A Possible New Treatment Option for Patients with Acute Myeloid Leukemia (AML)

AML is the most common form of adult leukemia accounting for some twenty-five percent of adult patients with leukemia.  The standard protocol for treatment involves a shot-gun approach using non- selective chemotherapy to induce successful remission.   Although this clinical methodology has shown to be effective for most patients, other avenues of treatment are needed for those who prove refractory to the standard approach and to those patients who cannot endure high dose chemotherapy.

The biology of cancer cells has progressed dramatically since the complete sequencing of the human genome.  As a result, it has been clearly established that cancer is the result of genetic mutations that involve either/or those genes referred to as proto-oncogenes involved in normal cell division and tumor suppressor genes involved in the normal suppression of cell division The new era of cancer treatment involves the development of methodologies to specifically target these mutations either by developing specialized drugs to target these changes or mobilizing the immune system through targeted immunotherapy.

Dr. Anuradha Illendula and his colleagues from the Department of Molecular Physiology and Biological Physics at the University of Virginia in Charlottesville, using the mouse animal model,  have developed a small molecule referred to as AI-10-49 that effectively binds to a transcription factor subunit referred to as core bind factor β (CBFβ).

Molecular Structure of AI-10-49 -

  

   

These investigators were able to show that the use of A!-10-49 not only prolonged the survival of mice transplanted with leukemic cells without any observable toxic effects but was also able to inhibit the proliferation of a sub-type of human AML cells grown in culture.  These findings are of particular importance for this approach may serves as a model for development of drugs specifically targeting "uninhibited cell division resulting from genetically altered transcription factor function."

Extreme Winter Weather in the Lower Latitudes and Warming of the Arctic Ocean

For the past two winters, the continental United States has experienced harsh weather conditions with unusual amounts of precipitation in the form of snow.  Meteorologists have established that arctic-born weather has been directed to the Northeastern, Midwestern and even Southeastern continental United States as a result of a shift in the direction, depth and pattern of the jet stream described as “wavy.”

Dr. Jennifer Francis, a climatologist, and her colleagues at Rutgers University in collaboration with Dr. Steven Vavrus from the University of Wisconsin at Madison have published data establishing a connection between warming in the Arctic Ocean and the extreme winter weather in the lower latitudes. 

  

Ordinarily sea ice exerts an influence on global temperature by its ability to reflect back solar radiation into space on account of its whiteness through what is referred to as the albedo effect.  However, as a result of the gradual warming of the planet due to the accumulation of greenhouse gases, the temperature in the Arctic has increased at twice the rate as the rest of the earth.   This increased temperature is accelerating the melting of Artic sea ice.  As this sea ice melts, it reduces the albedo effect and results in increased warming and therefore the further melting of sea ice.  This cycle of increased warming is referred to as negative feedback.

 

It seems that this warming trend in the Arctic has disrupted normal climate conditions in the following way - cold air that is usually contained within the Arctic region by so-called “polar vortex winds” has moved southward into the mid-latitudes as a result of the high pressure that is a direct consequence of the enhanced melting of the sea ice.   Accordingly, the lower latitudes have experienced unusually extreme winter weather.

If this explanation is proven to be correct for seasonal aberrations in weather in the lower latitudes, then these changes would suggest a permanent alteration in weather patterns for the regions impacted.

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
Lung	6.9
Thyroid	1.08
Brain and Nervous System	.6
Pelvic Bone	.003
Laryngeal Cartilage	.00072

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. 

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 -

Class	Mode of Action	Example
Β-lactam	Inhibits bacterial cell wall biosynthesis	Penicillin
Aminoglycoside	Inhibits protein synthesis in Gram-negative bacteria  such as Streptomyces griseus	Neomycin
Macrolide	Inhibits protein synthesis in Gram-positive bacteria such as Streptococcus pneumoniae by preferentially binding to the  50S component of the bacterial ribosome	Erythromycin
Tetracycline	Inhbits protein synthesis by preferentially binding to the  30S component of the bacterial ribosome	Tetracycline
Fluoroquinolone	Irreversibly binds to and inactivates key enzymes that maintain bacterial DNA	Norfloxacin

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.

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.    

The Role of Endogenous Retroviruses in B Cell Immune Response to Foreign Antigens

Over the course of evolution, retroviral infections have left remnants of their genetic footprint imprinted within the human genome.  This is believed to play such an important role in human biology that the collective genomes from viruses that innocuously inhabit the human body is referred to as the virome.

The virome is a part of the larger community of microbiota that shares a commensal or symbiotic relationship with the human body.   Important participants in this community are the gut microorganisms that collectively breakdown food, produce important nutrients, inhibit the growth of deleterious organisms and stimulate immune responses.

The immune reaction to an invasive organism typically results in the production of specific antibodies by circulating B cells in response to antigens presented by the offending organism.  There are two arms to B cell involvement – one involving T cell dependent (TD) processes and the other a T cell–independent (TI) response.   This latter response is elicited through the innate immune sensing pathways in antibody production through specific B cell receptor (BCR) cross-linking

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Dr. Ming Zeng and his colleagues at the Center for the Genetics of Host Defense at the University of Texas Southwestern Medical Center in Dallas, Texas studied the involvement of endogenous retroviruses (ERV) in innate immune pathways.

In the course of their investigation, they exposed mice to protein molecules ordinarily found on the outer membranes of invasive bacteria and viruses.  These proteins are known to invoke the TI-mediated B cell response.   What they discovered was that immunization with these antigens resulted in the enhanced production of endogenous retrovirus (ERV) RNAs in the responding B cells.  Furthermore, this response apparently triggered a sustained reaction against the specific antigens through enhanced immunoglobulin M production.

These findings are of particular interest, for they offer further validation for the role of endogenous retroviruses in the immune response to invasive and deleterious microorganisms.  A well-functioning immune system is absolutely essential for the individual life of the organism and has been perfected during the evolution of life on the planet.

Prevention and Cure of Rotavirus Infection

Rotavirus (RV) is an RNA virus that causes diarrhea leading to severe dehydration in children and moderate intestinal discomfort in adults.  Mice have proven to be a useful animal model in studying infection of RV – the findings in mice are consistent with what is found in regards to human infection as well.  In this model, it has been shown that the level of infection of this virus can be ascertained by the appearance of the appropriate viral antigens in feces.    It has also been shown that the typical target for RV is the epithelial cells that line the small intestine.  

Furthermore, it seems that the predominant antigen that activates host cell gene expression as a defense against infection in intestinal epithelial cells (IECs) is the protein flagellin – a major component of bacterial flagella.  Flagellin seems to be the dominant activator of the immune system in the intestine.   It has been shown that flagellin-activated responses protect mice against bacterial infection, chemical insult and radiation.  In addition, administration of flagellin to mice seems to reduce the likelihood of infection with a cultured and attenuated form of RV.

Benyue Zhang and his colleagues at the Center of Inflammation, Immunity and Infection at the Institute of Biomedical Sciences Georgia State University, Atlanta Georgia, sought to discover if the administration of flagellin could serve as a prophylactic to protect mice from a highly contagious and pathogenic mouse RV strain.

The result of this study was very encouraging since the data demonstrated that not only did the administration of flagellin to mice prevent the onset of RV infection, but also cured infected mice who suffered from a chronic infection of the virus.  Interestingly, their findings have shown that this protective effect was not dependent upon adaptive immunological responses nor did the underlying mechanism require the participation of Interferon (IFN) – a substance known for its potent anti-viral properties.

 

The data did show, however, that the flagellin-initiated response required Toll-like receptor 5 (TLR5) and the involvement of Dendritic cells that produce interleukin-22 (IL-22).  Interleukins are members of a family of cytokines that play an essential role in immune responses.  The net result of these processes is the expression of a so-called “protective gene expression program” within intestinal epithelial cells.

These results may have public health implications in regards to rotavirus infections within the human population.   This is of particular importance since it is estimated that RV infections result in the deaths of approximately 600,000 children annually throughout the world.