Saturday, July 7, 2018

A Rationale for the High Mortality Rate of Pancreatic Cancer

Pancreatic cancer is an especially aggressive cancer with a high mortality rate – only 6% of those affected survive beyond 5 years.  It is also the fourth most common death from cancer worldwide.  Even under conditions when it was supposedly caught early on, the adenocarcinoma was successfully resected and the liver was deemed to be free of the presence of metastatic legions, patients, nonetheless suffered from subsequent metastatic disease.  The obvious conclusion from this observation is that there are latent metastases that persist and that are only detectable microscopically.
Furthermore, these latent metastases were believed to represent a balance between cancer cell growth and cancer cell death precipitated by the participation of the immune system in countering this growth.  More recent evidence has indicated, however, that quiescent single disseminated cancer cells (DCCs) are involved.  An explanation for this quiescence has been elusive: although involvement of the immune system is suspected.  Of course, the question remains that if the immune system is involved why is it not able to eliminate these DCCs entirely.
Douglas T. Fearon and his colleagues from the John Hopkins University School of Medicine studied the role of adaptive immunity in response to DCCs using the mouse model.  Both mice and humans with pancreatic duct adenocarcinoma (PDA) show DCCs resident in liver.  in both cases, these cells display unusual phenotypic characteristics – negative for cytokeratin (CK) 19 and major histocompatibility complex class I (MHCI).

According to the authors, “The absence of MHCI and the occurrence of specific CD8+ T cells in the genetically engineered mouse model of PDA, and possible in patients with PDA, suggested that DCCs may be selected by an anticancer immune response during the metastatic process.” This rationale is represented by the image below.

The lack of the expression of MHCI in DCCs is indicative of Endoplasmic Reticulum (ER) stress.  ER stress occurs within cells in certain pathological conditions when there is an accumulation of unfolded proteins.  Many proteins vital to cell viability are maintained in precise folded configurations.  If the mechanism responsible for maintaining proteins in the folded state is disrupted, this results in so-called ER stress.  In this model, quiescent DCCs lacking the expression of MHCI elude destruction by the CD8+ T cells.  These surviving DCCs can then grow out into full blown metastases if the immune response is subsequently disrupted.  In other words, it is the immune response that selects for quiescent DCCs.  To test this hypothesis, the investigators used a mouse model that would allow them to introduce immunogenic PDA cells into seeded mice livers that were pre-immunized and contained only quiescent DCCs lacking MHC1 and CK19.  Those recipients that were not pre-immunized developed macro-metastases.   As a result, a subpopulation of PDA with the phenotypic characteristics of DCCs were found in vitro and those cells proved to be the precursors of DCCs in vivo.

The authors of this study conclude that, “A PDA-specific adaptive immune response selects DCCs, in which the ER stress response accounts for both quiescence and resistance to immune elimination. Accordingly, outgrowth of DCCs to macro-metastases requires not only relief from the cancer cell–autonomous ER stress response, but also suppression of systemic immunity. Thus, the ER stress response is a cell-autonomous reaction that enables DCCs to escape immunity and establish latent metastases.”

This finding may prove important in developing more effect therapeutic strategies for combating pancreatic cancer that currently has an unacceptably high mortality rate.  

Saturday, June 23, 2018

Somatic Mosaicism

A central concept in modern biology has been that in any individual, all cells contain identical copies of the DNA that establishes the phenotype of that individual.  This assumption seemed so critical to the life of the organism that it has never been routinely tested.  Current research challenges this assumption.

There is a condition referred to as Long QT Syndrome (LQTS).  The genetic form of this disease can result in life-threatening arrythmias of the heart.  In spite of the genetic correlation, only 30 percent of the patients studied tested positive for the genetic markers associated with LQTS.
Stephen R. Quake and his colleagues at Stanford University performed a detailed mosaic DNA analysis of an infant with perinatal LQTS.  As a result of this analysis, it was discovered that 8% of the heart cells were capable of arrythmia.   To further study this intriguing result, 7500 patients presenting with LQTS were studied for mosaicism.

Somatic mosaicism represents the occurrence and subsequent proliferation of DNA variants in cell lineages resulting from differentiation after fertilization.  It is now believed that this mosaicism may play a causal role in a variety of human ailments.  Furthermore, in the case of LQTS, a variant in the sodium channel protein NA 1.5 that is encoded by the SCN5A gene located on chromosome 3 may be the causative factor.

According to the authors, “One report suggests that 6.5% of de novo mutations presumed to be germline in origin may instead have arisen from postzygotic mosaic mutation events, and recent genetic investigations directly interrogating diseased tissues in brain malformations, breast cancer, and atrial fibrillation have revealed postzygotic causal mutations absent from germline DNA. Pathogenic mosaic structural variation is also detectable in children with neurodevelopmental disorders. However, a consequential category of genetic variation has not been surveyed systematically in clinical or research studies of other human diseases.”
These surprising results not only challenge the accepted assumption regarding the homogeneity of genetic information in every cell of the individual, it also may have profound implications for the etiology and treatment of human disease.

Saturday, May 26, 2018

Impact of the Changing Climate on Rio Grande

The current state of the Rio Grande as reported in the New York Times

Friday, May 11, 2018

The FOXG1 Syndrome

The so-called “FOXG1 Syndrome,” is a rare birth defect in which the infant who presents with this condition is abnormally small at birth and during the early stage of neuronal development, the head grows slowly; this eventually leads to an unusually small head in early childhood – a condition referred to as microcephaly.  Upon close examination there are number of brain anomalies that are present in patients with this condition –
  • thin or underdeveloped corpus collosum that connects the left and right hemispheres of the brain
  • reduction in the number of anatomical folds (gyri) that are present on the brain’s surface
  • reduced amount of white matter in the brain.  White matter is composed of the Axon bodies of the neurons (see diagram below) that connect the cell bodies of the neurons that make up the so-called grey matter.

Structure of the  Human Neuron

On account of the profound anomalies in brain structure associated with this syndrome, affected individuals present with severe and wide-ranging intellectual disabilities.  These can include involuntary muscular movements, difficulties walking, sleep disturbances, seizures and general irritability.  In addition, abilities in speech and language are often seriously impaired adversely affecting social interactions.  The FOXG1 syndrome has been grouped as an autistic-like disorder.  Although the range of impairments evident closely mirrors that of Rett syndrome, it is now classified as a distinct disease.

In terms of the etiology the FOXG1 syndrome, it is believed to be caused by a mutation in the FOXG1 gene.  The normal gene encodes for a the Forkhead Box G1 protein (see diagram below).  this protein seems to play an essential role in brain development where it functions as a transcription factor that normally represses the activity of certain genes when they are not required.  Extensive research has demonstrated that the FOXG1 gene product is involved in the development of the brain in early embryonic life.  The particular site of action of this transcription factor is the telencephalon that ultimately develops into the cerebrum that is involved in so many critical high-order functions in the human brain including language, sensory perception, learning and memory.

Artistic Rendering of the Forkhead Box G1 Protein

Finally, Rett syndrome is also believed to be caused by a different mutation in the FOXG1 gene leading to a dysfunctional Forkhead Box G1 protein.  Since the origin of these diseases are genetic in origin and impose their deleterious effects during embryonic development, a cure may ultimately reside in the introduction of the normal FOXG1 gene in utero.  This may indeed become a reality at some future time.

Friday, April 20, 2018

A Possible Effective Treatment for Ulcerative Colitis Using a Monoclonal Antibody

Ulcerative Colitis is serious ailment that has been shown to be an auto-immune disease that involves an attack by the ulcerative colitis patient’s own immune system against intestinal tissue.   According to a description of this disease as shown on the Mayo Clinic website –

“Ulcerative colitis is an inflammatory bowel disease (IBD) that causes long-lasting inflammation and ulcers (sores) in your digestive tract. Ulcerative colitis affects the innermost lining of your large intestine (colon) and rectum. Symptoms usually develop over time, rather than suddenly.

“Ulcerative colitis can be debilitating and can sometimes lead to life-threatening complications. While it has no known cure, treatment can greatly reduce signs and symptoms of the disease and even bring about long-term remission.

“Ulcerative colitis symptoms can vary, depending on the severity of inflammation and where it occurs. Signs and symptoms may include:
·         Diarrhea, often with blood or pus
·         Abdominal pain and cramping
·         Rectal pain
·         Rectal bleeding — passing small amount of blood with stool
·         Urgency to defecate
·         Inability to defecate despite urgency
·         Weight loss
·         Fatigue
·         Fever
·         In children, failure to grow

“Most people with ulcerative colitis have mild to moderate symptoms. The course of ulcerative colitis may vary, with some people having long periods of remission.”

As stated above, this disease has no known cure.  However, there is strategy that is being investigated by Wendy J. Komocsar. and her colleagues in the laboratories of Eli Lilly and Company, Indianapolis, IN that utilizes the production of a monoclonal antibody that blocks the activity of BAFF.  BAFF is a natural B-cell activating factor – this factor effectively enhances B-cell survival.  B cells are a subset of the immune repertoire of circulating lymphocytes that are responsible for the production of antibodies.  In addition, it has been demonstrated that the overexpression of BAFF results in severe autoimmune disorders in mice.  Furthermore, elevated levels of BAFF have been shown to be present in some patients with autoimmune diseases.  The monoclonal antibody that has bee produced that blocks BAFF is a potential drug referred to as tabalumab.

This type of approach may provide the potential for providing relief for individual’s suffering from a variety of autoimmune disorders.

Tuesday, February 27, 2018

The Molecular Biology of Celiac Disease

Celiac disease is a so-called, “autoimmune disease” that impacts an estimated one percent of the population.  An auto-immune disease is caused by an individual’s immune system attacking its own tissue.  Other examples of diseases that fit this classification are multiple sclerosis (MS), pemphigus, rheumatoid arthritis and systemic lupus.

In Celiac disease, the tissue that is impacted involves the microscopic villi that line the lumen of the small intestine.  These structures provide the surface area through which digested nutrients are absorbed (see image below).  The patient with celiac disease presents with unexplained loss of weight and fatigue, anemia and constipation for example.  The destruction of these highly complex structures is irreversible; if, this condition is left untreated, it can be deadly.

The trigger for this auto-immune response is the presence of gluten - a protein found in wheat and related plants.  Gluten is a protein that is prevalent in Western diets.  In addition, research studies have demonstrated that the agent (antigen) that induces the autoimmune response is not the intact gluten protein but the protein after it is modified by the enzyme transglutaminase 2 (TG2) within the small intestine.  It seems that in normal tissues, although TR2 is an abundant enzyme, it exists primarily in the inactive state.
Chaitan Khosla and his colleagues at the University of California at Stafford have recently demonstrated that there is a cellular enzyme protein 57 (ERp57) that inactivates TG2.  Normally, ERp57 is involved in the process of protein folding within the cell.  Furthermore, it has been established that ERp57 inactivates TG2 outside the cell within the extra-cellular environment.  These data suggest that the etiology of celiac disease may relate to the functionality of ERp57.

These findings are significant; for, a more detailed understanding of the biological chemistry of celiac disease may open avenues of therapy that have heretofore remained elusive. 

Saturday, February 17, 2018

Stem Cells and the Risk of Atherosclerotic Cardiovascular Disease

Atherosclerosis is a condition often associated with age that involves a narrowing of the lumen of the arteries usually associated with age (see image below).  This condition often leads to coronary heart disease.  Traditionally there are a number of risk factors that are generally associated with this syndrome – high blood pressure (hypertension), high cholesterol, heredity, life style, diet etc.  However, a significant percentage of those individuals that show evidence of atherosclerosis have no known risk factors.  Research done by Dr. Siddhartha Jaiswal and his colleagues that has been published in the New England Journal of Medicine (July, 2017) sheds significant light on the possible etiology of this perplexing reality.

Within the bone marrow, reside stem cells that are so-called, pluripotent cells; they are responsible for the production of the body’s complement of immune-competent cells such as red blood cells, white blood cells including lymphocytes, neutrophils etc.  It has been well documented that over the lifetime of the individual these stem cell undergo mutations that can lead to blood – hematopoietic – cancers such as leukemia.
According to Jaiswal, “Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer.”

Jaiswal and his associates now have evidence that CHIP may be the underlying cause of atherosclerotic cardiovascular disease of no known etiology.  The results of their studies indicate that the presence of CHIP in the cell population of circulating blood was associated with a near doubling of the incidence of atherosclerotic cardiovascular disease.  Furthermore, the common mutations that were present in CHIP were found to be in the genes DNMT3A, TET2 AND ASXL1.  These genetic mutations have also been shown to be associated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).   These clones seem to be more prevalent with age – more that 10% of persons older than 70 years carry such a mutation.

This finding is significant in that it shed further light upon the etiology of atherosclerosis.