Sunday, June 2, 2024

A Model for the organization of DNA in living organisms

 


This model was proposed in the 1970s

I must first remind the reader that the model I intend to postulate is purely speculative and is open to whatever criticisms and modifications that time and hard scientific evidence might demand. It seems to me that the basic strength of the scientific perspective is the use of the paradigm and the willing openness to allow empirical data to decide the ultimate usefulness of any conceptual model.

However, science like any other modern human institution has the tendency to become rigid in its outlook. I believe that at the present time there is a strong tendency to take a narrow and unbending stand concerning the evolution of life on the planet earth. No one who accepts the basic premise of scientific investigation is about to deny the existence of DNA, its inherent structure, and the role it plays in heredity. Also it is quite apparent that we as human beings coexist on the planet with a vast variety of living things each with its unique structures and adaptations. Various theories of evolution have attempted to explain the mechanism by which these forms have come into existence. Darwin, Mendel, and the brilliant work of modern molecular geneticists have elucidated the molecular structure and function of the actual genetic material. It has been clearly demonstrated how DNA by the very nature of its structure is capable of holding the biochemical information necessary for life; how it conserves this information, and how living things are able to call upon this information to organize the functions that are the definitive prerequisites for life. These mechanisms are not open to dispute since they represent hard data demonstrated over and over again.

However, it is my intention to show that there are certain explanations of phenomena that are strongly held but in fact rely on tenuous proofs. It is currently held that evolution has proceeded on planet earth through a process of spontaneous mutation of genetic material in which the resulting changes in characteristics of living forms are either rejected or reinforced by natural selection pressures. Allow me to give some examples. There exists now a variety of bacteria, Neisseria gonorrhoeae, that is the causative agent for the disease referred to as gonorrhea in humans that has become immune to penicillin. The argument to explain this event would be the following: a fortuitous mutation of the genetic material in this organism produced the ability to negate the effect of the antibiotic. This event was independent of the presence of penicillin in the environment of the organism. With this new characteristic the particular strain of bacteria that held the immunity of course would survive where its cohorts would perish. Hence the new natural condition selected for the organism with the immunity. This same rationale has been extended to encompass the entire evolution of living organisms on planet earth.

The contemporary view is that the information contained in the DNA is carefully conserved and fixed and is not generally subject to alteration by its environment except in the limited area of fortuitous mutational events. In my estimation A rigid model forbidding any sort of adaptive mechanism in the genetic material itself and if living structures actually adhered to such a model the planet earth would be probably be devoid of the richness and variety of the life that it in fact supports.

This perspective is not an original view of mine.  It is conceivable that within the organization of DNA there exists an inherent mechanism to allow for a non-random interaction between the environment and the structure of the information store.  It is with this thought in mind that I propose the following model:

1 -that there is a portion of the DNA that is rigidly fixed in information content in what is now referred to as genes in general and in the so-called introns in particular. Billions of years in the biosphere have established this information as being essential for life and substantial changes in this structure can prove deleterious.

2-there is a large portion of the DNA in organisms that has no apparent information content by nature of its seeming random and repetitive sequences. This DNA is far from trivial and some of this structure represents the basic language store from which the genetic material responds to environmental signals; allow me to elaborate.

Proteins, especially enzymes, are the intermediaries between the information stored in the DNA and the expression of this information into discrete characteristics. In point of fact discrete genes hold the information for the structure of discrete proteins. The genetic code has of course been definitely worked out. It is these proteins that act on the cellular environment of living things. Enzymes are specialized proteins and are responsible for the catalysis of all the diverse chemical reactions taking place within each and every living cell. Enzymes mediate cellular activity.

3 -The model I am proposing predicts the existence of quite another mechanism operating within the genetic material. The specificity of enzymes for their substrates has been well established. This specificity cannot be accidental but must rely on discrete and well-established chemical laws. In other words, there exists a particular relationship between amino acid sequences of enzymes and the exact structure of a particular enzyme allowing it to act upon a particular substrate, and also establishes the nature of that reactivity i.e. whether oxidative cleavage, reduction, synthesis etc.

This relationship will be found to be quite simple - computer analysis of amino acid sequences of different categories of enzymes i.e. proteases and oxidases as an example will reveal certain relationships. It is my prediction that it will eventually be shown that there exists particular patterns, arrangement and spacings of amino acids that give rise to certain classes of enzymes and that these patterns since they occur in proteins will be represented in the DNA of the gene having the information for the synthesis of that enzyme as is already understand.

It is my contention that the exact structure of a particular substrate contains enough information for the synthesis of a protein that can interact with it - there are only a limited number of ways cellular enzymatic systems can chemically modify substrates in its environment.  Examples of these are pathways for synthesis, degradation, oxidation or reduction, cleavage, methylation etc.  It is my contention that DNA sequences that correspond to the relationships between amino acid sequence and enzymatic activity are pre-existing within the seemingly random array of sequences within the genome that have no known purpose.   

Such arrays can be mobilized and activated by the appearance of new substrates in the cellular environment. Such a mechanism proposes the de-novo synthesis of a novel gene that has the information to create a novel enzyme to interact with the new substrate presented to the cellular environment.  This particular aspect of the model as of yet cannot fully explain the relationship between environmental change, the appearance of new substrates and enzymatic populations as related to gross characteristics. In multicellular organisms the degree of complexity is exceedingly high.

The above model describes a transient mechanism for adaptive change in genetic material .  In addition, I propose that there exists a mechanism for transferring these de-novo genes to the conserved population of DNA in other words into inheritable genes. If the environmental change persists then the new messenger RNA containing the information for the protein designed to interact with the novel substrate will exist over a prolonged time frame and therefore allowing reverse transcriptases the opportunity to integrate this new sequence within the genome.  It is at this stage that selection pressures play a significant role.

  • The following is a modification in part three of my proposition - dated July 19, 1982

Within the intervening sequences, the exons are composed of sequences of DNA that code for pieces of the primary sequence of proteins that are essential for determining the overall three-dimensional configuration of the resulting protein which in the case of an enzyme such as cytochrome P-450 or an antibody will also determine its specificity. Although these essential pieces can be fit together in innumerable ways there are only a finite number of mini sequences of amino acids probably containing highly conserved hydrophobic residues that produce configurational patterns resulting in active proteins.

The most essential feature of this model as I see it is that the capacity to respond to any new environmentally introduced signal i.e. to produce a novel protein with the required specificity that relies upon the existence of preformed genetic units, exons, that with the appropriate environmental signal can be recombined to allow for the synthesis of a de-novo protein. The advantage of this model is that it allows for more than merely a random selection process for the evolution of new biological activity.

The weakness of this model however lies with the fact that it rests upon the assumption that there exists a pre-existing mechanism that can be activated upon the appearance of a novel substrate and that can ultimately lead to the production of a particular sequence of amino acids and therefore into reproducible 3 dimensional configurations with discrete specificities that can bind to the new substrate.

However the existence or non-existence of such a mechanism is experimentally accessible either by direct synthesis of model sequences or sophisticated computer analysis of the many, many proteins in which both the three-dimensional configurations and primary sequences are already known. If such a language were indeed uncovered the possibilities would be endless for it would then be plausible to synthesize a protein de-novo with novel and predictable activity which in collaboration with genetic engineering could lead to the production of novel synthetic genes.

Wednesday, December 13, 2023

Exciting New Results in the Development of an Anti-Malaria Vaccine

 


An exciting recent development has been reported in the prestigious journal Science regarding the development of a anti-malaria vaccine that has been shown to substantially reduce childhood victims of this disease. This vaccine is referred to as RTS, S. or Mosquirix and made by GSK.

Analysis of the efficacy of this vaccine approved to combat the death of the young children demonstrated a 13% drop in mortality during a nearly 4 year duration. This result was reported by the World Health Organization (WHO). In addition it was also found that there was a 22% reduction in the incidence of severe malaria in children young enough to receive a three-shot series.

According to John Tanko Bawa, director of the malaria vaccine implementation at the Program for Appropriate Technology in Health (PATH) stated, “The RTS,S malaria vaccine is already saving lives.” Furthermore he noted that, “What we have seen is a considerable impact of a vaccine described as having modest efficacy.”

The results of this analysis is so impressive that it has been estimated that the mortality decline could ultimately save tens of thousands of lives if RTS,S, is more broadly utilized.

In regard to the actual mode of action of RTS,S vaccine, it binds to the circumsporozoite protein on the surface of P. falciparum parasite before it infects liver cells disrupting its life cycle so that it is unable to infect circulating red bloods where it exerts its deadly effect – a pre-erythrocytic vaccine.

This is a profoundly important development in regard to the control of the spread of malaria among susceptible human populations.

Friday, March 3, 2023

Breast Cancer Overview - 2023

 

Introduction

It is currently estimated that one in eight women (12.5%) in the United States will be diagnosed with breast cancer.  For example, In the year 2014 232,670 new breast cancer cases and 40,000 deaths were reported for women living in the United Sates. Age is the strongest risk factor for breast cancer. Surprisingly, breast cancer begins to rise in the third decade of life.  This unusual aspect of breast cancer, is postulated to be related to the effects of ovarian hormones – especially estrogen and progesterone - on breast tissue. More than 2/3 of all new cases occur after the age of 55 and women older than 65 have a relative risk greater than 4.0 when compared with those younger than 65.

For this reason, it is imperative that causative agents responsible for the transformation of normal breast tissue cells to a cancerous state be more fully understood; that women be encouraged to undergo the appropriate screening and health checkups; and that more anti-breast cancer therapies be developed to combat this disease.

Additional Risk Factors

In addition to the endogenous ovarian hormones as cited earlier, there are the following factors that may play a significant role in the etiology of breast cancer –

  • Genetic factors such as the BRCA1 and BRCA2 genetic mutations and family history of the disease pointing to genetic factors that are poorly understood.
  • High levels of HER2 (HER2+) – an epidermal growth factor –can trigger uncontrolled cell division in breast tissue.  TCHP is a combination drug treatment that includes docetaxel, carboplatin, trastuzumab, and pertuzumab. These are drugs that people take intravenously to kill cancer cells if they have early-stage HER2+ breast cancer.
  • Reproductive history
  • High dose radiation to the chest
  • High dose hormone therapy
  • Obesity
  • Alcohol Consumption
  • Environmental factors related to the abundance of carcinogenic compounds that permeate the environment.

Endogenous Estrogen Levels and the Etiology of Breast Cancer

The Data accumulated in the past few decades indicate that endogenous estrogens play a very important role in regard to the etiology of breast cancer.  For this reason it is important to understand how estrogens are produced and metabolized in the body.  Estrogen and Progesterone are steroid hormones, and the first step involving steroidogenesis in the human ovary is the transport of their precursor, cholesterol into the mitochondria.  This is followed by a number of enzyme-mediated steps that lead to the formation of Pregnenolone that is the precursor for all steroid hormones, and eventually to estrogen.

In premenopausal women, estradiol synthesized in the ovaries is the most predominant form; whereas in postmenopausal women, estrone is the most prevalent and is synthesized in the peripheral tissue.  Estrone is reversibly converted to estradiol through an enzyme-mediated reaction.  Testosterone, in turn, is converted to estradiol by the action of aromatase enzyme in the peripheral tissues.  Aromatase is the enzyme that mediates the rate-limiting step in the conversion of androgens like testosterone into estrogens.  On account of the paramount importance of this metabolic step, pharmaceuticals that can effectively block aromatase activity have proven to be important aspect of the treatment of estrogen-dependent diseases such as breast cancer, endometriosis, and endometrial cancer.

It has been well established that active genes within the DNA serve as molecular blueprints for the production of unique proteins.  The steps in chemical metabolism within all the cells in the human body are mediated by specific enzymes that act as highly specialized chemical catalysts.  Enzymes are proteins.  Without enzymes life on earth would not be possible.  The dictum, “one gene one enzyme” can be applied universally throughout life.

It is important to keep in mind that by the very nature of their integration into DNA, genes are inheritable.  It is not uncommon to find polymorphisms within genes that are slight variations in the structure of those genes and what is referred to as single nucleotide polymorphisms (SNPs) that represent a singular change in the gene.  These variations in genetic structure produce corresponding variations in the proteins that are encoded in the genes that are the blueprints for these proteins.

Given this overall view, genetic research in regards to breast cancer is guided by an investigation of the genes that encode the structure of the enzymes involved in estrogen production.  The driving motivation of some of this work is to find the answer to the following question – Could the polymorphisms and SNPs in the genes responsible for the production of estrogens that are found in breast cancer patients result in an over-production of estrogens?  Secondly, could this over-production trigger the onset of breast cancer?

Clinical data that reinforces the primacy of estrogens in the onset of breast cancer are the following:

  • Bilateral oophorectomy (ovary removal) significantly reduces breast-cancer risk, and that risk reduction is greater if the ovaries are removed earlier in life.
  • In addition, some of the well-established risk factors for breast cancer, including early onset of menarche (menstruation) (<12 years), late menopause (>55 years), nulliparity or having child late in life, are related to lifetime exposure of breast tissue to sex hormones.
  • Approximately 2/3 of breast tumors are estrogen receptor (ER) positive (ER+) and responsive to circulating estrogens, and that almost all ER negative (ER−) cases are resistant to endocrine therapy, it is important to elucidate the specific mechanisms by which estrogens are related to elevated breast cancer risk.

In fact, circulating primary hormones in postmenopausal women, increased circulating concentrations of estradiol, estrone, estrone-sulfate, and androstendione have been shown to correlate with higher breast cancer risk. A thorough analysis of 663 women who developed breast cancer and had not received any hormonal-based therapy, demonstrated that the risk of breast cancer significantly increased with higher endogenous levels of total estradiol, free estradiol, estrone, estrone-sulfate, androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and testosterone. Since this analysis was published, a few more prospective and case-control studies have been reported that have found similar results. It should be noted that the majority of populations studied were general populations with average breast cancer risk who were not taking any exogenous sex hormones.

In addition the levels of endogenous estrogens were studied in those patients that had a number of breast cancer risk factors including obesity, reproductive, demographic, and life style factors has been investigated by the Endogenous Hormones and Breast Cancer Collaborative Group in several studies. The results of these studies did not a show a statistical significance for the association between BMI (a metric whose value can be indicative of obesity) and breast cancer risk. However, in another cross-sectional analysis of 13 prospective studies by the same group, “estrogen and androgen levels were positively associated with obesity, smoking (15+ cigarettes daily) and alcohol consumption (20+g alcohol daily), and inversely linked with age.”

Although this summary does not include any data regarding the role of the level of endogenous androgens or progesterone in regard to the onset of breast cancer, the role of estrogens in the biology of breast cancer is very significant, and has led to the development of hormonal therapy medications as a way to limit the exposure of breast tissue to circulating estrogens. What follows is a more detailed look at these therapeutic approaches.

“Hormonal therapy medicines are used in four ways: (Jenni Sheng, MDJohns Hopkins University School of Medicine, Baltimore, MD)

“If the breast cancer is large and hormone receptor-positive, your doctor may recommend hormonal therapy before surgery to shrink the cancer. Treatments given before surgery are called neoadjuvant treatments, so hormonal therapy given this way is called neoadjuvant hormonal therapy.

 

“To reduce recurrence risk: If you’ve been diagnosed with early-stage hormone receptor-positive breast cancer, your treatment plan will include hormonal therapy after surgery and possibly other treatments to reduce the risk of the cancer coming back (recurrence). Treatments given after surgery are called adjuvant treatments, so hormonal therapy given this way is called adjuvant hormonal therapy.

“To stop advanced-stage cancer from growing: If you’ve been diagnosed with advanced-stage, hormone receptor-positive breast cancer, hormonal therapy can be used to help stop the cancer from growing.

“To reduce the risk of a first diagnosis: Hormonal therapy also can be used to reduce breast cancer risk in certain women who haven’t been diagnosed. Women with a much higher than average risk of breast cancer may take a hormonal therapy medicine preventively to reduce the risk of hormone receptor-positive breast cancer developing.

“How does hormonal therapy treat breast cancer?

Hormonal therapy medicines work in two ways:

  • by blocking estrogen production in the body

 

  • by blocking the effects of estrogen on breast cancer cells

“Hormonal therapy is not a treatment option for hormone receptor-negative breast cancer.

“It's important to know that hormonal therapy for breast cancer is different than hormone replacement therapy (HRT) for treating symptoms of menopause. HRT isn't used to treat breast cancer. HRT is taken by some women to treat troublesome menopausal side effects such as hot flashes and mood swings. HRT is used to raise estrogen levels that drop after menopause. HRT contains estrogen and can contain progesterone and other hormones. Hormonal therapy for breast cancer is exactly the opposite — it blocks or lowers estrogen levels in the body.

“Types of hormonal therapy to treat breast cancer

“There are three main types of hormonal therapy medicines used to treat breast cancer:

                     Aromatase inhibitors stop the body from making estrogen.

 

                     Selective estrogen receptor modulators (SERMs) block the action of estrogen on certain cells.

 

                     Selective estrogen receptor downregulators (ERDs) block the action of estrogen on certain cells.

 

                     Aromatase inhibitors

“Aromatase inhibitors lower estrogen levels by stopping the enzyme aromatase from changing other hormones into estrogen. In estrogen receptor-positive breast cancer, the hormone estrogen can stimulate the growth of breast cancer cells.

 

“There are three aromatase inhibitors used to treat breast cancer:

 

                     Arimidex (chemical name: anastrozole)

 

                     Aromasin (chemical name: exemestane)

 

                     Femara (chemical name: letrozole)

 

“Selective estrogen receptor modulators (SERMs)

“Selective estrogen receptor modulators (SERMs) block the effects of estrogen on breast cancer cells by sitting in the estrogen receptors. If a SERM is in the estrogen receptor, estrogen can’t attach to the cancer cell and the cell doesn’t receive estrogen’s signals to grow and multiply.

“There are three SERMs used to treat breast cancer:

 

                     Tamoxifen in pill form, also called tamoxifen citrate (brand name Nolvadex), and in liquid form (brand name: Soltamox)

 

                     Evista (chemical name: raloxifene)

 

                     Fareston (chemical name: toremifene)

 

“Selective estrogen receptor downregulators (SERDs)

“Selective estrogen receptor downregulators (SERDs), much like SERMs, block the effects of estrogen on breast cancer cells by sitting in the estrogen receptors. SERDs also lower the number of estrogen receptors and change the shape of breast cell estrogen receptors so they don’t work as well. There are two SERDs used to treat breast cancer:

 

                     Faslodex (chemical name: fulvestrant)

 

                     Orserdu (chemical name: elacestrant)

 

 

“Hormonal therapy side effects

Each hormonal therapy medicine may cause different side effects.

The most common side effects of the aromatase inhibitors are:

                     joint and bone pain

 

                     hot flashes

 

                     fatigue

 

                     weakness

“The most common side effects of the SERMs are:

                     hot flashes

 

                     vaginal discharge

 

                     mood swings

 

                     fatigue

 

“The most common side effects of the SERDs are:

                     nausea

 

                     bone pain

 

                     fatigue

 

                     hot flashes

 

                     injection site pain (for Faslodex only)

 

“For many years, women took hormonal therapy for five years after surgery for early-stage, hormone receptor-positive breast cancer. In most cases, the standard of care is five years of tamoxifen, or two to three years of tamoxifen followed by two to three years of an aromatase inhibitor, depending on menopausal status.

“Recent research has found that in certain cases, taking tamoxifen for 10 years instead of five years after surgery lowered a woman’s risk of recurrence and improved survival.

“In most cases, a post-menopausal woman diagnosed with early-stage, hormone receptor-positive breast cancer would take an aromatase inhibitor for five years after surgery to reduce the risk of recurrence. After that, if breast cancer had been found in the lymph nodes, called node-positive disease, a woman would take an aromatase inhibitor for an additional five years, for a total of 10 years of hormonal therapy treatment.

“Doctors call taking hormonal therapy for 10 years after surgery extended adjuvant hormonal therapy.

“Ovarian suppression or removal

“In pre-menopausal women, most of the estrogen in the body is made by the ovaries. In some cases, medicine may be used to stop the ovaries from functioning temporarily, called ovarian suppression or ovarian shutdown. Two medicines commonly used are:

                     Zoladex (chemical name: goserelin)

 

                     Lupron (chemical name: leuprolide)

 “These medicines are given as injections once a month for several months or every few months. They can be used alone or in combination with other hormonal therapy medicines to treat pre-menopausal women.

“Once you stop receiving the medicine, your ovaries usually begin functioning again. The time it takes for the ovaries to recover varies from woman to woman.

“Some women with a much higher than average risk of breast cancer may choose to have their ovaries removed, called prophylactic or preventive ovary removal, either before or after being diagnosed with breast cancer.”

This article is designed to summarize the known relationship between estrogen levels and the majority of breast cancers (ER+).  It is important to keep in mind that this area of scientific, medical and clinically-based research is constantly generating new data, and the findings presented above do not represent the last word on the understanding of this devastating illness.


Thursday, January 19, 2023

An approach to Cancer Treatment Combining Immunotherapy and Chemotherapy


Immunotherapy is an approach that focuses on and improving the body’s inherent capacity to attack tissue cells that have been transformed into cancerous cells. However, the current drawback of this approach is its inability to effectively distinguish the target cell from neighboring healthy cells. This is especially true for cancers that are derived from oncogene expression. Chemotherapy that has long been the mainstay of cancer treatment has a serious limitation of its own – actively growing cancer cells often develop a resistance to this kind of drug treatment.
Takmitsu Hattori and his colleagues at the Laura and Issac Perlmutter Cancer Center at New York University have attempted to overcome this impasse by developing a methodology that combines these two methodologies. Their approach is to effectively create a neoantigen, a hapten-peptide conjugate, which can preferentially combine with cancer cells and serve as a target for selective elimination.

These research scientists treated lung cancer with sotorasib – a drug that specifically targets KRAS – an oncogene that is involved in cell signaling pathways that are in involved in the control of cellular proliferation, cell development and cell death. Subsequently, they administered synthetically created antibodies designed to recognize the neoantigens that were the product of KRAS generated protein that had been bound to sotorasib. These administered antibodies were shown to have selectively killed even the sotorasib-resistant cells while leaving normal cells intact.


Sturcture of Sotorasib

These results show a great deal of promise in regard to adding to the repertoire of cancer treatment modalities.

 

Tuesday, January 17, 2023

A Vaccine for Respiratory Syncytial Virus (RSV) Virus May Soon be Available

This fall the general population has been plagued by an increased incidence of illnesses caused by three distinct viruses - COVID 19 (Coronavirus), Respiratory Syncytial Virus (RSV) and the Influenza Virus.

Infants and the elderly can be particularly impacted by severe illness with RSV. RSV is a negative-strand RNA virus. The term syncytial comes from the fact that host cells infected by the virus fuse and form large cells, syncytia. Although RSV infection is quite common and the respiratory issues it produces are usually not severe and of short durations, for infants and the elderly, it can produce severe and dangerous symptoms that may include difficulty breathing, abnormal respiratory sounds and coughing and wheezing that does not stop.




This fall, hospitalization of infants and the elderly with RSV has been particularly devastating. This reality has accelerated the development of a safe and effective vaccine against this virus. It has recently be reported in the prestigious journal, Science that two large trials have proven the efficacy of two vaccines against RSV infection. The data demonstrate that either vaccine can protect both infants and individuals over the age of 60. One of these vaccines also was found to protect infants for up to six months when given to women in the latter stage of pregnancy who could pass the antibodies induced by the vaccine to the fetus.

Some fifty years ago an initial attempt to develop a vaccine against RSV proved unsuccessful; a chemically inactivated intact virus was used in this particular vaccine. Not only did the vaccine fail to elicit a robust response to RSV infection, it also led to some fatalities and even worsened the symptoms of those treated from subsequent RSV infection.

It was reported that, “The new vaccines avoid this problem by relying on a key advance made by Barney Graham and co-workers at the National Institute of Allergy and Infectious Diseases in 2013”

They discovered that a key viral protein located on the surface of the viral membrane interacts with a particular receptor on the cell membrane of the target tissue and changes its shape allowing it to gain entry into the host cell. The team working on vaccine development led by Doctor Graham currently at the Morehouse School of Medicine (Atlanta, Georgia) used this knowledge to modify the viral protein so it remains fixed in this modified state. Once this modified antigen was introduced into the vaccine, it resulted in the production of higher levels of effective antibodies. This good news was established as a result of clinical trials run by GSK and Pfizer. This result illustrates how the knowledge gained from the study of viral biology can prove efficacious in the development of treatments against infection.




Friday, November 11, 2022

The Role of Microbial Metabolites in the Etiology of Colon Cancer

 It has been shown that a number cancers are caused by pathogens as the table below demonstrates


Disease

Causative Agent

 

T-cell Leukemia

HTLV-1 Human Retrovirus

Cervical Cancer

Human Papilloma Virus (HPV) 

Liver Cancer

Hepatitis B and Hepatitis C Virus (HBV and HCV)

Stomach Cancer

H.pylori – a Bacteria

 


This growing evidence involving the role of pathogens in the etiology of various cancers has led to numerous studies that look at a possible role of enteric microorganisms that naturally inhabit the human gut in the etiology of colon cancer.  The result of this kind of investigation has revealed that so-called genotoxic gut bacteria, whose metabolic product(s) can damage or mutate human DNA, may well be drivers of colorectal cancer (CRC) parthenogenesis.

Moreover, it has been recently reported in the prestigious journal, Science, by Dr. Cao and his colleagues that patients presenting with inflammatory bowel disease (IBD) – a condition that can lead to CRC – show the evidence of  diverse populations of  bacterial strains that can exert genotoxic activity.

 In this study, a particular bacterium, Monganella morganii, proved pf particular interest.  This organism is a Gramnegative bacterium that was discovered as an enriched population among individuals suffering from IBD and CRC.  The organisms of this type was identified as belonging to a class of bacteria that produce indolimines.  This is of special importance since indolimines have been found to promote tumor growth in mice.

 In addition to these findings, “Among the most well-described genotoxic bacteria are enterotoxigenic Bacteroides fragilis (ETBF) (3) that produce Bacteroides fragilis toxin (BFT), strains of Escherichia coli or other bacteria that produce colibactin (4), and Campylobacter jejuni strains that express cytolethal distending toxin (CDT) (5). The DNA-damaging properties of these strains and their toxins vary considerably, ranging from alkylating DNA interstrand cross-links for colibactin to deoxyribonuclease (DNase) activity for CDT (1, 4, 5). Intriguingly, ETBF and E. coli producing colibactin have been linked to IBD and CRC development using in vitro and in vivo models.”

The contribution of Dr. Chao and his colleagues made as cited in their study was the successful elucidation and characterization of the existence of some 18 strains of strains of enteric bacteria that actively produce genotoxins out of the 122 strains that were isolated for examination.

In the final analysis, the correlation between genotoxins found in the gut and the onset of IBD and CRC is of immense value and points to an avenue for future studies that may be of profound importance in regard to the ultimate prevention and treatment of these diseases.

 

Saturday, October 1, 2022

Immunotherapeutic Methodology Designed to Treat Lupus

Lupus is a disease in which the patient manifests certain symptoms that are a result of an autoimmune disease in which the patient’s immune system is producing antibodies against the individual’s own tissue(s).

The following is an overview of this condition as described on the website of the Mayo Clinic – (https://www.mayoclinic.org/diseases-conditions/lupus/symptoms-causes/syc-20365789)

“Lupus is a disease that occurs when your body's immune system attacks your own tissues and organs (autoimmune disease). Inflammation caused by lupus can affect many different body systems — including your joints, skin, kidneys, blood cells, brain, heart and lungs.

“Lupus can be difficult to diagnose because its signs and symptoms often mimic those of other ailments. The most distinctive sign of lupus — a facial rash that resembles the wings of a butterfly unfolding across both cheeks — occurs in many but not all cases of lupus.

“Some people are born with a tendency toward developing lupus, which may be triggered by infections, certain drugs or even sunlight. While there's no cure for lupus, treatments can help control symptoms.

Symptoms

Red, butterfly-shaped rash on nose and cheeks


 No two cases of lupus are exactly alike. Signs and symptoms may come on suddenly or develop slowly, may be mild or severe, and may be temporary or permanent. Most people with lupus have mild disease characterized by episodes — called flares — when signs and symptoms get worse for a while, then improve or even disappear completely for a time.

The signs and symptoms of lupus that you experience will depend on which body systems are affected by the disease. The most common signs and symptoms include:

Fatigue

Fever

Joint pain, stiffness and swelling

Butterfly-shaped rash on the face that covers the cheeks and bridge of the nose or rashes elsewhere on the body

Skin lesions that appear or worsen with sun exposure

Fingers and toes that turn white or blue when exposed to cold or during stressful periods

Shortness of breath

Chest pain

Dry eyes

Headaches, confusion and memory loss”



Autoimmune diseases as a class of ailments have been historically exceedingly difficult to treat. However, impressive inroads have been made in recent years using the rapidly advancing techniques embodies in immunotherapy. It has been reported in a recent issue of the prestigious scientific publication, Nature Medicine, from a medical team in Germany that five patients, four women and a man, have been successfully treated with their own immune cells that have been genetically engineered.

This technique involves isolating the patient’s own T cells – a subset of the immune system’s cellular repertoire – and genetically modifying them so that they would recognize those B cells that are involved in the autoimmune response unique to lupus and attack them by binding to a specific cell surface protein (antigen). This kind approach is referred to as T cell (CAR-T) therapy.

In this case, all five patients tolerated the therapy and their lupus-caused impaired organ function either improved or was resolved. As a result, these patients were no longer required to take immune-suppressive medication.

These results are quite encouraging and certainly are promising in regard to the treatment of lupus.