Catching a disease in its earliest stages can lead to more effective therapies. Stanford chemists have increased the likelihood of detecting these diseases via a test that is thousands of times mor…
A DNA Ultra-sensitive test for cancers, HIV
Catching a disease in its earliest stages can lead to more effective therapies. Stanford chemists have increased the likelihood of detecting these diseases via a test that is thousands of times more sensitive than current diagnostics.
A common theme in medicine is that detecting a disease early on can lead to more effective treatments. This relies partly on luck that the patient gets screened at the right time, but more important is that the testing techniques are sensitive enough to register the minuscule hints that diseases leave in the blood stream.
Graduate students Cheng-ting “Jason” Tsai and Peter Robinson prepare a gel electrophoreresis experiment to analyze a DNA-tagged biomarker. (Image credit: L.A. Cicero)
A new technique developed by a team of chemists at Stanford has shown promise to be thousands of times more sensitive than current techniques in lab experiments, and it is now being put to test in real-world clinical trials.
When a disease – whether it’s a cancer or a virus like HIV – begins growing in the body, the immune system responds by producing antibodies. Fishing these antibodies or related biomarkers out of the blood is one way that scientists infer the presence of a disease. This involves designing a molecule that the biomarker will bind to, and which is adorned with an identifying “flag.” Through a series of specialized chemical reactions, known as an immunoassay, researchers can isolate that flag, and the biomarker bound to it, to provide a proxy measurement of the disease.
The new technique, developed in the lab of Carolyn Bertozzi, a professor of chemistry at Stanford, augments this standard procedure with powerful DNA screening technology. In this case, the chemists have replaced the standard flag with a short strand of DNA, which can then be teased out of the sample using DNA isolation technologies that are far more sensitive than those possible for traditional antibody detections.
“This is spiritually related to a basic science tool we were developing to detect protein modifications, but we realized that the core principles were pretty straightforward and that the approach might be better served as a diagnostic tool,” said Peter Robinson, a co-author on the study and graduate student in Bertozzi’s group.
The researchers tested their technique, with its signature DNA flag, against four commercially available, FDA-approved tests for a biomarker for thyroid cancer. It outperformed the sensitivity of all of them, by at least 800 times, and as much as 10,000 times. By detecting the biomarkers of disease at lower concentrations, physicians could theoretically catch diseases far earlier in their progression.
“The thyroid cancer test has historically been a fairly challenging immunoassay, because it produces a lot of false positives and false negatives, so it wasn’t clear if our test would have an advantage,” Robinson said. “We suspected ours would be more sensitive, but we were pleasantly surprised by the magnitude.”
Putting basic research to use in a clinical setting has been a focus of Bertozzi’s since she arrived at Stanford.
“I moved to Stanford with the anticipation that translation of my students’ innovations to clinically impactful products and technologies would be enabled,” said Bertozzi, who is a faculty fellow of Stanford ChEM-H, as well as a professor, by courtesy, of radiology and of chemical and systems biology. “That goal is being delightfully fulfilled.”
Based on the success of the thyroid screening, the group has won a few grants to advance the technique into clinical trials. One trial underway in collaboration with the nearby Alameda County Public Health Laboratory will help evaluate the technique as a screening tool for HIV. Early detection and treatment of the virus can help ensure that its effects on the patient are minimized and reduce the chance that it is transmitted to others. This effort is supported by a pilot grant from Stanford-Spectrum, funded by the National Center for Advancing Translational Sciences at the National Institutes of Health.
“Many of our collaborators are excited that the test can be readily deployed in their lab,” said co-author Cheng-ting “Jason” Tsai, a graduate student in Bertozzi’s group. “In contrast to many new diagnostic techniques, this test is performed on pre-existing machines that most clinical labs are already familiar with.”
The researchers are also pursuing tests for Type 1 diabetes, for which early detection could help patients manage the disease with fewer side effects.
Antibodies are widely used biomarkers for the diagnosis of many diseases. Assays based on solid-phase immobilization of antigens comprise the majority of clinical platforms for antibody detection, but can be undermined by antigen denaturation and epitope masking. These technological hurdles are especially troublesome in detecting antibodies that bind nonlinear or conformational epitopes, such as anti-insulin antibodies in type 1 diabetes patients and anti-thyroglobulin antibodies associated with thyroid cancers. Radioimmunoassay remains the gold standard for these challenging antibody biomarkers, but the limited multiplexability and reliance on hazardous radioactive reagents have prevented their use outside specialized testing facilities. Here we present an ultrasensitive solution-phase method for detecting antibodies, termed antibody detection by agglutination-PCR (ADAP). Antibodies bind to and agglutinate synthetic antigen–DNA conjugates, enabling ligation of the DNA strands and subsequent quantification by qPCR. ADAP detects zepto- to attomoles of antibodies in 2 μL of sample with a dynamic range spanning 5–6 orders of magnitude. Using ADAP, we detected anti-thyroglobulin autoantibodies from human patient plasma with a 1000-fold increased sensitivity over an FDA-approved radioimmunoassay. Finally, we demonstrate the multiplexability of ADAP by simultaneously detecting multiple antibodies in one experiment. ADAP’s combination of simplicity, sensitivity, broad dynamic range, multiplexability, and use of standard PCR protocols creates new opportunities for the discovery and detection of antibody biomarkers.
Detecting the onset of cancer at the cellular level
A chemical profiling technique that has potential for detecting the onset of cancer at the cellular level has been developed by scientists with the Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California at Berkeley.
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| Carolyn Bertozzi was recently named Director of Berkeley Lab’s Molecular Foundry. She is a chemist with Berkeley Lab’s Materials Sciences and Physical Biosciences Divisions, a UC Berkeley professor, and an investigator with the Howard Hughes Medical Institute. | |
In a paper published in the Proceedings of the National Academy of Sciences (PNAS) that is now on-line, a team of researchers, led by chemist Carolyn Bertozzi, has reported a technique for rapidly profiling O-linked glycoproteins in living animals. Changes in O-linked protein glycosylation – the attachment of sugars to proteins through an oxygen atom on the protein – are known to correlate with cancers and other diseases, such as inflammations and bacterial infections. Until now, however, scientists have lacked a practical means of monitoring such changes in a physiological setting.
“With our profiling technique, we can take pictures over time of the sugars that coat a cell’s surface or are released by the cell into the bloodstream and monitor any changes that occur,” said Bertozzi. “We can then compare the sugars produced by cells that become cancerous with the sugars from normal cells. Ultimately, the idea would be to use this information to create a simple blood test that would diagnose a patient for cancer.”
Bertozzi is the Director of Berkeley Lab’s Molecular Foundry, a faculty scientist with Berkeley Lab’s Materials Sciences and Physical Biosciences Divisions, the T.Z. and Irmgard Chu Distinguished Professor of Chemistry and professor of Molecular and Cell Biology at UC Berkeley. She is also an investigator with the Howard Hughes Medical Institute (HHMI). Co-authoring the PNAS paper with her were Danielle Dube, Jennifer Prescher and Chi Quang, who were all members of her research group when this work was done.
The key to successful cancer treatment is detection at an early stage of development – the sooner the better. While detecting an over-abundance of an antigen has been used to create an effective blood test for prostate cancer, it is believed that even more effective blood tests for a large number of epithelial cancers, also known as carcinomas, could be realized if a practical means of detecting the sugars attached to blood-borne proteins were available. Most proteins are modified post-translationally (i.e., after a protein’s polypeptide chain has been formed), and one of the most common of these events is glycosylation, which can be either oxygen or nitrogen-linked. Glycoproteins are ubiquitous on the surfaces of most cells and help a cell communicate with its neighbors.
“Studies of cells in culture have suggested that monitoring changes in O-linked glycoproteins would be an effective biomarker for cancer, but for the past three decades if you wanted to know which glycans were present on a cell, you had to isolate the surface proteins one at a time,” said Bertozzi. “Our profiling technique lets you quickly scan all the proteins at once. Once we attach our tags and probes, the proteins either light up due to the presence of sugars or they don’t.”
The profiling technique developed by Bertozzi and her team starts by tagging certain glycoproteins with a metabolic label called N-azidoacetylgalactosamine (GalNAz). An over-secretion of the labeled glycoproteins, which form the lubricant that protects the surfaces of cells, is known to increase the potential of cancer to spread.
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| Profiling mucin-type O-linked glycoproteins by metabolic labeling with an azido GalNAc analog (Ac4GalNAz) followed by Staudinger ligation with a phosphine probe (Phos-FLAG). R and R’ are oligosaccharide elaborations from the core GalNAc residue. |
GalNAz has an azide group, which can be chemically tagged with probes that can be visualized. The probes react with the azide by virtue of a phosphine group, a process developed in Bertozzi’s laboratory called the Staudinger ligation, named for the German synthetic-organic chemist and Nobel laureate Hermann Staudinger, who first described the reaction between azides and a phosphines almost 100 years ago.
“After injection of mice with GalNAz, azide-labeled glycoproteins were observed in a variety of tissues,
including liver, kidney, and heart, and also in serum and on isolated splenocytes,” Bertozzi and her co-authors state in their PNAS paper. “B cell glycoproteins were robustly labeled with GalNAz but T cell glycoproteins were not, suggesting fundamental differences in glycosylation machinery or metabolism.
“Furthermore, GalNAz-labeled B cells could be selectively targeted with a phosphine probe by Staudinger ligation within the living animal. Metabolic labeling with GalNAz followed by Staudinger ligation provides a means for proteomic analysis of posttranslational modifications and for identifying O-linked glycoprotein fingerprints associated with disease.”
Berkeley Lab is a U.S. Department of Energy national laboratory located in Berkeley, California. It conducts unclassified scientific research and is managed by the University of California. Visit our Website at www.lbl.gov.
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Buy an acre of land in Arizona for a free trip to the Philippines
Contact Connie Dello Buono 408-854-1883 motherhealth@gmail.com or conniedbuono@gmail for this all paid one acre lot. Description: Concho lake land unit 3 lot 470 APN 107-31-295 apache county arizon…
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Education is our best investment
Charter schools are privately run, publicly funded, and irregularly regulated. John Oliver explores why they aren’t at all like pizzerias. Last Week Tonight host John Oliver devoted much of …
Source: Education is our best investment
Education is our best investment
Charter schools are privately run, publicly funded, and irregularly regulated. John Oliver explores why they aren’t at all like pizzerias.
Last Week Tonight host John Oliver devoted much of his Sunday show to delving into the serious issue of publicly-funded and privately-run charter schools.
Describing these schools as “the things that politicians love to praise” –including clips of Trump, George W. Bush and Barack Obama doing exactly that–Oliver nonetheless makes the case that these schools deserve a failing grade.
While these types of schools have become popular over the past couple of decades (there are now 6,700 U.S. charter schools with nearly 3 million students, he said) Oliver spent much of the program outlining various problems with charter schools, noting that “critics argue charters overstate their successes, siphon off talented students, and divert precious resources within a school district.” Oliver also pointed to the high number of charter schools that are forced to close due to mismanagement or other issues, with schools sometimes being shuttered abruptly in the middle of a school year.
In Canada, college students spends every other 4 months in internships.
In India, BS and MS in Computer Science can be completed in less years than in other countries.
At Stanford University, a BS in Computer Science can have a free MS in Computer Science for free. Low income families can send their children to Stanford for free if they passed the entrance/qualifying tests.
In San Jose, a Hammer Montessori style public elementary schools have less funding and was combined with Galarza Elem school.
Castillero Middle School in San Jose is the only bay area school with music classes.
Both schools were attended by my children.
De Anze City College are being flocked by many students (some are also enrolled in other universities). They are affordable.
Connie’s comments:
We need to pay our teachers more.
In 1982, my pay as a high school science teacher in the Philippines is $50 per month.
What we all misunderstand about each other during the election?
What we all misunderstand about each other during the election?
Bribery
Bribery is the act of giving money, goods or other forms of recompense to a recipient in exchange for an alteration of their behavior (to the benefit/interest of the giver) that the recipient would otherwise not alter. Bribery is defined by Black’s Law Dictionary as the offering, giving, receiving, or soliciting of any item of value to influence the actions of an official or other person in charge of a public or legal duty.[1]
Gifts of money or other items of value which are otherwise available to everyone on an equivalent basis, and not for dishonest purposes, is not bribery. Offering a discount or a refund to all purchasers is a legal rebate and is not bribery. For example, it is legal for an employee of a Public Utilities Commission involved in electric rate regulation to accept a rebate on electric service that reduces their cost for electricity, when the rebate is available to other residential electric customers. If the rebate was done to influence them to look favorably on the electric utility’s rate increase applications, however, that would be bribery, and unlawful.
The bribe is the gift bestowed to influence the recipient’s conduct. It may be money, goods, rights in action, property, preferment, privilege, emolument, objects of value, advantage, or merely a promise to induce or influence the action, vote, or influence of a person in an official or public capacity.[2]
In economics, the bribe has been described as rent. Bribery in bureaucracy has been viewed as a reason for the higher cost of production of goods and services.
Many types of payments or favors can constitute bribes: tip, gift, sop, perk, skim, favor, discount, waived fee/ticket, free food, free ad, free trip, free tickets, sweetheart deal, kickback/payback, funding, inflated sale of an object or property, lucrative contract, donation, campaign contribution, fundraiser, sponsorship/backing, higher paying job, stock options, secret commission, or promotion (rise of position/rank).
One must be careful of differing social and cultural norms when examining bribery. Expectations of when a monetary transaction is appropriate can differ from place to place. Political campaign contributions in the form of cash, for example, are considered criminal acts of bribery in some countries, while in the United States, provided they adhere to election law, are legal.
Politicians receive campaign contributions and other payoffs from powerful corporations, organizations or individuals in return for making choices in the interests of those parties, or in anticipation of favorable policy, also referred to as lobbying. This is not illegal in the United States and forms a major part of campaign finance, though it is sometimes referred to as the money loop[citation needed]. Convictions for this form of bribery are easier to obtain with hard evidence, that is a specific amount of money linked to a specific action by the bribed. Such evidence is frequently obtained using undercover agents, since evidence of a quid pro quo relation difficult to prove. See also influence peddling and political corruption. Recent evidence suggests that demands for bribes can adversely impact citizen level of trust and engagement with the political process.
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Coming soon at http://www.avatarcare.net . You may search more health related topics at http://www.clubalthea.com – current health blog Email motherhealth@gmail.com to be added in the database of care prov…
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Coming soon at http://www.avatarcare.net . You may search more health related topics at http://www.clubalthea.com – current health blog Email motherhealth@gmail.com to be added in the database of care prov…
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About our mission to engage consumers, use genetic tests, connect with providers to create more actionable health points
Many of us know someone who died of cancer. What if we know that cancer will grow in our body in few years and we can stop it before it reaches stage 1. What if we have a blood marker that can accu…
Treatment gaps in rheumatoid arthritis
By Rita Baron-Faust, MPH Even with health insurance, some patients with rheumatoid arthritis (RA) may not be adequately treated. This news comes from an analysis of a large nationwide pharmaceutica…
Treatment gaps in rheumatoid arthritis
By Rita Baron-Faust, MPH
Even with health insurance, some patients with rheumatoid arthritis (RA) may not be adequately treated. This news comes from an analysis of a large nationwide pharmaceutical claims database.
Analysis of claims data from 4.66 million American adults treated for RA between January 2005 and September 2008, finds that only two-thirds of patients with newly diagnosed disease received DMARD therapy during the first year after their diagnosis.
And 28% received no DMARDs at all, just treatment for symptoms.
Those patients receiving only symptomatic relief tended to be older and had more co-morbidities and contraindications to methotrexate, according to the industry-sponsored retrospective cohort study.
At the same time, the authors observe, “this population was arguably underserved because 38% of this inception cohort did not see a rheumatologist in year one, and 15% never saw one over a median of 2.3 years of follow-up.”
Although one-fifth did receive biologics within 12 months, there was extensive medication switching among the group, and a relatively rapid decline over time in patients who stayed on the drugs.
The analysis reveals a somewhat lower incidence of RA than other population studies, but a similar age and gender adjusted prevalence of RA (0.63% overall, and 0.33% in men and 0.92% in women).
While the data lack supporting clinical information, such administrative databases can reflect actual treatment patterns in daily clinical practice. The same patterns of treatment of RA have been seen in other studies, they note.
The study was aimed at determining whether physicians were following current American College of Rheumatology RA treatment guidelines.
There could be a number of reasons for the apparent under-treatment of patients, the study authors speculate: lack of physician awareness of, or disagreement with, treatment guidelines; and determinations that patients were too old, their disease too mild, or there were contraindications for therapy.
Patients may have also wanted to avoid drug treatment due to adverse effects or costs, they add.
Within 12 months after their diagnosis, 65%, 64%, and 20% of the incident cohort (those without an apparent prior diagnosis of arthritis) had been prescribed corticosteroids, non-biologic DMARDs, and TNF-inhibitors, respectively.
Americans who are ashamed that we have elected as our president a man bursting with prejudices and lies are right
By Leon Wieseltier This is a country of wildly different destinies, and the belief in equality does not make people equal: The unprecedented pace of change, the daze of historical acceleration in w…