THOR And Cancer

THOR may promote cancer, not Thor the Asgardian god, but THOR the long non-coding RNA. Targeting THOR via gene therapy may be a novel anti-cancer approach.  Abstract:

Large-scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. Here, we functionally characterize a novel ultraconserved lncRNA, THOR (ENSG00000226856), which exhibits expression exclusively in testis and a broad range of human cancers. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role. We discovered a conserved interaction of THOR with IGF2BP1 and show that THOR contributes to the mRNA stabilization activities of IGF2BP1. Notably, transgenic THOR knockout produced fertilization defects in zebrafish and also conferred a resistance to melanoma onset. Likewise, ectopic expression of human THOR in zebrafish accelerated the onset of melanoma. THOR represents a novel class of functionally important cancer/testis lncRNAs whose structure and function have undergone positive evolutionary selection.

Osimertinib Against Lung Cancer

Osimertinib is a relatively new molecularly-targeted anti-cancer therapy that targets EGF signaling, and has shown efficacy for EGFR mutation-positive advanced non-small-cell lung cancer. Abstract:

Background Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). Methods In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival. Results The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%). Conclusions Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .).

More On Combination Drug Therapy For Cancer

Combination drug therapy for cancer has been thought to always involve the drugs working together in an additive or even synergistic fashion.  However, one study shows that in some cases, the efficacy of drug combinations is solely due to patient-to-patient variability in response and the independent action of the drugs.  So, assume you have two patients, Bill and Mary, both with the same type of cancer, and they are given combination therapy with drugs A and B.  The traditional idea was that success would be due to A and B both working equally in both patients, or working synergistically; this new study suggests that in some cases, if you don’t know in advance which drug is best for what patient, you give both, and maybe Bill responds to A and Mary to B, and you see a success that you would not have seen if you had given both patients either A or B – so you get 100% success instead of 50%. Keep in mind that there are of course cases where combination therapy does wok additively or synergistically.  Abstract:

Combination cancer therapies aim to improve the probability and magnitude of therapeutic responses and reduce the likelihood of acquired resistance in an individual patient. However, drugs are tested in clinical trials on genetically diverse patient populations. We show here that patient-to-patient variability and independent drug action are sufficient to explain the superiority of many FDA-approved drug combinations in the absence of drug synergy or additivity. This is also true for combinations tested in patient-derived tumor xenografts. In a combination exhibiting independent drug action, each patient benefits solely from the drug to which his or her tumor is most sensitive, with no added benefit from other drugs. Even when drug combinations exhibit additivity or synergy in pre-clinical models, patient-to-patient variability and low cross-resistance make independent action the dominant mechanism in clinical populations. This insight represents a different way to interpret trial data and a different way to design combination therapies.

Vitamin D and Sleep Disorders

A study has shown that Vitamin D supplementation improves sleep quality in people aged 20-50 with sleep disorders. Abstract:

OBJECTIVES:

Sleep quality may be directly related with vitamin D serum level. Some studies found that people with lower vitamin D serum level experienced a lower sleep quality. Consequently, this study aimed at determining the effect of vitamin D supplements on sleep score and quality in 20-50 year-old people with sleep disorders.

METHODS:

This double blind, clinical trial was performed in November 2015-February 2016 on 89 people with sleep disorders based on Petersburg's Sleep Index. Patient samples were divided randomly into two groups: intervention and placebo. At the end of the study, the data on 89 subjects (44 in intervention group and 45 people in placebo group) were examined. Intervention group received a 50 000-unit vitamin D supplement, one in a fortnight for 8 weeks. Meanwhile, placebo group received placebo. Before and after intervention, Petersburg's Sleep Quality Questionnaire, International Physical Activity Questionnaire, general information questionnaire, sun exposure, vitamin D serum level and 3-day food record questionnaire were assessed and recorded for all participants. To analyze data, t-test, chi square, ANCOVA, U-Mann-Whitney and Wilcoxon statistical tests were used.

FINDINGS:

Based on the results of the present study, at the end of the study sleep score (PSQI) reduced significantly in vitamin recipients as compared with placebo recipients (P < 0.05). This difference was significant even after modifying confounding variables (P < 0.05).

CONCLUSION:

This study shows that the use of vitamin D supplement improves sleep quality, reduces sleep latency, raises sleep duration and improves subjective sleep quality in people of 20-50 year-old with sleep disorder.

CRISPR Targeting RNA

The CRISPR system is a crucially important, relatively new, system for targeted modification of DNA, and one that has implications for gene therapy.  It has been discovered that certain CRISPR enzymes can modify RNA; this opens up new avenues for the control of gene expression and novel therapeutic applications.  Abstract:

Double-stranded DNA (dsDNA) binding and cleavage by Cas9 is a hallmark of type II CRISPR-Cas bacterial adaptive immunity. All known Cas9 enzymes are thought to recognize DNA exclusively as a natural substrate, providing protection against DNA phage and plasmids. Here we show that Cas9 enzymes from both subtypes II-A and II-C can recognize and cleave single-stranded RNA (ssRNA) by an RNA-guided mechanism that is independent of a protospacer-adjacent motif (PAM) sequence in the target RNA. RNA-guided RNA cleavage is programmable and site-specific, and we find that this activity can be exploited to reduce infection by single-stranded RNA phage in vivo. We also demonstrate that Cas9 can direct PAM-independent repression of gene expression in bacteria. These results indicate that a subset of Cas9 enzymes have the ability to act on both DNA and RNA target sequences, and suggest the potential for use in programmable RNA targeting applications.

Gardens: where the earth meets the sky

I have been in a slump. It is mostly due to people at work behaving badly. Or just behaving in an incredibly disappointing way. This has been a process of gradual and steady realization that the people I believed in are flawed and not willing to change. It is like watching someone's image slowly erode in front of you. At the end of the process, nothing is left from the sharp features and characteristics of the person you knew. All you are left with is a knot of low willpower, silliness, unwillingness to take ownership for mistakes, misguided values and lack of discipline.

I do not have high expectations of anyone, and yet even the minimum expected at work is sometimes not met, and this jeopardizes my own function there. As a result, I am completely drained out of energy and hope. The only source of optimism are my meetings with students. Youth almost always brings the breeze of change and dynamism.

I have desperately tried to grasp onto the financial independence theme, and dream about times of unfettered existence, when I may revive whatever creative streak I have had in the past. But the timeline to independence is still murky and undecided upon. We have a major financial obligation to fulfill prior to scheduling our freedom day.

I have also tried to listen to Jocko's podcasts that describe the indescribable horrors of wars. Listening to episode 12 of Jocko's readings put things in perspective, and yet, it somehow did not diminish the anguish about my precious life being wasted on petty and useless things that the red tape spits in my face.

This morning I tried another remedy - watching Monty Don and his Paradise Gardens. It proved to be one of the most enchanting programs about gardens. I watched the first 20 minutes while cooking and I am planning on finishing the first episode over lunch.

If you are down these days and you love gardens, this Monty Don production will not disappoint you:

Intermittent Fasting Problem?

While there are a number of studies supporting benefits for of intermittent calorie restriction (ICR), a disturbing new study in mice suggests negative effects of ICR: an increase in cancer stem cells (CSCs) and enhancement of epithelial to mesenchymal transition, which promotes metastasis.  Keeping the mice in “continuous calorie restriction had no effect on tumor weight, metastasis, or the number of CSCs in tumors or blood” – not bad but not good either.  Speaking for myself, I eat three healthy meals per day (with approximately 12 hours between dinner and the subsequent breakfast), avoid overweight/obesity, and avoid any “fad diets.”  That’s what I’m doing, that is not necessarily a recommendation to anyone else.  Abstract:

The effect of intermittent calorie restriction (ICR) on cancer is controversial. In this study, we examined the effects of ICR and food content in syngeneic BALB/c mice injected with CT26 mouse colon cancer cells. Mice were subjected to 24-h fasting once a week for 4 weeks, and then provided with a control, high-calorie, or trans fatty acid-rich diet. While ICR resulted in increases in tumor weights, metastasis and in the number of cancer stem cells (CSCs) in the tumors or blood of mice fed the control and high-fat diets, it had no effect on body weight after 4 weeks. In particular, we detected increases in the numbers of CSCs in the tumor or blood on the day after starvation, when food overconsumption was detected. Conversely, continuous calorie restriction had no effect on tumor weight, metastasis, or the number of CSCs in tumors or blood. In the post-starvation period, energy metabolism in the tumor was altered from oxidative phosphorylation to glycolysis/lactate fermentation, with the acquisition of the epithelial-mesenchymal transition (EMT) phenotype. Hyperglycemia at the post-starvation period induced the expression of insulin-like growth factor-1, hypoxia-induced factor-1α and Nanog, as well as the phosphorylation of Stat3. Taken together, these findings suggest that ICR induces an increase in the number of CSCs and enhances EMT by promoting the Warburg/Crabtree effect following post-fasting food overconsumption.

Vitamin B Supplementation May Increase Lung Cancer Risk In Men

There is sometimes a "more is better" attitude that some people have towards vitamins, particularly vitamin supplements,  and that can be dangerous, as some vitamins can be harmful, even dangerous, with taken excessively. Getting vitamins in foods rather than in supplements is, when it is possible, usually preferable.  The article linked here suggests that vitamin B supplements, in this case vitamins B6 and B12, can increase lung cancer risk in men, particularly for male smokers.  Both patients and their doctors should be aware of these findings, and physicians should advise their patients, especially those at higher risk, accordingly.  Abstract:

Purpose Inconsistent findings have been reported of a link between the use of one-carbon metabolism-related B vitamins and lung cancer risk. Because of the high prevalence of supplemental vitamin B use, any possible increased association warrants further investigation. We examined the association between long-term use of supplemental B vitamins on the one-carbon metabolism pathway and lung cancer risk in the Vitamins and Lifestyle (VITAL) cohort, which was designed specifically to look at supplement use relative to cancer risk. Methods A total of 77,118 participants of the VITAL cohort, 50 to 76 years of age, were recruited between October 2000 and December 2002 and included in this analysis. Incident, primary, invasive lung cancers (n = 808) were ascertained by prospectively linking the participants to a population-based cancer registry. The 10-year average daily dose from individual and multivitamin supplements were the exposures of primary interest. Results Use of supplemental vitamins B6, folate, and B12 was not associated with lung cancer risk among women. In contrast, use of vitamin B6 and B12 from individual supplement sources, but not from multivitamins, was associated with a 30% to 40% increase in lung cancer risk among men. When the 10-year average supplement dose was evaluated, there was an almost two-fold increase in lung cancer risk among men in the highest categories of vitamin B6 (> 20 mg/d; hazard ratio, 1.82; 95% CI, 1.25 to 2.65) and B12 (> 55µg/d; hazard ratio, 1.98; 95% CI, 1.32 to 2.97) compared with nonusers. For vitamin B6 and B12, the risk was even higher among men who were smoking at baseline. In addition, the B6 and B12 associations were apparent in all histologic types except adenocarcinoma, which is the type less related to smoking. Conclusion This sex- and source-specific association provides further evidence that vitamin B supplements are not chemopreventive for lung cancer and may be harmful.

Exercise Sequence And Fitness

Strength, in this case lower body strength, is maximized by first training for strength followed by training for endurance (rather than the other way around) – which makes sense. For aerobic fitness, training order doesn’t matter, so the net conclusion one can make is to train for strength and then endurance when scheduling sequential training sessions. Abstract:

We conducted a systematic literature review and meta-analysis to assess the chronic effects of the sequence of concurrent strength and endurance training on selected important physiological and performance parameters, namely lower body 1 repetition maximum (1RM) and maximal aerobic capacity (VO2max/peak). Based on predetermined eligibility criteria, chronic effect trials, comparing strength-endurance (SE) with endurance-strength (ES) training sequence in the same session were included. Data on effect sizes, sample size and SD as well other related study characteristics were extracted. The effect sizes were pooled using, Fixed or Random effect models as per level of heterogeneity between studies and a further sensitivity analyses was carried out using Inverse Variance Heterogeneity (IVHet) models to adjust for potential bias due to heterogeneity. Lower body 1RM was significantly higher when strength training preceded endurance with a pooled mean change of 3.96 kg (95%CI: 0.81 to 7.10 kg). However, the training sequence had no impact on aerobic capacity with a pooled mean difference of 0.39 ml.kg.min-1 (95%CI: -1.03 to 1.81 ml.kg.min-1). Sequencing strength training prior to endurance in concurrent training appears to be beneficial for lower body strength adaptations, while the improvement of aerobic capacity is not affected by training order.

Youth Handles Stress Better

Chronic unpredictable stress (CUS) apparently can affect us – or at least female mice – differently based on age.  Thus the paper states: "We found that in young-adult female mice, CUS resulted in decreased anxiety-like behavior and enhanced cognitive performance, whereas in old female mice it led to weight loss, dysregulated locomotion and memory impairment."  It’s a young mouse’s world; the same likely applies to humans, also likely both sexes, but we need to study this.  Abstract:

Stress-related psychopathology is highly prevalent among elderly individuals and is associated with detrimental effects on mood, appetite and cognition. Conversely, under certain circumstances repeated mild-to-moderate stressors have been shown to enhance cognitive performance in rodents and exert stress-inoculating effects in humans. As most stress-related favorable outcomes have been reported in adolescence and young-adulthood, this apparent disparity could result from fundamental differences in how aging organisms respond to stress. Furthermore, given prominent age-related alterations in sex hormones, the effect of chronic stress in aging females remains a highly relevant yet little studied issue. In the present study, female C57BL/6 mice aged 3 (young-adult) and 20-23 (old) months were subjected to 8 weeks of chronic unpredictable stress (CUS). Behavioral outcomes were measured during the last 3 weeks of the CUS protocol, followed by brain dissection for histological and molecular end points. We found that in young-adult female mice, CUS resulted in decreased anxiety-like behavior and enhanced cognitive performance, whereas in old female mice it led to weight loss, dysregulated locomotion and memory impairment. These phenotypes were paralleled by differential changes in the expression of hypothalamic insulin and melanocortin-4 receptors and were consistent with an age-dependent reduction in the dynamic range of stress-related changes in the hippocampal transcriptome. Supported by an integrated microRNA (miRNA)-mRNA expression analysis, the present study proposes that, when confronted with ongoing stress, neuroprotective mechanisms involving the upregulation of neurogenesis, Wnt signaling and miR-375 can be harnessed more effectively during young-adulthood. Conversely, we suggest that aging alters the pattern of immune activation elicited by stress. Ultimately, interventions that modulate these processes could reduce the burden of stress-related psychopathology in late life. Molecular Psychiatry advance online publication, 19 December 2017; doi:10.1038/mp.2017.237.

Discovering New Microbiota

Here is an interesting article about the discovery process of discovering “causal microbes” – microbiota, including new strains, which affect human health positively or negatively.  Some strains have been found that protect mice against colitis, as well as those that produce an antimicrobial peptide in the intestine.  Abstract:

Microbiome-wide association studies have established that numerous diseases are associated with changes in the microbiota. These studies typically generate a long list of commensals implicated as biomarkers of disease, with no clear relevance to disease pathogenesis. If the field is to move beyond correlations and begin to address causation, an effective system is needed for refining this catalogue of differentially abundant microbes and to allow subsequent mechanistic studies. Here we demonstrate that triangulation of microbe-phenotype relationships is an effective method for reducing the noise inherent in microbiota studies and enabling identification of causal microbes. We found that gnotobiotic mice harbouring different microbial communities exhibited differential survival in a colitis model. Co-housing of these mice generated animals that had hybrid microbiotas and displayed intermediate susceptibility to colitis. Mapping of microbe-phenotype relationships in parental mouse strains and in mice with hybrid microbiotas identified the bacterial family Lachnospiraceae as a correlate for protection from disease. Using directed microbial culture techniques, we discovered Clostridium immunis, a previously unknown bacterial species from this family, that-when administered to colitis-prone mice-protected them against colitis-associated death. To demonstrate the generalizability of our approach, we used it to identify several commensal organisms that induce intestinal expression of an antimicrobial peptide. Thus, we have used microbe-phenotype triangulation to move beyond the standard correlative microbiome study and identify causal microbes for two completely distinct phenotypes. Identification of disease-modulating commensals by microbe-phenotype triangulation may be more broadly applicable to human microbiome studies.

What's In The Wine?

Resveratrol, which is found in wine as well as in other foodstuffs, has been thought to have a number of positive health benefits.  Here is a study that shows some activity against bone cancer cells.  Certain signaling pathways are involved, including suppression of Wnt signaling. Abstract:

Osteosarcoma is a high-grade bone sarcoma with strong invasive ability. However, treatment with traditional chemotherapeutic drugs is limited by low tolerability and side effects. Resveratrol has been reported previously to have selective antitumor effect on various tumor cells while little is known about its effects and underlying mechanism in osteosarcoma biology. In this study, we found that resveratrol inhibits proliferation and glycolysis, induces apoptosis and reduces the invasiveness of U2-OS cells in vitro. After treatment with resveratrol, the expression of related Wnt/β-catenin signaling pathway target genes, such as β-catenin, c-myc, cyclin D1, MMP-2 and MMP-9, was downregulated and an increased E-cadherin level was observed as well. Additionally, the dual luciferase assay results also indicated that resveratrol suppressed the activity of Wnt/β-catenin signaling pathway. Interestingly, we noticed that the expression of connexin 43 (Cx43) increased with the prolongation of resveratrol treatment time. To further investigate the relationship between Cx43 and the Wnt/β-catenin signaling pathway in osteosarcoma, we used lentiviral-mediated shRNA to knockdown the expression of Cx43. Knockdown of Cx43 activated the Wnt/β-catenin signaling pathway, promoted proliferation and invasion, and inhibited apoptosis of U2-OS cells. Taken together, our results demonstrate that the antitumor activity of resveratrol against U2-OS cells in vitro occurs through up-regulating Cx43 and E-cadherin, and suppressing the Wnt/β-catenin signaling pathway. Moreover, Cx43 expression is negatively related to the activity of the Wnt/β-catenin pathway in U2-OS cells.

APOE4 And Late-onset Alzheimer Disease

This link is to another paper showing an association between APOE4 and late-onset Alzheimer disease.  Understanding how the APOE4 gene variant enhances risk for this disease can help in the discover of novel therapeutic approaches.  Abstract:

APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a 'toxic' gain of function whereas the absence of ApoE is protective.

Essential Genes And Cancer Immunotherapy

Here is a paper looking at what genes may be essential for successful cancer immunotherapy. Abstract:

Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic loss-of-function mutations involved in resistance to these therapies, by using a genome-scale CRISPR-Cas9 library that consisted of around 123,000 single-guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8+ T cells. The genes that were most enriched in the screen have key roles in antigen presentation and interferon-γ signalling, and correlate with cytolytic activity in patient tumours from The Cancer Genome Atlas. Among the genes validated using different cancer cell lines and antigens, we identified multiple loss-of-function mutations in APLNR, encoding the apelin receptor, in patient tumours that were refractory to immunotherapy. We show that APLNR interacts with JAK1, modulating interferon-γ responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models. Our results link the loss of essential genes for the effector function of CD8+ T cells with the resistance or non-responsiveness of cancer to immunotherapies.

Restoring loss of function (gene therapy) may allow for successful cancer immunotherapy in those patients resistant to that therapeutic approach.  This study is the first necessary step in that direction and is therefore highly encouraging.

Party fair

Hello, everyone! 

It is cold, dark and unforgiving out, so it is time to experiment inside. Today, I decided to celebrate my day off with a "party" lunch. I toasted thinly sliced French bread, and prepared a few new recipes for appetizers. The first appetizer was easy deviled eggs, and the second - a chickpea-avocado spread. 

I happened to have all the ingredients in my refrigerator or the pantry. The toast was delicious with the avocado spread and a piece of roasted red pepper on top (I had a few peppers frozen from a jar). The eggs were spicy and a bit salty (due to the feta cheese). It was great to be inside on a frozen January day and enjoy a slow lunch.

Here are the two recipes:

Easy deviled eggs
Ingredients:
hard boiled eggs
crumbled feta cheese
chicken wing sauce (mine was from the dollar store)

Directions:
Peel the eggs; slice into two halves each egg. Carefully take out the yolks and mix with crumbled feta cheese and the spicy chicken wing sauce. Use any proportions that please you. Place the yolk mixture back into the egg whites, enjoy!

Garbanzo-avocado spread
Ingredients:
one can of garbanzo beans (15 oz)
two ripe avocados
the juice from 1/2 lemon
olive oil
salt
crushed garlic

Directions:
Mash the avocado and the garbanzo beans with a fork, add the salt, garlic, lemon juice and oil to taste. Mix and enjoy!

Mikelifesteer Homemade Uncrustables

Take two pieces of 100% whole wheat bread – I like to use double fiber bread, if available, to enhance the fiber intake. Remove the crust from the bread. Make the filling.  Two fillings that I have tried are:

Peanut butter, reduced fat cream cheese, low-sugar strawberry jam 

Peanut butter, reduced fat cream cheese, Musselman’s apple butter, cinnamon, raisins

In a ratio of approximately two heaping teaspoons of peanut butter to an equivalent amount of the other ingredients combined

You can of course try other components of the filling: prune butter, almond butter, various dried fruit and/or nuts, unsweetened apple sauce, chocolate, honey, wheat germ, etc.

Mix the filling and put in between the bread, and then seal the bread along the edges by pinching together.  Wrap in aluminum foil and bake for 30 minutes at 400 degrees F.  After cooling you can eat or freeze (it freezes very well).  I usually cut in half, so each one made is two servings for me.

As with all the baked materials I make, the homemade version is not going to be as sweet as the store-bought, but it will be healthier – and you’ll know exactly what’s in it, how it was made, etc.  In addition, when you eat healthier, your tastes change, so that you don’t always like very sweet things.

In fact, as a fan of apple pie and various baked goods based on apples – including those I make myself – I find one of the major flaws in store-bought apple pies and other such baked goods is that they are too sweet.  Rather than let the natural sweetness and tartness of the apples come through, they bury it under excessive sugar.  That’s coupled with – at least for the cheaper versions – using mushy apple filling that is barely recognizable as apples; in addition, the crust they have is too thin and too flaky.  I like thicker crust, less sweetness, fresher apples, just the right amount of seasoning – let the apples and apple based products (apple butter or apple sauce) themselves provide most of the flavor.  The same principle applies to these homemade uncrustables – no extra sugar is added; whatever sweetness and sugar is already present in the filling is what provides the flavor.

Myc Oncogene And Immune Detection Of Cancer

Activation of the Myc oncogene in cancer helps produce immune-suppressed conditions that aids in the evasion of tumor immune surveillance.

…we find that co-activation of Myc drives the immediate transition to highly proliferative and invasive adenocarcinomas marked by highly inflammatory, angiogenic, and immune-suppressed stroma. 

It therefore stands to reason that suppression if the Myc signaling can help restore anti-tumor immune function and that is what has been shown to occur, using agents that modify epigenetic changes in genes – changes that involve how the chromatin is modified (methylation, acetylation) instead of DNA sequence changes, with consequent alteration of gene expression. This is hopeful in the quest to improve anti-cancer immunotherapy.  Abstract:

Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/β-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint therapy for NSCLC.

BMI, Metabolic Syndrome, And Pancreatic Cancer

Here is study linking higher BMI, and higher fasting insulin levels (metabolic syndrome, insulin resistance), with an increased risk for pancreatic cancer.  The burden of morbidity and mortality caused by overweight/obesity is staggering, something to keep in mind when reading all the popular stories on the Internet that attempt to normalize obesity and rant about “fat shaming” and “body shaming.”  Being overweight is literally killing people, why normalize it?  Abstract:

BACKGROUND:

Risk factors for pancreatic cancer include a cluster of metabolic conditions such as obesity, hypertension, dyslipidemia, insulin resistance, and type 2 diabetes. Given that these risk factors are correlated, separating out causal from confounded effects is challenging. Mendelian randomization (MR), or the use of genetic instrumental variables, may facilitate the identification of the metabolic drivers of pancreatic cancer.

METHODS:

We identified genetic instruments for obesity, body shape, dyslipidemia, insulin resistance, and type 2 diabetes in order to evaluate their causal role in pancreatic cancer etiology. These instruments were analyzed in relation to risk using a likelihood-based MR approach within a series of 7110 pancreatic cancer patients and 7264 control subjects using genome-wide data from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Potential unknown pleiotropic effects were assessed using a weighted median approach and MR-Egger sensitivity analyses.

RESULTS:

Results indicated a robust causal association of increasing body mass index (BMI) with pancreatic cancer risk (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.09 to 1.65, for each standard deviation increase in BMI [4.6 kg/m2]). There was also evidence that genetically increased fasting insulin levels were causally associated with an increased risk of pancreatic cancer (OR = 1.66, 95% CI = 1.05 to 2.63, per SD [44.4 pmol/L]). Notably, no evidence of a causal relationship was observed for type 2 diabetes, nor for dyslipidemia. Sensitivity analyses did not indicate that pleiotropy was an important source of bias.

CONCLUSIONS:

Our results suggest a causal role of BMI and fasting insulin in pancreatic cancer etiology.

Of Worms And Men

Aging and the decline in function as a result of aging differs between individuals, in part through genetic variation that exists between the individuals.  A study in worms demonstrates one mechanisms whereby genetic differenced can manifest as differences in age-related functioning: through the nervous system.  This may have relevance to humans, as many pathways are similar between C. elegans and H. sapiens.

The rate of behavioural decline in the ageing population is remarkably variable among individuals. Despite the considerable interest in studying natural variation in ageing rate to identify factors that control healthy ageing, no such factor has yet been found. Here we report a genetic basis for variation in ageing rates in Caenorhabditis elegans. We find that C. elegans isolates show diverse lifespan and age-related declines in virility, pharyngeal pumping, and locomotion. DNA polymorphisms in a novel peptide-coding gene, named regulatory-gene-for-behavioural-ageing-1 (rgba-1), and the neuropeptide receptor gene npr-28 influence the rate of age-related decline of worm mating behaviour; these two genes might have been subjected to recent selective sweeps. Glia-derived RGBA-1 activates NPR-28 signalling, which acts in serotonergic and dopaminergic neurons to accelerate behavioural deterioration. This signalling involves the SIR-2.1-dependent activation of the mitochondrial unfolded protein response, a pathway that modulates ageing. Thus, natural variation in neuropeptide-mediated glia-neuron signalling modulates the rate of ageing in C. elegans.

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