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The process would include variable periods of hyperinsulinemia with the consequent systemic MYC activation of glycolysis, glutaminolysis, structural lipidogenesis and further exacerbation of hypoglycemia, the result of MYC's known role as an inhibitor of liver gluconeogenesis

The metabolic changes we describe in breast cancer arise in concert with IEM-like changes in oxidative phosphorylation as detected by increased values of the ratio lactate/pyruvate (Supplementary Table 2A, 2B) characteristic of Ox/Phos deficiency [25]. In our study, 76% (70/92) of the European breast cancer patients had lactate/pyruvate ratios values higher than the normal value of 25.8

four-fold higher frequency of cancer (including breast) in patients with energy metabolism disorders

growing recognition that cancer cells differ from their normal counterparts in their use of nutrients, synthesis of biomolecules and generation of energy

glutamine concentrations in the cancer patients were reduced to nearly 1/8 of the levels observed in the normal population

blood concentrations of aspartate (p = 1.7e-67, FDR = 8.3e-67) (Figure ​(Figure1E)1E) and glutamate (p = 6.4e-96, FDR = 6.2e-95) (Figure ​(Figure1F)1F) were nearly 10 fold higher than the normal ranges of 0–5 μM/L and 40 μM/L, respectively

glutamine consumption associated with parallel increases in glutamate and aspartate (Figure ​(Figure1A1A red arrows) is considered a hallmark of MYC-driven “glutaminolysis”

Gln/Glu ratio inversely correlates with i- late stage metabolic syndrome and with ii- increased chance of death

changes in glutamine consumption, reflected by the Gln/Glu ratio could provide a metabolic link between breast cancer initiation and diabetes, reflective of a systemic metabolic reprogramming from glucose to glutamine as the preferred source of precursors for biosynthetic reactions and cellular energy

lower Gln/Glu ratios inversely correlated with insulin resistance and the risk of diabetes

the metabolic dependencies of cancer characterized by excessive glycolysis, glutaminolysis and malignant lipidogenesis, previously considered a consequence of local tumor DNA aberration [23] could, instead, represent a systemic biochemical aberration that predates and very likely promotes tumorigenesis

these metabolic disturbances would be expected to remain extant after therapeutic interventions

accumulation of very long chain acylcarnitines such as C14:1-OH (p = 0.0, FDR = 0.0), C16 (p = 0.0, FDR = 0.0), C18 (p = 0.0, FDR = 0.0) and C18:1 (p = 1.73e-322, FDR = 1.16-321) and lipids containing VLCFA (lysoPC a C28:0) (p = 1.14-e95, FDR = 1.65e-95) in the blood of breast and colon cancer patients

Among the most powerful metabolic equations for MYC-activation is that which links the widely used MYC-driven desaturation marker ratio of SFA/MUFA to the MYC glutaminolysis-associated ratio of (Asp/Gln)

liver dysfunction shares many features with both IEM and cancer suggesting a role for hepatic dysfunction in carcinogenesis

cancer “conscripts” the human genome to meet its needs under conditions of systemic metabolic stress

Our data show that ascorbic acid selectively killed cancer but not normal cells, using concentrations that could only be achieved by i.v. administration

Ascorbate-mediated cell death was due to protein-dependent extracellular H2O2 generation, via ascorbate radical formation from ascorbate as the electron donor. Like glucose, when ascorbate is infused i.v., the resulting pharmacologic concentrations should distribute rapidly in the extracellular water space (42). We showed that such pharmacologic ascorbate concentrations in media, as a surrogate for extracellular fluid, generated ascorbate radical and H2O2. In contrast, the same pharmacologic ascorbate concentrations in whole blood generated little detectable ascorbate radical and no detectable H2O2. These findings can be accounted for by efficient and redundant H2O2 catabolic pathways in whole blood (e.g., catalase and glutathione peroxidase) relative to those in media or extracellular fluid

ascorbic acid administered i.v. in pharmacologic concentrations may serve as a pro-drug for H2O2 delivery to the extracellular milieu

H2O2 generated in blood is normally removed by catalase and glutathione peroxidase within red blood cells, with internal glutathione providing reducing equivalents

The electron source for glutathione is NADPH from the pentose shunt, via glucose-6-phosphate dehydrogenase. If activity of this enzyme is diminished, the predicted outcome is impaired H2O2 removal causing intravascular hemolysis, the observed clinical finding.

Only recently has it been understood that the discordant clinical findings can be explained by previously unrecognized fundamental pharmacokinetics properties of ascorbate

Intracellular transport of ascorbate is tightly controlled in relation to extracellular concentration

Intravenous ascorbate infusion is expected to drastically change extracellular but not intracellular concentrations

For i.v. ascorbate to be clinically useful in killing cancer cells, pharmacologic but not physiologic extracellular concentrations should be effective, independent of intracellular ascorbate concentrations.

It is unknown why ascorbate, via H2O2, killed some cancer cells but not normal cells.

There was no correlation with ascorbate-induced cell death and glutathione, catalase activity, or glutathione peroxidase activity.

H2O2, as the product of pharmacologic ascorbate concentrations, has potential therapeutic uses in addition to cancer treatment, especially in infections

Neutrophils generate H2O2 from superoxide,

i.v. ascorbate is effective in some viral infections

H2O2 is toxic to hepatitis C

Use of ascorbate as an H2O2-delivery system against sensitive pathogens, viral or bacterial, has substantial clinical implications that deserve rapid exploration.

Recent pharmacokinetics studies in men and women show that 10 g of ascorbate given i.v. is expected to produce plasma concentrations of nearly 6 mM, which are >25-fold higher than those concentrations from the same oral dose

As much as a 70-fold difference in plasma concentrations is expected between oral and i.v. administration,

Complementary and alternative medicine practitioners worldwide currently use ascorbate i.v. in some patients, in part because there is no apparent harm

Human Burkitt's lymphoma cells

We first investigated whether ascorbate in pharmacologic concentrations selectively affected the survival of cancer cells by studying nine cancer cell lines

Clinical pharmacokinetics analyses show that pharmacologic concentrations of plasma ascorbate, from 0.3 to 15 mM, are achievable only from i.v. administration

plasma ascorbate concentrations from maximum possible oral doses cannot exceed 0.22 mM because of limited intestinal absorption

For five of the nine cancer cell lines, ascorbate concentrations causing a 50% decrease in cell survival (EC50 values) were less than 5 mM, a concentration easily achievable from i.v. infusion

All tested normal cells were insensitive to 20 mM ascorbate.

Lymphoma cells were selected because of their sensitivity to ascorbate

As ascorbate concentration increased, the pattern of death changed from apoptosis to pyknosis/necrosis, a pattern suggestive of H2O2-mediated cell death

Apoptosis occurred by 6 h after exposure, and cell death by pyknosis was ≈90% at 14 h after exposure

In contrast to lymphoma cells, there was little or no killing of normal lymphocytes and monocytes by ascorbate

Ascorbate is transported into cells as such by sodium-dependent transporters, whereas dehydroascorbic acid is transported into cells by glucose transporters and then immediately reduced internally to ascorbate

Whether or not intracellular ascorbate was preloaded, extracellular ascorbate induced the same amount and type of death.

extracellular ascorbate in pharmacologic concentrations mediates death of lymphoma cells by apoptosis and pyknosis/necrosis, independently of intracellular ascorbate.

H2O2 as the effector species mediating pharmacologic ascorbate-induced cell death

Superoxide dismutase was not protective

Because these data implicated H2O2 in cell killing, we added H2O2 to lymphoma cells and studied death patterns using nuclear staining (19, 28). The death patterns found with exogenous H2O2 exposure were similar to those found with ascorbate

For both ascorbate and H2O2, death changed from apoptosis to pyknosis/necrosis as concentrations increased

Sensitivity to direct exposure to H2O2 was greater in lymphoma cells compared with normal lymphocytes and normal monocytes

There was no association between the EC50 for ascorbate-mediated cell death and intracellular glutathione concentrations, catalase activity, or glutathione peroxidase activity

H2O2 generation was dependent on time, ascorbate concentration, and the presence of trace amounts of serum in media

ascorbate radical is a surrogate marker for H2O2 formation.

whatever H2O2 is generated should be removed by glutathione peroxidase and catalase within red blood cells, because H2O2 is membrane permeable

The data are consistent with the hypothesis that ascorbate in pharmacologic concentrations is a pro-drug for H2O2 generation in the extracellular milieu but not in blood.

The occurrence of one predicted complication, oxalate kidney stones, is controversial

In patients with glucose-6-phosphate dehydrogenase deficiency, i.v. ascorbate is contraindicated because it causes intravascular hemolysis

ascorbate at pharmacologic concentrations in blood is a pro-drug for H2O2 delivery to tissues.

ascorbate, an electron-donor in such reactions, ironically initiates pro-oxidant chemistry and H2O2 formation

data here showed that ascorbate initiated H2O2 formation extracellularly, but H2O2 targets could be either intracellular or extracellular, because H2O2 is membrane permeant

More than 100 patients have been described, presumably without glucose-6-phosphate dehydrogenase deficiency, who received 10 g or more of i.v. ascorbate with no reported adverse effects other than tumor lysis

Pre-emptive, prospective, genotyping to make individualised drug therapy feasible is seen to contribute to personalised medicine

assumed to improve drug efficacy and safety

Potential benefits of pharmacogenomics (PGx) have been defined such as predicting intended response to medication by more accurate dosing, avoiding adverse drug reactions and therefore enhancing drug safety and reducing health care cost

survey among Dutch pharmacists revealed 14.7% recent users of PGx diagnostics [27], whereas in our cohort, the percentage was with 34.3% higher.

leading to enhancement of interleukin-12 secretion and natural killer cell function

VA preparations (Iscador Ltd) did not inhibit chemotherapy-induced cytostasis or cytotoxicity and showed an additive inhibitory effect at higher concentrations of VA.

A multivariable GEE model indicated that the odds for patients experiencing an AE following mAb therapy were nearly 5 times higher compared with that for mAb plus VA

Helixor VA preparations

previous in vitro investigations have shown that VA preparations have either no or minor effects on a range of CYPs, suggesting that VA-drug interactions based on drug metabolism are unlikely

mAb do not undergo hepatic metabolism but undergo proteolytic catabolism throughout the body

Ivermectin inhibits proliferation of human colon cancer and lung cancer cells both in vitro and in vivo

The anti-proliferative action, affecting both the bulk tumor cells and CSCs, was linked in this study to inhibition of WNT signaling

the anti-WNT IC50 of ivermectin is 5–10 times (~1–2 µM vs. 10 µM) lower than that of its toxic effect against chloride channels

oral bioavailability of the drug, as for other antiparasitic drugs discussed in this section, is very low

Toxicity studies in vivo have also demonstrated a wide therapeutic index for ivermectin

Its anti-proliferative activity has been demonstrated in a wide array of cancer cell lines representative of WNT-dependent cancers: non-small lung carcinoma [96], multiple myeloma [97], hepatoma [98], adrenocortical carcinoma [99], ovarian cancer [100] and glioblastoma

Niclosamide inhibits the canonical WNT pathway

In addition to inhibiting the canonical WNT pathway, niclosamide may mediate its anticancer activities through several other signaling pathways such as NOTCH [107], MTOR [108], NF-κB [97] and STAT3 [96]

It is produced predominately by antigen-simulated CD4+ T cells, while it can also be produced by CD8+ cells, natural killer (NK) cells, and activated dendritic cells (DC)

IL-2 is an important factor for the maintenance of CD4+ regulatory T cells

plays a critical role in the differentiation of CD4+ T cells into a variety of subsets

It can promote CD8+ T-cell and NK cell cytotoxicity activity, and modulate T-cell differentiation programs in response to antigen, promoting naive CD4+ T-cell differentiation into T helper-1 (Th1) and T helper-2 (Th2) cells while inhibiting T helper-17 (Th17) differentiation

Of note, Tregs, which act to dampen the immune response, constitutively express high levels of α chain

IL-2Rα is unique to IL-2 and is expressed by a number of immune cells including T regulatory cells (Treg), activated CD4+ and CD8+T cells, B cells, mature DCs, endothelial cells

some investigators evaluated the efficacy of regimens containing low-dose IL-2

IL-2 can promote the activation and cell growth of T and NK cells

Unfortunately, not all of patients would benefit from targeted therapy and nearly all patients who initially respond to targeted inhibitors inevitably develop acquired resistance to the treatment

IL-2 also stimulates T-regulatory cells that constitutively express CTLA-4 and can suppress immune reactions. Hence, IL-2 might enhance antitumor reactivity in the presence of CTLA-4 blockade

both HD and low-dose IL-2 therapy preferentially induce the expansion of CD4+CD25+Foxp3+ Treg and the Treg level remains elevated after each cycle of HD IL-2 therapy

Due to rapid elimination and metabolism via the kidney, IL-2 has a short serum half-life of several minutes

HD IL-2-induced severe toxicities including vascular leak syndrome (VLS), pulmonary edema, hypotension, and heart toxicities

HBOT was found to have a role in initiation and/or facilitation of angiogenesis and cell proliferation processes needed for axonal regeneration [67].

The observed reactivation of neuronal activity in the stunned areas found here, along with similar results in post-stroke patients

At the cellular level, HBOT can improve cellular metabolism, reduce apoptosis, alleviate oxidative stress and increase levels of neurotrophins and nitric oxide through enhancement of mitochondrial function (in both neurons and glial cells)

HBOT may promote the neurogenesis of endogenous neural stem cells

With regard to secondary injury mechanisms in mTBI, HBOT can initiate vascular repair mechanism and improve cerebral vascular flow [58], [59], [68], [69], promote blood brain barrier integrity and reduce inflammatory reactions [28] as well as brain edema

It might be possible that HBOT enables the metabolic change simply by supplying the missing energy/oxygen needed for those regeneration processes.

O3 not only remedied infection, but also had hemodynamic and anti-inflammatory properties

Stimulation of oxygen metabolism

In fungi, O3 inhibits cell growth at certain stages

With viruses, the O3 damages the viral capsid and upsets the reproductive cycle by disrupting the virus-to-cell contact with peroxidation.

Inactivation of bacteria, viruses, fungi, yeast and protozoa: Ozone therapy disrupts the integrity of the bacterial cell envelope through oxidation of the phospholipids and lipoproteins

Activation of the immune system

30 and 55 μg/cc

production of interferon and the greatest output of tumor necrosis factor and interleukin-2

Mechanism of action of O3 on the human lung

cascade of reactions like peroxidation of lipids leading to changes in membrane permeability,[41] lipid ozonation products (LOP) act as signal transducer molecules

Dietary antioxidants or free radical scavengers like vitamin E, C, etc., can prevent aforementioned effects of O3