Yet Another Problem For Fructose

Study on exercise recovery.  Conclusion of abstract:

CONCLUSIONS:

Mixed meals containing fat, protein, and either fructose or glucose elicit similar repletion of IMCLs and muscle glycogen. Under such conditions, fructose lowers whole-body glycogen synthesis and impairs subsequent exercise performance, presumably because of lower hepatic glycogen stores. This trial was registered at clinicaltrials.gov as NCT01866215.

Therefore, by interfering with glycogen synthesis, fructose "impairs subsequent exercise performance" - something that both professional athletes and the amateur person trying to keep in shape want to avoid at all costs.

Avoid exogenous fructose (that is, fructose not naturally found in healthy food like fruit) as much as possible.

A Double-Edged Sword: PDGF-DD

The same factors secreted by tumors to make them grow and metastasize can also trigger immune reactions against them.  This finding can help devise novel anti-cancer immunotherapy approaches.  Abstract:

Many tumors produce platelet-derived growth factor (PDGF)-DD, which promotes cellular proliferation, epithelial-mesenchymal transition, stromal reaction, and angiogenesis through autocrine and paracrine PDGFRβ signaling. By screening a secretome library, we found that the human immunoreceptor NKp44, encoded by NCR2 and expressed on natural killer (NK) cells and innate lymphoid cells, recognizes PDGF-DD. PDGF-DD engagement of NKp44 triggered NK cell secretion of interferon gamma (IFN)-γ and tumor necrosis factor alpha (TNF-α) that induced tumor cell growth arrest. A distinctive transcriptional signature of PDGF-DD-induced cytokines and the downregulation of tumor cell-cycle genes correlated with NCR2 expression and greater survival in glioblastoma. NKp44 expression in mouse NK cells controlled the dissemination of tumors expressing PDGF-DD more effectively than control mice, an effect enhanced by blockade of the inhibitory receptor CD96 or CpG-oligonucleotide treatment. Thus, while cancer cell production of PDGF-DD supports tumor growth and stromal reaction, it concomitantly activates innate immune responses to tumor expansion.

The Current Education Scam

And the subtitle is "The most infuriating article I have recently read"

Here is the article that triggered my indignation and fueled me sufficiently on a deep-freeze day to defrost, sit down and write:

A dying town

This attempt at journalism describes the plight of several people, who, according to the authors, are in their current plight due to their low level of education. And here is the supportive of this statement subtitle:

“Here in a corner of Missouri and across America, the lack of a college education has become a public-health crisis.”

The article is about Missouri Bootheel, the southeastern part of the state of Missouri, but it might as well describe countless other economically dying regions of the country.

And yet, instead of focusing on the real reasons for this large-scale human devastation across the country, this article instills “conclusions” that are manipulative, one-sided, judgmental and illogical. It is also highly offensive to the featured people.

Why do I claim that this article is judgmental?  Because, the authors claims that, “When people don’t have a plan B, it’s easy to lose hope.” 

Interestingly, I am not aware of too many people, no matter how high their education level is, who have multiple plans for their life and a long-term view on their development. How about you, dear authors, do you have plans B or C? How many of any high-powered individuals with a long list of educational degrees have a plan B? Every day, I meet highly educated people with impressive titles who have no idea what else they might do with their life if they were let go of their current positions. These are people who have dedicated two to 10+ years of their life to graduate studies. Some of them have entered the workforce at 35+. Our current education, no matter at what level, does not teach us to be flexible and to think ahead about plans B and C!

Why is this article illogical? Here is what the authors think, “He could have continued to law school, as he considered doing, and gone on to spend far fewer days worrying about stray sparks from power tools setting his jeans on fire. For some of his high-school classmates, college was their one-way ticket out of the Bootheel. It was for his younger sister, who now lives in Arkansas. The kids who didn’t go to college, or who didn’t finish, are the ones who stuck around”.

Alright, if we listen to the condescending advice of the authors, no one, not a single person in the U.S. should still live in Bootheel, MO (here is a new law for you, America: "no citizen left behind"). In fact, all other dying towns and cities across America should be abandoned as well. Everyone born in these places should get their college education and leave. They can become lawyers, for example!

By the way, dear authors, are you aware that some of these “dying” regions still produce smidgens of agricultural products? According to authors, “Farming is a tough industry, and he’s lost about $45,000 on his own crops over the past three years.”

Dear authors, do you think that America should close down all its farms? Then probably you should have given a bit more thought to your comparison of the prices of healthy food to these of fast food, ”A McDonald’s double cheeseburger is half the price of a packaged salad at Walmart.” Do you think that this absurdity has nothing to do with the fact that U.S. has systematically annihilated the farming in places like Bootheel, MO? Do you think that if we had a well-subsidized, local small-scale farmers, the prices of fresh produce, including these of salads, would still exceed the prices of fast food?

But let me focus on something slightly positive in this piece of “journalism”. The article does contain a grain of the real problem. “The jobs that once went to folks around here, they say, are now being done by robots or Mexicans or some combination of the two.”

Give people jobs. Make them proud of themselves again. And by the way, for some type of jobs, one does not need to go to college. One could go through apprenticeship and/or vocational training, and both would prepare for the job and pay the bills at the same time. This is the system established in one of the most developed and civilized countries in the world, Switzerland, and I have previously written about it. 

Instead, our current scam of education plunges young people into years of wasted time, buries them under piles of unnecessary information, and blinds them with false educational innovations that have no practical applications. Just look at the current curriculum of high schools, or glance at a college transcript of a Biology major undergrad who has taken “Roman Baths and Brothels” and “African Dances”. Surely, this type of “knowledge” combined with the debt attached to obtaining the “knowledge” would not have helped any of the people featured in the article!

Since one can twist and turn the reality in any direction, let me put forward another interpretation of the very same stories in this article. My interpretation is that whatever little education the main characters of the stories had, was not good enough, it was a waste of time. Their public education in elementary, middle and high school failed them, because it did not focus on the crucial things in life. Whatever education these people had, was useless, since it did not teach them how to take care of themselves and their finances. None of this is rocket science! How to take care of your health, how to eat healthy and how to budget could be taught in elementary and middle school. Just look what instructional videos on personal budgeting and finance were created in 1948.

The crux of the problem is that millions today are left without vocational training, at times when more or less every industry has pulled out of the U.S. and has gone for profit somewhere else. The current educational system cannot provide the solutions to the deepening economic crisis in the U.S. 

Only a revolution in the so-called "education industry" would allow us to face some of the problems mentioned in this article. This revolution should wipe out at least half of the pseudo-schools and programs in the country. Otherwise, the country roads that could bring people back home would be forgotten:

Country roads, take me home
To the place I belong
West Virginia
Mountain mamma, take me home
Country roads
Songwriters: John Denver / Taffy Danoff / William T Danoff

Antibodies To Watch In 2018

For those of you who like to keep track of such things, here is a list of clinically relevant antibodies that may prove therapeutically useful in 2018 and beyond. Abstract:

The pace of antibody therapeutics development accelerated in 2017, and this faster pace is projected to continue through 2018. Notably, the annual number of antibody therapeutics granted a first approval in either the European Union (EU) or United States (US) reached double-digits (total of 10) for the first time in 2017. The 10 antibodies granted approvals are: brodalumab, dupilumab, sarilumab, guselkumab, benralizumab, ocrelizumab, inotuzumab ozogamicin, avelumab, duvalumab, and emicizumab. Brodalumab, however, had already been approved in Japan in 2016. As of December 1, 2017, nine antibody therapeutics (ibalizumab, burosumab, tildrakizumab, caplacizumab, erenumab, fremanezumab, galcanezumab, romosozumab, mogamulizumab) were in regulatory review in the EU or US, and regulatory actions on their marketing applications are expected by the end of 2018. Based on company announcements and estimated clinical study primary completion dates, and assuming the study results are positive, marketing applications for at least 12 antibody therapeutics that are now being evaluated in late-stage clinical studies may be submitted by the end of 2018. Of the 12 candidates, 8 are for non-cancer indications (lanadelumab, crizanlizumab, ravulizumab, eptinezumab, risankizumab, satralizumab, brolucizumab, PRO140) and 4 are for cancer (sacituzumab govitecan, moxetumomab pasudotox, cemiplimab, ublituximab). Additional antibody therapeutics to watch in 2018 include 19 mAbs undergoing evaluation in late-stage studies with primary completion dates in late 2017 or during 2018. Of these mAbs, 9 are for non-cancer indications (lampalizumab, roledumab, emapalumab, fasinumab, tanezumab, etrolizumab, NEOD001, gantenerumab, anifrolumab) and 10 are for cancer indications (tremelimumab, isatuximab, BCD-100, carotuximab, camrelizumab, IBI308, glembatumumab vedotin, mirvetuximab soravtansine, oportuzumab monatox, L19IL2/L19TNF). Positive clinical study results may enable marketing application submissions in 2018. Brief summaries of these antibody therapeutics are provided in this installment of the 'Antibodies to watch' article series.

More On Neoantigens

Neoantigens – aberrant proteins produced by mutated genes (e.g., in cancer) – are associated with long-term survivors of pancreatic cancer, possibly because the neoantigens are stimulating anti-tumor immune responses.  Neoantigen production is also associated with response to anti-cancer immunotherapy.  Abstract:

Checkpoint blockade immunotherapies enable the host immune system to recognize and destroy tumour cells. Their clinical activity has been correlated with activated T-cell recognition of neoantigens, which are tumour-specific, mutated peptides presented on the surface of cancer cells. Here we present a fitness model for tumours based on immune interactions of neoantigens that predicts response to immunotherapy. Two main factors determine neoantigen fitness: the likelihood of neoantigen presentation by the major histocompatibility complex (MHC) and subsequent recognition by T cells. We estimate these components using the relative MHC binding affinity of each neoantigen to its wild type and a nonlinear dependence on sequence similarity of neoantigens to known antigens. To describe the evolution of a heterogeneous tumour, we evaluate its fitness as a weighted effect of dominant neoantigens in the subclones of the tumour. Our model predicts survival in anti-CTLA-4-treated patients with melanoma and anti-PD-1-treated patients with lung cancer. Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumours and rapidly evolving pathogens.

Exercise Instead Of Drugs For Knee Osteoarthritis

It should come as no surprise of readers of this blog that quadriceps (muscles of the front of the thigh) exercise can as effective as nonsteroidal anti-inflammatory drugs against knee osteoarthritis.  And yet, taking pills is the “default” for the medical profession – everything “solved” with drugs.  Abstract:

OBJECTIVES:

To examine the effect of home-based exercise on knee osteoarthritis among Japanese in comparison with that of nonsteroidal antiinflammatory drugs (NSAIDs).

DESIGN:

An open-labeled, randomized, controlled, multiclinic trial compared home-based quadriceps exercise with NSAIDs. Treatments were basically evaluated after 8 wks and compared with the baseline scores. Outcomes were evaluated with a set of psychometric measurements including the Western Ontario and McMaster Universities Arthritis Index (WOMAC), 36-Item Short-Form Health Survey (SF-36), Japanese Knee Osteoarthritis Measure (JKOM), and pain with the visual analog scale.

RESULTS:

A total of 142 patients entered this trial to provide the baseline data. After 21 cases withdrew, the final number analyzed was 121 cases: 63 for the exercise group and 58 for the NSAIDs group. Between these two groups, there was no significant difference in gender, age, body height and weight, body mass index, or each score at baseline. The subjects in both groups showed improvements in all scores at the end of intervention. The difference in improvement rate of each score between the two groups was not statistically significant, though the mean rank score measured with JKOM in the exercise was slightly better than that of the NSAIDs.

CONCLUSIONS:

Home-based exercise using quadriceps strengthening improves knee osteoarthritis no less than NSAIDs.

Tumor Mutations and anti-PD-1 Immunotherapy Response

Inhibitors of factors that themselves inhibit an anti-tumor response are promising therapeutic agents.  Here we see once again that response to such agents is related to the number of mutations a tumor has.  The more mutations, the more neoantigens produced – the more aberrant proteins produced that can be recognized by the immune system once the “brakes” are off.  Excerpts (figure shown is from the paper, which is freely accessible online):

Inhibitors of programmed death 1 (PD-1) protein or its ligand (PD-L1) have shown remarkable clinical benefit in many cancers. One emerging biomarker of response to anti–PD-1 therapy is the tumor mutational burden (i.e., the total number of mutations per coding area of a tumor genome). This finding is supported by the clinical activity of anti–PD-1 therapy in colorectal cancer with mismatch repair deficiency, a tumor subtype with a high tumor mutational burden, as compared with the colorectal cancer subtype with mismatch repair proficiency, which has a significantly lower tumor mutational burden and a poor response to these agents. 

To evaluate the relationship between the tumor mutational burden and the objective response rate, we plotted the objective response rate for anti–PD-1 or anti–PD-L1 therapy against the corresponding median tumor mutational burden across multiple cancer…We observed a significant correlation between the tumor mutational burden and the objective response rate (P<0.001). The correlation coefficient of 0.74 suggests that 55% of the differences in the objective response rate across cancer types may be explained by the tumor mutational burden. 

Diabetes Drugs Against Alzheimer’s Disease

Some findings of interest, relevant sections:

Studies in a mouse model of Alzheimer’s disease (AD) have shown how a drug that was originally developed to treat diabetes demonstrates what researchers in the U.K. and China call “clear promise” as a treatment for AD and other neurodegenerative disorders in humans. The studies, led by Christian Hölscher, Ph.D., at the U.K.’s Lancaster University, confirmed that AD mice treated using a triple-receptor agonist (TA) showed “significantly reversed memory loss,” as well as reduced neuroinflammation and oxidative stress, lower amyloid plaque load in the brain, and increased levels of brain-derived neurotropic factor (BDNF), a key growth factor that protects synaptic function… 

…Type 2 diabetes mellitus (T2DM) is a known risk factor for AD, and this association has motivated scientists to investigate whether antidiabetic drugs might also be effective against AD. Studies have shown that the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which have antidiabetic properties, can play a neuroprotective role in the brain and have demonstrated promising effects in animal models of AD. 

  Prof. Holscher’s team turned to a triple-receptor agonist that activates GIP-1, GIP, and glucagon receptors…The results showed that a daily injection of TA reversed memory loss in AD mice, which was assessed in a spatial water maze test. The drug also reduced levels of the mitochondrial proapoptotic signaling molecule BAX, increased the antiapoptotic signaling molecule Bcl-2, and boosted levels of BDNF. Levels of synaptophysin were also elevated, which the researchers say demonstrates protection against the synaptic loss that is seen in AD…

 

 …“Furthermore, TA treatment reduced the total amount of β-amyloid, reduced neuroinflammation (activated microglia and astrocytes), and oxidative stress in the cortex and hippocampus,” the authors write. “The results demonstrate for the first time that the novel GLP-1/GIP/Gcg receptor agonist has clear neuroprotective effects in the APP/PS1 mouse model of AD.” 

Given the “impressive” preclinical data demonstrating the neuroprotective properties of GLP-1, GIP, and glucagon receptor agonists, clinical trials are now under way to investigate the neuroprotective effects of the GLP-1 receptor agonists extendin-4 (Byetta®, Bydureon®) and liraglutide (Victoza®) in patients with AD or with Parkinson's disease, the authors note. “A pilot study testing the GLP-1 analogue liraglutide in AD patients showed promising results.”

That sounds like a very promising advance in the field of Alzheimer’s therapy, and also underscores the relationship between that disease and metabolic disorders.

Sauerkraut and meat

Some have a sweet tooth, I have a sour one. So, any recipe that includes, or could include, sauerkraut is tried in my household.
Below is my recent invention of a more or less edible meal that is easy to cook and warms up the house on a cold winter day. If you do not like the sour taste, this meal is not for you. However, if you love sauerkraut and you do eat meat, then you should try the recipe and even reinvent the combination of spices according to your preferences. I used ground turkey, but you could use any other meat.
Sauerkraut and ground turkey
Ingredients:
1 or 2 cans sauerkraut (27 oz)
2-3 pounds of ground meat (I used lean turkey)
1 large sweet onion, thinly chopped
1-2 Tbsp olive oil
spices: black pepper, salt, paprika, hot pepper flakes

Directions:
Heat the oil in a frying pan and soften the onion. Add the meat and crumble it until it is evenly brown (there should be no pink color left). Add the spices and mix well. Prepare a roasting pan with non-stick spray. In the pan, mix the meat with the sauerkraut. If you like the dish more sour, then use two cans of sauerkraut; otherwise, use just one. If you end up using two cans of sauerkraut, pour 2-3 cups of water, cover with foil and roast at 400F for an hour. The next 15 minutes of baking, remove the foil and continue cooking. If you use only one can of sauerkraut, use less water and shorten the baking time.