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PubMed2003

The opportunities and challenges of personalized genome-based molecular therapies for cancer: targets, technologies, and molecular chaperones.

There are now unprecedented opportunities for the development of improved drugs for cancer treatment. Following on from the Human Genome Project, the Cancer Genome Project and related activities will define most of the genes in the majority of common human cancers over the next 5 years. This will provide the opportunity to develop a range of drugs targeted to the precise molecular abnormalities that drive various human cancers and opens up the possibility of personalized therapies targeted to the molecular pathology and genomics of individual patients and their malignancies. The new molecular therapies should be more effective and have less-severe side effects than cytotoxic agents. To develop the new generation of molecular cancer therapeutics as rapidly as possible, it is essential to harness the power of a range of new technologies. These include: genomic and proteomic methodologies (particularly gene expression microarrays); robotic high-throughput screening of diverse compound collections, together with in silico and fragment-based screening techniques; new structural biology methods for rational drug design (especially high-throughput X-ray crystallography and nuclear magnetic resonance); and advanced chemical technologies, including combinatorial and parallel synthesis. Two major challenges to cancer drug discovery are: (1) the ability to convert potent and selective lead compounds with activity by the desired mechanism on tumor cells in culture into agents with robust, drug-like properties, particularly in terms of pharmacokinetic and metabolic properties; and (2) the development of validated pharmacodynamic endpoints and molecular markers of drug response, ideally using noninvasive imaging technologies. The use of various new technologies will be exemplified. A major conceptual and practical issue facing the development and use of the new molecular cancer therapeutics is whether a single drug that targets one of a series of key molecular abnormalities in a particular cancer (e.g. BRAF) will be sufficient on its own to deliver clinical benefit ("house of cards" and tumor addiction models). The alternative scenario is that it will require either a combination of agents or a class of drug that has downstream effects on a range of oncogenic targets. Inhibitors of the heat-shock protein (HSP) 90 molecular chaperone are of particular interest in the latter regard, because they offer the potential of inhibiting multiple oncogenic pathways and simultaneous blockade of all six "hallmark traits" of cancer through direct interaction with a single molecular drug target. The first-in-class HSP90 inhibitor 17AAG exhibited good activity in animal models and is now showing evidence of molecular and clinical activity in ongoing clinical trials. Novel HSP90 inhibitors are also being sought. The development of HSP90 inhibitors is used to exemplify the application of new technologies in drug discovery against a novel molecular target, and in particular the need for innovative pharmacodynamic endpoints is emphasized as an essential component of hypothesis-testing clinical trials.

Antineoplastic Agents↗

PubMed2004

An algorithm for molecular dissection of tumor progression.

The volumetric growth of tumor cells as a function of time is most often likely to be a complex trait, controlled by the combined influences of multiple genes and environmental influences. Genetic mapping has proven to be a powerful tool for detecting and identifying specific genes affecting complex traits, i.e., quantitative trait loci (QTL), based on polymorphic markers. In this article, we present a novel statistical model for genetic mapping of QTL governing tumor growth trajectories in humans. In principle, this model is a combination of functional mapping proposed to map function-valued traits and linkage disequilibrium mapping designed to provide high resolution mapping of QTL by making use of recombination events created at a historic time. We implement an EM-simplex hybrid algorithm for parameter estimation, in which a closed-form solution for the EM algorithm is derived to estimate the population genetic parameters of QTL including the allele frequencies and the coefficient of linkage disequilibrium, and the simplex algorithm incorporated to estimate the curve parameters describing the dynamic changes of cancer cells for different QTL genotypes. Extensive simulations are performed to investigate the statistical properties of our model. Through a number of hypothesis tests, our model allows for cutting-edge studies aimed to decipher the genetic mechanisms underlying cancer growth, development and differentiation. The implications of our model in gene therapy for cancer research are discussed.

Algorithms↗

PubMed2004

Fractal dimension in butterflies' wings: a novel approach to understanding wing patterns?

The geometrical complexity in the wings of several, taxonomically different butterflies, is analyzed in terms of their fractal dimension. Preliminary results provide some evidence on important questions about the (dis)similarity of the wing patterns in terms of their fractal dimension. The analysis is restricted to two groups which are widely used in the literature as typical examples of mimicry, and a small number of unrelated species, thus implying the consideration of only a fraction of the wing pattern diversity. The members of the first mimicry ring, composed by the species Danaus plexippus (better known as the monarch butterfly), and the two subspecies Basilarchia archippus obsoleta (or northern viceroy) and Basilarchia archippus hoffmanni (or tropical viceroy), are found to have a very similar value for the fractal dimension of their wing patterns, even though they do not look very similar at first sight. It is also found that the female of another species (Neophasia terlootii), which looks similar to the members of the previous group, does not share the same feature, while the Lycorea ilione albescens does share it. For the members of the second group of mimicry related butterflies, the Greta nero nero and the Hypoleria cassotis, it is shown that they also have very close values for the fractal dimension of their wing patterns. Finally, it is shown that other species, which apparently have very similar wing patterns, do not have the same fractal dimension. A possible, not completely tested hypothesis is then conjectured: the formation of groups by individuals whose wing patterns have an almost equal fractal dimension may be due to the fact that they do share the same developmental raw material, and that this common feature is posteriorly modified by natural selection, possibly through predation.

Animals↗

PubMed2006

Analysing grouping of nucleotides in DNA sequences using lumped processes constructed from Markov chains.

The most commonly used models for analysing local dependencies in DNA sequences are (high-order) Markov chains. Incorporating knowledge relative to the possible grouping of the nucleotides enables to define dedicated sub-classes of Markov chains. The problem of formulating lumpability hypotheses for a Markov chain is therefore addressed. In the classical approach to lumpability, this problem can be formulated as the determination of an appropriate state space (smaller than the original state space) such that the lumped chain defined on this state space retains the Markov property. We propose a different perspective on lumpability where the state space is fixed and the partitioning of this state space is represented by a one-to-many probabilistic function within a two-level stochastic process. Three nested classes of lumped processes can be defined in this way as sub-classes of first-order Markov chains. These lumped processes enable parsimonious reparameterizations of Markov chains that help to reveal relevant partitions of the state space. Characterizations of the lumped processes on the original transition probability matrix are derived. Different model selection methods relying either on hypothesis testing or on penalized log-likelihood criteria are presented as well as extensions to lumped processes constructed from high-order Markov chains. The relevance of the proposed approach to lumpability is illustrated by the analysis of DNA sequences. In particular, the use of lumped processes enables to highlight differences between intronic sequences and gene untranslated region sequences.

3' Untranslated Regions↗

PubMed2002

Location of stem cells for the enteric nervous system.

Hirschsprung disease is the result of aganglionosis of a variable length of the terminal bowel, which arises from the incomplete colonisation of the embryonic gut by vagal neural crest-derived cells (NCC) that migrate caudally from the pharyngeal gut to the rectum. We have previously shown that a very small group of NCC, at the leading edge of this wave of migration, can proliferate and differentiate to innervate the entire distal gut. It remains unknown if this capability is unique to those cells at the leading edge of NCC migration. The hypothesis tested was that NCC capable of acting as stem cells are found throughout the developing enteric nervous system (ENS). Gut was taken from mice at embryonic day 11.5 as the leading edge of NCC migration enters the colon. Terminal colon was separated as aganglionic recipient gut and its rostral end juxtaposed to the caudal end of the small intestine or caecum. The explants were cultured on nitrocellulose filters for up to 120 h, after which time the apposed segments had fused. The gut was then fixed and examined by immunohistochemistry to detect the neuronal markers PGP9.5 and nitric-oxide synthase (NOS) to assess development of enteric ganglia. NCC migrated from the proximal gut into the terminal colon, colonising it along its entire length. The pattern of NCC colonisation and differentiation of NOS-positive neurons was the same, regardless of whether the NCC were derived from the leading edge of migration in the caecum or from more proximal regions of the small intestine. Vagal NCC have the capacity to migrate into separated aganglionic terminal colon and differentiate into neurons. NCC at the leading edge of migration and those located more proximally within the gut demonstrate equivalent ability to migrate to and differentiate in the terminal rectum. Further studies are required to confirm which of these migrating NCC have the properties of ENS stem cells.

Animals↗

PubMed2001

Dietary chloride as a possible determinant of the severity of exercise-induced asthma.

Dietary sodium chloride (NaCl) has been shown to alter the severity of exercise-induced asthma, but it is not known if the sodium and chloride ions have independent effects in this regard. The hypothesis tested in the present study was that both a low sodium, low chloride diet and a high sodium, low chloride diet would improve post-exercise pulmonary function in subjects with exercise-induced asthma (EIA) compared to a normal NaCl diet (NSD); but that neither of these diets would have an effect on post-exercise pulmonary function in control (non-EIA) subjects. Eight subjects who suffered from EIA and eight subjects who did not (control) took part in a double-blind crossover study. Pre- and post-exercise pulmonary function was assessed after 2 weeks on a NSD, a low NaCl diet (LSD, low sodium, low chloride) or a sodium bicarbonate diet (NaHCO3 diet, high sodium, low chloride). A 1 week washout period occurred between diets. Altering dietary sodium or chloride had no effect on pre-exercise (baseline) pulmonary function in either group or on post-exercise pulmonary function in control subjects. However, both the LSD and the NaHCO3 diet lessened the deterioration in post-exercise pulmonary function in EIA subjects. Comparing results from pre- to post-exercise, forced expiratory volume in 1 s (FEV1) at 15 min post-exercise differed significantly (P < 0.05) between diets [mean (SEM) 7 (4)% on the LSD, 14 (4)% on the NaHCO3 diet, and 19 (2)% on the NSD]. Similar patterns were observed for forced vital capacity (FVC), forced expiratory flow rate at 25%-75% FVC and peak expiratory flow rate. The NaHCO3 diet lessened the deterioration of post-exercise pulmonary function, but not to the extent of LSD. These data suggest that both sodium and chloride contribute to the worsening of EIA symptoms seen after consuming a normal or high NaCl diet.

Acidosis↗

PubMed2005

Predicting the onset of net carbon uptake by deciduous forests with soil temperature and climate data: a synthesis of FLUXNET data.

We tested the hypothesis that the date of the onset of net carbon uptake by temperate deciduous forest canopies corresponds with the time when the mean daily soil temperature equals the mean annual air temperature. The hypothesis was tested using over 30 site-years of data from 12 field sites where CO(2) exchange is being measured continuously with the eddy covariance method. The sites spanned the geographic range of Europe, North America and Asia and spanned a climate space of 16 degrees C in mean annual temperature. The tested phenology rule was robust and worked well over a 75 day range of the initiation of carbon uptake, starting as early as day 88 near Ione, California to as late as day 147 near Takayama, Japan. Overall, we observed that 64% of variance in the timing when net carbon uptake started was explained by the date when soil temperature matched the mean annual air temperature. We also observed a strong correlation between mean annual air temperature and the day that a deciduous forest starts to be a carbon sink. Consequently we are able to provide a simple phenological rule that can be implemented in regional carbon balance models and be assessed with soil and temperature outputs produced by climate and weather models.

Air↗

PubMed2003

The BrainIT group: concept and core dataset definition.

INTRODUCTION: An open collaborative international network has been established which aims to improve inter-centre standards for collection of high-resolution, neurointensive care data on patients with traumatic brain injury. The group is also working towards the creation of an open access, detailed and validated database that will be useful for post-hoc hypothesis testing. In Part A, the underlying concept, the group coordination structure, membership guidelines and database access and publication criteria are described. Secondly, in part B, we describe a set of meetings funded by the EEC that allowed us to define a "Core Dataset" and we present the results of a feasibility exercise for collection of this core dataset. METHODS: Four group meetings funded by the EEC have enabled definition of a "Core Dataset" to be collected from all centres regardless of specific project aim. A paper based pilot collection of data was conducted to determine the feasibility for collection of the core dataset. Specially designed forms to collect the core dataset demographic and clinical information as well as sample the time-series data elements were distributed by both email and standard mail to 22 BrainIT centres. A deadline of two months was set to receive completed forms back from centres. A pilot data collection of minute by minute physiological monitoring data was also performed. FINDINGS: A core-dataset was defined and can be downloaded from the BrainIT web-site (go to "Core dataset" link at: www.brainit.org). Eighteen centres (82%) returned completed forms by the set deadline. Overall the feasibility for collection of the core data elements was high with only 10 of the 64 questions (16%) showing missing data. Of those 10 fields with missing data, the average number of centres not responding was 12% and the median 6%. An SQL database to hold the data has been designed and is being tested. Software tools for collection of the core dataset have been developed. Ethics approval has been granted for collection of multi-centre data as part of a pilot data collection study. INTERPRETATION: The BrainIT network provides a more standardised and higher resolution data collection mechanism for research groups, organisations and the device industry to conduct multi-centre trials of new health care technology in patients with traumatic brain injury.

Brain Injuries↗

PubMed2005

Expression profiling using human tissues in combination with RNA amplification and microarray analysis: assessment of Langerhans cell histiocytosis.

Advances in molecular genetics have led to sequencing of the human genome, and expression data is becoming available for many diverse tissues throughout the body, allowing for exciting hypothesis testing of critical concepts such as development, differentiation, homeostasis, and ultimately, disease pathogenesis. At present, an optimal methodology to assess gene expression is to evaluate single cells, either identified physiologically in living preparations, or by immunocytochemical or histochemical procedures in fixed cells in vitro or in vivo. Unfortunately, the quantity of RNA harvested from a single cell is not sufficient for standard RNA extraction methods. Therefore, exponential polymerase-chain reaction (PCR) based analyses, and linear RNA amplification including amplified antisense (aRNA) RNA amplification and a newly developed terminal continuation (TC) RNA amplification methodology have been used in combination with microdissection procedures such as laser capture microdissection (LCM) to enable the use of microarray platforms within individual populations of cells obtained from a variety of human tissue sources such as biopsy-derived samples {including Langerhans cell histiocytosis (LCH)} as well as postmortem brain samples for high throughput expression profiling and related downstream genetic analyses.

Gene Expression Profiling↗

PubMed2005

Permeability of marginal hybrid layers in composite restorations.

The goal of adhesive dentistry is to restore the peripheral seal of dentin lost from removal of enamel. Unfortunately, the hybrid layer (HL) that is used to create that seal is permeable to small ions or molecules, even in the absence of detectable, interfacial gap formation via nanoleakage. This nanoleakage results from several mechanisms including incomplete infiltration of adhesive monomers into demineralized collagen matrix, presence of hydrophilic monomers, and insufficient removal of solvent or water that remains trapped inside the HL. These mechanisms lead to a porous interface with nanometer-sized channels that increase the permeability of the HL. The null hypothesis tested in this study was that water and acidic solution storage are able to alter in vitro the resin-dentin interface, further increasing the marginal hybrid layer (MHL) permeability. Class II cavities were made in vitro. The specimens were stored in water for 1 week and in lactic acid solution for 3 days. Polyvinyl siloxane impressions of restoration margins were taken before and after storage in water and lactic acid solution. Polyether replicas were obtained using the silicon impressions as molds. Replicas and original samples were observed under scanning electron microscopy. Lines of water droplets were detected on MHLs and overlying adhesive only after storage. Replicas obtained after acidic solution storage showed great numbers of irregularities such as gaps, voids, and degradation of the dentin-restoration surface margin, but also a great number of droplets. Dentin-restoration resin interfaces absorb water and are damaged by storage in dilute lactic acid. The presence of water droplets probably indicates water that flows out of the interface during the setting time of the impression and thus represents an index of marginal HL water permeability.

Acrylic Resins↗

PubMed2002

Determining efficacy of mammographic CAD systems.

Computer-aided detection (CAD) system sensitivity estimates without a radiologist in the loop are straightforward to measure but are extremely data dependent. The only relevant performance metric is improvement in CAD-assisted radiologist sensitivity. Unfortunately, this is difficult to accurately assess. Without a large study measuring the improvement in CAD-assisted radiologist sensitivity over the same cases, it is not possible to make valid comparisons between systems. As multiple CAD systems become commercially available, comparison issues need to be explored and resolved. Data from clinical trials of 2 systems are examined. Statistical hypothesis tests are applied to these data. Additionally, sensitivities of 2 systems are compared from an experiment testing over the same 120 cases. Even with large databases, there is not sufficient evidence to conclude performance differences exist between the 2 systems. It is prohibitively expensive to show conclusive sensitivity differences between commercially available mammographic CAD systems.

Breast Neoplasms↗

PubMed2006

A comprehensive examination of CYP19 variation and risk of breast cancer using two haplotype-tagging approaches.

BACKGROUND: Numerous studies point to a positive relationship between elevated levels of estrogens and increased risk of breast. Androgens are converted to estrogens by the aromatase enzyme, which is encoded by the CYP19 gene. We recently published resequencing data on 88 polymorphisms identified in that gene. The hypothesis tested in this study was that polymorphisms, or haplotypes, in CYP19 are related to risk of breast cancer. METHODS: Incident cases of breast cancer were identified through the Division of Medical Oncology at the Mayo Clinic in Rochester, MN. Controls were patients visiting Mayo for an annual medical examination. Controls were frequency matched to cases based on age and region of residence. Tag-polymorphisms were selected using 2 methods: (1) 12 variants using the tag-selection method of Carlson et al. (Am J Hum Genet 74:106-120, 2004); and (2) 12 variants using the haplotype method of Stram (Genet Epidemiol 27:365-374, 2004). Six SNPs were selected by both methods. Genotyping was conducted using SNPStream, TaqMan and RFLP analyses. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Analyses were conducted among all cases and controls, or stratified by estrogen receptor alpha (ER) status and/or menopausal status. RESULTS: A total of 750 cases (60% postmenopausal) and 732 controls (75% postmenopausal) were included. No association with breast cancer risk was detected for individual variants, selected tagSNPs or hap-tag SNPs despite 80% power to detect OR as low as 1.49 for minor allele frequency (MAF) of 0.10. Similarly, stratified analyses based on ER status or menopausal status failed to detect any association with breast cancer risk. CONCLUSION: These analyses suggest that variants of CYP19 are not associated with risk of breast cancer.

Alleles↗

PubMed2005

Autism research: lessons from the past and prospects for the future.

The paper uses both the author's experience of research training, and the empirical studies of autism in which he participated over the last 40-plus years, to derive research lessons and to consider the needs and prospects for future research. Attention is drawn to: the importance of mentors; the need to use technologies in a hypothesis-testing fashion; the important of possible creative/innovative leaps and of recognition of the unexpected; the need to ask challenging questions and to recognize when the original ideas were mistaken. There is great value in broadening the scientific strategies used to investigate a particular condition and much is to be gained by deliberately seeking parallels with other conditions.

Autistic Disorder↗

PubMed2006

The detoxification limitation hypothesis: where did it come from and where is it going?

The detoxification limitation hypothesis is firmly entrenched in the literature to explain various aspects of the interaction between herbivores and plant toxins. These include explanations for the existence of specialist and generalist herbivores and for the prevalence of each of these. The hypothesis suggests that the ability of mammalian herbivores to eliminate plant secondary metabolites (PSMs) largely determines which plants, and how much, they can eat. The value of the hypothesis is that it provides a clear framework for understanding how plant toxins might limit diet breadth. Thus, it is surprising, given its popularity, that there are few studies that provide experimental support either for or against the detoxification limitation hypothesis. There are two likely reasons for this. First, Freeland and Janzen did not formally propose the hypothesis, although it is implicit in their paper. Second, it is a difficult hypothesis to test, requiring an understanding of the metabolic pathways that lead to toxin elimination. Recent attempts to test the hypothesis appear promising. Results suggest that herbivores can recognize mounting saturation of a detoxification pathway and adjust their feeding accordingly to avoid intoxication. One strategy they use is to ingest a food containing a toxin that is metabolized by a different pathway. This demonstrates that careful selection of food plants is a key to existing in a chemically complex environment. As more studies characterize the detoxification products of PSMs, we will better understand how widespread this phenomenon is.

Food Preferences↗

PubMed2006

The impact on juror verdicts of judicial instruction to disregard inadmissible evidence: a meta-analysis.

The effect on juror verdicts of judicial instructions to disregard inadmissible evidence was evaluated using meta-analysis. One hundred seventy-five hypothesis tests from 48 studies with a combined 8,474 participants were examined. Results revealed that inadmissible evidence (IE) has a reliable effect on verdicts consistent with the content of the IE. Judicial instruction to ignore the inadmissible evidence does not effectively eliminate IE impact. However, if judges provide a rationale for a ruling of inadmissibility, juror compliance may be increased. Contested evidence ruled admissible accentuates that information, resulting in a significant impact on verdicts. Suggestions for how the courts may mitigate the impact of inadmissible evidence more effectively are discussed.

Criminal Law↗

PubMed2007

Profile information matrix for nonlinear transformation models.

For semiparametric models, interval estimation and hypothesis testing based on the information matrix for the full model is a challenge because of potentially unlimited dimension. Use of the profile information matrix for a small set of parameters of interest is an appealing alternative. Existing approaches for the estimation of the profile information matrix are either subject to the curse of dimensionality, or are ad-hoc and approximate and can be unstable and numerically inefficient. We propose a numerically stable and efficient algorithm that delivers an exact observed profile information matrix for regression coefficients for the class of Nonlinear Transformation Models [A. Tsodikov (2003) J R Statist Soc Ser B 65:759-774]. The algorithm deals with the curse of dimensionality and requires neither large matrix inverses nor explicit expressions for the profile surface.

Algorithms↗

PubMed2026

Instruments for measuring body image in breast cancer patients: a systematic review of measurement properties.

PURPOSE: To evaluate the psychometric properties of PROMs for measuring body image in breast cancer patients. METHODS: In December 2024, a psychometric systematic review was performed in the nine databases. The COSMIN checklist was employed to evaluate the methodological quality and psychometric properties of the included body image measures. The level of evidence was assessed using the GRADE framework, and final recommendations were formulated for the scale. RESULTS: Thirty-eight articles evaluating fifteen PROMs were included in this review. Structural validity, internal consistency, and hypothesis testing had been most frequently evaluated. Measurement error had not been assessed for all PROMs. Twelve instruments show potential application value but require further research. The BAS-BC, PSPP, and ASI-R are not recommended for use, as these instruments do not meet the strict COSMIN thresholds for full recommendation. CONCLUSION: The BIS can be recommended as a temporary screening tool for assessing body image outcome in clinical practice. The BIRS can be tentatively advised for measuring specific postoperative body image changes. However, further comprehensive studies are required to validate the psychometric properties of existing PROMs.

Female↗

PubMed1987

Does transducer selection affect aortic arch velocities?

The hypothesis tested was that transducers of different types and shapes would produce different peak and mean ascending aortic (AAo) velocities. Additionally, we sought to determine if mean and peak velocity recorded from the descending aorta (DAo) were similar to velocities in the AAo. Twenty-eight consecutive individuals who had normal hearts were studied. AAo velocities were measured with four transducers including a nonimaging device that transmitted Doppler at right angles to the transducer handle, a 30-degree angled continuous wave transducer, an imaging transducer that transmitted Doppler in line with the transducer handle, and a second imaging transducer that sectored at 25 degrees to the transducer handle. DAo was studied with a standard in-line imaging transducer. Results showed that mean and peak AAo velocities recorded by transducers that transmitted off the axis of the transducer handle were similar, but the transducer that imaged along the transducer handle axis produced significantly lower peak and mean velocities. The problem that caused lower velocity for the on-axis transducer was inability to image the area immediately posterior to the sternum to permit alignment in the azimuthal dimension. The continuous wave transducer provided a wide spectral dispersion. Mean DAo velocity was similar to mean AAo velocity, but variability was large.

Adolescent↗