Saturday, February 28, 2015

The Frequency of Various Types of Cancers Explained

For more than a century, the medical world has known that certain kinds of cancers are far more prevalent than others.   The question, of course, that comes to mind is why is this so?  There has been much speculation concerning the answer to this important question.

Drs. Cristian Tomasetti and Bert Vogelstein form the Division of Biostatistics and Bioinformatics at the Department of Oncology at the Sidney Kimmel Cancer Center at John Hopkins University School of Medicine and the Department of Biostatistics at the John Hopkins Bloomberg School of Public Health in Baltimore MD conducted an exhaustive statistical analysis of patient data.  The following represents a summary of their results.

 The table below shows the relative lifetime risk of a number of different types of cancers.
Cancer by Tissue Type
Percentage of Lifetime Risk of Cancer
Brain and Nervous System
Pelvic Bone
Laryngeal Cartilage

Although some of these differences can be associated with certain risk factors such a smoking and alcohol use, ultraviolet light exposure and human papilloma virus (HPV) infection, such etiology only applies to specific populations.  In addition, environmental factors cannot explain the wide differences found in lifetime risks involving cancers of the alimentary tract – esophagus .51%, large intestine 4 82%, small intestine .20% and stomach .86%.
Interestingly, cancers of small intestine are three times less common than brain cancers even though the epithelial cells of the small intestine are far more exposed to environmentally dangerous substances than brain cells that are protected by the so-called blood –brain barrier.
Another factor that is often cited to explain differences in risk of various cancers is inherited genetic variation.  The statistical data shows, however, that this risk factor accounts for only between 5 and 10 percent of the etiology of cancer.

Therefore, there must be another cause that accounts for the wide variability shown in the table above.  The investigators went on to demonstrate that a very close correlation (81%) exists between the lifetime risk for a given cancer and the, “total number of divisions of the normal self-renewing cells (stem cells) maintaining the tissue’s homeostasis.”   From this perspective, it is the probability of sustaining deleterious random genetic mutations that transform a cell into a cancerous state that increases with the number of cell divisions of tissue-specific stem cells.

This may prove to be a very important finding in regards to understanding the etiology of cancer. 

Friday, February 13, 2015

A Promising New Class of Antibiotics

As mentioned in an earlier report, the current classes of antibiotics (See table below) being utilized to fight infection are no longer effective in regards to certain diseases, especially since many pathogenic organisms have developed an effective immunity against them. 

Classes of Antibiotics Currently in Use -

Mode of Action
Inhibits bacterial cell wall biosynthesis
Inhibits protein synthesis in Gram-negative bacteria  such as Streptomyces griseus
Inhibits protein synthesis in Gram-positive bacteria such as Streptococcus pneumoniae by preferentially binding to the  50S component of the bacterial ribosome
Inhbits protein synthesis by preferentially binding to the  30S component of the bacterial ribosome
Irreversibly binds to and inactivates key enzymes that maintain bacterial DNA

Note: Antibiotics are of no use in treating viral infections since the biology of the virus is markedly different than that of bacterial agents.

There is, however, some basis for renewed optimism in regard to this global public health concern.  Most antibiotics currently being utilized are natural products produced by cultured soil micro-organisms.  For varied reasons, some economic in nature, the synthetic production of antibiotics has been unable to adequately supply new and effective classes of antibiotics.  Uncultured bacteria, on the other hand, although large in number, have been an untapped resource for new antibiotics.

Dr  Losee Ling and his colleagues at the Novobiotic Team,  NovoBiotic Pharmaceuticals, LLC.  767C Concord Ave, Cambridge, MA have developed specific methodologies to grow uncultured organisms thereby opening up a vast new resource.  As a result of an exhausted screening of uncultured bacteria,  they discovered a new antibiotic that they have called teixobactin (see the structure below).

Teixobactin acts by inhibiting cell wall synthesis.  It  accomplishes this by binding to highly conserved constituents of the bacterial cell wall and, in this way, effectively interfering with cell wall synthesis resulting in bacterial cell death.  The investigators were able to demonstrate that no resistant strains were produced when teixobactin was used to undermine the growth of both Staphylococcus aureus and Mycobacterium tuberculosis- pathogens responsible for Staphylococcus infections and Tuberculosis, respectively .   According to Dr. Ling, “The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.”

This is a very exciting development in regards to global public health.

Wednesday, February 4, 2015

How Cells Overcome Oxidative Stress

At some point in the evolutionary past, living organisms began to use molecular oxygen in cellular respiratory metabolic pathways and therefore gained access to increased amounts of energy to support life.  This was especially important in the evolution of complex multi-cellular organisms.    Along with this new capability came the issue of dealing with the harmful by-products of oxidative respiration.  The most detrimental of these are reactive oxygen species (ROS) that are produced in the mitochondria – those organelles that generate most of the energy required for cellular processes within eukaryotic cells.

ROS can produce oxidative damage and have been shown to be involved in a number of serious human pathologies including Alzheimer’s, cancer, diabetes and Parkinson’s.  These reactive molecular species are also involved in cellular senescence and cell death.
In response to this threat - referred to as oxidative stress - cells have developed mechanisms designed to minimize the damage.   the ROS defense system localized in the mitochondria transforms highly reactive and potentially destructive superoxide anions (O2--)  to hydrogen peroxide (H2O2) that is subsequently broken down to water by ubiquitous peroxidase enzymes that use reduced glutathione (GSH) as their substrate.  Given the essential role that GSH plays in this mechanism, it is crucial that appropriate levels of this substance are maintained.   A key enzyme that is employed in providing high levels of GSH is the nicotinamide nucleotide transhydrogenase (TH) enzyme.

Dr. Leung and his colleagues at the Department of Integrative Structure and Computational Biology at the Scripps Research Institute in La Jolla CA studied the three dimensional structure of TH and elucidated its mechanism of action.  This kind of information is important in so far as it increases the overall understanding of how cells cope with oxidative stress.