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News Article | May 10, 2017
Site: www.eurekalert.org

CAMBRIDGE, MA - Lung adenocarcinoma, an aggressive form of cancer that accounts for about 40 percent of U.S. lung cancer cases, is believed to arise from benign tumors known as adenomas. MIT biologists have now identified a major switch that occurs as adenomas transition to adenocarcinomas in a mouse model of lung cancer. They've also discovered that blocking this switch prevents the tumors from becoming more aggressive. Drugs that interfere with this switch may thus be useful in treating early-stage lung cancers, the researchers say. "Understanding the molecular pathways that get activated as a tumor transitions from a benign state to a malignant one has important implications for treatment. These findings also suggests methods to prevent or interfere with the onset of advanced disease," says Tyler Jacks, director of MIT's Koch Institute for Integrative Cancer Research and the study's senior author. The switch occurs when a small percentage of cells in the tumor begin acting like stem cells, allowing them to give rise to unlimited populations of new cancer cells. "It seems that the stem cells are the engine of tumor growth. They're endowed with very robust proliferative potential, and they give rise to other cancer cells and also to more stem-like cells," says Tuomas Tammela, a postdoc at the Koch Institute and lead author of the paper, which appears in the May 10 online edition of Nature. In this study, the researchers focused on the role of a cell signaling pathway known as Wnt. This pathway is usually turned on only during embryonic development, but it is also active in small populations of adult stem cells that can regenerate specific tissues such as the lining of the intestine. One of the Wnt pathway's major roles is maintaining cells in a stem-cell-like state, so the MIT team suspected that Wnt might be involved in the rapid proliferation that occurs when early-stage tumors become adenocarcinomas. The researchers explored this question in mice that are genetically programmed to develop lung adenomas that usually progress to adenocarcinoma. In these mice, they found that Wnt signaling is not active in adenomas, but during the transition, about 5 to 10 percent of the tumor cells turn on the Wnt pathway. These cells then act as an endless pool of new cancer cells. In addition, about 30 to 40 percent of the tumor cells begin to produce chemical signals that create a "niche," a local environment that is necessary to maintain cells in a stem-cell-like state. "If you take a stem cell out of that microenvironment, it rapidly loses its properties of stem-ness," Tammela says. "You have one cell type that forms the niche, and then you have another cell type that's receiving the niche cues and behaves like a stem cell." While Wnt has been found to drive tumor formation in some other cancers, including colon cancer, this study points to a new kind of role for it in lung cancer and possibly other cancers such as pancreatic cancer. "What's new about this finding is that the pathway is not a driver, but it modifies the characteristics of the cancer cells. It qualitatively changes the way cancer cells behave," Tammela says. When the researchers gave the mice a drug that interferes with Wnt proteins, they found that the tumors stopped growing, and the mice lived 50 percent longer. Furthermore, when these treated tumor cells were implanted into another animal, they failed to generate new tumors. The researchers also analyzed human lung adenocarcinoma samples and found that 70 percent of the tumors showed Wnt activation and 80 percent had niche cells that stimulate Wnt activity. These findings suggest it could be worthwhile to test Wnt inhibitors in early-stage lung cancer patients, the researchers say. They are also working on ways to deliver Wnt inhibitors in a more targeted fashion, to avoid some of the side effects caused by the drugs. Another possible way to avoid side effects may be to develop more specific inhibitors that target only the Wnt proteins that are active in lung adenocarcinomas. The Wnt inhibitor that the researchers used in this study, which is now in clinical trials to treat other types of cancer, targets all 19 of the Wnt proteins. The research was funded by the Janssen Pharmaceuticals Transcend Program, the Lung Cancer Research Foundation, the Howard Hughes Medical Institute, and the Cancer Center Support grant from the National Cancer Institute.


News Article | May 11, 2017
Site: www.biosciencetechnology.com

Lung adenocarcinoma, an aggressive form of cancer that accounts for about 40 percent of U.S. lung cancer cases, is believed to arise from benign tumors known as adenomas. MIT biologists have now identified a major switch that occurs as adenomas transition to adenocarcinomas in a mouse model of lung cancer. They’ve also discovered that blocking this switch prevents the tumors from becoming more aggressive. Drugs that interfere with this switch may thus be useful in treating early-stage lung cancers, the researchers say. “Understanding the molecular pathways that get activated as a tumor transitions from a benign state to a malignant one has important implications for treatment. These findings also suggests methods to prevent or interfere with the onset of advanced disease,” said Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and the study’s senior author. The switch occurs when a small percentage of cells in the tumor begin acting like stem cells, allowing them to give rise to unlimited populations of new cancer cells. “It seems that the stem cells are the engine of tumor growth. They’re endowed with very robust proliferative potential, and they give rise to other cancer cells and also to more stem-like cells,” said Tuomas Tammela, a postdoc at the Koch Institute and lead author of the paper, which appears in the May 10 online edition of Nature. In this study, the researchers focused on the role of a cell signaling pathway known as Wnt. This pathway is usually turned on only during embryonic development, but it is also active in small populations of adult stem cells that can regenerate specific tissues such as the lining of the intestine. One of the Wnt pathway’s major roles is maintaining cells in a stem-cell-like state, so the MIT team suspected that Wnt might be involved in the rapid proliferation that occurs when early-stage tumors become adenocarcinomas. The researchers explored this question in mice that are genetically programmed to develop lung adenomas that usually progress to adenocarcinoma. In these mice, they found that Wnt signaling is not active in adenomas, but during the transition, about 5 to 10 percent of the tumor cells turn on the Wnt pathway. These cells then act as an endless pool of new cancer cells. In addition, about 30 to 40 percent of the tumor cells begin to produce chemical signals that create a “niche,” a local environment that is necessary to maintain cells in a stem-cell-like state. “If you take a stem cell out of that microenvironment, it rapidly loses its properties of stem-ness,” Tammela said. “You have one cell type that forms the niche, and then you have another cell type that’s receiving the niche cues and behaves like a stem cell.” While Wnt has been found to drive tumor formation in some other cancers, including colon cancer, this study points to a new kind of role for it in lung cancer and possibly other cancers such as pancreatic cancer. “What’s new about this finding is that the pathway is not a driver, but it modifies the characteristics of the cancer cells. It qualitatively changes the way cancer cells behave,” Tammela said. When the researchers gave the mice a drug that interferes with Wnt proteins, they found that the tumors stopped growing, and the mice lived 50 percent longer. Furthermore, when these treated tumor cells were implanted into another animal, they failed to generate new tumors. The researchers also analyzed human lung adenocarcinoma samples and found that 70 percent of the tumors showed Wnt activation and 80 percent had niche cells that stimulate Wnt activity. These findings suggest it could be worthwhile to test Wnt inhibitors in early-stage lung cancer patients, the researchers say. They are also working on ways to deliver Wnt inhibitors in a more targeted fashion, to avoid some of the side effects caused by the drugs. Another possible way to avoid side effects may be to develop more specific inhibitors that target only the Wnt proteins that are active in lung adenocarcinomas. The Wnt inhibitor that the researchers used in this study, which is now in clinical trials to treat other types of cancer, targets all 19 of the Wnt proteins. The research was funded by the Janssen Pharmaceuticals Transcend Program, the Lung Cancer Research Foundation, the Howard Hughes Medical Institute, and the Cancer Center Support grant from the National Cancer Institute.


News Article | May 16, 2017
Site: www.biosciencetechnology.com

Many diseases, including Parkinson’s disease, can be treated with electrical stimulation from an electrode implanted in the brain. However, the electrodes can produce scarring, which diminishes their effectiveness and can necessitate additional surgeries to replace them. MIT researchers have now demonstrated that making these electrodes much smaller can essentially eliminate this scarring, potentially allowing the devices to remain in the brain for much longer. “What we’re doing is changing the scale and making the procedure less invasive,” said Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study, which appears in the May 16 issue of Scientific Reports. Cima and his colleagues are now designing brain implants that can not only deliver electrical stimulation but also record brain activity or deliver drugs to very targeted locations. The paper’s lead author is former MIT graduate student Kevin Spencer. Other authors are former postdoc Jay Sy, graduate student Khalil Ramadi, Institute Professor Ann Graybiel, and David H. Koch Institute Professor Robert Langer. Many Parkinson’s patients have benefited from treatment with low-frequency electrical current delivered to a part of the brain involved in movement control. The electrodes used for this deep brain stimulation are a few millimeters in diameter. After being implanted, they gradually generate scar tissue through the constant rubbing of the electrode against the surrounding brain tissue. This process, known as gliosis, contributes to the high failure rate of such devices: About half stop working within the first six months. Previous studies have suggested that making the implants smaller or softer could reduce the amount of scarring, so the MIT team set out to measure the effects of both reducing the size of the implants and coating them with a soft polyethylene glycol (PEG) hydrogel. The hydrogel coating was designed to have an elasticity very similar to that of the brain. The researchers could also control the thickness of the coating. They found that when coated electrodes were pushed into the brain, the soft coating would fall off, so they devised a way to apply the hydrogel and then dry it, so that it becomes a hard, thin film. After the electrode is inserted, the film soaks up water and becomes soft again. In mice, the researchers tested both coated and uncoated glass fibers with varying diameters and found that there is a tradeoff between size and softness. Coated fibers produced much less scarring than uncoated fibers of the same diameter. However, as the electrode fibers became smaller, down to about 30 microns (0.03 millimeters) in diameter, the uncoated versions produced less scarring, because the coatings increase the diameter. This suggests that a 30-micron, uncoated fiber is the optimal design for implantable devices in the brain. “Before this paper, no one really knew the effects of size,” Cima said. “Softer is better, but not if it makes the electrode larger.” The question now is whether fibers that are only 30 microns in diameter can be adapted for electrical stimulation, drug delivery, and recording electrical activity in the brain. Cima and his colleagues have had some initial success developing such devices. “It’s one of those things that at first glance seems impossible. If you have 30-micron glass fibers, that’s slightly thicker than a piece of hair. But it is possible to do,” Cima said. Such devices could be potentially useful for treating Parkinson’s disease or other neurological disorders. They could also be used to remove fluid from the brain to monitor whether treatments are having the intended effect, or to measure brain activity that might indicate when an epileptic seizure is about to occur. The research was funded by the National Institutes of Health and MIT’s Institute for Soldier Nanotechnologies.


News Article | May 16, 2017
Site: www.eurekalert.org

Thin fibers could be used to deliver drugs or electrical stimulation, with less damage to the brain CAMBRIDGE, MA -- Many diseases, including Parkinson's disease, can be treated with electrical stimulation from an electrode implanted in the brain. However, the electrodes can produce scarring, which diminishes their effectiveness and can necessitate additional surgeries to replace them. MIT researchers have now demonstrated that making these electrodes much smaller can essentially eliminate this scarring, potentially allowing the devices to remain in the brain for much longer. "What we're doing is changing the scale and making the procedure less invasive," says Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering, a member of MIT's Koch Institute for Integrative Cancer Research, and the senior author of the study, which appears in the May 16 issue of Scientific Reports. Cima and his colleagues are now designing brain implants that can not only deliver electrical stimulation but also record brain activity or deliver drugs to very targeted locations. The paper's lead author is former MIT graduate student Kevin Spencer. Other authors are former postdoc Jay Sy, graduate student Khalil Ramadi, Institute Professor Ann Graybiel, and David H. Koch Institute Professor Robert Langer. Many Parkinson's patients have benefited from treatment with low-frequency electrical current delivered to a part of the brain involved in movement control. The electrodes used for this deep brain stimulation are a few millimeters in diameter. After being implanted, they gradually generate scar tissue through the constant rubbing of the electrode against the surrounding brain tissue. This process, known as gliosis, contributes to the high failure rate of such devices: About half stop working within the first six months. Previous studies have suggested that making the implants smaller or softer could reduce the amount of scarring, so the MIT team set out to measure the effects of both reducing the size of the implants and coating them with a soft polyethylene glycol (PEG) hydrogel. The hydrogel coating was designed to have an elasticity very similar to that of the brain. The researchers could also control the thickness of the coating. They found that when coated electrodes were pushed into the brain, the soft coating would fall off, so they devised a way to apply the hydrogel and then dry it, so that it becomes a hard, thin film. After the electrode is inserted, the film soaks up water and becomes soft again. In mice, the researchers tested both coated and uncoated glass fibers with varying diameters and found that there is a tradeoff between size and softness. Coated fibers produced much less scarring than uncoated fibers of the same diameter. However, as the electrode fibers became smaller, down to about 30 microns (0.03 millimeters) in diameter, the uncoated versions produced less scarring, because the coatings increase the diameter. This suggests that a 30-micron, uncoated fiber is the optimal design for implantable devices in the brain. "Before this paper, no one really knew the effects of size," Cima says. "Softer is better, but not if it makes the electrode larger." The question now is whether fibers that are only 30 microns in diameter can be adapted for electrical stimulation, drug delivery, and recording electrical activity in the brain. Cima and his colleagues have had some initial success developing such devices. "It's one of those things that at first glance seems impossible. If you have 30-micron glass fibers, that's slightly thicker than a piece of hair. But it is possible to do," Cima says. Such devices could be potentially useful for treating Parkinson's disease or other neurological disorders. They could also be used to remove fluid from the brain to monitor whether treatments are having the intended effect, or to measure brain activity that might indicate when an epileptic seizure is about to occur. The research was funded by the National Institutes of Health and MIT's Institute for Soldier Nanotechnologies.


News Article | May 16, 2017
Site: www.sciencedaily.com

Many diseases, including Parkinson's disease, can be treated with electrical stimulation from an electrode implanted in the brain. However, the electrodes can produce scarring, which diminishes their effectiveness and can necessitate additional surgeries to replace them. MIT researchers have now demonstrated that making these electrodes much smaller can essentially eliminate this scarring, potentially allowing the devices to remain in the brain for much longer. "What we're doing is changing the scale and making the procedure less invasive," says Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering, a member of MIT's Koch Institute for Integrative Cancer Research, and the senior author of the study, which appears in the May 16 issue of Scientific Reports. Cima and his colleagues are now designing brain implants that can not only deliver electrical stimulation but also record brain activity or deliver drugs to very targeted locations. The paper's lead author is former MIT graduate student Kevin Spencer. Other authors are former postdoc Jay Sy, graduate student Khalil Ramadi, Institute Professor Ann Graybiel, and David H. Koch Institute Professor Robert Langer. Many Parkinson's patients have benefited from treatment with low-frequency electrical current delivered to a part of the brain involved in movement control. The electrodes used for this deep brain stimulation are a few millimeters in diameter. After being implanted, they gradually generate scar tissue through the constant rubbing of the electrode against the surrounding brain tissue. This process, known as gliosis, contributes to the high failure rate of such devices: About half stop working within the first six months. Previous studies have suggested that making the implants smaller or softer could reduce the amount of scarring, so the MIT team set out to measure the effects of both reducing the size of the implants and coating them with a soft polyethylene glycol (PEG) hydrogel. The hydrogel coating was designed to have an elasticity very similar to that of the brain. The researchers could also control the thickness of the coating. They found that when coated electrodes were pushed into the brain, the soft coating would fall off, so they devised a way to apply the hydrogel and then dry it, so that it becomes a hard, thin film. After the electrode is inserted, the film soaks up water and becomes soft again. In mice, the researchers tested both coated and uncoated glass fibers with varying diameters and found that there is a tradeoff between size and softness. Coated fibers produced much less scarring than uncoated fibers of the same diameter. However, as the electrode fibers became smaller, down to about 30 microns (0.03 millimeters) in diameter, the uncoated versions produced less scarring, because the coatings increase the diameter. This suggests that a 30-micron, uncoated fiber is the optimal design for implantable devices in the brain. "Before this paper, no one really knew the effects of size," Cima says. "Softer is better, but not if it makes the electrode larger." The question now is whether fibers that are only 30 microns in diameter can be adapted for electrical stimulation, drug delivery, and recording electrical activity in the brain. Cima and his colleagues have had some initial success developing such devices. "It's one of those things that at first glance seems impossible. If you have 30-micron glass fibers, that's slightly thicker than a piece of hair. But it is possible to do," Cima says. Such devices could be potentially useful for treating Parkinson's disease or other neurological disorders. They could also be used to remove fluid from the brain to monitor whether treatments are having the intended effect, or to measure brain activity that might indicate when an epileptic seizure is about to occur.


News Article | May 26, 2017
Site: www.biosciencetechnology.com

Most women diagnosed with ovarian cancer undergo surgery to remove as many of the tumors as possible. However, it is usually impossible to eliminate all of the cancer cells because they have spread throughout the abdomen. Surgery is therefore followed by 18 weeks of chemotherapy. Delivering chemotherapy drugs directly to the abdomen through a catheter offers better results than other methods, but this regimen suffers from significant complications, and many patients are unable to complete it. MIT researchers who are working on an implantable device that could make intraperitoneal chemotherapy more bearable have published a new study that offers insight into how to improve chemotherapy strategies for ovarian cancer, and how to determine which patients would be most likely to benefit from this device. “As we entered into this project, our question was how do we get the same beneficial outcomes and reduce all the side effects?” said Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study. The findings suggest that the outcome of initial surgery plays a key role in the effectiveness of subsequent intraperitoneal chemotherapy. Cisplatin, one of the most commonly used drugs, effectively treats very tiny tumor cell clusters when it is delivered continuously or as a single large dose. But the researchers found that for larger tumor cell clusters, continuous delivery of cisplatin, at higher doses than are tolerable with the current periodic chemotherapy method, was more effective. The device they are developing would make delivery of such higher, continuous doses possible. Laura Tanenbaum, who recently received her Ph.D. from the Harvard-MIT Program in Health Sciences and Technology (HST), and HST PhD student Aikaterini Mantzavinou are the lead authors of the paper, which appears in the journal Gynecologic Oncology. Other authors are HST Ph.D. student Kriti Subramanyam and Massachusetts General Hospital gynecologic oncologist Marcela del Carmen. Ovarian cancer is usually not detected until the cancer has reached an advanced stage, with metastases covering organs throughout the peritoneal cavity, including the liver, bladder, and intestines. After surgery, known as “tumor debulking,” patients receive two types of chemotherapy to treat tumors left behind: intravenous delivery of paclitaxel and intravenous or intraperitoneal delivery of a platinum drug such as cisplatin. Intraperitoneal chemotherapy is pumped directly into the abdomen through a catheter every three weeks for a total of six cycles. This allows cisplatin to come in direct contact with the residual tumors, which has been shown to be more effective than intravenous delivery but is not tolerable for many patients. “It’s painful and the catheter can be a site of local infections,” Cima said. Several years ago, Cima and colleagues set out to develop an implantable device that could deliver cisplatin into the abdomen without all of the side effects produced by the catheter and the large, repeated cisplatin doses. As this project was neither traditional clinical research nor fundamental scientific research, enabling support came from the Koch Institute’s Frontier Research Program and then later on, the Bridge Project, a partnership between MIT’s Koch Institute and the Dana-Farber/Harvard Cancer Center. Their device is made of a drug-loaded polymer that could be inserted at the beginning of treatment and remain in place for the full treatment course, then removed with minimally invasive surgery. The researchers have tested proof-of-concept devices in mice and are now developing a version that could be tested in humans, though more animal studies are needed before human trials can begin. In their new study, the researchers set out to investigate how the size of the residual tumors would affect their response to continuous, low-dose cisplatin delivery. They believed that size would play some role because once tumors reach a certain size, the drug may not be able to penetrate all the way into the inner core of the tumors. To test this hypothesis, the researchers grew spherical ovarian cancer cell clusters 100 or 200 microns in diameter in a lab dish and exposed them to varying doses of cisplatin. Continuous, low-dose cisplatin delivery, similar to what tumors would receive from an implanted device, was as effective against 100-micron tumor spheroids as a single high dose, similar to that delivered by a catheter. However, by increasing the continuous cisplatin dose, the researchers found that they could treat the larger 200-micron spheroids more effectively than they could with the single high dose. This increased dose could be delivered using an implantable device, but it would not be tolerable for patients if given through an abdominal catheter. Cima believes that the findings may also help to explain some of the preliminary results of a recent, large clinical trial in which doctors found that intraperitoneal cisplatin delivery was no more effective than intravenous chemotherapy alone. This contradicted previous findings from smaller studies, indicating that cisplatin delivery by catheter improved patient survival. In the newer trial, conducted at about 500 treatment centers, surgeons admitted patients to the study based on size estimates of the tumors remaining after surgery. However, Cima said, this subjective evaluation may have resulted in patients entering the study whose tumors were too large to be helped by the current intraperitoneal therapy. This points to the importance of both developing a good method for screening patients before future trials begin, to make sure they are likely to benefit from the treatment, and devising new strategies to help surgeons remove as many tumors as possible, Cima said.


News Article | May 26, 2017
Site: www.biosciencetechnology.com

Most women diagnosed with ovarian cancer undergo surgery to remove as many of the tumors as possible. However, it is usually impossible to eliminate all of the cancer cells because they have spread throughout the abdomen. Surgery is therefore followed by 18 weeks of chemotherapy. Delivering chemotherapy drugs directly to the abdomen through a catheter offers better results than other methods, but this regimen suffers from significant complications, and many patients are unable to complete it. MIT researchers who are working on an implantable device that could make intraperitoneal chemotherapy more bearable have published a new study that offers insight into how to improve chemotherapy strategies for ovarian cancer, and how to determine which patients would be most likely to benefit from this device. “As we entered into this project, our question was how do we get the same beneficial outcomes and reduce all the side effects?” said Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study. The findings suggest that the outcome of initial surgery plays a key role in the effectiveness of subsequent intraperitoneal chemotherapy. Cisplatin, one of the most commonly used drugs, effectively treats very tiny tumor cell clusters when it is delivered continuously or as a single large dose. But the researchers found that for larger tumor cell clusters, continuous delivery of cisplatin, at higher doses than are tolerable with the current periodic chemotherapy method, was more effective. The device they are developing would make delivery of such higher, continuous doses possible. Laura Tanenbaum, who recently received her Ph.D. from the Harvard-MIT Program in Health Sciences and Technology (HST), and HST PhD student Aikaterini Mantzavinou are the lead authors of the paper, which appears in the journal Gynecologic Oncology. Other authors are HST Ph.D. student Kriti Subramanyam and Massachusetts General Hospital gynecologic oncologist Marcela del Carmen. Ovarian cancer is usually not detected until the cancer has reached an advanced stage, with metastases covering organs throughout the peritoneal cavity, including the liver, bladder, and intestines. After surgery, known as “tumor debulking,” patients receive two types of chemotherapy to treat tumors left behind: intravenous delivery of paclitaxel and intravenous or intraperitoneal delivery of a platinum drug such as cisplatin. Intraperitoneal chemotherapy is pumped directly into the abdomen through a catheter every three weeks for a total of six cycles. This allows cisplatin to come in direct contact with the residual tumors, which has been shown to be more effective than intravenous delivery but is not tolerable for many patients. “It’s painful and the catheter can be a site of local infections,” Cima said. Several years ago, Cima and colleagues set out to develop an implantable device that could deliver cisplatin into the abdomen without all of the side effects produced by the catheter and the large, repeated cisplatin doses. As this project was neither traditional clinical research nor fundamental scientific research, enabling support came from the Koch Institute’s Frontier Research Program and then later on, the Bridge Project, a partnership between MIT’s Koch Institute and the Dana-Farber/Harvard Cancer Center. Their device is made of a drug-loaded polymer that could be inserted at the beginning of treatment and remain in place for the full treatment course, then removed with minimally invasive surgery. The researchers have tested proof-of-concept devices in mice and are now developing a version that could be tested in humans, though more animal studies are needed before human trials can begin. In their new study, the researchers set out to investigate how the size of the residual tumors would affect their response to continuous, low-dose cisplatin delivery. They believed that size would play some role because once tumors reach a certain size, the drug may not be able to penetrate all the way into the inner core of the tumors. To test this hypothesis, the researchers grew spherical ovarian cancer cell clusters 100 or 200 microns in diameter in a lab dish and exposed them to varying doses of cisplatin. Continuous, low-dose cisplatin delivery, similar to what tumors would receive from an implanted device, was as effective against 100-micron tumor spheroids as a single high dose, similar to that delivered by a catheter. However, by increasing the continuous cisplatin dose, the researchers found that they could treat the larger 200-micron spheroids more effectively than they could with the single high dose. This increased dose could be delivered using an implantable device, but it would not be tolerable for patients if given through an abdominal catheter. Cima believes that the findings may also help to explain some of the preliminary results of a recent, large clinical trial in which doctors found that intraperitoneal cisplatin delivery was no more effective than intravenous chemotherapy alone. This contradicted previous findings from smaller studies, indicating that cisplatin delivery by catheter improved patient survival. In the newer trial, conducted at about 500 treatment centers, surgeons admitted patients to the study based on size estimates of the tumors remaining after surgery. However, Cima said, this subjective evaluation may have resulted in patients entering the study whose tumors were too large to be helped by the current intraperitoneal therapy. This points to the importance of both developing a good method for screening patients before future trials begin, to make sure they are likely to benefit from the treatment, and devising new strategies to help surgeons remove as many tumors as possible, Cima said.


News Article | April 27, 2017
Site: www.biosciencetechnology.com

Researchers at MIT, Brigham and Women’s Hospital, and the Charles Stark Draper Laboratory have devised a way to wirelessly power small electronic devices that can linger in the digestive tract indefinitely after being swallowed. Such devices could be used to sense conditions in the gastrointestinal tract, or carry small reservoirs of drugs to be delivered over an extended period. Finding a safe and efficient power source is a critical step in the development of such ingestible electronic devices, said Giovanni Traverso, a research affiliate at MIT’s Koch Institute for Integrative Cancer Research and a gastroenterologist and biomedical engineer at Brigham and Women’s Hospital. “If we’re proposing to have systems reside in the body for a long time, power becomes crucial,” said Traverso, one of the senior authors of the study. “Having the ability to transmit power wirelessly opens up new possibilities as we start to approach this problem.” The new strategy, described in the April 27 issue of the journal Scientific Reports, is based on the wireless transfer of power from an antenna outside the body to another one inside the digestive tract. This method yields enough power to run sensors that could monitor heart rate, temperature, or levels of particular nutrients or gases in the stomach. “Right now we have no way of measuring things like core body temperature or concentration of micronutrients over an extended period of time, and with these devices you could start to do that kind of thing,” said Abubakar Abid, a former MIT graduate student who is the paper’s first author. Robert Langer, the David H. Koch Institute Professor at MIT, is also a senior author of the paper. Other authors are Koch Institute technical associates Taylor Bensel and Cody Cleveland, former Koch Institute research technician Lucas Booth, and Draper researchers Brian Smith and Jonathan O’Brien. The research team has been working for several years on different types of ingestible electronics, including sensors that can monitor vital signs, and drug delivery vehicles that can remain in the digestive tract for weeks or months. To power these devices, the team has been exploring various options, including a galvanic cell that is powered by interactions with the acid of the stomach. However, one drawback to using this type of battery cell is that the metal electrodes stop working over time. In their latest study, the team wanted to come up with a way to power their devices without using electrodes, allowing them to remain in the GI tract indefinitely. The researchers first considered the possibility of using near-field transmission, that is, wireless energy transfer between two antennas over very small distances. This approach is now used for some cell phone chargers, but because the antennas have to be very close together, the researchers realized it would not work for transferring power over the distances they needed — about 5 to 10 centimeters. Instead, they decided to explore midfield transmission, which can transfer power across longer distances. Researchers at Stanford University have recently explored using this strategy to power pacemakers, but no one had tried using it for devices in the digestive tract. Using this approach, the researchers were able to deliver 100 to 200 microwatts of power to their device, which is more than enough to power small electronics, Abid said. A temperature sensor that wirelessly transmits a temperature reading every 10 seconds would require about 30 microwatts, as would a video camera that takes 10 to 20 frames per second. In a study conducted in pigs, the external antenna was able to transfer power over distances ranging from 2 to 10 centimeters, and the researchers found that the energy transfer caused no tissue damage. “We’re able to efficiently send power from the transmitter antennas outside the body to antennas inside the body, and do it in a way that minimizes the radiation being absorbed by the tissue itself,” Abid said. Christopher Bettinger, an associate professor of materials science and biomedical engineering at Carnegie Mellon University, describes the study as a “great advancement” in the rapidly growing field of ingestible electronics. “This is a classic problem with implantable devices: How do you power them? What they’re doing with wireless power is a very nice approach,” said Bettinger, who was not involved in the research. For this study, the researchers used square antennas with 6.8-millimeter sides. The internal antenna has to be small enough that it can be swallowed, but the external antenna can be larger, which offers the possibility of generating larger amounts of energy. The external power source could be used either to continuously power the internal device or to charge it up, Traverso said. “It’s really a proof-of-concept in establishing an alternative to batteries for the powering of devices in the GI tract,” he said. “This work, combined with exciting advancements in subthreshold electronics, low-power systems-on-a-chip, and novel packaging miniaturization, can enable many sensing, monitoring, and even stimulation or actuation applications,” Smith said. The researchers are continuing to explore different ways to power devices in the GI tract, and they hope that some of their devices will be ready for human testing within about five years. “We’re developing a whole series of other devices that can stay in the stomach for a long time, and looking at different timescales of how long we want to keep them in,” Traverso said. “I suspect that depending on the different applications, some methods of powering them may be better suited than others.” The research was funded by the National Institutes of Health and by a Draper Fellowship.


News Article | April 27, 2017
Site: news.mit.edu

Researchers at MIT, Brigham and Women’s Hospital, and the Charles Stark Draper Laboratory have devised a way to wirelessly power small electronic devices that can linger in the digestive tract indefinitely after being swallowed. Such devices could be used to sense conditions in the gastrointestinal tract, or carry small reservoirs of drugs to be delivered over an extended period. Finding a safe and efficient power source is a critical step in the development of such ingestible electronic devices, says Giovanni Traverso, a research affiliate at MIT’s Koch Institute for Integrative Cancer Research and a gastroenterologist and biomedical engineer at Brigham and Women’s Hospital. “If we’re proposing to have systems reside in the body for a long time, power becomes crucial,” says Traverso, one of the senior authors of the study. “Having the ability to transmit power wirelessly opens up new possibilities as we start to approach this problem.” The new strategy, described in the April 27 issue of the journal Scientific Reports, is based on the wireless transfer of power from an antenna outside the body to another one inside the digestive tract. This method yields enough power to run sensors that could monitor heart rate, temperature, or levels of particular nutrients or gases in the stomach. “Right now we have no way of measuring things like core body temperature or concentration of micronutrients over an extended period of time, and with these devices you could start to do that kind of thing,” says Abubakar Abid, a former MIT graduate student who is the paper’s first author. Robert Langer, the David H. Koch Institute Professor at MIT, is also a senior author of the paper. Other authors are Koch Institute technical associates Taylor Bensel and Cody Cleveland, former Koch Institute research technician Lucas Booth, and Draper researchers Brian Smith and Jonathan O’Brien. The research team has been working for several years on different types of ingestible electronics, including sensors that can monitor vital signs, and drug delivery vehicles that can remain in the digestive tract for weeks or months. To power these devices, the team has been exploring various options, including a galvanic cell that is powered by interactions with the acid of the stomach. However, one drawback to using this type of battery cell is that the metal electrodes stop working over time. In their latest study, the team wanted to come up with a way to power their devices without using electrodes, allowing them to remain in the GI tract indefinitely. The researchers first considered the possibility of using near-field transmission, that is, wireless energy transfer between two antennas over very small distances. This approach is now used for some cell phone chargers, but because the antennas have to be very close together, the researchers realized it would not work for transferring power over the distances they needed — about 5 to 10 centimeters. Instead, they decided to explore midfield transmission, which can transfer power across longer distances. Researchers at Stanford University have recently explored using this strategy to power pacemakers, but no one had tried using it for devices in the digestive tract. Using this approach, the researchers were able to deliver 100 to 200 microwatts of power to their device, which is more than enough to power small electronics, Abid says. A temperature sensor that wirelessly transmits a temperature reading every 10 seconds would require about 30 microwatts, as would a video camera that takes 10 to 20 frames per second. In a study conducted in pigs, the external antenna was able to transfer power over distances ranging from 2 to 10 centimeters, and the researchers found that the energy transfer caused no tissue damage. “We’re able to efficiently send power from the transmitter antennas outside the body to antennas inside the body, and do it in a way that minimizes the radiation being absorbed by the tissue itself,” Abid says. Christopher Bettinger, an associate professor of materials science and biomedical engineering at Carnegie Mellon University, describes the study as a “great advancement” in the rapidly growing field of ingestible electronics. “This is a classic problem with implantable devices: How do you power them? What they’re doing with wireless power is a very nice approach,” says Bettinger, who was not involved in the research. For this study, the researchers used square antennas with 6.8-millimeter sides. The internal antenna has to be small enough that it can be swallowed, but the external antenna can be larger, which offers the possibility of generating larger amounts of energy. The external power source could be used either to continuously power the internal device or to charge it up, Traverso says. “It’s really a proof-of-concept in establishing an alternative to batteries for the powering of devices in the GI tract,” he says. “This work, combined with exciting advancements in subthreshold electronics, low-power systems-on-a-chip, and novel packaging miniaturization, can enable many sensing, monitoring, and even stimulation or actuation applications,” Smith says. The researchers are continuing to explore different ways to power devices in the GI tract, and they hope that some of their devices will be ready for human testing within about five years. “We’re developing a whole series of other devices that can stay in the stomach for a long time, and looking at different timescales of how long we want to keep them in,” Traverso says. “I suspect that depending on the different applications, some methods of powering them may be better suited than others.” The research was funded by the National Institutes of Health and by a Draper Fellowship.


News Article | May 1, 2017
Site: www.rdmag.com

Using the gene-editing system known as CRISPR, MIT researchers have shown in mice that they can generate colon tumors that very closely resemble human tumors. This advance should help scientists learn more about how the disease progresses and allow them to test new therapies. Once formed, many of these experimental tumors spread to the liver, just like human colon cancers often do. These metastases are the most common cause of death from colon cancer. “That’s been a missing piece in the study of colon cancer. There is really no reliable method for recapitulating the metastatic progression from a primary tumor in the colon to the liver,” says Omer Yilmaz, an MIT assistant professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and the lead senior author of the study, which appears in the May 1 issue of Nature Biotechnology. The study builds on recent work by Tyler Jacks, the director of the Koch Institute, who has also used CRISPR to generate lung and liver tumors in mice. "CRISPR-based technologies have begun to revolutionize many aspects of cancer research, including building mouse models of the disease with greater speed and greater precision. This study is a good example of both,” says Jacks, who is also an author of the Nature Biotechnology paper. The paper’s lead authors are Jatin Roper, a research affiliate at the Koch Institute and a gastroenterologist at Tufts Medical Center, and Tuomas Tammela, a research scientist at the Koch Institute. For many years, cancer biologists have taken two distinct approaches to modeling cancer. One is to grow immortalized human cancer cells known as cancer cell lines in a lab dish. “We’ve learned a lot by studying these two-dimensional cell lines, but they have limitations,” Yilmaz says. “They don’t really reproduce the complex in vivo environment of a tumor.” Another widely used technique is genetically engineering mice with mutations that predispose them to develop cancer. However, it can take years to breed such mice, especially if they have more than one cancer-linked mutation. Recently, researchers have begun using CRISPR to generate cancer models. CRISPR, originally discovered by biologists studying the bacterial immune system, consists of a DNA-cutting enzyme called Cas9 and short RNA guide strands that target specific sequences of the genome, telling Cas9 where to make its cuts. Using this process, scientists can make targeted mutations in the genomes of living animals, either deleting genes or inserting new ones. To induce cancer mutations, the investigators package the genes for Cas9 and the RNA guide strand into viruses called lentiviruses, which are then injected into the target organs of adult mice. Yilmaz, who studies colon cancer and how it is influenced by genes, diet, and aging, decided to adapt this approach to generate colon tumors in mice. He and members of his lab were already working on a technique for growing miniature tissues known as organoids — three-dimensional growths that, in this case, accurately replicate the structure of the colon. In the new paper, the researchers used CRISPR to introduce cancer-causing mutations into the organoids and then delivered them via colonoscopy to the colon, where they attached to the lining and formed tumors. “We were able to transplant these 3-D mini-intestinal tumors into the colon of recipient mice and recapitulate many aspects of human disease,” Yilmaz says. Once the tumors are established in the mice, the researchers can introduce additional mutations at any time, allowing them to study the influence of each mutation on tumor initiation, progression, and metastasis. Almost 30 years ago, scientists discovered that colon tumors in humans usually acquire cancerous mutations in a particular order, but they haven’t been able to accurately model this in mice until now. “In human patients, mutations never occur all at once,” Tammela says. “Mutations are acquired over time as the tumor progresses and becomes more aggressive, more invasive, and more metastatic. Now we can model this in mice.” To demonstrate that ability, the MIT team delivered organoids with a mutated form of the APC gene, which is the cancer-initiating mutation in 80 percent of colon cancer patients. Once the tumors were established, they introduced a mutated form of KRAS, which is commonly found in colon and many other cancers. The scientists also delivered components of the CRISPR system directly into the colon wall to quickly model colon cancer by editing the APC gene. They then added CRISPR components to also edit the gene for P53, which is commonly mutated in colon and other cancers. “These new approaches reduce the time frame to develop genetically engineered mice from two years to just a few months, and involve very basic gene engineering with CRISPR,” Roper says. “We used P53 and KRAS to demonstrate the principle that the CRISPR editing approach and the organoid transplantation approach can be used to very quickly model any possible cancer-associated gene.” In this study, the researchers also showed that they could grow tumor cells from patients into organoids that could be transplanted into mice. This could give doctors a way to perform “personalized medicine” in which they test various treatment options against a patient’s own tumor cells. Fernando Camargo, a professor of stem cell and regenerative biology at Harvard University, says the study represents an important advance in colon cancer research. “It allows investigators to have a very flexible model to look at multiple aspects of colorectal cancer, from basic biology of the genes involved in progression and metastasis, to testing potential drugs,” says Camargo, who was not involved in the research. Yilmaz’ lab is now using these techniques to study how other factors such as metabolism, diet, and aging affect colon cancer development. The researchers are also using this approach to test potential new colon cancer drugs.

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