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PubMed2004

Polymer-drug compatibility: a guide to the development of delivery systems for the anticancer agent, ellipticine.

To establish a method for predicting polymer-drug compatibility as a means to guide formulation development, we carried out physicochemical analyses of polymer-drug pairs and compared the difference in total and partial solubility parameters of polymer and drug. For these studies, we employed a range of biodegradable polymers and the anticancer agent Ellipticine as the model drug. The partial and total solubility parameters for the polymer and drug were calculated using the group contribution method. Drug-polymer pairs with different enthalpy of mixing values were analyzed by physicochemical techniques including X-ray diffraction and Fourier transform infrared. Polymers identified to be compatible [i.e., polycaprolactone (PCL) and poly-beta-benzyl-L-aspartate (PBLA)] and incompatible [i.e., poly (d,l-lactide (PLA)], by the above mentioned methods, were used to formulate Ellipticine. Specifically, Ellipticine was loaded into PBLA, PCL, and PLA films using a solvent casting method to produce a local drug formulation; while, polyethylene oxide (PEO)-b-polycaprolactone (PCL) and PEO-b-poly (d,l-lactide) (PLA) copolymer micelles were prepared by both dialysis and dry down methods resulting in a formulation for systemic administration. The drug release profiles for all formulations and the drug loading efficiency for the micelle formulations were also measured. In this way, we compared formulation characteristics with predictions from physicochemical analyses and comparison of total and partial solubility parameters. Overall, a good correlation was obtained between drug formulation characteristics and findings from our polymer-drug compatibility studies. Further optimization of the PEO-b-PCL micelle formulation for Ellipticine was also performed.

Antineoplastic Agents↗

PubMed1997

Multistep carcinogenesis of breast cancer and tumour heterogeneity.

Breast cancer emerges by a multistep process which can be broadly equated to transformation of normal cells via the steps of hyperplasia, premalignant change and in situ carcinoma. The elucidation of molecular interdependencies, which lead to development of primary breast cancer, its progression, and its formation of metastases is the main focus for new strategies targetted at prevention and treatment. Cytogenetic and molecular genetic analysis of breast cancer samples demonstrates that tumour development involves the accumulation of various genetic alterations including amplification of oncogenes and mutation or loss of tumour suppressor genes. Amplification of certain oncogenes with concomitant overexpression of the oncoprotein seems to be specific for certain histological types. Loss of normal tumour suppressor protein function can occur through sequential gene mutation events (somatic alteration) or through a single mutational event of a remaining normal copy, when a germline mutation is present. The second event is usually chromosome loss, mitotic recombination, or partial chromosome deletion. Chromosome loci 16q and 17p harbour tumour suppressor genes, which seem to be pathognomonic for the development or progression of a specific histological subtype. There are an overwhelming number of abnormalities that have been identified at the molecular level which fit the model of multistep carcinogenesis of breast cancer. When the functions of all of these genes are known and how they participate in malignant progression, we will have the tools for a more rational approach to diagnosis, prevention and treatment. This review deals only with the factors that are involved in the conversion of a normal breast cell into a malignant cell rather than those required for invasion and metastases. A key critical long-term step in the molecular analysis of breast cancer will be to link the specific molecular damage with the effects of environmental carcinogens.

Breast Neoplasms↗

PubMed1995

Donor specific bone marrow cells suppress lymphocyte reactivity to donor antigens and differentially modulate TH1 and TH2 cytokine gene expression in the responder cell population.

Previous studies have shown that post-transplantation infusion of donor specific bone marrow following a non-specific potent immunosuppressive agent such as antilymphocyte globulin (ALG) can significantly enhance graft survival compared to ALG alone. This enhancement remains variable and is thought to occur through the induction of specific partial tolerance to the renal allograft, but the underlying cellular mechanisms have not been clearly identified. In order to improve the efficacy of this specific immunosuppressive treatment and to study the events leading to enhanced allograft survival, we sought to establish a simple in vitro model based on a mixed lymphocyte reaction (MLR). We show that cellular proliferation seen in a normal MLR can be suppressed by addition of donor specific bone marrow cells (BMC). Significantly, this suppression is not observed with either third party BMC or donor specific peripheral blood mononuclear cells (PBMC). We have defined the optimum conditions of bone marrow infusion regarding number of BMC, their handling and culture, and simple enrichment procedures. Using a semiquantitative polymerase chain reaction assay, we have studied the cytokine gene expression in MLR modulated by donor specific BMC. In an unmodified allogeneic response, the responder cells show increased expression of interleukin-2 (IL-2) gamma-interferon IFN-gamma and receptor (IL-2R) mRNA, and no IL-10 mRNA. When responder cells are cultured with BMC of the stimulator, there is a 256-fold decrease in IL-2 mRNA, and a 64-fold decrease in IFN-gamma and IL-2R mRNA. There is also a 64-fold increase in IL-10 mRNA. This effect is even more marked when the BMC are depleted of CD3+ cells. The kinetics of addition of donor specific BMC to the normal allogeneic MLR culture and specificity of the action of BMC are also elucidated. Our data suggest that the enhancement of graft survival observed with donor BMC may operate through decreased proliferation of reactive T cell clones (due to decreased IL-2/IL-2R) and suppressed monocyte functions (due to decreased IFN-gamma and increased IL-10 gene expression).

Bone Marrow↗

PubMed2003

The power and the limitations of cross-species protein identification by mass spectrometry-driven sequence similarity searches.

Mass spectrometry-driven BLAST (MS BLAST) is a database search protocol for identifying unknown proteins by sequence similarity to homologous proteins available in a database. MS BLAST utilizes redundant, degenerate, and partially inaccurate peptide sequence data obtained by de novo interpretation of tandem mass spectra and has become a powerful tool in functional proteomic research. Using computational modeling, we evaluated the potential of MS BLAST for proteome-wide identification of unknown proteins. We determined how the success rate of protein identification depends on the full-length sequence identity between the queried protein and its closest homologue in a database. We also estimated phylogenetic distances between organisms under study and related reference organisms with completely sequenced genomes that allow substantial coverage of unknown proteomes.

Animals↗

PubMed2005

Lateral fluid percussion brain injury: a 15-year review and evaluation.

This article comprehensively reviews the lateral fluid percussion (LFP) model of traumatic brain injury (TBI) in small animal species with particular emphasis on its validity, clinical relevance and reliability. The LFP model, initially described in 1989, has become the most extensively utilized animal model of TBI (to date, 232 PubMed citations), producing both focal and diffuse (mixed) brain injury. Despite subtle variations in injury parameters between laboratories, universal findings are evident across studies, including histological, physiological, metabolic, and behavioral changes that serve to increase the reliability of the model. Moreover, demonstrable histological damage and severity-dependent behavioral deficits, which partially recover over time, validate LFP as a clinically-relevant model of human TBI. The LFP model, also has been used extensively to evaluate potential therapeutic interventions, including resuscitation, pharmacologic therapies, transplantation, and other neuroprotective and neuroregenerative strategies. Although a number of positive studies have identified promising therapies for moderate TBI, the predictive validity of the model may be compromised when findings are translated to severely injured patients. Recently, the clinical relevance of LFP has been enhanced by combining the injury with secondary insults, as well as broadening studies to incorporate issues of gender and age to better approximate the range of human TBI within study design. We conclude that the LFP brain injury model is an appropriate tool to study the cellular and mechanistic aspects of human TBI that cannot be addressed in the clinical setting, as well as for the development and characterization of novel therapeutic interventions. Continued translation of pre-clinical findings to human TBI will enhance the predictive validity of the LFP model, and allow novel neuroprotective and neuroregenerative treatment strategies developed in the laboratory to reach the appropriate TBI patients.

Animals↗

PubMed1987

Growth hormone modifies the growth rate of enzyme-altered hepatic foci in male rats treated according to the resistant hepatocyte model.

Male and female Wistar rats were given an initiating i.p. injection of diethylnitrosamine (DEN; 200 mg/kg body wt). Two weeks later the rats were given a diet containing 0.02% (w/w) 2-acetylaminofluorene (2-AAF) for 2 weeks. In the middle of the 2-AAF treatment a 70% partial hepatectomy (PH) was performed. In order to identify the pituitary hormone responsible for the previously observed sex difference (male greater than female) in and influence of ectopic pituitary grafts on focal growth during 2-AAF/PH selection of enzyme-altered foci, male rats were treated with a continuous infusion of bovine growth hormone (bGH; 6 micrograms/h) or ovine prolactin (oPrl; 6 micrograms/h) by way of osmotic minipumps. Hormonal treatment was started 1 week after initiation and was finished 1 week after the 2-AAF selection period. All rats were killed 6 weeks after initiation and liver sections were stained for gamma-glutamyltransferase. The number of foci/cm2 as well as the area per focus and area ratio (mm2 foci/cm2 liver section) were calculated. Whereas no significant differences in the number of foci/cm2 were observed between the different groups of rats, bGH treatment of male rats decreased both the area/focus and the area ratio down to the female level. No significant effects were seen following oPrl administration when compared with control males. In vitro studies of subcellular preparations from the liver lobes obtained at PH showed that the sexually differentiated N-hydroxy-2-AAF sulfotransferase activity (male greater than female) in male rats was 'feminized', i.e. decreased, by bGH administration, but not by infusion of oPrl. The present investigation strengthens the view of growth hormone as an important determinant of sex differences in chemical carcinogenesis in rat liver, possibly via an influence on carcinogen metabolism.

2-Acetylaminofluorene↗

PubMed2003

Factors affecting hepatitis vaccination refusal at a sexually transmitted disease clinic among men who have sex with men.

BACKGROUND: Men who have sex with men (MSM) attending sexually transmitted disease (STD) clinics should be considered candidates for hepatitis A virus (HAV) and hepatitis B virus (HBV) vaccination. However, vaccination rates in STD clinics remain less than optimal. GOAL: The goal was to identify factors that affect HAV and HBV vaccination refusals. STUDY DESIGN: A survey was administered to MSM eligible for the vaccinations attending an STD clinic. Vaccines were offered at the end of the clinic visit. RESULTS: Rates of refusal of HAV (RefuseA) and HBV (RefuseB) vaccinations were 36% and 38%. Health motivation was associated with acceptance, while clinical barriers such as "want to test first for immunity," and "want to talk to own doctor first" were associated with refusal. "Not enough time this evening" was most strongly predictive of refusal, relative to strongly disagree (risk ratios [RRstrongly agree] and 95% confidence limits for RefuseA and RefuseB were 2.69 [1.43, 5.05] and 2.02 [1.05, 3.87], respectively). CONCLUSIONS: To increase acceptance, patients less health-motivated should be identified for prevaccination counseling. Some perceived barriers such as time may be a partial excuse; staff should identify and address other perceptions that may be influencing patients' decisions.

Adolescent↗

PubMed2025

Zea mays Meiotic Spindle Ultrastructure Reveals Kinetochore-Microtubule Interface and Embedded Membrane Components.

UNLABELLED: Introduction: Spindles are microtubules-based machines whose primary function is to accurately segregate chromosomes in both mitotic and meiotic cell division. The structure of spindles is critical for their function; errors in morphology or attachment to chromosomes lead to aneuploidy, potentially resulting in disease, infertility, and lethality. Electron microscopy studies have yielded fine-detail spindle ultrastructures in many plant and animal species, but no studies have investigated the spindle of Zea mays, a critical crop, and cytogenetic model system. METHODS: Here we use electron tomography (ET), reconstruction, and modeling to obtain three-dimensional, nanometer-resolution of the Z. mays meiotic spindle. Structures such as microtubules, kinetochores, vesicles, membrane channels, and nuclear envelope were modeled through a partial spindle reconstruction, and confirmed using immunostaining and live fluorescence microscopy. RESULTS: ET revealed that maize spindles contain 8-18 kinetochore microtubules (kMTs) per kinetochore, which are approximately 776 nm in diameter and 316 nm in depth. Small ∼37 nm vesicles were identified, as well as larger (∼5 µm long, 800 nm wide) membrane structures with channels that allow spindle microtubules to pass through. These membrane channels stain positively for the ER-marker protein disulfide isomerase. Imaging of prophase meiotic cells revealed a cross-hatch microtubule arrangement in the perinuclear ring on the external surface of the nuclear envelope, which also contained type II nuclear grooves with transnuclear microtubules passing from the nucleus to the cytoplasm. CONCLUSIONS: Z. mays meiotic spindles are similar to animal counterparts with a comparable number of kMTs and pre-spindle transnuclear microtubules but also plant-specific features such as Golgi-derived vesicles to assist cell plate formation, internal ER membrane channels, and a perinuclear microtubule ring that aids spindle assembly. Maize kinetochores have an electron-diffuse ball in cup morphology that is comparable in size to Drosophila kinetochores and larger than mammalian kinetochores. .

Zea mays↗

PubMed2006

Identification of Enterobacter sakazakii from closely related species: the use of artificial neural networks in the analysis of biochemical and 16S rDNA data.

BACKGROUND: Enterobacter sakazakii is an emergent pathogen associated with ingestion of infant formula and accurate identification is important in both industrial and clinical settings. Bacterial species can be difficult to accurately characterise from complex biochemical datasets and computer algorithms can potentially simplify the process. RESULTS: Artificial Neural Networks were applied to biochemical and 16S rDNA data derived from 282 strains of Enterobacteriaceae, including 189 E. sakazakii isolates, in order to identify key characteristics which could improve the identification of E. sakazakii. The models developed resulted in a predictive performance for blind (validation) data of 99.3 % correct discrimination between E. sakazakii and closely related species for both phenotypic and genotypic data. Three main regions of the partial rDNA sequence were found to be key in discriminating the species. Comparison between E. sakazakii and other strains also constitutively positive for expression of the enzyme alpha-glucosidase resulted in a predictive performance of 98.7 % for 16S rDNA sequence data and 100% for phenotypic data. CONCLUSION: The computationally based methods developed here show a remarkable ability in reducing data dimensionality and complexity, in order to eliminate noise from the system in order to facilitate the speed and reliability of a potential strain identification system. Furthermore, the approaches described are also able to provide valuable information regarding the population structure and distribution of individual species thus providing the foundations for novel assays and diagnostic tests for rapid identification of pathogens.

Cronobacter sakazakii↗

PubMed2005

Inhibited neurogenesis in JNK1-deficient embryonic stem cells.

The JNKs are components of stress signaling pathways but also regulate morphogenesis and differentiation. Previously, we invoked a role for the JNKs in nerve growth factor (NGF)-stimulated PC12 cell neural differentiation (L. Marek et al., J. Cell. Physiol. 201:459-469, 2004; E. Zentrich et al., J. Biol. Chem. 277:4110-4118, 2002). Herein, the role for JNKs in neural differentiation and transcriptional regulation of the marker gene, NFLC, modeled in mouse embryonic stem (ES) cells was studied. NFLC-luciferase reporters revealed the requirement for NFLC promoter sequences encompassing base pairs -128 to -98 relative to the transcriptional start site as well as a proximal cyclic AMP response element-activating transcription factor binding site at -45 to -38 base pairs for transcriptional induction in NGF-treated PC12 cells and neurally differentiated ES cells. The findings reveal common promoter sequences that integrate conserved signal pathways in both PC12 cell and ES cell systems. To test the requirement for the JNK pathway in ES cell neurogenesis, ES cell lines bearing homozygous disruptions of the jnk1, jnk2, or jnk3 genes were derived and submitted to an embryoid body (EB) differentiation protocol. Neural differentiation was observed in wild-type, JNK2(-/-), and JNK3(-/-) cultures but not in JNK1(-/-) EBs. Rather, an outgrowth of cells with epithelial morphology and enhanced E-cadherin expression but low NFLC mRNA and protein was observed in JNK1(-/-) cultures. The expression of wnt-4 and wnt-6, identified inhibitors of ES cell neurogenesis, was significantly elevated in JNK1(-/-) cultures relative to wild-type, JNK2(-/-), and JNK3(-/-) cultures. Moreover, the Wnt antagonist, sFRP-2, partially rescued neural differentiation in JNK1(-/-) cultures. Thus, a genetic approach using JNK-deficient ES cells reveals a novel role for JNK1 involving repression of Wnt expression in neural differentiation modeled in murine ES cells.

Animals↗

PubMed2006

Validity of radiographic evaluations of bone formation in a rat calvaria osteotomy defect model.

OBJECTIVE: The objective of this study was to evaluate the validity of radiographic evaluations of bone formation in a critical-size rat calvaria osteotomy defect model. METHODS: Bilateral, critical-size ( [symbol in text] 6 mm) calvaria osteotomy defects in 30 adult Sprague-Dawley rats treated with a rat platelet-rich plasma preparation or control treatments were evaluated by radiographic and histometric measures following a 4- or 8-week healing interval. Standardized radiographic images of the rat calvaria gross specimens were used to assess bone formation within the defect sites by visual evaluation of the grey scale by three masked examiners. The most central portion of each defect site was subject to histometric analysis using a PC-based image analysis system. Kappa statistics and percentage agreement between the radiographic and histometric analysis were estimated. RESULTS: Radiographic evaluations of bone formation are associated with significant weaknesses poorly representing actual healing events; kappa statistics (0.17) denoting slight agreement beyond chance. Perfect agreement between the histologic and radiographic analysis for defect sites showing complete and partial histologic bone fill was achieved 63% and 50% of the time, respectively. Agreement reached only 20% for sites with no/limited bone fill. When no/limited and partial bone fill occurred, the radiographic analysis tended to overestimate bone fill and underestimate bone fill when complete closure of the defect sites was observed in the histologic analysis. CONCLUSION: Low accuracy was observed when radiographic evaluations were employed in identifying and characterizing bone fill in the rat calvaria osteotomy defects. Assessment of bone healing in animal models aiming at treatment recommendations for clinical application must not solely be based on radiographic analysis, but should be confirmed using histologic observations.

Animals↗

PubMed2026

Acinetobacter guillouiae, a lipolytic strain isolated from sludge capable of partially depolymerising polyethylene terephthalate: genomic, proteomic, and biochemical insights.

Acinetobacter guillouiae I-MWF was isolated by incubating amorphous polyethylene terephthalate (PET) film in sludge samples. The strain partially depolymerised PET powder with 11.3% crystallinity, as confirmed by FT-IR, HPLC-UV, and LC-MS analyses. Extracellular enzymes released terephthalic acid (TPA), mono(2-hydroxyethyl) terephthalate (MHET), and bis(2-hydroxyethyl) terephthalate (BHET). Genomic analysis identified 18 putative extracellular hydrolases, including lipases and esterases, each with a conserved catalytic triad. Proteomic profiling revealed expression of two triacylglycerol lipases and two additional lipase-family proteins when the strain was cultivated with PET or a PET-Tween 80 mixture. These enzymes were cloned in Escherichia coli, but most formed insoluble, inactive inclusion bodies, and one was not expressed. Molecular modelling highlighted structural features likely to influence their catalytic interaction with PET. Although the strain partially depolymerised PET powder, it was unable to grow on PET, TPA, or ethylene glycol, indicating that PET depolymerisation occurs as a side activity rather than supporting growth. Instead, A. guillouiae displayed strong lipolytic activity and a clear preference for lipid-based substrates, achieving its highest growth with Tween 80. A lipid transporter was also expressed under these conditions, suggesting adaptation to hydrocarbon-rich environments. These findings indicate that A. guillouiae I-MWF can mediate partial PET depolymerisation without assimilating the resulting monomers, while preferentially growing on lipid-like substrates.

Acinetobacter↗

PubMedDate not supplied

Allometric scaling of strength in an independently living population age 55-86 years.

Most physiological functions vary allometrically with body size; however, few investigators have examined the relationship between strength and body size with allometric scaling. Thus, we hypothesized that allometric analysis would reveal that both the amount and quality of muscle are significant determinants of strength in the elderly. Allometric analyses were used to determine the influence of limb cross-sectional area (CSA), physical activity, demispan (distance between index-middle finger web and the sternal notch), leg length, and sex on grip and plantar flexor strength in men (n = 188) and women (n = 205) age 55-86 years. Physical activity was measured using a self-reporting questionnaire (Taylor et al. [1978] J Chron Dis 31:741-755). Forearm and leg CSA was estimated from anthropometry. There was an age-related decline in grip strength, independent of forearm CSA, demispan, and sex, equal to approximately 12% per decade, whereas plantar flexor strength adjusted for leg CSA, physical activity, and sex was reduced at a rate of approximately 15% per decade. The allometric models explained 71.4% (r = 0.845) and 38.8% (r = 0.623) of the variance in grip and plantar flexor strength, respectively. Model parameters were identified using multiple linear regression (P < 0.05). Thus, grip strength = forearm CSA(0.435). demispan(0.161). exp(3.905 - 0.012 age + 0.413 sex) and plantar flexor strength = leg CSA(0.223). physical activity (0.115). exp(5.867 - 0.015 age + 0.366 sex). These findings indicate that age-related reductions in muscle CSA do not fully account for strength declines with age. Physical activity is also important and partially explains these reductions.

Activities of Daily Living↗

PubMed1999

Animal models of spinal cord contusion injuries.

BACKGROUND AND PURPOSE: Traumatic spinal cord injury causes initial mechanical disruption of tissue, leading to a complex secondary sequence of pathophysiologic changes and neurologic impairment. These sequelae depend on the impact force delivered to the spinal cord at the time of injury. Successful clinical evaluation of the efficacy of any therapeutic regimen depends on the reliability and reproducibility of an experimental animal model. We describe a trauma device and the biomechanical parameters required to induce severe or moderate spinal cord contusion injury in cats and rats. METHODS: Recovery after injury was determined by behavioral, electrophysiologic, and histologic evaluations. RESULTS: Behavioral and electrophysiologic tests after injury clearly identified the experimental groups. A stable severe paraplegic state (defined as 6 months for cats and 8 weeks for rats), without evidence of behavioral or electrophysiologic recovery, was induced by a 65-Newton (N) load for cats and a 35-N load for rats. Moderate spinal cord contusion injury, from which cats and rats partially recovered after approximately 3 months and 4 weeks, respectively, was induced by a 45- and 25-N load, respectively. CONCLUSION: Use of these injury conditions provides reliable animal models for studies designed to evaluate potential therapeutic regimens for spinal cord injury.

Animals↗

PubMed2001

Comparative binding energy analysis of the substrate specificity of haloalkane dehalogenase from Xanthobacter autotrophicus GJ10.

Comparative binding energy (COMBINE) analysis was conducted for 18 substrates of the haloalkane dehalogenase from Xanthobacter autotrophicus GJ10 (DhlA): 1-chlorobutane, 1-chlorohexane, dichloromethane, 1,2-dichloroethane, 1,2-dichloropropane, 2-chloroethanol, epichlorohydrine, 2-chloroacetonitrile, 2-chloroacetamide, and their brominated analogues. The purpose of the COMBINE analysis was to identify the amino acid residues determining the substrate specificity of the haloalkane dehalogenase. This knowledge is essential for the tailoring of this enzyme for biotechnological applications. Complexes of the enzyme with these substrates were modeled and then refined by molecular mechanics energy minimization. The intermolecular enzyme-substrate energy was decomposed into residue-wise van der Waals and electrostatic contributions and complemented by surface area dependent and electrostatic desolvation terms. Partial least-squares projection to latent structures analysis was then used to establish relationships between the energy contributions and the experimental apparent dissociation constants. A model containing van der Waals and electrostatic intermolecular interaction energy contributions calculated using the AMBER force field explained 91% (73% cross-validated) of the quantitative variance in the apparent dissociation constants. A model based on van der Waals intermolecular contributions from AMBER and electrostatic interactions derived from the Poisson-Boltzmann equation explained 93% (74% cross-validated) of the quantitative variance. COMBINE models predicted correctly the change in apparent dissociation constants upon single-point mutation of DhlA for six enzyme-substrate complexes. The amino acid residues contributing most significantly to the substrate specificity of DhlA were identified; they include Asp124, Trp125, Phe164, Phe172, Trp175, Phe222, Pro223, and Leu263. These residues are suitable targets for modification by site-directed mutagenesis.

Binding Sites↗

PubMed2004

Development of biomarkers based on diet-dependent metabolic serotypes: characteristics of component-based models of metabolic serotypes.

Our research seeks to identify a serum profile, or serotype, that reflects the systemic physiologic modifications resultant from dietary restriction (DR), in part such that this knowledge can be applied for biomarker studies. Direct comparison suggests that component-based classification algorithms consistently out-perform distance-based metrics for studies of nutritional modulation of metabolic serotype, but are subject to over-fitting concerns. Intercohort differences in the sera metabolome could partially obscure the effects of DR. Further analysis now shows that implementation of component-based approaches (also called projection methods) optimized for class separation and controlled for over-fitting have >97% accuracy for distinguishing sera from control or DR rats. DR's effect on the metabolome is shown to be robust across cohorts, but differs in males and females (although some metabolites are affected in both). We demonstrate the utility of projection-based methods for both sample and variable diagnostics, including identification of critical metabolites and samples that are atypical with respect to both class and variable models. Inclusion of non-statistically different variables enhances classification models. Variables that contribute to these models are sharply dependent on mathematical processing techniques; some variables that do not contribute under one paradigm are powerful under alternative mathematical paradigms. In practical terms, this information may find purpose in other endeavors, such as mechanistic studies of DR. Application of these approaches confirms the utility of megavariate data analysis techniques for optimal generation of biomarkers based on nutritional modulation of physiological processes.

Animals↗

PubMed1991

Technique, pharmacokinetics, toxicity, and efficacy of intratumoral etanidazole and radiotherapy for treatment of spontaneous feline oral squamous cell carcinoma.

The histologic appearance, locoregional recurrence, and rate/site of metastases of spontaneous feline oral squamous cell carcinoma are similar to head and neck cancer in humans. A feasibility study of intratumoral Etanidazole, a hypoxic cell sensitizer, and radiation therapy were instituted in this model. Eleven cats with feline squamous cell carcinoma were treated with intratumoral Etanidazole and radiation therapy. Total Etanidazole doses were 1.5-24.0 gms/m2 (0.5-6.9 gms). The tumor partial response rate was 100% (11/11); the median volume regression was 70%. All cats have died as a result of tumor recurrence or tumor-related complications. Median survival was 116 days. Ten cats have been autopsied. Non-necrotic and necrotic tumor cells were identified at the treatment site in all cats. Pharmacokinetic studies were performed in six cats. Following intravenous infusion, the plasma elimination of the Etanidazole was biexponential. The systemic availability following intratumoral administration was 61.2 +/- 21.1%. Peak plasma Etanidazole levels were observed 14 minutes following intratumoral injection, after which elimination was biexponential. Thirty minutes following intratumoral Etanidazole administration, tumor Etanidazole levels were 62.8% of plasma levels. Feline squamous cell carcinoma appears to be a useful model of human head and neck cancer. Cats tolerate substantial doses of intratumoral and intravenous Etanidazole. Etanidazole and radiation therapy cause rapid regression, but not cure, of feline squamous cell carcinoma. There is a similarity between the intravenous kinetics of Etanidazole in humans and cats. Further studies in this model are planned.

Animals↗

PubMed2003

Network component analysis: reconstruction of regulatory signals in biological systems.

High-dimensional data sets generated by high-throughput technologies, such as DNA microarray, are often the outputs of complex networked systems driven by hidden regulatory signals. Traditional statistical methods for computing low-dimensional or hidden representations of these data sets, such as principal component analysis and independent component analysis, ignore the underlying network structures and provide decompositions based purely on a priori statistical constraints on the computed component signals. The resulting decomposition thus provides a phenomenological model for the observed data and does not necessarily contain physically or biologically meaningful signals. Here, we develop a method, called network component analysis, for uncovering hidden regulatory signals from outputs of networked systems, when only a partial knowledge of the underlying network topology is available. The a priori network structure information is first tested for compliance with a set of identifiability criteria. For networks that satisfy the criteria, the signals from the regulatory nodes and their strengths of influence on each output node can be faithfully reconstructed. This method is first validated experimentally by using the absorbance spectra of a network of various hemoglobin species. The method is then applied to microarray data generated from yeast Saccharamyces cerevisiae and the activities of various transcription factors during cell cycle are reconstructed by using recently discovered connectivity information for the underlying transcriptional regulatory networks.

Biology↗