Spontaneous Tumor Regression and Reversion: Insights and Associations with Reduced Dietary Phosphate.

Tumors that spontaneously shrink from unknown causes in tumor regression, and that return to normal cells in tumor reversion, are phenomena with the potential to contribute new knowledge and novel therapies for cancer patient survival. Tumorigenesis is associated with dysregulated phosphate metabolism and an increased transport of phosphate into tumor cells, potentially mediated by phosphate overload from excessive dietary phosphate intake, a significant problem in Western societies. This paper proposes that reduced dietary phosphate overload and reregulated phosphate metabolism may reverse an imbalance of kinases and phosphatases in cell signaling and cellular proliferation, thereby activating autophagy in tumor regression and reversion. Dietary phosphate can also be reduced by sickness-associated anorexia, fasting-mimicking diets, and other diets low in phosphate, all of which have been associated with tumor regression. Tumor reversion has also been demonstrated by transplanting cancer cells into a healthy microenvironment, plausibly associated with normal cellular phosphate concentrations. Evidence also suggests that the sequestration and containment of excessive phosphate within encapsulated tumors is protective in cancer patients, preventing the release of potentially lethal amounts of phosphate into the general circulation. Reducing dietary phosphate overload has the potential to provide a novel, safe, and effective reversion therapy for cancer patients, and further research is warranted.

Myopia, Sodium Chloride, and Vitreous Fluid Imbalance: A Nutritional Epidemiology Perspective.

Theories of myopia etiology based on near work and lack of outdoor exposure have had inconsistent support and have not prevented the rising prevalence of global myopia. New scientific theories in the cause and prevention of myopia are needed. Myopia prevalence is low in native people consuming traditional diets lacking in sodium chloride, and nutritional epidemiological evidence supports the association of rising myopia prevalence with dietary sodium intake. East Asian populations have among the highest rates of myopia associated with high dietary sodium. Similar associations of sodium and rising myopia prevalence were observed in the United States in the late 20th century. The present perspective synthesizes nutritional epidemiology evidence with pathophysiological concepts and proposes that axial myopia occurs from increased fluid retention in the vitreous of the eye, induced by dietary sodium chloride intake. Salt disturbs ionic permeability of retinal membranes, increases the osmotic gradient flow of fluid into the vitreous, and stretches ocular tissue during axial elongation. Based on the present nutritional epidemiology evidence, experimental research should investigate the effect of sodium chloride as the cause of myopia, and clinical research should test a very low-salt diet in myopia correction and prevention.

Can a Low-Phosphate Diet for Chronic Kidney Disease Treat Cancer? An Interdisciplinary Literature Review.

Background: Cancer therapeutics have a low success rate in clinical trials. An interdisciplinary approach is needed to translate basic, clinical, and remote fields of research knowledge into novel cancer treatments. Recent research has identified high dietary phosphate intake as a risk factor associated with cancer incidence. A model of tumor dynamics predicted that reducing phosphate levels sequestered in the tumor microenvironment could substantially reduce tumor size. Coincidently, a low-phosphate diet is already in use to help patients with chronic kidney disease manage high serum phosphate levels. Methods: A grounded-theory literature-review method was used to synthesize interdisciplinary findings from the basic and clinical sciences, including oncology, nephrology, nutritional epidemiology, and dietetic research on cancer. Results: Findings of tumor remission associated with fasting and a ketogenic diet, which lower intake of dietary phosphate, support the hypothesis that a low-phosphate diet will reduce levels of phosphate sequestered in the tumor microenvironment and reduce tumor size. Additionally, long-term effects of a low-phosphate diet may reverse dysregulated phosphate metabolism associated with tumorigenesis and prevent cancer recurrence. Conclusions: Evidence in this article provides the rationale to test a low-phosphate diet as a dietary intervention to reduce tumor size and lower risk of cancer recurrence.

Breast cancer, alcohol, and phosphate toxicity.

Alcohol consumption is associated with an increased risk of breast cancer, even at low alcohol intake levels, but public awareness of the breast cancer risk associated with alcohol intake is low. Furthermore, the causative mechanisms underlying alcohol's association with breast cancer are unknown. The present theoretical paper uses a modified grounded theory method to review the research literature and propose that alcohol's association with breast cancer is mediated by phosphate toxicity, the accumulation of excess inorganic phosphate in body tissue. Serum levels of inorganic phosphate are regulated through a network of hormones released from the bone, kidneys, parathyroid glands, and intestines. Alcohol burdens renal function, which may disturb the regulation of inorganic phosphate, impair phosphate excretion, and increase phosphate toxicity. In addition to causing cellular dehydration, alcohol is an etiologic factor in nontraumatic rhabdomyolysis, which ruptures cell membranes and releases inorganic phosphate into the serum, leading to hyperphosphatemia. Phosphate toxicity is also associated with tumorigenesis, as high levels of inorganic phosphate within the tumor microenvironment activate cell signaling pathways and promote cancer cell growth. Furthermore, phosphate toxicity potentially links cancer and kidney disease in onco-nephrology. Insights into the mediating role of phosphate toxicity may lead to future research and interventions that raise public health awareness of breast cancer risk and alcohol consumption.

Breast Cancer and Bone Mineral Density in a U.S. Cohort of Middle-Aged Women: Associations with Phosphate Toxicity.

Breast cancer is associated with phosphate toxicity, the toxic effect from dysregulated phosphate metabolism that can stimulate tumorigenesis. Phosphate toxicity and dysregulated phosphate metabolism are also associated with bone mineral abnormalities, including excessive bone mineral loss and deposition. Based on shared associations with dysregulated phosphate metabolism and phosphate toxicity, a hypothesis proposed in the present mixed methods-grounded theory study posits that middle-aged women with incidence of breast cancer had a greater magnitude of changes in bone mineral density over time compared with women who remained cancer-free. To test this hypothesis, a mixed-effects model was used to analyze the associations of breast cancer incidence with spinal bone mineral density changes in the U.S. Study of Women's Health Across the Nation. Compared with women in the cohort who remained cancer-free, women who self-reported breast cancer had higher bone mineral density at baseline, but had more rapid losses in bone mineral density during follow-up visits. These findings agree with the hypothesis that a greater magnitude of changes in bone mineral density over time is associated with breast cancer in a cohort of middle-aged women. The findings also have implications for studies investigating dysregulated phosphate metabolism and phosphate toxicity as causative factors of bone metastasis in metastatic breast cancer. Additionally, the authors previously found increased breast cancer risk associated with high dietary phosphate intake in the same cohort of middle-aged women, and more studies should investigate a low-phosphorus diet to reduce bone mineral abnormalities and tumorigenesis in breast cancer patients.

High Dietary Phosphorus Is Associated with Increased Breast Cancer Risk in a U.S. Cohort of Middle-Aged Women.

Research has shown that high amounts of dietary phosphorus that are twice the amount of the U.S. dietary reference intake of 700 mg for adults are associated with all-cause mortality, phosphate toxicity, and tumorigenesis. The present nested case-control study measured the relative risk of self-reported breast cancer associated with dietary phosphate intake over 10 annual visits in a cohort of middle-aged U.S. women from the Study of Women's Health Across the Nation. Analyzing data from food frequency questionnaires, the highest level of daily dietary phosphorus intake, >1800 mg of phosphorus, was approximately equivalent to the dietary phosphorus levels in menus promoted by the United States Department of Agriculture. After adjusting for participants' energy intake, this level of dietary phosphorus was associated with a 2.3-fold increased risk of breast cancer incidence compared to the reference dietary phosphorus level of 800 to 1000 mg, which is based on recommendations from the U.S. National Kidney Foundation, (RR: 2.30, 95% CI: 0.94-5.61, p = 0.07). Despite the lack of statistical significance, likely due to the small sample size of the cohort, the present nested case-control study's clinically significant effect size, dose-response, temporality, specificity, biological plausibility, consistency, coherence, and analogy with other research findings meet the criteria for inferred causality in observational studies, warranting further investigations. Furthermore, these findings suggest that a low-phosphate diet should be tested on patients with breast cancer.

Salt-Sensitive Hypertension: Mediation by Salt-Induced Hypervolemia and Phosphate-Induced Vascular Calcification.

Preventing hypertension by restricting dietary salt intake, sodium chloride, is well established in public health policy, but a pathophysiological mechanism has yet to explain the controversial clinical finding that some individuals have a greater risk of hypertension from exposure to salt intake, termed salt-sensitive hypertension. The present perspective paper synthesizes interdisciplinary findings from the research literature and offers novel insights proposing that the pathogenesis of salt-sensitive hypertension is mediated by interaction of salt-induced hypervolemia and phosphate-induced vascular calcification. Arterial stiffness and blood pressure increase as calcification in the vascular media layer reduces arterial elasticity, preventing arteries from expanding to accommodate extracellular fluid overload in hypervolemia related to salt intake. Furthermore, phosphate has been found to be a direct inducer of vascular calcification. Reduction of dietary phosphate may help reduce salt-sensitive hypertension by lowering the prevalence and progression of vascular calcification. Further research should investigate the correlation of vascular calcification with salt-sensitive hypertension, and public health recommendations to prevent hypertension should encourage reductions of both sodium-induced hypervolemia and phosphate-induced vascular calcification.

Dysregulated phosphate metabolism in autism spectrum disorder: associations and insights for future research.

Studies of autism spectrum disorder (ASD) related to exposure to toxic levels of dietary phosphate are lacking. Phosphate toxicity from dysregulated phosphate metabolism can negatively impact almost every major organ system of the body, including the central nervous system. The present paper used a grounded theory-literature review method to synthesise associations of dysregulated phosphate metabolism with the aetiology of ASD. Cell signalling in autism has been linked to an altered balance between phosphoinositide kinases, which phosphorylate proteins, and the counteracting effect of phosphatases in neuronal membranes. Glial cell overgrowth in the developing ASD brain can lead to disturbances in neuro-circuitry, neuroinflammation and immune responses which are potentially related to excessive inorganic phosphate. The rise in ASD prevalence has been suggested to originate in changes to the gut microbiome from increasing consumption of additives in processed food, including phosphate additives. Ketogenic diets and dietary patterns that eliminate casein also reduce phosphate intake, which may account for many of the suggested benefits of these diets in children with ASD. Dysregulated phosphate metabolism is causatively linked to comorbid conditions associated with ASD such as cancer, tuberous sclerosis, mitochondrial dysfunction, diabetes, epilepsy, obesity, chronic kidney disease, tauopathy, cardiovascular disease and bone mineral disorders. Associations and proposals presented in this paper offer novel insights and directions for future research linking the aetiology of ASD with dysregulated phosphate metabolism and phosphate toxicity from excessive dietary phosphorus intake.

Phosphate toxicity and SERCA2a dysfunction in sudden cardiac arrest.

Almost half of the people who die from sudden cardiac arrest have no detectable heart disease. Among children and young adults, the cause of approximately one-third of deaths from sudden cardiac arrest remains unexplained after thorough examination. Sudden cardiac arrest and related sudden cardiac death are attributed to dysfunctional cardiac ion-channels. The present perspective paper proposes a pathophysiological mechanism by which phosphate toxicity from cellular accumulation of dysregulated inorganic phosphate interferes with normal calcium handling in the heart, leading to sudden cardiac arrest. During cardiac muscle relaxation following contraction, SERCA2a pumps actively transport calcium ions into the sarcoplasmic reticulum, powered by ATP hydrolysis that produces ADP and inorganic phosphate end products. Reviewed evidence supports the proposal that end-product inhibition of SERCA2a occurs as increasing levels of inorganic phosphate drive up phosphate toxicity and bring cardiac function to a sudden and unexpected halt. The paper concludes that end-product inhibition from ATP hydrolysis is the mediating factor in the association of sudden cardiac arrest with phosphate toxicity. However, current technology lacks the ability to directly measure this pathophysiological mechanism in active myocardium, and further research is needed to confirm phosphate toxicity as a risk factor in individuals with sudden cardiac arrest. Moreover, phosphate toxicity may be reduced through modification of dietary phosphate intake, with potential for employing low-phosphate dietary interventions to reduce the risk of sudden cardiac arrest.

Biases in COVID-19 Case and Death Definitions: Potential Causes and Consequences.

This paper investigates three controversies involving potential causes and consequences of information bias in case and death definitions during the coronavirus disease (COVID-19) pandemic. First, evidence suggests China's surveillance data were biased and misinterpreted by the World Health Organization (WHO), prompting the WHO to advise nations to copy China's lockdowns. China appeared to use narrow diagnostic definitions that undercounted cases and deaths. Second, novel genomic data disseminated during the pandemic without adequate guidance from rigorous epidemiologic studies biased infection control policies in many countries. A novel genomic sequence of a virus is insufficient to declare new cases of a novel disease. Third, media reports of COVID-19 surveillance data in many nations appeared to be biased. Broadened surveillance definitions captured additional information, but unadjusted surveillance data disseminated to the public are not true cases and deaths. Recommendations include clarification of the proper use of diagnostic and surveillance case and death definitions to avoid information bias.

Correction: Brown, R.B. Sodium Chloride, Migraine and Salt Withdrawal: Controversy and Insights. Med. Sci. 2021, 9, 67.

There was an error in the original publication [...].

Cancer Cachexia and Dysregulated Phosphate Metabolism: Insights from Mutant p53 and Mutant Klotho Mouse Models.

The present perspective article proposes that cachexia, muscle wasting in cancer, is mediated by dysregulated phosphate metabolism and phosphate toxicity that can damage tissues in most major organ systems. A diet high in phosphorus fed to mice deficient in klotho, a cofactor that regulates phosphate metabolism, accelerates aging, sarcopenia, general organ atrophy, kyphosis, and osteoporosis. Similar effects are seen in phenotypes of mutant p53 mice that overexpress the p53 tumor suppressor gene. Although mutant p53 mice do not develop tumors compared to wild-type mice, mutant p53 mice have shorter mean lifespans. Furthermore, tumorigenesis is associated with the sequestration of excessive inorganic phosphate, and dangerous levels of phosphate are released into circulation during tumor lysis syndrome. In total, this evidence implies that tumorigenesis may be a compensatory mechanism that provides protective effects against systemic exposure to dysregulated phosphate metabolism and phosphate toxicity related to cachexia in cancer. Moreover, the hypothetical protection against phosphate toxicity afforded by tumorigenesis also provides an alternate explanation for putative tumor evasion of the immune system. Insights proposed in this perspective paper provide new directions for further research, with potential to develop novel interventions and clinical applications that modify dietary phosphate intake to reduce cachexia in cancer patients.

Hypertension, Anxiety and Obstructive Sleep Apnea in Cardiovascular Disease and COVID-19: Mediation by Dietary Salt.

This perspective paper used a grounded theory method to synthesize evidence proposing that sodium toxicity from excessive dietary salt intake is a potential common pathophysiological mechanism that mediates the association of hypertension, obstructive sleep apnea, and anxiety with cardiovascular disease and COVID-19. Increased anxiety in these conditions may be linked to a high-salt diet through stimulation of the sympathetic nervous system, which increases blood pressure while releasing catecholamines, causing a "fight or flight" response. A rostral shift of fluid overload from the lower to the upper body occurs in obstructive sleep apnea associated with COVID-19 and cardiovascular disease, and may be related to sodium and fluid retention triggered by hypertonic dehydration. Chronic activation of the renin-angiotensin-aldosterone system responds to salt-induced dehydration by increasing reabsorption of sodium and fluid, potentially exacerbating fluid overload. Anxiety may also be related to angiotensin II that stimulates the sympathetic nervous system to release catecholamines. More research is needed to investigate these proposed interrelated mechanisms mediated by dietary salt. Furthermore, dietary interventions should use a whole-food plant-based diet that eliminates foods processed with salt to test the effect of very low sodium intake levels on hypertension, anxiety, and obstructive sleep apnea in cardiovascular disease and COVID-19.

Sudden Infant Death Syndrome, Pulmonary Edema, and Sodium Toxicity: A Grounded Theory.

Sudden Infant Death Syndrome (SIDS) occurs unexpectedly in an otherwise healthy infant with no identifiable cause of death following a thorough investigation. A general hypervolemic state has been identified in SIDS, and fluid in the lungs suggests the involvement of pulmonary edema and hypoxia as the cause of death. The present perspective paper reviews pathophysiological, epidemiological, and dietary evidence in SIDS. A grounded theory is presented that proposes an association of SIDS with sodium toxicity from excessive sodium chloride intake, mediated by noncardiogenic pulmonary edema, hypoxia, and alveolar damage. The peak of SIDS cases occurs in infants 2-4 months of age, who are less efficient in excreting excessive dietary sodium load. Evidence implicating sodium toxicity in SIDS includes increased levels of sodium associated with fever and with inflammatory/immune responses in the lungs. Conditions in near-miss SIDS cases are linked to dysregulated sodium, and increased sodium dietary intake suggests that sodium toxicity from a high-salt diet potentially mediates the association of seasonality and socioeconomic status with SIDS incidence. In addition, exposure to sodium toxicity meets three main criteria of the triple risk model of SIDS. The proposed pathophysiological effects of pulmonary edema related to sodium toxicity in SIDS merit further investigations.

Low dietary sodium potentially mediates COVID-19 prevention associated with whole-food plant-based diets.

Compared with an omnivorous Western diet, plant-based diets containing mostly fruits, vegetables, grains, legumes, nuts and seeds, with restricted amounts of foods of animal origin, are associated with reduced risk and severity of COVID-19. Additionally, inflammatory immune responses and severe acute respiratory symptoms of COVID-19, including pulmonary oedema, shortness of breath, fever and nasopharyngeal infections, are associated with Na toxicity from excessive dietary Na. High dietary Na is also associated with increased risks of diseases and conditions that are co-morbid with COVID-19, including chronic kidney disease, hypertension, stroke, diabetes and obesity. This article presents evidence that low dietary Na potentially mediates the association of plant-based diets with COVID-19 prevention. Processed meats and poultry injected with sodium chloride contribute considerable amounts of dietary Na in the Western diet, and the avoidance or reduction of these and other processed foods in whole-food plant-based (WFPB) diets could help lower overall dietary Na intake. Moreover, high amounts of K in plant-based diets increase urinary Na excretion, and preagricultural diets high in plant-based foods were estimated to contain much lower ratios of dietary Na to K compared with modern diets. Further research should investigate low Na in WFPB diets for protection against COVID-19 and co-morbid conditions.

Non-Specific Low Back Pain, Dietary Salt Intake, and Posterior Lumbar Subcutaneous Edema.

Low back pain is the world's leading disability, but the etiology of the majority of low back pain is non-specific with no known cause. Moreover, overuse of opioids to treat low back pain is a widespread problem. This paper proposes that non-specific low back pain may be associated with excessive intake of dietary salt, potentially mediated by posterior lumbar subcutaneous edema. In addition to pain, symptoms of edema include swelling, tightness, and stiff joints, which are common complaints of people with low back pain, along with restricted lumbar range of motion and impaired mobility. Many global populations consume excess sodium chloride, which can lead to fluid overload in hypervolemia, and cause swelling and temporary weight gain associated with low back pain. Numerous conditions comorbid with low back pain are also potentially mediated by excessive salt intake, including migraine headache, hypertension, cardiovascular disease, venous thromboembolism, liver disease, respiratory disorders, chronic kidney disease, pregnancy complications, and multiple sclerosis. Novel approaches to identify and prevent the cause of non-specific low back pain have potential to reduce disability worldwide by reducing low back pain prevalence. More research is needed to confirm the involvement of dietary salt and posterior lumbar subcutaneous edema in non-specific low back pain.

Parkinson's Disease Etiology: Insights and Associations with Phosphate Toxicity.

The present paper investigated the association of Parkinson's disease etiology with phosphate toxicity, a pathophysiological condition in which dysregulated phosphate metabolism causes excessive inorganic phosphate sequestration in body tissue that damages organ systems. Excessive phosphate is proposed to reduce Complex I function of the mitochondrial electron transport chain in Parkinson's disease and is linked to opening of the mitochondrial permeability transition pore, resulting in increased reactive oxygen species, inflammation, DNA damage, mitochondrial membrane depolarization, and ATP depletion causing cell death. Parkinson's disease is associated with α-synuclein and Lewy body dementia, a secondary tauopathy related to hyperphosphorylation of tau protein, and tauopathy is among several pathophysiological pathways shared between Parkinson's disease and diabetes. Excessive phosphate is also associated with ectopic calcification, bone mineral disorders, and low levels of serum vitamin D in patients with Parkinson's disease. Sarcopenia and cancer in Parkinson's disease patients are also associated with phosphate toxicity. Additionally, Parkinson's disease benefits are related to low dietary phosphate intake. More studies are needed to investigate the potential mediating role of phosphate toxicity in the etiology of Parkinson's disease.

Relative risk reduction: Misinformative measure in clinical trials and COVID-19 vaccine efficacy.

Treatment and vaccine efficacy in clinical trials are often reported in the media and medical journals as the relative risk reduction. The present article explains why the relative risk reduction is a misinformative measure that promotes disinformation when reporting efficacy in clinical research studies such as randomized controlled trials for COVID-19 vaccines. The relative risk reduction is based on the relative risk, a proportional measure or ratio used in epidemiologic studies to estimate the probability of a disease associated with an exposure. The present article demonstrates how the relative risk reduction and relative risk obscure the magnitude of disease risk reduction in clinical research. The absolute risk reduction is shown to be a more precise and reliable measure of treatment and vaccine efficacy in clinical research studies. The absolute risk reduction reciprocal also measures the number needed to treat or vaccinate, and is a more accurate measure than the relative risk reduction for comparing risk reductions of clinical studies. Additionally, the present article reviews consequences of COVID-19 vaccine efficacy misinformation disseminated through media reports. The article concludes that relative risk reduction should not be used to measure treatment and vaccine efficacy in clinical trials. What is new?: •Unreliability of relative measures in clinical trials is graphically illustrated, demonstrating constant relative measures as absolute measures change.•Misuse of relative measures in clinical research is historically linked to misinterpretation of Jerome Cornfield's advice on measuring causative and associative effects.•Consequences of disinformation and misinformation related to COVID-19 vaccine efficacy and modern clinical medicine are described.•The proper use of absolute measures in meta-analyses is explained.

Sodium Chloride, Migraine and Salt Withdrawal: Controversy and Insights.

This paper examines evidence implicating migraine headache as a withdrawal symptom of excessive sodium chloride intake. Emerging research in food addiction posits that food and drug addictions share common features, such as withdrawal symptoms. Salt (sodium chloride) meets the criteria for the diagnosis of substance dependence, including withdrawal in which the substance is used to relieve withdrawal symptoms. The premonitory symptoms of migraine include food cravings for salty foods, which can alleviate migraine pain. Edema, possibly related to large amounts of salt consumed in binge eating, can cause approximately four pounds of retained fluid. This amount of fluid is similar to the fluid retained before the onset of migraine headache, which may be accompanied by polyuria. This paper proposes that inhibited withdrawal from highly processed food intake, rich in salt, mediates an association between increased sodium chloride intake and relief from migraine headache pain. The relief from withdrawal symptoms could also be a mediating factor that explains the controversial findings inversely associating dietary sodium intake with migraine history. Moreover, the withdrawal of retained sodium and edema related to the use of nonsteroidal anti-inflammatory drugs may elucidate a potential mechanism in medication overuse headache. Further research is needed to investigate the pain experienced from sodium chloride withdrawal in migraine headache.

Sodium Toxicity in the Nutritional Epidemiology and Nutritional Immunology of COVID-19.

Dietary factors in the etiology of COVID-19 are understudied. High dietary sodium intake leading to sodium toxicity is associated with comorbid conditions of COVID-19 such as hypertension, kidney disease, stroke, pneumonia, obesity, diabetes, hepatic disease, cardiac arrhythmias, thrombosis, migraine, tinnitus, Bell's palsy, multiple sclerosis, systemic sclerosis, and polycystic ovary syndrome. This article synthesizes evidence from epidemiology, pathophysiology, immunology, and virology literature linking sodium toxicological mechanisms to COVID-19 and SARS-CoV-2 infection. Sodium toxicity is a modifiable disease determinant that impairs the mucociliary clearance of virion aggregates in nasal sinuses of the mucosal immune system, which may lead to SARS-CoV-2 infection and viral sepsis. In addition, sodium toxicity causes pulmonary edema associated with severe acute respiratory syndrome, as well as inflammatory immune responses and other symptoms of COVID-19 such as fever and nasal sinus congestion. Consequently, sodium toxicity potentially mediates the association of COVID-19 pathophysiology with SARS-CoV-2 infection. Sodium dietary intake also increases in the winter, when sodium losses through sweating are reduced, correlating with influenza-like illness outbreaks. Increased SARS-CoV-2 infections in lower socioeconomic classes and among people in government institutions are linked to the consumption of foods highly processed with sodium. Interventions to reduce COVID-19 morbidity and mortality through reduced-sodium diets should be explored further.