography (PET) images using this algorithm. The registration accuracy for this application was evaluated, based on validation using expert-identified anatomical landmarks in 15 CT-PET image pairs. The algorithm's performance was comparable to the average accuracy observed for three expert-determined registrations in the same 15 image pairs.

Algorithms↗
PubMed1989

Pemphigoid, pemphigus and desmoplakin as antigenic markers of differentiation in normal and tumorigenic mouse keratinocyte lines.

The expression of differentiation stages in a murine epidermal cell transformation model has been investigated as a basis for studies of chemically-induced differentiation. Antibodies in sera of patients with the autoimmune diseases bullous pemphigoid and pemphigus vulgaris exhibit specific reactivity to antigenic determinants of basal and spinous cells, respectively, in sections of mouse and human epidermis. In addition, spinous cells in epidermis are reactive with a mouse monoclonal antibody to desmoplakin, a desmosomal component immunologically distinct from pemphigus. These antibodies were used to identify and attempt to quantify keratinocyte subpopulations in culture based on differentiation stage. Epidermal cell lines were cultured under conditions which favour proliferation (0.02 to 0.04 mM extracellular Ca2+, i.e. low Ca2+ conditions) or differentiation (0.1 mM to 1.4 mM Ca2+), as previously shown using primary cultures of mouse keratinocytes. Two independently-derived normal keratinocyte lines demonstrated Ca2(+)-dependent reactivity with pemphigoid and pemphigus antiserum, like that which has been observed in primary cultures. Furthermore, a Ca2+ and time-dependent reactivity with the three antisera was also observed in a papilloma cell line (derived from one of the normal cell lines after treatment in vitro with 7,12-dimethylbenz[alpha]anthracene). Papilloma cells cultured under conditions of low extracellular Ca2+ were comprised of three subpopulations: cells reactive only with pemphigoid anti-serum, cells reactive only with desmoplakin antibody. However, like the normal cell lines, papilloma cells underwent a transition to predominantly a spinous cell population (i.e. reactive with pemphigus and desmoplakin antibody) in response to extracellular Ca2+. A slower loss of pemphigoid antibody reactivity was noted in papilloma cells, consistent with an abnormal regulation of differentiation. The attempt to characterize these dynamic transitions from basal to spinous cell subpopulations in culture was considered to be prerequisite for the use of the model to investigate differentiation-inducing agents in carcinoma therapy.

Animals↗
PubMed1996

Enhancement of BALB/c 3T3 cells transformation by 1,2-dibromoethane promoting effect.

Two of the most representative halogenated aliphatic hydrocarbons, 1,2-dibromoethane and 1,1,2,2-tetrachloroethane, were tested in the two-stage cell transformation model for analysing the promoting ability. Both of these compounds had previously been found to exert genotoxic effects, probably acting as moderate initiators. BALB/c 3T3 cells were initiated with subtransforming doses of N-methyl-N-nitro-N-nitrosoguanidine or 3-methylcholanthrene and then exposed to a chronic treatment with different non-transforming dosages of the two haloalkanes. 1,1,2,2-Tetrachloroethane did not exert any promoting activity in that system. By contrast, significant promoting effects by 1,2-dibromoethane were observed both in cells treated with N-methyl-N-nitro-N-nitrosoguanidine and in cells treated with 3-methylcholanthrene. Promotion of the transformation process initiated with 3-methylcholanthrene was detectable when confluent cells in the chemical-treated plates were replated in the level-II amplification test. This experimental procedure allowed cells to perform further rounds of replications and transformed foci to became detectable. Results gave evidence for a promoting role of 1,2-dibromoethane in multistep carcinogenesis, probably responsible for the higher oncogenic ability of this compound with respect to 1,1,2,2-tetrachloroethane.

3T3 Cells↗
PubMed2003

A view-based approach to registration: theory and application to vascular image registration.

This paper presents an approach to registration centered on the notion of a view--a combination of an image resolution, a transformation model, an image region over which the model currently applies, and a set of image primitives from this region. The registration process is divided into three stages: initialization, automatic view generation, and estimation. For a given initial estimate, the latter two alternate until convergence; several initial estimates may be explored. The estimation process uses a novel generalization of the Iterative Closest Point (ICP) technique that simultaneously considers multiple correspondences for each point. View-based registration is applied successfully to alignment of vascular and neuronal images in 2-d and 3-d using similarity, affine, and quadratic transformations.

Algorithms↗
PubMedDate not supplied

Two-dimensional polyacrylamide gel electrophoresis in experimental hepatocarcinogenesis studies.

High resolution two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) in combination with computer-assisted densitometry was used to analyze sequential changes in polypeptide expression during chemically (aflatoxin Bl; AFB), spontaneously, and oncogene (v-Ha-ras, v-raf, and v-raflv-myc)-induced experimental rat hepatocarcinogenesis. Two-dimensional mapping of [35S]methionine and [32P]orthophosphate-labeled whole cell lysate and nuclear polypeptides revealed subsets of polypeptides specific for each transformation modality in the in vitro rat liver epithelial (RLE) transformation model. Many of the observed changes in whole cell lysate preparations were localized to specific subcellular organelles. Significant alterations in the expression of the extracellular matrix protein, fibronectin, as well as tropomyosin- and intermediate filament-related polypeptides (vimentin, beta-tubulin, cytokeratins 8, 14, and 18, and actin) were observed among the various transformant cell lines. Whereas alterations in the tropomyosin isoforms appeared to be transformation specific, concomitant modulation of intermediate filament expression was related more to the differentiation state of the individual cell lines than to the transformed phenotype. To integrate protein and DNA information of polypeptides believed to be critically involved during cellular transformation, N-terminal amino acid microsequencing of selected nuclear polypeptides was performed. Preliminary results suggest that N-terminal blockage of rat liver epithelial nuclear proteins to be minor (approximately 20%) with sequencing sensitivity of one pmol. These studies extend our on-going efforts toward the establishment of computerized database of rat liver epithelial cellular proteins (Wirth et al., Electrophoresis, 1991, 12, 931-954) to aid in the delineation of polypeptides critically involved in cellular growth and differentiation as well as transformation.

Amino Acid Sequence↗
PubMed2003

Occurrence of dysregulated oncogenes in primary plasma cells representing consecutive stages of myeloma pathogenesis: indications for different disease entities.

This study investigated the expression pattern in primary plasma cells (PCs) of putative oncogenes suggested to be involved in multiple myeloma (MM) development. cDNA archives were generated by global reverse transcription polymerase chain reaction from CD38++/CD19-/CD56-/++ aberrant PCs of a prospective cohort of 96 subjects, including healthy individuals, patients with monoclonal gammopathies of undetermined significance (MGUS), MM and MM with extramedullary manifestations (ExMM). The cDNA archives were analysed quantitatively for expression of the cyclin D1, fibroblast growth factor receptor 3 (FGFR3), C-MYC, C-MAF and cyclin D3 oncogenes. In addition, all patients were screened for IGH-MMSET hybrid transcripts. None of the analysed oncogenes was randomly distributed. C-MYC and cyclin D3 expression increased at the extramedullary transformation stage. Furthermore, C-MYC and cyclin D3 expression in CD56+ MM was similar to MGUS, whereas CD56- MM was similar to ExMM. FGFR3/IGH-MMSET was only observed among CD56+ MM patients, whereas an increased frequency of C-MAF dysregulation was seen among CD56- MM. High cyclin D1 expression levels were identified at similar frequencies at all stages, whereas the frequency of patients with low cyclin D1 levels increased during MM development. These data support the stepwise transformation model accumulating genetic alterations and proliferative capacity during MM initiation and development resulting in different clinical entities.

Cell Transformation, Neoplastic↗
PubMed2005

Requirement of mesodermal retinoic acid generated by Raldh2 for posterior neural transformation.

Studies in amphibian embryos have suggested that retinoic acid (RA) may function as a signal that stimulates posterior differentiation of the nervous system as postulated by the activation-transformation model for anteroposterior patterning of the nervous system. We have tested this hypothesis in retinaldehyde dehydrogenase-2 (Raldh2) null mutant mice lacking RA synthesis in the somitic mesoderm. Raldh2(-/-) embryos exhibited neural induction (activation) as evidenced by expression of Sox1 and Sox2 along the neural plate, but differentiation of spinal cord neuroectodermal progenitor cells (posterior transformation) did not occur as demonstrated by a loss of Pax6 and Olig2 expression along the posterior neural plate. Spinal cord differentiation in Raldh2(-/-) embryos was rescued by maternal RA administration, and during the rescue RA was found to act directly in the neuroectoderm but not the somitic mesoderm. RA generated by Raldh2 in the somitic mesoderm was found to normally travel as a signal throughout the mesoderm and neuroectoderm of the trunk and into tailbud neuroectoderm, but not into tailbud mesoderm. Raldh2(-/-) embryos also exhibited increased Fgf8 expression in the tailbud, and decreased cell proliferation in tailbud neuroectoderm. Our findings demonstrate that RA synthesized in the somitic mesoderm is necessary for posterior neural transformation in the mouse and that Raldh2 provides the only source of RA for posterior development. An important concept to emerge from our studies is that the somitic mesodermal RA signal acts in the neuroectoderm but not mesoderm to generate a spinal cord fate.

Aldehyde Oxidoreductases↗
PubMed2003

A registration-based approach to quantify flow-mediated dilation (FMD) of the brachial artery in ultrasound image sequences.

Flow-mediated dilation (FMD) offers a mechanism to characterize endothelial function and, therefore, may play a role in the diagnosis of cardiovascular diseases. Computerized analysis techniques are very desirable to give accuracy and objectivity to the measurements. Virtually all methods proposed up to now to measure FMD rely on accurate edge detection of the arterial wall, and they are not always robust in the presence of poor image quality or image artifacts. A novel method for automatic dilation assessment based on a global image analysis strategy is presented. We model interframe arterial dilation as a superposition of a rigid motion and a scaling factor perpendicular to the artery. Rigid motion can be interpreted as a global compensation for patient and probe movements, an aspect that has not been sufficiently studied before. The scaling factor explains arterial dilation. The ultrasound sequence is analyzed in two phases using image registration to recover both transformation models. Temporal continuity in the registration parameters along the sequence is enforced with a Kalman filter since the dilation process is known to be a gradual physiological phenomenon. Comparing automated and gold standard measurements (average of manual measurements) we found a negligible bias (0.05%FMD) and a small standard deviation (SD) of the differences (1.05%FMD). These values are comparable with those obtained from manual measurements (bias = 0.23%FMD, SD(intra-obs) = 1.13%FMD, SD(inter-obs) 1.20%FMD). The proposed method offers also better reproducibility (CV = 0.40%) than the manual measurements (CV = 1.04%).

Adult↗
PubMed2001

In vivo evaluation of 5-[(18)F]fluoro-2'-deoxyuridine as tracer for positron emission tomography in a murine pancreatic cancer model.

We used a murine tumor progression model for the evaluation of potential proliferation markers using positron emission tomography (PET). 5-[(18)F]-2'-deoxyuridine ([(18)F]FdUrd) was synthesized with >98% radiochemical purity and investigated in a pancreatic cancer model, transforming growth factor alpha transgenic mice crossbred to p53 deficient mice. Thymidylate synthase was increased already in premalignant lesions, whereas thymidine kinase 1 mRNA levels were up-regulated 4-fold in the pancreatic cancer specimen of these mice. PET imaging was performed after injection of 1 MBq of [(18)F]FdUrd and 1 MBq of [(18)F]fluoro-deoxyglucose. Animals with pancreatic cancer displayed focal uptake of both tracers. The [(18)F]FdUrd uptake ratio closely correlated with the proliferation index as evaluated in morphometric and fluorescence-activated cell sorter analysis. These results indicate the potential of our tumor model for the evaluation of PET tracers and suggest [(18)F]FdUrd as a tracer for the assessment of proliferation in vivo.

Animals↗
PubMed1984

Conversion through homologous recombination of the gene encoding Simian virus 40 115,000-molecular-weight super T antigen to a gene encoding a normal-size large T antigen variant.

We have previously cloned the gene encoding a 115,000-Mr super T antigen (115K super T antigen), an elongated form of the Simian virus 40 large T antigen, originating from the rat cell line V 11 F1 clone 1, subclone 7 (May et al., J. Virol. 45:901-913, 1983). DNA sequence analysis has shown that the 115K super T antigen gene contains notably an in-phase duplication of a sequence located in the region of tsA mutations. We have also shown that the 115K super T antigen gene is able to induce the formation of transformed foci in transfected rat cells. After rat cell cultures were transfected with the cloned gene encoding 115K super T antigen, we obtained a large number of transformants as reported in this paper. In these transformants, we detected a very high frequency of new T antigen variants, as shown by immunoprecipitation of the cell extracts with anti-simian virus 40 tumor serum followed by electrophoresis in sodium dodecyl sulfate-polyacrylamide gels. Based on these results and all of the data presently available, it appears likely that the input plasmid or cosmid DNAs containing the cloned gene were first subjected to recombination events that yield new variant T antigen genes before these recombinant genes become integrated. The new variant T antigens observed in the transformants were predominantly those comigrating with normal-size large T antigen. In fact, these latter variants appeared to be indistinguishable from wild-type large T antigen as judged by restriction mapping by Southern blotting of the total genomic DNA of the transformants. Models of intermolecular or intramolecular homologous recombination occurring between or within the input plasmid or input cosmid DNA molecules are proposed to account for the formation of such revertants.

Animals↗
PubMed1994

Increase in blood lactate during ramp exercise: comparison of continuous and threshold models.

Controversy persists regarding the mechanism underlying the lactate threshold. It has recently been argued that there is in fact no "threshold" and that blood lactate increases as a continuous function during exercise (Hughson J. Appl. Physiol. 62:1975-1981, 1987). In comparing continuous and threshold models, questions have been raised regarding the ramp rate, data sampling, and the mathematical models employed (Morton J. Appl. Physiol. 67:885-888, 1989). To address some of these concerns, we evaluated 61 subjects (mean age 45 +/- 15), who underwent maximal ramp treadmill tests with the ramp rate individualized such that test duration was approximately 10 min for each subject. The relationship between changes in blood lactate and oxygen uptake were evaluated using a modification of the log-log transformation model described by Beaver (J. Appl. Physiol. 59:1936-1940, 1985) and a continuous exponential plus constant model described by Hughson et al. (J. Appl. Physiol. 62:1975-1981, 1987). Model fitting, using mean squared error (MSE) and coefficient of determination (CD) for each method were as follows: [table: see text] The modified log-log model had a better fit as indicated by the lower MSE and higher CD, suggesting the change in lactate was better described by this model. However, the differences were so slight as to suggest: 1) a meaningful difference does not exist between the two; or 2) these methods may not be capable of detecting a difference, if one exists.

Adult↗
PubMed1994

Dithranol (anthralin) and 10-butyryl dithranol (butantrone) do not morphologically transform cultured C3H 10T1/2 C18 mouse embryo fibroblasts.

The ability of dithranol and 10-butyryl dithranol to induce morphological cell transformation was studied in cultured C3H 10T1/2 C18 fibroblasts. The cells were incubated with different concentrations of the test compounds for 48 h and cultured for 5 weeks thereafter. At the end of the culture period the cultures were fixed, stained and examined for the presence of transformed foci. Dithranol and 10-butyryl dithranol did not increase the formation of transformed foci, while the positive control compound, 7,12-dimethylbenz(a)anthracene (DMBA), induced a high frequency of transformations significantly different from controls. Thus the in vitro cell transformation model with uninitiated C3H 10T1/2 C18 fibroblasts is not able to detect the weak tumorigenic action of dithranol and 10-butyryl dithranol which has been observed in mouse skin.

Animals↗
PubMed1985

The relative gonadal index: an alternative index for quantification of reproductive condition.

Gonadal indices (i.e. GSI = gonadal wt/body wt X 100) commonly are used to quantify reproductive condition in fishes. These indices may be inappropriate with specimens of different sizes, however, for gonadal growth often is allometric. A new gonadal index (relative gonadal index, RGI) was developed to quantify the reproductive condition of animals independent of body size. The RGI is based on the underlying model W = alpha i X S beta i, where W is gonadal weight, S is body size (less gonadal weight if body weight is used), and alpha i and beta i are parameters to be estimated for gonadal developmental stage i. Assuming that a multiplicative lognormal error is appropriate, parameter estimates for alpha i and beta i were obtained by linear least squares regression for the log-transformed model ln(W) = beta i X ln(S) + ln(alpha i), where, in this form, beta i is the slope and ln(alpha i) is the intercept. Only if estimates of beta i do not differ significantly among ovarian developmental stages, as in our case, can a pooled estimate of beta be used to obtain the relative gonadal index, RGI = alpha i = W/S beta. Applicability of the RGI was tested using ovaries of three ecologically distinct fish species. The RGI was found to be more appropriate than the gonosomatic index for all three species.

Animals↗
PubMed1999

The expression of cytokeratin 18 in transitional cell carcinoma comparing with hepatoma.

The epithelium in kidneys and urinary bladders contain CK18 as in liver cells. The modulation of cytokeratin 18 during tumor transformation in hepatoma had been previously recognized through a series of biochemical and immunological approaches. A 14 KD hepatoma related molecules was found in the previous studies. We would like to utilize the hepatoma transformation model to study the changes in CK18 in transitional cell carcinoma, using immunoblotting and western blotting techniques. The result is that transitional cell carcinoma retain their CK18 molecule. Furthermore, CK18 related molecules similar to those seen in hepatoma also present in transitional cell carcinoma. The conclusions are transitional cell carcinoma contains CK18 related proteins similar to those seen in hepatoma tissues. We suggest that this element would be responsible for the change during the malignant transformation processes.

Blotting, Western↗
PubMed2000

Estimating data transformations in nonlinear mixed effects models.

A routine practice in the analysis of repeated measurement data is to represent individual responses by a mixed effects model on some transformed scale. For example, for pharmacokinetic, growth, and other data, both the response and the regression model are typically transformed to achieve approximate within-individual normality and constant variance on the new scale; however, the choice of transformation is often made subjectively or by default, with adoption of a standard choice such as the log. We propose a mixed effects framework based on the transform-both-sides model, where the transformation is represented by a monotone parametric function and is estimated from the data. For this model, we describe a practical fitting strategy based on approximation of the marginal likelihood. Inference is complicated by the fact that estimation of the transformation requires modification of the usual standard errors for estimators of fixed effects; however, we show that, under conditions relevant to common applications, this complication is asymptotically negligible, allowing straightforward implementation via standard software.

Arginine↗