Motherhealth Caregivers Bay Area In-Home Care Hollistic

Gene test can help some breast cancer patients avoid chemo

By Erin Allday

A large percentage of women with early-stage breast cancer who have been identified as having a high risk of recurrence should consider forgoing chemotherapy based on the biological makeup of their tumor, according to research published Wednesday.

Nearly half of early breast cancer cases that meet traditional criteria for high risk can be treated just as effectively without chemotherapy as with it, according to the study, which used genetic testing to analyze tumors. Those patients can instead be treated with surgery and, as needed, hormone therapy, researchers said.

The findings, published in the New England Journal of Medicine, are among the strongest to demonstrate how personalized medicine — applying treatments based on the genetic makeup of individuals or their disease — can be used to refine cancer therapies and, in this particular case, avoid over treating individuals, doctors said.

“Many breast cancer patients are over treated by chemotherapy. That’s been known,” said Dr. Laura van ‘t Veer, a UCSF molecular biologist who co-wrote the new paper. “However, we needed more precise measurements to tell us who are the ones who can really forgo chemotherapy.”

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The study used a test called MammaPrint, developed by van ‘t Veer and colleagues from the Netherlands Cancer Institute, where she worked before joining UCSF in 2010. Van ‘t Veer co-founded a company, called Agendia, that markets MammaPrint.

The MammaPrint test looks at 70 genes known to be associated with risk of cancer recurrence. The test, which has been widely used throughout Europe, was approved by the U.S. Food and Drug Administration in 2007, but it has been slow to catch on with American physicians, said van ‘t Veer and other doctors.

The new report is a landmark study that should have immediate implications for breast cancer care, said Dr. Laura Esserman, director of UCSF’s Carol Franc Buck Breast Care Center, who works with van ‘t Veer but was not part of the MammaPrint research.

“This kind of study 100 percent tells us that biology matters. It’s a huge step forward,” Esserman said. “We’re moving more and more into one size doesn’t fit all for cancer. This solidifies our ability to act on that.”

The study involved 6,693 women in Europe who were diagnosed with early-stage breast cancer. The risk of recurrence for each woman was determined two ways: by the MammaPrint test and by a more traditional clinical test that looks at the patient’s age, whether she’s gone through menopause and the size of the tumor, among other things.

Women who fell into a high-risk category on both tests received chemotherapy; women who were low risk in both did not. The rest of the women — about a third of the total, for whom the two tests did not match — were randomly assigned to either receive chemotherapy or not.

The study found that for the 1,550 women who were identified as high risk by traditional tests but low risk by genetic testing, the chance of recurrence — about 5 percent after five years — was almost identical whether they received chemotherapy or not. Women who received chemotherapy had a somewhat smaller chance of recurrence, but the result was not statistically significant.

In the United States, about 230,000 women are diagnosed with breast cancer every year, the majority of them with early-stage cancer, meaning it’s located only in the breast and, in some cases, the lymph nodes.

Without chemotherapy, roughly 25 percent of women with early-stage cancer will develop an invasive tumor in another part of their body — what’s known as metastasizing — after 10 years, van ‘t Veer said. But because there hasn’t been a good way to determine who is at risk of metastasizing, about 80 percent of those women receive aggressive chemotherapy treatment in the United States, she said.

That matters because chemotherapy involves toxic drugs that can have immediately unpleasant side effects — including hair loss, nausea and cognitive impairment — and cause long-term problems like heart disease and even secondary cancers. Some women may be unable to work or stick to their usual routine during the many months of chemotherapy treatment.

It can be tough to persuade doctors and patients to skip a treatment like chemotherapy that has become a standard of care, van ‘t Veer said. But given the drawbacks of chemotherapy, she expected many people to take note of the new research and consider scaling back care appropriately.

“To do less is always a difficult step. The mantra ‘less is more’ is not so easy to implement,” she said. “I think people have been waiting for this — they needed this level of evidence.”

Karuna Jaggar, executive director of the patient advocacy group Breast Cancer Action, said she welcomed any strong research that allows women to make informed decisions about their own care.

http://www.sfgate.com/health/article/Some-women-with-early-stage-breast-cancer-may-9182810.php#photo-8823587

45-55 yr old women outperform men on memory

By Lisa Kreiger

For women, middle age brings softer midsections, hot flashes and a kinder, gentler tennis serve.

But when it comes to the stuff that really matters — memory mettle — at least we’re better than men.

A new study proves that women age 45 to 55 outperform age-matched men on all measures of memory: episodic memory, executive function, semantic processing and estimated verbal intelligence.

The research — led by clinical neuropsychologist Dorene M. Rentz and a team at Boston’s Brigham and Women’s Hospital, linked to Harvard University — was published Monday in Menopause, the journal of the North American Menopause Society.

Middle-age women trounced men in tests like the “Face-Name Associative Memory Exam,” no surprise to anyone who’s ever had to nudge their male partner at a cocktail party.

Here’s the bad news, if you’re female: On average, you will have less memory next year than you do right now. Blame Father Time. Over the years, there’s a narrowing gap between male and female memories.

Connie’s comments: Sleep more, eat colored whole foods and de-stress.

Menopause’s infamous “brain fog”? It’s real. Women who are too young for or transitioning through menopause outperformed their elders in a number of key memory areas.

Scientists say that loss of estrogen is the problem. Declines in this hormone are linked with lower rates of initial learning and retrieval of previously recalled information. Happily, it did not influence memory storage.

“Brain fog and complaints of memory issues should be taken seriously,” says Dr. JoAnn Pinkerton of the Menopause Society, in a prepared statement. “This study and others have shown that these complaints are associated with memory deficits.”

But not all postmenopausal women experience memory or cognitive changes — and it remains unclear why some women experience these changes more acutely than others.

That’s especially comforting when the face that stares back at you in the mirror reminds you of your mother’s — a cherished memory.

Tired of owning your apartment, lease option to buy

If you are tired of handling a bunch of properties and looking to retire or commercial-residential properties are in dire need of repair located in war zones, and the owner wants out, we can lease them with option to buy (group of investors with Motherhealth LLC, wanted to take care of bay area apartments). Please email motherhealth@gmail.com for more info if you want to join the group of investor to take care of apartments or commercial properties in the bay area.
It’s structured this way:

1. Option money, tax free to the lessor (owner).

2. A Master long term lease, 30 years or greater as I recall, where you collect the rent, handle all the maintenance repairs, and you make a monthly payment to the lessor.

Benefits to the lessor:

1. There’s no capital gains due immediately (Lessor – owner), and even the option money is tax free.

2. On his death, due to stepped up basis, there’s little or nor estate tax due.

3. Lessee (Motherhealth) handles all the operational headaches

Benefit for the lessee:

1. You don’t have to go get a mortgage.
2. You can mortgage the leasehold, which might even cover payments such as option money to the lessor.
3. When the lessor dies, usually heirs want the money right away, and you can negotiate a advantageous sales price for yourself, buying out the lease. Heirs are usually motivated sellers.

4. With escalating commercial rents, you benefit from the upside.

5. On the other hand, if things go south, you can give it back to the lessor. The investor I know, who happened to be the lessor in one case, took the lease back (long story), and even made money doing so.

Glossary, the structure of life

Acquired immunodeficiency syndrome (AIDS) A viral disease caused by the human immunodeficiency virus (HIV).

Active site The region of an enzyme to which a substrate binds and at which a chemical reaction occurs.

AIDS Acquired immunodeficiency syndrome—an infectious disease that is a major killer worldwide.

Alpha helix A short, spiral-shaped section within a protein structure.

Amino acid A chemical building block of proteins. There are 20 standard amino acids. A protein consists of a specific sequence of amino acids.

Angstrom A unit of length used for measuring atomic dimensions. One angstrom equals 10^-10 meters.

Antibiotic-resistant bacteria A strain of bacteria with slight alterations (mutations) in some of their molecules that enable the bacteria to survive drugs designed to kill them.

Atom A fundamental unit of matter. It consists of a nucleus and electrons.

AZT (azido-deoxythymidine) A drug used to treat HIV. It targets the reverse transcriptase enzyme.

Bacterium (pl. bacteria) A primitive, one-celled microorganism without a nucleus. Bacteria live almost everywhere in the environment. Some bacteria may infect humans, plants, or animals. They may be harmless or they may cause disease.

Base A chemical component (the fundamental information unit) of DNA or RNA. There are four bases in DNA: adenine (A), thymine (T), cytosine (C), and guanine (G). RNA also contains four bases, but instead of thymine, RNA contains uracil (U).

Beta sheet A pleated section within a protein structure.

Chaperones Proteins that help other proteins fold or escort other proteins throughout the cell.

Chemical shift An atomic property that varies depending on the chemical and magnetic properties of an atom and its arrangement within a molecule. Chemical shifts are measured by NMR spectroscopists to identify the types of atoms in their samples.

COX-1 (cyclooxygenase-1) An enzyme made continually in the stomach, blood vessels, platelet cells, and parts of the kidney. It produces prostaglandins that, among other things, protect the lining of the stomach from digestive acids. Because NSAIDs block COX-1, they foster ulcers.

COX-2 (cyclooxygenase-2) An enzyme found in only a few places, such as the brain and parts of the kidney. It is made only in response to injury or infection. It produces prostaglandins involved in inflammation and the immune response. NSAIDs act by blocking COX-2. Because elevated levels of COX-2 in the body have been linked to cancer, scientists are investigating whether blocking COX-2 may prevent or treat some cancers.

Cyclooxygenases Enzymes that are responsible for producing prostaglandins and other molecules in the body.

Deoxyribose The type of sugar in DNA.

DNA (deoxyribonucleic acid) The substance of heredity. A long, usually double-stranded chain of nucleotides that carries genetic information necessary for all cellular functions, including the building of proteins. DNA is composed of the sugar deoxyribose, phosphate groups, and the bases adenine, thymine, guanine, and cytosine.

Drug target See target molecule.

Electromagnetic radiation Energy radiated in the form of a wave. It includes all kinds of radiation, including, in order of increasing energy, radio waves, microwaves, infrared radiation (heat), visible light, ultraviolet radiation, X-rays, and gamma radiation.

Enzyme A substance, usually a protein, that speeds up, or catalyzes, a specific chemical reaction without being permanently altered or consumed. Some RNA molecules can also act as enzymes.

Gene A unit of heredity. A segment of DNA that contains the code for a specific protein or protein subunit.

Genetic code The set of triplet letters in DNA (or mRNA) that code for specific amino acids.

HIV protease An HIV enzyme that is required during the life cycle of the virus. It is required for HIV virus particles to mature into fully infectious particles.

Human immunodeficiency virus (HIV) The virus that causes AIDS.

Inhibitor A molecule that “inhibits,” or blocks, the biological action of another molecule.

Isotope A form of a chemical element that contains the same number of protons but a different number of neutrons than other forms of the element. Isotopes are often used to trace atoms or molecules in a metabolic pathway. In NMR, only one isotope of each element contains the correct magnetic properties to be useful.

Kilodalton A unit of mass equal to 1,000 daltons. A dalton is a unit used to measure the mass of atoms and molecules. One dalton equals the atomic weight of a hydrogen atom (1.66 x 10^-24 grams).

MAD See multi-wavelength anomalous diffraction.

Megahertz A unit of measurement equal to 1,000,000 hertz. A hertz is defined as one event or cycle per second and is used to measure the frequency of radio waves and other forms of electromagnetic radiation. The strength of NMR magnets is often reported in megahertz, with most NMR magnets ranging from 500 to 900 megahertz.

Messenger RNA (mRNA) An RNA molecule that serves as an intermediate in the synthesis of protein.Messenger RNA is complementary to DNA and carries genetic information to the ribosome.

Molecule The smallest unit of matter that retains all of the physical and chemical properties of that substance. It consists of one or more identical atoms or a group of different atoms bonded together.

mRNA Messenger RNA.

Multi-dimensional NMR A technique used to solve complex NMR problems.

Multi-wavelength anomalous diffraction (MAD) A technique used in X-ray crystallography that accelerates the determination of protein structures. It uses X-rays of different wavelengths, relieving crystallographers from having to make several different metal-containing crystals.

NMR Nuclear magnetic resonance.

NMR-active atom An atom that has the correct magnetic properties to be useful for NMR. For some atoms, the NMR-active form is a rare isotope, such as ¹³C or ¹⁵N.

NOESY Nuclear Overhauser effect spectroscopy.

Non-steroidal anti-inflammatory drugs A class of medicines used to treat pain and inflammation. Examples include aspirin and ibuprofen. They work by blocking the action of the COX-2 enzyme. Because they also block the COX-1 enzyme, they can cause side effects such as stomach ulcers.

NSAIDs Non-steroidal anti-inflammatory drugs such as aspirin or ibuprofen.

Nuclear magnetic resonance (NMR) spectroscopy A technique used to determine the detailed, three-dimensional structure of molecules and, more broadly, to study the physical, chemical, and biological properties of matter. It uses a strong magnet that interacts with the natural magnetic properties in atomic nuclei.

Nuclear Overhauser effect spectroscopy (NOESY) An NMR technique used to help determine protein structures. It reveals how close different protons (hydrogen nuclei) are to each other in space.

Nucleotide A subunit of DNA or RNA that includes one base, one phosphate molecule, and one sugar molecule (deoxyribose in DNA, ribose in RNA). Thousands of nucleotides join end-to-end to create a molecule of DNA or RNA. See base, phosphate group.

Nucleus (pl. nuclei) 1.The membrane-bounded center of a cell, which contains genetic material. 2.The center of an atom, made up of protons and neutrons.

Phosphate group A chemical group found in DNA and RNA, and often attached to proteins and other biological molecules. It is composed of one phosphorous atom bound to four oxygen atoms.

Photosynthesis The chemical process by which green plants, algae, and some bacteria use the Sun’s energy to synthesize organic compounds (initially carbohydrates).

Prostaglandins A hormone-like group of molecules involved in a variety of functions in the body, including inflammation, blood flow in the kidney, protection of the stomach lining, blood clotting, and relaxation or contraction of muscles in the lungs, uterus, and blood vessels. The formation of prostaglandins is blocked by NSAIDs.

Protein A large biological molecule composed of amino acids arranged in a specific order determined by the genetic code and folded into a specific three-dimensional shape. Proteins are essential for all life processes.

Receptor protein Specific proteins found on the cell surface to which hormones or other molecules bind, triggering a specific reaction within the cell. Receptor proteins are responsible for initiating reactions as diverse as nerve impulses, changes in cell metabolism, and hormone release.

Resistance See antibiotic-resistant bacteria. Viruses can also develop resistance to antiviral drugs.

Retrovirus A type of virus that carries its genetic material as single-stranded RNA, rather than as DNA. Upon infecting a cell, the virus generates a DNA replica of its RNA using the enzyme reverse transcriptase.

Reverse transcriptase An enzyme found in retroviruses that copies the virus’ genetic material fromsingle-stranded RNA into double-stranded DNA.

Ribose The type of sugar found in RNA.

Ribosomal RNA RNA found in the ribosome.

RNA (ribonucleic acid) A long, usually single-stranded chain of nucleotides that has structural, genetic, and enzymatic roles. There are three major types of RNA, which are all involved in making proteins: messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). RNA is composed of the sugar ribose, phosphate groups, and the bases adenine, uracil, guanine, and cytosine. Certain viruses contain RNA, instead of DNA, as their genetic material.

Side chain The part of an amino acid that confers its identity. Side chains range from a single hydrogen atom (for glycine) to a group of 15 or more atoms.

Signal transduction The process by which chemical, electrical, or biological signals are transmitted into and within a cell.

Structural biology A field of study dedicated to determining the detailed, three-dimensional structures of biological molecules to better understand the function of these molecules.

Structural genomics A field of study that seeks to determine a large inventory of protein structures based on gene sequences. The eventual goal is to be able to produce approximate structural models of any protein based on its gene sequence. From these structures and models, scientists hope to learn more about the biological function of proteins.

Structure-based drug design An approach to developing medicines that takes advantage of the detailed, three-dimensional structure of target molecules.

Substrate A molecule that binds to an enzyme and undergoes a chemical change during the ensuing enzymatic reaction.

Synchrotron A large machine that accelerates electrically charged particles to nearly the speed of light and maintains them in circular orbits. Originally designed for use by high-energy physicists, synchrotrons are now heavily used by structural biologists as a source of very intense X-rays.

Target molecule (or target protein) The molecule on which pharmaceutical researchers focus when designing a drug. Often, the target molecule is from a virus or bacterium, or is an abnormal human protein. In these cases, the researchers usually seek to design a small molecule—a drug—to bind to the target molecule and block its action.

Transcription The first major step in protein synthesis, in which the information coded in DNA is copied (transcribed) into mRNA.

Translation The second major step in protein synthesis, in which the information encoded in mRNA is deciphered (translated) into sequences of amino acids. This process occurs at the ribosome.

Virus An infectious microbe that requires a host cell (plant, animal, human, or bacterial) in which to reproduce. It is composed of proteins and genetic material (either DNA or RNA).

Virus particle A single member of a viral strain, including all requisite proteins and genetic material.

X-ray crystallography A technique used to determine the detailed, three-dimensional structure of molecules. It is based on the scattering of X-rays through a crystal of the molecule under study.

Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer’s disease

We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer’s disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer’s disease.

Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia.

Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0±5.2 years compared with 41.1±7.4 years for those without these SNPs.

This haplotype thus appears to modify Alzheimer’s AAO, conferring a large (~10 years) protective effect.

The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene.

Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center.

In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population.

Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer’s disease AAO and open potential avenues for therapy.

About Eotaxin

The eotaxins are a CC chemokine subfamily of eosinophil chemotactic proteins.

Results

Association of a novel locus on chromosome 17 modifying Alzheimer’s AAO

Association analysis revealed a cluster of single-nucleotide variants comprising a haplotype on chromosome 17 approaching genome-wide significance for association with AAO of MCI (best P-value 6.43E−08). This P-value is genome-wide significant at the empirical threshold for European populations²⁹ and was well supported by association of multiple variants in the region (Figure 1 and Supplementary Table 1). Adjusted for APOE status, the regression model identified the same peak at chromosome 17 and improved the best P to a genome-wide significant 4.85E−08. APOE ε4 was not significant in this model. Permutation testing empirically supported the chromosome 17 peak as the top associated locus in our study (P=1E−06, the lowest achievable P-value; Supplementary Table 2). The regression model using AAO of dementia as the trait of interest also indicated this same region as the top hit, although the overall P-value was increased as a result of the diminished sample size for this variable (Supplementary Table 3). The Mendel software program, accounting for relatedness among the samples, identified the same locus as the top associated region in this study and achieved genome-wide significance (P=2.86E−08; Supplementary Table 4). Remarkably, the effect size of this haplotype was almost 10 years of delayed onset in carriers. Average AAO of MCI in carriers of the protective haplotype was 51.0±5.2 years compared with non-carriers age at MCI 41.1±7 years (mean±s.d.) (Figure 2).

Examination of the regional association plot on chromosome 17 revealed that the associated haplotype spans several chemokines, including some proinflammatory factors reported to be elevated in AD (Figure 3).³⁷ One chemokine subfamily, the monocyte chemoattractant proteins (MCPs), is implicated in neuronal death during sustained inflammation.³⁸ Four major MCPs reside within the genomic neighborhood associated in this study—MCP1 encoded by the CCL2 gene, MCP2 encoded by CCL7 gene, MCP3 encoded by CCL8 gene and MCP4 encoded by CCL13gene. Two additional genes in this locus include CCL1, encoding a well-characterized proinflammatory chemokine,³⁹ and CCL11, which encodes eotaxin-1, a chemokine whose serum and cerebrospinal fluid levels increase with age and correlate with reduced neurogenesis,⁴⁰ making it a promising candidate for modifying Alzheimer’s AAO.

To identify the genetic variants potentially causal for the large-effect size of the association peak, we functionally annotated all single-nucleotide variants in linkage disequilibrium with our association peak. The haplotype associated with AAO of MCI comprises 22 single-nucleotide variants spanning almost 80 kb (Figure 3 and Supplementary Table 5). Of these, the only single-nucleotide variant located within the coding portion of a gene, rs1129844 (NG_012212.1:g.5208G>A, NP_002977.1:p.Ala23Thr), encodes an alanine-to-threonine missense polymorphism at codon 23 in eotaxin-1 (CCL11 A23T). This missense polymorphism lies directly at the signal peptide cleavage site of the eotaxin-1 precursor protein and is predicted to alter its cleavage in silico (Supplementary Figure 3).⁴¹Differential secretion of mutant and wild-type eotaxin-1 in HEK-293T cells suggests that this mutation may enhance the secretion of eotaxin-1 (Supplementary Figure 3).

Association of eotaxin-1 levels with Alzheimer’s AAO and effect of the associated haplotype on eotaxin-1 levels in sporadic AD

A prerequisite for generalizability of our results is the presence of this allele in the general population. Within the Colombian data set, rs1129844 (G>A) was observed with a minor allele frequency of 0.14. In the general population, the minor allele frequency for rs1129844 is identical (0.14), making this variant a fairly common polymorphism with a prevalence in the general population matching that of APOE ε4 (minor allele frequency=0.15). Given the presence of this haplotype in the general population, we tested whether plasma levels of eotaxin-1 correlate with AAO in an independent Alzheimer’s cohort at the UCSF Memory and Aging Center (n=152). After controlling for CDR, APOE ε4 genotype and the age gap variable, we found that higher plasma eotaxin-1 levels were significantly correlated with higher AAO (F(6, 145)=2.81; P=0.012; β=0.0252, s.e.=0.0122; t-value=2.07, F-test for linear regression). APOE ε4 genotype was not significant in this model.

Finally, we asked whether the haplotype identified in the Antioquian early-onset Alzheimer’s cohort affects eotaxin-1 levels in the UCSF Memory and Aging Center Alzheimer’s cohort. In agreement with previous studies,⁴⁰ eotaxin-1 levels increased with age in the total cohort. However, when we stratified these samples by the presence of the onset-associated haplotype, we found that this haplotype decoupled the relationship between age and plasma levels of eotaxin-1 (Figure 4). In other words, we observed a linear increase in eotaxin-1 levels for non-haplotype carriers but not for haplotype carriers. This decoupling suggests that this haplotype exerts a complex regulatory effect on eotaxin-1 levels. Although the age-associated increase in eotaxin-1 levels has been correlated with reduced neurogenesis and memory impairment,⁴⁰ eotaxin-1 may elicit a hormetic response curve with normal or even neuroprotective effects within a certain interval, and deleterious effects at higher levels. By abrogating the linear increase between eotaxin-1 levels and age, the haplotype identified in this study may effectively constrain eotaxin-1 levels within this normal/protective realm. We observed a trend toward a protective effect of the associated haplotype on AAO in the UCSF cohort, although this effect was not significant (Supplementary Figure 5).

Figure 4.

The associated haplotype decouples plasma eotaxin-1 levels from age in haplotype carriers. Shaded regions show 95% confidence limits for the mean.

Full figure and legend (70K)Download Power Point slide (200 KB)

In silico identification of functional variants in extreme onset individuals

A complementary approach to association testing is bioinformatically screening the catalog of genetic variation we generated through whole-genome sequencing to identify putative functional variants. This bioinformatic screen for functional variants present in individuals at one extreme for AAO predicted eight variants to be deleterious to protein function (SIFT score less than or equal to 0.1) (Supplementary Table 6). Among these was rs150955128 (NM_000418.3:c.554G>A, NP_000409.1:p.Arg185His), an arginine-to-histidine amino-acid substitution at codon 185 of the interleukin 4 receptor (IL4R). The variant is present in seven of the late-onset genomes and absent from the early-onset genomes. An additional 8 of the 72 PSEN1 mutation carriers also have this variant. Of the predicted deleterious variants, carriers of rs150955128 displayed the largest difference in AAO versus non-carriers (50.5 versus 43.2 years), suggesting a protective effect in carriers of this variant. This variant is present with a minor allele frequency around 1% (G>A) but the Exome Aggregation Consortium browser (http://exac.broadinstitute.org/) revealed that the variant is largely restricted to Latino populations and virtually non-existent in Asian, African or European populations. This finding also underscores the importance of including racially and ethnically diverse populations in GWAS.⁴²

Top

Discussion

Through whole-genome sequencing of 72 individuals affected with early-onset familial AD caused by an E280A mutation in PSEN1, we have identified a haplotype on chromosome 17 associated with delayed AAO of MCI and dementia. The identified haplotype spans several chemokines, including CCL2, a proinflammatory chemokine implicated in the chronic neuroinflammation accompanying AD.¹⁸ In our study, the associated haplotype confers ~10 years of protection against AD onset among carriers in the Antioquian early-onset AD cohort. In the general population, this haplotype is relatively common, with an expected prevalence of around one in four people. Within this haplotype, we identified a missense polymorphism in eotaxin-1 (CCL11 A23T) lying directly at the signal peptide cleavage site and therefore we predict this variant may alter the cleavage and secretion of this chemokine. Indeed, we found enhanced secretion of the variant protein in an in vitro expression study. Extensive pathological commonalities between the Antioquian familial AD and the general form of the disease, and the relatively common prevalence of the identified haplotype, lend hope that this haplotype functions similarly (i.e., protectively) in the general population. In the UCSF cohort, we observed a protective trend for this haplotype on AAO, which requires a larger sample to validate.

Eotaxin-1 levels increase throughout life and this increase is correlated with reduced neurogenesis.⁴⁰ This raises the intriguing possibility that eotaxin-1 is a molecular effector of aging, the largest risk factor for developing AD. Here we show that plasma eotaxin-1 levels are correlated with AAO in an independent cohort of Alzheimer’s patients, implicating this chemokine as a novel modulator of Alzheimer’s AAO. Furthermore, carriers of the chromosome 17 haplotype in the UCSF cohort did not exhibit the typical increase of chemokine levels with age. As chemokines mediate both neuroprotection and injury,⁴³ we postulate a hormesis response model for eotaxin-1 levels whereby low to moderate levels of this chemokine elicit a normal or protective response, but higher levels ultimately lead to neurodegeneration and memory impairment. By decoupling eotaxin-1 levels from age, the haplotype identified in this study may protect against the deleterious effects accompanying high levels of this chemokine.

The protein product of CCL11 resulting from differential signal peptide cleavage is predicted to retain additional amino-acid residues at its N terminus, a key region specifying binding and activity of chemokines.⁴⁴ Recent structural studies have implicated a critical role for this region of eotaxin-1 in binding and activation of its receptor CCR3.⁴⁵ Similar to other AD-associated immune-response genes, this receptor is expressed highly in microglia.¹⁴ Therefore, it is reasonable to hypothesize altered eotaxin-1 signaling modulates neuroinflammation among carriers of the CCL11 A23T mutation.

Individuals at the extremes of a trait distribution are likely to be enriched for functional variants underlying that trait.

Through bioinformatic prediction of variants likely to alter gene function, we identified a Latino-specific variant in IL4R enriched in the latest-onset individuals in this study.

Similar to the eotaxin-1 receptor, IL4R is also highly expressed in microglia¹⁴ and its ligand, the anti-inflammatory cytokine interleukin-4, attenuates AD symptoms in transgenic mice.⁴⁶

Another ligand for IL4R is interleukin-13.

Taken together, interleukin-4 and interleukin-13 induce clearance of β-amyloid and improve memory in transgenic mice.⁴⁷

As these cytokines are known to cause the release of eotaxin-1 in certain human cell types upon binding IL4R,⁴⁸ we suggest that eotaxin-1 release may mediate β-amyloid clearance.

This finding thus dovetails with our implication of eotaxin-1 in modulating AAO, and highlights cytokine-mediated neuroinflammation as a promising pathway for therapeutic intervention in AD.

Clarifying the precise relationship between the identified haplotype and eotaxin-1 levels, and identifying the primary cellular sources and regulators of this chemokine in both healthy and diseased states, warrant further study.

As the incidence of AD doubles approximately every 5 years,⁴⁹ delaying the onset by this amount would consequently halve the disease incidence.

In this study, we identified a protective haplotype conferring a ~10-year protective effect in one monogenic early-onset Alzheimer’s population.

Therapies based on this protective haplotype offer the potential to reduce markedly the incidence of AD while enhancing the quality of life of millions of individuals.

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About hormesis

Hormesis is the term that describes any process in a cell or organism that exhibits a biphasic response to exposure to increasing amounts of a substance or condition.^[1]Within the hormetic zone there is generally a favorable biological responses to low exposures to toxins and other stressors. Hormesis comes from Greek hórmēsis“rapid motion, eagerness”, itself from ancient Greek hormáein “to set in motion, impel, urge on”. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses. Hormetics is the term proposed for the study and science of hormesis. A related concept is Mithridatism, which refers to the willful exposure to toxins in an attempt to develop immunity against them.

In toxicology, hormesis is a dose response phenomenon characterized by a low dose stimulation, high dose inhibition, resulting in either a J-shaped or an inverted U-shaped dose response. Such environmental factors that would seem to produce positive responses have also been termed “eustress“. The hormesis model of dose response is vigorously debated.^[2] The notion that hormesis is important for chemical risks regulations is not widely accepted.^[3]

The biochemical mechanisms by which hormesis works are not well understood. It is conjectured that low doses of toxins or other stressors might activate the repair mechanisms of the body. The repair process fixes not only the damage caused by the toxin, but also other low-level damage that might have accumulated before without having triggered the repair mechanism.

dose

About CCL24

Chemokine (C-C motif) ligand 24 (CCL24) also known as myeloid progenitor inhibitory factor 2 (MPIF-2) or eosinophil chemotactic protein 2 (eotaxin-2) is a protein that in humans is encoded by the CCL24 gene.^[1] This gene is located on human chromosome 7.^[2]

Function

CCL24 is a small cytokine belonging to the CC chemokine family. CCL24 interacts with chemokine receptor CCR3 to induce chemotaxis in eosinophils.^[3]This chemokine is also strongly chemotactic for resting T lymphocytes and slightly chemotactic for neutrophils.^[1]

Clinical significance

Elevated levels of eotaxin-2 has been seen in patients with aspirin-exacerbated respiratory disease (AERD), such as asthma. People with lower plasma levels of eotaxin-2 have not been showing tendency to develop aspirin inducible asthma.

About Chromosome 17

Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 83 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total DNA in cells.

Identifying genes on each chromosome is an active area of genetic research. Because researchers use different approaches to predict the number of genes on each chromosome, the estimated number of genes varies. Chromosome 17 likely contains between 1,200 and 1,500 genes. It also contains the HomeoboxB gene cluster.

The following diseases are related to genes on chromosome 17:

About Protein

Protein-related diseases can occur from a number of errors in the production and folding of proteins. An incorrect amino acid, a missing protein, or one that doesn’t fold as it should, for example, can lead to disease.

About Structure-base drug design

Structure-based drug design takes advantage of the detailed, three-dimensional structure of target molecules. If you think of the target molecule as a lock, this approach is like trying to design a key perfectly shaped to the lock if you’re given an armload of tiny metal scraps, glue, and wire cutters. Scientists can make a “mold” of the lock and of the natural molecule, called a substrate, that fits into the lock and opens the door. The goal is to plug the lock by finding a small molecule that fits inside and prevents the natural substrate from entering.

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