Cancer drops sparse chemical hints of its presence early on, but unfortunately, many of them are in a class of biochemicals that could not be detected thoroughly, until now.
Researchers at the Georgia Institute of Technology have engineered a chemical trap that exhaustively catches what are called glycoproteins, including minuscule traces that have previously escaped detection.
Glycoproteins are protein molecules bonded with sugar molecules, and they’re very common in all living things. Glycoproteins come in myriad varieties and sizes and make up important cell structures like cell receptors. They also wander around our bodies in secretions like mucus or hormones.
But some glycoproteins are very, very rare and can serve as an early signal, or biomarker, indicating there’s something wrong in the body – like cancer. Existing methods to reel in glycoproteins for laboratory examination are relatively new and have had big holes in their nets, so many of these molecules, especially those very rare ones produced by cancer, have tended to slip by.
 “These tiny traces are critically important for early disease detection,” said principal investigator Ronghu Wu, a professor in Georgia Tech’s School of Chemistry and Biochemistry. “When cancer is just getting started, aberrant glycoproteins are produced and secreted into body fluids such as blood and urine. Often their abundances are extremely low, but catching them is urgent.”
This new chemical trap, which took Georgia Tech chemists several years to develop and is based on a boronic acid, has proven extremely effective in lab tests including on cultured human cells and mouse tissue samples.
“This method is very universal,” said first author Haopeng Xiao, a graduate research assistant. “We get over 1,000 glycoproteins in a really small lab sample.”
In comparison tests with existing methods, the chemical trap, a complex molecular construction reminiscent of an octopus, captured exponentially more glycoproteins, especially more of those trace glycoproteins.
Wu, Xiao and Weixuan Chen, a former Georgia Tech postdoctoral researcher, who was also first author of the study alongside Xiao.
For chemistry whizzes, here’s a short summary of how the researchers made the octopus. They took a good thing and doubled then tripled down on it.
Those who recall high school chemistry class may still know what boric acid is, as do people who use it to kill roaches. Its chemical structure is an atom of boron bonded with three hydroxyl groups (H3BO3).
Boronic acids are a family of organic compounds that build on boric acid. There are many members of the boronic acid family, and they tend to bond well with glycoproteins, but their bonds can be less reliable than needed.
“Most boronic acids let too many low-abundance glycoproteins get away,” Wu said. “They can catch glycoproteins that are in high abundance but not those in low abundance, the ones that tell us more valuable things about cell development or about human disease.”
But the Georgia Tech chemists were able to leverage the strengths of boronic acids to develop a glycoprotein capturing method that works exceptionally well.
First, they tested several boronic acid derivatives and found that one called benzoboroxole strongly bound with each sugar component on the glycopeptide. (“Peptide” refers to the basic chemical composition of a protein.) 
Then they stitched many benzoboroxole molecules together with other components to form a "dendrimer," which refers to the resulting branch- or tentacle-like structure. The finished large molecule resembled an octopus ready to go after those sugar components.
In its middle, similarly positioned to an octopus’s head, was a magnetic bead, which acted as a kind of handle. Once the dendrimer caught a glycoprotein, the researchers used a magnet to grab the bead and pull out their chemical octopus along with its ensnared glycopeptides (e.g. glycoproteins).
“Then we washed the dendrimer off with a low pH solution, and we had the glycoproteins analysed with things like mass spectrometry,” Wu said.
The researchers have some ideas about how medical laboratory researchers could make practical use of the new Georgia Tech method to detect odd biomolecules emitted by cancer, such as antigens. For example, the chemical octopus could improve detection of prostate-specific antigens (PSA) in prostate cancer screenings.
“PSA is a glycoprotein. Right now, if the level is very high, we know that the patient may have cancer, and if it’s very low, we know cancer is not likely,” Wu said. “But there is a gray area in between, and this method could lead to much more detailed information in that gray area.”
The researchers also believe that developers could leverage the chemical invention to produce targeted cancer treatments. Immune cells could be trained to recognize the aberrant glycoproteins, track down their source cancer cells in the body and kill them.

Georgia Institute of Technologywww.news.gatech.edu/2018/05/04/chemical-octopus-catches-sneaky-cancer-clues-trace-glycoproteins

Researchers from Case Western Reserve University School of Medicine have discovered how unusually long pieces of RNA work in skin cells. The RNA pieces, called “long non-coding RNAs” or “lncRNAs,” help skin cells modulate connective tissue proteins, like collagen, and could represent novel therapeutic targets to promote skin repair.
In a recent study, researchers identified specific lncRNAs that control genes and behaviour of mouse skin cells. The team found 111 lncRNAs that work with a highly conserved protein network called the Wnt/β-catenin pathway. The Wnt/β-catenin pathway serves as a signalling hub that helps cells across species adjust gene expression in response to their environment. The new study connects this important pathway to a new form of genetic control—lncRNAs.
“LncRNAs are a newly discovered class of genes, and we’ve been working to elucidate their functions and mechanisms as they appear to be critical for human health,” said Ahmad Khalil, PhD, assistant professor of genetics and genome sciences and member of the Case Comprehensive Cancer Center at Case Western Reserve University School of Medicine. “Our findings show that the Wnt/β-catenin pathway activates certain lncRNAs to directly control gene expression in skin fibroblast cells.”
The team studied skin cells, called dermal fibroblasts, that help hair follicles develop, wounds heal, and generally maintain the structural integrity of skin. Fibroblasts orchestrate these important functions with the help of the Wnt/β-catenin pathway, among others. Sustained activation of the Wnt/β-catenin pathway can cause fibroblasts to overproduce connective tissue proteins, like collagen, causing harmful skin fibrosis. According to the new study, lncRNAs serve as an intermediary between Wnt/β-catenin and fibroblast genes.
The researchers showed fibroblasts genetically modified to overproduce β-catenin had 8-14 times higher levels of two specific lncRNAs when compared to control fibroblasts. The researchers named the lncRNAs Wincr1 and Wincr2—Wnt signalling induced non-coding RNA.” The lncRNA levels correlated with significantly higher levels of proteins that help fibroblasts move and contract. The findings suggest disrupting lncRNA levels could change how fibroblasts function in skin.  The study adds to a growing body of evidence that lncRNAs could represent a new arena for drug developers. LncRNAs are intriguing therapeutic targets—recent studies by Khalil and others have implicated lncRNAs defects in all kinds of diseases, including infertility and cancer.
Said Atit, “Specific lncRNAs that operate downstream of the Wnt/β-catenin pathway could serve as drug targets for chronic and acute skin fibrosis conditions.” The researchers are now working to understand how lncRNAs work in various animal models, and how their dysfunction may promote disease.
Case Western Reserve University School of Medicinehttps://tinyurl.com/yan5xss9

Blood stem cells give rise to all of our blood cells: the red blood cells that transport oxygen, the platelets that enable blood coagulation, and our immune cells that protect us from infections. Immune cells can, in turn, be divided into two groups; one that consists of cells with a very short life expectancy and a natural but rather unspecific ability to counteract infections (myeloid cells), and another that, in contrast, consists of very long-lived cells (lymphocytes) that specialize in combatting specific bacteria and viruses.
“The ability of blood stem cells to form all types of blood cells is a fundamental property that is also utilized in connection with bone marrow transplants. An increased understanding of these processes is crucial as immune cells in patients who undergo bone marrow transplants are regenerated very slowly, which results in a long period of immune sensitivity”, says David Bryder who was in charge of the study.
Despite the fact that all of our genes have been mapped, it is still largely unknown how the genes are controlled. What a cell can and cannot do is governed entirely by how the cell uses its genome. David Bryder and his colleagues have searched for genes expressed in immature blood cells but which disappear in connection with their further maturation. They then discovered the HLF gene, which caught their attention for two reasons: one, the gene controls what parts of our DNA are to be used, and two, the gene is directly involved in a rare but very aggressive type of blood cancer.
“Our studies revealed that if the immature blood cells are unable to shut down the HLF gene at the correct stage of development, the lymphocytes – the long-lived immune cells – are unable to form. As a result, you will only have one type of immune defence.”
A single cell must undergo a variety of changes to become cancerous. However, the earliest changes may involve the HLF gene, which give rise to a precursor to leukemia. Patients with leukemia in which the HLF gene is involved have a very poor prognosis, but it has been difficult to generate reliable models for studying the emergence, development and possible treatment of these leukemia more thoroughly. The researchers’ long-term goal is now to identify the mechanisms that can be used to break down these aggressive leukemia.
“The knowledge and experimental model systems we developed concerning how HLF affects blood cell development enables us to map the order of gene mutations that lead to HLF-generated leukemia, which is an important next step towards our goal”, concludes David Bryder.
Lund Universityhttps://tinyurl.com/yd2xl6b2

R-Biopharm Group recently announced a collaborative agreement with SSI, focusing on discovery and development of novel diagnostic approaches for the detection of tuberculosis infection.
The development of new diagnostic assays in the area of infectious diseases is a priority for R-Biopharm, a company with 30 years of experience in providing testing solutions for Clinical Diagnostics and Food & Feed analysis. R-Biopharm Group operates in various countries including subsidiaries in the UK, USA, Italy, France, Latin America, Brazil, Spain, Belgium, Australia, India and China as well as by a worldwide extensive network of more than 120 distributors.
“This collaborative agreement creates an opportunity to work with the world-leading scientists and inventors of novel biomarkers and vaccines in the area of tuberculosis research. Our Infectious Diseases Team is inspired to join efforts for the development of novel diagnostics for the tuberculosis patients throughout the world. At R-Biopharm we are concerned about rising numbers of tuberculosis cases and escalation of multidrug-resistant (MDR-TB) and extensively drug-resistant TB (XDR-TB). In cooperation with Statens Serum Institute we will have the potential to transform the current underserved market of tuberculosis diagnostics and provide alternative solutions for the detection of TB infection,” said Dr. Ralf Dreher, CEO and Founder of R-Biopharm Group.
SSI is one of Denmark’s largest research institutions in the health sector with over a century of experience in research, development and manufacturing of biologics. Led by Professor Peter Andersen, the research and development team at SSI are at the forefront in the development of novel vaccines and diagnostic agents for major diseases affecting global health. The program has brought several novel vaccine candidates in clinical trial within TB and Chlamydia as well as provided the ground work for the current industry standard in diagnostic tests for tuberculosis infection (IGRAs).
“We are excited for our collaboration with R-Biopharm, a leading industry partner in the field of infectious disease diagnostics. As a government research organization under the ministry of health, industrial involvement is pivotal to get our projects from the lab out to the benefit of patients. The strong research base at R-Biopharm is a great match for the SSI team and has been a fruitful synergy,” said Prof. Peter Andersen, Executive Vice President, Center for Vaccine Research at Statens Serum Institute.
Under the agreement, R-Biopharm and SSI will collaborate on research and development and responsibility for the commercialization of potential products.
www.r-biopharm.com

Visualizing cellular components and processes at the molecular level is important for understanding the basis of any biological activity. Fluorescent proteins (FPs) are one of the most useful tools for investigating intracellular molecular dynamics.
However, FPs have usage limitations for imaging in low pH environments, such as in acidic organelles, including endosomes, lysosomes, and plant vacuoles. In environments of pH less than 6, most FPs lose their brightness and stability due to their neutral pKa. pKa is the measure of acid strength; the smaller the pKa is, the more acidic the substance is.
“Although there are reports of several acid-tolerant green FPs (GFPs), most have serious drawbacks. Furthermore, there is a lack of acid-tolerant GFPs that are practically applicable to bioimaging,” says Hajime Shinoda, lead author of an Osaka University study that aimed to design acid-tolerant monomeric GFP that is practically applicable to live-cell imaging in acidic organelles. “In the current study, we developed an acid-tolerant GFP. We called it Gamillus.”
Gamillus is a GFP cloned from Olindias formosa (flower hat jellyfish) and exhibits superior acid tolerance (pKa=3.4) and nearly twice as much brightness compared with the reported GFPs. The fluorescence spectrum is constant between pH4.5 and 9.0, which falls between the intracellular range in most cell types. X-ray crystallography (a technique used for determining the atomic and molecular structure of a crystal, in this case, a Gamillus crystal) and point mutagenesis suggest the acid tolerance of Gamillus is attributed to stabilization of deprotonation in its chemical structure.
“The applicability of Gamillus as a molecular tag was shown by the correct localization pattern of Gamillus fusions in a variety of cellular structures, including ones that are difficult to target,” corresponding author Takeharu Nagai says. “We believe Gamillus can be a powerful molecular tool for investigating unknown biological phenomena involving acidic organelles, such as autophagy.”
Osaka Universityresou.osaka-u.ac.jp/en/research/2017/20171229_1