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PubMed2004

Screening for lung cancer: current status and future directions: Thomas A. Neff lecture.

Lung cancer is the number one cancer killer in North America. Currently, screening for lung cancer is not recommended. Therefore, patients will not receive a diagnosis until they present with symptomatic disease, which is usually advanced stage disease. Previous trials of screening with chest roentgenograms and sputum cytology have failed to show a decrease in lung cancer mortality. Some reports of screening with low-dose spiral CT scans have detected lung cancers at a smaller size (average size, 1.5 cm) than those usually detected by chest radiographs (mean size, 3.0 cm). Spiral CT scanning has been shown to detect between 58% and 85% of non-small cell lung cancers (NSCLCs) while they are in stage IA, and this compares favorably to the current medical practice, in which only 15% are detected as localized disease (Surveillance, Epidemiology, and End Results study data). This article summarizes the spiral CT screening data, and reviews some of the data related to screening with sputum cytology, sputum methylation, and autofluorescence bronchoscopy. Last, there is a brief discussion of some promising future strategies, with emphasis and data from studies presented at this Aspen Lung Conference.

Bronchoscopy↗
PubMed2006

Giles f. Filley lecture. Complex systems.

Physiologic systems in health and disease display an extraordinary range of temporal behaviors and structural patterns that defy understanding based on linear constructs, reductionist strategies, and classical homeostasis. Application of concepts and computational tools derived from the contemporary study of complex systems, including nonlinear dynamics, fractals and "chaos theory," is having an increasing impact on biology and medicine. This presentation provides a brief overview of an emerging area of biomedical research, including recent applications to cardiopulmonary medicine and chronic obstructive lung disease.

Biology↗
PubMed2006

Roger s. Mitchell lecture. Chronic obstructive pulmonary disease phenotypes and their clinical relevance.

Phenotype is defined as the outward physical manifestation of patients with chronic obstructive pulmonary disease (COPD); anything that is part of their observable structure, function, or behavior. As such, for patients with COPD, the time has come to move from a disease expressed solely by the degree of airflow limitation, to a much broader and resourceful characterization of COPD. Recent advances in the detection of specific clinical phenotypes, such as persistent hypoxemia, hyperinflation with inhomogeneous emphysema, frequent exacerbators, and patients with peripheral muscle dysfunction, are resulting in specific forms of approaches to include therapy that are affecting outcomes. Further, the investigation of the differential influence of gender on the development of COPD is finally catching our attention. In the area of basic science, we are beginning to understand different expressions of disease through genomics, proteomics, and metabonomics. Extensions of these findings and that of neglected aspects that may explain the clinical course of certain patients, such as their psychologic background, will certainly increase our understanding and provide more solid scientific rationale to the phenotypic characterization of patients with COPD. Further, such understanding will not only help explain the manifestations and course of the disease in particular patients but also help select for specific therapies. The hope is that, coupled with primary and secondary prevention, we can reverse the current epidemic and we can improve the well-being of patients affected by COPD.

Disease Progression↗
PubMedDate not supplied

Felix Hoppe-Seyler Lecture 1999. Cyclin dependent kinases and regulation of the fission yeast cell cycle.

The cyclin dependent kinases (CDKs), formed by complexes between Cdc2p and the B-cyclins Cig2p and Cdc13p, have a central role in regulating the fission yeast cell cycle and maintaining genomic stability. The CDK Cig2p/Cdc2p controls the onset of S-phase and the CDK Cdc13p/Cdc2p controls the onset of mitosis and ensures that there is only one S-phase in each cell. Cdc13p/Cdc2p can replace Cig2p/Cdc2p forthe onset of S-phase, suggesting that the increasing activity of a single CDK during the cell cycle is sufficient to drive a cell in an orderly fashion into S-phase and into mitosis. If S-phase is incomplete, then inhibition of Cdc13p/ Cdc2p prevents cells with unreplicated DNA from undergoing a catastrophic entry into mitosis. Control of CDK activity is also important to allow cells to exit the cell cycle and accumulate in G1 in response to nutritional deprivation and the presence of pheromone.

Awards and Prizes↗
PubMedDate not supplied

Felix Hoppe-Seyler Lecture 1996. Mechanisms of intracellular protein transport.

Discovery of the protein machinery of vesicle transport has followed the reconstitution of transport in a cell-free system, and established general mechanisms that underlie a broad variety of physiological processes, including cell surface growth, the biogenesis of distinct intracellular organelles, endocytosis, and the controlled release of hormones and neurotransmitters. Transport vesicles are formed as coat proteins assemble on membranes, are targetted by SNARE proteins, and fuse using a general mechanism involving SNAP proteins and the ATPase NSF.

Biological Transport↗
PubMed2006

RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture.

Papillary thyroid carcinoma (PTC) is frequently associated with RET gene rearrangements that generate the so-called RET/PTC oncogenes. In this review, we examine the data about the mechanisms of thyroid cell transformation, activation of downstream signal transduction pathways and modulation of gene expression induced by RET/PTC. These findings have advanced our understanding of the processes underlying PTC formation and provide the basis for novel therapeutic approaches to this disease.

Animals↗
PubMed1998

The Parkes Lecture. Heat and the testis.

The evidence for the lower temperature of the testes of many mammals is summarized, and the reasons suggested for the descent of the testes into a scrotum are discussed. Descriptions are given of the various techniques used for studying the effects of heat on the testis, whole body heating, local heating of the testes (by inducing cryptorchidism, scrotal insulation or immersion of the scrotum in a water bath), and heating of tissue or cell preparations in vitro. The effects of heat are discussed, effects on the testis (weight, histology, physiology, biochemistry and endocrinology), on the numbers and motility of spermatozoa in rete testis fluid and semen, on fertilizing ability of spermatozoa and on the subsequent development of the embryos produced when spermatozoa from heated testes are used to fertilize normal ova. The possible mechanisms for the damaging effects of heat are discussed, as well as the importance of heat-induced abnormalities in male reproduction in domestic animals and humans.

Animals↗
PubMed1999

The Amoroso Lecture. The human spermatozoon--a cell in crisis?

A great deal of evidence has accumulated in recent years to suggest that there has been a gradual increase in male reproductive pathology over the past 30-40 years, as evidenced by increased rates of testicular cancer and declining semen quality. The hypothesis is advanced that this phenomenon is causally related to the ability of male germ cells to generate reactive oxygen metabolites. When produced in low levels, such metabolites are thought to enhance sperm function by stimulating DNA compaction and promoting a redox-regulated cAMP-mediated pathway that is central to the induction of sperm capacitation. When produced in excessive amounts, the same metabolites stimulate DNA fragmentation and a loss of sperm function associated with peroxidative damage to the sperm plasma membrane. Free radical-induced mutations in the male germ line may also be involved in the aetiology of childhood cancer and recent increases in the incidence of seminoma. In light of these considerations, establishing the mechanisms for free radical generation by the male germ line and determining the factors that influence this activity are important objectives for future research in this area.

Adult↗
PubMed1999

The Parkes Lecture. Zona pellucida glycoprotein mZP3: a versatile player during mammalian fertilization.

All mammalian eggs are surrounded by a relatively thick extracellular coat, the zona pellucida (ZP), which facilitates fertilization of eggs by a single spermatozoon. The mouse egg ZP is constructed of only three glycoproteins, termed mZP1-3. Each of these glycoproteins consists of a unique polypeptide that is heterogeneously glycosylated with both asparagine-(N-)linked and serine/threonine-(O-)linked oligosaccharides. Polypeptides of ZP glycoproteins are highly conserved among mammalian species and are similar to polypeptides of egg vitelline envelope glycoproteins of fish, birds and amphibians. One of the mouse ZP glycoproteins, mZP3, serves as both a receptor for spermatozoa and an inducer of the acrosome reaction during fertilization. Free-swimming acrosome-intact spermatozoa recognize and bind to certain serine-(O-)linked oligosaccharides located close to the carboxy terminus of mZP3 polypeptide and, after binding, undergo the acrosome reaction (cellular exocytosis). In this review, in addition to the background information presented, results of recent experiments using homologous recombination to produce mZP3 null mice and site-directed mutagenesis to inactivate mZP3 as a sperm receptor and inducer of the acrosome reaction are presented and discussed.

Acrosome Reaction↗