Dr. Cedric Garland is an epidemiologist known for his research in the field of vitamin D deficiency. He has written upwards of 150 articles and books on the subject. Garland partnered with his late brother Frank C. Garland in some of this research.
Their most widely cited paper is Garland CF, Garland FC, Gorham ED, et al. “The Role of Vitamin D in Cancer Prevention.” American Journal of Public Health 2006;96(2):252-261. doi:10.2105/AJPH.2004.045260, cited 829 times according to Google Scholar.
National Representative on the International Federation of Clinical Chemistry and Laboratory Medicine, Secretary of African Federation of Clinical Chemistry and Laboratory Medicine, President of Zimbabwe College of Pathology.
Developed a new Department of Immunology in UZCHS. Developed the Zimbabwe External Quality Assurance Programme which later transformed into the Zimbabwe National Quality Assurance Programme where 138 Public and Private Clinical Laboratories are regularly monitored. Developed an MSc degree course in Clinical Biochemistry in UZCHS and BMLS degree course in Africa University, Mutare.
Head of Department of Chemical Pathology UZCHS, Founding Dean of Studies, UZ Bulawayo College of Health Sciences, Executive Secretary Clinical Quality Assurance Board, Parirenyatwa Group of Hospitals, Founding Vice-Chancellor and Professor of Great Zimbabwe University; Chief Editor of Journal of Biomedical Sciences and Public Health and Editorial board member on Journal of Thymology: Harzburg, Germany.
Doctors have been cautioned before that results from the A1C test don’t have pinpoint accuracy. A study published underscores that shortcoming as it applies to people who carry the sickle cell trait.
Glucose levels in the blood rise and fall all the time, so it can be tricky to look at a single exam to diagnose diabetes or manage the disease in people who have it. But one test gets around this problem.
The A1C test measures sugar that binds to hemoglobin molecules in red blood cells. It provides an average of blood sugar over the past three months, “so this has turned out to be an incredibly powerful test, both for the diagnosis and treatment of diabetes,” says Dr. Anthony Bleyer, a kidney specialist at the Wake Forest School of Medicine who was not involved in the study.
The problem is that the test results can vary, depending on circumstance. For example, people with anemia may get inaccurate readings. So do people who carry unusual types of hemoglobin, the best known being sickle cell trait.
Eight to 10 percent of African-Americans carry the sickle cell trait. But only people who inherit two copies of the sickle cell trait, one from each parent, develop the disease.
And a few years ago, scientists realized that A1C readings for African-Americans typically don’t match those from whites. They are generally higher.
“The test was really standardized based on white individuals, and there were just a small number of African-American individuals in that study,” Bleyer says.
And while the difference isn’t large, it can matter a lot, especially for people who are close to the line that defines diabetes. Someone who appears to be just under the line and diagnosed as having prediabetes may in fact have a higher level of A1C, which would push them into a diagnosis of diabetes.
Vagaries in these readings can also be misleading for people whose treatment is guided by this test, because doctors may be overly aggressive in controlling blood sugar, to the point that a patient can end up with seriously low blood sugar.
In a report published Tuesday in JAMA, the journal of the American Medical Association, scientists at Brown University and the National Institutes of Health examined data from two large studies to compare test results of African-Americans with and without the sickle cell trait.
The studies used standard A1C tests that had previously been shown to give low readings for people with the sickle cell trait. The scientists were surprised to find how big a difference it made.
About 4 percent of the people in the study who carried the sickle cell trait were diagnosed with diabetes, but they expect a test corrected for bias would have identified about 7 percent — nearly twice as many people.
“We were really shocked by that, honestly,” says Mary Lacy, a graduate student at Brown University and lead author of the study. “That’s huge!”
Likewise, they found 40 percent fewer cases of prediabetes than they expected among people carrying the sickle cell trait.
The test readings are only off by a few tenths of a percentage point, but that was enough to push many people below the cutoff points that indicate diabetes or prediabetes.
This observation is one reason doctors should be cautious in interpreting A1C results, researchers say.
“Doctors generally take the test fairly literally,” says Tamara Darsow, senior vice president for research and community programs at the American Diabetes Association. “How much this impacts care and the interpretation of A1C results I think is variable.”
The association’s guidance document cautions doctors that the A1C tests can be off by plus or minus 7 percent among people with unusual hemoglobin traits. As the new study underscores, that is more than enough variability to affect a diagnosis.
So instead of making a snap diagnosis, particularly for African-Americans, doctors could additionally run some more traditional blood-sugar tests. Those aren’t influenced by race or sickle cell status (though they can vary for other reasons).
“Information together from all of these tests can be much more powerful than those taken in isolation,” Darsow says.
The American Diabetes Association would ultimately like to come up with more concrete treatment guidelines, but for now their word to doctors is this: Be aware this is an issue and use your best judgment.
Source: HEALTH NEWS FROM NPR
To help you keep track of the literature and avoid feeling too overwhelmed, Science Careers asked scientists in a diverse range of fields to discuss how they integrate searching for papers, and reading them, into their working routine. Their responses have been edited for brevity and clarity.
Without keeping up with the literature, I can’t know what other people are doing or contextualize my work. In addition, through reading the literature I can find potential solutions to scientific barriers I am facing in my own research. But I do find it difficult to integrate this task into my daily routine. The demands on scientists in terms of outreach, administration, grant writing, teaching, and more are tremendous, and there are only 24 hours in a day.
– Lynn Kamerlin, associate professor of cell and molecular biology at Uppsala University in Sweden
Staying up to date with the literature is perhaps the single most important skill that remains crucial throughout a researcher’s career. Without knowing where the current gaps are, your findings will either be old hat or too out in left field to be cited right away. But there certainly are challenges. One of them is that reading papers can feel like dead time, because it is such a slow and absorbing process, and there are so many papers out there to digest. Reading can also feel disheartening, as you will often find that other people have already published on what you thought was a really novel or original idea. And so it can all too easily happen that this important task of investing in your knowledge gets prioritized lower than all the other apparently more urgent duties that you have as a scientist.
– Denis Bauer, team leader in transformational bioinformatics at the Commonwealth Scientific and Industrial Research Organisation in Sydney, Australia
Our job is to push the frontier of what is already known, so we need to be aware of where this frontier is. However, trying to stay up to date with the literature is tremendously difficult. As an assistant professor, my job is to not only do research but also to teach, obtain funding, do professional service including peer review, give talks, attend committee meetings, and more. This constant multitasking makes it difficult to carve out time for keeping up with papers. Another challenge lies in the immense amount of new work that constantly gets published. The number of journals and venues is very large, and it continues to grow. This is further aggravated if you work in a field that is multidisciplinary, because then this number is multiplied, becoming barely manageable.
– Belen Masia, assistant professor of computer science at the University of Zaragoza in Spain
It is extremely important to find what you need in the scientific literature, but it’s difficult for anyone to block out the necessary time. For young scientists in particular, there is the additional challenge of trying to stay on top of newly published literature while still building up knowledge of their research areas.
– John Borghi, former librarian and postdoctoral fellow at the California Digital Library in Oakland, California
Keeping up is essential, no doubt about it. To be able to provide novel results, you have to know what has been done before you. Plus, you want to benefit from all the ideas, data, and interpretations that have accumulated in the literature right up to that point. But it’s certainly hard to keep up. Thousands of papers are published daily. Another challenge for me is that my research is multi-faceted, so I need to read in my broader field, which covers a lot of ground.
– Juan Jose Negro, senior staff scientist in evolutionary ecology and conservation biology at the Doñana Biological Station in Seville, Spain
Our function as scientists is to push the envelope and create new knowledge and understanding, so we always need to be as up to date as we can be in our areas. But keeping up with the literature is potentially an overwhelmingly large task, and there are no deadlines attached to it. And so, among all the other things that I have responsibilities for, it often feels hard to prioritize.
– Jehannine C. Austin, associate professor of psychiatry and medical genetics at the University of British Columbia in Vancouver, Canada
To make a contribution to scientific research and effectively teach my students, I need to be very familiar with the current state of knowledge and with what ideas and methods are being used at the frontier of my field. But I find that keeping up with the literature always comes with a trade-off: Do I spend more time on my research projects, or do I read the latest papers?
– Ina Ganguli, assistant professor of economics at the University of Massachusetts in Amherst
To keep on top of my specialty area, I carry out regular, systematic literature searches using a tool called PubCrawler. PubCrawler automatically searches online publication databases using key search terms that I set up, and it sends me a weekly email highlighting all the new and potentially relevant papers, with a link to the abstract or full text. I find out about other recently published papers I ought to read from email alerts I get from the key journals in my area. I also become aware of new publications through colleagues who email me, and from social media. Twitter is an underutilized resource in science, but it’s great—if you follow the right people—for keeping your finger on the pulse of new work that is coming out.
Regarding finding the time, unless I am actively writing a grant or paper, it is harder for me to keep up with the literature, because it’s not an urgent, immediate, deadline-driven need. So I have a set time once a week, on Mondays, to look at the output of my literature searching tools. I sift through it all and then at least skim the papers that I find most relevant. I read journals’ tables of contents when I get them, usually also immediately downloading and at least skimming the papers that I find of most interest. Thorough reading of the full papers may be more sporadic.
– Austin
The tools I use to keep track of new literature are Feedly, which allows me to subscribe to the RSS feeds of relevant journals; a string of PubMed updates, which capture any relevant literature published outside those journals; and Twitter, which helps me identify what literature the broader scientific community is talking about.
I like spending a few minutes every morning skimming recent publications for articles that are especially interesting or relevant to my work. Coupled with a regular block every Friday devoted to more critical reading and lots of note taking, this generally allows me to stay up to date. Whatever routine you decide to set for yourself, I think the key is to find a way to interact with the literature regularly.
– Borghi
I continuously monitor the growing literature using the updates feature in Google Scholar, which recommends a selection of new papers to read based on your own publications. Monitoring the handful of main conferences in my field throughout the year, plus a couple of other relevant venues, also does a good job. Many conferences eventually publish their proceedings, and so whenever the lists of accepted papers get published, I also go through them as soon as I can and look at the papers that seem the most relevant to me. Sometimes, reading the abstract suffices. Other times, if it is closely related to my research, I print it for when I find time to go over it in more detail. Also, I make a point to regularly look at what leading researchers in my field publish and to talk to my peers.
– Masia
To know when relevant papers are published, I rely on alerts that the journals automatically send to highlight new publications that cite papers I found of interest previously. There is also substantial activity on social media, with journals promoting and researchers discussing new articles. Reddit Science’s Ask Me Anything, or AMA, forum discussions are a great way to hear about innovative research and talk to the authors directly. Recommender systems such as PubChase can also be great tools to hear about new papers early. However, most recommender systems find papers based on how similar they are to papers you previously read, which inevitably limits your exposure to tangential ideas that may be important to your research. I therefore like going through the tables of contents of my favorite journals.
In terms of how I find time for dealing with the literature, I usually go through email alerts as I get them to quickly become aware of the most important new publications. I also find that tweeting or blogging about one paper a week, or a day, is a good incentive for reading in depth. Twitter is particularly good, as it forces me to condense the paper’s relevant outcomes down to 140 characters, which then promptly triggers my memory as I go through my Twitter feed. Other advantages of Twitter are that it helps me find researchers with similar interests and helps me build a brand.
– Bauer
One way I keep track of new papers being published is by subscribing to emails that include the tables of contents of the top or most widely read journals in my field. In economics there is usually a long publication lag, so I also have to be aware of working papers getting published and new publications being presented at conferences and in seminars. Attending events and talking to others are very important ways to find out about the latest papers. I also follow some blogs written by economists and several economists on Twitter who tend to write about new papers.
To deal with the time pressure, I try to be efficient in how I scan the literature. I find it very useful to at least read through the titles and abstracts of the latest papers published in the journals, and then I decide carefully which papers I should read extensively.
– Ganguli
To keep up with new papers being published, I use a combination of RSS feeds from journals in my field, Google Scholar Updates, the reference manager Papers, and recommendations from senior scientists on Faculty of 1000 or directly from colleagues. Twitter is also becoming increasingly valuable as a tool for spreading exciting research, and I strongly recommend getting networked through social media. The volume of literature out there makes keeping track a collective effort, and it’s also good to have a venue for promoting your own work amid the sea of information.
But while I continuously scan what’s coming out, finding the time to read multiple papers in full is more difficult. And so, every few weeks, I try to download as many papers as I can—both newly published papers that are relevant to my work and older papers that I recently became aware of—and read them in chunks as the week progresses. Still, summer is best for reading—I have fewer teaching and administration obligations, so this is when I can really catch up with the literature.
– Kamerlin
For general background reading in my field, I usually start by looking at new articles that have cited my work, as the likelihood that I am interested in what they have to write about is much higher. Similarly, I look at both recent and past citations to papers I found interesting to find further reading. For more targeted literature searches, Google—both Google Scholar and just the normal search bar—and PubMed are great. If I am moving into a new area, I usually contact colleagues, including people I know through conferences, and ask them if they have recommendation lists for me.
– Kamerlin
I find that, nowadays, searching for past literature is the easy part. Search engines and Google Scholar, together with other tools which allow users to follow citations, do a good job. If discipline-specific conferences or journals exist, I also go through the papers published in them, going at least 5 years back. What I find much more challenging is how to organize the works that I read and knowledge I acquire, and how to search back through them. I first set up a dedicated digital database using existing tools. Mendeley is a well-known example; I myself use JabRef. Then I archive hard copies of most of the papers I read, with the main contributions written on their front page. It is of no use going through a bunch of papers if you are unable to remember what you read in them.
– Masia
For historical searches, I usually start with PubMed, searching terms that make the most sense to me and expanding my scope of those search terms if I get limited results. Once I have a selection of key or index papers for a topic of interest, I pull the relevant papers cited within them. I also find out which papers later cited my index papers, for example by finding them on Google Scholar. Often, through this process, I am able to develop new search terms to use in PubMed, so I may then again start the whole process iteratively.
– Austin
When conducting literature searches, I like to simultaneously look backward and forward: If I find a paper that I think describes a topic particularly well, I look at both the papers it cites and the papers that cite it. Tools like PubMed and Web of Science each have their own strengths and weaknesses but, if I’m trying to gain insight into a topic described in a paper, I typically start by using Google Scholar to look at the papers that reference the one I’m reading.
– Borghi
For broader searches, I have been applying “Ten Simple Rules for Searching and Organizing the Scientific Literature” for several years now with good results, although the technologies have changed slightly over time. Today, I usually start from the article that made me interested in the topic (what I call the seed paper) and read the papers that are cited in the references. For this I use ReadCube, as it helps prioritize papers by the number of citations they have. Then I also try to find a review article on PubMed, which helps me identify other research groups in the field whose work might not have been referred to in the seed paper but is nonetheless important. Finally, I try searches for research articles in PubMed and Google Scholar with very precise keywords and choose new seed papers from there, starting the process all over again. Eventually, this helps me establish connections between different schools of thought.
– Bauer
It’s easy to feel overwhelmed with the flow of information. The decision to be made is one of sensitivity versus specificity. I tend to prioritize specificity (whether the papers I find are on target for me) and accept lower sensitivity (I’m not going to find everything that could potentially be relevant). I have drawn a line that makes sense for me based on the principle of diminishing returns. Of course, where exactly to draw this line is likely different for everyone.
Regarding how to make sure nothing crucial escapes my attention, I try to send links to papers that I find to colleagues and students whom I think might be interested in them, given what I know about their work. My hope is that, in turn, they will send things that they come across to me too, and then perhaps I will miss less. I also find that, when I am writing grants and papers and engaging in more thorough systematic literature reviews, I can catch up on things I may have missed.
– Austin
It is important to be exposed to ideas and approaches from other disciplines, but there can be an overwhelming amount of information if we try to read everything that gets published, and sometimes it is difficult to know where to draw the line. I prioritize the papers that are directly related to my own projects, especially when I am writing literature reviews for publications or grant proposals. I also prioritize reading papers from the top journals in my main research areas to keep on top of which topics and methods are at the frontier of knowledge. And then if I have some spare time, I also try to read papers that are a little bit further from my main research topics.
There are certainly some times when you have that “I can’t believe I missed this paper” moment. But usually, if the papers are important enough, you will eventually find out about them through conference presentations, conversations with colleagues, Twitter, blogs, magazines, or other channels. You just hope you don’t have that moment when reading a report from a referee who isn’t happy that you missed an important citation!
– Ganguli
The number of papers out there makes it impossible not to miss important papers, especially when you are working in multiple disciplines. So I prioritize my reading in terms of what is most immediately relevant to what I am working on, and then I fan out from there as time allows.
– Kamerlin
Trying to read too broadly, too deeply, or too quickly is a sure path to information overload. So don’t try to read it all at once! Scientists who are feeling overwhelmed by the flow of information should take a step back and think about what exactly they’re looking for in the literature—and then prioritize the papers directly related to that question. It also helps to realize that, ultimately, a single scientist can’t read everything. A group of scientists navigating different branches of the literature can however cover a lot of ground. Personally, I’ve benefited greatly from collaborators and friends working in fields adjacent to my own pointing me toward things they’ve come across.
– Borghi
Young scientists sometimes tend to neglect the literature. They look at a number of related papers when they start working on their project, but then they fail to keep looking for more papers as their research—and the work of other researchers—progresses. They also rarely go back to the literature they’ve searched and read, even though it remains a great source of inspiration.
– Masia
Talk to librarians! Depending on their area of expertise, they may be able to give you specific advice about accessing important papers or navigating the scientific literature. Even if they don’t have specific subject area knowledge, librarians are an often-untapped source of knowledge about how scholarly information is organized, evaluated, and disseminated.
– Borghi
Remember that we walk on the shoulders of giants. Einstein would be a notable example, and Darwin’s work is still as relevant to evolutionary biologists today as it was in his day. In other words, don’t limit your literature searches to the 21st century.
– Negro
At the early stages of your research career, it’s especially important that you take the time each day to get up to speed with the literature. I would recommend trying the different tools available and experimenting with your reading routine until you find what works for you. There are so many great options out there, and people have different tastes in terms of what they are comfortable with. Also, don’t be afraid to ask your adviser for literature recommendations. Finally, it’s a good idea to set up a physical or virtual journal club to share papers and discuss ideas with your peers.
– Kamerlin
Source: Science
EFLM is proud to present its new website. Basically, the website mirrors the functionalities of the previous one. However, with a completly new graphic, and some new functions such as:
They will be glad to receive people’s feedback about the site: it will be of great help for improving it.
EFLM is proud to present its new website: www.eflm.eu
The study, published in Scientific Reports, opens up a promising new way of overcoming antibiotic resistance and could help scientists to design even more effective drugs.
“Antibiotics work in different ways, but they all need to bind to bacterial cells in order to kill them,” explains lead author Dr Joseph Ndieyira (UCL Medicine). “Antibiotics have ‘keys’ that fit ‘locks’ on bacterial cell surfaces, allowing them to latch on. When a bacterium becomes resistant to a drug, it effectively changes the locks so the key won’t fit any more. Incredibly, we found that certain antibiotics can still ‘force’ the lock, allowing them to bind to and kill resistant bacteria because they are able to push hard enough. In fact, some of them were so strong they tore the door off its hinges, killing the bacteria instantly!”
The researchers used sensitive equipment to measure the mechanical forces that four different antibiotics exerted on bacterial cells. They tested bacteria that were susceptible to antibiotics and those that had developed resistance. The antibiotics all exerted similar forces on susceptible bacteria, but the forces they exerted on resistant bacteria varied significantly. The antibiotics tested included vancomycin, a powerful antibiotic used as a last resort treatment for methicillin-resistant Staphylococcus aureus (MRSA) and other infections, and oritavancin, a modified version of vancomycin used against complex skin infections.
“We found that oritavancin pressed into resistant bacteria with a force 11,000 times stronger than vancomycin,” says Dr Ndieyira. “Even though it has the same ‘key’ as vancomycin, oritavancin was still highly effective at killing resistant bacteria. Until now it wasn’t clear how oritavancin killed bacteria, but our study suggests that the forces it generates can actually tear holes in the bacteria and rip them apart.”
Oritavancin is a fast-acting antibiotic that can kill bacteria in 15 minutes, whereas vancomycin takes 6-24 hours. Vancomycin works by disrupting vital processes in bacteria so they slowly stop functioning and die. Although oritavancin is a modified version of vancomycin, the new study suggests that it kills bacteria in a completely different way.
“Oritavancin molecules are good at sticking together to form clusters, which fundamentally changes how they kill bacteria,” explains Dr Ndieyira. “When two clusters dig into a bacterial surface they push apart from each other, tearing the surface and killing the bacteria. Remarkably, we found that conditions at the bacterial surface actually encourage clustering which makes antibiotics even more effective.”
The team developed a detailed mathematical model to describe how antibiotics behave at the surface of bacterial cells. The model could be used to screen promising new antibiotics, identifying new drugs that can kill bacteria by using brute force.
“Our findings will help us not only to design new antibiotics but also to modify existing ones to overcome resistance,” says Dr Ndieyira. “Oritavancin is just a modified version of vancomycin, and now we know how these modifications work we can do similar things with other antibiotics. This will help us to create a new generation of antibiotics to tackle multi-drug resistant bacterial infections, now recognized as one of the greatest global threats in modern healthcare.”
Source: Medical Express
An update from AFCC
The Foundation for Emerging Nations (FEN) has as its overall aim to support programmes that help to improve the quality and delivery of laboratory medicine services, particularly in emerging nations.
The FEN is able to support projects in emerging nations that are organised by societies, groups or individuals active in laboratory medicine provided that the project will lead to an outcome that:
Projects shall be educational in nature and may occur at undergraduate or postgraduate level. Suitable projects will be in line with the overall strategic direction of IFCC, (see www.ifcc.org) although the FEN is not restricted to supporting projects nominated by IFCC Members.
The FEN has limited resources and so can only support pilot projects or projects that will deliver results against defined objectives, normally within six months.
Applications will be considered twice each year with closing dates of 31 March and 30 September.
Oral bisphosphonates are common first line treatments for osteoporosis. However, approximately half of patients who begin osteoporosis treatment do not follow their prescribed treatment and/or discontinue treatment within a year. Identifying low adherence to medication – a problem commonly seen with many chronic diseases – is a critical issue as it jeopardizes the efficacy of treatment, leaving osteoporosis patients unprotected against fractures.
A newly published International Osteoporosis Foundation (IOF) and European Calcified Tissue Society (ECTS) Working Group position paper proposes measuring specific bone turnover markers (BTMs) in patients who have initiated use of oral bisphosphonates for postmenopausal osteoporosis as a clinically feasible and practical way to identify low adherence. BTMs can reflect the early effect of the drug on bone tissue. If a low response is detected shortly after treatment has been started, this can indicate low adherence or point to underlying causes of impaired response to medication.
Using the findings of the TRIO study [2] as the basis for their recommendations, the Working Group recommends measuring serum PINP (procollagen type 1 N-terminal propeptide) and CTX (collagen type 1 C-terminal telopeptide) levels at baseline and after 3 months of initiating treatment. The timing for the assessment at 3 months is optimal because the first weeks after the prescription is given is the critical period of primary non-adherence, when patients are most likely to have discontinued treatment.
The Working Group recommends that in those individuals where the decrease of the two BTMs, PINP and CTX does not exceed the least significant change (38% and 56%, respectively) assessment of adherence, or possibly investigation of secondary osteoporosis, should be carried out.
Professor Adolfo Diez-Perez, Co-Chair of the Joint IOF-ECTS Adherence Working Group, stated, “The use of bone turnover marker measurement to detect a lack of response to oral bisphosphonates is a practical and low-cost screening procedure which helps identify potential non-adherence in patients very early after treatment initiation. The patients benefit as this opens up opportunity for discussion and early intervention with noncompliant patients, or can indicate that secondary causes of osteoporosis need to be assessed.”
Co-Chair of the Working Group, Professor Richard Eastell, emphasized that “It will be interesting to further evaluate if these recommendations have an impact on adherence in a real-life setting.”
Source: Science Daily
Now, scientists at Washington University School of Medicine in St. Louis have exploited a common weak point in cancer cell metabolism, forcing tumor cells to reveal the backup fuel supply routes they rely on when this weak point is compromised. Mapping these secondary routes, the researchers also identified drugs that block them. They now are planning a small clinical trial in cancer patients to evaluate this treatment strategy. The research is published Jan. 24 in Cell Reports.
Studying human cancer cells and mice implanted with patients’ tumor samples, the researchers demonstrate that a double hit—knocking out the weak point and one of the tumor cells’ backup routes—shows promise against many hard-to-treat cancers. Though present in multiple cancer types, the weak point is particularly common in sarcomas—rare cancers of fat, muscle, bone, cartilage and connective tissues. Doctors treat sarcomas primarily with traditional surgery, radiation and chemotherapy, but such treatments often are not effective.
“We have determined that this metabolic defect is present in 90 percent of sarcomas,” said senior author Brian A. Van Tine, MD, PhD, an associate professor of medicine. “Healthy cells don’t have this weakness. We have been trying to create a therapy that takes advantage of the metabolic defect because, in theory, it should target only the tumor. Basically, the defect allows us to force the tumor cells to starve.”
To grow and proliferate, tumor cells must have basic building materials. The researchers’ strategy relies on the fact that the vast majority of sarcomas have lost the ability to manufacture their own arginine, a protein building block that cells need to make more of themselves. Lacking this ability, the cells must harvest arginine from the surrounding environment. The supply of arginine in the blood is abundant, and cancer cells have no trouble scavenging it. But remove this environmental supply of arginine and the cells have a problem.
“When we use a drug to deplete arginine in the blood, the cancer cells panic because they’ve lost their fuel supply,” Van Tine said. “So they rewire themselves to try to survive. In this study, we used that rewiring to identify drugs that block the secondary routes.”
Unlike most cancer therapies, depleting arginine in the blood does not affect healthy cells. Normal cells don’t rely on external sources of arginine because they don’t have the cancer’s metabolic defect. They continue to make their own arginine, so there is no induced starvation in normal cells even when there is no arginine in the blood. Van Tine said this strategy is based on the properties of a tumor—it shuts down tumor metabolism specifically and nothing else.
Unable to make or obtain external arginine, the tumor cells’ fuel supply routes are forced inward. The cells must begin to metabolize their internal supply of arginine in a process called autophagy, or “self-eating.” In the case of sarcomas, this state slows or pauses cancer growth but does not kill the cell. During this period, tumor cells appear to be buying time to find yet another internal work-around.
“Cancer doesn’t die when you halt its primary fuel supply,” Van Tine said. “Instead, it turns on all these salvage pathways. In this paper, we identified the salvage pathways. Then we showed that when you drug them, too, you kill cells. Our study showed that tumors actually shrink under these conditions. This is the first time tumors have been shown to shrink using just metabolism drugs and no other anti-cancer strategies.”
The arginine-depleting drug is currently in clinical trials investigating its safety and effectiveness against liver, lung, pancreatic, breast and other cancers. But so far, it has been ineffective likely because it has activated the salvage pathways allowing cancer growth to continue. The researchers said the drug may yet become a vital metabolic therapy for cancer as long as it is used in combination with other drugs targeting the backup pathways.
Van Tine and the study’s first author, Jeff C. Kremer, a PhD student in Van Tine’s lab, explained that when cancer cells with this metabolic defect are deprived of environmental arginine, they are forced to shift from a system that burns glucose to a system that burns a different fuel called glutamine. They showed that adding a glutamine inhibitor to the arginine-depleting drug is lethal to the cells. Eliminating arginine from the blood also rewires serine biology, another backup fuel, so adding serine inhibitors also causes cell death.
This strategy could be applied beyond rare sarcoma tumors because the metabolic defect is often present in other cancers, including certain types of breast, colon, lung, brain and bone tumors, the researchers said. The new study includes data showing similar anti-tumor responses in cell lines from these cancer types. Van Tine also pointed out that all of the drugs used in the study are either already approved by the U.S. Food and Drug Administration for other conditions or in ongoing clinical trials investigating cancer drugs.
Based on this study and related research, Van Tine and his colleagues at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine are planning a clinical trial of the arginine-depleting drug in patients with sarcomas.
“We will start with a baseline trial testing the arginine-depleting drug against sarcomas with this defect, and then we can begin layering additional drugs on top of that therapy,” Van Tine said. “Unlike breast cancer, for example, sarcomas currently have no targeted therapies. If this strategy is effective, it could transform the treatment of 90 percent of sarcoma tumors.
Source: medicalxpress.com
