Omega-3 Fatty Acids, Budwig Diet & their Antitumor Activity

Summary:

This is a long post so here is a short summary:

Omega-3 fatty acids have anti-inflammatory, antiproliferative, proapoptotic, antiangiogenetic, anti-invasion, and antimetastatic properties. Because Omega-3 fatty acids are pushing out of the cancer cells the glutathione much needed for the cancer cell survival, Omega-3 fatty acids can be also combined with chemo and with that increase or enable chemo effectiveness. However in high doses (around 10g-15g/day) Omega-3 fatty acids can also be used as a stand alone therapy. This has been demonstrated in humans and reported both anecdotally and in scientific journals. There is a huge amount of science supporting the anti cancer effect of Omega-3 fatty acids.

As a result, I would add Omega-3 fatty acids to virtually any anti cancer treatment strategy.

Due to the reasons mentioned below I would make sure that the Omega-3 therapy is support by co-administration of Honokiol, a natural extract from magnolia, available as a supplement and accessible online (if possible Honokiol at about 3g/day).

Introduction:

When I think of Omega-3 fatty acids in cancer treatment I first think of Dr. Johana Budwig, a German biochemist and pharmacist who held doctorate degrees in physics and chemistry. She was one of the first scientist to connect the (lack of the right) fatty acids consumption with cancer in humans.

Budwig’s theory was based on the work of Otto Warburg, a medical doctor and Nobel laureate. According to Budwig, Warburg theorized that cellular respiration, like many chemical reactions, was dependent upon the availability of a sulphydryl group and an unknown saturated fatty acid, which he failed to identify. From 1949 to 1952, Budwig and colleague H.P. Kaufmann developed a new techniques to identify and quantify fatty acids. She applied these techniques to investigate blood samples of healthy and sick individuals, documenting the differences in fatty acid profiles. Following her study, Budwig concluded that patients with cancer required highly unsaturated fatty acids (referred to as PUFA’s or polyunsaturated fatty acids, or Omega-3 and -6, specifically linoleic acid (LA) and linolenic acid (LNA)) necessarily for cell membrane formation and to support a healthy cellular respiration. (Ref.)

Budwig believed that the sulphydryl groups in the amino acids connected with the unsaturated fatty acids identified by her, form a lipoprotein important for the good functionality of the cellular membranes. Indeed, lipoproteins are the building blocks of the phospholipid bilayer, or as Budwig called them ― the external skin of the cell.

The proper function of cellular membranes is vital as it mediates the flow of various elements in and out and indeed years latter, in 1978, Peter Mitchell received a Nobel Prize for his work showing the relevance of ions movement across a membrane electrochemical potential difference for the energy production inside cells (Ref.).

Finally, Dr. Budwig , believed that diets lacking these fatty acids lead to impeded cellular metabolism. To address this issue, she proposed a diet that would include daily ingestion of cottage cheese and flaxseed oil. While the required fatty acids would be taken out of the flaxseed oil (which contains 18–20% LA, 58–60% LNA and lesser amounts of saturated and monounsaturated fat), the sulphydryl groups (next to cysteine and methionine) in cottage cheese would facilitated the mobilization of fat by increasing its solubility. Note that the same reaction did not occur with the saturated fats derived from pork fat. (Ref.)

Omega-3 fatty acids are hard to find in the typical western diet but they can be found in e.g. algae, mackerel, tuna and salmon:

The ideal total omega 3:omega-6 intake, which seems to be 1:1 or 1:2 (similar to that of precivilized man), is generally associated with a low incidence of diseases characterized by chronic inflammation, and therefore is desirable. However, the omega 3:omega-6 intake ratio in western countries is estimated at 1:10, probably due to the high dietary content of corn oil products, soybean oil and corn-fed animals. This imbalance favors production of proinflammatory lipid derivatives. In order to gain back the balance, it has been suggested to better increase omega-3 intake rather than try reduce omega-6 intake. (Ref.) This is because the same enzymes responsible for conversion of  omega-6 are also responsible for omega 3 conversion. So there is a competition between omega-3 and omega-6 for these enzymes (∆ 5 and ∆ 6 desaturases) and it seems that omega-3 has greater affinities for these enzymes. (Ref). So if we increase enough the intake of omega-3 we do not need to worry much about the omega-6 reduction.

Note: if we use eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as an omega-3 source we may still need to reduce omega-6 intake (this is because EPA and DHA will not need to use the enzymes mentioned above so those would still be available for omega-6).

Indeed, mammals lack the enzymes necessary to produce omega-3 PUFAs. Therefore, these essential fatty acids must be obtained from the diet. Plants can synthesize the first member of the omega-3 PUFA series, alpha linolenic acid (α-LNA). So we can eat the plants containing α-LNA. Sources of this fatty acid include soybeans, walnuts, dark green leafy vegetables such as kale, spinach, broccoli and Brussels sprouts, and seeds or their oils such as flaxseed, mustard seed and rapeseed (canola); however, the majority of these oils are also rich in LA, which is omega-6.

A source with one of the highest Omega-3 content seems to be flaxseed oil, which contains 18–20% LA, 58–60% LNA. and lesser amounts of saturated and monounsaturated fat.

Besides, flaxseed oil, dietary long-chain omega-3 PUFAs are found primarily in cold-water fish in forms of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Fish ingest EPA and DHA from phytoplankton and zooplankton. Deep water fish such as mackerel, tuna and salmon from colder temperatures have the highest content of EPA and DHA. Note that fish farming may have a marked influence on fatty acid composition according to diets supplied to the fish, so I would avoid that http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2572135/

Next to their anti cancer effects EPA and DHA are also:

• beneficial for bone health and turnover (Ref.1, Ref.2)
• Omega-3 (n-3) fatty acids are associated with a range of health benefits, particularly for heart disease and inflammatory conditions like arthritis (Ref.)
• recent clinical studies suggested that EPA/DHA supplementation may suppress cancer-related cachexia (Ref.)
• inhibits thrombosis (Ref.)
• lowers blood pressure (Ref.)
• etc.

Update February 2019: Indeed, demonstrating that the above are not just scientific claims, at the end of 2018, a small biotech company called Amarin experienced a 300% jump in a day of it’s stock price after publishing positive results of a clinical trial on its Omega-3 based product called Vascepa (Ref.). The results demonstrated clear positive effects of the Omega-3 product on patients with cardiovascular disease. This study took 7-years and included 8175 patients, taking the Omega-3 based product (EPA based) at a dose of 4g/day.

UC Davis Researchers in USA, had a Key Discovery in 2013, Involving Omega-3 Fatty Acids and Cancer. With that they demonstrated that Omega-3 have both anti angiogenesis (blocking of new vessel growth to the tumors) anti metastasis role. (Ref.1, Ref.2)

In conclusion, it is clear is that currently, there is a great amount of research available showing the fundamental role of fatty acids in the human body and the high relevance of their ingestion in cancer prevention and cancer treatment (Ref.) due to theirs anti-inflammatory, antiproliferative, proapoptotic, antiangiogenetic, anti-invasion, and antimetastatic properties (Ref.) Due to their pro oxidant action, Omega-3 Polyunsaturated fatty acids may work well with chemotheraphy. (Ref.)

Omega-3 fatty acids have anti cancer properties in humans:

Besides the theory of Dr. Budwig and all the anecdotal stories around that, there is a good amount of scientific research and even some published case reports, indicating that Omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti cancer properties in humans.

In 2005, a report has been published describing a case of a 78-yr-old man with malignant fibrous histiocytoma with multiple lesions in both lungs.  Following diagnosis, he declined conventional chemotherapy and elected nutritional intervention by increasing intake of omega-3 fatty acids and lowering intake of omega-6 fatty acids. He consumed 15 g of the long-chain omega-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) per day. Serial computed tomography scans and pulmonary x-rays revealed remarkably a slow and steady decrease in the size and number of bilateral nodules. He has no apparent side effects from consuming large quantities of fish and algae oils rich in DHA and EPA and he remains asymptomatic. (Ref.)

A study published in 2009, showed how a team of French researchers greatly improved outcome for late stage breast cancer patients been treated with chemotherapy by supplementing them daily with the Omega-3 fatty acid , DHA. All of the subjects had cancer which had metastasized to other parts of the body. They explained this as a result of the fact that tumour cells can be made more sensitive to chemotherapy than non-tumour cells when membrane lipids are enriched with docosahexaenoic acid. (Ref.)

Study in breast cancer patients concluding: Higher plasma DHA concentrations were associated to greater median time to progression (8.7 months) and OS (34 months) compared to patients with low plasma DHA levels (3.5 and 18 months, respectively). (Ref.)

Study in pancreatic cancer patient concluding: A significant increase in body weight (p < 0.00001) and lean body mass (p < 0.00001), a significant decrease in resting energy expenditure (p = 0.03), and an increase in OS (130–259 days vs 63–130 days) in patients who consumed an oral nutrition supplement enriched with n-3 PUFAs compared to those who consumed conventional nutrition (Ref.)

A case report of an ongoing (partial) remission of a female patient (41 years old) from estrogen receptor (ER)-positive/progesterone receptor (PR)-negative metastatic breast cancer in response to a combination treatment including Budwig diet and fish oil supplements: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756422/

Mechanisms:

Omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are highly relevant in cancer since they play important roles in cell membrane structure, fluidity, and cell signaling. This group of fatty acids (next to Omega-6) are referred to as polyunsaturated fatty acids (PUFAs). They are key components of phospholipid membranes and lipid rafts that serve to organize or separate molecules.

Here is a nice picture showing the difference between saturated (straight tails) and unsaturated fatty acids (kinked tails) http://www.intechopen.com/books/lipid-metabolism/overview-about-lipid-structure. The straight tails will lead to a more dense cell membrane while the kinked tails will lead to a less dense and more flexible membrane that will allow an easier movement of various substances in and out the cell.

The mechanisms by which Omega-3 induce apoptosis in tumor cells are not fully determined in molecular terms; however, the proposed main routes of action of Omega-3 are:

• incorporation into cell membranes, leading to changes in the distribution and function of key survival and death signals;
• generation of lethal levels of intracellular oxidative stress;
• modulation of eicosanoid metabolites;
• binding to nuclear receptors, leading to changes in gene expression.

Some of the main routes through which omega-3 PUFA are believed to act as anti cancer agents:

• incorporation into cell membranes, leading to changes in the distribution and function of key survival and death signals: Once ingested, omega–3 PUFAs, EPA and DHA are incorporated in tumor cell membranes. DHA, possesses an extremely flexible structure, more flexible than EPA.  As a result, physical-chemical alterations of molecular lipid microenvironments (rafts) take place on cell surface leading to changes in the activity/expression of membrane constituents (receptors, channels, enzymes, adapter proteins, etc.). Can disrupt pathways such as EGFR-Ras-ERK1/2 (Ref.) EPA and DHA have been shown to have beneficial effects on the plasma membrane and with this on the inhibition of various growth factors i.e. EGFR, IGF-II, RAS, PKC-B2, PGE2, NF-kb (Ref.).
  .
  Important pathways altered by Omega-3:
  • Inhibition of the Wnt/β-Catenin Pathway
  • Modulation of the Mitogen-Activated Protein Kinase (MAPK)/ERK (or Ras/Raf/MEK/ERK) Pathway
  • Inhibition of the PI3K/Akt/mTOR Pathway
  • Inhibition of the JAK-STAT Pathway
  • Inhibition of the NF-κB Pathway
    The modulation of all these pathways is discussed in details in the following reference: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773771/
    .
• Modulation of eicosanoid metabolites: Omega-6 compete with Omega-3 for incorporation into the cell membrane, and when the Omega-6, arachidonic acid, is present it gives rise to a different set of eicosanoids. These eicosanoids include stronger platelet aggregators and inflammatory mediators. This is why the ratio of Omega- 3:Omega-6 present in the membrane is highly important for determining the types of eicosanoids produced, anti- or pro-inflammatory. On the other hand when Omega-3 is incorporated into cell membranes can act as a precursor to a different type of eicosanoids (hormone like substances and include thromboxanes, prostaglandins, and leukotrienes) and impact in a different way cytokines that can have widespread effects on the human body.  Cytokines such as tumour necrosis factor α, interleukin-1 and interleukin-6 act to initiate an inflammatory reaction when released by the immune system. The Omega-3 are known to weaken this process by reducing the production of cytokines (Ref.) So, a main direct route for the omega-3 PUFA action is related to their possible metabolic conversion into bioactive molecules with powerful anti-inflammatory and proresolving action (i.e., resolvins, protectins, etc.) (Ref.).
  .
• Generation of lethal levels of intracellular oxidative stress: Another main possible direct route for the omega-3 PUFA action is related to their high peroxidability inducing alterations of the cell oxidative status and modulation of oxidative stress-dependent molecular pathways related to cell proliferation, apoptosis, or inflammation. (Ref.)
  Interestingly, Omega-3 PUFAs induce an active extrusion of intracellular reduced glutathione (GSH), depleting tumor cells of one of the most important antioxidant defences, and increasing thus tumor cell sensibility to lipid peroxidation and oxidative stress (Ref.) This is why DHA has been proposed as an effective adjuvant in cancer chemotherapy (Ref.)
  .
• Omega-3 also lowers intracellular cholesterol production via a direct inhibition of Hmgcr (Ref.) This is why I introduced Omega 3 as a part of the anti cholesterol strategy to kill cancer (Ref.)
  .
• DHA and thus Omega 3 also inhibits tthe activity of Na(+)/H(+) exchanger type 1 (NHE-1) (Ref.).  This is why I introduced Omega 3 as a part of the pH strategy to kill cancer (Ref.)

Below is a nice graph showing the conversion of LA and LNA (Sprecher’s pathway) from Wikipedia: https://en.wikipedia.org/wiki/File:EFA_to_Eicosanoid.png

EPA and DHA were shown to have different effects on plasma lipids. They also seem to have different effects on eicosanoid production; EPA is a competitive inhibitor of both the COX and LOX pathways, and DHA only inhibits the COX pathway. Their roles in cell membranes also seems to differ: DHA reduces membrane cholesterol content and increases membrane fluidity, while that is not observed with EPA. In some cases this has been shown to result in differential effects on tumorigenesis: For example, tumor cell death has been measured as a function of the incorporation of different fatty acids in different positions and in different phospholipids, and it has been found that DHA in phosphatidylcholine is cytotoxic to those specific tumor cells, while EPA and α-linolenic acid did not have this effect (Ref.1, Ref.2).

Omega-3 fatty acids have also an anti angiogenesis role (Ref., Ref.1, Ref.2).

Here is a very good paper on the anti cancer actions of EPA and DHA: http://www.hindawi.com/journals/jl/2013/261247/ and here is another one very recent http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773771/

Actually, things are a bit more complex: from the figure above what we can see is that LNA is metabolized in to EPA which is than converted into DHA. However, to inhibit angiogenesis, tumor growth, and metastasis, DHA has to be further metabolized (by cytochrome P450 (CYP) epoxygenases) in to epoxydocosapentaenoic acids (EDPs). EDP inhibits VEGF- and fibroblast growth factor 2-induced angiogenesis in vivo, and suppress endothelial cell migration and protease production in vitro via a VEGF receptor 2-dependent mechanism. (Ref.)

But there is a problem. That is called soluble epoxide hydrolase (sEH). This is an enzyme which breaks down and inactivates EDP relatively fast so that the patient may not have the chance to get the mots out of the anti-tumor action of EDP. (Ref.1, Ref.2)

It has been shown experimentally that when EDPs are coadministered with a low-dose soluble epoxide hydrolase inhibitor, EDPs are stabilized in circulation, causing ~70% inhibition of primary tumor growth and metastasis. (Ref.). With this in mind, recently scientist thought to add DHA to Regorafenib treatment. Regorafenib is an anti angiogenesis drug and a multikinase inhibitor, which by chance is also a soluble epoxide hydrolase (sEH) inhibitor. So the idea was to combine DHA with the Regorafenib’s sEH-inhibitor properties. Scientist applied this combination on Kidney cancer cells and the results was a synergistic anti cancer effect suggesting “that this nontoxic dietary supplement could be administered with regorafenib during therapy for advanced RCC and could be the basis of a clinical trial.” (Ref.1, Ref.2, Ref.3)

So off course, what would be my next step other than the search for soluble epoxide hydrolase (sEH) inhibitors, nontoxic and accessible. Fortunately, Honokiol was recently found to have sEH inhibition properties. (Ref.) This is great since Honokiol is a well known natural extract from magnolia, non toxic, accessible online and with great anti cancer effects.

Administration and Dose:

Oral supplements:

From the clinical trial: To achieve a sufficient incorporation of DHA into tissue cell membrane phospholipids, an amount of 1.8 g/day of DHA was chosen on the basis of earlier studies carried out in healthy individuals and recently reviewed (Arterburn et al, 2006). DHA was provided as 0.5 g capsules of DHASCO containing DHA-enriched triglyceride oil of algal origin (44% DHA providing 0.2-g DHA). DHASCO capsules were kindly supplied by Martek Biosciences Corp. (Columbia, MD, USA). Patients received nine capsules of DHASCO daily (representing 200 mg × 9=1.800 mg DHA/day), as three capsules at each meal. DHA was administered from inclusion before initiation of chemotherapy (a 7–10-day loading period) and then for the 5 months of chemotherapy. Patients were explicitly asked to avoid any intake of anti-oxidants. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779856/?report=classic

From the case report where malignant fibrous histiocytoma with multiple lesions in both lungs was effectively treated: he consumed 15 g of the long-chain omega-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) per day http://www.ncbi.nlm.nih.gov/pubmed/16201843

Budwig diet:

How to Make the Budwig Diet Mixture https://www.cancertutor.com/make_budwig/

Note: due to the reasons mentioned above I would make sure that the Omega-3 therapy is support by co-administration of Honokiol (if possible at about 3g/day).

Source:

Supplements:

This seems to be a good source as it is of vegetarian origin (i.e. no fish taste) and high dose: Ovega-3
In order to get to the right dose we would need to take 9 capsules/day of this one.

Diet:

From diet, flax and chia seeds, walnut etc. are sources of alha-Linoleic Acid that can be converted in EPA and DHA. Sources of DHA and EPA are fish oil, algae oil, krill oil. The best natural dietary sources of EPA and DHA include oily fish such as swordfish, atlantic salmon, gemfish and spanish mackerel, as well as oysters. Meats such as beef, chicken and lamb contain smaller amounts of n-3 FAs. (Ref.)

Fish species, Fresh or canned, and the related Omega-3 content (mg/100g):
Swordfish Fresh 1059; Salmon, Atlantic Fresh 689; Gemfish Fresh 441; Mackerel, spanish Fresh 411; Trout, rainbow Fresh 309; Warehou, silver Fresh 308; Dory, silver Fresh 303; Mullet, sea Fresh 299; Snapper Fresh 223; Redfish Fresh 194; Dory, john Fresh 188; Perch, brownband sea Fresh 167; Bream, yellowfin Fresh 146; Mullet, yelloweye Fresh 133; Perch, reef ocean Fresh 119; Tuna, yellowfin Fresh 117; Snapper, goldband Fresh 114; Ling, pink Fresh 113; Flathead, marbled Fresh 99; Barramundi, salt water Fresh 98; Barramundi, fresh water Fresh 89; Sardine Canned 2837 – 4044; Mackerel Canned 1409 – 3570; Salmon Canned 497 – 2738; Tuna Canned 177 – 370. (Ref.)

References:

Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779856/?report=classic

DHA during chemotherapy was devoid of adverse side effects and can improve the outcome of chemotherapy when highly incorporated. DHA has a potential to specifically chemosensitise tumours.

Epoxides Derived from Dietary Dihomo-Gamma-Linolenic Acid Induce Germ Cell Death in C. elegans http://www.nature.com/articles/srep15417

Essential Fatty Acids and Skin Health http://lpi.oregonstate.edu/mic/micronutrients-health/skin-health/nutrient-index/essential-fatty-acids

Potential Benefits of Omega-3 Fatty Acids in Non-Melanoma Skin Cancer (Ref.)

Omega-3 polyunsaturated fatty acids attenuate breast cancer growth through activation of a neutral sphingomyelinase-mediated pathway (Ref.)

The Effects of n-3 Fatty Acids and Bexarotene on Breast Cancer Cell Progression (Ref.)

Components of an Anticancer Diet: Dietary Recommendations, Restrictions and Supplements of the Bill Henderson Protocol  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257729/

Multi-targeted Therapy of Cancer by Omega-3 Fatty Acids http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2572135/

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) are essential fatty acids necessary for human health. Currently, the Western diet contains a disproportionally high amount of n-6 PUFAs and low amount of n-3 PUFAs, and the resulting high n-6/n-3 ratio is thought to contribute to cardiovascular disease, inflammation, and cancer. Studies in human populations have linked high consumption of fish or fish oil to reduced risk of colon, prostate and breast cancer, although other studies failed to find a significant association. Nonetheless, the available epidemiological evidence, combined with the demonstrated effects of n-3 PUFAs on cancer in animal and cell culture models, has motivated the development of clinical interventions using n-3 PUFAs in the prevention and treatment of cancer, as well as for nutritional support of cancer patients to reduce weight loss and modulate the immune system. In this review, we discuss the rationale for using long-chain n-3 PUFAs in cancer prevention and treatment and the challenges that such approaches pose in the design of clinical trials.

Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis http://www.pnas.org/content/110/16/6530.full.pdf

Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: Role for omega-3 epoxides http://www.biopestlab.ucdavis.edu/files/209378.pdf

Omega-3 polyunsaturated fatty acids and mitochondria, back to the future http://www.sciencedirect.com/science/article/pii/S2090123217300644

Background: Mitochondrion, a double-membrane bound organelle, plays a critical role in eukaryotic cells energy production. Further to its role as ATP-producing factory, mitochondrion has distinct role in a number of cellular functions including calcium and redox signaling, apoptosis, and autophagy. Extensive studies showed the crucial role of mitochondrial dysfunction in pathophysiology of different diseases such as cardiovascular diseases, neurodegenerative diseases, among others. Recently extensive evidences report the promising effects of omega-3 polyunsaturated fatty acids on mitochondrial structure and functions as well as mitochondrial diseases.

Scope and approach: In this paper, we critically review the available evidences on beneficial role of omega-3 polyunsaturated fatty acids on mitochondrial dynamic and biogenesis. We also discuss about chemistry, source, and bioavailability of omega-3 polyunsaturated fatty acids.

Key findings and conclusions: These findings lead to an upsurge of interest in finding a new effective therapeutic strategy based on targeting mitochondrial dysfunction for above-mentioned diseases. Recently, a great body of evidences obtained from experimental studies shows the promising role of omega-3 polyunsaturated fatty acids on mitochondrial function and dynamics. Different clinical trials have also addressed the promising role of omega-3 polyunsaturated fatty acids on different disease and these facts may be related to its favorable effects on mitochondria.

Phase II study of high‐dose fish oil capsules for patients with cancer‐related cachexia https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.20362

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

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