Typora should've been listed. Including another option might encourage editor hopping, but it's worth the mention.

It's comparable to IA Writer, ships with similar features that writers tend to enjoy (such as fully immersive mode, active paragraph highlighter, and fixed-height typing) while being more customizable. Obsidian is superior in capabilities to both, but Typora would be a good alternative to consider for people who are after simpler solutions.

Just like Obsidian and Zettlr, it's available on Linux too.

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"Quartz effectively turns your Markdown files and other resources into a bundle of HTML, JS, and CSS files (a website!)."

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• Open Access Button

• Unpaywall

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Short link to PubMed:

• pubmed.gov

And an incomplete list of unexpected CO₂ sources:

Process	Enzyme	Reaction
Pentose Phosphate Pathway	PGDH	Hexose (6C) → pentose (5C) + CO₂ (1C)
Fatty acid synthesis	KAS*	Malonyl (3C) + acetyl (2C) → ketobutyryl (4C) + CO₂ (1C)
Acetone synthesis	-	Acetoacetate (4C) → acetone (3C) + CO₂ (1C)
Oxoglutarate oxygenases	OGO	Oxoglutarate (5C) → succinate (4C) + CO₂ (1C)
Pyruvate synthesis from malate	ME	Malate (4C) → pyruvate (3C) + CO₂ (1C)
PEP synthesis	PEPCK	Oxaloacetate (4C) → pyruvate-enol-phosphate (3C) + CO₂ (1C)
Glycine cleavage system	GLDC	Glycine (2C) + THF (+0C) →→ methylene-THF (+1C) + CO₂ (1C)
Coenzime A synthesis	PPCD	PPC (12C) → P4P (11C) + CO₂ (1C)
Aldehyde dehydrogenase	ALDH	formyl-THF (+1C) → THF (+0C) + CO₂ (1C)
Taurine synthesis	CSAD	CSA/CA (3C) → hTau/Tau (2C) + CO₂ (1C)
Cholesterol synthesis	PPMD	Mevalonate-5-diphosphate (6C) → Isopentenyl diphosphate (5C) + CO₂ (1C)
Polyamine synthesis	SAMD	SAM (–0C) → dcSAM (–1C) + CO₂ (1C)
Other biogenic amine syntheses (AA decarboxylations)		†

*Preceded by carbon incorporation: gain followed by loss. But remains a reaction that releases carbon dioxide.

†Biochemical and Pharmacological Properties of Biogenic Amines

At last, an objective comparison of dietary toxins:

Since these coenzymes are recycled, the most expensive phase with them must be in adapting to different needs. Once the cell becomes adapted, it's a matter of replenishing obligatory losses. I've omitted some coenzymes for clarity.

The comparison makes it clear once again that the oxidation of glucose doesn't produce more CO₂ per molecule metabolized than fatty acids.

What explains the CO₂ effect is a difference in ATP production: fatty acid oxidation can yield about 25% more ATP than glucose on a carbon basis (P/C), resulting in less exposure to CO₂ to produce the same energy.

The NAD/FAD ratios in their complete catabolism:

• NAD 5:1 FAD -- Glucose
• NAD 2:1 FAD -- Fatty acids (rounded for common ones)

Someone may associate FAD with Complex II and have with the impression that fatty acid oxidation overwhelms Complex II. However, if we match substrates for energy yield and argue that glucose oxidation exposes the person to more CO₂, we must be consistent with the matching in other comparisons.

We're dealing with different pools of FAD:

• FAD within the ACADH-ETF-ETFDH complex (more about it below) is responsible for the marked decrease in the NAD/FAD ratio;

• FAD within SDH (Complex II) remains similarly affected by glucose and fatty acids.

These are separate routes of transferring electrons.

With a focus on the first mentioned route, the middle row shows the 4 enzymes of a standard β-oxidation cycle:

Lack of Myoglobin Causes a Switch in Cardiac Substrate Selection

Abbreviation	Enzyme	Function
ACADH	Acyl-CoA dehydrogenase	Oxidation
	..and the Trifunctional Protein (TFP) set:
ECH	Enoyl-CoA hydratase	Hydration
HADH	Hydroxyacyl-CoA dehydrogenase	Oxidation
KAT	Ketoacyl-CoA thiolase	Thiolysation

The bottom row of the image shows the respiratory complexes.

In between the middle and bottom rows, linking β-oxidation to respiratory dehydrogenases, are the mobile ETF and NAD molecules.

• ACADH → ETF → ETFDH
• HADH → NAD → Complex I

ETF stands for Electron-transfer Flavoprotein, which is carrier molecule and the FAD equivalent in purpose to NAD.

ETFDH (ETF Dehydrogenase) is a respiratory complex that metabolizes ETF. It's sometimes called ETF:Q-O (ETF-to-Quinone Oxidoreductase).

FAD occurs embedded in ACADH, and the same applies to each of these interacting proteins:

• ACADH (FAD) → ETF (FAD) → ETFDH (FAD)

It's fad everywhere, resembling a thiamin overdose support group.

The paths of these β-oxidation dehydrogenases (ACADH and HADH) eventually converge in ubiquinone.

	FAD-dependent		NAD-dependent
β-ox. Enzyme	ACADH		HADH
Carrier	ETF		NAD
Resp. Enzyme	ETFDH (ETF:Q-O)		Complex I (NADH:Q-O)
Carrier	⤷	UQ	⤶
Resp. Enzyme		Complex III
Carrier		Cyt c
Resp. Enzyme		Complex IV

Therefore, the extra FAD cycled in fatty acid oxidation doesn't involve SDH (Complex II), but the ACADH-ETF-ETFDH complex featured above.

Since every acetyl-CoA that's metabolized in the TCA cycle is derived oxidatively from a β-oxidation cycle, we'll have a succinate (from TCA cycle → SDH) molecule for every ETF (from β-oxidation → ETFDH); so, the different routes distribute electrons somewhat evenly between them, without burdening Complex II.

⠀Source: the internet, but possibly Albie's Principles of Biochemistry.

It's an almost even distribution because the last acetyl-CoA isn't derived oxidatively, but as a leftover product of the final β-oxidation cycle, which explains one less FAD needed in ACAD/ETF/ETFDH (check the original tables).

As a side note, the catabolism of certain amino acids and choline is also dependent on ETF-ETFDH.

Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease

Along the lines of taking energy into account, the ratio of ATP produced to oxygen consumed (P/O) indicates how fatty acid reliance needs less oxidation than anticipated, it's not too far behind glucose.

In addition, the components related to β-oxidation can cluster with the respiratory complexes to maximize efficiency and minimize damage. 'Respirasome' (CI + CIII₂ + CIV) is a known respiratory supercomplex, but we also have lesser-known associations, one of them coordinating ETFDH with CIII, while ACADH and ETF likely remain nearby.

Kinetic advantage of the interaction between the fatty acid β-oxidation enzymes and the complexes of the respiratory chain

An ETFDH-driven metabolon supports OXPHOS efficiency in skeletal muscle by regulating coenzyme Q homeostasis

Mitochondrial fatty acid oxidation and the electron transport chain comprise a multifunctional mitochondrial protein complex

"For steps 1–3, long-chain acyl-CoA substrates are transferred into mitochondria as acylcarnitines, which cross from the intermembrane space into VLCAD through CPTII in the inner membrane. VLCAD then accepts and catalyzes the released long-chain acyl-CoA substrate to its enoyl–CoA product with reduction of ETF. The protein complex promotes metabolite channeling for all these reactions.

For steps 4 and 5, reduced ETF is released from VLCAD into the mitochondrial matrix, where it is free to find its redox partner, ETFDH, and shuttle its reducing equivalents (QH2) to ETC complex III. Alternatively, for high catalytic efficiency of transfer of electrons from FAO to ETC, the ETF may remain associated with the macromolecular FAO–ETC complex and instead slide down the membrane-associated proteins to more efficiently contact ETFDH.

For steps 6 and 7, long-chain enoyl–CoAs, from VLCAD, channel directly to TFP where the next three reactions in the cycle occur, producing one molecule of acetyl-CoA and an acyl-CoA substrate that is two carbons shorter. As the acyl-CoAs become shorter, they become more hydrophilic, allowing them to be released into the matrix. NADH generated by the LCHAD reaction of TFP can directly channel to the NADH-binding domain of complex I.

For step 8, in complex I NADH is oxidized through iron–sulfur clusters to generate QH2 at the Q-binding domain, which is then transported through the membrane electron channel of complex I to complex III.

For steps 9 and 10, medium- and short-chain acyl-CoA substrates produced by TFP are transferred to MCAD and SCAD in the matrix or in a more weakly-associating peripheral domain of the multifunctional FAO–ETC complex. ETF is once again reduced and released to ETFDH, as in step 5. The remaining FAO reactions are catalyzed by monofunctional enzymes that are likely also weakly associated at the periphery of the complex.

For step 11, ETFDH oxidizes reduced ETF by reducing CoQ to QH2, which is then channeled to ETC complex III.

Finally, the acetyl-CoA generated by FAO is free to enter the TCA cycle or to be utilized for ketone body production (steps 12 and 13)."

For an overview:

If the cell starts to rely more on fatty acid oxidation and there is an excess of ubiquinol relative to Complex I use, electrons can flow back, leading to the formation of 'reactive oxygen species' and a purposeful disintegration of Complex I. This frees the associated Complex III to reorganize supercomplexes in a way that meets a different demand. Therefore, where fatty acid oxidation is dangerous, the body tries to regulate it as drugs.

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.

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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."

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• 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"

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