February 13, 2017 A depiction of the double helical structure of DNA. Its four coding units (A, T, C, G) are color-coded in pink, orange, purple and yellow. Credit: NHGRI

Why do some people get Type 2 diabetes, while others who live the same lifestyle never do?

For decades, scientists have tried to solve this mystery - and have found more than 80 tiny DNA differences that seem to raise the risk of the disease in some people, or protect others from the damagingly high levels of blood sugar that are its hallmark.

But no one "Type 2 diabetes signature" has emerged from this search.

Now, a team of scientists has reported a discovery that might explain how multiple genetic flaws can lead to the same disease.

They've identified something that some of those diabetes-linked genetic defects have in common: they seem to change the way certain cells in the pancreas "read" their genes.

The discovery could eventually help lead to more personalized treatments for diabetes. But for now, it's the first demonstration that many Type 2 diabetes-linked DNA changes have to do with the same DNA-reading molecule. Called Regulatory Factor X, or RFX, it's a master regulator for a number of genes.

The team reporting the findings in a new paper in the Proceedings of the National Academy of Sciences comes from the University of Michigan, National Institutes of Health, Jackson Laboratory for Genomic Medicine, University of North Carolina, and the University of Southern California.

They report that many diabetes-linked DNA changes affect the ability of RFX to bind to specific locations in the genomes of pancreas cell clusters called islets. And that in turn changes the cells' ability to carry out important functions.

Islets contain the cells that make hormones, including insulin and glucagon, which keep blood sugar balanced in healthy people. In people with diabetes, that regulation goes awry - leading to a range of health problems that can develop over many years.

"We have found that many of the subtle DNA spelling differences that increase risk of Type 2 diabetes appear to disrupt a common regulatory grammar in islet cells," says Stephen C.J. Parker, Ph.D., an assistant professor of computational medicine and bioinformatics, and of human genetics, at the U-M Medical School. "RFX is probably unable to read the misspelled words, and this disruption of regulatory grammar plays a significant role in the genetic risk of Type 2 diabetes."

Parker is one of four co-senior authors on the paper, which also includes Michael Boehnke, Ph.D., of the U-M School of Public Health's Department of Biostatistics, Francis Collins, M.D., Ph.D., director of the National Institutes of Health, and Michael L. Stitzel, Ph.D. of the Jackson Laboratory.

Prior to their current faculty positions Parker and Stitzel worked in Collins' lab at the National Human Genome Research Institute. Parker's graduate student, Arushi Varshney, is one of the paper's co-first authors with Laura Scott, Ph.D., and Ryan Welch, Ph.D., of the U-M School of Public Health's Department of Biostatistics and Michael Erdos, Ph.D., of the National Human Genome Research Institute.

They performed an extensive examination of DNA from islet samples isolated from 112 people. They characterized differences not just in DNA sequences, but also in the way DNA was packaged and modified by epigenetic factors, and the levels of gene expression products that indicated how often the genes had been read and transcribed.

This allowed them to track the "footprints" that RFX and other transcription factors leave on packaged DNA after they have done their job.

RFX and other factors don't bind directly to the part of a gene that encodes a protein that does a cellular job. Rather, they bind to a stretch of DNA near the gene - a runway of sorts.

But when genetic changes linked to Type 2 diabetes are present, that runway gets disrupted, and RFX can't bind as it should.

Each DNA change might alter this binding in a different way, leading to a slightly different effect on Type 2 diabetes risk or blood sugar regulation. But the common factor for many of these changes was its effect on the area where RFX is predicted to bind, in the cells of pancreatic islets.

So, says Parker, this shows how the genome - the actual sequence of DNAcan influence the epigenome, or the factors that influence gene expression.

The researchers note that a deadly form of diabetes seen in a handful of babies born each year may be related to RFX mutations. That condition, called Mitchell-Riley syndrome, involves neonatal diabetes and malformed pancreas, and is known to be caused by a rare autosomal recessive mutation of one form of RFX.

Explore further: Unique mapping of methylome in insulin-producing islets

More information: Genetic regulatory signatures underlying islet gene expression and type 2 diabetes, PNAS, http://www.pnas.org/cgi/doi/10.1073/pnas.1621192114

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Diabetes in your DNA? Scientists zero in on the genetic signature of risk - Medical Xpress

Lola Aiken, wife of the late Gov. George Aiken, is accompanied by then-Gov. Peter Shumlin as she waves to supporters during her 100th birthday celebration in June 2012. Aiken would live to age 102. STEFAN HARD / STAFF FILE PHOTO

Will it soon be possible for most of us to live to be 100?

Yes, experts told The Palm Beach Post last week, and genomic medicine will play a crucial role.

What is genomic medicine?

Its an emerging medical discipline that uses a persons gene map to make diagnostic decisions.

Its also the foundation for what former President Obama announced in his 2015 State of the Union address: the Precision Medicine Initiative.

Over the weekend, Dr. Georgia Dunston, founding director of the National Human Genome Center at Howard University and one of the nations leading genome experts, were in Palm Beach County. She spoke at different events connected to the West Palm Beach Alumnae Chapter of Delta Sigma Theta Sorority Inc. Founders Day Weekend.

The theme of the Friday Sunday gathering was Genomics: African ancestry and culture spirit, soul and body.

As Dunston explained of her work with the groundbreaking International Human Genome Project, The genome is the complete set of instructions for building and operating the human body. In 2003, scientists completed the sequence of the human genome, which shows the location of each of the 20,500 genes in the complete map of the human genome.

In lay terms, this means that we all have a vast, unique genetic map that doctors and researchers can now use to customize our health- related decisions.

Which medications work best with which genes.

Which gene sequences are more likely to develop which diseases.

Which environmental and lifestyle factors are most likely to affect given gene sequences.

Genomics is helping researchers discover why some people get sick from certain infections, environmental factors, and behaviors, while others do not. Because genes are inherited and shared among relatives, genomics is also helping researchers discover why certain diseases occur in some families and not others, and are more common in some ethnic groups and natural populations than others, said Dunston.

One of the events organizers, Dr. Eugenia Millender, president of the West Palm Beach Alumnae Chapter of Delta Sigma Theta, also has firsthand knowledge of the importance of genomics especially in African-American and other minority populations, as shes the director of the Florida Atlantic University Community Health Center, where genetic testing is available.

A psychiatric nurse practitioner and assistant professor at Florida Atlantic Universitys Lynn College of Nursing, Millender said, This is the most innovative development in the way we approach health care. We have to educate as many people as possible about the availability of this kind of testing.

She further explained that everything from our mental health to our pain threshold is dictated by our genomic map.

At Friday evenings free town hall meeting, the genetic testing company GeneSight was on hand to provide attendees information on how affordable the testing can be.

Millender noted that for those on Medicaid, GeneSight is offering the testing for free, and for those on insurance plans, the cost can be just a few hundred dollars, depending on their income.

Marian Stubbs, chairwoman for the 2017 Delta Sigma Theta Founders Day Weekend, cant wait for others to hear Dunston explain the potentially transformative benefits of genomic medicine.

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The secret to health and long life: It's in your genes - Rutland Herald

February 13, 2017 Four sub-types of pheochromocytoma/paraganglioma. Credit: Penn Medicine

Casting one of the largest genomic nets to date for the rare tumors of the autonomic nervous system known as pheochromocytoma and paraganglioma (PCC/PGL) captured several new mutations driving the disease that could serve as potential drug targets, researchers from Penn Medicine and other institutions reported this week in Cancer Cell.

Analyzing genetic data of 173 patients from The Cancer Genome Atlas, researchers, including senior author Katherine Nathanson, MD, a professor in the division of Translational Medicine and Human Genetics at the Perelman School of Medicine at the University of Pennsylvania and associate director for Population Science at Penn's Abramson Cancer Center, identified CSDE1 and fusion genes in MAML3 as drivers of the disease, both a first for any cancer type. The researchers also classified PCC/PGL into four distinct subtypes, each driven by mutations in distinct biological pathways, two of which are novel.

"What's interesting about these tumors is that while they are astonishingly diverse genetically, with both inherited and somatic drivers influencing tumorigenesis, each has a single driver mutation, not multiple mutations," Nathanson said. "This characteristic makes these tumors ideal candidates for targeted therapy." Other cancer types typically contain anywhere from two to eight of these driver mutations.

The discovery of these single drivers in PCC/PGL provides more opportunities for molecular diagnosis and prognosis in these patients, particularly those with more aggressive cancers, the authors said.

PGLs are rare tumors of nerve ganglia in the body, whereas PCCs form in the center of the adrenal gland, which is responsible for producing adrenaline. The tumor causes the glands to overproduce adrenaline, leading to elevated blood pressure, severe headaches, and heart palpitations. Both are found in about two out of every million people each year. An even smaller percentage of those tumors become malignant - and become very aggressive. For that group, the five-year survival rate is about 50 percent.

Matthew D. Wilkerson, MD, the Bioinformatics Director at the Collaborative Health Initiative Research Program at the Uniformed Services University, is the paper's co-senior author.

To identify and characterize the genetic missteps, researchers analyzed tumor specimens using whole-exome sequencing, mRNA and microRNA sequencing, DNA-methylation arrays, and reverse-phase protein arrays. The four molecularly defined subgroups included: a kinase-signaling subtype, a pseudohypoxia subtype, a cortical admixture subtype, and a Wnt-altered subtype. The last two have been newly classified.

The results also provided clinically actionable information by confirming and identifying several molecular markers associated with an increased risk of aggressive and metastatic disease, including germline mutations in SDBH, somatic mutations in ATRX (previously established in a Penn Medicine study), and new gene fusions - a genetic hybrid, of sorts - in MAML3.

Because the MAML3 fusion gene activates the Wnt-altered subtype, the authors said, existing targeted therapies that inhibit the beta-catenin and STAT3 pathways may also prove effective in certain PCC/PGL tumors.

Other mutations identified in the analysis may also serve as potential targets for drugs currently being investigated in other cancers. For example, glutaminase inhibitors are being tested in SDH-mutant tumors, including breast and lung, and ATR inhibitors are being investigated in blood cancers. Today, there are several U.S. Food and Drug Administration-approved targeted therapies for mutations, such as BRAF and FGFR1, among others, also found in PCC/PGL.

"The study gives us the most comprehensive understanding of this disease to date - which we believe will help researchers design better trials and target mutations that will ultimately help improve treatment for these patients," Nathanson said. "The next step is to focus more on aggressive cancers that metastasize and the drivers behind those tumors."

Explore further: Mutated ATRX gene linked to brain tumors potential biomarker for rare adrenal tumors too

More information: Lauren Fishbein et al, Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma, Cancer Cell (2017). DOI: 10.1016/j.ccell.2017.01.001

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In-depth gene search reveals new mutations, drug targets in rare adrenal tumors - Medical Xpress

When Nisa Leung was pregnant with her first child in 2012, her doctor in Hong Kong offered her a choice. She could take a prenatal test that would require inserting a needle into her uterus, or pay $130 more for an exam that would draw a little blood from her arm.

Leung opted for the simpler and less risky test, which analyzed bits of the baby's DNA that had made its way into her bloodstream. Then Leung went on to do what she often does when she recognizes a good product: look around for companies to invest in.

The managing partner at Qiming Venture Partners decided to put money into Chinese genetic testing firm Berry Genomics, which eventually entered into a partnership with the Hong Kong-based inventor of the blood test. Over the next few months, Berry is expected to be absorbed into a Chinese developer in a $625 million reverse merger. And Leung's venture capital firm would be the latest to benefit from a boom in so-called precision medicine, an emerging field that includes everything from genetic prenatal tests to customizing treatments for cancer patients.

China has made the precision medicine field a focus of its 13th five-year plan, and its companies have been embarking on ambitious efforts to collect a vast trove of genetic and health data, researching how to identify cancer markers in blood, and launching consumer technologies that aim to tap potentially life-saving information. The push offers insight into China's growing ambitions in science and biotechnology, areas where it has traditionally lagged developed nations like the U.S.

"Investing in precision medicine is definitely the trend," said Leung, who's led investments in more than 60 Chinese health-care companies in the past decade. "As China eyes becoming a biotechnology powerhouse globally, this is an area we will venture into for sure and hopefully be at the forefront globally."

New Chinese firms like iCarbonX and WuXi NextCode that offer consumers ways to learn more about their bodies through clues from their genetic make up are gaining popularity. Chinese entrepreneurs and scientists are also aiming to dominate the market for complex new procedures like liquid biopsy tests, which would allow for cancer testing through key indicators in the blood.

Such research efforts are still in early stages worldwide. But doctors see a future beyond basic commercial applications, aiming instead for drugs and treatment plans tailored to a person's unique genetic code and environmental exposure, such as diet and infections.

Isaac Kohane, a bioinformatics professor at Harvard University, says when it comes to precision medicine, the science community has "Google maps envy." Just as the search engine has transformed the notion of geography by adding restaurants, weather and other locators, more details on patients can give doctors a better picture on how to treat diseases.

For cancer patients, for example, precision medicine might allow oncologists to spot specific mutations in a tumor. For many people with rare ailments like muscle diseases or those that cause seizures, it allows for earlier diagnosis. Pregnant women, using the kind of tests that Leung used, could also learn more about the potential for a child to inherit a genetic disease.

The global interest in the field comes as the cost of sequencing DNA, or analyzing genetic information, is falling sharply. But a number of hurdles remain. Relying on just genes isn't enough, and there must also be background information on a patient's lifestyle and medication history.

Precision medicine applications also require heavy investment to store large amounts of information. A whole genome is more than 100 gigabytes, according to an e-mailed response to questions from Edward Farmer, WuXi NextCode's vice president of communications and new ventures. "So you can imagine that analyzing thousands or hundreds of thousands of genomes is a true big data challenge."

WuXi NextCode was formed after Shanghai-based contract research giant WuXi AppTec Inc. acquired genomic analysis firm NextCode Health, a spin-off from Reykjavik, Iceland-based Decode Genetics, which has databases on the island's population. Wuxi NextCode continues to have an office in Iceland, where the population is relatively homogenous and therefore good for gene discovery.

"Genomics today is like the computer industry in the '70s," said Hannes Smarason, WuXi NextCode's co-founder and chief operating officer. "We've made great progress but there's still a long way to go."

In China, Wuxi NextCode now offers consumers genetic tests that cost between about $360 and $1,160, providing more details on rare conditions a child might be suffering from or even the risk of passing on an inherited disease.

China is diverse, and with 1.4 billion people, the planet's most populous nation. WuXi NextCode announced a partnership with Huawei Technologies Co., China's largest telecommunications equipment maker, in May to enable different institutions and researchers to store their data.

The goal is to use that deep pool of information -- which ranges from genome sequences to treatment regimens -- to find more clues on tackling diseases. WuXi says that "this will in many instances enable the largest studies ever undertaken in many diseases."

Another Chinese player, iCarbonX, which received a $200 million investment from Tencent Holdings Ltd. and other investors in April, is valued at more than $1 billion. It announced last month that it had invested $400 million in several health data companies to enable the use of algorithms to analyze reams of genomic, physiological and behavioral data to provide customized medical advice directly to consumers through an app.

The global precision medicine market was estimated to be worth $56 billion in revenue at the end of 2016, with China holding about 4 percent to 8 percent of the global market, according to a December report from Persistence Market Research.

Encouraging interventions for some patients too early, even before they have life-threatening diseases, comes with risks and ethical questions, Laura Nelson Carney, an analyst at Sanford C Bernstein, wrote in a Jan. 6 note. Still, precision medicine research has many benefits, and some in China see the country's push as a significant opportunity "to scientifically leapfrog the West," she said.

In the U.S., universities, the National Institutes of Health and American drugmakers are part of a broad march into precision medicine.

Amgen Inc. bought Icelandic biotechnology company DeCode Genetics for $415 million in 2012, to acquire its massive database on Iceland's population. U.S.-based Genentech Inc. is collaborating with Silicon Valley startup 23andMe to study the genetic underpinnings of Parkinson's disease.

"Humans are computable," said Wang Jun, the chief executive officer of China's iCarbonX. "So we need a computable model that we can use to intervene and change people's status, that's the whole point."

SundayMonday Business on 02/13/2017

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China aims for share of precision medicine - Arkansas Online

John Ingle , Times Record News 1:49 p.m. CT Feb. 12, 2017

Times Record News business/metro editor John Ingle, left, asks questions as Dr. Jeremy Johnson of Olney Family Clinic explains the results of Ingle's GeneMed pharmacogenetic screening. The test helps determine which medications or combinations of medications can be most effective for a patient or which to avoid, based on their specific DNA.(Photo: Torin Halsey/Times Record News)Buy Photo

Well, the good news is my prescribed medications for diabetes and high blood pressure are genetically effective for my body's make-up.

Back in January, I agreed to undergo a simple pharmacogenetic screening at Olney Family Clinic in Olney, a relatively new tool physicians there are using to aid in the treatment oftheir patients more effectively. The procedure included sharing my medical history with Dr. Jeremy Johnson at the clinic, as well as that of my parents; I provided a list of my prescribed medications; and a mouth swab was done to collect the sample.

The screening is able to determine how well, if at all, medications metabolize in my body. If they break down too fast, they'll be absorbed well before they reach their active stage. If I don't have a specific enzyme required to break down the medication, it won't work at all.

"All of your risk assessments, you got a check mark on," said Johnson, a graduate of the John Peter Smith Family Medicine Residency program in Fort Worth. "I really don't have any recommendations to change your medicine, I just have information in case you ever have any situations."

In addition to determining the effectiveness of the medications I'm on, Johnson was also able to get information of what will and won't work in eight different drug categories including antiplatelets, muscle relaxants, opiods, anti-addictives, anti-ADHD, anti-convulsants, antidepressants and antipsychotics. The results provided specific medications that would work the best in each category.

A GeneMed pharmacogenetic screening shows genetically which medications a patient can or cannot metabolize well which can greatly increase the effectiveness of different treatments.(Photo: Torin Halsey/Times Record News)

For example, the pharmacogenetic testing revealed that I would have a reduced response to Plavix, but said Effient or Brilinta would work. The test also showed that I would respond better to the muscle relaxers Flexeril, Robaxin, Skelaxin or Soma instead of Zanaflex.

"It's cool information," Johnson said. "It gives your practitioner so much more information."

The screening also looked at other risks including hyperlipidemia and atherosclerosis (hardening and narrowing of arteries); thrombophilia (blood clotting); and hyperhomocysteinemia (a marker for heart disease). The results indicated I did not have an increased risk for those.

Johnson said test results for some of his patients have prompted him to alter their medications for more effective treatment of their illnesses. He said there have been no negative side effects for those patients. Physicians are trained in medical school and through national organizations courses of treatment for different illnesses. For example, he said, the first medication typically prescribed for a new diabetic is Metformin, not knowing if it will be compatible with that person's genetic make-up.

"You can go with your best information and do evidence-based research -- they tested this and said this is the perfect medicine," he said. "Well, now we've got anotherlevel (of knowledge). For his genetics, he can't take Metformin because he doesn't metabolize it correctly. Even though the book tells you to put them on that medicine, you can't because it's not right for him. So, we're doing more patient-specific therapies based on this GeneMed testing."

Johnson said he is hopeful pharmacogenetic testing will be something more physicians use and pharmaceutical and insurance companies push for so patients can get the most effective care from the very beginning of their treatment. While my results showed the medications I'm currently on fit my genetic disposition, the outcome also produced information that can be used years down the road.

"Prevention is what I'm supposed to be doing here," he said. "I'm not only supposed to be healing sick people, but really what insurance companies want and what longitudinal care you get with primary care doctors is prevention. We need to try to do prevention ... and this is another way of preventing illness."

Follow John Ingle on Twitter at @inglejohn1973.

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Genetic testing provides writer, doc in-depth info - Times Record News

ANN ARBOR, MI Why do some people get Type 2 diabetes, while others who live the same lifestyle never do?

For decades, scientists have tried to solve this mystery and have found more than 80 tiny DNA differences that seem to raise the risk of the disease in some people, or protect others from the damagingly high levels of blood sugar that are its hallmark.

But no one Type 2 diabetes signature has emerged from this search.

Now, a team of scientists has reported a discovery that might explain how multiple genetic flaws can lead to the same disease.

Theyve identified something that some of those diabetes-linked genetic defects have in common: they seem to change the way certain cells in the pancreas read their genes.

The discovery could eventually help lead to more personalized treatments for diabetes. But for now, its the first demonstration that many Type 2 diabetes-linked DNA changes have to do with the same DNA-reading molecule. Called Regulatory Factor X, or RFX, its a master regulator for a number of genes.

The team reporting the findings in a new paper in the Proceedings of the National Academy of Sciences comes from the University of Michigan, National Institutes of Health, Jackson Laboratory for Genomic Medicine, University of North Carolina, and the University of Southern California.

They report that many diabetes-linked DNA changes affect the ability of RFX to bind to specific locations in the genomes of pancreas cell clusters called islets. And that in turn changes the cells ability to carry out important functions.

Islets contain the cells that make hormones, including insulin and glucagon, which keep blood sugar balanced in healthy people. In people with diabetes, that regulation goes awry leading to a range of health problems that can develop over many years.

We have found that many of the subtle DNA spelling differences that increase risk of Type 2 diabetes appear to disrupt a common regulatory grammar in islet cells, says Stephen C.J. Parker, Ph.D., an assistant professor of computational medicine and bioinformatics, and of human genetics, at the U-M Medical School. RFX is probably unable to read the misspelled words, and this disruption of regulatory grammar plays a significant role in the genetic risk of Type 2 diabetes.

Parker is one of four co-senior authors on the paper, which also includes Michael Boehnke, Ph.D., of the U-M School of Public Healths Department of Biostatistics, Francis Collins, M.D., Ph.D., director of the National Institutes of Health, and Michael L. Stitzel, Ph.D. of the Jackson Laboratory.

Prior to their current faculty positions Parker and Stitzel worked in Collins lab at the National Human Genome Research Institute. Parkers graduate student, Arushi Varshney, is one of the papers co-first authors with Laura Scott, Ph.D., and Ryan Welch, Ph.D., of the U-M School of Public Healths Department of Biostatistics and Michael Erdos, Ph.D., of the National Human Genome Research Institute.

They performed an extensive examination of DNA from islet samples isolated from 112 people. They characterized differences not just in DNA sequences, but also in the way DNA was packaged and modified by epigenetic factors, and the levels of gene expression products that indicated how often the genes had been read and transcribed.

This allowed them to track the footprints that RFX and other transcription factors leave on packaged DNA after they have done their job.

RFX and other factors dont bind directly to the part of a gene that encodes a protein that does a cellular job. Rather, they bind to a stretch of DNA near the gene a runway of sorts.

But when genetic changes linked to Type 2 diabetes are present, that runway gets disrupted, and RFX cant bind as it should.

Each DNA change might alter this binding in a different way, leading to a slightly different effect on Type 2 diabetes risk or blood sugar regulation. But the common factor for many of these changes was its effect on the area where RFX is predicted to bind, in the cells of pancreatic islets.

So, says Parker, this shows how the genome the actual sequence of DNA -- can influence the epigenome, or the factors that influence gene expression.

The researchers note that a deadly form of diabetes seen in a handful of babies born each year may be related to RFX mutations. That condition, called Mitchell-Riley syndrome, involves neonatal diabetes and malformed pancreas, and is known to be caused by a rare autosomal recessive mutation of one form of RFX.

In addition to co-senior and co-first authors listed above, the studys authors include a range of researchers from several institutions. The study was funded by the National Institutes of Health (HL127984, DK062370, HG000024, DK099240, DK092251, DK093757, DK105561, DK072193, ZIA HG000024).Parker is a 2014 recipient of the American Diabetes Associations Pathway to Stop Diabetes grant, a type of grant awarded annually by the American Diabetes Association to provide up to $1.625 million to each scientist over a five- to seven-year grant term to spur breakthroughs in clinical science, technology, diabetes care and potential cures. Since launching in 2013 Pathway has awarded more than $36 million to 23 leading scientists.

Reference: PNAS, http://www.pnas.org/cgi/doi/10.1073/pnas.1621192114

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Diabetes in your DNA? Scientists zero in on the genetic signature of risk - University of Michigan Health System News (press release)

February 8, 2017 Betty Pei-tie Tsao, Ph.D., is the Richard M. Silver Endowed Chair for Inflammation Research at the Medical University of South Carolina and senior author on the Nature Genetics article. Credit: Medical University of South Carolina

Investigators at the Medical University of South Carolina (MUSC) report pre-clinical research showing that a genetic variant encoded in neutrophil cystolic factor 1 (NCF1) is associated with increased risk for autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis, and Sjgren's syndrome, in the January 2017 issue of Nature Genetics.

Data indicate that increased NCF1 protects against SLE while decreased NCF1 raises SLE risk and highlight the pathogenic role of reduced reactive oxygen species in autoimmune disease development.

Single-nucleotide polymorphisms (SNPs - pronounced 'snips') are the most common type of human genetic variation; each one represents a small difference in a nucleotide - the building blocks of our DNA. The Immunochip for fine-mapping is an important tool for conducting genome-wide association studies of the genetic components of disease. Researchers use the Immunochip to investigate DNA samples from people with a particular disease for linkage disequilibrium (LD) signals that illuminate associations between specific SNPs and the disease.

Autoimmune diseases such as SLE are known to have a strong genetic component and, to date, dozens of SNPs associated with SLE have been identified and included on the Immunochip. The Achilles heel is, of course, that the Immunochip cannot identify associations with SNPs that it does not include.

When MUSC researchers genotyped DNA samples from Chinese, European-American, and African-American SLE patients, they found a strong signal in the Chinese sample at the rs73366469 locus in the GTF2IRD1-GTF2I intergenic region at 7q11.23. This was puzzling because that locus was not consistent with SLE loci identified by other genome-wide association studies. Furthermore, the very strong signal in the Chinese sample appeared as a modest signal in the European-American sample and did not appear at all in the African-American sample.

"A true risk gene should be the same in all populations," explained Betty Pei-tie Tsao, Ph.D., Richard M. Silver Endowed Chair for Inflammation Research at MUSC and senior author on the article. "And for such a strong signal, we wondered, 'why hasn't anyone else seen it?' We wanted to find out if what we were seeing was true and explain it."

The team confirmed their finding using a different genotyping platform in an independent Asian sample provided by Nan Shen, M.D., Ph.D., professor of medicine and director of the Shanghai Institute of Rheumatology at Shanghai Jiao Tong University's School of Medicine. But, because rs73366469 did not show LD with any SNPs in the Immunochip, the researchers hypothesized that the SNP containing the true underlying risk factor was not included in it.

"We came into the study from our Asian samples and then started looking for this signal in other populations," said Tsao. "Every ethnic group has a different ancestral background and different LD patterns. We used the LD signal strength as a guide to find our way to the true risk gene - the particular variant that actually caused the increased risk for lupus."

Because the SNP they were looking for was most likely not included in the Immunochip, the team turned to the 1000 Genomes Project dataset, where they found two SNPs that were not only not on the Immunochip, but also produced stronger LD signals with rs73366469 in Asian patients than European or African patients. One of these two, rs117026326 located on intron 9 of GTF2I, showed a stronger association with SLE than either the original or the other locus from the 1000 Genomes Project.

As the researchers focused in on rs117026326, they saw that the NCF1 gene was nearby. This was important because NCF1, which encodes a subunit of NOX2, is thought to be related to SLE due to its role in activating the phagocytic complex NOX2.

Preclinical studies have shown that non-functional NOX2 exacerbates lupus in mice. Furthermore, NCF2, which encodes another subunit of NOX2, is associated with SLE risk in European Americans.

The strong association of rs117026326 with SLE and the functional implications of nearby NCF1 took the team to their next hypothesis: that the rs117026326 SNP might tag causal variants of NCF1 that were not present in the 1000 Genomes Project database.

But unraveling this mystery was not going to be easy.

"This is a very complex genomic region," explained Tsao. "The NCF1 gene has two nearly identical twins - NCF1B and NCF1C - that are 98% the same. But they are non-functional pseudo-genes. This makes working in this region of the human genome very difficult. That's why the next-generation sequencing method that the 1000 Genomes Project has been doing doesn't pertain to this region."

The researchers believed that mapping techniques commonly used by the larger projects, while efficient, limited their ability to find unique sequences among all the copies and duplications in this region. So, they decided to set up their own, novel PCR assay.

"You can't easily sequence this region using the next-generation techniques," said Tsao. "So, we had to do it the old-fashioned way, which was very time consuming and labor intensive. To genotype the region correctly, we used PCR to selectively amplify the NCF1 copies and conduct copy number variation tests. Then we only used samples with no copy number variation to examine the NCF1 variant. This method ensured that what we identified as an NCF1 variant was truly a variant."

Using this strategy, the team identified 67 SNPs, four of which had a strong association with rs117026326. After conducting a long series of multiple tests in samples from various ethnic populations, they gradually eliminated three of the four SNPs and determined that the one called p.Arg90His was the likely genetic variant causing SLE susceptibility across all populations.

In addition, p.Arg90His was associated with increased risk for other autoimmune diseases, including rheumatoid arthritis and Sjgren's syndrome.

The team also found that having only one copy of NCF1 was associated with a higher SLE risk, but having three or more NCF1 copies was associated with reduced SLE risk. Finally, while the underlying mechanism is unclear, the team found that having reduced NOX2-derived reactive oxygen species also raised the risk for these autoimmune diseases.

Tsao notes that perseverance was a critical component of this work. This work was started years ago when the team was at the University of California Los Angeles and was completed after moving to MUSC.

"We just stuck with it as a labor of love. Our lead author, Jian Zhao, devoted several years of his life to this project," explained Tsao." At the time we started, we didn't know it was going to be so complex. We just wanted to explain what we were seeing. It turned out to be quite a chase and very interesting and rewarding to finally bring this project to this point."

This work also points out an important unmet need in the field of genetic mapping.

"We need a more efficient platform to screen complex genome regions for variants. For a lot of diseases we've identified some, but not all, of the variants. There may be more variants hiding in these complex regions," said Tsao. "You have to sort it out like a puzzle. Autoimmune diseases share certain risk factors but also have unique genetic variants that drive the molecular pathogenesis of the disease. Each time you find a variant, you get more puzzle pieces and you can start to understand more about that disease and other autoimmune diseases as well."

Explore further: Genome study identifies risk genes in African Americans with inflammatory bowel disease

More information: Jian Zhao et al, A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases, Nature Genetics (2017). DOI: 10.1038/ng.3782

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Study of complex genetic region finds hidden role of NCF1 in ... - Medical Xpress

Induced pluripotent stem cells don't increase genetic mutations Science Daily Despite its immense promise, adoption of iPSCs in biomedical research and medicine has been slowed by concerns that these cells are prone to increased numbers of genetic mutations. A new study by scientists at the National Human Genome Research ...

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Induced pluripotent stem cells don't increase genetic mutations - Science Daily

The United States has long been the [genomic] industrys undisputed leader,but now China is emerging as Americas fiercest competitor.

Im very frustrated at how aggressively China is investing in this space while the U.S. is not moving with the same kind of purpose, said Eric Schadt, director of the Icahn Institute for Genomics and Multiscale Biology at Mount Sinai. China has established themselves as a really competitive force.

For China, the genomics revolution has been a chance to showcase its technical prowess as well as cultivate homegrown innovationTo succeed over the next generation, China hopes to emulate Western-style entrepreneurship to transform its economy.

[T]his past spring, Chinese officials launched a $9 billion investment in precision medicine, a wide-ranging initiative to not only sequence genes, but also develop customized new drugs using that data. The funding dwarfs a similar effort announced by President Obama a year ago that has an uncertain future in Trumps new administration.

The U.S. system has more dexterity and agility than the Chinese system, said [Denis Simon, executive vice chancellor of Duke Kunshan University in China]. But the learning curve in China is very powerful, and the Chinese are moving fast. The question is not if. The question is when.

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post:Chinas $9 billion effort to beat the U.S. in genetic testing

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China aggressively challenges US lead in precision medicine - Genetic Literacy Project

New method of genetic engineering indispensable tool in biotechnological applications Science Daily Research by Professor of Chemical and Biomolecular Engineering Huimin Zhao and graduate student Behnam Enghiad at the University of Illinois is pioneering a new method of genetic engineering for basic and applied biological research and medicine. and more »

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New method of genetic engineering indispensable tool in biotechnological applications - Science Daily

U.S. Army scientists, working with medical technology companies, have successfully tested and used products and techniques that have enabled Army surgeons to replace the severely burned skin of soldiers as well as transplant new hands and even faces.

At Duke University, researchers are studying zebra fish to learn how science and medicine might someday be able to regenerate severed human spinal cords.

These examples one already in practice and the other in the early research stages illustrate the potential that regenerative medicine offers for the future of medical care.

This research aims to go beyond easing the pain of life-threatening illnesses by changing the way diseases affect the body and then eradicating them.

The vast majority of currently available treatments for chronic and/or life-threatening diseases are palliative, Morrie Ruffin, managing director of the Alliance for Regenerative Medicine (ARM), told Healthline.

ARM, based in Washington, D.C., is considered the preeminent global advocate for regenerative and advanced therapies.

Other treatments delay disease progression and the onset of complications associated with the underlying illness, he said. Very few therapies in use today are capable of curing or significantly changing the course of disease.

Regenerative medicine has the unique ability to alter the fundamental mechanisms of disease, and thereby offer treatment options to patients where there is significant unmet medical need.

And it has the potential to address the underlying causes of disease, Ruffin said, representing a new and growing paradigm in human health.

The field encompasses a number of different technologies, including cell, gene, and tissue-based therapies.

Read more: Re-growing teeth and healing wounds without scars

With the Army breakthroughs, government investment was key.

The U.S. Department of Defense (DOD) has invested more than $250 million in regenerative medicine research over the past decade in an effort to make promising technologies available to wounded service members.

Dr. Wendy Dean is medical officer for the Tissue Injury and Regenerative Medicine Project Management Office at the U.S. Army Medical Materiel Development Activity at Fort Detrick, Md., home to the Armys Medical Research and Materiel Command.

Those investments have yielded a stress-shielding surgical bandage, Embrace, to reduce scarring after surgery, Dean told Healthline. The research has also enabled tremendous progress in burn care, allowing surgeons to improve recovery from severe burns with the use of novel skin replacement strategies, such as ReCell spray-on skin, or skin substitutes such as StrataGraft. These skin replacement methods reduce or eliminate the need for donor sites, a frequent request of burn patients.

These revolutionary products were not developed by the Army, Dean said, but were supported with research funding, initially through the Armed Forces Institute of Regenerative Medicine.

The DOD also has invested in hand and face transplantation efforts for service members and civilians whose injuries are so severe that conventional reconstruction is insufficient, she said.

Dean noted that DOD funding has supported 13 hand transplants to date, including a transplant for retired Sgt. Brendan Marrocco in 2012. He was the first service member to survive quadrilateral amputations sustained in combat. The funding also supported eight face transplants.

The Armys goal is to heal those injured in battle.

Regenerative medicine is still young, but it has shown tremendous progress over the last decade, Dean said. Our mission is to make wounded warriors whole by restoring form, function, and appearance. This field offers the best hope to someday fully restore lost tissue with tissue that is structurally, functionally, and aesthetically a perfect match. It may be years before the vision is a widespread reality, but the field is well on its way.

Read more: Regenerative medicine doctor says forget the pills

At Duke University, Kenneth Poss, professor of cell biology, and director of the Regeneration Next initiative, was the senior investigator for a study of spinal cord regeneration in zebra fish.

Those findings were published in November in the journal ScienceDaily.

In my lab, we are researching genetic factors that enable regeneration of tissues such as heart and spinal in nonmammalian animals like zebra fish, Poss told Healthline. A scientist in my lab, Mayssa Mokalled, led a study finding that a gene called connective tissue growth factor [CTGF] is important for spinal cord regeneration in zebra fish after an injury that completely severs the cord.

CTGF is necessary to stimulate cells called glia to form a tissue bridge across the severed parts of the spinal cord an early step in spinal cord regeneration.

Within eight weeks, the scientists found that zebra fish regenerate a severed spinal cord, including nerve cells, and fully reverse their paralysis.

Developing techniques to treat and reverse spinal cord damage, a paralyzing and often fatal injury, is a pressing need in regenerative medicine, Poss said.

Our findings present a step toward understanding which glial cells can be encouraged to help heal the spinal cord, and how to stimulate this activity, he said. This is just the first step in many before the findings could be applied to humans.

Poss is already planning trials with mice that he hopes to start in the next few months. Mice represent an important stage in applying his latest findings, he said.

Read more: Should you store or donate your childs umbilical cord blood?

So, why is regenerative medicine important?

Regenerative medicine seeks ways to re-grow or engineer healthy tissue without the need for transplants, Poss said. On a global scale, theres a tremendous organ shortage, and transplantation is an expensive and nonpermanent solution.

Imagine the number of lives that could be improved if, for example, we could find ways to use the bodys innate healing mechanisms to regenerate heart muscle in patients that are spiraling toward heart failure after a heart attack.

Imagine how many lives could be improved if we could find interventions that restore functional spinal cord tissue and reverse paralysis.

Ruffin of ARM sees a promising future for regenerative medicine.

We will continue to see the development of additional regenerative medicine therapies for a broad number of acute and chronic, inherited and acquired diseases and disorders, he said. Therapies in this area will continue to advance along the regulatory pathway, many of which are entering phase III clinical trials this year.

In fact, in the next two years, we are anticipating a number of U.S. and E.U. approvals in the cell and gene therapy sector, including therapies that address certain types of cancers, debilitating retinal disorders, rare genetic diseases, and autoimmune conditions. We also expect to see sustained investment, which will help fuel growth and product development within this sector.

A number of cell and gene therapies and technology platforms are demonstrating real potential to address areas of significant unmet medical need, Ruffin said.

These include cell therapies for blood cancers and solid tumors; gene therapies for rare genetic diseases as well as chronic conditions; and gene editing for the precise targeting and modification of genetic material of a patients cells to cure a broad range of diseases with a single treatment.

Poss at Duke talked about the ultimate quest.

Regenerative medicine has been most successful in restoring or replacing the hematopoietic tissue that creates blood, he said.

We still lack successful regenerative therapies for most tissues, Poss said. The future of regenerative medicine the holy grail will be stimulating the regeneration of healthy tissue in patients without adding cells or manufactured tissue.

Working out the details of innate mechanisms of regeneration in animals like salamanders, zebra fish, and mice, can inform this approach, he said. So can improvement in factor delivery and genome editing applications to encourage the regeneration of healthy tissue.

Ultimately, Poss said, regenerative medicine will change the toolbox of physicians and surgeons, with major impact on outcomes of diabetes, spinal cord injuries, neurodegenerative disease, and heart failure.

ARM says the public does not realize how far the field has progressed in recent years.

Currently, there are more than 20 regenerative medicine products on the market, Ruffin said, primarily in the therapeutic areas of oncology, musculoskeletal and cardiovascular repair, and wound healing.

More than 800 clinical trials are now underway to evaluate regenerative advanced therapies in a vast array of therapeutic categories, he said.

Were seeing a significant focus on oncology, cardiovascular disease, and neurodegenerative diseases, with more than 60 percent of trials falling into one of these three categories, he added. Even though the majority of people perceive regenerative medicine as something of the future, its actually here and now.

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Regenerative Medicine Has a Bright Future - Healthline

When Nisa Leung was pregnant with her first child in 2012, her doctor in Hong Kong offered her a choice. She could take a prenatal test that would require inserting a needle into her uterus, or pay $130 more for an exam that would draw a little blood from her arm.

Leung opted for the simpler and less risky test, which analyzed bits of the babys DNA that had made its way into her bloodstream. Then, Leung went on to do what she often does when she recognizes a good product: look around for companies to invest in.

The managing partner at Qiming Venture Partners decided to put money into Chinese genetic testing firm Berry Genomics, which eventually entered into a partnership with the Hong Kong-based inventor of the blood test. Over the next few months, Berry is expected to be absorbed into a Chinese developer in a 4.3 billion yuan ($625 million) reverse merger. And Leungs venture capital firm would be the latest to benefit from a boom in so-called precision medicine, an emerging field that includes everything from genetic prenatal tests to customizing treatments for cancer patients.

Source: Qiming Venture Partners

China has made the precision medicine field a focus of its 13th five-year plan, and its companies have been embarking on ambitious efforts to collect a vast trove of genetic and health data, researching how to identify cancer markers in blood, and launching consumer technologies that aim to tap potentially life-saving information. The push offers insight into Chinas growing ambitions in science and biotechnology, areas where it has traditionally lagged developed nations like the U.S.

Investing in precision medicine is definitely the trend, said Leung,whos led investments in more than 60 Chinese health-care companies in the past decade. As China eyes becoming a biotechnology powerhouse globally, this is an area we will venture into for sure and hopefully be at the forefront globally.

New Chinese firms like iCarbonX and WuXi NextCode that offer consumers ways to learn more about their bodies through clues from their genetic make up are gaining popularity. Chinese entrepreneurs and scientists are also aiming to dominate the market for complex new procedures like liquid biopsy tests, which would allow for cancer testing through key indicators in the blood.

iCarbonX founder Wang Jun.

Photographer: Calvin Sit/Bloomberg

Such research efforts are still in early stages worldwide. But doctors see a future beyond basic commercial applications, aiming instead for drugs and treatment plans tailored to a persons unique genetic code and environmental exposure, such as diet and infections.

Isaac Kohane, a bioinformatics professor at Harvard University, says when it comes to precision medicine, the science community has Google maps envy. Just as the search engine has transformed the notion of geography by adding restaurants, weather and other locators,more details on patients can give doctors a better picture on how to treat diseases.

For cancer patients, for example, precision medicine might allow oncologists to spot specific mutations in a tumor. For many people with rare ailments like muscle diseases or those that cause seizures, it allows for earlier diagnosis. Pregnant women, using the kind of tests that Leung used, could also learn more about the potential for a child to inherit a genetic disease.

The global interest in the field comes as the cost of sequencing DNA, or analyzing genetic information, is falling sharply. But a number of hurdles remain. Relying on just genes isnt enough, and there must also be background information on a patients lifestyle and medication history.

Precision medicine applications also require heavy investment to store large amounts of information. A whole genome is over 100 gigabytes, according toan e-mailed response to questions from Edward Farmer, WuXi NextCodes vice-president of communications and new ventures. So you can imagine that analyzing thousands or hundreds of thousands of genomes is a true big data challenge."

WuXi NextCode was formed after Shanghai-based contract research giant WuXi AppTec Inc. acquired genomic analysis firm NextCode Health, a spin-off from Reykjavik, Iceland-based Decode Genetics, which has databases on the islands population. Wuxi NextCode continues to have an office in Iceland, where the population is relatively homogenous and therefore good for gene discovery.

Source: WuXi NextCODE

"Genomics today is like the computer industry in the 70s," said Hannes Smarason, WuXi NextCodes co-founder and chief operating officer. "Weve made great progress but theres still a long way to go.

In China, Wuxi NextCode now offers consumers genetic tests that cost between about 2,500 yuan and 8,000 yuan, providing more details on rare conditions a child might be suffering from or even the risk of passing on an inherited disease.

China is diverse and with 1.4 billion people, the planets most populous nation. WuXi NextCode announced a partnership with Huawei Technologies Co.,Chinas largest telecommunications equipment maker, in May to enable different institutions and researchers to store their data.

The goal is to use that deep pool of information -- which ranges from genome sequences to treatment regimens -- to find more clues on tackling diseases. WuXi says that this will in many instances enable the largest studies ever undertaken in many diseases.

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The global precision medicine market was estimated to be worth $56 billion in revenue at the end of 2016,with China holding about 4 to 8 percent of the global market, according to a December report from Persistence Market Research.

Encouraging interventions for some patients too early, even before they have life-threatening diseases, comes with risks and ethical questions, Laura Nelson Carney,an analyst at Sanford C Bernstein, wrote in a Jan. 6 note. Still, precision medicine research has many benefits, and some in China see the countrys push as a significant opportunity "to scientifically leapfrog the West, she said.

In the U.S., universities, the National Institutes of Health and American drugmakers are part of a broad march into precision medicine.

Amgen Inc. bought Icelandic biotechnology company DeCode Genetics for $415 million in 2012, to acquire its massive database on Icelands population. U.S.-based Genentech Inc. is collaborating with Silicon Valley startup 23andMe to study the genetic underpinnings of Parkinsons disease.

Humans are computable," saidWang Jun, the chief executive officer of ChinasiCarbonX. "So we need a computable model that we can use to intervene and change peoples status, thats the whole point.

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China Turns to Precision Medicine in Fight Against Cancer ... - Bloomberg

Hear from our experts about MSK's groundbreaking approach to precision oncology and how it is changing the way we treat cancer.

Summary

Three leaders in precision oncology at MSK have released a State of the Union-stylereport on where the field is going. Learn how were already helping people with cancer, and how were uniquely prepared to address the many challenges that still remain in the field.

Highlights

Precision oncology also known as genome-based oncology or personalized cancer medicine is based on the idea that once we understand the genetic alterations that drive cancer cells to grow and spread, we can develop drugs to target them. Memorial Sloan Kettering has been a leader in the field by bringing together lab researchers and clinicians to focus on developing innovative ways to improve care for patients.

The concept seemed wildly futuristic as recently as two decades ago. Now, tens of thousands of people with cancer every year are benefiting from treatment with targeted therapies, which provide more-effective control of tumors while avoiding many harmful side effects common to more-traditional cancer treatments.

Using precision oncology in cancer patients is an attractive strategy, says Barry Taylor, Associate Director of MSKs Marie-Jose and Henry R. Kravis Center for Molecular Oncology (CMO). But its difficult, and there are great challenges. Were really only at the end of the beginning in this process.

More and more stories are coming out of these trials about patients whose cancer has been eliminated by some of these new drugs.

Jos Baselga MSK Physician-in-Chief

These challenges are twofold: Theyre scientific, as the genetic complexities of cancer are not completely understood; and societal, as currently only a small percentage of cancer patients have access to genetic testing and clinical trials.

Dr. Taylor along with MSKs Physician-in-Chief Jos Baselga and Director of Developmental Therapeutics David Hyman this week published an article in the journal Cell highlighting some of the many accomplishments in the field of precision oncology to date and acknowledging the barriers still to be overcome.

This report is like a State of the Union for genome-based oncology, Dr. Baselga explains. Its an in-depth description of where the field is today and where its going. MSK has been engaged in precision medicine for longer than most institutions, and were probably leading more clinical trials in this area than any other center.

The CMO, which was established in 2014 and is just one reason that MSK is at the forefront in this field, aims to identify the functional significance of genetic alterations in tumors so that people with cancer can receive the most individualized treatments. MSKs Human Oncology and Pathogenesis Program (HOPP), established eight years prior, brings together basic and clinical research, with the goal of bringing what happens in the lab into the clinic.

MSKs researchers have also created a genetic sequencing test called MSK-IMPACT, which looks for mutations in more than 400 genes that are known to play a role in cancer. This test is currently offered to all patients with advanced cancers, and the findings from it can help shepherd patients into clinical trials for drugs that are based on the unique characteristics of their tumors. MSK currently has about 30 clinical trials under way that assign patients to targeted therapy based on the results from MSK-IMPACT.

Despite the value in identifying which mutations are responsible for a cancers growth and spread an aspect of precision medicine that MSK and many other institutions are getting better and better at doing this is only part of the battle. Just because we know what causes a tumor to grow doesnt mean drugs are available to fix the problem.

Even for mutations that have effective drugs available, challenges remain. For one thing, tumor cells often evolve and develop resistance to the drugs that once worked against them, much like bacteria develop resistance to antibiotics. More research is needed to determine how this process occurs, and how new drugs can be developed to combat it.

Another aspect of tumor biology that makes precision medicine difficult to carry out is what is called tumor heterogeneity. This means that not all areas of a tumor have the same mutations; therefore drugs that are very effective at destroying one part of a tumor may have no effect on another part, which greatly reduces the chances that it can be completely eliminated.

Precision medicine is changing the way that many clinical trials are conducted.

MSK is already set up to address these challenges through the integration of our scientific and clinical missions, Dr. Taylor says. We have an enormous multidisciplinary team and an institutional commitment to building the infrastructure thats needed to move this work forward. Weve already removed many of the barriers to moving new treatments into clinical trials and collecting as much data as we can on those patients so that others can benefit in the future.

Because of the high volume of patients that MSK treats, both those with common cancers and those with rare ones, were able to identify large populations of patients with specific mutations very rapidly, Dr. Taylor says. This is the first step in designing these kinds of studies in which you are targeting a particular mutation with a particular therapy.

One aspect of precision medicine that MSK has been focused on is improving access to clinical trials. Weve opened up studies to patients at our MSK Cancer Alliance partners, and weve expanded our genetic sequencing out to those centers, Dr. Hyman says. This program is just starting, but the number is increasing.

If an MSK Cancer Alliance site does its own genetic testing, we will open our studies to them so that they can enroll their patients, he adds. If they dont do their own testing, we can analyze patients samples for them.

We've already removed many of the barriers to moving new treatments into clinical trials.

Barry S. Taylor Associate Director, CMO

Another area in which MSK has been at the forefront is expanding precision medicine trials to pediatric patients.

Pediatrics is an underserved patient population as far as trials, but weve been aggressive about lowering the age of eligibility so that younger patients can benefit from these new drugs sooner, Dr. Hyman says. In the past there have been ethical and safety concerns about conducting trials in children, but we think the best way to protect children is to give them access to the same drugs that our adult patients have.

He notes that for drugs that dont have available trials, pediatric patients may be able to get access to them through compassionate-use or expanded-access programs.

A patient describes her successful treatment as a result of participating in an MSK basket trial.

Overall, the way clinical trials are being conducted is changing. The traditional three-phase structure is less important in an era in which a drugs activity and effectiveness can be determined right from the beginning. Some drugs are going right from phase I or phase II to approval, Dr. Hyman says.

Drug development is not going to be easy, Dr. Baselga says. Its not going to be one-size-fits-all. Its going to be one gene at a time and one disease at a time. But more and more stories are coming out of these trials about patients whose cancer has been eliminated by some of these new drugs.

Another area that MSK is also focused on is the analysis of mutations in the DNA code. We need to go beyond genes and look at things on the epigenetic level, Dr. Baselga says. (Epigenetic changes affect which genes are activated to make proteins, without changing the genes themselves.) Investigators are developing new ways to analyze proteins in tumors to look for these kinds of changes.

MSK researchers are also looking at new ways to obtain genetic material to study. One of these methods involves isolating cell-free tumor DNA, which is found in patients blood. This technology, sometimes called liquid biopsy, would enable doctors to monitor patients disease by analyzing their blood, rather than repeatedly having to conduct biopsies. Its expected to provide new insight into how patients respond to targeted therapies, and how resistance develops.

One of the biggest challenges facing precision oncology and the cancer community is the sheer volume of data. Many efforts are now focusing on ways to aggregate findings from genetic studies and pooling the insights gained from clinical trials. One of these is AACR Project GENIE, a multicenter effort being coordinated by the American Association for Cancer Research, to which MSK has been the principal contributor.

Experts say that better data sharing will improve clinical decision-making and provide new information for diagnosis and treatment. Large compilations of data not only serve as a tool for cancer researchers around the world but also help to inform treatment decisions in community oncology centers.

MSK has been an early adopter of many of the approaches to analyzing these kinds of data, and an important part of data-sharing initiatives, Dr. Taylor says. I firmly believe that these technologies should be democratized to all patients, and sharing our data and analysis is an important part of that.

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With MSK Leading the Way, Precision Medicine Links Lab Research to Patient Care - Memorial Sloan Kettering Cancer Center (blog)

[Editors note: this article summarizes a paper (PAY WALL)published in the journalAnnual Review of Resource Economics.]

In a paper The Political Economy of Biotechnology Ron Herring of Cornell University and Robert Paarlberg of Harvard Kennedy School look for pushes and pulls in the material interests of advocates and opponents of these technologies seek reasons in political structures, social behaviour and public notions of acceptable risk.

[P]ublic disapproval of genetic engineering of crop plants, despite important science academies supporting the technology, is hard to comprehend.

[T]here is no evidence of GE crops grown so far posing new risks to humans, animals or the environment. The same public accepts drugs like insulin made with recombinant DNA technology. It discounts the risks thrown up during clinical trials. Its distrust of regulatory authorities charged with the approval of GE crops stands in contrast to its faith in medical regulators despite tragic errors: thalidomide approved for morning sickness caused birth defects in thousands of babies. What accounts for these differing standards?

Transnational environmental groups like Greenpeace have also been effective in stigmatizing GE crops as GMOs (genetically-modified organisms)

Environmentalists and private enterprise-hating leftists have also been able to paint GE technology as a conduit for corporate control of national agricultural systems.

In the case of GE crops, opponents have constructed uncertainty as risk.

Proving the absence of risk is impossible for science, the authors say.

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post:Explaining the Political Economy of Biotechnology Which Makes Recombinant DNA Technology Acceptable in Medicine But Not Genetic Engineering of Plant Crops

Link:

Why do people accept biotech in medicine but not GMO foods? - Genetic Literacy Project

February 9, 2017 Credit: NIH

A single blood test and basic information about a patient's medical status can indicate which patients with myelodysplastic syndrome (MDS) are likely to benefit from a stem cell transplant, and the intensity of pre-transplant chemotherapy and/or radiation therapy that is likely to produce the best results, according to new research by scientists at Dana-Farber Cancer Institute and Brigham and Women's Hospital.

In a study published in the New England Journal of Medicine, the investigators report that genetically profiling a patient's blood cells, while factoring in a patient's age and other factors, can predict the patient's response to a stem cell transplant and help doctors select the most effective combination of pre-transplant therapies. The findings are based on an analysis of blood samples from 1,514 patients with MDS, ranging in age from six months to more than 70 years, performed in collaboration with investigators from the Center for International Blood and Marrow Transplant Research.

MDS is a family of diseases in which the bone marrow produces an insufficient supply of healthy blood cells. Treatments vary depending on the specific type of MDS a patient has; donor stem cell transplants are generally used for patients with a high risk of mortality with standard treatments.

"Although donor stem cell transplantation is the only curative therapy for MDS, many patients die after transplantation, largely due to relapse of the disease or complications relating to the transplant itself," said the study's lead author, R. Coleman Lindsley, MD, PhD, of Dana-Farber. "As physicians, one of our major challenges is to be able to predict which patients are most likely to benefit from a transplant. Improving our ability to identify patients who are most likely to have a relapse or to experience life-threatening complications from a transplant could lead to better pre-transplant therapies and strategies for preventing relapse."

Researchers have long known that the specific genetic mutations within MDS patients' blood cells are closely related to the course the disease takes. The current study sought to discover whether mutations also can be used to predict how patients will fare following a donor stem cell transplant.

Analysis of the data showed that the single most important characteristic of a patient's MDS was whether their blood cells carried a mutation in the gene TP53. These patients tended to survive for a shorter time after a transplant, and also relapse more quickly, than patients whose cells lacked that mutation. This was true whether patients received standard "conditioning" therapy (which includes chemo- and/or radiation therapy) prior to transplant or received reduced-intensity conditioning, which uses lower doses of these therapies. Based on these results, doctors at Dana-Farber are now working on new strategies to overcome the challenges posed by TP53 mutations in MDS.

In patients 40 years old and over whose MDS didn't carry TP53 mutations, those with mutations in RAS pathway genes or the JAK2 gene tended to have a shorter survival than those without RAS or JAK2 mutations. In contrast to TP53 mutations, the adverse effect of RAS mutations on survival and risk of relapse was evident only in reduced-intensity conditioning. This suggests that these patients may benefit from higher intensity conditioning regimens, the researchers indicated.

The study also yielded key insights about the biology of MDS in specific groups of patients. Surprisingly, one in 25 patients with MDS between the ages of 18 and 40 were found to have mutations associated with Shwachman-Diamond syndrome (a rare inherited disorder that often affects the bone marrow, pancreas, and skeletal system), but most of them had not previously been diagnosed with it. In each case, the patients' blood cells had acquired a TP53 mutation, suggesting not only how MDS develops in patients with Schwachman-Diamond syndrome but also what underlies their poor prognosis after transplantation.

The researchers also analyzed patients whose MDS arose as a result of previous cancer therapy (therapy-related MDS). They found that TP53 mutations and mutations in PPM1D, a gene that regulates TP53 function, were far more common in these patients than in those whose disease occurred in the absence of previous cancer treatment.

"In deciding whether a stem cell transplant is appropriate for a patient with MDS, it's always necessary to balance the potential benefit with the risk of complications," Lindsley remarked. "Our findings offer physicians a guide - based on the genetic profile of the disease and certain clinical factors - to identifying patients for whom a transplant is appropriate, and the intensity of treatment most likely to be effective."

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Genetic profiling can guide stem cell transplantation for patients with myelodysplastic syndrome - Medical Xpress

February 9, 2017

A newly discovered mutation in the INPP5K gene, which leads to short stature, muscle weakness, intellectual disability, and cataracts, suggests a new type of congenital muscular dystrophy. The research was published in the American Journal of Human Genetics by researchers from the George Washington University (GW), St. George's University of London, and other institutions.

"The average pediatrician may only see one child with a rare disorder in his or her entire career. Even working with a team of specialists, it can sometimes take years for a child to be diagnosed with a specific rare disease," said Chiara Manzini, Ph.D., co-corresponding author for the study and assistant professor in the GW Institute for Neuroscience and in pharmacology & physiology at the GW School of Medicine and Health Sciences. "With a correct diagnosis, families have access to the best care and what to expect as far as the progression of the disease. From a research standpoint, we can develop new, targeted therapies to help these patients."

The research team found five individuals from four families presenting with variable clinical features, including muscular dystrophy, short stature, intellectual disability, and cataracts. While these indicators overlap with related syndromes, dystroglycanopathies and Marinesco-Sjgren syndrome, sequencing revealed a unique mutation in the gene INPP5K in the affected members of each family. This is what led the researchers to believe these individuals are presenting a new type of congenital muscular dystrophy.

Congenital muscular dystrophy is a group of muscular dystrophies characterized by muscle weakness, with its onset at or near birth. The cause is genetic mutations in genes responsible for making the proteins necessary to build and maintain muscles, and sometimes to correctly develop the eyes and the brain. However, the INPP5K gene is unique in that it has a different function than other genes associated with congenital muscular dystrophy. Most genes involved in congenital muscular dystrophy are responsible for maintaining contacts between muscle fibers, while this gene has a function inside the cell and regulates both signaling in response to factors like insulin, and protein trafficking.

"Now that we've identified the genetic mutation, we want to know why the disruption in the gene causes this disorder," said Manzini. "The unique mechanism of this gene could help us develop therapies we have not thought about before, and may move research in a different direction."

"Mutations in the inositol phosphatase INPP5K cause a congenital muscular dystrophy syndrome overlapping the dystroglycanopathies and Marinesco-Sjgren Syndrome" was published in The American Journal of Human Genetics.

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A new paper, co-written by faculty at Binghamton University, State University of New York, increases the understanding of Duchenne muscular dystrophy (DMD)one of the most common lethal genetic disordersand points to ...

Myotonic dystrophy type I (MD1) is a common form of muscular dystrophy associated with muscle wasting, weakness, and myotonia. These symptoms are linked to the accumulation of toxic gene transcripts in muscle cells that result ...

Duchenne muscular dystrophy is a chronic disease causing severe muscle degeneration that is ultimately fatal. As the disease progresses, muscle precursor cells lose the ability to create new musclar tissue, leading to faster ...

A potential way to treat muscular dystrophy directly targets muscle repair instead of the underlying genetic defect that usually leads to the disease.

Specific genetic errors that trigger congenital heart disease (CHD) in humans can be reproduced reliably in Drosophila melanogaster - the common fruit fly - an initial step toward personalized therapies for patients in the ...

A newly discovered mutation in the INPP5K gene, which leads to short stature, muscle weakness, intellectual disability, and cataracts, suggests a new type of congenital muscular dystrophy. The research was published in the ...

Kawasaki disease (KD) is the most common acquired heart disease in children. Untreated, roughly one-quarter of children with KD develop coronary artery aneurysmsballoon-like bulges of heart vesselsthat may ultimately ...

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Researchers find genetic cause of new type of muscular dystrophy - Medical Xpress

Newswise PHILADELPHIAKatalin Susztak, MD, PhD, an associate professor of Medicine and Genetics in the Perelman School of Medicine at the University of Pennsylvania, has received a $3 million grant from a consortium of pharmaceutical companies to identify genes and other characteristics that are signs of rapid decline in kidney function in patients with diabetic kidney disease.

This study, called TRIDENT (Transformative Research In DiabEtic NephropaThy) is the first such trial that will generate a multi-omics data set to pave the way for precision medicine treatment for diabetic kidney disease. Susztak and colleagues will collect, process, and study kidney biopsy tissue and harvest blood, urine, and genetic materials to generate multi-omics datasets. These will reveal molecular pathways and link them to biomarkers that characterize patients with rapid kidney-function decline compared to those with slower kidney-function decline. This analysis will help identify potential therapeutic targets for patients.

Members of the consortium -- Boehringer Ingelheim, GSK, and Regeneron -- will each contribute to the research strategy and implementation of the overall group in a precompetitive space. Each pharma member will be able to use the molecular networks identified by the consortium to continue individual company discovery efforts outside of the consortium, including developing drugs to interfere with the disease pathways.

One of the key hurdles in diabetic kidney disease research has been the lack of kidney tissue samples from patients with diabetes. Until now, only a few centers in the U.S. have performed biopsies on these patients. Additionally, animal and cell culture models do not fully mirror human versions of the disease, and human genetic studies to date have failed to identify consistent genetic variants associated with diabetic kidney disease.

Integrative analysis of the variables will help us paint a fuller and more accurate picture of the dynamics of the molecular systems that underlie this disease, said Susztak. This work is especially important now as the rate of diabetes prevalence in our country, and indeed the world, is continually accelerating.

Diabetic kidney disease is the most common cause of kidney disease in the United States; no new drugs have been registered for treating it since 2001. According to the Centers for Disease Control and Prevention (CDC), the risk of death for adults with diabetes and kidney disease is 50 percent higher than those with diabetes alone. It reports that 29.1 million people, or 9.3 percent of the US population, have diabetes, 27.8 percent of whom are undiagnosed. An additional 86 million more than one out of three adulthave pre-diabetes. Nine out of ten of these adults do not know that they have pre-diabetes. The CDC also reports that medical costs for people with diabetes are twice as high as for people without diabetes. Other research shows that of the approximately 400 million people with type 2 diabetes worldwide, about half will have kidney disease.

During the past few years, several new biomarkers have been identified that can potentially identify patients at risk for rapid loss of kidney function. For example, blood and urinary levels of the protein Kidney Injury Molecule-1 (KIM-1) and tumor necrosis factor receptor 1 and 2 levels can identify patients with rapidly declining renal function. While these markers are generating increased interest, critical questions remain, Susztak said.

These questions, which Susztak and her collaborators will seek to answer through the study, include:

Is rapid decline in kidney function a genetic tendency, the result of environmental factors, or a combination of both? What are the molecular pathways that cause rapid kidney function decline? How do the new biomarkers match up with molecular changes in the kidney or genetic predisposition? Are there additional biomarkers associated with fast and slow progression of kidney decline?

To help answer these questions, Susztak and colleagues will recruit and follow a cohort of 300 patients from 12 U.S. and Canadian clinical sites who have type 1 or type 2 diabetes and undergone a clinically indicated kidney biopsy.

Raymond Townsend, MD, director of the Hypertension Program and a professor of Medicine will direct the data coordinating center, Matthew B. Palmer, MD, PhD, an assistant professor of Pathology and Laboratory Medicine, will run the pathology core, and Jonathan J. Hogan, MD, clinical director of the Penn Glomerular Disease Center and an assistant professor of Medicine is the site principal investigator.

Editors note: Dr. Susztak has consulted previously for GSK and has received research support from Boehringer Ingelheim for a projects unrelated to TRIDENT.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.

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Penn Genetics Researcher Receives Grant From Pharmaceutical Consortium to Study Diabetic Kidney Disease - Newswise (press release)

H

AVANA He knew as a child that he wanted to be a doctor, like his father. He went to medical school, became a general surgeon and ultimately a heart specialist. He practiced at Cubas premier cardiovascular hospital, performed heart transplants, and published articles in medical journals.

For this, Roberto Mejides earned a typical doctors salary: about $40 a month.

It wasnt nearly enough, even with the free housing and health care available to Cubans, to support his extended family. So in 2014, Mejides left them behind, moving to Ecuador to earn up to $8,000 a month working at two clinics and performing surgeries.

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Its a common story here, where waiters, cabdrivers, and tour guides can make 10 to 20 times the government wages of doctors and nurses thanks to tips from tourists.

Doctors are like slaves for our society, said Sandra, an art student and photographers assistant who makes more than her mother, a physician. Its not fair to study for so many years and be so underpaid.

Cuba is waging an organized, intrusive war on Zika. Its working

Cuba is proud of its government-run health care system and its skilled doctors. But even with a raise two years ago, the highest paid doctors make $67 a month, while nurses top out at $40. That leaves many feeling demoralized and searching for ways to improve their lives.

Some enter the private economy by renting rooms to tourists, driving cabs, or treating private patients, quasi-legally, on the side. Thousands of others accept two-year government assignments to work as doctors abroad, collecting higher salaries for themselves and earning billions for the state, which helps keep the stagnant economy afloat. In fact, health workers are Cubas largest source of foreign exchange.

A few doctors, like Mejides, arrange foreign employment on their own, putting at risk their future ability to return to a government job in the health system back home.

Its hard to migrate and be alone, Mejides said in Spanish, during a video phone call from Ecuador toa reporter visiting Havana in October. Its stressful. I am in the wrong place. I should be with my family in my country, working and being rewarded properly.

Still, with his Ecuador earnings, he was able to buy his wife, two daughters, and two stepdaughters a $23,000 apartment in Havana, and he sends them $300 to $500 a month.

While doctors back in Cuba grumble about their low pay, they usually find ways to make do.

Sandras mother, Nadia, a genetics researcher, earns about as much as she pays a cleaning woman to maintain her three-bedroom Havana apartment. Whenever she can, she rents one of those rooms to tourists for $40 a night, making more in two nights than she does from her monthly earnings as a doctor. She asked that her full name not be used to avoid any problems with the government.

The rental income allows Nadia to have a modestly comfortable life and to be able to buy fruits and vegetables at farmers markets. But a restaurant meal is a rare treat, and traveling abroad is impossible.

Still, she loves her work and the intellectual challenge of her research into genetic diseases. She said many Cuban doctors are committed and provide excellent service, in part because of the ways they have learned to overcome shortages of equipment and technology.

We dont have all the electronic tools, so we have to learn to do things other ways, to diagnose just by external examination, she said, over a dinner of fish and rum at her apartment.

Shed like to earn more money, of course, and she understands why so many doctors, including many she knows, have chosen to leave Cuba.

Im not ambitious for money, she said. I get rent from visitors, and I get to live in Cuba. I have a nice house, and Im happy with what I have. But Im not a millionaire.

Trumps election threatens medical cooperation between US and Cuba

Cecilia, a 60-year-old former nurse who also asked that her full name not be used, spent 25 years working in government hospitals and clinics. To adapt to the shortages, she learned to make inventos medicos medical inventions using a chair or bench to raise the back of a patients bed, for example, or cutting the tip off an intravenous line to fashion an oxygen feed to a patients nose.

But she became disillusioned by the chronic shortages and the stress she saw in both her patients and colleagues.

The material scarcity is so overwhelming that it keeps people from dedicating all the passion, love, and brain power that they should to their patients in need, she said, sitting in a rocking chair in her third-floor Havana apartment. I was the one who had to face the patients and tell them we dont have the drug that you need. It was very common. And I didnt want to do that any more.

Doctors and nurses have the best intentions, but they face so many obstacles, there are so many things on their mind, she added. The doctor might be treating a patient but they are actually thinking: When I get home, at God knows what time, what am I going to feed my kid?

She quit nursing in the early 2000s and later began to pursue her passion, doing hands-on alternative medicine that combines techniques of massage, kinesiology, magnetic therapy, and so-called floral therapy, which uses extracts of flowers and herbs as healing agents.

Her work with private clients, who come to her apartment, is permitted under a license for massage, the only form of healing work included on a list of government-approved private services and businesses. Working three days a week, she earns almost $120 a month if all my appointments show up, she said. I use to make that in six months working at the hospital.

In the years after Fidel Castro seized power in 1959, Cuba invested heavily in education and science, training tens of thousands of doctors, nurses, and scientists. As a result, Cuba, a country of 11.2 million people, today has 90,000 doctors, the most per capita in the world.

About 25,000 of these doctors, along with 30,000 Cuban nurses and other health professionals, are working in 67 countries around the world. They earn about $8.2 billion in revenue for the government, according to a recent article in Granma, the official paper of the Cuban Communist Party.

The bulk of the doctors, about 20,000, are in Brazil and Venezuela. Over the last three years they provided treatment to 60 million Brazilians, mostly the rural poor, said Cristin Morales Fuhrimann, the Pan American Health Organizations representative in Havana.

Cuba receives about $5,000 a month per doctor from Brazil, pays each doctor about $1,200, and banks the rest, said John Kirk, a professor of Latin American studies at Dalhousie University in Halifax, Canada, who has researched Cubas program of medical missions. Most of the doctors shares are deposited in their Cuban bank accounts, requiring them to return home to collect it.

Cuba has too many doctors, so their main source of hard currency is to rent out medical services, Kirk said.

Once close allies of Havana, Brazil and Venezuela have been engulfed in political and economic crises that will cause them to reduce their use of Cuban doctors in the coming years.

That may lead Cuba to redeploy some doctors to other parts of the world, including the Middle East. In Qatar, an oil-rich emirate about as far from Cuba geographically and culturally as any place in the world, the so-called Cuban Hospital is fully staffed by 400 Cuban doctors, nurses, and technicians.

Cubas dispatch of doctors not only generates revenue, it is also an exercise in soft power that allows the country to spread its influence around the globe.

Its a major contribution to the health of the world, said Morales. They made a big difference in fighting Ebola in Africa, in the aftermath of Hurricane Matthew in Haiti.

Some Cuban doctors working overseas have defected to the United States, aided by a policy launched during the administration of George W. Bush that permitted Cuban medical personnel to go to the US with their spouses and children. In its last weeks in office, the Obama administration announced it was ending the program.

Since the Cuban Medical Professional Parole Program began in 2006, more than 9,000 medical professionals and their family members were approved for admission to the US. In the past four years, the number of entrants spiked, reaching almost 2,000 for the fiscal year that ended Sept. 30.

The Cuban government and the Pan American Health Organization protested the policy as a form of poaching that undermined Cubas health system and impeded newfound cooperation between the US and Cuba. In a statement, Obama acknowledged that the program risks harming the Cuban people.

Cuban doctors are in demand internationally because they come cheap, are well-trained, and work in a public health system that is highly organized and well-run. In Cuba, primary care clinics are available in every neighborhood. Specialists in cancer, immunology, genetic medicine, and cardiovascular disease staff the hospitals. Life expectancy rates, which two generations ago were at Third World levels, are today roughly equal to those in the United States.

Facing bleak odds, cancer patients chase one last chance in Cuba

But the absence of so many doctors also provokes complaints from patients, who say it keeps them from getting the best care. They also grouse that they have to bring their own food and bedsheets, wait for appointments or medications and provide gifts to doctors to ensure good treatment.

When the 61-year-old father of Concepcion, a young Cuban professional, was diagnosed with prostate cancer last summer, she used personal connections to enable her father to see a specialist promptly.

Concepcion, who asked that her full name not be used to avoid reprisals or damage to her professional standing, also provided daily gifts of food, cosmetics, and sometimes cash to doctors, nurses, and technicians while her father was hospitalized for a month in Holguin, a city in eastern Cuba.

Doctors are used to receiving gifts, she said. You give the gift and the attention starts getting better. If you stop and the attention goes down, you go back to handing out gifts. You feel sorry for the doctors because they work really hard under bad conditions and you always feel like theyre not being rewarded.

She estimated she spent about $500 on gifts and food, an amount she said would have doubled had he been hospitalized in pricier Havana.

Jose dos Santos, a Cuban journalist who needs regular treatment for his diabetes, said the care he receives is excellent. Bringing gifts to doctors has become a habit because we know that the job doctors do needs to be better rewarded, he said. We dont produce oil, he added, but we produce talent, and it makes sense that that talent is acknowledged and rewarded.

In December, Roberto Mejides moved again, this time to Merida, Mexico, where he plans to work for the next four years. His income will be roughly the same as in Ecuador, but now hes just 90 minutes by air from Havana. He hopes to bring his family to join him in the coming months,

My hopes have always been the same, to work honestly and to provide my family with an adequate life, he said. Someday, he added, he wants to return to Cuba: Its my country, my homeland.

Rob Waters can be reached at robwaters@pacbell.net Follow Rob on Twitter @robwaters001

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The Cuban hustle: Doctors drive cabs and work abroad to make up for meager pay - STAT

Fifteen faculty members from the School of Medicine are among the 47 investigators announced today by the Chan Zuckerberg Biohub.

The CZ Biohub is an independent nonprofit medical research organization that has the goal of harnessing the power of science, technology and human capacity to cure, prevent or manage all disease. It is funded through a $600 million commitment by the Chan Zuckerberg Initiative, which was created by Facebook founder Mark Zuckerberg and his wife Priscilla Chan, MD.

The investigators were selected from the three institutions participating in the CZ Biohub: Stanford, UC-San Francisco and UC-Berkeley. Each of the investigators will be given a five-year appointment and up to $1.5 million for research in their respective areas of expertise. More than 700 researchers applied for the funding; the selections were made by an international panel of 60 scientists and engineers.

The investigators include both senior researchers and up-and-coming faculty.

The 47 CZ Biohub investigators were introducing today are quite literally inventing the future of life science research, said Stephen Quake, PhD, co-president of CZ Biohub and professor of bioengineering and applied physics at Stanford. The CZ Biohub is distinguished by our emphasis on technology and engineering, and our researchers are inventing tools to accelerate science for the good of humanity.

We are honored to have so many of our scientists selected to pursuetheirinnovative and ambitious projectsat the Chan Zuckerberg Biohub,said Lloyd Minor, MD, dean of the School of Medicine. If past is prologue, givingsuch inventivethinkersthe freedom to conduct fundamental research will result in trulyoutstanding discoveries, moving us toward a future wherewe can both cure and preventwhat today seems incurable and unpredictable.

The 15 medical school faculty members are:

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15 School of Medicine researchers named CZ Biohub investigators - Stanford Medical Center Report

February 7, 2017 Credit:

Bacteria are not the sole cause of caries; tooth resistance also plays an instrumental role. Researchers from the University of Zurich demonstrate that mutated genes lead to defects in the tooth enamel and can therefore encourage the development of caries.

Why do some people develop caries even though they always brush their teeth carefully while others are less stringent regarding dental hygiene yet do not have any holes? Ultimately, both have bacteria on the surface of their teeth which can attack the enamel. Enamel forms via the mineralization of specific enamel proteins. If the outer layer of the teeth is defective, tooth decay can strike.

Researchers from the University of Zurich have now pinpointed a gene complex for the first time that is responsible for the formation of tooth enamel. Two teams from the Centre of Dental Medicine and the Institute of Molecular Life Sciences used mice with varying mutations of the enamel proteins involved in the so-called Wnt signaling pathway. Thanks to this transmission route, human and animal cells respond to external signals and specifically activate selected genes in the cell nucleus. The signaling pathway is essential for embryonal development and also plays a pivotal role in the development of cancer or physical malformations.

Mutations in proteins trigger defective tooth enamel

"All mice with mutations in these proteins exhibit teeth with enamel defects," explains Pierfrancesco Pagella, one of the study's two first authors. "Therefore, we demonstrated that there is a direct link between mutations in the genetic blueprints for these proteins and the development of tooth enamel defects." This genetic discovery goes a long way towards improving our understanding of the production of tooth enamel.

The team of researchers was the first in the world to use modern genetic, molecular and biochemical methods to study tooth enamel defects in detail. "We discovered that three particular proteins involved in the Wnt signaling pathway aren't just involved in the development of severe illnesses, but also in the qualitative refinement of highly developed tissue," says co-first author Claudio Cant from the molecular biologist research group lead by Prof. Konrad Basler. "If the signal transmission isn't working properly, the structure of the tooth enamel can change."

Increased risk of caries with defective tooth enamel

The hardness and composition of the tooth enamel can affect the progression of caries. "We revealed that tooth decay isn't just linked to bacteria, but also the tooth's resistance," says Thimios Mitsiadis, Professor of Oral Biology at the Center of Dental Medicine. Bacteria and their toxic products can easily penetrate enamel with a less stable structure, which leads to carious lesions, even if oral hygiene is maintained.

Understanding the molecular-biological connections of tooth enamel development and the impact of mutations that lead to enamel defects opens up new possibilities for the prevention of caries. "New products that hinder the progress of tooth caries in the event of defective tooth enamel will enable us to improve the dental health of patients considerably," adds Mitsiadis.

Explore further: Hair proteins are important in tooth enamel structure

More information: C. Cant, P. Pagella, T. D. Shajiei, D. Zimmerli, T. Valenta, G. Hausmann, K. Basler and T. A. Mitsiadis. A cytoplasmic role of Wnt--catenin transcriptional cofactors in tooth enamel formation. Science Signaling. February 7, 2017. DOI: 10.1126/scisignal.aah4598

Tooth decay is one of the most common chronic diseases worldwide. While oral hygiene and dietary choices promote tooth decay, genetics are also a factor in cavity formation.

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Researchers have developed computer simulations showing how lasers attack oral bacterial colonies, suggesting that benefits of using lasers in oral debridement include killing bacteria and promoting better dental health.

For decades, research has suggested a link between oral health and inflammatory diseases affecting the entire bodyin particular, heart attacks and strokes.

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Genetic defects in tooth enamel conducive to development of caries - Medical Xpress