Biomarkers in molecular medicine: cancer detection and diagnosis

In spite of advances in diagnostics and therapeutics, cancer remains the second leading cause of death in the U.S. Successful cancer treatment depends not only on better therapies but also on improved methods to assess an individual's risk of developing cancer and to detect cancers at early stages when they can be more effectively treated. Current cancer diagnostic imaging methods are labor-intensive and expensive, especially for screening large asymptomatic populations. Effective screening strategies depend on methods that are noninvasive and detect cancers in their early stages of development. There is increasing interest and enthusiasm in molecular markers as tools for cancer detection and prognosis. It is hoped that newly discovered cancer biomarkers and advances in high-throughput technologies would revolutionize cancer therapies by improving cancer risk assessment, early detection, diagnosis, prognosis, and monitoring therapeutic response. These biomarkers will be used either as stand-alone tests or to complement existing imaging methods.     

The molecular medicine of colorectal cancer

This report highlights some of the discussions at a Keystone Symposium entitled ‘The Molecular Medicine of Colorectal Cancer’ held at Taos, NM, USA, from 30 January to 4 February, 2001.     

A molecular machine biosensor: construction, predictive models and experimental studies

This paper describes the construction, operation and predictive modeling of a molecular machine, functioning as a high sensitivity biosensor. Embedded gramicidin A (gA) ionchannels in a self-assembled tethered lipid bilayer act as biological switches in response to target molecules and provide a signal amplification mechanism that results in high sensitivity molecular detection. The biosensor can be used as a rapid and sensitive point of care diagnostic device in different media such as human serum, plasma and whole blood without the need for pre and post processing steps required in an enzyme-linked immunosorbent assay. The electrical reader of the device provides the added advantage of objective measurement. Novel ideas in the construction of the molecular machine, including fabrication of biochip arrays, and experimental studies of its ability to detect analyte molecules over a wide range of concentrations are presented. Remarkably, despite the complexity of the device, it is shown that the response can be predicted by modeling the analyte fluid flow and surface chemical reactions. The derived predictive models for the sensing dynamics also facilitate determining important variables in the design of a molecular machine such as the ion channel lifetime and diffusion dynamics within the bilayer lipid membrane as well as the bio-molecular interaction rate constants.     

Exploring molecular genetics of bladder cancer: lessons learned from mouse models

Urothelial cell carcinoma (UCC) of the bladder is one of the most common malignancies worldwide, causing considerable morbidity and mortality. It is unusual among the epithelial carcinomas because tumorigenesis can occur by two distinct pathways: low-grade, recurring papillary tumours usually contain oncogenic mutations in FGFR3 or HRAS, whereas high-grade, muscle-invasive tumours with metastatic potential generally have defects in the pathways controlled by the tumour suppressors p53 and retinoblastoma (RB). Over the past 20 years, a plethora of genetically engineered mouse (GEM) models of UCC have been developed, containing deletions or mutations of key tumour suppressor genes or oncogenes. In this review, we provide an up-to-date summary of these GEM models, analyse their flaws and weaknesses, discuss how they have advanced our understanding of UCC at the molecular level, and comment on their translational potential. We also highlight recent studies supporting a role for dysregulated Wnt signalling in UCC and the development of mouse models that recapitulate this dysregulation.     

Animal models of infection and inflammation and their role in experimental nuclear medicine

In this review, basic aspects of nuclear medicine are described. One of the fields of research in nuclear medicine is the development of new radiopharmaceuticals for imaging infection and inflammation in humans. For this development, animal models are identified and modified to needs of a particular research question. In this review, a wide variety of models that are available in our laboratory are presented and the strengths and pitfalls are discussed.     

Immortalized cells as experimental models to study cancer

The development of cancer is a multi-step process in which normal cells sustain a series of genetic alterations that together program the malignant phenotype. Much of our knowledge of cancer biology results from the detailed study of specimens and cell lines derived from patient tumors. While these approaches continue to yield critical information regarding the identity, number, and types of alterations found in human tumors, further progress in understanding the molecular basis of malignant transformation depends upon the generation and use of increasingly sophisticated experimental models of cancer. Over the past several years, the recognition that telomeres and telomerase play essential roles in regulating cell lifespan now permits the development of new models of human cancer. Here we review recent progress in the use of immortalized human cells as a foundation for understanding the molecular basis of cancer.     

Open for Inspection: Problems in Representing a Humanised Wilderness

Historically, a large percentage of non-indigenous Australians have obtained knowledge of Aboriginal people through channels which provoke an aesthetic response (paintings, film, literature, etc.). More recently, inhabited national parks, such as Kakadu and Uluru, have offered a supposedly more direct engagement with contemporary Aboriginal life, yet this engagement is also filtered through a number of aesthetic discourses. The necessity for any social group to construct representations of itself arises out of the complexities and contingencies of the political landscape. Although such representations can and do reflect a number of political perspectives, Aboriginal people occasionally have the opportunity to convey their own view of the social and historical circumstances which continue to impinge upon their lives. Although national park boards of management often encourage this indigenous voice, I argue that the resulting aesthetic representations tend to elide and suppress the untidy moments which gave rise to them. This, I further suggest, presents problems for any attempt to represent the contemporary social and cultural reality of a particular group of people.     

Identification of control targets in Boolean molecular network models via computational algebra

Background

Many problems in biomedicine and other areas of the life sciences can be characterized as control problems, with the goal of finding strategies to change a disease or otherwise undesirable state of a biological system into another, more desirable, state through an intervention, such as a drug or other therapeutic treatment. The identification of such strategies is typically based on a mathematical model of the process to be altered through targeted control inputs. This paper focuses on processes at the molecular level that determine the state of an individual cell, involving signaling or gene regulation. The mathematical model type considered is that of Boolean networks. The potential control targets can be represented by a set of nodes and edges that can be manipulated to produce a desired effect on the system.

Results

This paper presents a method for the identification of potential intervention targets in Boolean molecular network models using algebraic techniques. The approach exploits an algebraic representation of Boolean networks to encode the control candidates in the network wiring diagram as the solutions of a system of polynomials equations, and then uses computational algebra techniques to find such controllers. The control methods in this paper are validated through the identification of combinatorial interventions in the signaling pathways of previously reported control targets in two well studied systems, a p53-mdm2 network and a blood T cell lymphocyte granular leukemia survival signaling network. Supplementary data is available online and our code in Macaulay2 and Matlab are available via http://www.ms.uky.edu/~dmu228/ControlAlg.

Conclusions

This paper presents a novel method for the identification of intervention targets in Boolean network models. The results in this paper show that the proposed methods are useful and efficient for moderately large networks.

     

Muscle injury: Review of experimental models

Skeletal muscle is the most abundant tissue in the human body. Its main characteristic is the capacity to regenerate after injury independent of the cause of injury through a process called inflammatory response. Mechanical injuries are the most common type of the skeletal muscle injuries and are classified into one of three areas strain, contusion, and laceration. First, this review aims to describe and compare the main experimental methods that replicate the mechanical muscle injuries. There are several ways to replicate each kind of mechanical injury; there are, however, specific characteristics that must be taken into account when choosing the most appropriate model for the experiment. Finally, this review discusses the context of mechanical injury considering types, variability of methods, and the ability to reproduce injury models.