Healthcare analytics, AI solutions for biological big data, providing an AI platform for the biotech, life sciences, medical and pharmaceutical industries, as well as for related technological approaches, i.e., curation and text analysis with machine learning and other activities related to AI applications to these industries.
Scientists build a living cellular organism with a genome smaller than any known in nature.
By Ruth Williams | March 24, 2016
By stripping down the genome of a mycoplasma bacterium to the minimal genes required for life,Craig Venter and colleagues have created a new organism with the smallest genome of any known cellular life form. The work, published in Sciencetoday (March 24), is the closest scientists have come to creating a cell in which every gene and protein is fully understood—but they are not quite there yet.
“In biology, as we’ve been trying to do genetic and biological engineering, we’re frustrated by the fact that . . . evolution has given us a real mess—it’s really just bubble gum and sticks, piecing together whatever works,” said biomedical engineer Chris Voigt of MIT who was not involved in the study. “This [work] is one of the first attempts at a grand scale to go in and try to clean up some of the mess . . . so that we can better understand the genetics.”
The quest to synthesize a minimal genome with only the essential genes for life is one researchers at the J. Craig Venter Institute (JCVI) in San Diego have been doggedly pursuing for the better part of two decades. Clyde Hutchison, an investigator at JCVI and lead author of the new study, explained the motivation: “We want to understand at a mechanistic level how a living cell grows and divides,” he told The Scientist, and yet, “there is no cell that exists where the function of every gene is known.” Possession of such fundamental knowledge, he added, would also put researchers “in a better position to engineer cells to make specific products,” like pharmaceuticals, Hutchinson said.
The team’s starting point was the bacterium Mycoplasma genitalium, which has the smallest known genome of any living cell with just 525 genes. However, it also has a very slow growth rate, making it difficult to work with. To practice synthesizing genomes and building new organisms, the team therefore turned to M. genitalium’s cousins, M. mycoides and M. capricolum, which have bigger genomes and faster growth rates. In 2010, Venter’s team successfully synthesized a version of the M. mycoides genome (JCVI-syn1.0) and placed it into the cell of a M. capricolum that had had its own genome removed. This was the first cell to contain a fully synthetic genome capable of supporting replicative life.
With the genome synthesis and transfer skills mastered, the next step was to make the genome smaller, explained Hutchison. One approach would be to delete the genes one by one and see which the cells could live without. But “we thought we knew enough, that it would be that much faster to design the genome, build it, and install it in a cell,” said Hutchison. The problem was, “we weren’t completely right about that,” he said. “It took quite a bit longer than we thought.”
Using JCVI-syn1.0 as their starting material, the researchers initially designed a minimal genome based on information from the literature and from mutagenesis studies that suggested which genes were likely essential. They divided this genome into eight overlapping segments and tested each one in combination with the complementary seven-eighths of the standard JCVI-syn1.0 genome. All but one of the designed segments failed to sustain viable cells.
Going back to the drawing board, the team decided to perform mutagenesis experiments on JCVI-syn1.0 to determine, categorically, which genes were required for life. Their experiments revealed that the genes fell into three groups: essential, nonessential, and quasiessential—those that aren’t strictly required, but without which growth is severely impaired. The failure to include these quasiessential genes in the initial design explained in large part why it had failed, explained Hutchison. “The concept of a minimal genome seems simple, but when you get into it, it’s a little more complicated,” he said. “There’s a trade-off between genome size and growth rate.”
Equipped with this knowledge, the team redesigned, synthesized, and tested new genome segments retaining the quasiessential genes. Three iterative cycles of testing later, the team had a genome that successfully supported life.
“This is a really pioneering next step in the use of synthetic biology,” said Leroy Hood, president of the Institute for Systems Biology in Seattle who also did not participate in the research.
Ultimately the team removed 428 genes from the JCVI-syn1.0 genome to create JCVI-syn3.0 with 473 genes (438 protein-coding genes and 35 RNA genes)—considerably fewer than the 525 genes of M. genitalium. Interestingly, the functions of around one-third of the genes (149) remain unknown. “I was surprised it was that high,” said Hood, “but I also think we kid ourselves about how much we know about the genomes of organisms. There’s still an enormous amount of dark matter.”
Some of these genes of unknown function appear to be conserved in higher eukaryotes, said Hutchison. “Those, in a way, are the most exciting,” he said, “because they might represent some new undescribed function that has spread through other life forms.”
C.A. Hutchison III et al., “Design and synthesis of a minimal bacterial genome,” Science, 351: 1414, 2016.
Design and synthesis of a minimal bacterial genome
A goal in biology is to understand the molecular and biological function of every gene in a cell. One way to approach this is to build a minimal genome that includes only the genes essential for life. In 2010, a 1079-kb genome based on the genome of Mycoplasma mycoides (JCV-syn1.0) was chemically synthesized and supported cell growth when transplanted into cytoplasm. Hutchison IIIet al. used a design, build, and test cycle to reduce this genome to 531 kb (473 genes). The resulting JCV-syn3.0 retains genes involved in key processes such as transcription and translation, but also contains 149 genes of unknown function.
INTRODUCTION In 1984, the simplest cells capable of autonomous growth, the mycoplasmas, were proposed as models for understanding the basic principles of life. In 1995, we reported the first complete cellular genome sequences (Haemophilus influenza, 1815 genes, and Mycoplasma genitalium, 525 genes). Comparison of these sequences revealed a conserved core of about 250 essential genes, much smaller than either genome. In 1999, we introduced the method of global transposon mutagenesis and experimentally demonstrated that M. genitalium contains many genes that are nonessential for growth in the laboratory, even though it has the smallest genome known for an autonomously replicating cell found in nature. This implied that it should be possible to produce a minimal cell that is simpler than any natural one. Whole genomes can now be built from chemically synthesized oligonucleotides and brought to life by installation into a receptive cellular environment. We have applied whole-genome design and synthesis to the problem of minimizing a cellular genome. RATIONALE Since the first genome sequences, there has been much work in many bacterial models to identify nonessential genes and define core sets of conserved genetic functions, using the methods of comparative genomics. Often, more than one gene product can perform a particular essential function. In such cases, neither gene will be essential, and neither will necessarily be conserved. Consequently, these approaches cannot, by themselves, identify a set of genes that is sufficient to constitute a viable genome. We set out to define a minimal cellular genome experimentally by designing and building one, then testing it for viability. Our goal is a cell so simple that we can determine the molecular and biological function of every gene.
RESULTS Whole-genome design and synthesis were used to minimize the 1079–kilobase pair (kbp) synthetic genome of M. mycoides JCVI-syn1.0. An initial design, based on collective knowledge of molecular biology in combination with limited transposon mutagenesis data, failed to produce a viable cell. Improved transposon mutagenesis methods revealed a class of quasi-essential genes that are needed for robust growth, explaining the failure of our initial design. Three more cycles of design, synthesis, and testing, with retention of quasi-essential genes, produced JCVI-syn3.0 (531 kbp, 473 genes). Its genome is smaller than that of any autonomously replicating cell found in nature. JCVI-syn3.0 has a doubling time of ~180 min, produces colonies that are morphologically similar to those of JCVI-syn1.0, and appears to be polymorphic when examined microscopically. CONCLUSION The minimal cell concept appears simple at first glance but becomes more complex upon close inspection. In addition to essential and nonessential genes, there are many quasi-essential genes, which are not absolutely critical for viability but are nevertheless required for robust growth. Consequently, during the process of genome minimization, there is a trade-off between genome size and growth rate. JCVI-syn3.0 is a working approximation of a minimal cellular genome, a compromise between small genome size and a workable growth rate for an experimental organism. It retains almost all the genes that are involved in the synthesis and processing of macromolecules. Unexpectedly, it also contains 149 genes with unknown biological functions, suggesting the presence of undiscovered functions that are essential for life. JCVI-syn3.0 is a versatile platform for investigating the core functions of life and for exploring whole-genome design.
Four design-build-test cycles produced JCVI-syn3.0.
(A) The cycle for genome design, building by means of synthesis and cloning in yeast, and testing for viability by means of genome transplantation. After each cycle, gene essentiality is reevaluated by global transposon mutagenesis. (B) Comparison of JCVI-syn1.0 (outer blue circle) with JCVI-syn3.0 (inner red circle), showing the division of each into eight segments. The red bars inside the outer circle indicate regions that are retained in JCVI-syn3.0. (C) A cluster of JCVI-syn3.0 cells, showing spherical structures of varying sizes (scale bar, 200 nm).
Abstract
We used whole-genome design and complete chemical synthesis to minimize the 1079–kilobase pair synthetic genome of Mycoplasma mycoides JCVI-syn1.0. An initial design, based on collective knowledge of molecular biology combined with limited transposon mutagenesis data, failed to produce a viable cell. Improved transposon mutagenesis methods revealed a class of quasi-essential genes that are needed for robust growth, explaining the failure of our initial design. Three cycles of design, synthesis, and testing, with retention of quasi-essential genes, produced JCVI-syn3.0 (531 kilobase pairs, 473 genes), which has a genome smaller than that of any autonomously replicating cell found in nature. JCVI-syn3.0 retains almost all genes involved in the synthesis and processing of macromolecules. Unexpectedly, it also contains 149 genes with unknown biological functions. JCVI-syn3.0 is a versatile platform for investigating the core functions of life and for exploring whole-genome design.
MOSCOW, March 22, 2016 — Experimental demonstration of copper components has expanded the list of potential materials suited to nanophotonic devices beyond gold and silver.
According to researchers from the Moscow Institute of Physics and Technology (MIPT), copper components are not only just as good as components based on noble metals, such as gold and silver, they can be easily implemented in integrated circuits using industry-standard fabrication processes. Gold and silver, as noble metals, may not enter into the requisite chemical reactions to create nanostructures readily and require expensive, difficult processing steps.
Nanoscale copper plasmonic waveguides on a silicon chip in a scanning near-field optical microscope (left) and their image obtained using electron microscopy (right). Courtesy of MIPT.
In nanophotonics, the diffraction limit of light is overcome by using metal-dielectric structures. Light may be converted into surface plasmon polaritons, surface waves propagating along the surface of a metal, which make it possible to switch from conventional 3D photonics to 2D surface plasmon photonics, also known as plasmonics. This allows control of light at the 100-nm scale, far beyond the diffraction limit.
Now researchers from MIPT’s Laboratory of Nanooptics and Plasmonics have found a solution to the problems posed by noble metals. Based on a generalization of the theory for so-called plasmonic metals, in 2012 they found that copper as an optical material is not only able to compete with gold, but it can also be a better alternative. Unlike gold, copper can be easily structured using wet or dry etching. This gives a possibility to make nanoscale components that are easily integrated into silicon photonic or electronic integrated circuits.
Silicon chip with nanoscale copper plasmonic components. Courtesy of MIPT.
It took more than two years for the researchers to purchase the required equipment, develop the fabrication process, produce samples, conduct several independent measurements and confirm their hypothesis experimentally.
“As a result, we succeeded in fabricating copper chips with optical properties that are in no way inferior to gold-based chips,” says the research leader Dmitry Fedyanin. “Furthermore, we managed to do this in a fabrication process compatible with the CMOS technology, which is the basis for all modern integrated circuits, including microprocessors. It’s a kind of revolution in nanophotonics.”
The researchers said that the optical properties of thin polycrystalline copper films were determined by their internal structure, and that controlling this structure to achieve and consistently reproduce the required parameters in technological cycles was the most difficult task.
Having demonstrated copper’s suitable material characteristics, as well as nanoscale manufacturing capability, the researchers believe the devices could be integrated with both silicon nanoelectronics and silicon nanophotonics. Such technologies could enable LEDs, nanolasers, highly sensitive sensors and transducers for mobile devices, and high-performance optoelectronic processors with several tens of thousands of cores for graphics cards, personal computers and supercomputers.
“We conducted ellipsometry of the copper films and then confirmed these results using near-field scanning optical microscopy of the nanostructures. This proves that the properties of copper are not impaired during the whole process of manufacturing nanoscale plasmonic components,” says Dmitry Fedyanin.
Surface plasmon polaritons can give a unique opportunity to manipulate light at a scale well below the diffraction limit reducing the size of optical components down to that of nanoelectronic circuits. At the same time, plasmonics is mostly based on noble metals, which are not compatible with microelectronics manufacturing technologies. This prevents plasmonic components from integration with both silicon photonics and silicon microelectronics. Here, we demonstrate ultralow-loss copper plasmonic waveguides fabricated in a simple complementary metal-oxide semiconductor (CMOS) compatible process, which can outperform gold plasmonic waveguides simultaneously providing long (>40 μm) propagation length and deep subwavelength (∼λ2/50, where λ is the free-space wavelength) mode confinement in the telecommunication spectral range. These results create the backbone for the development of a CMOS plasmonic platform and its integration in future electronic chips.
Broadening the productivity spectrum with middleware
Anne Paxton
March 2016—As James Beck, MT(ASCP), remembers it, middleware was introduced at his institution about the same time that the nursing department decided connectivity should be the province of the laboratory.
When the concept of docking and interfacing glucose testing devices came on the scene around the turn of the millennium, that was a turning point, says Beck, who is point-of-care testing coordinator for the University of Pittsburgh Medical Center–St. Margaret, which uses the Telcor middleware solution QML. “What had previously been a nursing-run program turned into a lab-run program just because of their unfamiliarity with the electronics and connectivity issues. Our nursing department, at least, felt, okay, this is the end of line for us—you take it on.”
At that point, middleware was considered revolutionary in its ability just to handle getting point-of-care data to the laboratory information system, never mind to the hospital information system. But between its beginnings a couple of decades ago and today, middleware has charted a more multidimensional role. It is increasingly being called upon as an agile and resourceful productivity manager, software vendors and users say.
It was about 2006–2007 that middleware’s role started to evolve from connectivity to more “productivity opportunities,” Maureen Marentette recalls. Middleware vendor Data Innovations (DI), where Marentette is director of North American sales, started in 1989 with the interfacing of instruments to the LIS as its focus. Now, products like DI’s Instrument Manager take the information that instruments provide plus what the LIS provides, and “they combine those two pieces to provide powerful management of results at a completely different level.”
With drivers available from more than 1,000 different instruments in anatomic pathology, molecular, microbiology, immunoassay, and more, DI has vastly multiplied the number of parameters it can manage, Marentette says. “We’ve got over 473 data fields that we can use to create very specific rules that are patient- and physician-specific as well as specimen-specific.”
For example, if an instrument is giving a bilirubin result, depending on the hospital, it might be a result on a newborn, a 10-year-old child, or an adult. “Whereas most LISs only handle reference ranges in years, using a middleware product you’re able to drill down to a reference range based on number of hours old, because that parameter can be significant for a newborn from a diagnostic perspective.”
Some LIS companies still use DI for their interface engine for point-to-point interfaces from each new instrument a hospital purchases into their LIS. But when a laboratory purchases Instrument Manager, Marentette notes, “if you switch from, say, a Beckman to a Sysmex hematology instrument, you can simply repurpose the connection you had for the first instrument and move it over to the new one, then just do the editing needed to recognize the codes that are unique to each instrument. It’s really just a tweaking rather than having to recreate the entire interface. So we’ve evolved from connectivity to being able to help labs with productivity and optimizing their workflow.”
These capabilities become particularly important for laboratories dealing with staffing constraints. Some Instrument Manager clients, for example, have 95 percent autoverification of their core chemistry lab results, she says, so those tests go straight into the LIS once released, and then into the HIS for interpretation by the physician.
Many labs are still using LIS autoverification protocols only about 40 percent of the time but could be doing much more, Marentette believes. “People kind of look at it over the short term. There is change management that goes into moving into a middleware product initially. It’s a cost thing, and there’s a knowledge piece, and it takes time to implement and get people to understand how much better off they would be with middleware.”
Focused specialization is what Sysmex’s middleware product WAM (Work Area Management) offers for hematology labs, says Anne Tate, MT(ASCP), IT/automation group manager at Sysmex America. “We concentrate on managing everything around the lavender top.” As a best-of-breed solution, WAM provides hematology-specific rules honed over the past 10 years and now used by more than 300 hematology labs serving 1,100 hospital sites, Tate says.
Sixty percent of Sysmex WAM clients are large integrated health networks, many of which use Sysmex instruments such as the DI-60 and its slidemaker/stainers and sorters, as well as Bio-Rad and Cellavision instruments. “We have instrument lines with one or two instruments on them, up to large systems with two automation lines. So we support both complex and the high-end markets.”
Multisite capability is one of WAM’s key features. “It’s a server-based system, so whatever results you have on site A, you’ll be able to see them on site B. So you can get delta checking and previous results and be able to correlate data from one site to another, but also apply the same standard rules. Doctors and other professionals are assured predictability in how the results are looked at and managed between sites,” Tate says.
She considers middleware as the “production floor” of the lab. “We manage all the results coming out of the instruments, applying rules and logic to either autovalidate to the LIS, or hold up results to do something further such as rerun, reflex, review, or maybe move to another Work Area Manager.”
More and more customers are demanding middleware when they purchase automation, Tate points out, and middleware is increasingly becoming an essential part of the lab. “We’ve always been important. But the LIS really depends on us to manage these combinations and multiple sites because that’s where our expertise is.”
Tate believes LISs have to concentrate on other issues. “LIS vendors really can’t know everything about vendors’ automation and all the changes and parts that go with it. LISs are concentrating their dollars on interfacing more with the EMR and medical necessity and other modules, but they depend on us for decision logic to process results for small to large automation.”
Keeping track of operator competency is another WAM capability. “With our management reports, you can search by user and track almost everything users are doing on the system, with competency based on whatever your criteria are.”
What Sysmex customers most like about the WAM middleware is “they don’t have to look at every result. It automates the process so they are assured that all the logic they would have done manually is being done consistently without a verification.”
At Dartmouth-Hitchcock Medical Center in Lebanon, NH, which includes a main hospital, several clinics, and a network of regional lab partners, Sysmex’s WAM is what allowed the laboratory to bring on the clinics and increase its volume in 2009, says Dorothy Martin, MT(ASCP), hematology supervisor.
The facility started with the Sysmex WAM 3.0, which communicates to Dartmouth-Hitchcock’s Cerner LIS and its Epic HIS. After upgrading to WAM 5.0 in November 2015, “we’ve increased our autovalidation to 87.5 percent, so that’s another 2.5 percent that we can autovalidate. Not only that, but we decreased our manual differential rate. Before, it was a little over four percent, then we brought it down to two percent. Because those manual diffs take longer, that’s less tech time we’re spending at the scope.”“Originally we were sending many tests out to a reference lab because we could not handle the volume, but Sysmex allowed us to expand and then bring on the regional partners. This is helping us to drive cost out of the system for our patients.” Her lab also has middleware for urinalysis and is exploring use of middleware in coagulation testing as a 2017 goal.
The 5.0 version also offers manager reports. “Before, in order to know my autoverification rate, I had to use my Cerner system and pull a number of different reports and export that data into Excel spreadsheets. Now, with a click of a button or two, I can mine all of that data out of my WAM system. We can create reports based on rules, based on our turnaround time, based on technologist. So it’s great. It’s quite amazing.”
Martin works with database coordinator Kari Agan who does the “rules building” and integration work with Cerner. “We actually work with Sysmex to create our rules so they do exactly what we want. We want them customized to be based on critical values in our facility.” For example, “I have different platforms in the main lab than we have in the smaller facilities. I have rules for our hematology-oncology population that are different than rules we would have for a patient who comes in for their primary care visit. WAM allows us that flexibility.”
The WAM has been a key contributor to Dartmouth-Hitchcock’s reputation as an innovator, Martin believes. “We’ve been on this Lean Six Sigma journey for a number of years, and I think that middleware and automation have helped us get to those Lean processes.” The distance among the Lebanon, Nashua, and Manchester laboratories has been a non-issue. “All the labs, even though they are as much as 70 miles apart, are tied into the same middleware on the same server and perform the same way. There’s no issue with networking at long distances and it’s done through the Dartmouth-Hitchcock secure network, so all the patient data is protected.”
With the standardization the middleware has allowed among the technologists, and the growth of the network and technical staff that it has facilitated, “we are really proud of how much Sysmex has helped us improve the processes in our lab,” Martin says.
Kerstin Halverson, point-of-care coordinator for Children’s Hospitals and Clinics of Minnesota, uses Telcor’s QML Data Management and Connectivity Solution to interface five instruments and seven manual device types for the roughly 120,000 POC tests per year, encompassing glucose, hemoglobin, rapid strep, pregnancy, blood gases, and urine dipsticks. “We have Sunquest as our LIS and Cerner as our HIS, and everything point of care flows through Telcor from either a device or via Telcor’s offshoot product called WebMRE for manual result entry.”
She handles most every issue involving the connection between point of care, middleware, and the LIS. “I’m the point person when we have to upgrade servers or add devices. I work pretty specifically with the vendors to make sure everything gets established and connected properly.” Over the years, her lab has gone from having only glucoses and blood gases interfaced to having five device types interfaced, and manual testing is electronically entered now too.
Halverson
Children’s Hospitals and Clinics, with its 2,200 credentialed operators, was the first of Telcor’s customers to go live with an e-learning interface between Telcor and the hospital’s e-learning software, PeopleSoft. “As a piece of this interface, tracking attendance at the annual competency fair that all staff must attend is now done electronically. This allows us to monitor point-of-care testing competency efficiently in one spot,” Halverson says.
This project required considerable lead time. “It was not something we switched on one day. It was probably a three-and-a-half-year project with Telcor to get all my POC courses in a table and then on a daily basis, using PeopleSoft, have that information be updated with all the additions, deletions, department changes, course passing and failing, and so on.” The whole process is now automatic, Halverson says, which is useful for dealing with so many operators over 11 different device types.
In her previous job, more than 13 years ago, “we did not have any middleware,” she notes. “At that time, we had glucometers connected through fax machines, not on the hospital’s network. But results weren’t electronically transferred to charts yet; the nurses would just see results on the device and chart them. There was still a lot of discussion about whether to bill for point of care back then, so some institutions probably did not worry about interfacing and getting things electronically recorded the way things have evolved now.” These days, “IT is one of my major focuses. I can’t do point of care without it.”
In her work as POC coordinator, competency takes a huge chunk of her time—for example, keeping records of diplomas for anyone who is doing moderately complex testing. She says Telcor is working on a way to store those records centrally in its database. “After competency, I would say I spend the most time making sure we’re meeting all the regulations on a daily basis, and by that I mean monitoring QC, making sure the instrumentation is up and functioning properly, and troubleshooting issues.”
A change she has greatly appreciated was moving the Telcor software from a single PC at her desk to a server. “I had two different campuses to travel between, and as much as I try to clone myself, I can’t. So having it moved to a server and having access to the server if I’m somewhere else has been a huge jump forward. I can do troubleshooting pretty much anywhere I need to go now.”
Halverson likens POC to a spiderweb with middleware at the center. “For me, the Telcor middleware ends up being the center of the web to help pull everything into one place where I can manage it. It passes everything along to the LIS, then eventually to the HIS, but it helps cut down on a lot of potential problems by locking people out who aren’t trained and keeping the interfaces up. It’s a one-stop shop.”
Today, some POC devices have their own data-management systems and others don’t, but Telcor is able to interface with them either way, says UPMC’s James Beck. “I can’t say that Telcor makes those systems obsolete. But from my perspective, the fewer systems I need to get into, the easier it is to do what I need to do. Which is basically oversee what’s going on in the system, make sure quality checks are being done, and make sure data is moving through the system and getting to the end users. The fewer systems there are for that data, the more likely the data is going to end up on the chart so that clinical decisions can be made on it.”
Most devices, he has found, are interfaceable through Telcor, which is installed in about 1,900 U.S. and Canadian hospitals. UPMC uses Abbott’s Precision Xceed Pro for glucose, and has seen unprecedented growth in the number of tests it conducts using Abbott i-Stat in the past nine months. The connectivity issues have been for the most part already resolved—“we have just been adding a lot more tests to the menu.”
The ABL blood gas analyzers, Beck says, are considered by many to be laboratory instruments, not point-of-care devices, because they are tabletops. But “this is another example of Telcor flexibility, because before, many of the instruments were being run by respiratory therapists and they had a hard time internalizing how to use that lab interface. They didn’t get enough repeat experience with it, the way a lab person would, and the standard lab interface was really failing them. They could not seem to get the hang of it as far as the flow of data.”Siemens’ Clinitek automatically uploads standard urinalysis dipstick and urine hCG testing results to Telcor and in turn to the EMR, Beck says. “So a person who is multitasking does not have to stay there. They can load up a device and walk away and know that the result is going to automatically upload.” Similarly, Accriva’s Hemochron Signature Elite is used for activated clotting time, and Avoximeter 1000E, another Accriva device, is used for co-oximetry testing and cardiac catheterization labs. Both also connect to Telcor.
Beck approached Telcor about taking over the interface, and the company appointed a dedicated analyst to work it out. “Then our next hurdle was actually to convince the LIS folks to allow us to do it. I said, ‘I can make life so much easier for these respiratory therapists if we can send the information through a middleware system like Telcor as opposed to a standard lab interface, which is full of rules and things to remember. I can cut 20-plus steps and mouse clicks and verifications out of their process.’ So it took a lot of convincing but finally they said, okay, go ahead and try it. And that actually got us a patient safety award for our facility improvement process. It was copied at other hospitals within our health system because they had the same dilemmas and we had a proven model that worked.”
There has been downtime, he says, but not due to the middleware. “Recently, our centralized information support actually disconnected our Telcor server so it stopped transmission unexpectedly. It ended up getting reported by our ED where a nurse was doing a urine dip and knew it should have crossed by a certain amount of time.” So temporarily, no data were moving.
But, he says, “The beauty of the computer age is that everything is basically held in a buffer so there’s no data loss. Everything performed during a downtime does get captured ultimately.” However, with one system processing information from 19 hospitals, catching up can take quite a while. “In fact, one of the things we requested was that they expand memory so the catch-up is quicker when there is some backlog of processing that needs to be done.”
Some operators are actually physicians—typically anesthesiologists—and Beck has found there is better appreciation among physicians generally about middleware. “Definitely five or 10 years ago, they could afford to be more distant from middleware awareness, but now they are aware in making sure the data gets to the chart.”
It’s a good thing, too, because point of care is growing. In fact, “we’re seeing explosions in point of care that are often exceeding the ability of one person to oversee.” For this reason, Beck is pleased that his middleware vendor is able to keep pace with the state of technology and even stay one step ahead. Middleware capability like that has become necessary, he says.
The potential customer base for middleware is wide-ranging, says Data Innovations’ Marentette. DI has diverse customers that include the Department of Defense and Department of Veterans Affairs, large academic health science centers, and reference labs. But the company is finding a market as well in smaller and midrange hospitals, which are increasingly looking at DI’s productivity and quality suite modules and its “management through metrics” data mining.
On the quality assurance side, Marentette points to Instrument Manager’s “moving averages” program which helps monitor how instruments are performing between quality control challenges. “If there is a problem when the moving averages go out, you can first of all stop testing and prevent those results from being released to the LIS. Therefore you have fewer edited reports. That really helps on the quality side. And using our specimen management workspace for autoverification, you can put in instructions on what to do when a particular value comes up.”The data mining involves pulling data out of the specimen management database to conduct population or research studies. “We’ve now added our laboratory intelligence, which enables real-time metrics monitoring, so you can look at what’s going on in your lab five minutes ago, identify issues, and drill down to what the challenge is.”
Middleware’s return on investment is twofold, Marentette believes. “It’s not just within the lab itself, but also what it means to the rest of the hospital organization and the ability to enhance the patient experience. For example, quicker turnaround time on tests for the emergency department lets physicians make faster patient diagnostic decisions, bringing better patient experience and contributing to the overall revenue of the organization. Then, within the lab itself, if you are using the autoverification, you can redeploy your staff and take on more work by bringing on new tests or doing some of the centralized testing you maybe sent to another lab before.”
Through its JResultNet software, which DI purchased from Dawning Technologies more than two years ago, the same middleware benefits are available to physician office labs, and Laboratory Production Manager is DI’s parallel product in the European marketplace. DI itself was acquired in 2015 by Roper Technologies, which also owns LIS giant Sunquest Information Systems. But DI is still a standalone company, Marentette emphasizes, noting that a range of LISs (including Epic’s Beaker) as well as IVD manufacturers use Instrument Manager as their connectivity and middleware solution.
Instrument Manager’s usefulness also becomes apparent when hospitals or integrated delivery networks do acquisitions. “We have the ability to interface multiple LISs into the same IM database, so if a hospital acquires another hospital and wants to put things together on the same system, you can do that seamlessly through one of our interfaces. The middleware is able to keep orders and results reporting management straight between systems. So it does make consolidation much simpler and streamlined.”
With the changing configuration of IT in health care, Sysmex’s Anne Tate sees a changing role for middleware ahead. “WAM provides everything the LIS needs to report immediately to the EMR. In some instances, we’re seeing where the WAM can go into clinics or small labs that don’t have an LIS, so eventually we may have to connect the WAM directly to the EMR. We’ve never done it yet, but we’re seeing movement in that respect.” She doesn’t expect it in the hospital environment. “But in standalone clinics, in nontraditional or non-hospital–supported environments, I do see it happening. We’ve already had requests for that.”
Middleware does come with a cost, but customers understand middleware’s value, Tate says. “We don’t get much pushback anymore on the cost of middleware because they see the value and return on investment: They’ll get vastly improved turnaround time, they can reallocate FTEs, and they get standardized results and less error.”
Abstract: Cabazitaxel provided a survival advantage compared with mitoxantrone in patients with castration-resistant prostate cancer refractory to docetaxel. Grade 3 to 4 (G3–4) neutropenia and febrile neutropenia were relatively frequent in the registrative XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC) trial, but their incidence was lower in the Expanded Access Program (EAP). Although cumulative doses of docetaxel are associated with neuropathy, the effect of cumulative doses of cabazitaxel is unknown. In this retrospective review of prospectively collected data, the authors assessed “per cycle” incidence and predictors of toxicity in the Italian cohort of the EAP, with a focus on the effect of cumulative doses of cabazitaxel.
The study population consisted of 218 Italian patients enrolled in the cabazitaxel EAP. The influence of selected variables on the most relevant adverse events identified was assessed using a Generalized Estimating Equations model at univariate and multivariate analysis.
“Per cycle” incidence of G 3 to 4 neutropenia was 8.7%, whereas febrile neutropenia was reported in 0.9% of cycles. All events of febrile neutropenia occurred during the first 3 cycles. Multivariate logistic regression analysis showed that higher prior dose of cabazitaxel was associated with decreased odds of having G3 to 4 neutropenia (OR = 0.90; 95% CI: 0.86–0.93; P < 0.01), febrile neutropenia (OR = 0.52; 95% CI: 0.34–0.81; P < 0.01) and G3 to 4 anemia (OR = 0.93; 95% CI: 0.86–1; P = 0.07). Patients with a body surface area >2 m2presented increased odds of having G 3 to 4 neutropenia (OR = 0.93; 95% CI: 0.86–1; P = 0.07), but decreased odds of having G3 to 4 anemia.
Among the toxicities assessed, the authors did not identify any that appeared to be associated with a higher number of cabazitaxel cycles delivered. Prior cumulative dose was associated with reduced G3 to 4 neutropenia and anemia. The apparent protective effect associated with higher doses of cabazitaxel is likely to be affected by early dose reduction and early toxicity-related treatment discontinuation. Because this analysis is limited by its retrospective design, prospective trials are required to assess the optimal duration of cabazitaxel treatment.
Several agents provide a survival advantage and symptom palliation in patients with docetaxel-refractory, metastatic castration-resistant prostate cancer (CRPC).1,2 These agents include cabazitaxel, enzalutamide, abiraterone, and radium 223.1,2 Presently, the treatment choice is influenced by several factors, including physician’s and patient’s preference, drug availability, reimbursement policies, performance status, organ function, as well as expected toxicity profile, but comparative efficacy data are lacking. Similarly to other taxane agents, cabazitaxel is frequently associated with bone marrow toxicity. In the XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC) trial,3 grade (G) 3–4 neutropenia and febrile neutropenia were reported in 82% and 8% of patients treated with cabazitaxel, respectively, whereas these adverse events were respectively reported in 33.9% and 5% of the Italian patients enrolled in the Expanded Access Program (EAP).4 Conversely, G3 to 4 neuropathy was a rare event both in the TROPIC and in the EAP study.3–5 To further analyze the safety profile of cabazitaxel, we retrospectively reviewed prospectively collected data about the most common toxicities reported in the Italian cohort of the EAP. “Per cycle,” rather than “per patient” incidence was computed, and an explorative analysis was performed to investigate potential predictors of toxicity. In view of the risk of cumulative toxicity (neuropathy) associated with docetaxel,6 the effect of prior cumulative dose of cabazitaxel was investigated in a multivariable model along with other potential predictive factors.
Treatment
At the time of the analysis, 1494 cycles had been administered to 218 patients included in the entire cohort, whereas a total of 553 cycles had been administered to 61 patients with a body surface area >2 sqm. Patients were administered a median of 6.0 (interquartile range: IR, 4–10) cycles. The median dose delivered was 24.00 mg/sqm (IR: 22.3–24.7). Each patient received a median cumulative dose of 149.9 mg/sqm (IR: 92.8–232.2). Sixty-four patients (29.6%) received at least 10 cycles (Table 2). Primary G-CSF prophylaxis was administered in 87 patients (39.9%), whereas G-CSF secondary prophylaxis was administered in 76 patients (34.8%). Therapy was delayed in 274 cycles, which was because of cabazitaxel toxicity only in 65 (23.7%) of these. Dose was reduced 52 times (Table 2), and in 45 cases dose reduction was because of cabazitaxel adverse events. In the safety population, the main reason for treatment discontinuation was disease progression (43.1%), followed by adverse event (24.5%) and physician’s decision (18.5%). Of note, in the subgroup of 64 patients receiving at least 10 cycles, 51.6% discontinued cabazitaxel because of investigator’s decision, and only 1 patient (1.6%) discontinued for toxicity (Table 3).
Table 2 Image Tools
Table 3 Image Tools
Safety
Overall incidence of toxicity per cycle is detailed in Table 4. Main G3 to 4 hematologic toxicities were neutropenia and anemia. The “per cycle” incidence rate of G3 to 4 neutropenia was 8.7%, whereas febrile neutropenia occurred only in 0.9% of all cycles and it was an early event, occurring during the first 3 cycles only (Figure 1). Main non hematologic toxicities were G2 asthenia/fatigue and G2 diarrhea, occurring in 3.7% and 0.8% of cycles, whereas G3 to 4 asthenia/fatigue and G3 to 4 diarrhea occurred in 1.8% and 0.4% of cycles. Four adverse events had a per cycle incidence >1% and were selected for univariate (Tables 5 and 6) and multivariate (Table 7) analysis GEE logistic regression analysis. Febrile neutropenia was also assessed because of its clinical relevance. Multivariate logistic regression analysis showed a significant reduction of the odds of having G3 to 4 neutropenia (−10%), febrile neutropenia (−48%) and anemia (−7%), per 10 mg/m2 increase of total prior dose of cabazitaxel. A body surface area >2 m2 was associated with increased odds of having G3 to 4 neutropenia (OR: 2.58; 95% CI = 1.50–4.43; P < 0.01), but decreased odds of having G3 to 4 anemia (OR: 0.10; 95% CI = 0.02–0.52; P < 0.01). Age as a continuous variable was not associated to an increased rate of any of the adverse events analyzed. Of note, higher previous dose of docetaxel appeared to be associated with a slightly, but statistically significant decreased odds of having G 3–4 anemia (OR: 0.859; 95% CI = 0.73−1.00; P = 0.06), G3 to 4 neutropenia (OR: 0.95; 95% CI = 0.91–0.99; P = 0.03), and G2 and G3 to 4 fatigue/asthenia (OR: 0.90; 95% CI = 0.84–0.96; P < 0.01). Twelve patients died within 30 days since last cabazitaxel treatment for causes judged to be unrelated to cabazitaxel by the local investigators. Three patients died as a result of treatment-emergent adverse events possibly related to cabazitaxel treatment. Of these 3 patients, 1 patient died after 1 cycle because of respiratory and renal failure, 1 patient died after 2 cycles because of respiratory failure and the third patient died after 3 cycles because of pancytopenia and hepatic failure.
Table 4 Image Tools
Figure 1 Image Tools
Table 5 Image Tools
Table 6 Image Tools
Table 7 Image Tools
DISCUSSION
In a cohort of 746 patients enrolled throughout Europe in the cabazitaxel EAP, G3 to 4 neutropenia, febrile neutropenia and G3 to 4 diarrhea occurred in 17%, 5.4% and 2.8% of patients, respectively.5The discrepancy of these results with those obtained in the TROPIC trial has been explained by study differences in patient characteristics, frequency of hematologic assessment, as well as proactive management of adverse events of cabazitaxel.5 Dose reductions were also more frequent in the EAP compared with the TROPIC trial (17.4% versus 12%) and may also have affected the safety profile.4,5 Furthermore, in the EAP versus the TROPIC trial, 1% versus 2% of patients died as a result of neutropenia, respectively. In our study cohort, only 3 deaths (≈1.3%) possibly related to cabazitaxel treatment were reported, whereas 12 patients died within 30 days since the last cabazitaxel dose for reasons, which were definitely judged to be unrelated to cabazitaxel by the local investigator. Treatment delay, which was reported in 274 cycles, was because of cabazitaxel toxicity approximately only in one-fourth of cases and to “other causes” in 180 cases. This finding may be related to the influence of logistic reasons (eg, waiting list) or patient’s compliance as a common cause of treatment delay. Dose reduction, which was reported in 52 cases, was mainly because of cabazitaxel adverse events. Ongoing phase III trials are assessing whether lower doses of cabazitaxel are equally effective and better tolerated than higher doses.7 In the analysis of our study cohort, the dose of 25 versus 20 mg/m^2 was associated with increased risk of G3 to 4 neutropenia (OR = 1.8; CI = 1.0–3.55; P = 0.049) in the multivariable model, but this result is likely to be confounded by patients who received the 25 mg/m^2 dose and then permanently interrupted treatment for toxicity. Differently from the results obtained in other series,5,8 we have not found the use of G-CSF to be associated with decreased incidence of G3 to 4 neutropenia, possibly because frailer patients are both more likely to experience G 3–4 neutropenia and to receive G-CSF prophylaxis. Similarly to the results obtained in the work by Heidenreich et al,8 we found that prior cumulative dose of docetaxel was associated with lower odds of G3 to 4 neutropenia. Reintroduction of docetaxel was reported to be a feasible option in selected patients, although docetaxel rechallenge is not supported by randomized-controlled trials.9,10 A favorable association of prior cumulative dose of docetaxel with G3 to 4 anemia and G 2–4 asthenia/fatigue was also reported, along with an overall low “per cycle incidence” of febrile neutropenia and G3 to 4 diarrhea and neutropenia. These toxicities do not recur throughout the course of the treatment in most of the cases. Higher prior cumulative dose of cabazitaxel was associated with lower risk of G3 to 4 neutropenia and febrile neutropenia, and the majority of G3 to 4 events of bone marrow toxicity occurred during the first 5 cycles. Heidenreich et al5 compared toxicities associated with first versus subsequent doses and reported higher odds of severe neutropenia at the first cycle versus subsequent cycles. This result is consistent with existing data.11 In our work, we found no evidence of cumulative toxicity for any of the adverse events considered in a multivariable model assessing their association with prior cumulative dose of cabazitaxel. In this regard, it is noteworthy that of the 64 patients receiving at least 10 cycles, only 1 (1.5%) had to interrupt treatment because of toxicity and approximately 50% (33 patients, 51.6%) suspended treatment because of investigator’s decision. Although continuation of docetaxel after 10 cycles does not appear to yield any benefit,12 the optimal duration of cabazitaxel treatment in nonprogressive patients is unknown.
No studies have been specifically conducted to assess the additional benefit associated with continuation of cabazitaxel treatment beyond 10 cycles. Nevertheless, the risk of rapidly progressive disease following cabazitaxel interruption must be carefully considered and discussed with the patient, especially in those with high disease burden who may experience clinical deterioration and be unable to resume systemic therapy.13 We also reported that patients with a body surface area greater than 2 m2 showed an OR of 2.58 for G3 to 4 neutropenia, but an OR of 0.1 for G3 to 4 anemia. We are unable to provide an explanation for this finding at the present time.
Our analysis has a number of limitations, including its retrospective nature, the arbitrary selection of the variables included in the multivariable model, the lack of sample size calculation, as well as the lack of assessment of peripheral neuropathy, which is a clinically relevant adverse event in patients receiving chemotherapy after first-line docetaxel6,14. Furthermore, the number of patients receiving >10 cycles was small and no patient received more than 17 cycles. In this regard, it must be noted that a report of 4 patients with CRPC cancer treated with >15 cycles of cabazitaxel found that peripheral neuropathy was the only clinically significant toxicity associated with cumulative doses.15 There is no established clinical variable predictive of cabazitaxel efficacy in the postdocetaxel setting, although preliminary evidence by our work group suggest that cabazitaxel could be more effective than novel hormonal agents in a number of clinical settings, which include patients with brain metastases,16 high Gleason score at diagnosis,17 and primary refractoriness to docetaxel.18 Similarly to other antineoplastic agents (eg, sunitinib19), cabazitaxel may also be more effective in patients showing greater treatment-related toxicity. A recent post-hoc analysis of the TROPIC trial suggested that treatment outcomes, in terms of Overall Survival, Progression Free Survival, and Prostate Specific Antigen response, were improved in patients developing G3 to 4 neutropenia.20 Our analysis confirms that the safety profile of cabazitaxel compares favorably with that of docetaxel, which was associated with G3 to 4 diarrhea, nail changes, and peripheral neuropathy in approximately 30% of the patients.21 Among the toxicities assessed, we did not identify any that appeared to be dependent on the cumulative dose of cabazitaxel priorly administered. As this finding is likely to be influenced by early dose reduction and early toxicity-related treatment discontinuation, it must be confirmed by prospective larger trials in patients with metastatic castration resistant prostate cancer.
REFERENCES
1. Omlin A, Pezaro C, Mukherji D, et al. Improved survival in a cohort of trial participants with metastatic castration-resistant prostate cancer demonstrates the need for updated prognostic nomograms. Eur Urol 2013; 64:300–306.
2. Rescigno P, Buonerba C, Bellmunt J, et al. New perspectives in the therapy of castration resistant prostate cancer. Curr Drug Targets 2012; 13:1676–1686.
3. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376:1147–1154.
4. Bracarda S, Gernone A, Gasparro D, et al. Real-world cabazitaxel safety: the Italian early-access program in metastatic castration-resistant prostate cancer. Future Oncol 2014; 10:975–983.
5. Heidenreich A, Bracarda S, Mason M, et al. Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer: results of the European compassionate-use programme. Eur J Cancer 2014; 50:1090–1099.
6. Oudard S, Kramer G, Caffo O, et al. Docetaxel rechallenge after an initial good response in patients with metastatic castration-resistant prostate cancer. BJU Int 2015; 115:744–752.
9. Di Lorenzo G, Buonerba C, Faiella A, et al. Phase II study of docetaxel re-treatment in docetaxel-pretreated castration-resistant prostate cancer. BJU Int 2011; 107:234–239.
10. Buonerba C, Palmieri G, Di Lorenzo G. Docetaxel rechallenge in castration-resistant prostate cancer: scientific legitimacy of common clinical practice. Eur Urol 2010; 58: 636-.
11. Culakova E, Thota R, Poniewierski MS, et al. Patterns of chemotherapy-associated toxicity and supportive care in US oncology practice: a nationwide prospective cohort study. Cancer Med 2014; 3:434–444.
12. Pond GR, Armstrong AJ, Wood BA, et al. Evaluating the value of number of cycles of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer. Eur Urol 2012; 61:363–369.
13. Di Lorenzo G, Buonerba C, de Placido S. Rapidly progressive disease in a castration-resistant prostate cancer patient after cabazitaxel discontinuation. Anticancer Drugs 2015; 26:236–239.
14. Buonerba C, Federico P, D’Aniello C, et al. Phase II trial of cisplatin plus prednisone in docetaxel-refractory castration-resistant prostate cancer patients. Cancer Chemother Pharmacol 2011; 67:1455–1461.
Scientists based at the Translational Genomics Research Institute have published a review heralding the promise of RNA sequencing (RNA-seq) for precision medicine. The scientists also note that progress will be needed on analytical, bioinformatics, and regulatory fronts, particularly in light of the transcriptome’s variety, dynamism, and wealth of detail. In this image, one aspect of RNA-seq is shown, the alignment with intron-split short reads. It reflects the alignment of mRNA sequence obtained via high-throughput sequencing and the expected behavior of the alignment to the reference genome when the read falls in an exon–exon junction. [Rgocs, Wikipedia] http://www.genengnews.com/Media/images/GENHighlight/thumb_Mar22_2016_Rgocs_RNASeqAlignment1872484040.jpg
It’s not an either/or situation. Both DNA sequencing and RNA sequencing hold clinical promise—diagnostically, prognostically, and therapeutically. It must be said, however, that RNA sequencing reflects the dynamic nature of gene expression, shifting with the vagaries of health and disease. Also, RNA sequencing captures more biochemical complexity, in the sense that it allows for the detection of a wide variety of RNA species, including mRNA, noncoding RNA, pathogen RNA, chimeric gene fusions, transcript isoforms, and splice variants, and provides the capability to quantify known, predefined RNA species and rare RNA transcript variants within a sample.
All these potential advantages were cited in a paper that appeared March 21 in Nature Reviews Genetics, in an article entitled, “Translating RNA Sequencing into Clinical Diagnostics: Opportunities and Challenges.” The paper, contributed by scientists based at the Translational Genomics Research Institute (TGen), was definitely optimistic about the clinical utility of RNA sequencing, but it also highlighted the advances that would have to occur if RNA sequencing is to achieve its promise.
In general, the very things that make RNA sequencing so interesting are the same things that make it so challenging. RNA sequencing would take the measure of a world—the transcriptome—that is incredibly rich. To capture all the relevant subtleties of the transcriptome, scientists will have to develop sensitive, precise, and trustworthy analytical techniques. What’s more, scientists will need to find efficient and reliable means of processing and interpreting all of the transcriptome data they will collect. Finally, they will need to continue integrating RNA-based knowledge with DNA-based knowledge. That is, RNA sequencing results can be used to guide the interpretation of DNA sequencing results.
In their Nature Reviews Genetics paper, the TGen scientists review the state of RNA sequencing and offer specific recommendations to enhance its clinical utility. The TGen scientists make a special point about the promise held by extracellular RNA (exRNA). Because exRNA can be monitored by simply taking a blood sample, as opposed to taking a tumor biopsy, it could serve as a noninvasive diagnostic indicator of disease.
“Detection of gene fusions and differential expression of known disease-causing transcripts by RNA-seq represent some of the most immediate opportunities,” wrote the authors. “However, it is the diversity of RNA species detected through RNA-seq that holds new promise for the multi-faceted clinical applicability of RNA-based measures, including the potential of extracellular RNAs as non-invasive diagnostic indicators of disease.”
The first test measuring exRNA was released earlier this year, the paper said, for use measuring specific exRNAs in lung cancer patients. And, the potential for using RNA-seq in cancer is expanding rapidly. Commercial RNA-seq tests are now available, and they provide the opportunity for clinicians to profile cancer more comprehensively and use this information to guide treatment selection for their patients.
In addition, the authors reported on several recent applications for RNA-seq in the diagnosis and management of infectious diseases, such as monitoring for drug-resistant populations during therapy and tracking the origin and spread of the Ebola virus.
Despite these advances, the authors also sounded a few cautionary notes. “There are currently few agreed upon methods for isolation or quantitative measurements and a current lack of quality controls that can be used to test platform accuracy and sample preparation quality,” they wrote. “Analytical, bioinformatics, and regulatory challenges exist, and ongoing efforts toward the establishment of benchmark standards, assay optimization for clinical conditions and demonstration of assay reproducibility are required to expand the clinical utility of RNA-seq.”
Overall, the authors remain hopeful that precision medicine will embrace RNA sequencing. For example, lead author Sara Byron, research assistant professor in TGen’s Center for Translational Innovation, said, “RNA is a dynamic and diverse biomolecule with an essential role in numerous biological processes. From a molecular diagnostic standpoint, RNA-based measurements have the potential for broad application across diverse areas of human health, including disease diagnosis, prognosis, and therapeutic selection.”
RNA Bacteriophages May Open New Path to Fighting Antibiotic-Resistant Infections
Micrograph image of RNA bacteriophages attached to part of the bacterium E. coli. A new study at Washington University School of Medicine in St. Louis suggests that bacteriophages made of RNA, a close chemical cousin of DNA, likely play a much larger role in shaping the bacterial makeup of worldwide habitats than previously recognized. [Graham Beards/Wikimedia]
Scientists at Washington University School of Medicine in St. Louis report that bacteriophages made of RNA likely play a much larger role in shaping the bacterial makeup of worldwide habitats than previously recognized. Their study (“Hyperexpansion of RNA Bacteriophage Diversity”), published in PLOS Biology, identified 122 new types of RNA bacteriophages in diverse ecological niches, providing an opportunity for scientists to define their contributions to ecology and potentially to exploit them as novel tools to fight bacterial infections, particularly those that are resistant to antibiotics.
“Lots of DNA bacteriophages have been identified, but there’s an incredible lack of understanding about RNA bacteriophages,” explained senior author David Wang, Ph.D., associate professor of molecular microbiology. “They have been largely ignored—relatively few were known to exist, and for the most part, scientists haven’t bothered to look for them. This study puts RNA bacteriophages on the map and opens many new avenues of exploration.”
Dr. Wang estimates that of the more than 1500 bacteriophages that have been identified, 99% of them have DNA genomes. The advent of large-scale genome sequencing has helped scientists identify DNA bacteriophages in the human gut, skin, and blood, as well as in the environment, but few researchers have looked for RNA bacteriophages in those samples (doing so requires that RNA be isolated from the samples and then converted back to DNA before sequencing).
As part of the new study, first author and graduate student Siddharth Krishnamurthy, and the team, including Dan Barouch, M.D., Ph.D., of Beth Israel Deaconess Medical Center and Harvard Medical School, identified RNA bacteriophages by analyzing data from samples taken from the environment, such as oceans, sewage, and soils, and from aquatic invertebrates including crabs, sponges, and barnacles, as well as insects, mice, and rhesus macaques.
RNA bacteriophages have been shown to infect Gram-negative bacteria, which have become increasingly resistant to antibiotics and are the source of many infections in health care settings. But the researchers also showed for the first time that these bacteriophages also may infect Gram-positive bacteria, which are responsible for strep and staph infections as well as MRSA (methicillin-resistant Staphylococcus aureus).
“What we know about RNA bacteriophages in any environment is limited,” Dr. Wang said. “But you can think of bacteriophages and bacteria as having a predator–prey relationship. We need to understand the dynamics of that relationship. Eventually, we’d like to manipulate that dynamic to use phages to selectively kill particular bacteria.”
Bacteriophage modulation of microbial populations impacts critical processes in ocean, soil, and animal ecosystems. However, the role of bacteriophages with RNA genomes (RNA bacteriophages) in these processes is poorly understood, in part because of the limited number of known RNA bacteriophage species. Here, we identify partial genome sequences of 122 RNA bacteriophage phylotypes that are highly divergent from each other and from previously described RNA bacteriophages. These novel RNA bacteriophage sequences were present in samples collected from a range of ecological niches worldwide, including invertebrates and extreme microbial sediment, demonstrating that they are more widely distributed than previously recognized. Genomic analyses of these novel bacteriophages yielded multiple novel genome organizations. Furthermore, one RNA bacteriophage was detected in the transcriptome of a pure culture of Streptomyces avermitilis, suggesting for the first time that the known tropism of RNA bacteriophages may include gram-positive bacteria. Finally, reverse transcription PCR (RT-PCR)-based screening for two specific RNA bacteriophages in stool samples from a longitudinal cohort of macaques suggested that they are generally acutely present rather than persistent.
Bacteriophages (viruses that infect bacteria) can alter biological processes in numerous ecosystems. While there are numerous studies describing the role of bacteriophages with DNA genomes in these processes, the role of bacteriophages with RNA genomes (RNA bacteriophages) is poorly understood. This gap in knowledge is in part because of the limited diversity of known RNA bacteriophages. Here, we begin to address the question by identifying 122 novel RNA bacteriophage partial genome sequences present in metagenomic datasets that are highly divergent from each other and previously described RNA bacteriophages. Additionally, many of these sequences contained novel properties, including novel genes, segmentation, and host range, expanding the frontiers of RNA bacteriophage genomics, evolution, and tropism. These novel RNA bacteriophage sequences were globally distributed from numerous ecological niches, including animal-associated and environmental habitats. These findings will facilitate our understanding of the role of the RNA bacteriophage in microbial communities. Furthermore, there are likely many more unrecognized RNA bacteriophages that remain to be discovered.
An image of a gold chip that traps ions for use in quantum computing has come first in EPSRC’s third science photography competition.
‘Microwave ion-trap chip for quantum computation’, by Diana Prado Lopes Aude Craik and Norbert Linke, from the University of Oxford, shows the chip’s gold wire-bonds connected to electrodes which transmit electric fields to trap single atomic ions a mere 100 microns above the device’s surface. The image, taken through a microscope in one of the university’s cleanrooms, came first in the Eureka category as well as winning overall against many other stunning pictures, featuring research in action, in the EPSRC competition – now in its third year.
Doctoral student Diana Prado Lopes Aude Craik, explained how the chip works: “When electric potentials are applied to the chip’s gold electrodes, single atomic ions can be trapped. These ions are used as quantum bits (‘qubits’), units which store and process information in a quantum computer. Two energy states of the ions act as the ‘0’ and ‘1’ states of these qubits.
Slotted electrodes on the chip deliver microwave radiation to the ions, allowing us to manipulate the stored quantum information by exciting transitions between the ‘0’ and ‘1’ energy states. “This device was micro-fabricated using photolithography, a technique similar to photographic film development. Gold wire-bonds connect the electrodes to pads around the device through which signals can be applied. You can see the wire-bonding needle in the top-left corner of the image. The Oxford team recently achieved the world’s highest-performing qubits and quantum logic operations.”
The development of the ion-trap chip was funded jointly by the EPSRC and the US Army Research Office.
The competition’s five categories were: Eureka, Equipment, People, Innovation, and Weird and Wonderful. Winning images feature:
A spectacular 9.5 meter wave created to wow crowds at the FloWave Ocean Energy Research Facility at the University of EdinburghAn iCub humanoid robot learning about how to play from a baby as part of robotics research taking place at Aberystwyth UniversityThe intense, blinding light of plasma formed by an ultrafast laser being used to process glass at the EPSRC Centre for Innovative Manufacturing in Ultra Precision at the University of CambridgeA beautiful rotating jet of viscoelastic liquid water resembling a spinning dancer that demonstrates the effect of adding a tiny amount of polymer to water and an example of fluid dynamics research at Imperial College London
One of the judges was Professor Robert Winston, he said: “This competition helps us engage with academics and these stunning images are a great way to connect the general public with research they fund, and inspire everyone to take an interest in science and engineering.”
To contact New Medicine, request a no-obligation 2-week access to nm|OK or to order nm|OK, please visit http://www.newmedinc.com.
Oncology Drug Development and Personalized Medicine Knowledgebase
Comprehensive resource covering all aspects of the global oncology sector
Detailed profiles of 5,000 new drugs in development and approved drugs worldwide
Detailed profiles of 2,250 companies worldwide developing and marketing therapeutic/in vivo imaging agents and/or in vitro diagnostics
Over 1,180 molecular markers identified as diagnostic and treatment targets
Thousands of affiliations/licensing agreements/spin-offs involving commercial entities and most major institutions worldwide
LAKE FOREST, Calif., April 12, 2016 /PRNewswire/ — New Medicine (http://www.newmedinc.com) has launched New Medicine’s Oncology KnowledgeBASE (http://www.nmok.net), a highly disciplined relational database that provides a comprehensive view of the global oncology sector.
nm|OK New Drugs and Marketed Drugs profiles
nm|OK provides detailed profiles of over 5,000 distinct drugs/in vivo imaging agents in development and on the market by:
developer/affiliate (over 1,000 pipelines)
generic name/brand name/other designation
technology/class
mechanism of action
cancer indications; over 100 indications
clinical indications; hundreds of indications
administration route
molecular target
biomarker/companion diagnostics
delivery technology
preclinical development status
clinical development by phase and status
clinical history, including trial protocols, interim and final results
New Medicine’s Oncology KnowledgeBASE (nm|OK) provides a comprehensive view of the status of the global oncology drug development and personalized medicine sector in terms of:
companies developing and marketing therapeutic/in vivo imaging agents and/or in vitro diagnostics
institutions/non-profits with affiliations/agreements in this sector
therapeutic agents in development or on the market globally (over 4,500 drugs in development)
molecular targets of approved drugs and of those currently evaluated in preclinical/clinical trials or identified as playing a role in cancer
From June 1995 to August 2008, New Medicine published Future Oncology, a comprehensive analytical newsletter tracking the evolution of global drug development in oncology. Despite of the incredible amount of effort in this area in the last 20 years, we currently face the same problems that were being tackled then, namely a lack of understanding as to the origins and mechanisms of malignancy. Despite the incredible global effort in this area and the remarkable scientific breakthroughs in biology and medicine, advanced cancer has remained an incurable disease. However, although cancer remains undefeated, treatment of this disease has created a huge global market comprised of drugs that, with few exceptions, provide marginal relief at a very high cost. Because the origins of this disease have remained obscure, there have been numerous approaches popularized at different times as to its treatment. Future Oncology has tracked these developments over time, from the rise of immunotherapy in the late 1990s to the subsequent discovery of oncogenes and tumor suppressors that shifted the emphasis from the labor intensive immunotherapy and gene transfer approaches to the relative simplicity of the production and delivery of monoclonal antibodies (MAb), oligonucleotides and small molecule drugs. Although some major advances have led to significant survival gains of patients with hematologic malignancies, they have not produced the same results in the treatment of metastatic solid tumors.
In the meantime, the competitive landscape underwent a major transformation. The archives follow the progress or demise of hundreds of commercial entities globally and hundreds of drugs, among some of the most successful to date as well some noted failures. The passage of time has produced many surprising winners and a few unexpected losers. Celgene, an unknown small company in 1995, has become a leading biotech juggernaut. Rituximab, a relatively low tech transformational therapy for the treatment of hematologic malignancies, developed by the small company Idec and approved in the USA in November 1997, may be considered the most successful anticancer agent to date both for significantly extending survival and for generating billions in sales for its developers and marketers. Since its first approval in 1995, Rituxan’s total global revenues exceeded $65 billion, including sales in the immunology sector beginning in FY 2013. Imatinib, launched in 2001, ushered the era of personalized medicine. Avastin, the first targeted treatment for solid tumors launched by Genentech in 2004, garnered over $60 billion in global revenues to date.
Novel clinically-available comprehensive genomic profiling of both DNA and RNA in hematologic malignancies.
Profiling of 3696 clinical hematologic tumors identified somatic alterations that impact diagnosis, prognosis, and therapeutic selection.
Abstract
The spectrum of somatic alterations in hematologic malignancies includes substitutions, insertions/deletions (indels), copy number alterations (CNAs) and a wide range of gene fusions; no current clinically available single assay captures the different types of alterations. We developed a novel next-generation sequencing-based assay to identify all classes of genomic alterations using archived formalin-fixed paraffin-embedded (FFPE), blood and bone marrow samples with high accuracy in a clinically relevant timeframe, which is performed in our CLIA-certified CAP-accredited laboratory. Targeted capture of DNA/RNA and next-generation sequencing reliably identifies substitutions, indels, CNAs and gene fusions, with similar accuracy to lower-throughput assays which focus on specific genes and types of genomic alterations. Profiling of 3696 samples identified recurrent somatic alterations that impact diagnosis, prognosis and therapy selection. This comprehensive genomic profiling approach has proved effective in detecting all types of genomic alterations, including fusion transcripts, which increases the ability to identify clinically-relevant genomic alterations with therapeutic relevance.
In addition to the concordance analysis, genomic profiling of the 76 test samples using FoundationOne Heme also identified 126 additional somatic alterations including clinically relevant genomic alterations in KRAS, TET2, EZH2, and DNMT3A.
Importantly, the study also showed that the molecular information supplied by the test can help accurately match patients with a particular targeted therapy.
In the study Foundation Medicine shared clinical data from genomic profiling of 3,696 hematologic malignancies submitted to its CLIA-certified, NYS-approved lab.
More than 90 percent of the specimens — 3,433 out of 3696 — were successfully characterized. The test identified at least one driver alteration in 95 percent of the tumor specimens, and results showed that 77 percent of the cases harbored at least one alteration linked to a commercially available targeted therapy or one that is in clinical development, the MSKCC researchers reported.
In addition, 61 percent of the cases harbored at least one alteration with known prognostic relevance in that tumor type.
In discussion of the results, the study authors argued that clinical merit of the test was underscored by the demonstrated ability to identify genetic lesions with prognostic and therapeutic relevance in specific diseases.
For example, the authors wrote, “In the case of B-cell ALL … the challenge has been that the critical genes … can be altered by whole gene/intragenic deletions, DNA base-pair substitutions, and larger indels, as well as chromosomal, intergenic, and cryptic rearrangements, which lead to expression of fusion transcripts.”
“Currently, most centers use an amalgam of DNA, FISH, and gene-specific RNA approaches to identify a subset of the most critical genetic lesions in B-ALL. Our assay provides a single profiling platform that can reliably identify all known actionable disease alleles relevant to B-ALL to improve diagnosis and risk-adapted therapy for B-ALL patients,” they wrote.
Biological process utilize amino acids almost uniquely one chiral form or the other. In terrestrial biology, only the L-amino acids is common in biological processes. If signature of life existed elsewhere in the D form it then be concluded that life had evolutionary beginning on that body. Detection of an enantiomeric excess of L over D would also be a powerful sign that life had existed on that body at one time, see link in here .
As we know powder XRD pattern of both the L- or D-amino acids are basically identical. This is primarily due to the fact that the chirality of the amino acids does not favor a specific orientation on the sample holder in the powder form. However, when the amino acids are crystallized in moisture environment, water molecule enters in the unit cell of the amino acid by changing its structure. In order to determine structural changes using x-ray diffraction, two samples of both L- and D-phenylalanine (min 98% and >99% purity, respectively; purchased from Sigma Aldrich Co. St. Louis Mo) directly on the x-ray sample holder, alumina single crystal (0001) face, see link in here. The picture below shows an example of the diffraction pattern for two specimens of D- and L- phenylalanine, fresh crystallized in pure water under the same conditions.
As we see from the picture above, the two peaks L and D do not have same position. For raw phenylalanine D and L enantiomers the laboratory x-ray diffraction pattern matches, despite the fact that Powder Diffraction File (PDF) that correspond to PDF# 11-0827 for D form and PDF# 37-1771 indicates detectable differences. This is due to a structure factor, which is invariant for both D and L forms. For fresh crystallized specimens of D and L forms, a difference can be distinguished. The diffraction peak D of D-Phenylalanine has a less d-spacing suggesting a more compact structure than L-Phenylalanine.
Comparing diffraction pattern for the entire range produced by L and D crystallized Phenylalanine in pure water, shifts occur in peak position and intensity. These differences are possibly due to stereo-specific interactions of D- and L- phenylalanine molecules with water molecules. The x-ray diffraction pattern for D and L form, a small part shown in the picture above, reflects new structural configurations such as rotation, slight deformation and/or translation of the phenylalanine molecule inside the unit cell. It is possible that D form crystallizes with more molecules of water than L form. Structural solution for freshly crystallized phenylalanine can be found using Rietveld refinement technique.
The implications of water effect on the structure of the amino acids can lead to similar effects on DNA structure as well as proteins and cells in human body.
STEADY PROGRESS: Warren and Lucia Prosperi’s Ether Day painting, which captures the first successful use of ether as an anesthetic, hangs in the domed amphitheater in which the historic event occurred more than 150 years ago.
In Carolus-Duran’s The Convalescent, a bearded man leans back, exhausted, into a pillow. Carolus-Duran, the name used by nineteenth-century French artist Charles Auguste Émile Durand, brings the viewer into the sickroom, rendering the emotions of illness through light, feature, and posture.
Studying this and other such paintings and recognizing elements of her own clinical experience in them has enriched Alice Flaherty’s appreciation of sickrooms and deathbeds. It is an appreciation that translates to the clinic.
“I was rounding on a woman who was dying of breast cancer,” says Flaherty ’90, an HMS associate professor of neurology at Massachusetts General Hospital. “I felt this empathic pain, so I asked her about her suffering. She calmly said she felt at peace, that she had been contemplating the quiet, lovely light in the room.”
“I realized that some of my empathy had been the projection of my own distress,” Flaherty continues. “Her description of the calm, empty, white spaces of her sickroom gave me the aesthetic distance that allowed me to see more of what was going on with her than I had seen when my eyes were screwed tight with imagined pain.”
Whether it’s a sickroom tableau, a portrayal of a surgery, or a portrait of a clinician or researcher, depictions of medicine in art have wide-ranging effects on those who view them. In addition to revealing the beauty in everyday clinical care, art inspired by medicine can connect doctors with the history of their profession, encourage them to confront ambiguities or consider alternative points of view, help situate their experiences within a larger context, soothe or sharpen emotions, and lead them to improve patient care in unexpected ways.
Alice Flaherty
Artists, subjects, and viewers connect on another level when the process for reconstructing a historical event in medicine or capturing the character of a portrait subject entails the same meticulous collection of data and keen observational skills practiced in medicine. That physicians and painters should find one another kindred spirits is not surprising given the intertwined histories and philosophies of naturalist art, science, and medicine.
Nature Studies
Ask Massachusetts-based artists Warren and Lucia Prosperi whether they feel an affinity with physicians and scientists, and they will elaborate on how they share a fascination with the nature of the human experience. To capture this fascination in their paintings, they allow themselves to be endlessly curious about the subject, struggle to balance involvement with detachment, and pursue their desire to craft scientifically accurate images based on close observation.
“We’re empiricists,” says Warren, a painter who, in collaboration with his wife, a photographer, has produced dozens of paintings for HMS-affiliated institutions. Most notable, perhaps, is their Ether Day, a work completed in 2001 and displayed in a surgical amphitheater, dubbed the Ether Dome, in the Bulfinch Building at Mass General. In that room in 1846, the use of inhaled ether as a surgical anesthetic was first demonstrated successfully.
The Prosperis adhere to the principles of naturalism, a movement that arose in Europe in the mid-nineteenth century as writers, visual artists, and filmmakers, inspired by advances in natural science, sought to apply scientific methods to their work. Reacting against the idealism and symbolism of romanticism, naturalist painters presented realistic depictions of everyday life with as little distortion as possible. An example of this style, and one that is among the more pervasive images of the caring physician in art, is the late-nineteenth century painting The Doctor by British artist Sir Samuel Luke Fildes. In the work, Fildes portrays a pensive clinician keeping watch over an ailing girl while her parents look on helplessly.
Naturalist artists gather vast amounts of data to ensure accuracy, and the Prosperis are no exception. They spend hours talking with and photographing portrait subjects until they’re satisfied that they’ve captured not only minute physical details but also the person’s essential character. For posthumous portraits and historical scenes, they conduct exhaustive archival research, consult experts on the period, and interview anyone who might have known the person or experienced an event firsthand.
“They sucked my bone marrow for details,” says Donald Barnett, a former HMS assistant clinical professor of medicine and now curator of the Joslin Diabetes Center Historical Commission. Barnett has advised the Prosperis on seven paintings depicting landmarks in Joslin’s history.
ARTISTS-IN-RESIDENCE: Warren and Lucia Prosperi’s studio contains several of the historical works on which they have collaborated, including The First Casualty at Bunker Hill, shown here, in part.
As a clinician, Barnett appreciates thorough information gathering. “Historical records tell the ‘what,’ not the ‘how,’” he says. “We brought in the details to turn a painting into a story, and we had a fanaticism for telling the story correctly.”
Details, Details
Demonstrating the effective use of ether during surgery launched U.S. medicine into the international spotlight. Little wonder that when planning to commemorate the 150th anniversary of that landmark event, the hospital’s service chiefs and physicians commissioned the Prosperis to paint a historically accurate version of what happened that day. The research the Prosperis undertook for Ether Day illustrates their dedication to telling stories correctly.
Although written documents and photographs yielded plenty of facts, crucial questions remained: Was surgeon John Collins Warren right- or left-handed? What was the nature of the incision he made? To what extent would red blood cells have oxidized and begun to separate from plasma in the basin used to capture the blood that flowed from the incision? Where would Warren and dentist William T. G. Morton, who administered the ether, have stood relative to the patient?
Over time, a detailed picture took shape. Whenever the Prosperis reached the limits of evidence, they and their consultants made logical deductions. Daguerreotypes in Harvard’s Fogg Museum, for example, show Warren holding his glasses in a manner that suggests he was right-handed. If true, that would mean he should be positioned to the patient’s right in the painting. The fact that blood would flow from the incision—this was a time before cauterization was used—meant someone would probably be there to sop it up, so given Warren’s position, the Prosperis put that person on the patient’s left along with a basin on a table. The possibility that ether wouldn’t work would have meant that the surgical team not only used restraints at the patient’s elbows and ankles but also assigned someone to hold the patient’s head still, likely from behind to remain out of Warren’s way. Thus, each decision about how to compose the scene helped another fall into place.
Reconstructing events feels like time travel, the Prosperis say, and that sense of witnessing the past with nearly photographic precision gets shared with the viewers.
“I remember being alone in the Ether Dome, feeling the history of that moment, and thinking that we had to do honor to what came before,” says Lucia. “It was a heavy responsibility.”
Adds Warren, “It was also great fun.”
Shades of Meaning
Beyond authenticity, the choices made in paintings of medical topics take on symbolic value and convey what it means to be a doctor, a patient, or part of an institution.
The doctor’s worried expression in Fildes’ iconic painting reminds practitioners that sometimes medicine reaches its limit and all it can offer is empathy with the human experience. When English artist John Collier turns the physician away from the viewer in his 1908 painting Sentence of Death, he is subtly directing the viewer’s gaze to the young male patient and his shocked expression, emphasizing how personally devastating the receipt of a terminal diagnosis can be. In Science and Charity, executed by the Spanish painter Pablo Picasso when he was 15 years old, the artist presents the doctor as the scientific observer of symptoms, focusing on his timepiece as he takes his patient’s pulse while a nurse provides compassionate care.
Paintings can also capture the moment a clinical procedure was first put into practice, such as the 1816 introduction of the stethoscope depicted in Ernest Board’s sunlit Laënnec Listening to the Chest of a Patient. In Board’s 1908 work, the early monaural cylinder itself and inventor René Laënnec take center stage. Although such paintings can boost present-day doctors’ and researchers’ confidence that their contributions could likewise change the course of medical history, artistic works can also be used to warn that not all new ideas pan out. For better or worse, French physician Simon Bernheim immortalized his hypothesis for curing tuberculosis using interspecies blood transfusions by hiring French naturalist artist Jules Adler to advertise his idea, which Adler did in The Transfusion of a Goat’s Blood.
EYE TO INNOVATION: In a mural for the Joslin Diabetes Center, Warren Prosperi depicted HMS faculty William Beetham, a surgeon; Lloyd Aiello, an ophthalmology professor; and Priscilla Holman, a nurse, performing a laser surgery procedure developed by Beetham and Aiello. The revolutionary procedure prevented bleeding-induced blindness in patients with diabetes.
When Barnett led the team choosing the subjects for the Joslin paintings, he tried to select caregivers and researchers who represented progress in diabetes research and treatment and to tell stories that embodied the Joslin’s values. One of the physicians selected was Priscilla White, a founding member of Joslin Clinic. White, who collected data from pregnant women for half a century, helped raise the survival rate of babies born to diabetic mothers from 56 percent to over 90 percent.
Another painting depicts a twentieth-century health care team conferring around the bed of a woman with diabetes and a foot infection. Although some people recoil from the “blood and guts” nature of the gangrenous limb, Barnett says, he believes it’s important to portray real patients who lose their legs to the disease. “Looking at the painting reminds doctors of the importance of taking care of the whole person,” he says.
Viewers’ reactions can be emotional as well as intellectual. For Barnett, standing in the Joslin lobby surrounded by the Prosperis’ paintings brings back fifty years of memories of caring for patients with juvenile diabetes.
“Tears would come to my eyes to see kids in their twenties going blind,” he says. “This art can make people aware of what it was like to be a patient or a doctor in those days, when diabetes was a war.”
Face Values
The walls of Flaherty’s office are papered with taped-up printouts of artwork by and about doctors and patients. Art books and sculptures crowd all available horizontal surfaces. Flaherty believes that repeated exposure to artistic renderings of bodies and illness can make them less threatening in reality, help health care practitioners process difficult clinical experiences, and reassure practitioners that their work fits into an older, larger context.
Nonetheless, she worries about putting too thick an aesthetic gloss on medicine.
“It makes our patients more interesting and less painful for us when we aestheticize their experience, but that also can over-anesthetize our ability to feel their pain,” she says.
Art, cautions Flaherty, can encourage doctors to ignore the messiness in real patients’ stories or to infer emotions that may not reflect patients’ actual experiences and feelings. It can, she adds, perpetuate an approach of treating patients like objects to be contemplated rather than as active participants in their own care.
At the same time, Flaherty is among those who believe that art serves doctors well when it “takes something that we encounter every day, and thought we knew, and makes us see that it is unique.”
Having witnessed physicians refer to a terrified-looking patient as “resting comfortably,” Flaherty thinks that art can teach doctors to pay attention.
“Doctors often see the jaundiced sclera but not the sad expression,” she says, “because it saves time if we ignore the pain. Looking closely at portraits can help us remember how to look at people.”
Flaherty says that close attention to facial expression helps her tell the impassivity of depression from that of Parkinson’s disease, Botox treatments, or simply personal demeanor. Occasional attempts to draw—Flaherty has taken some lessons from Warren Prosperi—have engaged her with patients’ affect even more. She has learned, for instance, that if an eyelid’s position changes by even a hundred microns, a face can be transformed from sadness to fear.
“I was talking to a patient once and said, ‘Oh, the light’s in your face,’ ” Flaherty remembers. “He said, ‘That’s so thoughtful of you.’ Don’t thank me, I thought, thank an artist.”
Stephanie Dutchen is a science writer in the HMS Office of Communications and External Relations.
Images: John Soares
Pain Management Overview
Pain management is important for ongoing pain control, especially if you suffer with long-term or chronic pain. After getting a pain assessment, your doctor can prescribe pain medicine, other pain treatments, or psychotherapy to help with pain relief.
Nearly any part of your body is vulnerable to pain. Acute pain warns us that something may be wrong. Chronic pain can rob us of our daily life, making it difficult and even unbearable. Many people with chronic pain can be helped by understanding the causes, symptoms, and treatments for pain – and how to cope with the frustrations.
You know your pain better than anyone — and as hard as it’s been to handle it, your experience holds the key to making a plan to treat it.
Each person and their pain are unique. The best way to manage your case could be very different from what works for someone else. Your treatment will depend upon things such as:
The cause
How intense it is
How long it’s lasted
What makes it worse or better
It can be a process to find your best plan. You can try a combination of things and then report back to your doctor about how your pain is doing. Together, you can tweak your program based on what’s working and what needs more help.
All Pain Is Not the Same
In order to make your pain management plan, your doctor will first consider whether you have sudden (“acute”) or long-term (“chronic”) pain.
Acute pain starts suddenly and usually feels sharp. Broken bones, burns, or cuts are classic examples. So is pain after surgery or giving birth.
Acute pain may be mild and last just a moment. Or it may be severe and last for weeks or months. In most cases, acute pain does not last longer than 6 months, and it stops when its underlying cause has been treated or has healed.
If the problem that causes short-term pain isn’t treated, it may lead to long-term, or “chronic” pain.
Chronic pain lasts longer than 3 months, often despite the fact that an injury has healed. It could even last for years. Some examples include:
Headache
Low back pain
Cancer pain
Arthritis pain
Pain caused by nerve damage
It can cause tense muscles, problems with moving, a lack of energy, and changes in appetite. It can also affect your emotions. Some people feel depressed, angry, or anxious about the pain and injury coming back.
Chronic pain doesn’t always have an obvious physical cause.
What Can I Do to Feel Better?
1. Keep moving. You might think it’s best to rest on the sidelines. But being active is a good idea. You’ll get stronger and move better.
The key is knowing what’s OK for you to do to get stronger and challenge your body, without doing too much, too soon.
Your doctor can let you know what changes to make. For instance, if you used to run and your joints can’t take that now because you have a chronic condition like osteoarthritis, you might be able to switch to something like biking or swimming.
2. Physical and occupational therapy. Take your recovery to the next level with these treatments. In PT, you’ll focus on the exact muscles you need to strengthen, stretch, and recover from injury. Your doctor may also recommend “occupational therapy,” which focuses on how to do specific tasks, like walking up and down stairs, opening a jar, or getting in and out of a car, with less pain.
3. Counseling. If pain gets you down, reach out. A counselor can help you get back to feeling like yourself again. You can say anything, set goals, and get support. Even a few sessions are a good idea. Look for a counselor who does “cognitive behavioral therapy,” in which you learn ways that your thinking can support you as you work toward solutions.
4. Massage therapy. It’s not a cure, but it can help you feel better temporarily and ease tension in your muscles. Ask your doctor or physical therapist to recommend a massage therapist. At your first appointment, tell them about the pain you have. And be sure to let them know if the massage feels too intense.
5. Relaxation. Meditation and deep breathing are two techniques to try. You could also picture a peaceful scene, do some gentle stretching, or listen to music you love. Another technique is to scan your body slowly in your mind, and consciously try to relax each part of your body, one by one, from head to toe. Any healthy activity that helps you unwind is good for you and can help you feel better prepared to manage your pain.
6. Consider complementary treatments such as acupuncture, biofeedback, and spinal manipulation. In acupuncture, a trained practitioner briefly inserts very thin needles in certain places on your skin to tap into your “chi,” which is an inner energy noted in traditional Chinese medicine. It doesn’t hurt.
Biofeedback trains you to control how your body responds to pain. In a session of it, you’ll wear electrodes hooked up to a machine that tracks your heart rate, breathing, and skin temperature, so you can see the results.
When you get spinal manipulation, a medical professional uses their hands or a device to adjust your spine so that you can move better and have less pain. Some MDs do this. So do chiropractors, osteopathic doctors (they have “DO” after their name instead of “MD”), and some physical therapists.
Are There Devices That Help?
Although there are no products that take pain away completely, there are some that you and your doctor could consider.
TENS and ultrasound. Transcutaneous electrical nerve stimulation, or TENS, uses a device to send an electric current to the skin over the area where you have pain. Ultrasound sends sound waves to the places you have pain. Both may offer relief by blocking the pain messages sent to your brain.
Spinal cord stimulation. An implanted device delivers low-voltage electricity to the spine to block pain. If your doctor thinks it’s an option, you would use it for a trial period before you get surgery to have it permanently implanted. In most cases, you can go home the same day as the procedure.
What About Medicine?
Your doctor will consider what’s causing your pain, how long you’ve had it, how intense it is, and what medications will help. They may recommend one or more of the following:
These may include over-the-counter pain relievers such as acetaminophen, aspirin, ibuprofen, or naproxen. Or you may need stronger medications that require a prescription, such as steroids, morphine, codeine, or anesthesia.
Some are pills or tablets. Others are shots. There are also sprays or lotions that go on your skin.
Other drugs, like muscle relaxers and some antidepressants, are also used for pain. Some people may need anesthetic drugs to block pain.
Will I Need Surgery?
It depends on why you’re in pain. If you’ve had a sudden injury or accident, you might need surgery right away.
But if you have chronic pain, you may or may not need an operation or another procedure, such as a nerve block (done with anesthetics or other types of prescription drugs to halt pain signals) or a spinal injection (such as a shot of cortisone or an anesthetic drug).
Talk with your doctor about what results you can expect and any side effects, so you can weigh the risks and the benefits. Also ask how many times the doctor has done the procedure they recommend and what their patients have said about how much relief they’ve gotten.
According to statistics published by the American Cancer Society in 2002, “50%–70% of people with cancer experience some degree of pain” (ACS 2002), which usually only intensifies as the disease progresses. Less than half get adequate relief of their pain, which negatively impacts their quality of life. The incidence of pain in advanced stages of invasive cancer approaches 80% and it is 90% in patients with metastases to osseous structures (Pharo and Zhou 2005).
Mediators of pain and inflammation are known to be secreted from tumor cells as well as infiltrating immune cells, activating and sensitizing primary afferent nociceptors (nociceptive pain) and damaging the nervous system (neuropathic pain). However, there has been difficulty in modeling cancer-induced pain in animals. This has hampered our understanding and therapeutic intervention of the clinical situation, especially concerning ovarian cancer patients. It has been shown that 85% of ovarian cancer patients in palliative care (during last two months of life) still report severe pain although 54% of these women were given high intensity pain medications such as morphine, still the mainstream pain medication for severe cancer-associated pain. Admittedly, more research into the ability of cancer to provoke pain and sensitize the central nervous system, is warranted, as well as development of new methods of analgesia for cancer-associated pain at end-of-life. Therefore, in collaboration with several colleagues, in vivo models of nociceptive and neuropathic pain will be integrated with my co-developed in vivo tumor models of ovarian cancer. This tumor model allows for noninvasive monitoring of tumor burden without the need for anesthesia, as necessitated by imaging strategies to quantitate tumor burden, such as bioluminescence and MRI.
Even in an era of promising new cancer therapies, cancer pain is one of the highest concerns for the patient, their clinician, and surrounding loved ones, especially impacting quality of life during palliative care. Over half of cancer patients have reported severe pain in the course of their disease (List MA J Clin Oncol 2000 18:877-84) and the statistics are worse for ovarian cancer patients, regardless whether during treatment or in palliative care (see below review).
Journal of Pain and Symptom Management Volume 33, Issue 1 , Pages 24-31, January 2007
Sharon J. Rolnick, PhD, MPH, Jody Jackson, RN, BSN, Winnie W. Nelson, PharmD, MS, Amy Butani, BA, Lisa J. Herrinton, PhD, Mark Hornbrook, PhD, Christine Neslund-Dudas, MA, Don J. Bachman, MS, Steven S. Coughlin, PhD
HealthPartners Research Foundation (S.J.R., J.J., A.B.), Minneapolis, Minnesota; Applied Health Outcomes (W.W.N.), Palm Harbor, Florida; Division of Research (L.J.H., D.J.B.), Kaiser Permanente Northern California, Oakland, California; Kaiser Permanente Center for Health Research (M.H.), Portland, Oregon; Josephine Ford Cancer Center (C.N.-D.), Henry Ford Health System, Detroit, Michigan; and National Center for Chronic Disease Prevention and Health Promotion (S.S.C.), Centers for Disease Control and Prevention, Atlanta, Georgia, USA
Abstract Previous studies indicate that the symptoms of many dying cancer patients are undertreated and many suffer unnecessary pain. We obtained data retrospectively from three large health maintenance organizations, and examined the analgesic drug therapies received in the last six months of life by women who died of ovarian cancer between 1995 and 2000. Subjects were identified through cancer registries and administrative data. Outpatient medications used during the final six months of life were obtained from pharmacy databases. Pain information was obtained from medical charts. We categorized each medication based on the World Health Organization classification for pain management (mild, moderate, or intense). Of the 421 women, only 64 (15%) had no mention of pain in their charts. The use of medications typically prescribed for moderate to severe pain (“high intensity” drugs) increased as women approached death. At 5–6 months before death, 55% of women were either on no pain medication or medication generally used for mild pain; only 9% were using the highest intensity regimen. The percentage on the highest intensity regimen (drugs generally used for severe pain) increased to 22% at 3–4 months before death and 54% at 1–2 months. Older women (70 or older) were less likely to be prescribed the highest intensity medication than those under age 70 (44% vs. 70%, P<0.001). No differences were found in the use of the high intensity drugs by race, marital status, year of diagnosis, stage of disease, or comorbidity. Our finding that only 54% of women with pain were given high intensity medication near death indicates room for improvement in the care of ovarian cancer patients at the end of life.
Cancer pain is a complexity concerning not only the peripheral and central nervous systems but the cancer cell, the tumor microenvironment, and tumor infiltrating immune cells and inflammatory mediators. The goal of this article is to briefly introduce these factors governing pain in the cancer patient and a discussion of animal models of pain in relation to cancer.
Pain is considered as either termed nociceptive pain (activations and sensitization of primary afferent “nociceptor” neurons or neuropathic pain (damage to sensory nerves). Mediators of pain and inflammation are known to be secreted from tumor cells as well as infiltrating immune cells, activating and sensitizing primary afferent nociceptors (nociceptive pain) and damaging the nervous system (neuropathic pain).
The first step in developing a pain control plan is talking with your cancer care team about your pain. You need to be able to describe your pain to your family or friends, too. You may want to have your family or friends help you talk to your cancer care team about your pain, especially if you’re too tired or in too much pain to talk to them yourself.
Using a pain scale is a helpful way to describe how much pain you’re feeling. To use the Pain Intensity Scale shown here, try to assign a number from 0 to 10 to your pain level. If you have no pain, use a 0. As the numbers get higher, they stand for pain that’s getting worse. A 10 means the worst pain you can imagine.
0
1
2
3
4
5
6
7
8
9
10
No pain
Worst pain
For instance, you could say, “Right now, my pain is a 7 on a scale of 0 to 10.”
You can use the rating scale to describe:
How bad your pain is at its worst
What your pain is like most of the time
How bad your pain is at its least
How your pain changes with treatment
Tell your cancer care team and your family or friends:
Where you feel pain
What it feels like – for instance, sharp, dull, throbbing, gnawing, burning, shooting, steady
How strong the pain is (using the 0 to 10 scale)
How long it lasts
What eases the pain
What makes the pain worse
How the pain affects your daily life
What medicines you’re taking for the pain and how much relief you get from them
– Consider specific pain syndrome problem and consultation
– continue analgesic titration
Mild (0-3)
Adjuvant analgesics
The clinical presentation of cancer pain depends on the histologic type of cancer, the location of the primary neoplasm, and location of metastases. (for example pain in breast cancer patients have different pain issues than patients with oral.cancer).
However, high grade serous ovarian cancer, the most clinically prevalent of this disease, usually presents as an ascitic carcinomatosis, spread throughout the peritoneum and mesothelium.
Ovarian cancer stem cells and mediators of pain
Although not totally accepted by the field, a discussion of ovarian cancer stem cells is warranted, especially in light of this discussion. Cancer stem cells are considered that subpopulation of cells in the bulk tumor exhibiting self-renewing capacity, generally resistant to chemotherapy, and therefore repopulate the tumor with new tumor cells. In this case, ovarian cancer stem cells could be more pertinent to the manifestations of pain than bulk tumor, as these cells would survive chemotherapy. This may be the case, as ovarian cancer pain may not be associated with overall tumor burden? Are there PAIN MEDIATORS secreted from ovarian cancer cells?
Some Known Pain Mediators Secreted from Ovarian Tumor Cells
Opioid analgesics: analgesia without loss of consciousness
Three main uses of opioids
Analgesia
Antitussive
Diarrhea
1954 – nalorphine, partial antagonists had analgesic effect. Morphine: Morpheus – Greek God of dreams
1) opiates: opium alkaloids including morphine, codeine, thebaine, papavarine
2) synthetic: meperedine, methadone
Chemistry
Antagonist properties associated with replacement of the methyl substituent on nitrogen atom with large group (naloxone and nalorphine replaced with allyl group)
Pharmacokinetic properties affected by C3 and C6 hydroxyl substitutions
CH3 at phenolic OH at C3 reduces first pass metabolism by glucoronidation THEREFORE codeine and oxycodeine have higher oral availability
Acetylation of both OH groups on morphine : heroin penetrates BBB : rapidly hydrolyzed to give monoacetylmorphine and morphine
Pharmaookinetics
Well absorbed from s.c., i.m., oral
Codeine and hydrocodeine higher absorption from oral:parental ratio because of extensive first pass metabolism
Most opioids are well absorbed orally but DECREASE potency due to first pass
Variable plasma protein binding
Brain distribution is actually low but opioids are very potent
Well distributed and may accumulate in skeletal muscle
Fentynyl (lipophilic) may accumulate in fat
Metabolism
Most opioids converted to polar metabolites so excreted by kidney ;IMPORTANT prolonged analgesia in patients with renal disease
Esters like meperidine and herion metabolized by tissue esterases
Glucoronidated morphine may have analgesic properties
Receptors
All three (mu, kappa, and delta) activate pertussis toxin sensitive G protein {Gi}
Opioids quiet pain (nociceptive) neurons by inhibiting nerve conduction (decrease entry of calcium or increase entry of potassium)
There are four major subtypes of opioid receptors:[12]
Tolerance: gradual loss of effectiveness over repeated doses
Physical Dependence: when tolerance develops continued administration of drug required to prevent physical withdrawal symptoms
With opioids see tolerance most with the analgesic, sedative, and antitussive effects; not so much with antidiarrheal effects
Major effects of opioids on Organ Systems
CNS
Analgesia – raise threshhold for pain
Euphoria – pleasant floating feeling but sometimes dysphoria (agitation)
Sedation –drowsiness but no amnesia; more frequent in elderly than young but can disrupt normal REM sleep
Respiratory depression – ALL opioids produce significant resp. depression by inhibiting the brain stem; careful in patients with impaired respiratory function like COPD or increased intracranial pressure
Cough suppression – tolerance can develop; may increase airway secretions
Miosis – constriction of pupils; seen with ALL agonists; treat with atropine
Rigidity – mostly seen with fentanyl; treat with opioid antagonist like nalozone
Emesis; naseua, vomiting
Peripheral
Cardiovascular – no real major effects; some specific compounds may have effects on blood pressure
GI – Constipation most common; loperamide (Immodium); pentazocine may cause less constipation; problem for treating cancer patients for pain; opioid receptors do exist in the GI tract but effect may be CNS as well as local
Biliary system – minor, may cause constriction of bile duct
GU (genitourinary) – reduced urine output by increased antidiuretic hormone
Uterus – may prolong labor
Neuroendocrine – opioid analgesics can stimulate release of ADH, prolactin
Other – opioid analgesics may cause flushing and warming of skin; release of histamine?
Specific Agents
Strong Agonists
Phenanthrenes –all are used for analgesia
Morphine
Hydromorphone
Oxymorphone
Heroin
Phenylheptylamine
Methadone – longer acting than morphine; tolerance and physical dependency slower to develop than with morphine; low doses of methadone may be used for heroin addict undergoing withdrawal
Phenyllpiperidines
Meperidine
Fentanyl (also sufentanil) which is 5-7 more times potent than fentanyl. Negative inotropic (contractile force) effects on heart
Levorphanol
Mild to Moderate Agonist
Phenanthrenes – most given in combo with NSAID
Codeine – antitussive, some analgesia
Oxycodone
Dihydrocodone
Hydrocodone
Propoxyphene – Darvon, low abuse and low analgesia compared to morphine
Phenylpiperidines
Diphenoxylate –used for diarrhea; not for analgesia and no abuse potential
Nalbulphine – strong kappa agonist and mu antagonist.. Analgesic
Buprenorphine – analgesic. Partial mu agonist has long duration. Slow dissocation from receptor makes resistant to naloxone reversal
Buterphanol – analgesia with sedation, kappa agonist
Pentazocine – kappa agonist with weak mu antagonism.Is an irritant so do no inject s.c.
Antagonists
Naloxone – quick reversal of opioid agonist action (1-2 hours); not well absorbed orally; pure antagonist so no effects by itself; no tolerance problems; opioid antidote
Naltrexone – well absorbed orally can be used in maintenance therapy because of long duration of action
Antitussives
Codeine
Dextromethorphan
Levoproposyphen
Noscapine
Other posts related to Pain, Cancer, and Palliative Care on this Open Access Journal Include
BIA 10-2474 is an experimental fatty acid amide hydrolase inhibitor[1] developed by the Portuguese pharmaceutical company Bial-Portela & Ca. SA. The drug was developed to relieve pain,[2][3] to ease mood and anxiety problems, and to improve movement coordination linked to neurodegenerative illnesses.[4] It interacts with the humanendocannabinoid system.[5][6] It has been linked to severe adverse events affecting 5 patients in a drug trial in Rennes, France, and at least one death, in January 2016.[7]
French newspaper Le Figaro has obtained Bial study protocol documents listing the the chemical name of BIA-10-2474 as 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide.[8] A Bial news release described BIA-10-2474 as “a long-acting inhibitor of FAAH”.[9]
Fatty acid amide hydrolase (FAAH) is an enzyme which degrades endocannabinoid neurotransmitters like anandamide,[10] which relieves pain and can affect eating and sleep patterns.[11][12] FAAH inhibitors have been proposed for a range of nervous-system disorders including anxiety, alcoholism, pain and nausea.
The Portuguese pharmaceutical company Bial holds several patents on FAAH enzyme inhibitors.[12][13][14][15]
No target organ was identified during toxicology studies and few adverse clinical findings were observed at the highest dose tested. For the single ascending dose part [of the clinical trial], a starting dose of 0.25 mg was judged to be safe for a first-in-human administration.[8]
The protocol defines no starting dose for the multi-dose treatment groups, noting that this will be based on the outcome of the single dose portion of the trial (an approach known as adaptive trial design). The authors note that nonetheless, the starting dose will not exceed 33% of the maximum tolerated dose (MTD) identified in the single dose groups (or 33% of the maximum administered dose if the MTD is not reached).[8]
In July 2015 Biotrial, a contract research organization, began testing the drug in a human phase oneclinical trial for the manufacturer. The study was approved by French regulatory authority, the Agence Nationale de Sécurité du Médicament (ANSM), on June 26, 2015, and by the Brest regional ethics committee on July 3, 2015.[20] The trial commenced on July 9, 2015,[21] in the city of Rennes, and recruited 128 healthy volunteers, both men and women aged 18 to 55. According to French authorities, the study employed a three-stage design with 90 of the volunteers having received the drug during the first two stages of the trial, with no serious adverse events being reported .[17][20] Participants of the study were to receive €1,900 and, in turn, asked to stay at Biotrial’s facility for two weeks during which time they would take the drug for ten days and undergo tests.[22]
In the third stage of the trial evaluating multiple doses, six male volunteers received doses by mouth, starting on 7 January 2016. The first volunteer was hospitalized at theRennes University Hospital on January 10, became brain dead,[17][23][24][25] and died on January 17.[26] The other five men in the same dosage group were also hospitalized, in the period of January 10 through January 13[27] four of them suffering injuries including deep hemorrhagic and necrotic lesions seen on brain MRI.[7] The six men who were hospitalised were the group which received the highest dose.[26] A neurologist at the University of Rennes Hospital Center, Professor Pierre-Gilles Edan, stated in a press conference with the French Minister for Health, that 3 of the 4 men who were displaying neurological symptoms “already have a severe enough clinical picture to fear that even in the best situation there will be an irreversible handicap” and were being given corticosteroids to control the inflammation.[27] The sixth man from the group was not showing adverse effects but had been hospitalized for observation.[25][28][29] Biotrial stopped the experiment on January 11, 2016.[4]
According to the document, BIA 10-2474 is 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide.
BIA 10-2474 “is designed to act as a long-active and reversible inhibitor of brain and peripheral FAAH,” notes the protocol. The compound “increases anandamide levels in the central nervous system and in peripheral tissues.”
The clinical trial protocol also notes that the company tested BIA 10-2474 on mice, rats, dogs, and monkeys for effects on the heart, kidneys, and gastrointestinal tract, among other pharmacological and toxicological evaluations.
The clinical trial, conducted by the company Biotrial on behalf of the Portuguese pharmaceutical firm Bial, was evaluating a pain relief drug candidate called BIA 10-2474 that inhibits fatty acid amide hydrolase (FAAH) enzymes. Blocking these enzymes prevents them from breaking down cannabinoids in the brain, a family of compounds that includes the euphoria-inducing neurotransmitter anandamide and Δ9-tetrahydrocannabinol, the major psychoactive component of marijuana.
Phase I clinical trials are conducted to check a drug candidate’s safety profile in healthy, paid volunteers. In this case, the drug caused hemorrhagic and necrotic brain lesions in five out of six men in a group who received the highest doses of the drug, said Gilles Edan, a neurologist at the University Hospital Center of Rennes.
The French health minister has stated the drug acted on natural receptors found in the body known as endocannibinoids, which regulate mood and appetite. It did not contain cannabis or anything derived from it, as was originally reported. All six trial participants were administered the doses simultaneously.
The trial was being performed at Biotrial, a French-based firm that was formed in 1989 and has conducted thousands of trials. A message on the company’s website stated that they are working with health authorities to understand the cause of the accident, while extending thoughts to the patients and their families. Bial has disclosed the drug was a FAAH (fatty acid amide hydrolase) inhibitor, which is an enzyme produced in the brain and elsewhere that breaks down neurotransmitters called endocannabinoids. Two scientists from the Nottingham Medical School who have worked with FAAH tried over the weekend to try and identify the drug by examining a list of drugs Bial currently has in its pipeline. They believe the culprit is one identified by the codename BIA 10-2474.
While safety issues like this are rare, they are not unheard of. In 2006, a clinical trial in London left six men ill. All were taking part in a study testing a drug designed to fight auto-immune disease and leukemia. Within hours of taking the drug TGN1412, all experienced a serious reaction, were admitted to intensive care, and had to be treated for organ failure.
The Duff Report, written in response to the TGN1412 trial, noted the medicine should have been tested in one person at a time. It also helped to put additional safety measures in place. The Medicines and Health Products Regulatory Agency (MHRA) now requires committees to look at pre-clinical data to determine the proper initial dose, and rules are in place to stop the trial if unintended reactions occur.
Other pharmaceutical companies, including Merck, Pfizer, Johnson & Johnson, Sanofiand Vernalis, have previously taken other FAAH inhibitors into clinical trials without experiencing such adverse events (e.g. respectively, MK-4409,[35][36]PF-04457845,JNJ-42165279,[37] SSR411298 and V158866.[38][39] Related enzyme inhibitor compounds such as URB-597 and LY-2183240 have been sold illicitly as designer drugs,[40][41] all without reports of this type of toxicity emerging, so the mechanism of the toxicity observed with BIA 10-2474 remains poorly understood.
From June 1995 to August 2008, New Medicine published Future Oncology, a comprehensive analytical newsletter tracking the evolution of global drug development in oncology. Despite of the incredible amount of effort in this area in the last 20 years, we currently face the same problems that were being tackled then, namely a lack of understanding as to the origins and mechanisms of malignancy. Despite the incredible global effort in this area and the remarkable scientific breakthroughs in biology and medicine, advanced cancer has remained an incurable disease. However, although cancer remains undefeated, treatment of this disease has created a huge global market comprised of drugs that, with few exceptions, provide marginal relief at a very high cost. Because the origins of this disease have remained obscure, there have been numerous approaches popularized at different times as to its treatment. Future Oncology has tracked these developments over time, from the rise of immunotherapy in the late 1990s to the subsequent discovery of oncogenes and tumor suppressors that shifted the emphasis from the labor intensive immunotherapy and gene transfer approaches to the relative simplicity of the production and delivery of monoclonal antibodies (MAb), oligonucleotides and small molecule drugs. Although some major advances have led to significant survival gains of patients with hematologic malignancies, they have not produced the same results in the treatment of metastatic solid tumors.
2012pharmaceutical
sjwilliamspa
