Why not make an impartial compilation of experiments on cancer and group them according to the effect of extra glucose (without additional factors) on cancer cells: supporting versus hindering proliferation? We can't go by the majority, but it's a starting place to question.

The line of thought would not be far from the idea that more glutamine should be delivered to cancer cells because they overconsume it to the point of depletion. Deficiencies can promote a more aggressive behavior, but it's not that we need the encouragement to load up on glutamine to compensate.

• Regional Glutamine Deficiency in Tumours Promotes De-differentiation through Inhibition of Histone Demethylation

A condition of generalized scarcity is common, and this would call for the replenishment of many compounds. For example, immune cells can also compete with cancer cells for glucose, but also glutamine and other nutrients that may be rapidly used up.

Gerson's approach consisted of a moderate caloric intake, better distributed in smaller and more frequent meals, which leans in favor of a controlled exposure. If I was against dietary toxins, I wouldn't mention him often because the original therapy asked for minimal fats. Sometimes tumors have a person attached to them, and the person must be fed on occasion. Looking for potential downsides helps to identify and counteract them, but also avoids cults*. In case anyone knows superior dietary therapies to that of Gerson, I wouldn't mind relegating it, no matter how unconventional.

• *Reflected on a thread such as our "Can glucose loading cure everything?"

It would be good to know how relevant fructose-1-phosphate would be on tissues that don't express ketohexokinase or glucokinase (a variant of hexokinase). Also, how high uric acid levels have to be to affect aconitase.

But it makes more sense to seek local nutrient repletion when you can target the misbehavior or exploit it.

In the previous experiment, they first manipulated Hypoxia-inducible Factor (HIF) to lift some of the metabolic inhibitions and only then pound glucose with insulin, intending to provoke oxidative stress. Otherwise, the effect was insignificant.

It's not difficult to picture glucose lessening the oxidative burst from vitamin C therapy when not much else is done to manipulate the fermentation pattern.

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

NADPH-producing enzyme	Origin of main substrate
G6PDH	Glucose
PGDH	Glucose
ME	Glutamine, glucose
IDH	Glutamine
MTHFDH	Glucose
ALDH	Glucose
GDH	Glutamine
NNT	Glutamine, fatty acids, glucose

Glucose may also spare glutamine in antioxidation.

By the great Matthew Vander Heiden and Sophia Lunt:

Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation

All of the carbons that occur in nucleotides can conceivably come from glucose. It's absurd.

Carbon source	Derivation	Carbons donated
Ribose	Glucose →→ ribose	5
Aspartate	Glucose →→ pyruvate → oxaloacetate → malate → asp	3
Formyl-THF	Glucose →→ serine →→ formyl	2
Glycine	Glucose →→ serine → glycine	2
Hydrocarbonate	Glucose →→ carbon dioxide → hydrocarbonate	1
Methylene-THF	Glucose →→ serine →→ methylene	1

Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides

It's also evident that the base of phospholipids and triglycerides can be derived from glucose in the form of glycerol.

Ceramide needs serine, which can come from glucose as well.
In addition, serine accepts the sulfur from homocysteine to yield cysteine, and then glutathione.

Expanding on the fates of glucose, pyruvate kinase (PK) is the last enzyme of glycolysis, responsible for the following simplified reaction:

• Phosphoenol-pyruvate (PEP) + ADP –(PK)→ pyruvate + ATP

PK has 4 variants:

Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis

The PK-M2 prevails in tumor cells and can occur as a dimer or as a tetramer:

• PK-M2 dimer is hypoactive → Less pyruvate and ATP
  • But the lower rate of conversion creates a metabolite congestion that spills over to the branches of glycolysis → More biosynthesis and antioxidation
    ⠀
• PK-M2 tetramer is hyperactive → More pyruvate and ATP

They differ in low and high affinity for the substrate PEP and give (tumor) cells more flexibility to rely on either state depending on needs for biosynthesis or energy. Excess ATP inhibits multiple metabolic steps and can be counterproductive.

Oxidative stress inhibits the enzyme, which is a convenient way to recreate the hypoactive situation above.

• Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses

Expressing PK-M2 is an advantage, not a requisite.

• No evidence for a shift in pyruvate kinase PKM1 to PKM2 expression during tumorigenesis
• M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth

The cell can adopt different strategies in diverting glucose from glycolysis:

Glucose 6-P Dehydrogenase—An Antioxidant Enzyme with Regulatory Functions in Skeletal Muscle during Exercise

• Modes 1 and 2 result in sudden loss of carbons as ribose for nucleotides, without or with decrapoxylation.
• Mode 3 represents a cycle for continuous production of NADPH until complete decrapoxylation. It may be an overlooked source of carbon dioxide. Note that it bypasses a reaction that's treated as irreversible (F6P ↶ F1,6P).
• Only mode 4 yields pyruvate with the net gain of regenerated ATP.

Rather than serving to normalize the redox state of cancer cells, glucose metabolism can easily go from redox neutral in straightforward fermentation to reductive in case of diversion with return.

If we arrive on pyruvate [3C]:

The metabolic fates of pyruvate in normal and neoplastic cells

Enzyme	Reaction description	Main changes	Km [low value: high affinity]
'PDC'	Oxidation to acetyl(CoA) [2C]	–2H –CO₂	0.02 mM (0.005-0.043 mM)
LDH	Reduction to lactate [3C]	+2H	0.1 mM (0.034-0.630 mM)
PC	Crapoxylation to oxaloacetate [4C]*	+HCO₃⁻ (+ATP)	0.265 mM (0.23-0.30 mM)
ME	Crapoxylation to malate [4C]	+2H +HCO₃⁻	0.75 mM
(GPT or) ALT	Amination to alanine [3C]	+NH₄	2.8 mM (0.07-12.50 mM)
N/A	Oxidation to acetate [2C] ?	+H₂O₂

Each has cytosolic and mitochondrial forms, with the exception of PDC. Pyruvate import (and not just its oxidation) may be impaired, and pyruvate is formed in amounts that are only comfortably processed by LDH.

Glutamate can be oxidized (through GDH) or transaminate to produce ketoglutarate. Pyruvate (through ALT (⇈)) can accept the amino group of glutamate to become alanine and yield ketoglutarate. So, pyruvate offers an alternative way to metabolize glutamate. Lactate is known to be elevated in cancer, but we now know that alanine is somewhat elevated too.

I'm aware of the ethyl-pyruvate experiments, but the picture is more complicated than apparent, in special for pyruvate derived from glucose.

• Exogenous pyruvate facilitates cancer cell adaptation to hypoxia by serving as an oxygen surrogate

Conversely (and beyond acidification):

• Lactic acidosis switches cancer cells from aerobic glycolysis back to dominant oxidative phosphorylation

But to get to this condition naturally, you'd need disturbing levels and the associated concerns to achieve it.

I have to stress that this is not vilify dextructose or levilose, but to put things into perspective. If we are extra cautious with folate to the point of discouraging its use preventively (!), we can't brush these aspects off, including the fact that glucose is a major carbon donor that keeps the folate cycle running, with glycolysis and its branches being overactive in cancer. And if we have antifolates as cancer therapies, folate should be present in enough quantities to matter as a carrier.

Insulin given in isolation may actually increase the competition for glucose and divert some of it away from cancer cells. If released in response to glucose, whether we get lipolysis under control or not, we would still have the issue of ongoing fermentation and the need for something to change the cell behavior:

• The Apoptotic Effect of HIF-1α Inhibition Combined with Glucose plus Insulin Treatment on Gastric Cancer under Hypoxic Conditions

Another factor to consider:

Inside the hypoxic tumour: reprogramming of the DDR and radioresistance

Additional information:

Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response

"Despite the many studies on tumour hypoxia, there is considerable confusion in the use of the terms “normoxia” and “hypoxia”. Oxygenation measurements in normal tissues show that they exhibit distinct normal ranges, which vary between tissues (Table 1)."

"However, “normoxia” is almost universally used to describe the “normal” oxygen levels in tissue culture flasks, i.e. about 20–21% oxygen (160 mmHg). Although this is not exact, as it is dependent on altitude and added CO2, for most situations, 20% is a good approximation. Despite the widespread usage of “normoxia”, this is far from an accurate comparator for peripheral tissue oxygenation. Even in lung alveoli, the oxygen level is reduced to about 14.5% oxygen (110 mmHg) by the presence of water vapour and expired CO2.[13] It drops further in arterial blood and, by the time it reaches peripheral tissues, the median oxygen levels range from 3.4% to 6.8% with an average of about 6.1% (Table 2).[13]"

"In defining “pathological hypoxia”, there are no absolutes; however, the reality is that all tumours tend to have median tumour oxygen levels <2% and, within that estimation, individual measurements can vary from about 6% (very rarely) down to zero with a significantly marked skewing towards the lower end of this range; frequently, most values are well below 1.3% oxygen (10 mmHg), especially in the more hypoxic tumours."

Cells can maintain a surprisingly high rate of oxygen consumption in hypoxia:

Metabolic Profiling of Hypoxic Cells Revealed a Catabolic Signature Required for Cell Survival

• Potassium cyanide (KCN) inhibits Complex IV (where most oxygen is supposed to be metabolized).

"[..]mitochondrial respiration can function at oxygen levels as low as 0.5% (Chandel et al., 1996; Rumsey et al., 1990)." (Luengo, 2021)

Despite the respiratory resistance, some cancer cells are found in severe hypoxia. You want them to respire normally with more glucose, but how, if little oxygen is available? They conserve oxygen by adopting an economical program. If these cancer cells keep up with the glucose flux and metabolize it liberally, it quickly depletes their oxygen and leads to further disturbances.

We can't turn our zealotry to fructose either:

Fructose contributes to the Warburg effect for cancer growth

↳ Direct Spectrophotometric Determination of Serum Fructose in Pancreatic Cancer Patients

↳ Fructose induces transketolase flux to promote pancreatic cancer growth

"The enzyme TKT requires thiamine-derived mitochondrial NAD+ as a cofactor, and NAD synthesis can be disrupted with the thiamine analogue oxythiamine."

I forgot to list DHEA in Locketol:

• ↳ Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation

Of interest, Heinz reported the following:

The Metabolism of Carcinoma Cells

"The carcinoma splits not only glucose to lactic acid, but also mannose, fructose and galactose, the velocity of the glycolysis being:

Toxin	Relative speed
Galactose	1
Fructose	2.5
Mannose	17
Glucose	18

Glucose is obviously attacked most rapidly and we might add the alpha-form of glucose as rapidly as the beta-form."

In comparison to abundance, glucose limitation is more supportive to increasing reliance on respiration and oxidative phosphorylation, because these are ways to maximize the efficiency in consuming a nutrient that can be depleted. Galactose is not metabolized fast enough to replace the mitochondrial yield. It's used in experiments when researchers want to make cells dependent on the mitochondrial metabolism.

Tumors can have regions with low levels of glucose, but pounding glucose in a state of metabolic derangement and hypoxia is more likely to intensify fermentation, and the typical structural abnormalities must follow.

These are not nutrient contraindications, more like anti-glorifications.

@haidut said in Vitamin C (IV route) doubles survival time in advanced pancreatic cancer patients:

The bioenergetic theory states that cancer cells uptake more glucose from the blood because they are functionally deficient in glucose. Namely, the glucose that enters cancer cells gets “wasted” by conversion into lactate, due to the cancer cells’ highly reductive state (e.g. low mitochondrial NAD+/NADH ratio) instead of being combusted through OXPHOS. So, the solution would be to provide more glucose, not less. Be that as it may, the Apatone approach is to use a molecule (vitamin C) that uses the same uptake/transport mechanisms as glucose, which results in its preferential accumulation inside cancer cells, and once inside the cancer cell this oxidized form of vitamin C (DHAA) corrects the reductive excess of cancer cells, and after some time they start to respire normally. In other words, Apatone works by converting “cancer” cells back into “normal” cells by gradually changing the redox state of such cells from high reduced to highly oxidized.

György, aerobic fermentation is redox neutral:

• Glucose + 2 NAD⁺ → 2 Pyruvate + 2 NADH
• 2 Pyruvate + 2 NADH → 2 Lactate + 2 NAD⁺

Combined:

• Glucose → 2 Lactate

How do you expect more glucose to solve the redox imbalance? It's the metabolic disinhibitions that do the trick, and controlled glucose exposure should be beneficial in the meantime.

Not shown above: about 1 ATP for every pyruvate or lactate formed. It's less than 1 because part of the glycolysis metabolites are diverted and lost.

But alternatively, it's possible to make use of the high flux to induce stress, leading to an overall helpful effect. Glucose must be paired with other compounds. Otherwise, you risk increasing the antioxidative capacity further.

• The Dual-Role of Methylglyoxal in Tumor Progression – Novel Therapeutic Approaches

We have the glucose treatment that Ray mentioned, but it was used along with oxygen therapy. Without an adjuvant, in addition to improve the antioxidative capacity, glucose abundance could even reinforce any inhibition of respiration. Straight from Herbie's publication:

Observations on the Carbohydrate Metabolism of Tumours

We had a craze on the Ray Peat Forum where a few members started to take ascorbic acid reacted with methylene blue for being mesmerized by the change in color. Consider this:

• 5.68 mmol/1 g ascorbic acid

For a single reaction, this would call for 1.8 g of methylene blue per gram of ascorbic acid. People take methylene blue on the low mg range or even less, such as 150 mcg (0.00015 g). It's likely that they're downing the instant solution with only a small fraction of vitamin C oxidized. Note that the reason why they combine them is to consume preoxidized vitamin C.

And this is without taking into account the multiple cycles that ascorbate undergoes in the body, making external manipulations of low doses somewhat redundant. Also, that the pharmacological uses for a considerable oxidative burst are way off from their method:

Review of high-dose intravenous vitamin C as an anticancer agent

"Vitamin C has different functions at physiological and pharmacological plasma concentrations. Oral vitamin C administration is associated with tightly controlled plasma concentrations regulated by the pharmacokinetic principles of bioavailability and clearance.[7] Saturation of bioavailability mechanisms occurs at oral doses of 400 mg daily equating to blood levels of 60–100 μM.[8] IV dosing bypasses this tight control, achieving plasma concentrations up to 20 mM.[7,8]

In vitro evidence suggests plasma concentrations of 10 mM are necessary for an antitumor effect and this appears achievable clinically only with IV administration.[8] Padayatty et al. postulated that the vitamin C-free radical species, ascorbyl radical, forms only when human plasma concentrations are greater than 10 mM and that it is this radical or its unpaired electron that induces oxidative damage in cancer cells.[8]

Casciari et al. published a trial to determine the dose necessary to achieve this level in humans.[57] In a single patient with colon cancer, they found that a dose of 60 g but not 30 g was effective at attaining this. A recent phase I trial of 24 patients demonstrated that IV vitamin C to a dose level of 1.5 g/kg three times per week was safe and achieved plasma concentrations >10 mM for several hours.[58] While average follow-up was only 10 weeks, this trial did not demonstrate objective tumor response at these levels.[58] Riordan et al. published a series of 24 patients treated with IV vitamin C 150 mg/ kg/day and 710 mg/kg/day.[59] The mean plasma level was 1.1 mM (below the expected therapeutic target). They did not demonstrate a correlation between dose and plasma concentration. The reason for this is unclear. Other factors such as critical illness, renal function and chemotherapy regimens may alter plasma vitamin C concentrations and affect the plasma concentration necessary for cytotoxicity.[58]"

You can find different values depending on the source, incomplete stalling, and ways to lower the effective dose, but the point is that to stand a chance to induce oxidative stress in distant cancer cells, the acute amount is much higher.

Ray was concerned about contaminants in synthetic ascorbic acid and would possibly sweat at the idea of combining it with an oxidant. Member 'jyb' alerted that methylene blue products can also be contaminated. It seems better to take them separately and renew the vitamin C dose often when you can't brutalize.

Related to the previous topic, Max Gerson and Ray endorsed niacin supplementation, but in moderate and repeated doses. Max recommended niacin (50 mg*) along with vitamin C (500 mg*) and aspirin (325 mg*), to be used orally multiple times a day. *If I'm not wrong.

@mexican_coke_fan

Thiamin and niacin supplementation has more basis than biotin, but for each of them we can find potential concerns.

It's easier to explain the beneficial effects of these vitamins through their systemic effects. Nutrients are usually a mix of good and bad in cancer. Example:

• Potential Role of Magnesium in Cancer Initiation and Progression
• Magnesium and its transporters in cancer: a novel paradigm in tumour development
• Magnesium and neoplasia: From carcinogenesis to tumor growth and progression or treatment
• Magnesium and cancer: a dangerous liason

To anticipate the point on dual disinhibition of pyruvate dehydrogenase complex (PDC) from thiamin with niacin, I don't have clear if we have a dosing range where niacin (as niacinic acid or niacinamide) supplementation could be counterproductive.

The focus is on:

• ↑Niacin → ↑NAD⁺ → ↑PDC

But what about the cytosolic dehydrogenases?

Think of it: where can we expect additional NAD⁺ to be preferentially consumed, in a pathway that's intensely upregulated (glycolysis) or one that's downregulated (pyruvate oxidation)?

If additional NAD⁺ favors Glyceral-3-Phosphate Dehydrogenase (GAPDH) in glycolysis, this could lead to the formation of more pyruvate, which then redistributes to new lactate, reinforcing the problem.

LDH is an efficient enzyme that prevails in excessive glucose catabolism. LDH regeneration of NAD⁺ is simpler and more assured than the elaborate mitochondrial shuttles and oxidative phosphorylation.

Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells

PDH has higher affinity for pyruvate than LDH, but lower capacity to metabolize it. PDH is also found in mitochondria, as opposed to the cytosolic LDH.

These sides are in equilibrium:

• Pyruvate + NADH + H⁺ ⇄ Lactate + NAD⁺

The form of lactate dehydrogenase expressed in cancer can be the A-dominant, with a set point in great bias towards lactate formation [→].
Where B-dominant LDH occurs, the site can be primed to recover pyruvate from lactate [←], and extra NAD⁺ could lead to an aggravation of the pattern.

• Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice
• Glucose feeds the TCA cycle via circulating lactate

Even though the concentration of metabolites can overcome the enzyme bias, in the presence of extra NAD⁺, A-dominant LDH should offer greater resistance to the recovery of pyruvate. This could result in a larger pool to maintain the following cycle running:

The Regulation and Function of Lactate Dehydrogenase A: Therapeutic Potential in Brain Tumor

GAPDH doesn't seem to be a limiting step in upregulated glycolysis, but we can't discard the possibility that it may happen:

• Four Key Steps Control Glycolytic Flux in Mammalian Cells
• ↳ Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step

Local negative effects from additional NAD⁺ is not an unreasonable concern:

Increased demand for NAD+ relative to ATP drives aerobic glycolysis

PDH disinhibition decreased fermentation and proliferation rate as expected, but the decrease occurred along with lowering the NAD⁺/NADH ratio. Next, they found that it's possible to restore proliferation through artificial NAD⁺ regeneration. This regeneration of NAD⁺ defeated the first levels of PDH disinhibition, despite a reduction in fermentation.

It also suggests that recycled NAD⁺ doesn't promote glycolysis, or at least not enough to counteract the share of pyruvate escaping fermentation.

The oxidation of NADH at Complex I is normally tied to ADP and Pi consumption (with proton dissipation) at Complex V. This dependency is a factor that limited proliferation. Additional NAD⁺ from supplements would be a way to bypass the protective limitation in the short term and it's an issue to consider.

We can also anticipate a comment on compartmentalization of NAD at this stage.

As before, we have the same mitochondrial dehydrogenase complexes (and others) competing for resources: PDC and KGDC. It's not difficult to imagine NAD⁺ favoring once again the uninhibited KGDC over PDC. In addition, if ketoglutarate (substrate of KGDC) is derived oxidatively from glutamate, why couldn't NAD⁺ promote its metabolism?

• Glutamate + NAD⁺ + H2O → Ketoglutarate + NH4⁺ + NADH + H⁺

Respiration can still occur when the availability of oxygen is low, but respiration is not the only way to reoxidize NADH formed inside mitochondria. The TCA cycle dehydrogenases working in reverse can serve this function:

• MDH: malate ↶ oxaloacetate
• SDH: succinate ↶ fumarate
• KGDH cannot, just like CS (citrate synthase), the reaction is irreversible in humans as far as I know.
• IDH: isocitrate ↶ ketoglutarate*

⠀*Part of the total ketoglutarate can be metabolized to succinyl-CoA and the other to isocitrate simultaneously.

Acute sources of mitochondrial NAD+ during respiratory chain dysfunction

The reactions indicated are all regenerating NAD⁺ consumed by KGDC, without necessarily involving the electron transport chain (gray). Diaphorases would be the NAD(P)H:Quinone Oxidoreductases (NQO).

SDH (yellow) shown above should be included too:

• Fumarate is a terminal electron acceptor in the mammalian electron transport chain
• Residual Complex I activity and amphidirectional Complex II operation support glutamate catabolism through mtSLP in anoxia

The stressful reversal:

I'm bringing these up because NADH formed in mitochondria won't invariably force oxidative phosphorylation.

Mitochondrial substrate-level phosphorylation ('mSLP') that was mentioned occurs following ketoglutarate oxidation. It's a reaction that they emphasize as an overlooked source of ATP in cancer ('SUCL' on the previous figure).

On the Origin of ATP Synthesis in Cancer

Process	Yield/glucose
cytosolic SLP	2 ATP (net)
mitochondrial SLP	2 ATP
(mitochondrial) OxP	28 ATP (varies)
Total	32 ATP

• (SLP ATP) ÷ Total ATP → (2 ATP + 2 ATP) ÷ 32 ATP ≈ 12% of energy from SLP in normal conditions

Some normal cells increase reliance on aerobic fermentation where the anabolic or antioxidant needs are high. How much fermentation and respiration occurs in cancer, where and when, is a long-standing debate. It's difficult to address a problem properly when we go by assumptions about its extent. Sidney Weinhouse began a series of valid questionings that are worth checking out:

• On Respiratory Impairment in Cancer Cells
• The Warburg hypothesis fifty years later

Salicylate is a major plasma metabolite following high doses of aspirin. Perhaps about half of the dose occurs unbound in these cases. For an idea of reachable levels:

Toxicology Facts and Formulas

Up to 2.2 mmol/L is considered therapeutic.

The inhibition constant of salicylic acid for carbonic anhydrases was less than 0.1 mmol/L.

As a side note on aspirin as an inhibitor, the effect that it has on COX-1 is commonly treated only as an inconvenient in its use, but it may not be all problematic:

• Cyclooxygenase-1 (COX-1) and COX-1 Inhibitors in Cancer: A Review of Oncology and Medicinal Chemistry Literature

For carbonic anhydrases, acetazolamide outperforms the compounds in question in almost every CA tested, which is why it's used as reference. It's nice that the two experiments posted earlier (thiamin and salicylic acid on CA) arrived on similar values for acetazolamide.

To compare the responses:

• Rapid determination of acetazolamide in human plasma

Learning to successfully search the scientific and medical literature

"[..]truncate with wild card symbols according to the syntax of any given software. An example of truncation is the asterisk used in PubMed to permit a search using any possible permutations of a root term. For instance, if you search PubMed for malignan*, PubMed will retrieve malignant, malignancy, malignancies, etc."

In Google Scholar, it's possible to switch from publications to profiles and find the most cited celebrities related to the searched term. For specific tags, seach using "label:desiredterm". It's useful if you're exploring an unfamiliar field.

---

Reading and Myopia: Contrast Polarity Matters

Abstract

"In myopia the eye grows too long, generating poorly focused retinal images when people try to look at a distance. Myopia is tightly linked to the educational status and is on the rise worldwide. It is still not clear which kind of visual experience stimulates eye growth in children and students when they study. We propose a new and perhaps unexpected reason. Work in animal models has shown that selective activation of ON or OFF pathways has also selective effects on eye growth. This is likely to be true also in humans. Using custom-developed software to process video frames of the visual environment in realtime we quantified relative ON and OFF stimulus strengths. We found that ON and OFF inputs were largely balanced in natural environments. However, black text on white paper heavily overstimulated retinal OFF pathways. Conversely, white text on black paper overstimulated ON pathways. Using optical coherence tomography (OCT) in young human subjects, we found that the choroid, the heavily perfused layer behind the retina in the eye, becomes about 16 µm thinner in only one hour when subjects read black text on white background but about 10 µm thicker when they read white text from black background. Studies both in animal models and in humans have shown that thinner choroids are associated with myopia development and thicker choroids with myopia inhibition. Therefore, reading white text from a black screen or tablet may be a way to inhibit myopia, while conventional black text on white background may stimulate myopia."

---

• MDCalc - "A free online medical reference for healthcare professionals that provides point-of-care clinical decision-support tools, including medical calculators, scoring systems, and algorithms"
  ⠀
• BioIcons - "A free library of open source icons for scientific illustrations using vector graphics software"
• SciDraw - "A website where you can find and share high quality drawings of animals, scientific setups, and anything for scientific presentations and posters"
• Chemix - "A free online editor for drawing lab diagrams"

---

'Hyphens versus Dashes' and 'Using Dashes' by a monster, to not misapply them, as above.

While Bulgaria is on a call with his supplier, sourcing the ingredients for Locketol, the polyphenol-based transketolase inhibitor, I would like to return to the previous experiment on thiamin functioning as a carbonic anhydrase inhibitor.

In such experiment, they used purified enzymes in direct exposure to a solution containing thiamin. We would have the tumor and the cell barrier. Concentrations of thiamin from massive doses probably decrease:

• Blood > Tumor with poor vascularization > Tumor cells

To achieve a free thiamin level of 85 nmol/L inside the cell must not be easy. And this half-inhibitory value is for the CA-2 (intracellular), not CA-9 and CA-12 (with superficial protrusions) that are more likely to encounter the high extracellular concentrations from exaggerated doses.

Proton Transport in Cancer Cells: The Role of Carbonic Anhydrases

"Measurements of CA-9 [CAIX] catalytic activity with gas-analysis mass spectrometry revealed that at a pH of 7.4, the enzyme's rate constant for hydration was faster than for dehydration [58]. At pH values below 6.8, however, the rate of dehydration exceeded the hydration rate. For pH 6.8, the rate constants for hydration and dehydration were essentially the same [58]. CA-9 displays an apparent pK of 6.84 and is inhibited at lower pH values [59]. Therefore, a low pHe could limit further H⁺-production by CA-9 in the extracellular space. In other words, at pH values below 6.8, CA-9 favors the dehydration reaction, while at pH values above 6.8 the hydration reaction is preferred [55]. Taken together, these observations indicate that CA-9 functions as a pH-stat that sets tumor pHe to an acidic value of around 6.8 [55–59]."

Therefore, if the inhibitory thiamin concentrations for CA-9 and CA-12 are similar to that for CA-2, a possible scenario is their inhibition without a simultaneous inhibition of CA-2 (one of the "CAi" shown above). In this situation, cells would continue to be alkalinized through the generation of CO2, but without its fast hydration on the other side.

The partial inhibition (on CA-9/12 without CA-2) would remain helpful. For example, in minimizing the degradation of extracellular matrix, easing the suppression of the immune system, and decreasing vascularization. Not being able to affect CA-2 wouldn't be too unfortunate because it's less specific to cancer, which would imply more burden to healthy cells along. Yet, if intracellular CAs are not targeted, the alkalinization inside the cell with CO2 formation would continue.

An advantage is that the lack of external hydration of CO2 may limit its diffusion, in special in a packed mass with poor circulation. The compartments would tend towards an equilibrium, and more CO2 inside the cell can compromise alkalinization.

The majority of thiamin occurs as thiamin diphosphate (TDP):

• Rapid HPLC Measurement of Thiamine and Its Phosphate Esters in Whole Blood

Perhaps not in blood after crazy doses, but possibly inside the cell. If TDP is another carbonic anhydrase inhibitor, its intracellular concentration can be high, with 949 nmol/L as an outlying example, and can add to the effect of free thiamin.

Also, compound 7 on the table below is salicylic acid:

Carbonic anhydrase inhibitors: Inhibition of mammalian isoforms I–XIV with a series of substituted phenols including paracetamol and salicylic acid

In a scenario where all target carbonic anhydrases are somehow inhibited and pyruvate is diverted from lactate, it would be good to verify if the alternative means to regulate proton concentration can't make up for it.

What is pH regulation, and why do cancer cells need it?

Manipulation of carbonic anhydrases impairs tumors and suggests that they're major contributors to the altered pH. But you can also find experiments where these other proteins were modified, resulting in compromised growth. They're druggable:

Proton Transport Inhibitors as Potentially Selective Anticancer Drugs

And inhibited carbonic anhydrases don't appear inert, they can occur near those proteins and may still cooperate with them in the transfer of buffered protons on either side:

Proton Transport in Cancer Cells: The Role of Carbonic Anhydrases

It's rarely mentioned that Ricky was also a thiamin pharmaco-enthusiast.

Warburg effect(s)—a biographical sketch of Otto Warburg and his impacts on tumor metabolism

"Warburg considered cancer to be a nutritional problem, one that could be avoided by maintaining an appropriate natural diet. As early as 1923, Warburg and Schoeller discussed starving cancer by drugs leading to “nutritional deprivation” [4]. In his last publication in 1970, he claimed that a cause for spontaneous “tumor metabolism” was either a lack of oxygen or a lack of vitamin B1 (thiamin)—both conditions increasing the production of lactic acid [25]. This line of thinking led him to consider the administration of vitamin supplements, which would enhance respiration and was considered to be a natural and safe application. Already in the 1940s, Warburg, who was asserted having cancer phobia, practiced his own recommendations in maintaining a disciplined lifestyle: he grew his own vegetables, drew water from an unpolluted well, had his bread baked with grains from wheat not treated with pesticides, and kept his own poultry. And, he did sports: long walks, horseback riding, or sailing [3]. After his favorite sister Lotte died of cancer in 1948, Warburg also quit smoking [4]. Warburg, being sensitized to the dangers of smoking, alcohol, and drugs, proposed to the German Ministry of Health to reduce cigarette smoking, motor vehicle exhausts, air pollution, and chemical additives in foods as cancer prevention measures. This was in 1954 and at that time without avail [3]."

↳ [25] Entstehung von Krebsstoffwechsel durch Vitamin-B1-Mangel (Thiaminmangel)

"Since the carcinogens known today produce about 80% of human cancer cases, one can prevent at least 80% of cancer by keeping carcinogens away from human cells. This leaves a remainder of at most 20% for "spontaneous" cancer, whose prevention is still a problem of science."

"We have developed a simple in-vitro test to investigate this problem. 10-day-old chicken embryos were divided into single cells using trypsin, which grew quickly in suitable culture media. Measuring the metabolism of such in vitro grown embryonic cells, one finds that either the purely aerobic metabolism, with which the embryonic cells grow in the body, is maintained; or that the embryonic metabolism switches to the fermentation metabolism of cancer cells. The switch can be reversible or irreversible. If it is irreversible, one can, based on all experiences of continued in-vitro cultivation, successfully transplant the fermenting cells onto animals."

"When applying the test, it has been shown that the switch from embryonic metabolism to cancer metabolism can be induced in two ways: either by temporarily placing B-vitamin-saturated cells under oxygen deficiency; or by temporarily placing oxygen-saturated cells under B-vitamin deficiency. Both methods have in common an inhibition of respiration, which must be irreversible and associated with an energy-equivalent increase in fermentation."

"Another result of the application of the test is that vitamin B1 occupies a special position among the B vitamins. Under our experimental conditions, the addition of 0.025 g per cm3 medium + vitamin B1, without the addition of other B vitamins, was sufficient to prevent the switch from embryonic metabolism to cancer metabolism, i.e., the development of cancer. Of course, this does not mean that the other B vitamins are unnecessary; but it only means that more vitamin B1 is required than the other B vitamins."

"The biochemical explanation is that the pathway of respiration and fermentation in the breakdown of carbohydrates to pyruvic acid is common, but then the pathways diverge, with pyruvic acid being hydrated to lactic acid by NADH on the fermentation pathway, while on the respiration pathway pyruvic acid is oxidized to acetic acid by vitamin B1. At the crossroads of respiration and fermentation, a competitive struggle between NADH and vitamin B1 for pyruvic acid takes place, in which respiration can only win if vitamin B1 is present in large excess over NADH."

"Medically, the consequence is that in the prevention of cancer by B vitamins, the dose of vitamin B1 should be increased as much as possible."

More from them:

• Massacration - Flight of the Chicken
• Massacration - Metal Warferas

Now a serious metal band with fine artists:

• Angra - Carry On (also this cover)
• Angra - Nothing to Say
• Angra - Carolina IV (metal.. Softened by the tropics)
• Angra - Rebirth
• Angra - Wuthering Heights (their turn to cover)
• Angra - Morning Star (part of it, if you're into technique)