Weight of evidence evaluation for chemical-induced immunotoxicity for PFOA and PFOS: findings from an independent panel of experts.

Immunotoxicity is the critical endpoint used by some regulatory agencies to establish toxicity values for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). However, the hypothesis that exposure to certain per- and polyfluoroalkyl substances (PFAS) causes immune dysregulation is subject to much debate. An independent, international expert panel was engaged utilizing methods to reduce bias and "groupthink". The panel concluded there is moderate evidence that PFOS and PFOA are immunotoxic, based primarily on evidence from animal data. However, species concordance and human relevance cannot be well established due to data limitations. The panel recommended additional testing that includes longer-term exposures, evaluates both genders, includes other species of animals, tests lower dose levels, assesses more complete measures of immune responses, and elucidates the mechanism of action. Panel members agreed that the Faroe Islands cohort data should not be used as the primary basis for deriving PFAS risk assessment values. The panel agreed that vaccine antibody titer is not useful as a stand-alone metric for risk assessment. Instead, PFOA and PFOS toxicity values should rely on multiple high-quality studies, which are currently not available for immune suppression. The panel concluded that the available PFAS immune epidemiology studies suffer from weaknesses in study design that preclude their use, whereas available animal toxicity studies provide comprehensive dataset to derive points of departure (PODs) for non-immune endpoints. The panel recommends accounting for potential PFAS immunotoxicity by applying a database uncertainty factor to POD values derived from animal studies for other more robustly supported critical effects.

Deceptology in cancer and vaccine sciences: Seeds of immune destruction-mini electric shocks in mitochondria: Neuroplasticity-electrobiology of response profiles and increased induced diseases in four generations - A hypothesis.

From Rockefeller's support of patent medicine to Gates' patent vaccines, medical establishment invested a great deal in intellectual ignorance. Through the control over medical education and research it has created a public illusion to prop up corporate profit and encouraged the lust for money and power. An overview of data on cancer and vaccine sciences, the status of Americans' health, a survey of repeated failed projects, economic toxicity, and heavy drug consumption or addiction among young and old provide compelling evidence that in the twentieth century nearly all classic disease categories (congenital, inheritance, neonatal, or induced) shifted to increase induced diseases. Examples of this deceptology in ignoring or minimizing, and mocking fundamental discoveries and theories in cancer and vaccine sciences are attacks on research showing that (a), effective immunity is responsible for defending and killing pathogens and defective cancerous cells, correcting and repairing genetic mutations; (b) viruses cause cancer; and (c), abnormal gene mutations are often the consequences of (and secondary to) disturbances in effective immunity. The outcomes of cancer reductionist approaches to therapies reveal failure rates of 90% (+/-5) for solid tumors; loss of over 50 million lives and waste of $30-50 trillions on too many worthless, out-of-focus, and irresponsible projects. Current emphasis on vaccination of public with pathogen-specific vaccines and ingredients seems new terms for drugging young and old. Cumulative exposures to low level carcinogens and environmental hazards or high energy electronic devices (EMF; 5G) are additional triggers to vaccine toxicities (antigen-mitochondrial overload) or "seeds of immune destruction" that create mini electrical shocks (molecular sinks holes) in highly synchronized and regulated immune network that retard time-energy-dependent biorhythms in organs resulting in causes, exacerbations or consequences of mild, moderate or severe immune disorders. Four generations of drug-dependent Americans strongly suggest that medical establishment has practiced decades of intellectual deception through its claims on "war on cancer"; that cancer is 100, 200, or 1000 diseases; identification of "individual" genetic mutations to cure diseases; "vaccines are safe". Such immoral and unethical practices, along with intellectual harassment and bullying, censoring or silencing of independent and competent professionals ("Intellectual Me Too") present grave concerns, far greater compared with the sexual harassment of 'Me Too' movement that was recently spearheaded by NIH. The principal driving forces behind conducting deceptive and illogical medical/cancer and vaccine projects seem to be; (a) huge return of investment and corporate profit for selling drugs and vaccines; (b) maintenance of abusive power over public health; (c) global control of population growth via increased induction of diseases, infertility, decline in life-span, and death. An overview of accidental discoveries that we established and extended since 1980s, on models of acute and chronic ocular inflammatory diseases, provides series of the first evidence for a direct link between inflammation and multistep immune dysfunction in tumorigenesis and angiogenesis. Results are relevant to demonstrate that current emphasis on vaccinating the unborn, newborn, or infant would induce immediate or long-term immune disorders (eg, low birth weight, preterm birth, fatigue, autism, epilepsy/seizures, BBB leakage, autoimmune, neurodegenerative or digestive diseases, obesity, diabetes, cardiovascular problems, or cancers). Vaccination of the unborn is likely to disturb trophoblast-embryo-fetus-placenta biology and orderly growth of embryo-fetus, alter epithelial-mesenchymal transition or constituent-inducible receptors, damage mitochondria, and diverse function of histamine-histidine pathways. Significant increased in childhood illnesses are likely due to toxicities of vaccine and incipient (eg, metals [Al, Hg], detergents, fetal tissue, DNA/RNA) that retard bioenergetics of mitochondria, alter polarization-depolarization balance of tumoricidal (Yin) and tumorigenic (Yang) properties of immunity. Captivated by complex electobiology of immunity, this multidisciplinary perspective is an attempt to initiate identifying bases for increased induction of immune disorders in three to four generations in America. We hypothesize that (a) gene-environment-immune biorhythms parallel neuronal function (brain neuroplasticity) with super-packages of inducible (adaptive or horizontal) electronic signals and (b) autonomic sympathetic and parasympathetic circuitry that shape immunity (Yin-Yang) cannot be explained by limited genomics (innate, perpendicular) that conventionally explain certain inherited diseases (eg, sickle cell anemia, progeria). Future studies should focus on deep learning of complex electrobiology of immunity that requires differential bioenergetics from mitochondria and cytoplasm. Approaches to limit or control excessive activation of gene-environment-immunity are keys to assess accurate disease risk formulations, prevent inducible diseases, and develop universal safe vaccines that promote health, the most basic human right.

Cancer; an induced disease of twentieth century! Induction of tolerance, increased entropy and 'Dark Energy': loss of biorhythms (Anabolism v. Catabolism).

Maintenance of health involves a synchronized network of catabolic and anabolic signals among organs/tissues/cells that requires differential bioenergetics from mitochondria and glycolysis (biological laws or biorhythms). We defined biological circadian rhythms as Yin (tumoricidal) and Yang (tumorigenic) arms of acute inflammation (effective immunity) involving immune and non-immune systems. Role of pathogens in altering immunity and inducing diseases and cancer has been documented for over a century. However, in 1955s decision makers in cancer/medical establishment allowed public (current baby boomers) to consume million doses of virus-contaminated polio vaccines. The risk of cancer incidence and mortality sharply rose from 5% (rate of hereditary/genetic or innate disease) in 1900s, to its current scary status of 33% or 50% among women and men, respectively. Despite better hygiene, modern detection technologies and discovery of antibiotics, baby boomers and subsequent 2-3 generations are sicker than previous generations at same age. American health status ranks last among other developed nations while America invests highest amount of resources for healthcare. In this perspective we present evidence that cancer is an induced disease of twentieth century, facilitated by a great deception of cancer/medical establishment for huge corporate profits. Unlike popularized opinions that cancer is 100, 200 or 1000 diseases, we demonstrate that cancer is only one disease; the severe disturbances in biorhythms (differential bioenergetics) or loss of balance in Yin and Yang of effective immunity. Cancer projects that are promoted and funded by decision makers are reductionist approaches, wrong and unethical and resulted in loss of millions of precious lives and financial toxicity to society. Public vaccination with pathogen-specific vaccines (e.g., flu, hepatitis, HPV, meningitis, measles) weakens, not promotes, immunity. Results of irresponsible projects on cancer sciences or vaccines are increased population of drug-dependent sick society. Outcome failure rates of claimed 'targeted' drugs, 'precision' or 'personalized' medicine are 90% (± 5) for solid tumors. We demonstrate that aging, frequent exposures to environmental hazards, infections and pathogen-specific vaccines and ingredients are 'antigen overload' for immune system, skewing the Yin and Yang response profiles and leading to induction of 'mild', 'moderate' or 'severe' immune disorders. Induction of decoy or pattern recognition receptors (e.g., PRRs), such as IRAK-M or IL-1dRs ('designer' molecules) and associated genomic instability and over-expression of growth promoting factors (e.g., pyruvate kinases, mTOR and PI3Ks, histamine, PGE2, VEGF) could lead to immune tolerance, facilitating cancer cells to hijack anabolic machinery of immunity (Yang) for their increased growth requirements. Expression of constituent embryonic factors would negatively regulate differentiation of tumor cells through epithelial-mesenchymal-transition and create "dual negative feedback loop" that influence tissue metabolism under hypoxic conditions. It is further hypothesized that induction of tolerance creates 'dark energy' and increased entropy and temperature in cancer microenvironment allowing disorderly cancer proliferation and mitosis along with increased glucose metabolism via Crabtree and Pasteur Effects, under mitophagy and ribophagy, conditions that are toxic to host survival. Effective translational medicine into treatment requires systematic and logical studies of complex interactions of tumor cells with host environment that dictate clinical outcomes. Promoting effective immunity (biological circadian rhythms) are fundamental steps in correcting host differential bioenergetics and controlling cancer growth, preventing or delaying onset of diseases and maintaining public health. The author urges independent professionals and policy makers to take a closer look at cancer dilemma and stop the 'scientific/medical ponzi schemes' of a powerful group that control a drug-dependent sick society before all hopes for promoting public health evaporate.

Analyses of repeated failures in cancer therapy for solid tumors: poor tumor-selective drug delivery, low therapeutic efficacy and unsustainable costs.

For over six decades reductionist approaches to cancer chemotherapies including recent immunotherapy for solid tumors produced outcome failure-rates of 90% (±5) according to governmental agencies and industry. Despite tremendous public and private funding and initial enthusiasm about missile-therapy for site-specific cancers, molecular targeting drugs for specific enzymes such as kinases or inhibitors of growth factor receptors, the outcomes are very bleak and disappointing. Major scientific reasons for repeated failures of such therapeutic approaches are attributed to reductionist approaches to research and infinite numbers of genetic mutations in chaotic molecular environment of solid tumors that are bases of drug development. Safety and efficacy of candidate drugs tested in test tubes or experimental tumor models of rats or mice are usually evaluated and approved by FDA. Cost-benefit ratios of such 'targeted' therapies are also far from ideal as compared with antibiotics half a century ago. Such alarming records of failure of clinical outcomes, the increased publicity for specific vaccines (e.g., HPV or flu) targeting young and old populations, along with increasing rise of cancer incidence and death created huge and unsustainable cost to the public around the globe. This article discusses a closer scientific assessment of current cancer therapeutics and vaccines. We also present future logical approaches to cancer research and therapy and vaccines.

Safety concerns and hidden agenda behind HPV vaccines: another generation of drug-dependent society?

Analyses of data and hidden agenda behind repeated failed outcomes of cancer research and therapy, status of American health, safety concerns for HPV vaccines and future research considerations are summarized in this commentary. A closer look at cancer science reveals that highly power structure (system) in medical establishment vs. anti-system and chaos in cancer research ('medical/scientific ponzi schemes') is potent recipe for failed therapeutics that kills patients but generates huge corporate profit. American health status ranks last among other developed nations despite the highest amount that USA invests in healthcare. This is a wake-up call to make sure that the evil part of human being does not prevent the health services that the public deserves. Otherwise, 'it does not matter how many resources you have, if you don't know, or don't want to know, how to use them, they will never be enough'. Answer to cancer and improved public health is possible only by switching the current corruptive and abusive culture of 'who you know' to a culture of 'what you know'. Policy makers and professionals in decision making roles are urged to return to common sense and logics that our Forefathers used to serve the public.

Is cancer a severe delayed hypersensitivity reaction and histamine a blueprint?

Longevity and accumulation of multiple context-dependent signaling pathways of long-standing inflammation (antigen-load or oxidative stress) are the results of decreased/altered regulation of immunity and loss of control switch mechanisms that we defined as Yin and Yang of acute inflammation or immune surveillance. Chronic inflammation is initiated by immune disruptors-induced progressive changes in physiology and function of susceptible host tissues that lead to increased immune suppression and multistep disease processes including carcinogenesis. The interrelated multiple hypotheses that are presented for the first time in this article are extension of author's earlier series of 'accidental' discoveries on the role of inflammation in developmental stages of immune dysfunction toward tumorigenesis and angiogenesis. Detailed analyses of data on chronic diseases suggest that nearly all age-associated illnesses, generally categorized as 'mild' (e.g., increased allergies), 'moderate' (e.g., hypertension, colitis, gastritis, pancreatitis, emphysema) or 'severe' (e.g., accelerated neurodegenerative and autoimmune diseases or site-specific cancers and metastasis) are variations of hypersensitivity responses of tissues that are manifested as different diseases in immune-responsive or immune-privileged tissues. Continuous release/presence of low level histamine (subclinical) in circulation could contribute to sustained oxidative stress and induction of 'mild' or 'moderate' or 'severe' (immune tsunami) immune disorders in susceptible tissues. Site-specific cancers are proposed to be 'severe' (irreversible) forms of cumulative delayed hypersensitivity responses that would induce immunological chaos in favor of tissue growth in target tissues. Shared or special features of growth from fetus development into adulthood and aging processes and carcinogenesis are briefly compared with regard to energy requirements of highly complex function of Yin and Yang. Features of Yang (growth-promoting) arm of acute inflammation during fetus and cancer growth will be compared for consuming low energy from glycolysis (Warburg effect). Growth of fetus and cancer cells under hypoxic conditions and impaired mitochondrial energy requirements of tissues including metabolism of essential branched amino acids (e.g., val, leu, isoleu) will be compared for proposing a working model for future systematic research on cancer biology, prevention and therapy. Presentation of a working model provides insightful clues into bioenergetics that are required for fetus growth (absence of external threat and lack of high energy-demands of Yin events and parasite-like survival in host), normal growth in adulthood (balance in Yin and Yang processes) or disease processes and carcinogenesis (loss of balance in Yin-Yang). Future studies require focusing on dynamics and promotion of natural/inherent balance between Yin (tumoricidal) and Yang (tumorigenic) of effective immunity that develop after birth. Lawless growth of cancerous cells and loss of cell contact inhibition could partially be due to impaired mitochondria (mitophagy) that influence metabolism of branched chain amino acids for biosynthesis of structural proteins. The author invites interested scientists with diverse expertise to provide comments, confirm, dispute and question and/or expand and collaborate on many components of the proposed working model with the goal to better understand cancer biology for future designs of cost-effective research and clinical trials and prevention of cancer. Initial events during oxidative stress-induced damages to DNA/RNA repair mechanisms and inappropriate expression of inflammatory mediators are potentially correctable, preventable or druggable, if future studies were to focus on systematic understanding of early altered immune response dynamics toward multistep chronic diseases and carcinogenesis.

Environmental immune disruptors, inflammation and cancer risk.

An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E2, nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented.

Chronic Inflammation: Synergistic Interactions of Recruiting Macrophages (TAMs) and Eosinophils (Eos) with Host Mast Cells (MCs) and Tumorigenesis in CALTs. M-CSF, Suitable Biomarker for Cancer Diagnosis!

Ongoing debates, misunderstandings and controversies on the role of inflammation in cancer have been extremely costly for taxpayers and cancer patients for over four decades. A reason for repeated failed clinical trials (90% ± 5 failure rates) is heavy investment on numerous genetic mutations (molecular false-flags) in the chaotic molecular landscape of site-specific cancers which are used for "targeted" therapies or "personalized" medicine. Recently, unresolved/chronic inflammation was defined as loss of balance between two tightly regulated and biologically opposing arms of acute inflammation ("Yin"-"Yang" or immune surveillance). Chronic inflammation could differentially erode architectural integrities in host immune-privileged or immune-responsive tissues as a common denominator in initiation and progression of nearly all age-associated neurodegenerative and autoimmune diseases and/or cancer. Analyses of data on our "accidental" discoveries in 1980s on models of acute and chronic inflammatory diseases in conjunctival-associated lymphoid tissues (CALTs) demonstrated at least three stages of interactions between resident (host) and recruited immune cells: (a), acute phase; activation of mast cells (MCs), IgE Abs, histamine and prostaglandin synthesis; (b), intermediate phase; down-regulation phenomenon, exhausted/degranulated MCs, heavy eosinophils (Eos) infiltrations into epithelia and goblet cells (GCs), tissue hypertrophy and neovascularization; and (c), chronic phase; induction of lymphoid hyperplasia, activated macrophages (Mfs), increased (irregular size) B and plasma cells, loss of integrity of lymphoid tissue capsular membrane, presence of histiocytes, follicular and germinal center formation, increased ratios of local IgG1/IgG2, epithelial thickening (growth) and/or thinning (necrosis) and angiogenesis. Results are suggestive of first evidence for direct association between inflammation and identifiable phases of immune dysfunction in the direction of tumorigenesis. Activated MFs (TAMs or M2) and Eos that are recruited by tissues (e.g., conjunctiva or perhaps lung airways) whose principal resident immune cells are MCs and lymphocytes are suggested to play crucial synergistic roles in enhancing growth promoting capacities of host toward tumorigenesis. Under oxidative stress, M-CSF may produce signals that are cumulative/synergistic with host mediators (e.g., low levels of histamine), facilitating tumor-directed expression of decoy receptors and immune suppressive factors (e.g., dTNFR, IL-5, IL-10, TGF-b, PGE2). M-CSF, possessing superior sensitivity and specificity, compared with conventional markers (e.g., CA-125, CA-19-9) is potentially a suitable biomarker for cancer diagnosis and technology development. Systematic monitoring of interactions between resident and recruited cells should provide key information not only about early events in loss of immune surveillance, but it would help making informed decisions for balancing the inherent tumoricidal (Yin) and tumorigenic (Yang) properties of immune system and effective preventive and therapeutic approaches and accurate risk assessment toward improvement of public health.

Unresolved inflammation: 'immune tsunami' or erosion of integrity in immune-privileged and immune-responsive tissues and acute and chronic inflammatory diseases or cancer.

INTRODUCTION: Unresolved inflammation is loss of balance between two biologically opposing arms of acute inflammation, 'Yin' (tumoricidal) and 'Yang' (tumorigenic) processes that cause disruption of protective mechanisms of immune system. HYPOTHESIS: Unresolved inflammation-induced exaggerated expression of apoptotic and/or wound healing mediators lead to fundamental erosion ('immune tsunami' or 'immune meltdown') of integrity in tissues that are naturally immune-responsive (immune surveillance); or immune-privileged (immune tolerance). 'Immune tsunami' refers to end results of acute or chronic immune dysfunction leading to inflammatory diseases or cancer. Acute inflammatory diseases including drug-induced cancer cachexia, would fit features of 'immune meltdown' that are otherwise described for end results of age-associated diseases. Pathogens induce rapid destruction of vascular integrity, gain access to tissues and cause excessive expression of apoptotic factors leading to multiple organ failure (MOF). Significant disruptions of immunological barriers and response shifts lead to chronic neurodegenerative and autoimmune diseases, tumor growth, malignancies and angiogenesis and loss of natural immune response balances. EXPERT OPINION: Strategies to promote (stabilize) inherent properties of innate immune cells ('tumoricidal' versus 'tumorigenesis') that would influence polarization of adaptive immune (T or B) cells are key in reducing or preventing incidence of inflammatory and vascular diseases or cancer during aging process.

Inflammation, aging, and cancer: tumoricidal versus tumorigenesis of immunity: a common denominator mapping chronic diseases.

Acute inflammation is a highly regulated defense mechanism of immune system possessing two well-balanced and biologically opposing arms termed apoptosis ('Yin') and wound healing ('Yang') processes. Unresolved or chronic inflammation (oxidative stress) is perhaps the loss of balance between 'Yin' and 'Yang' that would induce co-expression of exaggerated or 'mismatched' apoptotic and wound healing factors in the microenvironment of tissues ('immune meltdown'). Unresolved inflammation could initiate the genesis of many age-associated chronic illnesses such as autoimmune and neurodegenerative diseases or tumors/cancers. In this perspective 'birds' eye' view of major interrelated co-morbidity risk factors that participate in biological shifts of growth-arresting ('tumoricidal') or growth-promoting ('tumorigenic') properties of immune cells and the genesis of chronic inflammatory diseases and cancer will be discussed. Persistent inflammation is perhaps a common denominator in the genesis of nearly all age-associated health problems or cancer. Future challenging opportunities for diagnosis, prevention, and/or therapy of chronic illnesses will require an integrated understanding and identification of developmental phases of inflammation-induced immune dysfunction and age-associated hormonal and physiological readjustments of organ systems. Designing suitable cohort studies to establish the oxido-redox status of adults may prove to be an effective strategy in assessing individual's health toward developing personal medicine for healthy aging.

'Yin and Yang' in inflammation: duality in innate immune cell function and tumorigenesis.

BACKGROUND: The two stages of the acute inflammatory process are apoptosis ('Yin') and wound healing or resolution ('Yang'). Inflammation defends the host against unwanted elements. OBJECTIVE/METHODS: To present a discussion of pleiotropic roles of innate immune cells possessing 'tumoricidal' and/or 'tumorigenic' properties in inflammation-induced dysfunction of the immune system and the genesis of chronic inflammatory diseases, hyperplasia, precancer/neoplasia or tumor and angiogenesis. RESULTS/CONCLUSIONS: Loss of maintenance of the balance between apoptosis and wound healing and co-existence of death and growth factors in tissues could create 'immunological chaos' with accumulation of 'immune response mismatches'. Unresolved inflammation plays a role in the genesis of chronic inflammatory and autoimmune diseases and cancer. Identification of accumulated 'mismatched' death and growth factors during the developmental phases of immune dysfunction in target tissues or cancer microenvironment presents challenges and opportunities for future studies on diagnosis, prevention and therapy of these diseases.

Standardizing cancer biomarkers criteria: data elements as a foundation for a database. Inflammatory mediator/M-CSF as model marker.

The purpose of this position article was to design a set of criteria (data elements) for a wide range of cancer biomarkers (CBs) in an attempt to standardize biomarkers features through a common language as a foundation for a database. Data elements are described as a set of generic criteria, which should characterize nearly all biomarkers introduced in the literature. Data elements were extracted from the review of prominent features that biomarkers represent within various categories. The extracted characteristics of biomarkers produced a short list of shared and unique generic features such as biological nature and history; stage/phase of study; sensitivity and specificity; modes of action; risk assessment; validation status; technology, and recommendation status for diversified biomarkers. To tailor data elements on specific markers, a cytokine, such as macrophage-colony stimulating factor (M-CSF), which has been proposed as a 'potentially suitable biomarker' for diagnosis of ovarian, lung, breast, pancreatic, and colorectal cancers, was selected as a Model biomarker. Small scale clinical studies suggested the superior usefulness of M-CSF compared with traditional markers for cancer detection. A key criterion for selecting Model marker and tailoring data elements for detection of cancer was the comparison of data on its specificity and sensitivity with traditional markers. The design of data elements for standardizing CBs criteria is considered a Research Tool and a foundation for developing a comprehensive CBs database useful for oncology researchers for a wide range of biomarkers. Validation, integration and proper packaging, data visualization and recommendation of suitability of CBs, by a panel of experts, for technology development are important challenging next steps toward developing a reliable database, which would allow professionals to effectively retrieve and study integrated information on potentially useful markers; identify important knowledge gaps and limitations of data; and assess state of technologies and commercialization of markers at a point of need. Appropriate use of integrated information on biomarkers in clinical practices would eventually account for more cost-effective characteristics of an individual's state of health.

Developmental phases of inflammation-induced massive lymphoid hyperplasia and extensive changes in epithelium in an experimental model of allergy: implications for a direct link between inflammation and carcinogenesis.

Direct evidence that inflammation is linked to carcinogenesis has yet to be established. Very few data are available on the developmental phases of inflammation-induced immune dysfunction that may lead to tumorigenesis. In a series of studies conducted in the 1980s and 1990s, an experimental model of acute and chronic inflammation was established in guinea pig conjunctiva by topical application of fluoresceinyl ovalbumin (FLOA) for up to 30 months. In this updated report, some of the findings are reanalyzed and expanded to identify that at lease 3 developmental phases were involved during the entire course of inflammatory responses including (1) an acute response (phase A) involving IgE-mast cell sensitization and degranulation; (2) an intermediate phase (phase B), a desensitization phenomenon and loss of mast cell function and neovascularization; (3) a chronic response (phase C) and induction of massive lymphoid hyperplasia, follicular formation with germinal centers, increased swollen goblet cells, extensive epithelial thickening and thinning, and angiogenesis. The results suggest evidence of a direct association between inflammation and the development of tumor-like lesions in lymphoid tissues and extensive changes in adjacent epithelia. Confirmation that inflammation induces irreversible changes in lymphoid and epithelial tissues leading to lymphoid tumorigenesis and/or carcinogenesis requires further studies. Understanding the developmental phases of immune dysfunction may provide unique opportunities for diagnosis and treatment of inflammatory diseases, autoimmune disorders, and cancers including lymphomas associated with Sjogren syndrome, squamous cell carcinoma of the conjunctiva, and other lymphomas or epithelial cancers. It is suggested that inflammatory mediators are ideal targets (biomarkers) for diagnosis, chemoprevention, and therapy for several cancers.