Gene expression

The Dark and Light Side of Food As Information (Dietary RNAs Directly Impact Gene Expression)

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New insights in biology show that food is informational and can directly impact and even control the expression of your genes. The implications of this discovery are profound, and have both a light and dark side in need of deeper exploration…

A new study published in the journal BMC Genetics entitled, “Plant miRNAs found in human circulating system provide evidence of cross kingdom RNAi,” reveals that powerful little diet derived nucleic acids known as microRNAs (miRNAs), from commonly consumed plants, are present within the human circulatory system in what appear to be physiologically significant quantities. MiRNAs are comprised of ~ 22 nucleotide single strand non-coding RNAs, which regulate protein coding gene expression by interfering with messenger RNA’s ability to transcribe DNA into protein. This is why miRNAs are sometimes called RNA interference molecules.

The study found,

“…abundant plant miRNAs sequences from 410 human plasma small RNA sequencing data sets. One particular plant miRNA miR2910, conserved in fruits and vegetables, was found to present in high relative amount in the plasma samples. This miRNA, with same 6mer and 7mer-A1 target seed sequences as hsa-miR-4259 and hsa-miR-4715-5p, was predicted to target human JAK-STAT signaling pathway gene SPRY4 and transcription regulation genes.”

This discovery has profound implications, as the human JAK-STAT signalling pathway has a wide range of potential downstream effects. In fact, JAK-STAT transmits information from extracellular chemical signals to the cell nucleus resulting in DNA transcription and expression of genes involved in immunity, differentiation, proliferation, apoptosis — all of which relate to cancer risk and oncogenesis. But this is just the tip of the miRNA iceberg. There have, in fact, been hundreds of these miRNAs identified in commonly consumed foods in the agrarian diet, and they appear to have the ability to match up with hundreds of human gene targets. The implications of this are profound, if not possibly devastating when it comes to GMO food technology.

It is now widely accepted among conventional biologists that miRNAs regulate most of the protein coding genes in mammals. In fact, the profound difference in complexity between higher life forms such as humans relative to, say, earthworms, is attributable to the higher level of RNA complexity within the so-called ‘dark matter of the genome’ (the ~ 98.5% of the human genome that does not code for proteins).

But what research like this brings to the table is the even more provocative possibility that our genetic and epigenetic wellbeing may be wholly dependent on miRNAs existing outside of us within the gene-regulatory miRNAs embedded within our diet.

Can you imagine the difference between an evolutionarily conserved ancestral diet and a modern one comprised of synthetic components and highly processed GMO cereal grasses?

The New Epigenetic/Nutritional Paradigm: Cross-Kingdom Communication

The idea that the plants and animals we eat contribute to modulating the expression of our genome is known as cross-kingdom or inter-species genentic communication, and represents a significant departure from the classical view that the genetic infrastructure of species were closed off, hermetically sealed within the cell nucleus, and could not be accessed epigenetically from the outside in. We’ve moved from this atomistic, monadistic view to an open access one, where miRNAs operate like software upon the hardwired protein-coding sequences within a species’ genome, making for a much more complex and interdependent web of relationships, reminiscent of the Gaian concept of a biospheric interconnectivity between all the biotic elements of the Earth. As I discuss in another article,

“…this more “open access” model would permit species to alter and affect another’s phenotype in real-time, along with potentially altering its long-term evolutionary trajectory by affecting epigenetic inheritance patterns. This speaks to a co-evolutionary and co-operative model, with all areas of the tree of life, co-developing in a highly complex and seemingly highly intelligent, carefully orchestrated manner.”

And so, if plant derived miRNAs can survive cooking and digestion, as appears to be the case, and can accumulate in physiologically significant quantities, they will therefore alter gene expression, introducing the novel concept that mammalian genomes may have, in fact, evolved to outsource some of their regulation to nutrigenomic dimensions within their dietary milieux.

This, of course, has profound implications, such as validating the concept that an evolutionarily appropriate diet —  e.g. Paleo diet — would help to assure the optimal expression of the human genome. Conversely, the use of RNA interference technology by biotech corporations, such as Monsanto/Dow’s newly EPA approved RNAi corn, could have biologically devastating consequences to the health and wellbeing of those fed or exposed to its altered miRNA profiles. To learn more about this concerning possibility, read (and please share) my report: The GMO Agenda Takes a Menacing Leap Forward with EPA’s Silent Approval of Monsanto/Dow’s RNAi Corn

 

New tool tracks down distant regulators of gene expression, upends expectations

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Gene enhancers light up in distinctive patterns in different cell types in a fruit fly.

To put things simply, Harvard Medical School researcher Karen Adelman studies DNA “to see how genes get messed up in disease.”

Sometimes that means investigating mutations in the genes that make proteins. In sickle cell anemia, for example, a mutated gene builds improperly shaped hemoglobin that sticks together and reduces the ability of red blood cells to carry oxygen.

Adelman’s interest, however, lies in how otherwise normal genes are expressed—turned on or off—in the wrong amounts, at the wrong times or in the wrong tissues.

In the past few years, scientists have begun to appreciate how often these instructions come from DNA segments called enhancers located far from the genes they influence. Children can be born without a pancreas when a mutation in an enhancer disrupts the “go” signal to a gene 25,000 DNA bases away that is supposed to start growing the organ.

Mutations in these distant enhancers are increasingly being linked to many other diseases, including congenital heart diseases, type 2 diabetes, cancers and immunological disorders.

The problem? “There’s no good way to find those enhancers,” said Adelman, professor of biological chemistry and molecular pharmacology at HMS. “If something’s wrong, we don’t know where to look.”

That is now changing. Adelman and colleagues reported this week in Genes & Development that they repurposed a tool they developed in 2010, Start-seq, to generate maps of enhancers that are active in a given tissue type, disease or set of environmental conditions.

Adelman believes Start-seq will help researchers seeking the sources of disrupted gene expression as well as those trying to understand how enhancers work normally.

“How do enhancers give the right instructions in embryonic development and go wrong in cancer?” she said. “Not only is this stuff fascinating to explore, but we also need to answer these questions if we ever want to alter enhancers, such as to treat disease.”

Already, the team has made a surprising discovery that blurs the distinction between enhancers and the genes they regulate.

Who transcribes the transcribers?

Like the rest of her peers, Adelman was taught in school that enhancers simply send instructions, in the form of transcription machinery, to the genes they want to “switch on.” The machines copy the genes’ DNA into RNA and use that as a blueprint to build proteins.

But in 2010, researchers led by Michael Greenberg, the Nathan Marsh Pusey Professor and head of the Department of Neurobiology at HMS, discovered that enhancers in brain cells also spawn RNAs as they do their jobs—only these RNAs are tiny and short-lived, and they don’t code for proteins.

Since then, the community has debated: How common is this phenomenon? What purpose, if any, do the little RNAs serve?

Adelman and colleagues took advantage of the unique qualities of these RNAs to locate enhancers and get some answers.

“These RNAs are very different from the ones made at genes,” Adelman explained. “They’re generated, they fall off and then they’re quickly degraded. We developed a technique to find them when they’re still stuck to the enhancers.”

Rescued from the scrap heap

The Start-seq technique begins with cell samples. The researchers wash away long, mature RNAs and keep ones that are still stuck to the genome. They then pluck out short RNAs that have a chemical tag characteristic of RNA-construction machinery found at genes and enhancers.

Finally, the team sequences these RNAs, revealing where each came from on the genome.

The result: a list of just about every enhancer that was active at the time the sample was taken, along with their exact genetic sequences. While not perfect, Start-seq returns fewer false positives and false negatives than previous enhancer-detection methods, the authors found.

Poised to dive into the genetics and transcription dynamics that drive enhancers, the researchers can already answer one burning question: Around 95 percent of enhancers make RNA.

“This means transcription at enhancers and protein-coding genes have much more in common than we appreciated,” said Adelman. “Philosophically it makes sense—and it helps explain why protein-coding genes can act as enhancers—but it still turns things on their head quite a bit.”

The good news, she said, is that the vast knowledge scientists have gathered about control of protein-coding genes can now be applied to learning how enhancers work.

Community resource

The team is working to automate Start-seq so they can make it available to researchers throughout the HMS community and beyond.

The tool should enable people to search for overlaps between enhancer activity and genetic variants to tease out which variants might contribute to the biological phenomenon they’re studying, whether that is Parkinson’s disease or the differentiation of stem cells.

“We have plenty of neighbors who are hoping to identify relevant enhancers in their disease models,” Adelman said. “We hope to shine the flashlight on the right parts of the genome for them.”

Scientists identify brain molecule that triggers schizophrenia-like behaviors, brain changes

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Scientists at The Scripps Research Institute (TSRI) have identified a molecule in the brain that triggers schizophrenia-like behaviors, brain changes and global gene expression in an animal model. The research gives scientists new tools for someday preventing or treating psychiatric disorders such as schizophrenia, bipolar disorder and autism.

“This new model speaks to how schizophrenia could arise before birth and identifies possible novel drug targets,” said Jerold Chun, a professor and member of the Dorris Neuroscience Center at TSRI who was senior author of the new study.

The findings were published April 7, 2014, in the journal Translational Psychiatry.

What Causes Schizophrenia?

According to the World Health Organization, more than 21 million people worldwide suffer from schizophrenia, a severe psychiatric disorder that can cause delusions and hallucinations and lead to increased risk of suicide.

Although psychiatric disorders have a genetic component, it is known that environmental factors also contribute to disease risk. There is an especially strong link between psychiatric disorders and complications during gestation or birth, such as prenatal bleeding, low oxygen or malnutrition of the mother during pregnancy.

In the new study, the researchers studied one particular known risk factor: bleeding in the brain, called fetal cerebral hemorrhage, which can occur in utero and in premature babies and can be detected via ultrasound.

In particular, the researchers wanted to examine the role of a lipid called lysophosphatidic acid (LPA), which is produced during hemorrhaging. Previous studies had linked increased LPA signaling to alterations in architecture of the fetal brain and the initiation of hydrocephalus (an accumulation of brain fluid that distorts the brain). Both types of events can also increase the risk of psychiatric disorders.

“LPA may be the common factor,” said Beth Thomas, an associate professor at TSRI and co-author of the new study.

Mouse Models Show Symptoms

To test this theory, the research team designed an experiment to see if increased LPA signaling led to schizophrenia-like symptoms in animal models.

Hope Mirendil, an alumna of the TSRI graduate program and first author of the new study, spearheaded the effort to develop the first-ever animal model of fetal cerebral hemorrhage. In a clever experimental paradigm, fetal mice received an injection of a non-reactive saline solution, blood serum (which naturally contains LPA in addition to other molecules) or pure LPA.

  • Ten weeks after the mice were born, they were tested for schizophrenia-like symptoms. The researchers found that female mice given LPA-containing serum or LPA alone displayed hyperactivity upon stimulation, showed anxiety and had increased numbers of dopamine-producing neurons—all which are characteristic of schizophrenia and other psychiatric disorders.

The real litmus test to show if these symptoms were specific to psychiatric disorders, according to Mirendil, was “prepulse inhibition test,” which measures the “startle” response to loud noises. Most mice—and humans—startle when they hear a loud noise. However, if a softer noise (known as a prepulse) is played before the loud tone, mice and humans are “primed” and startle less at the second, louder noise. Yet mice and humans with symptoms of schizophrenia startle just as much at loud noises even with a prepulse, perhaps because they lack the ability to filter sensory information.

Indeed, the female mice injected with serum or LPA alone startled regardless of whether a prepulse was placed before the loud tone.

Next, the researchers analyzed brain changes, revealing schizophrenia-like changes in neurotransmitter-expressing cells. Global gene expression studies found that the LPA-treated mice shared many similar molecular markers as those found in humans with schizophrenia. To further test the role of LPA, the researchers used a molecule to block only LPA signaling in the brain.

This treatment prevented schizophrenia-like symptoms.

Implications for Human Health

This research provides new insights, but also new questions, into the developmental origins of psychiatric disorders.

For example, the researchers only saw symptoms in female mice. Could schizophrenia be triggered by different factors in men and women as well?

“Hopefully this animal model can be further explored to tease out potential differences in the pathological triggers that lead to disease symptoms in males versus females,” said Thomas.

In addition to Chun, Thomas and Mirendil, authors of the study, “LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage,” were Candy De Loera of TSRI; and Kinya Okada and Yuji Inomata of the Mitsubishi Tanabe Pharma Corporation.

Causes Of Autism Illuminated: Researchers Map A Molecular Network Of Crucial Protein Interactions

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genes and proteins
Researchers identified an entire molecular network that provides a map of some of the crucial protein interactions contributing to autism. 

Ever since the human genome was mapped, scientists (and those of us cheering from the sidelines) have been hoping to find the genetic basis for various diseases, including autism spectrum disorder (ASD). After a decade of research, however, it is clear the process is not just a matter of sequencing the genome of a group of patients and then figuring out which genetic variation all of them share — to understand the origins of disease, scientists also need to learn all the tiny, atom-sized interactions involved. In a new study, Stanford University researchers mapped an entire molecular network of crucial protein interactions that contribute to autism.

While “much work remains to be done,” Dr. Charles Auffray, of Université de Lyon, states this new research is “a bold attempt to leverage a number of rich sources of data and knowledge and to complement them with relevant additional measurements to unravel the molecular networks of ASD.” Auffray’s editorial appears alongside the published study in Molecular Systems Biology.

How, though, does learning the underlying protein interactions help scientists understand the disease of autism? A review of genes and proteins may help you see the link.

Not Just Genes, But Proteins

Like the proverbial snowflake, you are unique and so you possess a unique genome. (Your genome is the complete set of your genes.) Each and every cell inside your body contains this same genome, with all the very same genes, simple stretches of DNA containing instructions, and what your genes actually do is produce and regulate proteins that run everything in your body. Your genome is the blueprint, then, with proteins acting as the workers to carry out this important plan.

While all your cells contain the same genes, individual cells have specific missions to carry out, and so they either turn on or turn off different genes — this is referred to as gene expression. In fact, each cell in your body expresses only a fraction of its total genes, while silencing all the rest. Genes expressed in your liver cells, for example, are silenced in your skin cells; some genes expressed during your first year of life are silenced in the years thereafter.

While scientists know which protein a gene will make by looking at its code, what they don’t know is the amount of protein that will be made, which cells within a group of cells will make it, or when it will be made. However, they recognize these patterns of gene expression are a matter of inheritance as well as the environment. They also know gene expression is crucial, possibly even the key to health… and disease.

For the current study of autism, then, the scientists did not just look at genes, they also looked at gene expression — the protein interactions — in patients with autism. After identifying a “protein interaction module,” the researchers sequenced the genomes of 25 patients to confirm its involvement in autism and then validated these findings with data from 500 additional patients. Next, the team examined gene expression within the module, in part by using the Allen Human Brain Atlas. Here, they discovered the brain’s corpus callosum and oligodendrocyte cells — these cells help form myelin, the insulating sheath of brain cells necessary for high velocity nerve conduction — made important contributions to ASD; patients with autism, for instance, exhibited extensive gene mis‐expression in the corpus callosum, the bundle of nerve fibers connecting left and right brain hemispheres.

“Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease, and improves our understanding of its molecular pathology,” wrote the authors in their published research.

Though further research is needed to fully understand autism’s origins, this study “contributes to the development of an openly shared methodological framework and tools for data analysis and integration that can be used to explore the complexity underlying many other rare or common diseases,” Auffray said.

The researchers, then, not only discovered a new way to view a particular disorder, they have shared their methods to help others gain perspective on all disease.

Source: Li J, Shi M, Ma Z, et al. Integrated systems analysis reveals a molecular network underlying autism spectrum disorders. Molecular Systems Biology. 2014.

Distinct gene expression profiles of proximal and distal colorectal cancer: implications for cytotoxic and targeted therapy

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Colorectal cancer (CRC) is a heterogeneous disease with genetic profiles and clinical outcomes dependent on the anatomic location of the primary tumor. How location has an impact on the molecular makeup of a tumor and how prognostic and predictive biomarkers differ between proximal versus distal colon cancers is not well established. We investigated the associations between tumor location, KRAS and BRAF mutation status, and the messenger RNA (mRNA) expression of proteins involved in major signaling pathways, including tumor growth (epidermal growth factor receptor (EGFR)), angiogenesis (vascular endothelial growth factor receptor 2 (VEGFR2)), DNA repair (excision repair cross complement group 1 (ERCC1)) and fluoropyrimidine metabolism (thymidylate synthase (TS)). Formalin-fixed paraffin-embedded tumor specimens from 431 advanced CRC patients were analyzed. The presence of seven different KRAS base substitutions and the BRAF V600E mutation was determined. ERCC1, TS, EGFR and VEGFR2 mRNA expression levels were detected by reverse transcriptase-PCR. BRAF mutations were significantly more common in the proximal colon (P<0.001), whereas KRAS mutations occurred at similar frequencies throughout the colorectum. Rectal cancers had significantly higher ERCC1 and VEGFR2 mRNA levels compared with distal and proximal colon tumors (P=0.001), and increased TS levels compared with distal colon cancers (P=0.02). Mutant KRAS status was associated with lower ERCC1, TS, EGFR and VEGFR2 gene expression in multivariate analysis. In a subgroup analysis, this association remained significant for all genes in the proximal colon and for VEGFR2 expression in rectal cancers. The mRNA expression patterns of predictive and prognostic biomarkers, as well as associations with KRAS and BRAF mutation status depend on primary tumor location. Prospective studies are warranted to confirm these findings and determine the underlying mechanisms.

Blood mRNA biomarkers for detection of treatment response in acute pulmonary exacerbations of cystic fibrosis.

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Abstract

Background Acute pulmonary exacerbations accelerate pulmonary decline in cystic fibrosis (CF). There is a critical need for better predictors of treatment response.

Objective To test whether expression of a panel of leucocyte genes directly measured from whole blood predicts reductions in sputum bacterial density.

Methods A previously validated 10-gene peripheral blood mononuclear cell (PBMC) signature was prospectively tested in PBMC and whole blood leucocyte RNA isolated from adult subjects with CF at the beginning and end of treatment for an acute pulmonary exacerbation. Gene expression was simultaneously quantified from PBMCs and whole blood RNA using real-time PCR amplification. Test characteristics including sensitivity, specificity, positive and negative predictive values were calculated and receiver operating characteristic curves determined the best cut-off to diagnose a microbiological response. The findings were then validated in a smaller independent sample.

Results Whole blood transcript measurements are more accurate than forced expiratory volume in 1 s (FEV1) or C reactive protein (CRP) alone in identifying reduction of airway infection. When added to FEV1, the whole blood gene panel improved diagnostic accuracy from 64% to 82%. The specificity of the test to detect reduced infection was 88% and the positive predictive value for the presence of persistent infection was 86%. The area under the curve for detecting treatment response was 0.81. Six genes were the most significant predictors for identifying reduction in airway bacterial load beyond FEV1 or CRP alone. The high specificity of the test was replicated in the validation cohort.

Conclusions The addition of blood leucocyte gene expression to FEV1 and CRP enhances specificity in predicting reduced pulmonary infection and may bolster the assessment of CF treatment outcomes.

Source: Thorax.

 

A Transcriptional Signature for Active TB: Have We Found the Needle in the Haystack?

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Analysis of whole-genome RNA expression in human clinical samples is a relatively novel approach to biomarker development. The pattern of RNA expression (i.e., transcriptional signature) can provide a “biological snapshot” of the immune response to physiological stressors, and specific disease states may produce distinct transcriptional signatures. In this week’s issue of PLOS Medicine, Michael Levin and colleagues report that a blood RNA transcriptional signature can be used to diagnose active tuberculosis (TB) in high HIV/TB prevalence settings. Using blood samples from patients referred for TB evaluation at three sites in Cape Town, South Africa (cases from an outpatient TB clinic; controls from two hospitals) and one district hospital in Northern Malawi, the authors identified a minimal set of 44 transcripts that distinguished patients with TB from patients confirmed to have an alternative diagnosis. They then converted the complex expression data into a simple-to-calculate disease risk score, which was highly sensitive (93%, 95% CI [83–100]) and specific (88%, 95% CI [74–97]) for active TB.

Have We Found the Needle in the Haystack?

This landmark study advances the field in several critical ways. For the first time, a blood transcriptional signature for TB was defined by comparison with patients who have conditions that mimic TB in a high burden setting instead of with healthy controls or patients with sarcoidosis or auto-immune diseases [1]–[4]. The inclusion of controls for whom TB was in the list of differential diagnoses but ultimately excluded increases confidence that the blood transcriptional signature identified may be clinically relevant. Second, the authors developed the disease risk score, which provides a single measure of the degree to which an individual’s RNA expression is consistent with TB. The disease risk score can be calculated by simply subtracting the summed normalized intensities of down-regulated transcripts from those of up-regulated transcripts. By eliminating the need to use complicated bioinformatics to make predictions from the RNA expression data, the disease risk score could simplify the application of transcriptional signatures in clinical settings. Finally, the authors demonstrate convincingly the high diagnostic accuracy of their blood transcriptional signature. The results were impressive in their test set (20% of enrolled patients), including in HIV-infected and smear-negative sub-populations, and in an entirely independent validation dataset published years earlier [1].

Although the results are promising, key questions remain. First, can the results be reproduced in a truly representative population? State-of-the-art technology and bioinformatics are critical tools for identifying prospective targets, but the rigorous application of fundamental epidemiological principles will be indispensable to advancing these technologies into the clinical arena, where it will be necessary to show their utility in truly representative populations. Levin and colleagues describe an “intention-to-test” recruitment strategy but nonetheless enrolled a highly selected patient population. TB patients generally had advanced disease (over 90% of HIV-uninfected patients [96/106] and over 75% of HIV-infected patients [83/109] were smear-positive) and 28% (207 of 751) of patients were excluded because TB status was uncertain. The control group was recruited entirely from inpatient wards and most patients had non-respiratory diseases. These factors resulted in a spectrum bias towards the extremes of disease manifestations, which is known to inflate estimates of diagnostic accuracy [5]. Second, can a robust threshold be developed for the disease risk score that works in different settings? An inherent limitation of the microarray technology used in this study is that it provides only relative quantification of RNA expression so that intensity values are relevant only within, and not across, experiments [6]. Ultimately, to be clinically useful, a threshold will need to be defined a priori rather than on the basis of experimental data and the selected threshold will have to be consistent across geographic settings. Finally, can a platform be developed to enable measurement of the transcriptional signature in low-income countries? A number of novel technologies for quantitative multi-channel measurement of nucleic acid targets are in development. However, the cost and difficulty of assaying a 44-transcript signature seem prohibitive far into the future. Absent a transformative technology, it is difficult to envision transcriptional profiling having a meaningful impact in parts of the world where novel TB diagnostics are most needed [7].

Triage Testing: A Target for Future Research

As Levin and colleagues suggest, their 44-transcript DRS may be more useful as a triage (i.e., rule-out) test [8] because negative predictive value is high (98%, 95% CI [96–100]), while positive predictive value is sub-optimal (66%, 95% CI [46–87]) when TB prevalence is 20%, as is common in routine settings. The concept of a triage test deserves further attention in the TB diagnostics literature. An ideal triage test rules out disease when negative and triggers further testing when positive (e.g., a mammogram for breast cancer screening). Thus, a triage test requires near-perfect sensitivity (particularly when the consequence of missing disease is high) but only moderate specificity. If rapid and inexpensive, such a test could be used to determine which patients presenting with TB symptoms require confirmatory testing (e.g., automated nucleic acid amplification testing or culture) and for TB screening as is recommended in high-risk populations including people living with HIV and household contacts of active TB cases [9],[10].

The 44-transcript signature identified by the authors shows promise as a triage test and might be further optimized for this purpose during its further development. Indeed, it is likely that any set of host-derived biomarkers, especially if based on generic rather than antigen-stimulated immune responses, will have more difficulty achieving high specificity than high sensitivity. In this regard, the commonly used approach of selecting a diagnostic threshold that maximizes the number of correctly classified outcomes is misguided [11]. This cannot lead to a clinically useful test if neither sensitivity nor specificity is high enough to provide meaningful rule-out or rule-in value. Future work to establish a threshold for the 44-transcript signature as a triage test should focus on maximizing sensitivity, even at the cost of decreased specificity. Furthermore, focusing on developing a triage test at the discovery stage may lead to selection of a different set of transcripts that retains 100% sensitivity while providing even better specificity.

Summary

Levin and colleagues have provided compelling proof of the concept that a blood transcriptional signature can distinguish between TB and clinical mimics in high-incidence settings. The field can now move on to asking more practical questions to determine the feasibility and optimal use for an RNA expression-based biomarker for TB in clinical settings. Finding the right signature—the proverbial “needle in the haystack”—may require additional discovery work involving smaller sets of RNA transcripts and will certainly require validation of candidate signatures in diverse settings. Further discovery and validation studies should adhere to fundamental principles of high quality diagnostic evaluations [12], including enrollment of consecutive patients presenting for TB evaluation in representative health facilities. Even if validated, significant technical hurdles remain to translate these important findings to rapid, inexpensive, and simple assays that can impact patient outcomes in countries where TB is most prevalent. The search continues.

Source:PLOS

High Ran level is correlated with poor prognosis in patients with colorectal cancer.

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Abstract

Background

The Ras-like nuclear protein (Ran) is involved in the regulation of nuclear transport, microtubule nucleation and dynamics, and spindle assembly. Its fundamental function is nucleocytoplasmic transport of RNA and proteins. The expression and potential role of Ran in colorectal cancer (CRC) remain unclear. The aim of this study was to investigate the relationship between Ran expression and CRC characteristics. The potential role of Ran as a prognostic indicator was also evaluated.

Methods

We used immunohistochemistry and western blotting to detect Ran expression in 287 CRC tissues. The relationships between Ran expression and clinicopathological characteristics and overall survival rate were statistically analyzed.

Results

CRC tissues had significantly higher Ran expression than normal colorectal epithelial cells. Ran was positively correlated with depth of invasion, lymph node metastases, distant metastases, tumor differentiation, and tumor–node–metastasis stage. However, no correlation was found between Ran expression and patient age or sex. The overall survival rate was consistently and significantly lower in patients with Ran-positive tumors than in those with Ran-negative tumors.

Conclusion

Our findings emphasize the important role of Ran in differentiation, disease stage, and metastasis in human CRC. Ran may play an important role in the development of CRC and may serve as a novel prognostic indicator of CRC.

Source: International Journal of Clinical Oncology

Probiotics may save patients from deadly chemotherapy.

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If you or someone you love is facing the possibility of cancer or chemotherapy, make sure they read this story. Breakthrough new science conducted at the University of Michigan and about to be published in the journal Nature reveals that intestinal health is the key to surviving chemotherapy.

 

The study itself is very difficult for laypeople to parse, however, so I’m going to translate into everyday language while also offering additional interpretations of the research that the original study author is likely unable to state due to the nutritional censorship of medical journals and universities, both of which have an anti-nutrition bias.

The upshot is this: A clinical study gave mice lethal injections of chemotherapy that would, pound for pound, kill most adult human beings, too. The study authors openly admit: “All tumors from different tissues and organs can be killed by high doses of chemotherapy and radiation, but the current challenge for treating the later-staged metastasized cancer is that you actually kill the [patient] before you kill the tumor.” (See sources below.)

Chemotherapy is deadly. It is the No. 1 cause of death for cancer patients in America, and the No. 1 side effect of chemo is more cancer. But certain mice in the study managed to survive the lethal doses of chemo. How did they do that? They were injected with a molecule that your own body produces naturally. It’s production is engineered right into your genes, and given the right gene expression in an environment of good nutrition (meaning the cellular environment), you can generate this substance all by yourself, 24 hours a day.

The substance is called “Rspo1″ or “R-spondon1.” It activates stem cell production within your own intestinal walls, and these stem cells are like super tissue regeneration machines that rebuild damaged tissues faster than the chemotherapy can destroy them, thereby allowing the patient to survive an otherwise deadly does of chemo poison.

As the study showed, 50 – 75 percent of the mice who were given R-spondon1 survived the fatal chemotherapy dose!

The cancer industry needs to find a way to stop killing all their customers

The problem with the cancer industry today is that all the conventional cancer treatments keep killing the patients. This is bad for business. So the purpose of research like the R-spondon1 research mentioned here — which was funded by a government grant — is to find ways to keep giving patients deadly doses of high-profit chemotherapy without actually killing them. You slap a patient with a dose of R-spondon1 (sold at $50,000 a dose as a patented “drug,” of course), dose ‘em up with a fatal injection of chemotherapy, and then thanks to the R-spondon1 you get a repeat cancer customers instead of a corpse.

That’s called “good business practices” in the cancer industry, which is so far best known for turning patients into body bags rather than actually curing cancer.

(Yes, there is a reason why most oncologists would never undergo chemotherapy themselves. They know it doesn’t work on 98% of all cancers.)

Probiotics are likely the key to generating your own R-spondon1

Before I discuss why these findings are so important for followers of natural health and nutrition, let me first offer a disclaimer. The research mentioned here was conducted on mice, not humans, so it isn’t full proof that the same mechanism works in humans. Nevertheless, the reason mice are used for such research is because they are nearly identical to humans in terms of biology, gene expression, endocrine system function and more.

Furthermore, even though this study used an injection of R-spondon1 as the “activator” of gene expression in endothelial cells of the intestinal lining, in truth your cells already possess the blueprint to produce R-spondon1 on their own. In fact, human intestines are coated with a layer of epithelial cells that are regenerated every 4-5 days in a healthy person. This is only possible through the activation and continued operation of intestinal stem cells, a normal function for a healthy human.

And what determines the health of those stem cells more than anything else? Their local environment which is predominantly determined by gut bacteria. If your gut bacteria are in balance, the gene expression of your epithelial cells is normal and healthy. If your gut bacteria are out of whack, so to speak, the gene expression of your epithelial cells will be suppressed, thereby slowing or halting the regenerative potential of your intestinal cells. This is why people who have imbalanced intestinal flora also suffer from inflammatory intestinal conditions such as Crohn’s, IBS and so on.

Thus, probiotics are a key determining factor in the ability of your intestines to maintain the appropriate gene expression for the very kind of rapid cellular regeneration that can help your body survive a fatal dose of chemotherapy.

Meat and dairy cause devastating gut flora imbalances that may increase susceptibility to chemotherapy drugs

This may also explain why people who eat large quantities of processed meat, cheese and dead, pasteurized dairy products — especially when combined with starchy carbohydrates and processed sugars — are far more likely to die from chemotherapy than people who eat more plant-based diets. (There isn’t yet a source to substantiate this claim, but it’s something I’ve noted from considerable personal observation. You may have noticed it too among your own family members who have undergone chemotherapy treatments. Those with the worst diets seem to have far higher fatality rates.)

Those who consume processed meat and dead dairy have their intestines filled with fiber-less, difficult-to-digest proteins that are putrefied and sit in the intestines for 2 – 5 days, typically. Dietary sugars and carbohydrates then feed the bacteria fermentation process, resulting in the rapid growth and replication of sugar-feeding bacteria that displace the kind of healthy flora which best protect intestinal wall cells.

This imbalance, I suggest, increases susceptibility to chemotherapy toxicity while simultaneously impairing the ability of the patient to absorb key nutrients that protect healthy cells from the toxicity of chemo drugs. This may explain why patients who heavily consume meat, cheese and dairy diets tend to die so easily when exposed to chemotherapy.

But there’s something even more alarming about all this that everyone needs to know…

Antibiotics may also set you up to be killed by chemo

Although the research did not directly address this question, its findings seem to indicate that the kind of gut bacteria “wipeout” caused by antibiotics could prove fatal to a chemotherapy patient.

This is especially worrisome because many cancer patients are simultaneously prescribed antibiotics as they undergo chemotherapy. This could be a death sentence in disguise. While neither the antibiotics nor the chemo directly kill the patient, the combination of sterilized gut bacteria and highly-toxic chemotherapy drugs could multiply the toxicity and prove fatal. The death certificate, however, will say the patient died from “cancer,” not from the chemotherapy which is usually the actual cause of death.

And yet, every single day in America, patients who are taking antibiotics are subjected to multiple courses of chemotherapy. This may quite literally be a death sentence for those patients.

There’s also a self-fulfilling death spiral at work in all this: following the first round of chemotherapy, many patients suffer from weakened immune system that result in symptomatic infections. Physicians respond to this by prescribing antibiotics, resulting in the patient undergoing subsequent rounds of chemotherapy with “wiped out” gut flora. So the chemo causes the problem in the first place, and then the response to the problem by western doctors makes the next round of chemo fatal. This is a self-fulfilling death spiral of failed medicine.

Oncologists seem to have no awareness whatsoever of the importance of gut bacteria in allowing patients to protect their own healthy cells from the devastating effects of chemotherapy drugs. Many oncologists, in fact, actively discourage their patients from taking any sort of supplements during chemotherapy out of an irrational, anti-scientific fear that such supplements may “interfere” with the chemo and make the treatment fail.

This is one of the many ways in which oncologists get cancer patients killed.

Takeaway points from this article:

• New research shows that a substance generated by intestinal stem cells allows subjects to survive an otherwise fatal dose of toxic chemotherapy.

• Healthy gene expression of intestinal cells allows them to naturally produce protective molecules that support and boost cell regeneration.

• Probiotics may protect and support the intestinal stem cells that help cancer patients survive toxic chemotherapy. (More studies needed to explore this and document the impact.)

• Antibiotics may be a death sentence when followed by chemotherapy.

• Oncologists need to consider the risks and benefits of postponing chemotherapy in patients who are simultaneously taking antibiotics. The combination may be deadly. Conversely, they need to consider the benefits of encouraging chemotherapy patients to take probiotic supplements before beginning chemotherapy treatment.

Source: naturalnews.com

Veggie-Heavy Stress Reduction Regimen Shown to Modify Cell Aging

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Story at-a-glance

  • New research showed that eating a diet rich in vegetables while exercising and managing stress may modify cell aging and potentially help you live longer
  • Choosing a diet that encourages proper levels of leptin and insulin in your body, and thereby proper genetic expression, is likely the most powerful anti-aging diet there is
  • For most people, avoiding sugar, fructose, grains and processed foods while eating low-to-moderate protein and as much high-quality healthful fat as you want (saturated and monounsaturated) will optimize your general health and longevity
  • Exercise and regular stress reduction round out a simple anti-aging lifestyle plan.

Stress ManagementStress Management

The last time you went to your physician, did he or she ask you about your diet, your exercise habits or your methods of stress reduction? These should be a key point of discussion, as research continues to pour in about their importance to human health, disease prevention and increased lifespan.

Recently, a small study published in the Lancet once again confirmed that eating a diet rich in vegetables while exercising and managing stress may modify cell aging and potentially help you live longer.1

It’s not rocket science… the old adage ‘you are what you eat’ really is true, and combined with other healthy lifestyle factors is the best ‘fountain of youth’ currently known to humankind.

A Healthy Lifestyle Is Your Ticket to a Long Life

You’ve certainly heard about the importance of a healthy lifestyle before, but it deserves repeating because it truly is the closest thing to a magic ‘pill’ for life extension that you can find. In the latest study, men followed a healthy lifestyle, which consisted of:

  1. Eating a mostly whole-food, vegetable-rich diet (with few refined carbohydrates)
  2. Walking for 30 minutes six days a week
  3. 60 minutes of daily stress management (mostly yoga and meditation)
  4. A 60-minute support group session once a week

After five years, men in the healthy lifestyle group had an increase in telomere (the ends of your chromosomes) length compared to the control group. It has been suggested, not without controversy, that increasing telomere length slows down or even reverses aging.

However, it may be possible that the modifications in cell aging being attributed to telomere length increases may actually be a byproduct of healthy genetic expression gained by eating a whole-food, low-sugar diet.

Dr. Ron Rosedale Explains Telomere Science…

Dr. Ron Rosedale, M.D. is widely considered to be one of the leading anti-aging doctors in the US, and as such is highly qualified to discuss the complex issues behind using telomere length as an indicator of lifespan. There are numerous problems with the theory, including that fewer than 1 percent of people have the telomerase enzyme necessary to increase their chromosome’s telomere length.

Further, many cells, such as liver and kidney cells can’t lengthen telomeres, while cancer cells can increase telomere length. As Dr. Rosedale said:2

“The fact that telomeres shorten may actually allow us to live longer, as it may reduce the risk of cancer. The good news is that the telomeres in almost all the cells other than WBCs and stem cells do not increase, for if they did, dying of cancer would be all but certain.”

It may very well be that controlling telomere length specific to different diseases and cells may be a powerful way to improve health. But right now, we just don’t know enough about it to be certain. And it might be that the association between increased lifespan and telomere length is simply a correlation, not a cause. Dr. Rosedale explained:

“A major mistake made so frequently in medicine… is the confusion and interchange between correlation and cause. An example is the consistent reference to cholesterol being a cause of heart disease, when in fact it is an association, and even a weak one at that.

…Getting wrinkles is far more correlated, and is therefore a far better biomarker for aging than telomere length, however undergoing a dermabrasion is not likely to extend lifespan. Once again, it is science 101 to not confuse correlation with cause.

It could very well be, and in fact is likely, that reduced telomere length is a byproduct of the cell damage and turnover associated with aging, rather than a prime cause of it, though it likely does have some adverse repercussions especially to the immune system and possibly stem cells.”

How the Foods You Eat Impact Your Lifespan

So what does all of this mean for you, and, importantly, what does it have to do with the foods you choose to eat? Choosing a diet that encourages proper level of leptin and insulin in your body, and thereby proper genetic expression, is likely the most powerful anti-aging diet there is – and may also be involved, or at the very least associated, with the length of your telomeres, although this is only beginning to be explored. Dr. Rosedale continued:

“Life is dependent on the coordination of its constituent parts. This is especially true pertaining to the length of telomeres of the various cells and organs to maintain health but prevent a high risk of cancer.

…we are 15 trillion cells and 90 trillion bacteria that must work harmoniously as one for us to be healthy and remain alive. This requires an intricate orchestration of communication between the different parts. 

That includes the genes, telomeres, and telomerase. It is where, when, and how much they are played, like the keys of a piano playing an infinite variety of music from the same keys, that determine who we are, diabetic or not, and if we stay alive or die.

What we do want to do is slow down the reduction in the length of our telomeres in an organ and tissue-specific manner that can be orchestrated only through proper genetic expression. Leptin and insulin are among the most, if not the most powerful influences of this. And these in turn are controlled by what you eat.”

Insulin and Leptin Resistance: How These Disease-Causing States Happen

Leptin is a hormone that plays a key role in regulating your energy intake and energy expenditure. It may be one of the most important hormones in your body as it can determine your health and lifespan. Insulin is another, and  work in tandem with leptin. Both insulin and leptin resistance are associated with obesity, and impairment of their ability to transfer the information to receptors is the true foundational core of most all chronic degenerative diseases.

Your fat, by way of leptin, tells your brain whether you should be hungry, eat and make more fat, whether you should reproduce, or (partly by controlling insulin) whether to engage in maintenance and repair. In short, leptin is the way that your fat stores speak to your brain to let your brain know how much energy is available and, very importantly, what to do with it.

Therefore, leptin may be on top of the food chain in metabolic importance and relevance to disease. You become leptin-resistant by the same general mechanism that you become insulin-resistant – by continuous overexposure to high levels of the hormone. This happens when you eat a diet that is high in sugar (particularly fructose), grains, and processed foods. The same type of diet that will also increase inflammation in your body – as the sugar gets metabolized in your fat cells, the fat releases surges in leptin.

Over time, if your leptin receptors are exposed to excessive leptin, they will develop resistance, just as your insulin receptors can develop resistance to insulin. The best way to reestablish proper leptin (and insulin) signaling is to prevent those surges, and the only known way to do that is via diet. As such, diet can have a more profound effect on your health than any other known modality of medical treatment.

Eat This Way to Maximize Your Healthy Lifespan Potential

A strategic whole food diet, as detailed in my free nutrition plan, that emphasizes good fats and avoids blood sugar spikes coupled with targeted supplements will enhance insulin and leptin sensitivity so that your brain can once again hear the feedback signals from these hormones. The vegetable-rich, low-refined-carbs diet described in the featured study likely also played a role in enhancing the study participants’ insulin and leptin sensitivity (although this wasn’t measured), and perhaps this was involved in the changes in telomere length, as Dr. Rosedale’s theory seems to support. To reverse insulin and leptin resistance:

  • Avoid sugar, fructose, grains and processed foods
  • Eat a healthful diet of whole foods, ideally organic, and replace the grain carbs with:
    • No-to-low sugar and grain carbs
    • Low-to-moderate amount of protein
    • As much high-quality healthful fat as you want (saturated and monounsaturated). Most people need upwards of50-70 percent fats in their diet for optimal health. Good sources include coconut and coconut oil, avocados, butter, nuts, and animal fats. Also take a high-quality source of animal-based omega-3 fat, such as krill oil.

Remember Exercise and Stress Management, Too

Remember, about 80 percent of the health benefits you reap from a healthy lifestyle comes from your diet, and the remaining 20 percent from exercise – but it’s a very important 20 percent, as it acts in tandem with and boosts the benefits derived from a proper diet. Exercise is also one of the fastest and most powerful ways to lower your insulin and leptin resistance. For maximum benefits, you’ll want to make sure to include high-intensity interval training (HIIT), which has been found to help slow down aging.

Of course, the connections between stress and physical health are undeniable, as well, with chronic stress linked to lowered immune system function, heightened inflammatory response, altered hormonal balance and more. Energy psychology techniques such as the Emotional Freedom Technique (EFT) can be very effective by helping you to actuallyreprogram your body’s reactions to the unavoidable stressors of everyday life.

Exercising regularly, getting enough sleep, and meditation are also important “release valves” that can help you manage your stress. Together with a healthful diet and exercise, stress management makes up the ‘third Musketeer’ that is essential to leading a long, vital life.