Epistemology of the Origin of Cancer II: Fibroblasts Are the First Cells to Undergo Neoplastic Transformation.

Background/aims: Many questions in cancer biology remain unanswered. Perhaps the most important issues remaining to be addressed focus on the molecular basis of carcinogenesis. Today's cancer focus lies on genetics and gene expression, which is unlikely to explain the true cause of most cancers or lead to a cure.

Reversibility in male idiopathic osteoporosis possible.

Summary: A 44-year-old athletic man presented in 2009 with severe low back pain. Dual-energy x-ray absorptiometry revealed severe osteoporosis; serum testosterone was 189 ng/dL while serum estradiol (E2) measured by liquid chromatography/mass spectrometry was 8 pg/mL. DNA was extracted and sequenced from a blood sample from the patient since his maternal first cousin also had low bone mass and both patients were screened for aromatase dysfunction by PCR analysis for the CYP19A1 gene, which encodes aromatase.

Physics Essentials Enable Deeper Understanding in Signaling and Crosstalk of the Carcinogenesis Paradigm "Epistemology of the Origin of Cancer".

Radioactivity and radiation-induced mutations are believed to be primary causal examples of cancer-initiating events (stimulus). The assumption that an increase in cancer risk develops from any amount of radiation gave rise to the linear no-threshold model. This also led to the assumption that cancer is caused by somatic mutations as described by the somatic mutation theory.

Somatic Mutation Theory - Why it's Wrong for Most Cancers.

Hysteron proteron reverses both temporal and logical order and this syllogism occurs in carcinogenesis and the somatic mutation theory (SMT): the first (somatic mutation) occurs only after the second (onset of cancer) and, therefore, observed somatic mutations in most cancers appear well after the early cues of carcinogenesis are in place. It is no accident that mutations are increasingly being questioned as the causal event in the origin of the vast majority of cancers as clinical data show little support for this theory when compared against the metrics of patient outcomes. Ever since the discovery of the double helical structure of DNA, virtually all chronic diseases came to be viewed as causally linked to one degree or another to mutations, even though we now know that genes are not simply blueprints, but rather an assemblage of alphabets that can, under non-genetic influences, be used to assemble a business letter or a work of Shakespearean literature.

Genomics, microRNA, epigenetics, and proteomics for future diagnosis, treatment and monitoring response in upper GI cancers.

One major objective for our evolving understanding in the treatment of cancers will be to address how a combination of diagnosis and treatment strategies can be used to integrate patient and tumor variables with an outcome-oriented approach. Such an approach, in a multimodal therapy setting, could identify those patients (1) who should undergo a defined treatment (personalized therapy) (2) in whom modifications of the multimodal therapy due to observed responses might lead to an improvement of the response and/or prognosis (individualized therapy), (3) who might not benefit from a particular toxic treatment regimen, and (4) who could be identified early on and thereby be spared the morbidity associated with such treatments. These strategies could lead in the direction of precision medicine and there is hope of integrating translational molecular data to improve cancer classifications.

Acrodermatitis Enteropathica: A Novel SLC39A4 Gene Mutation in a Patient with Normal Zinc Levels.

Acrodermatitis enteropathica (AE) is a rare disease that results from a defective gene, SLC39A4, and is characterized by dermatitis, alopecia, and diarrhea. We report a case of AE presenting with only periorificial and acral dermatitis in which genetic testing revealed two novel compound heterozygous missense mutations for SLC39A4. This case demonstrates that not all AE mutations alter zinc transporters in the same manner and highlights the phenotypic variability of AE.

Cell-cell communication in the tumor microenvironment, carcinogenesis, and anticancer treatment.

The delineation of key molecular pathways has enhanced our knowledge of the biology of tumor microenvironment, tumor dissemination, and carcinogenesis. The complexities of cell-cell communication and the possibilities for modulation provide new opportunities for treating cancers. Cells communicate by direct and indirect signaling.

Epistemology of the origin of cancer: a new paradigm.

Background: Carcinogenesis is widely thought to originate from somatic mutations and an inhibition of growth suppressors, followed by cell proliferation, tissue invasion, and risk of metastasis. Fewer than 10% of all cancers are hereditary; the ratio in gastric (1%), colorectal (3-5%) and breast (8%) cancers is even less. Cancers caused by infection are thought to constitute some 15% of the non-hereditary cancers.

Imagine a world without cancer.

Background: Since the "War on Cancer" was declared in 1971, the United States alone has expended some $300 billion on research, with a heavy focus on the role of genomics in anticancer therapy. Voluminous data have been collected and analyzed. However, in hindsight, any achievements made have not been realized in clinical practice in terms of overall survival or quality of life extended.

Xeroderma pigmentosum family support group: Helping families and promoting clinical initiatives.

The past two decades of research into Xeroderma pigmentosum (XP), an autosomal recessive disease, has been marked by significant progress in understanding the molecular basis of this rare disease. More importantly, especially from the perspective of the affected families, is that this knowledge has been applied to diagnose the condition both in utero as well as in the very early days of life. The eight known XP genes and their different phenotypes present a number of challenges that the XP Workshop sponsored by the NIH in 2010 has highlighted.

Is pegylated interferon superior to interferon, with ribavarin, in chronic hepatitis C genotypes 2/3?

Over the past decade, significant improvements have been made in the treatment of chronic hepatitis C (CHC), especially with the introduction of combined therapy using both interferon and ribavarin. The optimal dose and duration of treatment is still a matter of debate and, importantly, the efficacy of this combined treatment varies with the viral genotype responsible for infection. In general, patients infected with viral genotypes 2 or 3 more readily achieve a sustained viral response than those infected with viral genotype 1.

Is benzene exposure from gasoline carcinogenic?

This article questions the basis for benzene as the carcinogenic surrogate in deriving health risk-based 'clean-up levels' for gasoline-impacted soil and groundwater at leaking underground storage tank properties. The epidemiological evidence suggests that acute myelogenous leukemia (AML) associated with chronic occupational benzene exposure can be best described by sigmoid dose-response relationships. A review of the molecular toxicology and kinetics of benzene points to the existence of threshold mechanisms in the induction of leukemia.

Acrodermatitis enteropathica: zinc therapy and possible identification of a carrier state through multiple hair zinc analyses over three decades.

We report on the successful use of repeated hair analyses over three decades to monitor zinc and copper status in two siblings with Acrodermatitis enteropathica who were treated with oral zinc sulfate beginning in 1975. Furthermore, we report for the first time that analysis of zinc in hair over a 30-yr period allows for the identification of individuals who might be heterozygous carriers of this autosomal recessive disease and who, therefore, would be expected to have hair zinc levels intermediate between normal, healthy individuals and those with Acrodermatitis enteropathica. Zinc treatment of the two patients with Acrodermatitis enteropathica resulted in remission of the signs and symptoms of the disease within the first month of therapy.

Positive inotropic and lusitropic effects of triiodothyronine in conscious dogs with pacing-induced cardiomyopathy.

Background: The effects of triiodothyronine (T3) on systemic hemodynamics, myocardial contractility (preload recruitable stroke work slope; Mw), and left ventricular (LV) isovolumic relaxation (time constant; tau) were examined before and after the development of pacing-induced cardiomyopathy in conscious dogs.

Methods: Dogs (n = 8) were chronically instrumented for measurement of aortic and LV pressure, dP/dtmax, subendocardial segment length, and cardiac output. Dogs received escalating doses (0.

Assessing health risks associated with DDT residues in soils in California: a Proposition 65 case study.

Population growth in California has increased the pressure to convert agricultural land to commercial, industrial, or residential uses. In the ensuing property transactions, buyers and sellers must address the presence of toxic materials in soils such as pesticides, several of which are known to the State of California to cause cancer under Proposition 65. While this statute does not specifically address soil contaminants, the potential scope of its enforcement is sufficiently broad that owners of former agricultural properties may be obliged to provide warning of exposure to potential buyers, occupants, or construction workers about exposure to residues in soil from pesticide applications.

On the carcinogenicity of cadmium by the oral route.

Cadmium and cadmium compounds are carcinogenic both by inhalation and by injection. For purposes of risk assessment, a prudent public health approach has been that, if a chemical has been demonstrated to be carcinogenic by one route, it should be considered carcinogenic by all routes. This policy has been questioned for several toxic metals including cadmium.

Chemicals and environmentally caused diseases in developing countries.

This chapter discusses international aspects of diseases resulting from exposure to chemical pollutants in the environment, with an emphasis on developing countries. These countries share many of the same problems of air, water, and pesticide pollution that face the more industrialized countries. In developing countries, however, the problems are compounded by a number of unique situations, viz.

The protective effects of glutathione against methylmercury cytotoxicity.

Mouse neuroblastoma cells exposed to 2.5 and 5.0 microM methylmercury for 24 h appeared rounded with the loss of processes.

Selenium modulates peroxidation in the absence of glutathione peroxidase in Musca domestica.

Adult houseflies fed a low-selenium diet showed a 73% decrease in total Se compared to those given 1.0 ppm Se in their drinking water. This decrease was associated with a 84.

A comparison of the effects of dietary cadmium on heart and kidney antioxidant enzymes: evidence for the greater vulnerability of the heart to cadmium toxicity.

This study demonstrates the greater susceptibility of the heart as compared to the kidney to cadmium in the presence of high dietary selenium. Male weanling rats were fed an adequate-copper low-selenium feed supplemented with 0, 10 or 50 ppm copper with or without 50 ppm dietary cadmium for 7 weeks. All rats received 0.

Relative importance of intracellular glutathione peroxidase and catalase in vivo for prevention of peroxidation to the heart.

The relative importance in vivo of catalase and the selenoenzyme glutathione peroxidase for protection against peroxidation was assessed in the rat heart. Each of these enzymes was modulated by feeding animals a low selenium diet either unsupplemented or supplemented with 0.5 parts per million of selenium, with or without the catalase inhibitor, 3-amino-1,2,4-triazole, in their drinking water.

Selenium-independent glutathione peroxidase activity associated with glutathione S-transferase from the housefly, Musca domestica.

1. A glutathione S-transferase having Se-independent glutathione peroxidase activity was isolated from 100,000 g supernatant from housefly homogenate. 2.

Cadmium-induced alterations in ocular trace elements. Influence of dietary selenium and copper.

The present report demonstrates, for the first time, that feeding rats 50 ppm cadmium for just 7 wk results in detectable levels of cadmium in the eye of rats. Furthermore, these ocular cadmium concentrations affect significant alterations in the levels of the essential trace elements selenium, calcium, iron, and copper in the eye. Rats were fed a low-selenium (less than 0.